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ASHP Midyear
Clinical Meeting
Symposium
Highlights
Proceedings of Selected Symposia conducted during the 36th Annual ASHP Midyear Clinical Meeting
December 2–6, 2001
New Orleans, Louisiana
ASHP Midyear Clinical Meeting
Symposium Highlights
Proceedings of Selected Symposia conducted during
the 36th Annual ASHP Midyear Clinical Meeting
December 2–6, 2001
New Orleans, Louisiana
The ASHP Midyear Clinical Meeting Symposium Highlights is a compilation
of select proceedings of live symposia held at the 36th Annual ASHP Midyear
Clinical Meeting. Each of the articles in the Highlights publication is based on
an industry-sponsored breakfast or dinner symposium or an Exhibitors’ Theater
presentation made between December 2 and 6, 2001, in New Orleans, Louisiana.
Copyright © 2002, American Society of Health-System Pharmacists, Inc.
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
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Table of Contents
Contemporary Issues in the Safe Handling of Cytotoxic Agents .................................................................................... 1
Using PDA Devices at the Point of Care ....................................................................................................................... 5
Synergy in Chemotherapy and Expanded Use of Taxanes .............................................................................................. 9
Combating CMV Infections in Immunocompromised Patients .................................................................................. 13
Interpreting Antimicrobial Susceptibility Tests ............................................................................................................ 17
Considerations for Use of Serotonin Type 3 Receptor Antagonists in Special Patient Populations ............................... 21
Antimicrobial Management in a Group of VA Medical Centers .................................................................................. 25
Antipsychotic Therapy: Managing Costs and Maximizing Outcomes ......................................................................... 29
Managing Patients at Risk for Postoperative Nausea and Vomiting ............................................................................. 33
Improving Outcomes in the Catheterization Laboratory with Direct Thrombin Inhibitors ......................................... 37
Current Therapies for Treatment of Community-Acquired Respiratory Tract Infections:
Where Do the Ketolides Fit? ................................................................................................................................... 41
Current and Emerging Pharmacotherapy for Postoperative Ileus ................................................................................. 45
Evidence-based Strategies for Treatment of Atherothrombosis with Antiplatelet Therapy ............................................ 49
Confronting the Threat of Terrorism: Strategies for Emergency Preparedness .............................................................. 53
Maximizing Cardiovascular and Renal Outcomes in the Diabetic Patient ................................................................... 57
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
Contemporary Issues in the Safe Handling of Cytotoxic Agents
An exhibitors’ theater held December 4, 2001, in conjunction with the ASHP Midyear Clinical Meeting
Supported by an unrestricted grant from SuperGen
Program moderator Roger W. Anderson, Dr.P.H.,
Director of the Division of Pharmacy at the M. D.
Anderson Cancer Center in Houston, Texas, began the
program with an overview of organized pharmacy’s long
involvement in the safe handling of cytotoxic agents.
Since the introduction of biological safety cabinets
(BSCs) in the early 1980s, occupational exposure to
hazardous drugs, especially antineoplastic agents, has been
substantially reduced. Recent reports in the literature
from the United States and around the world document
the extent of environmental contamination and worker
exposure in hospital pharmacies and other settings where
antineoplastic drugs are handled.
Sources of contamination include contaminated
drug vials, aerosols, leaks and spills related to preparation
and administration, accidents, movement of drugs and
personnel, hazardous waste disposal, and possibly the
BSCs themselves. A number of groups, including the
American Society of Health-System Pharmacists, are
reviewing and revising recommendations for handling
cytotoxic agents, use of personal protective equipment,
and means of containment, cleaning, and decontamination.
Occupational Exposure to Hazardous
Drugs in Health Care
Thomas H. Connor, Ph.D., is Senior Service Fellow at
the National Institute for Occupational Safety and Health
in Cincinnati, Ohio, and a widely recognized expert on
the safe handling of cytotoxic drugs. Although occupational exposure to antineoplastic agents and other
hazardous materials has been reduced by BSCs, workers
are still exposed, Connor said. Among those exposed are
workers in manufacturing, pharmacists and pharmacy
technicians, nursing personnel, physicians, operating
room personnel, cleaning and laundry room personnel,
veterinarians, and family members and friends of these
people.
Many of the drugs used to treat cancer are themselves carcinogenic. The International Agency for Research on Cancer carefully reviews the literature for all
types of possible exposures (e.g., occupational, environmental, medical) and classifies exposures according to
their potential to cause cancer, as follows:
Group 1: Human carcinogens (e.g., azathioprine,
chlorambucil, cyclophosphamide),
■ Group 2: Probable human carcinogens (e.g., doxorubicin, azacitidine, etoposide), and
■ Group 3: Possible human carcinogens (e.g.,
amsacrine, dacarbazine, mitoxantrone).
Data support a link between occupational exposure
to antineoplastic drugs and cancer. Three studies from
Denmark evaluated cancer outcomes in health care
workers (oncology nurses, oncologists, pharmacy technicians) and found an increase in the development of
cancers such as leukemia, non-Hodgkin’s lymphoma, and
nonmelanoma skin cancer. Other studies have looked at
adverse reproductive outcomes in oncology nurses and
found that exposure was linked to birth defects, fetal loss,
menstrual dysfunction, infertility, and low-birth weight.
Connor noted that these studies can be found at
www.uth.tmc.edu/schools/sph/an_agents.
Describing the various sources of contamination,
Connor said vials that arrive directly from the manufacturer are sometimes contaminated during transport when
a vial breaks and its contents get on other vials in the
shipping container. Leaks, spills, and the introduction of
drug into the environment also occur during preparation
and administration.
Connor has researched how spilled drug travels. For
example, he documented that drug spilled in the BSC can
get on the i.v. bag and travel to counters and even to
patient care areas. Contaminated gloves worn by personnel outside the BSC are another source. Liquid drugs
spilled onto the floor can get tracked throughout the
pharmacy and into the hospital. Connor said evidence is
growing to support the theory that BSCs that are exhausted back into the pharmacy through a second HEPA
filter may be contaminating the pharmacy area with
drugs. Even air conditioners move particulates around the
pharmacy.
There are several potential routes of exposure.
Workers can be exposed through skin contact. Oral
exposure can occur when drug on the hands of a worker
is ingested with food or drink. The most common
exposure route is inhalation of drug as particulates (e.g.,
droplets or dust particles) or vapors.
Monitoring for exposure has included biological,
■
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
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chemical, and environmental techniques. Biological
sampling techniques evaluate damage to DNA; common
endpoints for such determinations include urine mutagenicity, chromosomal aberrations, sister chromatid
exchange, and micronuclei. The biological endpoints are
rather crude, but Connor said new, more sensitive
methods are being developed that should be able to show
specific damage to DNA by certain antineoplastic agents.
Most of the biological endpoints used to date have been
nonspecific and insensitive, but they do give an indication
that some type of genotoxic damage has occurred.
Chemical analysis typically involves detection of
drug or metabolites in urine samples. Drug-specific
analytical methods are available, for example, for detecting ifosfamide, cyclophosphamide, and fluorouracil. The
methods used include gas chromatography, mass spectroscopy, and high-performance liquid chromatography.
Environmental sampling techniques include testing
wipes, air, gloves, and gowns for exposure to cytotoxic
drugs. Connor has participated in surface contamination
studies involving cyclophosphamide, fluorouracil, and
ifosfamide. In one study, surfaces (BSCs, counters, carts,
floors, chairs, and tables) were tested in the pharmacy and
treatment areas in six cancer centers in the United States
and Canada.1 Contamination was widespread; 75% of
pharmacy samples and 65% of treatment area samples
tested positive for at least one drug.
Connor participated in another study in which the
outpatient pharmacy area had been renovated and cleaned
and drug-preparation procedures modified (e.g., a closedcontainer PhaSeal system was used for antineoplastic
preparation).2 One baseline sample was taken at each of 18
locations (e.g., BSCs, floors, counters) before the renovation. After the pharmacy was renovated, cleaned, and
reopened, the investigators took six samples at various
locations every 28 days; levels of fluorouracil, ifosfamide,
and cyclophosphamide were well below baseline levels.
Identifying Sources of Contamination
Luci A. Power, M.S., Senior Consultant and CEO,
Power Enterprises, and Senior Pharmacist and Manager,
I.V. Additive Service, Department of Pharmaceutical
Services at the University of California—San Francisco,
reviewed an important study on drug contamination and
provided new recommendations for handling cytotoxic
drugs that minimize surface contamination.
Overview of Exposure and Contamination Study
A study by Sessink et al.3 was one of the first to document
sources of exposure and contamination all along the drug
chain. The study was conducted in a hospital in the
Netherlands. Samples were taken from four areas: the
inpatient pharmacy preparation area, outpatient pharmacy preparation area, outpatient administration area,
and inpatient oncology ward.
2
The presence of four drugs was tested—cyclophosphamide, ifosfamide, fluorouracil, and methotrexate.
High-performance liquid chromatography was used to
detect fluorouracil and methotrexate, and gas chromatography was used for cyclophosphamide and ifosfamide.
The following types of samples were taken: air (using
filters), surface wipes, used gloves, and urine of workers.
All of the preparation areas were equipped with
safety hoods in accordance with the standards in place in
1992. Personal protective equipment was worn during
preparation, but there was limited use of gowns and
gloves by nurses who administered the drugs. Samples were
taken from the outside of the drug vials, work surface in the
BSC, floor in front of the BSC, plastic preparation bins, and
outside of the final i.v. admixture preparation.
No drug was detected in air samples from the
preparation areas. Only 2 of 44 vials from the preparation
areas showed evidence of contamination on the outside.
Nine of 36 samples from preparation area work surfaces
were contaminated before and after drug preparation.
(Sessink et al. took samples early in the morning before
drug preparation began and again at the conclusion of the
workday.) Samples from the preparation area floors
showed high levels of contamination; fluorouracil was
detected in 17 of 24 samples. Of final products tested, 5
of 76 showed contamination.
The glove samples showed a high degree of contamination. All 14 pairs of gloves sampled in the inpatient preparation area were contaminated and all 6 of
those used to clean the hoods were contaminated. In the
outpatient area, five of seven pairs of gloves used in
preparation were contaminated, as were three of four
pairs used in cleaning the hoods. Fluorouracil was
detected on all of the inpatient preparation area glove
samples, cyclophosphamide was detected on one glove
sample from each of the inpatient preparation and hood
areas, and methotrexate was found on three preparation
area samples and two gloves that had been isolated from
the hood. Interestingly, when the gloves that were used to
mix fluorouracil and cyclophosphamide were compared
with those that were found to be contaminated, they did
not match.
Contamination was widespread in the outpatient
administration area. All floor samples taken from each of
five rooms showed contamination on all days, demonstrating how difficult it is to remove contaminants.
Cyclophosphamide, fluorouracil, and methotrexate were
all found in various amounts. In one instance, cyclophosphamide was detected at the beginning of the workday,
after the area had been cleaned at the end of the previous
day. The investigators determined that the contamination
occurred when the cleaning crews that came during the
night tracked drug into the room.
Testing in the oncology ward included four patient
rooms, the dirty utility room floor and sink, and cleaned
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
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bedpans and urinals. Methotrexate was detected in two
patient rooms, and cyclophosphamide was detected on
the dirty utility room floor and on one urinal.
Urine samples were taken from 25 pharmacy
technicians and nurses (15 technicians involved in drug
preparation, 4 nurses from the outpatient pharmacy, and
7 nurses from the inpatient administration department;
one subject worked as a pharmacy technician during the
day and as a nurse in the afternoon). Cyclophosphamide
or ifosfamide was detected in the urine of 8 of the 25
workers. Six of the eight individuals were not involved in
the preparation or administration of either drug. The
assumption is that these individuals were exposed to the
drugs through some form of contamination (e.g.,
touching a contaminated surface or inhaling drug
particles).
Solving the Contamination Problem
Existing cleaning techniques are inefficient, and surfaces
such as floors, tables, and chairs are extremely difficult to
clean. Surface contamination leads to air contamination,
and air sampling with filters is not effective with these
drugs. A Class II BSC does not prevent the generation of
contamination. The BSC is supposed to contain spills,
but the health care community is learning that BSCs are
not as effective as was hoped. Poor technique can lead to
spills and escape of drug from the BSC. Contamination
from outside sources such as drug packages occurs. It is
also believed that the open front of the cabinet facilitates
contamination.
Power suggested the following ways of improving
the process:
■ Observe and correct work practices, both inside and
outside the hood;
■ Observe and correct drug preparation techniques;
■ Observe and correct gloving techniques;
■ Minimize crowding in the BSC;
■ Change gloves frequently; and
■ Swab all final products before removal from the BSC.
Drug preparation and handling techniques are still
the most important elements in preventing cytotoxic
exposure. Workers should be trained in using negative
pressure, which they may not like because it is time
consuming. Staff should practice with a simulated
cytotoxic drug, such as fluorescein, and be able to
demonstrate competence.
Interventions To Ensure Safe Handling
Three new systems show promise for reducing antineoplastic drug exposure in pharmaceutical and hospital
workplaces. Robert T. Dorr, Ph.D., Professor of Pharmacology and Director of Pharmacology Research at the
Arizona Cancer Center of the University of Arizona in
Tucson, described these systems: total containment
cabinets (glove boxes), closed containment systems
(PhaSeal) for vials and tubing, and oxidizing agents for
chemotherapy inactivation. These new approaches should
be implemented in addition to existing precautionary
measures, Dorr said.
The availability of BSCs may have lulled health care
workers into a false sense of security about drug exposure.
The “dirtiest” air in the cabinet is located near the
opening in the front of the hood, yet workers prepare
antineoplastic drugs in this area of the BSC. Workers
have also become complacent about gloving and need to
be monitored and reminded to change gloves regularly.
Total Containment Cabinets
One alternative to the BSC is the total containment
cabinet, or isolator. This type of system was developed to
contain pathogens, such as the human immunodeficiency
virus, and has a nonexchangeable air supply in the work
area. Isolators, commonly called glove boxes, are closed
cabinets that have antechambers for premixing antineoplastic drugs on the left-hand side and afterchambers on
the right-hand side. The middle compartment is also
completely sealed, and built-in gloves are used during
drug compounding. The theory behind these systems is
that air inside the device, even if it is contaminated, will
never be exposed to or exchanged with room air because
there is no exhaust or ambient flow.
Isolators have not been widely used in drug
preparation. Dorr noted that isolators are cumbersome
because of the need to reach the arms deep inside the
work area. This is not easy to do for many people; usually
it requires pressing the chest against the front of the
equipment in order to reach the work area. The “one-sizefits-all” gloves also present a challenge to some people.
PhaSeal Drug Containment System
PhaSeal is a five-part, fully contained, closed system for
chemotherapy preparation and administration. Its
primary features are a double membrane and an expansion chamber that allows for pressure equalization. A
protective cover is permanently fastened to the drug vial,
and transfer of liquid occurs through tightly fitted
membranes. The sealed system also includes a customfitted injector that is locked onto a syringe. The PhaSeal
system has a built-in infusion set and adapter, which
facilitates drug administration.
Surface contamination studies with the PhaSeal
system have yielded positive results. In one surface area
study, only minimal quantities of cyclophosphamide or
fluorouracil were detected in wipe samples taken from
large areas (floors, sinks, waste bins, and tables) after
preparation with PhaSeal.4 Only one floor wipe tested
positive for cyclophosphamide at the level of detection,
which demonstrates considerable improvement over
historical data. These results were supported by another
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
3
study5 that demonstrated the ability of the PhaSeal system
to reduce contamination.
Dorr noted that the cost of the system is substantial, which may explain why this technology has not been
widely adopted in practice. Also, the system cannot yet be
universally applied to all vials. Preliminary results appear
promising, but a study comparing the PhaSeal system
with standard reconstitution procedures is needed.
Chemical Degradation of Antineoplastic Drugs
Health care workers are often surprised to find that most
antineoplastic drugs are not inactivated by ethanol. In
fact, antineoplastic drugs are probably more soluble in
ethanol than in water. What typically happens in drug
preparation is that a drop of drug that falls onto the BSC
surface gets swabbed with alcohol and spread around the
cabinet.
Sodium hypochlorite (bleach) is an effective
oxidizer that inactivates many antineoplastic drugs.6 The
problems with using undiluted bleach for surface decontamination are familiar to anyone who has ever used
bleach: It is toxic if splashed onto skin or eyes, causes
irritation if inhaled, corrodes stainless steel surfaces with
prolonged contact, and discolors clothes and colored
surfaces.
A two-step inactivator system, Surface Safe, has one
pad containing sodium hypochlorite in a soap solution (7
mL of 2% w/v sodium hypochlorite in 0.2% w/v
dodecylsulfate). This pad is used to deactivate drug, and a
second pad containing sodium thiosulfate (9 mL of 1%
w/v solution) is used to remove the bleach. The inactivating properties of sodium thiosulfate were discovered by
accident, Dorr noted, although this chemical has been
used for some time in cisplatin rescue and as an antagonist for mechlorethamine (nitrogen mustard) poisoning.
The chemical reaction initiated by the two pads results in
the formation of table salt, water, and inorganic sulfides.
Since pads used to clean up an antineoplastic drug
spill can leave residue from the inactivated drug, a third
cleanup step is needed in which water or isopropyl
alcohol is applied to clean the surface. Dorr studied the
efficacy of the Surface Safe system for cleanup of antineoplastic agents and found that for most drugs there is a
complete loss of the parent compound as well as loss of
4
mutagenicity. Surface Safe is not completely effective
against carmustine and mitoxantrone.
Proper use of the Surface Safe system involves the
following steps:
■ Put on latex or rubber gloves (gowns and mask are
optional, depending on institutional guidelines),
■ Carefully open pad 1 (hypochlorite) over the work
surface,
■ Apply the soaked pad to the contaminated area,
■ Carefully dispose of used pad 1 into the contaminated
waste receptacle,
■ Open pad 2 (thiosulfate) and apply to the areas wiped
with pad 1, and
■ Dispose of pad 2 in the contaminated waste receptacle.
On work surfaces exposed to antineoplastic drugs,
Surface Safe should be applied at least once per shift for
low-volume operations and two to three times per shift
for high-volume operations. Surface Safe should also be
applied immediately after any known minor spill or vial
or ampul leak.
References
1. Connor TH, Anderson RW, Sessink PJM et al. Surface contamination with antineoplastic agents in six cancer treatment centers in
the United States and Canada. Am J Health-Syst Pharm. 1999;
56:1427-32.
2. Connor TH, Anderson RW, Sessink PJ et al. Effectiveness of a
closed-system device in containing surface contamination with
cyclophosphamide and ifosfamide in an i.v. admixture area. Am J
Health-Syst Pharm. 2002; 59:68-71.
3. Sessink PJM, Boer KA, Scheefhals APH et al. Occupational
exposure to antineoplastic agents at several departments in a
hospital: environmental contamination and excretion of cyclophosphamide and ifosfamide in urine of exposed workers. Int Arch
Occup Environ Health. 1992; 64:105-12.
4. Sessink PJ, Rolf MAE, Ryden HS. Evaluation of the PhaSeal
hazardous drug containment system. Hosp Pharm. 1999; 34:
1311–7.
5. Connor TH, Anderson RW, Sessink PJ et al. Effectiveness of a
closed-system device in containing surface contamination with
cyclophosphamide and ifosfamide in an i.v. admixture area. Am J
Health-Syst Pharm. 2002; 59: 68–72.
6. Johnson EG, Janosik JE. Manufacturers’ recommendations for
handling spilled antineoplastic agents. Am J Hosp Pharm. 1989;
46: 318–9.
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
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Using PDA Devices at the Point of Care
A symposium held December 2, 2001, in conjunction with the ASHP Midyear Clinical Meeting
Supported by an educational grant from Roche Pharmaceuticals
Personal digital assistants (PDAs) and pocket PCs can be
invaluable tools for managing information and optimizing patient care, but they often are not utilized to their
full capability. In this hands-on symposium, Bill Felkey,
M.S., Associate Professor of Pharmacy Care Systems, and
Brent Fox, Pharm.D., Informatics Research Associate, of
the Auburn University School of Pharmacy at Auburn
University in Alabama, described tools that can help
pharmacists make optimal use of this technology.
Pharmacy Applications of Electronic
Technology
Felkey began by giving attendees a quiz to determine their
health system’s information technology IQ. Questions
included the following: Do you have a point-of-care
initiative under way for information? and Do you have a
telehealth strategy that includes e-commerce with patients?
Telehealth is the use of communication and
information technology to deliver health care services and
information over large and small distances. This includes
using electronic reference materials and educational
programs, a computerized order entry system, Web-enabled
business transactions, and e-commerce with patients.
Pharmacists can provide leadership in their institutions by proactively integrating telecommunication into
the health care system and converting pharmacies to ebusiness. This conversion progresses through several levels:
1. Creating a Web presence on the Internet. Pharmacy
Web sites are moving from placeholder status to
content management to self-care for patients.
2. Using intranet systems for messaging, publishing, and
collaboration within the institution.
3. Connecting to businesses, suppliers, and stakeholders.
4. Conducting transactions with consumers.
5. Supplying personal portable medical histories.
Felkey suggested the following steps for adopting
new technology:
■ Become computer literate.
■ Have a point-of-care device for every clinician
(workstation, terminal emulator, PDA, notebook, or
desktop).
■
■
■
Install core software on the device, e.g., medical and
drug information and patient education information.
Build and expand your Web presence.
Cherry-pick clinical applications.
PDA versus Pocket PC
In 2000, over 3.5 million PDAs were sold in the United
States. The Palm brand dominated the market, followed
by Handspring, Philips, Royal, Hewlett-Packard, and
others. All of these devices use the Palm operating system.
In the future, some of the PDA market is expected to
shift to Pocket PCs.
Fox and Felkey suggest Pocket PCs for people who
need a device for administrative use and PDAs for those
who need to download clinical data.
Information Resources for the PDA
The presenters demonstrated some drug information and
health care compendia available for use with PDAs.
5 Minute Clinical Consult. This site covers 1800
diseases and is updated four times a year for a fee of $65.
The entry for each disease has a basic description,
symptoms, including incidence and prevalence, signs and
symptoms, and risk factors; links to differential diagnosis
of that disease; nondrug therapies and drugs of choice;
follow-up and monitoring needs; associated conditions;
pregnancy and gender implications; ICD-9 codes; and
references used to write the entry. A link to a drug
information site provides extensive information on 5700
drugs. The information can be updated nightly.
Lexi-Drugs Platinum. This drug reference is based
on the Drug Information Handbook. Specialty information
can be added for cardiology, mental health, oncology, or
advanced-practice nursing. The database can be updated
several times per week.
Lexi-Interact. This drug interaction application
allows the user to review a comprehensive list of individual interactions or analyze a patient-specific drug
profile for potential interactions. Each of the 850
monographs provides a summary statement on the
interaction, a scientific and clinically relevant review of
applicable literature (including full citations), and a list of
strategies for preventing and managing the interaction.
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
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The potential for similar drugs to be involved in the same
interaction is also discussed.
DynaMed (Dynamic Medical Information
System) (www.dynamicmedical.com). This is an
interactive, real-time medical information system designed for use at the point of care. It contains basic
information on over 200 diseases and is updated daily.
Healthprolink. This resource facilitates pharmacists’ interventions along a continuum that includes
follow-up monitoring, adverse drug reaction reporting,
therapeutic interventions, and medication errors.
Hands-on Demonstrations
Felkey and Fox led participants in a practice session to
demonstrate some of the physical capabilities of PDAs.
They showed how to create shortcuts, use graffiti, and
beam information (data, to-do lists, etc.) from one PDA
to another. They demonstrated calendar entries and
reminder systems for important dates. They described
several ways to enter information into a pocket PC or a
PDA, including infrared beaming, downloading through
the syncing cradle, using a stylus or keyboard, and using
voice recognition.
Security Issues
Almost any type of information can be entered and filed
in a PDA, so security of sensitive information is a
concern. The presenters demonstrated ways of securing
patient-identifiable data. The Health Insurance Portability and Acountability Act (HIPAA) requires security
protection at every data collection point, repository,
client, and server. HIPAA regulations will dictate the level
of data security required for health care institutions.
PDA Product Review
Table 1 lists some PDAs currently available. Fox recommends checking the shopper.cnet.com Web site for
independent reviews and pricing information before
purchasing a PDA. He reviewed the features and benefits
of some PDAs; all of these use the Palm operating system
(OS), for which over 700 medical reference programs
exist. The Pocket PC currently uses only 111 medical
programs, but more will be available in the future.
Palm is the PDA market leader. Newer Palm
versions incorporate expansion capabilities for extra
memory, global positioning system (GPS) sensors, object
beaming, printing, and a multitude of accessories.
Handspring devices are relatively inexpensive, use
the Palm OS, and have expandable memory. Other
expansion capabilities include GPS sensors, e-books, and
PowerPoint slide-making. Handspring has 70 products
that can be added to the device, including wireless
modems, Bluetooth-enabled wireless communication
6
technology, multimedia, games, productivity tools, and
bar-code readers.
Sony PDAs are very small and thin. The Sony Clie
PEG-N760C has a color screen, 8 MB of standard
memory, and an MP3 music player. The PEG-T415 has a
monochrome screen and 8-MB standard memory, to
which 128 MB can be added. It is less than 1⁄2 inch thick
and weighs 4.3 ounces. The T415 comes with an enhanced infrared port and can be used as a remote control
for a variety of audiovisual components.
HandEra comes with 8 MB of standard memory
and up to 1 gigabyte of memory expansion. It has the
largest memory capability of any PDA or pocket PC. It
also has a rotatable screen.
Kyocera makes a combination PDA and telephone.
It has a monochrome screen, 8-MB memory, speakerphone, voice dialing, wireless e-mail, wireless Internet
access, the ability to send and receive faxes, and the ability
to record voice memos. It does not have memory expansion capabilities.
The Samsung SPHI300 PDA (available from
Sprint) weighs only 6 ounces and has a color screen, 8MB memory, voice dialing, wireless Internet, wireless email, the ability to send and receive faxes, and infrared
beaming capabilities and can record 10 memos up to one
minute long.
The DiskonKey is a device for people who do not
want to carry a PDA or notebook PC but need a portable
information source. It is a portable hard drive that holds
from 40 to 512 MB of data. It plugs into the USB port
on a computer (Windows or Macintosh), is automatically
recognized, and transfers files to and from the computer.
The price ranges from $50 to $200 depending on
memory size.
Handspring is introducing the Handspring Treo in
2002. It is a combination cell phone, PDA, and shortmessaging service or pager. It comes with 8 MB of memory
and no expansion capability and is available with or without
a keypad. It is only slightly larger than a credit card.
The Symbol incorporates enhanced battery
capability with a bar-code scanner using the Palm OS. It
can be used for medication administration checks at the
point of care.
Autros uses a device that integrates all aspects of
medication administration. It starts with computerized
physician order entry, incorporates clinical pharmacy
screening, bar-code scanning of the medication, and barcode scanning of the patient’s wristband to ensure that
the right patient gets the right drug at the right time. It is
also connected to the pharmacy inventory system.
PDA Applications
Felkey presented examples of applications available for
PDAs. With these applications, PDAs can access any
document on the Internet.
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Table 1
A Sample of the Hand-Held Computer/PDA Marketplace
Model
PALM OS MODELS
Palm m100
Palm m105
Palm m125
Palm IIIxe
Palm IIIc
Palm Vx
Palm VIIx
Palm m500
Palm m505
HandspringVisor Deluxe
Handspring Visor Prism
Handspring Visor Platinum
Handspring Visor Edge
Handspring Visor Neo
Handspring Visor Pro
Handspring Treo 180 and 180g
Handspring Treo 270 and 270g
Handera 333
OS
Memory:
Base +
Display Expansion
Expan- Wiresion
less
Modules Standard Size
Palm
Palm
Palm
Palm
Palm
Palm
Palm
Palm
Palm
Palm
Palm
Palm
Palm
Palm
Palm
Palm
Palm
Palm
Mono
Mono
Mono
Mono
Color
Mono
Mono
Mono
Colora
Mono
Color
Mono
Mono
Mono
Mono
Mono
Color
Mono
2M
8M
8 M + 64 M
8M
8M
8M
8M
8M + 64 M
8M + 64 M
8M + 16 M
8M + 16 M
8M + 16 M
8M + 16 M
8M + 16 M
16 M +16 M
16 M
16 M
8 M+1 Gig
No
No
Yes
No
No
No
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
Yes
No
No
No
No
No
No
Yes
No
No
No
No
No
No
No
No
Yes
Yes
No
Sm
Sm
Sm
Med
Med
Med
Med
Med
Med
Med
Lg
Med
Sm
Med
Med
Sm
Sm
Med
Palm
Palm
Palm
Mono
Mono
Color
8 M + 64 M Yes
8 M + 128 M Yes
8 M + 64 M Yes
No
No
No
Palm
Palm
Palm
Color
Mono
Color
8 M + 64 M
8M
8M
Yes
No
No
WINDOWS CE/POCKET PC MODELS
Compaq iPaq 3150 (retired)
Pocket PC Mono
Compaq iPaq 3135
Compaq iPaq 3650
Compaq iPaq 3670
Compaq iPaq 3760
Sony Clie PEG S320
Sony Clie PEG T415
Sony Clie PEG N610C/S
and N610C/V
Sony Clie PEG N760C
Kyocera QCP 6035
Samsung SPH-I300
Compaq iPaq 3850
Compaq iPaq 3870
Hewlett Packard Jornada 548
Hewlett Packard Jornada 565
Hewlett Packard Jornada 568
Casio Cassiopeia BE-300
Casio Cassiopeia EM 500
Casio Cassiopeia E-125
Casio Cassiopeia E-200
Toshiba e570
PROPRIETARY
Psion
Pocket PC
Pocket PC
Pocket PC
Pocket PC
2002
Pocket PC
2002
Pocket PC
2002
Pocket PC
Pocket PC
2002
Pocket PC
2002
Win.CE
Pocket PC
Pocket PC
Pocket PC
2002
Pocket PC
2002
Battery
Street
Price
($ US)
Comments
88
124
199
140
210
178
154
250
318
118
267
174
238
169
253
399
599
282
Limited memory
Good starter unit
Good entry model with expansion
Old design, inexpensive
Old, good color screen
Thin but not expandable
Slow wireless
New and Palm
High-quality color and new
Inexpensive and great expansion (all Visors)
Thick but good screen
Fast processor
Thin and uses modules
Fast processor
16 M standard; fast and rechargeable
Available 2002; SMS, Phone, PDA; “g” model—Graffiti
Available 2002; SMS, Phone, PDA; “g” model—Graffiti
Largest memory; 360º rotation of screen
Sm
Sm
Sm
Alkaline
Alkaline
Alkaline
Alkaline
Lithium ion
Lithium ion
Alkaline
Lithium ion
Lithium ion
Alkaline
Lithium ion
Alkaline
Lithium ion
Alkaline
Lithium ion
Lithium ion
Lithium ion
Alkaline or
Lithium ion
Lithium ion
Lithium ion
Lithium ion
147
299
320
Thin, jog wheel, Indiglo-like backlight
Thinnest PDA; enhanced IR for a/v control; dim screen
High-resolution color and 320 features
No
Yes
Yes
Sm
Lg
Sm
Lithium ion
Lithium ion
Lithium ion
340
500
500
Color + MP3 player
Combined factory cell phone and PDA
Combined factory cell phone and PDA
16 M + 1 Gig Yes
No
Med
Lithium polymer 169
Production terminated; limited onboard memoryb
Mono
Color
Color
Color
16 M + 1 Gig
32 M + 1 Gig
64 M + 1 Gig
64 M + 1 Gig
Yes
Yes
Yes
Yes
No
No
No
No
Med
Med
Med
Med
Lithium polymer
Lithium polymer
Lithium polymer
Lithium polymer
Inexpensive; limited onboard memoryb
Good price; fast; color
Increased standard memory
Latest-generation OS; good memory
Color
Yes
No
Lg
Lithium polymer 567
Fastest avail. processor; increased battery life
Yes
Yes
Lg
Lithium polymer 649
Integrated Bluetooth
Color
Color
64 M +128 M
or 1 Gig
64 M + 128 M
or 1 Gig
32 M + 64 M
32 M + 64 M
Yes
Yes
No
No
Med
Med
Lithium ion
315
Lithium polymer 507
Heavy
Removable battery; pricey for limited onboard memory
Color
64 M + 64 M Yes
No
Med
Lithium polymer 560
Removable battery; 64 M standard
Color
Color
Color
Color
16 M
16 M + 64 M
32 M + 96 M
64 M + 96 M
Yes
Yes
Yes
Yes
No
No
No
No
Med
Med
Med
Med
Lithium polymer
Lithium ion
Lithium ion
Lithium ion
178
276
298
539
Good price; more expansive options available
MMCs only—does not accept CF cards
Accepts CF cards, good price for std. memory
Internal CD and MMC slots
Color
64 M + 128 M Yes
or 1 Gig
No
Med
Lithium ion
569
Light; optional remote control
16 M+ 20 M
No
Med
Lithium ion
459
Scarce software
Color
Proprietary Mono
Yes
199
322
399
456
a
Special LCD material supports use in full sunlight.
b
Compared with other Pocket PCs.
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
7
iSilo.com is a free document reader that also
converts documents to a PDA-appropriate format.
Features include text compression and hyperlink use.
ISiloWeb.exe is a free desktop application used to
coordinate conversion of HTML files (downloaded from
the Web or in disk files) to documents readable by the
iSilo document reader program.
Adobe makes an Acrobat Reader that can be
downloaded to a pocket PC or PDA. It contains a tool
that will convert downloaded files into a version specific
for the device being used. Drag-and-drop techniques can
be used to copy the converted PDF file to an individual
PDA.
AvantGo is a mobile Internet service that provides
free interactive and personalized content and applications
for hand-held devices or Internet-enabled mobile phones.
It is used to customize the information received on a
PDA (e.g., stock quotes, sports news).
www.healthypalmpilot.com is a Web site that lists
over 700 medical resources available for use on a PDA.
www.palmgear.com contains over 13,000 software
titles available for download to a PDA. The software
covers general topics that are not necessarily related to
medicine.
