For many decades, aspirin was advised to prevent heart attacks, both for those who had pre-existing cardiovascular disease (CVD) and for preventing coronary heart disease (CHD). Baby aspirin (low dose aspirin — usually a 75-81 mg tablet) became an article of faith for heart protection in American adults. So, for many Americans, it came as a surprise that recent guidelines issued by the American Heart Association and the American College of Cardiology altered their recommendation on prescribing aspirin for primary prevention of CVD and CHD. Though UK and Europe had earlier changed their positions on the use of aspirin for heart attack prevention, American guidelines influence medical practice in many other parts of the world. So, the reasons for a change of stance in those guidelines need to be understood even in India.

How does aspirin reduce the risk?

CHD occurs through two main pathological processes affecting the arteries which supply blood to the heart. Atherosclerosis involves fat deposition in parts of the arterial wall along with fibrosis. Sometimes, these ‘plaques’ get calcified. If the plaques reduce the luminal diameter of the coronary artery, by growing to 70{44affb6c5789133b77de981cb308c1480316fee51f5fd5f1575b130f48379a33} or higher of that passage’s width (50{44affb6c5789133b77de981cb308c1480316fee51f5fd5f1575b130f48379a33} in case of the left main coronary artery), blood flow is significantly impeded. Especially during periods of high physical activity or stress, where raised blood pressure and high heart rate increase the oxygen requirement of the heart muscle. That demand-supply mismatch causes angina or chest discomfort. It settles on rest.

However, soft plaques are prone to rupture even if they are small and are not usually obstructive. When they rupture, their exposed fatty core comes into contact with the blood flowing through the artery. That activates ‘platelets’ which are part of the blood cells. Aggregation of platelets forms a clot. If large, the clot can fully block (occlude) the passage of blood. While ‘obstruction’ causes angina, ‘occlusion’ triggers a heart attack. Sometime, a rupturing plaque can produce angina even at rest or minimal exertion (unstable angina) before proceeding to a heart attack or myocardial infarction (MI). These acute states are often clubbed together as ‘Acute Coronary Syndromes’ (ACS).

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Aspirin is an anti-platelet drug which irreversibly inactivates the cyclooxygenase enzyme of the platelets and suppresses the production of a clotting promoter Thromboxane A2. This makes the platelets incapable of clumping together. Since the action of each dose is limited only to the platelets which are then in circulation, and a new generation of platelets keep getting produced to replace those that naturally die in a few days, a daily dose of aspirin is prescribed to prevent young and sticky platelets from clumping together.

Aspirin tracks from secondary to primary prevention

Initial clinical trials were aimed at evaluating the protective effect of aspirin in those who had a heart attack already. Several trials, in different parts of the world, unequivocally showed significant benefit in reducing deaths and recurrent heart attacks in persons who survived a heart attack or myocardial infarction. So, aspirin became an indispensable part of post-MI secondary prophylaxis for all persons who could tolerate the drug without gastro-intestinal side effects. It has also been used after insertion of coronary stents.

Given that success, attention turned to primary prevention. ‘Why not prevent the heart attack in the first place, by preventing clot formation on any plaque?’, was the question posed. In 2003, Wald and Law from the UK even proposed a six-drug combination ‘polypill’ to prevent heart attacks, for use in all persons aged over 55 years. Besides aspirin, the others chosen were a beta-blocker, a diuretic, an angiotensin converting enzyme inhibitor (ACE-I), a statin and folic acid.

The editor of the British Medical Journal (BMJ) went overboard, calling that untested hypothesis as the most important scientific publication in the BMJ for 50 years. Several polypill trials and separate aspirin trials followed, for primary prevention of CHD. Folic acid quickly disappeared as it was ineffective. Of the three blood pressure lowering drugs, beta-blockers and ACE-I stayed on initially for CHD, while diuretics proved their mettle in stroke prevention. As the undesirable metabolic effects of prolonged beta-blocker therapy on blood sugar, triglycerides and HDL cholesterol became known, that class of drugs made way for calcium channel blockers like amlodipine for blood pressure control in primary prevention. Statins continued to be constant. ACE-I and related Angiotensin Receptor Blockers (ARBs) earned a reputation for blood pressure control and vascular protection.

