Intensive Lipid-Lowering Slashes CVD in Elderly ACS Patients

 

(UPDATED) Elderly patients with stabilized acute coronary syndrome derive the biggest absolute bang for the buck from intensive lipid-lowering with ezetimibe and simvastatin combination therapy, according to a new analysis of the IMPROVE-IT study.

Among patients 75 years and older, adding ezetimibe to simvastatin significantly lowered the risk of cardiovascular events when compared with statin therapy alone, but the absolute reduction in risk was 10 times larger than the absolute benefit observed in younger patients.

As a result, just 11 individuals 75 years and older would need to be treated with the simvastatin/ezetimibe combination to prevent one primary endpoint event, a composite that includes cardiovascular morality, MI, stroke, unstable angina requiring hospitalization, and coronary revascularization after 30 days. In contrast, for those younger than 75 years, 125 patients would need to be treated with simvastatin/ezetimibe to prevent one cardiovascular event.

Richard Bach, MD (Washington University School of Medicine, St. Louis, MO), who led the new analysis, pointed out that the IMPROVE-IT study showed an overall benefit with the simvastatin/ezetimibe combination, but the latest analysis showing a larger magnitude of benefit in the elderly is attributable to their higher baseline risk.

“Most of the higher-risk groups analyzed in the IMPROVE-IT substudies derived a greater benefit with the more intensive lipid-lowering combination versus monotherapy approach,” he told TCTMD. “Whether one is high risk because of a prior CABG, diabetes, or other risk factors, there is a greater benefit. That certainly applies to the elderly subgroup as well. It does appear their high risk is translating into a greater absolute benefit with combination therapy.”

He added that some physicians may be reluctant to prescribe high-dose statin therapy because they may not be as well tolerated. “To see the safety profile of the combination here, and that ezetimibe was very well tolerated, it provides another option for clinicians to achieve better and more intensive lipid-lowering without adverse side effects.”

To see the safety profile of the combination here, and that ezetimibe was very well tolerated, it provides another option for clinicians to achieve better and more intensive lipid-lowering without adverse side effects. Richard Bach

Fatima Rodriguez, MD (Stanford University School of Medicine, CA), who was not involved in the study, also likened the greater magnitude of benefit in these elderly patients to their higher baseline risk. Age, she added, is one of the strongest predictors for recurrent adverse cardiovascular events and the elderly patients in this study had higher baseline rates of cardiovascular disease.

Rodriguez agreed that physicians sometimes fear that elderly patients won’t be able to tolerate aggressive risk-factor modification, including intensive LDL cholesterol-lowering with statins. “Of course, age is just a number and other factors need to be considered when prescribing preventive medications, such as frailty and life expectancy,” she said in an email. “However, we tend to overestimate risks and underestimate benefits in the elderly.”

Based on the new findings, as well as other data, Rodriguez said that elderly patients should be treated just like everybody else. “The lower the LDL cholesterol, the better.”  

Ann Marie Navar, MD, PhD (Duke Clinical Research Institute, Durham, NC), said there has been a lot of uncertainty about lipid management and prevention in older adults, but the current analysis reassures physicians who treat patients older than 75 years that they should continue with LDL-lowering. “There are 75-year-olds that I see in clinic that could reasonably expect to live another 20 years,” she said. “That’s a long time that we have to lower LDL and prevent cardiovascular disease.”

The new study was published online July 17, 2019, in JAMA Cardiology.

Randomized Trials Include Few Older Patients

The 2018 US guidelines for the treatment of cholesterol recommend moderate- or high-intensity statin therapy for patients 75 years and older with clinical atherosclerotic CVD and moderate-intensity statins for primary prevention among those with LDL cholesterol levels greater than 70 mg/dL. Although there is no specific treatment target, the guidelines highlight the risks of elevated LDL cholesterol levels at any age and recommend treatment to levels as low as safely possible.   

“It was the 2013 cholesterol guidelines that really differentiated people over age 75 and, because of limited data, essentially endorsed more moderate treatment instead of high-intensity regimens,” said Bach. “A lot of data has been acquired since then, and the new guidelines more liberally advise use of high-intensity therapy, but if you read them carefully, it’s still not endorsed to the same degree for patients younger than 75 years.” 

Randomized trials testing lipid-lowering therapies, including studies testing more intensive regimens, have typically excluded older patients. In the Cholesterol Treatment Trialists’ meta-analysis of 28 studies with nearly 187,000 patients, statin therapy, or the use of a more intensive regimen versus a less intensive regimen, was associated with a 21% reduction in vascular events with every 1.0-mmol/L reduction in LDL cholesterol. Although the finding was evident across all age groups, including those 75 years and older, just 8% of patients fell into this older category.

