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10.1136/bmjopen-2023-078197
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Original Research
Cardiovascular Medicine
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Impact of aspirin dose according to race in secondary prevention of atherosclerotic cardiovascular disease: a secondary analysis of the ADAPTABLE randomised controlled trial
http://orcid.org/0000-0003-2965-1504
Marquis-Gravel Guillaume 1guillaume.marquis.gravel@umontreal.ca

Mulder Hillary 1hillary.mulder@duke.edu

http://orcid.org/0000-0003-1732-9067
Wruck Lisa M 1lisa.wruck@duke.edu

Benziger Catherine P 2Catherine.Benziger@EssentiaHealth.org

Effron Mark B 3mark.effron@ochsner.org

Farrehi Peter M 4pfarrehi@med.umich.edu

Girotra Saket 5saket.girotra@utsouthwestern.edu

Gupta Kamal 6kgupta@kumc.edu

Kripalani Sunil 7sunil.kripalani@vumc.org

Muñoz Daniel 7daniel.munoz@vumc.org

Polonsky Tamar S 8tpolonsky@bsd.uchicago.edu

http://orcid.org/0000-0002-9544-838X
Whittle Jeff 9jwhittle@mcw.edu

Harrington Robert 10rharrington@med.cornell.edu

Rothman Russell 7russell.rothman@vumc.org

Hernandez Adrian F 11adrian.hernandez@duke.edu

Jones WS 12schuyler.jones@duke.edu

1 Duke Clinical Research Institute, Durham, North Carolina, USA
2 Heart and Vascular Center, Essentia Health, Duluth, Minnesota, USA
3 John Ochsner Heart and Vascular Institute, New Orleans, Louisiana, USA
4 University of Michigan, Ann Arbor, Michigan, USA
5 University Texas Southwestern Medical Center, Dallas, Texas, USA
6 University of Kansas Medical Center, Kansas City, Kansas, USA
7 Vanderbilt University Medical Center, Nashville, Tennessee, USA
8 University of Chicago Medicine, Chicago, Illinois, USA
9 Medical College of Wisconsin, Milwaukee, Wisconsin, USA
10 Stanford University, Stanford, California, USA
11 Duke University, Durham, North Carolina, USA
12 Duke University Medical Center, Duke Clinical Research Institute, Durham, North Carolina, USA
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

None declared.

Dr; guillaume.marquis.gravel@umontreal.ca
2024
7 8 2024
14 8 e07819726 7 2023
22 7 2024
Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Abstract

Objectives

To evaluate whether the effectiveness and safety of low (81 mg daily) versus high-dose (325 mg daily) aspirin is consistent across races among patients with established atherosclerotic cardiovascular disease (ASCVD).

Design

A secondary analysis of the randomised controlled trial ADAPTABLE was performed.

Setting

The study was conducted in 40 centres and one health plan participating in the National Patient-Centred Clinical Research Network (PCORnet) in the USA.

Participants

Among 15 076 participants with established ASCVD, 14 096 had self-reported race available and were included in the analysis. Participants were divided according to self-reported race as Black (n=1311, 9.3%), White (n=11 990, 85.1%) or other race (n=795, 5.6%).

Interventions

Participants were randomised to open-label daily aspirin doses of 81 mg versus 325 mg in a 1:1 ratio for a median of 26.2 months.

Primary and secondary outcomes measures

The primary effectiveness endpoint was a composite of death from any cause, hospitalisation for myocardial infarction or hospitalisation for stroke. The primary safety endpoint was hospitalisation for bleeding requiring blood product transfusion.

Results

Estimated cumulative incidence of the primary effectiveness endpoint at median follow-up with the 81 mg and the 325 mg daily doses were 6.70% and 7.12% in White participants (adjusted HR: 1.00 [95% CI: 0.88 to 1.15]); 12.27% and 10.69% in Black participants (adjusted HR: 1.40 [95% CI: 1.02 to 1.93]); and 6.88% and 7.69% in other participants (adjusted HR: 0.86 [95% CI: 0.54 to 1.39]) (p-interaction=0.12), respectively. There was no significant interaction between self-reported race and assigned aspirin dose regarding the secondary effectiveness and the primary safety endpoints.

