Representation of Patients With Chronic Kidney Disease in Clinical Trials of Cardiovascular Disease Medications: A Systematic Review

Abstract

Importance: Patients with chronic kidney disease (CKD) are at high risk for cardiovascular disease, but their systematic underrepresentation in cardiovascular randomized clinical trials (RCTs) limits the generation of appropriate evidence to guide cardiovascular risk management (CVRM).

Objective: To evaluate the underrepresentation of patients with CKD in cardiovascular RCTs, and to highlight evidence gaps in CVRM medications in this population.

Evidence review: A systematic search was conducted in ClinicalTrials.gov from February 2000 through October 2021 for RCTs with full-text publications. If no full-text publications were found in ClinicalTrials.gov, MEDLINE, Embase, and Google Scholar were also searched. Eligible RCTs were those evaluating the effectiveness of antiplatelets, anticoagulants, blood pressure-lowering drugs, glucose-lowering drugs, or cholesterol-lowering drugs in adults with cardiovascular disease or cardiovascular risk factors. Trials with a sample size of fewer than 100 patients were excluded.

Findings: In total, 1194 RCTs involving 2 207 677 participants (mean [SD] age, 63 [6] years; 1 343 970 males [64%]) were included. Since 2000, the percentage of cardiovascular RCTs excluding patients with CKD has increased from 66% to 79% (74% overall [884 RCTs]). In 864 RCTs (72%), more patients were excluded than anticipated on safety grounds (63% [306] of trials required no dose adjustment, and 79% [561] required dose adjustment). In total, 158 RCTs (13%) reported results for patients with CKD separately (eg, in subgroup analyses). Significant evidence gaps exist in most CVRM interventions for patients with CKD, particularly for those with CKD stages 4 to 5. Twenty-three RCTs (2%) reported results for patients with an estimated glomerular filtration rate less than 30 mL/min/1.73 m2, 15 RCTs (1%) reported for patients receiving dialysis, and 1 RCT (0.1%) reported for recipients of kidney transplant.

Conclusions and relevance: Results of this systematic review suggest that representation of patients with CKD in cardiovascular RCTs has not improved in the past 2 decades and that these RCTs excluded more patients with CKD than expected on safety grounds. Lack of reporting or underreporting of results for this patient population is associated with evidence gaps in the effectiveness of most CVRM medications in patients with all stages of CKD, particularly CKD stages 4 to 5.

Figure 1.. Overview of Exclusion of Patients With Chronic Kidney Disease (CKD) From Cardiovascular Randomized Clinical Trials (RCTs)

eGFR indicates estimated glomerular filtration rate; SCr, serum creatinine.

Figure 2.. Exclusion of Patients With Chronic Kidney Disease (CKD) Stratified by Prescription Recommendations

RCT indicates randomized clinical trial.

Figure 3.. Percentage of Randomized Clinical Trials (RCTs) With Analyses for Patients With Any or Stages 4 to 5 Chronic Kidney Disease (CKD)

Figure 4.. Heat Map of Analyses for Major Adverse Cardiovascular Events for Patients With Different Stages of Chronic Kidney Disease (CKD)

ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; CCB, calcium channel blocker; DAPT, double antiplatelet therapy; DOAC, direct oral anticoagulant; DPP-4 inhibitor, dipeptidyl peptidase 4; eGFR, estimated glomerular filtration rate; GLP-1 receptor agonist, glucagon-like peptide 1; MRA, mineralocorticoid receptor antagonist; PCSK9 inhibitor, proprotein convertase subtilisin/kexin type 9; RCT, randomized clinical trial; SAPT, single antiplatelet therapy; SGLT2 inhibitor, sodium-glucose cotransporter 2; TAPT, triple antiplatelet therapy.