Mechanism of Action and Pharmacodynamic Properties
Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. A variety of drugs that inhibit platelet function have been shown to decrease morbid events in people with established cardiovascular atherosclerotic disease as evidenced by stroke or transient ischemic attacks, myocardial infarction, unstable angina or the need for vascular bypass or angioplasty. This indicates that platelets participate in the initiation and/or evolution of these events and that inhibiting platelet function can reduce the event rate.
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.
Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other drugs, not all patients will have adequate platelet inhibition.
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.
After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/mL after a single 75-mg oral dose) occurred approximately 45 minutes after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.
Effect of Food
The effect of food on the bioavailability of the parent compound or active metabolite is currently not known.
Clopidogrel and the main circulating inactive metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable in vitro up to a concentration of 100 mcg/mL.
Clopidogrel is extensively metabolized by the liver. In vitro and in viv o, clopidogrel is metabolized according to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple cytochromes P450. 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. In vitro, this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.
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 elimination half-life of the inactive acid metabolite was 8 hours after single and repeated administration. Covalent binding to platelets accounted for 2% of radiolabel with a half-life of 11 days. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed.
Several polymorphic CYP450 enzymes activate clopidogrel. 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. The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and CYP2C19*3 alleles correspond to reduced metabolism. The CYP2C19*2 and CYP2C19*3 alleles account for 85% of reduced function alleles in whites and 99% in Asians. Other alleles associated with reduced metabolism include CYP2C19*4, *5, *6, *7, and *8, but these are less frequent in the general population. Published frequencies for the common CYP2C19 phenotypes and genotypes are listed in the table below.
Table 1 - CYP2C19 Phenotype and Genotype Frequency
| ||Frequency (%)Xie, et al. Annu Rev Pharmacol Toxicol 2001; 41: 815-50 |
| ||White (n=1356) ||Black (n=966) ||Chinese (n=573) |
|Extensive metabolism: CYP2C19*1/*1 ||74 ||66 ||38 |
|Intermediate metabolism: CYP2C19*1/*2 or *1/*3 ||26 ||29 ||50 |
|Poor metabolism: CYP2C19*2/*2, *2/*3 or *3/*3 ||2 ||4 ||14 |
To date, the impact of CYP2C19 genotype on the pharmacokinetics of clopidogrel's active metabolite has been evaluated in 227 subjects from 7 reported studies. Reduced CYP2C19 metabolism in intermediate and poor metabolizers decreased the Cmax and AUC of the active metabolite by 30-50% following 300- or 600 mg loading doses and 75 mg maintenance doses. Lower active metabolite exposure results in less platelet inhibition or higher residual platelet reactivity. To date, diminished antiplatelet responses to clopidogrel have been described for intermediate and poor metabolizers in 21 reported studies involving 4,520 subjects. The relative difference in antiplatelet response between genotype groups varies across studies depending on the method used to evaluate response, but is typically greater than 30%.
The association between CYP2C19 genotype and clopidogrel treatment outcome was evaluated in 2 post-hoc clinical trial analyses (substudies of CLARITY-TIMI 28Mega JL, Thakuria JV, Cannon CP, Sabatine MS. Sequence variations in CYP metabolism genes and cardiovascular outcomes following treatment with clopidogrel: insights from the CLARITY-TIMI 28 genomic study. 2008; ACC Meeting Abstract [n=465] and TRITON-TIMI 38Mega et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360:354-62 [n=1,477]) and 5 cohort studies (total n=6,489). In CLARITY-TIMI 28 and one of the cohort studies (n=765; TrenkTrenk et al. Cytochrome P450 2C19 681G>A polymorphism and high on clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug eluting or bare-metal stents. J Am Coll Cardiol 2008; 51, 20: 1952), cardiovascular event rates did not differ significantly by genotype. In TRITON-TIMI 38 and 3 of the cohort studies (n= 3,516; Collet,Collet JP et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. The Lancet 2009; 373: 309-317 Sibbing,Sibbing D et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J 2009: 1-7 GiustiGiusti et al. Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am J Cardiol 2009; 103:806811), patients with an impaired metabolizer status (intermediate and poor combined) had a higher rate of cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolizers. In the fifth cohort study (n=2,208; SimonSimon et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360(4):363-75), the increased event rate was observed only in poor metabolizers.
Pharmacogenetic testing can identify genotypes associated with variability in CYP2C19 activity.
There may be genetic variants of other CYP450 enzymes with effects on the ability to form clopidogrel's active metabolite.
