VYTORIN® (ezetimibe/simvastatin) Significantly Reduced Cardiovascular Events More than Simvastatin Alone in Patients Presenting with Acute Coronary Syndromes in the Investigational IMPROVE-IT Study

Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced 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 VYTORIN® (ezetimibe/simvastatin) – which combines simvastatin with the non-statin ZETIA® (ezetimibe) -- 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 today 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 70 mg/dL by adding ezetimibe to a statin further reduced cardiovascular events. In IMPROVE-IT, at seven years, 32.7 percent of patients taking VYTORIN 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 53 mg/dL versus 70 mg/dL, respectively), the 6.4 percent relative risk reduction observed in the VYTORIN arm in IMPROVE-IT was consistent with the treatment effect that had been projected based on prior studies of statins.

Merck plans to submit the data from IMPROVE-IT to the U.S. Food and Drug Administration in mid-2015 to support a new indication for reduction of major cardiovascular events for VYTORIN and ZETIA. VYTORIN and ZETIA are currently indicated for use along with a healthy diet to reduce elevated LDL cholesterol in patients with hyperlipidemia. The current U.S. Prescribing Information for both products states that the effect of ezetimibe on cardiovascular morbidity and mortality, alone or incremental to statin therapy, has not been determined.

“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.”

VYTORIN (ezetimibe/simvastatin) 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.

IMPROVE-IT compared very low LDL-C levels -- a range at or below 70 mg/dL

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 53 mg/dL in the VYTORIN group and 70 mg/dL in the simvastatin group, with a between-group difference of 17 mg/dL. When the IMPROVE-IT study was initiated in 2005, the optional recommended target LDL-C level in the United States for acute coronary syndrome patients and other groups considered to be at very high risk for cardiovascular events was <70 mg/dL. Prior cardiovascular outcomes studies of statins have not compared treatments at such low LDL-C levels (see Table).

At the start of the study, the average baseline LDL-C was approximately 95 mg/dL. Among treatment-naïve patients (about two-thirds of those in the study), the mean baseline LDL-C was 101 mg/dL. Among patients on prior lipid lowering therapy at enrollment, the mean baseline LDL-C was 80 mg/dL.

Additional efficacy and safety results from IMPROVE-IT

Patients in IMPROVE-IT were initially randomized to treatment with VYTORIN (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 VYTORIN experienced significant reductions compared to patients taking simvastatin alone on the three secondary composite efficacy endpoints, as follows:

• VYTORIN 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 VYTORIN and 40.3 percent of patients taking simvastatin only (hazard ratio of 0.948, p=0.034).
• VYTORIN 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 VYTORIN and 18.9 percent of patients taking simvastatin only (hazard ratio of 0.912, p=0.016).
• VYTORIN 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 VYTORIN 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.”

About VYTORIN® (ezetimibe/simvastatin)

VYTORIN contains ezetimibe and simvastatin. VYTORIN is indicated as adjunctive therapy to diet for the reduction of 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 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 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 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).

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 (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.

For additional information about the study, please see the accompanying study timeline.

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Please see Prescribing Information for VYTORIN (ezetimibe/simvastatin) at http://www.merck.com/product/usa/pi_circulars/v/vytorin/vytorin_pi.pdf and 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.