May 25, 2018
By Marilynn Larkin
NEW YORK (Reuters Health) - Canakinumab seems to reduce the risk of future cardiovascular events in high-risk patients with moderate-to-severe chronic kidney disease (CKD), researchers say.
"Patients with moderate-to-severe CKD are at very high risk for cardiovascular events and few therapies reduce that risk," Dr. Paul Ridker of Brigham and Women's Hospital in Boston told Reuters Health by email.
To assess whether canakinumab, a human monoclonal antibody targeting IL-1-beta, might lower the rates of cardiovascular events in these patients, Dr. Ridker and colleagues conducted a post-hoc analysis of the CANTOS study. CANTOS had shown that canakinumab (50 mg, 150 mg or 300 mg subcutaneously every three months) significantly reduced cardiovascular events in patients at high risk of such events compared to placebo, regardless of lipid therapy.
As reported online May 21 in the Journal of the American College of Cardiology, of 10,061 participants, 18.6% had a baseline estimated glomular filtration rate (eGFR) <60 ml/min/1.73 m2 but >30 ml/min/1.73 m2. These moderate CKD patients had higher incidence rates for major adverse vascular events compared with those with eGFR at or above 60 ml/min/1.73 m2 (6.92 vs. 4.13 per 100 person-years).
Random allocation of the CKD patients to all doses of canakinumab combined was associated with an 18% reduction in the risk of major adverse cardiovascular events (hazard ratio, 0.82), with a significant trend of fewer events observed across increasing doses (ptrend = 0.045).
This relative risk reduction was similar to that among those without CKD (HR, 0.86). However, due to higher absolute baseline risk, the absolute risk reduction attributable to canakinumab was much higher among those with CKD.
The largest cardiovascular benefits were seen among patients who achieved on-treatment hsCRP levels below 2 mg/l, measured after taking the first dose (HR, 0.68). Comparable effects were observed among patients with baseline albuminuria or diabetes.
Canakinumab had neither clinically meaningful benefits nor substantive harms with respect to serial measures of eGFR or creatinine over time in the trial overall or in the subgroup with CKD at baseline. No adverse renal events were reported during follow-up.
"Now we want to pursue a parallel trial in patients with severe kidney disease who are close to needing dialysis," Dr. Ridker said.
With respect to costs, Dr. Ridker noted that these can't be estimated based on current prices because canakinumab currently is an orphan drug with orphan indications only. Costs may be more accurately estimated, he said, if the U.S. Food and Drug Administration approves the drug for atherosclerosis based on the CANTOS study results.
Dr. David Cherney, a clinician scientist, Division of Nephrology at University Health Network in Toronto and coauthor of a related editorial, told Reuters Health, "Canakinumab reduces levels of harmful inflammation by blocking interleukin 1-beta, without affecting other parameters such as lipids. In the primary trial, canakinumab reduced cardiovascular risk, probably by reducing atherosclerosis risk."
"In the current analysis, these cardiovascular risks were observed in patients with kidney disease - a group of patients that frequently does not respond to cardioprotective therapies in expected ways," he said. "This beneficial effect appeared to be linked with suppressing inflammation."
However, he noted, "despite the cardiovascular benefits, there was no significant benefit on kidney protection."
"The caveat from a renal perspective is that the patients recruited into the trial did not necessarily have significant kidney disease, nor were they at especially high risk (presence of hypertension, albuminuria, kidney function decline etc.)," Dr. Cherney said. "Accordingly, the study results cannot necessarily be generalized or applied to patients at high kidney risk."
The CANTOS study was funded by Novartis. Dr. Ridker and seven coauthors have received funds from the company and two coauthors are employees and stockholders.
J Am Coll Cardiol 2018.
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