Underrepresentation of Individuals with CKD in CV Medication Trials Found Persistent Over 2 Decades

Individuals with chronic kidney disease continue to be underrepresented in cardiovascular randomized clinical trials (RCT), according to a new systematic literature review that found no improvement in CV study enrollment of this high-risk population over the past 2 decades. Further, review authors suggest that more potential study participants with CKD have been excluded from CV trials than would be expected based on safety grounds alone.

Writing in JAMA Network Open, lead investigator Julia Colombijn, MD/PhD student at University Medical Center Utrecht in the Netherlands, and colleagues found that the majority of CV RCTs that did report results for participants with CKD included those with milder disease, ie, CKD stage 3. There is very little data published on the 10% of individuals with stages 4 or 5 CKD. In clinical practice, Colombijn et al wrote, that means clinicians “must resort to extrapolating results from RCTs conducted in other populations, assuming that the treatment effects are comparable.” This is rarely optimal and undermines effective cardiovascular risk management (CVRM) for millions of people. 

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“The high cardiovascular risk in patients with CKD underscores the importance of effective cardiovascular risk management for these patients,” investigators wrote. “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.”

The research team cited previous data on poor representation of persons with CKD in CV RCTs that ends in 2014. The investigators were interested to see if inclusion had improved since then, particularly in light of the many recent trials evaluating new treatments, including SGLT-2 inhibitors and direct oral anticoagulants, and to probe gaps in evidence for CVRM therapy in this population. .

METHODS

Colombijn and colleagues searched databases including ClinicalTrials.gov MEDLINE, and Embase, from 2000 to 2021 for clinical trials that evaluated the effectiveness of antiplatelet agents, anticoagulants, antihypertensives, and antihyperglycemic and antihyperlipidemia agents in adults with CVD or CV risk factors. All trials included cohorts of more than 100 participants.

The final group of trials numbered 1194 and comprised 2 207 677 participants (mean age, 63 years, 64% men). The median follow-up time across trials was 24.0 months. Proportions of the trials investigating the treatment classes of interest were:

• Antihyperglycemics 46% (552)
• Antiplatelets and anticoagulants 19% (229)
• Antihypertensive agents 19% (221)
• Combination of these interventions 3% (30)

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.

FINDINGS

The researchers found that since 2000, the percentage of CV RCTs 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.

Colombijn and colleagues reported that 38% of all trials included in the study and 52% that excluded participants with CKD excluded those with CKD stages 1-3. Of significant note, during the 20-year period examined the exclusion of those with CKD 1-3 has remained stable while exclusion of participants with CKD stages 4-5 has increased.

They found that kidney function criteria used for exclusion were mostly heterogeneous but were generally based on eGFR (50%) or serum creatinine level (37%).

In nearly three-quarters (72%) of CV RCTs, more participants with CKD were excluded than expected on “safety grounds,” according to the findings. Those with CKD also were excluded from close to two-thirds (63%) of the 488 trials that required no dose adjustments based on renal function. Moreover, the investigators found exclusion of CKD-affected participants of more than 80% from trials that did require dose adjustments for kidney function or in which the study drug was contraindicated based on kidney function.

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.

“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 wrote.

"While excluding patients with CKD from RCTs due to safety concerns can be justifiable, the substantially more stringent kidney exclusion criteria compared with prescription thresholds in clinical practice suggest there were additional reasons for excluding patients with CKD," they concluded.

Source: 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. l JAMA Netw Open. 2024;7(3):e240427. doi:10.1001/jamanetworkopen.2024.0427