3. Evidence from novel OAC research and national cohort studies

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AVVEROES: Apixaban in Patients with Atrial Fibrillation.

N Engl J Med 2011; 364:806-817.

Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O'Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S; AVERROES Steering Committee and Investigators. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada. stuart.connolly@phri.ca

Background: Vitamin K antagonists have been shown to prevent stroke in patients with atrial fibrillation. However, many patients are not suitable candidates for or are unwilling to receive vitamin K antagonist therapy, and these patients have a high risk of stroke. Apixaban, a novel factor Xa inhibitor, may be an alternative treatment for such patients.

Methods: In a double-blind study, we randomly assigned 5599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable to receive apixaban (at a dose of 5 mg twice daily) or aspirin (81 to 324 mg per day), to determine whether apixaban was superior. The mean follow up period was 1.1 years. The primary outcome was the occurrence of stroke or systemic embolism.

Results: Before enrollment, 40% of the patients had used a vitamin K antagonist. The data and safety monitoring board recommended early termination of the study because of a clear benefit in favor of apixaban. There were 51 primary outcome events (1.6% per year) among patients assigned to apixaban and 113 (3.7% per year) among those assigned to aspirin (hazard ratio with apixaban, 0.45; 95% confidence interval [CI], 0.32 to 0.62; P<0.001). The rates of death were 3.5% per year in the apixaban group and 4.4% per year in the aspirin group (hazard ratio, 0.79; 95% CI, 0.62 to 1.02; P=0.07). There were 44 cases of major bleeding (1.4% per year) in the apixaban group and 39 (1.2% per year) in the aspirin group (hazard ratio with apixaban, 1.13; 95% CI, 0.74 to 1.75; P=0.57); there were 11 cases of intracranial bleeding with apixaban and 13 with aspirin. The risk of a first hospitalization for cardiovascular causes was reduced with apixaban as compared with aspirin (12.6% per year vs. 15.9% per year, P<0.001). The treatment effects were consistent among important subgroups.

Conclusions: In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage. (Funded by Bristol-Myers Squibb and Pfizer; ClinicalTrials.gov number, NCT00496769.).

Connolly SJ, Eikelboom J, Joyner C, et al for the AVERROES Steering Committee and Investigators. Apixaban in Patients with Atrial Fibrillation. N Engl J Med 2011; 364:806-817. DOI: 10.1056/NEJMoa1007432. http://www.nejm.org/doi/full/10.1056/NEJMoa1007432.

Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation.

Arch Intern Med. 2010 Sep 13;170(16):1433-41.

Hansen ML, Sørensen R, Clausen MT, Fog-Petersen ML, Raunsø J, Gadsbøll N, Gislason GH, Folke F, Andersen SS, Schramm TK, Abildstrøm SZ, Poulsen HE, Køber L, Torp-Pedersen C. Department of Cardiology, Copenhagen University Hospital Gentofte, Niels Andersens Vej 65 2900, Hellerup, Copenhagen, Denmark. mlh@heart.dk

Background: Patients with atrial fibrillation (AF) often require anticoagulation and platelet inhibition, but data are limited on the bleeding risk of combination therapy.

Methods: We performed a cohort study using nationwide registries to identify all Danish patients surviving first-time hospitalization for AF between January 1, 1997, and December 31, 2006, and their posthospital therapy of warfarin, aspirin, clopidogrel, and combinations of these drugs. Cox proportional hazards models were used to estimate risks of nonfatal and fatal bleeding.

Results: A total of 82,854 of 118,606 patients (69.9%) surviving AF hospitalization had at least 1 prescription filled for warfarin, aspirin, or clopidogrel after discharge. During mean (SD) follow-up of 3.3 (2.6) years, 13,573 patients (11.4%) experienced a nonfatal or fatal bleeding. The crude incidence rate for bleeding was highest for dual clopidogrel and warfarin therapy (13.9% per patient-year) and triple therapy (15.7% per patient-year). Using warfarin monotherapy as a reference, the hazard ratio (95% confidence interval) for the combined end point was 0.93 (0.88-0.98) for aspirin, 1.06 (0.87-1.29) for clopidogrel, 1.66 (1.34-2.04) for aspirin-clopidogrel, 1.83 (1.72-1.96) for warfarin-aspirin, 3.08 (2.32-3.91) for warfarin-clopidogrel, and 3.70 (2.89-4.76) for warfarin-aspirin-clopidogrel.

Conclusions: In patients with AF, all combinations of warfarin, aspirin, and clopidogrel are associated with increased risk of nonfatal and fatal bleeding. Dual warfarin and clopidogrel therapy and triple therapy carried a more than 3-fold higher risk than did warfarin monotherapy.

Hansen ML, Sorensen R, Clausen MT, et al. Risk of bleeding with single, dual or triple therapy with warfarin, aspirin and clopidogrel in patients with atrial fibrillation. Arch Intern Med. 2010;170:1433–1441. http://www.ncbi.nlm.nih.gov/pubmed/20837828

ACTIVE W: Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial.

Lancet 2006;367:1903-1912

ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Pfeffer M, Hohnloser S, Yusuf S. Health Research Institute, Hamilton, ON, Canada. connostu@phri.ca

Background: Oral anticoagulation therapy reduces risk of vascular events in patients with atrial fibrillation. However, long-term monitoring is necessary and many patients cannot achieve optimum anticoagulation. We assessed whether clopidogrel plus aspirin was non-inferior to oral anticoagulation therapy for prevention of vascular events.

