South Asian Representation in Cardiovascular Disease Randomized Controlled Trials

Abstract

Background

One in 4 individuals worldwide is of South Asian ancestry and is therefore at increased risk for cardiovascular disease (CVD). However, South Asian representation in CVD randomized controlled trials (RCTs) is not well known.

Objectives

The aim of this systematic review was to measure South Asian representation in CVD RCTs and extract post-randomization primary outcome estimates for this population.

Methods

We conducted a systematic review to identify major CVD RCTs published between 2018 and 2022. Each study was manually screened and reviewed to identify South Asian participants and representation rates. The protocol for this systematic review was prospectively registered in PROSPERO (South Asian Representation in Cardiovascular Clinical Trials; CRD42023396522).

Results

We included 310 RCTs, representing 1,036,737 total and 32,764 (3.2%) South Asian participants. Most South Asian participants (75.4%) were enrolled in trials in South Asia, and 65.2% were enrolled in a single trial in India. After excluding this trial, South Asian individuals represented 1.1% of total trial participants. South Asian representation was highest in trials studying coronary artery disease (9.0%), whereas no South Asian individuals were identified in trials studying heart failure, cardiac arrest, or valvular heart disease. Post-randomization data were available for 28,197 South Asian individuals, representing 7.3% of all participants with post-randomization data.

Conclusions

South Asian individuals are underrepresented in major CVD RCTs, and efforts to extend enrollment initiatives in RCTs to South Asian individuals are urgently needed. The extent to which this underrepresentation is a driver of elevated cardiovascular disease risk merits further study.

Central Illustration

South Asia includes the countries of Bangladesh, Bhutan, India, the Maldives, Nepal, Pakistan, and Sri Lanka. Individuals of South Asian descent are at considerably higher risk for atherosclerotic cardiovascular disease (ASCVD) compared with other populations. High rates of ASCVD among South Asian individuals have been observed throughout South Asia,¹ including India,² Pakistan,³ Bangladesh,⁴ Nepal,⁵ Sri Lanka,⁶ Bhutan,⁷ and the Maldives.⁸ Disproportionate CVD rates among individuals with South Asian ancestry relative to local populations have been noted throughout the global diaspora, including in the United States,⁹ Canada,¹⁰ Europe,¹¹ Oceania,^12,13 South America,^14,15 and South Africa.¹⁶

South Asian ASCVD risk is not fully predicted by existing risk assessment tools, including the Pooled Cohort Equations,¹⁷ UK QRISK3,^18,19 Framingham Risk Score,²⁰ and Systematic Coronary Risk Evaluation,²⁰ among others. Although there is emerging literature that seeks to explain the gap in predicted ASCVD risk in South Asian populations, the precise reasons for this risk gap are not yet well understood. As a result, global practice guidelines uniquely recognize South Asian ancestry as a “risk-enhancing factor” for ASCVD,^9,17,21, 22, 23, 24 and encourage practitioners to consider recommending lifestyle interventions, lipid-lowering therapies, diabetic drugs, and blood pressure (BP) medications earlier and/or more aggressively than in other racial/ethnic populations.

Analyses of cardiovascular disease (CVD) clinical trial enrollment have found that individuals of Asian ancestry are underrepresented in certain cohorts,25, 26, 27, 28 but may be more adequately represented in other cohorts.^29,30 However, there are very few analyses that disaggregate Asian populations and report specifically on South Asian trial representation rates. Only 1 study focused on South Asian CVD trial enrollment by examining outcome trials in type 2 diabetes mellitus and found that South Asian individuals were consistently underrepresented.³¹ However, systematic data on South Asian trial representation across all CVD indications remain lacking.

Despite high burdens of CVD, the degree to which South Asian individuals are included in randomized controlled trials (RCTs) that commonly inform clinical practice is unknown. Representation rates may serve as important statistics for policymakers, regulators, investigators, and institutions that are designing or implementing large-scale clinical trials. We sought to conduct a systematic review of South Asian representation in major CVD RCTs reported in major medical journals, compare representation to other racial/ethnic groups, and extract primary outcome estimates for South Asian individuals.

