Daniel J. Quinlan

Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials.

Background—Randomized trials and meta-analyses have reached conflicting conclusions about the role of thrombolytic therapy for the treatment of acute pulmonary embolism. Methods and Results—We performed a meta-analysis of all randomized trials comparing thrombolytic therapy with heparin in patients with acute pulmonary embolism. Eleven trials, involving 748 patients, were included. Compared with heparin, thrombolytic therapy was associated with a nonsignificant reduction in recurrent pulmonary embolism or death (6.7% versus 9.6%; OR 0.67, 95% CI 0.40 to 1.12, P for heterogeneity=0.48), a nonsignificant increase in major bleeding (9.1% versus 6.1%; OR 1.42, 95% CI 0.81 to 2.46), and a significant increase in nonmajor bleeding (22.7% versus 10.0%; OR 2.63, 95% CI 1.53 to 4.54; number needed to harm=8). Thrombolytic therapy compared with heparin was associated with a significant reduction in recurrent pulmonary embolism or death in trials that also enrolled patients with major (hemodynamically unstable) pulmonary embolism (9.4% versus 19.0%; OR 0.45, 95% CI 0.22 to 0.92; number needed to treat=10) but not in trials that excluded these patients (5.3% versus 4.8%; OR 1.07, 95% CI 0.50 to 2.30), with significant heterogeneity between these 2 groups of trials (P=0.10). Conclusions—Currently available data provide no evidence for a benefit of thrombolytic therapy compared with heparin for the initial treatment of unselected patients with acute pulmonary embolism. A benefit is suggested in those at highest risk of recurrence or death. The number of patients enrolled in randomized trials to date is modest, and further evaluation of the efficacy and safety of thrombolytic therapy for the treatment of high-risk patients with acute pulmonary embolism appears warranted.

Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials

BACKGROUND The optimum duration of prophylaxis against venous thromboembolism after total hip or knee replacement is uncertain. Our primary objective was to establish the efficacy of extended-duration prophylaxis on symptomatic venous thromboembolic events. METHODS We identified randomised trials comparing extended-duration prophylaxis using heparin or warfarin with placebo or untreated control in patients undergoing elective total hip or knee replacement by searching electronic databases (MEDLINE, EMBASE), references from retrieved articles, and abstracts from conference proceedings, and by contact with pharmaceutical companies and investigators. Two reviewers independently extracted data on study design, symptomatic and symptomless venographic venous thromboembolism, death, and bleeding outcomes. Results from individual trials were combined with the Mantel-Haenszel method. FINDINGS Nine studies met our inclusion criteria (3999 patients), eight with low molecular weight heparin, and one with unfractionated heparin. Extended-duration prophylaxis for 30-42 days significantly reduced the frequency of symptomatic venous thromboembolism (1.3% vs 3.3%, OR 0.38; 95% CI 0.24-0.61, numbers needed to treat [NNT]=50), with no statistical evidence of heterogeneity (x(2) test, p=0.69). There was a greater risk reduction in patients undergoing hip replacement (1.4% vs 4.3%, 0.33; 0.19-0.56, 34) compared with knee replacement (1.0% vs 1.4%, 0.74; 0.26-2.15, 250). A significant reduction in symptomless venographic deep vein thrombosis was also observed (9.6% vs 19.6%, 0.48; 0.36-0.63, 10). There was no increase in major bleeding but extended-duration prophylaxis was associated with excess minor bleeding (3.7% vs 2.5%, 1.56; 1.08-2.26, numbers needed to harm [NNH]=83). INTERPRETATION Among patients undergoing total hip or knee replacement, extended-duration prophylaxis significantly reduces the frequency of symptomatic venous thromboembolism. The reduction in risk is equivalent to about 20 symptomatic events per 1000 patients treated.

Comparative Pharmacodynamics and Pharmacokinetics of Oral Direct Thrombin and Factor Xa Inhibitors in Development

For the past five decades, there has been little progress in the development of oral anticoagulants, with the choices being limited to the vitamin K antagonists (VKAs). The situation is changing with the development of orally active small molecules that directly target thrombin or activated factor X (FXa). The two agents in the most advanced stages of development are dabigatran etexilate and rivaroxaban, which inhibit thrombin and FXa, respectively. Both are approved in the EU and Canada for venous thromboprophylaxis in patients undergoing elective hip- or knee-replacement surgery. Other agents in the early stages of development include several FXa inhibitors (apixaban, DU 176b, LY 517717, YM 150, betrixaban, eribaxaban [PD 0348292] and TAK 442) and one thrombin inhibitor (AZD 0837). With a predictable anticoagulant response and low potential for drug-drug interactions, these new agents can be given in fixed doses without coagulation monitoring. This renders them more convenient than VKAs. While the anticoagulant effect of the new thrombin and FXa inhibitors is similar, differences in the pharmacokinetic and pharmacodynamic parameters may influence their use in clinical practice. Here, we compare the pharmacokinetic and pharmacodynamic features of these new oral agents.

