Warfarin versus aspirin in the secondary prevention of stroke: The WARSS study

The role of anticoagulation in the secondary prevention of noncardioembolic stroke has long been an area of debate. Previous evidence has shown that anticoagulation is unsafe at an International Normalized Ratio between 3.0 and 4.5. Results of the recently published Warfarin-Aspirin Recurrent Stroke Study (WARSS) suggest that there is no difference between warfarin and aspirin in the prevention of recurrent ischemic stroke or death or in the rate of major hemorrhage. Differences in the therapeutic interventions used may have had an effect on the differences in endpoints achieved as compared with previous studies. Results of ongoing trials are anticipated to further clarify the role of anticoagulation in the secondary prevention of stroke.     

Cost-effectiveness of clopidogrel plus aspirin for stroke prevention in patients with atrial fibrillation in whom warfarin is unsuitable

Guidelines for atrial fibrillation (AF) recommend clopidogrel plus aspirin as an alternative stroke prevention strategy in patients in whom warfarin is unsuitable. A Markov model was conducted from a Medicare prospective using data from the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-A (ACTIVE-A) trial and other published studies. Base-case analysis evaluated patients 65 years old with AF, a CHADS(2) (congestive heart failure, 1 point; hypertension defined as blood pressure consistently >140/90 mm Hg or antihypertension medication, 1 point; age ≥75 years, 1 point; diabetes mellitus, 1 point; previous stroke or transient ishemic attack, 2 points) score of 2, and a lower risk for major bleeding. Patients received clopidogrel 75 mg/day plus aspirin or aspirin alone. Patients were followed for up to 35 years. Outcomes included quality-adjusted life-years (QALYs), costs (in 2011 American dollars), and incremental cost-effectiveness ratios. Quality-adjusted life expectancy and costs were 9.37 QALYs and $88,751 with clopidogrel plus aspirin and 9.01 QALYs and $79,057 with aspirin alone. Incremental cost-effectiveness ratio for clopidogrel plus aspirin was $26,928/QALY. With 1-way sensitivity analysis using a willingness-to-pay threshold of $50,000/QALY, clopidogrel plus aspirin was no longer cost effective when the CHADS(2) score was ≤1, major bleeding risk with aspirin was ≥2.50%/patient-year, the relative risk decrease for ischemic stroke with clopidogrel plus aspirin versus aspirin alone was <25%, and the utility of being healthy with AF on combination therapy decreased to 0.95. Monte Carlo simulation demonstrated that clopidogrel plus aspirin was cost effective in 55% and 73% of 10,000 iterations assuming willingness-to-pay thresholds of $50,000 and $100,000/QALY. In conclusion, clopidogrel plus aspirin appears cost-effective compared to aspirin alone for stroke prevention in patients with AF with a CHADS(2) of ≥2 and a lower risk of bleeding.     

The role of aspirin in cardiovascular prevention: implications of aspirin resistance

Aspirin is well recognized as an effective antiplatelet drug for secondary prevention in subjects at high risk of cardiovascular events. However, most patients receiving long-term aspirin therapy still remain at substantial risk of thrombotic events due to insufficient inhibition of platelets, specifically via the thromboxane A2 pathway. Although the exact prevalence is unknown, estimates suggest that between 5.5% and 60% of patients using this drug may exhibit a degree of "aspirin resistance," depending upon the definition used and parameters measured. To date, only a limited number of clinical studies have convincingly investigated the importance of aspirin resistance. Of these, few are of a sufficient scale, well designed, and prospective, with aspirin used at standard doses. Also, most studies do not sufficiently address the issue of noncompliance to aspirin as a frequent, yet easily preventable cause of resistance to this antiplatelet drug. This review article provides a comprehensive overview of aspirin resistance, discussing its definition, prevalence, diagnosis, and therapeutic approaches. Moreover, the clinical implications of aspirin resistance are explored in various cardiovascular disease states, including diabetes mellitus, hypertension, heart failure, and other similar disorders where platelet reactivity is enhanced.     

阿司匹林抵抗与脑卒中防治的现状

阿司匹林目前是预防缺血性脑卒中复发的最有效的抗血小板聚集药物,但很多患者长期规律口服治疗剂量的阿司匹林仍不能有效地阻止血栓性疾病的复发,即存在"阿司匹林抵抗现象"。其发生机制可能与药物的剂量、患者依从性、药物的相互作用、疾病的影响及基因多态性等有关。临床医师应明确阿司匹林抵抗的产生机制,并在临床上采取合适的措施来减少阿司匹林抵抗,从而取得理想的缺血性卒中预防及治疗效果。     

