Primary Prevention Statins in Older Patients: The Good News or the Bad News First?

James N. Kirkpatrick, MD; Gwen M. Bernacki, MD, MHSA

Disclosures

J Am Coll Cardiol. 2020;76(1):28-30. 

It is old news that older adults constitute an understudied population in clinical trials. Primary prevention statin trials are no exception because most have included few patients age >70 years. Moreover, despite much commentary and tangential evidence, there are no trials that have expressly examined effects of statins on noncardiovascular outcomes in older adults. Now, here's the good news: the paper by Zhou et al.[1] in this issue of the Journal offers a noteworthy investigation that heralds the importance of upcoming randomized clinical trials that address this topic.

Zhou et al.[1] performed a thorough secondary analysis of the ASPREE (Aspirin in Reducing Events in the Elderly) trial, a primary prevention study of use of aspirin among a representative (albeit predominantly white) sample of community-dwelling older adults age ≥70 years during 4.7 years in Australia and the United States. Zhou et al.[1] used inverse probability weighting in an observational cohort design to examine the traditional outcomes of overall mortality and cardiovascular morbidity and mortality, as well as outcomes of particular interest in older populations, namely, whether baseline statin use was beneficial in terms of disability-free survival. This was defined in this study as a composite of all-cause mortality, dementia, or persistent physical disability as measured by Katz Activities of Daily Living. Unlike the ASPREE parent trial that showed no difference in disability-free survival, increased overall mortality, and an increase in bleeding in the aspirin group,[2,3] Zhou et al.[1] found that baseline statin use was associated with a lower risk of persistent physical disability and adverse cardiovascular outcomes, despite a lack of association with disability-free survival.

It is also relatively old news that statins reduce adverse cardiovascular outcomes, but it remains unclear whether this reduction applies to older adults. Furthermore, whether this decline accompanies improvements in disability-free survival, dementia, or persistent disability remains an open question. Based upon patients' values, goals, and preferences, cardiovascular mortality (and even overall mortality) may not be the most important outcome for some older adults. Disability-free survival is seemingly an appropriate primary endpoint, yet improvements in disability alone could be big news for those who prioritize quality of life in their later years. Notably, Zhou et al.[1] reported "neutral news" on the association between statin use and dementia, as well as statin use and all-cause mortality, which confirmed the story line of previous studies.

This paper included excellent background and discussion sections that summarized the past decade's literature on the topic in a well-conceived, well-written piece. In addition, Zhou et al.[1] appropriately headlined their methodological rigor. The investigators eliminated outliers and displayed weighted cumulative incidence, taking into account competing risks. Furthermore, they accounted for multiple events that occurred per participant. They also subsequently conducted an exploratory analysis "in which participants were restricted to those who did not experience MACE prior to developing physical disabilities and compared these results with those of the main analysis." The investigators also used cancer as a negative outcome (because of no clear evidence of association between statins and cancer in older adults with underlying risk cardiovascular factors) and compared their results with older adults with cancer; they found no significant differences. They also conducted sensitivity analyses between use of statins and randomized aspirin on study outcomes (except for a loss of statistical significance for association of fatal cardiovascular disease, these analyses did not significantly alter results). In another exploratory analysis, the investigators noted that association of statin use with physical disability was lost when they restricted subjects who had no history of major adverse cardiovascular events at the time of developing a physical disability. The investigators rightly acknowledged that omitting cholesterol (low-density lipoprotein cholesterol) could lead to inadequate confounding adjustment, but they accounted for this confounding in their statistical modeling. In short, Zhou et al.[1] are to be commended for their efforts to avoid generating "fake news."

Still, there were limitations. Few study participants were age 85 years or older, and most participants were white. As the investigators noted, they were also unable to account for statin intolerance. Furthermore, this was an observational cohort study, and a direct causal link between statins and improvements in disability could not be definitively drawn from this analysis. Nonetheless, this study provides compelling background to editorialize on the importance of completing randomized controlled trials that examine primary prevention statin use among older adults. This leads to more good news and bad news.

The temporarily halted (due to COVID-19) PREVENTABLE (Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults; NCT04262206) trial (National Heart, Lung, and Blood Institute grant U19AG065188) aims to enroll 20,000 community-dwelling patients age ≥75 years without clinical evidence of cardiovascular disease at 100 U.S. sites. Participants will be randomized to atorvastatin 40 mg daily, or placebo. The trial will use a pragmatic design to identify outcomes (including dementia and physical disability as primary outcomes) over 5 years via electronic health records. Additional specific outcome measures include a cognitive function screen and assessments of physical function performed by telephone calls. In addition, an Australian randomized, placebo-controlled trial called STAREE (A Clinical Trial of Statin Therapy for Reducing Events in the Elderly; NCT02099123) will examine whether atorvastatin 40 mg daily will improve disability-free survival in 18,000 community-dwelling patients age ≥70 years. Primary outcome measures include the time from randomization to death or development of dementia (as measured by cognitive function tests), development of disability, and time to a major fatal or nonfatal cardiovascular event.

These trials will provide robust data on the cardiovascular and noncardiovascular benefits of statins in older adults, which is good news. Both trials will provide newsworthy data on outcomes relevant to older adults, and we can expect these trials to affect forthcoming guidelines on statin use among older adults. The bad news is that results will not be available for years (unless trials are stopped early), and enrollment for most clinical trials is currently paused in light of the COVID-19 pandemic. COVID-19 risks aside, a good number of our older patients will have succumbed to death or disability well before trial results are available.

The idea of waiting is not entirely appealing to clinical cardiovascular teams, patients, and their caregivers. Important data, such as that produced by Zhou et al.,[1] may tip the scales for many. Yet, in these complicated times, there are difficulties with quick judgments and publishing definitive statements based on secondary analyses. As always, clinical judgment must weigh the good news with the bad (and the confusing) to delineate individualized, patient-centered plans that take into consideration patients' goals, values, preferences, and social determinants of health. For example, for a frail 75-year-old with statin-induced myalgias, no consistent caregiver, and a list of medications that rivals a Tolstoy novel for length, the lack of definitive data on dementia and disability may warrant statin avoidance or statin deprescribing.[4] In contrast, a robust, cognitively intact 90-year-old who fears dementia and disability like the plague may decide these observational data favor statin initiation. In the meantime, participation in clinical trials like PREVENTABLE and STAREE, once they restart, offer the best prospect for more good news in the future.

The paper by Zhou et al.[1] has made a laudable contribution to the potential primary prevention of statin use in older adults and should not be relegated to the middle or end of a newscast. Rather, the much needed attention it brings to primary prevention of adverse outcomes in older adults deserves airtime, and in illustrating the importance of future randomized trials, it importantly calls us all to stay tuned.

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