New Data from IMPROVE-IT Study of VYTORIN® (ezetimibe/simvastatin) and TRA 2ºP TIMI 50 Study of ZONTIVITY® (vorapaxar) to be Presented at American College of Cardiology Scientific Sessions
February 25, 2015 8:00 am ET
Investigational data from IMPROVE-IT to be announced in Featured Clinical Research Session II
Merck (NYSE:MRK), known as MSD outside the United States and Canada,
announced today that new data from two trials of the company’s
cardiovascular medicines will be presented at the 2015 American College
of Cardiology Annual Scientific Sessions (ACC.15), March 14-16 in San
Diego. In all, eleven data presentations from company-sponsored studies
will be presented at ACC.15, including new data from the investigational
IMPROVE-IT (IMProved Reduction of Outcomes: VYTORIN Efficacy
International Trial) study of VYTORIN (ezetimibe/simvastatin) and
exploratory sub-analyses of the TRA 2°P TIMI 50 (Thrombin Receptor
Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events)
trial of ZONTIVITY (vorapaxar).
“The American College of Cardiology’s 64th Annual Scientific
Sessions provide an opportunity for Merck to share new data from two of
the largest cardiovascular outcomes trials of recent years,” said Dr.
Daniel Bloomfield, vice president, Cardiovascular Diseases, Merck
Research Laboratories. “We are pleased to share new data from these
important studies with the scientific community.”
The primary results from the IMPROVE-IT trial of VYTORIN, which combines
simvastatin with the non-statin ZETIA® (ezetimibe), were presented in
November 2014. VYTORIN and ZETIA are indicated for use along with a
healthy diet to reduce elevated LDL cholesterol in patients with
hyperlipidemia. The current U.S. Prescribing Information for VYTORIN and
ZETIA states that the effect of ezetimibe on cardiovascular morbidity
and mortality, alone or incremental to statin therapy, has not been
The TRA 2°P TIMI 50 study of ZONTIVITY (vorapaxar) supported the May
2014 approval of that medicine for the reduction of thrombotic
cardiovascular events in patients with a history of myocardial
infarction (MI) or in patients with peripheral arterial disease (PAD).
In TRA 2°P TIMI 50, ZONTIVITY was shown to reduce the rate of a combined
endpoint of cardiovascular death, MI, stroke and urgent coronary
revascularization. The U.S. Prescribing Information for ZONTIVITY
includes a boxed warning regarding bleeding risk, which states that
ZONTIVITY is not for use in patients with a history of stroke, transient
ischemic attack (TIA) or intracranial hemorrhage (ICH), or active
pathological bleeding. Antiplatelet agents, including ZONTIVITY,
increase the risk of bleeding, including ICH and fatal bleeding.
The following data will be presented at ACC.15:
IMPROVE-IT Data in Featured Clinical Research Session II
(Abstract #414-03) Reduction in Total (First and Recurrent)
Cardiovascular Events with Ezetimibe/Simvastatin compared with
Simvastatin Alone post-Acute Coronary Syndromes in the IMPROVE-IT
Trial. S. Murphy
- Monday, March 16 12:30 PM-12:45 PM PT. Location: Room 6E.
TRA 2°P TIMI 50 Trial
(Abstract #1131M-11) Vorapaxar and Acute Limb Ischemia: Insights
from the Thrombin Receptor Antagonist in Secondary Prevention of
Atherothrombotic Ischemic Events-TIMI 50 Trial. A. Gutierrez
Saturday, March 14; 11:00 AM-11:10 AM PT. Location: Vascular
Medicine Moderated Poster Theater, Poster Hall B1.
- Saturday, March 14; 11:00 AM-11:10 AM PT. Location: Vascular
(Abstract #905-04) The role of Vorapaxar in Patients with
Coronary Artery Bypass Grafting: Findings from the TRA 2P-TIMI 50
Trial. E. Kosova
- Sunday, March 15; 10:57 AM-11:08 AM PT. Location: Room 7B.
(Abstract #1131M-05) Vorapaxar and Peripheral Revascularization:
Insights from the TRA2P-TIMI 50 Trial. I. Gilchrist
Saturday, March 14; 10:15 AM-10:25 AM PT. Location: Vascular
Medicine Moderated Poster Theater, Poster Hall B1.
