双重抗血小板与华法林预防高危非瓣膜性心房颤动患者血栓栓塞的对照研究

目的 比较阿司匹林联合双嘧达莫与华法林预防高危非瓣膜性心房颤动(NVAF)患者血栓栓塞的有效性和安全性.方法 将确诊的140例高危NVAF患者,采用机械抽样法随机分为两组,分别给予调整剂量华法林抗凝治疗[华法林组78例,目标国际标准化比值(INR)为2.0～3.0,年龄>75岁者INR为1.6～2.5]和阿司匹林联合双嘧达莫治疗(联合治疗组62例,阿司匹林100mg1次/d+双嘧达莫100 mg 3次/d).观察两组患者死亡、血栓栓塞事件(缺血性脑卒中和周围动脉栓塞)及各种出血的发生率.结果 随访12～28个月.华法林组失访3例,发生缺血性脑卒中2例,严重出血2例,轻微出血6例;联合治疗组失访2例,发生缺血性脑卒中6例,周围动脉栓塞2例,轻微出血3例,无严重出血病例.华法林组血栓栓塞事件的发生率明显低于联合治疗组[2.7%(2/75)比13.3%(8/60),P<0.05];出血发生率高于联合治疗组,但差异无统计学意义[10.7%(8/75)比5.0%(3/60),P>0.05].结论 华法林抗凝治疗预防高危NVAF患者血栓栓塞事件的疗效优于阿司匹林联合双嘧达莫抗血小板治疗,当INR>3.0时出血发生率明显增加,严密监测下(INR 2.0～3.0)调整剂量华法林抗凝治疗安全有效.     

Warfarin plus aspirin more effective than aspirin alone for secondary prevention of MI

Compared with aspirin alone, aspirin plus warfarin (goal for international normalized ratio, 2-2.5) or warfarin alone (goal for international normalized ratio, 2.8-4.3) results in fewer re-infarctions and thromboembolic events. Treating 1000 patients for 1 year would result in approximately 10 fewer reinfarctions and 3 fewer strokes at a cost of 4 more major bleeding episodes. In addition, many patients will not be able to tolerate warfarin therapy. For highly motivated patients at low risk of bleeding, warfarin or warfarin plus aspirin is more effective than aspirin for secondary prevention of myocardial infarction.     

老年肺栓塞患者华法林长期抗凝治疗的效果与安全性评价

目的 探讨老年肺栓塞患者华法林长期抗凝治疗的效果、安全性和华法林剂量的动态变化,为经验性抗凝治疗提供依据.方法 选取肺栓塞门诊规律随访的抗凝治疗时间>12个月、年龄≥65岁的肺栓塞患者20例,根据随访记录统计患者出血、复发的情况以及华法林的用药剂量.结果 经CT肺动脉造影(CTPA)确诊的肺栓塞患者20例,其中男6例,女14例,年龄(73.55±5.76)岁,随访时间(22.60±11.45)个月;在随访期间,未出现颅内出血等严重威胁生命的出血,轻度出血5例,其中牙龈出血、鼻出血、咯血、结膜出血和左下肢皮肤淤斑各1例;20例患者中1例复发,复发率为5%;在长达24个月的随访时间中,患者华法林抗凝治疗的剂量无显著变化,达到充分抗凝的平均剂量为3.5 mg左右.结论 规范监测随访的肺栓塞患者长期抗凝治疗是安全有效的,其平均维持剂量约为3.5 mg,但需要规律检测国际标准化比值.     

老年心房纤颤患者不同抗栓治疗方案的临床观察

目的观察老年心房纤颤(房颤)患者使用口服抗凝药进行抗栓治疗的临床效果。方法选择2010—2011年年龄大于75岁持续性房颤患者232例。依据CHA2DS2系统评分大于2分栓塞风险较高,建议口服抗凝药抗栓治疗,HAS-BLED评分系统大于3分相对出血风险较高,需综合评估风险与收益选择治疗方案。根据不同的抗栓治疗方案将所有病例(232例)随机分为华法林组(95例)、阿司匹林组(103例)与氯吡格雷组(39例)。记录所有患者基本临床资料(性别、年龄、高血压病史、糖尿病史、卒中史、冠心病史等),观察各组间基本资料分布情况和口服药物6个月内定期随访患者不良事件的发生情况。结果在华法林组有高血压59例(62.1%),阿司匹林组75例(72.8%),高于氯吡格雷组7例(20.6%),经比较,差异有统计学意义(P0.01);其他基本临床资料3组间差异无统计学意义。华法林组CHAD2S2-VASc评分明显高于阿司匹林组和氯吡格雷组,差异有统计学意义(4.2±1.1 vs 3.9±0.9,3.6±0.7,P0.05);栓塞发生率氯吡格雷组4例(11.8)、阿司匹林组9例(8.7),与华法林组1例(1.1%)比较,差异有统计学意义(P0.05)。3组间HAS-BLE评分、轻微出血、大出血比较,差异无统计学意义。3组均无死亡病例。结论对于栓塞及出血风险均相对较高的老年房颤患者,使用口服抗凝药将国际标准化比值(INR)控制在2.0～3.0之间可明显降低栓塞发生率,并未明显增加出血风险。     

