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Pharmacotherapeutic Group: Platelet aggregation inhibitors excluding heparin. ATC Code: BO1AC/04.
Pharmacology: Pharmacodynamics: Clopidogrel is a prodrug, whose metabolites is an inhibitor of platelet aggregation. It must be metabolised by cytochrome P-450 (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 (GP) IIb/IIIa complex, thereby inhibiting platelet aggregation. Due to the irreversible binding, platelets exposed are affected for the remainder of their lifespan (approximately 7-10 days) and recovery of normal platelet function occurs at a rate consistent with platelet turnover. 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.
Repeated doses of 75 mg/day produced substantial inhibition of ADP-induced platelet aggregation from the 1st day; this increased progressively and reached steady state between days 3 and 7. At steady state, the average inhibition level observed with a dose of 75 mg/day was between 40% and 60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within 5 days after treatment was discontinued.
The safety and efficacy of clopidogrel have been evaluated in 5 double-blind studies involving >88,000 patients: Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study, a comparison of clopidogrel to acetylsalicylic acid (ASA), and the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY), Clopidogrel and Metoprolol Myocardial Infarction Trial (COMMIT) and Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-A) study, studies comparing clopidogrel to placebo, both drugs given in combination with ASA and other standard therapy.
Recent Myocardial Infarction (MI), Recent Stroke or Established Peripheral Arterial Disease (PAD): The CAPRIE study included 19,185 patients with atherothrombosis as manifested by recent MI (<35 days), recent ischaemic stroke (between 7 days and 6 months) or established PAD. Patients were randomised to clopidogrel 75 mg/day or ASA 325 mg/day, and were followed for 1-3 years. In the MI subgroup, most of the patients received ASA for the 1st few days following the acute MI.
Clopidogrel significantly reduced the incidence of new ischaemic events (combined endpoint of MI, ischaemic stroke and vascular death) when compared to ASA. In the intention to treat analysis, 939 events were observed in the clopidogrel group and 1020 events with ASA [relative risk reduction (RRR) 8.7%, (95% CI: 0.2-16.4); p=0.045], which corresponds, for every 1000 patients treated for 2 years, to 10 (CI: 0-20) additional patients being prevented from experiencing a new ischaemic event. Analysis of total mortality as a secondary endpoint did not show any significant difference between clopidogrel (5.8%) and ASA (6%).
In a subgroup analysis by qualifying condition (MI, ischaemic stroke and PAD), the benefit appeared to be strongest (achieving statistical significance at p=0.003) in patients enrolled due to PAD (especially those who also had a history of MI) (RRR=23.7%; CI: 8.9-36.2) and weaker (not significantly different from ASA) in stroke patients (RRR=7.3%; CI: -5.7 to 18.7). In patients who were enrolled in the trial on the sole basis of a recent MI, clopidogrel was numerically inferior, but not statistically different from ASA (RRR=-4%; CI: -22.5 to 11.7). In addition, a subgroup analysis by age suggested that the benefit of clopidogrel in patients >75 years was less than that observed in patients ≤75 years.
Since the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is not clear whether the differences in relative risk reduction (RRR) across qualifying conditions are real or a result of chance.
Acute Coronary Syndrome: The CURE study included 12,562 patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave MI), and presenting within 24 hrs of onset of the most recent episode of chest pain or symptoms consistent with ischaemia. Patients were required to have either electrocardiogram (ECG) changes compatible with new ischaemia or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. Patients were randomised to clopidogrel (300 mg loading dose followed by 75 mg/day, N=6259) or placebo (N=6303), both given in combination with ASA (75-325 mg once daily) and other standard therapies. Patients were treated for up to 1 year. In CURE, 823 (6.6%) patients received concomitant GPIIb/IIIa receptor antagonist therapy. Heparins were administered in >90% of the patients and the relative rate of bleeding between clopidogrel and placebo was not significantly affected by the concomitant heparin therapy.
The number of patients experiencing the primary endpoint [cardiovascular (CV) death, MI or stroke] was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% RRR (95% CI of 10-28%; p=0.00009) for the clopidogrel-treated group [17% RRR when patients were treated conservatively, 29% when they underwent PTCA with or without stent and 10% when they underwent coronary artery bypass graft (CABG)]. New CV events (primary endpoint) were prevented, with RRRs of 22% (CI: 8.6, 33.4), 32% (CI: 12.8, 46.4), 4% (CI: -26.9, 26.7), 6% (CI: -33.5, 34.3) and 14% (CI: -31.6, 44.2), during the 0-1, 1-3, 3-6, 6-9 and 9-12 month study intervals, respectively. Thus, >3 months of treatment, the benefit observed in the clopidogrel + ASA group was not further increased, whereas the risk of haemorrhage persisted (see Precautions).
