Patients with CKD Underrepresented in Cardiovascular Disease Medication Clinical Trials

Julia Colombijn

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Patients with chronic kidney disease (CKD) are at high risk for cardiovascular disease (CVD) and CVD-related mortality, yet findings from a recent systematic review suggest these patients are consistently underrepresented in cardiovascular clinical trials despite their need for effective cardiovascular risk management.¹

Results published in JAMA Network Open highlight the continued underrepresentation of patients with CKD in randomized clinical trials for cardiovascular disease medications throughout the past 2 decades, noting a subsequent negative impact on providers’ understanding of the effectiveness of these medications in this patient population.¹

Kidney dysfunction places more stress on the heart to circulate blood to the kidneys. This, paired with changes in blood pressure related to CKD, can potentially lead to heart disease. Most patients with CKD die from cardiovascular causes before they progress to kidney failure.²

“The high cardiovascular risk in patients with CKD underscores the importance of effective cardiovascular risk management for these patients,” wrote lead investigator Julia Colombijn, MD/PhD student at University Medical Center Utrecht in the Netherlands, and colleagues.¹ “Nevertheless, even though over 90% of patients with CKD are prescribed [cardiovascular risk management] medications, evidence is limited on the safety and effectiveness of these medications in this population.”

To assess the representation of patients with CKD in cardiovascular randomized clinical trials, investigators searched ClinicalTrials.gov through the Cochrane Central Register of Controlled Trials from inception (February 2000) through October 2021 using a combination of keywords for CVD, cardiovascular risk factors, and included interventions to identify planned, ongoing, terminated, and completed trials.¹

For inclusion, trials were required to evaluate 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 < 100 patients were excluded.¹

A total of 1194 trials involving 2,207,677 participants were included. Trial participants had a mean age of 63 (Standard deviation [SD], 6) years, were predominantly male (64%), and were followed up for a median of 24.0 (Interquartile range [IQR], 12.0-39.6) months. Glucose-lowering drugs were evaluated in 552 (46%) trials, antiplatelets and anticoagulants in 229 (19%), blood pressure–lowering drugs in 221 (19%), and a combination of these interventions in 30 (3%).¹

Outcomes of interest were the frequency of excluding patients with CKD, defined as the exclusion of patients meeting kidney-related eligibility criteria, and reporting results for patients with CKD through subgroup analyses or restriction of the study population. Investigators evaluated the frequency of excluding patients with CKD for different periods, medications, and dose recommendations.¹

Investigators noted since 2000, the percentage of cardiovascular clinical trials excluding patients with CKD has increased from 66% to 79%. Of the trials included in the study, 17 included patients receiving dialysis and a single trial included kidney transplant recipients.¹

Patients with an estimated glomerular filtration rate (eGFR) > 30 mL/min/ 1.73 m2, serum creatinine level < 2 mg/dL, or a history of CKD were excluded from 458 trials (38% of all included trials, and 52% of trials that excluded patients with CKD). Investigators pointed out the kidney exclusion criteria were mostly heterogeneous but were generally based on eGFR (50%) or serum creatinine level (37%).¹

In 864 (72%) clinical trials, more patients with CKD were excluded than expected on safety grounds. Patients with CKD were excluded in 306 of 488 trials (63%) in which no dose adjustment for the interventions on kidney function was required. The rate of exclusion of patients with CKD was > 80% in trials in which dose adjustments based on kidney function were necessary or interventions were contraindicated based on kidney function. However, 561 of 706 trials (79%) also excluded more patients with CKD than necessary on safety grounds.¹

Results for patients with CKD were reported separately in 158 (13%) trials, but investigators pointed out significant evidence gaps for most CRVM interventions for patients with CKD, especially those with stages 4 - 5.¹

“Lack of cardiovascular RCTs that reported results for patients with CKD has played a role in the significant evidence gaps in the effectiveness of most CVRM medications for patients with CKD, particularly CKD stages 4 to 5,” investigators concluded.¹

References:

1. ^{Colombijn JMT, Idema DL, van Beem S, et al. Representation of Patients With Chronic Kidney Disease in Clinical Trials of Cardiovascular Disease Medications: A Systematic Review. JAMA Netw Open. 2024;7(3):e240427. doi:10.1001/jamanetworkopen.2024.0427}
2. ^{Centers for Disease Control and Prevention. The Surprising Link Between Chronic Kidney Disease, Diabetes, and Heart Disease. Chronic Kidney Disease Initiative. July 12, 2022. Accessed March 7, 2024. https://www.cdc.gov/kidneydisease/publications-resources/link-between-ckd-diabetes-heart-disease.html}