CKD Increasingly Underrepresented in Trials of Cardiovascular Disease Medications – Renal and Urology News

Patients with chronic kidney disease (CKD) are increasingly excluded from randomized clinical trials (RCTs) of cardiovascular medications, a new study finds. Their “systematic exclusion” has led to substantial evidence gaps in using cardiovascular medications in this population.

According to Robin W. M. Vernooij, PhD, of University Medical Center Utrecht in the Netherlands, and colleagues, “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.” As CKD progresses to kidney failure, patients’ cardiovascular burden shifts from atherosclerotic cardiovascular disease to medial arterial calcification, cardiac arrhythmias, left-ventricular hypertrophy, and sudden cardiac death.

The investigators conducted a systematic review of 1194 cardiovascular RCTs conducted from 2000 to 2021 involving 2,207,677 patients. Over the period, the percentage of cardiovascular RCTs excluding patients with CKD increased from 66% to 79%, Dr Vernooij’s team reported in JAMA Network Open. Common exclusions involved patients with lower estimated glomerular filtration rate (eGFR), elevated serum creatinine, CKD, kidney failure, dialysis, and kidney transplant. Cardiovascular medication classes encompassed antithrombotics, antihypertensives, cholesterol-lowering drugs, as glucose lowering-drugs as well as combination pills.

In 864 RCTs (72%), more patients with CKD were excluded than anticipated on safety grounds, with 63% of trials requiring no dose adjustment for kidney function but nonetheless excluding patients with CKD; 79% required dose adjustment. Only 158 RCTs (13%) reported results for patients with CKD as a key subgroup.

Evidence is particularly lacking for the use of cardiovascular risk management interventions in patients with stage 4-5 CKD, Dr Vernooij’s team reported. Only 23 RCTs (2%) reported results for patients with an eGFR less than 30 mL/min/1.73 m², 15 RCTs (1%) reported on the dialysis population, and 1 RCT (0.1%) reported on kidney transplant recipients.

The small subset of cardiovascular medications that have been studied in CKD include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, β-blockers, calcium channel blockers, and thiazides, statins, ezetimibe, antiplatelets, anticoagulants, SGLT2 inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors.

Practical issues, such as the necessity for dose adjustments, unpredictability of treatment effects, or limited life expectancy, may have dissuaded researchers from including patients with CKD in their trials, according to Dr Vernooij’s team. Lower kidney function, vascular calcification, uremia, chronic inflammation, and immunosuppressive therapy to prevent graft rejection, and reduced life expectancy, can all influence the treatment effect, they noted. Statins’ benefits, for example, appear to diminish at kidney failure.

“Over 60% of patients with CKD have a history of cardiovascular disease, which is also the main cause of death in this population,” Dr Vernooij’s team added.