Is Old Really Gold? The Case Against Aspirin

Aaysha Cader, MD, MRCP

The recently concluded AHA Scientific Sessions provided for a myriad of sessions on antiplatelet therapy in cardiovascular disease (CVD).

The late-breaking TWILIGHT ACS trial reported a win for ticagrelor monotherapy among patients randomized after 3 months post-NSTE-ACS and PCI, in results consistent with the main TWILIGHT trial.1-2 TWILIGHT ACS showed a reduction of clinically significant bleeding with no increased risk of ischemic adverse events at 1 year, for those randomized to ticagrelor monotherapy versus aspirin plus ticagrelor (DAPT).1

That same day, an entire session aptly titled “Aspirin: who needs it anymore?” dedicated to the dissection of aspirin, featured a series of talks on the role for aspirin for the primary and secondary prevention of cardiovascular disease (CVD).

Questioning the potential “twilight” of aspirin therapy, Dr Roxana Mehran raised some pertinent issues particularly pertaining to bleeding risk and gastrotoxicity of aspirin, in addition to treatment failure/ “aspirin resistance” resulting from its enteric-coated preparation and potential drug-drug interactions.

Nevertheless, while aspirin may still remain in the game with respect to secondary prevention, 3 randomized clinical trials in primary prevention have ensured a “three strikes and you’re out” scenario for aspirin, culminating in a de-emphasis in the guidelines as well.

One of the best things about attending meetings is the effortless re-cap/ additional reading one does afterwards. Thus, in order to discern how such a fate befell aspirin, here’s a brief look at the “three A’s” of 2018 responsible for hitting the nail in the coffin:

 

The ARRIVE (Aspirin to Reduce Risks of Initial Vascular Events) trial

ARRIVE enrolled 12 546 patients (men ≥ 55 years with 2-4 risk factors and women ≥ 60 years with ≥risk factors for CVD) who were randomized to enteric-coated (EC) aspirin 100 mg/day versus placebo.3 ~29·5% of participants were women. Individuals with diabetes and those at high risk of bleeding were excluded. The primary endpoint was a composite outcome of time to first occurrence of CV death, MI, unstable angina, stroke, or transient ischemic attack.

After a median follow-up of 5 years, no significant differences were observed in the primary end-point between those assigned to aspirin vs placebo (4.29% vs 4.48%; p=0.6038), although the event rate was much lower than expected, thus making the study more representative of a low-risk population. The overall incidence of adverse events was similar in both groups, however, there were significantly more gastrointestinal bleeding events (predominantly mild) in the aspirin group than placebo (0.97% vs 0.46%; p=0·0007).

 

The ASPREE (Aspirin in Reducing Events in the Elderly) trial

This trial enrolled 19,114 healthy community-dwelling individuals across sites in Australia and the USA aged ≥ 70 years (or ≥ 65 years if  Black/ Hispanic in US) and devoid of CVD, dementia or disability who were randomized to 100 mg EC aspirin vs placebo.4-6

The primary end-point was a composite of death, dementia or persistent physical disability while secondary end points included major hemorrhage and cardiovascular disease (defined as any ischaemic event).4-6 At 56.4%, ASPREE enrolled the highest number of women from among the three trials.4 The median age of participants was 74 years.

The trial was terminated early at a median of 4.7 years of follow-up, as it was determined that no benefit would be derived with continued aspirin use in terms of primary end point. Accordingly, there were no significant differences in the primary composite outcomes (21.5 vs. 21.2 events per 1000 person-years; p = 0.79 ).4 However, rates of major bleeding were significantly higher in the aspirin group (8.6 vs. 6.2 events per 1000 person-years; p < 0.001),  with a progressive increase in the cumulative incidence of major hemorrhage across the follow-up period.5 The majority of these episodes were gastrointestinal bleeds, with the higher risk of upper GI bleeds being particularly more pronounced with aspirin (hazard ratio, 1.87; 95% CI, 1.32 to 2.66).5

