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2. Elderly patients: aspirin is no better tolerated than oral anticoagulation

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BAFTA: Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial.

The Lancet, Volume 370, Issue 9586, Pages 493 - 503, 11 August 2007

Mant J, Hobbs FD, Fletcher K, Roalfe A, Fitzmaurice D, Lip GY, Murray E; BAFTA investigators; Midland Research Practices Network (MidReC). Primary Care Clinical Sciences, University of Birmingham, Birmingham, UK. j.w.mant@bham.ac.uk

Background: Anticoagulants are more effective than antiplatelet agents at reducing stroke risk in patients with atrial fibrillation, but whether this benefit outweighs the increased risk of bleeding in elderly patients is unknown. We assessed whether warfarin reduced risk of major stroke, arterial embolism, or other intracranial haemorrhage compared with aspirin in elderly patients.

Methods: 973 patients aged 75 years or over (mean age 81·5 years, SD 4·2) with atrial fibrillation were recruited from primary care and randomly assigned to warfarin (target international normalised ratio 2—3) or aspirin (75 mg per day). Follow-up was for a mean of 2·7 years (SD 1·2). The primary endpoint was fatal or disabling stroke (ischaemic or haemorrhagic), intracranial haemorrhage, or clinically significant arterial embolism. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN89345269.

Findings: There were 24 primary events (21 strokes, two other intracranial haemorrhages, and one systemic embolus) in people assigned to warfarin and 48 primary events (44 strokes, one other intracranial haemorrhage, and three systemic emboli) in people assigned to aspirin (yearly risk 1·8% vs 3·8%, relative risk 0·48, 95% CI 0·28—0·80, p=0·003; absolute yearly risk reduction 2%, 95% CI 0·7—3·2). Yearly risk of extracranial haemorrhage was 1·4% (warfarin) versus 1·6% (aspirin) (relative risk 0·87, 0·43—1·73; absolute risk reduction 0·2%, −0·7 to 1·2).

Interpretation: These data support the use of anticoagulation therapy for people aged over 75 who have atrial fibrillation, unless there are contraindications or the patient decides that the benefits are not worth the inconvenience.

Mant J, Hobbs FD, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007;370:493–503. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2807%2961233-1/abstract

WASPO: A randomised controlled trial of warfarin versus aspirin for stroke prevention in octogenarians with atrial fibrillation (WASPO).

Age Ageing. 2007 Mar;36(2):151-6. Epub 2006 Dec 15.

Rash A, Downes T, Portner R, Yeo WW, Morgan N, Channer KS. Northern General Hospital, Medicine for the Elderly, Sheffield, UK.

Background: atrial fibrillation (AF) is the commonest chronic arrhythmia with a prevalence of 9% in octogenarians and accounts for 24% of the stroke risk in this population. Although trials demonstrate reductions in stroke with warfarin, audit data show that it is still underused. However, anti-coagulation in the very elderly is not without risk.

Methods: randomised open labelled prospective study of primary thromboprophylaxis for AF. Patients aged >80 and <90 were randomised to receive dose-adjusted warfarin (INR 2.0-3.0) or aspirin 300 mg. All patients had permanent AF, were ambulant, had Folstein mini mental score >25 and had no contraindications to either treatment. Follow-up was for 1 year with 3 monthly visits. The primary outcome measure was a comparative frequency of combined endpoints comprising death, thromboembolism, serious bleeding and withdrawal from the study.

Results: seventy-five patients (aspirin 39; warfarin 36) were entered (mean age 83.9, 47% male). There were significantly more adverse events with aspirin (13/39; 33%) than warfarin (2/36; 6%), P = 0.002. 10/13 aspirin adverse events were caused by side effects and serious bleeding; there were three deaths (two aspirin, one warfarin).

Conclusion: dose-adjusted warfarin was significantly better tolerated with fewer adverse events than aspirin 300 mg in this elderly population. Although aspirin 75 mg may have been better tolerated, there is no evidence for efficacy in AF at this dose.

Rash A, Downes T, Portner R, et al. A randomised controlled trial of warfarin versus aspirin for stroke prevention in octogenarians with atrial fibrillation (WASPO). Age Ageing 2007;36:151-6. doi: 10.1093/ageing/afl129. http://www.ncbi.nlm.nih.gov/pubmed/17175564

Effect of Age on Stroke Prevention Therapy in Patients With Atrial Fibrillation

Stroke 2009;40:1410-1416

van Walraven C, Hart RG, Connolly S, Austin PC, Mant J, Hobbs FD, Koudstaal PJ, Petersen P, Perez-Gomez F, Knottnerus JA, Boode B, Ezekowitz MD, Singer DE. University of Ottawa and Ottawa Health Research Institute Canada, Ottawa, Canada. carlv@ohri.ca

Background and Purpose: Stroke risk increases with age in patients who have nonvalvular atrial fibrillation. It is uncertain whether the efficacy of stroke prevention therapies in atrial fibrillation changes as patients age. The objective of this study was to determine the effect of age on the relative efficacy of oral anticoagulants (OAC) and antiplatelet (AP) therapy (including acetylsalicylic acid and triflusal) on ischemic stroke, serious bleeding, and vascular events in patients with atrial fibrillation.