Conclusion

Race is not an effect modifier on the impact of aspirin dosing on effectiveness and safety in patients with established ASCVD. In clinical practice, treatment decisions regarding aspirin dose in secondary prevention of ASCVD should not be influenced by race.

Trial registration number

NCT02697916.

CARDIOLOGY
Myocardial infarction
CLINICAL PHARMACOLOGY
Patient-Centered Outcomes Research Institute (PCORI) ASP-1502-27029 http://dx.doi.org/10.13039/100004326 Bayer Not applicable GMG: honoraria from Pharmascience, JAMP Pharma, Bayer, KYE, Novartis, Population Health Research Institute, and Canadian Heart Research Center; Research funding from Canadian Institutes of Health Research, Fonds de Recherche du Québec – Santé, Duke Clinical Research Institute, Bayer, Université de Montréal, Montreal Heart Institute; MBE: equity in and receives a pension from Eli Lilly and Company; SG is funded by the National Heart, Lung and Blood Institute (NHLBI, R56HL158803), and receives funding from the American Heart Association for editorial work. SKG: research PI for Medtronic, Boston Scientific and Abbott; RLR declares family-owned stocks from Moderna (not related to this study). WSJ: grants from Patient-Centered Outcomes Research Institute during the conduct of the study; grants from Boehringer Ingelheim, grants and personal fees from Bayer, grants and personal fees from Janssen Pharmaceuticals, personal fees from Bristol-Myers Squibb, grants from Merck, personal fees from Medscape, outside the submitted work. The other authors have no conflict to declare.
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pmcStrengths and limitations of this study

This study was embedded within in the daily routine of participants using a pragmatic, patient-oriented design.

The trial recruited 15 076 patients with the use of multimodal, low-touch recruitment strategies at the health-system level.

Race was self-reported, which may be associated with a reporting bias that is not possible to quantify.

Comparisons across races in this randomised trial should be viewed as hypothesis generating and may be subject to confounding by unmeasured variables.

Race was not available for 980 participants (6.5%) who could not be included in the analyses, which may potentially impact the external generalisability of the results.

Atherosclerotic cardiovascular disease (ASCVD) is associated with a high burden of mortality, morbidity and disability worldwide.1 In the USA, disparities in outcomes between Black and non-Black patients with ASCVD have been well-documented.24 These differences in clinical outcomes are affected by a complex combination of genetic, environmental, socio-economic, behavioural and healthcare access considerations.57

The antiplatelet medication aspirin inhibits platelet cyclooxygenase-1, prevents clinical events in patients with established ASCVD8 9 and is recommended in most patients for secondary prevention of cardiovascular events.1013 However, platelets of self-reported Black patients respond differently to aspirin compared with platelets of patients of other races in response to different types of agonists.14 However, whether aspirin dose impacts clinical outcomes differently in Black patients has not been studied before. Given the high burden of ASCVD on the healthcare system, the racial disparities in ASCVD outcomes and the different pharmacodynamic response to aspirin documented in self-reported Black individuals, it is important to determine whether the treatment effect of different doses of aspirin on clinical outcomes also differs. The pragmatic ADAPTABLE randomised controlled trial compared the effect of two different doses of aspirin on clinical outcomes and is well-poised to address this question.15 The main objective of this secondary analysis of the ADAPTABLE trial is to evaluate whether there is an interaction between race and aspirin dose (81 mg or 325 mg daily) in patients with established ASCVD.

