Dabigatran is effective with a favourable safety profile in normal and overweight patients undergoing major orthopaedic surgery: A pooled analysis

doi:10.1016/j.thromres.2012.07.004

Thrombosis Research

Volume 130, Issue 5, November 2012, Pages 818-820

https://doi.org/10.1016/j.thromres.2012.07.004 Get rights and content

Abstract

Introduction

Three pivotal phase 3 trials have demonstrated that oral dabigatran etexilate showed similar safety and efficacy to enoxaparin 40 mg once daily (qd) for venous thromboembolism (VTE) prevention in patients undergoing total knee or hip replacement. Obesity is an established independent risk factor for VTE.

Methods

A post-hoc pooled analysis of the three trials was performed to evaluate the safety and efficacy of dabigatran 220 mg qd versus enoxaparin 40 mg qd in patients with a normal body mass index (BMI) of > 20–25 kg/m², pre-obese patients (BMI > 25–30 kg/m²) and obese patients (BMI > 30 kg/m²). The primary efficacy endpoint was major VTE and VTE-related mortality; safety endpoints included major, clinically relevant, or any bleeding events.

Results

The mean BMIs for patients in the dabigatran and enoxaparin arms from all three trials, separately, were between 27.5 and 29.9 kg/m². Of the participants, 1417 (24.9%) had a normal BMI, 2373 (41.7%) were pre-obese and 1826 (32.1%) obese. In patients with normal BMI, the rates of the primary efficacy endpoint were significantly lower in the dabigatran than in the enoxaparin group (2.1% versus 4.3%; OR 0.48; 95% CI 0.24–0.97, P = 0.037). No significant difference between dabigatran and enoxaparin in the primary efficacy endpoint was observed in the other subgroups. Bleeding rates were also similar between treatments for BMI subgroups.

Conclusions

Dabigatran is an effective thromboprophylactic therapy for normal, pre-obese and obese patients, and outcomes in patients with a BMI > 25 kg/m² do not differ from the overall population.

Introduction

Studies have established that obesity is an independent risk factor for primary and recurrent venous thromboembolism (VTE) [1], [2], [3], [4].

Dabigatran etexilate (hereafter named dabigatran) is a new, oral, reversible direct thrombin inhibitor approved for the prevention of VTE in patients undergoing total knee and hip replacements (TKR/THR) and for the prevention of stroke in patients with atrial fibrillation. Three pivotal phase 3 trials [5], [6], [7] have demonstrated that oral (po) dabigatran 150 mg or 220 mg once daily (qd), initiated post-operatively showed similar safety and efficacy to subcutaneous (sc) enoxaparin 40 mg qd, administered before surgery, for VTE prevention in patients undergoing TKR and THR. In the most recent trial, prophylaxis with dabigatran 220 mg was superior to the enoxaparin regimen for reducing the risk of major VTE and VTE-related mortality after THR [7].

The objective of this study was to evaluate the safety and efficacy of dabigatran 220 mg po qd (the dose recommended for most patients, initiated after surgery) versus enoxaparin 40 mg sc qd (initiated before surgery) in patients with a normal body mass index (BMI) of > 20–25 kg/m², pre-obese patients (BMI > 25–30 kg/m²) and obese patients (BMI > 30 kg/m²) in three pivotal phase 3 trials [5], [6], [7].

Section snippets

Materials and methods

Data from patients receiving dabigatran etexilate 220 mg po qd or enoxaparin 40 mg sc qd with a BMI > 20–25 kg/m² (normal), > 25–30 kg/m² (pre-obese), > 30–35 kg/m² (obese class I), > 35–40 kg/m² (obese class II) or > 40 kg/m² (obese class III) from three phase 3 trials – RE-MODEL™, RE-NOVATE® and RE-NOVATE® II – were pooled for this post hoc analysis. Trial methodology is described in the original publications for the trials [5], [6], [7]. The dabigatran 150 mg qd group was excluded from the analysis based

Results

There was no difference in the demographic characteristics between the dabigatran (n = 2835) and enoxaparin (n = 2851) arms (see Table 1). The mean BMIs for patients in the dabigatran and enoxaparin arms from all three trials, separately, were between 27.5 kg/m² and 29.9 kg/m². Of the total number of patients, 1417 (24.9%) had a normal BMI (> 20–25 kg/m²), 2373 (41.7%) had a BMI > 25–30 kg/m² (pre-obese) and 1826 (32.1%) had a BMI > 30 kg/m² (obese) and were therefore included in the analysis.

In patients

Discussion

In this post-hoc analysis of three large phase 3 trials that included normal, pre-obese and obese (class I, II and III) patients undergoing TKR or THR, dabigatran 220 mg qd showed similar efficacy to enoxaparin 40 mg qd for the prevention of VTE, with no increased bleeding risk. The extent of obesity also did not appear to affect VTE occurrence or the risk of bleeding.

BMI has been the preferred anthropometric measure of obesity for many years. Obesity, as assessed by BMI, has been found to be a

Summary

In this analysis of normal and overweight patients undergoing TKR or THR, dabigatran 220 mg qd showed similar efficacy to enoxaparin 40 mg qd for the prevention of VTE, without increased bleeding risk.

Role of the funding body

The study and the analysis of data were sponsored by Boehringer Ingelheim.

Conflicts of interest statement

BE has been a consultant for Bayer Healthcare, Astellas, Takeda, Daiichi, Boehringer Ingelheim. OED has been a scientific consultant to AstraZeneca, Bayer/Johnson & Johnson, Boehringer Ingelheim, BMS, GSK, Pfizer and Sanofi-aventis. RF has no specific conflicts of interest to report. MF, AC, HN and SH are employees of Boehringer Ingelheim.

Acknowledgements

This study was sponsored by Boehringer Ingelheim Pharma GmbH & Co. KG. Writing and editorial assistance was provided by Elena Garonna of PAREXEL, who was contracted by Boehringer Ingelheim for these services.

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There are more references available in the full text version of this article.

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^☆: Presentation at a meeting: A poster on these results was presented at the XXIII Congress of the International Society on Thrombosis and Haemostasis, Kyoto, Japan, 23–28 July 2011.

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Brief communicationDabigatran is effective with a favourable safety profile in normal and overweight patients undergoing major orthopaedic surgery: A pooled analysis☆

Abstract

Introduction

Methods

Results

Conclusions

Introduction

Section snippets

Materials and methods

Results

Discussion

Summary

Role of the funding body

Conflicts of interest statement

Acknowledgements

Am J Med

J Thromb Haemost

Lancet

Eur J Vasc Endovasc Surg

Overweight, obesity, and the risk of recurrent venous thromboembolism

Arch Intern Med

Brief communication
Dabigatran is effective with a favourable safety profile in normal and overweight patients undergoing major orthopaedic surgery: A pooled analysis☆