Warfarin and aspirin give more benefit than aspirin alone but also more bleeding after myocardial infarction

The anticoagulant, warfarin, and the antiplatelet agent, aspirin, have been shown to have similar benefits after myocardial infarction. As these agents have different mechanisms of action, the beneficial effects of warfarin and aspirin may be additive after myocardial infarction. In the Warfarin, Aspirin, Reinfarction Study (WARIS II), the main outcome was a composite of death, non-fatal reinfarction or thromboembolic stroke, whichever came first over 4 years. Compared to aspirin alone (160 mg/day), the risk reduction was 19% (p = 0.03) with warfarin alone (INR of 2.8 IU) and 29% (p = 0.001) with the combination of aspirin and warfarin (aspirin, 75 mg/day; warfarin, INR of 2.2 IU). This difference in the first event with warfarin alone or the combination, represented a reduction in reinfarction and thromboembolic stroke rather than death. For reinfarction, compared to aspirin alone (117 of 1206), there was a reduction with warfarin alone (90 of 1216) and a further reduction with the combination (69 of 1208). For thromboembolic stroke, compared to aspirin (32 of 1206), there were similar reductions with warfarin and the combination. There were more major and minor bleeding in the warfarin groups than the aspirin group, with major bleeding occurring in 8, 33 and 28 patients taking aspirin, warfarin and aspirin and warfarin, respectively. In conclusion, as compared with aspirin alone, therapy with moderate-intensity warfarin combined with aspirin and high-intensity warfarin alone, resulted in a reduced risk of reinfarction and ischemic stroke but a higher risk of bleeding.     

Adverse effects and drug interactions of antithrombotic agents used in prevention of ischaemic stroke

Stroke is the third most common cause of death in the US. Primary prevention of stroke can be achieved by control of risk factors including hypertension, diabetes mellitus, elevated cholesterol levels and smoking. Approximately one-third of all ischaemic strokes occur in patients with a history of stroke or transient ischaemic attack (TIA). The mainstay of secondary prevention of ischaemic stroke is the addition of medical therapy with antithrombotic agents to control the risk factors for stroke. Antithrombotic therapy is associated with significant medical complications, particularly bleeding.Low-dose aspirin (acetylsalicylic acid) has been shown to be as effective as high-dose aspirin in the prevention of stroke, with fewer adverse bleeding events. Aspirin has been shown to be as effective as warfarin in the prevention of noncardioembolic ischaemic stroke, with significantly fewer bleeding complications. Ticlopidine may be more effective in preventing stroke than aspirin, but is associated with unacceptable haematological complications. Clopidogrel may have some benefit over aspirin in preventing myocardial infarction, but has not been shown to be superior to aspirin in the prevention of stroke. The combination of clopidogrel and aspirin may be more effective than aspirin alone in acute coronary syndromes, but the incidence of adverse bleeding is significantly higher. Furthermore, the combination of aspirin with clopidogrel has not been shown to be more effective for prevention of recurrent stroke than clopidogrel alone, while the rate of bleeding complications was significantly higher with combination therapy. The combination of aspirin and extended-release dipyridamole has been demonstrated to be more effective than aspirin alone, with the same rate of adverse bleeding complications as low-dose aspirin. When selecting the appropriate antithrombotic agent for secondary prevention of stroke, the adverse event profile of the drug must be taken into account when assessing the overall efficacy of the treatment plan.     

观察华法林及阿司匹林分别对非瓣膜性心房颤动患者血栓栓塞的影响

目的观察华法林及阿司匹林对非瓣膜性心房颤动患者血栓栓塞事件的影响。方法80例非瓣膜性心房颤动患者分为华法林组及阿司匹林组,阿司匹林组每天服用阿司匹林100 mg,华法林组根据国际标准化比值(INR)调整华法林用量,随访时间为2 a。结果阿司匹林组死亡2例,1例为缺血性卒中,另1例为心力衰竭;华法林组1例为猝死。阿司匹林组发生栓塞事件共8例,出血并发症3例;华法林组发生栓塞事件共3例,出血并发症7例。结论华法林可明显降低非瓣膜性房颤患者血栓栓塞事件,但出血并发症稍增多,关键是要严密随访INR。     

