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Randomized Controlled Trial
. 2023 Nov 1;8(11):1061-1069.
doi: 10.1001/jamacardio.2023.3364.

Effectiveness and Safety of Enteric-Coated vs Uncoated Aspirin in Patients With Cardiovascular Disease: A Secondary Analysis of the ADAPTABLE Randomized Clinical Trial

Amber Sleem  1 , Mark B Effron  2 , Amanda Stebbins  3 , Lisa M Wruck  3   4 , Guillaume Marquis-Gravel  5   6 , Daniel Muñoz  7 , Richard N Re  8 , Kamal Gupta  9 , Carl J Pepine  10 , Sandeep K Jain  11 , Saket Girotra  12 , Jeffrey Whittle  13 , Catherine P Benziger  14 , Peter M Farrehi  15 , Kirk U Knowlton  16 , Tamar S Polonsky  17 , Matthew T Roe  3 , Russell L Rothman  7 , Robert A Harrington  18 , W Schuyler Jones  3   6 , Adrian F Hernandez  3   6
Affiliations
Randomized Controlled Trial

Effectiveness and Safety of Enteric-Coated vs Uncoated Aspirin in Patients With Cardiovascular Disease: A Secondary Analysis of the ADAPTABLE Randomized Clinical Trial

Amber Sleem et al. JAMA Cardiol. .

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.

Trial registration: ClinicalTrials.gov Identifier: NCT02697916.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Effron reported receiving personal fees from Eli Lilly and Company; and holding stock and receiving a pension from Eli Lilly and Company outside the submitted work. Dr Marquis-Gravel reported receiving personal fees from JAMP Pharma, Boston Scientific, Novartis, CSI Pharmacy, KYE Pharmaceuticals, HSL Therapeutics, and Bayer, and receiving grants from Bayer outside the submitted work. Dr Re reported receiving grants from Health and Human Services during the conduct of the study. Dr Pepine reported receiving personal fees from AbbVie, Akros, BioCardia, BloomerTech, Caladrius, Imbria Pharmaceuticals, Ironwood Pharmaceuticals, Milestone Pharmaceuticals, Verily Life Sciences, and XyloCor Therapeutics; and grants from BioCardia, Caladrius, Duke Clinical Research Institute, Gatorade Foundation, McJunkin Family Foundation Trust, Mesoblast, the National Heart, Lung, and Blood Institute (NHLBI), WISE Program, Pfizer, Sanofi, University of Florida Clinical and Translational Science Institute, US Department of Defense, and XyloCor Therapeutics outside the submitted work. Dr Girotra reported receiving grants from the NHLBI outside the submitted work. Dr Roe reported being an employee and holding stock in AstraZeneca outside the submitted work. Dr Rothman reported receiving grants from the Patient-Centered Outcomes Research Institute (PCORI) during the conduct of the study. Dr Harrington reported receiving grants from CSL Behring and Janssen and receiving personal fees from Bristol Myers Squibb and Basking Biosciences outside the submitted work; consulting for Atropos Health, Bitterroot Bio, BridgeBio, Foresight Pharmaceuticals, and Edwards Lifesciences outside the submitted work; and being a member of the board of directors from American Heart Association and Cytokinetics outside the submitted work. Dr Hernandez reported receiving grants from American Regent, Amgen, Bayer, Boehringer Ingelheim, Merck, and Novartis; and receiving grants from Verily and personal fees from Cytokinetics and Bristol Myers Squibb outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Diagram of Patient Flow in the Analysis
Participants were randomly assigned to aspirin dose but not to aspirin formulation, which was at the discretion of the participant. For several analyses, participants were grouped by aspirin formulation regardless of aspirin dose (shown at the bottom of the figure). Regardless of aspirin dose, there were 7366 total participants taking enteric-coated aspirin and 3312 taking uncoated aspirin.
Figure 2.
Figure 2.. Cumulative Incidence of the Primary End Point (All-Cause Death, Myocardial Infarction [MI], or Stroke) by Randomly Assigned Aspirin Dose (81 or 325 mg) and by Self-Selected Aspirin Formulation (Enteric-Coated or Uncoated) From Participant Self-Reported, Electronic Health Record, and Claims Data
AHR indicates adjusted hazard ratio.
Figure 3.
Figure 3.. Cumulative Incidence of Bleeding Accounting for the Competing Risk of Death by Randomly Assigned Aspirin Dose (81 or 325 mg) and Self-Selected Aspirin Formulation (Enteric-Coated or Uncoated) From Participant Self-Reported, Electronic Health Record, and Claims Data
Major bleeding was defined as bleeding requiring blood product transfusion. AHR indicates adjusted hazard ratio.
See this image and copyright information in PMC

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