Recombinant C1 esterase inhibitor before coronary angiography may reduce renal injury
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Patients with chronic kidney disease who were assigned recombinant human C1 esterase inhibitor, or rhC1INH, before coronary angiography had a lower risk for renal injury compared with those assigned placebo, with a favorable safety profile, especially in those with multiple comorbidities, according to findings from the PROTECT study published in JACC: Cardiovascular Interventions.
“Our results confirm for the first time that complement inhibition by recombinant human C1 esterase inhibitor may be effective in the setting of renal ischemia and reperfusion injury, in particular in patients undergoing more invasive procedures,” Michael Osthoff, MD, senior consultant and head of clinical research in the division of internal medicine at University Hospital Basel in Switzerland, told Healio. “Moreover, the safety profile of this compound was favorable in an elderly patient population suffering from multiple comorbidities and polypharmacy, which is essential for the design of future trials in a similar patient population.”
Patients with chronic kidney disease
Anneza Panagiotou, MD, of the division of internal medicine at University Hospital Basel and of the department of clinical research and of biomedicine at University of Basel, and colleagues analyzed data from 77 patients (mean age, 77 years; 70% men) with chronic kidney disease who were scheduled to undergo elective coronary angiography between 2017 and May 2018. Patients were assigned 50 IU/kg rhC1INH (Ruconest, Pharming Technologies; n = 38) or placebo (n = 39), both of which were administered immediately before coronary angiography and 4 hours after the procedure.
“C1 esterase inhibitor is a human plasma protein with manifold targets and biological functions including a strong inhibition of the complement and kinin system and interactions with endothelial cells,” Panagiotou and colleagues wrote. “Conestat alfa (rhC1INH) is a recombinant human version derived from the breast milk of transgenic rabbits that shares an identical protein structure with plasma-derived C1 esterase inhibitor and is approved for the substitution treatment of hereditary angioedema.”
The primary efficacy outcome for this study was peak change of neutrophil gelatinase-associated lipocalin in urine from baseline to within 48 hours after coronary angiography. Secondary efficacy outcomes included contrast-induced acute kidney injury and contrast-induced nephropathy within 48 hours and an increase of serum cystatin C greater than 10% within 24 hours.
Within 48 hours, median peak change of urinary neutrophil gelatinase-associated lipocalin was lower in patients assigned rhC1INH compared with those assigned placebo in the per-protocol population (4.7 ng/mL vs. 22.5 ng/mL; P = .038). This was not observed in the modified intention-to-treat analysis (7.2 ng/mL vs. 22.5 ng/mL; P = .119).
In the subgroup of patients who underwent PCI, those assigned rhC1INH had a smaller median absolute and relative peak change in urinary neutrophil gelatinase-associated lipocalin compared with those assigned placebo (1.8 ng/mL vs. 26.2 ng/mL; P = .039). This corresponds to a mean percentage peak change of 11% in the rhC1INH group vs. 205% in the placebo group (P = .002).
Patients assigned rhC1INH had a lower incidence of a relevant cystatin C increase of at least 10% within 24 hours compared with those assigned placebo (16% vs. 33%; P = .045). The rates of contrast-induced nephropathy and contrast-associated acute kidney injury were similar in both groups. The rhC1INH and placebo groups also had similar rates of adverse events during 3 months of follow-up.
“Our trial is hopefully the start of a number of future trials looking at the inhibition of inflammatory cascades in patients at high risk of suffering a renal injury in the setting of coronary angiographies or other risk procedures (eg, coronary artery bypass grafting),” Osthoff said in an interview. “This will also include studies looking at different dosing regimens. Additionally, as recombinant human C1 esterase inhibitor is really a multiple-target multiple-action inhibitor, it is crucial to understand the exact mechanism how it exerts its beneficial actions in humans.”
‘Cautiously optimistic’
In a related editorial, Hitinder S. Gurm, MD, professor in the division of cardiovascular medicine at University of Michigan in Ann Arbor, wrote: “The field of contrast-associated acute kidney injury is filled with early studies of promising agents that failed to live up to their great expectations in subsequent confirmatory studies, and practice change should await confirmatory data. However, I remain cautiously optimistic and agree with the authors that the safety and efficacy signals in this study are promising, and combined with the preclinical data, invoke the need for an adequately powered randomized clinical trial evaluating appropriate clinical endpoints.” – by Darlene Dobkowski
For more information:
Michael Osthoff, MD, can be reached at michael.osthoff@usb.ch.
Disclosures: The study was supported by Pharming Technologies, the department of research of the University Basel and Fondation Machaon. Osthoff reports he received consulting fees from Pharming Biotechnologies B.V. Panagiotou reports no relevant financial disclosures. Gurm reports he is a consultant for Osprey Medical. Please see the study for all other authors’ relevant financial disclosures.
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