Keeping up with new and changing applications
can be simplified by registering for updates from
PalmGear.com or pdaMD.com. These sites send e-mail
updates and evaluations as new software applications
become available.
Conclusion
Technology in the Future
Portable, wireless communication devices (PDA, pocket
PC) provide a powerful infrastructure for telecommunication. Now that this infrastructure is in place, newer
technologies can address problems such as battery life and
memory capacity.
Technology is moving toward groupware so that
every computer, PDA, pocket PC, or other point-of-care
device within an institution can communicate with all of
the others. The next level will be integration of the
documentation function and the knowledge compendia
8
in a customized view so that users can view formularyspecific information tailored to their individual health
system.
One important technological focus is on the order
entry system. The Institute for Safe Medication Practices
advocates electronic prescribing and believes handwritten
prescriptions ought to be a thing of the past. A study by
Bates et al.1 showed that a computerized order entry
program reduced potentially harmful prescription errors
by 55%.
In addition to ensuring prescription legibility, the
computer or PDA can check for drug interactions,
adverse effects, and formulary inclusion when the drug is
prescribed. When this electronic infrastructure is adopted
by the prescriber, many other attributes of health care can
be integrated including lab orders, referrals, claims,
scheduling, medical and drug information, patient
education, and continuing medical education. Patients’
organizers can even be integrated into the system to help
the patients understand and schedule self-care techniques.
PDAs have great utility as teaching tools.
Google.com, one of the best search engines available, has
a library of anatomical images that can be used to help
explain diseases to patients. Since 82% of people learn
better visually, this can be a tremendous teaching tool. At
www.diseases-explained.com, explanations of the most
common diseases are ready for use in patient discharge
counseling.
PDAs can be important tools for communicating drug
and health care information, enhancing clinical decisionmaking, and improving patient education. As these
devices are integrated into health systems’ communication
infrastructure, they can be used to provide real-time
information and incorporate patient safety.
Reference
1. Bates DW, Leape LL, Cullen DJ et al. Effect of computerized
physician order entry and a team intervention on prevention of
serious medication errors. JAMA.1998; 280:1311-6.
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
®
Synergy in Chemotherapy and Expanded Uses of Taxanes
An exhibitors’ theater held December 4, 2001, in conjunction with the ASHP Midyear Clinical Meeting
Supported by an educational grant from Aventis Oncology
Synergy is one of the basic principles underlying the use
of antineoplastic drugs. In this symposium, Jill M.
Kolesar, Pharm.D., BCPS, Assistant Professor at the
University of Wisconsin School of Pharmacy in Madison,
discussed the scientific rationale for synergistic therapies.
Susan Goodin, Pharm.D., Director of the Division of
Pharmaceutical Science at the Cancer Institute of New
Jersey and Associate Professor of Medicine at UMDNJ/
Robert Wood Johnson Medical School in New
Brunswick, New Jersey, described the use of taxanes in
prostate, ovarian, and non-small cell lung cancer. Kolesar
and Goodin presented an update on the synergistic
activities of taxanes in breast cancer, which was prepared
by David Frame, Pharm.D., Director of Clinical
Hematology/Oncology Pharmacy Services at RushPresbyterian-St. Luke’s Medical Center in Chicago; Frame
was unable to attend the seminar.
Mechanisms of Synergy
Synergistic drug combinations are identified in preclinical
testing, evaluated in animal models, and confirmed in
clinical trials. Disease-specific cell lines are evaluated in
one group of cells treated with drug A, one with drug B,
and one with both A and B, and cytotoxicity is determined. Synergy occurs when the effect of the combination is greater than the sum of the individual effects.
Immune-deficient mice with induced tumors are then
treated with A, B, or A and B, and changes in tumor
volume are evaluated.
Synergy in humans is sometimes discovered
through case reports. Unusual clinical toxicity can
prompt studies that may identify novel mechanisms and
new combinations. Perceived synergies are evaluated by
treating one group of patients with medications representing the current standard of care and another group
with these plus other agents.
Synergistic effects may be pharmacokinetic
(changes in the absorption rate, availability, volume of
distribution, hepatic clearance, or renal clearance) or
pharmacodynamic (occurring when the drugs’ mechanism or target is similar but the toxicity of the agents does
not overlap). With antineoplastic agents, one of the
synergistic agents may increase the molecular targets of
the other agent, influence apoptosis, contribute to drug
resistance, or affect the cell cycle.
Case Studies
Kolesar used four cases to illustrate synergy; three are
presented here.
Case 1: CC, a 64-year-old woman with metastatic
breast cancer, received adjuvant therapy with cyclophosphamide, doxorubicin, and fluorouracil, and her
lifetime cumulative doxorubicin dose is 200 mg/m2.
She could be given paclitaxel plus doxorubicin or
docetaxel plus doxorubicin. Which do you recommend?
Paclitaxel and docetaxel have a similar mechanism
of action with a markedly different toxicity profile when
combined with doxorubicin. The combination of
paclitaxel and doxorubicin causes excessive toxicity;
docetaxel plus doxorubicin does not. Paclitaxel enhances
the nonlinearity of doxorubicin pharmacokinetics. It
decreases clearance of doxorubicin and doxorubicinol
(responsible for most of the cardiotoxicity) and may
decrease doxorubicin excretion. The net effect is an
increased area under the curve and consequent toxicity of
doxorubicin. Docetaxel causes minimal alterations in
doxorubicin pharmacokinetics, so toxicity is not increased.
Case 2: AF is a 60-year-old woman with metastatic
breast cancer. Her tumor is positive (3+) for HER2/
neu. She is scheduled to receive single-agent docetaxel.
Why might you want to add trastuzumab?
The HER2/neu oncogene, a predictor of breast
cancer survival, is overexpressed in 20–30% of breast
cancer patients. In vitro models determined that
trastuzumab shows cytotoxic synergy with docetaxel by
affecting apoptosis, but paclitaxel does not.
Case 3: PP is a 59-year-old woman newly diagnosed
with stage III ovarian cancer. First-line therapy
currently is carboplatin and paclitaxel. Preliminary
results from the SCOTROC trial suggest that
carboplatin plus docetaxel has equivalent efficacy with
reduced neuropathy. Why is this combination of
taxanes and carboplatin synergistic?
Since the docetaxel/carboplatin regimen minimizes
the overlap in toxicity between carboplatin and the
taxanes, it is a synergistic combination.
Summary
The mechanism of synergy may be related to the disease,
the drug, or the drug combination and can be difficult to
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
9
isolate. Synergy is important clinically because it can
influence the sequencing and toxicity profile of antineoplastics, and it is a consideration in drug development.
Synergistic Combinations for Breast Cancer
Drug treatment for breast cancer is typically divided into
neoadjuvant, or primary adjuvant, and palliative approaches. Some centers do not use neoadjuvant chemotherapy before surgery, but presurgical use of anthracycline
and taxane combination therapy is increasing.
There is no real consensus on which adjuvant
chemotherapy regimen to use after surgery. Historically,
CAF (cyclophosphamide, doxorubicin, and fluorouracil)
and CMF (cyclophosphamide, methotrexate, and
fluorouracil) have been used. An emerging regimen is AC
followed by T (doxorubicin and cyclophosphamide,
followed sequentially by a taxane).
Combinations of agents such as anthracyclines and
taxanes, often with the addition of trastuzumab, are
improving survival in patients with breast cancer recurrence.
Trastuzumab and Docetaxel
The addition of trastuzumab to chemotherapy has been
associated with a longer time to disease progression,
higher rate of objective response, longer duration of
response, lower rate of death at one year, longer survival,
and a 20% reduction in the risk of death.1 Single-agent
response rates with trastuzumab have not been high
(16%), but the drug has low toxicity and synergistic
action. Overall response rates with trastuzumab and
docetaxel are higher than those with either agent alone.
Docetaxel has an established role in metastatic
breast cancer treatment, and additional roles are emerging. Researchers conducted Phase II studies of a combination of docetaxel and platinum (cis or carbo) every three
weeks for at least six cycles along with weekly
trastuzumab.2 These studies showed higher overall
response rates in first-line metastatic cancer therapy with
the docetaxel–cisplatin–trastuzumab combination (79%)
than with the docetaxel–carboplatin–trastuzumab
combination (56%). Patients receiving carboplatin who
had positive tests for fluorescence in situ hybridization,
indicating HER2 gene amplification, had a median time
to disease progression of 12 months.
The combination of docetaxel–cisplatin–
trastuzumab was evaluated as induction chemotherapy for
locally advanced or inflammatory breast cancer before
surgery. In this small study of 16 patients, the overall
response rate was 100%.3 A larger study of 144 HER2/
neu-positive subjects is comparing docetaxel plus
trastuzumab with docetaxel–cisplatin–trastuzumab, and
preliminary results are good.
Capecitabine and Docetaxel
Capecitabine is approved for second-line breast cancer
chemotherapy, with 18–22% response rates. Capecitabine
10
and docetaxel have distinct mechanisms of action, no
overlap of key toxicities, and synergistic activity in breast
cancer. The synergy is mediated by taxane-induced
upregulation of thymidine phosphorylase.
In a Phase III study,4 capecitabine (1250 mg/m2
twice daily on days 1–14) was combined with docetaxel
(75 mg/m2 on day 1). This combination was compared
with docetaxel 100 mg/m2 used as a single agent. Overall
response rates were 40% with the combination and 30%
with docetaxel alone, a significant difference. With
combination therapy, the median time to disease progression was 6.1 months, compared with 4.2 months in the
single-agent group. Survival time increased from 11.5
months with docetaxel alone to 14.5 months with the
combination. Although some investigators were initially
concerned about the potential for toxicity, patients’
quality of life improved over time with the combination.
The National Surgical Adjuvant Breast and Bowel
Project and US Oncology are planning and conducting
trials of capecitabine–docetaxel in the neoadjuvant and
adjuvant settings.
Docetaxel and Anthracyclines
Combinations of docetaxel with an anthracycline (doxorubicin or epirubicin) are commonly used to treat breast
cancer. In Phase III studies, doxorubicin (A) and
docetaxel (T) (AT) were compared with doxorubicin and
cyclophosphamide (AC) as first-line therapy for metastatic breast cancer.5 The response rate for AT (60%) was
significantly higher than that for AC (47%). The same
investigators compared decetaxel–doxorubicin–cyclophosphamide (TAC) with fluorouracil–doxorubicin–cyclophosphamide (FAC) as first-line therapy for patients with
metastatic breast cancer. The TAC group showed an
overall response rate of 55%, compared with 42% for FAC.
Epirubicin is now approved for use in the United
States, so many clinicians are using fluorouracil–
epirubicin–cyclophosphamide (FEC). In a comparison of
epirubicin plus docetaxel (ET) with FEC as first-line
metastatic breast cancer treatment, the overall response
rates were 63% with ET and 31% with FEC.6
Because of its significant activity against metastatic
breast cancer, docetaxel is being studied as adjuvant
therapy. A study7 compared adjuvant chemotherapy with
doxorubicin and cyclophosphamide (AC) with docetaxel
and cyclophosphamide (TC) in patients who underwent
mastectomy or breast-conserving surgery for stage I–III
breast cancer. This regimen is followed by adjuvant
radiation therapy and tamoxifen if indicated. Preliminary
results at 27 months showed 17 relapses in the TC group,
compared with 24 relapses in the standard AC group.
Longer follow-up is necessary to assess the overall efficacy
and long-term toxicity of the TC and AC regimens.
Summary
The use of taxanes as adjuvant therapy for breast cancer is
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
®
increasing. Docetaxel shows synergy with many chemotherapeutic agents including trastuzumab, capecitabine,
gemcitabine, and the anthracyclines. Adjuvant therapy
with taxanes is being used to prolong the time to disease
progression. Early therapy may yield the greatest benefit.
Future treatment is likely to involve neoadjuvant combination therapy, especially for locally advanced breast cancer
(IIIB) and patients in earlier stages with larger tumors.
Uses of Taxanes beyond Breast Cancer
Paclitaxel and docetaxel, the first taxanes to be used in
clinical practice, are potent inhibitors of microtubule
function with important activity against several solid
tumors in humans. Current indications for paclitaxel
include ovarian and breast cancer, non-small cell lung
cancer (NSCLC), and Kaposi’s sarcoma; docetaxel is
indicated for breast cancer and NSCLC. Expanded uses
of these agents include gastric, bladder, head, neck, and
prostate cancer, non-Hodgkin’s lymphoma, and adjuvant/
consolidation therapy. The role of taxanes continues to
expand, and most cancer patients will be treated with a
taxane at some point in their therapy.
Prostate Cancer
Prostate cancer treatment is one of the largest growth
areas in the use of chemotherapy and the taxanes. Taxanes
have been studied extensively in hormone-refractory
prostate cancer (HRPC). Overexpression of Bcl2, one of
the mechanisms of chemotherapy resistance, may be
driven by androgen ablation. Taxanes phosphorylate Bcl2,
inactivating it and allowing cells to move further down
the apoptotic pathway. Early studies with taxanes showed
that response rates depended on dose density and the
frequency of administration. Phase II trials demonstrated
single-agent docetaxel response rates of 45–50%.
Estramustine is synergistic with taxanes. In a Phase
II trial,8 paclitaxel 90 mg/m2 was given by one-hour
infusion weekly for six of eight weeks, with estramustine
280 mg b.i.d. × three days before, the day of, and the day
after paclitaxel. Study results showed a prostate-specific
antigen (PSA) response in 58% of patients, median
progression-free survival of 6.1 months, and median
survival of 17.2 months at a median follow-up of 15
months. This response was better than that seen with
androgen withdrawal.
Combined estramustine and docetaxel have shown
benefits. A Phase II study9 with combined estramustine
(E) 280 mg p.o. t.i.d. on days 1–5 and docetaxel (D) 70
mg/m2 on day 2 showed a PSA response rate of 68%. In
patients with measurable disease, the overall response rate
was 55%. Survival at one year was 77%, with a median
progression-free survival of 5.1 months. Toxicities
included neutropenia, hyperglycemia, and vascular events
(a known toxicity of estramustine).
The SWOG 9916 trial is an ongoing intergroup
Phase III trial with patients stratified on the basis of
measurable disease. HRPC patients will receive either
mitoxantrone and prednisone or estramustine, docetaxel,
and dexamethasone. Survival is the primary endpoint;
quality of life is also being measured.
TAX 327 is a Phase III trial comparing intermittent
docetaxel 75 mg/m2 every three weeks versus weekly
docetaxel 30 mg/m2 versus mitoxantrone plus prednisone
in HRPC patients. Schedule dependency as well as the
contribution of estramustine is being investigated.
Ovarian Cancer
Paclitaxel is the standard for first-line treatment of ovarian
cancer. It has demonstrated clinical activity in cisplatinrefractory patients, but with significant toxicity. Because
of docetaxel’s Phase I activity in platinum-resistant
ovarian cancer, a Phase II trial10 in 50 patients evaluated
the combination of docetaxel and carboplatin in chemotherapy-naïve patients with stage III/IV disease. The
overall response rate was very high (81%). Median
progression-free survival had not been reached at the time
of publication but was >16 months. The major toxicity
was neutropenia.
The Scottish Gynecological Cancer Trials Group
studied 139 patients in a Phase I/II multicenter trial to
further investigate the efficacy of docetaxel in ovarian
cancer.11 This dose-escalation trial showed a 66% overall
response rate and progression-free survival of 16.6
months with combination docetaxel–carboplatin.
Recurrence is almost universal in ovarian cancer, so
progression-free survival is an important endpoint.
One reason for considering docetaxel in ovarian
cancer treatment is the toxicity of other treatments. In the
Scottish trial 86% of patients had neutropenia, but it was
not complicated. Importantly, 90% of patients completed
all chemotherapy cycles on time. Only low rates of fluid
retention and neuropathy were observed.
The SCOTROC trial12 is a Phase III comparison of
paclitaxel–carboplatin (PC) and docetaxel–carboplatin
(DC) as first-line chemotherapy for stage Ic–IV epithelial
ovarian cancer. All patients received six cycles of therapy
unless progressive disease or excessive toxicity was noted.
The primary endpoint was progression-free survival;
secondary endpoints were overall survival, quality of life,
toxicity, and response.
Over 1000 patients have been enrolled. To date,
79% of patients in the PC group have completed six
cycles of therapy, compared with 84% in the DC group.
Interim results showed a 62% response with the PC
regimen and 65% with the DC regimen. CA125 responses were seen in 76% of PC and 75% of DC
patients. Neurotoxicity was the most common nonhematological toxicity, observed more frequently in the
PC group. The incidence of both sensory and motor
neuropathy was much greater in the PC group. Neutrope-
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
11
nia, the dose-limiting toxicity of docetaxel, occurred in
94% of patients on DC, significantly higher than the
82% rate with PC. Neutropenic complications, however,
were reversible. Thrombocytopenia was similar in both
groups, indicating that the “platelet-sparing effect” often
attributed only to the paclitaxel–carboplatin combination
is probably a taxane effect. Patients reported a better
quality of life after completing the dosing cycles. Preliminary data suggest that one-year progression-free survival is
equivalent for DC and PC.
Non-small Cell Lung Cancer
Taxanes or taxane combinations are being used as firstand second-line therapies for advanced stage IIIB or IV
NSCLC treatment. These agents are increasingly being
used in locally advanced NSCLC as well.
The SWOG 9019 study demonstrated the efficacy
of cisplatin–etoposide with concurrent radiation, followed
by cisplatin–etoposide consolidation. Progression-free and
overall survival were prolonged by the addition of
consolidation therapy.
SWOG 950413 evaluated docetaxel as a substitute
for the cisplatin–etoposide consolidation phase in patients
with pathologic stage IIIB NSCLC. Patients received
cisplatin–etoposide concurrently with radiation until
radiation was completed, then docetaxel for three cycles.
The regimen was well tolerated, although neutropenia
increased in the consolidation phase. The overall response
rate was 52%. The site of first failure was the brain;
central nervous system metastases will be important in
the design of future trials.
Median survival in SWOG 9504 was 27 months,
almost double that seen with the cisplatin–etoposide
consolidation in SWOG 9019. One-year survival was
76%, two-year survival was 54%, and three-year survival
was 40% (rates were approximately 20% higher than
those seen in SWOG 9019). Survival data for the
docetaxel group are unprecedented in the literature.
An intergroup trial is under way using cisplatin–
etoposide radiation, followed by consolidation docetaxel
75 mg/m2 × three doses, followed by treatment with or
without ZD 1839, a novel agent.
Conclusion
Few drugs have had a greater impact than the taxanes on
the treatment of solid malignancies.
■ In prostate cancer, phase III trials of docetaxel
combinations are evaluating whether they will have an
impact on overall survival. Taxanes may provide the
greatest benefit if given earlier in the course of the
disease. Studies are ongoing in this setting.
12
■
■
In ovarian cancer, a different spectrum of toxicity is
seen with docetaxel (neutropenia) than with paclitaxel
(neurotoxicity), but progression-free survival rates are
similar with the two taxanes.
Taxanes are beginning to be used in consolidation
therapy for locally advanced NSCLC.
References
1. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy
plus a monoclonal antibody against HER2 for metastatic breast
cancer that overexpresses HER2. N Engl J Med. 2001; 344:78392.
2. Nabholtz, J-M, Paterson A, Dirix L et al. A Phase III randomized
trial comparing docetaxel (T), doxorubicin (A) and cyclophosphamide (C) (TAC) to FAC as first line chemotherapy (CT) for
patients (Pts) with metastatic breast cancer (MBC). Proc Am Soc
Clin Oncol. 2001; 20. Abstract 83.
3. Hurley J, Franco S, Velez P et al. Primary therapy with herceptin,
taxotere and cisplatin in locally advanced and inflammatory breast
cancer. Proc Am Soc Clin Oncol. 2001; 20:31b. Abstract 1871.
4. O’Shaughnessy, San Antonio Breast Cancer Symposium 2000.
5. Nabholtz J, Falkson G, Campos D et al. A Phase III trial
comparing doxorubicin (A) and docetaxel (T) (AT) to doxorubicin
and cyclophosphamide (AC) as first line chemotherapy for MBC.
Proc Am Soc Clin Oncol. 1999. Abstract 485.
6. Bonneterre J, Dieras V, Tubiana-Hulin M et al. 6 cycles of
epirubicin/docetaxel (ET) versus 6 cycles of 5FU epirubicin/
cyclophosphamide (FEC) as first line metastatic breast cancer
(MBC) treatment. Proc Am Soc Clin Oncol. 2001; 20. Abstract
163.
7. Jones S, Savin M, Holmes F et al. Preliminary results of a
prospective randomized trial of adjuvant chemotherapy for
patients (Pts) with stage I-III operable, invasive breast cancer
comparing 4 courses of adriamycin/cyclophosphamide (AC) to 4
courses of taxotere/cyclophosphamide (TC). Proc Am Soc Clin
Oncol. 2001; 20 Abstract 128.
8. Obasaju C, Hudes GR. Paclitaxel and docetaxel in prostate cancer.
Hematol Oncol Clin North Am. 2001;15:525-45.
9. Petrylak D, Shelton G, England-Owen C et al. Response and
preliminary survival results of a Phase II study of docetaxel (D) +
estramustine (E) in patients (Pts) with androgen-independent
prostate cancer (AIPCA). Proc Am Soc Clin Oncol. 2000; 19:33a.
Abstract 1312.
10. Markman M, Kennedy A, Webster K et al. Combination
chemotherapy with carboplatin and docetaxel in the treatment of
cancers of the ovary and fallopian tube and primary carcinoma of
the peritoneum. J Clin Oncol. 2001;19:1901-5.
11. Vasey PA, Atkinson R, Coleman R et al. Docetaxel-carboplatin as
first line chemotherapy for epithelial ovarian cancer. Br J Cancer.
2001; 84:170-8.
12. Vasey P. Preliminary results of the SCOTROC trial: a Phase III
comparison of paclitaxel-carboplatin (PC) and docetaxelcarboplatin (DC) as first-line chemotherapy for stage Ic-IV
epithelial ovarian cancer (EOC). Proc Am Soc Clin Oncol. 2001.
Abstract 804.
13. Gasper L, Gandara D, Chansky K et al. Consolidation docetaxel
following concurrent chemoradiotherapy in pathologic stage IIIb
non-small cell lung cancer (NSCLC) (SWOG 9504): patterns of
failure and updated survival. Proc Am Soc Clin Oncol. 2001;
20:315a. Abstract 1255.
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
®
Combating CMV Infections in Immunocompromised Patients
A symposium held December 5, 2001, in conjunction with the ASHP Midyear Clinical Meeting
Supported by an educational grant from Roche Pharmaceuticals
Cytomegalovirus (CMV) retinitis was once a rare disease
occurring among individuals with primary immunodeficiency syndromes or autoimmune disorders, people with
AIDS, and immunosuppressed cancer chemotherapy
patients. CMV disease is now a major cause of morbidity
and mortality in solid organ transplantation and bone
marrow transplantation. It is associated with an increased
risk of opportunistic infections, allograft injury, and
higher transplantation costs. CMV infection also seems to
increase the risk of acute and chronic rejection of allografts via immune-mediated vascular injury.
In this symposium, Craig R. Ballard, Pharm.D.,
HIV Pharmacotherapy Specialist, University of California
at San Diego Medical Center, San Diego, California,
reviewed the epidemiology, pathogenesis, and clinical
features of CMV disease in HIV infection and discussed
common treatment strategies. Curtis D. Holt, Pharm.D.,
Associate Clinical Professor and Director of Clinical
Research, Dumont UCLA Transplantation Program, Los
Angeles, California, described the effects of CMV in solid
organ transplant patients and presented an overview of
therapeutic options for combating CMV infection. Nasr
H. Anaizi, M.S., Ph.D., Clinical Specialist for Transplantation Therapeutics and Associate Professor of Pharmacology and Physiology, University of Rochester Medical
Center, Rochester, New York, highlighted emerging
trends in the treatment of CMV, presented new research
data, and explained the pharmacokinetic profile and the
advantages of newer treatment options.
Challenges in HIV Patients
The prevalence of HIV continues to increase worldwide,
particularly in Southeast Asia and Africa. In 2000, a total
of 36.1 million people were infected. The challenges of
CMV in the HIV population result from the viral load
and subsequent immune system compromise, with the
accompanying decrease in T cells, especially during later
stages of the disease, leading to the development of
opportunistic infections. Sustained CD4 lymphocyte
counts of <50 cells/mm3 lead to CMV and other serious
opportunistic infections.
Before the development of protease inhibitors in
1996, 20–40% of patients with AIDS developed symptomatic end-organ CMV disease. Since then, patients
receiving highly active antiretroviral therapy (HAART)
have experienced recovery of immune function. As CD4
cells increase to >100 cells/mm3 during HAART therapy,
there is a related decrease in the number of opportunistic
infections, including CMV.1 In a study of clinic patients
after HAART, CMV retinitis declined by 83%.
CMV is very prevalent; 40–100% of healthy 40year-olds are infected. This very large herpes virus remains
latent after primary infection. Transmitted through close
contact among children, sexual contact, transplacental
spread, blood transfusions, or organ transplantation,
primary infection usually is asymptomatic or has mononucleosis-like symptoms. After dormancy, CMV reactivates; in people infected with HIV this can result in endorgan disease such as retinitis, gastritis, colitis, pneumonitis, or a central nervous system infection.
Up to 90% of AIDS patients develop active CMV
infection, mostly CMV retinitis. Left untreated, the
disease can cause progressive retinal destruction and loss
of vision. CMV retinitis is diagnosed through funduscopic examination by an ophthalmologist; many patients
are asymptomatic at the time of diagnosis. Screening
patients for the following symptoms can aid in the
diagnosis: visual floaters, decreased visual acuity, loss of
peripheral vision, light flashes, blind spots, and blurred
vision. Retinal detachment is a late-stage complication of
retinitis, occurring when 30% or more of the eye is
infected with CMV. Early detection through regular eye
exams can reduce the risk of disease progression, especially in patients with CD4 levels of <50 cells/mm3.
Through suppression of HIV with HAART and better
therapeutic options, the goals of halting progression of
existing CMV retinitis lesions, preventing new lesions,
and preserving sight can be achieved.
Most of the agents available for the treatment of
CMV require activation by phosphorylation. Patients
receive induction therapy dosages, followed by maintenance therapy dosages (Table 1), and are cycled back to
induction therapy when virus reactivation occurs. Adverse
effects are common and include hematologic toxicity and
nephrotoxicity, requiring routine monitoring. Ganciclovir
was the first antiviral agent developed specifically for
CMV. Oral ganciclovir treatment remains controversial.
Two studies showed no significant difference in survival
rates. However, Syntex 164 study2 data revealed that the
use of oral ganciclovir in patients with CD4 counts of
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
13
<100 cells/mm3 decreases the incidence of and delays the
onset of CMV disease. Oral ganciclovir is generally well
tolerated and has a resistance rate of <1%. High doses are
needed for efficacy because of low oral bioavailability, and
patient compliance is a challenge, with adverse effects of
neutropenia, anemia, diarrhea, drug interactions, and
nephrotoxicity. Oral valganciclovir, newly approved by
FDA, offers convenient administration and blood levels
comparable to those with systemic ganciclovir.
Intravenous foscarnet has been shown to increase
survival rates when compared with ganciclovir, primarily
because of its ability to control HIV.3 Higher doses of
foscarnet (120 mg/kg/day) provide additional benefit in
terms of survival. The ability to control HIV has proven
to be very important in the treatment of CMV disease.
Combination therapy with foscarnet and ganciclovir has
shown favorable results; however, the need for long-term
i.v. access led to lower quality of life for patients with
reactivated CMV retinitis.
Adverse effects are common during treatment of
CMV retinitis. Ganciclovir is myelosuppressive, and
neutropenia is common. Foscarnet is nephrotoxic, leading
to electrolyte imbalances, possible seizures, and genital
ulcers. Cidofovir therapy showed promise initially, especially
with respect to the development of resistant strains;
however, nephrotoxicity, neutropenia, and multiple-dose
concomitant probenecid administration (in doses of 2 g) led
to undesirable effects. All systemic therapies require
venous access, with the risk of catheter-related infections.
Table 1
Dosages Used in CMV Retinitis Induction
and Maintenance Therapy
Treatment
Dosage
Frequency
INDUCTION
Ganciclovir
5 mg/kg i.v.a
q 12 hr × 14–21 days
Foscarnet
60 mg/kg i.v.b
90 mg/kg i.v.c
q 8 hr × 14–21 days
q12 hr × 14–21 days
Cidofovir
5 mg/kg i.v.d
q 7 days × 14 days 2
Ganciclovir
5 mg/kg i.v.
Once daily
Foscarnet
90–120 mg/kg i.v. Once daily
Cidofovir
5 mg/kg i.v.
Once every other week
Oral ganciclovir
1000 mg p.o.
3 times per day
Ganciclovir
implant
1 mg/hr
Lasts 6–9 months
MAINTENANCE
a
28–42 doses.
14
b
42–63 doses.
c
28–42 doses.
d
2 doses.
Intraocular weekly injections of ganciclovir or
foscarnet avoid the problems of long-term i.v. access;
however, there is no benefit to the unaffected eye or other
organs, and complications such as vitreous hemorrhage,
retinal detachment, and endophthalmitis often develop.
The ganciclovir implant has an eight-month duration of
action and delivers a higher concentration of drug to the
eye, suggesting additional benefit to overcome resistance,
but it can produce temporary reduction in visual acuity,
early retinal detachment, and endophthalmitis. The
implant does not provide adequate antiviral activity for
systemic or contralateral CMV disease; studies indicate a
31% rate of extraocular CMV disease in these patients.
CMV retinitis therapy can be discontinued in HIV
patients on a discretionary basis as immune system
recovery is achieved (CD4 count >100 cells/mm3 and
viral load controlled for more than three months).
CMV in Transplant Recipients
As in HIV patients, CMV is prevalent in transplant
recipients; 40–100% of hosts are seropositive. Serology
testing is very important in determining the relative risk
for transplant patients. In general, recipients excrete a fair
amount of CMV postoperatively, with peak concentrations occurring four to eight weeks after transplantation.
Administration of immunosuppressants enables CMV
particles to replicate and potentially cause end-organ
disease. When active infection occurs, immunosuppressant regimens can be manipulated to allow the host’s
immune system to react. Documented in 3–42% of solid
organ transplant patients, CMV infection requires
aggressive diagnostic and therapeutic intervention. The
rate of CMV infection varies, with rates of 5–29% in liver
recipients, 8–32% in kidney recipients, 9–35% in heart
transplant patients, and a much higher rate in lung (39–
41%) and pancreas (50%) recipients.4 Risk factors for
transplant recipients include the net state of immunosuppression (defined as the net effect of the immunosuppressant dosages required, the duration of immunosuppressant therapy, and the timing of immunosuppression); the
type of organ transplanted; immunomodulatory events,
such as prior hepatitis C infection; HLA mismatching;
cadaveric transplantation; retransplantation; and administration of blood products from a CMV-infected donor.
Serology testing of donors for CMV status is now
recognized as a very important management strategy.
Primary infection from CMV-positive donors to CMVnegative hosts occurs in 40–60% of patients. In up to
22% of transplant cases, both donor and host are seropositive; the rate of CMV infection in this group is 50%.
Transplant centers have learned through studies that
the time of the recipient’s greatest risk of viral infection is
four to eight weeks after surgery. Conventional antiviral
prophylaxis can be initiated at four weeks and continued
for the duration of the high-risk period (usually 100
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
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days). Another period of high risk for these patients is
immediately after discontinuation of CMV prophylaxis.
Direct effects of CMV infection in solid organ
transplant patients include flu-like symptoms (fever,
malaise, arthralgias, nausea, vomiting). Hematologic
changes may include leukopenia, atypical lymphocytosis,
and thrombocytopenia. The adverse effects of the immunosuppressant medications are similar, making these changes
difficult to distinguish from adverse drug reactions.
The indirect effects of CMV are numerous. The
rate of graft rejection may be increased by either latent or
primary infection.5 Reported cases of Epstein-Barr virus
(EBV)-associated posttransplant lymphoproliferative
disorder (PTLD) are attributed to indirect effects of
CMV in solid organ transplantation. Other indirect
effects are cellular effects of increased antigen and
cytokine expression, possibly leading to either allograft
rejection or a more chronic injury (e.g., atherosclerosis,
bronchiolitis, vanishing bile duct syndrome). Systemic
immune suppression can result from CMV infection in
transplant recipients; this is due to an
immunomodulating virus. This suppression can result in
other opportunistic infections such as coexisting fungal
infections (pneumocystis pneumonia) or fatal infections
such as aspergillosis.
Preventing CMV infection in solid organ transplant
recipients is one method of CMV management. Protective matching of seronegative donors to seronegative
recipients is an effective means of CMV prevention,
especially in elective transplant cases. Passive immunization, active immunization, and immunomodulators have
been investigated but have serious drawbacks.
For treating CMV infections in solid organ transplantation patients, ganciclovir is currently the standard
agent. The nephrotoxicity of foscarnet and cidofovir is a
major concern. Combination therapy with ganciclovir
followed by acyclovir, or ganciclovir plus CMV immune
globulin, has emerged as the preferred method of CMV
treatment.
Acyclovir has been studied primarily for CMV
prevention in kidney transplant recipients, and although
its pharmacokinetic profile has drawbacks, clinical data
from older trials suggest that it is well tolerated as
suppressive therapy in certain transplant populations.
Intravenous ganciclovir has emerged as the drug of
choice in many settings for the prevention and treatment
of CMV and EBV infection. After conversion to the
triphosphate form, it competitively blocks viral DNA
polymerase, preventing viral replication. Oral ganciclovir,
even with poor absorption and gastrointestinal adverse
effects, has a role when combined with i.v. therapy,
primarily as suppressive therapy. Studies have documented the effectiveness of ganciclovir against CMV, and
newer investigational agents such as fomivirsen, lobucavir,
and adefovir will likely be compared with ganciclovir.
Cytomegalovirus immune globulin is reserved
primarily for prevention of CMV in special (e.g., pediatric) populations or for treatment of severe or refractory
infections in combination with ganciclovir. Therapy is
expensive, with a regimen of five or six infusions required,
and clinical data6 have not shown CMV immune globulin as monotherapy to have a significant impact on CMV
disease in kidney or liver transplant patients.