Methods

This is a pre-specified analysis of the multi-centre, patient-centred, pragmatic ADAPTABLE randomised trial (NCT02697916) conducted in the USA. The detailed methodology and the main results have been published previously.15 16 A total of 15 076 patients with established ASCVD from 40 centres and one health plan from the National Patient-Centred Clinical Research Network (PCORnet) were randomised to open-label daily aspirin doses of 81 mg versus 325 mg in a 1:1 ratio. Detailed eligibility criteria are provided in online supplemental methods. Participants were divided according to self-reported race, as White, Black (self-reported as Black or African-American in the trial) or other (which includes Asians, American Indians or Alaska Natives, participants reporting multiple races and other races). Participants who did not report race at baseline or for whom race is missing were excluded from this analysis. Comorbidities and previous medical history of participants were captured from queries of electronic health records. The primary effectiveness endpoint was a composite of death from any cause, hospitalisation for myocardial infarction or hospitalisation for stroke. The individual components of the primary composite endpoint and coronary revascularisation (either percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG)) were key secondary endpoints. The primary safety endpoint was hospitalisation for bleeding requiring blood product transfusion. Adherence to treatment allocation was self-reported by participants through the study web portal or via telephone interviews with the study call centre. The intention-to-treat population of the ADAPTABLE trial was used for this secondary analysis, which includes all randomised participants. All participants provided written informed consent before entering in the trial. Patient partners (called Adaptors) were involved in the design, conduct and dissemination of the trial and its results. The Duke University institutional review board approved the overall programme (Pro00068525). The study is reported according to the Strengthening the reporting of observational studies in epidemiology (STROBE) statement (see appendix for STROBE checklist).17

Statistical analyses

Baseline continuous variables are presented as median and 25th/75th percentiles. Categorical variables are presented as counts and proportions. P values are reported from the X2 test for categorical measures and from the Kruskal–Wallis test for continuous variables. Missing values were excluded from descriptive statistical summaries.

To evaluate the association between race and clinical outcomes, unadjusted and adjusted Cox proportional hazards models were fit. The Fine–Grey method of accounting for the competing risk of death was used for non-lethal clinical outcomes (ie, hospitalisation for myocardial infarction, hospitalisation for stroke, coronary revascularisation and bleeding requiring blood product transfusion). Pre-specified adjustment factors of the multivariable model for the effectiveness endpoints were age, sex, body mass index (BMI), follow-up strata (3 month or 6 month intervals), non-internet use, current smoker, ethnicity, coronary artery disease (CAD), myocardial infarction, PCI, CABG, cerebrovascular disease, hypertension, hyperlipidemia, atrial fibrillation, congestive heart failure (CHF), peripheral artery disease (PAD), diabetes, prior aspirin dose and current use of P2Y12 inhibitors. Pre-specified adjustment factors of the multivariable model for the safety endpoint were age, sex, BMI, CAD, hypertension, diabetes, history of bleeds, use of non-steroidal anti-inflammatory drugs and current use of P2Y12 inhibitors. The comorbidities are self-reported by participants. The proportional hazards assumption was checked using weighted Schoenfeld residuals. Event rates for each clinical outcome were computed at the median follow-up time of 26.2 months using the Kalbfleisch and Prentice cumulative incidence function estimator for each racial group. Rates, counts, unadjusted and adjusted HRs (reference: White participants) or sub-distribution hazard ratios (SHR) and 95% cCIs were computed, and a forest plot was generated.

To evaluate the clinical outcomes by randomised aspirin dose and race, unadjusted and adjusted Cox proportional hazards models were fit with the covariates described above, race, randomised aspirin dose and an interaction term between randomised aspirin dose and race for the primary effectiveness endpoint, the primary safety endpoint and all-cause mortality. The Fine–Grey method was again used to account for the competing risk of death when evaluating non-lethal endpoints. The interaction term was included to assess if race modifies the effect of randomised aspirin dose on outcomes. A post hoc sensitivity analysis was performed to evaluate the interaction between aspirin dose and race, only including Black and White participants (excluding other races).

In a sensitivity analysis, the current self-reported aspirin dose was included in the model as a time-dependent exposure to account for non-adherence to randomised aspirin dose for the primary effectiveness endpoint, the primary safety endpoint and all-cause death. Models were fit with race, time-varying self-reported aspirin dose and an interaction term between self-reported aspirin dose and race. Adjustment measures were age, sex, ethnicity, prior aspirin dose, prior myocardial infarction, prior percutaneous intervention, history of atrial fibrillation, non-internet user at randomisation, baseline P2Y12 inhibitor use and history of bleeds. This methodology assumes that the decision to switch doses is not associated with factors related to the outcomes of interest beyond the baseline adjustment measures.

