Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced results from a pre-specified exploratory analysis of the investigational IMPROVE-IT study of more than 18,000 patients presenting with acute coronary syndromes. The new analysis shows that VYTORIN® (ezetimibe/simvastatin) – which combines simvastatin with the non-statin ZETIA® (ezetimibe) – reduced total (defined as initial and recurrent) cardiovascular events by 9% compared to simvastatin alone (incidence-rate ratio [IRR] 0.91, 95% CI 0.85-0.97, p=0.007; by treatment group, 4,562 vs. 4,983 total events, respectively). These data were presented as part of this afternoon’s late-breaking featured clinical research session at the 2015 American College of Cardiology Scientific Sessions.
The results on the trial’s primary endpoint of initial cardiovascular (CV) events – a composite of first CV death, non-fatal myocardial infarction, non-fatal stroke, re-hospitalization for unstable angina or coronary revascularization occurring at least 30 days after randomization – have been previously reported. For the primary endpoint, VYTORIN provided a 6.4% relative risk reduction compared to simvastatin alone (7-year event rates: 32.7% in the VYTORIN group vs. 34.7% in the simvastatin group; hazard ratio 0.936, p=0.016). The mean LDL-C at one year was 53 mg/dL in the VYTORIN group and 70 mg/dL in the simvastatin group. VYTORIN and ZETIA are indicated for use along with a healthy diet to reduce elevated LDL-C in patients with hyperlipidemia. The U.S. Prescribing Information for both products states that the effect of ezetimibe on CV morbidity and mortality, alone or incremental to statin therapy, has not been determined.
“In this new analysis, VYTORIN (ezetimibe/simvastatin) was shown to reduce the risk of total cardiovascular events, including those beyond the first event – in patients with already low LDL-C,” said Christopher Cannon, MD, professor of medicine at Harvard Medical School in the Cardiovascular Division at Brigham and Women’s Hospital. “The wealth of data from IMPROVE-IT is helping to address important scientific questions about the potential to further reduce cardiovascular risk in patients who have achieved very low LDL-C levels.”
In this analysis, researchers evaluated events comprising the primary endpoint during a median six year follow-up among the trial’s 18,144 participants. The analysis included 9,545 initial and recurrent events. Of these, 56% were first (i.e., primary composite endpoint) events, and 44% were subsequent events observed within that group. Among patients assigned to VYTORIN (ezetimibe/simvastatin), there were 2,572 first events and 1,990 subsequent events; among those assigned to simvastatin, there were 2,742 first events and 2,241 subsequent events. VYTORIN reduced total events by 9% vs. simvastatin alone (incidence-rate ratio [IRR] 0.91, 95% CI 0.85-0.97, p=0.007). This finding is based on the previously-reported 6.4% reduction in first events (HR 0.936 95% CI 0.887-0.988, p=0.016), along with a 12% reduction in recurrent events observed in the present analysis (IRR 0.88, 95% CI 0.79-0.98).
VYTORIN should not be taken with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products); or with gemfibrozil, cyclosporine, or danazol. VYTORIN also should not be taken by anyone with active liver disease, unexplained persistent elevations of hepatic transaminase levels, or hypersensitivity to the product; or by women who are pregnant, nursing or may become pregnant. ZETIA (ezetimibe) should not be taken by people with hypersensitivity to any component of the medication. Statin contraindications also apply when ZETIA is used with these drugs: statins are contraindicated in patients with active liver disease, unexplained persistent elevations in hepatic transaminase levels and in pregnant and nursing women. Refer to individual statin labels for details about who should not take that statin.
About the IMPROVE-IT Trial
IMPROVE-IT (IMProved Reduction of Outcomes: VYTORIN Efficacy International Trial) was led by the Thrombolysis In Myocardial Infarction (TIMI) Study Group of Brigham and Women’s Hospital and the Duke Clinical Research Institute (DCRI), and was sponsored by Merck. 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 CV events, as measured by a composite of CV 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 (VYTORIN) 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 79 mg/dL. 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 ≤125 mg/dL if lipid-lowering drug naïve or <100 mg/dL 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 70 mg/dL 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 VYTORIN® (ezetimibe/simvastatin)
VYTORIN contains ezetimibe and simvastatin. VYTORIN is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, and non–HDL cholesterol, and to increase HDL cholesterol in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia or mixed hyperlipidemia when diet alone is not enough.
The Prescribing Information for VYTORIN states that no incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established. VYTORIN is not indicated to reduce cardiovascular events in patients who have presented with acute coronary syndromes.
Selected cautionary information about VYTORIN
All patients starting therapy with VYTORIN, or whose dose of VYTORIN is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to promptly report any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing VYTORIN. VYTORIN should be discontinued immediately if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or suspected. VYTORIN contains simvastatin, which occasionally causes myopathy manifested as muscle pain, tenderness, or weakness with CK levels above 10 times ULN. Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment. The risk of myopathy, including rhabdomyolysis, is dose related.
The 10/80 mg dose of VYTORIN (ezetimibe/simvastatin) should not be started in new patients. The risk of myopathy, including rhabdomyolysis, is greater in patients taking simvastatin 80 mg compared with other statin therapies with similar or greater LDL cholesterol lowering efficacy, and with lower doses of simvastatin. The 10/80 mg dose of VYTORIN (ezetimibe/simvastatin) should be used only in patients who have been taking that dose chronically (e.g., for 12 months or more) without evidence of muscle toxicity. If a patient who is currently tolerating the 10/80 mg dose needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug interaction. Please read Warnings and Precautions in the Prescribing Information for additional information.
