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6. Poor evidence for aspirin in stable vascular disease

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Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index. A randomized controlled trial.

JAMA 2010; 303:841-848

Fowkes FG, Price JF, Stewart MC, Butcher I, Leng GC, Pell AC, Sandercock PA, Fox KA, Lowe GD, Murray GD; Aspirin for Asymptomatic Atherosclerosis Trialists. Centre for Population Health Sciences, University of Edinburgh, Scotland. gerry.fowkes@ed.ac.uk

Context: A low ankle brachial index (ABI) indicates atherosclerosis and an increased risk of cardiovascular and cerebrovascular events. Screening for a low ABI can identify an asymptomatic higher risk group potentially amenable to preventive treatments.

Objective: To determine the effectiveness of aspirin in preventing events in people with a low ABI identified on screening the general population.

Design, setting and participants: The Aspirin for Asymptomatic Atherosclerosis trial was an intention-to-treat double-blind randomized controlled trial conducted from April 1998 to October 2008, involving 28,980 men and women aged 50 to 75 years living in central Scotland, free of clinical cardiovascular disease, recruited from a community health registry, and had an ABI screening test. Of those, 3350 with a low ABI (< or = 0.95) were entered into the trial, which was powered to detect a 25% proportional risk reduction in events.

Interventions: Once daily 100 mg aspirin (enteric coated) or placebo.

Main outcome measures: The primary end point was a composite of initial fatal or nonfatal coronary event or stroke or revascularization. Two secondary end points were (1) all initial vascular events defined as a composite of a primary end point event or angina, intermittent claudication, or transient ischemic attack; and (2) all-cause mortality.

Results: After a mean (SD) follow-up of 8.2 (1.6) years, 357 participants had a primary end point event (13.5 per 1000 person-years, 95% confidence interval [CI], 12.2-15.0). No statistically significant difference was found between groups (13.7 events per 1000 person-years in the aspirin group vs 13.3 in the placebo group; hazard ratio [HR], 1.03; 95% CI, 0.84-1.27). A vascular event comprising the secondary end point occurred in 578 participants (22.8 per 1000 person-years; 95% CI, 21.0-24.8) and no statistically significant difference between groups (22.8 events per 1000 person-years in the aspirin group vs 22.9 in the placebo group; HR, 1.00; 95% CI, 0.85-1.17). There was no significant difference in all-cause mortality between groups (176 vs 186 deaths, respectively; HR, 0.95; 95% CI, 0.77-1.16). An initial event of major hemorrhage requiring admission to hospital occurred in 34 participants (2.5 per 1000 person-years) in the aspirin group and 20 (1.5 per 1000 person-years) in the placebo group (HR, 1.71; 95% CI, 0.99-2.97).

Conclusion: Among participants without clinical cardiovascular disease, identified with a low ABI based on screening a general population, the administration of aspirin compared with placebo did not result in a significant reduction in vascular events.

Trial registration: isrctn.org Identifier: ISRCTN66587262.

Fowkes FGR, Price JF, Steward MCW, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index. A randomized controlled trial. JAMA 2010; 303:841-848. http://www.ncbi.nlm.nih.gov/pubmed/20197530

Don’t add aspirin for associated stable vascular disease in a patient with atrial fibrillation receiving anticoagulation.

BMJ. 2008 Mar 15;336(7644):614-5.

Lip GY. University Department of Medicine, City Hospital, Birmingham B18 7QH. g.y.h.lip@bham.ac.uk Lip GHY.

Key points:

Adding aspirin to warfarin does not seem to prevent stroke and vascular events in patients with atrial fibrillation and stable vascular disease

Bleeding risks are much higher in patients prescribed both warfarin and aspirin

We should stop prescribing aspirin plus warfarin to prevent stroke and vascular events in stable patients with atrial fibrillation who are receiving anticoagulation treatment

Don’t add aspirin for associated stable vascular disease in a patient with atrial fibrillation receiving anticoagulation. BMJ. 2008 Mar 15;336(7644):614-5. http://www.bmj.com/content/336/7644/614

Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials.

Am Heart J. 2006; 152: 967–973.

Flaker GC, Gruber M, Connolly SJ, Goldman S, Chaparro S, Vahanian A, Halinen MO, Horrow J, Halperin JL; SPORTIF Investigators. Department of Medicine, University of Missouri-Columbia, Columbia, MO, USA.

