Differences in Cardiovascular Risk, Coronary Artery Disease, and Cardiac Events Between Black and White Individuals Enrolled in the PROMISE Trial

Key Points

Question  Are there differences in risk burden, plaque, and adverse cardiac events between Black and White individuals with stable chest pain?

Findings  In this cohort study of 8764 persons undergoing noninvasive cardiovascular testing, self-identified Black participants had a higher cardiovascular risk burden than White participants, yet there were similarly few major adverse cardiovascular events over a 2-year follow-up. Significant stenosis and high-risk plaque were associated with events in both groups; however, the prevalence of a coronary artery calcium score greater than 0, stenosis 50% or greater, and high-risk plaque was lower in Black individuals.

Meaning  The findings of this study suggest that, despite a higher risk burden in Black individuals, rates of epicardial coronary artery disease in Black persons were lower than in White persons, with a similarly low event rate.

Importance  Race and ethnicity have been studied as risk factors in cardiovascular disease. How risk factors, epicardial coronary artery disease, and cardiac events differ between Black and White individuals undergoing noninvasive testing for coronary artery disease is not known.

Objective  To assess differences in cardiovascular risk burden, coronary plaque, and major adverse cardiac events between Black and White individuals assigned to receive coronary computed tomography angiography (CCTA) or functional testing for stable chest pain.

Design, Setting, and Participants  A nested observational cohort study within the PROMISE trial was conducted at 193 outpatient sites in North America. A total of 1071 non-Hispanic Black (hereafter Black) and 7693 non-Hispanic White (hereafter White) participants with stable chest pain undergoing noninvasive cardiovascular testing were included. This analysis was conducted from February 13, 2015, to November 2, 2021.

Main Outcomes and Measures  The primary end point was the composite of death, myocardial infarction, or hospitalization for unstable angina over a median follow-up of 24.4 months.

Results  Among 1071 Black individuals (12.2%) (women, 646 [60.3%]; mean [SD] age, 59 [8] years) and 7693 White individuals (87.8%) (women, 4029 [52.4%]; mean [SD] age, 61.1 [8.4] years), Black participants had a higher cardiovascular risk burden (more hypertension and diabetes), yet there was a similarly low major adverse cardiovascular events rate over a median 2-year follow-up (32 [3.0%] vs 243 [3.2%]; P = .84). Sensitivity analyses restricted to the 79.8% (6993 of 8764) individuals with a normal or mildly abnormal noninvasive testing result and the 54.3% (4559 of 8396) not receiving statin therapy yielded similar findings. In comparison of Black and White individuals in the CCTA group (n = 3323), significant coronary stenosis (hazard ratio [HR], 7.21; 95% CI, 1.94-26.76 vs HR, 4.30; 95% CI, 2.62-7.04) and high-risk plaque (HR, 3.47; 95% CI, 1.00-12.06 vs HR, 2.21; 95% CI, 1.37-3.57) were associated with major adverse cardiovascular events in both Black and White patients. However, with respect to epicardial coronary artery disease burden, Black individuals had a less-prevalent coronary artery calcium score greater than 0 (45.1% vs 63.2%; P < .001), coronary stenosis greater than or equal to 50% (32 [8.7%] vs 430 [14.6%]; P = .001), and high-risk plaque (139 [37.6%] vs 1547 [52.4%]; P < .001).

Conclusions and Relevance  The findings of this study suggest that, despite a greater cardiovascular risk burden in Black persons, rates of coronary artery calcium, stenosis, and high-risk plaque observed via CCTA were lower in Black persons than White persons. This result suggests differences in cardiovascular risk burden and coronary plaque in Black and White individuals with stable chest pain.

Non-Hispanic Black or African American individuals comprise 13% of the US population yet are historically underrepresented in clinical trials and epidemiologic studies.¹ Black persons have a higher incidence of long-term coronary artery disease (CAD) morbidity and mortality compared with White persons.² These differences may be attributed to a higher burden of cardiovascular disease risk factors and differences in socioeconomic and health care delivery factors.

