Search for Agents to Prevent Contrast Nephropathy Continues

The recent finding that the experimental drug CMX-2043—developed to prevent ischemic-reperfusion injury (IRI)—does not reduce the risk of contrast-induced kidney injury compared to placebo dealt a setback to the search for agents to prevent the condition. The negative clinical trial results were presented at the American College of Cardiology (ACC) meeting, held this spring in Chicago.

Other products have been or are being tested for acute kidney injury (AKI)—including recombinant alkaline phosphatase, THR-184, and Bendavia—all targeting different pathways. Most recently, a trial in The New England Journal of Medicine found an increased risk of AKI, as a secondary outcome, in patients receiving rosuvastatin before cardiac surgery.

“There is a huge unmet need, but therefore a great opportunity for novel therapies to be evaluated, and hopefully, validated,” said lead investigator Deepak L. Bhatt, MD, MPH, Professor of Medicine, Harvard Medical School and Executive Director of Interventional Cardiovascular Programs, Brigham and Women’s Hospital Heart and Vascular Center. “In patients undergoing cardiac catheterization and especially percutaneous coronary intervention, there is a high rate of renal complications in those patients at elevated baseline risk for contrast-induced kidney injury.”

The CARIN trial (NCT02103959) included 361 patients undergoing angiography at 31 North American medical centers. All enrollees were considered at high risk of angioplasty due to acute coronary syndrome or poor stress test results. They also had mild-to-moderate or severe loss of kidney function, together with at least one additional risk factor such as diabetes, hypotension, or age over 75. Patients with heart attack, life-threatening arrhythmias, or total kidney failure were excluded.

Before angiography, patients were randomly assigned to receive placebo or CMX-2043—a derivative of α-lipoic acid analog developed to reduce cellular injury and organ damage due to IRI. “The thought was [CMX-2043] would be safe and potent, that it has multiple mechanisms of action, and that it’s active in multiple tissues, including the kidneys and the heart,” Bhatt said.

CMX-2043 was given at one of three fixed doses: a single dose of 2.4 or 3.6 mg/kg or two doses of 2.4 mg/kg. The primary outcome was reduction in the incidence of AKI, based on KDIGO criteria. Biomarkers of renal and cardiac injury and 90-day clinical outcomes and adverse events were evaluated as well.

At four days, the incidence of AKI was not significantly different across the four study groups: 25.6 percent for the single low dose of CMX-2043, 25.3 percent for the single low dose, 18.9 percent for two low doses, and 18.6 percent for placebo.

There were also no differences in adverse cardiac and kidney events, and no evidence of major side effects related to the CMX-2043 doses used. The study did not confirm the previously reported reduction in myocardial damage during stent placement.

The final results of the phase 2 CARIN trial showed no reduction in the primary outcome of contrast-induced acute kidney injury, as it had done in pre-clinical models. “Contrast-induced acute kidney injury remains a really significant problem in the population,” Bhatt said. “It remains an unmet clinical need to find drugs or devices or strategies to help reduce the risk.”

“The thought was that this drug had antioxidant and cell membrane stabilizing effects and that these benefits would translate into less kidney cell damage and heart muscle damage,” Bhatt commented. “But as is often the case in this field, drugs that seem to be good based on preclinical work, when used in humans don’t always have an effect.”

A previous randomized trial (SUPPORT-1) found that patients receiving the 2.4 mg/kg dose of CMX-2043 had a significant reduction in cardiac injury after percutaneous coronary intervention, based on standard cardiac biomarkers.

The negative clinical results with CMX-2043 don’t necessarily close off the possibility of some effective intervention targeting the α-lipoic acid pathway, according to Bhatt. “But the specific drug we tested, at least at the doses we tested, does not work.”

The study was funded by Ischemix LLC, the manufacturer of CMX-2043. In a statement, the company said it was performing further preclinical studies to understand the results observed in the CARIN trial.

One bright spot was that the study showed it is possible to recruit a sufficiently large group of patients at risk of renal and cardiac injury during percutaneous coronary intervention. “The design of this trial might serve as a useful template for future trials to efficiently determine whether novel agents that appear promising in animal studies are worth actually taking into larger, more expensive phase 3 evaluations,” Bhatt said. “Because in this case, we did actually prevent a large, 10,000-patient study that would have likely been negative from happening by efficiently studying this in about 300 patients.”

The CARIN results are a setback in the search to develop some effective means of preventing contrast-induced nephropathy in the large group of patients at high risk for this complication. Currently, the most effective approach to prevention is intravenous hydration—and even this isn’t always possible, especially in emergencies.

“There have been so many trials over the last 15 years, trying to find an agent that helps us in the cath lab to prevent kidney damage,” commented ACC Vice President C. Michael Valentine, MD. “It’s a huge problem, because there are so many patients who have concomitant kidney and heart disease. When patients come in with heart attacks or acute coronary syndromes and need catheterization, we’re in a double bind trying to protect their kidneys while saving their hearts.”