Pragmatic evaluation of events and benefits of lipid lowering in older adults (PREVENTABLE): Trial design and rationale

Abstract

Whether initiation of statins could increase survival free of dementia and disability in adults aged ≥75 years is unknown. PREVENTABLE, a double‐blind, placebo‐controlled randomized pragmatic clinical trial, will compare high‐intensity statin therapy (atorvastatin 40 mg) with placebo in 20,000 community‐dwelling adults aged ≥75 years without cardiovascular disease, disability, or dementia at baseline. Exclusion criteria include statin use in the prior year or for >5 years and inability to take a statin. Potential participants are identified using computable phenotypes derived from the electronic health record and local referrals from the community. Participants will undergo baseline cognitive testing, with physical testing and a blinded lipid panel if feasible. Cognitive testing and disability screening will be conducted annually. Multiple data sources will be queried for cardiovascular events, dementia, and disability; survival is site‐reported and supplemented by a National Death Index search. The primary outcome is survival free of new dementia or persisting disability. Co‐secondary outcomes are a composite of cardiovascular death, hospitalization for unstable angina or myocardial infarction, heart failure, stroke, or coronary revascularization; and a composite of mild cognitive impairment or dementia. Ancillary studies will offer mechanistic insights into the effects of statins on key outcomes. Biorepository samples are obtained and stored for future study. These results will inform the benefit of statins for increasing survival free of dementia and disability among older adults. This is a pioneering pragmatic study testing important questions with low participant burden to align with the needs of the growing population of older adults.

New statin use, mortality, and first cardiovascular events in older US Veterans by frailty status

“…This may also explain, in part, why our study showed a greater reduction in mortality risk compared to CVD events, similar to prior work by our group 7 . The ongoing STAtins in Reducing Events in the Elderly (STAREE) trial in Australia and Pragmatic Evaluation of Events and Benefits of Lipid‐Lowering in Older Adults (PREVENTABLE) trial in the United States, both primary prevention trials of atorvastatin vs placebo for adults ≥70 and 75 respectively, will definitively elucidate the role of statins for primary prevention among older adults, including those with frailty 31,32 …”

Awaiting the verdict: Statins and the road ahead for primary prevention in older adults

“…18,19 Both STAREE and PREVENTABLE are well positioned to examine this issue with respect to statin use, as both trials will include frail participants, will have suitable data to build a FI and are ascertaining cognitive function. 6,7 In summary, the results of Orkaby et al are reassuring, suggesting that the primary prevention benefits of statins for CVD observed in middle age populations likely also extend to older adults, including those 75 years or older and those more likely to be frail. 9 One must still be cautious with this interpretation, as it is conceivable that the observed differences reflect educational and socioeconomic differences between patients that did or did not initiate a statin.…”

“…6 In the United States, the Pragmatic Evaluation of evENTs And Benefits of Lipid-lowering in oldEr adults (PREVENTABLE) trial plans to enroll 20,000 community-dwelling adults ≥75 years free of cardiovascular disease and is similarly comparing atorvastatin 40 mg versus placebo on a primary outcome of survival free of dementia and persistent disability, with incident CVD being a secondary outcome. 7 The results from STAREE and PREVENTABLE are highly anticipated but are not expected for several years. STAREE has recently completed enrollment and expects at least three more years of follow-up.…”

“…6 Meanwhile, PREVENTABLE is still enrolling, with results not likely to be available until 2027 or later. 7 In the interim, the words of William Shakespeare seem relevant, albeit a bit dramatic, "I am to wait, and waiting so be hell. "…”

“…Statins of different potencies, such as atorvastatin, which is being tested in the STAREE and PREVENTABLE trials at a dosage of 40 mg per day, might have yielded different results. 6,7 This includes variations in side effects, a critical aspect not evaluated in this study. Third, it is unfortunate that parallel analyses for the incidence of dementia and disability are unlikely to be informative, given the significant challenges associated with pragmatically ascertaining those conditions.…”