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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PLAVIX safely and effectively. See full prescribing information for PLAVIX. PLAVIX®^ (clopidogrel bisulfate) tablets, for oral use Initial U.S. Approval: 1997 WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C GENE See full prescribing information for complete boxed warning.
- Effectiveness of Plavix depends on conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. (5.1, 12.3)
- Tests are available to identify patients who are CYP2C19 poor metabolizers. (12.5)
- Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers. (5.1) ----------------------------INDICATIONS AND USAGE--------------------------- Plavix is a P2Y 12 platelet inhibitor indicated for:
- Acute coronary syndrome
- For patients with non–ST-segment elevation ACS (unstable angina [UA]/non–ST-elevation myocardial infarction [NSTEMI]), Plavix has been shown to reduce the rate of myocardial infarction (MI) and stroke. (1.1)
- For patients with ST-elevation myocardial infarction (STEMI), Plavix has been shown to reduce the rate of MI and stroke. (1.1)
- Recent MI, recent stroke, or established peripheral arterial disease. Plavix has been shown to reduce the rate of MI and stroke. (1.2) ----------------------DOSAGE AND ADMINISTRATION----------------------
- Acute coronary syndrome (2.1)
- Initiate Plavix with a single 300-mg oral loading dose and then continue at 75 mg once daily.
- Initiating Plavix without a loading dose will delay establishment of an antiplatelet effect by several days.
- Recent MI, recent stroke, or established peripheral arterial disease: 75 mg once daily orally without a loading dose (2.2) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- Tablets: 75 mg, 300 mg (3) ---------------------------CONTRAINDICATIONS---------------------------------
- Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage (4.1)
- Hypersensitivity to clopidogrel or any component of the product (4.2) -----------------------WARNINGS AND PRECAUTIONS-----------------------
- CYP2C19 inhibitors: Avoid concomitant use of omeprazole or esomeprazole. (5.1)
- Bleeding: Plavix increases risk of bleeding. (5.2)
- Discontinuation: Premature discontinuation increases risk of cardiovascular events. Discontinue 5 days prior to elective surgery that has a major risk of bleeding. (5.3)
- Thrombotic thrombocytopenic purpura (TTP) has been reported. (5.4)
- Cross-reactivity among thienopyridines has been reported. (5.5) ------------------------------ADVERSE REACTIONS------------------------------ Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------
- Opioids: Decreased exposure to clopidogrel. Consider use of parenteral antiplatelet agent. (7.2)
- Nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRIs, SNRIs): Increases risk of bleeding. (7.3,7.4, 7.5)
- Repaglinide (CYP2C8 substrates): Increases substrate plasma concentrations. (7.6) ------------------------USE IN SPECIFIC POPULATIONS---------------------- Nursing mothers: Discontinue drug or nursing. (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 05/
FULL PRESCRIBING INFORMATION: CONTENTS WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C GENE 1 INDICATIONS AND USAGE* 1.1 Acute Coronary Syndrome (ACS) 1.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease 2 DOSAGE AND ADMINISTRATION 2.1 Acute Coronary Syndrome 2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Active Bleeding 4.2 Hypersensitivity 5 WARNINGS AND PRECAUTIONS 5.1 Diminished Antiplatelet Activity in Patients with Impaired CYP2C19 Function 5.2 General Risk of Bleeding 5.3 Discontinuation of Plavix 5.4 Thrombotic Thrombocytopenic Purpura (TTP) 5.5 Cross-Reactivity among Thienopyridines 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 CYP2C19 Inhibitors 7.2 Opioids 7.3 Nonsteroidal Anti-inflammatory Drugs (NSAIDs) 7.4 Warfarin (CYP2C9 Substrates)
7.5 SSRIs and SNRIs 7.6 Repaglinide (CYP2C8 Substrates) 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacogenomics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Acute Coronary Syndrome 14.2 Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial Disease 14.3 No Demonstrated Benefit of Plavix plus Aspirin in Patients with Multiple Risk Factors or Established Vascular Disease 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed.
1
FULL PRESCRIBING INFORMATION
WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO
LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE
The effectiveness of Plavix results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]****. Plavix at recommended doses forms less of the active metabolite and so has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene, (termed “CYP2C19 poor metabolizers”). Tests are available to identify patients who are CYP2C19 poor metabolizers [see Clinical Pharmacology (12.5)]****. Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.
