Clinical Trials

COMMIT Trial


The COMMIT Trial (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) was a randomized, double-blind, placebo-controlled trial with a 2x2 factorial design. In all, 45,853 patients from 1,250 centers in China presenting within 24 hours of the onset of symptoms of suspected MI with supporting ECG abnormalities were randomized to receive PLAVIX 75 mg once daily or placebo in combination with aspirin 162 mg once daily for 28 days or hospital discharge.


COMMIT Trial Results

COMMIT–45,852 STEMI Patients in the
Acute Care Setting1

Relative risk reduction of 7% for death before discharge, with PLAVIX + Aspirin rate of 7.5%, and Placebo + Aspirin 8.1% up to 28 days since randomization.

Lower all-cause mortality for ACS patient with STEMI (onset ≤24 hours) up to 28 days1,6

  • The primary outcome of death occurred in 7.5% of patients in the PLAVIX + aspirin group and 8.1% in the placebo + aspirin group during the scheduled treatment period.
  • 7% RELATIVE RISK REDUCTION for all-cause mortality (P=0.029).

Safety

In the COMMIT Trial of 45,852 STEMI Patients, the overall rate of non-cerebral major bleeding or cerebral bleeding was low and similar in both groups1


PLAVIX + aspirin in STEMI % Incidence
COMMIT–until hospital discharge or
up to 28 days1		 PLAVIX + aspirin
n=22,961		 Placebo + aspirin
n=22,891		 P-value
Major bleeding 0.6 0.5 0.59
Major non-cerebral bleeding 0.4 0.3 0.48
Fatal non-cerebral bleeding 0.2 0.2 0.90
Hemorrhagic stroke 0.2 0.2 0.91
Fatal hemorrhagic stroke 0.2 0.2 0.81
Other non-cerebral bleeding (nonmajor) 3.6 3.1 0.005
Any non-cerebral bleeding 3.9 3.4 0.004

Major bleeding rates were cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion.


In the COMMIT Trial, 11,934 patients were ≥70 years old6

The relative rate of major non-cerebral or cerebral bleeding was independent of age (event rates by age for PLAVIX and aspirin vs. placebo and aspirin: <60=0.3% vs. 0.4%; ≥60 to <70=0.7% vs. 0.6%; ≥70=0.8% vs. 0.7%

View the COMMIT Trial — Journal Abstract

The effectiveness of Plavix depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Poor metabolizers treated with Plavix at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers (See Full PLAVIX Prescribing Information for Complete BOXED WARNING).

PLAVIX is contraindicated in patients with active pathologic bleeding such as peptic ulcer or intracranial hemorrhage. Co-administering warfarin with PLAVIX increases the risk of bleeding. Co-administration of PLAVIX and NSAIDs increases the risk of gastrointestinal bleeding.1

TTP, sometimes fatal, has been reported following use of PLAVIX, sometimes after a short exposure (<2 weeks). TTP is a serious condition that requires urgent treatment including plasmapheresis (plasma exchange).1



CLARITY Trial � a bridging trial to COMMIT, which supports a 300 mg PLAVIX loading dose in a STEMI patient population


The CLARITY Trial (CLopidogrel as Adjunctive ReperfusIon TherapY) was a randomized, double-blind, placebo-controlled trial of 3,491 patients (5% US) from 319 centers in 23 countries presenting within 12 hours of the onset of ST-segment elevation acute myocardial infarction (MI) who were scheduled to receive thrombolytic therapy. Patients were randomized to receive a PLAVIX 300 mg loading dose, followed by PLAVIX 75 mg once daily or placebo up to the day of angiography. Those not receiving angiography received treatment up to day 8 or discharge, whichever came first. All patients received aspirin (150 mg-325 mg on the first day and 75 mg-162 mg/day thereafter). Patients were followed 30 days.