The 2021 American College of Cardiology/American Heart Association guidelines for the evaluation and diagnosis of chest pain provide a class 1 recommendation for coronary computed tomography angiography (CCTA) to evaluate stable chest pain in patients with intermediate to high risk for CAD and without known CAD.³ Coronary computed tomography angiography is a noninvasive imaging test that can directly visualize coronary plaque,^4-6 and the extent of plaque estimates the probability of major adverse cardiac events (MACE).⁷ Previous studies reported a lower prevalence and extent of coronary artery calcium (CAC) in asymptomatic Black persons compared with White persons.^8-14 For example, in the Multi-Ethnic Study of Atherosclerosis, Black persons were 22% less likely to have a CAC score greater than 0 and had a 31% lower mean CAC score than White persons.¹³ However, little is known about differences in symptomatic stable chest pain populations, including noncalcified coronary plaque and coronary artery stenosis noted on CCTA and their associations with MACE.

The Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial¹⁵ provides an opportunity to compare Black and White outpatients having noninvasive testing for suspected CAD.^16,17 We sought to assess differences between self-reported Black and White persons in (1) cardiovascular risk burden, (2) MACE, and (3) in the CCTA group, standardized core laboratory coronary plaque features.

The design of the PROMISE trial has been detailed elsewhere.^16,18 Briefly, PROMISE randomized 10 003 outpatients with suspected obstructive CAD to either functional testing (exercise, echocardiography, or nuclear stress testing) or anatomic testing via CCTA in 193 North American outpatient community and academic health centers to test the hypothesis that a CCTA testing strategy improves cardiac outcomes compared with functional testing. Enrollment began July 27, 2010, and was completed September 19, 2013. The present study was conducted from February 13, 2015, to November 2, 2021. All participants provided written informed consent for the parent trial, which was Health Insurance Portability and Accountability Act compliant and approved by local and central (Copernicus) institutional review boards; separate informed consent was not required.^16,18

Enrollment demographic characteristics, symptoms, cardiovascular risk factors, Framingham Risk Score, and 2013 atherosclerotic cardiovascular disease risk score were collected.¹⁹ A CAD risk equivalent was defined as history of diabetes, peripheral arterial disease, or cerebrovascular disease.¹⁶ Race was self-reported and defined according to the National Institutes of Health Policy on Reporting Race and Ethnicity Data.²⁰ Race was categorized as American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or other Pacific Islander, White, and multiracial. Ethnic categories were defined as Hispanic or Latino and not Hispanic or Latino. Our study focused on non-Hispanic Black (hereafter Black) and non-Hispanic White (hereafter White) participants, owing to the small sample sizes in the other groups.²¹

Socioeconomic status regarding educational level (percentage of persons aged ≥25 years with high school degree or higher), health insurance coverage (percentage of persons without health insurance), and income (median household income; percentage of persons in poverty) were taken from the US Census Bureau²² on a county, city, and town level and matched using the zip code of each participant’s PROMISE site from 2015 to 2019.

Participants randomized to the anatomic testing arm underwent CCTA.²³ Images were interpreted locally by centrally qualified readers, and these interpretations contributed to clinical decision-making. Images were also transferred to the PROMISE CT core laboratory for a second retrospective analysis as previously described.²⁴ Briefly, 6 readers with level 3 training in CCTA analyzed the data sets. The CCTA analysis was performed according to Society of Cardiovascular Computed Tomography guidelines.^17,25 The coronary artery calcium (CAC) Agatston score, degree of stenosis (0%, 1%-49%, 50%-69%, or ≥70% stenosis), the presence of plaque (calcified only, noncalcified only, and calcified and noncalcified plaque), and high-risk plaque features were evaluated.^17,25 High-risk plaque features were defined as positive remodeling (remodeling index, >1.1), low CT attenuation (mean CT number <30 Hounsfield units), napkin-ring sign (a ringlike peripheral higher attenuation with central low CT attenuation), or spotty calcification.¹⁷ Significant stenosis was defined as greater than or equal to 50% left main stenosis or greater than or equal to 70% stenosis in other coronary arteries. Interobserver agreement was determined by 50 randomly selected CCTA data sets independently read by all 6 readers (high-risk plaque: κ = 0.56; ≥70% stenosis or left main coronary artery stenosis ≥50% stenosis: κ = 0.69).