There was also an increased risk of all-cause mortality in the aspirin group versus placebo (12.7 vs 11.1 events per 1000 person-years; HR, 1.14; 95% CI, 1.01 to 1.29) with cancer being the major contributor to the higher mortality seen with aspirin.6 Thus, ASPREE concluded that the daily use of low-dose aspirin did not prolong disability-free survival among the elderly.6

 

The ASCEND (A Study of Cardiovascular Events in Diabetes) trial

A trial specifically designed to investigate the effects of aspirin in primary prevention among diabetics, ASCEND enrolled 15,480 individuals (~37. 5% women) in the United Kingdom with diabetes but no evident CVD who were randomized to 100 mg of aspirin daily versus placebo.7

During a mean follow-up of 7.4 years, those randomized to aspirin had a significantly lower percentage of serious vascular events in comparison to placebo (8.5% vs. 9.6%; P=0.01). However, this benefit was offset by significantly higher major bleeding events seen in the aspirin arm (4.1% vs. 3.2%, p=0.003), with no attenuation of the effect on bleeding over time. As with ARRIVE, the majority (41.3%) of major bleeding events were gastrointestinal, of which close to two thirds were in the upper GI tract. Thus, the trial concluded that the absolute benefits of aspirin in preventing CVD among diabetics were largely counterbalanced by the hazards of bleeding.

These trials formed the basis for the de-emphasis of aspirin in the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease, which recommended against the prophylactic use of aspirin among elderly (>70 years) and those at high bleeding risk. There was also a downgrade in class of recommendation for low dose aspirin for primary prevention in select 40 to 70 year-old adults at higher ASCVD risk but lower bleeding risk (Class II b).8

To add to this, a comprehensive meta-analysis of 13 trials comprising of 164 225 participants without cardiovascular disease by Zheng et al., found that aspirin use was associated with a significant reduction of cardiovascular events but also an increased risk of major bleeding events compared with no aspirin.9

As Dr Erin Michos, one of the co-authors of the Primary Prevention guidelines pointed out in her talk at AHA 2019, this poor performance of aspirin in terms of risk-benefit could be attributed to the improved adherence to other primary prevention methods, such a reduction of smoking, better control of blood pressure and importantly more aggressive lipids control by virtue of statins.

With the much-needed emphasis on bleeding and its detrimental effects, “less is more” has been the focus in recent times, at least for antiplatelet and antithrombotic drugs, with recognition of trials that withdraw rather than add to current drug treatments. Furthermore, the appropriate prescription of drugs and increased emphasis on lifestyle modification for primary prevention cannot be understated. The onus is on physicians to keep up to date and tailor drug prescriptions to the individual patient.

Also, in keeping with the spirit of on post-conference re-caps, highly recommend the following as additional reading:

  1. Marquis-Gravel G, Roe MT, Harrington RA, et al. Revisiting the Role of Aspirin for the Primary Prevention of Cardiovascular Disease. Circulation 2019;140(13):1115-1124.
  2. Ridker PM. Should Aspirin Be Used for Primary Prevention in the Post-Statin Era? N Engl J Med 2018;379(16):1572-1574.
  3. 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;373:1849-60.

References:

  1. Presented by Dr. Usman Baber at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 17, 2019.
  2. Mehran R, Baber U, Sharma SK, et al. Ticagrelor With or Without Aspirin in High-Risk Patients After PCI. N Engl J Med2019;381:2032-42
  3. 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. Lancet2018;392:1036-46.
  4. McNeil JJ, Woods RL, Nelson MR, et al. Effect of Aspirin on Disability-free Survival in the Healthy Elderly. N Engl J Med 2018;379:1499-1508.
  5. 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;379:1509-18.
  6. McNeil JJ, Nelson MR, Woods RL, et al. Effect of Aspirin on All-Cause Mortality in the Healthy Elderly. N Engl J Med 2018;379:1519-28.
  7. ASCEND Study Collaborative Group, Bowman L, Mafham M, et al. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. N Engl J Med 2018;379:1529-39.
  8. 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(11):e596-e646.
  9. Zheng SL, Roddick AJ. Association of Aspirin Use for Primary Prevention With Cardiovascular Events and Bleeding Events: A Systematic Review and Meta-analysis. JAMA 2019;321(3):277-287.

 

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