Aspirin Dosing in Cardiovascular Disease and Diabetes: Insights From ADAPTABLE

Nearly one-third of individuals with type 2 diabetes also have cardiovascular disease (1), and these individuals with both diabetes and atherosclerotic cardiovascular disease face significantly higher risks of premature death and serious adverse cardiovascular events in comparison with individuals with either condition alone (2). As a result, it is crucial to implement strategies that both prevent and effectively manage diabetes and cardiovascular disease. Comprehensive secondary prevention encompasses lifestyle modification, aggressive blood pressure and lipid control, use of antiplatelet agents, glycemic management, and administration of medications that have been shown to improve cardiovascular outcomes, such as sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists (3–5).

While the role of aspirin in primary prevention continues to spark debate, the efficacy of aspirin in reduction of cardiovascular morbidity and mortality in patients with established cardiovascular disease is well established (6). As a result, guidelines and clinical practice recommendations strongly recommend the use of aspirin to reduce recurrent atherosclerotic events in individuals with established cardiovascular disease (3–5). Determining the ideal aspirin dose is pivotal for all of these patients, but it becomes even more crucial for those living with diabetes due to the heightened prothrombotic environment linked to diabetes (7). Despite the importance of the optimal dose of aspirin in secondary prevention, controversy exists, and there has been significant historical variability in clinical practice regarding the use of low or high doses of aspirin in individuals with atherosclerotic cardiovascular disease (8).

In this setting, ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) was initiated to address optimal aspirin dosing (7,9). ADAPTABLE was an open-label, pragmatic, randomized controlled trial that involved >15,000 adults and was designed to test whether a strategy of aspirin at a dose of 325 mg/day would result in lower risk of death, hospitalization from myocardial infarction, or stroke among patients with established atherosclerotic cardiovascular disease in comparison with aspirin 81 mg daily. Additionally, the trial included assessment of the primary safety outcome of hospitalization due to major bleeding necessitating a blood-product transfusion in both treatment arms. Ultimately, the trial’s findings revealed no significant differences in cardiovascular events (hazard ratio [HR] 1.02, 95% CI 0.91–1.14) or major bleeding between the patients assigned to 81 mg compared with 325 mg daily (HR 1.18, 95% CI 0.79–1.77) (7).

In this issue of Diabetes Care, Narcisse et al. (10) present a subgroup analysis to identify the relationship between baseline diabetes status and adverse outcomes. The researchers also assess the efficacy and safety of both high- and low-dose aspirin in individuals with diabetes. Of the ADAPTABLE participants, 39% (n = 5,676) had a history of diabetes. Individuals with diabetes were slightly younger but had more comorbid conditions, including a greater prevalence of heart failure, chronic kidney disease, and history of previous bleeding complication, compared with those without diabetes. As seen in many previous studies, for those individuals with diabetes there were elevated rates of the primary outcome of death, myocardial infarction, or stroke (9.6%) compared with those without diabetes (5.9%) over a median duration of 26.2 months. While this hazard was attenuated after adjustment for baseline differences between the two groups, the hazard for the primary outcome remained 37% higher for those with diabetes. Notably, the rates of major bleeding were also increased for those with diabetes (0.78%) compared with those without diabetes (0.5%).

In comparing the effects of different doses in individuals with diabetes, no statistically significant difference was found between the 81 mg and 325 mg aspirin dosages for the primary composite cardiovascular end point (adjusted HR 0.98, 95% CI 0.83–1.16). These results were not modified by poor glycemic control at baseline (defined as a baseline HbA_1c >8%). Similarly, hospitalization for major bleeding with an associated blood transfusion did not vary significantly between aspirin 81 mg compared with aspirin 325 mg (adjusted HR 1.25, 95% CI 0.72–2.16). Notably, adherence to the prescribed aspirin dose, especially the 325 mg dose, was limited. Approximately 45% of those individuals assigned to the higher aspirin dose either switched or discontinued their dosage after randomization, with ∼33% switching to the lower dose. A sensitivity analysis using self-reported aspirin dose for patients with diabetes showed a trend toward higher rates of the primary composite cardiovascular end point for those who self-reported aspirin dose 81 mg compared with 325 mg, but the finding did not reach statistical significance (adjusted HR 1.21, 95% CI 1.00–1.48).

ADAPTABLE represents a laudable effort by the investigators to answer a crucial, patient-centered question about the ideal aspirin dosing in individuals with established atherosclerotic cardiovascular disease, a question that is especially pertinent for those with diabetes, a group with heightened cardiovascular risk. While the clinical question posed was of undeniable significance, it is also vital to underscore some novel methods and lessons learned from the conduct of this clinical trial that was unlikely to be supported by a traditional industry-sponsored randomized clinical trial. Notably, ADAPTABLE, funded by the Patient-Centered Outcomes Research Institute (PCORI), was the first pragmatic, large-scale comparative effectiveness trial using the National Patient-Centered Clinical Research Network (PCORnet), an expansive distributed research network spanning the U.S., made operational by aggregate electronic health records and claims data platforms (9). The study leveraged electronic health records technology to identify a large pool of eligible patients, conduct remote outreach and randomization of scale, and ascertain end points (9). Consent was given electronically, randomization to open-label aspirin dosage occurred directly to participants via a patient portal, and participants purchased their assigned dosage of aspirin at their local pharmacy. Multiple partners collaborated in this pragmatic research, including academicians, patients, health systems, and payers, with the goals of embedding a clinical trial in real-world practice, reducing the burden of research on patients and sites, and reducing the total costs of the trials. There have been and will be numerous insights from the study’s methods that will inform future pragmatic studies, including ways to improve end point validation (11) and address potential differences in adherence in the case of internet versus call-based follow-up (12). Importantly, the study provides evidence that such a large pragmatic trial is feasible and can be executed in the U.S.

Despite this success, it is important to note the same large limitation as in the overall trial: the significant nonadherence to the assigned doses, notably in the high aspirin dose group. This trial deviation may compromise the ability to distinguish differences in either safety or efficacy between the two groups. While the reasons for transitioning from the higher to the lower aspirin dose are not completely known, the decision to change dose in this open-label study was likely not random. Factors such as patient or provider preference, perceived adverse reactions, or contemporary treatment patterns might have influenced these choices. Thus, some ambiguity still exists as to whether the similar outcomes seen between the doses stem from true comparable efficacy and safety or are a consequence of dose crossovers.

Overall, the data support the continuation of the current guideline recommendations to use aspirin therapy at a dose of 75–100 mg/day, in the American College of Cardiology/American Heart Association guidelines (class 1-A recommendation) (4), and at a dose of 75–162 mg/day, in the American Diabetes Association Standards of Care in Diabetes (level of evidence A) (3). Future studies will likely shed further insight into the optimal antiplatelet dosing regimen including further comparison with monotherapy with PCY12 inhibitors such as clopidogrel.