华法林用于各卒中风险非瓣膜性房颤患者对其血栓栓塞与出血风险的影响

目的分析非瓣膜性房颤住院患者使用华法林进行抗凝治疗和国际标准化比值(INR)监测状况,以期更好地指导临床抗凝治疗,减少抗凝治疗中血栓栓塞和出血事件发生。方法收集2017年6-12月汕头大学医学院第一附属医院住院治疗的非瓣膜性房颤患者的临床资料、用药情况,监测患者住院期间INR值。采用CHA2DS2-VASc评分对所有患者进行卒中风险评估。随访2年,观察患者因血栓栓塞事件、出血事件再入院情况。结果本研究共纳入病例662例,其中144例使用华法林。在CHA2DS2-VASc评分分层中,中、高危卒中风险患者服用华法林组的INR处于1.5~2.5区间的比例高于无服用组(P<0.05)。在140例服用华法林且INR数据完整患者中,63例(45.0%)INR处于1.0~1.5区间,仅29例(20.7%)INR处于2.0~3.0区间;高危卒中风险患者INR在1.5~2.0组发生血栓栓塞、出血事件再次住院的比例低于INR非1.5~2.0组(P<0.05)。结论临床上华法林使用率低,抗凝强度低。对于中、高危卒中风险患者来说,正确服用华法林有助于将INR控制在1.5~2.5区间。当高危卒中患者的INR处于1.5~2.0区间时可减少血栓栓塞、出血风险的发生。     

Role of Emerging Antithrombotic Therapy in the Prevention of Cardioembolic Complications in Patients with Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is an independent risk factor of potentially catastrophic cardioembolic strokes. AF patients are categorized into high-, intermediate-, and low-risk for thromboembolic complications using the CHADS₂ or CHA₂DS₂-VASc scoring system. Oral anticoagulation using warfarin has been the standard therapy for stroke prevention in intermediate- to high-risk AF patients. However, warfarin use has been limited by several factors such as narrow therapeutic windows, drug-drug and drug-food interactions, and hemorrhagic complications. Rigorous research evaluated dual antiplatelet therapy of clopidogrel and aspirin (acetylsalicylic acid) as a potential alternative to warfarin in the ACTIVE W trial. Dual antiplatelet therapy of clopidogrel and aspirin was found to be inferior to warfarin in preventing stroke and systemic embolism with increased bleeding risk. Other extensive research has led to the development of new antithrombotic agents. Recently, dabigatran etexilate 150 mg twice daily, a direct thrombin inhibitor, was approved by the US FDA for stroke prevention in patients with non-valvular AF after it was found to be superior to warfarin in preventing thromboembolic events and associated with less bleeding in the RE-LY trial. It was also cost effective when compared with warfarin. Dabigatran can be considered in high-risk AF patients who are unable or unwilling to comply with the frequent laboratory and clinic visits that are required when receiving treatment with warfarin. Factor Xa inhibitors are another class of new anticoagulants that have been developed. Oral rivaroxaban was non-inferior to warfarin in thromboprophylaxis and with similar bleeding in the ROCKET-AF trial (HR 0.88; p=0.117). Apixaban, another factor Xa inhibitor, was superior to aspirin in reducing stroke and systemic embolism in patients with AF in the AVERROES trial (HR 0.45; p<0.001). The results of the ARISTOTLE trial, which is evaluating apixaban against warfarin in ～18 000 patients with AF, are expected to be available later this year. Edoxaban, another oral factor Xa inhibitor, is currently being evaluated against warfarin in the ENGAGE AF-TIMI 48 trial in ～20 000 patients with AF. With these new developments, there is a necessity for the clinical practitioner to become familiar with these new and upcoming therapies and guidelines. This review provides an overview of the available data regarding the clinical usefulness of these agents.     

Secondary prevention of stroke in patients with nonvalvular atrial fibrillation: optimal intensity of anticoagulation