Apixaban for stroke prevention in atrial fibrillation: a review of the clinical trial evidence

The objective of this review is to summarize data from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trials of apixaban for stroke prevention in patients with atrial fibrillation (AF). The ARISTOTLE trial compared apixaban with warfarin in 18 201 patients with AF and ≥ 1 additional risk factor for stroke. The AVERROES trial compared apixaban with aspirin in 5599 patients with AF who were at increased risk of stroke and for whom vitamin K antagonists were unsuitable. In ARISTOTLE, apixaban reduced the risk of stroke or systemic embolism by 21% compared with warfarin (1.27% vs 1.60% per year; hazard ratio, 0.79; 95% confidence interval, 0.66-0.95). The reduction was significant and demonstrated the superiority of apixaban over warfarin for the primary outcome of preventing stroke or systemic embolism (P = 0.01 for superiority). Apixaban also reduced all-cause mortality by 11% (P = 0.047) and major bleeding by 31% (P < 0.001) compared with warfarin. The benefits of apixaban observed in ARISTOTLE are further supported by the results from AVERROES, which demonstrated a 55% reduction in the risk of stroke or systemic embolism compared with aspirin. Risk of major bleeding was not significantly different between apixaban and aspirin. Subgroup analyses in both trials demonstrated that the effects of apixaban are highly consistent across various patient subpopulations. Discontinuation of study medication was significantly lower with apixaban than with either warfarin in ARISTOTLE or aspirin in AVERROES. Apixaban is the first new oral anticoagulant that has been shown to be superior to warfarin in reducing stroke or systemic embolism, all-cause mortality, and major bleeding in patients with AF. Moreover, in patients with AF who are considered unsuitable for warfarin therapy, apixaban was more effective than aspirin for stroke prevention and had a similar rate of major bleeding.     

Are major bleeding events from falls more likely in patients on warfarin?

There is no evidence of increased risk for major bleeding as a result of falls in hospitalized patients taking warfarin (strength of recommendation [SOR]: B, based on retrospective cohort studies). In the average patient taking warfarin for atrial fibrillation, the risk of intracranial hemorrhage from a fall is much smaller than the benefit gained from reducing risk of stroke (SOR: A, based on decision analysis of systematic reviews with sensitivity analysis).     

心房颤动住院患者抗凝治疗的回顾分析研究

目的通过对280例房颤住院患者的病历资料进行回顾性分析,旨在评价房颤患者的抗凝治疗情况。方法对我院2000年4月-2007年2月出院诊断为持续性房颤的280例患者的住院资料进行详细登记及回顾性总结,建立患者的数据库,利用SPSS软件进行分析。结果应用阿司匹林抗血小板治疗83例,发生脑栓塞14例(16.86%)。用华法林抗凝治疗的患者197例,发生脑栓塞8例(4.06%)(P<0.05),提示华发林抗凝治疗的脑卒中患者患病率低于应用阿司匹林的抗血小板治疗的患者。口服华发林过程中出现出血事件为21例,进行Logistic回归分析,结果提示与口服华发林相关的出血高危因素为慢性肝病,收缩压>160mmHg,年龄>70岁。结论华法林抗凝治疗优于阿司匹林的抗血小板治疗。口服华发林危险因素为慢性肝病,收缩压>160mmHg,年龄>70岁,单纯监测INR是不够的。     

Utilization of Parenteral Anticoagulants and Warfarin: Impact on the Risk of Venous Thromboembolism Recurrence in the Outpatient Setting

Background

Clinical guidelines recommend parenteral anticoagulation therapy with an early initiation of warfarin therapy for the treatment of patients with acute venous thromboembolism (VTE) and the prevention of recurrence.

Objectives

To evaluate the outpatient utilization of parenteral anticoagulant therapy and warfarin among patients with VTE, and to examine the effects of parenteral anticoagulant use and the time to warfarin initiation from VTE diagnosis on the risk for VTE recurrence.

Methods

The Truven Health MarketScan Commercial Claims Database was used to identify patients aged 18 to 64 years who had an outpatient claim for deep-vein thrombosis or pulmonary embolism between January 2010 and December 2011 (ie, index date) and had no VTE diagnosis or treatment during the 12 months before the index date, had no hospital or emergency department VTE claim within 7 days after the index outpatient VTE claim, and had received warfarin <30 days after the index date. A recurrent VTE event was defined as a VTE-related emergency department visit or hospitalization within 8 to 365 days after the index date. A Cox proportional hazards model was used to estimate the adjusted hazard ratio (HR) associated with VTE recurrence risk related to parenteral anticoagulant use and warfarin initiation timing.

Results

A total of 5820 patients were included in the study (mean age, 50.5 years); of these, 45% were female. A total of 75.7% (4403) of the patients receiving warfarin also received a parenteral anticoagulant, and the median time from VTE diagnosis to warfarin initiation was 5 days for parenteral anticoagulant users compared with 11 days for nonusers. Parenteral anticoagulant use was associated with a 49% recurrent VTE risk reduction (HR, 0.51; 95% confidence interval [CI], 0.43–0.60; P <.001). Each day of delayed warfarin initiation from the diagnosis of acute VTE was associated with a 1% increase in the risk for VTE recurrence (HR, 1.01; 95% CI, 1.01–1.02; P = .003).