The pharmacokinetics of clopidogrel's active metabolite is not known in these special populations.
In elderly (≥75 years) volunteers compared to young healthy volunteers, there were no differences in platelet aggregation and bleeding time. No dosage adjustment is needed for the elderly.
After repeated doses of 75 mg PLAVIX per day in patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min), inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy volunteers, however, the prolongation of bleeding time was similar to healthy volunteers receiving 75 mg of PLAVIX per day.
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. The mean bleeding time prolongation was also similar in the two groups.
In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in prolongation of bleeding time. In the large, controlled clinical study (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events; CAPRIE), the incidence of clinical outcome events, other adverse clinical events, and abnormal clinical laboratory parameters was similar in men and women.
The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to race/ethnicity (see CLINICAL PHARMACOLOGY: Pharmacogenetics).
The clinical evidence for the efficacy of PLAVIX is derived from four double-blind trials involving 81,090 patients: the CAPRIE study (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events), a comparison of PLAVIX to aspirin, and the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events), the COMMIT/CCS-2 (Clopidogrel and Metoprolol in Myocardial Infarction Trial / Second Chinese Cardiac Study) studies comparing PLAVIX to placebo, both given in combination with aspirin and other standard therapy and CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy Thrombolysis in Myocardial Infarction).
Recent Myocardial Infarction (MI), 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) objectively 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 2: Outcome Events in the CAPRIE Primary Analysis
|Patients || PLAVIX |
| aspirin |
|IS (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 the table, PLAVIX (clopidogrel bisulfate) was associated with a lower incidence of outcome events of every kind. The overall 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 again lower in the PLAVIX group.
The curves showing the overall event rate are shown in Figure 1. The event curves separated early and continued to diverge over the 3-year follow-up period.
| Figure 1: Fatal or Non-Fatal Vascular Events in the CAPRIE Study |
Although the statistical significance favoring PLAVIX over aspirin was marginal (P=0.045), and represents the result of a single trial that has not been replicated, the comparator drug, aspirin, is itself effective (vs. placebo) in reducing cardiovascular events in patients with recent myocardial infarction or stroke. Thus, the difference between PLAVIX and placebo, although not measured directly, 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.
In the meta-analyses of studies of aspirin vs. placebo in patients similar to those in CAPRIE, aspirin was associated with a reduced incidence of thrombotic events. There was a suggestion of heterogeneity in these studies too, with the effect strongest in patients with a history of myocardial infarction, weaker in patients with a history of stroke, and not discernible in patients with a history of peripheral vascular disease. With respect to the inferred comparison of PLAVIX to placebo, there is no indication of heterogeneity.
Acute Coronary Syndrome
The CURE study included 12,562 patients with acute coronary syndrome without ST segment elevation (unstable angina or non-Q-wave myocardial infarction) 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 segment 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/day) or placebo, and were treated for up to one year. Patients also received aspirin (75325 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 (9.30%) in the PLAVIX-treated group and 719 (11.41%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%â€“28%; p=0.00009) for the PLAVIX-treated group (see Table 3).
At the end of 12 months, the number of patients experiencing the co-primary outcome (CV death, MI, stroke or refractory ischemia) was 1035 (16.54%) in the PLAVIX-treated group and 1187 (18.83%) in the placebo-treated group, a 14% relative risk reduction (95% CI of 6%â€“21%, p=0.0005) for the PLAVIX-treated group (see Table 3).
In the PLAVIX-treated group, each component of the two primary endpoints (CV death, MI, stroke, refractory ischemia) occurred less frequently than in the placebo-treated group.
Table 3: Outcome Events in the CURE Primary Analysis
|Outcome ||PLAVIX |
|Relative Risk Reduction (%) |
| ||(n=6259) ||(n=6303) || |
|Primary outcome || 582 || (9.3%) ||719 (11.4%) ||20% |
| (Cardiovascular death, MI, Stroke) || || || ||(10.3, 27.9) |
| || || || ||P=0.00009 |
|Co-primary outcome ||1035 ||(16.5%) ||1187 (18.8%) ||14% |
| (Cardiovascular death, MI, Stroke, Refractory Ischemia) || || || ||(6.2, 20.6) |
| || || || ||P=0.00052 |
|All Individual Outcome Events: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. |
| CV death || 318 || (5.1%) ||345 (5.5%) ||7% |
| MI || 324 || (5.2%) ||419 (6.6%) ||23% |
| Stroke || 75 || (1.2%) ||87 (1.4%) ||14% |
| Refractory ischemia || 544 || (8.7%) ||587 (9.3%) ||7% |
The benefits of PLAVIX (clopidogrel bisulfate) were maintained throughout the course of the trial (up to 12 months).
| 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 (low molecular weight heparin), IV 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 (75325 mg once daily). The use of oral anticoagulants, non-study anti-platelet 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 |
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%, P=0.0001), 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%, P=0.003). The use of PLAVIX in CURE did not impact 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%, P=0.1658).
