The persistent underrepresentation of patients with chronic kidney disease in cardiovascular trials: a systematic review and evidence map of exclusion and outcomes

BackgroundPatients with chronic kidney disease (CKD) are at high risk for cardiovascular disease, but their systematic underrepresentation in cardiovascular randomised controlled trials (RCTs) limits appropriate evidence to guide cardiovascular risk management (CVRM). This systematic review aims to evaluate trends in the underrepresentation of patients with CKD in cardiovascular RCTs in the past 20 years and highlight evidence gaps for CVRM medications in this population. MethodsA systematic search was conducted in ClinicalTrials.gov from its inception in 2000 until October 2021, targeting RCTs evaluating the efficacy of CVRM medications on mortality, cardiovascular disease, and kidney failure in adults with cardiovascular disease or one or more cardiovascular risk factors. Two reviewers independently screened references and extracted data. Outcomes were the exclusion rate of patients with CKD over time and an evidence map of studies reporting results for this population. ResultsIn total, 1194 RCTs involving 2,207,677 participants were included. Since 2000, the percentage of cardiovascular RCTs that exclude patients with CKD has increased from 66% to 79% (74% overall, 884 RCTs). In 73% of RCTs, more patients were excluded than anticipated on safety grounds (63% without dose adjustment necessary and 79% of RCTs with dose adjustment necessary). In total, 158 RCTs (13%) reported results patients with CKD separately (e.g. in subgroup analyses). Significant evidence gaps exist for most CVRM interventions for patients with CKD, particularly for those with CKD stage 4-5. For patients with an eGFR <30 ml/min/1.73m2, 23 RCTs reported results, for dialysis patients 15 RCTs, and for kidney transplant patients only 1 RCT. ConclusionThe underrepresentation of patients with CKD in cardiovascular RCTs has not improved in the past two decades and three-quarters of RCTs excluded more patients than expected on safety grounds. A lack of RCTs that report results for patients with CKD has resulted in significant evidence gaps for most CVRM medications in all subgroups of patients with CKD, in particular for those with CKD stage 4-5. Primary funding sourceDutch Heart Foundation, 2020B008 RECONNEXT RegistrationPROSPERO (CRD42022296746)