1 INDICATIONS AND USAGE
1.1 Acute Coronary Syndrome (ACS)
- Plavix is indicated to reduce the rate of myocardial infarction (MI) and stroke in 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 should be administered in conjunction with aspirin.
- Plavix is indicated to reduce the rate of myocardial infarction and stroke in patients with acute ST-elevation myocardial infarction (STEMI) who are to be managed medically. Plavix should be administered in conjunction with aspirin.
1.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease
In patients with established peripheral arterial disease or with a history of recent myocardial infarction (MI) or recent stroke Plavix is indicated to reduce the rate of MI and stroke.
2 DOSAGE AND ADMINISTRATION
2.1 Acute Coronary Syndrome
In patients who need an antiplatelet effect within hours, initiate Plavix with a single 300-mg oral loading dose and then continue at 75 mg once daily. Initiating Plavix without a loading dose will delay establishment of an antiplatelet effect by several days [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)].
2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease
75 mg once daily orally without a loading dose [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)].
3 DOSAGE FORMS AND STRENGTHS
- 75 mg tablets: Pink, round, biconvex, film-coated tablets debossed with “75” on one side and “1171” on the other
5.5 Cross-Reactivity among Thienopyridines
Hypersensitivity including rash, angioedema or hematologic reaction has been reported in patients receiving Plavix, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines [see Contraindications (4.2) and Adverse Reactions (6.2)].
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed below and elsewhere in the labeling:
- Bleeding [see Warnings and Precautions (5.2)]
- Thrombotic thrombocytopenic purpura [see Warnings and Precautions (5.4)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions and durations of follow- up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Plavix has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for one year or more. The clinically important adverse reactions observed in trials comparing Plavix plus aspirin to placebo plus aspirin and trials comparing Plavix alone to aspirin alone are discussed below.
Bleeding
CURE
In CURE, Plavix use with aspirin was associated with an increase in major bleeding (primarily gastrointestinal and at puncture sites) compared to placebo with aspirin (see Table 1). The incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis, hematuria, and bruise.
The overall incidence of bleeding is described in Table 1.
Table 1: CURE Incidence of Bleeding Complications (% patients)
Event Plavix (+ aspirin) (n=6259)
Placebo (+ aspirin) (n=6303) Major bleeding* Life-threatening bleeding Fatal 5 g/dL hemoglobin drop Requiring surgical intervention Hemorrhagic strokes Requiring inotropes Requiring transfusion (≥4 units) Other major bleeding Significantly disabling Intraocular bleeding with significant loss of vision Requiring 2-3 units of blood Minor bleeding †
- Life-threatening and other major bleeding. † (^) Led to interruption of study medication.
COMMIT
In COMMIT, similar rates of major bleeding were observed in the Plavix and placebo groups, both of which also received aspirin (see Table 2).
Table 2: Incidence of Bleeding Events in COMMIT (% patients)
Type of Bleeding Plavix (+ aspirin) (n=22961)
Placebo (+ aspirin) (n=22891)
p-value
Major* noncerebral or cerebral bleeding Major noncerebral Fatal Hemorrhagic stroke Fatal
Other noncerebral bleeding (nonmajor) 3.6 3.1 0. Any noncerebral bleeding 3.9 3.4 0.
- Major bleeds were cerebral bleeds or noncerebral bleeds thought to have caused death or that required transfusion.
CAPRIE (Plavix vs Aspirin)
In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking Plavix versus 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for Plavix compared to 0.5% for aspirin.
Other bleeding events that were reported more frequently in the Plavix group were epistaxis and hematoma.
Other Adverse Events
In CURE and CHARISMA, which compared Plavix plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between Plavix and placebo.
In CAPRIE, which compared Plavix to aspirin, pruritus was more frequently reported in those taking Plavix. No other difference in the rate of adverse events (other than bleeding) was reported.
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of Plavix. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hemorrhages, including those with fatal outcome, have been reported in patients treated with Plavix.
- Blood and lymphatic system disorders : Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A
Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy, coadministration of Plavix with warfarin increases the risk of bleeding because of independent effects on hemostasis.
