Trends in cardiovascular eligibility criteria in clinical trials of hematologic malignancies:  a 20-year analysis

Abstract Background Patients with hematologic malignancies frequently have co-existing cardiovascular disease (CVD) that is either de-novo or a sequel of prior therapies. Nevertheless, clinical trials investigating anti-cancer therapies often exclude individuals with known CVD, therefore limiting the generalizability of trial results. We aimed to study temporal trends in the use of cardiovascular exclusion criteria across hematologic malignancy subtypes and treatment classes over the past 2 decades. Methods We analyzed data from the Aggregate Analysis of ClinicalTrials.gov (AACT) database, a publicly available repository of all trials registered within ClinicalTrials.gov. We identified trials initiated at or after January 1, 2020 studying interventions in Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, myeloproliferative neoplasms, and leukemia. Cardiovascular exclusions were defined as coronary artery disease, ischemic heart disease, heart failure, cardiomyopathy, arrhythmia, need for revascularization, and need for coronary artery bypass graft. Trends in the use of these exclusions were analyzed over five-year intervals using Chi-square tests. Results We identified a total of 12,194 clinical trials, of which 34.5% included at least one cardiovascular exclusion criterion. The proportion of trials with cardiovascular exclusions increased from 26.5% during 2000-2004 to 35.3% during 2020-2025 (p = 0.002). Comparing these time intervals, rates of cardiovascular exclusion increased from 16.6% to 31.7% for leukemia trials (p<0.001) and from 7.7% to 29.8% (p<0.001) for non-Hodgkin lymphoma trials. Rates of exclusion criteria remained stable for Hodgkin lymphoma, multiple myeloma, and myeloproliferative neoplasm trials. Among leukemia subtypes, chronic lymphocytic leukemia trials showed an increase in cardiovascular exclusion rate from 17.6% to 30.2% (p = 0.02) between 2000-2004 and 2020-2025. Trials investigating Bruton tyrosine kinase (BTK) and immune checkpoint inhibitors showed increases in cardiovascular exclusion rate, from 44% to 52.2% (p<0.001) and from 16.6% to 37.3 % (p<0.001), during the 20 year period. Conclusions Cardiovascular exclusions remain common in hematologic malignancy trials, limiting applicability to real-world populations. Our analysis identifies an increase in the use of cardiovascular exclusions in chronic lymphocytic leukemia trials, and particularly those investigating BTK inhibitors. The improved survival of patients with chronic lymphocytic leukemia, combined with the high prevalence of cardiovascular disease in that patient population, underscores the critical need to enroll patients with pre-existing cardiovascular disease in clinical trials to inform safe and effective treatment strategies.