The primary outcome of the study was MACE, defined as the composite end points of death, myocardial infarction, or hospitalization for unstable angina. Follow-up visits were performed at 60 days at the study sites and centrally by means of telephone or mail at 6-month intervals after randomization for a minimum of 1 year. Any potential MACE was adjudicated based on prospectively defined guidelines by an independent blinded adjudication committee.^16,18

Continuous variables are presented as means (SDs) or medians (IQRs); categorical variables are expressed as frequencies and percentages. Comparisons between Black and White participants were performed with a 2-sample t test or Wilcoxon rank-sum test for continuous variables and with a Fisher exact test for categorical variables. For comparisons of socioeconomic status variables, clustered SEs were used. Kaplan-Meier curves were generated for Black and White participants and compared using the log-rank test. Cox proportional hazards regression models were constructed to assess the association between Black and White self-reported race with MACE (in the entire cohort) and with CCTA features (in the CCTA group), adjusting for (model 1) age and sex; (model 2) age, sex, body mass index, hypertension, diabetes, hyperlipidemia, family history of CAD, CAD risk equivalent, metabolic syndrome, physical activity, and depression; and (model 3) model 2 plus socioeconomic status variables, including percentage with a high school diploma or more advanced degree, percentage with health insurance, percentage under the federal poverty line, and median household income.

In the CCTA group, we assessed the associations between CAC, coronary stenosis, and the presence of high-risk plaque with MACE in Black and White persons using Cox proportional hazards regressions model adjusting for the Framingham risk score. Hazard ratios for MACE conferred by coronary artery stenosis, CAC, and high-risk plaque in Black and White persons were compared using the χ² test. Testing for significance was 2-sided and unpaired, with P < .05 considered significant. All analyses were performed using Stata, version 16.1 (StataCorp LLP).

We included 1071 Black and 7693 White participants from both the anatomic CCTA group and the functional testing group in the analysis. The relative proportion of Black and White participants in PROMISE (12.2% vs 87.8%) was similar to that for individuals aged 45 years or older in the 2018 US Census (13.6% vs 86.4%) (eTable in the Supplement). White participants were slightly older (mean [SD], 61.1 [8.4] vs 59.3 [7.6] years; P < .001) and more frequently male (3664 [47.6%] vs 425 [39.7%]; P < .001) than Black participants (Table 1). Most Black (938 [87.6%]) and White (6808 [88.5%]) patients presented with atypical or nonanginal pain rather than typical angina. There was no significant difference in physician perception of the pretest likelihood of significant CAD (Table 1).

