Cardiovascular diseases are currently the leading cause of death in industrialised countries and are expected to become so in emerging countries by 2020. Among them, coronary artery disease (CAD) is the most prevalent manifestation and is associated with high mortality and morbidity. The clinical presentations of CAD include silent ischemia, stable angina, unstable angina, myocardial infarction (MI), heart failure, and sudden cardiac death. (1) Patients with chest pain represent a very substantial proportion of all acute medical hospitalisations in Europe and a major public health concern. (1, 2) Improvement of outcomes in patients with acute coronary syndrome (ACS) is therefore a major healthcare task. (2)

Platelets play a central role in atherothrombosis, the main pathologic substrate in ACS. Sufficient inhibition of platelet aggregation is therefore one of the key targets in the treatment of ACS. Blockade of the P2Y12 subtype of adenosine diphosphate (ADP) receptor on platelet cell membranes has been established as a key mechanism of platelet inhibition. (2)

The use of antiplatelet agents, specifically the thienopyridines, has become a standard of care in the approach to the patient presenting with an ACS. These medicines irreversibly inhibit the platelet by permanently binding to the surface P2Y12 receptor and blocking the downstream fibrinogen cross-linking between platelets, which leads to aggregation and thrombus. (3) Oral thienopyridines began with ticlopidine, a first-generation thienopyridine, which although an effective agent for the irreversible blocking of the platelet P2Y12 receptor, was found to have unfavourable side effects. The use of clopidogrel, a second-generation thienopyridine, almost completely replaced ticlopidine as the preferred P2Y12 inhibitor in ACS. (3) Current standard-of-care oral antiplatelet therapy for patients with ACS (unstable angina, UA; non-ST-elevation myocardial infarction, NSTEMI; ST-segment elevation myocardial infarction, STEMI) and following percutaneous coronary intervention (PCI) with stent implantation is the combination of aspirin and the thienopyridine P2Y12 inhibitor clopidogrel which is recommended for up to 1 year. (4)

Clopidogrel is one of the most studied drugs in clinical trials. Evidence obtained from large randomised trials demonstrated a consistently beneficial effect of using clopidogrel in ACS. (5) The clinical efficacy of clopidogrel has been demonstrated in both add-on therapy to aspirin in the settings of NSTE-ACS, PCI, and STEMI, and single antiplatelet therapy for secondary prevention. (4)

Clopidogrel was first investigated by the CAPRIE trial (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events). This was an international trial involving 19,185 patients. It was designed to assess the relative efficacy and safety of clopidogrel and aspirin in reducing the risk of ischemic stroke, MI or vascular death in patients with recent MI, stroke or established peripheral vascular disease. Although the result demonstrated marginal superiority of clopidogrel over aspirin, CAPRIE formed the basis for the approval of clopidogrel as a therapeutic agent for the reduction of thrombotic events in patients with recent MI, recent stroke or established peripheral vascular disease. (5) Since the CAPRIE trial was published in 1996, a number of studies have evaluated the complementary inhibitory properties of aspirin and clopidogrel in several settings, including ACS. (6)

Clopidogrel use in patients with non-ST-elevation myocardial infarction. The CURE trial (Clopidogrel in Unstable angina to prevent Recurrent Events) was another prospective randomised, placebo-controlled trial that evaluated the efficacy and safety of clopidogrel when added to aspirin in 12,562 patients presenting acutely with NSTEMI. (5) The CURE trial demonstrated that a 300mg clopidogrel loading dose (75mg maintenance dose) with concomitant aspirin therapy significantly reduced the occurrence of MI and recurrent ischemia compared with aspirin alone. (6) The superiority of clopidogrel over placebo observed in the CURE trial has paved the way for the routine use of dual anti-platelet therapy in patients with NSTEMI. (5)

Clopidogrel use in patients with ST-segment elevation myocardial infarction. Two more recent international, double-blind trials, CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy — Thrombolysis In Myocardial Infarction 28) and COMMIT/CCS-2 (Clopidogrel and Metoprolol in Myocardial Infarction Trial) investigated the use of clopidogrel in patients with acute STEMI. (5) Both trials demonstrated the benefit of dual antiplatelet therapy in patients with STEMI. (4)

In CLARITY, a total of 3,491 patients with STEMI treated with aspirin and fibrinolytic therapy were randomised to receive either clopidogrel (300 mg loading dose followed by 75 mg/day) or placebo. The incidence of the primary efficacy endpoint (composite of an occluded infarct-related artery on angiography or death or recurrent MI before angiography) was significantly reduced in the clopidogrel plus aspirin group versus aspirin alone (15% vs 21.7%, P<0.001). (4)

In COMMIT, a total of 45,852 patients with STEMI treated with aspirin also received either clopidogrel 75 mg or placebo for up to 4 weeks in hospital or until discharge. The rate of the composite endpoint of death, reinfarction, or stroke was significantly lower in patients receiving clopidogrel plus aspirin versus those receiving aspirin alone (9.2% vs 10.1%, P=0.002). A significant reduction in all-cause death (co-primary endpoint) was also noted with clopidogrel plus aspirin (7.5% vs 8.1% with aspirin alone, P=0.03). (4)

Clopidogrel in patients with percutaneous coronary intervention. The CREDO (Clopidogrel for the Reduction of Events During Observation) trial evaluated the benefit of 12-month treatment with clopidogrel (75 mg/day) after PCI and the effect of a pre-procedural clopidogrel loading dose (300 mg) in addition to aspirin therapy (81-325 mg) in patients undergoing elective PCI. Dual antiplatelet therapy was associated with a significant 27% relative reduction in the composite endpoint of death, MI, or stroke (P=0.02) at 1 year versus aspirin alone, whereas no significant benefit of the 300 mg loading dose of clopidogrel was apparent at 28 days. (4)

The above outlined clinical trials provide useful evidence of the benefit of clopidogrel in patients with ACS. (5) The body of evidence accumulated over the past decade establishes convincingly the role of dual antiplatelet therapy using aspirin and clopidogrel in a broad spectrum of cardiovascular patients. (7) Clopidogrel remains one of the most carefully studied antiplatelet agents and it is estimated that over 100,000 patients have been enrolled in randomised trials involving clopidogrel. (8)

Krka’s clopidogrel (Zyllt^®) has been present on the international market for more than 7 years, and due to its quality and trust it has gained over the years it has become the leading generic clopidogrel in Europe. Its efficacy and safety have been proven in post-authorisation safety and efficacy studies which prove that Krka’s clopidogrel is a therapy based on well-established clinical evidence. (9-15) These studies yielded important results and an extensive clinical database, which is not available for any other generic clopidogrel. The high efficacy and good safety, as well as the reasonable price of this generic clopidogrel, could undoubtedly contribute to better compliance with the treatment in more patients with ACS.