Nonvalvular atrial fibrillation (NVAF) is frequently seen in elderly people and has become a main cause of cardioembolic stroke. The efficacy of anticoagulation for primary prevention of stroke or transient ischaemic attacks (TIAs) in patients with NVAF has been established by prospective, randomised and controlled trials. Warfarin decreased the frequency of all strokes by 68% and the rate of the combined outcome of stroke, systemic embolism or death by 48%. Anticoagulation with warfarin using international normalised ratios (INRs) ranging from 2.0 to 3.0 is recommended for patients with NVAF, who have any of the risk factors identified by the Atrial Fibrillation Investigators (AFI) [previous stroke or TIA, history of hypertension, diabetes mellitus, advanced age (> or = 65 years old), congestive heart failure and coronary artery disease], the American College of Chest Physicians (ACCP) [increased age (> 75 years old), prior stroke, hypertension and heart failure], or the Stroke Prevention in Atrial Fibrillation (SPAF) investigators [women > 75 years old, prior stroke, systolic blood pressure > 160mm Hg, recent heart failure, and fractional shortening < 25% on echocardiography]. For the secondary prevention of stroke, the efficacy of adjusted-dose warfarin therapy has been demonstrated by 2 major randomised trials. SPAF III (INR 2.0 to 3.0) demonstrated a lower incidence of ischaemic stroke or systemic embolism (3.4 %/year) compared with low fixed-dose warfarin plus aspirin (acetylsalicylic acid) [11.9%]. The European Atrial Fibrillation Trial [EAFT] (INR 2.5 to 4.0) showed a lower incidence of all stroke (4.0 %/year) with adjusted-dose warfarin compared with placebo (12.0 %/year). The incidence of major bleeding in the adjusted-dose warfarin group in SPAF III and EAFT was 2.4 and 2.8 %/year, respectively. EAFT incidence rates for the occurrence of a first ischaemic or haemorrhagic complication analysed by INR range indicated that the rate was lowest at INRs of 2.0 to 2.9, and higher with INRs of 3.0 to 3.9. Therefore, the optimal intensity of anticoagulation for prevention of recurrent stroke seems to be an INR of between 2.0 and 3.0, as for primary prevention. Retrospective and prospective studies from Japan reported that in the elderly, haemorrhagic complications occur frequently with INRs above 2.6 and major ischaemic events cannot be prevented at INRs below 1.6. Therefore, an INR target between 1.6 and 2.6 may be an alternative for secondary prevention of stroke in elderly patients with NVAF who have a potential risk of bleeding, to avoid both major ischaemic and haemorrhagic events. Antiplatelets may be administered in patients who are unable to manage taking warfarin properly or who have a high risk of falling and subsequently sustaining a head injury, although the efficacy of antiplatelets for secondary prevention of stroke in NVAF has not yet been established.     

不同抗凝用药方案对房颤合并心衰患者疗效与安全性的网状Meta分析

目的:系统评价不同抗凝用药方案对房颤合并心衰患者疗效与安全性的差异,为房颤合并心衰的临床用药提供循证参考.方法:计算机检索各大中英文文献数据库,搜集房颤合并心衰患者抗凝方案的随机对照试验(RTCs).筛选文献后,用Cochrane手册5.3推荐的偏倚风险评估工具评价纳入研究质量.提取数据,使用Stata15.1软件进行...     

Non-vitamin-K oral anticoagulants (NOACs) for the prevention of secondary stroke

ABSTRACT

Introduction: In patients with atrial fibrillation (AF), oral anticoagulation with vitamin K antagonists (VKA) (warfarin, phenprocoumon) is effective both for primary and secondary stroke prevention with a 60–70% relative reduction in stroke risk compared with placebo. Mortality is reduced by 26%. VKA have a number of well-documented shortcomings which were overcome by non-vitamin-K oral anticoagulants (NOACs).

Areas covered: Results of randomized trials for four NOACs (apixaban, dabigatran, edoxaban, rivaroxaban) have been published (ARISTOTLE, RE-LY, ENGAGE, ROCKET-AF). In this review, the authors discuss the results in subgroups of patients with prior transient ischemic attacks or ischemic stroke. In aggregate, the NOACs are superior to warfarin for secondary prevention and result in a 50% reduction in intracerebral hemorrhage. Apixaban was superior to aspirin in the AVERROES trial and had a similar rate of major bleeding complications.

Expert opinion: NOACs add to the therapeutic options for secondary stroke prevention in patients with AF and offer advantages over warfarin including a favorable bleeding profile and convenience of use. Aspirin should no longer be used for secondary stroke prevention in patients with AF.     

