CHICAGO, IL\u2014Stopping statin therapy is noninferior to continued treatment when it comes to the risk of major cardiovascular events and all-cause mortality in older adults with at least two chronic conditions taking the lipid-lowering medications for primary prevention, according to results of the STREAM trial.<\/p>\n\n\n\n
Over 2 years of follow-up, the restricted mean event-free survival time was 2.0 weeks shorter in those who stopped statin therapy, which was less than the prespecified noninferiority margin of 5.2 weeks (95% CI -3.7 to -0.3; P<\/em> < 0.001), investigators reported this week at the American Heart Association Scientific Sessions.<\/p>\n\n\n\n During the first 2 years of follow-up, 10.7% of participants in the statin-discontinuation group and 8.2% in the continuation group had a primary-outcome event, which was defined as all-cause mortality, nonfatal MI, or nonfatal ischemic stroke. Acute MI occurred in 1.4% of patients who stopped statin therapy compared with 0.6% of those who kept taking the drugs. Acute ischemic stroke and all-cause mortality occurred in 1.9% and 8.2% of patients in the discontinuation arm versus 0.8% and 6.9% of those in the continuation group, respectively.<\/p>\n\n\n\n “We found that it was generally safe for the majority of older adults to stop statin therapy,” lead investigator Nicolas Rodondi, MD (University of Bern, Switzerland), told Cardiology Now News<\/em>. “One in 40 people [in the discontinuation group] have a cardiovascular event, but 39 did not over the 2 years.”<\/p>\n\n\n\n Despite the topline conclusions that statin discontinuation is noninferior to ongoing treatment, Rodondi stressed that STREAM is a nuanced trial. He, like many others on social media, pointed out that the event curves are separating over time.<\/p>\n\n\n\n We found that it was generally safe for the majority of older adults to stop statin therapy.<\/p>Nicolas Rodondi, MD<\/cite><\/blockquote><\/figure>\n\n\n\n “In the extended follow-up out to 4 years, the curves begin to diverge more,” he said, adding that the absolute risks remain small. “It’s only at the end that the difference [between study arms] begins to diverge.”<\/p>\n\n\n\n Older adults are frequently on multiple medications for competing disease states, and coming off medication is a topic that frequently comes up in conversations with patients, said Rodondi. However, any decision to stop statin therapy should be a conversation between patient and doctor. The decision to stop or continue treatment will depend on a mix of factors, including the clinical condition, values, life expectancy, pill burden, and possible side effects from statins.<\/p>\n\n\n\n Michael Nanna, MD (Yale School of Medicine, New Haven, CT), a cardiologist with a specialty in older adults with multiple comorbid conditions, said it’s important to put STREAM into context with other trials. In SAGA\/SITE<\/a>, investigators found that stopping statins was noninferior to continued therapy when it came to all-cause mortality in older adults without cardiovascular disease.<\/p>\n\n\n\n Nanna, in an editorial<\/a> accompanying the SAGA\/SITE publication in the The Lancet Healthy Longevity<\/em>, argued that noninferiority shouldn’t be interpreted as an automatic reason to deprescribe, though.<\/p>\n\n\n\n “STREAM makes that distinction even more important because unlike SAGA\/SITE, there is an actual signal of increased clinical events,” Nanna told Cardiology Now News<\/em>. “And neither trial demonstrated meaningful improvements in quality of life after stopping statins, which is much of the motivation to do it in the first place. The noninferiority margin permitted a degree of harm that may be difficult to justify clinically, particularly given the absence of measurable patient-centered benefits.”<\/p>\n\n\n\n Also, the STAREE<\/a> trial found that patients older than 70 years without cardiovascular disease started on lipid-lowering therapy had a significantly lower risk of major cardiovascular events than those treated with placebo, said Nanna. <\/p>\n\n\n\n Diverging Event Curves<\/strong><\/p>\n\n\n\n The STREAM trial, which was published simultaneously in the New England Journal of Medicine<\/em><\/a>, was an international, open-label, randomized trial in 1,880 adults 70 years or older who were taking statins for primary prevention. Patients were recruited from primary-care clinics or hospitals, had at least two chronic conditions, and were randomized to statin discontinuation or continued therapy. The mean age of participants was 77.5 years and 46.9% were women.<\/p>\n\n\n\n In the primary intention-to-treat analysis, the restricted mean event-free survival over 2 years was 96.5 weeks in the discontinuation group and 98.5 weeks in the continuation group. With 2 weeks less time until the clinical event over two years, the difference fell within the predefined noninferiority margin.<\/p>\n\n\n\n Over the full follow-up period (median 103 weeks), 12.7% and 9.2% of participants in the discontinuation and continuation groups had a primary outcome. For acute MI, the respective numbers were 1.6% and 0.6%; for acute ischemic stroke, 2.2% and 0.8%, respectively. All-cause mortality was 9.8% in the discontinuation arm versus 8.0% with continued statin therapy. <\/p>\n\n\n\n There was no difference in quality of life, sarcopenia risk, or medication adherence at 2 years, nor any difference in pain at 3 months or falls at 12 months.<\/p>\n\n\n\n In subgroup analyses, it appeared that patients with diabetes had a pattern of higher risk of events after stopping statin therapy, Additionally, those recruited from primary-care clinics, likely a proxy for healthier, older patients, were at a higher risk of primary-outcome events if they stopped treatment than those recruited from hospital who stopped. The 2-year restricted mean event-free survival was 3.4 weeks less in those recruited from doctors’ offices who stopped statins than in those who continued.<\/p>\n\n\n\n Hashing Through Noninferiority<\/strong><\/p>\n\n\n\n Nishant Shah, MD (Duke University Medical Center, Durham, NC), who wasn’t involved in the study, said it’s extremely important to study lipid-lowering therapies, the benefits and adverse effects, in older populations given that people are living longer.<\/p>\n\n\n\n “In fact, there are many 70-plus-year-olds that I know who are more functional than many 40- and 50-year-olds,” he told Cardiology Now News<\/em>. “So, in my opinion, it’s not fair to not keep those folks optimized in terms of cardiovascular risk if they still have a lot of functional years left in life.”<\/p>\n\n\n\n In general, Shah said STREAM should be interpreted with close attention paid to methodology and study trends.<\/p>\n\n\n\n he noninferiority margin permitted a degree of harm that may be difficult to justify clinically.<\/p>Michael Nanna<\/cite><\/blockquote><\/figure>\n\n\n\n “I think that’s really important because my interpretation is that there does seem to be a separation in cardiovascular risk in the folks that you discontinue therapy,” he said. “Even though it met the prespecified noninferiority margins, there was still a trend toward benefit in the people that continued statin therapy. I think we need to contextualize that and understand the limits of our statistical analyses before making concrete conclusions that would change practice.”<\/p>\n\n\n\n Nanna agreed.<\/p>\n\n\n\n “I think we need to do a much better job scrutinizing the assumptions behind noninferiority trials before allowing these conclusions into the literature,” said Nanna. “You can’t simply choose a generous noninferiority margin, demonstrate a clinically meaningful increase in heart attacks, strokes, or deaths, and then reassure clinicians that stopping treatment is ‘noninferior.’ At some point, we have to ask whether our statistical definitions of acceptable harm have lost touch with what patients would actually consider acceptable.”<\/p>\n\n\n\n More data in older patients are expected in the future. The PREVENTABLE<\/a> investigators are randomizing approximately 20,000 adults aged 75 years or older without cardiovascular disease, disability, or dementia, to atorvastatin 40 mg or placebo. The primary endpoint is survival free of new dementia or persisting disability through 4 years.<\/p>\n\n\n\n