The focus in the future will be on preemptive
therapy versus prophylaxis of CMV in organ transplant
patients. Diagnostic tests to identify CMV infection prior
to disease will be used, in addition to early initiation of
antiviral therapy in high-risk recipients, minimizing cost
with no resulting increase in CMV-associated morbidity
or mortality. Studies are needed to compare the overall
costs of universal prophylaxis with the use of laboratory
markers to identify and treat high-risk organ recipients.
CMV treatment and prophylaxis guidelines vary among
transplant centers but in general support prophylaxis
throughout the posttransplantation risk period .7
With the emergence of more effective therapies,
CMV as a complication of solid organ transplantation has
been minimized.
Emerging Trends in CMV Management
Adoptive cellular immunotherapy is the administration of
immune effector cells for the treatment or prevention of
disease. The clinical use of this therapy for CMV remains
investigational, but it is based on harvesting clones of
CMV-specific T lymphocytes from the blood of a donor,
then transferring the harvested cells to a bone marrow
transplant recipient without endangering the graft or the
patient. Results in animal studies have been good.
Valganciclovir was recently approved by FDA for
the treatment of CMV retinitis in AIDS patients. It is the
l-valyl ester and essentially a prodrug of ganciclovir that is
rapidly metabolized after oral administration to
ganciclovir and valine, primarily in the cells of the small
intestine and liver. Sugawara et al.8 investigated the
transport of ganciclovir and valganciclovir by intestinal
and renal transporters and determined that when valine is
added to ganciclovir the bioavailability of ganciclovir is
markedly enhanced.
In 1999, Jung and Dorr9 studied valganciclovir
bioavailability to determine whether serum concentrations could be achieved that were comparable to those
with intravenous and oral ganciclovir. This study included 18 patients, either HIV or CMV positive. Each
patient randomly received a single oral dose of
valganciclovir 360 mg or ganciclovir 1 g, or an i.v.
infusion of ganciclovir 5 mg/kg administered over one
hour. Mean ganciclovir peak levels were higher and were
achieved sooner with the 360-mg dose of valganciclovir
than with the oral 1-g ganciclovir dose. As expected, i.v.
ganciclovir achieved higher peak concentrations than
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
15
either oral formulation. This study showed that the
bioavailability of valganciclovir is approximately 60% (or
10 times) greater than that of oral ganciclovir. Through
mathematical extrapolation, the researchers concluded
that a 900-mg dose of valganciclovir should achieve the
same concentration as i.v. ganciclovir at a dose of 5 mg/kg.
Brown et al.10 in 1999 published a study to determine the dosage of valganciclovir that would achieve
serum concentrations comparable to those with i.v.
ganciclovir doses used for induction treatment of CMV
in HIV patients. Patients were randomized to fasting and
nonfasting groups, and given escalating daily doses of
valganciclovir (450, 875, 1750, and 2725 mg) for three
days, with a four-day washout period between dosing
periods. The researchers determined that a 900-mg dose
of valganciclovir administered with food achieved total
exposure (AUC24) comparable to i.v. ganciclovir 5 mg/kg.
Administration of valganciclovir with food slightly
delayed the peak serum concentration (Cmax), but the Cmax
value was not significantly affected.
The WV15376 trial (data on file, Roche Pharmaceuticals) led to the approval of valganciclovir for CMV
infection in HIV patients, comparing 80 patients who
received i.v. ganciclovir with 80 patients who received
valganciclovir at a dose of 900 mg every 12 hours for two
weeks followed by 900 mg every 24 hours for one week.
Pharmacokinetic parameters were monitored at 12 hours
and 24 hours after administration, while disease progression was evaluated by retinal photography. This study
revealed no difference in bioavailability of valganciclovir
versus i.v. ganciclovir.
An important study of valganciclovir pharmacokinetics by Pescovitz11 was performed in 28 liver transplant
recipients concurrently receiving immunosuppressant
therapy. Doses compared were as follows:
■ Ganciclovir 1 g p.o. t.i.d.
■ Valganciclovir 450 mg p.o. q 24 hr
■ Valganciclovir 900 mg p.o. q 24 hr
■ Ganciclovir 5 mg/kg q 24 hr by i.v. infusion over one
hour
Each drug regimen was followed by a washout period of
three to seven days.
As in the previous studies, the 900-mg dose of
valganciclovir was bioequivalent to i.v. ganciclovir, with
AUC24 values of 41.7 µg/mL • hr for valganciclovir and
48.2 µg/mL • hr for i.v. ganciclovir. One dose of oral
valganciclovir 450 mg was bioequivalent to oral
ganciclovir 3 g administered as 1 g t.i.d., with AUC24
values of 21.1 and 20.7 µg/mL • hr, respectively. For
prevention of CMV in most solid organ transplant
recipients, AUC24 values of 20–25 µg/mL • hr are
adequate. Pecovitz concluded that oral valganciclovir
therapy is effective for preventing and treating CMV
disease in organ transplant recipients.
16
Important differences were noted between the
results of trials in HIV patients and trials in transplant
recipients. A 450-mg dose of valganciclovir produced a
ganciclovir AUC24 in the transplant group (21 µg/mL •
24 hr) 61.5% higher than that in the HIV patient group
(13 µg/mL • hr). This difference could be due to higher
ganciclovir clearance in the HIV patients.
For 100 days of CMV prophylaxis, valganciclovir
450 mg once daily has an acquisition cost of $2400,
compared with $5400 for oral ganciclovir 1 g t.i.d.
Oral valganciclovir provides a more convenient
alternative to i.v. ganciclovir for high-risk patients. It also
eliminates the risk of catheter-related complications.
Better suppression of subclinical CMV disease is achievable with greater ganciclovir exposure and may translate
into improved long-term clinical outcomes. Clinical trials
in solid organ transplantation and bone marrow transplantation patients are needed to show the benefit of
prophylaxis with valganciclovir compared with other
agents.
References
1. Palella FJ Jr, Delaney KM, Moorman AC et al. Declining
morbidity and mortality among patients with advanced human
immunodeficiency virus infection. Outpatient Study Investigators.
N Engl J Med. 1998; 338:853-60.
2. Drew WL, Ives D, Lalezari FP et al. Oral ganciclovir as maintenance therapy for cytomegalovirus retinitis in patients with AIDS.
Syntex Cooperative Oral Ganciclovir Study Group. N Engl J Med.
1995; 333:615-20.
3. Studies of the Ocular Complications of AIDS Research Group in
collaboration with the AIDS Clinical Trials Group (ACTG).
Foscarnet-ganciclovir cytomegalovirus retinitis trial 4: visual
outcomes. Ophthalmology. 1994; 101:1250-61.
4. Sia IG, Patel R. New strategies for prevention and therapy of
cytomegalovirus infection and disease in solid-organ transplant
recipients. Clin Microbiol Rev. 2000; 13:83-121.
5. Fishman J, Rubin R. Infection in organ transplant recipients. N
Engl J Med. 1998; 338:1741-51.
6. Snydman DR, Falagas ME, Avery R et al. Use of combination
cytomegalovirus immune globulin plus ganciclovir for prophylaxis
in CMV-seronegative liver transplant recipients of a CMVseropositive donor organ: a multicenter, open-label study.
Transplant Proc. 2001; 33:2571-5.
7. Van der Bij W, Speich R. Management of cytomegalovirus
infection and disease after solid-organ transplantation. Clin Infect
Dis. 2001; 33(suppl 1):S32-7.
8. Sugawara M, Huang W, Fei YJ et al. Transport of valganciclovir, a
ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J
Pharm Sci. 2000; 89:781-9.
9. Jung D, Dorr A. Single-dose pharmacokinetics of valganciclovir in
HIV and CMV seropositive subjects. J Clin Pharmacol. 1999;
39:800-4.
10. Brown F, Banken L, Saywell K et al. Pharmacokinetics of
valganciclovir and ganciclovir following multiple oral dosages of
valganciclovir in HIV and CMV seropositive volunteers. Clin
Pharmacokinet. 1999; 37:167-76.
11. Pescovitz MD. Oral ganciclovir and pharmacokinetics of
valganciclovir in liver transplant recipients. Transpl Infect Dis.
1999; 1(suppl 1):31-4.
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
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Interpreting Antimicrobial Susceptibility Tests
An exhibitors’ theater held December 4, 2001, in conjunction with the ASHP Midyear Clinical Meeting
Supported by an educational grant from Roche Pharmaceuticals
NCCLS (formerly the National Committee on Clinical
Laboratory Standards) promotes the development and use
of voluntary consensus standards and guidelines for
medical testing, including criteria for interpretation of
antimicrobial susceptibility testing. In this symposium,
Christine Ginocchio, Ph.D., MT (ASCP), Director of
Microbiology, Virology, and Molecular Diagnostics,
North Shore-Long Island Jewish Health System, described the process of developing and implementing
NCCLS standards and reviewed recent changes in
antimicrobial susceptibility breakpoints. Jean-Marie
Pflomm, Pharm.D., BCPS, Clinical Coordinator of
Antibiotic Management, Memorial Sloan-Kettering
Cancer Center, outlined trends in and mechanisms of
resistance for Streptococcus pneumoniae and discussed how
the recent changes in NCCLS guidelines will affect the
clinical use of antimicrobials in hospitals. Annette
Avicolli, M.S., R.Ph., Clinical Liaison, Roche Pharmaceuticals, moderated the program.
Guidelines Development and Changes
Ginocchio began by explaining the importance of the
NCCLS guidelines in the selection, testing, and monitoring of antimicrobial therapy. She reviewed the NCCLS
consensus process, highlighting the extensive data
collection and open review phases. Once a set of guidelines is authorized and developed by the initial committee, it is distributed to over 100 reviewers from various
disciplines. For example, the subcommittee on antimicrobial susceptibility testing sends its documents for review
to representatives of microbiology laboratories, government agencies, various health care providers and educators, diagnostic microbiology industries, and the pharmaceutical industry. Comments from the field are incorporated into the document before its final acceptance as a
consensus standard. Although NCCLS does not mandate
compliance with its guidelines, most accrediting bodies
require laboratories to adhere to the NCCLS standards.
The subcommittee on antimicrobial susceptibility
testing has the following functions:
■ Develop standard reference methods for antimicrobial
susceptibility tests.
■ Provide quality control parameters for standard test
methods.
■
■
■
■
Establish interpretive criteria for the results of standardized susceptibility tests.
Provide suggestions for testing and reporting strategies
that are clinically relevant and cost-effective.
Refine standards and optimize the detection of
emerging resistance mechanisms through the development of new or revised methods, interpretive criteria,
and quality control parameters.
Educate users through multimedia communication of
standards and guidelines.
Table 1
Susceptibility Test/Report Groups
Group A
■
Routine, primary testing panel for specific organism
groups
Group B
■
■
■
■
■
■
Important clinically for nosocomial infections
Reported selectively for organisms resistant to group A
Selected specimen sources (cerebrospinal fluid [CSF])
Polymicrobial infections
Allergy, intolerance, failure to respond to group A agents
Epidemiology reporting to infection control
Group C
■
■
■
■
Alternative or supplemental antimicrobials for
endemic or epidemic strains resistant to several
primary drugs
Treatment of patients allergic to primary drugs
Treatment of unusual organisms
Epidemiology aid
Group U
■
Urinary tract isolates only
Group O
■
Clinical indication for group but not candidates for
general testing in United States
Group Inv
■
Not FDA approved
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
17
Foster a dialogue with users of these methods and
those who apply them.
The development of interpretive guidelines is based
on the pharmacokinetic properties of the drug, tissue and
fluid concentrations, in vitro susceptibility test data,
clinical efficacy studies, and understanding of resistance
mechanisms. First, susceptibility results are reported by
groups of drugs in which a representative from the class
of antimicrobials is used for primary testing, e.g.,
cefazolin for first-generation cephalosporins. Ginocchio
indicated that groups A and B in Table 1 should always
be reported. Assignment of agents to the specific test/
report groups is based on clinical efficacy, prevalence and
emergence patterns of resistance, cost, FDA status, and
current consensus recommendations from professional
organizations such as the Infectious Diseases Society of
America (IDSA). Selective antimicrobial reporting
improves the clinical relevance of the test reports,
minimizes the development of resistance, and controls the
overuse of new, toxic, or costly agents. Interpretive criteria
are then developed on the basis of the “bug–drug”
combination, isolate source, and drug class resistance
interpretations. Criteria for the three categories of
antimicrobial susceptibility (susceptible, resistant, and
intermediate) are presented in Table 2. Laboratory results
often include computer-generated messages or warnings,
which are important to consider in clinical decision-making.
New and revised NCCLS standards are released
each January. Ginocchio recommended a systematic
review of the annual changes by multiple disciplines,
including microbiology, pharmacy, infectious disease
(both adult and pediatric), and infection control.
The areas with the greatest potential impact are
1. Drug formulary: addition/deletion of antimicrobials,
restrictions on antimicrobial usage, cost.
2. Laboratory testing: new criteria and methods,
specialized testing, confirmatory testing, technical
training, test validation, quality control, cost,
workflow.
3. Antimicrobial susceptibility interpretive guidelines,
including messages and warnings: effect on past
antibiograms, inconsistencies in reporting, clinician
education, computer information
Once the appropriate hospital or health-system
committees review and accept the guidelines, the changes
can be implemented. Laboratory staff should be trained
in any new testing procedures. Information systems
should be updated to include new data and messages or
warnings. Pharmacy and medical staff should be educated
through grand rounds, conferences, the pharmacy and
therapeutics committee, and newsletters.
Antimicrobial resistance data from ongoing
surveillance systems (including hospital and unit-specific
antibiograms) should be used to optimize antimicrobial
Table 2
■
18
Susceptibility Criteria
Susceptible (S)
■
Infection may be appropriately treated with the dosage
of antimicrobial agent recommended for that type of
infection and infecting species.
Resistant (R)
■
■
■
Not inhibited by the usually achievable systemic
concentrations of the agent with normal dosage
schedules.
Fall in the range where specific resistance mechanisms
are likely.
Clinical efficacy has not been reliable in treatment
studies.
Intermediate (I)
■
■
■
Antimicrobial agents with minimum inhibitory
concentrations (MICs) that approach usually attainable blood and tissue levels and for which response
rates may be lower than in susceptible species.
Clinical applicability to sites where drugs are physiologically concentrated or where high dosages may be
used.
“Buffer zone” for uncontrolled technical factors.
usage and minimize resistance. Infection control practices, antimicrobial restriction, and ongoing interdisciplinary communication remain important tools for the
appropriate use of antimicrobial therapy.
NCCLS changes for 2002 include
■ New linezolid interpretations for Staphylococcus,
Enterococcus, and Streptococcus.
■ Haemophilus isolates from CSF should be tested with
ampicillin, third-generation cephalosporin,
meropenem, and chloramphenicol.
■ Recommend testing for mecA gene for serious infections with coagulase-negative staphylococci.
■ For Streptococcus pneumoniae isolates from CSF:
■
• Test penicillin, cefotaxime or ceftriaxone, and
meropenem via MIC method.
• Test vancomycin via MIC or disk method.
• Interpret susceptibility to cefepime as in Table 3.
(Cefepime does not have an FDA-approved
indication for meningitis.)
For S. pneumoniae isolates not from CSF:
• Add linezolid interpretations.
• Test tetracycline as class drug for doxycycline and
minocycline.
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
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• If isolate is tetracycline resistant, it may be more
susceptible to doxycycline and minocycline.
• New interpretive values for ceftriaxone and
cefotaxime (Table 3).
• Add breakpoints for cefepime (Table 3).
The new interpretive values for ceftriaxone and
cefotaxime are of particular importance. In the past, CSF
isolates were used to determine breakpoints; the 2002
standards use respiratory isolates. This modification
dramatically changes the resistance profile of S.
pneumoniae to third-generation cephalosporins.
Effects of Guideline Changes
Pflomm began the second presentation by noting that for
over 120 years S. pneumoniae has been the predominant
treatable pathogen in common infections such as otitis
media, meningitis, sinusitis, and pneumonia. Before the
1970s, S. pneumoniae infections were treated primarily
with penicillin. Since then, the increasing resistance
patterns can be traced from the first clinically resistant
isolate found in South Africa in the 1970s through
Europe in the 1980s and then the United States throughout the 1990s. The highest levels of penicillinnonsusceptible isolates occur in the eastern hemisphere.
Doern et al. conducted three consecutive
multicenter national surveillance studies from 1994
through 20001 that demonstrated a rate of S. pneumoniae
resistance far higher than past studies had indicated. They
found an overall 10% increase in resistance over a fiveTable 3
New MIC Breakpoints (µg/mL)
for pneumoniae
S
I
R
Meningitis
Cefepime ≤0.5 1
Cefotaxime ≤0.5 1
Ceftriaxone ≤0.5 1
≥4
≥2
≥2
Nonmeningitis
Cefepime
≤1
2
≥4
≤1
≤1
2
2
≥4
≥4
Cefotaxime
Ceftriaxone
year period. In their most recent study, November 1999
through December 2000,2 Doern et al. found that 35%
of S. pneumoniae isolates were resistant (includes intermediate susceptibility) to penicillin and 60% of that group
were highly resistant to penicillin (MIC >2 µg/mL). More
than 1500 isolates from 33 centers were included in the
study. Most of the resistant isolates were from sinus and
middle ear specimens and children less than five years of
age. Increased resistance was most prevalent in the
southeastern United States.
The primary mechanism for S. pneumoniae resistance is an alteration of penicillin-binding proteins. Since
other β-lactam antimicrobials have penicillin-binding
proteins, cross-resistance is common. Doern et al.2
showed significant resistance to other β-lactams in their
1999–2000 study and cross-resistance to antimicrobials
of other types.
Recalculating the resistance profiles using the new
NCCLS breakpoints for S. pneumoniae greatly reduces
those numbers. For example, the resistance profile for
amoxicillin–clavulanate decreased from 24.2% to 6%.
Similarly, at the January 2001 NCCLS Meeting, Focus
Technology data presented showed that with the new
breakpoints, ceftriaxones’s susceptibility will go from
82.3% to 95.1% (Figure 1).
The TRUST 4 (1999–2000) and TRUST 5 (2000–
2001) studies3 (9499 isolates from 238 labs) show an
increase in S. pneumoniae resistance to penicillin in the
United States from 16% to 17% and an increase in
resistance to azithromycin from 23% to 28%. These
studies show that S. pneumoniae intermediate resistance
to penicillin increased from 18% to 18.7% and high-level
penicillin resistance increased from 16% to 16.9%.
However, with the new NCCLS interpretive criteria for
Comments
Report only meningitis interpretations.
Therapy requires maximum doses of
cefotaxime or ceftriaxone.
Report interpretations only for
nonmeningitis, and include the
nonmeningitis notation on the report,
since there is not an FDA-approved
indication for the use of cefepime in
meningitis.
Report both interpretive criteria.
For cefotaxime: Use of interpretive
criteria for nonmeningitis requires
doses appropriate for serious
pneumoccal infections (at least 1 g
[adults] or 50 mg/kg [children] every 8
hours or more frequently).
MIC (µg/mL) Distribution
Figure 1. Ceftriaxone’s susceptibilities to S. pneumoniae
using the old breakpoints (0.5 µg/mL) vs. new breakpoints
(1.0 µg/mL).
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
19
S. pneumoniae, resistance profiles have dramatically
improved. For example, TRUST 4 results show that
13.3% of S. pneumoniae isolates had intermediate
resistance to ceftriaxone, compared with 3% of S.
pneumoniae isolates in TRUST 5.
Several factors influence resistance to S. pneumoniae:
■ Selective pressure of oral antimicrobial usage
■ Easily transmitted pathogen
■ Colonization (usually parents of children in daycare)
■ Chromosomal stability
■ Sufficient virulence
Pflomm outlined evidence supporting the
breakpoint changes:
1. Surveillance data4 showed patients were responding
clinically despite in vitro MIC data that were classified
as resistant. (The original breakpoints were determined using resistant strains for meningeal penetration.)
2. Pharmacokinetics and pharmacodynamics of
ceftriaxone5,6 display adequate free drug concentration
above the MIC for over 24 hours.
3. Clinical outcomes from numerous studies7-9 showed
no treatment failures or increase in mortality with
MICs less than 1 µg/mL.
Consequences of the breakpoint change include the
following:
■ β-lactam antimicrobials can comfortably be used in
community-acquired pneumonia.
■ Overuse of fluoroquinolones and other new antimicrobial classes may be avoided.
Pflomm reiterated the importance of multidisciplinary involvement in implementing NCCLS guidelines.
Pharmacists have a key role in education about appropriate antimicrobial therapy and use of the NCCLS inter-
20
pretations. Pflomm concluded by reviewing ways of
minimizing resistance:
■ Use antimicrobials only when necessary.
■ Avoid underdosing.
■ Follow published guidelines.
■ Monitor antibiogram for indicators.
■ Counsel patients on the prudent use of antimicrobials.
■ Encourage symptomatic treatment of nonspecific
upper-respiratory-tract infections, even with nasal
discharge, unless there is underlying serious illness.
■ Refer physicians to an article in March 20, 2001,
Annals of Internal Medicine for treatment guidelines
and tips for talking with patients.
References
1. Doern GV. Antimicrobial use and the emergence of antimicrobial
resistance with Streptococcus pneumoniae in the United States. Clin
Infect Dis. 2001; 33 (Suppl 3):S187-92.
2. Doern GV, Heilmann KP, Huyuh HK et al. Antimicrobial
resistance among clinical isolates of Streptococcus pneumoniae in the
United States during 1999–2000, including a comparison of
resistance rates since 1994–1995. Antimicrob Agents Chemother.
2001; 45:1721-9.
3. Selman LJ et al. In: Abstracts of the 40th ICAAC. 2000. Abstract
1789.
4. Feikin DR, Schuchat A, Kolczak M et al. Mortality from invasive
pneumococcal pneumonia in the era of antibiotic resistance, 19951997. Am J Public Health. 2000; 90:223-9.
5. Scully BE, Fu KP, Neu HC. Pharmacokinetics of ceftriaxone after
intravenous infusion and intramuscular injections. Am J Med.
1984; 77(4C):112-6.
6. Yuk J, Nightingale CH, Quintiliani R. Clinical pharmacokinetics
of ceftriaxone. Clin Pharmacokinet. 1989; 17(4):223-35.
7. Pallares R, Linares J, Vadillo M et al. Resistance to penicillin and
cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med. 1995; 333:474-80.
8. Heffelfinger JD, Dowell SF, Jorgensen JH et al. Management of
community-acquired pneumonia in the era of pneumococcal
resistance. Arch Intern Med. 2000; 160:1399-1408.
9. Sahm D. TSN Database. Paper presented at NCCLS January
2001 meeting.
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
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Considerations for Use of Serotonin Type 3 Receptor Antagonists in
Special Patient Populations
A breakfast symposium held December 4 and 6, 2001, in conjunction with the ASHP Midyear Clinical
Meeting
Supported by an educational grant from Roche Pharmaceuticals
Serotonin type 3 (5-HT3) receptor antagonists are a
critical part of the supportive care regimen of cancer
patients. These agents have been available for 10 years,
during which the market has evolved from primarily
intravenous administration to primarily oral administration and from one agent to three very efficacious agents
(Table 1). In this breakfast symposium, Susan Goodin,
Pharm.D., BCOP, Director of Pharmaceutical Sciences
at the Cancer Institute of New Jersey and Associate
Professor of Medicine at UMDNJ/Robert Wood Johnson
Medical School, reviewed the 5-HT3 antagonists and
their safety and adverse effect profiles, with emphasis on
patient subgroups in whom the adverse effect profile is
particularly relevant.
hensive Cancer Network (NCCN), Multinational
Association of Supportive Care in Cancer (MASCC),
American Society of Health-System Pharmacists (ASHP),
American Society of Clinical Oncologists (ASCO), and
European Society for Medical Oncology (ESMA)—have
held discussions with their thought leaders, reviewed the
existing data, and issued consensus guidelines on the use
of these medications. Worldwide, at least five other sets of
guidelines exist.
A draft set of consensus guidelines encompassing all
of the previous antiemetic guidelines was presented at the
May 2001 ASCO meeting in San Francisco. The highlights:
Drug
Dose Range
Evidence/
Confidence
Antiemetic Consensus Guidelines and
Special Populations
Dolasetron
mesylate
i.v.: 100 mg or 1.8 mg/kg
p.o.: 100 mg
Antiemetic agents have been studied extensively for
treating and preventing chemotherapy-induced emesis
(CIE). Five major organizations—the National Compre-
Granisetron
hydrochloride
i.v.: 10 mg/kg or 1 mg
High/High
p.o.: 2 mg (or 1 mg) Mod/High
Ondansetron
hydrochloride
i.v.: 8 mg or 0.15 mg/kg
p.o.: 24 mg or 8 mg b.i.d.
Table 1
Historical Overview of the U.S. 5-HT3
Antagonist Market
Formulation
Marketing
Date
Emetogenicity Level
of Chemotherapy
Ondansetron i.v.
Jan 1991
High
Ondansetron p.o.
Jan 1993
Moderate
Granisetron i.v.
Dec 1993
High
Granisetron p.o.
Mar 1995
High
Dolasetron i.v.
Fall 1997
High
Dolasetron p.o.
Fall 1997
Moderate
Ondansetron orally
disintegrating tablets
Fall 1999
High
High/High
High/High
High/High
Moderate
In general, the same doses are used for highly and
moderately emetic chemotherapy.
While guidelines are useful in minimizing variations in care, predicting outcomes and best treatment for
most patients, and maximizing contract prices, they also
have some weaknesses. Guidelines address all patients
according to the type of chemotherapy received and do
not take comorbidities into account. They cannot predict
outcomes and best treatments for every patient, and they
cannot address situations for which no data are available.
Patient populations whose antiemetic treatment
needs are not fully addressed by consensus guidelines
include pediatric patients, elderly patients, patients
receiving concomitant therapies, and patients with
hepatic or renal impairment.
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
21
Pediatric Patients
Many institutions have only one product on the formulary to treat both adults and children. All three of the
currently marketed 5-HT3 antagonists are approved for
CIE in pediatric patients, but none is approved for
patients younger than two years of age. In order to adopt
a single product for an institution’s formulary, clinicians
need more data confirming pediatric dosing information.
Elderly Patients
Goodin illustrated the need for special treatment in the
elderly by presenting a case for discussion. Each symposium participant was able to respond to treatment
questions by using an electronic number pad. Participants
entered their choice from a selection of possible answers.
The group results were then tabulated and included in
the case discussion.
Case 1: A 68-year-old white woman with relapsed
stage 4 breast cancer is scheduled to receive weekly
paclitaxel and trastuzumab. She has a 15-year history
of well-controlled hypertension and osteoarthritis. Her
current medications include atenolol 50 mg q.d.,
Vioxx (rofecoxib) 12.5 mg q.d. and Tagamet HB
(cimetidine) for occasional heartburn. She reports
significant nausea and vomiting with previous
chemotherapy.
When Goodin asked the attendees to indicate the
antiemetic they would use, 20% chose dolasetron, 33%
granisetron, 40% ondansetron, and 7% metoclopramide.
In the United States, 61% of malignancies occur in
patients age 65 or older. None of the package inserts of
the currently available 5-HT3 antagonists recommend
dosage adjustments for the elderly. However, elderly
patients warrant special evaluation. In an assessment of
7600 cancer patients age 55 and older, the two most
common major comorbidities were hypertension (43%)
and heart-related conditions (39%). Therefore, in view of
these comorbidities, careful evaluation is necessary in
selecting adjunctive therapy for elderly patients, particularly those receiving cardiotoxic chemotherapy.
Cardiotoxicity
Cardiotoxic chemotherapy agents include
■ Anthracyclines: Can cause cardiomyopathy, pericarditis, myocarditis, arrhythmias, and ECG changes
■ Paclitaxel: Can cause sinus bradycardia
■ Fluorouracil: Can cause coronary spasm with prolonged infusion
■ Trastuzumab: Causes cardiomyopathy in 7% of
patients
■ Arsenic: Can cause long QT intervals and heart block
22
The 5-HT3 antiemetics can also cause cardiotoxicity.
Asymptomatic, transient ECG changes of small magnitude have been observed with all of the currently marketed serotonin receptor antagonists.
Dolasetron can cause PR, QTc, and JT prolongation and QRS widening. The changes are related in
magnitude and frequency to blood levels of
hydrodolasetron, have been self-limiting, and resolved in
24 hours without treatment. Cardiovascular consequences, including heart block and arrhythmias, have
rarely been reported.
In the only trial that was designed to evaluate the
cardiotoxic effects of a 5-HT3 antagonist with an
anthracycline, granisetron1 was associated with sinus
bradycardia, changes in P waves, junctional escape beats,
and elongated PQ intervals.
Ondansetron2 has been associated with chest pain,
and ondansetron and dolasetron3 have been associated
with prolongations of PR, QRS, QT, QTc, and JT
intervals. Comparative trials of 5-HT3 antagonists4-6 have
indicated that all of these agents may cause prolongation
of QTc, QRS, PR, and QT intervals to varying degrees.
In comparative trials, these effects were observed significantly more often with dolasetron.
These cardiotoxicity trials have several drawbacks.
Because of the exclusion criteria, none of the trials
involved cardiotoxic chemotherapy agents in patients
with cardiac problems, so they did not measure the
significance of administering a combination of a 5-HT3
antagonist and cardiotoxic chemotherapy to a patient
with hypertension or other comorbidities. The guidelines
treat cardiotoxicity as a class effect with serotonin
antagonists and not clinically significant, but more data
are needed to make that determination, since data
currently available are from restricted clinical trials.
Practitioners may choose the 5-HT3 receptor antagonist
with the least apparent effects on ECG.
Drug Interactions
Case 2: A 25-year-old man with stage 3 testicular
cancer is being treated with bleomycin, etoposide, and
cisplatin. He has been taking sertraline for depression
prior to his cancer diagnosis. Which antiemetic would
you choose along with dexamethasone?
The audience response: 23% chose dolasetron, 23%
granisetron, 33% ondansetron, and 21% no therapy.
Many pharmacists regard 5-HT3 receptor antagonists as being free of drug interactions. However, more
insight into the metabolic pathways of these agents would
be helpful in making this determination, particulary since
they are being used long-term to prevent delayed nausea
and vomiting.
Ondansetron, dolasetron, and granisetron are
metabolized by different enzymatic pathways.
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Ondansetron is metabolized primarily by CYP2D6.
Dolasetron is a prodrug metabolized by carbonyl reductase to hydrodolasetron (which causes both therapeutic
and toxic effects) before being further metabolized by the
CYP2D6 pathway. Granisetron appears to be metabolized
primarily by the CYP3A pathway. All of these pathways
are part of the hepatic cytochrome P-450 pathway, and
other drugs metabolized by this pathway have the
potential to interact with these serotonin antagonists.
In addition to metabolic actions, pharmacokinetic
and pharmacodynamic interactions have been explored in
each of these antiemetics.
■ Dolasetron: Atenolol decreased hydrodolasetron
clearance by 27%. Cimetidine (seven days) increased
hydrodolasetron by 25%. Rifampin decreased
hydrodolasetron by 28%.
■ Granisetron: Ketoconazole inhibits granisetron
metabolism.
■ Ondansetron: Cyclophosphamide caused a 15%
decrease in area under the curve. No documented
drug interactions exist with temazepam, alfentanil,
fluorouracil, or cisplatin.
In Case 2, the patient is taking sertraline, a moderate CYD2D6 inhibitor, which could potentially cause an
interaction with the serotonin antagonists when both are
administered long-term.
Renal and Hepatic Dysfunction
Many chemotherapy patients are elderly and therefore
particularly susceptible to adverse events linked to renal
or hepatic impairment.
According to dolasetron package inserts, no dose
adjustments are necessary in patients with hepatic or renal
dysfunction. The insert for intravenous dolasetron states
that clearance of hydrodolasetron remains unchanged
with severe hepatic impairment but is decreased by 47%
with severe renal impairment. The insert for oral
dolasetron states that clearance of hydrodolasetron
decreases 42% with severe hepatic impairment and 44%
with severe renal impairment.
No granisetron dose adjustments are recommended
for patients with hepatic or renal dysfunction.
In hepatic dysfunction, a total daily ondansetron
dose of 8 mg should not be exceeded. No dose reductions
are recommended in renal dysfunction. In mild-tomoderate hepatic impairment, clearance was reduced
twofold and mean half-life was increased from 5.7 hours
to 11.6 hours. In severe hepatic impairment, clearance
was reduced twofold to threefold and volume of distribution increased with an increase in half-life to 20 hours. In
severe renal impairment (creatinine clearance < 30 mL/
min), clearance was reduced by 41% (95% Cl 20–57%).
Patients Receiving Chemotherapy with
Low to Intermediate Emetogenic Potential
Case 3: A 56-year-old man with stage 4 non-small cell
lung cancer is scheduled to receive gemcitabine
palliative chemotherapy. He has difficulty swallowing
because of tumor invasion. Which antiemetic would
you recommend: oral dolasetron, oral granisetron, i.v.
ondansetron, or rectal promethazine?
The audience response: 9% would recommend oral
dolasetron, 23% oral granisetron, 55% i.v. ondansetron,
and 12% rectal promethazine.
These answers probably reflect current treatment
patterns throughout the United States. Gemcitabine, an
agent with low emetogenicity, has approximately a 10%
chance of causing emesis. For most chemotherapy agents
with low emetogenicity, the risk of developing emesis is
estimated at 10–30%; these agents include irinotecan,
topotecan, paclitaxel, docetaxel, gemcitabine, and
fluorouracil. The guidelines recommend that no antiemetic be administered with these agents. But many
clinicians would prescribe an antiemetic despite the risk
of causing adverse effects such as headache, constipation,
and diarrhea, which vary in clinical significance from
patient to patient.
The audience responses were similar to data
collected from 225 oncologists to determine the degree to
which antiemetic guidelines are being followed in patients
receiving chemotherapy.7 5-HT3 receptor antagonists,
either alone (45%) or in combination with a corticosteroid (20%), were administered to 65% of patients treated
with low-emetogenicity chemotherapeutic agents.
