Printer Friendly

Updated IMPROVE-IT results show bigger benefits.


SAN DIEGO -- The presentation of the landmark IMPROVE-IT study at last November's American Heart Association scientific sessions told only half the story of the clinical impact of lipid-lowering with the combination of ezetimibe and simvastatin as opposed to simvastatin alone.

That's because the main analysis included only the patients' first cardiovascular events. Many who had a nonfatal first event went on to have a second, third, or fourth event. Additional events haven't been counted in acute coronary syndrome clinical trials, but should be, Sabina A. Murphy said at the annual meeting of the American College of Cardiology.

"Total events have implications for patient morbidity, clinical management, need for recurrent hospitalization, and total costs," said Ms. Murphy, head of biostatistics at the TIMI Study Group at Brigham and Women's Hospital, Boston.

In last November's initial findings from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), the combination of 10 mg ezetimibe/40 mg simvastatin (Vytorin) daily resulted in a modest yet statistically significant 6.4% relative risk reduction in the primary composite endpoint, compared with 40 mg of simvastatin alone, reported Dr. Christopher P. Cannon, professor of medicine at Harvard Medical School, Boston.

Most observers hailed this result as clinically important, since IMPROVE-IT was the first study to show that lowering cholesterol with a nonstatin reduces cardiovascular events, and it showed that the lower a patient's LDL cholesterol, the better the outcomes: The mean LDL with combination therapy was 54 mg/dL, compared with 70 mg/dL in controls.

The double-blind study included 18,144 patients randomized within 10 days of an acute coronary syndrome. The primary composite outcome comprised cardiovascular death, nonfatal MI, nonfatal stroke, rehospitalization for unstable angina, and coronary revascularization. The 6.4% relative risk reduction was based solely on first events, of which there were 5,314 during a median 6 years of follow-up. But there were also 4,231 subsequent primary endpoint events, including 2,297 second events, 972 third events, and 456 fourth ones.

While 170 fewer first events occurred with combination therapy than with simvastatin alone, there were 251 fewer additional or recurrent cardiovascular events in the ezetimibe/simvastatin group which were not incorporated in the initial analysis.

While the relative risk reduction for first primary endpoint events was 6.4% with combination therapy, the risk of additional events was reduced by 12%, resulting in a more substantial 9% relative risk reduction for total events.

For the prespecified secondary composite endpoint consisting of death due to coronary heart disease, nonfatal MI, or urgent coronary revascularization, the initial analysis based solely on first events showed an 8.8% relative risk reduction with ezetimibe/simvastatin. But the fuller view includes a 21% reduction in the risk of additional events, resulting in a 15% relative risk reduction for total events during a median 6 years of follow-up.

In an exploratory analysis examining the harder endpoints of cardiovascular death, nonfatal MI, or cerebrovascular accident, the relative risk reduction for total events was 12% with combination therapy. Ezetimibe/simvastatin was associated with a 13% reduction in all nonfatal MIs occurring during follow-up and a 23% reduction in nonfatal strokes, according to Ms. Murphy. Among every 1,000 IMPROVE-IT participants on ezetimibe/simvastatin rather than simvastatin alone for 1 year, there were 11 fewer total primary outcome events, including 5 fewer nonfatal Mis, 2 fewer nonfatal strokes, and 4 fewer revascularization procedures.

She reported serving as a consultant to Merck and receiving research grants from AstraZeneca, Daiichi Sanko, GlaxoSmithKline, and Merck.


Key clinical point: Adding up the total number of cardiovascular events avoided by a medication in IMPROVE-IT rather than just the first one--as has been customary--showed further benefit of combination therapy.

Major finding: While the combination of ezetimibe and simvastatin reduced the risk of a first cardiovascular event by 6.4% compared to simvastatin alone, as previously reported, a new analysis shows the combo reduced total events--including the additional ones that followed a patient's first--by a more robust 9%.

Data source: IMPROVE-IT, a randomized, double-blind, prospective study of more than 18,000 patients enrolled within 10 days of an acute coronary syndrome.

Disclosures: The presenter disclosed ties to Merck, which sponsored the study.
COPYRIGHT 2015 International Medical News Group
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2015 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Jancin, Bruce
Publication:Internal Medicine News
Date:Apr 15, 2015
Previous Article:Anticipation high for coming cardiology megatrials.
Next Article:Time to follow-up after positive FOBT varies widely.

Terms of use | Privacy policy | Copyright © 2018 Farlex, Inc. | Feedback | For webmasters