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Developing the Evidence to
Guide Medication Prescribing
to Older Adults
Jerry H. Gurwitz, M.D
Chief, Division of Geriatric Medicine
University of Massachusetts Medical School
Worcester, Massachusetts
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call from Dr. Pitts
To: Gurwitz, Jerry
Dr. Gurwitz,
Dr Pitts called this morning to see if
your talk at Medical Grand Rounds
tomorrow will be the same presentation
from the 70’s or if it has been updated.
It is much easier to write upon a
disease than upon a remedy. The
former is in the hands of nature and
a faithful observer with an eye of
tolerable judgement cannot fail to
delineate a likeness. The latter will
ever be subject to the whim, the
inaccuracies and the blunder of
mankind.
William Withering (1741-1799)
The Limits of Our Knowledge
AGS 2012 Beers Criteria
The Exclusion of Older Adults from
Participation in Acute Coronary
Syndrome (ACS) Clinical Trials
• 1960-1991: 61% of ACS trials
excluded older adults
• 1991-2000: 40% of ACS trials
excluded older adults
• 2007-2009: 30% of ACS trials
excluded older adults
• Average age of subjects has changed
very little.
Gurwitz et al. JAMA 1992; Lee et al. JAMA 2001; Dodd et al. JAGS 2011.
“With great age comes great
comorbidity.”
Fred Masoudi
The Exclusion of Older Adults with
Multimorbidity
• The most common chronic condition
that older adults experience is
multimorbidity.
• 2 of every 3 older adults have MCCs.
• 12% of Medicare beneficiaries with 6 of
more chronic conditions account for
43% of expenditures.
• Of 190 clinical trials that explicitly
considered MCCs in selection process,
94% excluded these patients.
Jadad et al. JAMA 2011.
“In theory, there is no difference
between theory and practice, but
in practice there is.”
Yogi Berra
Voltage Drop in Eligibility of Older
Persons in Clinical Trials
• Most older persons with heart failure do
not meet enrollment criteria for RCTs
• SOLVD (Studies of Left Ventricular
Dysfunction)
• Data from the National Heart Failure
Project (CMS-sponsored)
• Of 20,388 older patients hospitalized
with heart failure less than one in 5 met
SOLVD enrollment criteria.
Masoudi et al. Am Heart J 2003.
Outcomes in Clinical Trials
• 2007 (top-tier journals): Only a quarter
of clinical trials included outcomes of
relevance to older adults: health
status, physical function, and quality of
life.
• The perils of relying on surrogate
outcomes (e.g., milrinone,
rosiglitazone, others...)
Zulman et al. JGIM 2011; Svensson et al. JAMA Intern Med 2013.
Outcomes That Really Matter
Cross-Disease or Universal Health Outcomes
• Universal health outcomes define the
most important clinical effects of
chronic conditions and their treatments
–Symptom burden
–Functional capacity
–Self-rated health
–Survival
Tinetti et al. JAGS 2011.
Effects of Benefits and Harms on
Willingness to Take Medicine for Primary
Cardiovascular Disease Prevention
• 48-69% of patients were unwilling or
uncertain about taking medication with
average benefit causing mild fatigue,
nausea, or fuzzy thinking.
• Only 3% were willing to take medication
with adverse effects severe enough to
affect functioning.
Fried et al. Arch Intern Med 2011.
Adverse Drug Events (ADEs) are
very common
• 1,900,000 ADEs per year in nursing home
setting (40% preventable)
– 86,000 life threatening or fatal ADEs (70%
preventable)
• 1,900,000 ADEs per year among Medicare
enrollees in the ambulatory setting (28%
preventable)
– 180,000 life threatening or fatal (50% preventable)
Gurwitz et al. JAMA 2003; Gurwitz et al. Am J Med 2005.
Error Stage for Preventable
ADEs
Category
Percentage
Ordering
59%
Dispensing
5%
Administration
13%
Monitoring
80%
Drug Categories
Preventable events
Warfarin
12%
Atypical antipsych
12%
Loop diuretics
10%
Benzos (intermediate) 9%
Opioids
8%
ACE inhibitors
8%
Other antidepressants 7%
Antiplatelets
7%
Insulin
5%
Laxatives
5%
Involvement of Beers Criteria
Drugs in ADEs
• Beers criteria
drugs rarely
involved.
• Budnitz study:
Medication use
leading to ER visits
in older adults
<4%
96%
Budnitz et al. Ann Intern Med 2007.
1989 FDA Guideline for the Study of
Drugs Likely to be Used in the Elderly
• Patients included in clinical studies
should reflect the population that will
receive the drug when it is marketed.
• There is no good basis for the exclusion
of patients on the basis of advanced age
alone.
• If a drug will be used in conditions
where specific concomitant diseases are
likely to be present, an attempt should
be made to include in the treatment
population patients with other diseases.
European Medicines Agency’s
Geriatric Medicines Strategy
• Older people are the main users of
medications – not just a special population.
• Study populations should be representative of
the population across entire the age range.
• Chronologic age alone is inadequate for
characterizing study population.
• Excessive “confounder cleansing” should be
avoided.
• Study outcomes should appropriate.
Cerreta et al. NEJM 2012.
European Medicines Agency’s
Geriatric Medicines Strategy
• “We expect the age distribution of patients to
be representative in studies presented for
market authorization.”
• Post-marketing studies are required to
consolidate knowledge regarding risk of harm.
Cerreta et al. NEJM 2012.
The FDA Sentinel System
• Major initiative to improve the safety of
medical products
• Pilot program called Mini-Sentinel
• Goal is to develop capability for actively
monitoring the safety of approved medical
products using electronic health information in
claims systems, inpatient and outpatient
medical records, and patient registries.
• Network of Data Partners
• 100 million patients
Behrman et al. NEJM 2011.
Dabigatran and Bleeding
• Large number of post-marketing reports of
bleeding with dabigatran
• Mini-Sentinel evaluation of gastrointestinal
and intracranial hemorrhage risk
• Assessment suggested that bleeding rates are
not higher than those with warfarin
• Rates of bleeding are consistent with those
found in RCT (RE-LY)
Southworth et al. NEJM 2013.
Developing the Evidence
We need a multifaceted approach!
•
•
•
•
Eligibility criteria
Outcome measures
Sticks & carrots
Reducing risk
• Postmarketing surveillance
• Medical errors
• Patient-centered approach
Zulman et al. JGIM 2011; Gurwitz and Goldberg. Arch Intern Med 2011.