CLARITY Trial Results

  • Event rate: 15% for PLAVIX + aspirin (n=262) vs 21.7% for placebo + aspirin (n=377)
  • Absolute risk reduction: 6.7%
  • PLAVIX 75 mg + aspirin 75 to 162 mg vs placebo + aspirin 75 to 162 mg
  • Primary end point: composite of an occluded infarct-related artery on the predischarge angiography, or death or recurrent MI before angiography, discharge, or day 8, whichever came first

Safety

In the CLARITY trial of 3,491 STEMI patients, the incidence of fatal bleeding and intracranial hemorrhage was low and similar in both groups5,7


PLAVIX + aspirin in STEMI % Incidence
CLARITY–until angiography,
discharge, or day 85,7*		 PLAVIX + aspirin
n=1,733		 Placebo + aspirin
n=1,719
TIMI major bleeding through day
after angiography1		 1.3 1.1
Intracranial hemorrhage 0.5 0.7
Fatal bleeding 0.8 0.6

*Patients were scheduled to undergo angiography 48 to 192 hours after the start of study medication. For patients who did not undergo angiography, the primary end point was death or recurrent MI by day 8 or by hospital discharge if prior to day 8

†Major bleeding was defined as intracranial bleeding or bleeding associated with a fall in hemoglobin >5 g/dL.


View the CLARITY Trial — Journal Abstract

PLAVIX is contraindicated in patients with active pathologic bleeding such as peptic ulcer or intracranial hemorrhage. Co-administering warfarin with PLAVIX increases the risk of bleeding. Co-administration of PLAVIX and NSAIDs increases the risk of gastrointestinal bleeding.1

WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS

The effectiveness of PLAVIX is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 (See WARNINGS and PRECAUTIONS: Drug Interactions.*). PLAVIX at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with PLAVIX at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy (See Clinical Pharmacology.*). Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers (See Dosage and Administration.*).

Important Safety Information

CONTRAINDICATIONS

PLAVIX is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

PLAVIX is contraindicated in patients with hypersensitivity (eg, anaphylaxis) to clopidogrel or any component of the product. (See Adverse Reactions.*)

WARNINGS AND PRECAUTIONS

Avoid concomitant use of PLAVIX and drugs that inhibit CYP2C19 activity. Co-administration of PLAVIX with omeprazole, a proton pump inhibitor that is an inhibitor of CYP2C19, reduces the pharmacological activity of PLAVIX if given concomitantly or if given 12 hours apart. (See Drug Interactions.*)

Thienopyridines, including PLAVIX, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue PLAVIX 5 days prior to surgery.

Avoid lapses in therapy, and if PLAVIX must be temporarily discontinued, restart as soon as possible. Premature discontinuation of PLAVIX may increase the risk of cardiovascular events.

In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and PLAVIX has not been shown to be more effective than PLAVIX alone, but the combination has been shown to increase major bleeding.

TTP, sometimes fatal, has been reported following use of PLAVIX, sometimes after a short exposure (<2 weeks). TTP is a serious condition that requires urgent treatment including plasmapheresis (plasma exchange).

ADVERSE REACTIONS

Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction.

DRUG INTERACTIONS

Co-administering warfarin with PLAVIX increases the risk of bleeding.

Co-administration of PLAVIX and NSAIDs increases the risk of gastrointestinal bleeding.

USE IN SPECIFIC POPULATIONS

Nursing mothers: Discontinue drug or nursing, taking into consideration importance of drug to mother.

*Please See the Full PLAVIX Prescribing Information, Including BOXED WARNING

Indications

Acute coronary syndrome (ACS)

For patients with non-ST-segment elevation ACS [unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI)] including patients who are to be managed medically and those who are to be managed with coronary revascularization, PLAVIX has been shown to decrease the rate of a combined end point of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined end point of cardiovascular death, MI, stroke, or refractory ischemia.

For patients with ST-elevation myocardial infarction (STEMI), PLAVIX has been shown to reduce the rate of death from any cause and the rate of a combined end point of death, reinfarction, or stroke. The benefit for patients who undergo primary percutaneous coronary intervention is unknown.

The optimal duration of PLAVIX therapy in ACS is unknown.

Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, PLAVIX has been shown to reduce the rate of a combined end point of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.