Efficacy of aspirin for secondary prevention in patients with peripheral artery disease

Evaluation of: Berger JS, Krantz MJ, Kittelson JM, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials. JAMA 301, 1909–1919 (2009).

Aspirin decreases the risk of cardiovascular events in patients with prior coronary heart or cerebrovascular disease. The American College of Cardiology/American Heart Association guidelines recommend a low-dose aspirin regimen (75–325 mg/day) to reduce the risk of cardiovascular events in patients with peripheral artery disease (PAD). However, the effect of aspirin for secondary prevention in patients with PAD has not been well established. The paper under evaluation performed a meta-analysis of 18 trials to investigate the effect of aspirin on cardiovascular events (nonfatal myocardial infarction, nonfatal stroke and cardiovascular death) in patients with PAD. The results of this meta-analysis in a PAD cohort revealed that treatment with aspirin did not significantly reduce the combined end point of cardiovascular events; however, aspirin resulted in a significant reduction in the incidence of nonfatal stroke. This analysis raises a number of questions regarding the overall efficacy of aspirin in PAD and what should be the optimal antiplatelet therapy in patients with PAD: aspirin, clopidogrel or perhaps a combination of aspirin and clopidogrel.     

Prevention of anti-inflammatory drug-induced gastrointestinal damage: benefits and risks of therapeutic strategies

Patients who take non-steroidal anti-inflammatory drugs (NSAIDs) may develop serious gastrointestinal (GI) side effects in both the upper and lower GI tract. Those at risk should be considered for prevention with misoprostol, proton pump inhibitor (PPI) or COX-2 selective inhibitor (coxib) therapy. A coxib or an NSAID+PPI combination is considered to have comparable GI safety profiles, but evidence from direct comparison is limited. PPIs are effective in the prevention of upper GI events in endoscopy trials and in a few, small, outcome trials in patients at risk. Coxibs have been evaluated in endoscopic ulcer studies and clinical outcome trials, and shown to significantly reduce the risk of upper GI ulcer and complications. Moreover, unlike PPIs, coxibs significantly reduce toxicity in the lower GI tract compared with NSAIDs. Coxibs and possibly some NSAIDs also increase the risk of developing serious cardiovascular events, an effect which may depend on the drug, dose and duration of therapy. It is not known whether concomitant low-dose aspirin use, which occurs in more than 20% of patients, will reduce the incidence of cardiovascular events, although concomitant aspirin increases the risk of developing serious GI events in patients taking either an NSAID or a coxib. Such patients may require additional PPI co-therapy. Current prevention strategies with an NSAID+PPI, misoprostol or a coxib must be considered in the individual patient with GI and cardiovascular risk factors. A PPI+coxib is indicated in those at highest risk (e.g. previous ulcer bleeding). PPI therapy must be considered for the treatment and prevention of NSAID-induced dyspepsia.     

Prevention of anti‐inflammatory drug‐induced gastrointestinal damage: Benefits and risks of therapeutic strategies

Patients who take non‐steroidal anti‐inflammatory drugs (NSAIDs) may develop serious gastrointestinal (GI) side effects in both the upper and lower GI tract. Those at risk should be considered for prevention with misoprostol, proton pump inhibitor (PPI) or COX‐2 selective inhibitor (coxib) therapy. A coxib or an NSAID+PPI combination is considered to have comparable GI safety profiles, but evidence from direct comparison is limited. PPIs are effective in the prevention of upper GI events in endoscopy trials and in a few, small, outcome trials in patients at risk. Coxibs have been evaluated in endoscopic ulcer studies and clinical outcome trials, and shown to significantly reduce the risk of upper GI ulcer and complications. Moreover, unlike PPIs, coxibs significantly reduce toxicity in the lower GI tract compared with NSAIDs. Coxibs and possibly some NSAIDs also increase the risk of developing serious cardiovascular events, an effect which may depend on the drug, dose and duration of therapy. It is not known whether concomitant low‐dose aspirin use, which occurs in more than 20% of patients, will reduce the incidence of cardiovascular events, although concomitant aspirin increases the risk of developing serious GI events in patients taking either an NSAID or a coxib. Such patients may require additional PPI co‐therapy. Current prevention strategies with an NSAID+PPI, misoprostol or a coxib must be considered in the individual patient with GI and cardiovascular risk factors. A PPI+coxib is indicated in those at highest risk (e.g. previous ulcer bleeding). PPI therapy must be considered for the treatment and prevention of NSAID‐induced dyspepsia.     