Methods

Search strategy and selection criteria

We conducted a systematic review using PubMed to extract all citations of CVD trials published from 2018 to 2022 in the New England Journal of Medicine, the Journal of the American Medical Association, and The Lancet with “cardiovascular diseases” as a Medical Subject Heading (MeSH) major topic and clinical trial as a publication type (Supplemental Methods). The analysis was restricted to identify RCTs, including primary phase 3 CVD outcomes trials, that were most likely to inform contemporary clinical practice and CVD management guidelines while minimizing the likelihood of including the same therapeutic program. Multiple authors independently reviewed screening and eligibility criteria. Each article was screened for prespecified inclusion and exclusion criteria. Studies were included if they were published in the prespecified study period and could be identified as RCTs based on the reported randomization of participants and the publication of post-randomization data. Studies were excluded if the primary studied condition was not a form of CVD or the study was not designed as an RCT. Studies were additionally excluded if they represented additional secondary analyses or reporting of long-term outcomes of a previously published RCT but comprised the same original cohort in the primary report to avoid duplication of participants. Studies were excluded if they pertained to special populations, such as pregnant and pediatric populations.

Data analysis

Summary data were extracted from published reports and supplementary appendices. South Asian individuals were identified based on either self-reported data or country of origin (ie, India, Pakistan, Bangladesh, Sri Lanka, Nepal, the Maldives, or Bhutan). Racial/ethnic data were extracted directly from published papers or associated supplementary appendices. Trial enrollment and enrollment of South Asian individuals by primary trial sites were aggregated by country and global region, and aggregated by primary and secondary disease indication under investigation. Intervention types were classified as either pharmacologic, procedural, device-related, pharmacologic/procedural, or other intervention type. Clinical trial phase was extracted for each included study. We determined the proportion of studies reporting any participant-level post-randomization racial/ethnic data. We also estimated the reported representation rates for South Asian individuals across all studies and stratified representation rates by global region of primary site enrollment, clinical trial phase, type of intervention under investigation, publication year, journal, trial disease indication, and South Asian country of origin. Post-randomization representation rates were estimated for South Asian individuals and compared with other self-reported racial/ethnic groups. Trial findings for South Asian subgroups were independently reviewed by multiple authors.

Chi-square tests were used to assess differences in representation rates. Statistical analysis was performed using Microsoft Excel (Microsoft Excel for Windows). The protocol for this systematic review was prospectively registered in PROSPERO (South Asian Representation in Cardiovascular Clinical Trials; CRD42023396522) and followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) reporting guidelines.³² This study utilized previously published data and was therefore exempt from review by an institutional review board.

Role of the funding source

There was no funding source for this study.

Results

We identified 417 potentially eligible studies in PubMed published in 3 major medical journals from 2018 to 2022 that underwent manual review and screening, of which 107 trials were excluded (Figure 1). A total of 310 studies were included in the systematic review (Supplemental Table 2).

Figure 1.

Study Selection and Flow Diagram

Each trial identified through database search was manually screened for inclusion and exclusion criteria. Of 417 studies that were initially identified, 310 studies met inclusion and exclusion criteria, and were included for further review. CVD = cardiovascular disease; RCT = randomized controlled trial.

A total of 1,036,737 participants were enrolled across 310 included CVD RCTs, and of all trial participants, 32,764 (3.16%) could be identified as South Asian based primarily on country of origin. The majority (65.2%) of all 32,764 South Asian participants were enrolled in a single trial (ACS QUIK [Acute Coronary Syndrome Quality Improvement in Kerala]) that enrolled 21,374 individuals in India.³³ After excluding this trial, South Asian individuals represented 1.1% (11,390 individuals) of 1,036,737 total trial participants. South Asian trial representation rates by year during the inclusion period are shown in the Central Illustration.

Central Illustration.

Representation of South Asian Individuals Among Trial Participants by Year

Trial participation totals and rates among total trial participants and South Asian participants over time (2018 to 2022). The percentage of South Asian participants was calculated annually based on the number of South Asian participants as a proportion of total trial participants.

Although 35 trials clearly enrolled South Asian individuals, only 19 reported the number of South Asian individuals enrolled. When considering only the 35 trials that reported enrolling any South Asian individuals, 32,764 (15.6%) of 210,511 total trial participants could be identified as South Asian. After excluding the ACS QUIK trial, 11,390 (6.0%) of 189,137 trial participants could be identified as South Asian. When considering only the 19 trials that reported enrolling any South Asian individuals and reported the number of South Asian individuals enrolled, 32,764 (27.6%) of 118,614 total trial participants could be identified as South Asian. After excluding the ACS QUIK trial, 11,390 (11.7%) of 118,614 trial participants could be identified as South Asian. Only 6 of the 19 trials reported post-randomization data for South Asian participants, and a summary table of these trials is shown in Table 1. All trials enrolling South Asian individuals are shown in Table 2.

Table 1.

