Global representation of heart failure clinical trial leaders, collaborators, and enrolled participants: a bibliometric review 2000–20

Abstract

Background The geographic representation of investigators and participants in heart failure (HF) randomized clinical trials (RCTs) may not reflect the global burden of disease. Aims We assessed the geographic diversity of RCT leaders and explored associations with geographic representation of enrolled participants among impactful HF RCTs. Methods and Results We searched MEDLINE, EMBASE, and CINAHL for HF RCTs published in journals with impact factor ≥10 between January 2000 and June 2020. We used the Jonckheere-Terpstra test to assess temporal trends and multivariable logistic regression models to explore associations between predictors and outcomes. There were 414 eligible RCTs. Only 80 of 828 trial leaders (9.7%; 95% CI: 7.8% to 11.8%), and 453 of 4656 collaborators (9.7%; 95% CI: 8.8% to 10.6%) were from outside Europe and North America, with no change in temporal trends and greater disparities in large RCTs. The adjusted odds of trial leadership outside Europe and North America were lower with industry funding (aOR: 0.33; 95% CI: 0.15 to 0.75; P = 0.008). Among 157,416 participants in whom geography was reported, only 14.5% (95% CI: 14.3% to 14.7%) were enrolled outside Europe and North America, but odds of enrolment were ten-fold greater with trial leadership outside Europe and North America (aOR: 10.0; 95% CI 5.6–19.0; P < 0.001). Conclusions Regions disproportionately burdened with HF are under-represented in HF trial leadership, collaboration, and enrolment. RCT leadership outside Europe and North America is independently associated with participant enrolment in under-represented regions. Increasing research capacity outside Europe and North America could enhance trial diversity and generalizability.

The need for increased pragmatism in cardiovascular clinical trials

“…The limited organization and follow-up required to conduct pragmatic trials also offers the potential to conduct robust research in regions with limited research infrastructure and trained personnel, which are grossly under-represented in trials relative to disease prevalence 1 . For example, the SSaSS trial 62 , which was conducted in 600 rural villages in China (~21,000 participants), demonstrated that the use of a salt substitute (75% sodium chloride and 25% potassium chloride) reduced the risk of stroke compared with regular salt (100% sodium chloride).…”

“…However, as investigators, regulators, policy-makers and patients become more reliant on evidence-based results to support clinical care, the failure of contemporary RCTs to address the entire spectrum of clinically relevant questions is becoming increasingly apparent. Most cardiovascular RCTs conducted to date have been primarily ‘explanatory’ in nature; that is, they were designed to study the efficacy of interventions in ‘optimized’ conditions, with highly selected patient populations and protocolized assessments of safety and efficacy 1 , 2 . Although such trial designs increase internal validity, they provide limited information about the effectiveness of the intervention in the great variety of scenarios that exist in routine clinical practice but were not represented in the RCT, thereby compromising the generalizability of the trial results 1 , 3 .…”

“…Most cardiovascular RCTs conducted to date have been primarily ‘explanatory’ in nature; that is, they were designed to study the efficacy of interventions in ‘optimized’ conditions, with highly selected patient populations and protocolized assessments of safety and efficacy 1 , 2 . Although such trial designs increase internal validity, they provide limited information about the effectiveness of the intervention in the great variety of scenarios that exist in routine clinical practice but were not represented in the RCT, thereby compromising the generalizability of the trial results 1 , 3 . Therefore, whereas the demonstration of efficacy in explanatory RCTs is commonly the stepping-stone for an intervention being approved by regulators and introduced into the market, the degree to which the intervention is beneficial in routine clinical practice often remains unclear.…”

Factors Associated With Racial and Ethnic Diversity Among Heart Failure Trial Participants: A Systematic Bibliometric Review

“…Trial populations, however, tend to be much more homogeneous in demographics and comorbidities than patients in clinical settings. 4–7…”

“…Trial populations, however, tend to be much more homogeneous in demographics and comorbidities than patients in clinical settings. [4][5][6][7] There are concerns that race and ethnicity data may be inadequately reported in RCTs, but reporting is essential to understanding the interplay between race and ethnicity and treatment outcomes both in clinical and research settings. 7 Race and ethnicity are heterogenous social constructs that may influence the estimated treatment effect in RCTs due to variations in healthcare system engagement, quality of care, and socioeconomic factors.…”