Methods: This is an analysis of the Atrial Fibrillation Investigators database, which contains patient level-data from randomized trials of stroke prevention in atrial fibrillation. We used Cox regression models with age as a continuous variable that controlled for sex, year of randomization, and history of cerebrovascular disease, diabetes, hypertension, and congestive heart failure. Outcomes included ischemic stroke, serious bleeding (intracranial hemorrhage or systemic bleeding requiring hospitalization, transfusion, or surgery), and cardiovascular events (ischemic stroke, myocardial infarction, systemic embolism, or vascular death).

Results: The analysis included 8932 patients and 17 685 years of observation from 12 trials. Patient age increased risk of ischemic stroke (adjusted hazard ratio per decade increase 1.45; 95% CI, 1.26 to 1.66), serious bleeding (1.61; 1.47 to 1.77), and cardiovascular events (1.43; 1.33 to 1.53). Compared with placebo, OAC and AP significantly reduced the risk of ischemic stroke (OAC, 0.36; 0.29 to 0.45; AP, 0.81; 0.72 to 0.90) and cardiovascular outcomes (OAC, 0.59; 0.52 to 0.66; AP, 0.81; 0.75 to 0.88), whereas OAC increased risk of serious bleeding (1.56; 1.03 to 2.37). The relative benefit of OAC versus placebo or AP did not vary by patient age for any outcome. Compared with placebo, the relative benefit of AP for preventing ischemic stroke decreased significantly as patients aged (P=0.01).

Conclusions: As patients with atrial fibrillation age, the relative efficacy of AP to prevent ischemic stroke appears to decrease, whereas it does not change for OAC. Because stroke risk increases with age, the absolute benefit of OAC increases as patients get older.

van Walraven C, Hart RG, Connolly S, Austin PC, Mant J, Hobbs FD, Koudstaal PJ, Petersen P, Perez-Gomez F, Knottnerus JA, Boode B, Ezekowitz MD, Singer DE. Effect of age on stroke prevention therapy in patients with atrial fibrillation. Stroke 2009;40:1410-1416. doi: 10.1161/STROKEAHA.108.526988. http://stroke.ahajournals.org/content/40/4/1410.short

Elderly patients: aspirin is no better tolerated than oral anticoagulation

Further data come from elderly patients.  This is the BAFTA trial, the Birmingham Atrial Fibrillation Treatment of the Aged trial. When we conducted this trial it was perceived that warfarin was not well tolerated in elderly patients, and that aspirin was a better alternative.  Well, in this trial you see that for the primary endpoint, warfarin clearly superior to aspirin over 50% reduction in stroke and thromboembolic events with warfarin compared to aspirin.  So, no surprises: warfarin superior to aspirin.  I would emphasise the point that the BAFATA trial was done in primary care in elderly patients, aged over 75.  This was a trial run by general practitioners. 

But the important thing in the BAFTA trial was the fact that there was no significant difference in major bleeding, and no significant difference in intra-cranial bleeding, between the warfarin-treated patients and the aspirin-treated patients. 

We have other data, also in elderly patients.  This is the WASPO trial, a very small trial done in octogenarians. It’s too small to make too much comment on the efficacy endpoints but look at the adverse effect rate.  You see that patients in this trial, randomised to warfarin or aspirin, you see markedly increased risk of adverse effects on aspirin compared to warfarin.  A 44% combined outcome event rate in aspirin-treated patients, 33% of which are side effects, compared to warfarin, which is in the minority.  So even in octogenarians, aspirin is not well tolerated when used for stoke prevention in atrial fibrillation.

Age is a very important driver of stroke.  The risk of stroke in atrial fibrillation starts to rise from age 65.  As shown on this slide, this is data from the AF Investigators, it shows very clearly that as the patient gets older, the stroke rate goes higher, as does the cardiovascular event rate. So no surprises there.  But as the patient gets older, the absolute gain in terms of reduction in stroke and vascular events gets larger and larger with anticoagulant therapy.  That’s the black dots there.  So the absolute difference between the red dots, the untreated patients, compared to the treated patients, the black dots, gets larger as the patient gets older.  However, if you look at antiplatelet therapy; as the patient gets older the absolute difference of benefit of antiplatelet therapy declines as the patient gets older. 

Turning now to panel B, which is serious bleeding.  With increasing age, serious bleeding does rise.  But no surprises, with antithrombotic therapy, whether with aspirin or with warfarin, it also rises slightly compared to no therapy.  But the absolute difference in terms of serious bleeding on antithrombotic therapy compared to no therapy is far outweighed by the absolute gain in terms of the reduction in stroke, as well as cardiovascular events, by treating with anticoagulant therapy.  So in elderly patients, really the best therapy, if you and I are serious about stroke prevention, is anticoagulant therapy.

Aspirin safety: 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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