Statins Beneficial in Elderly, Guidelines Should Be Strengthened

Nancy A. Melville

November 18, 2020

Contrary to historical evidence, among older people, elevated LDL cholesterol levels increase risk for heart attack and cardiovascular disease, and older patients benefit as much, if not more, from statins and other cholesterol-lowering drugs than do younger people, two new studies show.

"By contrast with previous historical studies, our data show that LDL cholesterol is an important risk factor for myocardial infarction and atherosclerotic cardiovascular disease in a contemporary primary prevention cohort of individuals aged 70 to 100 years," say Borge Nordestgaard, MD, of University of Copenhagen, and colleagues in the first of the two studies, published this week in The Lancet.

"By lowering LDL cholesterol in healthy individuals aged 70 to 100 years, the potential for preventing myocardial infarctions and atherosclerotic cardiovascular disease is huge, and at a substantially lower number needed to treat when compared with those aged 20 to 69 years," they add.

"These findings support the concept of the cumulative burden of LDL cholesterol over one's lifetime and the progressive increase in risk for atherosclerotic cardiovascular disease, including myocardial infarction, with age," add Frederick J. Raal, PhD, and Farzahna Mohamed, MB BCh, of the University of the Witwatersrand, South Africa, in an editorial published with both new studies in The Lancet.

The studies underscore the need for clinicians to consider continued risks associated with elevated LDL in older age, they stress.

They add that statins are also benefical for younger persons at risk to prevent conditions from worsening.

"The average age of patients in all the trials analyzed was older than 60 years, an age when atherosclerotic cardiovascular disease is already well established," the editorialists say.

"Lipid-lowering therapy should be initiated at a younger age, preferably before age 40 years, in those at risk to delay the onset of atherosclerosis, rather than try to manage the condition once fully established or advanced," they stress.

No RCTs Have Included Patients Older Than 70

For persons aged 40 to 75 years, elevated LDL cholesterol levels are a known risk factor for myocardial infarction and atherosclerotic cardiovascular disease, and there is consensus in guidelines regarding treatment with statins.

However, the risk for people older than 70 is controversial. Some studies show little or no association between elevated LDL cholesterol levels and an increased risk for myocardial infarction.

Contributing to the uncertainty is that few of the randomized controlled trials that have investigated the question have included patients older than 70.

As a consequence, many practice guidelines have noted that the level of evidence in older patients is low, and some organizations have lowered the strength of recommendations regarding the treatment for older patients in comparison with younger patients.

Primary Prevention: CV Events Increase With Elevated LDL in Older Age

Nordegestaard and colleagues studied data on 91,131 people living in Copenhagen, Denmark, who did not have atherosclerotic cardiovascular disease or diabetes at baseline and were not taking statins.

Of the participants, 10,592 were aged 70 to 79 years, and 3188 participants were aged 80 to 100 years.

Over an average follow-up period of 7.7 years, 1515 participants had a first myocardial infarction, and 3389 developed atherosclerotic cardiovascular disease.

In the primary prevention cohort, after multivariate adjustment, the risk of having a heart attack per 1.0 mmol/L increase in LDL cholesterol was increased in the group overall (hazard ratio [HR], 1.34). The increased risk was observed for all age groups, including those aged 80 to 100 (HR, 1.28), 70 to 79 (HR, 1.25), 60 to 69 (HR, 1.29), 50 to 59 (HR, 1.28), and 20 to 49 (HR, 1.68).

Risk for atherosclerotic cardiovascular disease was also raised per 1.0 mmol/L increase in LDL cholesterol overall (HR, 1.16) and in all age groups, particularly those aged 70 to 100 years.

Greater elevations in LDL cholesterol (5.0 mmol/L or higher, indicative of possible familial hypercholesterolemia) were associated with a notably higher risk for heart attack after multivariate adjustment in people aged 80 to 100 (HR, 2.99). Risk was also higher among those aged 70 to 79 (HR, 1.82).

The highest incidence was in those older than 70. The rate was 8.5 heart attacks per 1000 people per year among those aged 80 to 100 and 5.2 heart attacks per 1000 in those aged 70 to 79. The rates were 2.5 per 1000 among those 60 to 69, 1.8 for those aged 50 to 59, and 0.8 for those aged 20 to 49.