Prevention of secondary stroke and transient ischaemic attack with antiplatelet therapy: the role of the primary care physician [corrected

BACKGROUND: Stroke risk is heightened among patients who have had a primary stroke or transient ischaemic attack (TIA). The primary care physician is in the best position to monitor these patients for stroke recurrence. Because stroke recurrence can occur shortly after the primary event, guidelines recommend initiating antiplatelet therapy as soon as possible. Aspirin, with or without extended-release dipyridamole (ER-DP), and clopidogrel are options for such patients. Low-dose aspirin (75-150 mg/day) has the same efficacy as higher doses but with less gastrointestinal bleeding. Clopidogrel remains an option for prevention of secondary events and may benefit patients with symptomatic atherothrombosis, but its combined use with aspirin can harm patients with multiple risk factors and no history of symptomatic cerebrovascular, cardiovascular or peripheral vascular disease. RESULTS: Low dose aspirin is effective in secondary stroke prevention. Trials assessing aspirin plus ER-DP have shown that the combination is more effective than aspirin monotherapy in preventing stroke, with efficacy increasing among higher risk patients, notably those with prior stroke/TIA. Clopidogrel does not appear to have as much advantage over aspirin in secondary stroke prevention as aspirin plus ER-DP. Smoking cessation and cholesterol, blood glucose and blood pressure control are also important concerns in preventing recurrent stroke. In choosing pharmacological therapy, the physician must consider the individual patient's risk factors and tolerance, as well as other issues, such as use of aspirin among patients with ulcers. CONCLUSION: Antiplatelet therapy is effective in secondary stroke prevention. Low dose aspirin can be used first-line, but aspirin plus ER-DP improves efficacy. Clopidogrel is another option in secondary stroke prevention, especially for aspirin-intolerant patients, but it appears to have less advantage over aspirin than aspirin plus ER-DP, and its combined use with aspirin has only marginally better efficacy and increased bleeding risk.     

Anti-platelet drugs (aspirin, ticlopidine, etc)

Previous clinical trials have shown that anti-platelet drugs, such as aspirin and ticlopidine, are approved for prevention of serious cardiovascular events in special populations who are at increased risk of cardiovascular events. Of these trials, the Antithrombotic Trialists' Collaboration (ATT) meta-analysis includes approximately 200,000 patients: Anti-platelet therapy was associated with a 34% reduction in the risk of nonfatal myocardial infarction, a 25% reduction in the risk of stroke, and a 15% reduction in the risk of vascular death. Also in patients with acute coronary syndrome (acute myocardial infarction and unstable angina), both aspirin and ticlopidine have been shown to prevent serious cardiovascular events.     

Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial

OBJECTIVE: We investigated in general practice the efficacy of antiplatelets and antioxidants in primary prevention of cardiovascular events in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: The Primary Prevention Project (PPP) is a randomized, open trial with a two-by-two factorial design aimed to investigate low-dose aspirin (100 mg/day) and vitamin E (300 mg/day) in the prevention of cardiovascular events in patients with one or more cardiovascular risk factors. The primary end point was a composite end point of cardiovascular death, stroke, or myocardial infarction. A total of 1,031 people with diabetes in the PPP, aged >/=50 years, without a previous cardiovascular event were enrolled by 316 general practitioners and 14 diabetes outpatient clinics. RESULTS: The PPP trial was prematurely stopped (after a median of 3.7 years) by the independent data safety and monitoring board because of a consistent benefit of aspirin compared with the control group in a population of 4,495 patients with one or more major cardiovascular risk factors. In diabetic patients, aspirin treatment was associated with a nonsignificant reduction in the main end point (relative risk [RR] = 0.90, 95% CI 0.50-1.62) and in total cardiovascular events (0.89, 0.62-1.26) and with a nonsignificant increase in cardiovascular deaths (1.23, 0.69-2.19). In nondiabetic subjects, RRs for the main end point, total cardiovascular events, and cardiovascular deaths were 0.59 (0.37-0.94), 0.69 (0.53-0.90), and 0.32 (0.14-0.72), respectively. No significant reduction in any of the end points considered could be found with vitamin E in either diabetic or nondiabetic subjects. CONCLUSIONS: Our data suggest a lower effect of primary prevention of cardiovascular disease (CVD) with low-dose aspirin in diabetic patients as opposed to subjects with other cardiovascular risk factors. If confirmed, these findings might indicate that the antiplatelet effects of aspirin in diabetic patients are overwhelmed by aspirin-insensitive mechanisms of platelet activation and thrombus formation, thus making the balance between benefits and harms of aspirin treatment unfavorable. Further large-scale trials investigating the role of aspirin in the primary prevention of CVD in diabetic patients are urgently needed.     

