Download File

The Ohio State University 1
Question 5A: Prepare a report that evaluates the overall quality of the dossier. That is, how
well did the manufacturers follow the AMCP Format for Formulary Submissions Version 2.1?
Briefly discuss what was done well, what content was missing, and where the instructions were
not followed.
The dossier assembled for prasugrel was completed in August 2009 following the AMCP
Format for Formulary Submissions Version 2.1. Overall, the dossier is fairly adequate in
following the format with some exceptions. The product information is clear and concise but
lacks information on off-label indications, market share information, and pharmacogenomic
evidence. It includes clinical studies on the disease state, minor economic studies and one costeffectiveness economic study but lacks other key studies such as systematic reviews and metaanalyses. Most studies did not abide by the page limitations set up by the AMCP Format for
Formulary Submissions Version 2. One cost-effectiveness study is included but does not follow
the format suggestion of placing it under modeling report with the BIM. The overall product
cost was included but not clearly stated. In general the dossier allows for adequate analysis of
prasugrel’s strengths and weaknesses but could be improved by including more concise clinical
information.
1. Product Information
REQUESTED BY VERSION 2.1
COMPLETE INFORMATION IN DOSSIER
Section 1.1
a. Generic, brand name and therapeutic class Yes
b. Dosage forms, strengths, package sizes
Includes forms and strengths but not package sizes
c. NDC number
Yes
d. Copy of product labeling/literature
Yes. This can be found in the Appendix
e. The AWP and WAC cost per unit size
Yes
f. AHFS or other drug classification
Yes
g. FDA Approved and other Studied
Yes
Indications
h. Current or pending off-label indications
No. No current data available.
i. Pharmacology
Yes
The Ohio State University 2
j. Pharmacokinetics/Pharmacodynamics
Yes
k. Contraindications
Yes
l. Warnings/Precautions/Adverse Effects
Yes
m. Interactions
Partial. Drug/drug information was included. The
manufacturer did not include drug/food and drug/disease
interactions.
n. Dosing and Administration
Yes
o. Access
Yes
p. Current or anticipated market share
No. Not available at this time
information
q. Co-Prescribed/Concomitant Therapies
Yes
r. Comparison with primary comparator
Yes
products
REQUESTED BY VERSION 2.1
COMPLETE INFORMATION IN DOSSIER
Section 1.2
1.2.1 Disease Description
Description of specific patient subpopulations No. The dossier includes how different subpopulations
in which the drug is expected to be most
react to the disease state but not where prasugrel is
effective (Markers, diagnostic or generic
expected to be most effective.
criteria to identify)
a. Epidemiology and relevant risk factors
Yes
b. Pathophysiology
Yes
c. Clinical presentation
Yes
d. Societal and/or economic impact
Yes
1.2.2 Approaches to Treatment
a. Approaches to treatment – principal
Yes
options/practice patterns
b. Description of alternative treatment options Yes
(both drug and non-drug)
c. Place and anticipated use of therapy in
Yes
The Ohio State University 3
treatment
d. Proposed ancillary disease or care
Yes
management intervention strategies that are
intended to accompany the product at launch
e. Relevant treatment guidelines from national Yes
or international bodies
f. Expected outcomes of therapy
Yes
g. Other key assumptions and their rationale
Yes
Section 1.3 Evidence for Pharmacogenomic
No. The manufacturer did not include any data
Tests and Drugs
2. Supporting Clinical and Economical Information
The prasugrel dossier includes three summaries of key clinical studies: one safety trial,
one efficacy and safety trial, and one efficacy comparison to clopidogrel. All three trials were
double blind, randomized trials and included all of the required items listed in the format. The
dossier also includes five outcome studies and economic supporting data: four retrospective cost
studies and one cost-effectiveness study. No studies regarding off-label uses or prospective
effectiveness were included. Systematic reviews, meta-analyses and prospective studies
examining health status or quality of life were not included. Each study had an evidence table
spreadsheet that included both negative and positive findings. All but one of the studies exceeds
the maximum pages allowed.