华法令、阿斯匹林预防心房颤动患者缺血性脑卒中的远期随访

目的了解并比较华法令、阿斯匹林预防心房颤动患者缺血性脑卒中的远期效果。方法分别对三组82例、106例、127例心房颤动患者口服华法令、阿斯匹林及对照组治疗进行临床、大便隐血、国际正常比(INR)、头颅CT或MR扫描并定期随访,随访时间分别为(50±2.8)月(、40±2.0)月和(43±3.2)月。结果缺血性脑卒中和短暂性缺血发作(TIA)的发生率华发令组(10.9%),明显较阿斯匹林组(18.10%)、对照组(25.40%)低(P<0.05,P<0.01),阿斯匹林组显著比对照组低(P<0.05)。出血发生率华法令组、阿斯匹林组及对照组分别为3.66%、2.86%、2.38%(P>0.05),死亡率分别为6.10%、6.67%、10.32%(P>0.05),均无显著性差异。缺血性脑卒中引起的死亡率分别为1.22%、1.90%、4.76%,对照组显著高于其他两组(P<0.05)。结论华法令、阿斯匹林预防心房颤动患者缺血性脑卒中的发生均有效,华法令优于阿斯匹林。华法令、阿斯匹林降低其缺血性脑卒中引起的死亡率。     

A randomised controlled trial of warfarin versus aspirin for stroke prevention in octogenarians with atrial fibrillation (WASPO)

BACKGROUND: atrial fibrillation (AF) is the commonest chronic arrhythmia with a prevalence of 9% in octogenarians and accounts for 24% of the stroke risk in this population. Although trials demonstrate reductions in stroke with warfarin, audit data show that it is still underused. However, anti-coagulation in the very elderly is not without risk. METHODS: randomised open labelled prospective study of primary thromboprophylaxis for AF. Patients aged >80 and <90 were randomised to receive dose-adjusted warfarin (INR 2.0-3.0) or aspirin 300 mg. All patients had permanent AF, were ambulant, had Folstein mini mental score >25 and had no contraindications to either treatment. Follow-up was for 1 year with 3 monthly visits. The primary outcome measure was a comparative frequency of combined endpoints comprising death, thromboembolism, serious bleeding and withdrawal from the study. RESULTS: seventy-five patients (aspirin 39; warfarin 36) were entered (mean age 83.9, 47% male). There were significantly more adverse events with aspirin (13/39; 33%) than warfarin (2/36; 6%), P = 0.002. 10/13 aspirin adverse events were caused by side effects and serious bleeding; there were three deaths (two aspirin, one warfarin). CONCLUSION: dose-adjusted warfarin was significantly better tolerated with fewer adverse events than aspirin 300 mg in this elderly population. Although aspirin 75 mg may have been better tolerated, there is no evidence for efficacy in AF at this dose.     

Low-dose warfarin and low-dose aspirin in the primary prevention of ischemic heart disease

The thrombotic component in ischemic heart disease (IHD) is now universally recognized. It is therefore logical to consider modifying both fibrin formation and platelet function in primary (as well as secondary) prevention. The scientific case for evaluating lower-dose warfarin in primary prevention rests on the implications of the secondary prevention trials, increasing evidence of an association between the level of factor VII coagulant activity, VIIc, and the incidence of IHD, and the results of short-term lower-dose trials for the prevention of venous thrombosis and thromboembolism. The general case for considering aspirin in primary prevention is well known, but the potential value of low-dose aspirin in men at high risk needs to be established. Currently available evidence suggests that the combination of lower doses of both warfarin and aspirin in primary prevention may be effective and safe. The objective of the factorial Thrombosis Prevention Trial is to demonstrate a reduction in the incidence of IHD in men at high risk attributable to low-dose warfarin or low-dose aspirin, or both, with 1 group receiving both active treatments. The feasibility of this trial has been demonstrated. An International Normalized Ratio of about 1.5, achieved with an average daily dose of 4.6 mg warfarin, has resulted in no increase in the number of men ever reporting minor bleeding episodes, although rectal bleeding occurs more frequently in those men who do report this symptom.     

Antiplatelet therapy in secondary stroke prevention

This article focuses on recent data about the safety and effectiveness of antiplatelet therapies for secondary stroke prevention. Highlights include a discussion of changes in the professional labeling for aspirin and the results of a low- versus high-dose aspirin trial (Aspirin after Carotid Endarterectomy trial). Safety issues regarding aspirin also are considered. Other topics include a review of recent data on thrombotic thrombocytopenic purpura (TTP) associated with ticlopidine and a brief update on clopidogrel. A summary of discussions related to the European Stroke Prevention Study 2 data and Food and Drug Administration consideration of combination dipyridamole/aspirin therapy are presented.     