In the IMPROVE-IT study, which was published in 2014 and later published in the New England Journal of Medicine, more than 18,000 patients with stabilized ACS were randomized to simvastatin/ezetimibe (40/10 mg) or simvastatin (40 mg) alone. After a median of 6 years follow-up, treatment with the more intensive combination lowered the risk of the primary endpoint by 6%, a modest reduction that was statistically significant. Of the patients in the trial, 2,798 were 75 years and older, 5,173 were 65 to 75 years, and 10,173 were younger than 65 years. The LDL cholesterol reductions with ezetimibe/simvastatin and simvastatin monotherapy were similar across the age groups, with the combination lowering LDL levels by approximately 15 to 17 mg/dL more than monotherapy alone. 

We tend to overestimate risks and underestimate benefits in the elderly. Fatima Rodriguez

Treating individuals 75 years and older with the combination of simvastatin and ezetimibe lowered the absolute risk of the primary composite endpoint by 8.7% when compared with individuals treated with simvastatin alone (HR 0.80; 95% 0.70-0.90). In contrast, treatment with simvastatin/ezetimibe lowered the absolute risk of the composite primary endpoint by 0.8% among those ages 65 to 74 years (HR 0.96; 95% 0.87-1.06) and by 0.9% for those younger than 65 years (HR 0.97; 95% CI 0.90-1.05).

The interaction between age and treatment effect for ezetimibe/simvastatin for the primary endpoint was significant (P = 0.02 for interaction).

Treatment was also well tolerated across the age groups, with rates of rhabdomyolysis, myopathy, or liver enzyme elevations not increasing with age (and not increased with the combination therapy). Newly diagnosed cancer, cataracts, and neurocognitive events increased among the older patients, but events were not any different among patients treated with ezetimibe/simvastatin or simvastatin alone.

To TCTMD, Bach said that observational research has shown there is a treatment gap when it comes to prescribing effective therapies to aggressively lower cardiovascular risk in the elderly. If physicians don’t pay attention to more intensive risk modification in their older patients, it is an opportunity missed for reducing their risk of morbidity and mortality, he said.

“There’s that risk-treatment paradox where the elderly have a higher risk but physicians are more reluctant to apply more intensive therapeutic interventions because of a fear of complications, side effects, or adverse effects,” he told TCTMD. “That applies to statin use. Observational studies still suggest that age is one of the more important factors that correlates with physician prescribing less intensive therapy, even among patients that have had an acute coronary syndrome.” 

With respect to the findings, particularly the large absolute benefit observed in those aged 75 years and older, Navar expressed some caution, noting this was a subgroup analysis of a trial where the overall effect of ezetimibe on top of simvastatin was modest at best. She noted, however, that these older patients had a 20% relative reduction in the primary endpoint, which was larger than that observed in the main trial. Given the higher baseline risk of the older cohort, this led to a higher absolute risk reduction, she said. “The number needed-to-treat of 11 is really remarkable for a lipid-lowering drug.”  

In her practice, Navar said that unless the patient has other competing risks that might limit their lifespan, she opts for high-intensity statins in older patients, similar to how she would treat younger patients.

“The recommendation is moderate-to-high intensity statin therapy but I think this study provides a bit more clarity that similar to what we’ve seen in other studies, lower is better, regardless of age,” she said. “Given the dearth of data in patients older than 75, I would hope this would inform the next iteration of the guidelines. Right now the recommendation for ezetimibe for those with LDL over 70 [mg/dL] and CVD only extends to those under age 75. At least based on these data, it seems reasonable to extend that recommendation to all adults with CVD and LDL over 70, regardless of age.”

Filling a Gap in the Literature

In an editorial accompanying the study, Antonio Gotto, MD, DPhil (Weill Cornell Medicine, New York, NY), states the IMPROVE-IT analysis addresses an important gap in the literature, noting that the PROSPER study with pravastatin was one of the few randomized trials testing lipid-lowering therapy in older individuals. More recently, the EWTOPIA 75 study investigators showed a benefit of ezetimibe in elderly Japanese patients with elevated LDL cholesterol levels and no history of CVD.  

These new data, he states, provide support for the safety and efficacy of high-intensity lipid-lowering therapy in older adults. “In all cases, before therapy is initiated, it is important that patient-physician discussions take place, including a thorough assessment of the risks and benefits of statin therapy, and that a shared decision is made,” writes Gotto. “The study by Bach et al should be very useful in informing this discussion and decision-making.”

More information is coming, too. An 18,000-patient study is testing whether atorvastatin 40 mg in healthy individuals older than 70 years lowers the risk of all-cause mortality or the development of fatal and nonfatal CVD events, dementia, or disability. The study, known as STAREE, is not expected to be completed for a couple of years.