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Aspirin Therapy

Aspirin Therapy for Type 2 Diabetes

Primary prevention

Secondary prevention

Aspirin dosage and formulation

(See Strength of Recommendations Taxonomy (SORT) for explanation of Grade A-C)

SEMDSA 2017 Recommendations
Aspirin is currently not recommended for the primary prevention of cardiovascular disease in patients with diabetes mellitus (who have not yet had a cardiovascular event)
B
Aspirin is strongly recommended for the secondary prevention of cardiovascular disease in type 2 diabetes
A
The optimal aspirin dose for secondary prevention is not known. SEMDSA endorses the 2011 Canadian Cardiovascular Society Guidelines recommendation to use 75 mg to 162 mg of regular aspirin per day
C
Patients with established cardiovascular disease who are intolerant to aspirin should be offered an alternative platelet aggregation inhibitor
C
Improved vascular protection is more effectively achieved with inhibition of the renin-angiotensin-aldosterone system and lipid modifying therapies
A

 

PRIMARY PREVENTION 

Individuals with type I and type 2 diabetes mellitus are recognised to have accelerated cardiovascular age approximately 10 to 15 years in advance of the chronological age.1 The management of diabetes mellitus seeks to address the consequent reduction in life expectancy evident in these individuals 2 by addressing both behaviour and using targeted pharmacological therapies. 

The evidence for the use of aspirin in primary prevention of cardiovascular disease is lacking despite in vitro evidence of increased platelet aggregation that might be expected to benefit from platelet inhibition with aspirin. Tests in patients with diabetes suggest that platelets may be more resistant to the inhibitory effects of aspirin.3

Numerous studies have suggested that in the general population aspirin reduces non-fatal myocardial infarction in men who have no previous history of cardiovascular disease, but this data cannot be extrapolated to women. Prior to the Women’s Health Study (WHS) published in 2005, of the 5 trials addressing the primary prevention of cardiovascular disease with aspirin, 3 had been trials which exclusively assessed men. The WHS concluded that the use of aspirin for primary prevention in women resulted in a reduction of stroke risk without altering the risk of myocardial infarction or death from cardiovascular causes.4 

The Antithrombotic Trialists’ meta-analysis reviewed 95, randomised trials of antiplatelet therapy that had been published up to 1997, including only 5000 individuals with diabetes in 9 of the trials; when high risk subjects without diabetes were compared to subjects with diabetes, it was not possible to show any significant benefit in the subjects with diabetes.5 

Specific primary prevention trials focusing on patients with type 2 diabetes, including the Early Treatment of Diabetic Retinopathy Study, the Japanese Prevention of Atherosclerosis with Aspirin in Diabetes Trial and the Prevention of Progression of Arterial Disease and Diabetes (POPADAD) Trial, have failed to show any clinically significant benefits for mortality, myocardial infarction or stroke.6,7,8

Conversely, aspirin use increases the risk of gastrointestinal bleeding by 50% to 70% regardless of dose or formulation; this risk may be increased in individuals with diabetes but also individuals > 70 years of age.9

The National Institute for Health and Care Excellence (NICE) in the UK performed a risk benefit analysis for aspirin use in type 2 diabetes in 2015 and found possible marginal benefits for primary cardiovascular disease prevention, but the risk of harm was excessive.10 NICE has issued a strong recommendation that aspirin not be offered to patients with type 2 diabetes for primary prevention. Other anti-platelet agents are also not recommended for primary prevention.

The ASCEND trial (A Study of Cardiovascular Events in Diabetes) and the ACCEPT-D (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes) are currently ongoing and may give clarity to this issue in the next year or two. In the meantime, SEMDSA endorses and adopts the NICE recommendations for primary prevention.