- Saturday, March 14; 10:15 AM-10:25 AM PT. Location: Vascular
(Abstract #1131M-03) Statin Intensity and Outcome in Patients
with Peripheral Artery Disease: Insights from the TRA2P-TIMI 50 Trial.
Saturday, March 14; 10:00 AM-10:10 AM PT. Location: Vascular
Medicine Moderated Poster Theater, Poster Hall B1.
- Saturday, March 14; 10:00 AM-10:10 AM PT. Location: Vascular
Additional Merck-sponsored Data
(Abstract #1125M-09) Baseline LDL-C and Clinical Outcomes with
Addition of Ezetimibe to Statin in 18,144 Patients Post ACS. R.
Saturday, March 14; 10:45 AM-10:55 AM PT. Location: Acute
Coronary Syndromes Moderated Poster Theater, Poster Hall B1.
- Saturday, March 14; 10:45 AM-10:55 AM PT. Location: Acute
(Abstract #1125M-07) Risk Stratification for Cardiovascular
Events in the IMPROVE-IT Trial. E. Bohula
Saturday, March 14; 10:30 AM-10:40 AM PT. Location: Acute
Coronary Syndromes Moderated Poster Theater, Poster Hall B1.
- Saturday, March 14; 10:30 AM-10:40 AM PT. Location: Acute
(Abstract #1133M-05) Cholesterol in Remnant-Lipoproteins as
Measured by Different Methods. P. Toth
Saturday, March 14; 10:15 AM-10:25 AM PT. Location: Stable
Ischemic Heart Disease Moderated Poster Theater, Poster Hall B1.
- Saturday, March 14; 10:15 AM-10:25 AM PT. Location: Stable
(Abstract #1194-364) Ezetimibe Does Not Increase Fasting Glucose
Levels More than Statins Alone in Non-Diabetic, Hypercholesterolemic
Patients. P. Toth
- Sunday, March 15; 9:45 AM-10:30 AM PT. Location: Poster Hall B1.
(Abstract #1211-119) Low LDL-Cholesterol Target
Achievement in Statin-Treated Patients in Clinical Practice in China
and Europe: Results of the Dyslipidemia International Study (DYSIS) A.
- Sunday, March 15; 3:45 PM-4:30 PM PT. Location: Poster Hall B1.
(Abstract # 1261-347) Effect of Beta-Blockade on
Cardiovascular Event Rates in Patients with Asymptomatic Aortic
Stenosis C. Bang
- Monday, March 16; 9:45 AM-10:30 AM PT. Location: Poster Hall B1.
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.
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.
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 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 (ezetimibe/simvastatin) 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.
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
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 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 ZONTIVITY (vorapaxar)
ZONTIVITY is indicated for the reduction of thrombotic cardiovascular
events in patients with a history of MI or with PAD. ZONTIVITY has been
shown to reduce the rate of a combined endpoint of cardiovascular death,
MI, stroke, and urgent coronary revascularization. ZONTIVITY inhibits
the protease-activated receptor-1 (PAR-1), the primary receptor for
thrombin, which is considered to be the most potent activator of
platelets. The PAR-1 pathway participates in the formation of blood
clots through the activation and aggregation of platelets.
ZONTIVITY is a once-daily tablet containing 2.08 mg vorapaxar,
equivalent to 2.5 mg vorapaxar sulfate. ZONTIVITY was studied only as an
addition to aspirin and/or clopidogrel and should be used with aspirin
and/or clopidogrel according to their indications or standard of care.
There is no experience with use of ZONTIVITY alone as the only
administered antiplatelet agent.
Additional selected safety information about ZONTIVITY
ZONTIVITY is contraindicated in patients with a history of stroke, TIA,
or ICH and in patients with active pathological bleeding such as ICH or
peptic ulcer. Discontinue ZONTIVITY in patients who experience a stroke,
TIA, or ICH.
Antiplatelet agents, including ZONTIVITY, increase the risk of bleeding,
including ICH and fatal bleeding. ZONTIVITY increases the risk of
bleeding in proportion to the patient’s underlying bleeding risk.