3. Modeling Report
The manufacturer included one budget impact model (BIM). The model includes an
overview, parameters, analyses and results of the model. The payer perspective is included for
both the managed care organization and the hospital. However, no results on discounting were
included; the manufacturer stated that ongoing clinical trials are assessing whether discounting is
associated with negative clinical outcomes. The model includes assumptions associated with the
findings but does not account for multiple aspects of care such as consequences and indirect
costs to the patient.
The Ohio State University 4
A cost-effectiveness model is not included in the modeling report but the costeffectiveness of prasugrel was compared to the cost-effectiveness of clopidogrel in section 2 of
the dossier. This economic study only includes prasugrel and clopidogrel as treatment options;
other therapies and clinical pathways were not discussed when considering cost-effectiveness.
4. Product Value and Overall Cost
The manufacturer summarizes all clinical and economic information presented in
pervious sections. The section includes key information on prasugrel and several evidence tables
that summarize the drug’s therapeutic efficacy and economic evaluation. A summary of
pharmacoeconomic studies is included but it did not clearly state the value of the product. The
unit daily cost of prasugrel as well as total absolute savings is clearly stated in the projected
impact on budget section.
5. Supporting Information
Relevant clinical and pharmacoeconomic references are made in each section and a
model is included with the dossier.
The Ohio State University 5
\ Question 5B: Analyze the manufacturers’ value proposition for prasugrel (Effient®). Does the
clinical and economic data presented in the dossier and model support the manufacturer’s value
arguments? Has the manufacturer excluded any information that would refute their value
argument? Include an analysis of the economic model, key studies not included and any
potentially misleading information contained in the dossier.
The Effient ® (prasugrel) dossier provides extensive clinical evidence which concluded a
decrease in ACS rehospitalization events. Furthermore, the economic model provides a thorough
account of potential costs to Pitt Street Health. The evaluation of the dossier provides sufficient
evidence through numerous clinical trials for recommending prasugrel in certain patient
populations.
Clinical Evidence Evaluation
The overall value proposition of prasugrel for patients with acute coronary syndrome
(ACS) who are to be managed with percutaneous coronary intervention (PCI) is not directly
stated in the dossier. Through interpretation of the dossier’s clinical data, the overall product
value can be argued to reduce the rate of combined endpoints of cardiovascular death, nonfatal
myocardial infarction (MI) or nonfatal stroke in comparison to clopidogrel.
The evaluation of the published clinical trials were graded using the Delfini Validity &
Usability Grading Scale for Summarizing the Evidence for Interventions and is presented below.
Table 1. Evidence based on Effient® Dossier
Reference
Study
Limitations
Strengths
Parameters
 LTA requires precise
 Sample size large
Wiviott, et
RCT, DB
al. 20071
multicenter,
sample conditions for
enough to detect
double-
processing and a
90% power
dummy,
significant portion did  Multicenter
active
not meet standards
 Similar baseline
comparator-
and were excluded
characteristics
controlled,
2-phase
 Exclusions potentially
reduced the power of
among
participants
Delfini Clinically
Grade
Useful?
B
Yes
The Ohio State University 6
crossover
study
the study
 No washout period
 Frequent endpoint
measurements and
between MD
various laboratory
treatments
analyses were
 Funding by Eli Lilly
used.
