Alexander T. Cohen

Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high‐risk abdominal surgery

The aim of this study was to assess whether the synthetic factor Xa inhibitor fondaparinux reduced the risk of venous thromboembolism more efficiently than the low molecular weight heparin dalteparin in patients undergoing major abdominal surgery.

The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement: the EXPRESS study.

Summary.  Background: Ximelagatran and its subcutaneous (s.c.) form melagatran are novel direct thrombin inhibitors for the prevention and treatment of thromboembolic disease. Methods: In a double‐blind study, 2835 consecutive patients undergoing total hip or knee replacement were randomized to either melagatran/ximelagatran or enoxaparin. Melagatran 2 mg was started immediately before surgery; 3 mg was then administered postoperatively, followed by 24 mg of oral ximelagatran b.i.d. beginning the next day. Enoxaparin 40 mg, administered subcutaneously o.d., was started 12 h before surgery. Both treatments were continued for 8–11 days. The main efficacy outcome measures were major venous thromboembolism (VTE); [proximal deep vein thrombosis (DVT), non‐fatal and/or fatal pulmonary embolism (PE), death where PE could not be ruled out], and total VTE (proximal and distal DVT; PE; death from all causes). DVT was detected by mandatory bilateral ascending venography at the end of the treatment period or earlier if clinically suspected. The main safety outcome was bleeding. Results: The rates of major and total VTE were significantly lower in the melagatran/ximelagatran group compared with the enoxaparin group (2.3% vs. 6.3%, P = 0.0000018; and 20.3% vs. 26.6%, P < 0.0004, respectively). Fatal bleeding, critical site bleeding and bleeding requiring reoperation did not differ between the two groups. ‘Excessive bleeding as judged by the investigator’ was more frequent with melagatran/ximelagatran than with enoxaparin. Conclusions: In patients undergoing total hip or knee replacement, preoperatively initiated s.c. melagatran followed by oral ximelagatran was significantly more effective in preventing VTE than preoperatively initiated s.c. enoxaparin.

The Changing Pattern of Venous Thromboembolic Disease

A review of 14,667 necropsy reports for every year from 1965 to 1990 and 6,436 diagnostic venograms performed from 1976 to 1990 was undertaken at a single teaching hospital. A progressive reduction in the percentage of necropsies reporting fatal pulmonary embolism from 6.1 to 2.1%, occurred over the 25-year period (chi(2) tests for linear trend with time p < 0.00001). Over the last decade, there has been a significant reduction in the rate of venographically diagnosed postoperative deep vein thrombosis (DVT) from 49.9 to 24.7 per 100,000 population (p < 0.0001) which was in marked contrast to the constant rate of non-postoperative DVT. Our findings suggest that the introduction of thromboprophylactic measures, in addition to changes in hospital practice, may have had a highly significant effect on the pattern of this serious, but potentially avoidable disease.

Safety assessment of new antithrombotic agents: Lessons from the EXTEND study on ximelagatran ☆

BACKGROUND Ximelagatran, the first oral direct thrombin inhibitor, was shown to be an effective antithrombotic agent but was associated with potential liver toxicity after prolonged administration. OBJECTIVES AND METHODS The aim of the EXTEND study was to assess safety and efficacy of extended administration (35 days) of ximelagatran or enoxaparin for the prevention of venous thromboembolism after elective hip replacement and hip fracture surgery. A follow-up period, including assessment of liver enzymes (in particular alanine aminotransferase; ALAT), until post-operative day 180 was planned, with visits at days 56 and 180. RESULTS Randomization and administration of study drugs were stopped following a report of serious liver injury occurring 3 weeks after completion of ximelagatran treatment. At the time of study termination, 1158 patients had been randomized and 641 had completed the 35-day treatment; with 303 ximelagatran and 265 enoxaparin patients remaining in the study through to the day 56 follow-up visit. Overall, 58 patients showed an ALAT increase to >2x upper limit of normal: 31 treated with enoxaparin, 27 with ximelagatran. Three ximelagatran patients also showed symptoms potentially related to liver toxicity. Eleven ximelagatran patients showed an ALAT increase after study treatment ended. The clinical development of ximelagatran was terminated and the drug withdrawn from the market. Evaluation of the relative efficacy of the two treatments as specified in the protocol was impossible due to the premature termination of the study. CONCLUSIONS Prolonged administration of ximelagatran was associated with an increased risk of liver toxicity. In a substantial proportion of patients, ALAT increase occurred after treatment withdrawal. The findings seen with ximelagatran should be considered when designing studies with new antithrombotic agents.

