As one door closes … so does another

Aspirin has had several ups and downs over the past few years. In 2012, I reviewed the recommendation that aspirin should no longer be used for primary prophylaxis of cardiovascular and cerebrovascular disease.

Now, I don the cloak and pick up the scythe of the Grim Reaper once more to tell of its fall from grace in the prevention of thromboembolism in the management of atrial fibrillation (AF).

So why is AF important? Non-valvular AF is a disease of ageing; prevalence of 0.3/1000 population at <45 years of age, but 64/1000 population at age >75 years.

Alongside the symptoms, which include extreme fatigue, breathlessness, chest pains and palpitations, AF increases the risk of a stroke fivefold greater than if the individual is in sinus rhythm. In addition, stroke mortality is higher in AF patients. Worryingly, the risk of stroke does not appear to be different for paroxysmal or continuous AF. This risk is also higher in women unless they are under 65 and have no other risk factors.

The Royal College of Physicians consensus statement in 2012(1) provided key recommendations for AF including:

• Detection of AF must be improved; a national screening programme should be introduced.
• Uptake of oral anticoagulants must be increased and methods of engaging patients in their AF management should be improved.
• In relation to rate and rhythm control for AF, relief of symptoms should be the goal of treatment.
• Aspirin should not be used for stroke prevention in AF as it is ineffective; patients who are taking aspirin solely for this purpose should be reviewed.
• Newer oral anticoagulants (NOACs; for example, direct thrombin and factor Xa inhibitors) are an option for patients who cannot tolerate, have an allergy to, or who cannot achieve satisfactory anticoagulant control on warfarin.

Two august bodies – the European Society of Cardiology (ESC) and the Scottish Intercollegiate Guideline Network (SIGN) – have also reinforced this view and concluded that aspirin has no place in stroke prevention in AF unless no other drug is possible.

The SIGN recommendation comes in their guidance document no.129 Antithrombotics: Indications and Management published in August 2012.(2)

ESC produced a ‘focused update’(3) of their 2010 guidelines for the management of AF in the European Heart Journal last year. The update was produced in collaboration with the European Heart Rhythm Association. The review group was chaired by Professor John Camm, a world-renowned electrophysiologist from St George’s in London.

The death knell for aspirin comes early in the paper. It states; “The evidence for effective stroke prevention with aspirin in AF is weak, with evidence for harm, as data indicate that the risk of major bleeding or intracranial haemorrhage with aspirin is not significantly different to that of oral anticoagulants, especially in the elderly.”

Aspirin has been more or less written out of the guidelines for stroke prevention in this update. The guidelines now confine aspirin to only those patients who refuse any OAC and cannot tolerate the combination of aspirin–clopidogrel. So, aspirin is no longer a choice for preventing stroke in AF; it should only be used in AF in the case of a comorbidity, such as occlusive vascular disease.

It is noteworthy that the 2012 update also includes a positive recommendation for the use of the NOACs. On the basis of the results of clinical trials,(4-7) the guidelines state that the NOACs offer comparable, if not superior, efficacy, safety, and convenience compared with warfarin.

It remains to see what the National Institute for Health and Care Excellence has to say on the matter when it produces its own update on AF next year.

It would be wrong, however, to think that the ESC document is just about stopping aspirin use. It is an excellent guide to the management of AF, including a thorough review of the evidence for the NOACs, and is highly recommended reading for anyone working with patients with AF.

The WOEST Trial(8) compared the use of double therapy (clopidogrel and oral anticoagulants) and triple therapy (with aspirin as well). At one-year follow up, the rate of bleeding was significantly higher in the triple therapy cohort but with no increase in thrombotic events.

An Australian paper(9) has presented more bad news, suggesting a link between aspirin use and neovascular age-related macular degeneration – this increased risk was independent of cardiovascular disease or smoking.

And finally, higher dose aspirin has been ‘blamed’ for the apparent lack of significance in the ticagrelor arm of the PLATO trial in the US.(10)

The debate still goes on over its potential benefit in cancer; the Women’s Health Initiative(11) trial suggests that aspirin use was associated with a lower melanoma risk in post-menopausal Caucasian women. The longer it is taken, the greater the prevention: use for >five years reduced the risk by 30%.

Although aspirin has taken a few hits recently, I believe it remains an important drug in the management of established cardiovascular and cerebrovascular disease,  particularly given the years of austerity and limited funding for the National Health Service still to come.

It is cheap, it is a bit nasty, but for many people, it still works!

1. Royal College of Physicians of Edinburgh. Consensus statement on the prevention of atrial fibrillation (AF)-related stroke. www.rcpe.ac.uk/clinical-standards/standards/rcpe-af-consensus-statement-2012.pdf?utm_medium=email&utm_source=MGP+Ltd&utm_campaign=2179923_201302_esc_email_tutorial&utm_content=paragraph1&dm_i=HEZ,1AQ1F,7SZRSZ,4EA0O,1 (accessed 16 April 2013)
2. SIGN. www.sign.ac.uk/guidelines/fulltext/129/ (accessed 16 April 2013).
3. Camm A et al. Focused update of the ESC guidelines for the management of atrial fibrillation. Eur Heart J 2012;33:2719–47.
4. Connolly S et al. AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806–17.
5. Connolly S et al. Dabigatran vs. warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51.
6. Connolly S et al. Newly identified events in the RE-LY trial. N Engl J Med 2010;363:1875–6.
7. Patel M, Mahaffey K, Garg J et al. ROCKET AF Investigators. Rivaroxaban vs. warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883–91.
8. Dewilde WJM et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open label, randomised, controlled trial. Lancet 2013;381:1107–15.
9. Liew G. The association of aspirin use with age-related macular degeneration. JAMA Intern Med 2013;173(4):258–64.
10. Mahaffey KW et al. Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial. Circulation 2011; 27 June (early online).
11. Gamba CA et al. Aspirin is associated with lower melanoma risk in post-menopausal Caucasian women. Cancer 2013;119;1562–9.