Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons

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Abstract

Objective To analyse clinical outcomes with new oral anticoagulants for prophylaxis against venous thromboembolism after total hip or knee replacement.

Design Systematic review, meta-analysis, and indirect treatment comparisons.

Data sources Medline and CENTRAL (up to April 2011), clinical trials registers, conference proceedings, and websites of regulatory agencies.

Study selection Randomised controlled trials of rivaroxaban, dabigatran, or apixaban compared with enoxaparin for prophylaxis against venous thromboembolism after total hip or knee replacement. Two investigators independently extracted data. Relative risks of symptomatic venous thromboembolism, clinically relevant bleeding, deaths, and a net clinical endpoint (composite of symptomatic venous thromboembolism, major bleeding, and death) were estimated using a random effect meta-analysis. RevMan and ITC software were used for direct and indirect comparisons, respectively.

Results 16 trials in 38 747 patients were included. Compared with enoxaparin, the risk of symptomatic venous thromboembolism was lower with rivaroxaban (relative risk 0.48, 95% confidence interval 0.31 to 0.75) and similar with dabigatran (0.71, 0.23 to 2.12) and apixaban (0.82, 0.41 to 1.64). Compared with enoxaparin, the relative risk of clinically relevant bleeding was higher with rivaroxaban (1.25, 1.05 to 1.49), similar with dabigatran (1.12, 0.94 to 1.35), and lower with apixaban (0.82, 0.69 to 0.98). The treatments did not differ on the net clinical endpoint in direct or indirect comparisons.

Conclusions A higher efficacy of new anticoagulants was generally associated with a higher bleeding tendency. The new anticoagulants did not differ significantly for efficacy and safety.

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Rapid planetesimal formation in turbulent circumstellar discs

Anders Johansen, Jeffrey S. Oishi, Mordecai-Mark Mac Low … (2007)

The initial stages of planet formation in circumstellar gas discs proceed via dust grains that collide and build up larger and larger bodies (Safronov 1969). How this process continues from metre-sized boulders to kilometre-scale planetesimals is a major unsolved problem (Dominik et al. 2007): boulders stick together poorly (Benz 2000), and spiral into the protostar in a few hundred orbits due to a head wind from the slower rotating gas (Weidenschilling 1977). Gravitational collapse of the solid component has been suggested to overcome this barrier (Safronov 1969, Goldreich & Ward 1973, Youdin & Shu 2002). Even low levels of turbulence, however, inhibit sedimentation of solids to a sufficiently dense midplane layer (Weidenschilling & Cuzzi 1993, Dominik et al. 2007), but turbulence must be present to explain observed gas accretion in protostellar discs (Hartmann 1998). Here we report the discovery of efficient gravitational collapse of boulders in locally overdense regions in the midplane. The boulders concentrate initially in transient high pressures in the turbulent gas (Johansen, Klahr, & Henning 2006), and these concentrations are augmented a further order of magnitude by a streaming instability (Youdin & Goodman 2005, Johansen, Henning, & Klahr 2006, Johansen & Youdin 2007) driven by the relative flow of gas and solids. We find that gravitationally bound clusters form with masses comparable to dwarf planets and containing a distribution of boulder sizes. Gravitational collapse happens much faster than radial drift, offering a possible path to planetesimal formation in accreting circumstellar discs.

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Natural history of venous thromboembolism.

Clive Kearon (2003)

Most deep vein thromboses (DVTs) start in the calf, and most probably resolve spontaneously. Thrombi that remain confined to the calf rarely cause leg symptoms or symptomatic pulmonary embolism (PE). The probability that calf DVT will extend to involve the proximal veins and subsequently cause PE increases with the severity of the initiating prothrombotic stimulus. Although acute venous thromboembolism (VTE) usually presents with either leg or pulmonary symptoms, most patients have thrombosis at both sites at the time of diagnosis. Proximal DVTs resolve slowly during treatment with anticoagulants, and thrombi remain detectable in half of the patients after a year. Resolution of DVT is less likely in patients with a large initial thrombus or cancer. About 10% of patients with symptomatic DVTs develop severe post-thrombotic syndrome within 5 years, and recurrent ipsilateral DVT increases this risk. About 10% of PEs are rapidly fatal, and an additional 5% cause death later, despite diagnosis and treatment. About 50% of diagnosed PEs are associated with right ventricular dysfunction, which is associated with a approximately 5-fold greater in-hospital mortality. There is approximately 50% resolution of PE after 1 month of treatment, and perfusion eventually returns to normal in two thirds of patients. About 5% of treated patients with PE develop pulmonary hypertension as a result of poor resolution. After a course of treatment, the risk of recurrent thrombosis is higher (ie, approximately 10% per patient-year) in patients without reversible risk factors, in those with cancer, and in those with prothrombotic biochemical abnormalities such as antiphospholipid antibodies and homozygous factor V Leiden.