Summary Table of Cardiovascular Disease Randomized Controlled Trials With Post-Randomization Data For South Asian Participants

First Author (Journal, Year)	Trial Name	Population	Study Type	Intervention(s)	Primary Outcome	Total Participants	South Asian Participants	South Asian Participants With Post randomized Data	South Asian Primary Outcomes
Huffman et al33 (JAMA, 2018)	ACS QUIK	Patients hospitalized with acute NSTEMI or STEMI	Randomized controlled trial	Cluster randomized at hospital level to receive care via quality improvement tool kit vs usual care	Composite of all-cause death, reinfarction, stroke, or major bleeding at 30 days	21,374	21,374	21,374	Adjusted OR: 0.98 (95% CI: 0.80-1.21)
Yusuf et al40 (NEJM, 2021)	TIPS-3	Men 50 y of age or older and women 55 y of age or older without known cardiovascular disease but elevated INTERHEART Risk Score	Randomized controlled trial	Randomized in 2 by 2 by 2 factorial design to polypill (simvastatin 40 mg, atenolol 100 mg, hydrochlorothiazide 25 mg, ramipril 10 mg) or placebo daily, aspirin 75 mg or placebo daily, and vitamin D or placebo monthly	Composite of major cardiovascular events, heart failure, resuscitated cardiac arrest, and arterial revascularization	5,713	3,034	3,034	HR: 0.61 (95% CI: 0.35-1.06)b
Jafar et al43 (NEJM, 2020)	COBRA-BPS	Patients 40 y of age or older with hypertension	Randomized controlled trial	Cluster randomized at community level to receive multicomponent intervention (community health worker visits for BP monitoring, physician training, and care coordination) vs usual care	Mean change in systolic blood pressure from baseline to 24 months	2,645	2,645	2,645	Between-group mean systolic BP reduction: 5.2 mm Hg (95% CI: 3.2-7.1 mm Hg)
Webster et al39 (JAMA, 2018)	TRIUMPH	Patients 18 y of age or older with persistent hypertension (systolic BP >140 mm Hg or diastolic BP >90 mm Hg; or concomitant diabetes mellitus or CKD and systolic BP >130 mm Hg or diastolic BP >80 mm Hg)	Randomized controlled trial	Randomized to receive triple combination pill therapy (telmisartan 20 mg, amlodipine 2.5 mg, and chlorthalidone 12.5 mg) vs usual carea	Proportion achieving target systolic/diastolic BP (<140/90 mm Hg or <130/80 mm Hg in patients with diabetes or CKD)	700	700	700	Between-group adjusted difference in post-randomization systolic BP: −9.8 mm Hg (95% CI: −7.9 to −11.6 mm Hg), and in diastolic BP: −5.0 mm Hg (95% CI: −3.9 to −6.1 mm Hg)
Arabi et al42 (NEJM, 2019)	PREVENT	Medical, surgical, or trauma patients considered adults based on local standards, weighed at least 45 kg, expected to stay in ICU for at least 72 h, and no contraindications to heparin-based thrombophylaxis	Randomized controlled trial	Randomized to receive either intermittent pneumatic compression in addition to pharmacologic thrombophylaxis vs pharmacologic thrombophylaxis alone	Incident proximal lower-limb deep vein thrombosis after third day since randomization until ICU discharge, death, attainment of full mobility, or trial day 28	2,003	184	182	RR could not be calculatedc
Bhatt et al41 (NEJM, 2019)	REDUCE-IT	Patients aged 45 y or older with established CVD or aged 50 y or older with diabetes mellitus and 1 additional CVD risk factor with fasting triglyceride levels between 150 and 499 mg/dL and LDL between 41-100 mg/dL on statin therapy for at least 4 wk	Randomized controlled trial	Randomized to receive icosapent ethyl 2 g twice daily vs placebo	Composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina	8,179	262	262	HR: 0.49 (95% CI: 0.24-1.02)

BP = blood pressure; CKD = chronic kidney disease; CVD = cardiovascular disease; ICU = intensive care unit; LDL = low-density lipoprotein; JAMA = Journal of the American Medical Association; NEJM = New England Journal of Medicine; NSTEMI = non–ST-segment elevation myocardial infarction; STEMI = ST-segment elevation myocardial infarction.

^a3.4% of participants at 6 months still receiving triple combination pill therapy had been uptitrated to a higher dose.

^bFor effects of polypill and aspirin vs double placebo for the primary outcome.

