Edoxaban versus placebo, aspirin, or aspirin plus clopidogrel for stroke prevention in atrial fibrillation

Summary

As non-valvular atrial fibrillation (AF) brings a risk of stroke, oral anticoagulants (OAC) are recommended. In ‘real world’ clinical practice, many patients (who may be, or perceived to be, intolerant of OACs) are either untreated or are treated with anti-platelet agents. We 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. We performed a network meta-analysis of published data from 24 studies of 203,394 AF patients to indirectly compare edoxaban with aspirin alone, aspirin plus clopidogrel, and placebo. Edoxaban 30 mg once daily significantly reduced the risk of all stroke, ischaemic stroke and mortality compared to placebo and aspirin. Compared to aspirin plus clopidogrel, there was a lower risk of intra-cranial haemorrhage (ICH). Edoxaban 60 mg once-daily had a reduced risk of any stroke and systemic embolism compared to placebo, aspirin, and aspirin plus clopidogrel. Mortality rates for both edoxaban doses were estimated to be lower compared to any anti-platelet, and significantly lower compared to placebo. With overall reduced risk of ischemic stroke and ICH, both edoxaban doses bring a NCB 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. In conclusion, edoxaban is likely to provide even 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.

Note: The review process for this paper was fully handled by Christian Weber, Editor in Chief.

Keywords

Oral anti-coagulation - atrial fibrillation - edoxaban - warfarin - aspirin - clopidogrel

• 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; 08: 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 Bucher HC, Guyatt GH, Griffith LE. et al. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol 1997; 50: 683-691.
• 9 Lumley T. Network meta-analysis for indirect treatment comparisons. Stat Med 2002; 21: 2313-2324.
• 10 Hoaglin DC, Hawkins N, Jansen JP. et al. Conducting indirect-treatment-comparison and network-meta-analysis studies: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 2. Value Heal 2011; 14: 429-437.
• 11 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.
• 12 Cameron C, Coyle D, Richter T. et al. Systematic review and network meta-analysis comparing antithrombotic agents for the prevention of stroke and major bleeding in patients with atrial fibrillation. Br Med J Open 2014; 04: e004301.
• 13 Rasmussen LH, Larsen TB, Graungaard T. et al. Primary and secondary prevention with new oral anticoagulant drugs for stroke prevention in atrial fibrillation: indirect comparison analysis. Br Med J 2012; 345: e7097.
• 14 Lip GY, Larsen TB, Skjøth F. et al. Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibrillation. J Am Coll Cardiol 2012; 60: 738-746.
• 15 Skjøth F, Larsen TB, Rasmussen LH. et al. Efficacy and safety of edoxaban in comparison with dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation. An indirect comparison analysis. Thromb Haemost 2014; 111: 981-988.
• 16 Verdecchia P, Angeli F, Lip GY. et al. Edoxaban in the evolving scenario of nonvitamin K antagonist oral anticoagulants imputed placebo analysis and multiple treatment comparisons. PLoS One 2014; 09: e100478.
• 17 Dogliotti A, Paolasso E, Giugliano RP. Current and new oral antithrombotics in non-valvular atrial fibrillation: a network meta-analysis of 79,808 patients. Heart 2014; 100: 396-405.
• 18 Jadad AR, Moore RA, Carroll D. et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials 1996; 17: 1-12.
• 19 Franchini AJ, Dias S, Ades AE. et al. Accounting for correlation in network meta-analysis with multi-arm trials. Res Synth Methods 2012; 03: 142-160.
• 20 Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med 2004; 23: 1351-1375.
• 21 Singer DE, Chang Y, Fang MC. et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med 2009; 151: 297-305.
• 22 Banerjee A, Lane DA, Torp-Pedersen C. et al. Net clinical benefit of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a ‘real world’ atrial fibrillation population: a modelling analysis based on a nationwide cohort study. Thromb Haemost 2012; 107: 584-589.
• 23 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.
• 24 Connolly SJ, Eikelboom J, Joyner C. et al. AVERROES Steering Committee and Investigators.. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806-817.
• 25 National Institute of Health and Care Excellence (NICE).. Clinical guideline 180: The management of atrial fibrillation. www.nice.org.uk.
• 26 Royal College of Physicians.. Sentinel Stroke National Audit Programme (SSNAP). Clinical audit first pilot public report; August 2013. Available at: https://www.rcplondon.ac.uk/projects/sentinel-stroke-national-audit-programme.
• 27 Lip GYH, Laroche C, Dan GA. et al. A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry. Europace 2014; 16: 308-319.
• 28 NICE Implementation collaboration.. Consensus: Supporting local implementation of NICE guidance on use of the novel (non-Vitamin K antagonist) oral anticoagulants in non-valvular AF. www.nice.org.uk.