The role of clopidogrel in the management of acute coronary syndromes

BACKGROUND: Despite significant advances in the management of coronary heart disease, myocardial infarction (MI) is still associated with a mortality rate of 45%. Acetylsalicylic acid (ASA) has been the oral antiplatelet drug of choice until recently. Thienopyridines such as clopidogrel have been shown to provide significant benefits in the management of acute coronary syndromes (ACS), either as an alternative to or in combination with ASA therapy. OBJECTIVE: The purpose of this article was to review the available scientific literature evaluating the use of clopidogrel in the management of ACS. METHODS: Relevant published data were identified through searches of the English-language literature indexed on MEDLINE and International Pharmaceutical Abstracts through April 2003. Search terms included thienopyridines, platelet aggregation inhibitors, clopidogrel, ticlopidine, acute coronary syndrome, myocardial infarction, and percutaneous coronary intervention. Pertinent conference abstracts were also included. RESULTS: The results of 3 large clinical trials-Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), Effect of Pretreatment with Clopidogrel and Aspirin Followed by Long-Term Therapy in Patients Undergoing Percutaneous Coronary Intervention (PCI-CURE), and Clopidogrel for the Reduction of Events During Observation (CREDO)-support prolonged use of clopidogrel (up to 12 months) in combination with ASA in patients with non-ST-segment elevation MI and patients undergoing a percutaneous coronary intervention (PCI). A significant increase in bleeding events was observed in the group that received clopidogrel plus ASA compared with ASA alone in the CURE (major bleeding, P = 0.001; minor bleeding, P < 0.001) and PCI-CURE (minor bleeding, P = 0.03) trials. Use of the combination of clopidogrel and ASA with other antiplatelet and/or anticoagulant agents has not been studied extensively. CONCLUSIONS: Use of the combination of clopidogrel and ASA for up to 9 months is recommended for the medical management of non-ST-segment elevation MI and after a PCI. The increased risk of bleeding must be taken into account, and use of this combination with other agents that affect bleeding risk should be considered carefully.     

不同负荷剂量氯吡格雷对急性冠脉综合征患者PCI的疗效观察

目的 比较不同负荷剂量氯吡格雷对急性冠脉综合征(ACS)患者经皮冠状动脉介入(PCI)治疗的临床疗效.方法 入选144例我院自2006-06～2007-01诊断为ACS行PCI治疗的患者,随机分两组,分别于术前6 h给予300 mg和600 mg负荷剂量氯吡格雷,观察服药前、服药后2、4和6 h血小板聚集率,主要终点事件为住院期间出血、靶血管重建、休克以及死亡等不良事件,次要终点为术后1个月主要心脏不良事件发生情况.结果 600 mg氯吡格雷负荷剂量组和300 mg氯吡格雷负荷剂量组均在4～6 h达到血小板抑制程度的稳定状态,服用600 mg氯吡格雷负荷剂量组血小板聚集率降低更为显著.住院期间两组不良事件发生情况差异无统计学意义(P>0.05).1个月随访主要心脏不良事件差异无统计学意义.结论 600 mg氯吡格雷虽能产生更强的血小板抑制,但对减少临床不良事件发生并无显著优势.     

The CURE trial: using clopidogrel in acute coronary syndromes without ST-segment elevation

In a large, randomized, placebo-controlled trial in centers that use a conservative approach to acute coronary syndromes, the antiplatelet drug clopidogrel (Plavix) decreased the rate of the combined end point of cardiovascular death, nonfatal myocardial infarction, or stroke by 20% in patients presenting with acute coronary syndromes without ST-segment elevation. The benefit was at the cost of an increase in bleeding, however. This strategy may need to be tailored in centers that use a more aggressive treatment strategy of early angiography and revascularization.     

Pantoprazole for the prevention of gastrointestinal bleeding in high-risk patients with acute coronary syndromes

Purpose

The aim of this study is to evaluate the preventive effect of proton pump inhibitors on gastrointestinal (GI) bleeding in patients with acute coronary syndromes (ACS) who are at high risk for GI bleeding.

Materials and Methods

We enrolled 665 patients with ACS who had one or more of the following risk factors for GI bleeding: 75 years of age or older, history of peptic ulcer disease, history of GI bleeding, cardiogenic shock, and chronic renal dysfunction (serum creatinine, >2 mg/dL). Patients were randomly assigned to receive 40 mg of pantoprazole or placebo twice daily for 7 days, in addition to standard treatment of ACS. The primary end point was the occurrence of GI bleeding during hospitalization.

