Aspirin: Enteric-Coated vs. Uncoated Formulations in Cardiovascular Disease Prevention


Aspirin, a medication that has been in use since its introduction in the 1890s, is renowned for its effectiveness in preventing ischemic cardiovascular events, such as myocardial infarction (MI), stroke, and transient ischemic attack.

Its mechanism of action involves the irreversible inhibition of cyclooxygenase 1 (COX-1) synthase, which reduces the production of thromboxane A2, an eicosanoid crucial for platelet aggregation.

This property makes aspirin a cornerstone in the secondary prevention of atherosclerotic cardiovascular disease (ASCVD). However, aspirin’s benefits are not without risks, as it can lead to adverse effects, including gastrointestinal (GI) tract bleeding, intracranial hemorrhage (ICH), and generalized bleeding.

One strategy to mitigate the GI side effects of aspirin is the development of enteric-coated formulations. These coatings delay the tablet’s breakdown until it reaches the higher pH environment of the duodenum, potentially reducing gastric erosion. Nevertheless, it remains unclear whether enteric-coated aspirin truly provides a safer alternative to uncoated aspirin.

While clinicians and healthcare providers have historically recommended enteric-coated aspirin to minimize GI ulceration and bleeding, robust scientific evidence supporting its superiority in terms of safety has been lacking.

The Controversy Surrounding Enteric-Coated Aspirin

The association of enteric-coated aspirin with secondary prevention of cardiovascular disease has long been a subject of debate. Several studies have suggested that the enteric coating may reduce aspirin’s bioavailability due to delayed dissolution and absorption.

In 2021, the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness) trial sought to evaluate the safety and effectiveness of high-dose (325 mg) vs. low-dose (81 mg) daily aspirin in a large cohort of 15,076 patients with established ASCVD. Surprisingly, the trial revealed no statistically significant difference between high and low-dose aspirin regarding primary composite endpoints (all-cause death, hospitalization for MI, or hospitalization for stroke) or major bleeding.

This post hoc secondary analysis of the ADAPTABLE trial aimed to provide further insights into the safety and efficacy of enteric-coated aspirin compared to uncoated aspirin in the context of ASCVD secondary prevention.

The results of this analysis did not demonstrate any substantial difference in the effectiveness or safety outcomes when considering the formulation of aspirin, regardless of the dose participants were assigned. While previous pharmacodynamic studies had indicated that enteric coating might impede aspirin’s dissolution and absorption, the clinical outcomes analyzed in this study painted a different picture. These findings raise questions about the necessity of enteric coating and the optimal formulation and dose for individual patients.

Bioavailability Concerns

One of the key arguments against enteric-coated aspirin is the issue of reduced bioavailability, potentially leading to limited cardiovascular protection. Studies such as those conducted by Cox et al. and Grosser et al. have shown that enteric-coated aspirin can result in less inhibition of thromboxane A2 compared to uncoated aspirin.

This discrepancy raises concerns about whether enteric-coated aspirin provides adequate platelet inhibition to reduce cardiovascular events. However, the current study’s analysis did not reveal any clear differences in clinical outcomes, suggesting that enteric coating did not compromise aspirin’s effectiveness in providing cardiovascular protection in this patient population.

The Role of Acid-Reducing Medications

Acid-reducing medications, including proton pump inhibitors and histamine type 2 receptor antagonists, have been utilized to buffer aspirin within the stomach. These medications can alter the pH, composition, and ionic strength in the stomach, potentially affecting the dissolution of enteric formulations of aspirin. Some studies have shown mixed effects on the ability of enteric-coated aspirin to inhibit platelet aggregation when administered alongside acid-reducing medications. However, there is a lack of comprehensive research addressing whether combining acid-reducing medications with enteric-coated aspirin results in adverse clinical outcomes.

Safety Profile

Enteric coating has been suggested to offer better protection against GI tract bleeding and other major bleeding events.

Early studies, like the one conducted by Hawthorne et al., indicated that enteric coating significantly reduced gastric mucosal toxic effects compared to nonenteric coating, even at high aspirin doses. However, more recent research has suggested that both enteric-coated and uncoated aspirin can cause gastric complications and erosion with long-term use. A meta-analysis also found inconclusive evidence regarding GI tract protection with enteric-coated aspirin.

In the present study, while the point estimate for major bleeding with enteric-coated aspirin showed an 18% relative risk reduction, the wide 95% confidence interval prevented reliable conclusions about bleeding risk.

Interestingly, no significant difference in safety outcomes was observed between enteric-coated and uncoated aspirin. This finding implies that enteric coating may not confer a significant safety advantage in terms of bleeding events.

Dosing Considerations

It’s worth noting that more participants in the study randomly assigned to receive lower-dose aspirin (81 mg) opted for enteric-coated formulations, possibly due to the perception that low-dose aspirin is gentler on the GI tract. However, the analysis did reveal a small but significant association between aspirin dose and major bleeding in the enteric-coated aspirin cohort. This observation could partially explain the overall lack of bleeding difference seen in the ADAPTABLE trial.


The use of aspirin in the secondary prevention of ASCVD remains a topic of ongoing research and debate. While enteric-coated aspirin has been proposed as a potential solution to mitigate GI side effects, it has faced criticism due to concerns about reduced bioavailability. The analysis of the ADAPTABLE trial presented here adds valuable insights into this debate.

In this study, the choice of aspirin formulation, whether enteric-coated or uncoated, did not significantly affect the effectiveness or safety outcomes in ASCVD patients. This finding challenges the conventional wisdom regarding enteric coating’s benefits in terms of safety and efficacy. It also raises questions about the necessity of enteric-coated aspirin in clinical practice.

Overall, this post hoc secondary analysis underscores the complexity of aspirin therapy and the need for further research to optimize its use in individual patients. While enteric-coated aspirin may offer some advantages in specific scenarios, it may not be a one-size-fits-all solution. Clinicians and healthcare providers should carefully consider patient characteristics, preferences, and risk profiles when choosing the appropriate aspirin formulation and dose for secondary prevention of ASCVD. Future studies are warranted to delve deeper into the intricate nuances of aspirin therapy and its impact on patient outcomes.

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