Edoxaban versus placebo, aspirin, or aspirin plus clopidogrel for stroke prevention in atrial fibrillation. An indirect comparison analysis.

Blann AD, Skjøth F, Rasmussen LH, Larsen TB, Lip GY.
Thromb Haemost. 2015 Jul 28;114(2):403-9. doi: 10.1160/TH15-05-0383. Epub 2015 Jun 11.

Background

Patients with non-valvular atrial fibrillation (AF) are at risk of stroke and systemic embolism. Therefore, oral anticoagulants (OACs) are recommended; either vitamin-K antagonists or NOACs [1].
Because of disadvantages of VKAs, many patients remain untreated or are treated with anti-platelet agents [2-4].
These disadvantages could be abolished by using a NOAC, which overall have a better relative efficacy and safety profile than VKAs [5-7].
The effectiveness and safety of the NOAC edoxaban were examined in the ENGAGE AF trial, comparing the two once-daily doses of edoxaban with dose-adjusted warfarin in AF patients with moderate-to-high-risk of stroke over a median followup period of 2.8 years [7].
In the present study, it was hypothesised that edoxaban has a better net clinical benefit (NCB, balancing the reduction in stroke risk vs increased risk of haemorrhage) than no treatment or anti-platelet agents.
A network meta-analysis of published data from 24 studies of 203,394 AF patients in clinical trial populations and in ‘real world’ unselected general populations was performed to indirectly compare once daily edoxaban 30 mg and 60 mg with aspirin alone, aspirin plus clopidogrel, and placebo.
Data were obtained from 1,486 titles from 23 eligible trials with 31 direct comparisons enrolling 71,022 patients, and a community study of 132,372 patients [8]. Data were extracted for the endpoints of all stroke, ischaemic stroke, systemic embolism, mortality, ICH and acute myocardial infarction, for all treatment modes (placebo, aspirin monotherapy, aspirin plus clopidogrel, adjusted dose VKA and the two dosing regimens of edoxaban. [7,9]

Main results

• Edoxaban 30 mg once daily significantly reduced the risk of all stroke, ischaemic stroke and mortality compared to placebo and aspirin, based on indirect comparison analyses. (stroke: RR resp. 0.46 and 0.60 for placebo and aspirin; ischaemic stroke: RR resp. 0.55 and 0.52; death: RR resp 0.64 and 0.82)
• Edoxaban 60 mg once daily significantly reduced the risk of any stroke and systemic embolism compared to placebo, aspirin, and aspirin plus clopidogrel, based on indirect comparison analyses.(stroke: RR 0.36 and 0.46, respectively, for placebo and aspirin; ischaemic stroke: RR 0.39 and 0.37; death: RR 0.67 and 0.86).
• Edoxaban 60 mg eenmaal daags verminderde het risico van een beroerte en systemische embolie significant in vergelijking met placebo, aspirine en aspirine plus clopidogrel, op basis van indirecte vergelijkingsanalyses.
• Mortality rates for both edoxaban doses were estimated to be lower compared to any anti-platelet, and significantly lower compared to placebo.
• Edoxaban is likely to provide as good or even better protection from stroke and intracranial haemorrhage than placebo, aspirin alone, or aspirin plus clopidogrel.
• Both edoxaban doses would also bring a net clinical benefit of mean (SD) 1.68 (0.15) saved events per 100 patients per year compared to anti-platelet drugs in a clinical trial population. The NCB was demonstrated to be lower, at 0.77 (0.12) events saved (p< 0.01) when modeled to data from a ‘real world’ cohort of AF patients. 

Conclusion

Edoxaban is likely to provide better protection from stroke and ICH than placebo, aspirin alone, or aspirin plus clopidogrel in both clinical trial populations and unselected community populations. Both edoxaban doses would also bring a positive NCB compared to anti-platelet drugs or placebo/non-treatment based on ‘real world’ data.

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References

1. Camm AJ, Lip GY, De Caterina R, et al.; ESC Committee for Practice Guidelines (CPG). 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Eur Heart J 2012; 33: 2719–2747.
2. Romero-Ortuno R, O’Shea D. Aspirin versus Warfarin in Atrial Fibrillation. Age Ageing 2012; 41: 250–254.
3. Boulanger L, Kim J, Friedman M, et al. Patterns of use of antithrombotic therapy and quality of anticoagulation among patients with non-valvular atrial fibrillation in clinical practice. Int J Clin Pract 2006; 60: 258–264.
4. Monte S, Macchia A, Pellegrini F, et al. Antithrombotic treatment is strongly underused despite reducing overall mortality among high-risk elderly patients hospitalized with atrial fibrillation. Eur Heart J 2006; 27: 2217–2223.
5. Sardar P, Chatterjee S, Wu WC, et al. New oral anticoagulants are not superior to warfarin in secondary prevention of stroke or transient ischaemic attacks, but lower the risk of intracranial bleeding: insights from a meta-analysis and indirect treatment comparisons. PLoS One 2013; 8: e77694.
6. Sardar P, Chatterjee S, Chaudhari S, et al. New oral anticoagulants in elderly adults: evidence from a meta-analysis of randomized trials. J Am Geriatr Soc 2014; 62: 857–864.
7. Giugliano RP, Ruff CT, Braunwald E, et al. ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369: 2093–2104.
8. Olesen JB, Lip GYH, Lindhardsen J, 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.
9. Roskell NS, Lip GY, Noack H, 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.