All hypothesis tests are two-sided, and p values of <0.05 are considered statistically significant. No penalty for multiple comparisons are applied in this exploratory analysis. Missing data were imputed using fully conditional specification methods across multiple datasets. Analysis was performed by the Duke Clinical Research Institute (Durham, NC) using SAS version 9.4 (SAS Institute, Inc. Cary, NC).

Patient and public involvement

Nine patient partners with lived experience of cardiovascular diseases (the Adaptors) meet twice a month during the design and conduct phases of the ADAPTABLE trial, and they were also invited in the executive and steering committees. They engaged in the development of the research question. They also provided input and developed initiatives to optimise recruitment and retention. The results of the ADAPTABLE trial were disseminated to study participants in a lay manner at the same time the study was published. Details of patient involvement in the trial have been described previously.18 19

Results

From 15 076 participants, 14 096 had self-reported race available and were included in the analysis, among which 1311 (9.3%) were Black, 11 990 (85.1%) were White and 795 (5.6%) had another self-reported race. The proportion of participants randomised to the 81 mg aspirin dose was similar across races (Black: 50.6%; White: 50.2%; other race: 53.7%; p=0.15). Black participants were more frequently female and more likely to have a number of comorbid conditions, including hypertension, diabetes, CHF and PAD (table 1). In general, adherence was significantly higher in White participants compared with Black participants and participants with other races (table 2). Baseline characteristics of the 980 participants who were excluded because race was not available are reported in online supplemental table 1.

Table 1 Baseline characteristics by race

Characteristic	Overall (n=14 096)	Black (n=1311)	White (n=11 990)	Other (n=795)	P value	
Age (years)	68 (61–74)	64 (57–70)	68 (62–74)	64 (56–71)	<0.001	
Female	4394 (31.2%)	705 (53.8%)	3426 (28.6%)	263 (33.1%)	<0.001	
Hispanic ethnicity	464 (3.3%)	8 (0.6%)	122 (1.0%)	334 (42.0%)	<0.001	
Current smoking	1307 (9.6%)	222 (17.4%)	1008 (8.7%)	77 (10.1%)	<0.001	
 Missing, n	465	37	392	36		
Weight (kg)	90 (78–104)	91 (78–106)	90 (79–104)	83 (73–99)	<0.001	
 Missing, n	1806	86	1650	70		
Body mass index (kg/m2)	30 (27–34)	32 (27–37)	30 (27–34)	29 (26–34)	<0.001	
 Missing, n	2121	104	1914	103		
Medical history						
 Missing, n	309	16	279	14		
Coronary artery disease	12 904 (93.6%)	1219 (94.1%)	10 950 (93.5%)	735 (94.1%)	0.559	
Previous myocardial infarction	4985 (36.2%)	606 (46.8%)	4010 (34.2%)	369 (47.2%)	<0.001	
Previous CABG	3335 (24.2%)	300 (23.2%)	2816 (24.0%)	219 (28.0%)	0.027	
Previous PCI	5605 (40.7%)	579 (44.7%)	4659 (39.8%)	367 (47.0%)	<0.001	
Cerebrovascular disease	2439 (17.7%)	290 (22.4%)	2022 (17.3%)	127 (16.3%)	<0.001	
Hypertension	11 755 (85.3%)	1238 (95.6%)	9828 (83.9%)	689 (88.2%)	<0.001	
Hyperlipidemia	12 174 (88.3%)	1165 (90.0%)	10 346 (88.3%)	663 (84.9%)	0.002	
Atrial fibrillation	1158 (8.4%)	66 (5.1%)	1033 (8.8%)	59 (7.6%)	<0.001	
Congestive heart failure	3234 (23.5%)	513 (39.6%)	2499 (21.3%)	222 (28.4%)	<0.001	
Peripheral artery disease	3267 (23.7%)	431 (33.3%)	2593 (22.1%)	243 (31.1%)	<0.001	
Diabetes	5334 (38.7%)	752 (58.1%)	4153 (35.5%)	429 (54.9%)	<0.001	
History of bleeding	1173 (8.5%)	167 (12.9%)	934 (8.0%)	72 (9.2%)	<0.001	
Significant bleeding disorder	160 (1.2%)	23 (1.8%)	132 (1.1%)	5 (0.6%)	0.044	
Significant gastrointestinal bleed	885 (6.4%)	127 (9.8%)	696 (5.9%)	62 (7.9%)	<0.001	
Intracranial haemorrhage	194 (1.4%)	29 (2.2%)	158 (1.3%)	7 (0.9%)	0.016	
Prior aspirin dose						
 Missing, n	482	38	406	38		
 No aspirin	529 (3.9%)	44 (3.5%)	454 (3.9%)	31 (4.1%)	0.001	
 81 mg	11 183 (82.1%)	1087 (85.4%)	9454 (81.6%)	642 (84.8%)	
 162 mg	303 (2.2%)	14 (1.1%)	279 (2.4%)	10 (1.3%)	
 325 mg	1599 (11.7%)	128 (10.1%)	1397 (12.1%)	74 (9.8%)	
Medications						
 Missing, n	625	55	512	58		
P2Y12 Iinhibitor	2981 (22.1%)	297 (23.6%)	2477 (21.6%)	207 (28.1%)	<0.001	
Non-steroidal anti-inflammatory drugs	2262 (16.8%)	137 (10.9%)	2031 (17.7%)	94 (12.8%)	<0.001	
Medications for upset stomach	4872 (36.2%)	388 (30.9%)	4251 (37.0%)	233 (31.6%)	<0.001	
CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention

Table 2 Adherence by race and treatment assignment

Outcomes	Black# events (rate)	White# events (rate)	Other# events (rate)	P value	
Adherence composite: aspirin discontinuation or dose switch		
 81 mg	114 (12.39)	837 (9.07)	78 (13.00)	<0.001	
 325 mg	397 (67.36)	2657 (37.68)	210 (61.58)	<0.001	
Aspirin discontinuation		
 81 mg	59 (6.04)	491 (5.11)	50 (7.94)	0.009	
 325 mg	85 (8.74)	747 (8.19)	54 (10.70)	0.231	
Dose switch		
 81 mg	59 (6.41)	355 (3.85)	33 (5.50)	0.002	
 325 mg	333 (56.50)	2055 (29.15)	163 (47.79)	<0.001	

Over the median follow-up of 26.2 months, the cumulative incidence of the primary effectiveness endpoint was 6.9% in White participants, 11.5% in Black participants and 7.3% in other participants. The unadjusted HRs for Black participants and for other participants versus White participants were 1.68 (95% CI: 1.42 to 1.99) and 1.15 (95% CI: 0.90 to 1.48) (overall p value <0.001), respectively. The adjusted HRs for Black participants and other participants versus White participants were 1.11 (95% CI: 0.91 to 1.34) and 0.85 (95% CI: 0.66 to 1.10) (overall p value=0.20), respectively. There were no significant differences in any of the secondary effectiveness and safety endpoints between racial categories in adjusted analyses (figure 1).

Figure 1 Cumulative incidence at the median follow-up and adjusted HRs for the effectiveness and safety endpoints by race. Adjustment variables for the effectiveness endpoints include age, sex, BMI, follow-up strata, non-internet use, current smoker, CAD, MI, PCI, CABG, CVD, hypertension, hyperlipidaemia, atrial fibrillation, CHF, PAD, diabetes, prior aspirin dose and P2Y12 use. Adjustment variables for the safety endpoint include age, sex, BMI, CAD, hypertension, diabetes, history of bleeds, NSAIDs and P2Y12 use. Rates are calculated as the estimated cumulative incidence at the median follow-up (26.2 months). Abbreviations: BMI, body mass index; CABG: coronary artery bypass grafting; CAD, coronary artery disease; CHF, congestive heart failure; CIF, cumulative incidence function; CVD, cardiovascular disease; MI, myocardial infarction; NSAID, nonsteroidal anti-inflammatory drugs; PAD, pulmonary artery disease; PCI, percutaneous coronary intervention.

