Index Volume 5 January- December 1970

Abstract

Dabigatran etexilate is the first oral anticoagulant to be approved in the United States in decades. It works directly by inhibiting clot-bound and free factor IIa (ie, thrombin) and indirectly by inhibiting platelet aggregation induced by thrombin. It is approved in the United States for stroke prophylaxis in nonvalvular atrial fibrillation. There is evidence to suggest that it is also effective for the treatment of acute venous thromboembolism and venous thromboembolism prophylaxis after knee and hip replacement surgery. Dabigatran etexilate therapy does not require laboratory monitoring, an advantage over warfarin. Unlike the earlier direct thrombin inhibitor, ximelagatran, it has demonstrated no potential for serious hepatotoxicity. It is also subject to a much lower degree of interpatient variability in dose response, has no diet–drug interactions, and has fewer clinically significant drug–drug interactions compared with warfarin. Dabigatran etexilate appears to be a valuable addition to our anticoagulant armamentarium.     

The Cheno Cooperative Study: Its Meaning for Gallstone Treatment

Abstract

Novel oral anticoagulants (OACs), including dabigatran etexilate, rivaroxaban, and apixaban, are available alternative anticoagulant therapy to vitamin K antagonists. The US Food and Drug Administration (FDA) has approved dabigatran, rivaroxaban, and apixaban for the treatment of appropriate patients for specific clinical indications. Therapeutic advantages of prescribing the new OACs are related to their predictable pharmacokinetic and pharmacodynamic properties. Dabigatran, rivaroxaban, and apixaban have all been shown to be noninferior to warfarin treatment for stroke prevention in respective phase 3 clinical trials; dabigatran and apixaban were shown to be superior to warfarin as preventive therapy. Dabigatran, rivaroxaban, and apixaban are all approved agents for stroke prevention in patients with nonvalvular atrial fibrillation in the United States and Europe. Among these agents, rivaroxaban is the only FDA-approved drug for the treatment of venous thromboembolism. This article reviews the major clinical trials that investigated the efficacy and safety of the new OACs and the use of these agents in special clinical situations.     

Dabigatran etexilate: a possible replacement for heparinoids and vitamin K antagonists?

Dabigatran etexilate is the first oral anticoagulant to be approved in the United States in decades. It works directly by inhibiting clot-bound and free factor IIa (ie, thrombin) and indirectly by inhibiting platelet aggregation induced by thrombin. It is approved in the United States for stroke prophylaxis in nonvalvular atrial fibrillation. There is evidence to suggest that it is also effective for the treatment of acute venous thromboembolism and venous thromboembolism prophylaxis after knee and hip replacement surgery. Dabigatran etexilate therapy does not require laboratory monitoring, an advantage over warfarin. Unlike the earlier direct thrombin inhibitor, ximelagatran, it has demonstrated no potential for serious hepatotoxicity. It is also subject to a much lower degree of interpatient variability in dose response, has no diet-drug interactions, and has fewer clinically significant drug-drug interactions compared with warfarin. Dabigatran etexilate appears to be a valuable addition to our anticoagulant armamentarium.     

Heparin and warfarin: use of anticoagulants in the prevention and treatment of venous thrombosis and pulmonary embolism.

The physician frequently encounters the problems of deep vein thrombosis and pulmonary embolism. Recently, a number of studies have been published which are of considerable help in the management of these disorders. It has been shown that in many cases, low-dose heparin is effective in the prevention of both venous thrombosis and pulmonary embolism. However, once venous thrombosis has already occurred, it is necessary to use full-dose heparin, preferably by the continuous intravenous route, with maintenance of the partial thromboplastin time (PTT) at 1 1/2 times the control at all times. Although monitoring the PTT may not prevent hemorrhage, it will help prevent further thrombosis. Heparin is generally continued for seven to ten days. During this time warfarin is generally begun, and it is important to continue the patient on warfarin for five to seven days while the patient is receiving intravenous heparin therapy. After stopping heparin, oral anticoagulation with warfarin should be continued for six weeks. Then, in the absence of a previous history of venous thromboembolism or a known predisposing condition, it is safe to abruptly discontinue anticoagulation in most patients.     