In comparison with White participants, Black participants had significantly higher body mass index (mean [SD], 32.3 [6.6] vs 30.4 [6.1]; P < .001; calculated as weight in kilograms divided by height in meters squared), more hypertension (885 [82.6%] vs 4813 [62.6%]; P < .001), diabetes (345 [32.2%] vs 1414 [18.4%]; P < .001), CAD risk equivalent (388 [36.2%] vs 1724 [22.4%]; P < .001), metabolic syndrome (466 [43.5%] vs 2803 [36.4%]; P < .001), and a sedentary lifestyle (624 of 1068 [58.4%] vs 3640 of 7678 [47.45]; P < .001), but less dyslipidemia (618 [57.7%] vs 5270 [68.5%] P < .001), family history of premature CAD (266 of 1068 [24.9%] vs 2595 of 7667 (33.9%]; P < .001), and history of depression (166 [15.5%] vs 1706 [22.2%]; P < .001). Overall, the mean (SD) number of reported cardiovascular risk factors per patient was higher in Black compared with White participants (2.47 [1.04] vs 2.35 [1.08]; P < .001). Regarding baseline cardiovascular medication use, Black participants were more likely to receive β-blockers (300 of 1016 [29.5%] vs 1800 of 7380 [24.4%]; P = .001) and angiotensin-converting enzyme inhibitors (554 of 1016 [54.5%] vs 3116 of 7380 [42.2%]; P < .001), but less likely to use statin therapy than White participants (424 of 1016 [41.7%] vs 3413 of 7380 (46.3%]; P = .007). More Black participants were from sites that had a lower percentage of high school or more advanced degree graduates (mean [SD], 87.6% [5.3%] vs 89.8% [5.0%]; P < .001), a higher percentage without health insurance (mean [SD], 11.2% [5.2%] vs 9.6% [4.9%]; P = .002), a higher percentage under the poverty line (mean [SD], 18.5% [7.2%] vs 15.9% [7.4%]; P = .005), and lower median household income (mean [SD], $57 756 [$20 008] vs $62 678 [$24 134]; P = .04).

Overall, 275 of 8764 individuals (3.1%) developed a MACE during median follow-up of 24.4 (IQR, 17.1-33.3) months. There was no significant difference in the rate of MACE between Black and White participants (32 [3.0%] vs 243 [3.2%]; P = .84) (Table 1, Figure 1). In the multivariable-adjusted models, Black persons did not have a statistically significantly higher rate of MACE than White persons after adjusting for age, male sex, body mass index, hypertension, diabetes, hyperlipidemia, family history of CAD, CAD equivalent, metabolic syndrome, physical activity, and depression (Table 2, model 2: HR, 1.00; 95% CI, 0.69-1.46; P = .51). There was no significant change when the model was further adjusted for socioeconomic status variables including educational level, percentage without health insurance, percentage of persons in poverty, and median household income (Table 2, model 3).

Our first sensitivity analysis was restricted to the majority of participants with normal or mildly abnormal anatomic or functional testing (6993 of 8764 [79.8%]). As expected, the MACE rate was lower (156 of 6993 [2.2%]) over a median follow-up of 24.4 months than in the overall population. Otherwise, the results between race and MACE were similar as in the overall population. Our second sensitivity analysis was restricted to persons not receiving statin therapy (4559 of 8396 [54.3%]). The findings on race and MACE were again similar as in the overall population.

In the CCTA arm of PROMISE (n = 3323), we found that Black persons were more likely to have a calcium score of 0 (54.9% in Black vs 36.8% in White persons; P < .001) and less likely to have a calcium score greater than 400 (8.1% in Black vs 14.4% in White persons; P = .001), consistent with previous work demonstrating less calcified plaque in Black compared with White asymptomatic individuals.^8-13 Black persons were also less likely to have stenosis greater than or equal to 50% (32 [8.7%] vs 430 [14.6%]; P = .001) and less likely to have high-risk plaque features (139 [37.6%] vs 1547 [52.4%]; P < .001) (Table 3).

After adjusting for age, sex, and risk factors (Table 2, model 2), Black participants compared with White participants, had lower CAC scores (β = −0.13; 95% CI −0.24 to −0.03; P = .01) and lower prevalence of high-risk plaque (OR, 0.66; 95% CI, 0.51-0.84; P = .001). Black individuals were not associated with severe stenosis (OR, 0.77; 95% CI, 0.44-1.34; P = .35). There was no significant change in an additional model including these variables plus socioeconomic status (Table 2, model 3). Associations between CCTA features and MACE were similar between Black and White participants after adjusting for the Framingham risk score (Figure 2). For example, the HR for significant stenosis was 7.21 (95% CI, 1.94-26.76) for Black individuals compared with 4.30 (95% CI, 2.62-7.04) for White individuals and, for high-risk plaque, the HR was 3.47 (95% CI, 1.00-12.06) for Black individuals compared with 2.21 (95% CI, 1.37-3.57) for White individuals.

