Some Improvement in Post-ACS Outcomes with Adjunctive Ezetimibe

June 3, 2015

Some Improvement in Post-ACS Outcomes with Adjunctive Ezetimibe

  1. Harlan M. Krumholz, MD, SM

A combination of ezetimibe and simvastatin was associated with better outcomes at 7 years than statin monotherapy.

  1. Harlan M. Krumholz, MD, SM

Ezetimibe was first approved in July 2002 for lowering LDL cholesterol, and now an industry-funded, randomized, controlled trial has examined its effect on patient outcomes. The IMPROVE-IT researchers tested whether ezetimibe (10 mg), added to simvastatin (40 mg), produced better outcomes than simvastatin alone in patients recently hospitalized with an acute coronary syndrome and with relatively low LDL cholesterol levels. The primary endpoint was a composite of death from cardiovascular disease, a major coronary event, or nonfatal stroke.

The trial enrolled 18,144 patients (mean age, 64) at 1147 sites in 39 countries. At the time of the qualifying event, 34% were taking statins. In patients with LDL cholesterol >79 mg/dL on two measurements, simvastatin was increased to 80 mg; this occurred in 27% of the monotherapy group and 6% of the combination group. At 1 year, LDL cholesterol was 69.9 mg/dL in the monotherapy group and 53.2 mg/dL in the combination group, a significant difference.

The primary endpoint at 7 years occurred in 34.7% of the monotherapy group and 32.7% of the combination group (hazard ratio, 0.93). Rates of death and of medication discontinuation did not differ significantly between the two groups.


This first, long-awaited outcomes trial of the effect of this billion-dollar blockbuster drug, even as a combination with a statin, is quite welcome. There are several caveats: The study population was very specific, stand-alone ezetimibe was not tested, and a quarter of the patients in the comparator group were taking high-dose simvastatin, which is no longer recommended. Nevertheless, the trial provides evidence that can be used to better inform patients about their options and supports the use of ezetimibe, with a statin, as an option for safely lowering risk, even among people with quite low LDL cholesterol levels. Of note, the findings do not say anything about how other cholesterol-lowering drugs might affect risk. Finally, many monotherapy patients were not receiving high-intensity statin therapy, which is currently the standard of care for acute coronary syndrome patients, regardless of LDL cholesterol level.

Editor Disclosures at Time of Publication

  • Disclosures for Harlan M. Krumholz, MD, SM at time of publication Consultant / Advisory board United Healthcare; VHA, Inc.; Premier, Inc. Equity ImageCor; Me2Health Grant / Research support FDA; NIH-NHLBI; Commonwealth Fund; The Catherine and Patrick Weldon Donaghue Medical Research Foundation; Robert Wood Johnson Foundation; Medtronic; Johnson and Johnson; Chinese National Center for Cardiovascular Disease; FDA; CMS Editorial boards; American Journal of Managed Care; American Journal of Medicine; Archives of Medical Science; Central European Journal of Medicine; Critical Pathways in Cardiology; Current Cardiovascular Risk Reports; JACC: Cardiovascular Imaging; Journal of Cardiovascular Medicine; Circulation: Cardiovascular Quality and Outcomes Leadership positions in professional societies American Board of Internal Medicine (Chair, Assessment 2020 Task Force)


Reader Comments (5)

Victor Kantariya Physician, Family Medicine/General Practice

The findings prompt another look into whether the strong relationship between Lipid-Modifying Therapy and Post-ACS Outcomes. It`s possible that Nonobstructive coronary artery(CA) disease is associated with an increased risk of MI and complications with "normal" CA are not associated with atherosclerosis. In addition both statins and ezetimibe have pleotropic effects (non-lipid related mechanism) which can be related to Post-ACS Outcomes. Victor Kantariya MD

Anders Hernborg, M.D., PhD h.c. Physician, Family Medicine/General Practice, Hyltebruk, Sweden

When the results of IMPROVE-IT were announced in Nov 2014 and commented upon here by Prof H Krumholz I tried to get him to comment on the difference in primary endpoint results between diabetics (4,933 individuals, 27.2%) and non-diabetics (13,202, 72.8%). No response. I have seen many comment that results were specially good in diabetics, HR 0.86 [95%CI 0.78-0.94]. But I have seen no comment on the self-evident: then the result for non-diabetics (73 % of all particiants) must be worse: HR 0.98 [95%CI 0.92-1.04], that is a non-significant result. As by chance in the figure S2 (page 41 in the Supplementary Appendix) the p-value is there for diabetics (p=0.023) but the non-significant p-value for non-diabetics IS NOT THERE.
Could my favourite among US cardiologists Harlan Krumholz please comment on how to interprete these subgroup results for non diabetics. I know you should normally be cautious about subgroup results, but here we have a "subgroup" of 73 % of all participants and a far from significant result for that group. How do we generalize this result to non diabetics after a acute coronary syndrome?

DAVID NEWMAN Physician, Emergency Medicine, Icahn SOM at Mount Sinai

Power calculation and sample size adjusted three times when it became apparent the trial would fail planned effect size goals. Moved the goal posts. Meanwhile, no impact on mortality or stroke, and absolute effects on nonfatal MI and revascularization were, at best, piddly. Lipstick on a pig.

Victor Castilla Physician, Family Medicine/General Practice, South Central Family Health Center

I still think that ezetimibe is too expensive and the benefits are too low. I think it will be more beneficial (and cheaper) for the patient to be switch from simvastatin to atorvastatin since the reduction in LDL cholesterol with simvastatin 80 mg is 47% (41% with the recommended dose of 40 mg) and the reduction with atorvastatin 80 mg is 55%.

Camille Kilgore Other Healthcare Professional, Cardiology, Research

Patients were refractory to high dose statins and pre selection of investigators were determined based on various doses of statin with or without ezetamide. During the pre selection it was determined that use of ezetamide use varied amongst investigators. The outcome is consistent with the trials seen thus far with PCSK9 use.

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