Novel Oral Factor Xa and Thrombin Inhibitors in the Management of Thromboembolism

The last decade has seen the evaluation of several new oral anticoagulants that directly target thrombin or activated factor X (FXa). All demonstrate a rapid onset of action, a low potential for food and drug interactions, and a predictable anticoagulant effect that obviates the need for routine coagulation monitoring. Those agents at the most advanced stages of clinical development are a direct thrombin inhibitor, dabigatran, and direct FXa inhibitors, rivaroxaban and apixaban. Dabigatran and rivaroxaban are approved in more than 70 countries for prevention of venous thromboembolism in patients undergoing elective hip or knee arthroplasty, and apixaban is being considered for approval by regulatory agencies for this indication. Dabigatran was shown in a large phase III trial to be more effective and safer than warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation and has recently been approved for this indication. Edoxaban, an oral FXa inhibitor, is also being evaluated in phase III clinical trials. This review summarizes the pharmacology, clinical trial results, and future role of the new oral anticoagulants in clinical practice.

Unfractionated and low-molecular-weight heparin as adjuncts to thrombolysis in aspirin-treated patients with ST-elevation acute myocardial infarction: a meta-analysis of the randomized trials.

Background— There is uncertainty about the role of intravenous unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) in patients with ST-elevation myocardial infarction (STEMI) treated with aspirin and thrombolysis. Methods and Results— We performed a meta-analysis of the randomized trials to assess the effect of UFH and LMWH on reinfarction, death, stroke, and bleeding. Fourteen trials involving a total of 25 280 patients were included (1239 comparing intravenous UFH versus placebo or no heparin; 16 943 comparing LMWH versus placebo; and 7098 comparing LMWH versus intravenous UFH). Intravenous UFH during hospitalization did not reduce reinfarction (3.5% versus 3.3%; odds ratio [OR], 1.08; 95% CI, 0.58 to 1.99) or death (4.8% versus 4.6%; OR, 1.04; 95% CI, 0.62 to 1.78) and did not increase major bleeding (4.2% versus 3.4%; OR, 1.21; 95% CI, 0.67 to 2.18) but increased minor bleeding (19.6% versus 12.5%; OR, 1.72; 95% CI, 1.22 to 2.43). During hospitalization/at 7 days, LMWH compared with placebo reduced the risk of reinfarction by approximately one quarter (1.6% versus 2.2%; OR, 0.72; 95% CI, 0.58 to 0.90; number needed to treat [NNT]=167) and death by ≈10% (7.8% versus 8.7%; OR, 0.90; 95% CI, 0.80 to 0.99; NNT=111) but increased major bleeding (1.1% versus 0.4%; OR, 2.70; 95% CI, 1.83 to 3.99; number needed to harm [NNH]=143) and intracranial bleeding (0.3% versus 0.1%; OR, 2.18; 95% CI, 1.07 to 4.52; NNH=500). The reduction in death with LMWH remained evident at 30 days. LMWH compared with UFH during hospitalization/at 7 days reduced reinfarction by ≈45% (3.0% versus 5.2%; OR, 0.57; 95% CI, 0.45 to 0.73; NNT=45), did not reduce death (4.8% versus 5.3%; OR, 0.92; 95% CI, 0.74 to 1.13) or increase major bleeding (3.3% versus 2.5%; OR, 1.30; 95% CI, 0.98 to 1.72), but increased minor bleeding (22.8% vs 19.4%; OR, 1.26; 95% CI, 1.12 to 1.43). The reduction in reinfarction remained evident at 30 days. Conclusions— In aspirin-treated patients with STEMI who are treated with thrombolysis, intravenous UFH has not been shown to prevent reinfarction or death. LMWH given for 4 to 8 days compared with placebo reduces reinfarction by approximately one quarter and death by ≈10% and when directly compared with UFH reduces reinfarction by almost one half. These data suggest that LMWH should be the preferred antithrombin in this setting.