Antithrombotic secondary prevention after stroke

Opinion statement In patients with transient ischemic attack (TIA) or ischemic stroke of noncardiac origin, antiplatelet drugs are able to decrease the risk of stroke by 11% to 15%, and decrease the risk of stroke, myocardial infarction (MI), and vascular death by 15% to 22%. Aspirin leads to a moderate but significant reduction of stroke, MI, and vascular death in patients with TIA and ischemic stroke. Low doses are as effective as high doses, but are better tolerated in terms of gastrointestinal side effects. The recommended aspirin dose, therefore, is between 50 and 325 mg. Bleeding complications are not dose-dependent, and also occur with the lowest doses. The combination of aspirin (25 mg twice daily) with slow-release dipyridamole (200 mg twice daily) is superior compared with aspirin alone for stroke prevention. Ticlopidine is effective in secondary stroke prevention in patients with TIA and stroke. For some end points, it is superior to aspirin. Due to its side-effect profile (neutropenia, thrombotic thrombocytopenic purpura [TTP]), ticlopidine should be given to patients who are intolerant of aspirin. Prospective trials have not indicated whether ticlopidine is suggested for patients who have recurrent cerebrovascular events while on aspirin. Clopidogrel has a better safety profile than ticlopidine. Although not investigated in patients with TIA, clopidogrel should also be effective in these patients assuming the same pathophysiology than in patients with stroke. Clopidogrel is second-line treatment in patients intolerant for aspirin, and first-line treatment for patients with stroke and peripheral arterial disease or MI. A frequent clinical problem is patients who are already on aspirin because of coronary heart disease or a prior cerebral ischemic event, and then suffer a first or recurrent TIA or stroke. No single clinical trial has investigated this problem. Therefore, recommendations are not evidence-based. Possible strategies include the following: continue aspirin, add dipyridamole, add clopidogrel, switch to ticlopidine or clopidogrel, or switch to anticoagulation with an International Normalized Ratio (INR) of 2.0 to 3.0. The combination of low-dose warfarin and aspirin was never studied in the secondary prevention of stroke. In patients with a cardiac source of embolism, anticoagulation is recommended with an INR of 2.0 to 3.0. At the present time, anticoagulation with an INR between 3.0 and 4.5 cannot be recommended for patients with noncardiac TIA or stroke. Anticoagulation with an INR between 3.0 and 4.5 carries a high bleeding risk. Whether anticoagulation with lower INR is safe and effective is not yet known. Treatment of vascular risk factors should also be performed in secondary stroke prevention.     

Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with non-valvular atrial fibrillation

OBJECTIVE: To determine optimal intensity of international normalized ratio (INR) of warfarin therapy for the prevention of ischemic events in patients with non-valvular atrial fibrillation (NVAF), we evaluated the risk of severe recurrent stroke, systemic embolism and major hemorrhagic complications according to INR and age. METHODS: We carried out the National Cardiovascular Center (NCVC) NVAF Secondary Prevention Study and analyzed data with those of Japanese Nonvaluvular Atrial Fibrillation-embolism Secondary Prevention Cooperative Study to elucidate relationships of major stroke and hemorrhage with INR and age. In both studies, all patients with cardioembolic stroke were given warfarin, monitored with INR every month, and followed up for primary endpoints of stroke and embolism to other parts of the body, and for secondary endpoints of major hemorrhagic complications requiring blood transfusion or hospitalization. We regarded ischemic stroke with NIH stroke scale (NIHSS) score > or = 10 or systemic embolism as a major ischemic event and ischemic stroke with NIHSS score <10 as a minor ischemic event. There were 203 patients enrolled in total (152 men and 51 women). We investigated the relationship of occurrence of the events with INR and age, and calculated the incidence rates of major and minor ischemic events and major hemorrhagic events. RESULTS: During the mean follow-up of 653 days, major ischemic stroke and systemic embolism occurred in only 4 patients with INR <1.6, minor ischemic stroke in 10 patients with INR 1.50-2.66, and major hemorrhage in 9 patients with INR 2.30-3.56. Patients with major ischemic or hemorrhagic events were significantly older than those without any events (75+/-4 years vs. 67+/-7 years, p<0.001 unpaired t test). Incidence rates of any events at INR < or = 1.59, 1.60-1.99, 2.00-2.59 and > or = 2.60 were 8.6%, 3.8%, 4.9%, and 25.7%/year, respectively. CONCLUSIONS: Major ischemic or hemorrhagic events occur often in the elderly NVAF patients, in whom an INR value of between 1.6 and 2.6 seems optimal to prevent such events.     

糖尿病与卒中二级预防

糖尿病是脑卒中的重要危险因素。对糖尿病患者进行积极降糖治疗,对于卒中一级预防有重要意义。糖尿病是卒中复发的独立危险因素,其在不同亚型卒中复发中的作用是不同的。强化降糖治疗在卒中二级预防中的作用尚未明确。     

Antiplatelet agents for secondary prevention of stroke

Patients with recent ischemic stroke or transient ischemic attack (TIA) face a high risk of recurrent stroke as well as an increased risk of myocardial infarction and sudden cardiac death. In the absence of a clearly established indication for long-term anticoagulation, such as atrial fibrillation, antiplatelet agents are the antithrombotic drugs of choice for preventing recurrent vascular events. For many years, aspirin (ASA) has been the first-line therapy for patients at high risk of vascular ischemic events. Two large clinical trials have established the superiority of the combination of ASA and extended-release dipyridamole (ASA/ERDP) over ASA alone in patients with recent noncardioembolic ischemic stroke or TIA. Clopidogrel, another antiplatelet agent, is a reasonable alternative to ASA, but its superiority to ASA in patients with a history of stroke has not been as clearly established. The combination of ASA and clopidogrel, which is effective in patients with acute coronary syndrome, has not been shown to be either effective or safe, compared with either agent alone, in stroke patients, although there may be some benefit to this combination in patients with acute TIA. The results from a large randomized trial comparing ASA/ERDP with clopidogrel, anticipated soon, will further assist clinicians in choosing among available antiplatelet agents.