|Pharmacotherapeutic group: platelet aggregation inhibitors excl. Heparin, ATC Code: B01AC30.Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. Clopidogrel must be metabolised 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. 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 medicinal products, not all patients will have adequate platelet inhibition.Repeated doses of clopidogrel 75 mg per day produced substantial inhibition of ADP‑induced platelet aggregation from the first day; this increased progressively and reached steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and 60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within 5 days after treatment was discontinued.Acetylsalicylic acid inhibits platelet aggregation by irreversible inhibition of prostaglandin cyclo‑oxygenase and thus inhibits the generation of thromboxane A2, an inducer of platelet aggregation and vasoconstriction. This effect lasts for the life of the platelet.Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400 mg was taken within 8 hours before or within 30 minutes after immediate release aspirin dosing (81 mg), a decreased effect of ASA on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.The safety and efficacy of clopidogrel plus ASA have been evaluated in three double‑blind studies involving over 61,900 patients: the CURE, CLARITY and COMMIT studies, comparing clopidogrel plus ASA to ASA alone, both treatments given in combination with other standard therapy.The CURE study included 12,562 patients with non‑ST segment elevation acute coronary syndrome (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 ischaemia. Patients were required to have either 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=6,259) plus ASA (75‑325 mg once daily) or ASA alone (N=6,303), (75‑325 mg once daily) and other standard therapies. Patients were treated for up to one year. In CURE, 823 (6.6%) patients received concomitant GPIIb/IIIa receptor antagonist therapy. Heparins were administered in more than 90% of the patients and the relative rate of bleeding between clopidogrel plus ASA and ASA alone was not significantly affected by the concomitant heparin therapy. The number of patients experiencing the primary endpoint [cardiovascular (CV) death, myocardial infarction (MI), or stroke] was 582 (9.3%) in the clopidogrel plus ASA group and 719 (11.4%) in the ASA group, a 20% relative risk reduction (RRR) (95% CI of 10%‑28%; p=0.00009) for the clopidogrel plus ASA group [17% relative risk reduction when patients were treated conservatively, 29% when they underwent percutaneous transluminal coronary angioplasty (PTCA) with or without stent and 10% when they underwent coronary artery bypass graft (CABG)]. New cardiovascular events (primary endpoint) were prevented, with relative risk reductions 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, beyond 3 months of treatment, the benefit observed in the clopidogrel plus ASA group was not further increased, whereas the risk of haemorrhage persisted (see section 4.4). The use of clopidogrel in CURE was associated with a decrease in the need for 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 1,035 (16.5%) in the clopidogrel plus ASA group and 1,187 (18.8%) in the ASA group, a 14% relative risk reduction (95% CI of 6%-21%, p=0.0005) for the clopidogrel plus ASA group. This benefit was mostly driven by the statistically significant reduction in the incidence of MI [287 (4.6%) in the clopidogrel plus ASA group and 363 (5.8%) in the ASA group]. There was no observed effect on the rate of rehospitalisation for unstable angina.The results obtained in populations with different characteristics (e.g. 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 2,172 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 second 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.In patients with acute ST‑segment elevation MI, safety and efficacy of clopidogrel have been evaluated in 2 randomised, placebo‑controlled, double‑blind studies, CLARITY and COMMIT.The CLARITY trial included 3,491 patients presenting within 12 hours 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=1,752) plus ASA or ASA alone (n=1,739), (150 to 325 mg as a loading dose, followed by 75 to 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 myocardial infarction 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% beta blockers, 54.7% ACE inhibitors and 63% statins.Fifteen percent (15.0%) of patients in the clopidogrel plus ASA group and 21.7% in the group treated with ASA alone 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 hours of the onset of the symptoms of suspected MI with supporting ECG abnormalities (i.e. ST elevation, ST depression or left bundle‑branch block). Patients received clopidogrel (75 mg/day, n=22,961) plus ASA (162 mg/day), or ASA alone (162 mg/day) (n=22,891), for 28 days or until hospital discharge. The co‑primary endpoints were death from any cause and the first 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 plus ASA 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 hours.|
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with DuoPlavin in all subsets of the paediatric population in the treatment of coronary atherosclerosis. See 4.2 for information on paediatric use.