Wiviott et
Multicenter,
 77% of subjects male
 Large sample size
al. 20052
RCT,
 No statistical power
with 80% power
parallel-
to detect clinically
in order to detect
group, ITT,
meaningful
significant
DB, active
differences in
differences in
comparator-
efficacy endpoints
safety outcomes
controlled
trial
A
Yes
A
Yes
 Reduced power for
primary safety
endpoint due to low
bleeding rates
 Short study period,
one clopidogel arm,
funding from Eli Lilly
Wiviott et
RCT, DB,
al. 20073
double
 Funding from Eli
Lilly
 Sample size
adequate for 90%
dummy,
 Did not use highest
parallel-
possible dose of
 Length of study
group with
clopidogrel
 Randomized
active
comparator,
 Mostly white males
power
 Double-blinded
participated in study
ITT,
multicenter
RCT = randomized controlled trial, DB = double blind, PC = placebo controlled, ITT = intent to
treat
LTA= Light Transmission Aggregometry
MD = maintenance dose
The Ohio State University 7
The evidence presented in the clinical trials of the dossier provides strong evidence
sufficient for use in making health care decisions. The conducted studies were all large, double
bind, randomized control trials. Each trial also had a power of at least 80% to have the ability to
detect clinically significant differences in either safety or efficacy outcomes.
Although all clinical trials were thought to be of some use in making clinical decisions,
there were a few limitations. The TRITON-TIMI 38 trial used standard doses of clopidogrel
whereas physicians have adopted using higher loading and maintenance doses. While this is a
limitation to TRITON-TIMI 38, PRINCIPLE-TIMI 44 addressed this limitation and proved the
high loading and maintenance doses of clopidogrel are not superior in efficacy to standard doses
of prasugrel. The JUMBO-TIMI 26 trial was predominately male, which was viewed as a
limitation, but the occurrence of an ACS event is more common among the male population.
The manufacturer of prasugrel, Eli Lily, conducted all studies.
Summary of pharmacoeconomic evidence:
In order for prasugrel to be economical for Pitt Street Health, a decrease in ACS-related
rehospitalization would be essential. Most economic outcome studies present in the dossier
consist of costs of ACS events in a managed care setting. The only trial that took into account
the cost-effectiveness of prasugrel came from the results from the TRITON-TIMI 38 trial. The
clinical trial endpoints are index hospitalization resource use and cost, follow-up, life expectancy
projections, and cost-effectiveness analysis versus clopidogrel.
The trial found the index hospitalization cost to not differ between treatment groups.4
Follow-up costs for rehospitalization were estimated to be $221/patient lower with prasugrel than
clopidogrel (P=0.20). Life expectancy due to cardiovascular death, nonfatal MI or nonfatal
stroke was found to be higher for prasugrel as well. The overall cost-effectiveness analysis
conducted found treatment with prasugrel to decrease overall costs due to lower rate of
rehospitalization involving PCI, making prasugrel the economically dominant treatment
strategy.4
Additional ongoing studies are being conducted to determine whether discontinuing
treatment with a thienopyridine after one year is associated with negative clinical outcomes.
When this data becomes available, reevaluation will be necessary to determine the effect on
outcomes. Also, it is projected that clopidogrel will lose patent at the end of 2011 and therefore
The Ohio State University 8
needs to be taken into consideration when analyzing the economical effectiveness of prasugrel.
Since only one trial for cost-effectiveness has been presented, additional cost-effectiveness and
cost-benefit trials are needed.
Economic Evidence Evaluation of prasugrel
The manufacturer developed a budget impact model (BIM) for a managed care
organization (MCO) or hospital. The model was designed to estimate the impact of including
prasugrel on the formulary in addition to clopidogrel. The model design is flexible and helpful
within the context of the Pitt Street formulary. The BIM can be used to assess prasugrel’s
potential budget impact of Pitt Street using MCO-specific and hospital-specific demographics
and costs.
The model concludes addition of prasugrel to the formulary for people hospitalized with
a diagnosis of ACS and undergoing a PCI reduces the total annual costs for Pitt Street.5
Furthermore, adding prasugrel to the formulary would decrease the number of disease-related
events, but would increase the number of bleeding events.
