Clinical Trials


PLAVIX (clopidogrel bisulfate) efficacy and safety profile

STUDY/NUMBER
OF PATIENTS		 PATIENT TYPE TREATMENT REGIMEN PRIMARY ENDPOINT

CAPRIE Trial2


(N=19,185) 		Recent MI, recent ischemic stroke, or established PAD PLAVIX vs. aspirin Combined: MI, ischemic stroke, or vascular death

CURE Trial3


(N=12,562)		 ACS: unstable angina, non-ST-segment elevation MI (UA/NSTEMI) PLAVIX + aspirin vs. placebo + aspirin Combined primary: MI, stroke, or CV death

Combined co-primary: MI, stroke, CV death, or refractory ischemia

COMMIT Trial5


(N=45,852)		 ACS: ST-segment elevation acute MI (STEMI) PLAVIX + aspirin vs. placebo + aspirin All-cause mortality

Combined: Death, reinfarction, or stroke

  • CAPRIE Trial

     The CAPRIE trial was a 19,185-patient, 304-center, international, randomized, double-blind, parallel-group study comparing PLAVIX (75 mg daily) to aspirin (325 mg daily). The patients randomized had: 1) recent histories of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) established peripheral arterial disease. Patients received randomized treatment for an average of 1.6 years (maximum of 3 years).

    The trial’s primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular.

  • CURE Trial

     The CURE study included 12,562 patients with ACS without ST-elevation (UA or NSTEMI) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia. Patients were required to have either ECG changes compatible with new ischemia (without ST-elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. The patient population was largely Caucasian (82%) and included 38% women, and 52% patients ≥65 years of age.

    Patients were randomized to receive PLAVIX (300-mg loading dose followed by 75 mg once daily) or placebo, and were treated for up to one year. Patients also received aspirin (75-325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization.

  • COMMIT Trial

     In patients with STEMI, the safety and efficacy of PLAVIX were evaluated in the randomized, placebo-controlled, double-blind study, COMMIT. COMMIT included 45,852 patients presenting within 24 hours of the onset of the symptoms of myocardial infarction with supporting ECG abnormalities (i.e., ST-elevation, ST-depression or left bundle-branch block). Patients were randomized to receive PLAVIX (75 mg once daily) or placebo, in combination with aspirin (162 mg per day), for 28 days or until hospital discharge, whichever came first.

    The primary endpoints were death from any cause and the first occurrence of re-infarction, stroke, or death.

    The patient population included 28% women, 58% age ≥60 years (26% age ≥70 years), 55% patients who received thrombolytics, 68% who received ACE-inhibitors, and only 3% who underwent PCI.

  • CLARITY Trial – 3,491 ACS Patients With STEMI


    CLARITY was a bridging study to COMMIT, which supports a 300-mg PLAVIX loading dose in a STEMI patient population.

IMPORTANT SAFETY INFORMATION

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 (5.1)]. 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 (12.5)]. Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers [See Dosage and Administration (2.3)].

CONTRAINDICATIONS

  • PLAVIX is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.
  • PLAVIX is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product.

WARNINGS AND PRECAUTIONS

  • The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 and by concomitant medications that interfere with CYP2C19. Avoid concomitant use of PLAVIX with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of PLAVIX.
  • 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

  • Avoid concomitant use of PLAVIX with omeprazole or esomeprazole, which has been shown to reduce anti-platelet activity in impaired CYP2C19 function. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of the clopidogrel active metabolite. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the pharmacological activity of PLAVIX than omeprazole or esomeprazole.
  • Coadministering warfarin with PLAVIX increases the risk of bleeding.
  • Coadministration 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.

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 endpoint of cardiovascular death, myocardial infarction (MI), or
stroke as well as the rate of a combined endpoint 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 endpoint of death, re-infarction, 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 endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.

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