The Use of Aspirin in Primary Prevention of Cardiovascular Disease

V Sandys, M Barry

Aspirin, the most frequently prescribed medicine in Ireland, was first synthesised in 1897 by Felix Hoffmann at Bayer pharmaceuticals. In 1982 British pharmacologist John Vane was awarded the Nobel Prize in Physiology or Medicine for illustrating the suppression of prostaglandins and thromboxanes production by aspirin. In Ireland, aspirin accounts for 4.8% of GMS prescribing, at a cost of €21,332,277 million per year. While its use in secondary prevention of cardiovascular disease is well documented, the indication for aspirin use in primary prevention of cardiovascular disease remains unclear.

Analysis of the HSE GMS prescribing database from Jan 2014 to Dec 2014 reveals 2.44 million prescription items dispensed for aspirin in 281,000 patients at a total cost of €17.5 million. The ingredient cost of aspirin is 20% of the total cost associated with dispensing, resulting in a cost of €62.25 per patient per year. Some 65 % of patients are on long term aspirin therapy i.e. > 6 months. The majority of these patients are over 70 years of age. Some 10,881 patients on long term aspirin (6.1%) were not dispensed cardiovascular or diabetic drugs. This includes statins, beta blockers, ACE-I/ARB, CCB, oral hypoglycemics, insulin, nitrates and warfarin. Of this 10,881, 6,466 are female, composing 59% of long term users not on any other cardiovascular medication and 20% of this subgroup is made up of females < 65 years of age. On extrapolation of the numbers from the GMS scheme, and assuming the same proportions for the DP and LTI schemes, there were a total of 244,424 patients on long term aspirin in 2014. 15,061 of patients on long term aspirin were not on concurrent cardiovascular or diabetic medication, suggesting a proportion of patients with low cardiovascular risk who are being treated with aspirin for greater than 6 months.

Guidelines concerning aspirin use in primary prevention are conflicting. Available data on aspirin in primary prevention suggests some potential in reducing cardiovascular events2-4 however, this net benefit is possibly offset by adverse side effects from bleeding.3 A systematic review of the available data notes that the reduction in myocardial infarction risk is observed in men only, with no effect of aspirin being observed amongst the majority of women.3,5 The benefit of cardiovascular risk reduction with aspirin is amplified in patients with hypertension and decreased GFR, presumably secondary to the increased cardiovascular risk associated with these conditions.6 Our data shows a high prevalence aspirin use, with a subgroup of female patients with low cardiovascular risk who are being treated with long term aspirin.

Results from the Women’s Health Study suggest that aspirin is ineffective in the majority of female patients < 65 years.5 Following a 10 year follow up of 39,876 healthy women > 45 years, there was no significant reduction in the primary endpoint of major cardiovascular events (2.39% in aspirin group, versus 2.6 % in placebo, P=0.13), although risk of all cause and ischaemic stroke were reduced (17% reduction, p= 0.04). A subgroup analyses of the trial in patients concluded that aspirin significantly reduced the risk of major CVD, ischaemic stroke and MI only amongst patients over 65 years, with the risk of major cardiovascular events reduced by 26% (RR 0.74, P=0.008), and the risk of MI reduced by 30%. (RR 0.66, p= 0.04).5

Treatment with aspirin is not without its risks.  Meta-analysis has reported an increased risk of non-fatal major extracranial bleeding with aspirin, with increases in haemorrhagic stroke, major bleeding, and GI bleeding.2,4 There are numerous associated drug-drug interactions, with a significant increased risk of cerebrovascular events in the four weeks following discontinuation. Notably, aspirin does have statistically significant cancer benefit. In a meta-analysis by Rothwell et al, aspirin reduced colorectal related mortality by 20% at 3 years onward, and it has been suggested that this be taken into account in the assessment of risk benefit ratio in primary prevention.3 Currently, however, the guidelines carry conflicting recommendations. Several clinical trials are awaited to clarify the issue, examining a population of patients with estimated rates of coronary events of 1-2% per person-years, particularly diabetics.3,4 At present, ESC guidelines do not recommend aspirin in patients without overt cardiovascular disease because of the increased risk of major bleeding. Antiplatelet therapy may be considered, however, in hypertensive patients without a history of CVD, but with reduced renal function or high cardiovascular risk. Antiplatelet therapy is not recommended in diabetics without overt evidence of atherosclerotic disease.8

In the clinical context, we recommend that if a patient is deemed of a sufficiently high risk to merit statin therapy, they are likely to require aspirin treatment. Conversely, if a patient’s cardiovascular risk is low, they are unlikely to require they are unlikely to require treatment with either aspirin or statins.

V Sandys, M Barry

National Centre for Pharmacoeconomics, St James’s Hospital, James’s St, Dublin 8

Email: sandysv@tcd.ie

References 

  1. References 
    1. Sneader, W. “The discovery of aspirin: A reappraisal”. BMJ (Clinical research ed.) (2000) 321: 1591–1594.
    2. Baigent C., Blackwell L., Collins  R., et al; Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. (2009) 373:1849-1860
    3. Brotons, Carlos et al. “A systematic review of aspirin in primary prevention: is it time for a new approach?.” American Journal of Cardiovascular Drugs 15.2 (2014): 113-133.
    4. Halvorsen, Sigrun et al. “Aspirin therapy in primary cardiovascular disease prevention: a position paper of the European Society of Cardiology working group on thrombosis.” Journal of the American College of Cardiology 64.3 (2014): 319-327.
    5. Ridker, Paul M et al. “A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.” New England Journal of Medicine 352.13 (2005): 1293-1304.
    6. Lennart Hansson et al. “Effects of intensive blood-pressure lowering and low dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial.” The Lancet (1998) Vol 351, June 13
    7. Alliance Pharmaceuticals Ireland. “Summary of Product Characteristics Nu-Seals 75” March 2015. Retrieved from www.medicines.ie/medicine/4842/SPC/Nu-Seals+75/
    8. Perk J., De Backer G., Gohlke  H., et al; European Guidelines on cardiovascular disease prevention in clinical practice. The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J. (2012) 33:1635-1701.

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