The model anticipates the use of prasugrel in treatment of patients hospitalized with ACS
prior to undergoing PCI and will receive a once-daily maintenance dose thereafter. This place
in therapy is supported by clinical trial data presented in the dossier and analysis of class review
of thienopyridine agents. The BIM allows adjustments to provide estimates for relevant
populations who are to be treated with a thienopyridine drug. Clinical trials are currently being
conducted to determine treatment with a thienopyridine after one year to be beneficial. With
this assumption, patients took the thienopyridine for up to 15 months after PCI.5
The limitations of the model can be found in some of the assumptions made. The model
assumes a 100% adherence rate of clopidogrel and prasugrel. The BIM only accounts for
prasugrel and clopidogrel and therefore lacks consideration of other thienopyridine agents.
Additionally, it does not take into account other medications required to prevent an additional
ACS event from occurring. The BIM uses clinical outcomes per patient characteristics observed
in TRITON TIMI 38 trial, which was 75% male with a median age of 61 years. A major
weakness of the model is that it did not thoroughly take into account clopidogrel going generic at
the end of 2011 and how this will impact the MCO and hospital.
The Ohio State University 9
Overall, the economic information provided for the treatment of ACS managed with PCI
was thorough and could be applied to Pitt Street Health for formulary decision.
References
1. Wiviott S, Trenk D, Frelinger A, O’Donoghue M, Neumann FJ, Michelson AD, Angiolillo
DJ, Hod H, Montalescot G, Miller D, Jakubowski JA, Cairns R, Murphy SA, McCabe CH,
Antman EM, Braunwald E. Prasugrel compared with high loading- and maintenance – dose
clopidogrel in patients with planned percutaneous coronary intervention: The prasugrel in
comparison to clopidogrel for inhibition of platelet activation and aggregation thrombolysis
in myocardial infarction 44 trial. Circulation. 2007 Dec 3;116:2923-32.
2. Wiviott S, Antman EM, Winters KJ, Weerakkody G, Murphy S, Behounek BD, Carney RJ,
Lazzam C, McKay RG, McCabe CH, Braunwald E. Randomized comparison of prasugrel
(CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in
percutaneous coronary intervention: Results of the joint utilization of medications to block
platelets optimally (JUMBO)-TIMI 26 trial. Circulation. 2005 Jun 20;111:3366-73.
3. Wiviott S, Braunwald E, McCabe C, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ,
Ardissino D, De Servi S, Murphy S, Riesmeyer J, Weerakkody G, Gibson C, Antman E.
Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007
Nov 15;357(20):2001-15.
4. Mahoney KM, Wang K, Arnold SV, et al. Cost-effectivess of prasugrel vs. clopidogrel in
patients with acute coronary syndromes and planned percutaneous coronary intervention:
results from the trial to assess improvement in therapeutic outcomes by optimizing platelet
inhibition with prasugrel thrombolysis in myocardial infarction TRITON-TIMI-38.
Circulation. 2010;121:71-79.
5. Effient® (prasugrel) Dossier. Eli Lilly and Daiichi-Sankyo. Prepared using AMCP format for
formulary submissions, version 2.1.
The Ohio State University 10
Question 5C: How does the recent emergence of non-responders to antiplatelet therapy (both
those determined by platelet function testing and genetic testing) play into an appropriate
formulary decision?
Currently, the recommended treatment for acute coronary syndromes (ACS) is dual
antiplatelet therapy with aspirin and Plavix® (clopidogrel). However, a major concern in recent
years concerning this standard of care is the recent emergence of non-responders to clopidogrel.
Since clopidogrel is a prodrug, it requires biotransformation to its active metabolite via the
cytochrome P-450 (CYP) enzymes, most notably by CYP3A4, 3A5, 2C9, 2B6 and 2C19.1,2
CYP2C19 is the major enzyme involved in clopidogrel nonresponsiveness, and the *2, *3, *4
and *5 alleles have all been known to cause decreased metabolism of clopidogrel and are termed
loss-of-function alleles. The *2 allele is most frequent in Caucasians (13%), African Americans
(18%) and Asians (30%).2 It has been suggested that patients with these loss-of-function alleles
have reduced conversion of clopidogrel to its active metabolite and therefore have an increased
risk of cardiovascular events.
