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Comparison of the Novel Oral Anticoagulants Apixaban, Dabigatran, Edoxaban, and Rivaroxaban in the Initial and Long-Term Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis.

Cohen AT, Hamilton M, Mitchell SA, Phatak H, Liu X, Bird A, Tushabe D, Batson S - PLoS ONE (2015)

Bottom Line: Apixaban treatment was associated with the most favourable safety profile of the NOACs, showing a statistically significantly reduced risk of 'major or clinically relevant non-major (CRNM) bleed' compared with rivaroxaban (0.47 [0.36, 0.61]), dabigatran (0.69 [0.51, 0.94]), and edoxaban (0.54 [0.41, 0.69]).Dabigatran was also associated with a significantly lower risk of 'major or CRNM bleed' compared with rivaroxaban (0.68 [0.53, 0.87]) and edoxaban (0.77 [0.60, 0.99]).In contrast, reductions in 'major or CRNM bleed' for initial/long-term treatment were significantly better with apixaban compared with all other NOACs, and with dabigatran compared with rivaroxaban and edoxaban.

View Article: PubMed Central - PubMed

Affiliation: Guy's and St Thomas' Hospitals, King's College, London, United Kingdom.

ABSTRACT

Background: Anticoagulation with low molecular weight heparin and vitamin K antagonists is the current standard of care (SOC) for venous thromboembolism (VTE) treatment and prevention. Although novel oral anti-coagulants (NOACs) have been compared with SOC in this indication, no head-to-head randomised controlled trials (RCTs) have directly compared NOACs. A systematic review and network meta-analysis (NMA) were conducted to compare the efficacy and safety of NOACs for the initial and long-term treatment of VTE.

Methods: Electronic databases (accessed July 2014) were systematically searched to identify RCTs evaluating apixaban, dabigatran, edoxaban, and rivaroxaban versus SOC. Eligible patients included adults with an objectively confirmed deep vein thrombosis (DVT), pulmonary embolism (PE) or both. A fixed-effect Bayesian NMA was conducted for outcomes of interest, and results were presented as relative risks (RR) and 95% credible intervals (Crl).

Results: Six Phase III RCTs met criteria for inclusion: apixaban (one RCT; n = 5,395); rivaroxaban (two RCTs; n = 3,423/4,832); dabigatran (two RCTs; n = 2,539/2,568); edoxaban (one RCT; n = 8,240). There were no statistically significant differences between the NOACs with regard to the risk of 'VTE and VTE-related death. Apixaban treatment was associated with the most favourable safety profile of the NOACs, showing a statistically significantly reduced risk of 'major or clinically relevant non-major (CRNM) bleed' compared with rivaroxaban (0.47 [0.36, 0.61]), dabigatran (0.69 [0.51, 0.94]), and edoxaban (0.54 [0.41, 0.69]). Dabigatran was also associated with a significantly lower risk of 'major or CRNM bleed' compared with rivaroxaban (0.68 [0.53, 0.87]) and edoxaban (0.77 [0.60, 0.99]).

Conclusions: Indirect comparisons showed statistically similar reductions in the risk of 'VTE or VTE-related death for all NOACs. In contrast, reductions in 'major or CRNM bleed' for initial/long-term treatment were significantly better with apixaban compared with all other NOACs, and with dabigatran compared with rivaroxaban and edoxaban. Results from the current analysis indicate that the NOACs offer clinical benefit over conventional therapy while highlighting relative differences in their bleeding profile.

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Related in: MedlinePlus

Network of evidence for the meta-analysis.†Primary and sensitivity analyses used pooled data from the EINSTEIN DVT and EINSTEIN PE trials [28].
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pone.0144856.g002: Network of evidence for the meta-analysis.†Primary and sensitivity analyses used pooled data from the EINSTEIN DVT and EINSTEIN PE trials [28].