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Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial.

Michael Lassen, Gary Raskob, Alexander Gallus … (2010)

Low-molecular-weight heparins such as enoxaparin are preferred for prevention of venous thromboembolism after major joint replacement. Apixaban, an orally active factor Xa inhibitor, might be as effective, have lower bleeding risk, and be easier to use than is enoxaparin. We assessed efficacy and safety of these drugs after elective total knee replacement. In ADVANCE-2, a multicentre, randomised, double-blind phase 3 study, patients undergoing elective unilateral or bilateral total knee replacement were randomly allocated through an interactive central telephone system to receive oral apixaban 2.5 mg twice daily (n=1528) or subcutaneous enoxaparin 40 mg once daily (1529). The randomisation schedule was generated by the Bristol-Myers Squibb randomisation centre and stratified by study site and by unilateral or bilateral surgery with a block size of four. Investigators, patients, statisticians, adjudicators, and steering committee were masked to allocation. Apixaban was started 12-24 h after wound closure and enoxaparin 12 h before surgery; both drugs were continued for 10-14 days, when bilateral ascending venography was scheduled. Primary outcome was the composite of asymptomatic and symptomatic deep vein thrombosis, non-fatal pulmonary embolism, and all-cause death during treatment. The statistical plan required non-inferiority of apixaban before testing for superiority; analysis was by intention to treat for non-inferiority testing. The study is registered at ClinicalTrials.gov, number NCT00452530. 1973 of 3057 patients allocated to treatment (1528 apixaban, 1529 enoxaparin) were eligible for primary efficacy analysis. The primary outcome was reported in 147 (15%) of 976 apixaban patients and 243 (24%) of 997 enoxaparin patients (relative risk 0.62 [95% CI 0.51-0.74]; p<0.0001; absolute risk reduction 9.3% [5.8-12.7]). Major or clinically relevant non-major bleeding occurred in 53 (4%) of 1501 patients receiving apixaban and 72 (5%) of 1508 treated with enoxaparin (p=0.09). Apixaban 2.5 mg twice daily, starting on the morning after total knee replacement, offers a convenient and more effective orally administered alternative to 40 mg per day enoxaparin, without increased bleeding. Bristol-Myers Squibb; Pfizer. Copyright 2010 Elsevier Ltd. All rights reserved.

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Author and article information

Contributors

: Role: clinical assessor

: Role: associate professor

: Role: clinical assessor

: Role: professor

Journal

Journal ID (nlm-ta): BMJ

Journal ID (iso-abbrev): BMJ

Journal ID (publisher-id): bmj

Title: BMJ : British Medical Journal

Publisher: BMJ Publishing Group Ltd.

ISSN (Print): 0959-8138

ISSN (Electronic): 1756-1833

Publication date Collection: 2012

Publication date (Print): 2012

Publication date (Electronic): 14 June 2012

Volume: 344

Electronic Location Identifier: e3675

Affiliations

[1 ]Division of Pharmacology and Clinical Evaluation, Medicines for Human Use, Spanish Agency for Medicines and Medical Devices, Parque Empresarial Las Mercedes, Edificio 8, C/Campezo 1, Madrid, 28022, Spain

[2 ]Department of Clinical Pharmacology, Hospital Clínico San Carlos, Madrid, Spain

Author notes

Correspondence to: A Gómez-Outes agomezo@ 123456aemps.es

Article

Publisher ID: goma002058

DOI: 10.1136/bmj.e3675

PMC ID: 3375207

PubMed ID: 22700784

SO-VID: cdb095f2-7c66-4158-af36-2210cb2f031b

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This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons

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Most cited references 46

Rapid planetesimal formation in turbulent circumstellar discs

Natural history of venous thromboembolism.

Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial.

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