Effectiveness and safety of combined antiplatelet and anticoagulant therapy: a critical review of the evidence from randomized controlled trials

Antiplatelet and anticoagulant drugs are effective for the prevention of arterial and venous thrombosis but patients continue to experience major cardiovascular events despite their use. Strategies to improve the effectiveness of antithrombotic therapies include selecting the optimal drug and dosing regimen, the use of combinations of antiplatelet and anticoagulant drugs and the development of new more effective drugs to replace existing therapies. Evidence from randomized controlled trials indicates that the combination of aspirin and an anticoagulant is more effective than aspirin alone for the prevention of recurrent cardiovascular events in patients with acute coronary syndrome and is more effective than anticoagulation alone for the prevention of thromboembolic events in patients with mechanical heart valves, but at a cost of increased bleeding. Randomized controlled trials provide no evidence for improved effectiveness of combination therapy compared with antiplatelet therapy alone for the prevention of recurrent cardiovascular events in patients with non-cardioembolic stroke or peripheral artery disease, or compared with anticoagulant therapy alone for the prevention of stroke in patients with atrial fibrillation. Despite lack of evaluation in randomized controlled trials, combination therapy is commonly used in patients with separate indications for antiplatelet therapy (e.g., acute coronary syndrome, recent coronary artery stent) and anticoagulant therapy (e.g., atrial fibrillation with at least one additional risk factor for stroke). Randomized trials are urgently required to evaluate the effectiveness and safety of combining antiplatelet and anticoagulant therapy in these settings.     

Optimal management of platelet function after coronary stenting

Opinion statement Coronary stenting elicits vessel wall damage, and subsequent activation of platelets is implicated as a major component of complications such as acute, subacute, and late stent thrombosis. As such, dual antiplatelet therapy using aspirin and clopidogrel has become a routine adjunct to coronary stenting. Use of aspirin and clopidogrel with or without glycoprotein IIb/IIIa inhibitors after coronary stenting reduces the complication rate and improves long-term outcomes. Dual antiplatelet therapy using aspirin and clopidogrel is recommended for at least 4 weeks with bare metal stents, and for 3 to 6 months with drug-eluting stents for prevention of major adverse cardiac events. After coronary stenting, 1 year of dual antiplatelet therapy is recommended for prevention of future cardiac events. However, despite the use of antiplatelet agents, stent thrombosis occurs in approximately 1% of patients, with an increased likelihood of occurrence in high-risk patients or a lesion subset of patients. Although the incidence of stent thrombosis is low, stent thrombosis usually presents as acute coronary syndrome and the mortality rate is up to 45%. Thus, considering the widespread use of stents, a considerable number of people are inadequately protected from thrombotic events despite current standard antiplatelet therapy using aspirin and clopidogrel. A concern with clopidogrel is the loading time and loading dose required to achieve and maintain optimal inhibition of platelet aggregation. The current recommendation for ensuring maximum antiplatelet activity is administration of a 300-mg loading dose of clopidogrel initiated at least 6 hours prior to percutaneous coronary intervention (PCI), and ideally the day before. If this is not possible, a loading dose of 600 mg of clopidogrel should be administered at least 2 hours before PCI. Recently, new combinations of antiplatelet agents (ie, triple therapy using aspirin, clopidogrel, and cilostazol) and new drugs with potent antiplatelet effects (ie, Prasugrel [currently being developed by Sankyo Pharmaceuticals and Ube Pharmaceuticals in Japan and by Eli Lilly and Co. (Indianapolis, IN) in the United States], Cangrelor [currently being developed by AstraZeneca Pharmaceuticals, Wilmington, DE], and AZD6140) have been evaluated in clinical trials; such treatments may help reduce the number of cardiac events after coronary stenting.     