Effect of race/ethnicity on the efficacy of warfarin: potential implications for prevention of stroke in patients with atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice. It affects approximately 6% of persons over 65 years of age and is independently associated with a 4- to 5-fold higher risk of ischaemic stroke and a 2-fold higher risk of death. Randomized controlled trials have shown that treatment with adjusted-dose oral vitamin K antagonists (primarily warfarin with a target international normalized ratio [INR] of 2.0-3.0) reduces the relative risk of ischaemic stroke by two-thirds (an approximately 3% reduction in annual absolute risk), but is associated with a 0.2% excess annual absolute risk of intracranial haemorrhage (ICH). However, in 'real world' studies, the risk reductions in ischaemic stroke with warfarin have been significantly lower (25-50% relative risk reduction) than in selected trial samples. Moreover, more than 90% of patients enrolled in the sentinel trials were White/European. This raises the question of whether the beneficial results of warfarin can be extrapolated to persons of colour. Important differences in stroke risk profile and responsiveness to warfarin exist across racial/ethnic groups, such that one cannot assume a priori that there is a net benefit of warfarin therapy for AF patients of all racial/ethnic groups.Among patients with ischaemic stroke, AF is more likely to be implicated as the cause of stroke in the White population than in other racial/ethnic groups. Furthermore, AF may be a stronger predictor of ischaemic stroke among the White population than in Black or Hispanic/Latino populations. Approximately one-third of strokes in AF patients are noncardioembolic. Warfarin has been shown to be ineffective in preventing recurrent noncardioembolic strokes. Many persons of colour with AF have other risk factors that predispose them to noncardioembolic stroke, which may partially explain why warfarin has been reported to be less efficacious in preventing strokes in non-White patients with AF, even after adjustment for co-morbidities and anticoagulation monitoring. Notably, the background incidence of ICH is higher in Black, Hispanic and Asian patients than in White patients. Any greater than expected increases in bleeding secondary to anticoagulation may potentially offset any benefit gained from cardioembolic stroke reduction, although this has not been fully resolved.Finally, there are racial/ethnic differences in the prevalence of certain polymorphisms in genes that influence warfarin pharmacokinetics and pharmacodynamics (e.g. cytochrome P450 2C9 and vitamin K epoxide reductase). The Asian population generally appear to require the lowest daily dose of warfarin to maintain a given INR target, with the White population requiring an intermediate daily dose and the Black population requiring the highest daily dose. These differences must be taken into account when administering warfarin in order to minimize the risk of under- or over-anticoagulation.In summary, warfarin is highly effective in preventing ischaemic strokes in White patients with AF at a modestly higher risk of ICH. Whether the same net clinical benefit extends to persons of colour is unproven. Given the rapidly changing demographic nationally and internationally, additional research is needed to resolve this important question.     

不同抗凝强度华法林治疗非瓣膜性房颤的安全性及缺血性脑卒中发生的危险因素评估

目的 评估华法林不同抗凝强度治疗非瓣膜性房颤的安全性,以及缺血性脑卒中发生的危险因素。方法 纳入2012年1月—2013年12月收治的130例非瓣膜性房颤患者,根据华法林抗凝治疗的强度分为中强度组：华法林中等强度抗凝治疗,国际标准化比率(international normalized ratio,INR)控制在2.0＜INR≤3.0;低强度组：华法林低等强度抗凝,INR控制在1.6≤INR≤2.0,记录2组患者治疗和随访期间缺血性脑卒中、出血栓塞等不良反应的发生率,ROC曲线法分析INR诊断抗凝出血风险,多因素Logistic回归分析患者缺血性脑卒中的危险因素。结果 中强度组缺血性脑卒中、短暂性脑缺血发作和外周动脉栓塞发生率分别为6.70%,3.45%和1.72%,与低强度组的8.33%,4.17%和4.17%比较,无统计学差异(P>0.05);中强度组华法林用量(3.13±0.45)mg·d^-1,INR值2.61±0.32,出血发生率为24.14%;低强度组华法林用量(2.63±0.32)mg·d^-1,INR值 1.84±0.30,出血发生率为9.72%。采用INR诊断患者出血风险,ROC曲线下面积为0.858(95%CI：0.791~0.924),INR的cut-off值2.85,该值下判断出血敏感性为81.1%,特异性为67.2%;多因素logistic回归分析发现年龄、合并高血压、糖尿病、心力衰竭、脑卒中病史、INR、治疗窗内时间、卒中危险评分是非瓣膜性房颤患者缺血性脑卒中发生的独立危险因素(P<0.05)。结论 中、低强度华法林抗凝治疗均有较好的抗凝效果,非瓣膜性心房颤动患者伴有血栓栓塞危险因素应尽早应用华法林抗凝治疗,严密监测INR,INR值控制在1.6≤INR≤2.0,降低和避免出血并发症。     

Predictors of Warfarin Use in Atrial Fibrillation Patients in the Inpatient Setting

Background

There is substantial published evidence that warfarin reduces the risk of stroke in patients with atrial fibrillation (AF). However, the current literature suggests that not all patients who could benefit from warfarin receive the drug.