Changing stance on aspirin

Aspirin went through the phases of universal acceptance, doubt, debate and revised recommendations in the arena of primary prevention. While it remains undisputed for secondary prevention, a question has been posed as to whether the benefits of aspirin use in primary prevention of CHD unequivocally exceed the risks of severe bleeding in the brain or stomach. Over time, evidence has built up, through clinical trials, meta-analyses and post-marketing surveillance. As evidence grew, recommendations changed.

In May 2009, the Anti-Thrombotic Trialists’ Collaboration (ATT) published a study in The Lancet, saying, “In primary prevention without previous disease, aspirin is of uncertain net value as the reduction in occlusive events needs to be weighed against any increase in major bleeds”. British clinical practice became more guarded against the routine use of aspirin for primary prevention of CHD. Clinical trials continued to evaluate the role of aspirin, alone or in combination. As statins effectively reduced harmful blood lipids like LDL cholesterol, blood pressure lowering drugs brought that risk factor under control, smoking rates declined in western populations, healthier dietary habits were adopted and physical activity was promoted, questions were raised about the additional benefit of aspirin.

In 2017, a review by Paltrano and colleagues in the Journal of the American College of Cardiology (JACC) stated that the role of anti-platelet drugs in the primary prevention of atherothrombosis “remains controversial because of the uncertain balance of the potential benefits and risks when combined with other preventive strategies.” CHD risk increases with age. The risk of severe bleeding due to aspirin also increases with age. So, it is especially necessary to weigh benefits versus risks in that age group and ask the question whether those benefits cannot be achieved by other means, including non-drug measures.

The remarkable benefits of a Mediterranean diet and other prudent diets on primary prevention of CHD have been well demonstrated in clinical trials and long-term cohort studies. Blood pressure and cholesterol lowering drugs too have shown great benefit for primary prevention. So, why risk aspirin for primary prevention, even if it can continue for secondary prevention? That line of thinking has emerged in recent years.

Further, there has been criticism that most risk calculators overestimate the 10-year risk of a cardiovascular event, as they do not take into account other treatment benefits that are likely to reduce that risk during that long period.

Recent American guidelines

The US Preventive Services Task Force (USPSTF) published its most recent guidelines in the April 26, 2022 issue of the Journal of the American Association (JAMA). It recommended against the use of low dose aspirin for prevention of cardiovascular disease in people 60 years or older. It left the decision on use of aspirin, in persons aged 40-59 years who have a predicted 10{44affb6c5789133b77de981cb308c1480316fee51f5fd5f1575b130f48379a33} or higher risk of a cardiovascular event in the next 10 years, to the treating physician. It concluded that the net benefit of aspirin use in this group is small. The decision is to be individualised, based on the nature of risk factors and associated conditions like diabetes.

It does not make sense, for example, to put a heavy smoker on aspirin because of a high 10-year risk, without getting that person to stop smoking. Especially since smoking increases the risk of sub-arachnoid bleeding where use of aspirin can compound the danger.

One of the arguments used to promote the routine use of aspirin for primary prevention of CHD was that the drug was also protective against colorectal cancer. This was initially based on tenuous evidence. The USPSTF, in a detailed review of available evidence, found it inadequate to support a protective effect. Hence, the overall benefits do not outweigh the risks in the overall 40-59 year age group. It further concluded “with moderate certainty that initiating aspirin use for the primary prevention of CVD events in adults 60 years or older has no net benefit.”

Guidelines for primary prevention of CHD and CVD undergo periodic revisions, based on objective evaluation of best available evidence to date. The recent change in guidelines, to dis-favour the routine use of aspirin for this purpose, takes into account the reduction in anticipated benefit from aspirin due to the increased protection being offered by other drugs and non-drug measures while the risk of serious bleeding complications with aspirin use remains undiminished. There will be subsets of individuals where the drug may be cautiously employed, if the anticipated benefits are high due to associated risk factors and the drug is well tolerated. It may still be selectively used, even if the mantle of ‘magic drug’ has slipped away and routine use is best avoided.

K. Srinath Reddy is President, Public Health Foundation of India, and previously headed the Department of Cardiology, AIIMS, Delhi. He was the first Indian president of the World Heart Federation.