Nonresponsiveness to clopidogrel was first reported in a prospective study that evaluated
clopidogrel responsiveness in 60 consecutive patients with ST-segment-elevation acute
myocardial infarction (STEMI) within six hours of onset. All 60 patients received primary
percutaneous coronary intervention (PCI) and were treated with 300 mg of clopidogrel followed
by 75mg/day for the next 3 months. There was a 35-60% reduction in ex-vivo platelet
aggregation, and no significant inhibition of platelets as detected by the thrombin-related
activating peptide (TRAP). These results suggest that clopidogrel is less effective in the
presence of high-thrombin, which is characteristic of ACS. While this study has many
limitations, such as being observational with a small sample size, it has led to further
investigation regarding variable response to clopidogrel.3
In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet
Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38, 1,477
patients provided a DNA sample that allowed for further investigation in their response to
clopidogrel versus prasugrel. Primary efficacy outcomes of the trial include a composite of
death from cardiovascular causes, MI, or stroke. Secondary outcomes include definite or
probable stent thrombosis. Of the 1,477 patients who gave a DNA sample, 34% had at least one
CYP2C19 reduced-function allele. When comparing the carriers to non-carriers, carriers of the
The Ohio State University 11
reduced function allele had a relative reduction of 32.4% in exposure to the active metabolite of
clopidogrel. These results confer strong evidence between CYP genetic variations and reduced
platelet inhibition which theoretically leads to an increased risk for recurrent ischemic events in
patients taking clopidogrel. While this study does demonstrate that patients with CYP2C19 lossof-function alleles have less exposure to active metabolite, it does not prove that these patients
are at an increased risk of recurrent MI.1
In a meta-analysis including 23 studies, carriers of the *2 loss-of-function allele exhibited
a significant increase (42%) in the rate of major adverse cardiovascular events (MACE), the
primary endpoint. Furthermore, there was a three to six fold increase in the risk of definite or
probable stent thrombosis in carriers versus non-carriers. In addition, CYP2C19 gene variant
showed an increase in all-cause and cardiovascular mortality, leading to a 20% increase risk for
death. The meta-analysis concluded that among patients that carry the loss-of-function allele,
those with a high baseline cardiovascular risk are at the highest risk for experiencing MACE
when treated with clopidogrel. Many of the studies evaluated were observational and came from
prospective or retrospective registries. Further limitations were observed, leading to
questionable confidence in the reported results.4
In addition to CYP2C19, clopidogrel is also subject to efflux from P-glycoprotein
encoded by ABCB1. Polymorphisms in ABCB1, most notably 3435C→T, affect drug transport
and efficacy and, when combined with variants in CYP2C19, lead to increased risk in
cardiovascular outcomes in patients treated with clopidogrel or prasugrel. The patient population
studied came from the TRITON-TIMI 38 trial and were divided into four groups based on their
ABCB1 3435C→T genotype and CYP2C19 status. When considering both ABCB1 and
CYP2C19, variants demonstrated independent increased risk of cardiovascular death, MI or
stroke. While these results strongly suggest an increased risk of MACE in patients with genetics
variants, patients studied were largely Caucasian and healthy. Furthermore, there was restricted
power to detect association between ABCB1 variants and outcomes reported.5
A prospective cohort study looked at 259 young patients who survived one MI. Those
possessing the *2 allele compared with wild-type homozygotes displayed a significant increase
in the primary endpoint, including death from any cause, non-fatal stroke or MI and stent
thrombosis. Any patient who possessed two loss-of-function alleles of CYP2C19 or ABCB1
variant allele were at the highest risk for developing the primary outcome. However, this study
The Ohio State University 12
was not randomized and genotyping was only performed for the *2 and *1 alleles. While
