Question Does enteric coating on aspirin reduce effectiveness or increase safety in patients with cardiovascular disease?
Findings In this post hoc secondary analysis of 10 678 participants with atherosclerotic cardiovascular disease from the ADAPTABLE randomized clinical trial, there were no significant differences in the primary effectiveness (death, hospitalization for myocardial infarction, or hospitalization for stroke) or safety (major bleeding) end points between enteric-coated aspirin and uncoated aspirin among participants, regardless of which dose of aspirin they were assigned.
Meaning These findings suggested that enteric coating on aspirin is not associated with changes in the effectiveness or safety of aspirin for secondary prevention of cardiovascular events, allowing patients to determine the aspirin formulation.
Abstract
Importance Clinicians recommend enteric-coated aspirin to decrease gastrointestinal bleeding in secondary prevention of coronary artery disease even though studies suggest platelet inhibition is decreased with enteric-coated vs uncoated aspirin formulations.
Objective To assess whether receipt of enteric-coated vs uncoated aspirin is associated with effectiveness or safety outcomes.
Design, Setting, and Participants This is a post hoc secondary analysis of ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness), a pragmatic study of 15 076 patients with atherosclerotic cardiovascular disease having data in the National Patient-Centered Clinical Research Network. Patients were enrolled from April 19, 2016, through June 30, 2020, and randomly assigned to receive high (325 mg) vs low (81 mg) doses of daily aspirin. The present analysis assessed the effectiveness and safety of enteric-coated vs uncoated aspirin among those participants who reported aspirin formulation at baseline. Data were analyzed from November 11, 2019, to July 3, 2023.
Intervention ADAPTABLE participants were regrouped according to aspirin formulation self-reported at baseline, with a median (IQR) follow-up of 26.2 (19.8-35.4) months.
Main Outcomes and Measures The primary effectiveness end point was the cumulative incidence of the composite of myocardial infarction, stroke, or death from any cause, and the primary safety end point was major bleeding events (hospitalization for a bleeding event with use of a blood product or intracranial hemorrhage). Cumulative incidence at median follow-up for primary effectiveness and primary safety end points was compared between participants taking enteric-coated or uncoated aspirin using unadjusted and multivariable Cox proportional hazards models. All analyses were conducted for the intention-to-treat population.
Results Baseline aspirin formulation used in ADAPTABLE was self-reported for 10 678 participants (median [IQR] age, 68.0 [61.3-73.7] years; 7285 men [68.2%]), of whom 7366 (69.0%) took enteric-coated aspirin and 3312 (31.0%) took uncoated aspirin. No significant difference in effectiveness (adjusted hazard ratio [AHR], 0.94; 95% CI, 0.80-1.09; P = .40) or safety (AHR, 0.82; 95% CI, 0.49-1.37; P = .46) outcomes between the enteric-coated aspirin and uncoated aspirin cohorts was found. Within enteric-coated aspirin and uncoated aspirin, aspirin dose had no association with effectiveness (enteric-coated aspirin AHR, 1.13; 95% CI, 0.88-1.45 and uncoated aspirin AHR, 0.99; 95% CI, 0.83-1.18; interaction P = .41) or safety (enteric-coated aspirin AHR, 2.37; 95% CI, 1.02-5.50 and uncoated aspirin AHR, 0.89; 95% CI, 0.49-1.64; interaction P = .07).
Conclusions and Relevance In this post hoc secondary analysis of the ADAPTABLE randomized clinical trial, enteric-coated aspirin was not associated with significantly higher risk of myocardial infarction, stroke, or death or with lower bleeding risk compared with uncoated aspirin, regardless of dose, although a reduction in bleeding with enteric-coated aspirin cannot be excluded. More research is needed to confirm whether enteric-coated aspirin formulations or newer formulations will improve outcomes in this population.
Aspirin has been one of the most widely used medications since its introduction in the 1890s.1 Its irreversible inhibition of both cyclooxygenase 1 synthase reducing production of the eicosanoid thromboxane A2 needed for platelet aggregation makes it ideal for prevention of ischemic cardiovascular events, such as myocardial infarction (MI), stroke, and transient ischemic attack1–3 but at the price of substantial adverse effects, including gastrointestinal (GI) tract bleeding, intracranial hemorrhage (ICH), and generalized bleeding.4 Enteric coating of aspirin delays the breakdown of the tablet until it is in the higher pH of the duodenum and has been shown to reduce gastric erosion5 but has not been shown to reduce gastrointestinal bleeding.6–9 Historically among clinicians and advanced practice providers such as nurse practitioners and physician assistants, it has been recommended for patients to use enteric-coated aspirin over the plain pressed uncoated formulations to minimize GI tract ulceration and bleeding,10 but to our knowledge, no study has shown that the enteric-coated formulation is safer than uncoated aspirin.
The association of enteric-coated aspirin with secondary prevention of cardiovascular disease is controversial. Several studies have proposed that the enteric coating reduces the bioavailability of aspirin due to reduced dissolution and absorption.2,11–14 In 2021, the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness) trial evaluated the safety and effectiveness of high-dose (325 mg) vs low-dose (81 mg) daily aspirin in 15 076 patients with established atherosclerotic cardiovascular disease (ASCVD).15 The results of the trial showed no statistical significance between high- and low-dose aspirin on the primary composite end points of all-cause death, hospitalization for MI, or hospitalization for stroke, as well as no significant difference in major bleeding between the 2 doses of aspirin.15 The present post hoc secondary analysis of the ADAPTABLE trial was designed to provide insight into the effectiveness and safety of enteric-coated aspirin compared with uncoated aspirin among patients with ASCVD.
