Ezetimibe/simvastatin used in a fixed-dose combination Significantly Reduced Cardiovascular Events More than Simvastatin Alone in Patients Presenting with Acute Coronary Syndromes in the Investigational IMPROVE-IT Study Français
KIRKLAND, QC, Nov. 19, 2014 /CNW Telbec/ - Merck, known as MSD outside of Canada and the United States, announced on November 17, 2014, that the investigational IMPROVE-IT study met its primary and all secondary composite efficacy endpoints. In IMPROVE-IT, patients taking the LDL-cholesterol-lowering medicine ezetimibe/simvastatin in a fixed-dose combination - the fixed-dose combination of ezetimibe/simvastatin is not available in Canada; the individual components: simvastatin (ZOCOR®) and ezetimibe (EZETROL®) are available in Canada - experienced significantly fewer major cardiovascular events (as measured by a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, re-hospitalization for unstable angina or coronary revascularization occurring at least 30 days after randomization) than patients treated with simvastatin alone. The results from this 18,144-patient study of high-risk patients presenting with acute coronary syndromes were presented on November 17 during the late-breaking clinical trials session at the American Heart Association 2014 Scientific Sessions.
Because high-risk patients treated with statins, including those on treatment with low levels of LDL-cholesterol (LDL-C), continue to be at increased cardiovascular risk, IMPROVE-IT was designed to address whether lowering LDL-C to well under 1.8 mmol/L by adding ezetimibe to a statin further reduced cardiovascular events. In IMPROVE-IT, at seven years, 32.7 percent of patients taking ezetimibe/simvastatin in a fixed-dose combination experienced a primary endpoint event compared to 34.7 percent of patients taking simvastatin alone (hazard ratio of 0.936, p=0.016). Based on the LDL-C range compared in the study's treatment arms (at one year, a mean LDL-C of 1.37 mmol/L versus 1.8 mmol/L, respectively), the 6.4 percent relative risk reduction observed in the ezetimibe/simvastatin arm in IMPROVE-IT was consistent with the treatment effect that had been projected based on prior studies of statins.
ZOCOR® and EZETROL® are currently indicated for use along with a healthy diet to reduce elevated LDL (bad) cholesterol in patients with hyperlipidemia. ZOCOR® is also indicated to reduce the risk of myocardial infarction, ischemic stroke and total mortality, by reducing CHD deaths. Current labeling for EZETROL® states that the effects of ezetimibe given either alone or in addition to a statin or fenofibrate on cardiovascular morbidity and mortality have not been established.
"In IMPROVE-IT, the addition of ezetimibe to a statin resulted in a further reduction in cardiovascular events compared to statin therapy alone, which is the first time this has been directly shown in a study of a non-statin cholesterol-lowering medicine," said study co-chairs, Drs. Eugene Braunwald of Harvard Medical School and Robert Califf of Duke University. "The IMPROVE-IT data also address an important scientific question about lowering LDL-C to very low levels."
"Despite the progress made in cardiovascular care, cardiovascular disease represents the 2nd leading cause of death in Canada,1" added Dr. Armstrong, Director of the Canadian Virtual Coordinating Centre for Global Collaborative Cardiovascular Research (VIGOUR) ) at the University of Alberta. "Of note, more than 80 Canadian investigators and over 1000 Canadian patients participated in the IMPROVE-IT International trial. Hence, the results of this trial are relevant to the Canadian medical community."
IMPROVE-IT compared very low LDL-C levels -- a range at or below 1.8 mmol/L
In IMPROVE-IT (IMProved Reduction of Outcomes: VYTORIN Efficacy International Trial), the LDL-C levels compared were very low. At one year, the mean LDL-C level was 1.37 mmol/L in the ezetimibe/simvastatin group and 1.8 mmol/L in the simvastatin group, with a between-group difference of 0.44 mmol/L. When the IMPROVE-IT study was initiated in 2005, the optional recommended target LDL-C level for acute coronary syndrome patients and other groups considered to be at very high risk for cardiovascular events was 1.8 mmol/L per NCEP ATP III guidelines (2004 update). Prior cardiovascular outcomes studies of statins have not compared treatments at such low LDL-C levels (see Table).
Table: LDL-C Comparison Ranges Between Treatment Arms in Selected Trials* |
|||||
Trial |
IDEAL(2005) |
TNT(2005) |
PROVE-IT |
A to Z |
IMPROVE-IT(2014) |
LDL-C Comparison Range (mmol/L)§ |
2.7 |
2.6 |
2.5 |
2.0 |
1.8 |
*Blazing, et al. Am H J 2014; 168: 205-212. §All values are expressed as means except PROVE-IT and A to Z, which are expressed as medians. |
At the start of the study, the average baseline LDL-C was approximately 2.5 mmol/L. Among treatment-naïve patients (about two-thirds of those in the study), the mean baseline LDL-C was 2.6 mmol/L. Among patients on prior lipid lowering therapy at enrollment, the mean baseline LDL-C was 2.1 mmol/L.
Additional efficacy and safety results from IMPROVE-IT
Patients in IMPROVE-IT were initially randomized to treatment with ezetimibe/simvastatin 10/40 mg or simvastatin 40 mg. Patients were followed for up to nine years, with a median clinical follow-up of approximately six years. In this event-driven study, 5,314 primary endpoint events were reported.