Results

During a median time of hospitalization of 12 days, 12 (3.6%) of 332 patients in the placebo group had an occurrence of GI bleeding, as compared with 4 (1.2%) of the 333 patients in the pantoprazole group (P = .046, Fisher exact test). The log-rank test showed a significant difference between the 2 groups in the time to the occurrence of GI bleeding (P = .015). Major GI bleeding occurred in 5 (1.5%) patients in the placebo group but only in 1 (0.3%) in the pantoprazole group (P = .12). Pneumonia developed in 22 (6.6%) patients in the placebo group and 24 (7.2%) in the pantoprazole group (χ² = 0.077, P = .88). The 30-day mortality was 10.2% (34/332) in the placebo group and 10.5% (35/333) in the pantoprazole group.

Conclusions

In patients with ACS who are at high risk for GI hemorrhage, prophylactic treatment with pantoprazole could reduce the risk of GI bleeding with no significant effects on the incidence of hospital-acquired pneumonia and 30-day mortality.     

Predictors of delay in presentation to the ED in patients with suspected acute coronary syndromes

Delays in seeking medical attention for patients with acute coronary syndromes (ACS) preclude early application of life-saving treatment and diminish efficacy. Previous studies suggest 3-hour delays between onset of symptoms and ED arrival in patients with typical presentations of acute myocardial infarction (AMI). A prospective observational study was conducted in an urban ED measuring lag time (LT) among adults presenting within 48 hours of onset of symptoms suggestive of ACS. Univariate and multiple regression analyses were performed on 5 predictors: age, sex, symptoms at presentation, and 2 different outcomes (AMI and ACS). Three hundred seventy-four patients were enrolled. Mean age was 63 years with 38% 70 years or older. Seventy-three percent of all patients with suspected ACS presented with chest pain, 27% with atypical symptoms. Overall mean LT was 8.7 hours (standard deviation 11). In subgroup analysis, patients aged >/=70 years were more likely to have LTs >12 hours (29% vs. 19% P =.043) and patients without chest pain had longer mean LTs (11.6 vs. 7.6 hours, P =.01). Delay in ED presentation is group specific. Advanced age and patients with atypical symptoms are predictive of longer LTs. Contrary to previously published data, patients with symptoms suspicious for ACS can delay an average of 9 hours, which might alter current thinking in the prevention and care of these patients.     

Troponin level and efficacy of abciximab in patients with acute coronary syndromes undergoing early intervention after clopidogrel pretreatment

Objective We investigated how does troponin level (TnT) affect the benefit achieved by abciximab in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) after pretreatment with a high loading dose of clopidogrel. Methods The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT 2) trial included 2,022 patients with non-ST elevation ACS undergoing PCI who were randomized to abciximab or placebo after pretreatment with 600 mg of clopidogrel. The patients were divided into groups with elevated TnT level (n = 1,049) and no elevated TnT level (n = 973). The primary end point of the trial was the composite of death, myocardial infarction and urgent reintervention at 30 days. Results In patients with elevated TnT level the incidence of the primary end point was 13.1% in the abciximab group Vs. 18.3% in the placebo group [relative risk (RR): 0.70; 95% confidence interval (CI), 0.52–0.95, P = 0.02]. The combined incidence of death or myocardial infarction was 12.9% in the abciximab group vs. 17.9% in the placebo group (RR: 0.71; 95% CI, 0.52–0.96, P = 0.03). In contrast, the incidence of the primary end point in patients with no elevated TnT level was identical in both treatment groups (4.6%). The risk of bleeding was not related to TnT level. Conclusions Baseline troponin level affects the benefit of abciximab in patients with ACS undergoing PCI after pretreatment with a high loading dose of clopidogrel. Abciximab reduces the risk of ischemic events only in patients with ACS and elevated troponin level.     