Which patients should receive aspirin for primary prevention of cardiovascular disease? An economic evaluation

Low-dose aspirin is a standard care for secondary prevention of cardiovascular disease (CVD). Its use in primary prevention is less widely accepted, however, despite recent meta-analyses and US and European guidelines supporting its use in individuals at increased CVD risk. The aim of this study was to define which patients should receive aspirin for primary prevention of CVD using data from four European countries. Based on the clinical data from two meta-analyses, a state-transition model was developed to compare the costs and effects of no treatment and low-dose aspirin as primary prevention for CVD over 10 years. The model was applied to patients at different 10-year risks (2-5%) of fatal CVD according to the SCORE equation. Direct costs from the perspective of the healthcare payer were used (base year 2003). Country-specific discounting was applied. Treating patients with a 10-year risk of fatal CVD of 2% or higher with low-dose aspirin resulted in lower total costs and more quality-adjusted life-years gained in the UK, Germany and Spain. In Italy, savings started at a 10-year fatal CVD risk of 3%. This difference was due to the higher cost of gastrointestinal bleeding in Italy. Monte Carlo analysis showed that aspirin was dominant in more than 90% of patients at a 10-year risk of 4% and 5% in the four countries. In conclusion, low-dose aspirin treatment becomes cost-saving at a very low 10-year risk of fatal CVD. The cost of gastrointestinal bleeding defines the level at which low-dose aspirin becomes cost-saving.     

New antiaggregants and their importance for the practitioner

Since the introduction of Aspirin in the 1950s many substances have been introduced with an antiplatelet effect. Only few have been proved to be superior to aspirin in some clinical settings. Ticlopidin and its biochemical analog clopidogrel block the ADP-induced platelet aggregation. Clopidogrel having a better profile in terms of adverse events has been established over ticlopidin. It can be used for secondary prevention in patients with stroke, myocardial infarction or peripheral arterial disease instead of aspirin, certainly in cases with aspirin intolerance or with relapsing cardiovascular event under treatment with aspirin. For a general substitution of aspirin through clopidogrel hard evidence is still lacking. The combination aspirin + clopidogrel has been proved superior to aspirin in the treatment of patients with unstable angina or myocardial infarction without ST-segment elevation. For an extension of this indication to other clinical entities further evidence is needed. GPIIb/IIIa blockers are a well established treatment modality in patients undergoing coronary catheter interventions. Oral GPIIb/IIIa blockers, probably because of their pharmacokinetic profile, have proved to be insufficient in protecting from cardiovascular events compared to aspirin. Practical aspects concerning use of the newer antiplatelet agents during pregnancy, preoperatively and in spinal anesthesia are discussed.     

急性冠脉综合征部分特殊人群抗血小板治疗研究进展

抗血小板治疗是急性冠脉综合征（acute coronary syndrome, ACS）患者治疗的基石,而阿司匹林联合一种P2Y12 受体抑制剂是目前指南的I类推荐。抗血小板治疗在降低ACS患者心血管主要不良事件的同时,也增加了其出血风险。因此,对于部分特殊人群如高龄、合并糖尿病、卒中/短暂性脑缺血发作（TIA）及接受溶栓的ST段抬高型心肌梗死（STEMI）患者,在评估缺血风险与出血风险的同时,其抗血小板治疗的方案呈现着巨大的个体差异,本文就目前部分特殊人群的抗血小板治疗的研究进展进行综述。     

Antiaggregation: aspirin

Many randomized trials have shown aspirin as an effective antiplatelet drug for the secondary prevention of cardiovascular events. The NNT (number needed to treat) to prevent 1 vascular event is about 25. The NNH (number needed to harm) inducing one cerebral bleeding is about 1'000, to provoke one severe extracerebral bleeding about 100-200. The primary prevention can be recommended only for high risk patients for cardiovascular events (annual risk of 1-1.5% or more), calculated on the basis of the Framingham data, the Sheffield tables or in analysis of U.S. Preventive Services Task Force. The mechanisms of action, interactions and the "aspirin-resistance" are briefly discussed.     

