Expert Review: Thrombosis

Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibrillation

Background
Atrial fibrillation (AF) as an age-related disease represents an increasing challenge to Western societies due to its increasing prevalence, and the burden of stroke and thromboembolism associated with this common arrhythmia. Patients with non-valvular AF (NVAF) are exposed to an increased risk of ischemic stroke and systemic embolism, as well as mortality, which is reduced by antithrombotic therapy2,3. However, severe bleeding complications, including intracranial haemorrhage have limited the optimal use of vitamin K antagonists (VKAs), particularly in the elderly4. This is despite the net clinical benefit balancing stroke against serious bleeding, largely being in favour of oral anticoagulation (rather than non-anticoagulation)5.

Oral direct factor Xa inhibitors and oral direct thrombin inhibitors specifically targeting only one coagulation factor have been developed. Their efficacy and safety have been investigated for prevention of ischemic stroke and systemic embolism in patients with NVAF with dabigatran in the RE-LY trial (150 mg and 110 mg bid)6,7, rivaroxaban in the ROCKET AF trial (20 mg od)8, and apixaban in the ARISTOTLE trial (5 mg bid)9 versus INR-adjusted warfarin.
All trials showed non-inferiority or superiority for the efficacy outcome of combined ischemic stroke and systemic embolism. Rates of major bleeding complications were similar or even reduced in comparison with warfarin for all three novel oral anticoagulants (NOAC). The current scientific discussion aims at defining differentiating efficacy/safety profiles for the NOACs in patients suffering from NVAF.

Knowledge Gap
A head to head comparison of these NOACs would require a large number of patients, thus be expensive and therefore unlikely to be performed.

Aim of the Study
The aim of this study was to indirectly compare the three agents for major efficacy and safety outcomes. Studies were assessed for comparability and the hazard ratio and corresponding uncertainty were estimated by the Butcher method.

Methods
Studies were assessed for comparability and the hazard ratio and corresponding uncertainty were estimated by the Butcher method.

Results
The estimated hazard ratio of stroke or systemic embolism was 0.74 for dabigatran 150 vs rivaroxaban (95%CI 0.56-0.97), 1.02 for dabigatran 110 mg versus rivaroxaban (95%CI 0.79-1.32), 1.22 for apixaban versus dabigatran 150 mg (95%CI 0.91-1.62), 0.88 for apixaban versus dabigatran 110 mg (95%CI 0.67-1.15) and 0.90 for apixaban versus rivaroxaban (95%CI 0.71-1.13). The estimated hazard ratio of major bleeding was 0.89 for dabigatran 150 mg versus rivaroxaban (95%CI 0.73-1.09), 0.77 for dabigatran 110 mg rivaroxaban (95%CI 0.63-0.94), 0.74 for apixaban versus dabigatran 150 mg (95%CI 0.61-0.91), 0.86 for apixaban versus dabigatran 110 mg (95%CI 0.7-1.06) and 0.66 for apixaban versus rivaroxaban (95%CI 0.54-0.81).

Conclusion
These data indicate no significant difference in efficacy between dabigatran (both doses) and apixaban for the prevention of stroke or systemic embolism in patients with NVAF. It appears however that apixaban is associated with less major bleeding than dabigatran 150 mg or rivaroxaban and that rivaroxaban is less effective than dabigatran 150 mg in preventing stroke or systemic embolism. Such an indirect comparison should be used only to generate hypotheses which need to be tested in a dedicated randomised trial comparing the three drugs directly.

Clinical Impact:
The results of this study highlight the relevance of the NOACs; all consistently indicate the substantial benefit of the NOACs for the patients suffering from AF and the potential reduction of harm by bleeding complications seen when compared to VKA. Thus, the net clinical benefit favours NOACs compared to VKAs for many patients. Also, stroke prevention is central to the holistic management of AF, as recently highlighted by a consensus document from the German AF-NET/European Heart Rhythm Association1.
Since the results from a large (and expensive) head-to-head randomised controlled trial may take years to be performed, current data should help decide doctors whether to change to or to start with one of the NOACs depending on the individual thrombotic or bleeding risk.

Corresponding author from original paper
Prof. Gregory Y. H. Lip, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham B18 7QH, United Kingdom.
E-mail g.y.h.lip@bham.ac.uk.

References:
1. Kirchhof P, Lip GY, Van Gelder IC, et al. Comprehensive risk reduction in patients with atrial fibrillation: Emerging diagnostic and therapeutic options. Executive summary of the report from the 3rd AFNET/EHRA consensus conference. Thromb Haemost 2011; 106: 1012–1019.
2. Roskell NS, et al. Treatments for stroke prevention in atrial fibrillation: a network meta-analysis and indirect comparisons versus dabigatran etexilate. Thromb Haemost 2010; 104: 1106–1115.
3. Hart RG, et al. Adjusted-dose warfarin versus aspirin for preventing stroke in patients with atrial fibrillation. Ann Intern Med 2007; 147: 590–592.
4. Wilke T, et al. Oral anticoagulation use by patients with atrial fibrillation in Germany. Adherence to guidelines, causes of anticoagulation under-use and its clinical outcomes, based on claims-data of 183,448 patients. Thromb Haemost 2012; 107: 1053–1065.
5. Olesen JB, et al. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: A net clinical benefit analysis using a ‘real world’ nationwide cohort study. Thromb Haemost 2011; 106: 739–749.
6. Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139–1151.
7. Connolly SJ, et al. Newly identified events in the RELY trial. N Engl J Med 2010; 363: 1875–1876.
8. Patel MR, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883–891.
9. Granger CB, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981–992.
10. Mantha S, Ansell J. An Indirect Comparison of Dabigatran, Rivaroxaban and Apixaban for Atrial Fibrillation. Thromb Haemost 2012; 108: 476–484.

Citation: JACC 2012; 60:738

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