The use of clopidogrel in CURE was associated with a decrease in the need of thrombolytic therapy (RRR=43.3%; CI: 24.3%, 57.5%) and GPIIb/IIIa inhibitors (RRR=18.2%; CI: 6.5%, 28.3%).
The number of patients experiencing the co-primary endpoint (CV death, MI, stroke or refractory ischaemia) was 1035 (16.5%) in the clopidogrel-treated group and 1187 (18.8%) in the placebo-treated group, a 14% RRR (95% CI of 6-21%, p=0.0005) for the clopidogrel-treated group. This benefit was mostly driven by the statistically significant reduction in the incidence of MI [287 (4.6%) in the clopidogrel-treated group and 363 (5.8%) in the placebo-treated group]. There was no observed effect on the rate of rehospitalisation for unstable angina.
The results obtained populations with different characteristics (eg, unstable angina or non-Q-wave MI, low to high risk levels, diabetes, need for revascularisation, age, gender, etc) were consistent with the results of the primary analysis. In particular, in a post hoc analysis in 2172 patients (17% of the total CURE population) who underwent stent placement (Stent-CURE), the data showed that clopidogrel compared to placebo, demonstrated a significant RRR of 26.2% favouring clopidogrel for the co-primary endpoint (CV death, MI, stroke) and also a significant RRR of 23.9% for the 2nd co-primary endpoint (CV death, MI, stroke or refractory ischaemia). Moreover, the safety profile of clopidogrel in this subgroup of patients did not raise any particular concern. Thus, the results from this subset are in line with the overall trial results.
The benefits observed with clopidogrel were independent of other acute and long-term CV therapies [eg, heparin/low molecular weight heparin (LMWH), GPIIb/IIIa antagonists, lipid-lowering drugs, β-blockers and ACE inhibitors]. The efficacy of clopidogrel was observed independently of the dose of ASA (75-325 mg once daily).
In patients with acute ST-segment elevation MI, safety and efficacy of clopidrogrel have been evaluated in 2 randomised, placebo-controlled, double-blind studies, CLARITY and COMMIT.
The CLARITY trial included 3491 patients presenting within 12 hrs of the onset of a ST elevation MI and planned for thrombolytic therapy. Patients received clopidogrel (300 mg loading dose, followed by 75 mg/day, n=1752) or placebo (n=1739), both in combination with ASA (150-325 mg as a loading dose, followed by 75-162 mg/day), a fibrinolytic agent and, when appropriate, heparin. The patients were followed for 30 days. The primary endpoint was the occurrence of the composite of an occluded infarct-related artery on the predischarge angiogram, or death or recurrent MI before coronary angiography. For patients who did not undergo angiography, the primary endpoint was death or recurrent MI by day 8 or by hospital discharge. The patient population 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% β-blockers, 54.7% ACE inhibitors and 63% statins. Fifteen percent (15%) of patients in the clopidogrel group and 21.7% in the placebo group reached the primary endpoint, representing an absolute reduction of 6.7% and a 36% odds reduction in favor of clopidogrel (95% CI: 24, 47%; p<0.001), mainly related to a reduction in occluded infarct-related arteries. This benefit was consistent across all prespecified subgroups including patients' age and gender, infarct location and type of fibrinolytic or heparin used.
The 2x2 factorial design COMMIT trial included 45,852 patients presenting within 24 hrs of the onset of the symptoms of suspected MI with supporting ECG abnormalities (ie, ST elevation, ST depression or left bundle-branch block). Patients received clopidogrel (75 mg/day, n=22,961) or placebo (n=22,891), in combination with ASA (162 mg/day), for 28 days or until hospital discharge. The co-primary endpoints were death from any cause and the 1st occurrence of re-infarction, stroke or death. The population included 27.8% women, 58.4% patients ≥60 years (26% ≥70 years) and 54.5% patients who received fibrinolytics.
Clopidogrel 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), representing an absolute reduction of 0.5% and 0.9%, respectively. This benefit was consistent across age, gender and with or without fibrinolytics and was observed as early as 24 hrs.
Atrial Fibrillation: The ACTIVE-W and ACTIVE-A studies, separate trials in the ACTIVE program, included patients with atrial fibrillation (AF) who had at least 1 risk factor for vascular events. Based on enrollment criteria, physicians enrolled patients in ACTIVE-W if they were candidates for vitamin K antagonist (VKA) therapy (eg, warfarin). The ACTIVE-A study included patients who could not receive VKA therapy because they were unable or unwilling to receive the treatment.
The ACTIVE-W study demonstrated that treatment with vitamin K antagonists was more effective than with clopidogrel and ASA.
The ACTIVE-A study (N=7554) was a multicenter, randomized, double-blind, placebo-controlled study which compared clopidogrel 75 mg/day + ASA (N=3772) to placebo + ASA (N=3782). The recommended dose for ASA was 75-100 mg/day. Patients were treated for up to 5 years.
