Sam Schulman

Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism

BACKGROUND The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an alternative therapy to warfarin for patients who have acute venous thromboembolism. METHODS In a randomized, double-blind, noninferiority trial involving patients with acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days (interquartile range, 8 to 11), we compared oral dabigatran, administered at a dose of 150 mg twice daily, with warfarin that was dose-adjusted to achieve an international normalized ratio of 2.0 to 3.0. The primary outcome was the 6-month incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths. Safety end points included bleeding events, acute coronary syndromes, other adverse events, and results of liver-function tests. RESULTS A total of 30 of the 1274 patients randomly assigned to receive dabigatran (2.4%), as compared with 27 of the 1265 patients randomly assigned to warfarin (2.1%), had recurrent venous thromboembolism; the difference in risk was 0.4 percentage points (95% confidence interval [CI], -0.8 to 1.5; P<0.001 for the prespecified noninferiority margin). The hazard ratio with dabigatran was 1.10 (95% CI, 0.65 to 1.84). Major bleeding episodes occurred in 20 patients assigned to dabigatran (1.6%) and in 24 patients assigned to warfarin (1.9%) (hazard ratio with dabigatran, 0.82; 95% CI, 0.45 to 1.48), and episodes of any bleeding were observed in 205 patients assigned to dabigatran (16.1%) and 277 patients assigned to warfarin (21.9%; hazard ratio with dabigatran, 0.71; 95% CI, 0.59 to 0.85). The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar in the two groups. Adverse events leading to discontinuation of the study drug occurred in 9.0% of patients assigned to dabigatran and in 6.8% of patients assigned to warfarin (P=0.05). CONCLUSIONS For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring. (ClinicalTrials.gov number, NCT00291330.)

Prevention of VTE in Nonsurgical Patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND VTE is a serious, but decreasing complication following major orthopedic surgery. This guideline focuses on optimal prophylaxis to reduce postoperative pulmonary embolism and DVT. METHODS The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS In patients undergoing major orthopedic surgery, we recommend the use of one of the following rather than no antithrombotic prophylaxis: low-molecular-weight heparin; fondaparinux; dabigatran, apixaban, rivaroxaban (total hip arthroplasty or total knee arthroplasty but not hip fracture surgery); low-dose unfractionated heparin; adjusted-dose vitamin K antagonist; aspirin (all Grade 1B); or an intermittent pneumatic compression device (IPCD) (Grade 1C) for a minimum of 10 to 14 days. We suggest the use of low-molecular-weight heparin in preference to the other agents we have recommended as alternatives (Grade 2C/2B), and in patients receiving pharmacologic prophylaxis, we suggest adding an IPCD during the hospital stay (Grade 2C). We suggest extending thromboprophylaxis for up to 35 days (Grade 2B). In patients at increased bleeding risk, we suggest an IPCD or no prophylaxis (Grade 2C). In patients who decline injections, we recommend using apixaban or dabigatran (all Grade 1B). We suggest against using inferior vena cava filter placement for primary prevention in patients with contraindications to both pharmacologic and mechanical thromboprophylaxis (Grade 2C). We recommend against Doppler (or duplex) ultrasonography screening before hospital discharge (Grade 1B). For patients with isolated lower-extremity injuries requiring leg immobilization, we suggest no thromboprophylaxis (Grade 2B). For patients undergoing knee arthroscopy without a history of VTE, we suggest no thromboprophylaxis (Grade 2B). CONCLUSIONS Optimal strategies for thromboprophylaxis after major orthopedic surgery include pharmacologic and mechanical approaches.

Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients

Summary.  The definition of major bleeding varies between studies on surgical patients, particularly regarding the criteria for surgical wound‐related bleeding. This diversity contributes to the difficulties in comparing data between trials. The Scientific and Standardization Committee (SSC), through its subcommittee on Control of Anticoagulation, of the International Society on Thrombosis and Haemostasis has previously published a recommendation for a harmonized definition of major bleeding in non‐surgical studies. That definition has been adopted by the European Medicines Agency and is currently used in several non‐surgical trials. A preliminary proposal for a parallel definition for surgical studies was presented at the 54th Annual Meeting of the SSC in Vienna, July 2008. Based on those discussions and further consultations with European and North American surgeons with experience from clinical trials a definition has been developed that should be applicable to all agents that interfere with hemostasis. The definition and the text that follows have been reviewed and approved by relevant co‐chairs of the subcommittee and by the Executive Committee of the SSC. The intention is to seek approval of this definition from the regulatory authorities to enhance its incorporation into future clinical trial protocols.