^cOf the South Asian trial participants, none of the 86 trial participants in the pneumatic compression trial arm and none of the 96 trial participants in the control arm experienced the primary outcome, so a relative risk (RR) could not be calculated.

Table 2.

Cardiovascular Disease Randomized Controlled Trials That Enrolled South Asian Individuals

DOI	Trial Name	Total Participants	South Asian Participants	South Asian Participants With Post-Randomized Data
10.1001/jama.2017.21906	ACS QUIK	21,374	21,374	21,374
10.1056/NEJMoa2028220	TIPS-3	5,713	3,034	3,034
10.1056/NEJMoa1911965	COBRA-BPS	2,645	2,645	2,645
10.1001/jama.2018.10359	TRIUMPH	700	700	700
10.1056/NEJMoa1812792	REDUCE-IT	8,179	262	262
10.1056/NEJMoa1816150	PREVENT	2,003	184	182
10.1056/NEJMoa1915922	ISCHEMIA	5,179	941	Not reported
10.1056/NEJMoa1801174	ODYSSEY OUTCOMES	18,924	835	Not reported
10.1056/NEJMoa2209051	INVICTUS	4,531	791	Not reported
10.1056/NEJMoa1908419	TWILIGHT	7,119	610	Not reported
10.1001/jama.2020.12443	TAILOR-PCI	5,302	364	Not reported
10.1056/NEJMoa1908077	THEMIS	19,271	292	Not reported
10.1016/S0140-6736(18)30832-8	MANAGE	1,754	259	Not reported
10.1056/NEJMoa2108749	MASTER DAPT	4,434	186	Not reported
10.1056/NEJMoa1808783	ART	3,102	150	Not reported
10.1056/NEJMoa1915925	ISCHEMIA-CKD	777	92	Not reported
10.1016/S0140-6736(19)30038-8	ENCHANTED	2,227	35	Not reported
10.1056/NEJMoa2101897	LAAOS III	4,811	8	Not reported
10.1001/jama.2020.4871	OPTIMISE	569	2	Not reported
10.1056/NEJMoa2104508	PARADISE-MI	5,661	Not reported	Not reported
10.1056/NEJMoa1901118	PIONEER 6	3,183	Not reported	Not reported
10.1056/NEJMoa1811744	CREDENCE	4,401	Not reported	Not reported
10.1001/jama.2021.18463	PARALLAX	2,572	Not reported	Not reported
10.1056/NEJMoa2022190	EMPEROR-Reduced	3,730	Not reported	Not reported
10.1056/NEJMoa2108269	AMPLITUDE-O	4,076	Not reported	Not reported
10.1056/NEJMoa1911303	DAPA-HF	4,744	Not reported	Not reported
10.1056/NEJMoa1908655	PARAGON-HF	4,822	Not reported	Not reported
10.1056/NEJMoa1813959	RE-SPECT ESUS	5,390	Not reported	Not reported
10.1056/NEJMoa2107038	EMPEROR-Preserved	5,988	Not reported	Not reported
10.1056/NEJMoa2210645	PROMINENT	10,497	Not reported	Not reported
10.1056/NEJMoa1916870	THALES	11,016	Not reported	Not reported
10.1056/NEJMoa1812389	DECLARE-TIMI 58	17,160	Not reported	Not reported
10.1056/NEJMoa1817083	AUGUSTUS	4,614	Not reported	Not reported
10.1001/jama.2022.2910	REMAP-CAP	1,824	Not reported	Not reported
10.1056/NEJMoa2105911	REMAP-CAP/ ATTACC/ACTIV-4a	2,219	Not reported	Not reported

Total enrollment and South Asian enrollment based on trial characteristics are shown in Table 3. A plurality of trials enrolled in North America, Europe, and Oceania (48.4%, 150 of 310 total trials) but only 2 of 386,887 participants enrolled could be identified as South Asian (0.001%). Most South Asian individuals enrolled in the included CVD RCTs were from trials in South Asia, which enrolled 24,719 South Asian participants (75.4% of the 32,764 South Asian individuals enrolled in all CVD RCTs) (Table 3). The majority of the 310 trials evaluated pharmacologic interventions (56.5%, 175 trials), procedural interventions (22.3%, 69 trials), or both (11.3%, 35 trials). There were 76 trials that reported any post-randomization race or ethnicity data and accounted for 424,696 total trial participants. Twenty (26.3%) of these 76 trials enrolled individuals in North America, Europe, and Oceania, but none of the 103,850 trial participants could be identified as South Asian. Fifty-two (68.4%) of these 76 trials were global trials, but only 5,324 (1.8%) of 295,506 total trial participants could be identified as South Asian. Most South Asian individuals enrolled in CVD RCTs that reported post-randomization race or ethnicity data were from trials in South Asian countries, which enrolled 24,719 South Asian participants (82.3% of all 30,043 South Asian individuals in this subset of trials) (Supplemental Table 3).

