Study Lays Groundwork for Pivotal Trial of Impella CP for LV Unloading Before PCI

CHICAGO, IL—In a pilot study, unloading the left ventricle with the Impella CP mechanical circulatory support device (Abiomed) and delaying PCI by 30 minutes appeared to be feasible and safe in patients with STEMI who did not have cardiogenic shock, setting the stage for a pivotal trial to determine whether the approach can limit ischemia-reperfusion injury and ultimately improve outcomes in this population.

All 50 patients in this preliminary study had the Impella CP implanted and were then randomized to PCI either immediately or after a 30-minute delay. Results presented by Navin Kapur, MD (Tufts Medical Center, Boston, MA), reported here at the American Heart Association (AHA) 2018 Scientific Sessions and published simultaneously online in Circulation, show that delaying reperfusion—which was associated with an increase in door-to-balloon time from 73 to 97 minutes—did not increase adverse events or infarct size at 30 days.

“For interventional operators and cardiologists, the disruptive concept of [this] trial is that we are testing whether it’s safe, whether it’s feasible, and whether there’s an early sign of efficacy with this idea of first unloading and then this second concept of delaying reperfusion for 30 minutes,” Kapur told TCTMD.

By successfully enrolling patients, completing the trial, and demonstrating no increase in adverse outcomes or infarct size by delaying PCI after unloading, investigators have established the feasibility and safety of the approach, Kapur said.

“There was no evidence that the delay was imposing any prohibitive risk that would preclude us from going to a pivotal trial,” he added. A multicenter pivotal trial that will randomize patients to immediate PCI without unloading or to unloading followed by PCI after a 30-minute delay is currently being planned and is expected to launch next year.

Commenting for TCTMD, Manesh Patel, MD (Duke University Medical Center, Durham, NC), said the investigators should be congratulated because organizing people and getting them on board to do a randomized study in an urgent situation like acute MI can be a challenge.

“The feasibility part, I think they’ve shown that they can organize and do that, and I think that’s important because we’ve got to get to a pivotal trial,” Patel said.

Safety, however, is more difficult to assess because, by chance, patients randomized to immediate PCI after unloading had a time from symptom onset to LV unloading that was 24 minutes longer than those randomized to delayed PCI, meaning that total ischemic time was similar in both groups, he said. That complicates interpretation of the results regarding infarct size. In addition, Patel said, the lack of a control arm including patients not treated with Impella CP—which will be included in the pivotal trial—does not allow for a full assessment of safety.

As for the potential of this strategy, Patel said, “I’m hopeful, but I’m also cautious.” In his accompanying editorial, he includes a table of 13 randomized trials that tested percutaneous support devices in various settings. And he told TCTMD that more than 30 pharmacologic agents have been studied for limiting ischemia-reperfusion injury, with little success.

That highlights the challenge in this field, Patel said. “One thing we’ve shown that works is opening the artery fast, and we’re doing that well. . . . To demonstrate benefit on top of that is complicated and hard.”

That said, this unloading plus delayed PCI strategy should be studied further in adequately powered trials, Patel indicated.

“The good news is that we’re randomizing and testing the device in a new indication, and I would suggest that we carry that out to its full potential against a standard control arm before it’s widely used in this indication,” he said. “I think we should be saying that there’s now demonstrated ability to do the study, we need to go carry it out, and as an interventional community, we need to embrace it and figure out ways to do the randomized trial for this and other indications.”

Heading Off Heart Failure

Though remarkable progress has been made in the treatment of MI over the past four or five decades, subsequent heart failure remains a problem, Kapur said, noting that 1-year heart failure hospitalization after MI correlates with infarct size.

There has been a lot of preclinical work done on mechanically unloading the left ventricle to reduce infarct size and reduce the development of heart failure after MI, with evidence suggesting that unloading alone is not sufficient, Kapur said. Unloading plus a delay of 30 minutes before PCI “actually conditions the myocardium so that when you do open the artery there’s less reperfusion injury, and as a result the infarct size is even smaller,” Kapur said.

The STEMI Door to Unloading (DTU) pilot study, conducted at 14 US centers, is the first test of that concept in patients with STEMI who do not have cardiogenic shock. The mean age of the patients was 60, and 24% were women.

Impella CP was successfully implanted and removed after a minimum of 3 hours of support in all patients in the study. In the delayed group, operators were allowed to shorten the time between unloading and PCI if clinically necessary, but no bailout was needed.

The primary safety outcome was MACCE (CV death, reinfarction, stroke, or major vascular events), with two events (CV death and stroke) in the immediate PCI arm and three (CV death and two events related to flow-limiting dissections of the femoral artery when removing the device) in the delayed arm.

There were no significant differences between groups in terms of bleeding, LV thrombus, or ventricular tachycardia/fibrillation.

The measure of efficacy was infarct size as a percentage of LV mass assessed using cardiac magnetic resonance imaging at 30 days. This was 15% in the immediate arm and 13% in the delayed arm (P = 0.53). Infarct size did not correlate with door-to-balloon times, which were longer in the delayed arm.

“What that suggests is that maybe once you’re on the platform of unloading, you should be less concerned about the door-to-balloon time potentially and more targeting this concept of door-to-unload,” Kapur said. “Because the unloading itself—we’re arguing—is a therapy. It’s not simply an adjunct to support a high-risk PCI, but it actually is doing something that’s therapeutically beneficial to the heart.”

Although it remains to be proven in the pivotal trial, Kapur said this may represent another example of a device that can change the course of patients with heart failure, like the MitraClip (Abbott) did in COAPT. “Heart attacks lead to heart failure, and so now with another interventional approach we think we can change the trajectory of heart failure by again focusing on the ventricle, just like we do with COAPT, and as a result reducing the burden of heart failure for society in general.”

Patel looks forward to the pivotal trial of the unloading strategy with Impella. “I hope that something will be shown,” he said. “We recognize that there’s still an unmet need and that those patients, even after we open their artery quickly, a significant number of them do go on to get heart failure and go on to have cardiovascular events.”