Author + information
- aRobertson Centre for Biostatistics & Clinical Trials, University of Glasgow, Glasgow, Scotland, United Kingdom
- bNational Heart & Lung Institute, Imperial College, London, United Kingdom
- ↵∗Address for correspondence:
Prof. John G.F. Cleland, Robertson Centre for Biostatistics & Clinical Trials, University of Glasgow, University Avenue, Glasgow G12 8QQ, Scotland, United Kingdom.
“Convictions are more dangerous enemies of truth than lies.”
—Friedrich Nietzsche (1)
The title of this article will upset many cardiologists and homoeopathists. However, there is as much evidence from randomized, placebo-controlled trials that use of long-term aspirin delivers cardiovascular benefits as there is for any homeopathic remedy; neither discipline knows what dose of aspirin is effective; presumably a “homeopathic dose” would at least be safe (Online Appendix). Is the current belief in aspirin just driven by publication-bias and an uncritical, semi-religious belief in inherited teachings? After all, aspirin is a nonsteroidal anti-inflammatory drug and other agents of this class have caused concerns about increased cardiovascular risk (Online Appendix). Why should aspirin be different?
In this issue of JACC: Heart Failure, the WARCEF (Warfarin Versus Aspirin in Reduced Ejection Fraction) trial investigators report that, compared to warfarin, aspirin does not increase the risk of hospitalization for heart failure (2). This result contrasts with those of 2 previous trials that showed an increase in such risk (3,4). In WARCEF, 2,305 patients with heart failure in sinus rhythm and with a left ventricular ejection fraction ≤35% were randomized to either adjusted-dose warfarin with target international normalized ratio of 2.75 (acceptable range: 2.0 to 3.5) or aspirin 325 mg daily in a double-blind, double-dummy design. As such, WARCEF was both the largest and most methodologically robust trial comparing warfarin and aspirin for heart failure. These results allay some of the fears raised by previous trials that aspirin could increase the risk of congestion but they provide no evidence that either warfarin or aspirin should be given routinely to patients with heart failure in sinus rhythm. What a great opportunity to reduce unhelpful polypharmacy; not only of antithrombotic therapy but also of potentially harmful treatments given to reduce the risk of gastrointestinal hemorrhage (Online Appendix).
Aspirin is a nonspecific cyclo-oxygenase inhibitor that blocks the production of a range of prostaglandins (Online Appendix). Many prostaglandins are thought to have beneficial actions, including vasorelaxation, maintenance of glomerular filtration, and reductions in platelet adhesion to vessel walls; whereas others, such as thromboxane, increase platelet aggregation, providing a theory to support the supposed benefits of aspirin in patients with coronary artery disease. Aspirin is a “nuclear” option, destroying indiscriminately both the benefits and risks conferred by prostaglandins. The balance of beneficial and harmful effects of aspirin is likely to vary according to the clinical setting (Online Appendix). In the presence of ulcerated plaque, benefit may greatly outweigh risk. In the presence of stable plaque, the balance is less clear. Hemorrhage into plaque, aggravated by inhibiting thromboxane, may destabilize it. In heart failure, prostacyclin may be an important counter-regulatory mechanism that causes vasorelaxation, protects renal function, and reduces sodium retention, thereby reducing the risk of worsening heart failure (Online Appendix). This may be a mechanism by which angiotensin-converting enzyme (ACE) inhibitors exert benefit.
Few trials have randomized patients to receive antithrombotic or not in patients with heart failure. The largest of these (WASH [Warfarin/Aspirin Study in Heart Failure]) included only 279 patients but showed some evidence of harm with aspirin; warfarin was not obviously superior to receiving no antithrombotic treatment at all (3). There is a great deal of evidence that the benefits of ACE inhibitors are diminished in the presence of antiplatelet therapy (5), predominantly aspirin, for which there are at least 4 possible explanations: 1) it may not be true and is just a chance finding in one of many retrospective analyses (unlikely given the strength of the interaction); 2) aspirin may interfere with the beneficial effects of ACE inhibitors, which is biologically plausible; 3) ACE inhibitors and aspirin may exert benefit through a common pathway but the effects are not additive (statistically plausible); and 4) alternatively, antiplatelet therapy may just be a surrogate for something else, such as ischemic heart disease, and such patients derive less benefit from an ACE inhibitor. Further retrospective analyses are unlikely to resolve, with confidence, which of these explanations is true. The evidence for an interaction between aspirin and other disease-modifying therapies for heart failure, including beta-blockers and mineralocorticoid antagonists is less strong and subject to similar explanations (6) (Online Appendix).
