NEW ORLEANS – Introduced to the U.S. market in 2008 as an upgraded alternative to the intra-arterial balloon pump, the Impella 2.5 showed clear signs of better performance in high-risk patients undergoing percutaneous coronary intervention in a multicenter, randomized trial with 447 patients.
But once Impella 2.5 entered the U.S. market, enrollment into the study slowed dramatically. Eventually, researchers stopped the trial substantially short of its enrollment target, and the pivotal study’s primary end point did not show a statistically significant benefit for Impella 2.5.
Dr. William O'Neill
The trial also ran into a second problem with a major confounding issue: Interventional cardiologists used rotational atherectomy more aggressively in Impella-treated patients. They seemingly were emboldened by the added cardiac support, and Impella-treated patients had an unbalanced rate of adverse effects.
Despite these problems, the trial results showed a role for the Impella device in high-risk, low-cardiac-output patients undergoing PCI (percutaneous coronary intervention), Dr. William O’Neill said at the annual meeting of the American College of Cardiology.
"This device produces superb hemodynamic support during high-risk interventions. It really allows a more complete procedure that leads to fewer late events," said Dr. O’Neill, an interventional cardiologist and executive dean for clinical affairs at the University of Miami. "With these [high-risk] patients, we skate rapidly over thin ice. This device allows us the luxury of taking more time and doing a more complete and safer procedure. I think [that capability] will translate into increased use [of the device] in these high-risk patients."
Experts who heard the trial results were split on their interpretation of the findings.
"This was a negative study. What is driving the differences you see? I don’t understand how to reconcile the results with your conclusion to go ahead [with using] this device," commented Dr. Ron Waksman, director of experimental angioplasty at Washington (D.C.) Hospital Center.
PROTECT II was a prospective, multicenter, randomized, controlled trial of the Impella Recover LP 2.5 system vs. IABP (intra-aortic balloon pump) in patients undergoing nonemergent, high-risk PCI. The trial began in November 2007 at 67 U.S. sites, 4 sites in Canada, and 1 site in the Netherlands. It enrolled patients with either unprotected left main coronary disease and a left ventricular ejection fraction of 35% or less, or patients with triple-vessel coronary disease and an ejection fraction of 30% or less. The primary end point was the 30-day rate of death, MI, stroke, need for repeat revascularization, need for cardiovascular surgery or vascular surgery for limb ischemia, acute renal dysfunction, increased aortic insufficiency, severe hypotension, need for cardiopulmonary resuscitation, ventricular tachycardia, or failure to reopen the target coronaries by PCI.
The patients averaged 67 years old, 80% were men, and 56% had New York Heart Association class III or IV heart failure. Their average Society of Thoracic Surgeons (STS) mortality score was 6, their average SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score was 30, and 63% were considered ineligible for surgery. "The population was "extraordinarily high risk, the most complex patients ever enrolled in a multicenter, randomized, controlled trial, Dr. O’Neill said. There were 447 patients enrolled in PROTECT II before the study’s data and safety monitoring board stopped the trial last December. This number was 70% of the number of patients originally identified as needed to produce a statistically significant result for the primary end point. Enrollment into the study sharply slowed once the Impella device came onto the U.S. market in June 2008.
During PCI, the participating operators generally managed the Impella patients more aggressively. Heparin was given to 94% in the Impella arm and to 82% in the IABP control arm. Rotational atherectomy was performed in 15% of the Impella patients and in 10% of patients in the IABP arm, a statistically significant difference. Also, participating operators used atherectomy more aggressively in the Impella patients, with an average of five atherectomy passes per patient, compared with two passes in the IABP patients.
Although this shift in treatment approach may have ultimately benefited some of the Impella patients, it also "increased the major adverse event rate and confounded the analysis," Dr. O’Neill said. "About 70% of patients treated with atherectomy in the Impella group had an adverse event" – primarily rises in the level of creatine kinase–myoglobin – "compared with about 35% treated with atherectomy in the IABP group," he said in an interview. "It was a procedural imbalance that was hard to control for" in the safety and efficacy analysis.
There was no statistically significant difference for the study’s primary outcome, the combined major adverse event rate in the intention-to-treat analysis at 30 days after treatment, as well as at 90 days after treatment. However, at both time points, patients in the Impella arm showed trends toward lower major adverse events rates. At 30 days, the Impella patients had a 36% rate, compared with a 40% rate in the IABP patients. At 90 days, the rates reached 41% and 50%, respectively.