Response to “Role of Orally Available Antagonists of Factor Xa in the Treatment and Prevention of Thromboembolic Disease: Focus on Rivaroxaban”

The recent article by Morell and colleagues (J Clin Pharmacol. 2010 Feb 2; DOI: 10.1177/00912700 09355814) contains certain inaccuracies with regard to the phase III RECORD program study designs. In addition, some of their interpretations of the methodology are open to question. With regard to the inaccuracies in the article, Morell and colleagues state that the RECORD1 study compared rivaroxaban with enoxaparin for 5 to 9 days after total hip replacement (THR), whereas the study actually compared 31 to 39 days of thromboprophylaxis with both agents.1 The duration of treatment in RECORD1 is incorrectly given as 10 to 14 days in Table II. It is also incorrectly described as a study in patients undergoing knee replacement surgery in this table. The authors incorrectly state, with regard to the incidence of bleeding, that the RECORD2 study used the higher US dosing of enoxaparin (30 mg twice daily) when the dosing regimen used was 40 mg once daily (od).2 The duration of therapy in the rivaroxaban arm of RECORD2 was 31 to 39 days, not up to 36 days, as described in Table II. In addition, enoxaparin was started 12 to 24 hours after surgery in the RECORD4 study, not 12 to 14 hours after surgery, as given in Table II. The evaluation of the RECORD program study designs by Morell and colleagues requires comment. The authors question the appropriateness of the enoxaparin dosing regimens used in the RECORD1, 2, and 3 studies. Enoxaparin 40 mg od is an approved dosing regimen that is used widely outside the United States. RECORD was a global clinical development program; therefore, the comparisons with this enoxaparin regimen are considered appropriate and valid. Regarding RECORD2, it is clearly stated that the aim of the study was to confirm the benefits of extended-duration prophylaxis after THR, and the greater efficacy of rivaroxaban compared with enoxaparin that was demonstrated has always been considered a consequence of extended-duration prophylaxis.2 Morell and colleagues question the relevance of the primary end point in the individual studies (total venous thromboembolism [VTE]) because it includes venographically detected events. However, the Food and Drug Administration (FDA) has accepted the appropriateness of this end point in clinical trials of this nature.3 Morell and colleagues also state that the primary end point used in the apixaban phase II total knee replacement trial did not include venographically diagnosed VTE; in fact, the end point included asymptomatic VTE detected by venography4 The authors incorrectly report these results as rates of symptomatic VTE and all-cause mortality. Stating that the apixaban trials used a more clinically relevant end point and rigorous study design compared with rivaroxaban trials is, therefore, incorrect. The FDA discussion regarding the efficacy of rivaroxaban was based on the primary end point of the pooled analysis, as well as total VTE. Analysis of the incidence of symptomatic events was not possible in the individual studies because of low event rates but was possible when data from all 4 studies were pooled. The results of this pooled analysis are not reported by Morell and colleagues but show that rivaroxaban significantly reduces the incidence of symptomatic VTE and all-cause mortality (the primary end point of the pooled analysis) compared with enoxaparin at day 12 ± 2 (0.5% vs 1.0%, respectively; P = .001), over the total treatment duration (0.6% vs 1.3%, respectively; P < .001), and the total study duration (0.8% vs 1.6%, respectively; P < .001).5 The article claims that the pooled analysis of the RECORD data was conducted without appropriate controls for the differences between the individual trials. In the published pooled analysis of the RECORD1–3 studies6 and in the pooled analysis of the RECORD1–4 studies conducted by the sponsor, the heterogeneity in study design of the individual trials was accounted for by analyses of 3 study pools, including the day 12 ± 2 active treatment pool (the enoxaparin-controlled period across all studies). Financial disclosure: Dr Turpie received honoraria as a member of the RECORD steering committee and has served as a consultant to Bayer Schering Pharma AG.

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