genotyping is currently available, it is very costly and requires the use of specialty laboratory
equipment. Furthermore, it requires 6-10 days for processing; this would significantly delay the
administration of clopidogrel and in order for clopidogrel to be effective it should be started
immediately. In comparison to prasugrel, clopidogrel requires two steps for activation compared
to prasugrel’s one. Studies have displayed little susceptibility for drug interactions in patients
taking prasugrel.2
Another meta-analysis looked at the results of loss-of-function alleles in the CURE study
as well as the ACTIVE A study. In the CURE study, results show clopidogrel’s effect was
consistent in all subgroups for primary and secondary endpoints between carriers of loss-offunction alleles and non-carriers. In addition, major bleeding rates were also similar. In the
ACTIVE A study, results were consistent in all subgroups regardless of functional allele carrier
status. This led to the conclusion that efficacy and safety of clopidogrel is not altered by
CYP2C19 loss-of-function allele status. This study had limitations which include a small
population, limited power, and mostly Latin American or European patient involvement.6
As a result of the data presented here, the Food and Drug Administration (FDA) mandate
that clopidogrel include a black box warning in its label to notify prescribers and patients about
the possible reduced effectiveness.6 While it is apparent that patients taking clopidogrel are
exposed to less active metabolite, there are no randomized trials to confirm that this affects
clinical outcomes. Because prasugrel is not activated in the same manner as clopidogrel, it is not
subject to the same possibility of decreased effectiveness, leading to the question if it should be
used over clopidogrel. Because of the lack of data proving that clopidogrel users suffer an
increase in MACE resulting from less active metabolite generation, we cannot rule out its use in
practice. It does, however, support the addition of a more consistent and stronger antiplatelet
agent to formulary in cases where high platelet inhibition is necessary.
In conclusion, when determining which therapy is more appropriate for patients, a riskbenefit analysis is necessary. In low to medium risk patients, the use of clopidogrel may be
acceptable because a lower platelet inhibition level may be all that is required to see effect. If it
is known that the patient has a loss-of-function allele, this would be taken into account as another
risk factor for recurrent ischemic events. If, however, the patient is considered high risk,
prasugrel may be more appropriate since higher levels of platelet inhibition are necessary.
The Ohio State University 13
References
1. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt, JT, Walker JR, Antman EM,
Macias W, Braunwald E, Sabatine MS. Cytochrome P-450 polymorphisms and response to
clopidogrel. N Engl J Med. 2009 Jan 22;360(4):354-62.
2. Momary KM, Dorsch MP, Bates ER. Genetic causes of clopidogrel nonresponsiveness:
which ones really count? Pharmacotherapy. 2010;30(3):265-74.
3. Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, Novikov I, Pres
H, Savion N, Varon D, Hod H. Clopidogrel resistance is associated with increased risk of
recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation.
2004 Jun 7;109:3171-75.
4. Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barthelemy O, Cayla G, Beygui
F, Montalescot G. Cardiovascular risk in clopidogrel-treated patients according to
cytochrome P450*2 loss-of-function allele or proton pump inhibitor coadministration. J Am
Coll Cardiol. 2010 July 6;56(2):134-43.
5. Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM, Braunwald E,
Sabatine MS. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after
treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic
analysis. Lancet. 2010 Oct 16;376:1312-19.
6. Pare G, Mehta SR, Yusuf S, Phil D, Anand SS, Connolly SJ, Hirsh J, Simonsen K, Bhatt DL,
Fox KAA, Eikelboom JW. Effects of CYP2C19 genotype on outcomes of clopidogrel
treatment. N Engl J Med. 2010 Oct 28;363(18):1704-14.
The Ohio State University 14
Question D: What consideration, if any, should be given to patients who are taking Effient or
other antiplatelet agents and concomitantly taking a PPI?
