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Author(s): 

Ganesh Bhat1, Athish Shetty2

Author Affiliations: 

1Professor, Department of Gastroenterology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India; 2Assistant Professor, Department of Gastroenterology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India

Correspondence to: 

Ganesh Bhat, Department of Gastroenterology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India

Email:
drbhatgs@redifffmail.com

Journal Issue: 
Volume 50: Issue 4: 2020
Cite paper as: 
J R Coll Physicians Edinb 2020; 50: 403–4

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Title: Major GI bleeding in older persons using aspirin: incidence and risk factors in ASPREE randomized trial.

Authors: Mahady SE, Margolis KL, Chan A, et al.

Journal: Gut 2020; 0:1-8, doi: 10.1136/gutjnl-2020-321585

Financial and Competing Interests: No conflict of interests declared

Summary

As the aging population increases globally, adopting cost-effective preventive measures to maintain a healthy and active lifestyle in this demographic is a challenge. The major causes of disability in the older population can be due to atherosclerotic cardiovascular disease, cancer and dementia. Aspirin as a primary preventive strategy may be effective against atherosclerotic vascular diseases, cancer and dementia. 1, 2, 3

Efficacy of Aspirin in secondary prevention of atherosclerotic cardiovascular events is well established. 4 Recently, aspirin as a primary prophylaxis against cardiovascular diseases has been studied in three major trials ARRIVE, ASCEND, and ASPREE5, 6, 7. In the ARRIVE trial, Aspirin was used in patients with moderate to high cardiovascular risk. In the ASCEND trial, aspirin was used in patients with diabetes mellitus (DM) and in the ASPREE trial elderly patients were enrolled. Of these three studies, only the ASCEND trial has shown a significant reduction in the rate of major adverse cardiovascular events and this was accompanied by a significant increase in major bleeding. The ASPREE trial was designed to address the composite primary end point termed “disability free life”, resulting from cardiovascular disease events, cancer and dementia. Unfortunately, the study was prematurely ended due to lack of efficacy for the primary endpoint.

In general, Aspirin usage is associated with increased risk of bleeding including gastrointestinal tract8. Robust data is lacking on significant gastrointestinal bleeding with the low dose aspirin being used as a primary preventative strategy in the older population. Mahady et al studied major GI bleeding in older people using aspirin: Incidence and risk factors in the ASPREE randomized control trial9. ASPREE trial was a double blind trail which enrolled 19,114 apparently healthy Australian and US adults over 70-years-old or Black and Hispanic adults over 65 year old in US were recruited. Participants were randomised and given either 100 mg per day of enteric coated Aspirin or a placebo. There were 137 upper gastrointestinal bleeds (89 in the aspirin group and 54 in the placebo group) and 127 lower GI bleeds (73 in the aspirin group and 54 in the placebo group), representing a 60% increase in incidence of bleeding during the study period. There were two fatal bleeds in the placebo group. On multivariate analyses, age, smoking, hypertension, chronic kidney disease and obesity were associated with increased risk of bleeding. The absolute 5-year risk of bleeding was only 0.25% for a 70-year-old without aspirin compared to 5.03% for an 80 year old taking aspirin with additional risk factors. The study concluded that 5-year absolute risk of overall GI bleeding up by 60%, compared to healthy younger individuals.

Opinion

There has been a significant increase in the aging population in the last few decades due to improvement in life expectancy resulting from major healthcare advances. Risk of atherosclerotic cardiovascular disease doubles with each decade of life beyond traditional risk factors10. In the older population, usage of over the counter medications - especially nonsteroidal anti-inflammatory drugs (NSAIDs) due to chronic pain along with multiple comorbidity – increases the risk of gastrointestinal bleeding both by mucosal irritation and by potentiating aspirin’s antiplatelet effect.

In view of serious adverse events including bleeding, other primary preventive strategies should be the first line against atherosclerotic cardiovascular diseases in the elderly. The usage of aspirin should be tailored to individuals after assessing risk and benefit.11 Bleeding risk in the elderly is determined by multiple factors such as prior history of GI bleeding, liver and renal disease, fall risk, frailty and concomitant usage of other drugs like NSAIDs. Further, it is advisable to use low dose aspirin alone, if aspirin usage is deemed necessary. To reduce the risk of GI bleeding, usage of enteric coated aspirin along with proton pump inhibitor may also be considered. Caution must be practised when prescribing aspirin in elderly patients who are obese, have a history of significant smoking, history of renal dysfunction or chronic liver disease, due to increased risk of bleeding. Other questions regarding aspirin use still exist. Should older people undergo an upper GI endoscopy to rule out H. Pylori gastritis and gastroduodenal ulcers before starting aspirin? Does the eradication of H. Pylori infection decrease the risk of upper GI bleeding? Should adults who are taking aspirin for primary prevention of cardiovascular disease without any adverse effects, continue to use this medication after 70 years of age? Should individuals who are doing well with aspirin for secondary prevention after indexed cardiovascular events, continue this as life-long therapy after over 70 years of age? At present we do not have the answers to these questions. Additionally, these results cannot be extrapolated to the older population of other ethnic and geographical groups. We know that with increase in age, the risk of clinically significant GI bleeding increases. There is a need to balance the benefit of aspirin in reducing the risk of morbidity and mortality associated with atherosclerotic cardiovascular with risk of GI bleeding. Future studies should assess these points to find a solution. To summarise, aspirin is not a magic bullet as a primary preventive strategy against atherosclerotic cardiovascular disease, cancer and dementia in the older population. These individuals need to be educated about the risk of complications with “over the counter” usage of aspirin for primary prevention. 

References

1 Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 2002; 324: 71-86.

2 Rothwell PM, Fowkes FGR, Belch JFF et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011; 377(9759): 31-41.

3 Broe GA, Crayson DA, Creasey HM et al. Anti-inflammatory drugs against Alzeimer disease at low doses. Arch Neurol 2000; 57(11): 1586-91.

4 Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 372: 1849-60.

5 Gaziano JM, Brotons C, Coppolecchia R, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet. 2018; 392(10152):1036–46.

6 Group ASC, Bowman L, Mafham M, et al. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. 2018; 379(16):1529–39.

7 McNeil JJ, Wolfe R, Woods RL, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018; 379(16):1509–18.

8 Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Am J Gastroenterol 2008; 103:2890–2907.

9 Mahady SE, Margolis KL, Chan A, et al. Major GI bleeding in older persons using aspirin: incidence and risk factors in the ASPREE randomised controlled trial. Gut. 2020; 0:1-8, doi: 10.1136/ gutjnl-2020-321585.

10 Savji N, Rockman CB, Skolnick AH et al. association between advanced age and vascular disease in different arterial territories: a population database over 3.6 million subjects. J Am Coll Cardiol. 2013 Apr 23; 61(16): 1736-43.

11 Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/ American heart association Task force on clinical practice guidelines. Circulation 2019; 140: e596-646.

 

Financial and Competing Interests: 
No conflict of interests declared
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