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Schuyler Jones W, et al.. "Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease". New England Journal of Medicine. 2021. 384(21):1981-1990.
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Clinical Question

In adults with established atherosclerotic cardiovascular disease, does full dose aspirin 325 mg lower the risk of death, stroke, myocardial infarction more than aspirin 81 mg?

Bottom Line

In patients with established atherosclerotic disease, aspirin 325 mg does not lower the risk of death, stroke, or myocardial infarction compared with aspirin 81 mg, and those in the 325 mg group were more likely to switch their dose to aspirin 81 mg.

Major Points

The ACC/AHA aspirin guidelines do not specify the dose of aspirin for patients with atherosclerotic disease, while the ESC (European Society of Cardiology) specifies low-dose aspirin in this patient population. Registry data show considerable variability in post-MI aspirin dosage. The question of the optimal dose of aspirin remains uncertain despite multiple studies on aspirin for secondary prevention.

The ambiguity in optimal aspirin dosage is reflected in some of the landmark secondary prevention trials. The 1996 CAPRIE[1] study found clopidogrel 75 mg superior to aspirin 325 mg. The 2006 study CHARISMA[2] found no benefit in adding clopidogrel 75 mg to 75 - 162 mg aspirin.

ADAPTABLE's negative findings point to a potentially nill difference among aspirin dosages in the context of real-world patient follow-up scenarios. The legitimacy of the finding is undercut by the lack of adherence past 1 year of the full 325 mg dose aspirin. The high rate of cross-over from 325 mg to 81 mg aspirin demonstrates a remarkable patient preference for the 81 mg aspirin dosage. Further, the safety outcome of lack of major GI bleeding as measured by need for transfusion is a low sensitivity but high specificity marker of adverse bleeding events. While convenient to the study design, this measure of GI bleeding likely underestimates the true rate of GI bleeding in this population without providing insight underlying cause of this bleeding.

The ADAPTABLE trial is notable for demonstrating successful execution of pragmatic trial in the United States. Other pragmatic trials have been conducted in Europe including ASCEND[3] and TASTE[4],[5]. The benefit of this trial design is large sample size and low cost. These factors allow for trials with high data quality to answer clinically relevant questions within real-world study conditions. However, as seen ADAPTABLE trial's high cross-over from full dose aspirin to low dose, there is potential for confounding factors secondary to patient behavior and preference.


As of November 2021, no clinical guidelines have been updated to reflect the findings of this study.


  • Multicenter, open-label, parallel-group, 1:1 randomized, controlled trial
  • N=15,076
    • Aspirin 81 mg (n=7,540)
    • Aspirin 325 mg (n=7,536)
  • Setting: 40 centers in the PCORnet, via patient portal or call center
  • Enrollment: April 2016 to June 2019
  • Mean follow-up: 26.2 months
  • Analysis: Intention-to-treat with time-to-first-event analysis
  • Primary outcomes:
    • Effectiveness: Time to first occurrence in the composite of death, hospitalization for myocardial infarction, or hospitalization for stroke
    • Safety: Hospitalization for major bleeding requiring blood-product transfusion
  • Secondary outcomes:
    • Coronary revascularization
    • Death
    • Hospitalization for myocardial infarction
    • Hospitalization for stroke
    • Hospitalization for transient ischemic attack


Inclusion Criteria

ASCVD defined as:

  • Prior myocardial infraction
  • Prior coronary revascularization
  • Established stenosis ≥ 75% of at least one coronary artery
  • History of chronic ischemic heart disease, coronary artery disease, or ASCVD

AND one or more Enrichment Criteria:

  • age ≥ 65 years
  • Cr ≥ 1.5 mg/dL
  • Diabetes mellitus
  • Current cigarette smoker
  • Cerebrovascular disease
  • Peripheral artery disease
  • Heart failure (systolic or diastolic)
  • LVEF < 50%
  • Systolic blood pressure ≥ 140 mmHg
  • LDL cholesterol > 130 mg/dL

Exclusion Criteria

  • Significant allergy to aspirin
  • GI bleeding within the past 12 months
  • Bleeding disorder precluding aspirin use
  • Current or planned ticagrelor use
  • Pregnant or nursing females
  • No exclusion for age, comorbidities, or concomitant medications

Baseline Characteristics

  • Median age: 67.6 years
  • Male: 68.7%
  • Black 8.7%
  • Asian: 1.0%
  • Other race: 6.5%
  • Hispanic: 3.2%
  • Other ethnicity: 6.7%
  • Prior MI: 35.4%
  • Prior coronary revascularization within 5 years of enrollment: 53.0%
  • Prior daily aspirin at time of enrollment: 96.0%
    • Prior aspirin 81 mg: 85.3%
    • Prior aspirin 162 mg: 2.3%
    • Prior aspirin 325 mg: 12.2%
  • Prior P2Y12 inhibitor 22.3%
    • Prior clopidogrel 92.5%


  • Randomized to 325 mg aspirin or 81 mg aspirin


Comparisons are aspirin 81 mg vs. aspirin 325 mg

Primary Outcomes

Death or hospitalization secondary to stroke or MI:
7.28% vs. 7.51% (HR 1.02; 95% CI 0.91 - 1.14; P = 0.75)
Hospitalization for major bleeding requiring blood transfusion:
0.63% vs. 0.60% (HR 1.18 CI 0.79 - 1.77; P = 0.41)

Secondary Outcomes

Death from any cause
3.80% vs. 4.43% (HR 0.87; 95% CI 0.75 - 1.01)
Hospitalization for MI
2.99% vs. 2.87% (HR 1.06; 95% CI 0.88 - 1.27)
Hospitalization for stroke
1.23% vs. 1.27%% (HR 1.09; 95% CI 0.82 - 1.45)
Occurrence of PCI or CABG
6.05% vs. 5.96% (HR 1.04; 95% CI 0.92 - 1.19)
Hospitalization for TIA
0.23% vs. 0.35% (HR 1.18; 95% CI 0.79 - 1.77)

Subgroup Analysis

Aspirin discontinuation 81 mg vs. 325 mg
7.0% vs. 11.1%
Aspiring dose switching from 325 mg to 81 mg vs. 81 mg to 325 mg
41.6% vs. 7.1%
Median days exposure to assign aspirin dose 81 mg vs. 325 mg
650 days vs 434 days
Subgroup analysis on patient characteristics were performed and found non-significant in all of the subgroups
  • Age (65 years or older)
  • Sex
  • Race (Black, White, other)
  • Ethnicity (Hispanics, Non-Hispanic)
  • Diabetes
  • CKD
  • P2Y12 inhibitor use
  • Study visit method (internet, non-internet)
  • Weight (75 Kg or greater)


  • High rate of unequal cross-over particularly from the 325 mg group negatively impacts the study conclusions of non-significance[6]
    • A secondary analysis should have been performed to evaluate aspirin as time varying co-variate or an analysis participants remaining in their treatment group
  • Integration of patient equipoise (lack of patient dose preference) might have limited crossover[7]
  • Dose-weight and dose-height interactions not investigated [8]
  • Trial design could have included a pilot or a run-in period to minimize cross-over confounding[9]


  • The Patient-Centered Outcomes Research Institute

Further Reading