Proton Pump Inhibitors (PPIs) are often administered to patients in combination with
thienopyridines to help reduce the risk of gastrointestinal bleeding after Acute Coronary
Syndrome (ACS) or percutaneous coronary intervention (PCI). The role of thienopyridine-class
antiplatelet drugs such as Plavix® (clopidogrel) and Effient® (prasugrel) are well established in
the treatment of ACS by various clinical trials and meta-analyses, and as a result, their use has
increased exponentially in recent times. Clopidogrel is currently the second-best-selling drug in
the world.1 However, its range of potential interactions with other drugs is yet to be fully
explored because of its fast introduction to the market.2 Several studies have shown that PPIs,
such as omeprazole, lansoprazole etc., can diminish the antiplatelet effects of clopidogrel, and
questions have been raised regarding the safety of using these drugs in combination.
It is necessary to look at what ways the use of PPIs interfere with the antiplatelet effects
and clinical benefits of thienopyridines. One hypothesis is that absorption of thienopyridines is
increased in an acidic environment, and therefore the use of PPIs could diminish drug
absorption.3 The second and more controversial concern is the possible competitive inhibition
by PPIs of the cytochrome P450 isoenzyme CYP2C19, which is responsible for metabolic
activation of clopidogrel. Genetic polymorphisms of the CYP2C19 allele are associated with an
increased risk of adverse effects for patients treated with clopidogrel, thereby supporting the
concept that diminished CYP2C19 activity can have a detrimental effect on outcomes. PPIs are
thought to be converted by CYP2C19 as well, which reduces bioavailability of the enzyme. The
resulting effect would be a reduced antiplatelet activity and the emergence of clopidogrel
resistance in patients.4
Many experiments have been conducted to test this second hypothesis regarding
CYP2C19 activity. Cohort studies from the U.S. and Canada provided data on the clinical
effectiveness of clopidogrel in combination with PPIs.5,6 Both studies demonstrate that
concomitant therapy of clopidogrel with PPIs is associated with increased risk of
rehospitalization for ACS.7 In response to these findings, both the U.S. Food and Drug
Administration (FDA) and the European Medicines Agency advised physicians to re-evaluate the
need for treatment with a PPI in patients taking clopidogrel and discouraging their combined use
without a compelling indication.
The Ohio State University 15
However, at this time scarce data is available that shows a definitive interaction between
PPI use and the clinical benefit of clopidogrel. Because there is no data from randomized trials,
there is controversy that patients prescribed a PPI and thienopyridine have high risk baseline
characteristics compared to patients not in need of a PPI. This leads to the question of whether
PPIs are decreasing the effectiveness of clopidogrel or if these patients on PPIs are more likely to
develop ischemic events regardless. More limitations arise in the fact that risks have been
overestimated due to incomplete control of confounding variables and biased patient selection.
Other studies such as the one Gilard et. al performed indicated only a partial reduction in the
antiplatelet action of clopidogrel and concluded that even if a drug-drug interaction was
occurring, clopidogrel still provides some benefit.8
More recent studies have been conducted on a larger scale and take into account
limitations from past studies. O’Donoghue et al. analyzed a subgroup of the TRITON-TIMI 38
trial and the PRINCIPLE-TIMI 44 trial, concluding that the concurrent use of PPIs did not
attenuate the clinical efficacy of clopidogrel.3 Preliminary results of a randomized double-blind
trial of the PPI omeprazole versus placebo in patients taking clopidogrel plus aspirin showed no
evidence for clinically relevant adverse cardiovascular interactions with PPIs.9 In the TRITON
TIMI-38 trial, the primary endpoint was the composite of a myocardial infarction (MI) or
cardiovascular death. Approximately 13,600 patients with ACS were randomly assigned to
prasugrel or clopidogrel. Thirty-three percent of these patients were on a PPI at randomization,
and the result show that no association exists between PPI use and risk of the primary endpoints
mentioned for patients treated with clopidogrel or prasugrel.3
The PRINCIPLE-TIMI 44 consisted of 201 patients undergoing elective PCI that were
randomly assigned to prasugrel or high-dose clopidogrel. Results for this trial suggest mean
inhibition of platelet aggregation was lower for patients on a PPI than for those not on a PPI after
a 600 mg clopidogrel loading dose. A more modest difference was seen with and without a PPI
after a 60 mg loading dose of prasugrel. It is important to note that prasugrel showed more
potent and consistent inhibition of platelet aggregation than high-dose clopidogrel, and almost no
patients experienced significantly less platelet inhibition when combining prasugrel with a PPI.