Conclusions

Overall, 1 in 4 patients with VTE who had received warfarin in the outpatient setting did not receive parenteral anticoagulation therapy. Among those who received warfarin, its initiation was not always timely, despite its positive effects on reducing VTE recurrence. These findings highlight the potential quality-of-care concerns associated with the failure to use or the delayed implementation of guideline-recommended VTE treatment, and the need to improve compliance with clinical guidelines in the treatment of patients with VTE.Venous thromboembolism (VTE) encompasses deep-vein thrombosis (DVT) and pulmonary embolism (PE). VTE is a chronic disease that is associated with a high risk for recurrence, especially during the initial months of therapy.1–7 The risk for VTE recurrence is higher for patients with “unprovoked” VTE (ie, VTE occurring in the absence of malignancy or any of the factors of “provoked” VTE) than for patients with provoked VTE (ie, VTE occurring within 3 months of hospitalization, major surgery, pregnancy, trauma, or fracture).8 The rates of VTE recurrence in patients with unprovoked VTE have been estimated at 10% after 1 year and 30% after 5 years of the first VTE event compared with patients with VTE provoked by surgery, in whom the recurrence rates are estimated to be 1% after 1 year and 3% after 5 years.8VTE recurrence is recognized as an important risk factor for mortality and long-term complications, such as postthrombotic syndrome after DVT and pulmonary hypertension after PE. Recurrent VTE events also pose a significant economic burden to the healthcare system. In a recent retrospective analysis of claims data, patients with VTE recurrence were found to have 2.2-fold to 3-fold higher healthcare costs in the 1 year after their first VTE event, which was primarily driven by an increase in inpatient services utilization.7The American College of Chest Physicians (ACCP) recommends initial parenteral anticoagulant therapy as an option for the initial treatment of acute DVT or PE.8 The ACCP guidelines recommend the early initiation of warfarin therapy rather than delayed initiation (eg, on the same day as parenteral therapy is started), and the continuation of parenteral anticoagulation therapy for a minimum of 5 days until the international normalized ratio (INR) is ≥2.0 for at least 24 hours. The ACCP also recommends continuation of anticoagulation therapy for 3 months in patients with acute DVT and PE to allow for the complete treatment of the acute episode of VTE and to prevent recurrent episodes of VTE.8The outpatient treatment of uncomplicated VTE has become more common since the availability of subcutaneous low-molecular-weight heparin (LMWH) therapy as an alternative to intravenous unfractionated heparin for the treatment of VTE.8–10 Although the administration of heparin therapy and INR monitoring are much easier in the inpatient setting, there are challenges associated with the outpatient treatment of VTE. The outpatient use of LMWH requires the coordination of care, laboratory monitoring, and patient education and participation in treatment.11It remains unclear how well parenteral anticoagulation therapy utilization in the outpatient clinical practice is consistent with the treatment guidelines for VTE. In addition, although previous randomized clinical trials suggest that the early initiation of warfarin therapy with a shorter course of heparin therapy for approximately 5 days is as effective as the delayed initiation of warfarin with a 10-day course of heparin, and that this approach has the benefit of reducing the risk for heparin-induced thrombocytopenia,8 it remains unclear how well this recommendation has been adopted in real-world clinical settings.The objectives of this study were to assess the utilization of parenteral anticoagulation therapy and the timing of the initiation of warfarin for the treatment of VTE in the outpatient setting, and to examine the effects of parenteral anticoagulation therapy and the timing of warfarin initiation relative to a diagnosis of VTE on the risk of VTE recurrence.

KEY POINTS

• ▸ Recurrent venous thromboembolism (VTE) is a risk factor for mortality and long-term, serious complications; the risk for recurrence is especially high in the early months of an acute VTE event.
• ▸ Recurrent VTE poses a significant economic burden to the healthcare system.
• ▸ Current clinical guidelines recommend the early addition of warfarin to parenteral anticoagulation to reduce the risk for VTE recurrence.
• ▸ In this study of 4403 patients with acute VTE who received parenteral anticoagulants in the outpatient setting, only 25% of patients received warfarin on the same day of initiating parenteral anticoagulant therapy; 52% received warfarin 3 days after initiating parenteral anticoagulant therapy.
• ▸ Overall, parenteral anticoagulation plus warfarin reduced the risk for recurrent VTE by 49% over 1 year.
• ▸ In this study, each day that the initiation of warfarin was delayed from the VTE diagnosis translated to a 1% increase in VTE recurrence risk.