Objective

To evaluate patient-related demographic and clinical factors that could influence warfarin use or other anticoagulant use in hospitalized patients with AF.

Study Design

Retrospective observational study using claims data from the Wolters Kluwer Pharma Solutions Hospital Patient Level Database, evaluating characteristics of patients hospitalized in the US between 1 November 2003 and 31 October 2004.

Setting

Hospital care.

Patients

The study included 44 193 patients aged ≥40 years who were hospitalized between 1 November 2003 and 31 October 2004 and had a diagnosis of AF during hospitalization (AF did not need to be the cause of hospitalization).

Interventions

Use of warfarin or other anticoagulants (unfractionated heparin [UFH] or low-molecular-weight heparin [LMWH]) was evaluated.

Main Outcome Measures

A logistic regression model was used to identify factors associated with warfarin use, international normalized ratio (INR) monitoring, or the use of anticoagulants (UFH or LMWH).

Results

In this analysis of hospitalized patients with AF in the real-world setting, about 56% of patients received anticoagulation therapy with warfarin. Elderly patients aged ≥75 years were less likely to be treated with warfarin than younger patients, but patients between the ages of 60 and 74 years were more likely to use warfarin than their younger counterparts. Except for patients with congestive heart failure or vascular malformation, patients with other bleeding risk factors (hepatic disease, renal disease, aspirin use, and fractures) were significantly less likely to receive warfarin than those without these risk factors. CHADS₂ scores for stroke risk of 2 and 3 were associated with a significantly higher likelihood of warfarin treatment than scores of 0 or 1. Patients admitted through a routine admission (an outpatient department) were significantly more likely to be prescribed warfarin than patients admitted through an emergency room. Patients aged ≥75 years and aspirin users were more likely to have their INR monitored during hospitalization. With respect to other anticoagulant use, females and older patients (≥65 years) were less likely to use UFH or LMWH, and patients with renal disease or vascular malformation and those receiving aspirin were more likely to use UFH or LMWH than patients without these conditions/not receiving aspirin. Patients admitted through the emergency room were more likely to receive an anticoagulant than patients admitted through an outpatient department, an inpatient transfer, or any other source.

Conclusions

Older age, female sex, and certain risk factors for bleeding, including hepatic disease, renal disease, aspirin use, and fractures, were associated with a lower likelihood of warfarin treatment, while a higher stroke risk (as indicated by CHADS₂ scores) was associated with a higher likelihood of warfarin treatment, in hospitalized patients with a diagnosis of AF. The likelihood of INR being monitored increased for patients aged ≥75 years and for aspirin users. Older patients and female patients were less likely to be prescribed other anticoagulants (UFH or LMWH) also.     

房颤患者华法林初始剂量及出血危险因素的调查分析

目的:比较两种华法林初始剂量在房颤患者中应用的安全性及有效性,并探讨其出血相关危险因素.方法:采用回顾性调查方法,将某医院服用华法林的住院房颤患者按初始剂量分为超低剂量组(1.25～1.875 mg)和低剂量组(2.5～3.0 mg),比较两组患者抗凝的安全性和有效性指标.同时采用Logistic回归分析主要的出血危险因素.结果:超低剂量患者各项安全性指标与低剂量组均无统计学差异(P＞0.05);但前者首次达到目标国际标准化比值(INR)的时间较后者显著延长(P＜0.05),同时INR低于目标范围的比例显著增加且INR的控制率显著降低(P＜0.001).年龄＞65岁,肝功能不全,出血体质,卒中史,联用胺碘酮会显著增加华法林的出血风险(OR＞1且P＜0.05).结论:房颤患者应用超低初始剂量华法林抗凝的出血风险与低初始剂量相当但血栓风险增加;对于联用胺碘酮的患者,应加强出血风险的监护.     