In this post hoc secondary analysis of ADAPTABLE, a large multicenter, pragmatic, randomized clinical trial, we evaluated the association of aspirin formulation (enteric-coated vs uncoated aspirin) with the effectiveness and safety of aspirin in secondary prevention of ASCVD. The results of this analysis did not show any difference in the effectiveness or safety outcomes analyzed by formulation of aspirin consumed regardless of the dose of aspirin participants were randomly assigned. While prior pharmacodynamic studies2,18 have found that enteric coating impedes the temporal dissolution of the aspirin in the small intestine and limits overall drug absorption, the results of the present study suggest no clear differences in clinical outcomes and should promote further discussion about the appropriate formulation and dose for individual patients.
Due to reduced aspirin bioavailability and the possibility of limited cardiovascular protection, the value of enteric-coated aspirin has been called into question during the last few decades. Cox et al18 reported on a 2-week patient volunteer study comparing the bioavailability of aspirin and inhibition of thromboxane A2 between enteric-coated aspirin and uncoated aspirin. They found that 100% of patients using uncoated aspirin showed higher than 95% thromboxane A2 inhibition compared with 87% of patients receiving enteric-coated aspirin (P < .001). A similar study by Grosser et al10 with 400 patients showed that 83% of patients who took a single-dose of enteric-coated aspirin (325 mg) had greater than 60% reduction in cyclooxygenase activity in 8 hours compared with 100% of patients who took a single dose of uncoated aspirin (325 mg). A sensitivity analysis in the present study using enteric coating and aspirin as time dependent variables also showed that the enteric coating did not modify the outcome response to aspirin dose over time. While it is not known what level of aspirin-induced platelet inhibition is needed to decrease cardiovascular events, this finding implies that enteric coating did not limit the effectiveness of aspirin in providing cardiovascular protection in this patient population.
Acid-reducing medications, such as proton pump inhibitors and histamine type 2 receptor antagonists, used to buffer aspirin within the stomach, have been shown to affect dissolution of the enteric formulations of aspirin by altering the pH, composition, and ionic strength in the stomach.19 The effect on the ability of enteric-coated aspirin to inhibit platelet aggregation has been mixed, with 1 study20 showing no effect with lansoprazole and another study21 showing reduced platelet aggregation when pantoprazole was given with enteric-coated aspirin. Although the pharmacodynamics suggest that enteric-coated aspirin may be less effective than uncoated aspirin, there are no studies, to our knowledge, addressing the question of whether combining ARM with enteric-coated aspirin will result in more adverse clinical outcomes. In the present analysis, we found that the primary efficacy end point of death from any cause, hospitalization for MI, or hospitalization for stroke had similar cumulative incidences reported across 26.2 months in both the enteric-coated aspirin and uncoated aspirin cohorts, regardless of whether patients were also taking ARM.
In terms of the safety profile, enteric coating has been postulated to have better protection against GI tract bleeding and other major bleeding events.22 A double-blind placebo-controlled crossover trial by Hawthorne et al23 showed that enteric coating virtually eliminated gastric mucosa toxic effects compared with nonenteric coating at both high and low doses of aspirin, with similar inhibition of prostaglandin synthesis. Since then, a follow-up study has shown that while this may be true with short-term use, long-term administration of both enteric-coated aspirin or uncoated aspirin causes gastric complications and the development of erosion.24 A meta-analysis demonstrated less-than-convincing effects of GI tract protection with enteric-coated aspirin.25 However, the point estimate for major bleeding with enteric-coated aspirin in the present study showed an 18% relative risk reduction, although the 95% CI was wide, so that a reduction in bleeding with enteric-coated aspirin cannot be reliably excluded. Similar to the lack of an association of enteric coating with the efficacy of aspirin, no significant difference in safety outcomes was observed with enteric-coated aspirin compared with uncoated aspirin in this analysis. We found that more participants randomly assigned to receive the lower dose aspirin (81 mg) took enteric-coated aspirin, while more participants randomly assigned to receive the 325-mg dose used uncoated aspirin. As these data were based on data at randomization and not on the actual drug taken throughout the study, there is no discernable reason for this difference. The rationale behind this finding could be that more patients were given low-dose aspirin because of the perception that low-dose aspirin is less irritating to the GI tract than high-dose aspirin.
When major bleeding was evaluated within formulation cohorts, there was no association with aspirin dose among participants using uncoated aspirin and a small but significant association among patients using enteric-coated aspirin at 325 mg compared with 81 mg. The lack of bleeding difference in the participants using uncoated aspirin may account for the apparent lack of difference in major bleeding seen in the overall ADAPTABLE trial. The results of the present study for the enteric-coated aspirin cohort differed from those of other trials in which no difference in major bleeding was noted; however, in those trials, formulation of aspirin used was not mentioned.26,27
It has been proposed that the coadministration of ARM with enteric-coated aspirin would decrease the frequency of bleeding. However, we were unable to demonstrate a clinical interaction between ARM and the presence of enteric coating associated with either major bleeding or GI tract bleeding in this analysis.
In this post hoc secondary analysis of data from the ADAPTABLE randomized clinical trial, there were no significant differences in the primary effectiveness or safety end points between enteric-coated aspirin and uncoated aspirin among participants with established ASCVD although a reduction in bleeding with enteric-coated aspirin cannot be reliably excluded. More research is needed to confirm whether enteric-coated aspirin formulations or newer formulations will improve ischemic and bleeding outcomes among patients with ASCVD
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