A study was conducted in Italy to determine
whether patients receiving chemotherapy of low to
moderate emetogenicity actually needed an antiemetic.8
In this multicenter, observational study, the researchers
looked at patients being treated with taxanes, gemcitabine,
and irinotecan and the percentage of those patients
receiving a serotonin antagonist, either alone or in
combination with a corticosteroid. The percentages of
patients treated with a serotonin antagonist with or
without a steroid were as follows:
Taxanes (n = 209) 86%
Gemcitabine (n = 300) 59%
Irinotecan (n = 93) 96%
In patients administered taxanes, protection from
vomiting and nausea was achieved in 93% and 71%,
respectively, of those receiving a 5-HT3 antagonist and
100% and 82% of those not receiving a 5-HT3 antagonist. In patients administered gemcitabine, vomiting and
nausea were prevented in 92% and 75% of those receiving a 5-HT3 antagonist and 97% and 78% of those not
receiving a 5-HT3 antagonist. In patients administered
irinotecan, vomiting and nausea were prevented in 82%
and 41% of those receiving a 5-HT3 antagonist (results
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
23
for those not receiving a 5-HT3 antagonist were not
provided, since most patients in this group received a 5HT3 antagonist). The patients taking 5-HT3 antagonists
did not achieve better protection than those receiving
different or no antiemetic prophylaxis. These data point
out the difficulty in controlling nausea and a potential
lack of efficacy of 5-HT3 antagonists for this purpose.
On average, 30–40% of cancer patients receive
moderately emetogenic chemotherapy, 30–40% receive
low emetogenic chemotherapy, and 10–15% receive
highly emetogenic chemotherapy. In many institutions,
cancer chemotherapy patients automatically receive a
serotonin antagonist regardless of the emetogenic potential of their chemotherapy regimen. On the basis of the
published guidelines for antiemetic therapy, pharmacies
can significantly decrease their expenses by eliminating
this practice and treating only those patients who actually
need antiemetic therapy.
Nausea as a Significant Outcome
Case 4: The 25-year-old man being treated for stage 3
testicular cancer (described in Case 2) received a
serotonin antagonist daily for five days as recommended by the symposium audience. Four days after
completion of therapy, he came to the clinic complaining of significant nausea but no vomiting and
reported that he had been unable to eat for the past
two days. What would you recommend for the
treatment of his nausea?
The audience response: 31% chose lemon drops,
29% granisetron, 25% ondansetron, and 15% dolasetron.
Two small studies involving predominantly women,
a trial conducted in 19839 and repeated in 199610 in
which patients ranked adverse effects, found that nausea
ranked number 2 and number 1, respectively. These
studies show that nausea is still a significant adverse
outcome of cancer chemotherapy and is a concern of
patients. All of the guidelines state that the 5-HT3
antagonists are equal in relation to the primary efficacy
variable of no emesis. However, clinicians need to be
aware that the guidelines address emesis, not nausea.
Nausea may become an even more important adverse
event as doses of serotonin antagonists are decreased.
As shown in Case 4, delayed emesis is another
potential outcome of chemotherapy. While the mechanism of delayed emesis is not clear, the risk of emesis in
the acute care setting predicts the risk of delayed emesis.
24
Since clinical trials have shown that serotonin antagonists
used in combination with dexamethasone are no better at
treating delayed emesis than dexamethasone alone,
audience response suggests that 5-HT3 antagonists are
potentially being overused for this indication.
Conclusion
Drugs used in the supportive care of cancer patients
should not add to the adverse effect burden of chemotherapy agents, thereby harming the patient. Over the
years, the focus of attention on the serotonin antagonists
has shifted from efficacy to cost containment, then to
guidelines for use. Pharmacists should examine the
guidelines in their own institutions—and then look
beyond the guidelines to individualize therapy for their
patients.
References
1. Jantunen IT, Kataja VV, Muhonen TT et al. Effects of granisetron
with doxorubicin or epirubicin on ECG intervals. Cancer
Chemother Pharmacol. 1996; 37:502-4.
2. Ballard HS, Bottino G, Bottino J. Ondansetron and chest pain.
Lancet. 1992; 340:1107. Letter.
3. Hesketh P, Navari R, Grote T at al. Double-blind, randomized
comparison of the antiemetic efficacy of intravenous ondansetron
in the prevention of acute cisplatin-induced emesis in patients
with cancer. J Clin Oncol. 1996; 14:2242-9.
4. Lofters WS, Pater JL, Zee B et al. Phase III double-blind
comparison of dolasetron mesylate and ondansetron and an
evaluation of the additive role of dexamethasone in the prevention
of acute and delayed nausea and vomiting due to moderately
emetogenic chemotherapy. J Clin Oncol. 1997; 15:2966-73.
5. Baltzer L, Kris MG, Hinkley L at al. Reversible electrocardiographic interval prolongations following the specific serotonin
antagonists ondansetron (OND) and dolasetron mesylate (DM): a
possible drug class effect without sequelae? Proc Am Soc Clin
Oncol. 1994; 13:433. Abstract 1489.
6. Audhuy B, Cappelaere P, Martin M et al. A double-blind,
randomised comparison of the anti-emetic efficacy of two
intravenous doses of dolasetron mesilate and granisetron in
patients receiving high dose cisplatin chemotherapy. Eur J Cancer.
1996; 32A(5):807-13.
7. Roila et al. Proc MASCC. 2000.
8. Roila F, Verena De Angelis S, Palazzo F et al. Antiemetic
prescriptions and effectiveness in cancer patients submitted to
chemotherapy of intermediate emetogenic potential. Proc Am Soc
Clin Oncol. 2001; 20. Abstract 1587.
9. Coates A, Abraham S, Kaye SB, et al. On the receiving end—
patient perception of the side-effects of cancer chemotherapy. Eur
J Cancer Clin Oncol. 1983; 19:203-8.
10. Griffin AM, Buttow PN, Coates A et al. On the receiving end. V:
Patients perceptions of the side effects of cancer chemotherapy in
1993. Ann Oncol. 1996; 7:189-95.
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
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Antimicrobial Management in a Group of VA Medical Centers
An exhibitors’ theater held December 3, 2001, in conjunction with the ASHP Midyear Clinical Meeting
Supported by an unrestricted educational grant from Roche Pharmaceuticals
Program moderator Melissa Neff, Pharm.D., Veterans
Affairs (VA) Heartland Pharmacy Benefits Manager, VA
Medical Center, Kansas City, Missouri, briefly described
the origins of a Veterans Integrated Service Network
(VISN) antimicrobial therapy management program to
set the stage for presentations by her VA colleagues. A
VISN is a geographic group of 8 to 12 VA medical
centers. VISN 15 encompasses eight VA medical centers
in eastern Kansas, all of Missouri, and southern Illinois.
The VISN 15 antimicrobial therapy management
program arose from Neff ’s suggestion to the infectious
disease team six years ago (when she was the sole infectious disease pharmacist) that guidelines for the use of
antimicrobials in the VA medical center would be helpful.
Devising an Antimicrobial Formulary
Stephen A. Klotz, M.D., Professor of Medicine, Section
of Infectious Diseases, University of Arizona, and
Research Service, Southern Arizona Veterans Affairs
Health Care System, Tucson (formerly associated with the
Kansas City VA Medical Center), described the process of
devising an antimicrobial formulary for the eight medical
centers in the VISN.
In years past, each of these eight medical centers
had its own antimicrobial formulary, although a central
unrestricted VA formulary was available. A VISN
antimicrobial formulary committee comprising all six
infectious disease physicians, all eight chiefs of pharmacy,
and all eight chiefs of microbiology was formed to
establish guidelines for cost-effective empiric antimicrobial therapy. Once-daily intravenous (i.v.) antimicrobial
administration and prompt transition from i.v. to oral
therapy were emphasized to minimize costs associated
with pharmacy and nursing time required to prepare and
administer i.v. doses. Inclusion in the formulary of
antimicrobials that are available in both injectable and
oral dosage forms facilitates the i.v.-to-oral conversion.
In devising an antimicrobial formulary for the
VISN, internists and infectious disease physicians were
surveyed about their preferred antimicrobial choices for
common infectious problems in hospitalized patients.
The choices were narrowed to the smallest possible
number, on the basis of efficacy and cost considerations.
The formulary reflected the fact that the VA population is
primarily an elderly one. Empiric guidelines with prescribing restrictions were published. Committee members
found that efforts to visit each medical center and educate
prescribers about the new guidelines through antimicrobial or infectious disease conferences (preferably with
meals provided) were instrumental in convincing the
prescribers to adopt the new guidelines. Educational
programs also helped the professional staff stay up-to-date
on trends in infectious diseases. The antimicrobial
formulary committee’s activities were supported by
unrestricted grants from pharmaceutical manufacturers,
although many of the manufacturers’ products were not
included in the formulary.
Changes in the formulary were made annually on
the basis of requests from committee members and
evidence supporting the need for a change. Changes were
kept to a minimum (two to seven per year) by limiting
changes to those that could be communicated reasonably
easily to all prescribers.
Research on antimicrobial use was among the
responsibilities of the antimicrobial formulary committee,
with assistance from other staff as needed. For example,
Neff determined that only 1 in 10 to 1 in 4 prescribed i.v.
antimicrobial doses is actually administered to intensive
care patients, because of the challenge of administering
the many i.v. medications required by such patients and
the large fluid volume involved. Another research project
examined outcomes in all VISN patients hospitalized
with bacteremia between 1994 and 2000. Cost of drug
therapy was among the outcomes studied. More than
2500 patients were included, and the results will be
published soon. An analysis of the costs of antimicrobial
therapy in the 15 patients hospitalized in 1999 at the
Kansas City VA Medical Center with Escherichia coli
bacteremia revealed that a wide variety of antimicrobials
were used—at a total cost of $7551—despite the fact that
all of the blood isolates were susceptible to the preferred
formulary antimicrobial, ceftriaxone. If appropriate
dosages of ceftriaxone (1 g/day) had been used instead,
the total cost would have been $5962, which represents a
cost savings of $100 per patient. If that amount were
extrapolated to the entire VISN, the cost savings could be
substantial.
In summary, the VISN formulary promoted highquality, cost-effective care by reducing inappropriate and
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
25
wasteful antimicrobial use. The process used to establish
the formulary required cooperation and improved
communication among infectious disease physicians,
microbiologists, and pharmacists. Educational efforts in
implementing the new guidelines for antimicrobial use
brought staff members up-to-date in their knowledge of
current infectious disease treatment issues.
Microbiologists’ Role
William R. Bartholomew, Ph.D., Professor of Pathology
and Laboratory Medicine, University of Kansas Medical
School, Kansas City, Kansas, and Director of Microbiology and Immunology, Pathology and Laboratory Medicine Service, VA Medical Center, Kansas City, Missouri,
described the role that VISN microbiologists played in
developing a cost-effective antimicrobial formulary.
In the past when each medical center in the VISN
had its own formulary, each laboratory had its own
instrumentation, methods, and reporting format. The
VISN microbiologists recognized the need for consistency
among the eight medical centers in antimicrobial susceptibility testing because of the importance of test results in
patient care and formulary decisions. The collaboration of
microbiologists, infectious disease physicians, clinical
pharmacists, and the infection control coordinator in
each medical center was sought in standardizing laboratory instrumentation, methods, and reporting. VISN
microbiologists shared susceptibility data and used e-mail
and scientific programs to facilitate communication about
issues involved in standardization.
After evaluating instruments for antimicrobial
susceptibility testing, the microbiologists selected the
Vitek system, a microtube dilution system. Selection of
the instrument by the microbiologists, on the basis of
scientific considerations, was preferable to an administrative decision based on less relevant considerations. The
Vitek system uses test panels with microwells containing
various concentrations of multiple lyophilized antimicrobials. A suspension of the test microorganism is incubated
in the panel, and a machine scans the microwells for
microbial growth.
To the extent possible, the panels chosen for use in
antimicrobial susceptibility testing should contain
formulary drugs, to avoid reporting that an isolate is
susceptible to a nonformulary antimicrobial. The panels
used by the VISN may suppress reporting of certain
antimicrobials and microorganisms (e.g., susceptibility to a
second- or third-generation cephalosporin when an
organism is susceptible to a first-generation cephalosporin).
VISN microbiologists also standardized laboratory
methods. Some microorganisms (e.g., Streptococcus
pneumoniae) fail to grow in a microtube dilution system
such as Vitek, and alternative testing methods are needed.
26
Disk diffusion provides only an interpretation (i.e.,
whether the microorganism is susceptible or resistant to
an antimicrobial), not the minimum inhibitory concentration (MIC). The E-test method provides both the
MIC and interpretation, but it is labor intensive. For
both disk diffusion and the E-test method, a blood agar
plate is inoculated with a microorganism, and then filter
paper disks that are impregnated with various antimicrobial agents are placed on the agar plate. The E-test
method differs from disk diffusion in that strips with a
drug concentration gradient also are placed on the agar
plate. After the plate is incubated, the zones of inhibition
are measured to determine whether the organism is
susceptible or resistant to the antimicrobial in the disk.
With the E-test method, the MIC also is indicated by the
place where the zone of inhibition crosses the strip (the
drug concentrations are printed on and read from the
strip). The VISN microbiologists established standardized
procedures for the use of these assays.
The VISN microbiologists developed standardized
report forms to provide the information needed to
identify microorganisms and document antimicrobial
susceptibility in a consistent manner. The standardized
microbiology reports indicate the time and site from
which the culture was obtained. A preliminary microbiology report might indicate that a lactose-positive, gramnegative rod was isolated, and the final report might
confirm that it is E. coli. Antimicrobial susceptibility
reports list the drugs tested; the interpretation (i.e.,
susceptibility), MIC, or both; the recommended dosage;
and the daily cost of treatment (Table 1). A $6 administrative fee for each dose is included in the daily cost of
treatment to account for pharmacy and nursing time
involved in preparation and administration of each dose.
Cost of treatment varied with changes in purchasing
contracts (all eight medical centers now purchase antimicrobials as a group instead of individually as was done in
the past).
Monitoring for the emergence of antimicrobial
resistance was among the most important roles of the
VISN microbiologists. The standardization of instrumentation and methods among the eight medical centers in
the VISN facilitated and improved the accuracy of
detection of resistance. Antibiograms (Table 2) with
susceptibility data for certain microorganisms and
antimicrobials are helpful in following trends in resistance
and suggesting possible changes in the antimicrobial
formulary.
In summary, VISN microbiologists played a vital
role in developing a cost-effective antimicrobial formulary
by standardizing laboratory instrumentation, methods,
and reporting. Monitoring for antimicrobial resistance
facilitates timely formulary decisions.
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Table 1
Susceptibility Report for Escherichia coli
Minimum Inhibitory
Concentration
(µg/mL)
Interpretationa
Antimicrobial
Usual Dosage Regimen
Cost ($) per Dayb
(Usual Daily Dosage)
≤2
S
15 mg/kg i.v. q 24 hr
2
S
1–2 g i.v. q 4–6 hr
33.62 (12 g)
Ampicillin–sulbactam
≤4
S
1.5–3 g i.v. q 6–8 hr
54.39 (12 g)
Aztreonam
≤8
S
1–2 g i.v. q 8 hr
44.49 (3 g)
Cefazolin
≤8
S
1–2 g i.v. q 8 hr
20.07 (3 g)
Cefotetan
≤ 16
S
1–2 g i.v. q 12 hr
35.96 (4 g)
Cefepime
≤4
S
1–2 g i.v. q 12–24 hr
28.64 (2 g)
Ceftriaxone
≤8
S
1 g i.v. q 24 hr
24.77 (1 g)
Gentamicin
≤ 0.5
S
7 mg/kg i.v. q 24 hr
Imipenem–cilastatin
≤4
S
0.5 g i.v. q 6–8 hr
Levofloxacin
≤1
S
250–500 mg p.o. q 24 hr
Cefpodoxime
≤1
S
Ticarcillin–clavulanate
≤ 16
S
3.1 g i.v. q 6 hr
51.84 (12.4 g)
Trimethoprim–sulfamethoxazole
≤ 10
S
Trimethoprim
5 mg/kg i.v. q 6–8 hr
36.82 (1.05 g
trimethoprim)
Amikacin
Ampicillin
a
b
6.69 (1 g)
8.33 (490 mg)
80.00 (2 g)
2.00 (500 mg)
S = susceptible.
Cost per day includes a $6 administration fee for each dose.
Table 2
Kansas City VA Medical Center
Antibiogram for 2000
Microorganism
Number of
Resistance
Isolates Tested (% of Isolates)
Staphylococcus aureus
(methicillin resistant)
401
58
Staphylococcus epidermidis
(methicillin resistant)
221
69
20
20
10
10
20
10
17
17
23
18
Enterococcus faecalis
252
6
Enterococcus faecium
75
87
Haemophilus influenzae
(ampicillin resistant)
Streptococcus pneumoniae
From blood or sterile sites
Penicillin resistant
Ceftriaxone resistant
From sputum and other sites
Penicillin resistant
Ceftriaxone resistant
Pharmacists’ Role
Todd S. Krueger, Pharm.D., Assistant Professor,
Department of Pharmacy Practice, University of Missouri—Kansas City School of Pharmacy, and Department
of Research, VA Medical Center, Kansas City, Missouri,
described the role of the pharmacy department in the
VISN antimicrobial therapy management program.
The pharmacy budget (more than $58 million in
1997) was a substantial chunk of the overall budget for
the VISN ($605 million in 1997), so cost was a major
(albeit not the only) consideration in implementing a
VISN-wide antimicrobial formulary. The bargaining
power of the group of eight institutions facilitated
bidding for the best contract price on antimicrobials.
The eight institutions in the VISN varied in size,
patient population, and other characteristics. The varied
needs of these institutions and a lack of communication
were barriers to implementing the VISN-wide formulary.
The changes made in establishing the new formulary were
considered drastic by many clinicians. For example,
ceftazidime was replaced by cefepime, and ticarcillin–
clavulanate was replaced by piperacillin–tazobactam.
Levofloxacin supplanted ciprofloxacin, and i.v. forms of
quinolones were removed from the formulary more
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
27
recently. To ease the transition to the new formulary,
inservice education programs about infectious disease
topics that highlighted formulary changes were provided
for attending physicians and residents.
A pocket reference (4 inches wide and 8 inches
high) containing the formulary and guidelines for empiric
antimicrobial use was distributed to all residents and
attending physicians. The formulary lists dosage forms,
usual dosage, and daily cost of treatment for anti-infective
agents (including antifungal and antiviral agents). The
empiric therapy guidelines address both inpatient and
outpatient therapy and are organized by type of infection.
The likely pathogens for each infection and various
antimicrobial choices, with the least expensive therapy
first, are listed.
The indications for use of restricted antimicrobials
also are listed in the pocket reference. Certain drugs
(linezolid and quinupristin–dalfopristin) require an
infectious disease consultation before dispensing.
The formulary is updated annually through a
continuous quality assurance (QA) process. The QA
process was designed to determine whether formulary
antimicrobials are the primary agents prescribed and the
reasons if they are not prescribed. The appropriateness of
the formulary is evaluated on the basis of antimicrobial
resistance patterns. The possibility that the VISN-wide
formulary may not be appropriate for specific institutional resistance patterns is considered.
The study of patients hospitalized with bacteremia,
described by Klotz, is part of the continuous QA process.
Data collection began six years ago and continues today.
Patient demographic data, microbiology data for all
isolates, and patient outcome information have been
recorded for six years. Pharmacy data are available from a
shorter period because of difficulties accessing the data
from the computer system. Nonformulary antimicrobial
use will be analyzed by institution and service or provider
to areas for additional educational interventions and to
re-evaluate the formulary. Antimicrobial resistance data
will be taken into consideration in evaluating the formulary, assuming that resistance patterns in patients with
bacteremia are representative of all infections.
Acceptance of the VISN-wide formulary has
increased over time. There is an ongoing need to reassess
the antimicrobial agents included in the formulary,
especially when new antimicrobials are marketed.
Evaluating prescribing patterns (use of nonformulary and
formulary agents) can help guide formulary changes and
educational efforts. Pharmacists play an important role in
these activities.
28
Home I.V. Antimicrobial Program
Klotz described the home i.v. antimicrobial component of
the VISN antimicrobial therapy management program.
Discharged patients received i.v. antimicrobials at
home before implementation of the VISN antimicrobial
therapy management program, although care of the i.v.
line and catheter was unpredictable and knowledge of
how to monitor for antimicrobial-induced adverse effects
was minimal. The diagnosis may not have been correct or
complete. In many cases, the antimicrobial choice and
dosage were inappropriate, and the duration of therapy
was usually longer than necessary.
Implementation of a home i.v. antimicrobial program
as part of the VISN antimicrobial program involved
recruiting a nurse with skill and experience in inserting
peripheral i.v. lines and catheters. A pharmacist knowledgeable about compounding i.v. antimicrobial admixtures
was recruited. An infectious diseases physician was included
to supervise and collaborate with other team members.
Workload data from 1999 and 2000 reveal few
problems (and no infectious complications) with peripheral i.v. lines or catheters in the home setting (four events
in 5576 patient-days in 1999, and two events in 2173
patient-days in 2000). The most commonly used i.v.
antimicrobials were vancomycin and ceftriaxone. Daily
use of ceftriaxone with oral metronidazole was also
common, especially for foot complications in patients
with diabetes mellitus. This therapy was cost-effective.
Infectious problems varied widely. Common sources of
patient referrals included orthopedic surgery, the diabetic
foot care clinic, and the HIV clinic.
Implementation of the home i.v. antimicrobial
program required coordination among several departments. Pharmacies with a complete range of i.v. admixture compounding services and equipment were needed,
as was the help of pharmacists knowledgeable about
home use of infusion pumps and devices. The pharmacies
provided supplies for patients to use in administering
medications and caring for their i.v. lines and catheters.
The nurse member of the home i.v. antimicrobial team
was a member of the infection control committee, and
the infection control nurse helped track patients with
resistant microorganisms.
Infectious disease and microbiology personnel
collaborated in isolating the causative microorganism,
making a correct diagnosis, and selecting an appropriate
antimicrobial. Coordination with a local home health
care agency or infusion company was needed for patients
at remote locations to ensure that antimicrobials were
delivered and round-the-clock nursing care was available.
The VISN home i.v. antimicrobial program reduced
the need for hospital beds and bed-day costs, home health
care payments, and antimicrobial expenditures. It probably
reduced the rate of infectious complications in i.v. lines and
catheters, although this has not been formally studied.
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Antipsychotic Therapy: Managing Costs and Maximizing Outcomes
A symposium held December 3, 2001, in conjunction with the ASHP Midyear Clinical Meeting
Supported by an unrestricted educational grant from Janssen Pharmaceutica Products, LP
The development of atypical antipsychotic drugs during
the past decade has dramatically improved the treatment
outlook for patients with schizophrenia. Although drug
costs are higher with the atypical agents than with
conventional agents, overall treatment cost is lower. At
this symposium, Jose A. Rey, Pharm.D., Associate
Professor of Pharmacy Practice, Nova Southeastern
University College of Pharmacy, Fort Lauderdale, Florida,
presented a pharmacoeconomic perspective on antipsychotic therapy. Raymond C. Love, Pharm.D., Associate
Professor and Vice-Chair, Department of Pharmacy
Practice and Science, University of Maryland School of
Pharmacy, Baltimore, moderated the program and
discussed strategies for increasing treatment adherence
and the role of long-acting antipsychotics. Henry A.
Nasrallah, M.D., Professor of Psychiatry, Neurology, and
Internal Medicine, University of Mississippi Medical
Center, Jackson, described pharmacoeconomic implications of the adverse effects of antipsychotic agents. Rohan
Ganguli, M.D., Chief of Clinical Services, Western
Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania,
presented a rationale and recommendations for switching
antipsychotics, should that be necessary.
Drug Costs versus Treatment Costs of
Schizophrenia
Schizophrenia often appears in patients in their 20s,
causing them to face a lifetime of treatment and potential
inability to contribute significantly to the work force or
society. Schizophrenia is a very expensive burden on
health care resources, as it often requires chronic care and
repeated hospitalizations that may last for weeks or
months. Adding to the high costs of hospital and outpatient care are drug costs, which account for 5–10% of the
health care dollar devoted to treating schizophrenia. The
annual cost of treating schizophrenia in the United States
was reported in 1993 to be $33 billion, half of which was
direct costs.1 Only 3% was drug costs. The indirect costs,
which are difficult to measure, include lost workdays and
effects on the quality of life.
Decreasing drug cost has only a small effect on the
overall cost of care. The average monthly costs for treatment
of schizophrenia with atypical antipsychotic agents are as
follows (based on average wholesale price data for the year
ending in June 2001, from IMS Health, NDTI):
Drug
Dose (mg/day)
Monthly Cost ($)
Quetiapine
319
231
Risperidone
4
207
Olanzapine
14
380
Ziprasidone
103
243
Olanzapine and risperidone were compared in a
study of 523 Department of Veterans Affairs patients
with schizophrenia and an average age of 50 years.2 At
average daily doses of risperidone 4.6 mg and olanzapine
14.6 mg, there was no significant difference in hospitalization rates or the number of hospital days per patient
per year. The average cost per patient per month was
$100 for risperidone and $170 for olanzapine. Monthly
outpatient costs were not significantly different.
In 1995–1996, Rey and others found that hospital
days and costs were significantly reduced in patients
treated with risperidone and clozapine (savings of
$47,000/patient/year with risperidone and $28,000/
patient/year with clozapine).
In 1997–1998, rehospitalization rates were studied
in Miami Veterans Affairs patients treated with depot
formulations of haloperidol or fluphenazine who were
switched to olanzapine or risperidone.3 Patients on a
depot antipsychotic had 23 hospitalizations per year. This
was reduced to 13 per year when the patients were
switched to an atypical antipsychotic. The average
number of days patients spent in the hospital was also
reduced. Compliance rates were 83% with haloperidol
decanoate and 89% with the atypical antipsychotics.
Atypical antipsychotics are more efficacious than
older agents in treating schizophrenia. As a class, the
atypical antipsychotics have similar outcomes, with
reduced extrapyramidal effects, but other adverse effects
and comorbid conditions need to be monitored. Cost
differs among the atypical agents; clinicians should begin
therapy with the least expensive agent.
Increasing Treatment Adherence
Relapse and rehospitalization rates in schizophrenia are
often related to nonadherence to therapy (noncompliance). Health care providers should consider what might
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
29
cause the patient to stop the medication and try to
determine a regimen that the patient will adhere to.
The compliance rate for patients with schizophrenia
is not much different than for other diseases. The median
noncompliance rate is 41% for schizophrenic outpatients
taking oral medication and 25% for those on depot
medications.4 Noncompliance rates are 55–71% for
arthritis and 54–82% for seizure disorders.
In a study of why patients with schizophrenia
stopped their medication, the most commonly stated
reason was adverse effects, followed by thinking that they
did not need the medication.5
For psychiatric patients in a family or residential
setting, taking medication is often surrounded by conflict
with caregivers and seen as an issue of power or control. A
patient who is newly noncompliant may be experiencing
such issues. The better the relationship between the
patient and the health care provider, the more likely it is
that the patient will comply with medications.
Addressing adverse effects and maximizing tolerance is a way of enhancing compliance. In addition to
adjusting dosage regimens and doses to enhance an
individual’s ability to tolerate the medication, health care
personnel need to reassure patients and help them see how
to include taking their medications in their daily routine.
There is evidence that the use of depot
antipsychotics and newer drugs such as clozapine can help
prevent hospital readmission. A study by Weiden in 1995
found rehospitalization rates of 50% in one year and 81%
in two years in patients on conventional antipsychotics
(haloperidol, chlorpromazine, thioridazine). Hogarty in
1979 found that patients taking oral fluphenazine had
rehospitalization rates of 40% in the first year and almost
65% in the second year. When these patients were
switched to fluphenazine depot, the readmission rate was
35% in the first year. In the second year, it was 40%—
almost a 25% reduction. Somewhat lower rates of
rehospitalization were found in a study by Schooler et al.
in 1997 of patients who received fluphenazine decanoate
and weekly family therapy. These patients had supportive
families, and crisis counseling was available for patients
who were decompensating. The rehospitalization rate was
10.6% in the first year and 25% at two years.
Patients taking oral atypical antipsychotics have
shown rehospitalization rates comparable to those of
patients taking conventional depot agents. For example,
studies have demonstrated readmission rates of 18% in
the first year and 28% in the second year in patients
started in clozapine.
A study by Love and colleagues for the Maryland
state pharmacy and therapeutics committee looked at
patients on risperidone, olanzapine, clozapine, haloperidol decanoate, and fluphenazine decanoate to see whether
the more costly agents produced better outcomes. The
atypical agents were significantly better than the
decanoates at keeping patients out of the hospital.
30
A long-acting i.m. formulation of risperidone is
currently under review by FDA.6 The drug is embedded in a
copolymer matrix. The polymer “microspheres” disintegrate
gradually to release the drug. Drug release peaks at about
five weeks and tapers off over the following two weeks.
The manufacturer, Janssen Pharmaceutica, conducted a 15-week trial of the pharmacokinetics of this
formulation.7 The study included 4 weeks of treatment
with oral risperidone, followed by five biweekly injections
of long-acting risperidone. Trough concentrations were
very similar between the oral and long-acting i.m. dosage
forms, but peak concentrations were much lower with the
i.m. form. Prolactin increases and possibly extrapyramidal
effects are related to peak concentrations.
In a 12-week, double-blind study, the new formulation of risperidone at all doses showed efficacy superior to
placebo.8 Extrapyramidal symptoms appeared to be dosedependent but infrequent. Weight gain was not significant (average 1.2 kg with the higher dose).
Pharmacists will have an important role in the use
of this new agent, in terms of education and drug
delivery. This agent is likely to differ from conventional
depot antipsychotics in efficacy, safety, and tolerability.
The stigma associated with conventional depot agents
needs to be minimized to increase patient acceptance.
Newer atypical antipsychotics have been shown to
reduce rehospitalization rates compared with conventional agents. These agents, including the new formulation of risperidone, offer promise for keeping patients out
of the hospital and maximizing functionality.
Pharmacoeconomic Implications of
Adverse Effects
Potential hidden costs of antipsychotic therapy are related
to adverse effects. The newer atypical agents are less likely
than older agents to cause extrapyramidal symptoms.
However, complications such as obesity, diabetes,
dyslipidemia, and QTc prolongation have been associated
with these agents.
Weight Gain
When clozapine was introduced, effects such as extreme
weight gain, diabetes, and seizures were reported. With
olanzapine, weight gain starting within a few weeks of
medication initiation was reported. However, only in the
past two years have reports of complications related to
this weight gain begun appearing in the literature.
Quetiapine was not used much after its introduction in
1997, but prescribing of this agent is increasing and
adverse effect data may appear.
Weight gain is a common and serious problem.
Body weight is measured as body mass index (BMI):
weight in kilograms divided by the square of the height in
meters. A BMI less than 19 kg/m2 is considered underweight, optimal weight is 20–25 kg/m2, overweight is 26–
30 kg/m2 (60% of Americans fall into this category), and
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obesity is greater than 30 kg/m2. Many patients with
chronic mental illness have a BMI in the 30s.
Tiredness, sweating, back pain, arthritis, shortness
of breath, loss of bladder control, snoring, and sleep apnea
are associated with overweight.9,10 These symptoms are
similar to negative symptoms of schizophrenia. Other
consequences of being overweight include cardiovascular
disease, heart attack, ischemia, cerebrovascular accident,
and diabetes.
Diabetes
The literature contains reports of diabetes and diabetic
ketoacidosis developing in association with atypical
antipsychotic agents, predominantly clozapine and
olanzapine. Some such cases are being reported with
quetiapine and risperidone, but whether these are actually
related to the drug is uncertain.
Research on Portland Veterans Affairs patients
receiving olanzapine indicates that within one year of
starting the drug the rate of diabetes doubled (from
14.5% to 28%).11 In the patients who remained on
olanzapine, the diabetes rate did not change in the second
year but increased to 35% in the third year.
Clozapine is also associated with diabetes. However,
since this agent is used for refractory patients, there is no
choice but to continue the drug and manage the diabetes.
Suspected ECG Effect
Ziprasidone is the most recently marketed atypical
antipsychotic agent. It was initially reported to cause QTc
prolongation, but later this appeared to be an exaggeration. Pfizer Inc. studied the pattern of QTc prolongation
with all the atypical antipsychotics in patients with
schizophrenia.12 After baseline ECG, patients were given a
metabolic inhibitor specific to their drug. For example,
ziprasidone patients were given ketoconazole because it
inhibits the 3A4 cytochrome P450 and patients on
risperidone were given paroxetine because it inhibits 2D6
cytochrome P450. According to repeat ECGs, the
atypical agents appeared to be safe. Ziprasidone did have
the longest QTc interval, but there was no change from
baseline to the post-metabolic-inhibitor ECG at the time
of peak ziprasidone blood levels. The reason there was no
excessive or substantial increase in QTc interval may be
that there are metabolic pathways for ziprasidone other
than the 3A4 cytochrome P450 pathway and that a
substantial portion goes through pathways not affected by
metabolic inhibitors. Nonetheless, FDA required notification of the risk of QTc prolongation in the product
information. This study showed that thioridazine caused
the greatest QTc prolongation; the drug’s labeling now
has a black-box notification about this effect.
Costs of Drug Effects
Not surprisingly, treatment costs differ among agents. Of
the atypical agents, olanzapine is the most expensive, and
quetiapine at higher doses is also fairly expensive. How-
ever, the hidden costs of caring for patients on atypical
agents cannot be ignored. Drugs may need to be given to
combat adverse effects of the atypical agents, and patients
may need to be monitored with lab tests or ECGs. Patients
may have to see their primary care physician more often and
obtain referrals to specialists. Also, 70–90% of patients
with schizophrenia are cigarette smokers. Smoking
induces the 1A2 cytochrome P-450, which also oxidizes
olanzapine. Therefore, smokers need higher olanzapine
doses than nonsmokers—almost double the dose—to get
the same effect; this causes higher drug costs.
