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1. Poor evidence for the efficacy of aspirin

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Hart meta-analysis: Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.

Ann Intern Med. 2007 Jun 19;146(12):857-67.

Hart RG, Pearce LA, Aguilar MI. Department of Medicine (Neurology), University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA. hartr@uthscsa.edu.

Background: Atrial fibrillation is a strong independent risk factor for stroke.

Purpose: To characterize the efficacy and safety of antithrombotic agents for stroke prevention in patients who have atrial fibrillation, adding 13 recent randomized trials to a previous meta-analysis.

Data sources: Randomized trials identified by using the Cochrane Stroke Group search strategy, 1966 to March 2007, unrestricted by language.

Study selection: All published randomized trials with a mean follow-up of 3 months or longer that tested antithrombotic agents in patients who have nonvalvular atrial fibrillation.

Data extraction: Two coauthors independently extracted information regarding interventions; participants; and occurrences of ischemic and hemorrhagic stroke, major extracranial bleeding, and death.

Data synthesis: Twenty-nine trials included 28,044 participants (mean age, 71 years; mean follow-up, 1.5 years). Compared with the control, adjusted-dose warfarin (6 trials, 2900 participants) and antiplatelet agents (8 trials, 4876 participants) reduced stroke by 64% (95% CI, 49% to 74%) and 22% (CI, 6% to 35%), respectively. Adjusted-dose warfarin was substantially more efficacious than antiplatelet therapy (relative risk reduction, 39% [CI, 22% to 52%]) (12 trials, 12 963 participants). Other randomized comparisons were inconclusive. Absolute increases in major extracranial hemorrhage were small (< or =0.3% per year) on the basis of meta-analysis.

Limitation: Methodological features and quality varied substantially and often were incompletely reported.

Conclusions: Adjusted-dose warfarin and antiplatelet agents reduce stroke by approximately 60% and by approximately 20%, respectively, in patients who have atrial fibrillation. Warfarin is substantially more efficacious (by approximately 40%) than antiplatelet therapy. Absolute increases in major extracranial hemorrhage associated with antithrombotic therapy in participants from the trials included in this meta-analysis were less than the absolute reductions in stroke. Judicious use of antithrombotic therapy importantly reduces stroke for most patients who have atrial fibrillation.

Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146: 857-867. http://www.ncbi.nlm.nih.gov/pubmed/17577005

SPAF-I: Stroke Prevention in Atrial Fibrillation Study. Final results.

Circulation. 1991 Aug;84(2):527-39.

Background: Atrial fibrillation in the absence of rheumatic valvular disease is associated with a fivefold to sevenfold increased risk of ischemic stroke.

Methods and main results: The Stroke Prevention in Atrial Fibrillation Study, a multicenter, randomized trial, compared 325 mg/day aspirin (double-blind) or warfarin with placebo for prevention of ischemic stroke and systemic embolism (primary events), and included 1,330 inpatients and outpatients with constant or intermittent atrial fibrillation. During a mean follow-up of 1.3 years, the rate of primary events in patients assigned to placebo was 6.3% per year and was reduced by 42% in those assigned to aspirin (3.6% per year; p = 0.02; 95% confidence interval, 9-63%). In the subgroup of warfarin-eligible patients (most less than 76 years old), warfarin dose-adjusted to prolong prothrombin time to 1.3-fold to 1.8-fold that of control reduced the risk of primary events by 67% (warfarin versus placebo, 2.3% versus 7.4% per year; p = 0.01; 95% confidence interval, 27-85%). Primary events or death were reduced 58% (p = 0.01) by warfarin and 32% (p = 0.02) by aspirin. The risk of significant bleeding was 1.5%, 1.4%, and 1.6% per year in patients assigned to warfarin, aspirin, and placebo, respectively.

Conclusions: Aspirin and warfarin are both effective in reducing ischemic stroke and systemic embolism in patients with atrial fibrillation. Because warfarin-eligible patients composed a subset of all aspirin-eligible patients, the magnitude of reduction in events by warfarin versus aspirin cannot be compared. Too few events occurred in warfarin-eligible patients to directly assess the relative benefit of aspirin compared with warfarin, and the trial is continuing to address this issue. Patients with nonrheumatic atrial fibrillation who can safely take either aspirin or warfarin should receive prophylactic antithrombotic therapy to reduce the risk of stroke.

Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation. 1991;84:527-39, doi:10.1161/01.CIR.84.2.527

Poor evidence for the efficacy of aspirin

I’m Gregory Lip from the University of Birmingham in the United Kingdom and I’m here to speak about stroke prevention in patients with atrial fibrillation (AF). 

We have lots of data from the randomised trials in relation to preventing stroke in AF.  I show here a meta-analysis, from Bob Hart - published in 2007, of the original historical trials that examined antithrombotic therapy in patients with AF.

We have on the left panel the original trials comparing oral anticoagulant therapy versus placebo control; and the use of anticoagulant therapy, its actually warfarin, reduced the risk of stroke by 64%, and also reduced all-cause-mortality by 26%.

On the right we have antiplatelet therapy, and if you look at the antiplatelet therapy trials and do the meta-analysis of these trials, there’s a 22% reduction in stroke.  A 22% reduction is similar to what you see if you simply give antiplatelet therapy to patients with cardiovascular risk factors, or vascular disease.  Atrial fibrillation commonly co-exists with vascular disease, so it’s no surprise that you see this 22% reduction.

If you confine the data to the trials that examine aspirin only, within the red box on the slide, combining the trial in a meta-analysis of the aspirin-only trials, there is a reduction of 19%.  But this is not significant; the confidence intervals go from -1 to about 35%.  By convention in a meta-analysis this is not statistically significant.

You will also see that this 19% reduction is driven by the one positive trial, the SPAF I trial, which is highlighted in the green box. In the SPAF I trial aspirin was used at 325 mg once a day. It was reported that aspirin, compared to placebo control, reduced the risk of stroke by 42%. So please note that this result was driven by the single trial that was positive for aspirin in patients with atrial fibrillation.

But the devil is in the detail.  This slide shows the detail of the SPAF-I trial.  You will see that patients in AF were divided into Anticoagulation Eligible (Group 1) patients and Anticoagulation Ineligible (Group 2) patients.  In Group 1, patients were randomised to warfarin, aspirin or placebo.  In Group 2, the anticoagulation ineligible patients were randomised to aspirin or placebo.

Look at the detail of the results here. In the Group 1 patients, aspirin: 1 event.  Placebo: 18 events; translating to a suggested 94% reduction in stroke compared to the placebo control.  I’m certainly not aware of any intervention to prevent stroke that reduces stroke by over 90% compared to placebo.

Let’s look at Group 2.  Aspirin-treated patients: 25 events.  Placebo-treated patients: 28 events.  Risk reduction of 8%, not significant.  The SPAF-I investigators combined the data to get this headline result of 42% risk reduction overall for aspirin versus placebo.  So that is the one, single positive trial for aspirin for stroke prevent in atrial fibrillation.

In conclusion, the evidence for aspirin’s efficacy in stroke prevention is pretty weak.

Aspirin efficacy: 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.

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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