Table 3.

South Asian Trial Representation Rates by Trial Characteristics

	No. of Trials	All CVD Trials, %	Total Participants, N	South Asian Participants, n	South Asian Participants, %
Total	310		1,036,737	32,764	3.16
Region
North America, Europe, Oceania	150	48.4	386,887	2	0.0
South America, Africa, Asiaa	38	12.3	139,960	0	0.0
Globalb	119	38.4	485,171	8,043	1.7
South Asia	3	1.0	24,719	24,719	100.0
Intervention type
Pharmacologic	175	56.5	688,500	7,370	1.1
Procedure	69	22.3	82,062	1,191	1.5
Device	26	8.4	41,766	184	0.4
Pharmacologic and procedure	35	11.3	212,431	24,019	11.3
Other clinical	5	1.6	11,978	0	0.0
Publication year
2018	62	20.0	274,189	23,168	8.4
2019	75	24.2	250,338	1,533	0.6
2020	53	17.1	117,254	4,044	3.4
2021	60	19.4	179,976	3,228	1.8
2022	60	19.4	214,980	791	0.4
Journal
NEJM	144	46.5	575,372	10,030	1.7
JAMA	82	26.5	168,833	22,440	13.3
Lancet	84	27.1	292,532	294	0.1
Clinical trial phase
II	24	7.7	12,379	0	0.0
II/III	2	0.6	532	0	0.0
III	81	26.1	316,749	22,663	7.2
III/IV	4	1.3	26,706	0	0.0
IV	18	5.8	38,808	2	0.0

Abbreviations as in Table 1.

^aExcluding South Asian countries (ie, India, Pakistan, Bangladesh, Nepal, Sri Lanka, Maldives, and Bhutan) in Asia.

^bTrial conducted at clinical sites across multiple global regions.

Among trials with a listed trial phase, nearly all South Asian individuals were enrolled in phase III trials with almost no South Asian individuals in phase II or phase IV trials (Table 3).

As shown in Table 2, we identified 13 trials that reported enrolling South Asian participants but did not provide post-randomization data for South Asian individuals. Of these trials, only the ART trial (Arterial Revascularisation Trial)³⁴ listed a South Asian country as the only Asian country. However, the ART trial did not provide outcome estimates for Asian participants and was thus not included in Table 1. Notably, the MANAGE (Management of Myocardial Injury After Noncardiac Surgery) trial³⁵ only included sites in 2 Asian countries, India and the Philippines, with the far majority of Asian participants enrolled in India (n = 259) compared with the Philippines (n = 9). However, the MANAGE trial similarly did not provide outcome estimates for Asian participants. The remaining 11 trials enrolled in other Asian countries in addition to South Asian countries, including China, Japan, and/or Korea. Therefore, it was not possible to extract outcome estimates for South Asian individuals from these remaining trials.

Of the 32,764 South Asian individuals included in CVD RCTs, the majority were from India (84.1%, 27,553 participants) with fewer participants from Sri Lanka (5.7%, 1,870 participants), Bangladesh (3.8%, 1,229 participants), and Pakistan (2.7%, 895 participants) (Supplemental Figure 1). An unknown number of participants were enrolled from Nepal due to lack of disaggregated reporting, and no participants were enrolled from the Maldives or Bhutan.

The most commonly studied conditions across the 310 trials included coronary artery disease (CAD) (21.29%, 66 trials), cerebrovascular accident (16.77%, 52 trials), heart failure (12.26%, 38 trials), atrial fibrillation (9.03%, 28 trials), and venous thromboembolism (7.10%, 22 trials). As shown in Supplemental Table 1, most South Asian participants were enrolled in trials studying CAD (9.0%, 24,844 of 277,512 total participants), hypertension (3.4%, 3,382 of 98,597 total participants), or ASCVD screening and/or prevention (1.5%, 3,034 of 199,298 total participants). No South Asian individuals could be identified in trials studying heart failure, cardiac arrest, or valvular heart disease (Supplemental Table 1).