Aspirin and other antiplatelet drugs in the prevention of venous thromboembolism

While there is good evidence for a protective effect of aspirin against occlusive vascular events in individuals with arterial disease, its role in preventing venous thromboembolism (VTE) is unclear. In this article we review the role of aspirin and other antiplatelet drugs in prevention of venous thromboembolism in surgical patients, high risk medical patients requiring aspirin for other reasons, patients with myeloproliferative disorders, long distance travellers and patients receiving treatment with the IMiD class of drugs. Overall, data from the PEP study and Anti-Platelet Trialists' systematic review show that aspirin reduces the risk of VTE by around 25% in high risk surgical patients. Data from retrospective and before/after studies also suggest efficacy in reducing VTE in myeloma patients on IMiD drugs in combination with dexamethasone or chemotherapy. However, there has been no direct comparison with coumarins or heparin to indicate that aspirin is the optimal form of thromboprophylaxis. In patients who require aspirin because of high risk of arterial vascular occlusion (including patients with polycythaemia vera and essential thrombocythaemia), the additional small reduction in VTE risk is an added benefit with no additional risk associated. There is no evidence for a role of aspirin in prevention of travel-related thrombosis. At present there is no clear evidence that aspirin is the drug of choice for the prevention of VTE in any patient group.     

Between Scylla and Charybdis: antithrombotic therapy in hematopoietic progenitor cell transplant patients

Patients who undergo hematopoietic progenitor cell transplant may require antithrombotic therapy for a variety of reasons-history of vascular events or developing new ones during therapy. For patients with arterial disease, use of antiplatelet therapy is based on acuity. For primary prevention of an arterial event, aspirin can be withheld at the start of transplant. On the other hand, in the face of a patient experiencing an acute myocardial infarction, aspirin should be given, no matter what the degree of thrombocytopenia is. Patients with cardiac 'hardware'-stents and mechanical valves-pose difficult issues because as higher risk patients (especially patients with recent implantation of a drug eluting stent) they require more aggressive anticoagulation, even in the face of severe thrombocytopenia. Anticoagulation with heparin is dependent on the platelet count with full dose recommended for a platelet count over 50 × 10(9)/L and prophylactic dosing with platelets in the 20-50 × 10(9)/L range. If the patient develops a distal venous thrombosis, then simple observation can be used, but more proximal thrombosis or pulmonary embolism requires consideration of anticoagulation. Central venous catheter thrombosis is best treated by line removal, as the risk of bleeding is high if the device is left in. The advent of new anticoagulants with minimal drug and food interactions may offer better choices for therapy for these difficult patients. This is also an area in which clinical trials would be helpful to clarify the treatment choices.     

Preventing stroke in patients with atrial fibrillation: current treatments and new concepts

Atrial fibrillation (AF) is common, and it increases the risk of stroke. Placebo-controlled trials consistently showed that warfarin reduces the risk of stroke by two thirds, and a meta-analysis of trials of aspirin show a one-fifth reduction. Meta-analysis of trials directly comparing warfarin and aspirin shows that warfarin reduces the risk of stroke compared with aspirin by about one third. Major advisory bodies recommend risk stratification of patients with AF and prophylactic therapy with warfarin for patients at higher risk. There are several problems with warfarin therapy, which have resulted in a widely documented underuse. These problems include a narrow therapeutic window, marked variability in pharmacokinetics, and contraindications. There are new promising approaches to stroke prevention in AF. One of these is combination antiplatelet therapy. In a large randomized trial, the combination of dipyridamole and aspirin has been shown to have additive benefits against stroke. The combination of clopidogrel and aspirin results in additive benefits against vascular events, with only a modest increase in bleeding. A trial of combined antiplatelet therapy in AF is warranted. Occlusion of the left atrial appendage, either with a transvenous device or with surgery, is another strategy that is being explored. A direct thrombin inhibitor, ximelagatran, has been shown to have an excellent pharmacokinetic profile and is being developed as an oral agent for stroke prevention in AF, and it will not need regular monitoring. (Am Heart J 2003;145:418-23.)     

Recent developments in the use of antiplatelet agents to prevent cardiovascular events

Platelets are pivotal contributors to arterial thrombosis. Dual antiplatelet therapy with aspirin and clopidogrel has become the standard of care for the secondary prevention of cardiovascular events in patients with acute coronary syndromes and after percutaneous coronary intervention. Clinical evidence of the continued risk of cardiovascular events plus pharmacodynamic evidence of substantial variability in on-treatment platelet reactivity has supported the development of new therapeutic strategies, using established agents and new antiplatelet drugs. This article will highlight recent pivotal clinical trials seeking to advance the use of antiplatelet therapy in patients with cardiovascular disease.     