However, at high concentrations in vitr o, clopidogrel inhibits CYP2C9.
7.5 SSRIs and SNRIs
Since selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding.
7.6 Repaglinide (CYP2C8 Substrates)
The acyl-β-glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8. Plavix can increase the systemic exposure to drugs that are primarily cleared by CYP2C8, thereby needing dose adjustment and appropriate monitoring.
Plavix increased repaglinide exposures by 3.9-fold to 5.1-fold [see Clinical Pharmacology (12.3)]. Avoid concomitant use of repaglinide with Plavix. If concomitant use cannot be avoided, initiate repaglinide at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg. Increased frequency of glucose monitoring may be required during concomitant use.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B
Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day, respectively (65 and 78 times the recommended daily human dose, respectively, on a mg/m^2 basis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, Plavix should be used during pregnancy only if clearly needed.
8.3 Nursing Mothers
Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from clopidogrel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Safety and effectiveness in pediatric populations have not been established.
A randomized, placebo-controlled trial (CLARINET) did not demonstrate a clinical benefit of clopidogrel in neonates and infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial shunt. Possible factors contributing to this outcome were the dose of clopidogrel, the concomitant administration of aspirin and the late initiation of therapy following shunt palliation. It cannot be ruled out that a trial with a different design would demonstrate a clinical benefit in this patient population.
8.5 Geriatric Use
Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with Plavix were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with Plavix were 60 years and older, 26% of whom were 70 years and older.
The observed risk of bleeding events with Plavix plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials, respectively [see Adverse Reactions (6.1)]. No dosage adjustment is necessary in elderly patients.
8.6 Renal Impairment
Experience is limited in patients with severe and moderate renal impairment [see Clinical Pharmacology (12.2)].
8.7 Hepatic Impairment
No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology (12.2)].
10 OVERDOSAGE
Platelet inhibition by Plavix is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were vomiting, prostration, difficult breathing, and gastrointestinal hemorrhage in animals.
Based on biological plausibility, platelet transfusion may restore clotting ability.
11 DESCRIPTION
Plavix (clopidogrel bisulfate) is a thienopyridine class inhibitor of P2Y 12 ADP platelet receptors. Chemically it is methyl (+)-( S )-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4 H ) acetate sulfate (1:1). The empirical formula of clopidogrel bisulfate is C 16 H 16 ClNO 2 S•H 2 SO 4 and its molecular weight is 419.9.
The structural formula is as follows:
Clopidogrel bisulfate is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°.
In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women.
12.3 Pharmacokinetics
Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.
Absorption
After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.
Effect of Food
Plavix can be administered with or without food. In a study in healthy male subjects when Plavix 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC (^) 0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite C (^) max. Similar results were observed when a Plavix 300 mg loading dose was administered with a high-fat breakfast.
Metabolism
Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. The active metabolite is formed mostly by CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and CYP3A. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.
The C (^) max of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. C (^) max occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: 4-fold the dose results in 2.0-fold and 2.7-fold the C (^) max and AUC, respectively.
Elimination
Following an oral dose of 14 C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half- life of the active metabolite is about 30 minutes.
Drug Interactions
Effect of other drugs on Plavix
Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.
Proton pump inhibitors (PPI)
The effect of proton pump inhibitors (PPI) on the systemic exposure to the clopidogrel active metabolite following multiple doses of Plavix 75 mg evaluated in dedicated drug interaction studies is presented in Figure 1.
Figure 1: Exposure to Clopidogrel Active Metabolite Following Multiple Doses of Plavix 75 mg Alone or with Proton Pump Inhibitors (PPIs)
Co-administered PPI Effect on active metabolite AUC Mean and 90% confidence interval
Dexlansoprazole, 60 mg
Lansoprazole, 30 mg
Pantoprazole, 80 mg
Omeprazole, 80 mg
0.4 0.6 0.8 1.0 1.2 1. Change relative to Plavix administered alone
Pharmacodynamic and pharmacokinetic parameters measured in these studies showed that the interaction was highest with omeprazole and least with dexlansoprazole.
