In the wake of recent discussions about the role of Asprin in cardiovascular disease prevention in the European Society of Cardiology Congress 2018, Dr. Mangesh Tiwaskar, a noted physician shares his views and throws light on this topic.

Role of low dose aspirin therapy has been proved unquestionably for the secondary prevention of the Cardiovascular Diseases or Events (CVD or CVE). Prone to the known benefits of aspirin for people who already have CVD, researchers have explored whether taking aspirin might protect people who have no known cardiovascular disease. There were many publications supporting the role of aspirin in primary prevention of CVD. There are also good number of publications against the use of aspirin for primary prevention. But its role in primary prevention has now raised few eyebrows recently especially after the publication of two very interesting trials:

1. Effects of aspirin for primary prevention in persons with Diabetes Mellitus (ASCEND) 
2. Use of aspirin to reduce the risk of initial vascular events in patients at moderate risk of CVD (ARRIVE)

Aspirin: Historical Pearls

Aspirin, one of the oldest, popular and widely used drugs in medicine in various doses and for various indications – primarily as Non-Steroidal Anti-Inflammatory Drug (NSAID) and as an antiplatelet agent. It was aspirin which features in history dating back to the period of Hippocrates and Galen, when the bark of the willow tree was famous for its analgesic and anti-inflammatory properties. Impressively, similar records were also far-flung in Mesopotamian, Greek, and Chinese civilizations. Subsequently, a purified form of Salicylic acid and then it’s conversion to acetylsalicylic acid (ASA) was achieved from the bark of willow in 1904.

It is fascinating to quote that, in the first recorded clinical trial in history, Reverend Edward Stone of the Royal Society of London demonstrated the efficacy of ground, dried bark from the English willow tree for treating the symptoms of malaria. But it was in 1971, exact pharmacological mechanism of action of irreversible Cyclooxygenase (COX) inhibition and related suppression of Prostaglandin production was discovered, which is responsible for the antiplatelet effects in the lower doses.

Later studies revealed that the antithrombotic effects of aspirin were the result of acetylation of COX in platelets. And it was established that low-dose aspirin (≥ 30 mg/day) can effectively suppress platelet aggregation without affecting important endothelial cell functions. Contrary to this, it was ascertained that inhibition of inflammatory cell function requires higher and more frequent dosing of aspirin.

ASCEND and ARRIVE trials

In European Society of Cardiology congress 2018 at Munich, two RCTs of Aspirin versus Placebo for primary CV prevention in patients with moderate risk of CVD were presented – namely ASCEND by Prof Jane Armitage (Oxford, UK) and ARRIVE by Prof J M Gaziano (Boston, MA, USA). They aimed to address the fact whether aspirin treatment can prevent a first CV event.

ASCEND matriculated 15,480 patients with diabetes with no CVD randomised to Aspirin 100 mg vs Placebo. The primary outcome endpoints were serious vascular events (SVE), a composite of non-fatal myocardial infarction (MI), non-fatal stroke, Transient Ischaemic Attack (TIA) or CV death, and the safety outcome was major bleeding.

While ARRIVE inducted 12,546 subjects with a moderate estimated CV risk (20-30% 10-year CVD risk, 10-20% CHD risk) but without known diabetes or CVD. The primary endpoints were time to first occurrence of a composite of CV death, MI, unstable angina (UA), stroke and TIA and safety endpoints included bleeding events and incidence of adverse events.

In ASCEND, the composite primary outcomes did not differ significantly between treatment arms (event rate 8.5% vs 9.6%, HR: 0.88, 95% CI: 0.79-0.97, P=0.01) after the mean follow-up of 7.4 years, but major bleeding was increased in the aspirin group vs placebo (4.1% vs. 3.2%, HR: 1.29, 95% CI: 1.09-1.52, P=0.003). Bleeding risk increased with increasing baseline 5-year risk of SVE.

In ARRIVE Trial, the intention-to-treat analysis showed no difference in the primary endpoint between the aspirin group vs placebo group (HR: 0.96, 95% CI: 0.81-1.13, P=0.60) after the median follow-up of 5 years. Increased incidences of GI bleeding were reported in Aspirin arm vs placebo (HR 2.11; 95% CI: 1.36-3.28; P=0·0007)

So, both the trials concluded that there was no added CV benefit for use of aspirin in a primary prevention setting of diabetes patients or individuals with moderate CV risk. Although use of aspirin reduced SVE in diabetes patients, the absolute benefit was counterbalanced by the increased risk of bleeding. Amusingly during the discussions, it was emphasised that the patients in these trials were well controlled for risk factors, hence there were fewer events because of reduced risk bestowed due to other risk lowering medications like anti-hypertensives, lipid lowering agents etc. Aspirin did not add any benefit.

Results of the ARRIVE are published in The Lancet (August 26, 2018) and results of the ASCEND are published in NEJM (August 26, 2018).

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.