Patients With CKD Remain Underrepresented in Trials of CV Meds

Patients with chronic kidney disease (CKD) are no more likely to be included in trials of medications aimed at reducing cardiovascular risks now than they were about two decades ago, resulting in lingering gaps in knowledge about the various drugs’ effects in this population, according to a systematic review.

In fact, the proportion of trials evaluating CV therapies that excluded at least some subgroups of patients with CKD has risen over the years, increasing from 66% in studies published from 2000 to 2005 to 79% in those published from 2021 to 2023.

“I think it’s important to raise awareness about the lack of data because that’s the first step towards addressing it,” said Julia Colombijn, MSc (University Medical Center Utrecht, the Netherlands), lead author of the paper, which was published online Thursday in JAMA Network Open.

In fully 72% of the trials considered by Colombijn et al, more patients with CKD were excluded than would be expected based on safety concerns. Overall, just 13% of RCTs reported separate results for patients with CKD, and only 3% exclusively enrolled patients from this population.

The general lack of evidence of the effects of antiplatelets, anticoagulants, and medications for lowering blood pressure, cholesterol, and glucose was particularly pronounced for patients with more severe CKD (ie, stages 4 and 5).

Speaking with TCTMD, Colombijn stressed that given how commonly kidney disease is present in patients who are being treated to lower their cardiovascular risk, these findings raise questions about how the medical community is going to clarify these therapies’ impact in the CKD population. Medications typically are used in sicker patients in everyday practice as compared with those in a clinical trial setting, she noted.

Additional data on CV drug effects in the setting of CKD could come by making a more concerted effort to actively recruit patients with kidney disease into future trials, which would allow for stratified analyses, or by conducting separate trials exclusively focused on this population, she suggested.

How CKD May Interact With CV Drugs

Patients with CKD have a high risk for cardiovascular disease and are more likely to die from it than from kidney-related causes. Nonetheless, as observed in prior studies and reviews, they often have been excluded from trials of CV risk-reducing therapies due to concerns about both safety and effectiveness.

But it’s important to know how these medications will behave in the CKD setting because the interplay evolves as kidney disease worsens. “As CKD progresses to kidney failure, patients’ CVD burden shifts from atherosclerotic CVD to medial arterial calcification, cardiac arrhythmias, left ventricular hypertrophy, and sudden cardiac death,” Colombijn et al explain.

The increased CV risk observed in patients with CKD might be expected to strengthen the absolute beneficial effect of drugs designed to lower CV risk when used in this population, they say. But, on the other hand, “lower life expectancy and the induction of additional pathways in CVD pathophysiological processes, which are not inhibited by traditional cardiovascular risk management medications, could offset these benefits and render treatment futile.”

I think it’s important to raise awareness about the lack of data because that’s the first step towards addressing it. Julia Colombijn

To see whether the representation of patients with CKD in trials of CV medications has improved over time, and to get a better idea of where the biggest gaps in evidence exist, Colombijn and her colleagues searched the literature for RCTs with publications between February 2000 and May 2023. Trials were eligible if they included at least 100 adult patients with CVD or CV risk factors and evaluated one or more of the following drug types: antiplatelets, anticoagulants, antihypertensives, glucose-lowering drugs, and cholesterol-lowering drugs.

The researchers identified 1,194 trials that included more than 2.2 million participants (mean age 63 years; 64% men). The trials most frequently studied glucose-lowering drugs (46%), followed by antiplatelets and anticoagulants (19%), antihypertensives (19%), cholesterol-lowering drugs (14%), or a combination (3%).

Overall, roughly three-quarters of trials excluded at least a subgroup of patients with CKD. Patients with CKD stages 4 and 5 were increasingly likely to be excluded over time, whereas the proportion of patients with milder forms of CKD who were excluded remained stable.

The researchers highlighted key areas in which there were gaps in the evidence: only 2% of RCTs presented results for patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m², 1% had results for patients receiving dialysis, and just one trial presented data for kidney transplant recipients.

Looking at the specific medications, trials of antiplatelets and anticoagulants were most likely to report results in patients with CKD, although few of the studies presented data for those with an eGFR below 45 mL/min/1.73 m².

Newer glucose-lowering medications like the sodium-glucose cotransporter 2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists have been evaluated in patients with CKD in multiple RCTs, but there remains little evidence in this population for older drugs in this class, including metformin, insulin, and the sulphonylureas.

Overall, Colombijn said, there is some evidence from trials to guide use of CV medications in patients with milder forms of CKD but little regarding the treatment of patients with more advanced disease, including those who require dialysis or a transplant. “In practice, this means that you have to treat these patients based on studies or data from studies in which they have not participated,” with uncertain impact, she said.

Looking for Other Sources of Data

Senior author Robin Vernooij, PhD (University Medical Center Utrecht), noted that some of these cardiovascular medications have been given to patients with CKD for many years. Thus, it would be a surprise to see new trials designed to assess their impacts in this particular population, especially since many of the drugs are generic and inexpensive.

It might, then, be necessary to look to other sources of data—observational studies, for instance—to explore the effects of various CV medications in patients with CKD, Vernooij told TCTMD.

Indeed, Colombijn said, it might not be feasible to get additional trials to answer these questions, “so in that sense, I think the real-world data are pivotal in obtaining at least estimates about effects of medications for these patients.”

She pointed out that many of the trials of CV medications are driven by cardiologists and vascular medicine specialists and said CKD may sometimes be underrecognized by these clinicians, who are more focused on risk factors like diabetes, hypertension, and smoking. For future trials, a key factor in improving representation of patients with CKD “is also raising awareness among healthcare professionals in the field of cardiology and not only within nephrology,” Colombijn said.

The American Heart Association has an eye on this issue as well. It released a presidential advisory in October 2023 noting that “there is a high burden of poor cardiovascular-kidney-metabolic health in the population, which affects nearly all organ systems and has a particularly powerful impact on the incidence of cardiovascular disease.”