Background: Aspirin is used in combination with anticoagulant therapy in patients with atrial fibrillation (AF), but evidence of additional efficacy is not available.

Methods: We compared ischemic events and bleeding in the SPORTIF III and IV randomized trials of anticoagulation with warfarin (international normalized ratio 2-3) or fixed-dose ximelagatran. Low-dose aspirin (<100 mg/d) was allowed based on prevailing guidelines.

Results: The 14% of patients receiving aspirin more often had diabetes (27.5% vs 23%, P < .01), coronary artery disease (69% vs 41%, P < .01), previous stroke or transient ischemic attack (26% vs 20%, P < .01), and left ventricular dysfunction (41% vs 36%, P < .01). Addition of aspirin to either warfarin or ximelagatran was associated with no reduction in stroke or systemic embolism. Major bleeding occurred significantly more often with aspirin plus warfarin (3.9% per year) than with warfarin alone (2.3% per year, P < .01), aspirin plus ximelagatran (2.0% per year), or ximelagatran alone (1.9% per year). The rate of myocardial infarction with aspirin and warfarin (0.6% per year) was not significantly different from that with ximelagatran alone (1.0% per year), warfarin alone (1.0% per year), or aspirin and ximelagatran (1.4% per year).

Conclusions: Aspirin combined with anticoagulant therapy was associated with no reduction in stroke, systemic embolism, or myocardial infarction in patients with AF. Aspirin combined with warfarin was associated with an incremental rate of major bleeding of 1.6% per year. No increased major bleeding occurred with aspirin and ximelagatran. These results suggest that the risks associated with addition of aspirin to anticoagulation in patients with AF outweigh the benefit.

Flaker GC, Gruber M, Connolly SJ, Goldman S, Chaparro S, Vahanian A, Halinen MO, Horrow J, Halperin JL; the SPORTIF Investigators. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J. 2006; 152: 967–973. http://www.ncbi.nlm.nih.gov/pubmed/17070169

Poor evidence for aspirin in stable vascular disease

Turning to this point of stable vascular disease, there have been a number of studies where patients with peripheral artery disease have been randomised to aspirin or placebo.  I show here the triple ‘A’ trial, the Aspirin for Asymptomatic Atherosclerosis trial. This is one of a number of studies which have tried to address this.  The other ones being JPAD the Japanese Peripheral Artery Disease trial, and the Scottish POPADAD trial in diabetics with vascular disease.  These trials, quite interestingly, all broadly show the same thing; in terms of the primary endpoint of cardiovascular events including stroke, aspirin conferred no advantage in terms of trying to reduce the risk of mortality or, for that matter, important cardiovascular events.

However, if you look at the downside, in terms of major bleeding, you will see certainly this very important trend toward an increased risk of major bleeding, the hazard ratio is 1.71, which is certainly suggestive of an important major bleed risk by having concomitant aspirin compared to placebo, even in patients with stable vascular disease, not necessarily in atrial fibrillation.

Therefore this is a clear message to take away.  If a patient with stable vascular disease (and we’re talking arbitrarily about 12 months with no acute coronary syndrome, with no acute intervention or revascularisation, and no acute presentation with a coronary event), these patient, if they have atrial fibrillation and need anticoagulant therapy, there is no necessity at all to add in antiplatelet therapy on top of warfarin, on top of oral anticoagulant. There is no evidence of benefit in terms of reducing cardiovascular events.  What you do see, however, is a substantial increase in the risk is major bleeding, and certainly a 2.4-fold increase in the risk of intracranial bleeding, and that latter bit is very scary.

This also applies to the novel oral anticoagulants.  I show here one old slide, just to say that this is not new news in a sense, even with the new oral anticoagulants there are data to show this.  This is a relatively old slide, even from five years ago, if you look at a direct thrombin inhibitor, the old direct thrombin inhibitor, ximelagatran, now withdrawn, you will see for the efficacy endpoints of stroke and myocardial infarction and death, by adding aspirin on top of the anticoagulant there is no added advantage. However, and you also see this clearly with warfarin, if you look at bleeding you will see very clearly an increase by the addition of aspirin on top of the oral anticoagulant.  So the message to take away; if your patient has stable vascular disease and atrial fibrillation who needs anticoagulation, whether it’s warfarin or even one of the new anticoagulant drugs, there is no indication really to add aspirin on top of the anticoagulant. 

Vascular disease: 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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