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4. Additional evidence on the efficacy of oral anticoagulation and the bleeding risk with aspirin

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Antithrombotic treatment and the risk of death and stroke in patients with atrial fibrillation and a CHADS2 score=1.

Thromb Haemost. 2010;103:833-840

Gorin L, Fauchier L, Nonin E, de Labriolle A, Haguenoer K, Cosnay P, Babuty D, Charbonnier B. Service de Cardiologie, Pôle Coeur Thorax Vasculaire, Centre Hospitalier Universitaire Trousseau et Faculté de Médecine, Université François Rabelais, Tours, France.

In patients with atrial fibrillation (AF) and an intermediate risk of stroke (CHADS2 score =1), available evidence from clinical trials is inconclusive and the present guidelines for the management of AF indicate that the choice between oral anticoagulant and aspirin in these patients is open. Our goal was to evaluate whether, in patients with AF and only one moderate risk factor for thromboembolism, treatment with an oral anticoagulant is appreciably more beneficial than treatment with an antiplatelet agent. Among 6,517 unselected patients with AF, 1,012 of them (15.5%) had a CHADS2 score of 1 and were liable to treatment with an antiplatelet agent or an anticoagulant. An oral anticoagulant was prescribed for 606 patients (59.9%) and an antiplatelet agent or no antithrombotic treatment for 406 (40.1%). During follow-up (median=793 days, interquartile range=1,332 days), 105 deaths (10.4%) and 19 strokes (1.9%) were recorded. The administration of an anticoagulant was associated with a lower rate of events (relative risk=0.42, 95% confidence interval 0.29-0.60, p<0.0001) than when no anticoagulant was prescribed. Results remained similar after adjustment for age and other confounding factors. In contrast, prescription of an antiplatelet agent was not associated with a lower risk of events. Factors independently associated with an increased risk of events were older age (p<0.0001), concomitant heart failure (p=0.0002), diabetes (p=0.0025), lack of prescription of an anticoagulant (p<0.0001) and permanent AF (p=0.04). Thus, prescription of an anticoagulant is independently associated with a decreased risk of death or stroke among patients with AF and a CHADS2 score =1.

Gorin L, Fauchier L, Nonin E, et al. Antithrombotic treatment and the risk of death and stroke in patients with atrial fibrillation and a CHADS2 score=1. Thromb Haemost. 2010;103:833-840. http://www.ncbi.nlm.nih.gov/pubmed/20135077

Low-Dose Aspirin for Prevention of Stroke in Low-Risk Patients With Atrial Fibrillation: Japan Atrial Fibrillation Stroke Trial.

Stroke. 2006; 37: 447-451

Sato H, Ishikawa K, Kitabatake A, Ogawa S, Maruyama Y, Yokota Y, Fukuyama T, Doi Y, Mochizuki S, Izumi T, Takekoshi N, Yoshida K, Hiramori K, Origasa H, Uchiyama S, Matsumoto M, Yamaguchi T, Hori M; Japan Atrial Fibrillation Stroke Trial Group. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan. satoz@medone.med.osaka-u.ac.jp

Background and purpose: Although the efficacy of anticoagulant therapy for primary prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF) has been established, efficacy of antiplatelet therapy for low-risk patients is disputable in Japanese patients because of the frequent hemorrhagic complications. We examined the efficacy and safety of aspirin therapy in Japanese patients with NVAF in a prospective randomized multicenter trial.

Methods: Patients with NVAF were randomized to an aspirin group (aspirin at 150 to 200 mg per day) or a control group without antiplatelet or anticoagulant therapy. Primary end points included cardiovascular death, symptomatic brain infarction, or transient ischemic attack.

Results: A total of 426 patients were randomized to aspirin group and 445 to no treatment. The trial was stopped earlier because there were 27 primary end point events (3.1% per year; 95% CI, 2.1% to 4.6% per year) in the aspirin group versus 23 (2.4% per year; 95% CI, 1.5% to 3.5% per year) in the control group, suggesting a low possibility of superiority of the aspirin treatment for prevention of the primary end point. In addition, treatment with aspirin caused a marginally increased risk of major bleeding (7 patients; 1.6%) compared with the control group (2 patients; 0.4%; Fisher exact test P=0.101).

Conclusions: For prevention of stroke in patients with NVAF, aspirin at 150 to 200 mg per day does not seem to be either effective or safe. Further prospective studies are needed to determine the best preventive therapy for cerebrovascular events in Japanese patients with NVAF.

Sato H, Ishikawa K, Kitabatake A, et al. on behalf of the Japan Atrial Fibrillation Stroke Trial (JAST) Group. Low-Dose Aspirin for Prevention of Stroke in Low-Risk Patients With Atrial Fibrillation: Japan Atrial Fibrillation Stroke Trial. Stroke. 2006; 37: 447-451. http://www.ncbi.nlm.nih.gov/pubmed/16385088

ACTIVE A: Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation.