     

Ximelagatran: direct thrombin inhibitor

Warfarin sodium is an effective oral anticoagulant drug. However, warfarin has a narrow therapeutic window with significant risks of hemorrhage at therapeutic concentrations. Dosing is difficult and requires frequent monitoring. New oral anticoagulant agents are required to improve current anticoagulant therapy. Furthermore, while warfarin is effective in venous disease, it does not provide more than 60% risk reduction compared with placebo in venous thrombosis prophylaxis and considerably lower risk reduction in terms of arterial thrombosis. Ximelagatran is an oral pro-drug of melagatran, a synthetic small peptidomimetic with direct thrombin inhibitory actions and anticoagulant activity. As an oral agent, ximelagatran has a number of desirable properties including a rapid onset of action, fixed dosing, stable absorption, apparent low potential for medication interactions, and no requirement for monitoring of drug levels or dose adjustment. It has a short plasma elimination half-life of about 4 hours in cases of unexpected hemorrhage or need for reversal. Its main toxicity relates to the development of abnormal liver biochemistry and/or liver dysfunction with "long-term" use of the drug. This usually occurs within the first 6 months of commencing therapy, with a small percentage of patients developing jaundice. The biochemical abnormality usually resolves despite continuation of the drug. The cause of this toxicity remains unknown. Clinical studies to date have shown that ximelagatran is noninferior to warfarin in stroke prevention in patients with nonvalvular atrial fibrillation, noninferior to standard therapy as acute and extended therapy of deep vein thrombosis (DVT), and superior to warfarin for the prevention of venous thromboembolism post-major orthopedic surgery. It has also been shown to be more effective than aspirin alone for prevention of recurrent major cardiovascular events in patients with recent myocardial infarction.     

老年慢性房颤患者抗栓治疗调查研究

目的探讨老年慢性房颤患者脑卒中预防。方法对我院就诊的老年慢性房颤患者资料进行随访调查,对比服用华法林和阿斯匹林药物后,患者缺血性脑卒中及脑出血并发症的发生率。结果华法林组缺血性脑卒中发病率同阿司匹林组比较显著下降;华法林组与阿司匹林组并发非致死性出血机率无统计学差异。结论对于老年慢性房颤患者缺血性脑卒中的预防,华法林比阿司匹林效果明显。     

Evaluation of Dabigatran for Appropriateness of Use and Bleeding Events in a Community Hospital Setting

Background

Warfarin has been the predominant anticoagulant for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). Its disadvantages are well-known and include a narrow therapeutic index, drug interactions, and the need for frequent monitoring. Dabigatran etexilate, a direct thrombin inhibitor, presents less complexity in prescribing and has emerged as an alternate therapy to warfarin. Although dabigatran does not require routine monitoring, concerns associated with its use include the lack of a reversal agent, complex dose adjustments, and limited guidance to the management of drug interactions.

Objectives

The goals of this study are to describe and to evaluate the use of dabigatran at a community hospital to identify areas for improvement in its prescribing.

Methods

This retrospective chart review of patients at a community hospital in St Louis, MO, included patients who received at least 1 dose of dabigatran between December 2010 and June 2012. The appropriateness of dabigatran was evaluated based on recommendations approved by the US Food and Drug Administration for stroke prophylaxis in the setting of NVAF. The composite end point of bleeding included hospital readmission within 1 year of receiving at least 1 dose of dabigatran at the study institution secondary to bleeding, bleeding associated with a decrease in hemoglobin level by ≥2 g/dL or transfusion of ≥2 units of blood, or a notation of bleeding in the patient''s medical record.

Results

Of the 458 patients included in the evaluation, 76 (16.6%) patients receiving dabigatran were using an inappropriate regimen of this drug, based on dose and frequency on the first day of therapy of dabigatran or the presence of valvular disease. Many patients (42.3%) received at least 1 dose of a concomitant parenteral anticoagulant. The composite end point for bleeding was reported in 66 (14.4%) patients, including 23 (5%) with confirmed gastrointestinal bleeding.

