Aspirin for Primary Prevention—Unveiling a Historical Truth and Choosing the Right Patient

The 3 large aspirin primary prevention trials of 2018 ARRIVE, ASCEND, and ASPREE were received by physician community with an enthusiastic perception of culmination of a long standing controversy.^1–3 There was no major reduction of cardiovascular events in these trials but these patients had increased GI and major bleeding (hazard ratio 1.29-2.1). These results were seen as a light at the end of long tunnel of confusion that arose from differing recommendations from scientific bodies and societal guidelines over time. The largest and most recent meta-analysis of 15 randomized controlled trials involving 1,65,000 patients, half of whom were on aspirin has reinforced the above results. ⁴ There was no reduction in all cause death in the first 5 years and the reduction in cardiovascular (CV) death which was demonstrated was seen only in patients with a high 10 yr ASCVD (atherosclerotic cardiovascular death) risk. Expectedly there was increase in nonfatal bleeds. The number of patients who need to take this pill to prevent a MI (myocardial infarction), TIA (transient ischemic attack), ischemic stroke are, respectively, 357, 370, and 500, while number needed to cause major bleed, GI (gastrointestinal) bleed or intracranial bleed are 222.385 and 1000, respectively. These figures imply that prescription of aspirin for primary prevention needs to be limited to carefully selected high-risk population with low bleeding risks. Predictably the large imposing data resulted in downgrading of aspirin in the guidelines (Table 1).

Careful look at the data from historical timeline of aspirin primary prevention trials tells us none of them actually generated unequivocal evidence to create an unchallenged indication for this drug (Figure 1). The authoritative position of aspirin as a drug for secondary prevention was never matched by its primary prevention data. On one side was the potential benefit from reduction in MI, TIA, and strokes resulting in decrease in CV and total mortality while the other side was GI, and intracranial bleeds contributing to morbidity and mortality. There was additional interest in onco prevention properties of aspirin, which was however never shown to have a clinical impact. The first trials published in 1988 and 1989—the British male doctors and US physicians’ health study included nonselected doctors. Subsequent studies were conducted in patients with CV risk factors. In all these studies, despite heterogeneity of results, there was an inconsistent reduction of nonfatal MI with aspirin but constantly counterbalanced by safety issues of bleeding thus hard end point of mortality reduction was not seen. Beyond the year 2000, in the journey of primary prevention aspirin faced increasingly stiff competition as risk factors were better managed and statin usage increased. ⁵ Aggressive primary prevention strategies focused on plaque burden reduction and plaque stabilization, factors on which aspirin has no role. These measures contributed to reduction in event rates and hence made it statistically more difficult to demonstrate a benefit with antiplatelet drugs, retaining their concerning safety issues.

Table 1.

Guidelines and Recommendations for Aspirin for Primary CVD Prevention.

Society	Guidelines	Class	Level
European Society of Cardiology 2016	Not recommended in individuals without CVD.	III	B
European Society of Cardiology 2019	Patients with diabetes and high/very high risk aspirin (75-100 mg/day) may be considered in absence of clear contra indications. Not recommended in patients with diabetes and moderate risk of CVD.	II b III	A B
American Society of Cardiology 2019	Low dose aspirin (75-100 mg) for select adults 40 to 70 yr who are at high ASCVD risk but not at high risk of bleeding. Not to be administered for ASCVD prevention among adults >70 yr. Not to be administered for ASCVD prevention for any age who are at a risk of bleeding.	II b III III	A B C

Source: Compiled from published guidelines.

Figure 1.

Source: J Am Coll Cardiol. 2019 Jun 18.

Abbreviations: AAA, Aspirin for Asymptomatic Atherosclerosis; AASER, Acido Acetil Salicilico en la Enfermedad; ARRIVE, Aspirin to Reduce Risk of Initial Vascular Events; ASCEND, A Study of Cardiovascular Events in Diabetes; ASPREE, Aspirin in Reducing Events in the Elderly; BMD, British Male Doctors Trial; CI, confidence interval; ETDRS, Early Treatment Diabetic Retinopathy; HOT, Hypertension Optimal Treatment; JPAD2, Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes; JPPP, Japanese Primary Prevention Project; PHS, Physician’s Health Study; POPADAD, Prevention of Progression of Arterial Disease and Diabetes; PPP, Primary Prevention Project; RR, risk ratio; WHS, Woman Health study.

How would one see the application of this data on Indian patients? Issues concerning MI in India differ from published data from the west in several aspects which may have relevance to current issue. The mean age of ACS in India is younger (55 years) making the target preventive population at least 10 years younger who may be less prone to bleeding risks. ⁶ Guidelines too are more lenient to prescribing aspirin in younger patients. ACS in our country occurs in patients with poorly controlled risk factors. Moreover, it is predominantly STEMI (ST Elevation MI) with delayed presentation of large infarcts and subsequent serious and impactful outcomes like heart failure. It is clinical and economic prudence to use every strategy available to prevent these unfavorable consequences. Metabolic risk factors are more important in our population, and use of aspirin in such a population has not been systematically studied. ⁷ Lastly, the reduction in incidence of ACS achieved in developed countries by effective preventive strategies, which partly explained the futility of aspirin has not yet percolated to this part of the world. This would mean that NNT figures may be much smaller, if a real-world trial is conducted in India. Practicing physicians would be erring if they infer from the data from large studies that aspirin as a primary prevention tool should be relegated to recycle bin. Mechanistically its ability to prevent MI and TIA is irrefutable. The continuing clinical challenge is to be able to constantly identify the high-risk population and protect them from vascular events. Globally as well as in India, physicians need to make clinical judgement based on individual assessment to see if magnitude of the absolute benefit exceeds the magnitude of the absolute risk.