"The absolute risk [of cardiovascular events] is of course much higher in the elderly than those under the age of 75, but what was a surprise was how clear our results were on a relative risk scale, that the risk associated with elevated LDL was as high in people aged 80 to 100 as the younger patients," Nordestgaard, of the Copenhagen University Hospital, Denmark, told Medscape Medical News.

With regard to the benefits of cholesterol-lowering drugs, the study showed that the number needed to prevent one heart attack over 5 years was 80 among those aged 80 to 100; the number was 439 for people aged 50 to 59.

With regard to stronger statins, when moderate-intensity statins were used, the number needed to treat to prevent one cardiovascular disease event of any type dropped to 42 for patients aged 80 to 100. It was 88 for those aged 70 to 79, 164 for those aged 60 to 69, 345 for those aged 50 to 59, and 769 for those aged 20 to 49.

"The clinical significance of this is that it appears those in older age groups indeed benefit from cholesterol-lowering therapy," Nordestgaard said. "I think many people have this idea that LDL is not important over the age of about 70 to 75, but that's not the case."

"These robust findings are novel," he and his colleagues stress.

Despite these observational findings, the South African editorialists note that "whether lipid-lowering therapy should be initiated for primary prevention in people aged 75 years or older is unclear," owing to the host of risks and benefits that need to be balanced.

The findings of an ongoing randomized, placebo-controlled trial (STAREE) may answer this question, they say. It is investigating primary prevention in 18,000 older patients (≥70 years) who are being randomly assigned to receive atorvastatin 40 mg/d or placebo. The study is seeking to determine whether statin treatment extends the length of a disability-free life, which will be assessed on the basis of survival outside permanent residential care. Results are expected in 2022–2023.

Unequivocal Reductions in Events in Elderly, Comparable to Younger Patients

In the second study, Baris Gencer, MD, of Brigham and Women's Hospital, Boston, Massachusetts, and colleagues evaluated the effects of statins and other cholesterol-lowering drugs, including ezetimibe and PCSK9 inhibitors, in older vs younger patients.

The systematic review and meta-analysis of 29 randomized controlled trials, also published in The Lancet, were presented virtually as a poster as part of the American Heart Association (AHA) Annual Meeting. It included data on 244,090 patients, including 21,492 aged 75 and older.

The meta-analysis included studies of cardiovascular outcomes of a guideline-recommended LDL cholesterol–lowering drug, with a median follow-up of at least 2 years and inclusion of data on patients aged 75 years and older.

The results showed that over a median follow-up of 2.2 to 6 years, statin use by older patients was associated with a relative risk reduction of major vascular events of 26% per 1 mmol/L reduction in LDL cholesterol (P = .0019), which was comparable to a risk reduction of 15% per 1 mmol/L reduction in LDL cholesterol for patients younger than 75 years (P = .37 compared with older patients).

Treatment of older patients with LDL cholesterol–lowering drugs was also associated with significantly improved outcomes in cardiovascular death (risk ratio [RR], 0.85), myocardial infarction (RR, 0.80), stroke (RR 0.73), and coronary revascularization (RR, 0.80).

"We found an unequivocal reduction in the risk of major vascular events with both statin and non-statin LDL cholesterol-lowering treatments, which was similar to that seen in younger patients," the authors write.

"Cholesterol-lowering medications are affordable drugs that have reduced risk of heart disease for millions of people worldwide, but until now, their benefits for older people have remained less certain," said lead author Marc Sabatine, MD, also of Brigham and Women's Hospital, in a Lancet press release.

"Our analysis indicates that these therapies are as effective in reducing cardiovascular events and deaths in people aged 75 years and over as they are in younger people. We found no offsetting safety concerns, and together, these results should strengthen guideline recommendations for the use of cholesterol-lowering medications, including statin and non-statin therapy, in elderly people."

The editorialists agree: "More than 80% of fatal cardiovascular events occur in individuals older than 65 years, and the incidence of cardiovascular events is increasing in those older than 80 years; therefore, the findings of Gencer and colleagues' study should encourage the use of lipid-lowering therapy in older patients."

The authors of the two studies have disclosed no relevant financial relationships. Raal has received research grants, honoraria, or consulting fees for advisory board membership, professional input, and lectures on lipid-lowering drug therapy from Amgen, Regeneron, Sanofi, Novartis, and the Medicines Company.

Lancet. Published November 10, 2020. First study, Full text, Second study, Full text; Editorial

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