Using the clinical and CCTA phenotypes in the PROMISE trial, we sought to examine differences in the cardiovascular risk burden, CCTA features, and MACE in self-identified Black and White individuals having noninvasive testing for stable chest pain. In our analysis, (1) Black participants had a higher cardiovascular risk burden than White participants, but similar low incidence of MACE over a median follow-up of 24.4 months; (2) despite higher cardiovascular risk, Black persons had less-prevalent epicardial CAD than White persons; and (3) most associations between CCTA features and MACE were similar between Black and White people.

To our knowledge, this study is the first to compare risk factors and MACE in Black and White individuals, with in-depth characterization of coronary plaque, including noncalcified plaque and high-risk plaque features, in a symptomatic ambulatory population undergoing noninvasive testing for stable chest pain. We found a higher cardiovascular risk burden in Black participants than in White participants, but a similar low incidence of MACE over a median follow-up of 24.4 months. These findings are concordant with acute coronary syndrome populations in whom there was higher cardiovascular risk burden on presentation and similar short-term mortality despite lower rate of coronary angiography/intervention in Black patients compared with White patients.^27-29 Black individuals who presented with acute coronary syndrome were less likely than White individuals to have clinically significant coronary obstruction or multivessel disease.^30,31 Similarly, among individuals referred for angiographic evaluation of stable angina (American College of Cardiology National Cardiovascular Data Registry, N = 375 886), Black race was not associated with in-hospital mortality and Black individuals had a lower prevalence of obstructive CAD than White individuals. Our results extend these findings to the much broader population of Black and White individuals having noninvasive imaging for stable chest pain.

The 2021 American College of Cardiology/American Heart Association guidelines for the evaluation and diagnosis of chest pain now provide a class 1 recommendation for CCTA to evaluate stable chest pain in patients at intermediate to high risk without known CAD.³ Based on this guideline, CCTA may be used with increasing frequency for both Black and White patients, making exploration of population differences more relevant to clinical care decisions. The high-quality CCTA phenotyping in the PROMISE trial allows for the first detailed characterization of differences in coronary artery plaque between Black and White individuals with stable chest pain. Consistent with previous studies in asymptomatic populations,^8-13 we report a lower prevalence and extent of CAC on calcium scoring CT in Black individual compared with White individuals, even after adjusting for CAD risk factors. The source of these differences remained unexplained, but a genome-wide association study in African American individuals with type 2 diabetes identified single-nucleotide variants associated with CAC, and these single-nucleotide variants in the targeted domain were most often expressed in individuals with European ancestry.³² Similar to invasive coronary angiography reports in individuals with acute coronary syndrome, we found that Black individuals had a lower prevalence of coronary stenosis compared with White individuals.³³ Although Black individuals were less likely to have coronary plaque, they were more likely to have exclusively noncalcified plaque than White individuals (Table 3)—a finding with important implications for the use of calcium-scoring CT vs CCTA. Another novel finding relates to the presence of high-risk plaque visible on CCTA, as we found that Black individuals had 34% lower odds of having high-risk plaque compared with White individuals, after adjusting for demographics and CAD risk factors. Although some of the difference may be associated with the overall lower prevalence of coronary plaque in Black individuals, this incongruous situation in which Black individuals had more cardiovascular risk factors, yet less coronary plaque on CCTA and similar 2-year MACE, underscores the limits of our understanding of the relationship between risk factors and plaque in Black and White persons.

