Effect of Simvastatin-Ezetimibe Compared With Simvastatin Monotherapy After Acute Coronary Syndrome Among Patients 75 Years or Older: A Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: Limited evidence is available regarding the benefit and hazard of higher-intensity treatment to lower lipid levels among patients 75 years or older. As a result, guideline recommendations differ for this age group compared with younger patients.

Objective: To determine the effect on outcomes and risks of combination ezetimibe and simvastatin compared with simvastatin monotherapy to lower lipid levels among patients 75 years or older with stabilized acute coronary syndrome (ACS).

Design, setting, participants: In this prespecified secondary analysis of the global, multicenter, prospective clinical randomized Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), outcomes and risks were compared by age among patients 50 years or older after a hospitalization for ACS. Data were collected from October 26, 2005, through July 8, 2010, with the database locked October 21, 2014. Data were analyzed May 29, 2015, through March 13, 2018, using Kaplan-Meier curves and Cox proportional hazards models.

Interventions: Double-blind randomized assignment to combined simvastatin and ezetimibe or simvastatin and placebo with follow-up for a median of 6 years (interquartile range, 4.3-7.1 years).

Main outcomes and measures: The primary composite end point consisted of death due to cardiovascular disease, myocardial infarction (MI), stroke, unstable angina requiring hospitalization, and coronary revascularization after 30 days. Individual adverse ischemic and safety end points and lipid variables were also analyzed.

Results: Of 18 144 patients enrolled (13 728 men [75.7%]; mean [SD] age, 64.1 [9.8] years), 5173 (28.5%) were 65 to 74 years old, and 2798 (15.4%) were 75 years or older at randomization. Treatment with simvastatin-ezetimibe resulted in lower rates of the primary end point than simvastatin-placebo, including 0.9% for patients younger than 65 years (HR, 0.97; 95% CI, 0.90-1.05) and 0.8% for patients 65 to 74 years of age (hazard ratio [HR], 0.96; 95% CI, 0.87-1.06), with the greatest absolute risk reduction of 8.7% for patients 75 years or older (HR, 0.80; 95% CI, 0.70-0.90) (P = .02 for interaction). The rate of adverse events did not increase with simvastatin-ezetimibe vs simvastatin-placebo among younger or older patients.

Conclusions and relevance: In IMPROVE-IT, patients hospitalized for ACS derived benefit from higher-intensity therapy to lower lipid levels with simvastatin-ezetimibe compared with simvastatin monotherapy, with the greatest absolute risk reduction among patients 75 years or older. Addition of ezetimibe to simvastatin was not associated with any significant increase in safety issues among older patients. These results may have implications for guideline recommendations regarding lowering of lipid levels in the elderly.