Ximelagatran: a new type of oral anticoagulant

OBJECTIVES: This assessment sought to evaluate the comparative benefit and adverse effect profile of ximelagatran, as well as the clinical issues surrounding its potential use. METHODS: We performed a Dialog OneSearch across BIOSIS Previews, EMBASE, MEDLINE, PASCAL, and ToxFile to identify published literature. PubMed and The Cochrane Library were also searched. Gray literature was identified by searching a variety of Web sites of health technology assessment and related agencies and their associated databases. The manufacturer's Canadian office, AstraZeneca, was invited to submit information. RESULTS: Ximelagatran is the first oral agent from a new class of anticoagulants called direct thrombin inhibitors. Other oral anticoagulants require routine blood monitoring; ximelagatran does not. Ximelagatran has been evaluated in the areas of venous thromboembolism management, particularly after orthopedic surgery, and stroke prevention in patients with atrial fibrillation. Overall, ximelagatran's efficacy appears comparable to other anticoagulants in these clinical settings. Also, bleeding rates were generally similar between ximelagatran and comparators but, as for warfarin, bleeding risk increases with higher ximelagatran doses. In addition, there is no specific antidote to help manage ximelagatran-induced bleeding. Finally, significantly more patients exposed to long-term ximelagatran developed elevated liver enzymes more than three times the upper normal limit, compared with patients on comparator anticoagulants. CONCLUSIONS: Given its apparent simplicity of use, ximelagatran carries the potential to replace, at least in part, anticoagulants currently used in the management of venous thromboembolism or for preventing stroke in atrial fibrillation patients. However, the safety of ximelagatran will not be fully known without further evaluation and surveillance for potential liver toxicity. There is also a need to evaluate its use in special populations such as patients with renal failure and patients using several concurrent medications.     

Prothrombin time ratio and other factors associated with bleeding in patients treated with warfarin

We previously showed that the risk of major hemorrhage in patients with venous thromboembolism treated with warfarin was strongly related to duration of anticoagulant therapy. We here report the results of a more detailed analysis of factors other than duration of warfarin therapy associated with the risk of hemorrhage in these patients. Almost 7% of patients had a major hemorrhage on warfarin and an additional 23.7% had at least one minor bleeding episode. Age, female sex, and congestive heart failure were associated with small increases in the risk of major hemorrhage but not with the risk of minor bleeding. A prothrombin time ratio greater than 2.5 was associated with a fourteen-fold increase in the risk of a major hemorrhage (95% CI 5.1, 42.7), but major hemorrhages occurred in patients on warfarin at all measured values of the prothrombin time ratio. Taken together with the findings from our previous analysis, the study suggests that prevention of bleeding in patients on warfarin would best be accomplished by minimizing the duration of warfarin therapy, by scrupulous monitoring of the prothrombin time ratio, and by considering the "therapeutic range" for the prothrombin time ratio to be somewhat less than 2.0-2.5.     

Ximelagatran, an oral thrombin inhibitor without the need for regular monitoring of the anticoagulant status

In two recent clinical trials, the effectiveness of ximelagatran, an oral thrombin inhibitor, was demonstrated as anticoagulant therapy for patients with atrial fibrillation and as secondary prophylaxis for patients following a myocardial infarction, respectively. This may be of relevance for the often life-long treatment of patients with anticoagulants, as with ximelagatran frequent monitoring of the anticoagulant status is not necessary, in contrast to treatment with warfarin-like drugs.     

D-003 and warfarin interaction on the bleeding time and venous thrombosis experimentally induced in rats

D-003 is a mixture of higher aliphatic primary acids isolated and purified from sugarcane wax, the main component of which is octacosanoic acid. D-003 exhibits a cholesterol-lowering effect as well as antiplatelet and antithrombotic effects in experimental models. Warfarin is a coumarin derivative with anticoagulant activity that acts as a vitamin K antagonist. Since in clinical practice warfarin and D-003 could be administered together, the objective of this study was to evaluate the effects of the simultaneous administration of both drugs on the bleeding time and the venous thrombosis experimentally induced in rats. The combined therapy of minimally effective doses of D-003 and warfarin produced an antithrombotic effect significantly higher than those produced by each monotherapy. Likewise, the prolongation of bleeding time induced by warfarin was increased by the simultaneous administration with D-003, showing a synergistic effect between both drugs.     