Dabigatran and atrial fibrillation: the alternative to warfarin for selected patients

For patients with atrial fibrillation and a high risk of thrombosis, the standard prophylaxis is warfarin, an anticoagulant, at a dose adjusted to the INR. Warfarin and aspirin are both reasonable choices for patients with a moderate risk of thrombosis. Dabigatran, an oral anticoagulant that inhibits thrombin, has been authorised for patients with atrial fibrillation and a moderate or high risk of thrombosis, without associated valvular abnormalities. Clinical evaluation of dabigatran is based on a randomised "non-inferiority" trial comparing two doses of dabigatran (110 mg and 150 mg) taken twice daily, and adjusted-dose warfarin, in 18 113 patients treated for an average of 21 months. Overall mortality was about 4% per year and did not differ between the 3 groups. There was a greater reduction in the annual incidence of stroke or systemic embolism with the higher dose of dabigatran (1.1%) than with warfarin (1.7%). This is not the case for the lower dose (1.5%). In patients with good INR control, the difference in favour of the higher dose of dabigatran was no longer statistically significant. All-cause treatment discontinuation rates were higher with dabigatran than with warfarin (21% versus 17%, p<0.001). The incidence of serious bleeding did not differ statistically between warfarin and the higher dose of dabigatran (3.57% versus 3.32%), but was lower with the lower dose of dabigatran (2.87%). Compared with warfarin, dabigatran appears to be associated with about a 0.2% excess of myocardial infarction (0.73% versus 0.53%). Dyspepsia is also more frequent with dabigatran (6% versus 1.4%). Hepatic adverse effects appear to be mild but need to be monitored. The effects of dabigatran are potentiated by combination with P-glycoprotein inhibitors and drugs that impair renal function. Combination with other antithrombotic agents should also be avoided. Treatment with dabigatran does not require monitoring of haemostasis, whereas vitamin K inhibitors necessitate close INR monitoring. In contrast, renal function must be monitored, as renal impairment increases the risk of bleeding. Unlike vitamin K antagonists, there is no antidote for dabigatran overdose. In practice, warfarin remains the standard drug for patients with atrial fibrillation and a moderate or high risk of thrombosis. Aspirin is an alternative for moderate-risk patients. When the risk is significant and the INR cannot be maintained within the target range despite close monitoring, dabigatran is the alternative to warfarin, provided the patient is closely monitored, especially for changes in renal function.     

Clopidogrel hydrogen sulphate for atrial fibrillation

INTRODUCTION: Atrial fibrillation is a common cardiac rhythm abnormality with a considerable cardiovascular disease burden worldwide. It is an independent major risk factor for stroke. Stroke prevention with anticoagulation or antiplatelet agents has been an important area of clinical research. Warfarin is the most widely used antithrombotic therapy for stroke prophylaxis for last several years, and now dabigatran (150 mg b.i.d.) is more effective than warfarin in stroke prevention in individuals at increased of stroke. In addition, several studies have evaluated the efficacy of clopidogrel for stroke prophylaxis either alone or in combination with aspirin. AREAS COVERED: This review summarizes the key findings of the trials looking at the efficacy of clopidogrel in stroke prevention. A literature search was performed using PubMed and Google Scholar. The trials that evaluated the efficacy of clopidogrel in preventing atherothrombotic events or stroke were also included. EXPERT OPINION: Clopidogrel prevents more vascular events, including stroke, in patients with a recent myocardial infarction, stroke or peripheral vascular disease than aspirin. Combination of clopidogrel and aspirin provides a greater reduction of stroke than aspirin or clopidogrel monotherapy, but at an increased risk of bleeding. Dual antiplatelet therapy (clopidogrel and aspirin) is inferior to warfarin in primary stroke prevention for patient with atrial fibrillation and thus should be considered for stroke prophylaxis only in patients ineligible for warfarin. However, with the advent of newer agents, like direct thrombin inhibitors and Factor Xa inhibitors, the role of antiplatelet therapy for stroke prevention in atrial fibrillation remains unclear.     

Antithrombotic options for atrial fibrillation in 2012

Atrial fibrillation (AF) is a common arrhythmia in clinical practice. An important component of the management of patients with AF involves prevention of thromboembolism and stroke. Coumarins, such as warfarin had been the only available oral antithrombotic agent for prevention of thromboembolism for many decades. Following intestinal absorption, coumarins inhibit multiple steps of the clotting cascade that leads to inhibition of coagulation factors II, VII, IX and X. In addition to delayed and variable inhibition of coagulation, coumarin therapy has a narrow therapeutic window for optimal balance of risk and benefit, which requires regular assessment of the international normalized ratio (INR) to monitor coagulation. A quest for safer, more effective therapies that do not need monitoring has led to the development of dabigatran, rivaroxaban, and apixaban. In this article, we review these newer antithrombotic agents and discuss role of these drugs in clinical practice.     

