Decades of recommendations to give aspirin for primary prevention of cardiovascular events, based on over-optimistic interpretation of inconclusive data, were recently overturned after a randomised clinical trial with 100 000 person-years of follow-up found aspirin actually increased all-cause mortality.
Several other primary prevention trials of aspirin also failed to show meaningful reductions in cardiovascular events.
Furthermore, a trial of 17 444 patients undergoing orthopaedic surgery suggested increases in myocardial infarction (MI) with aspirin 160 mg per day.
Many people randomised in primary prevention trials undoubtedly had undiagnosed atherosclerotic cardiovascular disease (ASCVD).
Now that recommendations for prophylactic use of aspirin for primary prevention have been largely reversed, writes John Cleland in JAMA Cardiology, the stage is set to reconsider the strength of evidence for giving aspirin for secondary prevention.
No single trial provides conclusive evidence that long-term administration of aspirin improves outcomes for chronic ASCVD. Belief in aspirin for this indication is based on flawed meta-analyses that evolved over decades.
A meta-analysis is useful for confirming that relevant trials with seemingly conclusive results are consistent with the totality of evidence, but no such trial exists. A meta-analysis of inconclusive trials does not provide robust evidence of efficacy or safety but can be used to plan future trials that might provide definitive results.
Most clinicians trust that trials included in a meta-analysis are of reasonable quality, that at least some of the trials included will show a clearly positive result, and that reporting is unbiased. Those who read the original articles on chronic aspirin therapy will be disappointed.
However, peer pressure and concerns about litigation often compel physicians to practice defensive medicine. Consequently, even if doubts about efficacy exist, aspirin may be prescribed by physicians to treat their own anxieties rather than for a patient’s benefit.
Strangely, some argue that aspirin should be used for chronic ASCVD because the evidence that it is ineffective is inconclusive, but surely this is a reason for more trials rather than prescribing a treatment with potentially serious adverse effects.
It is widely taught that thrombosis is the primary mechanism underlying acute vascular events. However, plaque haemorrhage leading to rupture and ulceration may often be the primary trigger for thrombosis.
There is little downside to giving antithrombotic agents to prevent secondary thrombosis on an ulcerated plaque but once the plaque has healed, any benefit from a reduction in platelet aggregation with aspirin may be balanced or outweighed by increases in plaque haemorrhage, suppression of endothelial prostacyclin-mediated protection, and increases in clinically overt bleeding.
Moreover, long after most placebo-controlled trials of aspirin were conducted, the widespread introduction of lipid-lowering agents will have reduced the lipid content of the plaque, reducing the risk of rupture of lipid gruel through a thin fibrous cap and increasing the proportion of ruptures due to plaque haemorrhage.
The pathological substrate underlying vascular occlusion has evolved, reducing the relevance of ancient trials. Plaque haemorrhage might also increase the proportion of coronary occlusions presenting as sudden death, thereby reducing the rate of nonfatal MI without reducing mortality.
Similarly, cerebral infarction is often not associated with clinically obvious neurological events. Disability due to vascular events is rarely reported in aspirin trials. When trials of antiplatelet therapy fail to show concordant effects on vascular events and mortality, the results should be treated with deep suspicion.
Surprisingly, there are only two substantial, placebo-controlled trials of aspirin that enrolled patients with chronic ASCVD in the absence of a recent vascular event.
In the Aspirin Myocardial Infarction Study (AMIS), 4 524 patients were randomised to aspirin 1000 mg per day or placebo, with a mean delay after MI of 25 months. Cardiovascular events were not reduced over the following three years, but there was a trend to increased mortality, especially among women.
The authors concluded: “… aspirin is not recommended for routine use in patients who have survived an MI”.
Maybe the dose was too high, but that does not prove that smaller doses are effective.
In the Swedish Angina Pectoris Aspirin Trial (SAPAT), 2 035 patients with a clinical diagnosis of angina were randomised to aspirin 75 mg per day or placebo by their primary care physicians. Investigations, such as exercise tests, radionuclide scans, or coronary angiography, were not required to confirm the presence of disease.
Over a median follow-up of 50 months, there were approximately five fewer MIs per 1 000 patient-years follow-up in those assigned to aspirin with no effect on stroke, vascular deaths, or mortality.
Lasting benefits can be delivered by short-term interventions given at the right time. The Second International Study of Infarct Survival (ISIS-II) trial, published in 1988, randomised 17 187 patients with an acute MI to aspirin 162.5 mg per day or placebo, double-blind, for just 28 days, after which aspirin was stopped; there was no reason to initiate aspirin due to a lack of evidence.
Those randomised to aspirin had a similar reduction in mortality at both 35 days and 10 years, in the absence of long-term aspirin therapy.
The US Veterans Administration trial of unstable angina showed similar results. After three months, mortality was slightly lower with aspirin 324 mg per day, but nine months after stopping aspirin, the reduction in mortality was clear.
These trials suggest that aspirin should be given after an acute cardiovascular event in much the same manner as antibiotics for infection; usually a short course rather than life-long treatment.
The Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness (ADAPTABLE) trial compared the effects of aspirin 81 mg per day to 325 mg per day on MI, stroke, or death in patients with chronic, stable ASCVD and found no difference in such events.
Unfortunately, no patients were randomised to avoidance of antiplatelet therapy, although many patients with ASCVD do not take aspirin, perhaps because they are less convinced by the evidence than their doctors. The ADAPTABLE trial was a lost opportunity to get some evidence that some dose of aspirin is effective long-term for chronic ASCVD.
The edifice of antiplatelet trials for chronic ASCVD has no solid foundations but is built on shifting sands. Forty years ago, dogma dictated that ventricular ectopy after an MI should be treated with class I antiarrhythmic drugs; many believed a placebo-controlled trial was unethical.
When the results of the Cardiac Arrhythmia Suppression Trial (CAST) were published in the New England Journal of Medicine showing a 250% increase in mortality with class I agents, the accompanying editorial said that the results “… have astounded most observers and challenge much of the conventional wisdom about antiarrhythmic drugs….”
For many decades, routine, lifelong administration of β-blockers after MI was also recommended by guidelines. Recent randomised trials of withholding or withdrawing β-blockers after MI cast doubt on this advice. Antiplatelet therapy dogma should now be subjected to the same scrutiny.
Randomised trials withdrawing all antiplatelet therapy three to six months after a vascular event or procedure should be done. There is no randomised trial comparing antiplatelet therapy with placebo in patients who have received a coronary stent, but short-term suspension of antiplatelet therapy appears safe, and therefore, such patients should be included.
Given an accurate account of the evidence and in the absence of physician bias, patients should be happy to be randomised to placebo.
However, despite the lack of evidence, many clinicians are trapped by the antiplatelet dogma. Perhaps a trial comparing 75 mg of aspirin once daily to a less intense antithrombotic intervention, such as aspirin or clopidogrel 75 mg once or twice per week, might not be too heretical?
If this showed no substantial difference in disability or mortality, it would pave the way to placebo-controlled trials of complete withdrawal of long-term antiplatelet therapy for ASCVD.
John Cleland, MD, PhD1 – British Heart Foundation Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health, University of Glasgow.
European Heart Journal article –Is aspirin useful in primary prevention? (Open access)
See more from MedicalBrief archives:
Aspirin reduces cardiovascular events in elderly with raised Lp(a) – ASPREE analysis
Large trial produces ‘best evidence’ of aspirin benefits in reducing CVD risk
Mortality benefit to adding rivaroxaban to aspirin in coronary artery disease — COMPASS trial