Among White participants, the estimated cumulative incidence of the primary effectiveness endpoint was 6.7% with the 81 mg aspirin dose and 7.1% with the 325 mg aspirin dose (unadjusted HR: 0.97 [95% CI: 0.85 to 1.11]; adjusted HR: 1.00 [95% CI: 0.88 to 1.15]). Among Black participants, the estimated cumulative incidence of the primary effectiveness endpoint was 12.3% with the 81 mg aspirin dose and 10.7% with the 325 mg aspirin dose (unadjusted HR: 1.36 [95% CI: 0.99 to 1.86]; adjusted HR: 1.40 [95% CI: 1.02 to 1.93]). The estimated cumulative incidence of the primary effectiveness endpoint in participants with other self-reported races was 6.9% with the 81 mg aspirin dose and 7.7% with the 325 mg aspirin dose (unadjusted HR: 0.86 [95% CI: 0.53 to 1.39]; adjusted HR: 0.86 [95% CI: 0.54 to 1.39]). There was no significant interaction between randomised dose and race for the primary effectiveness endpoint (p unadjusted=0.13; p adjusted=0.12), for the primary safety endpoint (p unadjusted=0.36; p adjusted=0.46) and for the secondary effectiveness endpoints (figure 2). A post hoc sensitivity analysis evaluating the interaction between aspirin dose and race, only including a Black and White participants (excluding other races), is presented in online supplemental table 2). The cumulative incidence function of the primary effectiveness endpoint by race and aspirin dose is presented in figure 3. The results of the analysis of interaction between race and assigned aspirin dose were consistent in a sensitivity analysis considering adherence to aspirin dose, in which there was no significant interaction between time-dependent self-reported aspirin dose and race (table 3).

Figure 2 Cumulative incidence at the median follow-up and adjusted HRs for the effectiveness and safety endpoints by randomised aspirin dose and by race. Adjustment variables for the effectiveness endpoints include age, sex, BMI, follow-up strata, non-internet use, current smoker, CAD, MI, PCI, CABG, CVD, hypertension, hyperlipidaemia, atrial fibrillation, CHF, PAD, diabetes, prior aspirin dose and P2Y12 use. Adjustment variables for the safety endpoint include age, sex, BMI, CAD, hypertension, diabetes, history of bleeds, NSAIDs and P2Y12 use. Reference group for the HR is 325 mg. Rates are calculated as the estimated cumulative incidence at median follow-up (26.2 months). Abbreviations: BMI, body mass index; CABG: coronary artery bypass grafting; CAD, coronary artery disease; CHF, congestive heart failure; CIF, cumulative incidence function; CVD, cardiovascular disease; MI, myocardial infarction; NSAID, nonsteroidal anti-inflammatory drugs; PAD, pulmonary artery disease; PCI, percutaneous coronary intervention.

Figure 3 Cumulative incidence function of the primary effectiveness endpoint by race and aspirin dose.

Table 3 Effect of time-varying self-reported aspirin dose by race

	Taking 81 mg	Taking 325 mg	Unadjusted	Adjusted	
Outcome race	Rate per 100 patient-year (Events)	Rate per 100 patient-year (Events)	HR (95% CI)(ref: 325 mg)	InteractionP value	HR (95% CI)(ref: 325 mg)	InteractionP value	
Primary effectiveness endpoint	
 White	3.57 (466)	2.92 (246)	1.20 (1.03–1.40)	0.27	1.18 (1.01–1.38)	0.33	
 Black	6.33 (94)	4.21 (33)	1.49 (1.00–2.22)	1.46 (0.98–2.17)	
 Other	3.20 (29)	4.23 (18)	0.74 (0.41–1.33)	0.71 (0.40–1.28)	
All-cause death	
 White	2.00 (267)	1.62 (138)	1.16 (0.95–1.43)	0.75	1.11 (0.90–1.37)	0.82	
 Black	2.90 (45)	2.37 (19)	1.19 (0.69–2.03)	1.15 (0.67–1.96)	
 Other	1.95 (18)	1.85 (8)	0.99 (0.43–2.27)	0.95 (0.41–2.18)	
Primary safety endpoint	
 White	0.29 (38)	0.24 (20)	1.22 (0.71–2.11)	0.82	1.19 (0.69–2.05)	0.84	
 Black	0.71 (11)	0.37 (3)	1.92 (0.53–6.87)	1.83 (0.51–6.58)	
 Other	0.54 (5)	0.23 (1)	2.37 (0.28–20.3)	2.30 (0.27–19.7)	
Rates are computed as the number of events per 100 patient years of follow-up on the dose in question.