N Engl J Med 2009; 360:2066-2078

ACTIVE Investigators, Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M, Chrolavicius S, Yusuf S.

Background: Vitamin K antagonists reduce the risk of stroke in patients with atrial fibrillation but are considered unsuitable in many patients, who usually receive aspirin instead. We investigated the hypothesis that the addition of clopidogrel to aspirin would reduce the risk of vascular events in patients with atrial fibrillation.

Methods: A total of 7554 patients with atrial fibrillation who had an increased risk of stroke and for whom vitamin K-antagonist therapy was unsuitable were randomly assigned to receive clopidogrel (75 mg) or placebo, once daily, in addition to aspirin. The primary outcome was the composite of stroke, myocardial infarction, non-central nervous system systemic embolism, or death from vascular causes.

Results: At a median of 3.6 years of follow-up, major vascular events had occurred in 832 patients receiving clopidogrel (6.8% per year) and in 924 patients receiving placebo (7.6% per year) (relative risk with clopidogrel, 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.01). The difference was primarily due to a reduction in the rate of stroke with clopidogrel. Stroke occurred in 296 patients receiving clopidogrel (2.4% per year) and 408 patients receiving placebo (3.3% per year) (relative risk, 0.72; 95% CI, 0.62 to 0.83; P<0.001). Myocardial infarction occurred in 90 patients receiving clopidogrel (0.7% per year) and in 115 receiving placebo (0.9% per year) (relative risk, 0.78; 95% CI, 0.59 to 1.03; P=0.08). Major bleeding occurred in 251 patients receiving clopidogrel (2.0% per year) and in 162 patients receiving placebo (1.3% per year) (relative risk, 1.57; 95% CI, 1.29 to 1.92; P<0.001).

Conclusions: In patients with atrial fibrillation for whom vitamin K-antagonist therapy was unsuitable, the addition of clopidogrel to aspirin reduced the risk of major vascular events, especially stroke, and increased the risk of major hemorrhage. (ClinicalTrials.gov number, NCT00249873.)

The ACTIVE Investigators. Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation. N Engl J Med 2009; 360:2066-2078. DOI: 10.1056/NEJMoa0901301. http://www.ncbi.nlm.nih.gov/pubmed/19336502

Additional evidence on the efficacy of oral anticoagulation and the bleeding risk with aspirin

Other data are available.  This is French data set from Gorin and colleagues. If you look at anticoagulant-treated patients, there’s a clear and significant reduction in stroke and mortality.  Don’t forget from the original historical trials, anticoagulant therapy reduced stroke, but also reduced mortality.  If you look at antiplatelet therapy, none of the p values is significant.  So if you and I are serious about preventing stroke and mortality in patients with atrial fibrillation, it’s oral anticoagulant therapy.

Well, if we don’t give aspirin to high risk or moderate risk patient, why don’t we give it to low risk patients, because there’s a perception that we need to give aspirin to somebody… because it’s a good drug?  This was tested in the Japanese AF Stroke Trial where low-risk atrial fibrillation patients were randomised to aspirin or control. If you look at the primary endpoint which was stroke and other thromboembolic complications, there was no difference between aspirin and control for thromboembolic complications, but if you look at the safety aspects, particularly major bleeding and intracranial bleeding, there was a trend toward worse outcomes with aspirin-treated patients.

I spoke about the ACTIVE W trial a bit earlier which compared warfarin versus aspirin plus clopidogrel combination therapy.  As part of the ACTIVE trial programme there was the ACTIVE A trial, and that shown on this slide. In this trial, patients who were deemed unsuitable for anticoagulation therapy with warfarin were randomised to aspirin/clopidogrel or aspirin monotherapy.  For stroke, we see that aspirin/clopidogrel combination therapy does offer a little bit extra advantage in terms of a 28% reduction in stroke. 

But let’s look again at the bleeding risk.  This is partly highlighted earlier, if you have combination antiplatelet therapy with aspirin/clopidogrel, we’re talking about major bleed rates in the region of just about 2%, which is the ballpark figure if you gave the patients warfarin.  So, aspirin/clopidogrel might offer a little bit extra advantage in terms of reducing stroke but the cost is a risk of major bleeding which is comparable to that seen with oral anticoagulant therapy.  But the point for highlighting again the ACTIVE-A trial is on the bottom table.  If you look at the reasons for enrolment into ACTIVE-A, 50% was on the basis of physician assessment that the patient was inappropriate for warfarin therapy.  There are other studies which clearly show that physician assessment is actually pretty nebulous when you come to discussing stroke risk and bleeding risk.  Also of note, 26% were because of patient preference, in other words, usually patient refusal.  Sometimes, of course, despite all out efforts to try to star a patient on antithrombotic therapy, particularly as until only recently we had only warfarin, which is an inconvenient drug with disadvantages, very clearly patient preferences come into the equation.  Perhaps this will all change now with the novel oral anticoagulants. 

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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.

NHS IQ: GRASP-AF

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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