Results from Investigational IMPROVE-IT Study of VYTORIN® (ezetimibe and simvastatin) Published in the New England Journal of Medicine
June 3, 2015 4:00 pm ET
Merck (NYSE: MRK),
known as MSD outside the United States and Canada, today announced that
the New England Journal of Medicine published the results
of the IMPROVE-IT trial, an investigational study comparing treatment
with VYTORIN® (ezetimibe and simvastatin) to treatment with
simvastatin alone in more than 18,000 patients presenting with acute
of IMPROVE-IT were first presented at the American Heart Association
Scientific Sessions in November, 2014. In IMPROVE-IT, patients taking
the LDL-cholesterol-lowering medicine VYTORIN— 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.
“IMPROVE-IT was designed to answer a very important scientific question
about the relationship between cardiovascular risk and lowering LDL-C to
very low levels with ezetimibe in combination with a statin, and we are
pleased that the results are now being published in NEJM,” said Eugene
Braunwald, M.D., study co-chair, founding chair of the TIMI Study Group
at Brigham and Women’s Hospital. “We are very grateful to our
investigators and to the participating patients for their commitment to
completion of this complex, nine-year study. The analyses of the 18,000
patient IMPROVE-IT study are a robust addition to the many other
important studies on the importance of lowering LDL-C.”
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. Merck has
submitted the data from the IMPROVE-IT study to the U.S. Food and Drug
Administration to support a new indication for reduction of
cardiovascular events for ZETIA (ezetimibe) and VYTORIN (ezetimibe and
In November 2014, Merck announced IMPROVE-IT met its primary and all
secondary composite efficacy endpoints. In IMPROVE-IT, at seven years,
32.7 percent of patients taking VYTORIN experienced a first primary
endpoint event (major cardiovascular event) compared to 34.7 percent of
patients taking simvastatin alone, corresponding to a 6.4% relative risk
reduction (absolute risk reduction 2%, hazard ratio of 0.936, 95% CI
0.887 to 0.988, p=0.016). The mean LDL-C in the study at one year was 53
mg/dl in the VYTORIN arm and 70 mg/dl in the simvastatin arm.
In a separate exploratory analysis of major vascular events, the risk
reduction in the VYTORIN arm compared to the simvastatin alone arm was
consistent with the treatment effect that had been projected based on
prior studies of statins.
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, new, relapsing or progressing cancer was reported in
10.2 percent of patients in both treatment groups.
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 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 and
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 and 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 (ezetimibe and
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 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 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 (ezetimibe and
simvastatin) 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 (ezetimibe) 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 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
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Please see Prescribing Information for VYTORIN (ezetimibe and
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
Pamela Eisele, (267) 305-3558
Tracy Ogden, (267) 305-2301
Justin Holko, (908) 740-1879