ADAPTABLE

Published

Schuyler Jones W, et al.. "Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease". New England Journal of Medicine. 2021. 384(21):1981-1990.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

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

Bottom Line

Among patients with established atherosclerotic disease, aspirin 325 mg/d is no better than 81 mg/d at reducing the risk of death, stroke, or myocardial infarction.

Major Points

Various guideline-issuing bodies recommend antiplatelet therapy for patients with established atherosclerotic disease, but only a subset provides recommendations regarding dosing. For example, the ACC/AHA guidelines do not specify the aspirin dose, while the European Society of Cardiology specifies low-dose aspirin in this patient population. At the same time, registry data show considerable variability in post-MI aspirin dosage. The question of the optimal dose of aspirin has remained uncertain despite multiple studies on aspirin for secondary prevention.

Published in 2021, the Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness (ADAPTABLE) trial enrolled some 15,000 individuals with stable atherosclerotic cardiovascular disease and randomized patients to aspirin 325 mg/d or 81 mg/d. Patients were followed for the primary efficacy outcome of death or hospitalization for MI or stroke, using a time-to-first-event analysis. With median follow-up of just over 2 years, there were no differences in the primary efficacy outcome (7.28% vs. 7.51%; HR 1.02). The rate of major bleeding, using the strict definition of hospitalization for bleeding that required transfusion, was similar between groups. There was a high rate of crossover in the high-dose group, with about 40% of patients switching from 325 mg/d to 81 mg/d. The authors conclude that aspirin 81 mg/d has similar efficacy and risks compared to 325 mg/d and is associated with better adherence.

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 and TASTE. The benefit of this trial design is its large sample size and low cost. These factors allow for trials with high-quality data to answer clinically relevant questions within real-world study conditions.

Guidelines

AHC/ACC Guideline for Chronic Coronary Disease (2023, adapted)

• In patients with CCD and no indication for oral anticoagulant therapy, low-dose aspirin 81 mg (75-100 mg) is recommended to reduce atherosclerotic events.

Design

• Multicenter, open-label, parallel-group, 1:1 randomized, controlled trial
• N=15,076 outpatients with stable atherosclerotic cardiovascular disease
  • Aspirin 81 mg/d
  • Aspirin 325 mg/d
• Setting: 40 centers in the PCORnet
• Enrollment: 2016-2019
• Mean follow-up: 26 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 MI, or hospitalization for stroke
  • Safety: Hospitalization for major bleeding requiring blood-product transfusion
• Secondary outcomes: coronary revascularization, death, hospitalization for MI / stroke / TIA

Population

Inclusion Criteria

Adults with atherosclerotic cardiovascular disease (ASCVD) defined as:

• Prior myocardial infarction
• 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

From the 81-mg/d group.

• 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%

Interventions

• Randomized to aspirin 81 mg/d or 325 mg/d

Outcomes

Comparisons are aspirin 81 mg vs. aspirin 325 mg

Primary Outcomes

Efficacy

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)

Safety

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 (Hispanic, non-Hispanic)
• Diabetes
• CKD
• P2Y12 inhibitor use
• Study visit method (internet, non-internet)
• Weight (75 kg or greater)

Criticisms

• High rate of unequal cross-over particularly from the 325 mg group negatively impacts the study conclusions of non-significance
  • 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
• Dose-weight and dose-height interactions not investigated
• Trial design could have included a pilot or a run-in period to minimize cross-over confounding

Funding

• The Patient-Centered Outcomes Research Institute