Platelet inhibition in the management of thrombosis

The role of platelets in the initation of arterial thrombosis is clear. In venous thrombosis as well, platelets may in some circumstances play a significant role. For these reasons, and because of the complications and limitations of anticoagulant therapy, antithrombotic trials have been launched with several agents which inhibit platelet function. Regarding postoperative deep vein thrombosis, neither aspirin nor dipyridamole alone appears effective, although the combination offers promise. Results with dextrans are conflicting. In recurrent idiopathic deep vein thrombosis, sulfinpyrazone may be beneficial. On the arterial side, transient cerebral ischemic attacks may be favorably affected by either aspirin or sulfinpyrazone. Prevention of thromboembolism associated with prosthetic heart valves appears possible with combination warfarin-dipyridamole therapy, and the beneficial effect of sulfinpyrazone on shortened platelet survival in this group suggests that this agent may also be effective. Sulfinpyrazone may also be beneficial in preventing thrombosis in arteriovenous canulas. The issue which has attracted the greatest attention and about which no clear answer exists at present is whether antiplatelet agents can modify the course of acute myocardial infarction. Several trials with aspirin are currently underway, and it would be premature to recommend its use in this condition until the results of these trials are available, probably in 1975.     

Design and Rationale of the RE‐DUAL PCI Trial: A Prospective,Randomized, Phase 3b Study Comparing the Safety and Efficacy of Dual Antithrombotic Therapy With Dabigatran Etexilate Versus Warfarin Triple Therapy in Patients With Nonvalvular Atrial Fibrillation Who Have Undergone Percutaneous Coronary Intervention With Stenting

Antithrombotic management of patients with atrial fibrillation (AF) undergoing coronary stenting is complicated by the need for anticoagulant therapy for stroke prevention and dual antiplatelet therapy for prevention of stent thrombosis and coronary events. Triple antithrombotic therapy, typically comprising warfarin, aspirin, and clopidogrel, is associated with a high risk of bleeding. A modest‐sized trial of oral anticoagulation with warfarin and clopidogrel without aspirin showed improvements in both bleeding and thrombotic events compared with triple therapy, but large trials are lacking. The RE‐DUAL PCI trial (NCT 02164864) is a phase 3b, a strategy of prospective, randomized, open‐label, blinded‐endpoint trial. The main objective is to evaluate dual antithrombotic therapy with dabigatran etexilate (110 or 150 mg twice daily) and a P2Y12 inhibitor (either clopidogrel or ticagrelor) compared with triple antithrombotic therapy with warfarin, a P2Y12 inhibitor (either clopidogrel or ticagrelor, and low‐dose aspirin (for 1 or 3 months, depending on stent type) in nonvalvular AF patients who have undergone percutaneous coronary intervention with stenting. The primary endpoint is time to first International Society of Thrombosis and Hemostasis major bleeding event or clinically relevant nonmajor bleeding event. Secondary endpoints are the composite of all cause death or thrombotic events (myocardial infarction, or stroke/systemic embolism) and unplanned revascularization; death or thrombotic events; individual outcome events; death, myocardial infarction, or stroke; and unplanned revascularization. A hierarchical procedure for multiple testing will be used. The plan is to randomize ～ 2500 patients at approximately 550 centers worldwide to try to identify new treatment strategies for this patient population.     