Diagnosis,prognosis and therapeutic management of acute pulmonary embolism

Pulmonary embolism (PE) is a leading cause of mortality worldwide. Recognizing PE and administering anticoagulants can significantly improve patient outcomes by reducing mortality rates and preventing recurrent events. For more than 50 years, standard therapy has involved parenteral anticoagulation followed by long-term therapy with the vitamin K antagonist warfarin. However, management of warfarin therapy is challenging due to its narrow therapeutic range and interactions with genetic and environmental factors. Direct oral anticoagulants (DOACs) have been developed to simplify anticoagulation and avoid the concerns associated with warfarin. DOACs are administered at a fixed dosage without routine monitoring and have few drug interactions. In recent years, DOACs have received FDA approval for the treatment of acute deep venous thrombosis (DVT) and PE based on the results of well-conducted clinical trials. This review discusses approaches to the diagnosis and treatment of PE and the use of DOACs as an alternative to warfarin treatment for the management of the disease. While many of the indications for DOACs and concepts discussed apply to both DVT and PE, our focus will be acute PE.     

New anticoagulants for the prevention and treatment of venous thromboembolism

Anticoagulant therapy is effective at preventing the development of venous thromboembolism in high-risk patients, and reduces morbidity and mortality in individuals with established thromboembolic disease. Vitamin K antagonists and heparins are currently the most commonly used anticoagulant drugs, but they have practical limitations. Therefore, new antithrombotic agents with predictable dose-responses (thereby decreasing the need for monitoring without compromising efficacy or safety), ideally available in an oral formulation and with a rapidly reversible anticoagulant effect, are needed. New drugs fulfilling some of the above criteria have been developed and have proven to be effective agents for the treatment and prevention of venous thromboembolism.     

达比加群酯治疗ACS心房颤动的研究进展

我国流行病学调查显示,35岁及以上人群心房颤动加权患病率为0.71％,随年龄增长患病率明显增高,房颤人群的脑卒中风险明显高于非房颤人群,房颤的疾病负担是一个重要的公共卫生问题,而抗凝治疗能够降低房颤患者的血栓栓塞风险.达比加群酯作为新型口服抗凝药目前在临床上得到了应用.其口服后经胃肠吸收,在体内转化为有抗凝活性的达比加...     

Non—Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation and Venous Thromboembolism: Where are we Now?

Abstract

Four non-vitamin-K antagonist oral anticoagulants (NOACs) are now available and are variously approved for stroke prevention in atrial fibrillation and the management of venous thromboembolism. On the whole, these drugs offer clear benefits over warfarin, overcoming problems with unpredictable individual responses and avoiding the need for frequent and resource-intensive monitoring. Sufficient data are now available to recommend the use of particular NOACs in defined settings. As a group these drugs offer a real alternative to warfarin; their more widespread use for stroke prevention in atrial fibrillation, in the management of venous thromboembolism, and perhaps in other settings promises to bring real clinical gains for at-risk populations worldwide. This review highlights the growing importance of effective anticoagulation therapy at a time when cardiovascular risk profiles are evolving, discusses the relative merits of the NOACs over warfarin, and describes the use of specific agents in specific patient populations.     

Differences in patient outcomes and chronic care management of oral anticoagulant therapy: an explorative study

Background  

The oral anticoagulant therapy - provided to prevent thrombosis - is known to be associated with substantial avoidable hospitalization. Improving the quality of the oral anticoagulant therapy could avoid drug related hospitalizations. Therefore, this study compared the patient outcomes between Dutch anticoagulant clinic (AC) regions taking the variation in chronic care management into account in order to explore whether chronic care management elements could improve the quality of oral anticoagulant therapy.     

重度子痫前期合并脑静脉血栓的相关性研究

目的：探讨重度子痫前期合并脑静脉血栓（CVT）形成的相关因素与疗效分析。方法：给予本院34例重度子痫前期合并CVT患者脱水、抗凝治疗,同时给予激素治疗23例,给予肝素或低分子素治疗28例,尿活素静脉窦内置管接触性溶栓20例,全部患者给予华法林口服,进行抗凝血治疗。结果：本组治疗后的总有效31例（91.18%）,3例无效均为视力未恢复正常。发病相关因素有子痫前期毛细血管受损而组织液外溢13例（38.24%）、产后长时间卧床10例（29.41%）、产后大量出汗7例（20.59%）、发病前未进行防治血栓措施4例（11.76%）。4个月后复查,2例患者部分再通,其余均完全康复。结论：早期给予重度子痫前期并CVT患者抗凝、溶栓治疗,可得到很好的预后。     

Current concepts of the antiplatelet and anticoagulant treatment in the prevention of stroke