Methods: Patients were enrolled if they had atrial fibrillation plus one or more risk factor for stroke, and were randomly allocated to receive oral anticoagulation therapy (target international normalised ratio of 2.0-3.0; n=3371) or clopidogrel (75 mg per day) plus aspirin (75-100 mg per day recommended; n=3335). Outcome events were adjudicated by a blinded committee. Primary outcome was first occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death. Analyses were by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00243178.

Results: The study was stopped early because of clear evidence of superiority of oral anticoagulation therapy. There were 165 primary events in patients on oral anticoagulation therapy (annual risk 3.93%) and 234 in those on clopidogrel plus aspirin (annual risk 5.60%; relative risk 1.44 (1.18-1.76; p=0.0003). Patients on oral anticoagulation therapy who were already receiving this treatment at study entry had a trend towards a greater reduction in vascular events (relative risk 1.50, 95% CI 1.19-1.89) and a significantly (p=0.03 for interaction) lower risk of major bleeding with oral anticoagulation therapy (1.30; 0.94-1.79) than patients not on this treatment at study entry (1.27, 0.85-1.89 and 0.59, 0.32-1.08, respectively).

Conclusion: Oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation at high risk of stroke, especially in those already taking oral anticoagulation therapy.

Connolly S, Pogue J, Hart R, et al; ACTIVE Writing Group of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:1903-1912. doi:10.1016/S0140-6736(06)68845-4. http://www.ncbi.nlm.nih.gov/pubmed/16765759

Evidence from novel OAC research and national cohort studies

The whole landscape has changed with the availability of the novel oral anticoagulant drugs.  Here I show the AVERROES trial. This was a trial of the oral Factor Xa inhibitor apixaban compared to aspirin in patients who had refused warfarin, or had failed on warfarin or who were deemed unsuitable for warfarin.   This trial was stopped early because there was clear superiority of the anticoagulant apixaban over aspirin.  Importantly, if you look at major bleeding or intracranial haemorrhage, there was no significant difference apixaban, an anticoagulant, or aspirin. 

Furthermore, if you look at tolerability as reflected by permanent discontinuation of study medication, if anything apixaban - an anticoagulant - was better tolerated than aspirin. 

We also see data for the lack of efficacy, and also lack of safety, for aspirin from huge nationwide cohort studies.  This is one such study, from Denmark, where you see in the top panel, compared to warfarin, as the reference, aspirin – if anything – there is very little difference in terms of fatal and non-fatal bleeds.  If you look at fatal bleeds alone, there is no difference between warfarin and aspirin-treated patients. However, if you combine antiplatelet therapy with anticoagulant therapy, there is - no surprise – an increase in bleeding risk.

Looking at the bottom panel, you will see that in terms of reduction in stroke, in aspirin-treated patients compared to warfarin as an index, there is a very clear increase in the risk of stroke with aspirin compared to warfarin.  Adding aspirin to warfarin also confers no added advantage, so when you combine aspirin with warfarin you do significantly increase the risk of bleeding but you don’t actually gain anything by reducing the risk of stroke.

So, if aspirin monotherapy doesn’t work terribly well, what about adding it to another antiplatelet such as clopidogrel?  This was tested in the ACTIVE W. This trial was stopped because there was clear superiority in terms of the reduction of stroke and other thromboembolic events in favour of anticoagulant therapy compared to aspirin/clopidogrel in combination.  If you look at the stroke endpoint, again warfarin is superior to aspirin and clopidogrel by about 28% in terms of fewer strokes. 

But look at major bleeding risks.  In terms of major bleeds, which was the primary safety endpoint, anticoagulant therapy with warfarin the major bleed rate was 2.2% per year.  On aspirin/clopidogrel combination therapy the major bleed rate was 2.4% per year.  So it’s not really a lot of difference between aspirin/clopidogrel and warfarin-treated patient in terms of major bleeding.

Also, if you look at patients even at the lower end of risk, like those with a CHADS2 score of one, you will see that warfarin is clearly superior to aspirin/clopidogrel for reducing stroke.  If you look at bleeding, there’s really not that much difference between warfarin and aspirin/clopidogrel patients anyway.

OAC superiority: Questions

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Please find below additional resources that you might find useful when learning about stroke prevention in AF

GRASP the initiative

A report from October 2012 on the practicalities of GRASP-AF and its benefits for primary care practitioners.  The report incudes a national summary of GRASP-AF patient treatment and a series of recommendations for commissioners and practitioners on the how stroke risk among AF patients can be reduced.
Report download

The AF Report

An expert report on AF and the prevention of stroke in the UK.  The AF Report was written for a general audience and presents a thorough and current distillation of the evidence and issues in AF stroke prevention.  The report also identifies current challenges and areas where action is needed to improve the care of AF patients. Download report

The AF Stroke Risk Calculator

A simple online tool for the calculation of CHADS2 and CHADSVASc scores for AF patients.  The calculator was designed to be intuitive and sufficiently easy-to-use for patients to calculate their own risk of stroke.


The NHS Improving Quality website contains a wealth of helpful, practical information on GRASP-AF

The videos

Below are video clips from Dr Matt Fat and Dr Andreas Wolff on several aspects of AF patient care and the reduction of stroke risk.

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