ABSTRACT
Background
Cardiac surgery patients with severe preoperative left ventricular (LV) dysfunction are at high risk for poor postoperative outcomes including prolonged ventilation, renal failure and post-cardiotomy cardiogenic shock (PCCS). Mortality and morbidity remain high for patients who develop PCCS, thus mandating the availability of more effective prophylactic and treatment options.
Methods
The Impella®-Protected Cardiac Surgery Trial (IMPACT) is a prospective, multicenter, single-arm pilot study assessing Impella 5.5® use prior to weaning from cardiopulmonary bypass in high-risk cardiac surgery patients. Key inclusion criteria are a baseline LV ejection fraction ≤25% or ≤35% with significant mitral regurgitation and planned mitral valve replacement or repair (MVR), and undergoing planned, on-pump isolated coronary artery bypass grafting, MVR, aortic valve replacement, or a combination of these with or without tricuspid valve replacement. The primary effectiveness endpoint is the rate of PCCF at hospital discharge. The primary safety endpoint is the composite of all-cause mortality, stroke and new requirement for renal replacement therapy evaluated through 90 days post-operation. Additional secondary endpoints include hospital and ICU lengths of stay, vasoactive-inotropic score, duration of mechanical ventilation and cardiovascular mortality. A concurrent registry will aim to collect data on patients not approached for study enrollment or who do not meet all inclusion and exclusion criteria.
Conclusions
IMPACT results will provide data on trial and technique feasibility, patient selection criteria and aid in informing future trial designs.
Trial Registration
ClinicalTrials.gov, NCT05529654, https://clinicaltrials.gov/study/NCT05529654
Background
Patients with severe left ventricular dysfunction (left ventricular ejection fraction (LVEF)<35%) comprise approximately 10% of all cardiac surgeries and are at high risk for poor postoperative outcomes. Data from the Society of Thoracic Surgeons (STS) National Adult Cardiac Surgery Database indicates that with decreasing LVEF there is an increase in mortality, stroke, renal failure, prolonged ventilation, deep sternal wound infection and reoperation rates. Specifically, the rate of at least one of these events occurring was up to 31.9% in patients with a preoperative EF <35%. Long-term outcomes similarly worsen with decreasing preoperative LVEF. , An analysis by Ahmed et al showed a twofold increase in all-cause mortality risk at 10 years in patients with an LVEF ≤30% compared to patients with a normal LVEF, defined as ≥60%. This risk of poor outcomes combined with public reporting has disincentivized providers from treating this high-risk cohort surgically.
Low cardiac output syndrome (LCOS), of which postcardiotomy cardiogenic shock (PCCS) is the most severe state, is a particularly serious postoperative complication associated with increased risk of complications, resource utilization and mortality. , PCCS is commonly defined by a cardiac index <2.2 L/min/m 2 with a systolic blood pressure <90 mmHg (or need for pharmacologic support to maintain a systolic blood pressure >90mmHg) and signs of end organ hypoperfusion. It is reported to occur in 2% to 10% of all adult cardiac surgery patients. , and has a mortality rate between 24% and 64%, with higher rates in those patients receiving extracorporeal membrane oxygenation (ECMO). , In an analysis of the STS database, Soltesz et al reported mortality in patients with preoperative LVEF ≤35% undergoing isolated coronary artery bypass grafting (CABG) to be 5.0% in those without PCCS, while in those with PCCS mortality was 30.3%. A similar result was shown in patients undergoing CABG with mitral valve surgery. In patients with a preoperative LVEF ≤35%, a recently developed machine learning model identified PCCS risk is heightened in patients with preoperative end-organ dysfunction and when case complexity requires prolonged cross-clamp and cardiopulmonary bypass time.
Current PCCS standard of care consists of pharmacologic and temporary mechanical circulatory support (tMCS) to either improve or sustain cardiac output, blood pressure and end-organ perfusion. However, there is a clear relationship between poor outcomes and high-dose or use of multiple pharmacologic agents. , Recent EACTS/STS/AATS guidelines recommend patients with a VIS > 30 or a VIS >20 with low cardiac output or hypoperfusion be considered for escalation to tMCS. However, there remains a paucity of data supporting the choice of tMCS device type and the exact timing of deployment.