Physicians should consider the underlying risk of bleeding before
General risk factors for bleeding include older age, low body weight,
reduced renal or hepatic function, and history of bleeding disorders.
Use of certain concomitant medications (e.g., anticoagulants,
fibrinolytic therapy, chronic nonsteroidal anti-inflammatory drugs,
selective serotonin reuptake inhibitors, serotonin norepinephrine
reuptake inhibitors) also increases the risk of bleeding. Avoid
concomitant use of warfarin or other anticoagulants.
Withholding ZONTIVITY for a brief period will not be useful in managing
an acute bleeding event because, due to its long half-life, significant
inhibition of platelet aggregation remains four weeks after
discontinuation. There is no known treatment to reverse the antiplatelet
effect of ZONTIVITY.
Strong CYP3A inhibitors increase and inducers decrease ZONTIVITY
exposure. Avoid concomitant use of ZONTIVITY with strong CYP3A4
inhibitors or inducers.
Based on the increased inherent risk of bleeding in patients with severe
hepatic impairment, ZONTIVITY is not recommended in these patients.
Bleeding, including life-threatening and fatal bleeding, is the most
commonly reported adverse reaction with ZONTIVITY (vorapaxar). Among
post-MI or PAD patients with no history of stroke or TIA, three-year
bleeding rates (shown with hazard ratios and 95% confidence intervals)
in patients who added ZONTIVITY (vorapaxar) or placebo, respectively, to
aspirin and/or clopidogrel were:
—GUSTO moderate or severe bleeding,a 3.7% vs 2.4%, HR 1.55
—GUSTO severe bleeding,a 1.3% vs 1.0%, HR 1.24 (0.92-1.66)
—Any GUSTO bleeding (severe/moderate/mild),a 27.7% vs 19.8%,
HR 1.52 (1.43-1.61)
—ICH, 0.6% vs 0.4%, HR 1.46 (0.92-2.31)
—Fatal bleeding, 0.2% vs 0.2%, HR 1.15 (0.56-2.36)
—Clinically significant bleeding,b 15.5% vs 10.9%, HR 1.47
Additional Information about the IMPROVE-IT Trial
IMPROVE-IT was a 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). Patients were randomized to receive
ezetimibe/simvastatin (VYTORIN) or simvastatin alone, and were followed
for up to nine years, with a median clinical follow-up of approximately
six years. The primary efficacy endpoint was the 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).
Additional Information about the TRA 2°P TIMI 50 Trial
TRA 2°P TIMI 50 was a multi-center, randomized, double-blind,
placebo-controlled trial of 26,449 patients with a history of
spontaneous MI within the prior two weeks to twelve months, ischemic
stroke, or documented (symptomatic) PAD. Among all randomized patients,
20,170 had a history of MI or PAD and had no history of stroke or TIA
(contraindications for ZONTIVITY include a history of stroke or TIA).
Patients were randomized to receive daily treatment with ZONTIVITY or
placebo in addition to standard of care that included aspirin and/or a
thienopyridine (principally clopidogrel), and were followed for up to
four years, with a median follow-up of 2.5 years. The primary efficacy
endpoint was the composite of CV death, MI, stroke, and UCR, and the key
secondary efficacy endpoint was the composite of CV death, MI, and
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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
Please see Prescribing Information, including Boxed Warning, for
ZONTIVITY (vorapaxar) at http://www.merck.com/product/usa/pi_circulars/z/zontivity/zontivity_pi.pdf
and Medication Guide for ZONTIVITY at http://www.merck.com/product/usa/pi_circulars/z/zontivity/zontivity_mg.pdf
a GUSTO severe bleeding: fatal, intracranial, or bleeding
with hemodynamic compromise requiring intervention; GUSTO moderate
bleeding: bleeding requiring transfusion of whole blood or packed red
blood cells without hemodynamic compromise.
b Clinically significant bleeding: bleeding requiring medical
attention including ICH, or clinically significant overt signs of
hemorrhage with a drop in Hgb ≥3 g/dL (or, when Hgb is not available, an
absolute drop in Hct ≥9%).
Pamela Eisele, 267-305-3558
Michael Close, 267-305-1211
Justin Holko, 908-423-5088