PROTECT Series of Clinical Studies Provides Mounting Evidence for Impella® Support in High-Risk PCI

Looking at the data from the PROTECT Series—PROTECT I, PROTECT II RCT², and PROTECT III—William O’Neill, MD, medical director of the Center for Structural Heart Disease at Henry Ford Hospital believes that “the totality of clinical data in favor of Impella supported high-risk PCI allows interventional cardiologists to be confident they are using the optimal treatment and technologies to help achieve complete revascularization in a single setting, improve procedural hemodynamic stability, and improve patient quality of life.”

Current PROTECT Series Clinical Trial Data

In September 2019 at the Transcatheter Cardiovascular Therapeutics (TCT) annual scientific symposium, Jeffrey Popma, MD presented an interim analysis of the ongoing PROTECT III study. Dr. Popma highlighted the following findings from the PROTECT Series of clinical trials to date:

• The “high-risk” indication for PCI is founded on a procedural benefit of hemodynamic stability enabling a more thorough revascularization and leading to a post-discharge clinical benefit of reduced adverse events and improved cardiac function
• Decisions to provide hemodynamic support during PCI should accordingly be made in the context of providing complete revascularization and evaluated based on improvement in outcomes out-of-hospital
• In the post-approval era, compared to PROTECT II, PROTECT III patients are older, include more women, and receive more complex procedures, yet 90-day MACCE is lower
• Emerging data validated in the multicenter cVAD Study indicate a potential additional benefit in these patients to reduce the risk of acute kidney injury^{8, 10, 11}

Largest FDA Study of High-risk PCI Patients

Such statements are based on solid clinical evidence. The PROTECT Series is the largest-ever FDA study of hemodynamically supported high-risk PCI patients, enrolling 1,366 patients as of July 2019.

22% Relative Risk Reduction in 90-day MAEs

Although the PROTECT II randomized, controlled trial (RCT) was discontinued early, results from the final cohort of patients, representing 69% of the planned enrollment, demonstrated significant results. Data from the 448 patients in the PROTECT II study revealed a 22% relative risk reduction in 90-day major adverse events (MAEs) compared with intra-aortic balloon pump (40.0% MAE rate in the Impella arm versus 51.0% in the IABP arm, P=0.023.)²

Impella Lowers MACCE Rates

In addition, patients in the Impella arm of the PROTECT II study experienced significantly lower MACCE rates at 90 days—a 29% reduction, (22% versus 31% in IABP arm, P=0.034)—when MACCE was defined using the “more prognostically relevant” periprocedural myocardial infarction definition of new Q-waves or CK-MB elevation ≥ 8x ULN within 72 hours post-PCI for periprocedural myocardial infarction, instead of the cutoff of the ≥ 3x ULN for cardiac biomarker elevation originally defined for the trial.³

Patients Benefit from More Complete Revascularization Procedures

PROTECT II data also revealed that Impella maintains patient hemodynamics allowing for more complete revascularization5 and that the benefit was more pronounced with extensive revascularization.⁶ With extensive revascularization, the difference in cumulative incidence of MACCE at 90 days was 15.0% in the Impella arm versus 29.3% in the IABP arm, P=0.006.6

Other PROTECT II Procedural and Clinical Benefits

Other procedural and clinical benefits demonstrated in PROTECT II include:²

53% reduction in hypotensive events (defined as MAP<65 mmHg) per patient in the Impella arm compared with the IABP arm (0.45 versus 0.96, p=0.001).

Impella 2.5 provided better hemodynamic support than IABP during high-risk procedures, as determined by the maximal drop in cardiac power output (CPO) from baseline (-4.2 ± 24 vs -14.2 ± 27 W, P=0.001).²

Impella facilitated more extensive atherectomy

In both the IABP and Impella arms of the PROTECT II study, there was an average 22% relative increase in LVEF from baseline (P<0.001) and a 59% improvement in NYHA functional class III/IV (P<0.001) at 90 days.

Economic Impact of Treating High-Risk Patients with Impella

Finally, in the first economic analysis to compare the resource utilization costs for Impella versus IABP in patients requiring acute hemodynamic support in the United States, Gregory et al. concluded that for high-risk patients with advanced heart failure undergoing PCI, Impella “reduced major adverse events, critical care and readmission length of stay, and readmission cost over the 90-day EOC (episode of care), and was determined to be cost-effective over the long-term.”^{7, 9}

PROTECT III Reveals Further Reductions in 90-Day MACCE With Impella Support

PROTECT III, the ongoing, prospective, single-arm, FDA post-approval study for the post-marketing approval (PMA) of Impella 2.5® and Impella CP® in high-risk PCI, has included 898 patients at 45 sites in the U.S. between March 2017 and July 2019. Jeffrey Popma, MD, announced findings from the interim analysis demonstrating a reduction in the primary endpoint of major adverse cardiac and cerebrovascular events (MACCE) at 90 days with Impella-supported Protected PCI, compared to the PROTECT II study.

Although the PROTECT III study patients had, according to Dr. Popma, “arguably more complex anatomic lesions”—e.g., number of vessels treated per patient in the PROTECT III study was higher and the amount of atherectomy used was significantly higher—outcomes between the PROTECT II study and the PROTECT III study were very comparable using the same criteria.

The 90-day MACCE rate in the PROTECT III study is lower than the IABP control arm from the PROTECT II study. The composite MACCE rate in the IABP arm was 31% compared to the Impella 2.5 and Impella CP arm at 16.8% (p<0.0001).

Strong Clinical Evidence Base for High-Risk PCI with Impella Support

Thus, as Dr. Popma stated at TCT 2019, “We are in a very good place now, with our understanding and clinical evidence base for high-risk PCI with left ventricular support.”