PROTECTION-AMI: Experimental Agent Does Not Prevent Reperfusion Injury

NEW ORLEANS, LA—A novel drug that inhibits delta-protein kinase C, an enzyme that has been tied to reperfusion injury, failed to reduce infarct size in patients undergoing percutaneous coronary intervention (PCI) in a phase IIb study. Results were presented April 5, 2011, at the American College of Cardiology Scientific Session/i2 Summit.

The drug, known as delcasertib, has been shown in animal models to reduce infarct size. And in human subjects undergoing primary PCI for anterior STEMI, the phase I/II DELTA MI trial found that intracoronary administration of delcasertib had positive effects on CK-MB measurements and ST recovery, according to principal investigator A. Michael Lincoff, MD, of the Cleveland Clinic Coordinating Center for Clinical Research (Cleveland, OH).

No Difference Across Range of Doses

Based on these precedents, Dr. Lincoff and colleagues conducted the PROTECTION-AMI trial, which enrolled 1,176 acute STEMI patients with planned primary PCI at 114 sites in 18 countries. Patients in the main cohort who had anterior STEMI (n = 908) were assigned to receive placebo or 1 of 3 delcasertib doses (50 mg/hr, 150 mg/hr, or 450 mg/hr) given intravenously for approximately 2.5 hours immediately after randomization.

In patients who went on to receive PCI, measurements of CK-MB area under the curve (AUC; primary endpoint) were similar regardless of treatment group, as was ST-segment recovery AUC on continuous 24-hour ECG (table 1).

Table 1. Periprocedural Outcomes

At 3 months, clinical event rates, the prevalence of LVEF 30% or lower, and NT-proBNP levels also were equivalent irrespective of treatment arm (table 2).

Table 2. Outcomes at 3 Months

The researchers also conducted a prospective analysis of results stratified according to pre-PCI TIMI flow, “on the hypothesis that with an open artery, reperfusion may already have occurred prior to administration of the drug and thus the opportunity to reduce reperfusion injury may have been diminished,” Dr. Lincoff said.

“When the primary endpoint was analyzed according to entry TIMI flow, it is clear that patients who entered with an occluded artery [TIMI 0/1] had a much higher myocardial enzyme release, nearly twice that of those who entered with an open artery [TIMI 2/3],” he explained, adding that the difference amounted to nonsignificant reduction of 15 to 18% in CK-MB AUC.

Delcasertib was associated with no reductions in myocardial infarct size or improvements in clinical outcome in this study, Dr. Lincoff said. Still, “[o]ther potential applications to ischemia reperfusion injury with this agent may be investigated.”

No Clear Target for Preventing Myocardial Damage

Panelist Sanjay Kaul, MD, of Cedars-Sinai Medical Center (Los Angeles, CA), congratulated Dr. Lincoff on a well-performed study but commented, “unfortunately another one bites the dust.”

“This compound joins a long list of treatment interventions targeting reperfusion injury where the promise of cardioprotection seen in experimental models has not been translated to clinical trial evidence,” he said, outlining possible reasons why the trial did not meet its primary endpoint despite earlier signs of delcasertib's benefit.

For one, animal and human studies have critical differences, because in animal models researchers can know the exact duration of ischemia and timing of treatment. Also, PROTECTION-AMI focused on “the correct population, anterior MI, but perhaps the extent of MI was not large enough for the treatment effects to be discernible,” Dr. Kaul noted, suggesting that the route of administration and dosing may be other issues.

Because the drug is so nontoxic and appears to have no adverse effects, Dr. Lincoff said, “these doses were very high and also shown to provide blood levels, and what appear to be tissue levels, similar to what you get with intracoronary [administration], with the advantage that [the drug] was on board in 17 minutes, before you actually intervened in the artery.”

Dr. Kaul concluded by questioning whether reperfusion injury was even an appropriate therapeutic target for myocardial salvage in humans. “Why have clinical studies failed to confirm beneficial effects? I'm not aware of any treatment intervention that has yielded a positive [trial], which leads me to conclude that either reperfusion injury does not occur in humans or, if it occurs, it's not preventable,” he quipped. “And if it is preventable, trials are not designed optimally to be able to answer this question.”

Dr. Lincoff agreed, noting, “That of course is the big rub with reperfusion injury. Until you develop a therapy that actually prevents it, you can't show it exists.

“We're doing so well over the years with the reperfusion part of our treatment,” he continued. “We bring patients with door-to-balloon times now of less than 1 hour, we get high rates of TIMI flow in virtually all patients, reocclusion is almost unheard of. If we're going to make progress in reducing late left ventricular dysfunction . . . , we will need to be intervening in some way to protect myocardium. So these approaches are valuable as the next frontier, but it's very frustrating because we don't really know what we're aiming at.”

 

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Source:
Lincoff AM. Selective inhibition of delta protein kinase C to reduce infarct size after primary percutaneous intervention for acute myocardial infarction: The PROTECTION-AMI phase IIb clinical trial. Presented at: American College of Cardiology Annual Scientific Session/i2 Summit; April 5, 2011; New Orleans, LA.

 

 

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