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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 Financial Disclosure Information NONE 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.