Perioperative cardiac risk reduction

Cardiovascular complications are the most common cause of perioperative morbidity and mortality. Noninvasive stress testing is rarely helpful in assessing risk, and for most patients there is no evidence that coronary revascularization provides more protection against perioperative cardiovascular events than optimal medical management. Patients likely to benefit from perioperative beta blockade include those with stable coronary artery disease and multiple cardiac risk factors. Perioperative beta blockers should be initiated weeks before surgery and titrated to heart rate and blood pressure targets. The balance of benefits and harms of perioperative beta-blocker therapy is much less favorable in patients with limited cardiac risk factors and when initiated in the acute preoperative period. Perioperative statin therapy is recommended for all patients undergoing vascular surgery. When prescribed for the secondary prevention of cardiovascular disease, aspirin should be continued in the perioperative period.     

Aspirin for the primary prevention of cardiovascular disease: latest evidence

ABSTRACT

Introduction: While the clinical merits of aspirin in secondary cardiovascular disease (CVD) prevention remain undisputed, its role in primary prevention is controversial. Recently, three trials of primary prevention reported neutral net benefit results or evidence of harm for aspirin in patients with no overt CVD.

Areas covered: This article aims to inform clinical practitioners by appraising the current body of evidence on the use of aspirin for primary CVD prevention, ranging from general pharmacology to clinical outcomes and future directions.

Expert opinion: Based on meta-analyses incorporating latest trials in the field of primary prevention, the modest reduction in ischemic events with aspirin, if any, is offset by a modest increase in nonfatal bleeding. Improved control of CVD risk factors and broader use of statins may have reduced the thrombotic complications of atherosclerosis, thus limiting the opportunity for aspirin to prevent clinical CVD events in the contemporary era. As such, decision-making about aspirin for primary prevention is challenging even when selected patients are considered and involves careful weighing of risks and benefits. Ongoing investigations conducted in patients with cancer could rapidly modify the current perception of the unfavorable benefit-risk ratio of aspirin in patients with no overt CVD.     

Dipyridamole may be used safely in patients with ischaemic heart disease

It is thought that up to 50% of patients with cerebrovascular disease will have concurrent ischaemic heart disease. Dipyridamole co-formulated with aspirin has been shown to increase the relative reduction in risk of second stroke in patients with prior stroke/transient ischaemic attack beyond that obtaining with aspirin alone. We have sought to resolve the question of whether dipyridamole treatment increases the risk of cardiac adverse events in patients with co-existing ischaemic heart disease. The published literature, periodic safety update reports, the randomised controlled trials of antiplatelet agents in stroke prevention and those including dipyridamole in cardiovascular indications, have been reviewed and analysed. The early reports of serious adverse cardiac effect attributable to dipyridamole occurred in patients with severe coronary artery disease using dipyridamole as a stress test adjunct to cardiac imaging. The randomised controlled trials databases show no evidence of mortality and only isolated cases of significant cardiac morbidity attributable to dipyridamole at recommended oral doses in patients with ischaemic heart disease. We conclude that patients with cerebrovascular and mild to moderate concomitant ischaemic heart disease may be treated safely with dipyridamole for the secondary prevention of stroke.     

Dose of aspirin in the treatment and prevention of cardiovascular disease: current and future directions

In meta-analyses of randomized trials of aspirin among patients with prior occlusive vascular disease events (secondary prevention), doses from 75 mg to more than 1500 mg daily provide similar benefits on myocardial infarction, stroke, and cardiovascular death. In acute myocardial infarction and during acute occlusive stroke, a loading dose of 162.5 to 325 mg is necessary to achieve a rapid clinical antithrombotic effect. In primary prevention trials, predominantly among men, aspirin (75 mg daily to 325 mg on alternate days) reduced the risk of a first myocardial infarction. In a large-scale trial in women, aspirin (100 mg on alternate days) reduced risk of a first stroke. In subgroup analyses of women older than age 65, aspirin significantly reduced first myocardial infarction and ischemic stroke. Direct comparisons of higher doses may yield additional cardiovascular benefits. At present, daily doses of 75 to 325 mg aspirin are sufficient for long-term treatment and prevention of cardiovascular disease.     