The major evidence gap for antithrombotic agents in heart failure is placebo-controlled studies. There is a stronger evidence base comparing different antithrombotic therapies in patients with heart failure. Randomized trials comparing aspirin and clopidogrel, an antiplatelet agent that does not inhibit cyclo-oxygenase, suggest that glomerular filtration rate and exercise capacity were consistently greater and plasma concentrations of natriuretic peptides were generally lower on clopidogrel but no difference in morbidity or mortality was observed (7) (Online Appendix). Randomized trials of aspirin compared to warfarin show that warfarin reduces the risk of stroke but increases major bleeding; overall mortality was similar on aspirin and warfarin (3,4) (Online Appendix). The absolute reduction in stroke events with warfarin compared to aspirin was approximately 1 event for every 200 patient-years of follow-up; approximately 20% of strokes were fatal (1 less fatal stroke per 1,000 patient-years) and only one-third of survivors had moderate or severe persisting disability (1 disabling stroke prevented for every ∼800 patient-years of follow-up). The importance of occult or incident atrial fibrillation to strokes in patients with heart failure is uncertain. In summary, we have little evidence that 1 antithrombotic agent is superior to another and little evidence that any agent is superior to none.
So why do we use antithrombotic agents in heart failure? Cardiologists will generally respond that they are not treating the heart failure; they are treating the associated coronary artery disease. So what evidence is there that patients with coronary artery disease benefit from long-term aspirin? Surprisingly, at least to most cardiologists, no trial of long-term aspirin administration to patients with proven coronary disease has shown a reduction in mortality (Online Appendix). Of special relevance to patients with heart failure, all substantial, placebo-controlled, long-term trials of aspirin after a myocardial infraction have used >300 mg/day. Indeed, these studies, conducted in the 1970s with high doses of aspirin, with or without dipyridamole, before the modern era of heart failure diagnosis and therapy, showed trends to a worse outcome in patients with heart failure if they were assigned to aspirin (Figure 1A) (8,9). The aspirin-advocate, now exasperated, desperate, and confused, begins clutching for straws. What about the antiplatelet trialists’ meta-analysis! This is poor evidence. If an intervention requires a meta-analysis of large, individually neutral clinical trials, then the benefit is unlikely to be clinically useful (Online Appendix). Moreover, the results of the antiplatelet meta-analysis for patients after a myocardial infarction is driven by improbably large effects in smaller trials; larger trials were neutral or trended to harm (Figure 1B) (Online Appendix).
The aspirin advocate, even more desperate and confused by this time, exclaims “but these trials are old and used too high a dose of aspirin.” I agree, but absence of evidence is a poor argument to do something — imagine the mess we would get into with this approach to care! The only substantial placebo-controlled trial of aspirin after myocardial infarction (The Second International Study of Infarct Survival; ISIS-2) may then be mentioned (Online Appendix). This trial showed a benefit for patients assigned to aspirin for up to 10 years after the event. However, aspirin was only administered for 28 days; the study provides no support for long-term aspirin use. Perhaps a course of aspirin should be administered after a myocardial infarction just as we might give a course of antibiotics for pneumonia? How did we get into the mess of giving life-long aspirin based on this evidence? Finally, the cardiologist might invoke the U.S. Physicians study of healthy volunteers (Online Appendix). After 100,000 participant-years of follow-up this study was stopped for futility, showing just 1 cardiovascular death difference between aspirin and placebo. Hardly a positive result! True, there was a reduction in nonfatal myocardial infarction, but why this did not translate into a reduction in mortality defies explanation; perhaps an increase in aspirin-induced sudden death is responsible (6,10) (Online Appendix)?
If we are going to use aspirin for generations to come, we should know which doses are effective and safe. Unfortunately, dose-comparison studies are not very helpful because if no dose of aspirin is known to be effective, then there is no reference-dose! In the acute setting, few new antiplatelet agents have built on the design of the only positive trial (ISIS-2) and shown that antiplatelet therapy must be administered for longer than a month. Recent reports of dual antiplatelet trials suggest that shorter courses of therapy may be superior to longer ones after percutaneous coronary intervention (Online Appendix). Perhaps 28 days would suffice? This has enormous financial repercussions and is important for patients who complain about polypharmacy. Recently, it was announced that a study comparing low-dose rivaroxaban, aspirin, and the combination was stopped because 1 or both rivaroxaban arms were superior to aspirin (Online Appendix). If rivaroxaban monotherapy is not inferior to the combination, then it might become the new gold standard against which other treatments should be tested. The results of a large study comparing low-dose rivaroxaban to placebo patients with heart failure with reduced ejection fraction are keenly awaited (11); unfortunately, the study is conducted on a background of antiplatelet therapy.
In summary, research into antithrombotic therapy could be entering a golden era after the dark days of dogma. If we are uncertain, we can progress. If we are certain and we are wrong, we are in trouble. As Nietzsche said, “convictions are more dangerous enemies of truth than lies.”
For supplemental references, please see the online version of this paper.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Dr. Cleland has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation
- ↵Goodreads. Friedrich Nietzsche quotes. Available at: http://www.goodreads.com/quotes/41091-convictions-are-more-dangerous-foes-of-truth-than-lies. Accessed June 28, 2017.
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