Conclusions

High-risk medications such as dabigatran require monitoring of prescribing habits to improve patient safety and outcomes. Various initiatives, such as pharmacist interventions, therapeutic interchanges, and obtaining appropriate patient parameters, can be implemented in the practice setting to ensure the appropriate use of oral anticoagulants and improved patient outcomes.Oral anticoagulation has changed drastically in the past 4 years with the US Food and Drug Administration (FDA) approval of 3 new agents—dabigatran, rivaroxaban, and apixaban. Warfar-in has had a primary role in oral anticoagulation therapy for many decades. Although its efficacy and safety have been established, therapy with warfarin is associated with significant challenges, including the need for frequent monitoring, drug interactions, a delayed time to onset, and a narrow therapeutic index.1,2 The challenges associated with warfarin not only affect its efficacy, but they also impact patient satisfaction. These concerns have contributed to the development of novel oral anticoagulants, beginning with dabigatran etexilate.Dabigatran etexilate, a direct thrombin inhibitor, was approved by the FDA in October 2010 and is the first novel oral anticoagulant approved to reduce the risk for stroke in patients with nonvalvular atrial fibrillation (NVAF).3 Results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study demonstrated the superiority of dabigatran 150 mg orally twice daily compared with warfarin for the prevention of stroke and systemic embolism in patients with NVAF.4 In that study, the rate of major bleeding was similar between the agents; however, dabigatran demonstrated a lower risk for intracranial hemorrhage, but with an increased risk for major gastrointestinal (GI) bleeding, compared with warfarin.4A recent analysis performed by the FDA confirmed these findings.5,6 In this analysis, compared with warfarin, dabigatran demonstrated lower rates of ischemic stroke, intracranial hemorrhage, and death; however, dabigatran was associated with a significant increase in major GI bleeding.5,6 In April 2014, dabigatran received new FDA indications for the treatment of patients with deep-vein thrombosis (DVT) and pulmonary embolism (PE) and for the risk reduction of recurrent DVT and PE in previously treated patients. Two studies, RE-COVER and RE-COVER II, compared dabigatran 150 mg twice daily with warfarin for the treatment of DVT and PE after 5 to 10 days of parenteral anticoagulation. Both studies demonstrated dabigatran''s noninferiority to warfarin.7,8 When the RE-COVER study was initiated, dabigatran was the only agent approved by the FDA for the risk reduction of recurrent venous thromboembolism (VTE).In November 2011, rivaroxaban, a factor Xa inhibitor, was the second novel oral anticoagulant to receive FDA approval to reduce the risk for stroke in patients with NVAF.9 Results from the ROCKET AF trial demonstrated the noninferiority of rivaroxaban to warfarin for the first occurrence of stroke or systemic embolism.10 In November 2012, rivaroxaban received an additional indication for the treatment of and reduction in the risk for recurrent VTE. Two studies, EINSTEIN-DVT and EINSTEIN-PE, compared rivaroxaban (at an initial dose of 15 mg twice daily for 3 weeks, followed by 20 mg once daily) with enoxaparin 1 mg/kg twice daily for at least 5 days with warfarin and then continued with warfarin after the target international normalized ratio (INR) of 2.0 to 3.0 was reached.11,12 Both studies demonstrated the noninferiority of rivaroxaban to warfarin in time to first recurrent DVT or PE event.11,12In December 2012, the factor Xa inhibitor apixaban was the newest novel oral anticoagulant to receive FDA approval to reduce the risk for stroke in patients with NVAF.13 The ARISTOTLE trial compared apixaban 5 mg twice daily (or 2.5 mg twice daily in select patients) with warfarin.14 Apixaban was superior to warfarin for the primary end point of reducing the risks for stroke and systemic embolism. Superiority to warfarin was primarily attributable to reductions in hemorrhagic stroke and ischemic stroke with hemorrhagic transformation compared with warfarin.14In AVERROES, patients with NVAF who were not candidates for therapy with warfarin were randomized to treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily in select patients) or to aspirin 81 mg to 324 mg once daily.15 The primary objective of the study was to determine if apixaban was superior to aspirin for preventing the outcomes of stroke or systemic embolism. This trial was stopped early on the basis of a prespecified interim analysis that showed significant reductions in stroke and systemic embolism with apixaban compared with aspirin, but apixaban was associated with a modest increase in major bleeding.15

KEY POINTS

• ▸ Anticoagulation has changed drastically in the past 4 years in the United States with the FDA approval of novel oral anticoagulants, starting with dabigatran in 2010, rivaroxaban in 2011, and apixaban in 2012.
• ▸ These new anticoagulants present a safe alternative to warfarin for the prevention of stroke and systemic embolism in the setting of nonvalvular atrial fibrillation (NVAF).
• ▸ However, although anticoagulation has been simplified with the novel oral drugs, many safety issues must be considered when prescribing these agents.
• ▸ This retrospective chart review at a community hospital analyzed the appropriateness use of dabigatran, the first novel anticoagulant to receive FDA approval for the treatment of NVAF.
• ▸ Of the 458 patients included in this study, 76 patients were prescribed an inappropriate, mostly too high, dose of dabigatran.
• ▸ Although dabigatran is only approved for the treatment of NVAF, 13 patients had valvular disease.
• ▸ The majority of the patients were also receiving concomitant medications that are known to have drug interactions with dabigatran.
• ▸ These results indicate that high-risk medications require better monitoring of prescribing habits to improve patient safety and outcomes.

The current guidelines for the treatment of atrial fibrillation provide a class I recommendation for warfarin (level of evidence A) and dabigatran, rivaroxaban, and apixaban (level of evidence B) for the prevention of thromboembolism in patients with a CHA₂DS₂-VAS_c score of ≥2.16Dabigatran provides an effective alternative therapy to warfarin. It offers a predictable pharmacokinetic profile, which eliminates the need for routine monitoring of serum drug concentrations. Approximately 80% of dabigatran is excreted renally and requires dose reductions for patients with reduced creatinine clearance.17 Although dabigatran addresses some of the challenges associated with warfarin, there are remaining issues regarding the use of dabigatran.Warfarin interacts with numerous medications, disease states, and a variety of foods containing vitamin K; however, there is a great deal of clinical experience and resources available to effectively manage many of warfarin''s interactions.1 Unlike warfarin, dabigatran is not metabolized by cytochrome P450 enzymes and has fewer drug interactions. Although several drug interactions with dabigatran and P-glycoprotein inducers and inhibitors have been identified, little guidance has been provided on how to address them in practice.18Additional concerns surrounding dabigatran include the lack of a reversal agent and the lack of availability of laboratory testing to determine its degree of anticoagulation activity. Dabigatran prolongs markers of coagulation, such as the activated partial thromboplastin time (aPTT) and ecarin clotting time, and may potentially impact INR values. The aPTT can only provide an approximation of the anticoagulation effect of dabigatran, and the INR is relatively insensitive to the degree of anticoagulation. The ecarin clotting time is a more specific parameter to determine the effect of anticoagulation19; however, most laboratories are not adequately equipped to perform the laboratory test. Without laboratory parameters to guide dosing adjustments, it is unclear how to balance the drug interactions that have been identified to potentially increase or decrease dabigatran serum concentrations. The lack of monitoring also makes it difficult to manage special populations that typically require dosage adjustments (eg, the elderly, obese patients, underweight patients, and those with renal dysfunction).Since dabigatran became the first oral anticoagulant to be introduced to the US market, and the first to be included on hospital formularies, there has been a dramatic shift in the approach to anticoagulation. Laboratory markers of anticoagulation effect are no longer reliable, drug interactions require significantly less dose adjustments, and renal function continually needs to be addressed.20 The purpose of this study was to evaluate the use of dabigatran at a community hospital between December 2010 and June 2012 and to identify prescribing areas that can be improved to ensure appropriate use and patient outcomes.     