Opioids
Co-administration of 5 mg intravenous morphine with 600 mg loading dose of clopidogrel in healthy adults decreased the AUC and C (^) max of clopidogrel’s thiol metabolites by 34%. Mean platelet aggregation was higher up to 2 to 4 hours with morphine co-administration.
Effect of Plavix on other drugs
In vitro studies have shown that the glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8. Concomitant administration of repaglinide with Plavix increased the systemic exposure to repaglinide (AUC (^) 0-∞) by 5.1-fold following the loading dose (300 mg) and by 3.9-fold on day 3 of the maintenance dose (75 mg) of Plavix [see Drug Interactions (7.6)].
12.5 Pharmacogenomics
CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects,
14 CLINICAL STUDIES
14.1 Acute Coronary Syndrome
CURE
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.
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.
The patient population was largely White (82%) and included 38% women, and 52% age ≥ years of age. Only about 20% of patients underwent revascularization during the initial hospitalization and few underwent emergent or urgent revascularization.
The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.3%) in the Plavix-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p <0.001) for the Plavix-treated group (see Table 4).
Table 4: Outcome Events in the CURE Primary Analysis
Outcome Plavix (+ aspirin)*
(n=6259)
Placebo (+ aspirin)*
(n=6303)
Relative Risk Reduction (%) (95% CI)
Primary outcome (Cardiovascular death, MI, stroke)
582 (9.3%) 719 (11.4%) 20% (10.3, 27.9) p <0. All Individual Outcome Events:† CV death
MI
Stroke
318 (5.1%)
324 (5.2%)
75 (1.2%)
345 (5.5%)
419 (6.6%)
87 (1.4%)
7% (-7.7, 20.6) 23% (11.0, 33.4) 14% (-17.7, 36.6)
- Other standard therapies were used as appropriate. † (^) The individual components do not represent a breakdown of the primary and coprimary outcomes, but rather the total number of subjects experiencing an event during the course of the study.
Most of the benefit of Plavix occurred in the first two months, but the difference from placebo was maintained throughout the course of the trial (up to 12 months) (see Figure 2).
Figure 2: Cardiovascular Death, Myocardial Infarction, and Stroke in the CURE Study
The effect of Plavix did not differ significantly in various subgroups, as shown in Figure 3. The benefits associated with Plavix were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH, intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE inhibitors. The efficacy of Plavix was observed independently of the dose of aspirin (75-325 mg once daily). The use of oral anticoagulants, nonstudy antiplatelet drugs, and chronic NSAIDs was not allowed in CURE.
Figure 3: Hazard Ratio for Patient Baseline Characteristics and On-Study Concomitant Medications/Interventions for the CURE Study (continued)
Subgroup N Plavix n(%) Placebo n(%) Favors Plavix^ Favors Placebo Heparin/LMWH Yes 11611 559 (9.7) 682 (11.7) No 951 23 (4.9) 37 (7.7) Aspirin(mg) <100 1927 80 (8.5) 96 (9.7) 100-200 7428 345 (9.2) 402 (10.9)
200 3201 157 (9.9) 221 (13.7) GPIIb/IIIa Antag Yes 823 58 (15.7) 87 (19.2) No 11739 524 (8.9) 632 (10.8) Beta-Blocker Yes 10530 484 (9.2) 594 (11.3) No 2032 98 (9.9) 125 (12.0) Ace Inhibitor Yes 7749 433 (11.2) 522 (13.5) No 4813 149 (6.3) 197 (8.1)
Overall 12562 582 (9.3) 719 (11.4)
0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1. Hazard Ratio (95% CI)
The use of Plavix in CURE was associated with a decrease in the use of thrombolytic therapy ( patients [1.1%] in the Plavix group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the Plavix group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%). The use of Plavix in CURE did not affect the number of patients treated with CABG or PCI (with or without stenting), ( patients [36.0%] in the Plavix group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%).
COMMIT
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 was 28% women and 58% age ≥60 years (26% age ≥70 years). Fifty-five percent (55%) of patients received thrombolytics and only 3% underwent PCI.
As shown in Table 5 and Figure 4 and Figure 5 below, Plavix significantly reduced the relative risk of death from any cause by 7% (p=0.029), and the relative risk of the combination of re- infarction, stroke or death by 9% (p=0.002).
