Jones WS, Mulder H, Wruck LM, et al. Comparative effectiveness of aspirin dosing in cardiovascular disease. N Engl J Med. 2021;384(21):19811990. .

Aspirin is one of the World’s most widely used drugs and has been studied extensively in randomized controlled trials for myriad indications. While many think of it first as an analgesic or antipyretic, aspirin of course forms the backbone of primary and secondary prevention of cardiovascular events (stroke and myocardial infarction). Its potent, irreversible antiplatelet effects have the potential to prevent disease but also to cause it (i.e., bleeding), and it should therefore be used with caution and precision.

This multicenter, pragmatic, open-label, randomized controlled trial presented a comparison of 81 mg versus 325 mg aspirin in patients with established atherosclerotic disease. This included adult patients with prior myocardial infarction, coronary revascularization procedure, coronary angiogram with more than 75 percent stenosis of at least one coronary artery, or history of coronary artery disease with one additional enrichment criterium (e.g., age > 65 years, serum creatinine > 1.5 mg/dL, diabetes mellitus, cerebrovascular disease, peripheral arterial disease, left ventricular ejection fracture < 50%, or current cigarette use). Patients on or with plans to initiate therapeutic anticoagulation or use ticagrelor were excluded. Identification of patients was accomplished using an electronic health record query, patient consent was garnered through an online portal, and participants were randomly assigned to their dose of aspirin, which they purchased over the counter. Follow-up visits were performed either every three or every six months (randomly assigned) and were conducted over the online patient portal or by telephone. The primary effectiveness outcome was a composite of death, hospitalization for myocardial infarction, or hospitalization for stroke, and the primary safety outcome was hospitalization for major bleeding with an associated blood-product transfusion.

A total of 15,076 patients were enrolled and underwent randomization between April 2016 and June 2019 and were followed until June 2020 for an overall median follow-up of 26.2 months. As expected, most patients before study enrollment were on 81 mg aspirin (85%) while a minority were on the 325 mg dosing (12%). A slight majority of patients on the study had previous coronary artery revascularization by percutaneous coronary intervention or by coronary artery bypass grafting, and comorbidities such as hypertension (83%), dyslipidemia (86%), and diabetes mellitus (38%) were common. A portion (22%) were also taking P2Y12 platelet inhibitors at enrollment. The median age of patients in the study was 67 years and most were men. The composite outcome occurred in 590 patients in the 81 mg group and 569 in the 325 mg group (hazard ratio, 1.02; 95% CI, 0.91-1.14). The outcomes were similar across age, sex, and various subgroups of comorbidities. The primary safety outcome occurred in 53 patients in the 81 mg group and in 44 patients in the 325 mg group (hazard ratio, 1.18; 95% CI, 0.79-1.77). Subgroup analyses on the primary safety outcome for patients with pre-existing P2Y12 inhibitors were not reported. Aspirin discontinuation was reported by 7 percent and 11.1 percent of patients in the 81 mg versus 325 mg groups, respectively. Switching treatment categories occurred in 7.1 percent and 41.6 percent in the 81 mg and 325 mg groups, respectively.

This study further establishes 81 mg as the appropriate dose for patients with atherosclerotic disease. While no increased harm was observed with the higher dose of aspirin, the primary safety outcome was stringent and included more severe presentations of bleeding that may have missed more subtle, less severe bleeding occurring with the higher dose. While this study demonstrates no additional benefits (or risks) to higher doses of aspirin for atherosclerotic disease, we should be careful not to extrapolate this data to other conditions for other indications. For example, Dr. Bianca Rocca and colleagues examined biomarkers of aspirin effect in patients with essential thrombocytosis in a randomized double-blind trial and found that a twice daily regimen of aspirin 100 mg performed better than a daily dose.1  Whether this translates to reduced thromboembolic outcomes in these patients is yet to be determined but nonetheless demonstrates the seemingly endless, but pertinent, questions that still need to be answered about how to use aspirin. This study used unique enrollment and follow-up methods, and its success will undoubtedly be a template for future comparative effectiveness studies. Hopefully, hematologists will take note of the power and simplicity of this study design to employ pragmatic, multicenter, randomized controlled trials like this one to answer simple but important medical management questions in patients with hematologic diseases.

Dr. Houghton indicated no relevant conflicts of interest.

1.
Rocca
B
,
Tosetto
A
,
Betti
S
, et al
.
A randomized double-blind trial of 3 aspirin regiments to optimize antiplatelet therapy in essential thrombocytopenia
.
Blood
.
2020
;
136
(
2
):
171
182
.