Statins Cut CV Risk but Don’t Boost Disability-Free Survival in Healthy Elderly

The use of statins in healthy older adults doesn’t lead to a longer life free from disability and dementia when compared with not taking the lipid-lowering medications, but the drugs are associated with a significantly decrease in major adverse cardiovascular events, including MI and stroke, according to a secondary analysis from the ASPREE randomized study.

After a median follow-up of 4.7 years, there was no difference in the primary endpoint, a composite that included all-cause mortality, dementia, or persistent physical disability between statin users and nonusers. In terms of secondary endpoints, there was an observed 25% relative reduction in the risk of persistent physical disability among statin users (P = 0.02) and a 32% lower risk of major adverse cardiovascular events (P < 0.001).

“To our knowledge, this is the first completed study to evaluate the association of statin use with disability-free survival, a robust measure of healthy, productive, and independent life in older adults and an overarching goal of geriatric healthcare,” write Zhen Zhou, MD (University of Tasmania, Hobart, Australia), and colleagues in the Journal of the American College of Cardiology paper published July 7, 2020. “Comparing our study results with findings from the main ASPREE trial, which showed minimal cardiovascular benefits but high bleeding risk from aspirin, primary prevention with statins seems to be a more promising strategy for healthy aging.” 

Ann Marie Navar, MD, PhD (Duke Clinical Research Institute, Durham, NC), who wasn’t involved in the analysis, said the absence of a mortality benefit in these healthy older adults isn’t particularly surprising given the relatively short follow-up period. Even with modern medical therapy, the prevention of MI and other cardiovascular events might not translate into a downstream effect on survival for some time.

“They may not have been followed long enough to really see that impact on mortality,” she told TCTMD. “Also, this is a relatively older population with a lot of competing risks . . . It may be that people are dying from other causes that we just can’t expect statins to decrease.”

It may be that people are dying from other causes that we just can’t expect statins to decrease. Ann Marie Navar

Many therapies, Navar added, are taken by patients not just to live longer, but also to also avoid disease and disability. “It’s really important to patients to prevent heart attacks even it doesn’t mean they’re going to live longer,” she said. “If it means they can live without acute illnesses, I think that’s really important. And the study did show that there was a decrease in physical disability.”

This latest ASPREE analysis reinforces the need for large-scale randomized trials testing statins in elderly patients, according to Seth Martin, MD (Johns Hopkins Hospital, Baltimore, MD). Such trials are currently underway, including the 18,000-patient STAREE trial from Australia-based researchers and the National Institutes of Health-sponsored PREVENTABLE study, both of which are testing the effect of atorvastatin 40 mg in elderly patients.

With a sufficiently high enough baseline risk of cardiovascular disease, as well as high enough baseline LDL-cholesterol levels, statins will likely lower the risk of mortality in older patients, Martin suspects. “I believe in the properly selected elderly patient, we’re going to see a mortality benefit with statin therapy,” he told TCTMD.

ASPREE, Aspirin, and Statins

The ASPREE trial, which was conducted in Australia and the United States, randomized individuals 70 years or older (or older than 65 years if Black or Hispanic in the US) without cardiovascular disease, dementia, or disability to treatment with aspirin or placebo. Of the 18,096 patients included the secondary analysis, 5,629 were taking a statin at baseline. Statin users were more likely to be female and to have diabetes, chronic kidney disease, hypertension, obesity, and a family history of cardiovascular disease, but these variables were adjusted for in a propensity score-based inverse probability of treatment weighting analysis.

Despite no reduction in the risk of disability-free survival with statin therapy, there was a 44% lower risk of MI (P < 0.001) and a 25% lower risk of stroke (P = 0.02). There was also an observed reduction in the risk of fatal cardiovascular disease (HR 0.71; 95% 0.51-0.99).

In an editorial, James Kirkpatrick, MD, and Gwen Bernacki, MD (both from University of Washington, Seattle), predict that STAREE and PREVENTABLE will provide newsworthy data on the cardiovascular and noncardiovascular benefits of statins in older adults. The bad news is that these trials—both of which are paused because of the COVID-19 pandemic—won’t be completed for many years, they warn, and the idea of waiting for those results might not be “appealing” to doctors and their patients. The ASPREE analysis “may tip the scales for many,” write Kirkpatrick and Bernacki, although they do caution about making quick judgments 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,” they write.

To TCTMD, Navar said the decision to start statin therapy comes down to the patient’s 10-year risk of cardiovascular disease. “We know that statins lower heart disease risk almost irrespective of starting LDL-cholesterol levels,” she said. “The benefit is proportional to how much they lower LDL. So, if somebody has established heart disease or a bunch of risk factors for heart disease, that’s really the trigger for me to start treatment.”

In an older population, such as those included in ASPREE, Navar also takes into account the patient’s overall life expectancy and priorities. Those are important considerations across the age spectrum, but they become increasingly important in an older population. “There are some 70-year-olds I see in clinic who are likely to live 20 years,” she said. “Those patients are very different than the ones who may only have a 3- to 5-year life expectancy. The aggressiveness of prevention usually takes into account how long I expect them to survive.”

Martin echoed the approach. “It’ll be a shared decision where we’ll look at their personal situation in terms of risk factors and we’ll consider their preferences and make the best decision we can together,” he said. If the patient is healthy and free from cancer, chronic kidney disease, or other comorbidities plus would be expected to benefit from treatment given their risk profile, then Martin sees statins as a good option. “Of course, if they’re going to die of something else sooner, you’re not going to see a mortality benefit,” he said. “While we await the clinical trials, we have to use our best judgement. I have every reason to believe that if somebody has high risk and has high lipids, and they don’t have competing risks, that they’re going to benefit from treatment.”

If there is some uncertainty in starting statins, Martin also noted that coronary artery calcium screening can rule out some patients, such as those with calcium score of zero.

Awaiting STAREE and PREVENTABLE

Despite the reduction in major adverse cardiovascular events observed in ASPREE, Navar emphasized that it is not a randomized controlled trial. While the researchers adjusted for confounding variables, it is nearly impossible to account for the myriad of reasons why some patients are started on statin therapy and others are not.

“Those trials will take the selection bias out of the equation,” said Navar, referring to STAREE and PREVENTABLE. The EWTOPIA trial, which was presented 2 years ago at the American Heart Association’s annual meeting, showed that addition of ezetimibe was superior to placebo for reducing atherosclerotic cardiovascular events in Japanese patients 75 years and older, she noted. STAREE and PREVENTABLE will look not just at cardiovascular outcomes with statin therapy, but also at important endpoints such as cognitive decline, disability, and quality of life.

In an older population, Navar said, polypharmacy also must be considered, given that patients can be treated with a range of therapies depending on their risk factors and comorbidities. “The number of medications that older people take can really start to skyrocket,” she said. “Beyond just a fear of statins, we often see older adults asking if there is a way to cut down on my pill burden. Statins are often part of the conversation, but so are other medications part of the CV risk armamentarium.”