Unadjusted model is a Cox proportional hazards model with race and aspirin dose during follow-up as time-dependent variable.

Model includes age, sex, race, prior aspirin dose, prior MImyocardial infarction, prior PCIpercutaneous coronary intervention, history of AFib, non-internet user at randomization, history of bleeds and baseline P2Y12 use.

Discussion

In this secondary analysis of the ADAPTABLE randomised trial, the main finding is that race does not modify the effect of aspirin dosing (81 mg or 325 mg daily) on clinical endpoints in secondary prevention of ASCVD. In Black participants only, the observed event rates of the primary effectiveness endpoint were higher with the 81 mg daily dose (12.3%) versus the 325 mg daily dose (10.7%) (adjusted HR: 1.40 [95% CI: 1.02 to 1.93]), but the overall interaction between race and aspirin dose was not significant (adjusted p value=0.12), indicating that the treatment effect of aspirin dose is consistent across races. Black and non-Black participants in ADAPTABLE had significant differences in demographic characteristics and comorbid conditions, which mirror observational and registry studies of patients with ASCVD. In a study from the National Cardiovascular Data Registry (NCDR) Chest Pain—MI Registry including 155 397 acute MI patients (7.3% black) from 753 US sites from 2008 to 2016, Black patients also had a higher burden of cardiovascular risk factors despite being younger on average, and they were also more likely to be women.3

Previous real-world studies have shown racial discrepancies in ASCVD management and outcomes. In carotid stenosis treated with endarterectomy, Black patients are less likely prescribed evidence-based medications like aspirin and are more likely to experience a major cardiovascular and cerebrovascular events.4 In the above-mentioned NCDR Chest Pain MI Registry study, the 30-day readmission rate after MI was significantly higher in Black patients compared with non-Black patients.3 However, readmission rate was similar across races following multivariable adjustment, suggesting that socioeconomic factors, clinical presentations and comorbidities are responsible for the observed racial disparities in outcomes. In our study, the event rates were also significantly higher in Black versus White participants (unadjusted HR: 1.68; 95% CI: 1.42 to 1.99; overall p value across races <0.001), but the association was no longer significant after covariate adjustment (adjusted HR: 1.11; 95% CI: 0.91 to 1.34; overall p value across races=0.20), thus confirming the registry data, and suggesting that race by itself is not intrinsically related to an adverse prognosis, but that other factors are responsible for this disparity in outcomes. Our results, along with the real-world observational data, call for future studies evaluating the determinants of these differential racial outcomes and implementing strategies to mitigate these disparities.