Gastrointestinal bleeding after percutaneous coronary intervention

Percutaneous coronary intervention (PCI) is now performed in a wide range of patients with coronary artery disease. Complications of PCI include in-stent re-stenosis and in-stent thrombosis. According to the recent 2005 guidelines of the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions, dual antiplatelet therapy with low-dose aspirin and thienopyridine derivatives such as ticlopidine and clopidogrel should be used in patients who have undergone PCI. A serious complication of dual antiplatelet therapy is bleeding, most of which arise from the gastrointestinal (GI) tract. In this article we review published studies about GI bleeding in patients who have undergone PCI. The prevalence of GI bleeding in patients who are administered dual antiplatelet therapy following PCI is approximately 2%, and GI bleeding after PCI is associated with increased morbidity, mortality, duration of hospitalization and cost. Advanced age, a history of peptic ulcer disease, co-administration of non-steroidal anti-inflammatory drugs, co-administration of anticoagulants, and physiological stress are considered to be the major risk factors for GI bleeding in patients undergoing antiplatelet therapy following PCI. Recent clinical and experimental studies indicate that administration of low-dose aspirin may also increase the risk of adverse events in the small intestine. Although some prophylactic strategies such as proton-pump inhibitor, H? receptor antagonist and eradication of Helicobacter pylori are proposed, there are few randomized controlled trials assessing the best strategy for the prevention of GI bleeding after PCI. Further extensive studies are required to ascertain the beneficial effect of prophylactic agents for dual antiplatelet therapy following PCI.     

Network meta-analysis: simultaneous meta-analysis of common antiplatelet regimens after transient ischaemic attack or stroke.

Network meta-analysis can provide estimates of treatment efficacy of multiple treatment regimens, even when direct comparisons are unavailable. We used network meta-analysis to compare commonly used antiplatelet regimens in the prevention of serious vascular events after transient ischaemic attack (TIA) or stroke. We performed direct meta-analyses of randomized, controlled trials evaluating antiplatelet agents after TIA or stroke. We chose the endpoint stroke, myocardial infarction, and vascular death. Network meta-analysis was then used to estimate the relative efficacy of the various antiplatelet regimens. Twenty-four trials involving 42688 TIA or stroke patients who suffered 6830 serious vascular events were included. In the network meta-analysis, all antiplatelet regimens (aspirin, aspirin plus dipyridamole, thienopyridines, and combination of aspirin and thienopyridines) were significantly more effective than placebo. The combination of aspirin and dipyridamole was more effective than thienopyridines (OR, 0.84; 95% CI, 0.73-0.97) and more effective than aspirin (OR, 0.78; 95% CI, 0.70-0.87). Our analysis suggests that the most powerful antiplatelet regimen in the prevention of serious vascular events after TIA or stroke is the combination of aspirin and dipyridamole. Network meta-analysis could be used to synthesize accumulating evidence from clinical trials in a broad range of vascular disorders.     

70岁以上心房颤动患者109例抗栓治疗分析

目的分析70岁以上老年心房颤动(房颤)患者治疗情况,探讨老年房颤患者抗栓治疗策略、疗效、安全性和影响因素。方法 70岁以上老年房颤患者109例,按年龄分为3组:70～79岁组(22例),80～89岁组(70例),90岁以上组(17例),回顾性分析治疗疗效、安全性和影响因素。结果所有患者中,抗栓治疗81例。单用阿司匹林30例,单用氯吡格雷34例,阿司匹林合用氯吡格雷11例,使用华法林抗凝治疗6例。70～79岁组抗血小板治疗20例(90.9%),抗凝治疗1例(4.5%);80～89岁组抗血小板治疗43例(61.4%),抗凝治疗4例(5.7%);90岁以上组抗血小板治疗12例(70.6%),抗凝治疗1例(5.9%)。房颤并存肿瘤者24例(22.0%)。既往发牛过十二指肠球部溃疡、出血性胃炎或血小板减少等出血性疾病又发生过深静脉血栓或腔隙性脑梗死等缺血性疾病的患者10例(9.2%)。抗血小板治疗中发牛深静脉栓塞、心房血栓等患者4例(5.3%),治疗后发生胃肠道出血者2例(2.7%),抗凝治疗后发生胃肠道出血、恼出血者各1例(33.3%)。结论高龄老年房颤患者抗栓治疗不充分,且存在多种复杂的病理生理状态,导致了高血栓危险和高出血风险。     

New look at antiplatelet agent-related peptic ulcer: an update of prevention and treatment