冠心病患者阿司匹林抵抗与复发心血管事件的发生及相关危险因素分析

【目的】探讨冠心病患者阿司匹林抵抗(AR)与复发心血管事件的发生及相关危险因素。【方法】选取本院收治的冠心病住院患者270例作为研究对象,采用血栓弹力图分析其 AR 情况,270例中76例有 AR 者作为AR 组,194例对阿司匹林敏感者作为动脉粥样硬化(AS)组,对比两组心血管事件发生率,分析 AR 与心血管事件的关系。【结果】AR 组出现心血管事件的几率为39.47%(30/76),显著高于 AS 组的12.37%(24/194),且两组相比较差异有显著性(P <0.05);270例患者中54例复发心血管事件的患者作为复发组,216例未复发心血管事件者作为未复发组,复发组高血压、糖尿病、吸烟、饮酒、抗血小板用药依从性差、AR 发生率显著高于未复发组,年龄、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)显著高于未复发组,高密度脂蛋白胆固醇(HDL-C)显著低于未复发组,且两组相比较差异均具有显著性(P <0.05);多因素 Logistic 回归分析显示 AR、抗血小板用药依从性差、糖尿病、年龄是冠心病患者复发心脑血管事件的独立危险因素,其中 AR 与复发心脑血管事件呈正相关关系。【结论】AR 会增加冠心病患者复发心脑血管事件的几率。     

Rivaroxaban (Xarelto) for acute coronary syndrome

The standard antithrombotic therapy for treatment of patients with acute coronary syndrome (ACS) is dual antiplatelet therapy with aspirin and clopidogrel (Plavix) or another thienopyridine, plus a parenteral anticoagulant while the patient is hospitalized, followed by antiplatelet therapy alone after discharge. The addition of the oral anticoagulant warfarin (Coumadin, and others) to dual antiplatelet therapy is generally not recommended for this indication because of fluctuations in its anticoagulant effect and the risk of bleeding. A recently published trial found that addition of a low dose of the oral anticoagulant rivaroxaban (Xarelto) to antiplatelet therapy after discharge reduced the risk of major cardiovascular events without increasing the incidence of fatal bleeding.     

Perioperative antiplatelet therapy

Aspirin is recommended as a lifelong therapy that should never be interrupted for patients with cardiovascular dis- ease. Clopidogrel therapy is mandatory for six weeks after placement of bare-metal stents, three to six months after myocardial infarction, and at least 12 months after placement of drug-eluting stents. Because of the hypercoagulable state induced by surgery, early withdrawal of antiplatelet therapy for secondary prevention of cardiovascular disease increases the risk of postoperative myocardial infarction and death five- to 10-fold in stented patients who are on continuous dual antiplatelet therapy. The shorter the time between revascularization and surgery, the higher the risk of adverse cardiac events. Elective surgery should be postponed beyond these periods, whereas vital, semiurgent, or urgent operations should be performed under continued dual antiplatelet therapy. The risk of surgical hemorrhage is increased approximately 20 percent by aspirin or clopidogrel alone, and 50 percent by dual antiplatelet therapy. The present clinical data suggest that the risk of a cardiovascular event when stopping antiplatelet agents preoperatively is higher than the risk of surgical bleeding when continuing these drugs, except during surgery in a closed space (e.g., intracranial, posterior eye chamber) or surgeries associated with massive bleeding and difficult hemostasis.     

Migraine and coronary heart disease in women and men

OBJECTIVE: We evaluated migraine as an independent risk factor for subsequent coronary heart disease (CHD) events among women in the Women's Health Study (WHS) and men in the Physicians' Health Study (PHS). BACKGROUND: Although several studies have suggested that migraine is associated with increased risk of stroke, there are few and conflicting data on whether migraine predicts risk of future CHD events. METHODS: The WHS is an ongoing randomized, double-blind, placebo-controlled trial of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer in 39876 women health professionals aged > or =45 years in 1993, and the PHS is a completed randomized, double-blind, placebo-controlled trial of aspirin and beta-carotene in the primary prevention of cardiovascular disease and cancer in 22071 men physicians aged 40 to 84 years in 1982. Primary endpoints were defined as major CHD (nonfatal myocardial infarction [MI] or fatal CHD) and total CHD (major CHD plus angina and coronary revascularization). RESULTS: After adjusting for other CHD risk factors, female health professionals and male physicians reporting migraine were not at increased risk for subsequent major CHD (women: relative risk [RR], 0.83; 95% confidence interval [CI], 0.53 to 1.29; men: RR, 1.02; 95% Cl, 0.79 to 1.31) or total CHD (women: RR, 1.01; 95% Cl, 0.76 to 1.34; men: RR, 0.98; 95% Cl, 0.82 to 1.18). When considered separately, there was also no increase in risk of MI or angina. CONCLUSION: These prospective data suggest that migraine is not associated with increased risk of subsequent CHD events in women or men.