"March 11, 2010 - The FDA has put a new "black box" warning on the anti-clotting drug Plavix, the second best-selling drug in the world.
The new label warns that normal doses of Plavix have a potentially deadly lack of effect in 2% "...
Mechanism Of Action
Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.
Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel's active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of Plavix. Repeated doses of 75 mg Plavix per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg Plavix per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.
Elderly ( ≥ 75 years) and young healthy subjects had similar effects on platelet aggregation.
After repeated doses of 75 mg Plavix per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation.
After repeated doses of 75 mg Plavix per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects.
In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women.
Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.
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 AUC0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a Plavix 300 mg loading dose was administered with a high-fat breakfast.
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. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.
The Cmax 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. Cmax 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: increasing the dose by a factor of four results in 2.0- and 2.7-fold increases in Cmax and AUC, respectively.
Following an oral dose of 14C-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.
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
Pharmacodynamic and pharmacokinetic parameters measured in these studies showed that the interaction was highest with omeprazole and least with dexlansoprazole.
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, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. Genetic variants of other CYP450 enzymes may also affect the formation of clopidogrel's active metabolite.
The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and *3 alleles are nonfunctional. CYP2C19*2 and *3 account for the majority of reduced function alleles in white (85%) and Asian (99%) poor metabolizers. Other alleles associated with absent or reduced metabolism are less frequent, and include, but are not limited to, CYP2C19*4, *5, *6, *7, and *8. A patient with poor metabolizer status will possess two loss-of-function alleles as defined above. Published frequencies for poor CYP2C19 metabolizer genotypes are approximately 2% for whites, 4% for blacks and 14% for Chinese. Tests are available to determine a patient's CYP2C19 genotype.
A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metabolizer groups, evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg per day and 600 mg followed by 150 mg per day, each for a total of 5 days. Decreased active metabolite exposure and diminished inhibition of platelet aggregation were observed in the poor metabolizers as compared to the other groups. When poor metabolizers received the 600 mg/150 mg regimen, active metabolite exposure and antiplatelet response were greater than with the 300 mg/75 mg regimen (see Table 3). An appropriate dose regimen for this patient population has not been established in clinical outcome trials.
Table 3: Active Metabolite Pharmacokinetics and
Antiplatelet Responses by CYP2C19 Metabolizer Status
|Cmax (ng/mL)||300 mg (24 h)||24 (10)||32 (21)||23 (11)||11 (4)|
|600 mg (24 h)||36 (13)||44 (27)||39 (23)||17 (6)|
|75 mg (Day 5)||12 (6)||13 (7)||12 (5)||4 (1)|
|150 mg (Day 5)||16 (9)||19 (5)||18 (7)||7 (2)|
|IPA (%)*||300 mg (24 h)||40 (21)||39 (28)||37 (21)||24 (26)|
|600 mg (24 h)||51 (28)||49 (23)||56 (22)||32 (25)|
|75 mg (Day 5)||56 (13)||58 (19)||60 (18)||37 (23)|
|150 mg (Day 5)||68 (18)||73 (9)||74 (14)||61 (14)|
|VASP-PRI (%) †||300 mg (24 h)||73 (12)||68 (16)||78 (12)||91 (12)|
|600 mg (24 h)||51 (20)||48 (20)||56 (26)||85 (14)|
|75 mg (Day 5)||40 (9)||39 (14)||50 (16)||83 (13)|
|150 mg (Day 5)||20 (10)||24 (10)||29 (11)||61 (18)|
|Values are mean (SD)
* Inhibition of platelet aggregation with 5mcM ADP; larger value indicates greater platelet inhibition
† Vasodilator-stimulated phosphoprotein – platelet reactivity index; smaller value indicates greater platelet inhibition
Some published studies suggest that intermediate metabolizers have decreased active metabolite exposure and diminished antiplatelet effects.
The relationship between CYP2C19 genotype and Plavix treatment outcome was evaluated in retrospective analyses of Plavix-treated subjects in CHARISMA (n=2428) and TRITON-TIMI 38 (n=1477), and in several published cohort studies. In TRITON-TIMI 38 and the majority of the cohort studies, the combined group of patients with either intermediate or poor metabolizer status had a higher rate of cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolizers. In CHARISMA and one cohort study, the increased event rate was observed only in poor metabolizers.