Mentions: Table 2 summarises the characteristics of each study. The reported mean age of patients and the percentage of female patients were similar across trials. All studies were judged to be of good quality (S1 Table) although there were some differences between the trials in terms of study design and patient characteristics: AMPLIFY [21], Hokusai-VTE [23], RECOVER [24] and RECOVER II [22] were double-blind, whereas the EINSTEIN DVT [19] and EINSTEIN PE [20] trials were open-label. AMPLIFY [21] reported 89.8% of patients as having an unprovoked VTE, whereas the pooled analysis of the EINSTEIN DVT/PE studies [28] and Hokusai-VTE [23] reported 63.5% and 65.7%, respectively. This suggests some variation in the baseline risk of VTE between trials, as patients with an unprovoked VTE may have a higher risk of recurrence [29]. Finally, the EINSTEIN DVT [19] and EINSTEIN PE [20] trials had treatment periods of 3, 6 or 12 months (at discretion of clinician), Hokusai-VTE [23] had a maximum treatment duration of 12 months compared with a treatment duration of 6 months in the remaining trials [21, 22, 24]. Initial treatment (≥5 days) with an approved parenteral anticoagulant was required in the RE-COVER [24], RE-COVER II [22] (LMWH in the majority of patients [~90%]) and Hokusai-VTE studies [23] (enoxaparin or unfractionated heparin [UFH]) prior to receiving a NOAC or warfarin, in contrast to AMPLIFY [21] and the EINSTEIN studies [19] where treatments were administered as single regimens. There was variation in the definition of the primary efficacy outcome across the studies. The ‘VTE and VTE-related death’ endpoint comprised reported events of DVT, fatal or non-fatal PE, and VTE-related death. This was reported in the trial publications as follows: AMPLIFY [21]–adjudicated composite of recurrent VTE or death related to VTE. Recurrent VTE included fatal or non-fatal PE and DVT; RE-COVER [24]–composite of VTE or death associated with VTE; RE-COVER II [22]–VTE or VTE-related death; EINSTEIN DVT [19], EINSTEIN PE [20] and Hokusai-VTE [23]–composite of DVT and non-fatal or fatal PE. All studies reported a consistent definition of bleeding outcomes as defined by the International Society on Thrombosis and Haemostasis [30]. The network of trials used is shown in Fig 2. The raw data used in the NMA are presented in S2 Table.


Comparison of the Novel Oral Anticoagulants Apixaban, Dabigatran, Edoxaban, and Rivaroxaban in the Initial and Long-Term Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis.

Cohen AT, Hamilton M, Mitchell SA, Phatak H, Liu X, Bird A, Tushabe D, Batson S - PLoS ONE (2015)

Network of evidence for the meta-analysis.†Primary and sensitivity analyses used pooled data from the EINSTEIN DVT and EINSTEIN PE trials [28].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4696796&req=5

pone.0144856.g002: Network of evidence for the meta-analysis.†Primary and sensitivity analyses used pooled data from the EINSTEIN DVT and EINSTEIN PE trials [28].
Mentions: Table 2 summarises the characteristics of each study. The reported mean age of patients and the percentage of female patients were similar across trials. All studies were judged to be of good quality (S1 Table) although there were some differences between the trials in terms of study design and patient characteristics: AMPLIFY [21], Hokusai-VTE [23], RECOVER [24] and RECOVER II [22] were double-blind, whereas the EINSTEIN DVT [19] and EINSTEIN PE [20] trials were open-label. AMPLIFY [21] reported 89.8% of patients as having an unprovoked VTE, whereas the pooled analysis of the EINSTEIN DVT/PE studies [28] and Hokusai-VTE [23] reported 63.5% and 65.7%, respectively. This suggests some variation in the baseline risk of VTE between trials, as patients with an unprovoked VTE may have a higher risk of recurrence [29]. Finally, the EINSTEIN DVT [19] and EINSTEIN PE [20] trials had treatment periods of 3, 6 or 12 months (at discretion of clinician), Hokusai-VTE [23] had a maximum treatment duration of 12 months compared with a treatment duration of 6 months in the remaining trials [21, 22, 24]. Initial treatment (≥5 days) with an approved parenteral anticoagulant was required in the RE-COVER [24], RE-COVER II [22] (LMWH in the majority of patients [~90%]) and Hokusai-VTE studies [23] (enoxaparin or unfractionated heparin [UFH]) prior to receiving a NOAC or warfarin, in contrast to AMPLIFY [21] and the EINSTEIN studies [19] where treatments were administered as single regimens. There was variation in the definition of the primary efficacy outcome across the studies. The ‘VTE and VTE-related death’ endpoint comprised reported events of DVT, fatal or non-fatal PE, and VTE-related death. This was reported in the trial publications as follows: AMPLIFY [21]–adjudicated composite of recurrent VTE or death related to VTE. Recurrent VTE included fatal or non-fatal PE and DVT; RE-COVER [24]–composite of VTE or death associated with VTE; RE-COVER II [22]–VTE or VTE-related death; EINSTEIN DVT [19], EINSTEIN PE [20] and Hokusai-VTE [23]–composite of DVT and non-fatal or fatal PE. All studies reported a consistent definition of bleeding outcomes as defined by the International Society on Thrombosis and Haemostasis [30]. The network of trials used is shown in Fig 2. The raw data used in the NMA are presented in S2 Table.

