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
Today’s Merck is a global healthcare leader working to help the
world be well. Merck is known as MSD outside the United States and
Canada. Through our prescription medicines, vaccines, biologic
therapies 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, visit www.merck.com and connect
with us on Twitter, Facebook and YouTube.
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.
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 health care
legislation in the United States and internationally; global trends
toward health care 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 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.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
MerckMedia:Pamela Eisele, 267-305-3558orMichael Close,
267-305-1211orInvestors:Justin Holko, 908-740-1879
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