Conclusion
The use of atypical antipsychotics helps reduce schizophrenia treatment costs by reducing inpatient hospitalization, but adverse effects and their treatment need to be
part of the cost-effectiveness equation. Nasrallah believes
that the atypical agents are equally efficacious and that
each patient’s medication regimen should be based on
susceptibility to adverse effects as well cost-effectiveness.
Switching Antipsychotic Agents
Rationale for Switching
The health care provider’s view of reasons to switch
antipsychotic medications is different from the patient’s
view. Health care providers may want to switch agents
because of lack of efficacy, adverse effects, or noncompliance. Patients in one survey rated weight gain and sedation
as the worst adverse effects of medication. Results of another
survey suggest that patients’ main reason for wanting to
switch medications is lack of efficacy, followed by weight
gain. In a self-administered survey, some 90% of respondents said their medication and their physical health were
both very important. About 60% of patients were
satisfied with their medication but 45% were satisfied
with their physical health. Seventy percent said weight
was important but only about 25% were satisfied with
their weight. In the same survey, 38% of patients reported
weight gain and 34% reported sedation while on atypical
antipsychotics. Most of these patients were on traditional
antipsychotic agents, but many of those who cited weight
gain as a reason for switching were on atypical
antipsychotics. Patients on both types of antipsychotics
reported some intolerance because of sedation.
When adverse effects, not efficacy, are the reason for
considering a switch, practitioners should proceed with
caution. For some patients, the risk of exacerbation of the
illness is too great; some have harmed themselves or
others during an exacerbation. Other circumstances in
which switching may not be advisable are recent recovery
from a psychotic episode and recent noncompliance with
oral medication but current compliance with a depot
preparation. Before any switch, the patient, caretaker, and
provider need to commit themselves to the new therapy
and agree to close monitoring during the switch.
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
31
Approaches to Switching
There are a number of approaches for switching between
agents, from abruptly stopping one drug and then slowly
starting the other to overlapping the two agents. With
abrupt discontinuation, patients are less likely to make
errors. But this method risks exacerbation of the illness and
withdrawal reactions; it is not recommended for clozapine
patients. With abrupt discontinuation, the switch should
be made in a safe, secure inpatient setting, since the
patient will be medication free for a period of time.
Gradual titration or a crossover switch may be
advantageous if relief from extrapyramidal symptoms is
needed. If the taper is too quick, however, both medications could be given at subtherapeutic doses.
For preventing relapse, overlapping therapies is the
safest switch method, but this method is not ideal from
the standpoint of drug-related adverse effects. Patients can
“get stuck” in the transition; if the patient seems to be
doing well, there may be reluctance on the part of the
patient, family, or prescriber to change therapy. In this
case, the patient may continue on two medications
because it appears that the combination of agents is
keeping the patient stable.
Withdrawal Symptoms
Withdrawal symptoms that may occur when an antipsychotic drug is discontinued include anticholinergic
withdrawal, rebound akathisia and dystonia (usually
within the first few days), rebound parkinsonism (within
the first week), and withdrawal dyskinesia (usually within
the first four weeks).13
Kinon et al.14 switched two groups of patients from
conventional antipsychotics or risperidone to olanzapine.
Patients in the first group had previous antipsychotic
therapy stopped abruptly and then were assigned to either
immediate initiation of olanzapine 10 mg/day or stepwise
olanzapine initiation. The second group had tapered
discontinuation of the previous antipsychotic followed by
either immediate initiation of olanzapine 10 mg/day or
stepwise olanzapine initiation. Efficacy was equal at the
end of three weeks. Sleep disturbances occurred in the
abrupt discontinuation and tapered initiation group.
There was a slight advantage in efficacy at week one for
tapered discontinuation and immediate initiation.
Goldstein15 reported that at least 25% of patients
who were abruptly switched to quetiapine from haloperidol and risperidone had adverse effects, primarily somnolence. When quetiapine was abruptly withdrawn, the
most frequently reported adverse effects were vomiting
and insomnia.
Recommendations
Before any switch of antipsychotic agents, the patient
should have a baseline clinical evaluation. Good collaboration with the patient and family is needed; all must be
educated on the process and the support that is needed
during the switch.
32
Ganguli discussed the following considerations in a
switch to risperidone.
■ Drug interactions with other psychotropics are minimal.
■ Elderly patients require smaller doses.
■ Change one agent at a time, and start with the agent
that is being taken at a higher chlorpromazineequivalent dose.
■ Stabilize the patient on risperidone. Then decrease and
stop the initial antipsychotic. Re-evaluate the
risperidone dose once the initial agent is discontinued.
■ Oral solution may be indicated to counter noncompliance in a supervised clinical setting.
■ Adverse effects may respond to small decreases in dose
(0.5–1 mg/day).
■ Benzodiazepines may be used to manage insomnia,
anxiety, and agitation in the initial phases.
Ganguli made the following recommendations for
monitoring when switching or starting on atypical
antipsychotics:
■ Obtain baseline physical examination, blood pressure,
and weight and height to calculate BMI.
■ Evaluate for tardive dyskinesia.
■ Monitor blood pressure, weight, and tardive dyskinesia on an ongoing basis.
A switch from one antipsychotic agent to another
may be necessary for a substantial proportion of patients,
usually because of adverse effects or lack of efficacy at the
doses that are tolerated.
References
1. Health care reform for Americans with severe mental illness: report
of the National Advisory Mental Health Council. Am J Psychiatry.
1993; 150:1447-65.
2. Byerly M et al. Paper presented at APA Institute of Psychiatric
Services. Orlando, FL; 2001 Oct.
3. Delgado et al. Paper presented at NIMH-NCDEU meeting. Boca
Raton, FL; 2000 Jun.
4. Young JL et al. Medication noncompliance in schizophrenia:
codification and update. Bull Am Acad Psychiatry Law. 1986;
14(2):105-22.
5. Hellewell JSE, Cantillon M. Paper presented at Eleventh Congress
of European College of Neuropsychopharmacology. Paris, France;
1998 Oct 31–Nov 4.
6. Eerdekens M et al. Presented at 40th Annual NCDEU. Boca
Raton, FL; 2000 May 30–Jun 2.
7. Eerdekens M et al. Presented at 22nd Congress of CINP. Brussels,
Belgium; 2000 Jul 9–13.
8. Kane J et al. Paper presented at APA Institute on Psychiatric
Services. Orlando, FL; 2001 Oct 10–14.
9. National Task Force on the Prevention and Treatment of Obesity.
JAMA. 1996; 276:1907–15.
10. Carek PJ, Sherer JT, Carson DS. Management of obesity: medical
treatment options. Am Fam Physician. 1997; 55:551-8,561-2.
11. Casey DE. Paper presented at APA annual meeting. New Orleans,
LA; 2001 May 5–10.
12. Pfizer Study 054. FDA Psychopharmacological Drug Advisory
Committee. 2000 Jul 19.
13. Weiden PJ, Aquila R, Dalheim L et al. J Clin Psychiatry. 1997; 58
(suppl 10):63–72.
14. Kinon BJ et al. Paper presented at 39th Annual New Clinical
Drug Evaluation Unit Meeting. Boca Raton, FL; 1999 Jun 1–4.
15. Goldstein JM. Presented at 1998 APA annual meeting.
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
®
Managing Patients at Risk for Postoperative Nausea and Vomiting
Breakfast symposia held December 3-6, 2001, in conjunction with the ASHP Midyear Clinical Meeting
Supported by an educational grant from GlaxoSmithKline
Nausea and vomiting are frequent, distressing, and
potentially dangerous occurrences in many surgical
patients. John Leslie, M.D., M.B.A., professor of
anesthesiology and medical director of postoperative
services at the Scottsdale, Arizona, campus of the Mayo
Clinic Hospital, discussed methods for identifying
patients at high risk for postoperative nausea and vomiting (PONV) and described options for treating or
preventing PONV. His presentation focused on the types
of patients likely to get sick, those who will need prophylactic versus rescue medication, and the tools that
pharmacists can use to identify those patient groups.
Causes of PONV
PONV is caused by numerous factors involving multiple
receptor systems. Causes can include smells, sounds, and
stress along with stimulation of the chemoreceptor trigger
zone, gastrointestinal tract, and vomiting center. Studies
have shown that the two most common postoperative
events after anesthesia for outpatient surgery are dizziness
and PONV, with the highest incidence of emetic episodes
occurring in the first two hours after surgery.1,2 These
emetic episodes are triggered by so many factors that it is
impossible to treat all patients successfully. By identifying
patients at high risk for PONV, however, clinicians can
improve patient care and decrease health care costs.
Patients at high risk for PONV should be treated
prophylactically; antiemetic efficacy decreases 20–40%
when medications are used as rescue rather than prophylactic treatment. In certain patient groups, prevention of
PONV is imperative. Examples include patients whose
jaws are wired shut, patients with full stomachs prior to
surgery, and craniotomy patients. In a study of 199 adults
undergoing elective craniotomy, 50% suffered from
postoperative nausea.3 In these patients, vomiting can
cause massive increases in intracranial pressure and blood
pressure with potentially disastrous outcomes.
Over 300 articles investigating PONV were
published in 2000 and 2001. The primary research areas
included specific PONV risk-prediction tools or riskstratification formulas and selection of the ideal or most
cost-effective antiemetic.
PONV Risk Prediction
Leslie reviewed several important clinical studies4–9 involving
risk assessment tools for predicting PONV. The variables
that most commonly predict high risk include female sex, a
history of PONV or motion sickness, young age, use of
volatile anesthetics, use of nitrous oxide, and use of opioids.
These studies used complicated mathematical
formulas to calculate PONV risk. A group of clinicians
has posted many of these risk-prediction algorithms on
the Web (www.medal.org/); they can be downloaded free
of charge, even to a personal digital assistant. These
algorithms can help clinicians predict PONV susceptibility and facilitate more selective prophylactic therapy.
Despite the wealth of clinical evidence that PONV
susceptibility can be predicted, treatment regimens vary
considerably. In a recently published study, descriptions
of three clinical scenarios (low, medium, and high risk for
PONV) were sent to practicing anesthesiologists, who
were asked to describe the PONV regimen they would
use in each case.10 The researchers needed 11 different
prophylaxis regimens to encompass 80% of the practice
patterns reported by the 240 respondents, demonstrating
the lack of standardized prophylactic routines.
The American Society of Health-System Pharmacists (ASHP) guideline for the pharmacologic management of nausea and vomiting, including PONV,11 lists
drugs and other factors known to induce nausea and
vomiting and predispose patients to PONV. This document divides risk factors into those that are
■ Patient-specific (age, sex, weight, threshold for nausea,
psychological stress, delayed gastric emptying)
■ Attributable to the operative procedure (indication for
surgery, type of surgery, duration of procedure,
intubation procedure)
■ Related to the anesthetic (preanesthetic medication,
oral intake, gastric distention, anesthetic agent,
reversal of muscle relaxant, use of opioids), and
■ Due to postoperative factors (presence of pain, patient
movement, oral intake).
In 2000, the PONV Advisory Board listed the
following risk factors:
■ High-risk patient factors: history of PONV, motion sickness, young female, preoperative nausea and vomiting
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
33
■
■
High-risk surgical factors: laparoscopy, major breast,
strabismus, ENT, craniotomy, and plastic surgery
Other contributing risk factors: age, anxiety, opioid
use, obesity, aspirin use, dehydration, pain, surgery
duration >1 hr, outpatient surgery, anesthetic technique, inhaled anesthetics, and shoulder, gynecological, oral, and major intra-abdominal surgery
Antiemetic Drug Classes for PONV
Several classes of drugs, working by different mechanisms,
are used to prevent or treat PONV. The most commonly
used medication categories are dopamine D2 receptor
antagonists, anticholinergics, antihistamines, and serotonin type 3 (5-HT3) receptor antagonists. If treatment
with a drug from one class is unsuccessful, a subsequent
drug should be chosen from a different class.
1. Dopamine D2 antagonists
Droperidol (Inapsine) 10–20 mg/kg to 25–75 µg/kg
(0.625–1.25 mg) i.v., i.m.
Metoclopramide (Reglan, Maxalon) 0.1–0.2 mg/kg
i.v., i.m. or 10–20 mg p.o.
Thiethylperazine (Torecan) 10 mg i.m., p.o., rectally
Prochlorperazine (Compazine) 5–10 mg p.o., i.m., i.v.
or 10–25 mg rectally
Trimethobenzamide (Tigan) 200 mg i.m., rectally, or
250 mg p.o.
2. Anticholinergics
Atropine 10 µg/kg (crosses blood–brain barrier)
Scopolamine (TransDerm Scop) 5–10 µg/kg (0.2–1.0
mg i.v., i.m., s.c. or 1 transdermal patch of 0.5 mg
3. Antihistamines
Diphenhydramine (Benadryl) 1–2 mg/kg i.v., i.m.
Hydroxyzine (Vistaril or Atarax) 25–100 mg i.m. or
25–50 mg p.o
Meclizine (Antivert)
Promethazine (Phenergan) 0.25–0.5 mg/kg i.v., i.m.
or 12.5–25 mg p.o., rectally
4. Miscellaneous
Ephedrine 5–25 mg i.v., i.m.
Dexamethasone 0.10–0.2 mg/kg
Benzquinamide (Emete-Con) 25–50 mg i.m.
Ginger root (Zingiber officinale) 0.5 mg p.o.
Acupressure or acupuncture
Positive suggestion or hypnosis
5. 5-HT3 Receptor Antagonists
Ondansetron (Zofran) 4-mg dose i.v. (prevention or
rescue); i.v., p.o., ODT (orally disintegrating
tablet) formulations (oral dose 16 mg)
Granisetron (Kytril) 1-mg dose i.v., p.o. (not FDA
approved for PONV)
Dolasetron (Anzemet) 12.5-mg dose i.v. (prevention
or rescue); i.v., p.o. formulations (oral dosing may
be higher)
Tropisetron Under investigation
34
5-HT3 Receptor Antagonists
The only serotonin receptor antagonists approved for
PONV are ondansetron and dolasetron.
Ondansetron was the first serotonin receptor antagonist approved for PONV, and it has been studied extensively
for both treatment and prevention. The approved dose is 4
mg i.v.; it is most effective when used prophylactically. Leslie
reiterated his advice that high-risk patients should always
be given prophylaxis because the same level of efficacy
cannot be achieved with rescue therapy.
A new formulation of ondansetron, ODT, has been
evaluated for use in postdischarge nausea and vomiting.12
A group of 60 outpatient gynecologic laparoscopy
patients received ondansetron 4 mg i.v. at induction of
anesthesia and were sent home with either ondansetron
ODT 8 mg or placebo every 12 hours for two doses.
Patients receiving ondansetron ODT showed a substantial
reduction in nausea compared with placebo, but the
results were not statistically significant because of the
small sample size. However, differences in the incidence
of postdischarge vomiting and patient satisfaction were
significant. Patients found ondansetron ODT easier to
take than standard tablets or suppositories.
Dolasetron is approved for PONV at a dose of 12
mg i.v. for prevention or rescue. Some clinicians have
expressed concern that the maximum efficacy seen with
dolasetron (60%) did not reach the level shown in
ondansetron trials (75%); Leslie cautioned against directly
comparing these studies because of the different patient
populations, anesthesia techniques, and other factors.
Cost-effectiveness and Efficacy of 5-HT3 Receptor
Antagonists
Several studies have compared ondansetron and
dolasetron for the prevention of PONV. Dolasetron 12.5
or 25 mg i.v. was compared with ondansetron 4 mg or 8
mg i.v. in a study of 200 ENT outpatients.13 Complete
response (no vomiting or rescue antiemetics) rates ranged
from 72% to 76%, leading researchers to conclude that
these drugs were comparable. However, these rates were
higher than the complete response rates noted in the
pivotal trials reported in the product information for both
ondansetron and dolasetron. The authors stated that a
potential limitation of this study was the lack of a placebo
arm. Inclusion of a placebo arm may have helped
determine whether antiemetic therapy was required in
this patient population. In another study in the same
publication, dolasetron showed better efficacy than
ondansetron in the first 2 hours after surgery, while
ondansetron showed better 24-hour efficacy.
Another study compared PONV prophylaxis using
dolasetron 25 or 50 mg i.v., ondansetron 4 mg i.v., and
placebo.14 Only the 50-mg dolasetron dose was comparable to ondansetron 4 mg. On the basis of this finding,
some clinicians are reluctant to use the 12.5-mg
dolasetron dose recommended in the package insert;
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
®
instead, they use double the recommended dose of
dolasetron to ensure efficacy comparable to that of
ondansetron. Some institutions have switched from
ondansetron to dolasetron for cost reasons, but the
drawback is that dolasetron exhibits only 30% efficacy in
rescue, leading to dose escalations.
Studies done to determine the best time for
prophylactic medication administration have shown
mixed results. In a recently published study,15 complete
responses to dolasetron 12.5 mg i.v. (no rescue medications and no emesis 24 hours postoperatively) were not
significantly different when treatment was given 10–15
minutes before induction, at the end of the laparoscopy
(79 ± 48 minutes later than induction), or at the end of
anesthesia (93 ± 52 minutes later than induction). An
ondansetron i.v. timing study16 compared ondansetron 2
mg at the start of surgery and 2 mg after surgery, 4 mg
before induction, 4 mg after surgery, and placebo. The
group who received 4 mg at the end of surgery had a
significantly reduced incidence of PONV as well as
reduced time to oral intake, ambulation, discharge
readiness, and resumption of normal diet and fluid
intake. However, the authors concluded that a much
larger sample size (approximately 100 in each group)
would be required to demonstrate statistical significance
between the “at induction” and “end of surgery” treatment groups in all of the endpoints.
Ondansetron and dolasetron are difficult to
compare because of differences in dosing and onset of
action. With ondansetron, the most effective dose is 4 mg
i.v., as recommended in the package insert. With
dolasetron, the 12.5-mg i.v. dose is approved but is
actually the minimally effective dose. Because dolasetron
is a prodrug and requires conversion to its active metabolite hydrodolasetron, some clinicians believe it provides
slower onset of action, leading to delayed antiemetic
action compared with ondansetron.
Guidelines for Preventing PONV
The ASHP guidelines contain the following recommendations for PONV prevention11:
■ Patients who are at high risk of vomiting should
receive antiemetic prophylaxis against PONV.
■ When prophylaxis is indicated, droperidol or a 5-HT
3
receptor antagonist is recommended for adult and
pediatric patients.
■ Other medications that have been studied extensively
and that are considered to be alternatives include
chlorpromazine, prochlorperazine, metoclopramide,
and promethazine.
■ Because droperidol and 5-HT receptor antagonists
3
are effective, the choice of agent should be based on
patient-specific factors and cost. Metoclopramide and
prochlorperazine should generally not be used in
pediatric patients.
■ Droperidol or 5-HT receptor antagonists are recom3
mended for adult and pediatric patients with established PONV.
■ When patients do not respond to initial therapy with
an antiemetic agent, it is recommended that an agent
from another pharmacologic class be added, that the
dose of the antiemetic be increased to the maximum
within an accepted range, or that a combination of
both approaches be used.
Most clinicians favor treatment with the 5-HT3
receptor antagonists because of their efficacy, lack of
adverse effects, and lack of drug interactions during the
postoperative period.
Although some practitioners object to standing
orders, such orders can provide a logical sequence of dose
and class changes to achieve maximal efficacy against
PONV, avoid inappropriate medication use, and improve
compliance with proven PONV regimens.
A meta-analysis of the world’s literature was
conducted to determine which drugs were best for
prevention of early and late nausea and vomiting, with
minimal adverse effects.17 Ondansetron 4 mg i.v. was the
most effective at preventing early nausea as well as early
vomiting. For prevention of late nausea (0–24 hr),
droperidol showed the greatest benefit, although it was
not statistically superior to ondansetron 4 or 8 mg i.v. For
prevention of late vomiting (0–24 hr), ondansetron is the
most effective agent for children. Droperidol in a patientcontrolled analgesia device was the most beneficial for
adults. Droperidol had the highest rate of adverse effects.
Multimodal Therapy
Multimodal therapy uses a combination of
1. Two or three antiemetic medications acting at
different receptor sites,
2. Less-emetogenic anesthesia techniques and agents,
3. Generous intravenous hydration, and
4. Aggressive pain control.
A multimodal regimen might consist of a combination of a serotonin receptor antagonist, a dopamine D2
antagonist, and dexamethasone. Total i.v. anesthesia
would be used (no inhalants) along with supplemental
oxygen, antiemetics, and postoperative nonopioid
analgesics. This technique, although expensive, is very
effective in the highest-risk patients in whom nausea and
vomiting absolutely must be prevented. In one study,18 60
laparoscopy outpatients received multimodal prophylaxis
consisting of ondansetron 1 mg i.v., droperidol 0.625 mg,
dexamethasone 10 mg, aggressive hydration (25 mL/kg),
and preemptive analgesia (ketorolac 30 mg i.v.). The
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
35
patients developed no PONV. The cost of this regimen
may be prohibitive, however.
In a study of recovery after inguinal herniorraphy,19
researchers compared placebo with a combination of
ondansetron 4 mg i.v., droperidol 0.625 mg, and
ketorolac 30 mg. With the multimodal technique,
patients had reduced pain, nausea, and vomiting and
significantly improved satisfaction. Multimodal patients
were also able to go home earlier; some were able to
bypass the postanesthesia care unit entirely.
Dexamethasone is effective for PONV prophylaxis
and without documented adverse effects, although
concerns have been raised about its potential to adversely
affect wound healing. A study20 to determine whether
dexamethasone use increased the risk of surgical wound
complications showed no differences in wound infection
rates (versus placebo), but patients in the dexamethasone
group exhibited less nausea and improved home readiness. Dexamethasone is usually given in combination
with a 5-HT3 receptor antagonist for maximal efficacy.
Leslie concluded his presentation by listing the
“kitchen sink” of things that he personally would request
if he were undergoing anesthesia and if cost presented no
obstacle. His pharmacologic kitchen sink includes a 5HT3 receptor antagonist, droperidol, and dexamethasone.
Opioids, intubation, neuromuscular blockers, nitrous
oxide, and inhalation anesthetics are avoided. Included
are aggressive i.v. hydration, aggressive pain control,
delayed oral intake, oral suction if the gut is distended,
patient education as a type of hypnotherapy, wrist
stimulation, minimal movement, and minimal airway
and pharyngeal stimulation.
Conclusion
Many PONV issues remain unresolved, including the use
of prophylaxis versus rescue therapy, the identification
and stratification of high-risk patients, and the selection
and stratification of drug classes for therapy. Leslie
reiterated the importance of stratifying PONV high-risk
patients into appropriate prophylactic protocols that
include specific procedures and anesthetic techniques.
The selection of a universal PONV risk-assessment tool
and the distinction between no-, low-, and high-risk
patients have yet to be resolved.
Treatment in patients with PONV should be rapid
and the results monitored, with different classes of
antiemetics used if one therapy fails. Preventive therapy is
recommended for patients with a history of PONV and
those who must not vomit. Monotherapy is not an
effective preventive approach for very high-risk patients,
who benefit from combination or multimodal techniques.
Adjunct therapies can dramatically improve the efficacy
of prophylactic drugs. Safety is still an issue with any
antiemetic drug, especially concerning administration to
pregnant women.
36
Pharmacists should help educate clinicians about
PONV prevention and monitor the efficacy of routines
used in their institutions.
References
1. Chung et al. What are the factors causing prolonged stay after
ambulatory anesthesia? Anesthesiology. 1998; 89:A3.
2. Kranke et al. Distribution of emetic episodes after volatile
anesthetics versus propofol. Anesth Analg. 1999; 88:S16.
3. Fabling JM, Gan TJ, Guy J et al. Postoperative nausea and
vomiting. A retrospective analysis in patients undergoing elective
craniotomy. J Neurosurg Anesthesiol. 1997; 9(4):308-12.
4. Cohen MM, Duncan PG, DeBoer DP et al. The postoperative
interview: assessing risk factors for nausea and vomiting. Anesth
Analg. 1994; 78:7-16.
5. Koivuranta M, Laara E. A survey of postoperative nausea and
vomiting. Anaesthesia. 1998; 53(4):413-4.
6. Apfel CC, Greim CA, Haubitz I et al. A risk score to predict the
probability of postoperative nausea and vomiting in adults. Acta
Anaesthesiol Scand. 1998; 42:493-4.
7. Sinclair DR, Chung F, Mezei G. Can postoperative nausea and
vomiting be predicted? Anesthesiology. 1999; 91(1):109-8.
8. Bardiau et al. Determination of PONV risk factors before and after
an antiemetic prophylactic policy. Anesthesiology. 2000; 92:A-1110.
9. Junger A, Hartmann B, Benson M et al. The use of an anesthesia
information management system for prediction of antiemetic
rescue treatment at the postanesthesia care unit. Anesth Analg.
2001; 92(5):1203-9.
10. Macario A, Chung A, Weinger MB. Variation in practice patterns
of anesthesiologists in California for prophylaxis of postoperative
nausea and vomiting. J Clin Anesth. 2001;13(5):353-60.
11. American Society of Health-System Pharmacists. ASHP therapeutic guidelines on the pharmacologic management of nausea and
vomiting in adult and pediatric patients receiving chemotherapy
or radiation therapy or undergoing surgery. Am J Health-Syst
Pharm. 1999; 56:729-64.
12. Gan et al. Ondansetron disintegrating tablets (ODT) reduces
post-discharge emesis and increases patient satisfaction. Anesthesiology. 2000; 92:A-34.
13. Dolasetron appears more cost-effective than ondansetron.
Anesthesiol News. 1999 (12).
14. Korttila K, Clergue F, Leeser J et al. Intravenous dolasetron and
ondansetron in prevention of postoperative nausea and vomiting:
a multicenter, double-blind, placebo-controlled study. Acta
Anaesthesiol Scand. 1997; 41(7):914-22.
15. Chen X, Tang J, White PF et al. The effect of timing of dolasetron
administration on its efficacy as a prophylactic antiemetic in the
ambulatory setting. Anesth Analg. 2001; 93:906-11.
16. Tang J, Wang B, White PF et al. The effect of timing of
ondansetron administration on its efficacy, cost-effectiveness, and
cost-benefit as a prophylactic antiemetic in an ambulatory setting.
Anesth Analg. 1998; 86:274-82.
17. Tramer MR. A rational approach to the control of postoperative
nausea and vomiting: evidence from systematic reviews. Part 1.
Efficacy and harm of antiemetic interventions, and methodological issues. Acta Anaesthesiol Scand. 2001; 45:4-13.
18. Vomiting can be abolished among ambulatory surgery patients.
Anesthesiol News. 1999 (12).
19. Coloma et al. Recovery after inguinal herniorraphy: effect of a
multimodal prophylaxis routine on outcome. Anesthesiology. 2000;
92:A-38.
20. Coloma et al. Dexamethasone in anorectal surgery: does it increase
the risk of wound complications? Anesthesiology. 2000; 92:A-5.
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
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Improving Outcomes in the Cath Lab with Direct Thrombin Inhibitors
A symposium held December 3, 2001, in conjunction with the ASHP Midyear Clinical Meeting
Supported by an educational grant from The Medicines Company
Effective anticoagulation is essential in the prevention and
treatment of many clinical disorders. The availability of
low-molecular-weight heparins, glycoprotein IIb/IIIa
receptor inhibitors, and direct thrombin inhibitors has
expanded the safety and efficacy of anticoagulation but
increased the complexity of determining the optimal
agent and treatment regimen. This program, moderated
by Michael Reed, Pharm.D., professor of pediatrics at
Case-Western Reserve University School of Medicine and
Director of the Clinical Pharmacology and Toxicology
Program at Children’s Hospital in Cleveland, addressed
these advances in anticoagulation and described the use of
newer agents in percutaneous coronary intervention (PCI).
Anticoagulation in PCI
Fred Feit, M.D., Director of Cardiac Catheterization and
Intervention and Associate Professor of Medicine at New
York University Medical Center, reviewed the molecular
basis of action and clinical effects of conventional and newer
anticoagulants and used this information to define the
optimal antithrombotic and antiplatelet regimen for PCI.
Antithrombin drugs should be studied in the
context of both the soluble coagulation system and the
platelet aggregation system, said Feit. In the coagulation
system, factors Xa and Va and calcium come together on
membranes, including the platelet surface membrane, to
form the prothrombinase complex, which converts prothrombin to thrombin. Thrombin is the body’s most potent
aggregator of platelets. Thrombin inhibitors are either
indirect, requiring an antithrombin agent for activity, or
direct. Platelets can be blocked with products such as
aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitors,
which work on the final common pathway, or by thrombin
inhibitors that block thrombin-mediated platelet activation.
When reviewing the mechanisms and efficacy of
these agents, it is important to take into account relevant
safety issues. In PCI, the two primary types of complications to consider are ischemia and bleeding. Ischemic
complications include death, myocardial infarction (MI),
stent thrombosis, urgent target vessel revascularization,
and CK-MB elevation. Bleeding complications include
hemorrhage, blood transfusion, and thrombocytopenia.
Antithrombin Agents
Antithrombin agents include heparin and direct throm-
bin inhibitors. Heparin is an indirect thrombin inhibitor
that joins with antithrombin and enhances its ability to
dock with and inactivate thrombin. The unfavorable
characteristics of heparin include nonspecific binding to
many proteases and endothelial cells, which reduces its
effect in acute coronary syndromes (ACS), neutralization by
platelet factor (PF)-4; ineffectiveness against clot-bound
thrombin; platelet aggregation; nonlinear pharmacokinetics;
and the risk of heparin-induced thrombocytopenia (HIT).
Unlike heparin, direct thrombin inhibitors
(bivalirudin, hirudin, and argatroban) are effective against
clot-bound thrombin and provide predictable anticoagulation but do not require a cofactor, are not neutralized by
PF-4 or plasma proteins, do not cause platelet aggregation, and do not cause thrombocytopenia.
The prototype direct thrombin inhibitor is hirudin,
a potent, nearly irreversible bivalent inhibitor. Early trials
comparing heparin and hirudin showed that hirudin
patients had reductions in ischemic events and rest pain.
However, a larger trial showed excessive bleeding in
patients taking hirudin, so the agent was never marketed
for treatment of ACS or acute MI, but is limited to the
prevention of thromboembolic complications in patients
with HIT and associated thromboembolic disease.
Bivalirudin was modeled after the hirudin molecule
and has distinctly different properties than hirudin,
including a shorter half-life and reversible binding
properties. In the pivotal Bivalirudin Angioplasty Trial,1,2
bivalirudin was compared with high-dose heparin during
coronary angioplasty for unstable angina. Originally
published in 1995, the complete data set was further
analyzed, adjudicated, and published in 2001. Bivalirudin
patients showed a statistically significant reduction in the
cumulative probability of death, MI, or revascularization
at 7 (22%) and 90 days (18%). There was also a 53%
reduction in ischemic complications at 7 days and a 46%
reduction at 90 days with bivalirudin versus heparin in
patients who had suffered an MI within the two previous
weeks. An unexpected finding was the marked reduction
in hemorrhage with bivalirudin versus heparin. This
reduction of both ischemic and hemorrhagic events is of
particular importance in populations at increased risk for
complications associated with PCI, notably in patients
with renal impairment.
The TIMI (Thrombolysis in Myocardial Infarction)-8
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
37
study compared the efficacy and safety of bivalirudin and
heparin in patients with unstable angina or non-Q-wave
MI. The infusion of study drugs was titrated to maintain
activated partial thromboplastin time (aPTT) at 55–85
seconds for first 72 hours. Primary endpoints of death or
nonfatal MI were evaluated through hospital discharge or
14 days whichever occurred first. Although the trial was
prematurely discontinued, preliminary results showed that
80–90% of bivalirudin patients maintained an aPTT
between 80 and 90 seconds at every time point between 6
and 72 hours. With heparin, 20% of patients achieved the
target aPTT at 6 and 12 hours, 51% at 24–48 hours, and
40% by 72 hours. Through 14 days, the incidence of death
or nonfatal MI was 2.9% in bivalirudin-treated patients (n =
86) and 9.2% in heparin-treated patients (n = 65). Major
hemorrhage occurred in 4.6% of heparin patients and in
none of the patients given bivalirudin.3
Antiplatelet Agents
Glycoprotein IIb/IIIa Receptor Inhibitors. The glycoprotein (GP) IIb/IIIa receptor inhibitors act as antagonists
of fibrinogen binding to the GP IIb/IIIa receptor, which
is the major platelet surface receptor involved in the final
common pathway of platelet aggregation. The three drugs
in this class are abciximab, eptifibatide and tirofiban.
Tirofiban has approved indications for ACS in
combination with heparin, including patients undergoing
PCI. Eptifibatide is approved for use in ACS or PCI.
Abciximab is approved for use in PCI or unstable angina
not responding to conventional medical therapy when PCI
within 24 hours is planned.
Several clinical trials have demonstrated improved
ischemic event rates in patients undergoing balloon
angioplasty and receiving a GP IIb/IIIa receptor inhibitor.
Improving the incidence of ischemic events, however, has
generally come at the cost of an increased rate of bleeding
complications in spite of lower doses of heparin. The
EPISTENT trial4 was conducted to determine the
efficacy of the GP IIb/IIIa inhibitor abciximab in
improving long-term outcomes in stent implantation.
The one-year results of EPISTENT5showed a statistically
significant mortality advantage of stenting with
abciximab compared with stenting alone or balloon
angioplasty with abciximab. However, some clinicians
(including Feit) do not believe this study had the power
to reliably examine mortality.
Thienopyridines. Thienopyridines include ticlopidine
and clopidogrel, which inhibit platelet aggregation
induced by adenosine diphosphate (ADP). The efficacy
and safety of ticlopidine were studied in the STARS6 trial.
In this study, patients received aspirin alone, aspirin and
warfarin, or aspirin and ticlopidine after coronary
stenting. The risk of death, MI, bypass surgery, or
revascularization of the target lesion was 0.5% with
aspirin and ticlopidine versus 2.7% with aspirin and
warfarin and 3.6% with aspirin alone.