Patients randomized in the ACTIVE program were those presenting with documented AF ie, either permanent AF or at least 2 episodes of intermittent AF in the past 6 months, and had at least 1 of the following risk factors: Age ≥75 years or 55-74 years and either diabetes mellitus requiring drug therapy, or documented previous MI or documented coronary artery disease; treated for systemic hypertension; prior stoke, transient ischaemic attack (TIA) or non-central nervous system (CNS) systemic embolus; left ventricular dysfunction with left ventricular ejection fraction <45%; or documented peripheral vascular disease. The mean CHADS2 score was 2 (range 0-6).
Seventy-three percent (73%) of patients enrolled into the ACTIVE-A study were unable to take VKA due to physician assessment, inability to comply with international normalised ratio (INR) monitoring, predisposition to falling or head trauma, or specific risk of bleeding; for 26% of the patients, the physician's decision was based on the patient's unwillingness to take VKA.
The patient population included 41.8% women. The mean age was 71 years, 41.6% of patients were ≥75 years. A total of 23% of patients received antiarrhythmics, 52.1% β-blockers, 54.6% ACE inhibitors and 25.4% statins.
The number of patients who reached the primary endpoint (time to first occurrence of stroke, MI, non-CNS systemic embolism or vascular death) was 832 (22.1%) in the group treated with clopidogrel + ASA and 924 (24.4%) in the placebo + ASA group.
The benefit of clopidogrel + ASA was noted early and was maintained throughout the duration of the study up to 5 years; the rate of primary events was consistently lower in the clopidogrel + ASA group compared with the placebo + ASA group.
The reduction in the risk of major vascular events in the group treated with clopidogrel + ASA was primarily due to a large reduction in the incidence of strokes. Strokes occurred in 296 (7.8%) patients receiving clopidogrel + ASA and 408 (10.8%) patients receiving placebo + ASA.
The rate of ischaemic stroke was significantly lower in the clopidogrel + ASA group than in the placebo + ASA group (6.2% vs 9.1%; RRR, 32.4%; 95% CI, 20.2-42.7%).
The risk of stroke of any severity was reduced with the use of clopidogrel + ASA. In addition, 46 fewer non-disabling strokes and 69 fewer disabling or fatal strokes were reported with clopidogrel + ASA as compared to placebo + ASA.
There was a trend for reduction in the rates of MI in the group treated with clopidogrel + ASA (RRR, 21.9%; 95% CI, -3% to 40.7%; p=0.08). The rates of non-CNS systemic embolism and death from vascular causes were similar between the 2 groups.
The effectiveness of clopidogrel + ASA was noted early and was maintained throughout the duration of the study up to 5 years; the rate of stroke was consistently lower in the clopidogrel + ASA group compared with the placebo + ASA group.
Clopidogrel + ASA reduced the total number of hospital days for CV causes. The total number of days of CV hospitalizations was 30,276 for clopidogrel + ASA and 34,813 for placebo + ASA.
Paediatric Studies: A randomised, 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. In this study, 906 paediatric patients (neonates and infants) with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial shunt were randomised to receive clopidogrel 0.2 mg/kg/day (n=467) or placebo (n=439) along with concomitant background therapy up to the time of 2nd stage surgery. The mean time between shunt palliation and first administration of study medicinal product was 20 days. Approximately 88% of patients received concomitant ASA (range of 1-23 mg/kg/day). There was no significant difference between groups in the primary composite endpoint of death, shunt thrombosis or cardiac related intervention prior to 120 days of age following an event considered of thrombotic nature [89 (19.1%) for the clopidogrel group and 90 (20.5%) for the placebo group]. Bleeding was the most frequently reported adverse reaction in both clopidogrel and placebo groups; however, there was no significant difference in the bleeding rate between groups.
Pharmacokinetics: Absorption: After single and repeated oral dose of 75 mg/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 min after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.
The kinetics of the main circulating metabolite were linear (plasma concentrations increased in proportion to dose) in the dose range of 50-150 mg of clopidogrel.
Distribution: Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable in vitro over a wide concentration range.
Metabolism: Clopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is metabolised according to 2 main metabolic pathways: One (1) mediated by esterases and leading to hydrolysis into its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple CYP450. Clopidogrel is first metabolised 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.
The peak plasma concentration (Cmax) of the active metabolite is twice as high following a single clopidogrel 300 mg loading dose as it is after 4 days of 75-mg maintenance dose. Peak plasma concentration occurs approximately 30-60 min after dosing.
Elimination: Following an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted in the urine and approximately 46% in the faeces in the 120-hr interval after dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life (t½) of approximately 6 hrs. The elimination t½ of the main circulating (inactive) metabolite was 8 hrs after single and repeated administration.
