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Time for a New Approach to Studying Older People with Ischemic Heart Disease

The challenge of medical management in older adults with ischemic heart disease (IHD) in the setting of limited evidence was highlighted several decades ago, and arguably there has been only limited progress since that time. In contemporary practice, this challenge is becoming even more urgent with the aging of the U.S. population. The challenge is that evidence based on younger populations may have limited applicability to older adults. Older adults with IHD are distinctly different from younger ones. For example, because of biological changes, including poor renal clearance and lower muscle mass, pharmacokinetics and pharmacodynamics are different. In addition, other phenotypic characteristics of aging (geriatric impairments) such as cognitive impairment and frailty may affect the potential benefits or harms of a given medication. Also, polypharmacy is common, and there is high potential for drug–drug interactions that can lead to unexpected consequences. Moreover, the phenotype of atherosclerosis itself may be different, with more extensive coronary calcification and greater likelihood of multivessel disease. Therefore, in current practice, the risk of therapies for IHD in older adults—for example, bleeding with antithrombotic agents—must be balanced with the potential benefits in the setting of very limited evidence. Multiple investigations have found that older adults are often excluded, explicitly or implicitly, from cardiovascular clinical trials. For example, it was found in 2011 that 25% of heart failure trials had an explicit upper age limit. Another study that analyzed late-breaking clinical trials at the 2011 Scientific Sessions of the American Heart Association found that eight of 22 (36%) did not include older adults and that mean age in the remaining trials was aged 54 to 66. The study by Bourgeois and colleagues provides contemporary evidence that this problem is not improving. The authors performed a search of all drug trials for IHD registered at ClinicalTrials.gov from January 2006 to January 2016. Eight hundred thirty-nine trials met their inclusion criteria; these trials most commonly studied antithrombotic agents (N = 355), lipid-modifying agents (N = 132), and antihypertensive medications (N = 67). The main finding was that 53% of these studies explicitly excluded older adults. In trials in which age data were available, the mean age was 62.7; the estimated proportion of subjects aged 65 and older was 42.5% and of those aged 75 and older was 12.3%. The authors conclude by calling for a reexamination of trial practices to ensure adequate inclusion of older adults in future studies. The study has several strengths. First, the authors focus on a problem of significant clinical importance given demographic trends in the next several decades. They defined “elderly” as aged 65 and older, although many geriatricians and investigators now define elderly as aged 75 and older. Using 75 and older would have resulted in an even greater underrepresentation of older adults. Second, they used a rigorous methodology, including efforts to contact investigators when trial results were not readily available. Third, their registry-based approach used publicly available data that can potentially be adapted for future surveillance efforts. Most of the trials that Bourgeois and colleagues analyzed were relatively small (77% with <500 subjects) and performed at single centers (60%). Because the trial (rather than the enrolled participants) was the unit of analysis, these small trials influenced the primary outcome to the same degree as larger studies. Phase 1 trials were included, and these were more likely to exclude older adults than other phases. By convention, Phase 1 trials often involve small cohorts of young, healthy volunteers to determine drug tolerability and characterize pharmacokinetics. Conversely, the majority of Phase 3 trials analyzed did not have an upper age cutoff. Nevertheless, it seems clear that the older population is underrepresented. The authors highlight an important problem that has persisted despite guidance from the Food and Drug Administration (FDA) more than 25 years ago that, “for drugs likely to be used in the elderly, older patients should be included in clinical trials in reasonable numbers.” Because this study and others have defined the problem of underrepresentation of older adults so well, we believe it is time for practical solutions. Some of these efforts are underway. For example, pragmatic trials aim to enroll participants with as few exclusions as possible, to maximize external validity. The Patient-Centered Outcomes Research Institute–funded trial comparing lowwith high-dose aspirin for secondary prevention in IHD, Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness, is one such effort; the study aims to enroll 20,000 participants, with no upper age limit. Nevertheless, simply enrolling representative numbers of older adults will not solve the problem. The inclusion of older adults may seem like an advance—but we will learn too little if they only represent an underpowered This editorial comments on the article by Bourgeois et al.