Clopidogrel hydrogen sulphate for atrial fibrillation

Introduction: Atrial fibrillation is a common cardiac rhythm abnormality with a considerable cardiovascular disease burden worldwide. It is an independent major risk factor for stroke. Stroke prevention with anticoagulation or antiplatelet agents has been an important area of clinical research. Warfarin is the most widely used antithrombotic therapy for stroke prophylaxis for last several years, and now dabigatran (150 mg b.i.d.) is more effective than warfarin in stroke prevention in individuals at increased of stroke. In addition, several studies have evaluated the efficacy of clopidogrel for stroke prophylaxis either alone or in combination with aspirin.

Areas covered: This review summarizes the key findings of the trials looking at the efficacy of clopidogrel in stroke prevention. A literature search was performed using PubMed and Google Scholar. The trials that evaluated the efficacy of clopidogrel in preventing atherothrombotic events or stroke were also included.

Expert opinion: Clopidogrel prevents more vascular events, including stroke, in patients with a recent myocardial infarction, stroke or peripheral vascular disease than aspirin. Combination of clopidogrel and aspirin provides a greater reduction of stroke than aspirin or clopidogrel monotherapy, but at an increased risk of bleeding. Dual antiplatelet therapy (clopidogrel and aspirin) is inferior to warfarin in primary stroke prevention for patient with atrial fibrillation and thus should be considered for stroke prophylaxis only in patients ineligible for warfarin. However, with the advent of newer agents, like direct thrombin inhibitors and Factor Xa inhibitors, the role of antiplatelet therapy for stroke prevention in atrial fibrillation remains unclear.     

Evaluation and management of atrial fibrillation

Atrial fibrillation (AF) is the most common clinically encountered arrhythmia affecting 0.4% of the general population. Its prevalence increases with age, affecting more than 6% of people over 80 years of age. The annual risk of ischemic stroke in patients with lone AF is approximately 1.3%. This annual risk increases up to 10% -12% in patients with a prior stroke or transient ischemic attack. Randomized clinical trials (RCT) comparing adjusted-dose oral anticoagulation and placebo showed a risk reduction of 61% (95% CI 47% to 71%). The absolute risk reduction for stroke with oral anticoagulants is about 3% per year. Aspirin has been shown in meta-analyses to have on average a 20-25% relative risk reduction, and is inferior to oral anticoagulants. In high risk patients with AF warfarin is a class I ACC/AHA indication unless there is a contraindication for anticoagulation. Unfortunately, this therapy requires frequent monitoring with blood samples and the interaction with food and several medications makes its use difficult and sometimes unreliable. It requires strict patient compliance and its use is also linked to potentially serious bleeding complications. In clinical practice, less than 60% of patients who do not have contraindications to oral anticoagulation are actually receiving them. Additionally, of those that receive oral anticoagulation, less than 50% are consistently within therapeutic targets. As such, the "real world" efficacy of a strategy towards prescribing oral anticoagulants is likely significantly lower than that demonstrated in clinical trials. As such, the need to discover other methods of anticoagulation with oral bioavailability, predictable pharmacokinetics, and minimal interactions with diet and other pharmacological agents is imperative. Low molecular weight heparin has a more predictable bioavailability and a longer half-life, but its subcutaneous mode of administration and long-term risks, in particular, osteoporosis makes the chronic use of this medication non-feasible. Antiplatelet agents such as clopidogrel have proven efficacy and superiority compared to aspirin to prevent systemic vascular events in at-risk patient populations, but currently they do not play an important role in the prevention of AF related thromboembolic events. The ACTIVE study is a randomized trial comparing the combination of clopidogrel and aspirin therapy to oral anticoagulation with warfarin in patients with AF, and was unfortunately terminated prematurely by the data safety and monitoring board because of increased events in the antiplatelet arm. Direct thrombin inhibitors, such as ximelagatran, may be as effective as warfarin for stroke-risk reduction in patients with AF. No anticoagulation monitoring is needed and it has excellent bioavailability, with a twice-daily oral dose. Elevation of liver enzymes was an initial concern regarding the use of this new drug, which is not available for general use. Ongoing pharmacological research and future clinical trials may one day leave the "warfarin days" behind. Unfortunately, the new therapies that are being tested seem to be at least several years away from being available on a widespread basis. In this review, we discuss the underlying pathophysiology of AF and stroke. We also provide a comprehensive discussion regarding various available therapies to treat AF.     