A prospective study: prediction of the first variceal haemorrhage in schistosomal and non schistosomal liver disease

A prospective study was conducted on liver disease patients without previous history of bleeding (haematemesis and/or melena) to identify those at highest risk of bleeding. A hundred and twenty non-alcoholic patients (96 males and 24 females), ages ranging from 30 to 60 years were studied. Patients were followed for up to two years or to time of bleeding (mean 18 +/- 7.3 months), during which 34 (28.3%) patients bled. Schistosomal patients showed less incidence of bleeding (12.1%, p < 0.05) than those with mixed aetiology (Schistosoma and cirrhosis 23.5%, and chronic active hepatitis and schistosoma 44.4%). The presence of positive viral markers (either HCV antibodies or HBsAg) was associated with a higher percent of bleeding during the follow-up period (43.2% and 45.4%, respectively), than those negative for these markers (21.7%, 24.4%, respectively). Univariate analysis showed the following significant risk factors associated with bleeding: modified child classification, reduced platelet count, endoscopic findings of cherry red spots, gastric varices and increased grade of oesophageal varices. Multivariate analysis revealed that the risk of bleeding was significantly related to the presence of cherry red spots, the presence of gastric varices, grade of oesophageal varices and the patient's prothrombin time. In conclusion, bleeding from oesophageal varices is a frequent and serious event in patients with chronic liver disease. The risk of variceal bleeding from liver disease with mixed aetiology (schistosomiasis associated with viral hepatitis HBV or HCV) was found to be significantly higher than that with schistosomal aetiology alone. The endoscopic findings of cherry red spots, gastric varices, increased grade of oesophageal varices and to a lesser extent the prothrombin time were found to be high risk factors. Patients having those risk factors should be considered for prophylactic measures.     

Efficacy and Safety of Oral Anticoagulants in Older Adult Patients With Atrial Fibrillation: Pairwise and Network Meta-Analyses

ObjectiveTo evaluate the efficacy and safety of oral anticoagulants for older adult patients with atrial fibrillation (AF).DesignPairwise and network meta-analyses.Setting and ParticipantsPatients with AF aged ≥75 years.MethodsPubMed, Embase, and the Cochrane library were searched for published randomized controlled trials and adjusted observational studies evaluating the use of a non–vitamin K antagonist oral anticoagulants (NOACs), vitamin K antagonist, or antiplatelet drug for the prevention of stroke. The primary efficacy and safety outcomes were the composite of stroke and systemic embolism (SSE) and major bleedings.ResultsThis study included 38 studies enrolling 1,022,908 older adult patients with AF. Results from pairwise meta-analyses showed that NOACs were superior to warfarin for all outcomes, except that dabigatran increased the risk of gastrointestinal (GI) bleedings. Aspirin was associated with a higher risk of SSE and ischemic stroke than warfarin or NOACs. Results of network meta-analyses indicated that apixaban significantly reduced the risk of SSE, major bleedings, and GI bleedings than warfarin, rivaroxaban, and dabigatran. Apixaban, edoxaban, rivaroxaban, and dabigatran reduced the risk of ischemic stroke and intracranial bleeding compared to warfarin. Dabigatran showed lower risk of all-cause mortality than warfarin and of intracranial bleeding than rivaroxaban.Conclusions and ImplicationsNOACs are of at least equal efficacy, or even superior to warfarin. The safety profile of individual NOAC agents was significantly different, as apixaban performs better than the other oral anticoagulants in reducing major bleeding and GI bleeding, whereas dabigatran increased the risk of GI bleeding.     

A flexible loading dose schedule for warfarin therapy

A flexible loading dose schedule for inducing anticoagulation with warfarin was assessed in 31 consecutive patients. 55% reached the therapeutic range (prothrombin ratio between 2 and 4:1) by Day 2 (40 hours after the first dose) and this figure rose to 77% on Day 3 and to 87% on Day 4. All patients had a PTR between 1.7 and 4.2 on Day 5. Patients with evidence of cardiac failure and abnormal liver function, and those taking medications known to interact with warfarin required lower doses and ran a higher PTR when compared with the total group of patients. This schedule offers a useful means of safely and rapidly inducing warfarin therapy in all patients.     

