Another Study Links Stopping Statins to MACE in the Elderly

There’s more observational evidence—this time from a nationwide database in Denmark—that statin discontinuation in the elderly is associated with an increase in major adverse cardiac events. But disentangling any causative effect from other late-life considerations, including a shift in care goals to a more-palliative approach, will require a randomized controlled trial, authors of the analysis conclude.

“It is only an association,” lead author Wade Thompson, PharmD, PhD (University of Southern Denmark, Odense), stressed to TCTMD. “In an individual person's context based on their life expectancy, their goals, their preferences, statin discontinuation could still be on the table, keeping in mind that patients would want to discuss this potential excess risk with their healthcare providers. And this would be a part of the decision, but it's not the only determinant of the decision.”

Other recent studies from Italy and France, as well as a large meta-analysis from the Cholesterol Treatment Trialists’ Collaboration, point to an uptick in cardiovascular events among older adults stopping their statins. But earlier studies have made the case that the side effects of a medication that might take years to deliver a benefit, not to mention the added pill burden, are not worth it in older patients, a group largely excluded from clinical trials, particularly if they have no evidence of cardiovascular disease.

The current analysis differs from prior studies in that it’s focused exclusively on patients 75 and older and also looks separately at primary and secondary prevention patients, Thompson noted. Even so, “our findings are in line with those earlier studies in terms of [seeing] this kind of small, increased rate of cardiovascular events following discontinuation.”

Commenting on the study for TCTMD, Jawahar L. Mehta, MD, PhD (University of Arkansas for Medical Sciences, Little Rock), pointed out that the reasons for statin discontinuation go beyond pill burden or late-life care and include side effects like myalgia and forgetfulness as well as the inability to afford too many medicines. These results are “not entirely unexpected,” he said. “There are similar data in patients who stopped taking aspirin or beta-blockers: a rebound increase in blood pressure is seen in patients who stop taking antihypertensives.”

Thompson and colleagues reported their findings online December 2, 2021, in JAMA Network Open.

Stopping Statins

Thompson et al delved into data from a range of national Danish registries to analyze statin prescription trends for both primary and secondary CVD prevention, as well as mortality. Patients (n = 67,418) were included if they had been taking long-term statins as of January 1, 2011, and then were analyzed according to whether they filled their prescription thereafter or continued on a statin through the end of December 2016. Patient outcomes were then tracked through a median duration of 5.5 years in the primary prevention cohort and 4.2 years in the secondary prevention cohort, with discontinuation rates of 37% and 36%, respectively.

For both groups, MACE rates were lower among patients who remained on statins, corresponding to one excess MACE for every 112 discontinuations in the primary prevention group (HR 1.32; 95% CI 1.18-1.48) and one per 77 discontinuations in the secondary prevention group (HR 1.28; 95% CI 1.18-1.39). A similar pattern was seen in rates of MI, rates of ischemic stroke/TIA, and rates of death due to MI or stroke, all of which were higher in those who discontinued as compared with those who didn’t.

Of note, while the higher event rates were seen in both the primary and secondary prevention “discontinuers,” the magnitude of the difference was greater for patients initially prescribed statins following a CVD diagnosis.

“Our results provide important evidence on statin discontinuation in people receiving long-term statin treatment for both primary and secondary prevention,” Thompson et al conclude. “Clinicians and policy makers should be aware of a possible increased risk of MACE associated with discontinuation of long-term statin treatment.”

Other Considerations

What’s trickier to tease out, however, are the reasons for discontinuation. In some cases, Thompson et al note, “statin discontinuation may reflect an overall preference for less medical care and a willingness to shift from preventive or curative goals of care to a more-palliative approach.”

There are hints of that in this analysis: patients who discontinued statins were also less likely to undergo CABG surgery and tended to have fewer visits to their general practitioner.

“That may reflect a preference for less-intensive care, but that's very speculative because we didn't really investigate that,” Thompson said to TCTMD. “We were trying to kind of contextualize our results a little bit by looking at some of those things post hoc, but I would be very cautious in drawing a conclusion around that.”

At least one randomized controlled trial is ongoing, he noted, and focused on statin discontinuation in older patients taking the drug for primary prevention—the group he described as being “the most-compelling population to study.”

For now, “we cannot prove causality here, we can’t make firm conclusions about the effects of discontinuing statins, but it is suggestive or hypothesis-generating,” Thompson said. “We do need more-definitive evidence on this topic because there’s this potential signal now, from three separate studies, suggesting a possible association.”

The most-recent US guidelines for use of statins in primary prevention for adults 75 and older urges a clinician-patient risk discussion in the absence of “strong” clinical trial evidence. For secondary prevention of atherosclerotic cardiovascular disease (ASCVD), it “may be reasonable” to initiate statins in patients ≥ 75 years old with elevated LDL cholesterol, but also to stop statins in the face of functional decline, multimorbidity, frailty, or reduced life expectancy—both Class IIb recommendations.

By contrast, the European guidelines of 2019 take a somewhat stronger position noting that statins are recommended “for older people with ASCVD in the same way as for younger patients (Class I),” but also note that initiation of statins for primary prevention in those older than 75 “may be considered” if patients are at high risk (Class IIb).

To TCTMD, Mehta agreed that a prospective study would be “ideal, but extremely difficult, if not impossible, to do.”

And while a rebound effect has been seen in patients stopping other cardiovascular medications, the specific reasons for this in the setting of statin discontinuation are unclear. “The mechanism of a small but significant increase in MACE following discontinuation of statins is not known, but may be due to an increase in lipids, and may be [due to an] increase in inflammation and platelet activation,” he said in an email. “Statins are known to suppress both.”