Current tMCS strategies for PCCS include intra-aortic balloon pump (IABP), veno-arterial ECMO (VA-ECMO) and miniaturized transvalvular axial flow pump (Impella 5.5®, Abiomed, Johnson & Johnson MedTech Heart Recovery, Danvers, MA). Currently, IABP is the most commonly employed form of tMCS. ; however, reported outcomes of prophylactic use of IABP in high-risk cardiac surgery patients are mixed with no survival benefit being reported in randomized trials, but meta-analyses identifying improved outcomes. ,,, Importantly, none of these studies focused on patients with severe preoperative LV dysfunction—the population most likely to require and potentially benefit from tMCS. VA-ECMO is commonly deployed once pharmacologic and IABP fail to provide sufficient hemodynamic support. A recent meta-analysis reported a hospital survival of 36.1% for PCCS patients placed on ECMO. Unlike IABP and VA-ECMO, the Impella® pump directly unloads the LV without significantly increasing afterload. Traditionally, tMCS is often initiated reactively, only after LCOS or PCCS has developed, and/or escalation to high dose pressors has ensued.
The Impella 5.5® is currently FDA approved for the treatment of cardiogenic shock of different etiologies including PCCS, as it offers flows of up to 5.5 L/min and lower adverse event rates. , There is growing interest in protected cardiac surgery with preemptive use of tMCS, including Impella® in high-risk cardiac surgery patients. whereby the pump is implanted prior to separation from cardiopulmonary bypass (CPB), and PCCS is possibly averted. Recently, consideration of intraoperative initiation of tMCS in patients at high-risk for LCOS was given a Class IIa, Level C recommendation. There has yet to be a prospective study investigating outcomes in PCCS patients supported with the Impella 5.5® device.
Five studies have reported outcomes of high-risk cardiac surgery patients undergoing planned, intraoperative use of Impella® devices. ,,,, Ranganath, et al reported results of their single-center retrospective review of 13 subjects with baseline LVEF ≤30% undergoing CABG. All subjects had planned placement of either the Impella 5.0® or Impella LD® and results showed 100% postoperative survival. Most recently, Benke, et al reviewed results of their single-center, retrospective study which included 14 subjects with a baseline LVEF ≤30% undergoing either CABG, aortic valve replacement (AVR), CABG+AVR or CABG+mitral valve reconstruction. Planned, intraoperative placement of the Impella 5.0® or Impella 5.5® yielded a 93% 30-day survival. Several smaller case series and case reports have reported similarly promising results of the planned, intraoperative use of Impella® in high-risk patients undergoing mitral valve and CABG surgeries. ,,
Current data on protected cardiac surgery with the Impella®, although promising, remains limited to small case series with variation in surgeries performed, timing of Impella® support initiation (concomitantly with CPB weaning vs after CPB weaning) and Impella® pump utilized. The Impella® Protected Cardiac Surgery Trial (IMPACT) will assess the feasibility of completing a trial investigating preemptive transvalvular unloading in patients with severe LV dysfunction, study design and patient selection criteria to inform future trial designs.
Methods
Study design
IMPACT is a prospective, multicenter, single-arm pilot study with a concurrent registry (ClinicalTrials.gov NCT05529654) conducted at up to 25 sites in the United States of America. The study has completed enrollment and is currently in the follow-up phase. IMPACT is sponsored by Abiomed, J&J MedTech Heart Recovery (Danvers, MA) and conducted under a U.S. FDA Investigational Device Exemption (#G210059). The study assesses the feasibility of completing a trial investigating Impella® 5.5 protected cardiac surgery to improve postoperative outcomes in patients with severely reduced left ventricular function. IMPACT was approved by WCG (Cary, North Carolina) and by the local IRB when necessary, and all enrolled patients signed informed consent.