This post hoc study has limitations. First, although the PROMISE trial included a diverse pool of patients with suspected CAD, it may not reflect the broader population in whom CAD is not suspected. The number of Black participants in these analyses is modest; however, PROMISE has a similar racial and ethnic distribution to the general population (eTable in the Supplement). Second, our follow-up was limited to a median of 24.4 months. Thus, our results should be interpreted in the context of 2-year MACE and may not capture differences that would emerge over 10 years. Our study may be underpowered to detect the differences in MACE between Black and White individuals owing to the low rate of MACE. Because of the small sample size of other racial and ethnic groups in the PROMISE trial, the present study included only White and Black persons. We recognize self-reported race to be an inadequate surrogate for inherited predisposition for disease (genetic pathways) and environmental risks (social determinants of health),³⁴ both of which may affect CAD but were not collected in PROMISE. Socioeconomic status was estimated based on the US Census data from the recruiting site, because individual-level zip codes were not available. Prevention and lifestyle variables were not included in the analysis. In addition, CCTA allows for assessment of epicardial CAD but cannot evaluate microvascular disease, which could potentially explain the similar risk of MACE despite the lower burden of epicardial CAD between Black and White individuals.

In a contemporary population of outpatients having noninvasive testing for suspected CAD, we found that Black participants had a higher cardiovascular risk burden but less-prevalent epicardial CAD on CCTA compared with White participants. Black and White persons had a similar risk of MACE over a median 24.4-month follow-up.

Accepted for Publication: November 3, 2021.

Published Online: December 22, 2021. doi:10.1001/jamacardio.2021.5340

Correction: This article was corrected on February 2, 2022, to fix a numeric error in the Key Points.

Corresponding Author: Michael T. Lu, MD, MPH, Cardiovascular Imaging Research Center, Massachusetts General Hospital, Harvard Medical School, 165 Cambridge St, Ste 400, Boston, MA 02114 (mlu@mgh.harvard.edu).

Author Contributions: Dr Lu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Zhang, Olalere, Abidov, Ferencik, Hoffmann, Lu.

Acquisition, analysis, or interpretation of data: Zhang, Olalere, Mayrhofer, Bittner, Emami, Meyersohn, Puchner, Moloo, Dolor, Mark, Ferencik, Hoffmann, Douglas, Lu.

Drafting of the manuscript: Zhang, Puchner, Hoffmann, Lu.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Zhang, Mayrhofer, Ferencik.

Obtained funding: Hoffmann, Douglas.

Administrative, technical, or material support: Zhang, Olalere, Mayrhofer, Meyersohn, Puchner, Hoffmann, Douglas, Lu.

Supervision: Bittner, Ferencik, Hoffmann, Douglas, Lu.

Conflict of Interest Disclosures: Dr Abidov reported receiving grants from Astellas Pharma, Boehringer Ingelheim, and Kiniksa outside the submitted work. Dr Moloo reported other from University of Colorado Clinical trial support during the conduct of the study. Dr Mark reported receiving grants from the National Heart, Lung, and Blood Institute and National Institutes of Health during the conduct of the study and grants from HeartFlow, Merck, and Mayo Clinic outside the submitted work. Dr Ferencik reported receiving grants from American Heart Association during the conduct of the study; grants from the National Institutes of Health and consulting fees from Biograph Inc outside the submitted work. Dr Hoffmann reported receiving consulting fees from Duke University and Recor Medical and grants from KOWA, Astra Zeneca, Medimmune, and HeartFlow on behalf of Massachusetts General Hospital outside the submitted work. Dr Douglas reported receiving grants from HeartFlow outside the submitted work. Dr Lu reported receiving grants from AstraZeneca/MedImmune and Kowa, and consulting fees from PQBypass outside the submitted work. No other disclosures were reported.

Funding/Support: The Prospective Multicenter Imaging Study for Evaluation of Chest Pain was funded by National Heart, Lung, and Blood Institute grants R01HL098237, R01HL098236, R01HL098305, and R01HL098235.

Role of the Funder/Sponsor: The funding organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.