38
Data from EPISTENT indicate that patients
randomized to placebo who received pretreatment with
ticlopidine had a rate of ischemic events similar to that of
patients randomized to abciximab who did not receive
pretreatment with a thienopyridine.
Bivalirudin and GP IIb/IIIa Studies
The CACHET7 trial compared clinical outcomes in
patients undergoing PCI who were treated with
bivalirudin with provisional abciximab and those treated
with a combination of planned abciximab and low-dose
heparin. The seven-day endpoints studied were death,
MI, revascularization, and hemorrhage, which occurred
in 14% of patients in the heparin/planned abciximab
group but only 3.5% in the bivalirudin/provisional
abciximab group. Although this was a small study, it
demonstrated the positive impact of bivalirudin on both
ischemic and bleeding endpoints.
Part I of the REPLACE trial was conducted in 77
U.S. sites and showed that bivalirudin reduced the triple
endpoint of MI, revascularization, and clinically significant bleeding (TIMI-major and minor bleeding or
transfusions) by 22% compared with heparin in patients
undergoing angioplasty with or without stent implantation. With bleeding alone as the endpoint, the bivalirudin
group had a 39% reduction in protocol-defined major
bleeding and a 35% reduction in clinically significant
bleeding. Part II of the REPLACE trial will compare a
heparin plus GP IIb/IIIa inhibitor group with a group
receiving bivalirudin alone and a provisional GP IIb/IIIa
inhibitor. The trial should be completed in 2002.
Conclusion
On the basis of these trials and his own clinical practice,
Feit concluded that the regimen of bivalirudin with
provisional use of a GP IIb/IIIa receptor antagonist offers
the best balance of efficacy and safety during PCI. Pretreatment of patients with clopidogrel prior to PCI is
highly advisable (through the use of a loading dose or
starting clopidogrel 24–48 hours before the procedure).
Bivalirudin, the only antithrombin agent labeled for use
during PCI, is an extremely potent thrombin inhibitor
that blocks the generation of fibrin and has a profound
effect on platelet activation.
Economic Impact of PCI Complications
After the efficacy and safety of antithrombotic agents are
considered, the economic impact of therapy should be
assessed. Dawn Bell, Pharm.D., BCPS, Director of
Pharmacy Affairs at The Medicines Company, reviewed
some basic principles of economic analysis and reimbursement realities.
Cost-effectiveness
Cost-effectiveness is not the same as cost saving. Very few
modern medical innovations actually save money. Cost-
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
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effectiveness means that the expenditure of resources is
worth the benefit gained. A more expensive new treatment may be cost-effective if it improves life expectancy
or quality of life and the cost per additional year of life
gained is competitive with other potential uses for the
same health care dollar. Cost-effectiveness is measured as
the cost per year of life saved, not the amount of money
saved. By our society’s standards, anything that costs less
than $50,000 per year of life saved is cost-effective.
Cost-effective Antithrombotic Therapy
Bell presented three ways that improved antithrombotic
therapy can be cost justified: by reducing procedural
complications sufficiently to offset drug cost, by replacing
a more costly antithrombotic agent with no loss of efficacy,
and by improving short-term and long-term outcomes
sufficiently to justify higher cost (i.e., cost effectiveness).
Reducing Procedural Complications
Ischemic complications are expensive, and avoiding them
will save money for the hospital. In the major PCI trials,
the rate of death, MI, and revascularization has been
approximately 10% with heparin use. Studies have shown
that the incremental cost of ischemic complications
ranges from $2,658 to $16,847, depending on the
additional medical care needed.
Glycoprotein IIb/IIIa inhibitors have been shown
to decrease ischemic complications and should therefore
save money, but there are economic tradeoffs. In the
EPIC trial,8 a GP IIb/IIIa inhibitor reduced 30- and 60day ischemic endpoints but increased in-hospital bleeding
episodes. A potential cost savings of $622 per patient
attributable to reduced acute ischemic events was offset
by a $521 cost increase from bleeding episodes.
When Bell was an Associate Professor of Clinical
Pharmacy at West Virginia University (WVU), she
became concerned that post-PCI bleeding rates at her
institution were much higher than those in most published clinical trials. She discovered that the GP IIb/IIIa
trials used the bleeding definition of TIMI-major, which
translates into a >5 g/dL drop in hemoglobin or an
intracranial hemorrhage. WVU was measuring bleeding
by using transfusion rates, which encompass both TIMImajor and TIMI-minor bleeding. Although clinical trials
may also show lower bleeding rates because of patient
exclusion criteria, in the real world of clinical practice
bleeding complications occur in 3.5–8.5% of patients.
For patients who received transfusions at WVU,
length of stay was almost triple that of patients who were
not transfused. Bell hypothesized that the administration
of blood products might actually be a marker for a more
acutely ill patient, which would help explain the extended
length of stay. She tested this hypothesis by conducting a
random study of 22 patients who received transfusion
matched for age, gender, and illness severity with 44
control patients. After neutralizing the effects of severe
illness, Bell predicted that length of stay and cost of
hospitalization would not differ significantly between the
two groups. However, length of stay was almost doubled
in the group that received transfusions, despite controlling for other known predictors of increased length of
stay. There was a statistically significant increase in cost of
approximately $3000 in those transfusion patients, due
primarily to room charges and intensive care unit costs.
Costs are relatively low in West Virginia because of lower
wage costs; for the United States as a whole, the average
cost of a major bleeding complication ranges from $7000
to $8000. Even “minor” bleeding complications are not
really minor, adding an average of 2.38 days to a hospital
stay compared with the 2.44 seen with major bleeds.
The Bivalirudin Angioplasty Trial (BAT)2 also
examined the cost of complications. Using information in
nationally representative databases, this analysis determined
that, excluding drug costs, bivalirudin saves from $591 to
$850 in complications when compared with heparin.
Replacing a More Costly Antithrombotic
Pharmacoeconomic models comparing the cost of
treating PCI patients with planned versus provisional GP
IIb/IIIa therapy (with bivalirudin as the base anticoagulant) demonstrate the breakeven point for bivalirudin use.
If eptifibatide is the perfect agent and is used in 80% of
1000 cases, and if use of bivalirudin decreased eptifibatide
use to 50%, the reduction in eptifibatide costs would
offset the cost of bivalirudin.
Modeling studies show that if a hospital typically
uses eptifibatide or abciximab in 80% of PCI cases, it can
decrease its overall costs by instituting a protocol using
bivalirudin in all PCI cases, with a IIb/IIIa inhibitor used
only provisionally when PCI results are not satisfactory.
The REPLACE-2 study is expected to confirm that
bivalirudin provides sufficient anticoagulation during
PCI, eliminating the need for a GP IIb/IIIa inhibitor in
all but a select few. In this double-blind trial, 6000
patients will be randomized to one of two treatment
arms: GP IIb/IIIa plus heparin or bivalirudin with a
provisional GP IIb/IIIa.
Improving Short-term and Long-term Outcomes
A PCI outcome modeling study was done to measure the
potential cost-effectiveness of improved antithrombotic
therapy. The model looked at survival after PCI on the
basis of factors such as age, sex, days in the hospital, and
occurrence of acute ischemic complications. The cost of
complications was based on the Harvard Clinical Research
Institute HCRI data set, a cost model that includes 3200
patients nationwide. The study assumed that the base rate
of ischemic complications is 6.5% and that the cost of
bivalirudin is $335. Using these assumptions, the model
showed that only a 20% relative risk reduction is necessary
for bivalirudin to meet the accepted cost-effectiveness criterion of $50,000/year of life saved. Cost-effectiveness of bivalrudin is also being prospectively evaluated in REPLACE-2.
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
39
Conclusion
Ischemic and hemorrhagic complications are costly and
common in patients undergoing PCI. Ischemic complications cost $2,000–$20,000 per event and bleeding complications cost $3,000–$8,000 per event. Reimbursement
rates continue to decline as costs continue to rise. The
REPLACE-2 trial will determine the cost-effectiveness of
bivalirudin, from both a hospital and a societal standpoint.
Practical Identification of Bleeding
Complications in PCI
To put this information into perspective for practicing
pharmacists, Vikas Gupta, Pharm.D., BCPS, Manager
of Clinical Strategy Development at Owen Healthcare
Inc. in Naperville, Illinois, demonstrated a method for
integrating the data into day-to-day practice.
Most pharmacists, especially in community practice
settings, do not know the bleeding rates in their hospitals.
Gupta created a plan to identify bleeding rates associated
with PCI in a community hospital by using diagnosisrelated group (DRG) and International Classification of
Diseases, 9th Edition (ICD-9) coding data.
Study Method
Gupta conducted a nonrandomized comparison using
procedure and diagnosis codes and descriptions from the
Scripps Trendstar database. He analyzed DRGs 112 (PCI)
and 116 (PCI with stent placement) from October 1, 1999,
to September 30, 2000, for the Scripps Memorial Hospital
in La Jolla, California. Only patients who underwent PCI
were evaluated, using procedure codes 36.01–36.05 to
separate them from other procedures covered under DRG
116 (pacemaker placement, etc.). Transfusion requirements
and administration of a glycoprotein inhibitor (GPI) were
identified with ICD-9 procedure code 99.04 (packed red
blood cells [PRBCs]) or 99.20 (injection or infusion of a
platelet inhibitor). Patients with bleeding were identified
with a manual review of each diagnosis code for ICD-9
diagnosis codes that included hemorrhage, hematoma,
bleeding, epistaxis, hematemesis, or other description that
can be associated with bleeding.
Results
A total of 1692 cases were coded for DRG 112 or 116
during that time period. Six percent of those cases were
pacemaker/electrophysiologic testing, so the actual
number of PCI cases was 1584. Of those patients, 8.3%
were coded for a bleeding diagnosis with or without
PRBCs. Of that 8.3%, 31% had a hemorrhage in their
diagnosis, 25% had hematoma, 22% had posthemorrhagic anemia, 18% were given PRBCs only, and the
remainder consisted of intracranial hemorrhage and all
miscellaneous diagnoses.
Gupta looked at the data to see what percentage of
patients who had a bleeding complication also received a
GPI. He found that 71% of patients with a bleeding
40
diagnosis had received a GPI. At this institution overall,
50–55% of patients are given a GPI.
Conclusion and Comment
The data were compared with the incidence of major
bleeding observed in clinical studies. Overall bleeding
rates (major and minor), as indicated by coding, totaled
8.3%, which is similar to rates reported in the literature.
Major bleeding as indicated by coding was 4.7% and within
the range reported in the literature. A greater number of
patients in the all-bleeding group was given a GPI.
An important limitation of this analysis is that the
timing of the events could not be verified by coding data.
The investigators could not determine whether transfusion occurred before or after PCI.
Such an analysis may assist other institutions in
identifying their bleeding complication rates. Pharmacists
can conduct this study in their own hospitals by requesting DRG data from medical records and sorting the data
by codes in a spreadsheet.
DRG changes that took effect on October 1, 2001,
may make coding and determining bleeding rates in
individual institutions somewhat easier. DRG 112 has been
removed, and the following codes have been changed:
DRG 516: PCI procedure with acute MI (AMI),
with or without a stent
DRG 517: PCI without an AMI but with a stent
DRG 518: PCI without AMI and without stent
References
1. Bittl JA, Strony J, Brinker JA et al. Treatment with bivalirudin
(Hirulog) as compared with heparin during coronary angioplasty
for unstable or post-infarction angina. N Engl J Med. 1995;
333:764-9.
2. Bittl JA, Chaitman BR, Feit F et al. Bivalirudin versus heparin
during coronary angioplasty for unstable or postinfarction angina:
final report reanalysis of the Bivalirudin Angioplasty Study. Am
Heart J. 2001; 142:952-9.
3. Antman EM, Braumwald E. A second look at bivalirudin. Am
Heart J. 2001; 142:929-31. Editorial.
4. Lincoff AM, Califf RM, Moliterno DJ et al. Complementary
clinical benefits of coronary-artery stenting and blockade of
platelet glycoprotein IIb/IIIa receptors. Evaluation of Platelet IIb/
IIIa Inhibition in Stenting Investigators. N Engl J Med. 1999;
341:319-27.
5. Topol EJ, Mark DB, Lincoff AM et al. Outcomes at 1 year and
economic implications of platelet glycoprotein IIb/IIIa blockade in
patients undergoing coronary stenting: results from a multicentre
randomised trial. EPISTENT Investigators. Evaluation of Platelet
IIb/IIIa Inhibitor for Stenting. Lancet. 1999; 354:2019-24.
6. Leon MB, Baim DS, Popma JJ et al. A clinical trial comparing
three antithrombotic-drug regimens after coronary-artery stenting.
Stent Anticoagulation Restenosis Study Investigators. N Engl J
Med. 1998; 339:1665-71.
7. Topol EJ. Evolution of improved antithrombotic and antiplatelet
agents: genesis of the Comparison of Abciximab Complications
with Hirulog [and back-up Abciximab] Events Trial (CACHET).
Am J Cardiol. 1998; 82(8B):63P-68P.
8. Mark DB, Talley JD, Topol EJ et al. Economic assessment of
platelet glycoprotein IIb/IIIa inhibition for prevention of ischemic
complications of high-risk coronary angioplasty. EPIC Investigators. Circulation. 1996; 94:629-35.
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Current Therapies for Treatment of Community-Acquired Respiratory Tract
Infections: Where Do the Ketolides Fit?
A symposium held December 4, 2001, in conjunction with the ASHP Midyear Clinical Meeting
Supported by an educational grant from Aventis Pharmaceuticals
This symposium addressed the problem of developing
antimicrobial resistance in organisms that cause community-acquired respiratory tract infections (RTIs). Challenges of treating RTIs and potential therapeutic options
were explored. Community-acquired RTIs include
pneumonia, acute maxillary sinusitis, pharyngitis,
tonsillitis, and chronic bronchitis. Several pathogens are
responsible for these infections, the most prevalent being
Streptococcus pneumoniae. John C. Rotschafer,
Pharm.D., FCCP, Professor, College of Pharmacy,
University of Minnesota, Minneapolis, reviewed the
principles of bactericidal versus bacteriostatic action and
their impact on drug selection and antimicrobial resistance. David P. Nicolau, Pharm.D., Coordinator for
Research, Department of Medicine Division of Infectious
Diseases and Department of Pharmacy, Hartford Hospital, presented an overview of the clinical and economic
implications of resistance. Debra A. Goff, Pharm.D.,
Clinical Associate Professor, Infectious Disease Specialist,
Ohio State University Medical Center, reviewed current
and forthcoming therapies for RTI.
Dead Bugs Don’t Mutate
Logic dictates that a bactericidal antimicrobial is more
desirable than a bacteriostatic compound (Table 1).
Clinical data supporting such logic are limited, however.
Conditions for which bactericidal therapy is recommended include endocarditis, meningitis, osteomyelitis,
syphilis, prosthetic device infection, neutropenic fever,
and severe life-threatening sepsis. Bactericidal agents
diminish the propensity of bacteria to develop resistance
since dead bacteria cannot go on to become resistant.
But resistance is a substantial problem for some bactericidal antimicrobials: vancomycin, β-lactams, and
fluoroquinolones. Issues of antimicrobial resistance and
drug choice are more complicated than whether the
antimicrobial kills or inhibits the growth of the bacteria.
Antimicrobials bind to a strategic site within the
bacterial cell, such as a penicillin-binding protein,
ribosome, or DNA gyrase. Once bound, the antimicrobial metabolically poisons the bacterium, ultimately
Table 1.
Definitions of Bactericidal versus
Bacteriostatica
Bactericidal:
Actual bacterial killing
MBC/MIC ≤ 4 µg/mL
Bacteriostatic:
Inhibition of bacterial growth
MBC/MIC > 4 µg/mL
Tolerance:
MBC/MIC ≥ 32 µg/mL
a
Values are ratio of minimum bactericidal concentration
(MBC) to minimum inhibitory concentration (MIC).
resulting in death. Antimicrobials kill in either a timedependent or a concentration-dependent fashion.
Theoretically, bactericidal agents are associated with
■ A faster rate of kill,
■ More rapid sterilization of the site of infection,
■ Quicker resolution of the patient’s signs and symptoms of infection, and
■ Possible reduction in the duration of therapy.
The data, however, do not fully support the theory
that there is a clinical difference between bactericidal and
bacteriostatic agents. Bactericidal action alone does not
guarantee clinical and microbiologic cure of infection or
prevent bacterial resistance. Instead, antimicrobial action
and the development of resistance are a function of
specific pairings of antimicrobial and bacterial pathogens.
Questions that can be asked in determining antimicrobial
effects and resistance include the following:
■ What is the mutational frequency?
■ Does the antimicrobial have single or multiple
mechanisms of action?
■ Does the pathogen have single or multiple
mechanisms for resistance?
■ What is the level (frequency, magnitude, and duration) of antimicrobial exposure?
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
41
Is the environment (e.g., pH, oxygen tension)
conducive to antimicrobial penetration?
■ Is the drug highly protein bound?
■ What is the difference between antimicrobial
concentrations in the blood and the infection site?
■ Is a foreign device present?
Underdosing, overuse, and misuse of antimicrobials
have been shown to influence the prevalence of antimicrobial resistance in hospitals. Vancomycin is a bactericidal antimicrobial, but it kills bacteria more slowly than
do the β-lactams.1, 2 In one study, vancomycin use was
associated with higher mortality than cloxacillin use3 and
was an independent risk factor for vancomycin-resistant
Enterococcus (VRE).4 In another study, cloxacillin plus
gentamicin achieved better results than vancomycin plus
gentamicin as short-course therapy for endocarditis.5
Overuse or underdosing of ceftazidime may
precipitate an extended-spectrum β-lactamase (ESBL)
problem with Klebsiella or Enterobacter spp. Piperacillin–
tazobactam can be substituted for ceftazidime, but Amp
C [inhibitor resistant TEM]-like enzymes or overproduction of ESBL can inactivate tazobactam.6 Treatment of
these organisms with imipenem or fluoroquinolones may
precipitate multiresistant Acinetobacter baumannii.
Macrolides have three mechanisms of resistance to
S. pneumoniae7:
1. Ribosomal (erm): About 30% of all strains; methylation occurs, which in turn alters the binding of
macrolide to the 50S ribosome and conveys
resistance to all macrolides.
2. Efflux pump (mef): About 70% of all strains;
macrolide is pumped out of the bacteria; varies
among individual macrolides.
3. 23S rRNA or ribosomal protein mutations: Only
20 strains reported.
Testing for macrolide resistance is problematic,
because disk diffusion susceptibility testing utilizes
erythromycin as the class disk. Laboratories can quickly
compare susceptibility to erythromycin versus
clindamycin to identify the type of resistance mechanism
(erm versus mef ). Resistance to clindamycin confers ermmediated resistance.
Bacterial resistance can be transferred vertically or
horizontally through acquisition of a plasmid or
transposon. Mechanisms of bacterial resistance are not
mutually exclusive; multiple mechanisms coexist in the
same organism. Current uses of antimicrobials promote
resistance: antimicrobials in animal feed, fish tanks, and
hand soap.
■
Implications of Resistance
Resistance is defined in terms of the minimum inhibitory
concentration (MIC) of the antimicrobial in vitro.
However, to be clinically relevant, MIC breakpoints must
be interpreted in relation to the pharmacokinetics and
pharmacodynamics of the antimicrobial in vivo. The
current MIC breakpoints for µ-lactam resistance in S.
pneumoniae were selected on the basis of the limited
penetration of these agents into the cerebrospinal fluid
during meningitis therapy. Thus, their relevance to the
management of RTIs is debatable.
Increasing antimicrobial resistance coupled with
multiple comorbidities of many patients with community-acquired pneumonia (CAP) leads to challenging and
complicated therapy. An understanding of the complexity
of the host–drug–bug triad can help increase the likelihood
of positive patient outcomes. Clinical and microbiologic
outcomes have been the conventional criteria for evaluating antimicrobial effectiveness. It is important to also
consider duration of effect, rate of response, and economic
variables when evaluating antimicrobial therapy.
Microbiologic surveillance utilizes penicillinresistance profiles as a marker for susceptibility to other
antimicrobials. Centers for Disease Control and Prevention data for S. pneumoniae in CAP show that the
microbiologic breakpoints for susceptibility can be shifted
so that antimicrobial sensitivity is possible through MICs
up to 2 µg/mL (Figure 1).8
Resistance to macrolides has been increasing in the
United States largely because of an increase in use of these
agents. A large national surveillance study reported 25–
35% macrolide resistance. Most macrolide prescriptions
are written in the outpatient setting, where there often are
no microbiologic data to confirm the pathogen and its
susceptibility, and infections are mild to moderate in
severity and could resolve spontaneously without treat-
Heffelfinger JD, et al. Arch Intern Med 2000; 160: 1399–1408.
Figure 1. Breakpoints for susceptibility (s = susceptible, I =
Intermediate, R = resistant) of S. pneumoniae.
42
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■
■
Individual antimicrobials differ with respect to
optimization of microbiology, pharmacology, and
toxicity profiles; potential for the development of
resistance; and impact on total cost of care.
To address these issues, new antimicrobials are
required that are active against emerging resistant
organisms.
Current and Forthcoming Therapies
Figure 2. Use of pharmacokinetic and pharmacodynamic
characteristics to minimize resistance and maximize
outcomes. [C] = concentration.
ment. These factors lead to uncertainty about whether the
problem is resistance or possibly patient noncompliance.
In 2000, only seven reports of macrolide treatment
failures were published. Studies show that mef resistance
(efflux pump) in macrolides is more prevalent (71%) in
the United States. This type of resistance can be overcome
by adequate concentrations of the antimicrobial at the site
of infection. Macrolides and ketolides achieve high
intrapulmonary concentrations, which explains why
there are fewer reported clinical failures than would be
expected.
Pharmacokinetic and pharmacodynamic parameters
can help predict the potential for maximally effective
therapy and optimal bacterial eradication, thus minimizing the development of resistance (Figure 2). CAP is a
serious socioeconomic burden. It is one of the leading
causes of death in the United States, resulting in about
45,000 deaths per year. Resistance leads to increased use
of health care resources and costs (e.g., reconsultations,
additional prescriptions for antimicrobials, and hospitalization). There are indirect costs to be considered as well,
including lost productivity and absenteeism.
Nicolau concluded with the following points:
■ Increasing prevalence of antimicrobial resistance in
S. pneumoniae threatens the usefulness of our current
panel of antimicrobials.
■ In the case of penicillin, the implications of in vitro
resistance for management of RTIs are dependent
upon the site of infection, highlighting the need for
pharmacokinetic and pharmacodynamic breakpoints.
■ The negative clinical impact of conventional
antimicrobial therapies is becoming apparent in
RTIs, including CAP.
Three sets of guidelines for treatment of CAP have been
published (Centers for Disease Control and Prevention
Drug-Resistant Streptococcus pneumoniae Therapeutic
Working Group, American Thoracic Society, and Infectious
Diseases Society of America).8-10 The guidelines make diferent recommendations for first-line antimicrobial therapy
in CAP, so it is important to be familiar with all three.
When determining antimicrobial therapy for RTIs,
it is important to know local resistance patterns.
Is resistant S. pneumoniae suspected? Does the agent
cover atypicals (Mycoplasma, Legionella, and Chlamydia)?
Is enteric gram-negative coverage needed?
Current Options
Several classes of antimicrobials can be used in treating
RTIs. Cephalosporins provide coverage against grampositive and gram-negative pathogens but have no activity
against atypicals and little activity against penicillinresistant S. pneumoniae (PRSP). Ceftriaxone and
cefotaxime currently have the most favorable S.
pneumoniae resistance profile of the cephalosporins.
However, third-generation cephalosporins have been
associated with VRE.
Penicillins do not cover atypicals and are not useful
for high-level PRSP. Amoxicillin–clavulanate is useful for
anaerobic infections such as aspiration pneumonia.
Penicillin G and ampicillin have the most favorable S.
pneumoniae resistance profiles of the penicillin class.
Doxycycline is recommended as second-line
therapy for outpatients less than 60 years of age who do
not have cardiopulmonary disease, risk factors for PRSP,
aspiration, or enteric gram-negative pathogens. Tetracyclines are less reliable than macrolides against S.
pneumoniae, so they should be reserved for patients who
have allergies or intolerance to macrolides. Tetracycline
has been overused in animal feeds, so it has acquired
plasmid-mediated resistance.
Quinolones provide coverage for atypicals, grampositives (including high-level PRSP), and common
gram-negatives. They are the drugs of choice for highlevel PRSP. Treatment guidelines vary in recommending
them as first-line or second-line therapy. Generally,
quinolones are recommended as first-line agents if
another agent has failed (macrolide or β-lactam), or the
patient has a documented high-level PRSP infection or
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
43
an allergy to an alternative agent. Currently most
quinolones have a low rate of resistance to S. pneumoniae.
The American Thoracic Society guidelines recommend
reserving the quinolones as second-line therapy to
preserve the low resistance profile. Since the mechanism
for quinolone resistance is conferred by a mutation of the
target sites of DNA gyrase or topoisomerase IV, the
implication of mutations is that once susceptibility is
decreased, widespread resistance occurs.
Macrolides provide coverage against typical and
atypical pathogens and are a good choice for penicillinallergic patients. Azithromycin and clarithromycin are
preferred over erythromycin because of better coverage of
atypicals, fewer gastrointestinal adverse effects, and better
patient compliance. Macrolides should not be used alone
in patients with PRSP, aspiration, or enteric gramnegatives.
Sulfa (trimethoprim–sulfamethoxazole) is not active
against atypicals and is no longer recommended because
of resistance.
Linezolid is not recommended but is an option. It
provides activity against PRSP but is very expensive.
Oxazolidinones should be reserved for VRE.
Quinupristin–dalfopristin is not recommended but
is an option. It provides activity against PRSP but is very
expensive and available only in i.v. form. Streptogramins
should be reserved for VRE.
Agents on the Horizon
The ketolides are a new class of antimicrobials structurally related to the 14-member ring macrolides with a
3-keto structure replacing the L-cladinose moiety of
macrolides. Ketolides have a mechanism of action similar
to that of macrolides: prevention of bacterial protein
synthesis and prevention of ribosomal assembly. Ketolides
and macrolides bind at two sites on the bacterial ribosome. Telithromycin, the first ketolide, binds 10 times
more tightly than erythromycin and 6 times
more tightly than clarithromycin to wild-type ribosomes.
Telithromycin’s spectrum of activity includes
S. pneumoniae (both penicillin- and erythromycinresistant strains), gram-negative bacteria involved in
RTI (Haemophilus influenzae and Moraxella catarrhalis),
and atypical and intracellular organisms (Chlamydia,
Legionella, and Mycoplasma spp.). Telithromycin has been
specifically designed to overcome macrolide resistance.
This agent is approved in Europe and is currently
undergoing FDA review.
44
Ertapenem, a newly approved carbapenem, has a
long half-life, which enables once-a-day dosing. It is
active against gram-positives, gram-negatives, and
anaerobes. Ertapenem is not active against atypicals,
Pseudomonas aeruginosa, A. baumannii, or Enterococcus
faecalis.
Daptomycin, an investigational lipopeptide
antimicrobial, has an impressive spectrum against grampositives, PRSP, VRE, and multidrug-resistant
S. pneumoniae.
Conclusion
Goff concluded by emphasizing the importance of local
resistance profiles. Be aware of these patterns, she said.
Always assess clinical outcomes of patients receiving
antimicrobials for RTIs. Identify clinical failures and
investigate the cause. Position new antimicrobials on
the basis of clinical need.
References
1. Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin
or vancomycin plus rifampin in methicillin-resistant Staphyloccus
aureus endocarditis. Ann Intern Med. 1991; 115:674-80.
2. Karchmer AW. Staphyloccus aureus and vancomycin: the sequel.
Ann Intern Med. 1991; 115:739-41.
3. Gonzalez C, Rubio M, Romero-Vivas J et al. Bacteremic
pneumonia due to Staphyloccus aureus: a comparison of disease
caused by methicillin-resistant and methicillin-susceptible
organisms. Clin Infect Dis. 1999; 29:1171-7.
4. Van Houten MA, Uiterwaal CS, Heesen GJ et al. Does the
empiric use of vancomycin in pediatrics increase the risk for gramnegative bacteremia? Pediatr Infect Dis. 2001; 20:171-7.
5. Fortun J, Navas E, Martnez-Beltran J et al. Short-course therapy
for right-side endocarditis due to Staphyloccus aureus in drug
abusers: cloxacillin versus glycopeptides in combination with
gentamicin. Clin Infect Dis. 2001; 33:120-5.
6. Rice LB. Successful interventions for gram-negaitve resistance to
extended-spectrum beta-lactam antibiotics. Pharmacotherapy.
1999; 19:120S-8S.
7. Tait-Kamradt A, Davies T, Appelbaum PC et al. Two new
mechanisms of macrolide resistance in clinical strains of Streptococcus pneumoniae from Eastern Europe and North America.
Antimicrob Agents Chemother. 2000; 44:3395-401.
8. Heffelfinger JD, Dowell SF, Jorgensen JH et al. Management of
community-acquired pneumonia in the era of pneumococcal
resistance: a report from the Drug-Resistant Streptococcus
pneumoniae Therapeutic Working Group. Arch Intern Med. 2000;
160:1399-408.
9. Niederman MS, Mandell LA, Azueto A et al. Guidelines for the
management of adults with community-acquired pneumonia.
Diagnosis, assessment of severity, antimicrobial therapy, and
prevention. Am J Respir Crit Care Med. 2001; 163:1730-54.
10. Bartlett JG, Dowell SF, Mandell LA et al. Practice guidelines for
the management of community-acquired pneumonia. Infectious
Diseases Society of America. Clin Infect Dis. 2000; 31:347-82.
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
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Current and Emerging Pharmacotherapy for Postoperative Ileus
A symposium held December 2, 2001, in conjunction with the ASHP Midyear Clinical Meeting
Supported by an educational grant from Adolor Corporation
Ileus is a mechanical bowel obstruction characterized by
severe colicky abdominal pain and distention, absence of
passage of stool, vomiting, fever, and dehydration. This
symposium addressed the problem of postoperative ileus
(POI), which is transient impairment of bowel motility
after surgery. The entire symposium (continuingeducation credit offered) can be reviewed at
www.medscape.com/cmecircle/pharmacotherapy.
Clinical and Cost Impact
POI occurs so frequently that it is often considered an
inevitable response to surgery, even though it has a
negative impact on patient morbidity and health care
costs. Linda Bernstein, Pharm.D., President and CEO
of Vita Media Corporation in San Francisco, discussed
the clinical and cost impact of POI.
After surgery, the gastrointestinal (GI) tract recovers
sequentially. The average length of time for recovery after
major abdominal surgery is 0 to 24 hours for the small
intestine, 24 to 48 hours for the stomach, and 48 to 72
hours for the large intestine.
The duration of POI is related to the anatomic
location of surgery (with the longest duration after colon
surgery), the degree of surgical manipulation, and the
magnitude of inflammatory responses. There are no data
to suggest that POI has a beneficial effect.
The pathogenesis has not been definitively determined, but contributing factors include sympathetic
inhibitory reflexes, inflammatory mediators, and postoperative use of opioids.
POI causes significant morbidity and discomfort
and prolongs hospital stay. It delays resumption of a
normal diet, causing increased catabolism and the risk of
malnourishment, hypoalbuminemia, and poor healing.
Mobilization (i.e., walking) is delayed, increasing the risk
of pulmonary complications.
POI costs nearly $1 billion annually in the United
States, including the costs of nasogastric (NG) intubation, intravenous hydration, additional nursing care,
laboratory tests, and more hospital days. The time
required for recovery of intestinal peristaltic function and
resumption of oral intake is a major barrier to reducing
postsurgical length of stay (and therefore cost).
Managing Adverse Effects of
Postoperative Analgesia
Peter J. S. Koo, Pharm.D., Associate Clinical Professor
of Pharmacy and Pain Management Specialist at the
University of California at San Francisco, discussed
balancing the need for postoperative pain relief with the
adverse effects of pain medications.
Koo discussed some potential obstacles to effective
pain management:
1. Professional responsibility versus liability. Responsibility means giving the appropriate medication at an
appropriate dose and by an appropriate route.
Increased responsibility for pain management can
expose pharmacists to greater liability, which can be
reduced by setting realistic pain management expectations at the outset.
2. Inaccurate assessment and unrealistic therapeutic goal
setting. Therapeutic goals should be based not on an
absolute level, but on the functional ability the patient
would like to achieve and the degree of pain the
patient finds tolerable. Translators can aid in identifying the patient’s goals if language is a barrier.
3. Undesirable opioid adverse effects. Dependency and
addiction can be minimized when clinicians set,
monitor, and achieve realistic goals.
Opioid Doses, Pharmacokinetics, and
Pharmacogenetics
The 10-mg parenteral dose of morphine, the dose at
which 70% of postsurgical patients will have pain relief, is
the standard with which all other opiates are compared.
Subtle differences among opiates include their likelihood
of causing emesis, hypotension, and central nervous
system (CNS) depression; the likelihood of these effects is
greatest with morphine, less with hydromorphone, and
(among the three agents) least with fentanyl. Elderly
patients are more susceptible to the CNS effects of
morphine. The opioid doses shown in Table 1 are
equivalent.
The serum half-life of opioids correlates poorly with
analgesic duration. Drugs with a long half-life (e.g.,
methadone, levorphanol) can accumulate if given
frequently enough to effectively relieve pain. The duration of action of an intraspinal analgesic depends on the
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
45
Table 1
Equivalent Doses of Opiods
Patient-Controlled Analgesia (PCA)
IV Intermittent Bolus Push
IM/SC Intermittent Injection
Morphine 1 mg q 6 minutes
Morphine 6 mg qh
Morphine 10 mg q 3 hours
Hydromorphone 0.2 mg q 6 minutes
Hydromorphone 1 mg qh
Hydromorphone 2 mg q 3 hours
Fentanyl 10 µg q 6 minutes
hydrophilic and lipophilic properties of the compound,
not on its half-life. Oral absorption (except with methadone) is poor because of a significant first-pass effect in
the liver. Rectal absorption is usually better than oral
because of the portacaval bypass.
Scientists have discovered ethnic variations in the
incidence of cytochrome P-450 2D6 deficiencies.
