Aspirin dosing after ACS: is twice-daily therapy the solution to aspirin resistance?
Despite substantial advances in antithrombotic therapy, patients presenting with acute coronary syndrome (ACS) remain at considerable risk of recurrent ischemic events. This residual risk is particularly pronounced among individuals with diabetes mellitus or clinical features associated with increased platelet turnover and so-called aspirin resistance. The ANDAMAN trial, recently published in the European Heart Journal, revisits a long-standing pharmacological question: could twice-daily aspirin dosing improve clinical outcomes after ACS by overcoming variability in platelet inhibition 1. Aspirin exerts its antithrombotic effect through irreversible inhibition of platelet cyclooxygenase-1 (COX-1), thereby suppressing thromboxane A₂ production and platelet activation. However, several clinical and biological factors—including diabetes mellitus, obesity, systemic inflammation, and accelerated platelet turnover—may attenuate its inhibitory effect. In such settings, newly generated platelets may escape inhibition between dosing intervals, theoretically allowing partial recovery of platelet activity during once-daily therapy. This observation has provided the rationale for more frequent aspirin administration in selected high-risk populations.
The ANDAMAN trial was a prospective, multicentre randomised study designed to test this hypothesis in patients with ACS and either diabetes mellitus or clinical features associated with aspirin resistance. A total of 2484 patients were randomised to receive enteric-coated aspirin either once daily (100 mg) or twice daily (100 mg morning and evening) in addition to guideline-directed therapy. The primary endpoint was major adverse cardiovascular events (MACE), defined as a composite of death, myocardial infarction, stroke, urgent coronary revascularisation, stent thrombosis, or acute arterial thrombotic events. The principal safety outcome was major bleeding according to the Bleeding Academic Research Consortium (BARC) criteria 1. After a median follow-up of 18 months, the primary endpoint occurred in 7.7% of patients receiving twice-daily aspirin compared with 8.8% in those treated with the conventional once-daily regimen (HR 0.90, 95% CI 0.69–1.19; p = 0.42). Importantly, major bleeding rates were similar between groups (1.9% vs 2.1%). Overall, intensified aspirin dosing did not translate into a statistically significant reduction in ischemic events while maintaining a comparable safety profile.
At first glance, these findings may appear somewhat disappointing. However, they offer valuable insights into the complex interplay between platelet biology and residual thrombotic risk after ACS. The concept of aspirin resistance has long been debated, and although laboratory assays may identify incomplete platelet inhibition in certain patients, translating these observations into clinically meaningful therapeutic strategies has proven challenging 2. Moreover, contemporary ACS management already involves potent platelet inhibition through dual antiplatelet therapy (DAPT), typically combining aspirin with a P2Y12 receptor inhibitor such as ticagrelor or prasugrel. In this context, optimising aspirin pharmacodynamics alone may provide only limited incremental benefit, particularly when alternative pathways of platelet activation are already effectively targeted. Previous attempts to enhance aspirin efficacy—whether through higher doses or alternative dosing schedules—have similarly failed to demonstrate consistent clinical advantages 3. Interestingly, the ANDAMAN trial also emerges in a period where the role of aspirin within antithrombotic therapy is increasingly being re-evaluated. Several recent studies have explored strategies aimed at reducing aspirin exposure rather than intensifying it. Trials such as TWILIGHT and GLOBAL LEADERS have suggested that early aspirin withdrawal while maintaining potent P2Y12 inhibition may reduce bleeding risk without compromising ischemic protection 4,5. Against this evolving background, intensifying aspirin therapy appears somewhat countercurrent to the broader trend toward minimising aspirin exposure in selected patients.
Nevertheless, the trial has several strengths worth emphasising. It enrolled a large population of high thrombotic risk and achieved excellent follow-up. Furthermore, the pragmatic design reflects contemporary real-world practice and provides reassuring safety data regarding intensified aspirin dosing. Certain limitations should also be acknowledged. First, the study may not have been powered to detect modest differences in clinical outcomes, and a small benefit cannot be entirely excluded. Second, the identification of patients with suspected aspirin resistance relied on clinical characteristics rather than platelet-function testing, which may have diluted the population most likely to benefit from intensified dosing. Finally, widespread use of modern antiplatelet therapies may have reduced the incremental impact of modifying aspirin pharmacokinetics.
Taken together, the ANDAMAN trial provides important evidence that twice-daily aspirin dosing does not significantly improve outcomes in high-risk ACS patients compared with the standard once-daily regimen. These findings reinforce the notion that addressing residual thrombotic risk likely requires strategies beyond simply modifying aspirin dosing, including optimized P2Y12 inhibition, individualized antithrombotic approaches, and aggressive management of cardiometabolic risk factors. In the era of increasingly tailored antithrombotic therapy, this study serves as a reminder that more drug exposure does not necessarily translate into better clinical outcomes. The future may lie less in intensifying aspirin therapy and more in refining the broader antithrombotic strategy.