A Comparison of Six Weeks with Six Months of Oral Anticoagulant Therapy after a First Episode of Venous Thromboembolism

Background The optimal duration of oral anticoagulant therapy after a first episode of venous thromboembolism is still a matter of debate. Methods We performed a multicenter trial comparing six weeks of oral anticoagulant treatment with six months of such therapy in patients who had a first episode of venous thromboembolism. Anticoagulant therapy consisted of warfarin or dicumarol. Of the 902 patients enrolled, 5 were later excluded because they had congenital protein C deficiency; 443 were randomly assigned to receive six weeks of oral anticoagulant therapy with a targeted international normalized ratio (INR) of 2.0 to 2.85, and 454 were randomly assigned to receive six months of such therapy. The initial diagnoses were confirmed by means of venography in cases of deep-vein thromboses (n = 790) and with perfusion–ventilation scanning or angiography in cases of pulmonary embolism (n = 107); recurrences were confirmed in the same way. Results After two years of follow-up, there had been 123 recurrences of ...

Antithrombotic Therapy for Atrial Fibrillation Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND The risk of stroke varies considerably across different groups of patients with atrial fibrillation (AF). Antithrombotic prophylaxis for stroke is associated with an increased risk of bleeding. We provide recommendations for antithrombotic treatment based on net clinical benefit for patients with AF at varying levels of stroke risk and in a number of common clinical scenarios. METHODS We used the methods described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines article of this supplement. RESULTS For patients with nonrheumatic AF, including those with paroxysmal AF, who are (1) at low risk of stroke (eg, CHADS(2) [congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischemic attack] score of 0), we suggest no therapy rather than antithrombotic therapy, and for patients choosing antithrombotic therapy, we suggest aspirin rather than oral anticoagulation or combination therapy with aspirin and clopidogrel; (2) at intermediate risk of stroke (eg, CHADS(2) score of 1), we recommend oral anticoagulation rather than no therapy, and we suggest oral anticoagulation rather than aspirin or combination therapy with aspirin and clopidogrel; and (3) at high risk of stroke (eg, CHADS(2) score of ≥ 2), we recommend oral anticoagulation rather than no therapy, aspirin, or combination therapy with aspirin and clopidogrel. Where we recommend or suggest in favor of oral anticoagulation, we suggest dabigatran 150 mg bid rather than adjusted-dose vitamin K antagonist therapy. CONCLUSIONS Oral anticoagulation is the optimal choice of antithrombotic therapy for patients with AF at high risk of stroke (CHADS(2) score of ≥ 2). At lower levels of stroke risk, antithrombotic treatment decisions will require a more individualized approach.

Extended Use of Da bi gat ran, Warfarin, or Placebo in Venous Thromboembolism

BACKGROUND Dabigatran, which is administered in a fixed dose and does not require laboratory monitoring, may be suitable for extended treatment of venous thromboembolism. METHODS In two double-blind, randomized trials, we compared dabigatran at a dose of 150 mg twice daily with warfarin (active-control study) or with placebo (placebo-control study) in patients with venous thromboembolism who had completed at least 3 initial months of therapy. RESULTS In the active-control study, recurrent venous thromboembolism occurred in 26 of 1430 patients in the dabigatran group (1.8%) and 18 of 1426 patients in the warfarin group (1.3%) (hazard ratio with dabigatran, 1.44; 95% confidence interval [CI], 0.78 to 2.64; P=0.01 for noninferiority). Major bleeding occurred in 13 patients in the dabigatran group (0.9%) and 25 patients in the warfarin group (1.8%) (hazard ratio, 0.52; 95% CI, 0.27 to 1.02). Major or clinically relevant bleeding was less frequent with dabigatran (hazard ratio, 0.54; 95% CI, 0.41 to 0.71). Acute coronary syndromes occurred in 13 patients in the dabigatran group (0.9%) and 3 patients in the warfarin group (0.2%) (P=0.02). In the placebo-control study, recurrent venous thromboembolism occurred in 3 of 681 patients in the dabigatran group (0.4%) and 37 of 662 patients in the placebo group (5.6%) (hazard ratio, 0.08; 95% CI, 0.02 to 0.25; P<0.001). Major bleeding occurred in 2 patients in the dabigatran group (0.3%) and 0 patients in the placebo group. Major or clinically relevant bleeding occurred in 36 patients in the dabigatran group (5.3%) and 12 patients in the placebo group (1.8%) (hazard ratio, 2.92; 95% CI, 1.52 to 5.60). Acute coronary syndromes occurred in 1 patient each in the dabigatran and placebo groups. CONCLUSIONS Dabigatran was effective in the extended treatment of venous thromboembolism and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo. (Funded by Boehringer Ingelheim; RE-MEDY and RE-SONATE ClinicalTrials.gov numbers, NCT00329238 and NCT00558259, respectively.).

Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

This article about hemorrhagic complications of anticoagulant and thrombolytic treatment is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Bleeding is the major complication of anticoagulant and fibrinolytic therapy. The criteria for defining the severity of bleeding vary considerably between studies, accounting in part for the variation in the rates of bleeding reported. The major determinants of vitamin K antagonist (VKA)-induced bleeding are the intensity of the anticoagulant effect, underlying patient characteristics, and the length of therapy. There is good evidence that VKA therapy, targeted international normalized ratio (INR) of 2.5 (range, 2.0-3.0), is associated with a lower risk of bleeding than therapy targeted at an INR > 3.0. The risk of bleeding associated with IV unfractionated heparin (UFH) in patients with acute venous thromboembolism is < 3% in recent trials. This bleeding risk may increase with increasing heparin dosages and age (> 70 years). Low-molecular-weight heparin (LMWH) is associated with less major bleeding compared with UFH in acute venous thromboembolism. Higher doses of UFH and LMWH are associated with important increases in major bleeding in ischemic stroke. In ST-segment elevation myocardial infarction, addition of LMWH, hirudin, or its derivatives to thrombolytic therapy is associated with a small increase in the risk of major bleeding, whereas treatment with fondaparinux or UFH is associated with a lower risk of bleeding. Thrombolytic therapy increases the risk of major bleeding 1.5-fold to threefold in patients with acute venous thromboembolism, ischemic stroke, or ST-elevation myocardial infarction.

The duration of oral anticoagulant therapy after a second episode of venous thromboembolism

BACKGROUND A consensus has not been reached about the optimal duration of oral anticoagulant therapy after a second episode of venous thromboembolism. METHODS In a multicenter trial, we compared six months of oral anticoagulant therapy with anticoagulant therapy continued indefinitely in patients who had had a second episode of venous thromboembolism. Of 227 patients enrolled, 111 were randomly assigned to six months of anticoagulation and 116 were assigned to receive anticoagulant therapy indefinitely; for both groups, the target international normalized ratio was 2.0 to 2.85. The initial episodes of deep-vein thrombosis (n = 193) and pulmonary embolism (n = 34), as well as recurrent episodes, were all objectively confirmed. RESULTS After four years of follow-up, there were 26 recurrences of venous thromboembolism that fulfilled the diagnostic criteria, 23 in the group assigned to six months of therapy (20.7 percent) and 3 in the group assigned to continuing therapy (2.6 percent). The relative risk of recurrence in the group assigned to six months of therapy, as compared with the group assigned to therapy of indefinite duration, was 8.0 (95 percent confidence interval, 2.5 to 25.9). There were 13 major hemorrhages, 3 in the six-month group, (2.7 percent) and 10 in the infinite-treatment group (8.6 percent). The relative risk of major hemorrhage in the six-month group, as compared with the infinite-treatment group was 0.3 (95 percent confidence interval, 0.1 to 1.1). There was no difference in mortality between the two groups. CONCLUSIONS Prophylactic oral anticoagulation that was continued for an indefinite period after a second episode of venous thromboembolism was associated with a much lower rate of recurrence during four years of follow-up than treatment for six months. However, there was a trend toward a higher risk of major hemorrhage when anticoagulation was continued indefinitely.

Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction that can lead to devastating thromboembolic complications, including pulmonary embolism, ischemic limb necrosis necessitating limb amputation, acute myocardial infarction, and stroke. METHODS The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS Among the key recommendations for this article are the following: For patients receiving heparin in whom clinicians consider the risk of HIT to be > 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) (Grade 2C). For patients receiving heparin in whom clinicians consider the risk of HIT to be < 1%, we suggest that platelet counts not be monitored (Grade 2C). In patients with HIT with thrombosis (HITT) or isolated HIT who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagulants (Grade 2C). In patients with HITT and renal insufficiency, we suggest the use of argatroban over other nonheparin anticoagulants (Grade 2C). In patients with acute HIT or subacute HIT who require urgent cardiac surgery, we suggest the use of bivalirudin over other nonheparin anticoagulants or heparin plus antiplatelet agents (Grade 2C). CONCLUSIONS Further studies evaluating the role of fondaparinux and the new oral anticoagulants in the treatment of HIT are needed.

Evidence-Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to guide best practices. METHODS The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also address anticoagulation management services and intensive patient education. CONCLUSIONS We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have not been adequately studied.