SECONDARY PREVENTION 

The benefits of aspirin therapy for secondary prevention of cardiovascular disease in patients with diabetes are well established and there has been no change to the recommendation of aspirin for type 2 diabetes mellitus and established cardiovascular risk, provided there is no contraindication to its use. Clopidogrel may offer benefit to individuals with intolerance to aspirin.11

ASPIRIN DOSAGE AND FORMULATION

Numerous studies have used aspirin both for primary and secondary prevention in varying doses from 30-600 mg. There is no randomised controlled trial which proves the benefits of doses of 75-162 mg of daily aspirin. However, these doses are better tolerated and as effective as higher doses in preventing cardiovascular events. In addition lower doses are associated with fewer events of bleeding.11,12 The increased risk for gastrointestinal haemorrhage applies to both primary and secondary prevention. 9

The risk of upper gastrointestinal bleeding may not be reduced by the use of enteric coated or buffered formulations.13,15 “Aspirin Resistance” has been described in diabetic patients using a variety of methods of measurement,16 but other studies have not shown this to be the case.17 One trial suggested that a more frequent dosing schedule of aspirin may reduce platelet reactivity in diabetic patients,18 but these observations alone are insufficient to empirically recommend higher doses at this time.19

Authors: Hilton Kaplan and Tanya Kinvig
Editors: Aslam Amod and Zaheer Bayat

References

  1. Booth GL, Kapral Mk, Fung K, TU JV. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet 2006; 368:29-36
  2. Manuel DG, Schultz SE. Health related quality-of-life and health adjusted life expectancy of people with diabetes in Ontario, Canada 1996-1997. Diabetes Care 2004; 27:407-14
  3. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Influence of aspirin resistance on platelet function profiles in patients on long-term aspirin and Apidra grew after percutaneous coronary intervention. Am J Cardiol 2006; 97:38-43
  4. Ridker PM, Cook NR, Lee IM et al. A randomised trial of low dose aspirin for primary prevention of cardiovascular disease in women. N Engl J Med 2005; 352:1293-304
  5. Collaborative overview of randomised trials of antiplatelet therapy-I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106
  6. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. ETDRS Investigators. JAMA 1992; 268:1292-300
  7. Ogawa H, Nakayama M, Morimoto T, et al. Low dose aspirin for primary prevention of atherosclerotic events in patients with type II diabetes: a randomised controlled trial. JAMA 2008; 300:2134-41
  8. Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo-controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BM J 2008; 337: a1840.
  9. Derry S, Loke YK. Risk of gastrointestinal haemorrhage was long term use of aspirin: meta-analysis. BMJ 2000; 321:1183-7
  10. National Institute for Health and Care Excellence (NICE). Type 2 diabetes in adults: management. NICE Guideline [NG28]. 2015. https://www.nice.org.uk/guidance/ng28. Accessed January 28, 2016.
  11. Bell AD, Roussin A, Cartier R, et al. The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society guidelines. Can J Cardiol 2011; 27 (suppl A): S1-59
  12. Pearson TA, Blair SN, Daniels SR, et al. AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation 2002; 106 (3) 388-91
  13. Risk of upper gastrointestinal bleeding and perforation associate with low-dose aspirin as plain and enteric coated formulations: De Abajo F.J, Rodrguez L.A.G. BMC Pharmacology 2001 1:1
  14. Kelly J.P, Kaufman D.W., Jurgelon J.M. et al : Risk of aspirin associated major upper gastrointestinal bleeding with enteric coated or buffered product. Lancet 1996,348:1413-1416
  15. Aspirin Therapy in Diabetes; American Diabetes association; Diabetes Care 2003 Jan;26(suppl 1): s87-s88
  16. Larsen S.b, Grove E.L., Neergard-Petersen S, Wurtz M, Hvas A-M, Kristensen S.D. Determinants of reduced antiplatelet effects of aspirin in patients with stable coronary artery disese. PLoS One 2015;10:e0126767
  17. Zaccardi F, Rizzi A,Petrucci,G, et al.In vivo platelet activation and aspirin responsiveness in type 1 diabetes. Diabetes 2016;65:503-509 93.
  18. Bethel M.A, Harrison P, Sourij H, et al. Randomized controlled trial comparing impact on platelet reactivity of twice-daily with once-daily
  19. Standards of Medical Care in Diabetes. American Diabetes Association. January 2017

Drugs mentioned

NeoHealth® ID 20108 · updated 9/28/2021