Seventy six of 310 trials reported participant-level post-randomization data for White, Black, Hispanic, and/or Asian individuals, which represented 364,157 participants (Figure 2). Of these total participants, post-randomization data were available for 28,197 South Asian individuals (7.7%), whereas post-randomization data were available for 269,426 White individuals (74.0%), 22,019 Black individuals (6.0%), and 11,923 Hispanic individuals (3.3%). Of all the post-randomization data for South Asian individuals that were available, 75.8% was from a single trial (ACS QUIK) that enrolled individuals in India.³³ After excluding this trial, South Asian individuals represented 2.0% (6,823 individuals) of trial participants with available post-randomization data.

Figure 2.

Representation of Racial/Ethnic Groups Among Post-Randomized Subgroup Analyses Over Time

Trends in post-randomization trial data stratified by racial and ethnic group over time. The number of participants refers to individuals with available post-randomization outcome data stratified by racial and ethnic group.

Discussion

Findings on South Asian Representation in Clinical Trials

Although South Asian individuals comprise nearly a quarter of the global population and have well-documented excess CVD risk, they represent a small minority of CVD trial participants (Central Illustration). Representation was particularly poor in Western countries and Oceania despite South Asian individuals representing the largest ethnic minority in Canada and the United Kingdom, and a large growing population in several other European countries and in Australia.^11,12 Only a small minority of trials were conducted in South Asian countries. Few RCTs reported South Asian participant-level data, which limits the generalizability of study findings to South Asian individuals. Lack of representation is a well-documented source of disparities across domains. Limited data collected by trials incompletely characterizes the diversity of South Asian populations. Most South Asian individuals in CVD trials were from India, and no data were available for individuals from Nepal, the Maldives, or Bhutan. Disaggregated studies of South Asian groups show significant risk heterogeneity based on country of descent.^18,36 Nearly one-half of the trials that enrolled South Asian individuals did not report South Asian enrollment statistics, thus underscoring the importance of both recruitment and data reporting and disaggregation. Among trials that reported the number of South Asian participants, several studies aggregated South Asian participants with individuals with ancestry from other Asian countries, which highlights the importance of disaggregating data from Asian participants both during enrollment and data reporting and analysis. Of the few RCTs with South Asian participant-level data that we identified, most enrolled individuals outside of the United States and Europe, which may limit the generalizability of study findings to South Asian Americans whose cardiovascular risk factor profiles may be affected by unique environmental and sociocultural factors.³⁷ Not a single South Asian appeared to be enrolled in trials for several disease indications. We also demonstrate underreporting of data among CVD trial participants across racial/ethnic groups, including Black, Hispanic, and Asian individuals. These findings support ongoing efforts to generate evidence among historically underrepresented subgroups in cardiovascular studies through improvements in global trial enrollment efforts, especially in the Global South, including multiple countries in the Caribbean, Latin America, and certain African nations that also harbor growing communities of individuals of South Asian ancestry.

Findings on Trial Results for South Asian Participants

Trials with dedicated enrichment for South Asian individuals highlight that generalizability from other groups cannot be assumed, and care delivery systems providing cardiovascular care may affect South Asian populations differently than other populations.^32,38 The available South Asian participant-level data were primarily derived from a single trial (ACS QUIK),³² which showed implementation of process and outcome measures for patients with acute myocardial infarction may not consistently improve cardiovascular outcomes and mortality in South Asia to the same degree experienced in high-income countries implementing quality improvement programs.^33,38 Further research is needed to understand whether the lack of improvement in major adverse cardiovascular event rates was driven by South Asian participant characteristics or hospital characteristics. The TRIUMPH (TRIple Pill vs. Usual care Management for Patients with mild-to-moderate Hypertension) trial³⁹ randomized individuals in Sri Lanka with poorly controlled hypertension to low-dose triple combination antihypertensive therapy and demonstrated improved proportions of South Asian individuals achieving blood pressure targets. However, follow-up time was limited to 6 months, and rates of adverse cardiovascular events were not measured. Improving care quality for patients with acute myocardial infarction is a global priority in low-income and middle-income countries,²³ yet there are gaps in implementing this global priority as quality improvement efforts in high-income countries that showed reductions in racial and ethnic disparities may need additional corroboration to ensure such reductions extend to South Asian populations.³⁸ Although certain South Asian care delivery systems routinely provide medications with no cost sharing, future work is necessary to assess whether lack of observable reductions in cardiovascular risk among South Asian populations is related to health system infrastructure or payment and reimbursement models. Importantly, we found no other major CVD trials, including trials studying novel stents or other innovative percutaneous revascularization procedures, that provided post-randomization data for South Asian individuals with CAD, despite disproportionately high rates of ischemic heart disease among South Asian individuals and smaller coronary artery luminal diameters.⁹