Table 5: Outcome Events in COMMIT
Event Plavix (+ aspirin) (N=22961)
Placebo (+ aspirin) (N=22891)
Odds ratio (95% CI)
p-value
Composite endpoint: Death, MI, or Stroke* 2121 (9.2%) 2310 (10.1%) 0.91 (0.86, 0.97) 0. Death Nonfatal MI† Nonfatal Stroke†
1726 (7.5%) 270 (1.2%) 127 (0.6%)
1845 (8.1%) 330 (1.4%) 142 (0.6%)
0.93 (0.87, 0.99) 0.81 (0.69, 0.95) 0.89 (0.70, 1.13)
- 9 patients (2 clopidogrel and 7 placebo) suffered both a nonfatal stroke and a nonfatal MI. † (^) Nonfatal MI and nonfatal stroke exclude patients who died (of any cause).
Figure 4: Cumulative Event Rates for Death in the COMMIT Study *
- All treated patients received aspirin.
Figure 6: Effects of Adding Plavix to Aspirin on the Combined Primary Endpoint across Baseline and Concomitant Medication Subgroups for the COMMIT Study
Subgroup N Gender Male 33093 Female 12759 Age at entry (years) < 60 19087 60-69 14831 70+ 11934 Hours since onset < 6 15452 6 to <13 15072 13 to 24 15328 SBP(mmHg) < 120 15399 120-139 16200 140-159 9020 160+ 5233 Heart rate (bpm) < 70 10137 70-89 22262 90-109 10209 110+ 3244 Fibrinolytic agent given Yes 22794 No 23058 Overall* 45852
Plavix n(%)
1274 (7.7) 847 (13.3) 485 (5.0) 745 (10.1) 891 (14.9) 709 (9.2) 738 (9.8) 674 (8.8) 797 (10.4) 693 (8.6) 388 (8.5) 243 (9.2) 268 (5.3) 898 (8.1) 632 (12.3) 323 (19.9) 1003 (8.8) 1118 (9.7) 2121 (9.2)
Placebo n(%) Favors Plavix Favors Placebo
1416 (8.6) 894 (14.0) 512 (5.4) 835 (11.2) 963 (16.2) 830 (10.8) 808 (10.8) 672 (8.8) 892 (11.6) 770 (9.5) 399 (8.9) 249 (9.6) 315 (6.2) 952 (8.5) 683 (13.5) 360 (22.2) 1122 (9.9) 1188 (10.3) 2310 (10.1) 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1. Odds Ratio (99% CI)
- CI is 95% for Overall row only
14.2 Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial Disease
CAPRIE
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). To be eligible to enroll, patients had to have: 1) recent history of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; and/or 3) established peripheral arterial disease (PAD). 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.
Table 6: Outcome Events in the CAPRIE Primary Analysis
Patients Plavix n=
Aspirin n= Ischemic stroke (fatal or not) MI (fatal or not) Other vascular death
438 (4.6%) 275 (2.9%) 226 (2.4%)
461 (4.8%) 333 (3.5%) 226 (2.4%) Total 939 (9.8%) 1020 (10.6%)
As shown in Table 6, Plavix was associated with a lower incidence of outcome events, primarily MI. The overall relative risk reduction (9.8% vs 10.6%) was 8.7%, p=0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was lower in the Plavix group.
The curves showing the overall event rate are shown in Figure 7. The event curves separated early and continued to diverge over the 3-year follow-up period.
Figure 7: Fatal or Nonfatal Vascular Events in the CAPRIE Study
The statistical significance favoring Plavix over aspirin was marginal (p=0.045). However, because aspirin is itself effective in reducing cardiovascular events in patients with recent myocardial infarction or stroke, the effect of Plavix is substantial.
The CAPRIE trial enrolled a population that had recent MI, recent stroke, or PAD. The efficacy of Plavix relative to aspirin was heterogeneous across these subgroups (p=0.043) (see Figure 8). Nonetheless this difference may be a chance occurrence because the CAPRIE trial was not designed to evaluate the relative benefit of Plavix over aspirin in the individual patient subgroups. The benefit was most apparent in patients who were enrolled because of peripheral arterial disease and less apparent in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, Plavix was not numerically superior to aspirin.