Acute Coronary Syndrome
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.
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)*
|Placebo (+ aspirin)*
|Relative Risk Reduction (%) (95% CI)|
|Primary outcome (Cardiovascular death, MI, stroke)||582 (9.3%)||719 (11.4%)||20% (10.3, 27.9)
p < 0.001
|All Individual Outcome Events:†|
|CV death||318 (5.1%)||345 (5.5%)||7% (-7.7, 20.6)|
|MI||324 (5.2%)||419 (6.6%)||23% (11.0, 33.4)|
|Stroke||75 (1.2%)||87 (1.4%)||14% (-17.7, 36.6)|
|* Other standard therapies were
used as appropriate.
† The individual components do not represent a breakdown of the primary and co-primary 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
In CURE, the use of Plavix was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics, 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, non-study 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
The use of Plavix in CURE was associated with a decrease in the use of thrombolytic therapy (71 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), (2253 patients [36.0%] in the Plavix group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%).
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.
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 the COMMIT Analysis
|Event||Plavix (+ aspirin)
|Placebo (+ aspirin)
|Odds ratio (95% CI)||p-value|
|Composite endpoint: Death, MI, or Stroke*||2121 (9.2%)||2310 (10.1%)||0.91 (0.86, 0.97)||0.002|
|Death||1726 (7.5%)||1845 (8.1%)||0.93 (0.87, 0.99)||0.029|
|Non-fatal MI**||270 (1.2%)||330 (1.4%)||0.81 (0.69, 0.95)||0.011|
|Non-fatal Stroke**||127 (0.6%)||142 (0.6%)||0.89 (0.70, 1.13)||0.33|
|* The difference between the composite endpoint and the
sum of death+non-fatal MI+non-fatal stroke indicates that 9 patients (2
clopidogrel and 7 placebo) suffered both a non-fatal stroke and a non-fatal MI.
** Non-fatal MI and non-fatal 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 5: Cumulative Event
Rates for the Combined Endpoint Re-Infarction, Stroke or Death in the COMMIT
* All treated patients received aspirin.
The effect of Plavix did not differ significantly in various pre-specified subgroups as shown in Figure 6. The effect was also similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history (see Figure 7). Such subgroup analyses should be interpreted cautiously.
Figure 6: Effects of Adding
Plavix to Aspirin on the Combined Primary Endpoint across Baseline and
Concomitant Medication Subgroups for the COMMIT Study
* Three similar-sized prognostic index groups were based on absolute risk of primary composite outcome for each patient calculated from baseline prognostic variables (excluding allocated treatments) with a Cox regression model.
Figure 7: Effects of Adding
Plavix to Aspirin in the Non-Prespecified Subgroups in the COMMIT Study
Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial Disease
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.
Table 6: Outcome Events in
the CAPRIE Primary Analysis
|Ischemic stroke (fatal or not)||438 (4.6%)||461 (4.8%)|
|MI (fatal or not)||275 (2.9%)||333 (3.5%)|
|Other vascular death||226 (2.4%)||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 8. The event curves separated early and continued to diverge over the 3-year follow-up period.
Figure 8: Fatal or Non-Fatal
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 included a population that was randomized on the basis of 3 entry criteria. The efficacy of Plavix relative to aspirin was heterogeneous across these randomized subgroups (p=0.043). It is not clear whether this difference is real or a chance occurrence. Although the CAPRIE trial was not designed to evaluate the relative benefit of Plavix over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker 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.
Lack of Established Benefit of Plavix plus Aspirin in Patients with Multiple Risk Factors or Established Vascular Disease
The CHARISMA trial was a 15,603 subject, randomized, double-blind, parallel group study comparing Plavix (75 mg daily) to placebo for prevention of ischemic events in patients with vascular disease or multiple risk factors for atherosclerosis. All subjects were treated with aspirin 75-162 mg daily. The mean duration of treatment was 23 months. The study failed to demonstrate a reduction in the occurrence of the primary endpoint, a composite of CV death, MI, or stroke. A total of 534 (6.9%) patients in the Plavix group versus 573 (7.4%) patients in the placebo group experienced a primary outcome event (p=0.22). Bleeding of all severities was more common in the subjects randomized to Plavix.
Prescribing Document Revised: December 2013This monograph has been modified to include the generic and brand name in many instances.
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