Bottom Line: Apixaban treatment was associated with the most favourable safety profile of the NOACs, showing a statistically significantly reduced risk of 'major or clinically relevant non-major (CRNM) bleed' compared with rivaroxaban (0.47 [0.36, 0.61]), dabigatran (0.69 [0.51, 0.94]), and edoxaban (0.54 [0.41, 0.69]).Dabigatran was also associated with a significantly lower risk of 'major or CRNM bleed' compared with rivaroxaban (0.68 [0.53, 0.87]) and edoxaban (0.77 [0.60, 0.99]).In contrast, reductions in 'major or CRNM bleed' for initial/long-term treatment were significantly better with apixaban compared with all other NOACs, and with dabigatran compared with rivaroxaban and edoxaban.

View Article: PubMed Central - PubMed

Affiliation: Guy's and St Thomas' Hospitals, King's College, London, United Kingdom.

ABSTRACT

Background: Anticoagulation with low molecular weight heparin and vitamin K antagonists is the current standard of care (SOC) for venous thromboembolism (VTE) treatment and prevention. Although novel oral anti-coagulants (NOACs) have been compared with SOC in this indication, no head-to-head randomised controlled trials (RCTs) have directly compared NOACs. A systematic review and network meta-analysis (NMA) were conducted to compare the efficacy and safety of NOACs for the initial and long-term treatment of VTE.

Methods: Electronic databases (accessed July 2014) were systematically searched to identify RCTs evaluating apixaban, dabigatran, edoxaban, and rivaroxaban versus SOC. Eligible patients included adults with an objectively confirmed deep vein thrombosis (DVT), pulmonary embolism (PE) or both. A fixed-effect Bayesian NMA was conducted for outcomes of interest, and results were presented as relative risks (RR) and 95% credible intervals (Crl).

Results: Six Phase III RCTs met criteria for inclusion: apixaban (one RCT; n = 5,395); rivaroxaban (two RCTs; n = 3,423/4,832); dabigatran (two RCTs; n = 2,539/2,568); edoxaban (one RCT; n = 8,240). There were no statistically significant differences between the NOACs with regard to the risk of 'VTE and VTE-related death. Apixaban treatment was associated with the most favourable safety profile of the NOACs, showing a statistically significantly reduced risk of 'major or clinically relevant non-major (CRNM) bleed' compared with rivaroxaban (0.47 [0.36, 0.61]), dabigatran (0.69 [0.51, 0.94]), and edoxaban (0.54 [0.41, 0.69]). Dabigatran was also associated with a significantly lower risk of 'major or CRNM bleed' compared with rivaroxaban (0.68 [0.53, 0.87]) and edoxaban (0.77 [0.60, 0.99]).

Conclusions: Indirect comparisons showed statistically similar reductions in the risk of 'VTE or VTE-related death for all NOACs. In contrast, reductions in 'major or CRNM bleed' for initial/long-term treatment were significantly better with apixaban compared with all other NOACs, and with dabigatran compared with rivaroxaban and edoxaban. Results from the current analysis indicate that the NOACs offer clinical benefit over conventional therapy while highlighting relative differences in their bleeding profile.

Show MeSH
Related in: MedlinePlus