华法林预防非瓣膜性心房颤动患者脑梗死的临床研究

目的 探讨华法林预防非瓣膜性心房颤动(NVAF)患者并发脑梗死的疗效和安全性.方法 选择NVAF患者136例,按随机数字表法分为华法林组[口服华法林钠片,初始剂量为2.0mg/d,目标国际标准化比值(INR)为2.0～3.0]、阿司匹林组(口服阿司匹林100 mg/d)和对照组(未用抗栓药物).常规门诊随访,调整华法林剂量并记录三组患者的终点事件和不良反应发生情况,随访时间18个月.结果 136例患者失访4例,进入研究的132例患者中,男77例,占58.3%.华法林组口服华法林钠片的剂量为(2.5±1.0)mg.随访期间共发生主要终点事件12例,其中华法林组1例(2.50%,1/40)、阿司匹林组4例(9.52%,4/42)、对照组7例(14.00%,7/50),三组主要终点事件发生率比较差异无统计学意义(x2=2.084,P=0.353).伴随≥3种危险因素的三组之间生存曲线比较差异有统计学意义(x2=6.404,P=0.041).华法林组出血并发症发生率高于阿司匹林组[5.00%(2/40)比2.38%(1/42)],但差异无统计学意义(P＞0.05).结论 伴随≥3种危险因素的NVAF患者,华法林可改善患者的生存率,华法林导致出血并发症多数发生在INR＞3.0.严密监测下(INR 2.0～3.0)的调整剂量华法林安全有效.     

替格瑞洛与氯吡格雷对冠状动脉三支病变介入治疗患者住院期间及长期临床结果比较

目的 分析比较替格瑞洛与氯吡格雷对冠状动脉三支病变介入治疗后患者的疗效及安全性。方法 选择冠状动脉三支病变并接受经皮冠状动脉介入 (PCI)治疗的患者119例,随机分为2组,术后给予氯吡格雷组患者氯吡格雷加阿司匹林的双联抗血小板治疗12个月,给予替格瑞洛组患者替格瑞洛加阿司匹林的双抗治疗12个月,在术后第1、3、6、9、12个月分别对患者进行随访。结果 12个月2组患者的全因死亡率分别为10.7%和8.9%,组间比较差异无统计学意义（χ2 = 0.103,P＞0.05）。12个月内替格瑞洛组的主要心血管不良事件（MACE）事件发生率为26.8%,氯吡格雷组为46.4%,组间比较差异具有统计学意义（χ2 = 4.819,P＜0.05）。随访期间氯吡格雷组和替格瑞洛组发生TIMI小出血或TIMI轻微出血的例数分别为7例和16例,组间比较差异具有统计学意义（χ2 = 4.432,P＜0.05）。氯吡格雷组与替格瑞洛组发生TIMI主要出血的患者分别为2例和3例,组间比较差异无统计学意义（P＞0.05）。结论 替格瑞洛相较氯吡格雷可有效减少冠心病三支病变介入治疗后患者MACE事件的发生率。替格瑞洛相较氯吡格雷使患者TIMI小出血和轻微出血的风险增加,但不增加TIMI主要出血的风险。     

The Association of Health Literacy With Time in Therapeutic Range for Patients on Warfarin Therapy

Patients on warfarin therapy need to achieve and maintain anticoagulation control in order to experience the benefits of treatment while minimizing bleeding risk. Low health literacy skills may hinder patients' ability to use and adhere to warfarin in a safe and effective manner. The authors conducted this study to evaluate the relationship between health literacy and anticoagulation control among patients on chronic warfarin therapy. Participants were recruited from 2 diverse anticoagulation clinics in North Carolina. Time in therapeutic range (TTR) for warfarin therapy was used as a measure of anticoagulation control. Health literacy was assessed using the short form of the Test of Functional Health Literacy in Adults (S-TOFHLA). Of the 198 study participants, 51% had limited health literacy (S-TOFHLA score of 0–90) and 33% had poor anticoagulation control (TTR <50%). Participants with limited health literacy were less likely to correctly answer warfarin-related knowledge questions. Limited health literacy was significantly associated with TTR <50% (adjusted odds ratio = 2.34, 95% CI [1.01, 5.46]). Findings indicate that limited health literacy is associated with poor anticoagulation control for patients on warfarin therapy. Lack of medication understanding may hinder the safe and effective use of this narrow therapeutic index drug.     

Cost-Utility Analysis of Apixaban versus Warfarin in Atrial Fibrillation Patients with Chronic Kidney Disease

Background

Warfarin use for stroke prevention in atrial fibrillation (AF) patients with chronic kidney disease is debated. Apixaban was shown to be safer than warfarin, with superior reduction in the risk of stroke, systemic embolism, mortality, and major bleeding irrespective of kidney function.