In the ADAPTABLE trial, there was no significant difference in effectiveness and safety between the two aspirin doses (81 mg and 325 mg once daily) in secondary prevention of ASCVD.15 The rationale for studying this question is that platelet COX-1 selectivity of aspirin decreases as the dose increases, with a more pronounced COX-2 affinity at higher doses.20 There is biological plausibility to expect that self-reported race could modify the association between aspirin dose and clinical outcomes. In a study by Infeld and colleagues comparing platelet response to aspirin in 209 self-reported Black versus 282 self-reported European-American patients with or without ASCVD, suppression of platelet activity with aspirin from baseline, as assessed with light transmission aggregometry in response to 0.5 mmol/L of arachidonic acid, was significantly less pronounced in Black individuals (95% CI: − 53.5,–12.1; p<0.01).14 However, Black patients had lower platelet reactivity at baseline, and racial response to aspirin differed across the spectrum of the agonists used for testing platelet reactivity (collagen, ADP or epinephrine). This raises the hypothesis that Black patients may require different aspirin doses to benefit from a similar treatment effect than non-Black individuals. Our study is the first to have specifically assessed the differential outcomes of aspirin dosing in ASCVD according to race and did not identify race as an effect modifier. However, significantly more primary effectiveness events were observed with the 81 mg dose compared with the 325 mg dose in Black participants only (after multivariable adjustment), raising the hypothesis that platelet reactivity inhibition with higher aspirin doses may be more pronounced in Black patients. While no strong conclusion can be drawn from a non-significant subgroup interaction analysis in a neutral randomised trial, the enrollment of a smaller cohort of Black participants may have limited our power to identify a significant interaction. The results were consistent in a sensitivity analysis when only Black and White participants were considered (excluding other races), except for a significant interaction between aspirin dose and race for stroke. In Black participants, the 325 mg aspirin dose was associated with a significant reduction in the risk of stroke compared with the 81 mg aspirin dose but not in White participants (adjusted p value for interaction: 0.028). However, given that the absolute stroke event rate is very low, that this is a post hoc analysis, that the main comparison between aspirin doses was neutral for strokes and that no penalty for multiple comparisons were made, this finding should be viewed as exploratory and hypothesis-generating only.

Our study has limitations worth mentioning. First, race was self-reported, which may be associated with a reporting bias that is not possible to quantify. Random misclassification of race would, however, tend to bias our estimate towards the null. Second, although substantial efforts were made to enrol a diverse and inclusive patient population in ADAPTABLE with the help of a patient–partner advisory board, a large majority of participants were White (85.1%), and as noted above, the small number of Black participants may have limited our power to detect a difference. Third, comparisons across races in this randomised trial should be viewed as hypothesis generating and may be subject to confounding by unmeasured variables. Fourth, our study did not collect blood samples to determine platelet reactivity while on aspirin. Fifth, race was not available for 980 participants (6.5%) who could not be included in the analyses. This may potentially impact the external generalisability of the results if the distribution of baseline characteristics and of outcome rates across race groups differs in these excluded patients compared with patients included in the analysis. Sixth, the potential modifying effect of race on aspirin dose could not be assessed for clinically relevant bleeding that did not require transfusions because the latter were not captured, which may underestimate the treatment effect. Finally, the differences in adherence rates across races add additional complexity to the interpretation of the associations between aspirin dose and race observed in this analysis.

In conclusion, in this secondary analysis of the ADAPTABLE randomised trial, race was not an effect modifier on the impact of aspirin dosing on effectiveness and safety in patients with established ASCVD. In clinical practice, treatment decisions regarding aspirin dose in secondary prevention of ASCVD should not be influenced by race.

supplementary material

10.1136/bmjopen-2023-078197 online supplemental file 1

10.1136/bmjopen-2023-078197 online supplemental file 2

Acknowledgements

We thank the Adaptors (patient partner investigators) involved in the conduct of the trial: Desiree Davidson, Kevin Edgley, Greg Merritt, PhD, Linda S. Brown, Henry Cruz, Nadina Zemon, Tom E. McCormick III, MS, Jacqueline Alikhaani, BA, Ken C. Gregoire, and Bill Larsen (in memoriam).

Data availability statement

No data are available.

Review Process File
7 8 2024

Funding: This secondary analysis of ADAPTABLE has been funded by Bayer (investigator initiated research grant). The ADAPTABLE trial was upported through a Patient-Centered Outcomes Research Institute (PCORI) Award (ASP-1502-27029).

Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2023-078197).

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient consent for publication: Not applicable.

Ethics approval: This study involves human participants and was approved by The Duke University IRB approved the overall program. The IRB # is Pro00068525. Participants gave informed consent to participate in the study before taking part.

Patient and public involvement: Patients and/or the public were involved in the design, conduct, reporting or dissemination plans of this research. Refer to the Methods section for further details.
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