CHAPTER 4 194 instance sex; females with HF tend to be older and so are patients with multiple comorbidities. With the exception of conducting trials specifically in older patients, such as the SENIORs trial for beta-blockers in ≥70-year-olds,33 designing phase III efficacy trials with sufficient representation for every age stratum greatly increases costs and complexity. When efforts to ensure equitable female enrolment and justified comorbidity-based exclusions are in place, age distribution of enrolled patients could be expected to accordingly shift to cover a greater proportion of older patients. Racial/ ethnic variations in response to HFrEF treatment are established34; exemplified by the first race-based US Food and Drug Administration (FDA) approval of hydralazine-isosorbide dinitrate combination, which favorable response was elicited solely among Black patients.35,36 Further, pooled subgroup results from DAPA-HF and EMPEROR-reduced trials for SGLT2 inhibitors in HFrEF revealed attenuated pooled hazard ratios in Whites compared to Black and Asian subgroups.37 However, compared to sex and age, generalizability of evidence in HFrEF based on race/ ethnicity is the least understood. At present, estimation of generalizability by race/ ethnicity is hindered by sparse reporting of race/ethnicity data in trials. Only half had information on race/ethnicity15 whereas observational data are typically restricted to individual countries due to law and privacy issues, and is scarce for lowincome regions. Inter-national registries such as ESC heart failure long-term registry, ASIAN heart failure registry and INTER-CHF have successfully bridged HF patients across national borders within select continents. These examples therefore set the stage for extension to future cross-continental registries to allow understanding of the HF landscape across the globe.38–40 Understanding racial/ethnic diversity in HFrEF trials depends very much on the reference geographical location and its racial/ethnic composition. Given that majority of trials are weighted towards North American and Western European patients, an example on assessing racial representativeness of the ASCEND-HF trial on nesiritide was possible with the Get With The Guidelines-Heart Failure registry for U.S. hospitalized HF patients.41 Based on comparison with the registry, study investigators found adequate representation of Black patients in the trial though registry black patients experienced worse outcomes compared to their trial equivalents.41 Clinical trials conducted in the U.S. are usually inclusive of racial/ethnic groups.42 Over time, globalization of contemporary HF trials has successfully
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