The Economic Burden of Ischemic Stroke and Major Hemorrhage in Medicare Beneficiaries with Nonvalvular Atrial Fibrillation: A Retrospective Claims Analysis

Background

Understanding the economic implications of oral anticoagulation therapy requires careful consideration of the risks and costs of stroke and major hemorrhage. The majority of patients with atrial fibrillation (AF) are aged ≥65 years, so focusing on the Medicare population is reasonable when discussing the risk for stroke.

Objective

To examine the relative economic burden associated with stroke and major hemorrhage among Medicare beneficiaries who are newly diagnosed with nonvalvular atrial fibrillation (NVAF).

Methods

This study was a retrospective analysis of a 5% sample of Medicare claims data for patients with NVAF from 2006 to 2008. Patients with NVAF without any claims of AF during the 12 months before the first (index) claim for AF in 2007 (baseline period) were identified and were classified into 4 cohorts during a 12-month follow-up period after the index date. These cohorts included (1) no claims for ischemic stroke or major hemorrhage (without stroke or hemorrhage); (2) no claims for ischemic stroke and ≥1 claims for major hemorrhage (hemorrhage only); (3) ≥1 claims for ischemic stroke and no major hemorrhage claims (stroke only); and (4) ≥1 claims each for ischemic stroke and for major hemorrhage (stroke and hemorrhage). The 1-year mean postindex total all-cause healthcare costs adjusted by the Centers for Medicare & Medicaid Services Hierarchical Condition Categories (HCC) score were compared among the study cohorts. Results: Of the 9455 eligible patients included in this study, 3% (N = 261) of the patients had ischemic stroke claims only, 3% (N = 276) had hemorrhage claims only, and <1% (N = 13) had both during the follow-up period. The unadjusted follow-up healthcare costs were $63,781 and $64,596 per patient for the ischemic stroke only and the hemorrhage only cohorts, respectively, compared with $35,474 per patient for those without hemorrhage or stroke claims. After adjustment for HCC risk score, the mean incremental costs for patients with stroke claims only and hemorrhage claims only, relative to those without stroke or hemorrhage claims, were $26,776 (95% confidence interval [CI], $20,785-$32,767; P <.001) and $26,168 (95% CI, $20,375-$31,961; P <.001), respectively.

Conclusion

The economic burden of managing patients with NVAF who experience ischemic stroke and hemorrhage were similarly significant during the first year after a diagnosis of NVAF. The burden of major bleeding complications on patients, clinicians, and payers should not be overlooked, and these complications should be considered in conjunction with the cost-savings associated with ischemic stroke risk reduction in future cost-benefit evaluations of oral anticoagulation therapy.Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia.1,2 The most recent estimates (published in 2013) of the prevalence of AF in the United States are for 2010 and range from 2.7 million to 6.1 million.3,4 The prevalence of AF doubles with each decade of life after the age of 60 years and occurs in approximately 10% of the US population aged ≥80 years.5–7 A recent study estimates that the number of patients with AF in the United States could potentially reach 12.1 million by 20303; other estimates range from 5.6 million to 12 million patients with AF by 2050.4Patients with AF have an approximate 5-fold increased risk for stroke compared with patients in normal sinus rhythm.4 Furthermore, the percentage of strokes that can be attributed to AF increases steeply with age, with rates of 1.5% in patients aged 50 to 59 years and 23.5% in those aged 80 to 89 years.4 The term “nonvalvular atrial fibrillation” (NVAF) is used to describe cases of AF that occur in the absence of rheumatic mitral valve disease, mitral valve repair, or a prosthetic heart valve.8 NVAF affects approximately 85% of the overall population with AF and is a substantial medical burden for Medicare beneficiaries (aged ≥65 years) in the United States.9,10The current evidence-based clinical guidelines recommend the use of oral anticoagulation in patients with NVAF who are at an intermediate to high risk for stroke.8,11 Although the efficacy of oral anticoagulation therapy to prevent stroke in patients with NVAF is well-established, it is also associated with a risk of bleeding.12–15 Understanding the relative economic burdens of stroke and major hemorrhage is important when considering the costs and benefits of anticoagulation therapy.Several studies have reported the incremental costs associated with stroke alone or with hemorrhage alone using different NVAF payer populations (ie, commercial or Medicare), and a few recent studies have provided incremental cost data for stroke and hemorrhage for the Medicare population, reporting significant incremental costs in the year after the stroke or hemorrhage index dates.7,16–20 Other studies have analyzed the incremental costs associated with stroke alone or with hemorrhage alone, or have analyzed these costs for a commercial population with NVAF.21–24 Most of these studies were done in separate patient populations and different time periods, making assessment of the relative economic burden of stroke versus bleeding difficult. By contrast, our study provides the cost estimates for these 2 conditions simultaneously based on the same patient population, which allows a more appropriate comparison of the economic implication of these 2 major consequences of oral anticoagulation therapy for the prevention of stroke among patients with NVAF.The prespecified objective in our study was to assess the relative economic burden (including Medicare Part D costs) associated with ischemic stroke and with major hemorrhagic events (ie, intracranial and gastrointestinal [GI] bleeding) among Medicare beneficiaries with newly diagnosed NVAF in the 12 months after the NVAF index diagnosis.