In addition to drugs that are contraindicated because of an increased risk of myopathy/rhabdomyolysis, grapefruit juice should be avoided. Use caution when prescribing VYTORIN with a fenofibrate, and immediately discontinue both drugs if myopathy is diagnosed or suspected. Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be used when prescribing VYTORIN with colchicine.
The dose of VYTORIN should not exceed 10/10 mg daily in patients receiving verapamil, diltiazem or dronedarone, and 10/20 mg daily in patients receiving amiodarone, amlodipine or ranolazine. For patients with homozygous familial hypercholesterolemia (HoFH) taking lomitapide, the dose should not exceed 10/20 mg/day (or 10/40 mg/day for patients who have previously taken simvastatin 80 mg/day chronically, e.g., for 12 months or more, without evidence of muscle toxicity); patients initiating lomitapide should have their dose of VYTORIN reduced by 50%. The benefits of combined use of VYTORIN with these drugs, other fenofibrates, or niacin (≥1 g/day) should be carefully weighed against the potential risk of myopathy/rhabdomyolysis. Caution should be used when Chinese patients taking niacin (≥1 g/day) are coadministered doses of VYTORIN exceeding 10/20 mg/day; Chinese patients should not receive VYTORIN 10/80 mg with niacin.
Persistent elevations in hepatic transaminase can occur. Liver function tests should be performed at treatment initiation and thereafter when clinically indicated. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, therapy should be interrupted promptly and not restarted unless an alternate etiology is found.
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including simvastatin.
In clinical trials, the most commonly reported side effects, regardless of cause, included headache (5.8 percent), increased ALT (3.7 percent), myalgia (3.6 percent), upper respiratory tract infection (3.6 percent), and diarrhea (2.8 percent).
VYTORIN (ezetimibe/simvastatin) tablets contain ezetimibe and simvastatin: 10 mg of ezetimibe and 10, 20, 40, or 80 mg of simvastatin (VYTORIN 10/10, 10/20, 10/40, or 10/80 mg, respectively). The usual dosage range is 10/10 mg/day to 10/40 mg/day; patients should not be titrated to the restricted 10/80-mg dose.
About ZETIA (ezetimibe)
ZETIA, administered alone or in combination with a statin, is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, apolipoprotein B, and non-HDL cholesterol in patients with primary (heterozygous familial and non-familial) hyperlipidemia when diet alone is not enough.
The Prescribing Information for ZETIA states that the effect of ZETIA on cardiovascular morbidity and mortality has not been determined. ZETIA is not indicated for use with a statin to further reduce cardiovascular events in patients who have presented with acute coronary syndromes.
Selected cautionary information about ZETIA
When using ZETIA with a statin, also follow the label recommendations for that specific statin.
When ZETIA was coadministered with a statin, consecutive elevations in hepatic transaminase levels (greater than or equal to 3 times ULN) were slightly higher (1.3 percent) than those of statins alone (0.4 percent). Liver function tests should be performed when ZETIA is added to statin therapy and according to statin recommendations. Should an increase in ALT or AST greater than or equal to 3 times ULN persist, consider withdrawal of ZETIA and/or the statin.
Patients should be advised to promptly report muscle pain, tenderness, or weakness. Risk for skeletal muscle toxicity increases with higher statin doses, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs. Discontinue drug if myopathy is diagnosed or suspected.
ZETIA is not recommended in patients with moderate to severe hepatic impairment.
The coadministration of ZETIA (ezetimibe) with fibrates other than fenofibrate is not recommended until use in patients is adequately studied. Exercise caution when using ZETIA and cyclosporine concomitantly because exposure to both drugs is increased. Cyclosporine concentrations should be monitored in these patients.
ZETIA should be used in pregnant or nursing women only if the benefit outweighs the risk.
In clinical trials, regardless of causality assessment, the most frequent side effects for ZETIA coadministered with a statin versus a statin alone included nasopharyngitis (3.7 percent vs 3.3 percent), myalgia (3.2 percent vs 2.7 percent), upper respiratory tract infection (2.9 percent vs 2.8 percent), arthralgia (2.6 percent vs 2.4 percent), and diarrhea (2.5 percent vs 2.2 percent); for ZETIA administered alone vs placebo: upper respiratory tract infection (4.3 percent vs 2.5 percent), diarrhea (4.1 percent vs 3.7 percent), arthralgia (3.0 percent vs 2.2 percent), sinusitis (2.8 percent vs 2.2 percent), pain in extremity (2.7 percent vs 2.5 percent), and fatigue (2.4 percent vs 1.5 percent).
About Merck
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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 2014 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).
Please see Prescribing Information for VYTORIN (ezetimibe/simvastatin) at http://www.merck.com/product/usa/pi_circulars/v/vytorin/vytorin_pi.pdfand the Patient Information for VYTORIN at http://www.merck.com/product/usa/pi_circulars/v/vytorin/vytorin_ppi.pdf
Please see Prescribing Information for ZETIA (ezetimibe) at http://www.merck.com/product/usa/pi_circulars/z/zetia/zetia_pi.pdf and the Patient Information for ZETIA at http://www.merck.com/product/usa/pi_circulars/z/zetia/zetia_ppi.pdf
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