Patients taking antiplatelet agents for the prevention of cardiovascular diseases who develop gastrointestinal bleeding represent a serious challenge in clinical practice. The initial step in reducing gastrointestinal risk of antiplatelet therapy is to assess whether the patient has a continued need for antiplatelet therapy. The next step is to eliminate the risk factors that may place the patient at increased gastrointestinal risk. In the management of bleeding ulcer patients with high-risk stigmata of recent hemorrhage, resuming antiplatelet agents at 3-5 days after the last dosing is a reasonable strategy. However, patients with low-risk stigmata can keep taking antiplatelet agents immediately following endoscopy. In the management of aspirin-related uncomplicated peptic ulcers in patients requiring antiplatelet therapies, continuing aspirin plus a powerful proton pump inhibitor is the choice of treatment. Patients who require antiplatelet agents for the prevention of cardiovascular diseases should be tested and treated for Helicobacter pylori infection before starting antiplatelet therapy. Additionally, those with high risks for upper gastrointestinal bleeding should receive co-therapy with a gastroprotective drug, preferably a proton pump inhibitor at standard dose. H2-receptor antagonist can significantly reduce upper gastrointestinal bleeding risk in patients taking low-dose aspirin but it is ineffective in the prevention of upper gastrointestinal bleeding in clopidogrel users. Although several retrospective studies reported that patients prescribed clopidogrel who also took proton pump inhibitors had significant increases in cardiovascular events, the current evidence from a prospective randomized trial does not justify a conclusion that proton pump inhibitors are associated with cardiovascular events among clopidogrel users.     

Combined Antiplatelet Therapy in Atrial Fibrillation:

Atrial fibrillation (AF), the most commonly encountered cardiac rhythm disorder, affects approximately 1% of the general population and is associated with serious complications, most notably ischemic stroke. AF-associated stroke occurs at an annual rate of 4.5%. Anticoagulation therapy with warfarin has been demonstrated in randomized controlled trials to reduce the risk for AF-related stroke by two thirds, but warfarin therapy is markedly underused in clinical practice because of its narrow therapeutic window and its implications on quality of life. This article reviews the present knowledge and potential future research avenues for the role of antiplatelet therapy in AF as an alternative to anticoagulation with warfarin for prevention of AF-associated stroke. Antiplatelet therapy recently has been shown to be protective against thrombotic events related to blood stasis. There is ample evidence from experimental and clinical studies that a combination of different antiplatelet agents may increase antithrombotic efficacy compared to monotherapy. Accordingly, a series of randomized controlled trials (ACTIVE [Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events]) has been designed to vigorously examine the role of combined antithrombotic therapy for prevention of vascular events, including stroke in high-risk AF patients. The ACTIVE program began patient enrollment in spring 2003. (J Cardiovasc Electrophysiol, Vol. 14, pp. S60-S63, September 2003, Suppl.)     

Platelet Inhibition in Cardiovascular Disease Management: Aspirin and Beyond

Intracoronary thrombosis is the central event in the pathophysiology of the acute coronary syndromes and of the complications of percutaneous coronary intervention. Hemostasis and thrombosis involve a complex series of interactions of both platelets and the coagulation system. Standard antithrombotic therapy for cardiovascular disease typically combines use of antiplatelet therapy with aspirin and antithrombin therapy with heparin. Ticlopidine appears to be a reasonable alternative as an antiplatelet agent in the patient who is intolerant of aspirin. The combination of ticlopidine and aspirin may be especially effective in preventing coronary events in the post-coronary stenting patient. Clopidogrel may offer incremental benefit beyond aspirin in a broad array of vascular diseases, but the cost effectiveness of such a strategy remains to be determined. Finally, potent antiplatelet therapy with platelet glycoprotein IIb/IIIa receptor inhibition clearly improves angioplasty outcomes and may have a role in the treatment of patients with acute coronary syndromes.     

