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.
In the per-protocol analysis, at 30 days the Impella patients had a major adverse event rate of 35%, compared with 43% in the IABP patients, which was not a statistically significant difference. At 90 days, the rates reached 41% and 51%, respectively, a difference that was statistically significant.
Dr. O'Neill addressed concerns that the major adverse event measure included many elements of sharply differing clinical importance. “What drove the difference [between the two study arms] was death, myocardial infarction, and need for urgent revascularization – not the small stuff. The real major adverse cardiac events were significantly better” when the Impella device was used, he said in an interview.
An analysis of several prespecified subgroups also highlighted certain types of patients who had significant benefit from the Impella device for the study's primary end point. Among the 88% of patients in the study who were not treated with rotational atherectomy, the 30-day major adverse event rate reached 30%, compared with 42% in the IABP patients, a statistically significant difference. A significant difference in the primary outcome in favor of the Impella patients also occurred in the subgroup that had an STS mortality score lower than 10.
The results also showed a strong trend toward a better primary outcome in the Impella-treated patients when the analysis excluded the first Impella-treated patient for each operator, a finding that highlighted an important learning curve in using the device, Dr. O'Neill said.
Analysis also showed that the 90-day rate of major adverse events in the Impella patients fell from 48% in 2008 to 39% in 2009 and to 37% in 2010. In contrast, the rate in the IABP patients stayed fairly constant (at 47%-52%) in all 3 years, again highlighting the role of experience with the Impella device in achieving better patient outcomes, he said.
“I think many clinicians will see [from these data] that Impella provides a lot of safety,” Dr. O'Neill said.
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Device Useful for Selected Patients
The results that Dr. O'Neill presented support the use of the Impella 2.5 device in certain clinical situations, specifically in extremely high-risk patients who have a low left ventricular ejection fraction and need protection when undergoing multivessel PCI. Having access to this type of adjunctive device is important, especially for high-risk patients. I can see myself using this device in patients similar to those enrolled in PROTECT II.
It's unfortunate that the trial did not give a definitive answer to the questions posed in the study. The trial was designed as a superiority trial and did not meet its primary end point. The results do not give us a scientific answer on when to use the device because the study stopped early. But studies like this can inform us tremendously on how to manage very high-risk patients. It's a tremendous effort to undertake the study and find the patients who would benefit from this device.
We saw in the results that physicians who used the Impella device had the confidence to more aggressively use atherectomy. That can't be proved, but it appears to be so. The higher use of rotational atherectomy resulted in more creatine kinase–myoglobin elevations in that arm, but the Impella group had fewer critically important MIs (defined as a CK-MB rise of more than eight times the upper limit of normal).
ROXANA MEHRAN, M.D., is professor of medicine and director of interventional cardiovascular research at Mount Sinai Medical Center in New York. She has been a consultant to or received honoraria from Cardiva, Ortho-McNeil, Regado, the Medicines Company, Abbott Vascular, AstraZeneca, and Cordis. She has received research grants from Bristol-Myers Squibb and Sanofi-Aventis.