Despite the observed attenuation of the in-vitro antiplatelet effects of clopidogrel and prasugrel
in patients treated with a PPI, there were no clear indications of the use of a PPI to be associated
with an increased risk of adverse clinical outcomes. Modest inhibition of antiplatelet effects of
The Ohio State University 16
either clopidogrel or prasugrel are likely to have been insufficient to translate into an increased
risk of adverse outcomes.3 Finally, higher risk of adverse outcomes was not observed for
patients on PPIs with diminished CYP2C19 activity caused by a reduced-function allele. This
refutes the hypothesis that reduced activity of the cytochrome enzyme contributes to increased
risk of ACS or other cardiovascular outcomes.
In conclusion, there is no clear evidence that taking thienopyridines with PPIs results in
decrease efficacy of the antiplatelet agents. Physicians and pharmacists should keep in mind the
interaction possibly exists and monitor patients appropriately; however, no evidence suggests
that clopidogrel cannot be used with PPIs effectively. While older studies detected concomitant
use of PPIs with clopidogrel lead to increased risk of MI or other cardiovascular adverse
outcomes, they failed to take into account an inherently biased patient selection. Most patients
taking PPIs with antiplatelet drugs have a higher likelihood to develop cardiovascular disorders
to begin with compared to those not taking PPIs. Data provided by recent studies like those
mentioned above demonstrate that the diminished function of CYP2C19 activity does not
associate with increased adverse outcomes for patients on PPIs, and that while antiplatelet
activities of clopidogrel and prasugrel are attenuated, this does not affect clinical outcomes. On
the part of the health-care practitioner, a risk-benefit analysis is necessary to choose which
antiplatelet therapy is more appropriate in the setting of a PPI. Because prasugrel has been
proven to be more efficacious in the presence of a PPI, it may be more appropriate for higher risk
patients. However, in low risk patients that do not require as much platelet inhibition,
clopidogrel may be a suitable alternative.
References
1. IMS Health [internet]. Top ten global pharmaceutical products. IMS Health Inc.; c2010.
Updated periodically.
2. Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular outcomes and mortality
in patients using clopidogrel with proton pump inhibitors after percutaneous coronary
intervention or acute coronary syndrome. Circulation. 2009 Nov 23;120:2322-29.
3. O’Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y,
Michelson AD, Hautvast RW, Ver Lee PN, Close SL, Shen L, Mega JL, Sabatine MS,
Wiviott SD. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with
The Ohio State University 17
or without a proton-pump inhibitor: an analysis of two randomized trials. Lancet. 2009 Sep
1;374:989-97.
4. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence.
Journal of the American College of Cardiology. 2005;45:1157-64.
5. Ho PM, Maddox TM, Wang L et al. Risk of adverse outcomes associated with concomitant
use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA.
2009 Jul 1;301:937-44.
6. Juurlink DN, Gomes T, Ko DT et al. A population based study of the drug interaction
between proton pump inhibitors and clopidogrel. CMAJ. 2009 Mar 31;180:713-8.
7. Boxel OS, Oijen MGH, Hagenaars MP, Smout AJPM, Siersema PD. Cardiovascular and
gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large
Dutch cohort study. American Journal of Gastroenterology. 2010 Aug 24;105:2430-36.
8. Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, Mansourati J, Mottier D,
Abgrall JF, Boschat J. Influence of omeprazole on the antiplatelet action of clopidogrel
associated with aspirin. Journal of the American College of Cardiology. 2008;51:256-60.
9. Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular
events and mortality in patients receiving clopidogrel. Alimentary Pharmacology and
Therapeutics. 2010 Apr 31;31:810-23.