Pharmacogenetics: 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 are nonfunctional. The CYP2C19*2 and CYP2C19*3 alleles account for the majority of reduced function alleles in White (85%) and Asian (99%) poor metabolisers. 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 metaboliser status will possess 2 loss-of-function alleles as defined in previous texts. Published frequencies for poor CYP2C19 metaboliser 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 metaboliser groups (ultrarapid, extensive, intermediate and poor), evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg/day and 600 mg followed by 150 mg/day, each for a total of 5 days (steady state). No substantial differences in active metabolite exposure and mean inhibition of platelet aggregation (IPA) were observed between ultrarapid, extensive and intermediate metabolisers. In poor metabolisers, active metabolite exposure was decreased by 63-71% compared to extensive metabolisers. After the 300 mg/75 mg dose regimen, antiplatelet responses were decreased in the poor metabolisers with mean IPA (5 mM ADP) of 24% (24 hrs) and 37% (day 5) as compared to IPA of 39% (24 hrs) and 58% (day 5) in the extensive metabolisers and 37% (24 hrs) and 60% (day 5) in the intermediate metabolisers. When poor metabolisers received the 600 mg/150 mg regimen, active metabolite exposure was greater than with the 300 mg/75 mg regimen. In addition, IPA was 32% (24 hrs) and 61% (day 5), which were greater than in poor metabolisers receiving the 300 mg/75 mg regimen, and were similar to the other CYP2C19 metaboliser groups receiving the 300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not been established in clinical outcome trials.
Consistent with the results, in a meta-analysis including 6 studies of 335 clopidogrel-treated subjects at steady state, it was shown that active metabolite exposure was decreased by 28% for intermediate metabolisers, and 72% for poor metabolisers while platelet aggregation inhibition (5 mM ADP) was decreased with differences in IPA of 5.9% and 21.4%, respectively, when compared to extensive metabolisers.
The influence of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been evaluated in prospective, randomized, controlled trials. There have been a number of retrospective analyses; however, to evaluate this effect in patients treated with clopidogrel for whom there are genotyping results: CURE (n=2721), CHARISMA (n=2428), CLARITY-TIMI 28 (n=227) and TRITON-TIMI 38 (n=1477) as well as a number of published cohort studies.
In TRITON-TIMI 38 and 3 of the cohort studies (Collet, Sibbing, Giusti) the combined group of patients with either intermediate or poor metaboliser status had a higher rate of CV events (death, MI and stroke) or stent thrombosis compared to extensive metabolisers.
In CHARISMA and 1 cohort study (Simon), an increased event rate was observed only in poor metabolisers when compared to extensive metabolisers.
In CURE, CLARITY, ACTIVE-A and 1 of the cohort studies (Trenk), no increased event rate was observed based on metaboliser status.
None of these analyses was adequately sized to detect differences in outcome in poor metabolisers.
Special Populations: The pharmacokinetics of the active metabolite of clopidogrel is not known in these special populations.
Gender: 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 (CAPRIE), the incidence of clinical outcome events, other adverse clinical events and abnormal clinical laboratory parameters was similar in men and women.
Elderly: 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.
Paediatric Patients: No information available.
Hepatic Impairment: After repeated doses of clopidogrel 75 mg/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 2 groups.
Renal Impairment: After repeated doses of clopidogrel 75 mg/day in patients with severe renal impairment (creatinine clearance from 5-15 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 clopidogrel 75 mg/day.
Ethnicity: The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to ethnicity (see Pharmacogenetics as aforementioned). From literature, limited data in Asian populations are available to assess the clinical implication of genotyping of this CYP on clinical outcome events.
Toxicology: Preclinical Safety Data: During preclinical studies in rat and baboon, the most frequently observed effects were liver changes. These occurred at doses representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day and were a consequence of an effect on hepatic metabolising enzymes. No effect on hepatic metabolising enzymes was observed in humans receiving clopidogrel at the therapeutic dose.
At very high doses, a poor gastric tolerability (gastritis, gastric erosions and/or vomiting) of clopidogrel was also reported in rat and baboon.
There was no evidence of carcinogenic effect when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats when given at doses up to 77 mg/kg/day (representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day).
Clopidogrel has been tested in a range of in vitro and in vivo genotoxicity studies, and showed no genotoxic activity.
Clopidogrel was found to have no effect on the fertility of male and female rats and was not teratogenic in either rats or rabbits. When given to lactating rats, clopidogrel caused a slight delay in the development of the offspring. Specific pharmacokinetic studies performed with radiolabelled clopidogrel have shown that the parent compound or its metabolites are excreted in the milk.
Consequently, a direct effect (slight toxicity), or an indirect effect (low palatability) cannot be excluded.