The Use of Vitamin K in Patients on Anticoagulant Therapy

Anticoagulation with antivitamin K (AVK) is very effective for primary and secondary prevention of thromboembolic events. However, questions persist about the risks and management of over-anticoagulation. For reversal of excessive anticoagulation by warfarin, AVK withdrawal, oral or parenteral vitamin K administration, prothrombin complex or fresh frozen plasma may be used, depending on the excess of anticoagulation, the existence and site of active bleeding, patient characteristics and the indication for AVK. In over-anticoagulated patients, vitamin K aims at rapid lowering of the international normalized ratio (INR) into a safe range to reduce the risk of major bleeding and therefore improving patient outcome without exposing the patient to the risk of thromboembolism due to overcorrection, resistance to AVK, or an allergic reaction to the medication. The risk of bleeding increases dramatically when the INR exceeds 4.0–6.0, although the absolute risk of bleeding remains fairly low, <5.5 per 1000 per day. Patient characteristics, including advanced age, treated hypertension, history of stroke, and concomitant use of various drugs, affect the risk of bleeding. The absolute risk of thromboembolism associated with overcorrection appears to be in the same range as the risk of bleeding due to over-anticoagulation. The use of vitamin K in patients with warfarin over-anticoagulation lowers excessively elevated INR faster than withholding warfarin alone; however, it has not been clearly demonstrated that vitamin K treatment does, in fact, lower the risk of major hemorrhage. As vitamin K administration via the intravenous route may be complicated by anaphylactoid reactions, and via the subcutaneous route by cutaneous reactions, oral administration is preferred. A dose of 1–2.5mg of oral phytomenadione (vitamin K₁), reduces the range of INR from 5.0–9.0 to 2.0–5.0 within 24–48 hours, and for an INR >10.0, a dose of 5mg may be more appropriate. Overcorrection of the INR or resistance to warfarin is unlikely if the above doses of vitamin K are used. Vitamin K is less effective for over-anticoagulation after treatment with acenocoumarol or phenprocoumon than after treatment with warfarin.     

华法林与阿司匹林用于老年阵发性房颤患者抗凝治疗的临床对比研究

目的探讨并比较华法林与阿司匹林对于老年阵发性房颤患者抗凝治疗的临床价值。方法选取我院2007年3月至2009年10月收治罹患阵发性房颤的老年患者180例,采用随机数字表法分为阿司匹林组和华法林组,每组各90例;其中阿司匹林组患者采用阿司匹林口服疗法,华法林组患者采用华法林口服疗法,两组患者均在治疗过程中依据INR检测值行剂量调整;比较两组患者血栓栓塞,出血,消化道反应及过敏发生率等。结果华法林组组患者血栓栓塞,消化道及过敏反应发生率均明显低于阿司匹林组,组间比较差异显著(P<0.05);但阿司匹林组与华法林组患者出血发生率组间比较无显著差异(P>0.05)。结论在严密监测患者INR指标条件下,相较于阿司匹林,华法林用于老年阵发性房颤患者抗凝治疗临床效果显著,且不良反应发生风险小。     

Enhanced antithrombotic effect of warfarin associated with low-dose alcohol consumption

A 58-year-old Caucasian man was receiving long-term anticoagulation with warfarin for the prevention of ischemic stroke; his international normalized ratio (INR) had been stable. His INR increased when he began consistent, low-dose beer consumption for its perceived cardiovascular protection. After he stopped drinking the alcohol, his anticoagulation control improved and returned to previous levels. Information on the effects of alcohol, particularly beer, is limited in nonalcoholic patients who receive warfarin therapy. This case reveals a potential for low-dose beer consumption to elevate INR. We propose that the increased antithrombotic effect of warfarin involved protein-binding interactions and decreased warfarin metabolism through the cytochrome P450 (CYP) enzyme system. Concurrent administration of aspirin and other drugs that are metabolized through or are inhibitors of the CYP system may have enhanced the interaction that occurred in this patient. Caution should be used whenever warfarin and alcohol in any amount are taken together, especially in patients receiving many drugs, and close monitoring of the INR is warranted.