Acute coronary syndromes: identifying the appropriate patient for prasugrel

Acute coronary syndrome (ACS) remains the leading cause of morbidity and mortality. More than half of patients presenting with ACS will experience a recurrent ischemic event; thus, preventing recurrent events is essential to reduce morbidity and mortality associated with ACS. While dual antiplatelet therapy with aspirin and clopidogrel has been the foundation of management for patients presenting with ACS, clopidogrel is limited by delayed antiplatelet effect and a variable patient response. Prasugrel is more potent, has a more rapid and consistent antiplatelet effect, and has been associated with improved outcomes compared with clopidogrel in select patients with ACS. Although prasugrel reduces the risk of recurrent cardiovascular events, it also increases the risk of major bleeding. Careful patient selection will improve the likelihood that patients treated with prasugrel will experience the benefit of this antiplatelet agent with the lowest possible risk of an adverse event. This article reviews the data supporting the use of prasugrel in ACS with an emphasis on characteristics that will help identify the most appropriate patient for this therapy.     

Efficacy and safety of prasugrel in acute coronary syndrome patients

Ischemic heart disease is the primary cause of death worldwide. The pathophysiological process of cardiovascular diseases is linked to atheromatous plaque formation, while plaque rupture releases thrombogenic elements, which lead to activation of platelets, blood clotting and formation of thrombi. Platelet inhibitors are used to prevent thrombosis. The present systematic review discusses the efficacy of prasugrel in terms of platelet inhibition potential and clinical prevention of cardiovascular outcomes. The balance between reduction of ischemic events as a measure of drug efficacy and the risk of bleeding is reviewed. Other adverse events observed in patients treated with this platelet inhibitor are discussed, including hematological complications, and cutaneous and hepatic idiosyncratic reactions. The complex relationship between prasugrel use and cancer promotion is also described.     

Enoxaparin in acute coronary syndromes

Enoxaparin is a low-molecular-weight heparin (LMWH) derivative that exerts its anticoagulant activity through antithrombin III, an endogenous inhibitor of factor Xa and thrombin IIa. Unlike its unfractionated heparin (UFH) counterparts, enoxaparin has a greater bioavailability, lower incidence of heparin-induced thrombocytopenia and more stable and predictable anticoagulation, allowing fixed dosing without the need for monitoring. These advantages make it an attractive anticoagulant to be used in acute coronary syndrome management. Indeed, several clinical trials and meta-analyses have consistently demonstrated the efficacy of enoxaparin in reducing cardiovascular events and mortality in this population. Although initial clinical trials with enoxaparin during the early conservative approach suggested superior efficacy without differences in safety compared with UFH, emerging data in the current era of early revascularization approach indicate that superior effects of enoxaparin over heparin in reducing clinical events should be balanced against an increase in major hemorrhagic complications. Enoxaparin is a rational alternative to UFH in patients presenting with either unstable angina/non-ST-elevation myocardial infarction or ST-elevation myocardial infarction, with a clinically modest increase in bleeding complications.     

Aspirin, ticlopidine, and clopidogrel in acute coronary syndromes: underused treatments could save thousands of lives

Aspirin is the cornerstone of therapy for unstable angina and acute myocardial infarction and the foundation on which other therapies are added, both in the short term and the long term. Yet, despite clear data, aspirin is woefully underused or is often used late. Prompt administration of aspirin could save thousands of lives each year. Ticlopidine and clopidogrel have a synergistic effect when used with aspirin, and can also have a role in treating patients who are aspirin-resistant or have diffuse atherosclerosis.     

Tirofiban in acute coronary syndromes

Acute coronary syndromes represent a major health problem in terms of incidence and mortality. Intracoronary platelet-rich thrombi may develop in response to plaque rupture, and are involved in the pathogenesis of all acute coronary syndromes. The glycoprotein IIb/IIIa receptor, a platelet surface integrin, plays a key role in platelet aggregation once it has been activated by specific ligands. The development of glycoprotein IIb/IIIa inhibitors has revolutionized the management of acute coronary syndromes. Tirofiban is one of three parenteral glycoprotein IIb/IIIa inhibitors in clinical use, and many trials have demonstrated its clinical efficacy and low rate of adverse effects in patients with non-ST-segment elevation acute coronary syndrome. This article reviews the data concerning its use in the clinical settings of acute coronary syndromes and percutaneous coronary angioplasty, and discusses its benefits in different treatment strategies and in association with other drugs. In particular, the role of early, upstream tirofiban coupled with early aggressive revascularization in the management of high-risk non-ST-segment elevation acute coronary syndromes is emphasized.