Although recommendations in several countries target South Asian individuals for early preventive CVD interventions,^9,22, 23, 24 the evidence base for CVD prevention may not be fully generalizable to South Asian individuals. We identified 3 trials that reported South Asian post-randomization data, though these trials did not appear to assess South Asian subgroup treatment effect differences. The TIPS-3 trial (The International Polycap Study 3)⁴⁰ provided the second largest source of post-randomization data for South Asian individuals and studied the effects of aspirin, vitamin D, and a polypill containing a statin and multiple antihypertensive agents on the prevention of cardiovascular events among individuals at high risk for CVD. Although the trial showed that combined treatment with a polypill and aspirin reduced the rates of cardiovascular events among all participants, it did not show a significant reduction in rates among South Asian individuals, despite South Asian individuals representing 53.1% of all trial participants. Similarly, the REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) trial⁴¹ studied the effects of icosapent ethyl on reducing triglyceride levels and residual cardiovascular risk for patients with or at risk of CVD who were already receiving adequate statin therapy. Across the trial population, the risk of ischemic events and cardiovascular death was lower in the intervention arm, but subgroup analyses revealed that statistically significant reductions in the primary composite endpoint were only observable in the aggregated regions of North America, Western Europe, Oceania, and South Africa where the majority of trial participants were enrolled. Among trial participants enrolled in India who received icosapent ethyl, there was an observable trend towards cardiovascular risk reduction, but too few individuals were enrolled to achieve statistically significant differences relative to the placebo arm. Finally, the PREVENT (Pneumatic Compression for Preventing Venous Thromboembolism) trial⁴² enrolled individuals at risk of venous thromboembolism to study the effects of intermittent pneumatic compression in addition to pharmacologic thromboprophylaxis. Although the study showed no added benefit from intermittent pneumatic compression on deep vein thrombosis among critically ill patients, too few South Asian individuals were enrolled to detect a single deep vein thrombosis in either the intervention or control arms. Although efforts to broadly increase South Asian trial enrollment are necessary for equitable trial representation, this study highlights the importance of powering such trials to enable adequate subgroup analysis to better infer generalizability across a diverse group of individuals. Global trials enrolling individuals across countries and regions may need to enhance enrollment in South Asia to determine whether interventions that lead to statistically significant differences in cardiovascular risk in North America and Western Europe have similar effects in South Asian populations.

In South Asian countries, individuals residing in rural areas bear a large portion of the CVD burden. The COBRA-BPS (Control of Blood Pressure and Risk Attenuation-Bangladesh, Pakistan, and Sri Lanka) trial⁴³ showed that community health workers can be an affordable and effective method of controlling blood pressure among South Asian individuals in rural settings. It is also one of very few trials that examined differences in South Asian subgroups by enrolling individuals in Bangladesh, Pakistan, and Sri Lanka. Given the rise in cardiovascular mortality in low-income and middle-income countries, low-cost interventions that integrate into existing public health infrastructure could be effective at mitigating the global burden of CVD experienced by South Asian individuals. However, the study was underpowered to detect differences in secondary outcomes, including cardiovascular events. Therefore, additional research is necessary to study whether community health workers can meaningfully improve cardiovascular outcomes across South Asian countries and subgroups.

Barriers to South Asian Trial Participation

Barriers to South Asian trial participation may include cultural/language discordance, awareness of research, trust, prohibitive logistic or cost concerns, and systematic bias.¹¹ In Western countries, South Asian individuals represent minority populations that may not be currently targeted for CVD trial enrollment, and sociodemographic factors may play a role. In low-income countries with South Asian populations, trial design and implementation could be cost-prohibitive. Operational barriers may exist that lead to complex regulatory mechanisms which limit trial implementation in low-income countries. Further research is needed to specifically examine drivers of CVD RCT participation for South Asian individuals.