In patients with ST-segment elevation acute myocardial infarction, safety and efficacy of clopidogrel have been evaluated in two randomized, placebo-controlled, double-blind studies, COMMIT- a large outcome study conducted in China - and CLARITY- a supportive study of a surrogate endpoint conducted internationally.
The randomized, double-blind, placebo-controlled, 2—2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of the onset of the symptoms of suspected 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/day) or placebo, in combination with aspirin (162 mg/day), for 28 days or until hospital discharge whichever came first.
The co-primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death.
The patient population included 28% women, 58% patients ≥60 years (26% patients ≥70 years) and 55% patients who received thrombolytics, 68% received ace-inhibitors, and only 3% had percutaneous coronary intervention (PCI).
As shown in Table 4 and Figures 4 and 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 4: Outcome Events in the COMMIT Analysis
|Event ||PLAVIX |
|Odds ratio |
| Composite endpoint: Death, MI, or StrokeThe 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. ||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 |
||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 |
| Figure 4: Cumulative Event Rates for Death in the COMMIT StudyAll treated patients received aspirin. |
| Figure 5: Cumulative Event Rates for the Combined Endpoint Re-Infarction, Stroke or Death in the COMMIT StudyAll treated patients received aspirin. |
The effect of PLAVIX did not differ significantly in various pre-specified subgroups as shown in Figure 6. Additionally, the effect was 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 very cautiously.
| Figure 6: Effects of Adding PLAVIX to Aspirin on the Combined Primary Endpoint across Baseline and Concomitant Medication Subgroups for the COMMIT Study |
| Figure 7: Effects of Adding PLAVIX to Aspirin in the Non-Prespecified Subgroups in the COMMIT Study |
The randomized, double-blind, placebo-controlled CLARITY trial included 3,491 patients, 5% U.S., presenting within 12 hours of the onset of a ST elevation myocardial infarction and planned for thrombolytic therapy. Patients were randomized to receive PLAVIX (300-mg loading dose, followed by 75 mg/day) or placebo until angiography, discharge, or Day 8. Patients also received aspirin (150 to 325 mg as a loading dose, followed by 75 to 162 mg/day), a fibrinolytic agent and, when appropriate, heparin for 48 hours. The patients were followed for 30 days.
The primary endpoint was the occurrence of the composite of an occluded infarct-related artery (defined as TIMI Flow Grade 0 or 1) on the predischarge angiogram, or death or recurrent myocardial infarction by the time of the start of coronary angiography.
The patient population was mostly Caucasian (89.5%) and included 19.7% women and 29.2% patients ≥65 years. A total of 99.7% of patients received fibrinolytics (fibrin specific: 68.7%, non-fibrin specific: 31.1%), 89.5% heparin, 78.7% beta-blockers, 54.7% ACE inhibitors and 63% statins.
The number of patients who reached the primary endpoint was 262 (15.0%) in the PLAVIX-treated group and 377 (21.7%) in the placebo group, but most of the events related to the surrogate endpoint of vessel patency.
Table 5: Event Rates for the Primary Composite Endpoint in the CLARITY Study
| ||Clopidogrel |
|OR ||95% CI |
|*The total number of patients with a component event (occluded IRA, death, or recurrent MI) is greater than the number of patients with a composite event because some patients had more than a single type of component event. |
|Number (%) of patients reporting the composite endpoint ||262 (15.0%) ||377 (21.7%) ||0.64 ||0.53, 0.76 |
|Occluded IRA || || || || |
| N (subjects undergoing angiography) ||1640 ||1634 || || |
| n (%) patients reporting endpoint ||192 (11.7%) ||301 (18.4%) ||0.59 ||0.48, 0.72 |
| Death || || || || |
| n (%) patients reporting endpoint ||45 (2.6%) ||38 (2.2%) ||1.18 ||0.76, 1.83 |
| Recurrent MI || || || || |
| n (%) patients reporting endpoint ||44 (2.5%) ||62 (3.6%) ||0.69 ||0.47, 1.02 |