In the Very Elderly, High-Intensity Lipid-Lowering Worked Safely in IMPROVE-IT

Batya Swift Yasgur, MA, LSW

July 23, 2019

People older than age 75 years seem to benefit as least as much as those aged 65-74 years from high-intensity lipid-lowering therapy after a hospitalization for acute coronary syndrome (ACS), suggests a prespecified analysis from the IMPROVE-IT trial.

It showed a 8.7% absolute reduction in risk of a broad cardiovascular (CV) endpoint in such very elderly patients who took ezetimibe on top of simvastatin in the trial, compared with similarly aged people randomized to simvastatin monotherapy.

But the absolute risk reduction was only 0.8% for those aged 65-74 and 0.9% for patients aged 50 to 64. The age interaction was significant at P = .02 in the analysis encompassing all of the more than 18,000 patients randomized in the trial.

Low-density-lipoprotein cholesterol (LDL-C) levels in all three age groups had improved similarly and significantly in the analysis published July 17 in JAMA Cardiology.

Notably, the number needed to treat to prevent one primary endpoint was 125 for the patients younger than 75 years but only 11 for those age 75 and older over the follow-up averaging 6 years.

The primary endpoint had consisted of CV death, myocardial infarction, stroke, unstable angina hospitalization, or revascularization more than 30 days after the ACS hospitalization.

"In light of these observations, continuing to treat elderly patients after an ACS with moderate rather than higher-intensity lipid-lowering therapy will represent a missed opportunity to incrementally improve long-term outcomes for this high-risk population," lead author Richard G. Bach, MD, Washington University School of Medicine, St Louis, Missouri, told theheart.org | Medscape Cardiology.

The main IMPROVE-IT trial had compared the effect of the higher-intensity lipid-lowering therapy with simvastatin monotherapy in recently stabilized ACS patients aged 50 years or older. Overall, it showed a significant 6.4% relative reduction in the risk of the primary endpoint with the combination therapy over 7 years.

The trial, Bach explained, "enrolled patients with no upper age limit, which gave us the opportunity to examine the effect of age on outcome on the benefit of intensive lipid-lowering with ezetimibe combined with simvastatin vs simvastatin monotherapy."

Indeed, the "big surprise" in the current post-hoc analysis "was the trend toward more reduction in relative risk in older patients, which was not seen in any other randomized lipid-lowering trial with clinical endpoints," Dan Streja, MD, University of California Los Angeles, told theheart.org | Medscape Cardiology.

Streja, who was not involved with the analysis, noted that the "combination of statin plus ezetimibe is considered safer than high-dose statin and certainly more affordable" than the PCSK9 inhibitors alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen).

He emphasized that patient-physician discussions should focus on the risks and benefits of statin therapy using a shared decision model. The current study "should be very useful in informing this decision and decision-making," he said.

"The analysis by Bach et al addresses an important gap in the literature," in that prior studies of lipid-modifying therapy either excluded or entered very few patients age 75 or older, agreed an accompanying editorial from Antonio M. Gotto Jr, MD, DPhil, Weill Cornell Medicine, New York City.

"While the results reported by Bach et al are part of a post-hoc analysis, they provide valuable information for both the patient and the practitioner. They strongly support the benefit of intensive therapy to reduce LDL-C levels in elderly individuals with atherosclerotic cardiovascular disease."

Of the 18,144 patients aged 50 years or older in IMPROVE-IT, 56% were younger than age 65, 29% were aged 65 to 74 years, and 15% were 75 or older when they were randomly assigned to receive once-daily 40 mg simvastatin plus either 10 mg/d ezetimibe or a placebo.

The oldest group had a mean age of 79 years at the start of the trial and 85 by its end.

Table. Reduction in Rate of Primary Endpoint at 7 Years by Age Groupa, Simvastatin plus Ezetimibe vs Simvastatin Monotherapy

Age Group (years)

Absolute Reduction in Rate (%)

HR (95% CI)

< 65

0.9

0.97 (0.90 - 1.05)

65 - 74

0.8

0.96 (0.87 - 1.06)

≥ 75

8.7

0.80 (0.70 - 0.90)

a P = .02 for interaction

Abbreviations: CI, confidence interval; HR, hazard ratio

"Some prior studies of higher-intensity lipid-lowering in elderly patients have shown a higher rate of abnormal liver function tests with high-dose statins," Bach said. So, "there is concern that myalgias and myopathy may be more frequent with high-intensity statin therapy in the elderly."

In IMPROVE-IT, he said, the rate of rhabdomyolysis and myopathy and the rates of liver-enzyme elevation were very low, did not increase with age, and didn't seem to be elevated by combined simvastatin-ezetimibe, compared with simvastatin monotherapy.

The analysis shows higher-intensity therapy "to be well-tolerated across all age groups, and the incidence of liver-related and muscle-related adverse events was not increased by that combination in the elderly patients," he said.

Rates of newly diagnosed cancers, cataracts, and neurocognitive events increased with age, but rates were not significant increases in either treatment group overall or within age groups.

Rates of hemorrhagic stroke were not significantly different between the two arms in those age ≥ 75 years (hazard ratio, 2.38; 95% confidence interval, 0.91 - 6.16; interaction of risk by age, P = .15).

As described by Gotto in his editorial, "The ongoing Statin Therapy for Reducing Events in the Elderly [STAREE] trial will provide additional information regarding the use of statin therapy in healthy individuals older than 70 years. It is evaluating the effects of statin therapy (atorvastatin, 40 mg/d) on overall survival and disability-free survival in 18,000 participants in Australia, with results expected in 2020."

IMPROVE-IT was supported by Merck & Co. Bach reported grants from Merck & Co during the conduct of the study; grants from CSL Behring and MyoKardia outside the submitted work; and personal fees from Armaron Bio, Novo Nordisk, and Pharmacosmos outside the submitted work. Gotto disclosed personal fees for serving on the Board of Directors of Esperion Therapeutics, consulting for Kowa Pharmaceuticals, and serving on the Data Safety Monitoring Board of Akcea Pharmaceuticals. Streja has disclosed no relevant financial relationships.

JAMA Cardiol. Published online July 17, 2019. Full text, Editorial

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