In addition to the significant result on the primary composite efficacy endpoint, patients taking ezetimibe/simvastatin experienced significant reductions compared to patients taking simvastatin alone on the three secondary composite efficacy endpoints, as follows:
- Ezetimibe/simvastatin reduced the incidence of the composite endpoint of death due to all causes, major coronary events, and non-fatal stroke; this endpoint occurred in 38.7 percent of patients taking ezetimibe/simvastatin and 40.3 percent of patients taking simvastatin only (hazard ratio of 0.948, p=0.034).
- Ezetimibe/simvastatin reduced the incidence of the composite endpoint of death due to coronary heart disease (CHD), non-fatal myocardial infarction (MI), and urgent coronary revascularization with either percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) occurring at least 30 days after randomization; this endpoint occurred in 17.5 percent of patients taking ezetimibe/simvastatin and 18.9 percent of patients taking simvastatin only (hazard ratio of 0.912, p=0.016).
- Ezetimibe/simvastatin reduced the incidence of the composite endpoint of cardiovascular death, non-fatal MI, documented unstable angina that requires admission into a hospital, all revascularization (including both coronary and non-coronary) occurring at least 30 days after randomization, and non-fatal stroke; this endpoint occurred in 34.5 percent of patients taking ezetimibe/simvastatin and 36.2 percent of patients taking simvastatin only (hazard ratio of 0.945, p=0.035).
There were no significant differences between treatment groups in adverse events of special interest, which included myopathy and rhabdomyolysis, gallbladder adverse events, liver enzyme elevations greater than or equal to three times the upper limit of normal (ULN) and cancer. These safety findings from IMPROVE-IT were generally consistent with current labeling for ezetimibe. Among 9,067 patients in the ezetimibe/simvastatin group vs. 9,077 patients in the simvastatin group, myopathy was reported in 0.2 percent vs. 0.1 percent of patients, respectively; rhabdomyolysis was reported in 0.1 percent vs. 0.2 percent; gallbladder-related adverse events were reported in 3.1 percent vs. 3.5 percent; cholecystectomy was reported in 1.5 percent vs. 1.5 percent; and alanine aminotransferase (ALT) and/or aspartate transaminase (AST) elevations (greater than or equal to three times ULN, consecutive) were reported in 2.5 percent vs. 2.3 percent of patients. Over seven years, cancer was reported in 10.2 percent of patients in both treatment groups.
"We believe that the IMPROVE-IT study makes an important scientific contribution to the body of evidence relating LDL-cholesterol levels to cardiovascular risk," said Dr. Roger Perlmutter, president, Merck Research Laboratories. "We are grateful to our collaborators at Harvard and Duke who led the study, their fellow investigators, and to the thousands of patients around the world who participated in this study for their efforts."
Additional information about the IMPROVE-IT study
IMPROVE-IT was an international, multi-center, randomized, double-blind active comparator trial of 18,144 high-risk patients presenting with acute coronary syndromes (ACS), including unstable angina (UA), non-ST-segment elevation acute myocardial infarction (NSTEMI), and ST-segment elevation acute myocardial infarction (STEMI). The study assessed the incidence of major cardiovascular events, as measured by a composite of cardiovascular death, non-fatal MI, non-fatal stroke, re-hospitalization for ACS, or coronary revascularization (occurring 30 days or more after the initial event), in patients treated with ezetimibe/simvastatin in a fixed-dose combination compared with patients treated with simvastatin alone.
All patients in the trial were started at doses of ezetimibe/simvastatin 10/40 mg or simvastatin 40 mg. Prior to a 2011 protocol amendment, the dose could be titrated to ezetimibe/simvastatin 10/80 mg or simvastatin 80 mg if successive LDL-C values exceeded 2.0 mmol/L. The study enrolled patients within 10 days of ACS hospitalization who had sufficient risk as defined in the protocol and who had an initial LDL-C of ≤3.2 mmol/L if lipid-lowering drug naïve or <2.6 mmol/L if on a prior prescription lipid-lowering therapy identified as no more potent than simvastatin 40 mg/day. The LDL-C entry limitations were designed to enroll patients reasonably anticipated to achieve LDL-C levels of 1.8 mmol/L or less in the simvastatin only cohort, which was the optional recommended target set in the 2004 update to the Adult Treatment Panel (ATP) III guidelines.
About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside Canada and the United States. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information about our operations in Canada, visit www.merck.ca.
Forward-Looking Statement
This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.
Risks and uncertainties include, but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and healthcare legislation in the United States and internationally; global trends toward healthcare cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck's ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck's patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.
Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2013 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).
1. Statistics Canada, 2014
ZOCOR® Registered trademarks of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Used under license.
EZETROL® Registered trademark of MSP Singapore Company, LLC. Used
SOURCE: Merck Canada Inc.
For further information: Media Contacts: Annick Robinson, Merck Canada, (438) 837-2550; Stephanie Lyttle, NATIONAL Public Relations, 514-843-2365; Investor Contacts: Joseph Romanelli, Merck Canada, (908) 423-5185; Justin Holko, (908) 423-5088
Share this article