Oral Anticoagulation in Patients With Liver Disease

Patients with liver disease are at increased risks of both thrombotic and bleeding complications. Many have atrial fibrillation (AF) or venous thromboembolism (VTE) necessitating oral anticoagulant agents (OACs). Recent evidence has contradicted the assumption that patients with liver disease are “auto-anticoagulated” and thus protected from thrombotic events. Warfarin and non–vitamin K–antagonist OACs have been shown to reduce thrombotic events safely in patients with either AF or VTE. However, patients with liver disease have largely been excluded from trials of OACs. Because all currently approved OACs undergo metabolism in the liver, hepatic dysfunction may cause increased bleeding. Thus, the optimal anticoagulation strategy for patients with AF or VTE who have liver disease remains unclear. This review discusses pharmacokinetic and clinical studies evaluating the efficacy and safety of OACs in patients with liver disease and provides a practical, clinically oriented approach to the management of OAC therapy in this population.     

Alternatives to chronic warfarin therapy for the prevention of stroke in patients with atrial fibrillation

Atrial fibrillation (AF) is associated with a fivefold increased risk for stroke due to thromboembolic events. Warfarin remains the standard medical therapy for decades in these patients but is difficult to use safely and conveniently. Chronic warfarin therapy is contraindicated in 14% to 44% of patients with AF who are at risk for stroke. In clinical practice, warfarin is prescribed to only 15% to 60% of patients with AF who are at high risk for thromboembolic events and have no clear contraindication to their use. Alternatives to warfarin include (i) antiplatelet therapy; (ii) new oral anticoagulants; and (iii) exclusion of the left atrial appendage (LAA) as a major embolic source. Dual antiplatelet therapy with aspirin and clopidogrel was superior to aspirin alone in reducing the risk of stroke in patients unsuitable to warfarin. Furthermore, a number of newer oral anticoagulants are currently under investigation for stroke prevention in AF. Oral direct thrombin or factor Xa inhibitors are in the most advanced stages of development. Given that about 90% of the source of thromboembolism occurs in the LAA in patients with non-valvular AF, occlusion of flow into the LAA may prevent thrombus formation in the appendage and hence reduction of stroke. Recently, several devices have been employed percutaneously with encouraging results in selected patients. Current review summarizes the latest clinical trial data pertinent to dual-antiplatelet therapy, several newer antithrombotic agents and LAA occlusion.     

What's new in stroke? The top 10 studies of 2009-2011: part II

Five studies published between 2009 and 2011 are reviewed that importantly inform stroke prevention for patients with atrial fibrillation (AF) or with cervical carotid artery stenosis. Two large, phase III randomized trials tested novel oral anticoagulants for stroke prevention in patients with AF: the direct thrombin inhibitor dabigatran 150 mg twice daily was superior to adjusted-dose warfarin (RE-LY trial) and the direct factor Xa inhibitor apixaban was far superior to aspirin in patients deemed unsuitable for warfarin (AVERROES trial). For both novel anticoagulants, major bleeding rates were similar to the comparator treatment. Clopidogrel plus aspirin was more efficacious than aspirin alone for prevention of stroke in patients with AF deemed unsuitable for warfarin, but major bleeding was significantly increased with dual antiplatelet therapy (ACTIVE A trial). Two large randomized trials (CREST, ICSS) provide the best available data on the short-term risks of carotid artery stenting vs. endarterectomy. In both trials, periprocedural stroke was more frequent with stenting than with endarterectomy, but the increased risk was largely confined to patients >70 years old. For younger patients, periprocedural risks were comparable with stenting or endarterectomy, but long-term outcomes are required to assess the relative merits of the two procedures.     

A review of therapeutic strategies for risk reduction of recurrent stroke

Although cardiovascular disease (CVD) is a major source of morbidity and mortality in the United States, a relatively small percentage of deaths related to CVD result from ischemic stroke. However, the impairment and costs associated with stroke are large--and largely preventable. Large-scale trials have demonstrated benefit with antihypertensive therapy for secondary prevention, showing significantly reduced rates of stroke and cardiovascular events. Statins have shown efficacy in primary stroke prevention, and one trial showed reduced incidence of stroke and cardiovascular events in patients with recent stroke or transient ischemic attack (TIA). The merits of antiplatelet therapy in primary and secondary stroke prevention have been demonstrated across numerous trials and meta-analyses. Trials assessing aspirin plus clopidogrel or aspirin plus extended-release dipyridamole for preventing secondary stroke have produced somewhat contradictory findings. This review discusses the relationship between CVD and risk of secondary stroke or TIA and summarizes secondary prevention strategies, focusing on antiplatelet agents, to provide guidance for the practicing cardiologist. Certain combination therapies appear to be more effective for secondary prevention of stroke or TIA than therapy with single antiplatelet agents. The choice of agents may be important, based on results of several trials. The ongoing, large-scale, comparative Prevention Regimen for Effectively Avoiding Second Strokes (PR. FESS) trial should provide cardiologists with more definitive recommendations.     

