Author + information
- Alberto Aimo, MD,
- Andrea Ripoli, EngD,
- Raffaele De Caterina, MD, PhD and
- Michele Emdin, MD, PhD∗ ( )()
- ↵∗Scuola Superiore Sant’Anna and Fondazione Toscana Gabriele Monasterio, Via G. Moruzzi 1, 56124 Pisa, Italy
We have read with interest the study by Madelaire et al. (1) investigating the prognostic impact of low-dose aspirin in patients with new-onset heart failure (HF) and without atrial fibrillation. Among 5,450 patients on low-dose aspirin (defined as 75 to 150 mg daily), 3,840 were propensity matched to 3,840 non-aspirin users on the basis of demographic variables, comorbidities, and medical therapies. The primary endpoint, a composite of all-cause mortality, myocardial infarction (MI), and stroke, occurred in 1,554 patients (40.5%) in the aspirin group and in 1,604 (41.8%) in the non-aspirin group. Aspirin use was associated with a similar risk of the primary endpoint (hazard ratio: 0.98, 95% confidence interval: 0.91 to 1.05), as well as of bleeding, but with a 25% higher risk of HF readmission and a 34% higher risk of MI. Unexpectedly, no difference in the primary endpoint was observed even among patients with ischemic HF.
The authors address an important, highly debated issue (2,3). However, their conclusions against aspirin prescription to all HF patients, including those with ischemic etiology, are questionable after careful examination of the statistical approach adopted.
Because the expected benefit from aspirin in patients with chronic HF is small, prospective studies on this topic should be very large to ensure adequate statistical power, and then to provide reliable conclusions. The sample size is calculated after estimating the likelihood of outcome occurrence in treated and untreated patients (4). If outcome probability is 0.405 in the aspirin group and 0.415 in the non-aspirin group (as in the 2 matched groups in this study), up to 35,744 patients should be randomized to aspirin or placebo to reliably assess aspirin efficacy, even when making the most conservative assumptions (1-tailed test, power 0.80, α error probability 0.05). When performing a 2-tailed test, which does not exclude a priori a deleterious effect of aspirin, the patient number becomes as high as 45,294 (Figure 1). In other words, the size to yield meaningful results should be 5- to 6-fold higher than the one evaluated in this retrospective analysis. With regard to ischemic HF, population sizes become 6,356 and 8,040 under the previous assumptions, that is, 3- to 4-fold greater than in the present study. The intrinsic limitations of retrospective studies and the propensity-matching approach cast further shadows on the authors’ conclusions. Most notably, several meaningful variables, such as left ventricular ejection fraction, are not available. Furthermore, aspirin treatment is started because of a perception of a higher risk of cardiovascular events, which probably cannot be captured by the small number of variables considered in propensity-matching analysis. This may explain the apparently greater risk of MI among patients on aspirin.
To recapitulate, low-dose aspirin is recommended in all patients with stable ischemic heart disease (5), and is a pathophysiologically sound treatment for ischemic HF (1,2). Further studies on aspirin in HF are warranted and should be carefully designed. In particular, because the expected benefit from aspirin is small, very large populations must be assessed to ensure adequate statistical power, and then to provide reliable conclusions.
Please note: Dr. De Caterina has received lecture fees, honoraria, and research funding from Sanofi, Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi Sankyo, Novartis, Merck, and Portola. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
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