About 80% of strokes have ischemic origin. Therapeutical options of acute stroke are still limited and the occurrence of recurrent strokes is remarkably high. Consequently, the adequate stroke prevention has a high importance. The two main components of prevention are the inhibition of platelet aggregation and the anticoagulant therapy. Results of multicenter drug trials showed that antiaggregation therapy can reduce the risk of recurrent stroke by ca. 25%. Acetylsalicylate has been used for stroke prevention for decades. Nowadays, there is a broad spectrum of available platelet aggregation inhibitors. The efficacy of these new drugs is higher than that of acetylsalicylate. According to recent therapeutical guidelines, the antiaggregation therapy of patients with non-cardiometabolic stroke should be optimized individually. The most frequent cause of cardiogenic stroke is atrial fibrillation. The importance of anticoagulation therapy has been proved by large multicenter studies. Absolute therapeutical indications are the elder age, additional risk factors, previous stroke. Therapeutical guidelines in other cardiological disorders associated with high risks for stroke need further drug trials. Fifty years after the introduction of warfarin, in the last years new direct thrombin inhibitors have been developed. These drugs have the same efficacy as warfarin but they are a more safety and have more simply therapeutical administration.     

When deep venous thrombosis fails to respond to therapy

BACKGROUND: Deep venous thrombosis in primary care is usually treated with rest, analgesics, intravenous or low-molecular-weight heparin, and coumadin. In some cases, however, a less familiar course of diagnosis and management is required. METHODS: We describe the case of a 53-year-old truck driver who had an acute deep venous thrombosis of his right lower extremity, which failed to respond to routine therapy with heparin and warfarin. A literature search was undertaken to research the differential diagnosis and management of deep venous thrombosis and to review specifically the role of venal caval filters and inherited thrombotic disorders and occult cancer in this context. RESULTS AND CONCLUSION: The ultimate diagnosis in our patient appeared to be signet ring cell cancer of the colon that had metastasized to the right thigh. This case is an example of the inherent limitations of even an aggressive diagnostic and therapeutic approach to the entity of refractory deep venous thrombosis.     

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。     

Recent pharmacological advances for treating venous thromboembolism: are we witnessing the demise of warfarin?

Vitamin K antagonists, such as warfarin, have been the mainstay in treatment and prophylaxis of venous thromboembolism. However, warfarin has many disadvantages including a narrow therapeutic window, numerous potential drug interactions, modulation of effect by alcohol and foods containing vitamin K and genetic variation in metabolism of warfarin, all of which contribute to the unpredictability of therapy. This has provided the impetus for developing new oral anticoagulants with a rapid onset of action, wide therapeutic window, predictable and reversible action, with few drug or dietary interactions, no requirement for routine coagulation monitoring or dose adjustment and acceptable cost. No single agent incorporates all these characteristics, but new factor Xa and direct thrombin inhibitors are being introduced into clinical practice that fulfil some of these aims. Here, we briefly discuss the current practice with its limitations and pitfalls, and then review important trials that have launched new oral anticoagulants into clinical practice.     

血栓弹力图在预防肺癌患者PICC相关性静脉血栓中的应用

目的 探讨血栓弹力图在预防肺癌患者经外周静脉置入中心静脉导管（peripherally inserted centralcatheters,PICC）相关性静脉血栓中的作用。方法 将264例肺癌患者按随机数字表法分为干预组和对照组各132例。干预组患者分别于PICC置管前1 d、置管后4周内每周检测1次血栓弹力图（thromboelastography,TEG）,血液高凝者行抗凝治疗。对照组患者按常规PICC置管,并于置管前1 d、静脉血栓形成后行TEG检测。2组患者均于PICC置管后4周内每周行血管超声检测1次,比较2组PICC相关性静脉血栓发生率、观察血液高凝状态者抗凝治疗前后TEG参数变化及静脉血栓者血栓形成前后TEG参数变化。结果 67例置管后血液高凝状态者行抗凝治疗后,TEG各参数与治疗前比较,均P＜0.05,差异有统计学意义;干预组PICC相关性静脉血栓发生率为0.76%、对照组为19.70%,2组相关性静脉血栓比较,χ2 = 25.791,P＜0.01,差异有统计学意义。26例静脉血栓形成者TEG参数与PICC置管前比较,均P＜0.05,差异有统计学意义。结论 采用TEG预测肺癌PICC患者静脉血栓,并建立个体化的抗凝治疗,可有效预防PICC相关性静脉血栓的形成,保证PICC临床应用安全。