An Independent Medical Monitor (IMM) will review all site reported adverse events to determine whether the event requires CEC adjudication. The Clinical Events Committee (CEC) will adjudicate all endpoint-related events and all deaths with an event onset date through 90 days postoperation for relatedness to the surgical procedure, the study device and the study device procedure. CEC members are independent physician experts in cardiothoracic surgery and cardiology (see Supplementary material for additional information). Echocardiograms collected at baseline, hospital discharge and 90 days postoperation are analyzed by an independent core lab.
Study population
The IMPACT study population is comprised of patients with severely depressed left ventricular function undergoing cardiac surgery ( Figure 1 ). Key inclusion criteria of the study are hemodynamically stable adults aged ≥18 years, with a baseline LVEF ≤25%, or ≤35% with significant mitral regurgitation (MR) and planned MVR, undergoing isolated CABG, MVR or AVR, or a combination of these with or without tricuspid valve repair or replacement (TVR). The index cardiac surgery must be performed on cardiopulmonary bypass including aortic cross-clamping and cardioplegic arrest. Key exclusion criteria include an unresponsive state, cardiac arrest or mechanical circulatory support within 24 hours of the index procedure, or any inotrope use within 72 hours of the index procedure. The complete list of inclusion and exclusion criteria is provided in Table I . The inclusion and exclusion criteria have been modified since first enrollment. These changes are outlined in Supplementary Table I.
Overall IMPACT study design.
Table I
Inclusion and exclusion criteria
| Inclusion criteria |
|---|
|
| Exclusion criteria |
|
Patients meeting all inclusion and no exclusion criteria and having signed informed consent are presented to the central IMPACT Enrollment Committee prior to enrollment in the study. The Enrollment Committee reviews the inclusion and exclusion criteria as well as additional patient characteristics to ensure the patient is high-risk. IMPACT Steering Committee members and the study sponsor’s medical officer comprise the Enrollment Committee (Supplementary Table II). Subjects are considered enrolled in the study at the time of skin incision for arterial access for the purpose of placing the Impella 5.5®, or chest skin incision in the case of direct aortic Impella 5.5® placement. A transesophageal echocardiogram after induction of anesthesia documenting the absence of intracardiac thrombus is mandatory before enrollment. Baseline characteristics of the enrolled subjects and the index procedures performed are provided in Tables II and III .
Table II
Baseline characteristics of enrolled subjects
| Parameter |
Subjects
( N = 100) |
|---|---|
| Age, years | 63.5 [58.5, 70.0] |
| Sex, female | 21% (21/100) |
| Body mass index, kg/m2 | 27.6 [24.3, 31.0] ( n = 99) |
| Baseline LVEF 1, % | 25.0 [21.6, 28.9] ( n = 97) |
|
New York Heart Association Classification
I II III IV |
9.2% (9/98) 37.8% (37/98) 44.9% (44/98) 8.2% (8/98) |
| STS PROM, % | 4.1 [2.5, 7.1] |
| Primary Indication for Surgery | |
|
Primary Indication for CABG
Angina AMI Chronic CAD Cardiomyopathy/Heart Failure Other |
6.6% (6/91) 6.6% (6/91) 67.0% (61/91) 14.3% (13/91) 5.5% (5/91) |
|
Primary Indication for Mitral Valve Surgery
Complication from another procedure Endocarditis Mechanical complication from a MI Valvular heart disease Other |
0% (0/31) 0% (0/31) 3.2% (1/31) 83.9% (26/31) 12.9% (4/31) |
|
Primary Indication for Tricuspid Valve Surgery
Complication from another procedure Endocarditis Mechanical complication from a MI Valvular heart disease Other |
0% (0/7) 0% (0/7) 0% (0/7) 71.4% (5/7) 28.6% (2/7) |
|
Primary Indication for Aortic Valve Surgery
Complication from another procedure Endocarditis Mechanical complication from a MI Valvular heart disease Other |
0% (0/17) 5.9% (1/17) 0% (0/17) 88.2% (15/17) 5.9% (1/17) |
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