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CARIN: Novel drug does not prevent kidney injury from contrast during PCI
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CHICAGO — A novel modified alpha lipoic acid was not effective at preventing kidney injury from contrast dyes administered during PCI.
Deepak L. Bhatt, MD, MPH, FACC, explained during a press conference at the American College of Cardiology Scientific Session that contrast-induced kidney injury is a common problem in patients with diabetes or kidney disease undergoing PCI, but, aside from trying to limit the amount of contrast, the only available therapy is prehydration.
Deepak L. Bhatt
“There are a number of different things that have been attempted to reduce contrast nephropathy,” said Bhatt, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital, professor of medicine at Harvard Medical School and Chief Medical Editor of Cardiology Today’s Intervention. “But from a bottom-line perspective, other than giving patients [IV] saline before the procedure, nothing else has clearly been demonstrated to reduce that risk. Therefore, we need new therapies.”
In the CARIN trial, Bhatt and colleagues assessed the safety and efficacy of CMX-2043 (Ischemix LLC), a novel derivative of alpha lipoic acid, which had been shown to be cardioprotective during stenting in a small prior study.
“The thought was that this would be something that would be safe and potent,” Bhatt said. “The compound has multiple mechanisms of action that are active in several tissues, including in the kidneys and heart. The compound is an antioxidant stabilizing cell membranes and hopefully allowing cells to survive when they’re under stress.”
Bhatt and colleagues randomly assigned 361 patients who were scheduled for an angiogram and who had impaired kidney function and at least one other risk factor to receive one of three dosing regimens of CMX-2043 or placebo: 2.4 mg/kg, 3.6 mg/kg or 2.4 mg/kg given twice with 24 hours in between doses.
The primary endpoint was reduction in acute kidney injury. Secondary endpoints included MACE, major adverse kidney events, reduction in cardiac injury and reduction in incidence of Type 4A MI. The researchers also documented treatment-emergent adverse events.
Compared with the placebo group, the groups assigned to all three doses of CMX-2043 showed no significant differences in the incidence of acute kidney injury, which ranged from approximately 20% to 25%, Bhatt said.
“What’s interesting is that the rate of kidney events in all the arms are quite high,” he said. “The drug didn’t reduce these very high rates.”
There were no significant differences between the groups in any other endpoints, Bhatt said.
“Acute kidney injury is a major problem in contemporary PCI, with an incidence of about 20% to 25% in high-risk patients,” Bhatt concluded. “Unfortunately, this particular approach with this drug did not reduce acute kidney injury. We were unable to replicate or confirm previous findings that this compound is cardioprotective.
“There still remains an unmet clinical need to find agents that reduce contrast nephropathy and protect kidneys during angiographic procedures. The design of this trial might serve as a template for future trials to efficiently determine whether novel agents that appear promising in animal studies are worth taking into larger, more expensive phase 3 evaluations. In this case, we prevented a large phase 3 study that likely would have been negative.” – by Erik Swain
Reference:
Bhatt DL, et al. Joint ACC/New England Journal of Medicine Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; April 2-4, 2016; Chicago.
Disclosure: The study was funded by Ischemix LLC. Bhatt reports financial ties with numerous pharmaceutical and medical device companies.
Perspective
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Athena Poppas, MD, FACC
This is a challenge that we have looked at in a number of different ways. Kidney disease has some interaction with MI and morbidity and length stay. We have hydration as a therapy, and we know prehydration is effective, but in this cohort only half the patients received adequate prehydration because of some of the constraints of moving patients through the system faster. To see the failure of an alternative therapy is frustrating. Inflammation in kidney injury is complex, and we keep trying to address it in different ways.
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