Approximately 6% to 8% of African Americans, 12% to
20% of Caucasians, 59% of Tanzanians, and 3% to 39%
of Asians are deficient. Patients who seem resistant to an
opiate may be 2D6-deficient, requiring treatment with an
active metabolite instead of a prodrug.
Spinal Opiate Considerations
Postsurgical spinal-opioid effects last 8 to 12 hours, with
rapid escalation of pain at the end of the effect. Patients
need bridge therapy for pain through PCA, instead of
immediate conversion to oral therapy. Spinal opiates have
additive effects with sedative–hypnotics, so agents such as
lorazepam and diazepam should be avoided. Spinal
opiates can affect intestinal motility and micturition.
Opiate-Induced Adverse Effects
When opioids are used for postoperative analgesia,
opiate-induced adverse effects must be considered. These
include
■ Ileus and constipation, which are uncomfortable
especially when patients are immobilized.
■ Sedation, particularly in elderly patients or those
taking other sedatives. Those patients should start
with hydromorphone instead of morphine and receive
lower, more frequent doses.
■ Hypotension, in which case hydration should be
increased and i.v. analgesics should be given in small,
frequent doses. If hypotension does not resolve, the
patient should be switched to fentanyl.
■ Respiratory depression, especially with large i.v.
boluses of opiates or opiates in combination with
other respiratory depressants. Intravenous doses
should be low but frequent. With i.m. doses, there is
less respiratory depression in association with peak
serum opiate levels. Benzodiazepines should be
avoided in young and elderly patients taking opiates.
■ Emesis incidence is 16% with morphine. Use antiemetics judiciously or use alternative opiate analgesics.
46
■
Dependency and addiction. Pharmacists need to be
aware of the current controversy and abuse potential
with oxycodone and fentanyl patches.
Conclusion
The keys to balancing postoperative analgesia and
management of adverse effects are knowledge of the drug
products and coordination of care.
Current Pharmacotherapy
Elaine Taylor, Pharm.D., Clinical Assistant Professor at
the University of Texas at El Paso and the University of
Texas at Austin College of Pharmacy, reviewed the
pathophysiology and current treatment strategies in POI.
She discussed the effects of surgery on the GI tract, the
limitations of current pharmacotherapy, and the areas
being targeted for future therapies.
Pathophysiology of POI
The primary function of the small intestine is absorption
and digestion of food. Food is mixed with bile and
pancreatic juices into chyme, then moved through the
small intestine by a motion called segmentation. The slow
movement of chyme exposes it to a large surface area and
aids nutrient absorption. The intensity of segmentation is
affected by the parasympathetic and sympathetic nervous
systems. After nutrients have been absorbed, chyme
enters the large intestine, and a sweeping motion known
as the migratory motor complex (MMC) begins, which
forms the peristaltic waves. Each wave is initiated more
distally until the residue is moved from the small to the
large intestine. MMC also sweeps out bacteria and
intestinal secretions. It occurs only during fasting; eating
causes it to stop and segmentation to resume.
The large intestine absorbs water and electrolytes
and stores fecal matter until it is expelled. Long, slow
contractions sweep over the large intestine three to four
times a day to propel residue toward the rectum, usually
during or after eating. The MMC is not present in the
colon.
GI motility is controlled extrinsically by the
parasympathetic (increases gut motility) and sympathetic
(inhibits bowel function) nervous systems. Motility is also
controlled by the intrinsic nervous system, which is
specific to the GI tract and structurally different in the
colon than in the small intestine. Colonic movement
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
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relies more on innervation from the extrinsic nervous
system for regulation. Motility of the colon is significantly affected by the high sympathetic outflow that
occurs during surgery.
Surgery elicits a stress response, activating inhibitory neural reflexes and causing the release of numerous
neurotransmitters and inflammatory mediators that affect
gastric motility. This response causes the release of
endogenous endorphins and enkephalins that activate
central and peripheral opioid receptors, adding to the
effect of opiate analgesics on GI motility. These receptor
sites are targets for upcoming therapies.
Management
Management of POI is supportive and includes epidural
local anesthetics, opioid-sparing analgesics, NG intubation, mobilization, early postoperative oral feeding, and
the use of prokinetic agents.
Prokinetic agents such as metoclopramide are
commonly used postoperatively to prevent or reduce
POI. Other commonly used medications include erythromycin, laxatives, and naloxone. Clinical trials with these
agents have had conflicting results, partly because POI is
poorly defined. Other trial limitations include the use of
different endpoints, varying administration times and
treatment durations, different operative procedures, and
small sample sizes. Studies often do not identify the
analgesics or other medications used.
The most commonly used endpoints in clinical
trials have inherent flaws. The presence of bowel sounds is
sometimes used, but sounds can originate in the small
bowel as well as the colon and can easily be overlooked.
In addition, sounds may indicate mixing and not propulsive movements. Flatus is used as an endpoint but is
dependent on patient reporting and does not always
correlate with bowel function. Bowel movement is the
most commonly used endpoint and is generally accepted
as the key indicator of ileus resolution. However, only the
distal bowel, rather than the entire GI tract, may be
functioning. Attempts have been made to gather better
objective information with instruments to measure
intraluminal pressure, migration of radiopaque markers,
and noninvasive electrical measurements, but these do
not always correlate with clinical resolution. The best
definition of POI resolution includes a combination of
bowel movement and good oral intake.
Metoclopramide is one of most commonly prescribed agents for POI. It has been evaluated in prospective, randomized, double-blind, placebo-controlled trials
of 20 to 115 patients undergoing surgical procedures
ranging from exploratory laparoscopy to extensive abdominal surgery. In all trials, metoclopramide was administered
on the day of surgery and continued for up to five days or
until oral intake. The doses, regimens, and end points
varied among the trials. Results showed no difference
between metoclopramide and placebo in treating POI.
Erythromycin is thought to act as a motilin agonist.
It stimulates MMC and postprandial activity. The highest
quantity of motilin receptors is found in the gastric
antrum and proximal duodenum, but erythromycin
stimulates motilin receptors and MMC only in the small
intestine. Two studies showed no difference in efficacy
between erythromycin and placebo.
Laxatives are commonly used in combination with
prokinetic agents. There are no randomized clinical
studies available to indicate their degree of effectiveness.
In one unblinded, nonrandomized study, 20 consecutive
gynecological surgery patients were given milk of magnesia and bisacodyl suppositories. Their duration of ileus
was three days, and length of stay decreased from eight
days to four days. Laxatives probably have some effect on
POI, but the degree of that effect is unknown.
Naloxone and nalmefene are opioid antagonists that
have positive effects on the opioid receptors in the GI
tract but can also be absorbed through the GI tract and
cross the blood–brain barrier.
Conclusion
POI is a self-limiting condition associated with discomfort and increased morbidity. Many factors contribute to
its development, and many pharmacologic and
nonpharmacologic methods have been tried to relieve it.
Although prokinetic agents are widely used, studies have
not demonstrated a benefit. As our understanding of the
pathophysiology of POI increases, more effective therapies may be developed. Management will always depend
on a combination of therapies. Development of targeted
therapies that reduce POI and decrease length of stay will
have a significant impact on patient care.
Emerging Pharmacotherapy
William K. Schmidt, Ph.D., Vice President of Scientific
Affairs at Adolor Corporation in Exton, Pennsylvania,
discussed opioid receptor physiology in relation to
emerging therapies under investigation for the management of POI.
Postoperative morphine and other opioid analgesics
stimulate opioid receptors in the GI tract and in the
brain. Opioid receptors in the brain are responsible for
analgesia, sedation, respiratory depression, and the
potential for addiction. Opioid receptor stimulation in
the GI tract causes POI. Because of blockade by the
blood–brain barrier, peripheral receptors in the gut are
exposed to a higher concentration of opioids than CNS
receptors. Even patients who develop tolerance to the
CNS effects of opioids do not become tolerant to the GI
effects. Opioid receptors in the GI tract are molecularly
identical to those in the brain, but the treatment of ileus
requires selective blocking of GI opioid receptors without
affecting CNS receptors. Alvimopan is a selective blocker
of GI receptors that does not cross the blood–brain
barrier and has no effect on CNS opioid receptors.
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
47
GI Effects of Opioids
Opioids cause multiple GI effects besides constipation,
including
■ Decreased gastric motility and emptying, leading to
increased gastroesophageal reflux.
■ Inhibition of propulsion in the small intestine, causing
delayed absorption of medications.
■ Inhibition of propulsion in the large intestine, causing
straining, incomplete evacuation, bloating, and
abdominal distention.
■ Increased amplitude of nonpropulsive segmental
contractions, leading to spasm, abdominal cramps,
and pain.
■ Constriction of the sphincter of Oddi, leading to
biliary colic and epigastric discomfort.
■ Increased anal sphincter tone and impaired reflex
relaxation with rectal distention, leading to impaired
ability to evacuate the bowel.
■ Diminished gastric, biliary, pancreatic, and intestinal
secretions and increased absorption of water from
bowel content, resulting in hard, dry stool that is
difficult to expel.
Trials of Narcotic Antagonists
Narcotic antagonists have been studied to determine their
efficacy in antagonizing opioid-induced adverse GI effects.
■ Oral naloxone reverses opioid effects but has limited
systemic absorption. It crosses the blood–brain barrier,
so it can reverse analgesia and precipitate withdrawal.
■ Nalmefene was chemically altered to limit its penetration of the blood–brain barrier. The glucuronide
compound showed in vitro effects but was not
effective in vivo.
■ Methylnaltrexone has shown some benefit by blocking
opiate effects in the GI tract without reversing
analgesia. Studies have been small, however, and the
potency of the compound is low.
Alvimopan
Alvimopan is a synthetic, pure opioid receptor antagonist
that combines high potency with peripheral restriction. It
works locally in the GI tract to block the adverse effects
of opioid narcotics, with minimal systemic absorption.
Eli Lilly & Company conducted the initial clinical
studies of alvimopan in healthy volunteers. Those studies
demonstrated the drug’s ability to reverse the action of
oral loperamide, intravenous morphine, oral morphine,
and other oral opioids. A Phase II study showed that
alvimopan did not reverse the analgesic effect of therapeutic doses of morphine.
Alvimopan was studied in the treatment of opioid
bowel dysfunction, including constipation, nausea,
48
cramping, malabsorption syndromes, and other symptoms. In this Phase II study, the subjects (>100) had been
taking a variety of opioids for chronic pain (duration of
one week to more than 10 years) or were taking methadone for opiate withdrawal. One group of patients
received a single dose of placebo or alvimopan 0.5, 1.5, or
3 mg. Another group received ascending doses on
consecutive days. In the single-dose group, the 0.5-mg
dose more than doubled the probability of having a bowel
movement within 12 hours; subjects who received the 3mg dose had a 100% chance of having a bowel movement. Stool weight also increased proportionately with
increased dose. The incidence of hard, dry stool fell from
67% with placebo to 26% with the 0.5-mg dose and
12% at the 1.5-mg dose. The incidence of moderate to
severe straining decreased from 100% with placebo to
15% to 30% in the alvimopan group.
Patients’ overall satisfaction with their bowel movements was also measured. In the placebo group, 66%
reported no change, while 74% of patients who received
alvimopan 0.5 mg reported greater satisfaction. At the 3mg dose, some patients experienced a peripheral opioid
withdrawal syndrome resulting in diarrhea. The time to
first bowel movement was 4.5 to 7.5 hours after dosing.
In another Phase II study, subjects underwent
partial colectomy (15 patients), simple hysterectomy (36
patients), or radical hysterectomy (27 patients). Two
hours before surgery, subjects received placebo, alvimopan
1 mg, or alvimopan 6 mg; they continued the dose b.i.d.
starting on postoperative day 1. The endpoints measured
were pain, opioid consumption, nausea, bloating,
abdominal cramping, and times to first liquid, first solid,
first flatus, first bowel movement, and hospital discharge.
With the 6-mg dose, time to first bowel movement was
reduced by 48 hours, time to solid diet was reduced by
1.3 days, and time to discharge was reduced by 1.4 days.
Patients showed no change in pain scores or in the
amount of morphine consumed for optimal pain relief.
Unanticipated benefits observed in this trial were a
reduction in postoperative nausea of more than 50% and
elimination of postoperative vomiting.
The timing of the first dose of alvimopan is critical
for an optimal outcome. Because its action is intraluminal, the drug must have time to reach the colon by the
onset of surgery. Study protocols call for dosing two hours
before surgery.
Conclusion
Alvimopan has the potential to improve the management
of POI and opioid bowel dysfunction. It has GI-specific
activity, does not reverse analgesia, and in early trials, has
shown a low adverse effect rate. Additional trials are
needed to determine clinical efficacy and safety. Phase III
trials are currently underway.
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
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Evidence-Based Strategies for Treatment of Atherothrombosis
A symposium held December 3, 2001, in conjunction with the ASHP Midyear Clinical Meeting
Supported by an educational grant from Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership
In this symposium, Nasser M. Lakkis, M.D., Director of
Invasive Cardiology, Ben Taub General Hospital, Baylor
College of Medicine, Houston, Texas, reviewed the
clinical implications of antiplatelet agents in the pathophysiology of acute coronary syndromes (ACS) and the
relationship between risk of stroke, myocardial infarction
(MI), and peripheral arterial disease. Cathy A. Sila,
M.D., Associate Medical Director, Cerebrovascular
Center, The Cleveland Clinic Foundation, Cleveland,
Ohio, then described appropriate strategies for early
intervention and long-term antiplatelet therapy in the
management of ischemic stroke and presented results of
clinical trials investigating antithrombotics as
monotherapy (warfarin, clopidogrel, and aspirin) and in
combination therapy (clopidogrel plus aspirin) for stroke
prevention. Jean M. Nappi, Pharm.D., FCCP, BCPS,
Professor of Pharmacy and Vice-Chair, Department of
Pharmacy Practice, Medical University of South Carolina,
Charleston, concluded the session by discussing changing
strategies in the management of ACS.
ACS Pathophysiology and Antiplatelet
Agents
Atherosclerotic plaque rupture, erosion, or disruption
with superimposed thrombus is the most important
underlying pathophysiology leading to ACS. Despite
treatment with aspirin, intravenous heparin, and intravenous glycoprotein (GP) IIb/IIIa inhibitors, the rate of
cardiovascular death or reinfarction remains 6–15% for
ACS patients at 30 days and 6–8% per year over the next
two years.1
Pathophysiology
Atherosclerosis involves large and medium-size vessels.
Buildup of atheroma begins in childhood; as it progresses,
the atheroma occludes blood flow, resulting in ischemia.
Ischemia is manifested as angina, peripheral vascular
disease (PVD) or claudication, and stroke. Plaque remains
stable until a stimulus causes it to rupture, with resultant
ACS, stroke, or PVD possibly leading to amputation.2
ACS consists of three conditions, unstable angina,
non-ST segment elevation MI (NSTEMI), and ST
segement elevation MI (STEMI). In patients with
NSTEMI or unstable angina, the thrombus only partially
occludes the lumen of the vessel, which leads to ST
segment depression or T wave changes on the ECG. In
patients with STEMI the thrombus completely occludes
the lumen of the vessel, and this leads to ST segment
elevation on the ECG. Unstable angina and NSTEMI are
the focus of the following discussion of ACS.
In the past 15–20 years, studies have shown that
platelets have a significant role in the pathophysiology of
ACS. Despite their small size, platelets have multiple
surface receptors. The three most important are adenosine
diphosphate (ADP) receptors, GP IIb/IIIa receptors, and
thromboxane A-II receptors. A 1998 meta-analysis of
treatment options for ACS, including aspirin, heparin,
β-blockade, thrombolytic therapy, calcium blockade, and
early percutaneous transluminal coronary angioplasty
(PTCA), showed that patients treated with aspirin had a
50% reduction in adverse events (death or MI) at 30
days. All other therapies were shown to be inferior to
aspirin. These data indicate that platelets play the most
important role in ACS.
GP IIb/IIIa Receptor Blockers
GP IIb/IIIa receptor blockers (abciximab, eptifibatide,
tirofiban) are effective agents in ACS or in patients
undergoing PTCA, but reported clinical outcomes vary
because of differences in chemical structure of the
individual agents, variations in study design, different
types of patient populations, and differences in duration
of therapy.
ADP Receptor Blockers
A number of studies have evaluated ADP receptor
blockers. The CAPRIE trial3 evaluated clopidogrel 75 mg
daily, as monotherapy versus aspirin 325 mg daily in
stable patients 35 days after an MI or within six months
of a stroke and patients with established peripheral
arterial disease. At the end of the three-year trial,
clopidogrel-treated patients were found to have improved
outcomes: a significant (8.7%) decrease in the composite
endpoints of MI, stroke and vascular death combined.
Results from the CLASSICS trial4 demonstrated the
safety and efficacy of clopidogrel plus aspirin versus
ticlopidine plus aspirin. Patients in the CLASSICS trial
who received clopidogrel plus aspirin demonstrated
significantly fewer adverse effects than those who received
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
49
ticlopidine and aspirin; this led to the prescribing of
combination therapy with clopidogrel and aspirin in
stented patients.
CURE Trial
The CURE trial 5 evaluated the safety and efficacy of
clopidogrel in addition to standard therapy including
aspirin in patients with ACS. The CURE trial involved
patients with unstable angina or non-Q-wave MI, onset
of chest pain within 24 hours of presentation, and ECG
evidence of ischemia manifested by ST depression or Qwave inversion or elevated cardiac enzymes. Patients
initially received standard therapies β-blockers, nitrates,
calcium-channel blockers, heparin, or invasive procedures.
The patients were randomized to receive clopidogrel (as a
one-time, 300-mg loading dose followed by a maintenance
dose of 75 mg daily) plus aspirin 75–325 mg or placebo
plus aspirin 75– 325 mg.
The CURE investigators’ rationale for choosing
patients with ST depression was based on GUSTO IIb
data6 that established ST depression as an additional
indicator of high risk. TIMI II7 revealed that enzyme
changes such as increased troponin are a predictor of
increased mortality.
Clopidogrel in addition to standard therapy,
including aspirin, significantly reduced the occurrence of
the primary endpoint of MI, stroke, or cardiovascular
death at 12 months by approximately 20%. Within the
first 30 days after randomization, there was a 21% relative
risk reduction (RRR) in the primary endpoint and an
18% RRR in the primary endpoint from 30 days to the
end of the study. These data show no evidence of clinical
deterioration (or catch-up phenomenon) at 12-month
follow-up.
The CURE trial also examined the criteria for
intervention in refractory ischemia. In the placebo group,
more patients required thrombolytics, indicating a
progression from non-ST elevation MI to ST elevation
MI. Also, more patients required cardiac catheterization,
PTCA, coronary artery bypass grafts (CABG), or balloon
angioplasty in the hospital, and more experienced
refractory angina. Again, the combination of clopidogrel
and aspirin appeared to significantly reduce the secondary
endpoint of refractory ischemia and its complications by
14%, which was significant (p < 0.001).
Investigators also examined the consistency of
outcomes among the subgroups of participants, which
clearly demonstrated that patients receiving combination
therapy experienced fewer adverse cardiac events. In ACS
patients with a history of revascularization, such as CABG
or angioplasty, the event rate for the placebo group was
14.6, whereas the group receiving combination therapy
had an event rate of 8.4. The benefit of clopidogrel plus
standard therapy was consistent across all subgroups,
including patients older or younger that age 65, with or
50
without diabetes, at low, medium, or high risk, or undergoing vascularization or no vascularization.
In CURE, bleeding was categorized as major or
minor, and major bleeding was further classified as lifethreatening or non-life-threatening. Clopidogrel in
addition to standard therapy significantly increased the
risk of major bleeding compared with placebo plus aspirin
(3.7% vs 2.7%, p = 0.001). Major bleeding occurred
most frequently in the gastrointestinal tract or at a
surgical incision site or the site of an arterial puncture.
There were no significant increases in life-threatening
bleeds, which included hemorrhagic stroke or intracranial
hemorrhage. The CURE bleeding rates at nine months of
therapy were comparable to those for GP IIb/IIIa receptor
blockers in the PRISM-PLUS trial.8
PCI-CURE Trial
The PCI-CURE trial9 evaluated the outcomes of patients
in the CURE trial who were treated with angioplasty.
Percutaneous coronary intervention (PCI) was performed
at an average of six days from randomization. Patients
receiving clopidogrel prior to PCI had an event rate of
4.5% at 30 days, compared with 6.4% in the placebo
group. There was an overall (including events before and
after PCI) 31% reduction in cardiovascular death or
myocardial infarction (p = 0.002). Bleeding complications
at 30 days were similar in both combination therapy and
aspirin-only groups receiving PCI, with a slight increase
in minor bleeding beyond 30 days in the combination
therapy patients.
Further Studies
In 2002, the results of the CREDO trial will be presented, which will compare outcomes at one year for
elective PCI. Clopidogrel is also being evaluated in
patients with ST elevation MI.
Stroke Prevention
Prevention strategies for stroke include identification and
control of risk factors: hypertension, diabetes, hyperlipidemia, and cigarette smoking. Therapy for stroke
prevention should be subtype-specific, since stroke is not
a homogeneous disease. For most stroke patients, surgery
is not first-line therapy and antithrombotic therapies are
recommended. Antithrombotic agents include warfarin,
aspirin, ADP receptor blockers (clopidogrel and
ticlopidine), and combination therapy with aspirin and
dipyridamole or aspirin and clopidogrel.
Clinical Trial Data
Clinical trials have compared warfarin versus placebo or
warfarin versus aspirin in patients with nonvalvular atrial
fibrillation without history of transient ischemic attack
(TIA) or stroke. American College of Chest Physicians
(ACCP) guidelines for antithrombotic therapy10 in
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patients with nonvalvular atrial fibrillation indicate that
most patients should receive warfarin as first-line therapy,
although patients whose intrinsic stroke risk is low
enough can receive aspirin.
Aspirin
Three studies, the Physicians’ Health Study, British
Physicians’ Study, and Boston Nurses’ Study, have
demonstrated that aspirin does not reduce the risk of
stroke in low-risk patients. A meta-analysis from the
Antiplatelet Trialists’ Collaboration11 evaluated minor
neurologic or major cerebrovascular events and showed
that the greatest benefit of aspirin was prevention of MI.
The reduction in risk for nonfatal stroke was 20–25%.
There is still no consensus on the optimal dose of aspirin
for prevention of stroke, but the ACCP guidelines
recommend 50–325 mg/day.
Clopidogrel and Ticlopidine
In the TASS study,12 3000 patients with TIAs were treated
with ticlopidine 250 mg twice daily or aspirin 650 mg twice
daily. Primary endpoints (stroke or death) were significantly
reduced in the ticlopidine patients. Although beneficial
for prevention of stroke, ticlopidine has not emerged as
first-line therapy because of its adverse effect profile.
Clopidogrel3 is associated with significantly fewer
hematologic effects and does not require any routine
hematologic monitoring. The combined event rate
reduction was significant at 8.7% (MI, stroke, cardiovascular death). Clopidogrel was better tolerated from a
gastrointestinal (GI) standpoint than ticlopidine and did
not require monitoring of complete blood cell counts
during therapy.
Dipyridamole and Stroke Prevention
Several studies of aspirin and dipyridamole have failed to
demonstrate any additional benefit from the combination
of these two drugs over aspirin alone. In the ESPS-213
study, a very low dose of aspirin (25 mg twice a day) and
a very high dose of dipyridamole (200 mg twice a day)
were administered. The primary endpoint of stroke and
death was reduced 13% (compared with placebo) with
low-dose aspirin alone, 15% with extended-release
dipyridamole alone, and 24% with both aspirin and
dipyridamole. For the endpoint of stroke, there was an
overall 23% RRR with aspirin and dipyridamole combination therapy. There was no significant decrease in the
endpoint of death or MI between the dipyridamole plus
aspirin and aspirin alone.
Warfarin
In the WARS trial,14 warfarin and aspirin were compared
for stroke prevention in the following subgroups: lacunar
mechanism, large vessel disease, large vessel carotid artery
disease (intracranial), and cryptogenic stroke. The twoyear event rates for primary endpoints of stroke or death
were 17.8% for warfarin and 16% for aspirin.
Other Trials
The MATCH trial (Management of Atherothrombosis
with Clopidogrel in High-Risk Patients) is now evaluating patients from high-risk groups defined as prior stroke,
prior MI, active angina, symptomatic peripheral artery
disease, or diabetes mellitus within the previous three
years. Other clinical trials are ongoing.
Changing Strategies in the Treatment of ACS
Intravenous Glycoprotein IIb/IIIa Inhibitors
The GP IIb/IIIa inhibitors may improve patient outcomes when conventional therapies have not succeeded.
Despite the effectiveness of aspirin in preventing cardiac
events, patients with ACS who undergo PCI continue to
challenge the limits of conventional therapy. At 30 days
post-PCI, patients treated with i.v. GP IIb/IIIa inhibitors
have event rates of up to 5%, meaning there is opportunity for improvement in terms of patient care. A metaanalysis by Roux and colleagues15 compiled data from all
the ACS trials. The results showed that high-risk patients
clearly benefit most, whereas low-risk patients had no
difference in event rate between conventional therapy and
GP IIb/IIIa inhibitors. Additional data from TIMI-1816
demonstrated that early PCI is clearly a superior strategy
and should be the standard of practice. High-risk patients
seem to benefit the most from early intervention, with a
composite event rate of 7.4% versus 10.5% in the
conventional therapy group (p = 0.009).
Oral GP IIb/IIIa Inhibitors
Chew and colleagues17 pooled data from the EXCITE,
OPUS, and SYMPHONY trials. The results of this
evaluation of 26,000 patients who had received oral GP
IIb/IIIa inhibitors showed an increase in mortality rates;
therefore, these agents are no longer being investigated.
Combination Therapy
Documentation of aspirin resistance provides additional
evidence supporting combination oral antiplatelet
therapy. Fewer hematologic adverse effects than
ticlopidine, plus a slight cost advantage, identify
clopidogrel as the agent of choice for high-risk patients,
including
■ ACS prior aspirin users,
■ Coronary artery disease patients in whom
revascularization is not an option,
■ Patients with multiple admissions for ACS/PCI,
■ Diabetic patients,
■ Patients with sirolimus- or taxane-eluting stents, and
■ CABG surgery patients.
Thebault et al.18 administered clopidogrel as a 300mg oral loading dose, followed by 75 mg daily, plus
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
51
aspirin and compared this regimen with aspirin alone in
healthy volunteers. Within six hours after the loading
dose, antiplatelet effects were almost equivalent to levels
after 10 days of therapy. The safety of combination
therapy with clopidogrel and aspirin, as well as the 300mg clopidogrel loading dose, was shown in the CLASSICS trial to be significantly better than with the combination of ticlopidine and aspirin.
Aspirin Resistance
Aspirin resistance is important because patients in whom
aspirin fails have worse clinical outcomes. A large study of
aspirin resistance at the University of Chicago19 evaluated
patients with TIA or ischemic stroke in an outpatient
setting. Approximately 75% achieved complete inhibition
of platelet function after treatment with a standard adult
dosage of aspirin 325 mg daily, 15% were considered
resistant to aspirin, and 10% had variable responses. Data
from the PRISM-PLUS trial of intravenous tirofiban in
ACS patients and from the ESSENCE trial, using lowmolecular-weight heparin, found similar results.
Conclusion
Antiplatelet agents including aspirin, i.v. GP IIb/IIIa
receptor antagonists, and ADP receptor blockers such as
clopidogrel are effective in the management of patients
with ACS including those undegoing PCI. Clopidogrel in
addition to standard therapy, including aspirin, significantly reduced the occurrence of the primary endpoint of
MI, stroke, or cardiovascular death at 12 months by
approximately 20%. A growing number of patients may
benefit from combined clopidogrel plus aspirin therapy.
Clopidogrel is now the preferred thienopyridine (over
ticlopidine).
References
1. Libby P. Current concepts of the pathogenesis of the acute
coronary syndromes. Circulation. 2001; 104:365-72.
2. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995; 92: 657-71.
3. Gent M. The CAPRIE trial: culmination of the preregistration
program for clopidogrel. Clopidogrel versus aspirin in patients at
risk of ischaemic events. Semin Thromb Hemost. 1999; 25 (Suppl
2):1-2.
4. Mehta SR, Yusuf S. The Clopidogrel in Unstable angina to
prevent Recurrent Events (CURE) trial programme; rationale,
design, and baseline characteristics including a meta-analysis of the
effects of thienopyridines in vascular disease. Eur Heart J. 2000;
21(24):2033-41.
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5. Bertrand ME, Rupprecht H-J, Urban P et al. Double-blind study
of the safety of clopidogrel with and without a loading dose in
combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting. Circulation. 2000;
102:624-9.
6. Armstrong PW, Fu Y, Chang WC et al. Acute coronary syndromes
in the GUSTO-IIb trial: prognostic insights and impact of
recurrent ischemia. The GUSTO-IIb Investigators. Circulation.
1998; 18:1860-8.
7. Gersh BJ, Chesdero JH, Braunwalk E et al. Coronary artery
bypass graft surgery after thombolytic therapy in the Thrombolysis
in Myocardial Infarction Trial, TIMI II. J Am Coll Cardiol. 1995;
2:395-402.
8. The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms
(PRISM-PLUS) Study Investigators. Inhibition of the platelet
glycoprotein IIb/IIIa receptor with tirofiban in unstable angina
and non-Q-wave myocardial infarction. N Engl J Med. 1998;
338:1488-97.
9. Mehta SR, Yusuf S, Peters RJ et al. Effects of pre-treatment with
clopidogrel and aspirin followed by long-term therapy in patients
undergoing percutaneous coronary intervention: the PCI-CURE
study. Lancet. 2001; 358:527-33.
10. Hirsch J, Dalen J, Guyatt G. The Sixth (2000) ACCP guidelines
for antithrombotic therapy for prevention and treatment of
thrombosis. American College of Chest Physicians. Chest. 2001;
119:1S-2S.
11. Antiplatelet Trialists’ Collaboration. Collaborative overview of
randomised trials of antiplatelet therapy-1: prevention of death,
myocardial infarction, and stroke by prolonged antiplatelet
therapy in various categories of patients. BMJ. 1994; 308:81-106.
12. Hass WK, Easton JD, Adams HP Jr et al. A randomized trial
comparing ticlopidine hydrochloride with aspirin for the
prevention of stroke in high-risk patients. Ticlopidine Aspirin
Stroke Study Group. N Engl J Med. 1989; 321:501-7.
13. Diener HC, Cunha L, Forbes C et al. European Stroke Prevention
Study 2. Dipyridamole and acetylsalicylic acid in the secondary
prevention of stroke. J Neurol Sci. 1996; 143:1-13.
14. Mohr JP, Thompson JL, Lazar RM et al. A comparison of warfarin
and aspirin for the prevention of recurrent ischemic stroke. N Engl
J Med. 2001; 345:1444-51.
15. Roux S, Christeller S, Ludin E. Effects of aspirin on coronary
reocclusion and recurrent ischemia after thrombolysis: a metaanalysis. J Am Coll Cardiol. 1992; 19:671-7.
16. TACTICS–TIMI 18 shows positive results of invasive approach.
Cardiovasc J S Afr. 2001; 12:58-9.
17. Chew DP, Molitemo DJ. A critical appraisal of platelet glycoprotein IIb/IIIa inhibition. J Am Coll Cardiol. 2000; 36:2026-35.
18. Thebault JJ, Kieffer G, Lowe GP et al. Repeated-dose pharmacodynamics of clopidogrel in healthy subjects. Semin Thromb
Hemost. 1999; 25(Supp2):9-14.
19. Helgason CM, Bolin KM, Holl JA et al. Development of aspirin
resistance in persons with previous ischemic stroke. Stroke. 1994;
25:2331-6.
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Confronting the Threat of Terrorism: Strategies for Emergency Preparedness
A symposium held December 2, 2001, in conjunction with the ASHP Midyear Clinical Meeting
Supported by an educational grant from GlaxoSmithKline
Health professionals must be able to recognize and
respond to bioterrorism attacks. This symposium, chaired
by James C. McAllister, III, M.S., Director of Pharmacy
at the University of North Carolina Hospitals in Chapel
Hill, addressed biological warfare and emotional and
physical preparation and response.
Agents of Bioterrorism
Rekha Murthy, M.D., Director of Hospital Epidemiology in the Division of Infectious Diseases at Cedars-Sinai
Medical Center in Los Angeles, reviewed the clinical
aspects of critical biological agents.
Bioterrorism is the use of biological agents (bacteria, viruses, and toxins) to intentionally produce illness or
intoxication. Biological agents are used as weapons
because they can cause mass casualties at low cost, they
are easy to obtain, and they are difficult to detect since
they are invisible, odorless, and tasteless. The delayed
onset of disease allows time for the perpetrator to escape.
Aerosol is the most likely route for exposure; others
include food or water; medicine, devices, or blood; and
fomites. With an aerosol, the aim is to create an invisible
cloud of particles 0.5–10 mm in diameter that can stay
suspended for long periods of time and can reach the
alveoli. Aerosols of most agents produce systemic diseases.
Bioterrorism victims display symptoms that overlap
with many nonspecific illnesses. Health care workers
should suspect bioterrorism if an unusual number of
patients show similar symptoms, there is an unusual
presentation of symptoms, patients have a similar set of
exposures, or a previously healthy individual has an
unexplained infectious disease.
The biological agents of greatest concern are
Bacillus anthracis (anthrax), the smallpox virus, Yersinia
pestis (plague), botulinum toxin, Francisella tularensis
(tularemia), and filoviruses and arenaviruses (viral
hemorrhagic fevers, or VHF). These agents are ideal
biological weapons: They are infectious via aerosol, can
infect susceptible civilian populations, cause high
morbidity and mortality, can be transmitted person-toperson (smallpox, plague, VHF), are difficult to diagnose
and treat, and have been previously developed for
biological warfare.
Anthrax
B. anthracis is a large, gram-positive, aerobic, sporeforming bacterium. The mechanism is essentially the
same for all three types of anthrax infection: cutaneous,
inhalation, and gastrointestinal (GI). Spores enter the
tissue, germinate, then multiply, releasing bacteria that
secrete damaging exotoxins. Through bloodstream
invasion, spores can spread to multiple sites, including the
meninges. The inhalation form is particularly damaging
because spores are transported to the lymph nodes, where
they cause hemorrhagic mediastinitis or lymphadenatis.