Antiplatelet therapy in the prevention of ischemic vascular events: literature review and evidence-based guidelines for drug selection.

BACKGROUND: New antiplatelet drugs are being developed and many clinical trials evaluating the benefits of antiplatelet drugs for the secondary prevention of ischemic events in patients with atherosclerotic vascular disease have been performed. HYPOTHESIS: An updated systematic review and evidence-based guidelines for the appropriate selection of antiplatelet drugs may be beneficial to physicians and healthcare organizations attempting to create or update current clinical practice guidelines or clinical pathways aimed at caring for these patients. METHODS: (1) A systematic review of the recent literature on the relative efficacy and safety of aspirin, ticlopidine, and clopidogrel was undertaken; (2) an evidence-based, expert panel approach using a modified Delphi technique to create explicit guidelines for prescribing antiplatelet therapy was instituted; and (3) the recommendations of an expert panel were summarized. RESULTS: Consensus guidelines were developed for the utilization of aspirin, ticlopidine, or clopidogrel for the prevention of ischemic events in patients with manifestations of atherosclerotic vascular disease (prior myocardial infarction, prior ischemic stroke, or established peripheral arterial disease) who are at increased risk for recurrent ischemic events. Based on efficacy and safety, clopidogrel was recommended as the drug of choice for patients with established peripheral arterial disease; aspirin or clopidogrel should be considered in patients with prior myocardial infarction (with clopidogrel favored for patients who have had a recurrent event while on aspirin or in whom aspirin is contraindicated); aspirin or clopidogrel should be considered as first-line treatment in patients with prior ischemic (nonhemorrhagic) stroke--however, clopidogrel is the favored drug in patients in whom other antiplatelet drugs are either contraindicated or who have had recurrent events while on therapy. CONCLUSIONS: Myocardial infarction, ischemic stroke, and peripheral arterial disease are all clinical manifestations of the same underlying disease process (atherosclerosis), with thrombus formation on the disrupted atherosclerotic plaque (atherothrombosis) being a common precipitating factor of ischemic events in patients suffering from these disorders. An evidence-based approach was used to develop a practice guideline, based on available published evidence, for the appropriate utilization of antiplatelet agents (aspirin, ticlopidine, or clopidogrel). These guidelines may be of use to multidisciplinary teams wishing to create or update clinical guidelines or clinical pathways which address the care of patients with atherosclerotic vascular disease. New antiplatelet agents such as clopidogrel may be more effective and associated with lower risk of selected adverse effects (such as gastrointestinal distress, gastrointestinal hemorrhage, and neutropenia) than those previously used to prevent thrombus formation in the setting of atherosclerotic arterial disease. Combination antiplatelet therapy is being evaluated as an option for those patients who experience recurrent events on a single antiplatelet agent.     

Adjunctive therapies in the cath lab. Subacute stent thrombosis developing twelve days after discontinuation of ticlopidine treatment

The two structurally related thienopyridines, ticlopidine and clopidogrel in addition to aspirin, have become the standard regimen for prevention of subacute thrombosis (SAT) after coronary stent implantation. Although both regimens are highly effective, ticlopidine suffers from severe hematologic side effects. Recent trials encourage shorter duration of therapy with these agents. However, the optimal duration of antiplatelet therapy after stenting is still not clear. We report a case of SAT developing 12 days after discontinuation of 2 weeks of aspirin plus ticlopidine therapy. We believe that the present data are still not clear regarding the optimum duration of antiplatelet therapy after stenting.