Results of an economic model to assess the cost-effectiveness of enoxaparin, a low-molecular-weight heparin, versus warfarin for the prophylaxis of deep vein thrombosis and associated long-term complications in total hip replacement surgery in the United States

BACKGROUND Premature death due to pulmonary embolism is a short-term complication of deep vein thrombosis (DVT). The long-term clinical course after DVT can be further complicated by excess mortality, recurrent venous thromboembolism (VTE), and the post-thrombotic syndrome (PTS), which may produce sizable long-term economic burdens. OBJECTIVE The goal of this study was to determine the cost-effectiveness of the low-molecular-weight heparin (LMWH) enoxaparin versus warfarin for the universal prophylaxis of DVT and associated long-term complications in US patients undergoing total hip replacement surgery (THRS). METHODS A model was constructed to assess the long-term cost-effectiveness of the 2 treatments. Patients undergoing THRS were exposed to a short-term risk of developing a DVT. Patients surviving a DVT were exposed to increased risk of long-term complications of DVT, including PTS, recurrent VTE, and increased mortality. Published literature, augmented by expert opinion, served as input for the models resource use and costs for DVT prophylaxis, clinical diagnosis, and treatment of DVT, VTE, and PTS. RESULTS When the analysis included only the short-term consequences of DVT, therapy with enoxaparin resulted in a net cost of

Postoperative Melagatran/Ximelagatran for the Prevention of Venous Thromboembolism following Major Elective Orthopaedic Surgery : Effects of Timing of First Dose and Risk Factors for Thromboembolism and Bleeding Complications on Efficacy and Safety.

133 per patient and a net increase of 0.04 quality-adjusted life-years (QALYs) per patient. Thromboprophylaxis with enoxaparin versus warfarin resulted in

Benefits of deep-vein thrombosis prophylaxis in the nonsurgical patient: The MEDENOX trial

3733 per QALY saved. In contrast, when the long-term consequences of DVT were included, enoxaparin resulted in net lifetime savings of

Extended Thromboprophylaxis following Lower Limb Arthroplasty: What Do the Clinical Trials Mean?

89 per patient and net QALY benefits of 0.16 per patient. CONCLUSIONS To the best of our knowledge, this is the first US economic analysis comparing DVT prophylaxis with the LMWH enoxaparin versus warfarin that included the long-term complications of DVT. Our model suggests that use of enoxaparin in patients undergoing THRS reduces the economic burden associated with these long-term complications.

Assessment of bleeding after concomitant administration of antiplatelet and anticoagulant agents in lower limb arthroplasty

AbstractObjectives: To examine the influence of timing of postoperative initiation of subcutaneous melagatran followed by oral ximelagatran, and of risk factors for venous thromboembolism (VTE; including deep vein thrombosis [DVT] and pulmonary embolism [PE]) and bleeding complications, on the efficacy and safety of this regimen, compared with preoperative enoxaparin sodium, following total hip replacement (THR) or total knee replacement (TKR) surgery. Design: Statistical analyses of efficacy and safety in subgroups of the METHRO III intention-to-treat population. Main outcome measures: Main efficacy outcome measures were major VTE (proximal DVT, PE or VTE-related death) and total VTE (distal or proximal DVT, fatal or non-fatal PE). The main safety outcome measures were blood transfusion, severe bleeding events, blood loss, bleeding-related adverse events and need for reoperation. Results: In the combined THR and TKR population, melagatran initiated 4–<8 hours postoperatively was non-inferior to enoxaparin sodium with respect to the risks of total VTE (absolute risk reduction [ARR] 0; 95% confidence interval [CI] ∼-4.4, 4.4) and major VTE (ARR −0.63; 95% CI −2.94, 1.67). The rate of major VTE was unaffected by the different risk factors. In the combined THR and TKR population, blood transfusion requirements were lower with melagatran/ximela-gatran than enoxaparin sodium (odds ratio 0.83; 95% CI 0.71, 0.96; p = 0.016). Conclusions: Melagatran/ximelagatran initiated 4–<8 hours postoperatively provided a comparable level of protection against total and major VTE to preoperative enoxaparin sodium. Major VTE rates and safety were consistent across different patient subgroups. Subcutaneous melagatran followed by fixed-dose oral ximelagatran offers an alternative to the standard European low molecular-weight heparin regimen in a wide range of patients.

The significance of distal vein thrombosis and bilateral disease

Venous thromboembolism (VTE) is a common complication of hospitalized patients, imposing a major clinical and economic burden. Three of four cases of fatal pulmonary embolism occur in nonsurgical settings, but thromboprophylaxis is far less common in medical than in surgical patients. This is mainly attributable to the heterogeneity of nonsurgical populations and lack of high-quality evidence to support specific thromboprophylactic measures. The recent Prophylaxis of Venous Thromboembolism in MEDical Patients With ENOXaparin (MEDENOX) trial addressed this deficiency by assessing the need for and the benefit:risk ratio of thromboprophylaxis in a well-defined group of medical patients immobilized with severe illness. The MEDENOX study showed that these patients are at significant risk of VTE. Enoxaparin, 40 mg once daily for 6 to 14 days, reduced the risk of VTE by 63% without increasing adverse events. It is anticipated that data from the MEDENOX study will be incorporated into future consensus guidelines on the prevention of VTE. Further studies are required to assess the benefit:risk ratio of therapy in other clearly-defined medical groups.