Periprocedural Management and Approach to Bleeding in Patients Taking Dabigatran

Case Presentation: A 78-year–old man with atrial fibrillation, hypertension, and a history of ischemic stroke 2 years earlier presents to the emergency department with hematemesis and melena. He is taking dabigatran (150 mg twice daily) for stroke prevention, and his last dose was taken 12 hours earlier. His hemoglobin is 5.9 g/dL, platelet count is 185×109/L, and calculated creatinine clearance is 26 mL/min. The activated partial thromboplastin time (aPTT) is 83 s and the thrombin time (TT) is >150 s. How would you manage this patient? The Randomized Evaluation of Long-Term Anticoagulant Therapy trial conducted in 18 113 patients with atrial fibrillation demonstrated that, compared with warfarin, dabigatran at a dose of 150 mg twice daily reduced the risk of stroke or systemic embolism by one third and was associated with a similar rate of major bleeding; at a dose of 110 mg twice daily, the risk of stroke or systemic embolism with dabigatran was similar to that with warfarin, but dabigatran reduced the risk of major bleeding by one fifth.1 Both doses of dabigatran reduced the risk of intracranial bleeding by two thirds compared with warfarin. The risk of stroke was consistently reduced in all of the patient subgroups, but in those over the age of 75 years, the higher dose of dabigatran was associated with an increased risk of extracranial bleeding.2 Prescribing guidelines for dabigatran vary by country and should be reviewed before starting the drug. The majority of atrial fibrillation patients with ≥1 additional risk factor for stroke are eligible for dabigatran. Absolute contraindications are uncommon, but include impaired renal function with a calculated creatinine clearance <15 mL/min in the United States or <30 mL/min in the rest of the world. Dabigatran has not been evaluated in patients with valvular atrial fibrillation or …

Association between asymptomatic deep vein thrombosis detected by venography and symptomatic venous thromboembolism in patients undergoing elective hip or knee surgery.

Summary.  Background: Venography is commonly used to compare the efficacy of different thromboprophylaxis strategies for preventing deep vein thrombosis (DVT) in patients undergoing total hip replacement (THR) or total knee replacement (TKR). Methods: We explored the relation between asymptomatic DVT and symptomatic venous thromboembolism (VTE) in patients undergoing THR or TKR treated with standard doses of enoxaparin (30 mg b.i.d. or 40 mg o.d.) by comparing the incidence of asymptomatic DVT in venographic studies with the incidence of symptomatic VTE in studies where venography was not performed. Results: In 10 venographic studies involving 5796 patients, the incidence of asymptomatic DVT after THR was 13.2% [95% CI, 12.2–14.2%] and after TKR was 38.1% (95% CI, 35.5–40.8%). In two studies involving 3500 patients who did not undergo venography, the 90‐day incidence of symptomatic VTE after THR was 2.7% (95% CI, 2.1–3.4%) and after TKR was 1.8% (95% CI, 0.9–2.7%). For every symptomatic VTE in THR studies where venography was not performed there were five asymptomatic DVTs in the venographic studies; for TKR, the ratio was 1:21. The incidence of asymptomatic DVT and the symptomatic VTE/asymptomatic DVT ratio was influenced by the venogram reading committee (Gothenburg vs. Hamilton: total DVT after THR, 19.5% vs. 8.7%, P < 0.0001; for TKR, 42.7% vs. 27.2%, P < 0.0001). Conclusions: Comparisons across trials show a consistent relation between asymptomatic venographic DVT in patients undergoing elective THR or TKR surgery and symptomatic VTE in patients not undergoing venography. Differences exist in the strength of the relation depending on the type of surgery and the venogram reading committee.

Idarucizumab The Antidote for Reversal of Dabigatran

Four non–vitamin K antagonist oral anticoagulants (NOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, are currently licensed as alternatives to heparins and vitamin K antagonists for the prevention and treatment of venous thromboembolism and for the prevention of stroke in patients with nonvalvular atrial fibrillation. Dabigatran is the only NOAC that inhibits thrombin; the others inhibit factor Xa. All of the NOACs are at least as effective as vitamin K antagonists for the prevention of stroke in patients with atrial fibrillation and for the treatment of venous thromboembolism, and they are associated with less life-threatening bleeding, in particular less intracranial hemorrhage.1,2 Nonetheless, serious bleeding can occur with NOACs. In addition, patients taking NOACs may sustain trauma and may require urgent surgery or interventions. Consequently, the availability of specific reversal agents for NOACs could improve patient management during these emergency situations. Idarucizumab is a humanized monoclonal antibody fragment that has been developed as a specific reversal agent for dabigatran. In vitro and ex vivo studies have demonstrated that idarucizumab promptly restores dabigatran-prolonged coagulation parameters to baseline values,3–5 and studies in healthy volunteers and patients with life-threatening bleeding or requiring emergency surgery or invasive procedures show that it completely reverses the anticoagulant effects of dabigatran within minutes in the majority of patients. Idarucizumab was recently licensed in the United States and Europe. This article summarizes the pharmacology and clinical data on the use of idarucizumab to reverse dabigatran. The first step in the development of idarucizumab was to immunize mice with dabigatran-derived haptens coupled to carrier proteins to produce antibodies against dabigatran.3 Monoclonal antibodies exhibiting the highest affinity for dabigatran were selected, and the antigen-binding fragment (Fab) was isolated (Figure 1). Murine protein sequences were replaced …