Trial registration: ClinicalTrials.gov identifier: NCT00202878.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Bach reported receiving 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. Dr Cannon reported receiving grants and personal fees from Merck & Co during the conduct of the study; grants from Amgen, Inc, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo Company, Ltd, Janssen Pharmaceutica, and Merck & Co outside the submitted work; and personal fees from Aegerion, Alnylam, Amarin Corporation, Amgen, Inc, Boehringer-Ingelheim, Bristol-Myers Squibb, Corvidia Therapeutics, Eisai Co, Ltd, Innovent, Janssen Pharmaceutica, Kowa Pharmaceuticals America, Inc, Merck & Co, Pfizer, Inc, Regeneron Pharmaceuticals, Inc, and Sanofi-Aventis outside the submitted work. Dr Giugliano reported grants from Merck & Co during the conduct of the study; personal fees from Akcea Therapeutics, Inc, Amarin Corporation, Amgen, Inc, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo Company, Ltd, and Pfizer, Inc, outside the submitted work; and grants from Amgen, Inc, and Daiichi Sankyo Company, Ltd, outside the submitted work. Dr Lokhnygina reported receiving grants from Merck & Co during the conduct of the study and grants from Merck & Co, GlaxoSmithKline, and Amylin Pharmaceuticals, Inc (a wholly owned subsidiary of AstraZeneca), outside the submitted work. Dr Bohula reported receiving grants from Merck & Co during the conduct of the study; grants from Eisai Co, Ltd, and Amgen, Inc, outside the submitted work; personal fees from Merck & Co, Novartis, Novo Nordisk, Servier Laboratories, Daiichi Sankyo Company, Ltd, Lexicon, Kowa Pharmaceuticals America, Inc, and Medscape outside the submitted work; and being a member of the TIMI Study Group that has received institutional research grant support through Brigham and Women’s Hospital from Abbott Laboratories, Amgen, Inc, Astra Zeneca, Critical Diagnostics, Daiichi Sankyo Company, Ltd, Eisai Co, Ltd, Genzyme, Gilead Sciences, Inc, GlaxoSmithKline, Intarcia Therapeutics, Janssen Research and Development, The Medicines Company, MedImmune, LLC, Merck & Co, Novartis, Pfizer, Inc, Poxel SA, Roche Diagnostics, and Takeda Pharmaceutical Company, Ltd. Dr Califf reported serving on the board of directors for Cytokinetics, Inc, and as chairman of the board of the People-Centered Research Foundation outside the submitted work and personal fees from Verily, Merck & Co, Amgen, Inc, Biogen, Inc, Genentech, and Eli Lilly and Company outside the submitted work. Dr Braunwald reported grants through his institution and uncompensated consultancies and lectures from Merck & Co during the conduct of the study; grants from Daiichi Sankyo Company, Ltd, Novartis, Astra Zeneca, and GlaxoSmithKline outside the submitted work; personal fees from Theravance Biopharma, Inc, Cardurion Pharmaceuticals, MyoKardia, Inc, Medscape, Verve Therapeutics, Sanofi-Aventis, and IV Communications outside the submitted work; and uncompensated consultancies and lectures from Novartis and The Medicines Company outside the submitted work. Dr Blazing reported grants and nonfinancial support from Merck & Co during the conduct of the study and personal fees from Merck & Co and Amgen, Inc, outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Kaplan-Meier Curves for Study Outcomes

Outcomes were measured during 84 months of follow-up for patients randomized to simvastatin-ezetimibe (added ezetimibe) therapy vs simvastatin monotherapy (monotherapy) and stratified by age at randomization. CVD indicates cardiovascular disease; MI, myocardial infarction.

Figure 2.. Forest Plot of Study Therapy and Event Rates

Effect of simvastatin-ezetimibe therapy vs simvastatin monotherapy on 7-year cardiovascular event rates for the primary composite efficacy end point and selected individual, composite component, and safety end points, according to categorical age groups at randomization, including hazard ratios (HRs) and interaction terms. CVD indicates cardiovascular disease; MI, myocardial infarction. aIndicates Kaplan-Meier percentages through 7 years of follow-up. bComputed for each age subgroup level from Cox proportional hazard regression models. All models were adjusted for randomization strata (prior therapy to lower lipid levels, diagnosis of acute coronary syndrome [ACS], and participation in the EARLY ACS study), age group, study treatment, and age group × treatment interaction.

Figure 3.. Evaluation of Age Associated With Outcomes

A, Association of the primary end point with age at randomization for patients randomized to simvastatin-ezetimibe (added ezetimibe) vs simvastatin monotherapy (monotherapy) using restricted cubic spline analysis. Reference level consists of patients aged 65 years at randomization. B, Rates of cardiovascular disease (CVD) death, myocardial infarction (MI), or ischemic stroke among patients younger than 75 years and 75 years or older. Patients are stratified by TIMI Risk Score for Secondary Prevention (TRS 2°P; 0-2 indicates low-intermediate; ≥3, high) and randomized treatment. ARD indicates absolute risk decrease; HR, hazard ratio; and ITT, intention to treat. aP < .001 for trend. bP = .11 for interaction. cP = .18 for interaction.