Spores can germinate and multiply in the lymph nodes
for 1 to 60 days. The toxins cause a hyperinflammatory
response that can lead to shock and death.
Inhalational Anthrax. To contract anthrax, a
person must inhale 8000–15,000 spores. The incubation
period is 1–60 days. Initial symptoms (2–5 days) are
fever, nonproductive cough, myalgia, and overwhelming
malaise. Terminal symptoms begin rapidly and include
very high fever, dyspnea, cyanosis, respiratory compromise, hemorrhagic mediastinitis and pleural effusion, and
rapid progression to shock and death. Historically, the
mortality rate is 90%. Mortality with the recent outbreak
was 45%, probably because of the early institution of new
types of antimicrobials.
Anthrax symptoms are like those of influenza;
differentiation is based on an abnormal chest x-ray with
mediastinal widening, infiltrates, and pleural effusion.
Cutaneous Anthrax. After 1–12 days of incubation, cutaneous anthrax presents with a papule that
progresses to a vesicle then rapidly to a pruritic and
edematous black eschar. Constitutional symptoms
include fever, malaise, headache, and regional adenopathy. Mortality is 20% without treatment and < 1% with
treatment. Patients with cutaneous anthrax on the head
and neck are treated as if they had been exposed to
aerosolized anthrax.
GI Anthrax. GI anthrax can occur after ingestion
of contaminated meat. The incubation period last from
hours up to seven days. Symptoms include fever, acute
gastroenteritis, vomiting, and bloody diarrhea. Patients
also develop intestinal eschar similar to cutaneous anthrax
lesions. The disease progresses to generalized toxemia
with a mortality rate of 50–100% despite treatment.
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53
Anthrax Therapy. The recommended regimen for
postexposure prophylaxis is as follows:
Adults: Ciprofloxacin 500 mg p.o. b.i.d.,
or doxycycline 100 mg p.o. b.i.d.
Children: Ciprofloxacin 10–15 mg/kg p.o. q 12 hr,
or doxycycline as follows:
>8 yr and 45 kg: 100mg b.i.d.
>8 yr and ≤45 kg: 2.2 mg/kg p.o. b.i.d.
≤8 yr: 2.2 mg/kg p.o. b.i.d.
This regimen is based on the assumption that the organism burden is low (monotherapy is acceptable), that there
are intracellular spores (treat for 60 days), and that late
reactivation is possible (penicillinase activity is not an issue).
The recommended regimen for clinical inhalational
anthrax is as follows:
Adults: Ciprofloxacin 400 mg i.v. q 12 hr initially,
then penicillin G 4 million units i.v. q 4 hr
or doxycycline 100 mg i.v. q 12 hr if strain
proven susceptible
Children: Ciprofloxacin 20–30 mg/kg i.v. daily
divided into two doses initially,
then ciprofloxacin 20–30 mg/kg i.v. daily
divided into two doses
or penicillin G 50,000 units/kg i.v. q 6 hr
in children <12 yr
4 million units i.v. q 4 hr in children >12 if
strain proven susceptible
Because of the mortality associated with inhalational anthrax, two or more concomitant antimicrobial
agents are recommended. Agents used in conjunction
with ciprofloxacin or doxycycline include rifampin,
vancomycin, imipenem, chloramphenicol, penicillin and
ampicillin, clindamycin, and clarithromycin. When
clinically improved, the patient can be switched to oral
therapy to complete the 60-day treatment cycle, with or
without rifampin. Although penicillin is active against
anthrax, β-lactamases are produced.
For cutaneous anthrax, ciprofloxacin and doxycycline are given as monotherapy for 60 days. Intravenous
therapy with a multidrug regimen is recommended for
cutaneous anthrax with signs of systemic involvement,
extensive edema, or lesions on the head and neck.
An anthrax vaccine is not available to the public but
has been used in the military. It is a three-dose regimen,
but some data shows that two doses may be effective.
Smallpox
Smallpox can be transmitted by airborne droplet nuclei or
by contact with the vesicles. It spreads through communities at varying rates. Airborne transmission requires close
contact (within 3 feet). Attack rates vary from 1.5% to
88% depending on severity of the index case, population
density, and susceptibility of the community.
Smallpox has an incubation period of 7–17 days.
54
The prodrome at 2–4 days includes an abrupt onset of
fever, malaise, headache, backache, vomiting, occasional
(15% of cases) delirium, and a transient erythematous
rash. Skin eruptions begin on the face, hands, and
forearms and spread to the lower extremities and then to
the trunk over seven days. The lesions follow a synchronous progression from macules to vesicles to pustules to
scabs. Lesions may appear on palms and soles. The
lesions, which can leave depressed depigmented scars, are
infectious until the scabs are completely separated.
Chickenpox (varicella) and smallpox (variola)
present with similar symptom. In contrast to smallpox,
chickenpox lesions start on the trunk and spread outward,
with varying stages seen on the body simultaneously.
Smallpox has a mortality rate of 30% in individuals
without immunity. The United States and many other
countries stopped vaccination in the 1970s; persons
vaccinated before 1972 are assumed to be susceptible.
Therapy consists of supportive care; there are no effective
antiviral agents available. Postexposure prophylaxis
(within four days) with the smallpox vaccine can attenuate or prevent the disease.
Plague
The most common form of plague is bubonic, but the
greatest threat of the use of plague in bioterrorism is
aerosolized transmission of pneumonic plague. After an
incubation period of one to three days, patients develop
an overwhelming pneumonia that rapidly progresses to
dyspnea, cyanosis, hemoptysis, and death from respiratory collapse and sepsis.
Pneumonic plague is treated with streptomycin,
gentamicin, and tetracycline. Those in close contact with
an infected person should receive prophylaxis with
tetracycline, doxycycline, or trimethoprim–sulfamethoxazole for seven days. Patients should be isolated until two
to three days of therapy have been completed. There is no
vaccine against plague.
Dealing with Panic and Stress
Wayne M. Sotile, Ph.D., Director of Psychological
Services at the Wake Forest University Cardiac Rehabilitation Program in Winston-Salem, North Carolina,
discussed posttraumatic stress reactions to terrorism and
ways of promoting resilience for our families, staff,
patients, and selves.
Feeling fear and compassion after the September
2001 terrorist attacks does not constitute posttraumatic
stress disorder (PTSD). Symptoms of true PTSD are
chronic intrusiveness for more than a month, avoidance
of life situations or activities, and hyperarousal, including
startle responses, impaired concentration, irritability, and
insomnia. If PTSD continues, individuals exhibit an
increased rate of spouse abuse, divorce, panic attack,
substance abuse, reclusiveness, depression, and suicide.
The best predictor of PTSD is neuroticism, defined as
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difficulty tolerating uncomfortable emotions and the
tendency to express and experience negative affect when
confronted with new events. Other predictors include a
previous psychiatric history, an internal locus of control
(belief that one can control things), and using rigid coping
techniques.
People’s usual first response to a horrific event is
disbelief and shock. The next set of reactions varies. Some
people feel violated and respond with anger and revenge.
Some respond with paralysis, feeling a lack of control and
waiting for the stressful event to disappear. Others move
toward resilience and end up with positive adaptation.
Resilience requires flexibility—recognizing that we
cannot control an event but can control our reaction to it.
Coping strategies can focus on eliminating the
problem or dealing with the consequences of the problem. Health care professionals need to promote emotionfocused coping: distracting ourselves from what is
bothering us, engaging in healthy pleasures, and soothing
ourselves through caring interactions with others.
To help each other cope with stress, we can meet
regularly with staff and family to discuss the problem,
and we can offer education in coping. We can provide
supportive communication—defining concerns, providing information, collaborating, empathizing, reassuring,
problem-solving (to give an illusion of control), and
offering a safe place for emotional release. We can
reinforce resilience by reminding people that they have
coped with difficulty before.
We must assure children that we will try to make their
lives safe. We should limit children’s exposure to traumatic
images and monitor our own reactions. We need to avoid
statements that may not be understood, allow children to
express their feelings, and maintain comforting rituals.
Consider referring someone to a mental health
specialist if you feel persistently uncomfortable with them,
the problem seems impossible or hopeless, the person
claims nothing helps, atypical behaviors and emotional
reasoning persist, or you doubt your ability to help.
To help others and to help ourselves, we should
Protect: Validate the problem without catastrophizing.
Direct: Encourage getting on with life.
Connect: Facilitate caring contact.
Detect: Who is struggling.
Select: Those who need referral and encourage it.
Pharmacy and Community Preparedness
Jim Jorgenson, M.S., Director of Pharmacy Services at
the University of Utah Hospitals and Clinics and Associate Dean of the Utah College of Pharmacy in Salt Lake
City, summarized government activities regarding
chemical and biological terrorism, reviewed pharmacy’s
role in planning for and responding to a chemical or
biological disaster, examined available assets and support,
and reviewed lessons learned.
Hospital Preparedness
Many hospitals have limited capacity to care for large
numbers of patients in mass disasters and to coordinate
with regional and federal agencies. Pharmacy should be a
key player in initiating hospital disaster preparedness.
Besides medication delivery, pharmacists can be involved
in planning, product selection, decisions about which
therapies are used, and providing information to physicians and patients.
Plans for responding to a disaster should encompass
three phases: immediate response capabilities, care delivery
after the first 72 hours, and extended care for mass casualties. Any current disaster plan should be assessed to determine its adequacy for dealing with a biological or
chemical disaster. The pharmacy should have a list of
antidotes, have sufficient written reference materials (in
case the Internet is unavailable), and know the quantities
of drugs on hand and available through the wholesaler.
Developing a Plan
A hospital or institutional disaster plan should include
input from a hospital disaster coordinator (if any),
emergency medicine, epidemiology, infection control,
laboratory, public relations, administration, and security.
Steps in developing a plan include
1. List potential agents to focus on in your institution
(e.g., anthrax, plague, smallpox, and nerve gas).
2. On the basis of the agents selected, identify the
antidotes and supportive measures you should have
available (e.g., antimicrobials, atropine, pralidoxime,
and supportive agents such as benzodiazepines).
3. Plan for medication distribution. If the necessary
agents have been identified, develop standing orders
and consider preprinting labels. Determine points of
access for drug distribution that are easy to reach and
can be secured. Plan for staff prophylaxis as well as
patient treatment. Prepare an alternative recordkeeping method in case the computer system is not
accessible. Determine your staffing needs. Consider
investing in automated counting equipment to speed
distribution. Have preprinted patient information on
hand. Coordinate with the security department if the
pharmacy will be locked down. Plan for a means of
communicating if landlines and cell phones are not
working. (Jorgensen’s pharmacy purchased two-way
radio systems for the staff.)
4. Plan inventory requirements on the basis of the
number of expected patients and speed of stock
replenishment. Include sufficient inventory for
hospital staff prophylaxis. Coordinate with other area
hospitals and community pharmacies. Wholesalers are
an important partner in your first response. Determine their estimated local inventory, how quickly you
can get it, and how quickly they can get inventory
from other locations. Do not stockpile.
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
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Inventory Resources
A key resource for individual facilities is the National
Pharmaceutical Stockpile (NPS), developed by the
Centers for Disease Control and Prevention (CDC) as
part of the Bioterrorism Preparedness and Response
Program within the 1999 Department of Health and
Human Services Bioterrorism Initiative.
The NPS is a two-part program. Part 1 includes
medication push packs stored in secret locations around
the country and deliverable to any U.S. site within 12
hours. The medications and supplies are prepacked and
not customizable.
Part 2 is the vendor-managed inventory. Through
the Department of Veterans Affairs, CDC has contracted
with vendors to set aside emergency medications and
supplies that could be used during an attack. If needed,
the NPS would notify vendors and have medications
delivered to individual facilities within 24–36 hours.
These orders are customizable to the incident.
FEMA teams can be mobilized and sent anywhere.
They bring significant amounts of medicine with them to
support first-response capabilities: antimicrobials, pain
medications, immunizations, i.v. fluids, antidotes, and
treatment for rescue dogs.
Disaster medical assistance teams, usually sponsored
by a local hospital, are available through the federal Office
of Emergency Management. Many of the 80 existing
teams include pharmacists.
Conclusion
It is essential to have a well-thought-out plan for chemical
or biological attacks. To develop a practical plan, establish
relationships in the community as well as the hospital.
Important community relations include fire, police, and
emergency medical personnel; the state health department; the media; the board of pharmacy; and poison
control centers.
To effectively handle a chemical or biological
disaster, you must plan realistically, increase training
efforts, practice your response, and learn from natural
events (e.g., hurricanes). Examine your current system for
inefficiencies and correct them. Take time to interact with
and learn from community planners and champions
within your organization.
What Pharmacy Managers Need To Know
Victor Perini, Director of Pharmacy at Methodist
Healthcare (MHMH) in Memphis, Tennessee, described
the role of the health-system pharmacist in emergency
preparedness. He also discussed hospital and local disaster
planning, pharmaceutical stockpiling, and scenarios
involving anthrax and nerve gas.
According to the American Society of HealthSystem Pharmacists,1 every pharmacy director should
become informed of local plans for emergency prepared56
ness, especially as related to pharmaceuticals; ensure that
hospital plans are coordinated with local, state, and
federal plans; ensure that appropriate stock is on hand;
and avoid stockpiling without regard to local plans. Every
health-system pharmacist should become informed of the
potential agents and the related diagnostic and treatment
issues, share scientific information related to pharmaceuticals with health professionals and the public, strongly
discourage stockpiling by individuals, and consider
volunteering in advance to assist in stockpile deployment.
Although large stockpiles are discouraged, the
pharmacy is responsible for having the right drug in the
right place at the right time. MHMH developed an
inventory plan based on probable types of attack and the
implementation capability of U.S. enemies.
The critical time frame for medication distribution:
0–12 hours:
Depend on hospital stockpile.
12–24 hours: Local stockpile will be deployed;
NPS will be mobilized.
24–48 hours: NPS will be deployed; distribution
will begin.
48–72 hours: NPS will be distributed.
To determine the optimal size for your institution’s
stockpile, first find out if there is a local stockpile, what it
contains, and how many patients it will treat. Other
useful information includes the location of the stockpile,
who will distribute it, where it will be distributed, and
whether it includes pediatric dosage forms. This information may be available through the local public health
department, emergency management agency, state health
department, FBI field office, CDC bioterrorism emergency number (770-488-7100), or U.S. Army Medical
Research Institute of Infectious Disease (301-619-2833).
MHMH personnel developed scenarios involving
the most common biological weapons and the drugs
needed to treat various levels of exposure to those
weapons, including prophylaxis for hospital staff. They
examined their inventories of the most commonly used
drugs—ciprofloxacin, doxycycline, gentamicin, tetracycline, rifampin, atropine, pralidoxime, and benzodiazepines—to determine the number of patient days of
treatment on hand. Then they created a stockpile to meet
the needs identified through their scenarios, taking into
account local and national stockpiles. They added the
necessary medications to their inventory and included
them in their monthly checklist of expiration dates. They
coordinated their inventory with other area hospitals and
community pharmacies, rotating medications whenever
possible to avoid stocking expired medication.
Reference
1. Draft statement on the role of health-system pharmacists in
counterterrorism. Bethesda, MD: American Society of HealthSystem Pharmacists; 2001 Nov 14.
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
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Maximizing Cardiovascular and Renal Outcomes in the Diabetic Patient
A dinner symposium held December 2, 2001, in conjunction with the ASHP Midyear Clinical Meeting
Supported by an educational grant from Merck
Persons with diabetes mellitus (DM) are at significantly
increased risk of developing cardiovascular and renal
disease. This symposium addressed the role of certain
antihypertensive and lipid-lowering therapies in reducing
the risk of diabetic complications. The speakers were
Robert D. Toto, M.D., Associate Professor of Medicine
at the University of Texas Southwestern Medical School
in Dallas; Thomas D. Giles, M.D., Professor of Medicine and Director of Cardiovascular Research and
Director of the Program in Heart Failure and Hypertension at Louisiana State University Health Sciences Center
in New Orleans, who also moderated; and Thomas
Force, M.D., Professor of Medicine at Tufts University
School of Medicine in Boston.
Hypertension, DM, and Renal Disease
Lowering blood pressure (BP), reducing proteinuria, and
inhibiting angiotensin II synthesis or binding to the type
1 receptor are all important treatment goals in patients
with hypertension, DM, and renal disease. The mechanism used to lower BP has an impact on renal outcomes.
Since angiotensin II receptor antagonists (ARBs) are
renoprotective in type 2 DM patients with early and late
nephropathy, these agents should be the antihypertensive
drugs of choice for such patients.
Modifiable Risk Factors
Modifiable risk factors for renal disease and cardiovascular
morbidity and mortality in type 2 DM patients include
hypertension, renal insufficiency, and proteinuria. Systolic
hypertension is a major predictor of end-stage renal
disease (ESRD), not only in DM.
Angiotensin II plays an important role in progression of renal failure. It increases pressure and causes
hypertension in the glomerular capillary; this damages
glomerular cells and causes proteinuria. Nonhemodynamic
effects include inflammation and fibrosis; these worsen
proteinuria and lead to renal failure.
In the early stages of DM, patients develop
microalbuminuria (urine albumin: creatinine ratio of 30–
300 mg albumin/g of creatinine). Type 2 DM patients
with microalbuminuria and a stable glomerular filtration
rate eventually become macroalbuminuric (>300 mg/g).
Hypertension, angiotensin II, and proteinuria are
interrelated in patients with progressing renal disease.
Angiotensin-converting-enzyme (ACE) inhibitors and
angiotensin II type 1 (AT1) receptor antagonists disrupt
the injury from this triad and improve outcomes.
Clinical Trials
A trial of the ACE inhibitor captopril in patients
with type 1 DM and overt nephropathy
(macroalbuminuria) showed that captopril protected
against deterioration of renal function.1 The trial lasted
four years, with another two years of follow-up. By the
end of follow-up, serum creatinine had doubled in 75%
of patients in the placebo group and 30% in the captopril
group. ESRD and death were lower in captopril group.
BP control between the groups was similar during the
trial. Captopril produced a marked reduction in proteinuria; proteinuria increased with conventional therapy.
Studies of ACE inhibitors in type 2 DM showed
various effects on renal function. ESRD was not included
as an outcome in those trials. Three studies published in
September 2001 addressed the effects of ARB inhibitors
in type 2 DM patients with nephropathy.2-4
IRMA 2. IRMA 22 was a multicenter, randomized,
double-blind, placebo-controlled trial comparing the AT1
receptor antagonist irbesartan 150 mg and 300 mg with
other proven antihypertensive medications (excluding
ACE inhibitors, ARBs, and dihydropyridine calciumchannel blockers) in 590 hypertensive patients with type
2 DM and microalbuminuria.
Development of overt nephropathy was reduced
significantly (by 70%) in the 300-mg irbesartan group,
but with a dose of 150 mg the reduction was 39% (not
statistically significant). This was a much greater risk
reduction than seen in prior studies of microalbuminuric
type 2 DM patients given ACE inhibitors.
RENAAL. The RENAAL trial3 was a study of 1513
patients with type 2 DM and nephropathy at 250 centers
in 29 countries. The study hypothesis was that long-term
treatment with losartan (an ARB) versus placebo (alone
or in combination with conventional non-ACE-inhibitor
therapy) in type 2 DM patients with nephropathy will
increase the time to first event and decrease the incidence
of a composite endpoint of doubling of the baseline
serum creatinine concentration, ESRD, or death. Subjects
were 31–70 years of age, with a urine albumin:creatinine
ratio >300 µg/g and serum creatinine concentration of
1.3–3 µg/dL.
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
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Patients were maintained on conventional antihypertensive therapy (excluding ACE inhibitors or other
ARBs) for six weeks, then randomized to receive either
losartan 50 mg q.d. or placebo. Conventional therapy was
added to both treatment arms to achieve BP less than
140/90 mm Hg. The losartan dose was titrated up to 100
mg if BP of 140/90 was not achieved. After an average
follow-up of 3.4 years, there was a 16% reduction in the
losartan group compared with placebo for the primary
composite outcome of doubling of baseline serum
creatinine, ESRD, or death, using intent-to-treat analysis.
When the components of the composite endpoints
were evaluated (ESRD, doubling of baseline serum
creatinine concentration, and death), researchers found
that ESRD was reduced by 28% with losartan. There was
a 32% risk reduction in first hospitalization for heart
failure. Losartan also significantly reduced proteinuria
(35%). BP was reduced in both the losartan and the
placebo group. Therefore, the benefits of losartan are
largely independent of BP control. Even in patients
whose serum creatinine doubled, progression of renal
disease was delayed by losartan.
IDNT. The Irbesartan in Diabetic Nephropathy
Trial (IDNT)4 was a multinational, double-blind,
randomized comparison of placebo (conventional
therapy) with amlodipine or irbesartan 75, 150, or 300
mg q.d. in 1715 hypertensive patients with type 2 DM.
The primary endpoint was the same composite of
doubling of baseline serum creatinine, ESRD, or death
used in the RENAAL trial, with a target BP below 135/
85 mm Hg. After three years, there was a 20% relative
risk reduction in the primary composite endpoint with
irbesartan versus placebo and 23% relative risk reduction
with irbesartan versus amlodipine.
Irbesartan and amlodipine exhibited equivalent BPlowering effects, but irbesartan caused a greater reduction
in albuminuria. The researchers concluded that irbesartan
is renoprotective in hypertensive, proteinuric type 2 DM
patients beyond BP control, compared with both
amlodipine and conventional therapy.
The combined results from 3818 patients in these
three trials demonstrated that lowering BP coupled with
reducing proteinuria and blockade of angiotensin II at the
type 1 receptor improved renal and cardiovascular outcomes
in both microalbuminuric and macroalbuminuric
patients with type 2 DM. This evidence that early and
late intervention using regimens containing ARBs is
renoprotective beyond BP lowering in type 2 DM has
important implications for limiting the progression of
diabetic renal disease.
Conclusion
Lowering BP, reducing proteinuria, and inhibiting
angiotensin II synthesis or binding to the type 1 receptor
are all important treatment goals in many progressive
renal diseases. Clinical trials have shown that ACE
58
inhibitors reduce cardiac diseases but have little effect on
renal disease. Clinical evidence demonstrates that ARBs
are renoprotective in type 2 DM patients with early and
late nephropathy and should be the antihypertensive
drugs of choice for such patients.
A Cardiovascular Disease
Cardiovascular and renal risk factors in DM include
hypertension, proteinuria, hyperglycemia, dyslipidemia,
obesity, smoking, physical inactivity, and ethnicity. DM
causes a twofold to fourfold increase in cardiovascular risk
and is the leading cause of nontraumatic lower-extremity
amputations and new cases of ESRD and blindness.
Cardiovascular Complications and Risk Factors
Cardiovascular complications include macrovascular
disease, microvascular disease, and cardiomyopathy. DM
patients have increased vulnerability to hypertensive
injury because of risk factor clustering, disturbed BP
regulation with increased vascular load, disturbed vascular
performance with decreased vessel compliance, synergy
between BP and hyperglycemia, and decreased microvascular protection through impaired blood flow autoregulation. Accelerated atherosclerosis leads to cardiovascular
disease and ultimately to 80% of diabetic mortality. DM
patients with no history of myocardial infarction (MI) are
as likely to have a future MI as people without DM who
have already had an MI. Preexisting cardiovascular disease
is present in 50% of those newly diagnosed with type 2
DM. Even DM patients with ESRD receiving dialysis are
more likely to die from cardiac disease than other causes.
Systolic BP is a major source of cardiovascular risk
in DM. With a systolic pressure of 120 mm Hg, a DM
patient is three times as likely to suffer morbidity or
mortality as a person without DM. Proteinuria is an
independent and a combined risk factor for mortality in
type 2 DM. DM patients with elevated systolic BP and
proteinuria have two to three times the mortality risk
associated with having only one of those risk factors.
DM patients have an increased risk of heart failure,
MI mortality, coronary heart disease (CHD), and
reinfarction. DM is linked to vascular disease through the
renin–angiotensin–aldosterone system (RAAS). Hyperglycemia activates this system, causing multiple adverse
effects in the endothelial cell. Additional adverse cardiovascular effects are mediated by both glucose and the
products of RAAS activation.
When stimulated by hyperglycemia, RAAS activation has the following effects:
■ Oxygen free radicals are produced that can deplete the
body of the nitric oxide (NO) or endothelium-derived
relaxation factor required to relax arterial smooth
muscle. The result is vasoconstriction and atherosclerosis leading to hypertension.
■ Proteins are glycosylated to form advanced glyco-
A M E R I C A N S O C I E T Y O F H E A LT H - S Y S T E M P H A R M AC I S T S
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sylation end products, some of which can stimulate
macrophages and monocytes to produce cytokines
that cause vasoconstriction.
■ The amount of plasminogen activation inhibitor 1
is increased, leading to a prothrombotic state.
■ Protein kinase C is stimulated, contributing to a biochemical cascade that activates vascular remodeling.
The traditional RAAS cascade starts with angiotensinogen, which is converted by renin to angiotensin I,
then converted by ACE to angiotensin II. Angiotensin II
can then follow one of two pathways: AT1 receptor stimulation or aldosterone secretion. AT1 receptor stimulation
causes vasoconstriction, cell growth, sympathetic activation, and sodium and fluid retention. Aldosterone is one
of the chief mediators of connective tissue remodeling.
Oxidative stress may be produced by auto-oxidation of
sugars and unsaturated lipids. It causes damage by
inhibiting NO and producing oxygen free radicals.
Serum and tissue ACE concentrations are
dysregulated in DM patients, which affects cardiovascular
disease through changes in peptide degradation.
Pharmacologic Treatment
Lowering hemoglobin A1c (HbA1c) reduces the risk of DM
complications, but BP control is more effective in controlling microvascular outcomes than tight glucose control. The
HOT trial5 showed that even small BP reductions in DM
patients lead to significant improvements in the incidence
of MI, stroke, and cardiovascular mortality.
In the HOPE6 trial, ACE inhibitor treatment led to
dramatic reductions in the risk of MI, stroke, and cardiovascular death in both DM and nondiabetic patients.
Even the appearance of new DM was reduced, suggesting
that ACE inhibition may affect DM development.
These trials indicate that ACE inhibitors lower the
risk of cardiovascular complications in DM patients. The
combination of an ACE inhibitor with a calcium-channel
blocker is more beneficial than either one alone.
RAAS system activation plays a major role in mediating DM-induced vascular injury via hemodynamic and
nonhemodynamic events that result in atherosclerosis and
glomerulosclerosis. Angiotensin II appears to be a principal
mediator of the resulting vascular injury. The most effective
blockade of angiotensin II occurs at the AT1 receptor.
Decreasing Cardiovascular Risk through
Lipid Management
The most effective intervention in a DM patient is
aggressive treatment of the lipid abnormalities that
accompany DM. Men and women with DM are at
increased risk for cardiovascular complications, which are
the leading cause of death in DM patients. Observational
studies suggest that a DM patient without clinical
evidence of cardiovascular disease has the same risk of
having a cardiovascular event within seven years as a
nondiabetic who has already suffered a cardiac event.
The third Adult Treatment Panel (ATP III) of the
National Cholesterol Education Program (NCEP)
classified DM as a cardiovascular risk equivalent. ATP III
defined metabolic syndrome, which indicates increased
cardiovascular risk, as a composite of five factors: abdominal obesity, serum triglyceride concentration ≥150 mg/
dL, high-density-lipoprotein (HDL) cholesterol <40 mg/
dL for men and <50 mg/dL for women, BP >130/85 mm
Hg, and fasting serum glucose concentration >110 mg/
dL. Physicians are encouraged to treat diabetic patients as
if they have preexisting cardiovascular disease.
DM is defined by a fasting serum glucose concentration ≥126 mg/dL. The normal glucose concentration is
≤110 mg/dL. Patients with fasting blood glucose concentrations between 110 and 126 mg/dL are considered to
have impaired glucose tolerance. When fasting blood
glucose levels rise from normal to impaired, even a small
increase in HbA1c corresponds to a much greater risk of
cardiovascular disease.
Clinical Trials
UKPDS. UKPDS7 examined the contribution of
intensive glucose control in DM patients. Over 10 years
of observation, the median HbA1c was 7% for patients in
the intensive control group versus 7.9% in the group
using conventional therapy. Patients in the intensive
control group had reductions in the risk of any DMrelated endpoint (12%), DM-related deaths (10%), MI
(16%), and microvascular disease (25%). The risk of
stroke increased by 11%. This study determined that the
primary risk factors for development of coronary artery
disease in patients with type 2 DM are increased LDL
cholesterol, decreased HDL cholesterol, hyperglycemia,
increased systolic BP, and smoking.
Scandinavian Simvastatin Survival Study. The
Scandinavian Simvastatin Survival Study (4S)8 changed
the approach to DM treatment. This study was designed
to evaluate the mortality benefits of simvastatin in
patients with established CHD. The DM subgroup of
patients treated with simvastatin demonstrated a risk
reduction of 55% for major CHD events and 37% for
any atherosclerotic event. Total mortality in DM patients
was reduced by 43%. Dramatic reductions were also
observed in patients with impaired glucose tolerance.
Evidence from this study indicated that use of a
hydroxymethylglutaryl-CoA reductase inhibitor, or statin,
to lower LDL cholesterol led to significantly improved
cardiovascular outcomes in DM patients.
AFCAPS/TexCAPS. The AFCAPS/TexCAPS
study9 demonstrated that statins are useful for primary
prevention of cardiovascular disease. In this study,
lovastatin was compared with placebo for prevention of
the first major coronary event in men and women
without clinically evident atherosclerotic cardiovascular
disease and with average LDL and total cholesterol levels
MIDYEAR CLINICAL MEETING SYMPOSIUM HIGHLIGHTS
59
and below-average HDL cholesterol levels. After five
years, diabetic study subjects with no previous evidence of
cardiovascular disease had a greater than 40% reduction
in the risk of first acute major coronary event. Significant
risk reductions were also seen in nondiabetic subjects.
MRC/BHF Heart Protection Study. Results from
the MRC/BHF Heart Protection Study were scheduled
for publication in spring 2002. Researchers in this British
study evaluated over 20,000 individuals at high risk for
CHD because of prior MI or other CHD, occlusive
disease of noncoronary arteries, or DM or treated
hypertension in the absence of known MI or vascular
disease. The study targeted patient groups in whom there
was little prior direct evidence of benefit, including
women, patients older than 70, persons with DM, those
with noncoronary vascular disease, and those with average
or below average cholesterol levels. All patients were
required to have a total cholesterol concentration >135
mg/dL. Patients were randomized to receive either
simvastatin or placebo. Half of the study subjects received
antioxidant vitamins, which did not have an impact on
deaths, MIs, strokes, or other vascular outcomes in any of
the groups studied.
Study subjects who took simvastatin during this
five-year trial were 24% less likely to have a cardiovascular
event than those taking placebo. Risk reductions were
seen for CHD, stroke, and revascularization. Patients
with a history of cerebrovascular and peripheral vascular
disease benefited, as did those with a history of previous
MI. The benefits increased with the duration of
simvastatin therapy. There was also a trend toward
reduction of nonvascular deaths, with no increase in
noncardiac morbidity and mortality because of aggressive
lowering of LDL cholesterol levels. The risk of hospitalization for worsening angina also decreased.
Benefits were similar in men and women. Older
patients (>70 years of age) had better results than younger
patients. Patients who entered the study with a high risk
for CHD but a low baseline LDL cholesterol concentration (<100 mg/dL) had a reduced risk of heart attack,
stroke, or death if they were in the simvastatin group.
Rates of vascular deaths, neoplasms, and myalgias were no
higher in the simvastatin group than with placebo.
Even allowing for noncompliance, the researchers
concluded that simvastatin 40 mg daily safely reduces the
risk of heart attack, stroke, or revascularization by at least
one third. Irrespective of cholesterol level, age, sex, or
other treatments, five years of statin treatment typically
prevents these major vascular events in about 100 of every
1000 patients with previous MI, 80 of every 1000
patients with other CHD, 70 of every 1000 DM patients
age 40 and over, 70 of every 1000 patients who have had
a previous stroke, and 70 of every 1000 patients with
other peripheral vascular disease. The investigators found
no evidence that lowering cholesterol adversely affected
the rates of nonvascular causes of death, cancers, or
60
hemorrhagic strokes.
The American Diabetes Association and APT III
both now state that lowering LDL cholesterol is the
primary goal in treating patients with diabetic
dyslipidemia. Secondary strategies should address HDL
cholesterol and triglycerides. Some clinicians use combination therapy with statins plus niacin or a fibrate to
concomitantly affect these three components of
dyslipidemia. This combination, while potentially
effective, leads to increased cost, complexity of therapy,
potential interactions, and adverse effects and may not be
necessary; statins may also lower triglycerides. The ability
of statins to lower LDL cholesterol has been shown to
predict their ability to lower triglycerides.
Conclusion
Recent primary and secondary prevention studies have
shown dramatic reductions in cardiovascular events in
DM patients treated with statins. These reductions have
been at least as great as those achieved in nondiabetic
patients. Results from these studies prompted the ATP III
to set goals for lipid-lowering therapy in DM patients,
even in the absence of obvious vascular disease, that are
the same as those for nondiabetic patients with preexisting coronary or peripheral vascular disease.
References
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2. Parving HH, Lehnert H, Brochner-Mortensen J et al. The effect of
irbesartan on the development of diabetic nephropathy in patients
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3. Brenner BM, Cooper ME, de Zeeuw D et al. Effects of losartan on
renal and cardiovascular outcomes in patients with type 2 diabetes
and nephropathy. N Engl J Med. 2001; 345:861-9.
4. Lewis EJ, Hunsicker LG, Clarke WR et al. Renoprotective effect
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8. Pyorala K, Pederson TR, Kjekshus J et al. Cholesterol lowering
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coronary heart disease. A subgroup analysis of the Scandinavian
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9. Downs JR, Clearfield M, Weis S et al Primary prevention of acute
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