Oral anticoagulants in development: focus on thromboprophylaxis in patients undergoing orthopaedic surgery.

Current anticoagulant provision is dominated by parenteral heparin and oral warfarin, which act by inhibiting several steps of the coagulation pathway indirectly. Recent research efforts have focused on the identification of small molecule inhibitors of the coagulation enzymes as novel therapies for thrombotic disorders. There has been particular success in developing nonpeptidic, orally available, small molecules to directly inhibit the key proteases, factor IIa and factor Xa.Of the new oral anticoagulants in development, the two agents in the most advanced stage are dabigatran etexilate (BIBR 1048) and rivaroxaban (BAY 59-7939), which inhibit factor IIa and factor Xa, respectively. Other agents in the early stages of development include several Xa inhibitors (LY-517717, YM150, DU-176b and apixaban [BMS-562247]), a factor IXa inhibitor (TTP889), and an orally active glycosaminoglycan enhancer (odiparcil [SB-424323]), which indirectly enhances thrombin inhibition via heparin cofactor II. Results have been reported from important, phase II dose-finding studies, and a number of registration-track phase III studies have been initiated, reflecting the drive towards potentially more effective, but primarily safer and more convenient therapies for the prevention and treatment of venous and arterial thrombosis. Indeed, two unmet needs for anticoagulation that can be easily identified are safety and ease of use. Safety relates primarily to the incidence of major bleeding and this remains the key concern of orthopaedic surgeons, over and above any efficacy advantage, and convenience of use, which centres on oral administration replacing the need for injections.The clinical development of these new anticoagulants is following the well tested strategy of dose-ranging and registration studies in major orthopaedic surgery, prior to development in arterial indications. There are a number of subtle issues, including the timing of the first perioperative dose, duration of prophylactic treatment and definition/assessment of study endpoints that can influence study outcome and require careful consideration when evaluating study results with new agents and in the comparison with established agents, and which are considered in this review.It is anticipated that over the next 3 years, at least one of these agents will be successfully licensed for the prevention of venous thromboembolism after major orthopaedic surgery, which will act as a springboard for the gradual replacement of current anticoagulants.

Major Bleeding, Mortality, and Efficacy of Fondaparinux in Venous Thromboembolism Prevention Trials

Background— Bleeding is a strong predictor of death in patients hospitalized for arterial thrombosis who are treated with antithrombotic therapy, but the prognostic importance of bleeding in patients receiving antithrombotic prophylaxis for venous thromboembolism is uncertain. Methods and Results— Using Cox proportional hazards modeling, we examined the association between major bleeding and death at 30 days using pooled individual patient data from 8 large randomized controlled trials (n=13 085) comparing fondaparinux with control (low-molecular-weight heparin or placebo) for the prophylaxis of venous thromboembolism in hospitalized surgical or medical patients. Patients who developed major bleeding were older, were more likely to be male, had a lower body weight and lower creatinine clearance, and were more likely to be receiving fondaparinux. At 30 days, the risk of death was 7-fold higher among patients with a major bleeding event (8.6% versus 1.7%; adjusted hazard ratio, 6.96; 95% confidence interval, 4.60 to 10.51). There was a consistent pattern of reduced mortality in patients treated with fondaparinux irrespective of whether patients experienced major bleeding (6.8% versus 11.4%; hazard ratio, 0.58; 95% confidence interval, 0.27 to 1.23) or no major bleeding (1.5% versus 1.9%; hazard ratio, 0.77; 95% confidence interval, 0.59 to 1.02; P for heterogeneity=0.47). Conclusions— Major bleeding in hospitalized surgical and medical patients participating in venous thromboembolism prevention trials is a strong predictor of mortality.