The U.S. Food and Drug Administration has previously issued draft guidance on improving the racial and ethnic diversity in clinical trials, including through the use of relevant action plans.⁴⁴ Such goals may be advanced if similar measures are adopted and advanced by other regulatory and funding agencies.⁴⁴

Study Limitations

Trial data may be limited by inadequate reporting of participant-level racial/ethnic data, including different reporting methods (ie, participant self-reporting, categorization by country of origin). Most South Asian individuals could only be identified based on country of origin, and lack of consistent self-reporting of racial/ethnic heritage could also bias representation rates. Pregnant and pediatric populations were excluded given differences in clinical practice guidelines for CVD but merit separate areas of future research. This systematic review was also restricted to a few medical journals and to a 5-year period to facilitate efficient manual screening and review as well as to focus on contemporary practice-changing clinical trials (ie, primary phase 3 CVD outcomes trials often principally published in these journals). Restricting the review to these journals also minimized the likelihood of double-counting the same therapeutic program. Nevertheless, this study design may have excluded some studies published outside this period and in other journals that enrolled South Asian individuals. Estimates could also have been affected by the inability to include studies with available participant-level post-randomization data, but the absence of absolute numbers of participants in subgroup analyses. Finally, the lack of disaggregated reporting may have affected representation rates if South Asian individuals were aggregated with individuals from other Asian countries.

Conclusions

Although practice guidelines encourage potential earlier adoption of lifestyle interventions and pharmacologic therapy to mitigate ASCVD risk in South Asian individuals,^9,17,22, 23, 24 there remains a paucity of data from RCTs in major medical journals evaluating the efficacy of either approach. Although this systematic review was limited to trials included in 3 major medical journals, South Asian underrepresentation may also be pronounced in other studies informing ASCVD guidelines. The extent to which both limited RCT representation and limited data collection contribute to persistent gaps in ASCVD risk for South Asian individuals merits further study. Efforts to extend enrollment initiatives in RCTs to individuals of South Asian ancestry are urgently needed, and the result of this systematic review can be used to guide the development of regulatory standards regarding South Asian trial enrollment and standardized data collection and reporting. Parallel efforts to conduct epidemiologic and multiomics studies of CVD in South Asian populations may also be necessary to inform trial design and implementation. Concerted global efforts to study CVD interventions in South Asian individuals are necessary to refine South Asian–specific recommendations for CVD prevention, risk assessment, and management.

Data Sharing Statement

Data collected for this study is available via the PubMed inquiry as detailed in the Methods as well as via request from the corresponding author.

Funding Support and Author Disclosures

Dr Patel has received support from National Heart, Lung and Blood Institute grant K08HL168238 and National Human Genome Research Institute grant U01HG011719. Dr Natarajan has received research grants from Allelica, Amgen, Apple, Boston Scientific, Cleerly, Genentech / Roche, Ionis, Novartis, and Silence Therapeutics, personal fees from AIRNA, Allelica, Apple, AstraZeneca, Bain Capital, Blackstone Life Sciences, Bristol Myers Squibb, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Esperion Therapeutics, Foresite Capital, Foresite Labs, Genentech / Roche, GV, HeartFlow, Magnet Biomedicine, Merck, Novartis, Novo Nordisk, TenSixteen Bio, and Tourmaline Bio, equity in Bolt, Candela, Mercury, MyOme, Parameter Health, Preciseli, and TenSixteen Bio, royalties from Recora for intensive cardiac rehabilitation, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. Dr Uppal has received fees from BrightEdge outside the submitted work. Dr Bhatt discloses the following relationships: Advisory Board: Angiowave, Antlia Bioscience, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, E-Star Biotech, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, NirvaMed, Novo Nordisk, Repair Biotechnologies, Stasys, Tourmaline Bio; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); Consultant: Alnylam, Altimmune, Broadview Ventures, Corcept Therapeutics, Corsera, GlaxoSmithKline, Hims, SERB, SFJ, Summa Therapeutics, Worldwide Clinical Trials; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research, Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Duke Clinical Research Institute, Engage Health Media, HMP Global (Editor in Chief, Journal of Invasive Cardiology), Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Philips (Becker's Webinar on AI), Population Health Research Institute, WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor); Progress in Cardiovascular Diseases (Deputy Editor); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Alnylam, Amarin, Amgen, AstraZeneca, Atricure, Bayer, Boehringer Ingelheim, Boston Scientific, CellProthera, Cereno Scientific, Chiesi, Cleerly, CSL Behring, Faraday Pharmaceuticals, Fractyl, Idorsia, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, MiRUS, Moderna, Novartis, Novo Nordisk, Pfizer, PhaseBio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Cleerly. Dr Natarajan has received investigator-initiated grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis; has received personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Novartis, and Roche/Genentech; is a cofounder of TenSixteen Bio; is a scientific advisory board member of Esperion Therapeutics, geneXwell, and TenSixteen Bio; and his spouse is employed at Vertex Pharmaceuticals, all unrelated to the present work. Dr Patel has reported that he has no relationships relevant to the contents of this paper to disclose.