New Analysis from Investigational IMPROVE-IT Study Shows VYTORIN® (ezetimibe/simvastatin) Reduced Total (Initial and Recurrent) Cardiovascular Events More than Simvastatin Alone in Patients Presenting with Acute Coronary Syndromes


March 16, 2015 3:30 pm ET

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

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

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

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

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

About Merck

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filings with the Securities and Exchange Commission (SEC) available at
the SEC’s Internet site (

Please see Prescribing Information for VYTORIN
(ezetimibe/simvastatin) at
and the Patient Information for VYTORIN at

Please see Prescribing Information for ZETIA (ezetimibe) at
and the Patient Information for ZETIA at

Pamela Eisele, 267-305-3558
Michael Close, 267-305-1211
Justin Holko, 908-740-1879

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