Abstract
Coronary artery disease (CAD) is the leading cause of heart failure with reduced ejection fraction (HFrEF). Coronary artery bypass grafting (CABG) improves long-term mortality in HFrEF. Percutaneous coronary intervention (PCI) is often performed as an alternative to CABG in patients at high surgical risk. However, in patients with HFrEF and limited myocardial reserve, PCI may result in haemodynamic instability, increasing risk and precluding optimal revascularisation. Mechanical circulatory support (MCS) during high-risk PCI may enhance haemodynamic stability during the procedure and enable complete revascularisation. We thus performed the PROTECT IV trial to determine whether PCI with routine use of the Impella CP microaxial flow pump improves early and late outcomes in patients with HFrEF and complex CAD compared with PCI with or without use of an intra-aortic balloon pump (IABP). PROTECT IV is a prospective, multicentre, randomised, parallel-controlled, open-label, superiority trial with an adaptive design. Patients with complex CAD and left ventricular ejection fraction ≤40% (n=1,252) deemed at excessive surgical risk for bypass grafting by the Heart Team will be randomised in a 1:1 ratio to PCI with Impella CP versus PCI with or without an IABP. The primary endpoint is the composite of all-cause death, stroke, myocardial infarction, unplanned clinically driven revascularisation, durable left ventricular assist device implant or heart transplant, or other hospitalisation for cardiovascular causes at 3-year follow-up, with at least 1-year follow-up in all patients. Prespecified substudies will evaluate the impact of MCS on renal function, the procedural role of right heart catheterisation, and the utility of myocardial viability assessment. The PROTECT IV trial will determine whether routine MCS with Impella CP during high-risk PCI improves the prognosis of patients with complex CAD and HFrEF.
Coronary artery disease (CAD) is the leading cause of heart failure with reduced ejection fraction (HFrEF)12. Patients with reduced left ventricular ejection fraction (LVEF) have a poor quality of life, frequent hospitalisations and high mortality. The Surgical Treatment for Ischemic Heart Failure (STICH) extension study showed that at 10 years, the rates of death from any cause, death from cardiovascular causes, and death from any cause or hospitalisation for cardiovascular causes were significantly lower in patients who underwent coronary artery bypass grafting (CABG) in addition to guideline-directed medical therapy (GDMT) than in those who received GDMT alone3. The role of revascularisation with percutaneous coronary intervention (PCI) in HFrEF has been challenged by the recent Revascularisation for Ischemic Ventricular Dysfunction (REVIVED)-BCIS2 trial, which showed no clear benefit of PCI over GDMT alone4. However, this trial was smaller than STICH, its follow-up was shorter, and the enrolled patients had no or only mild ischaemic and heart failure (HF) symptoms, with rates of previous myocardial infarction (MI) and three-vessel disease indicating less complex and less active CAD than in STICH. Non-randomised studies comparing PCI with CABG in patients with left ventricular (LV) dysfunction have reported conflicting results56. A propensity-adjusted study of 2,126 patients from the New York State database reported similar rates of survival at a median 2.9-year follow-up with PCI compared with CABG in patients with multivessel disease and LV dysfunction6, whereas an observational analysis of 4,794 propensity-matched patients with LVEF ≤35% undergoing PCI or CABG in Ontario, Canada reported increased mortality after PCI at a median follow-up of 5.2 years5. However, patients with complex CAD and HFrEF are often poor candidates for CABG. Real-world data demonstrate that PCI is performed rather than CABG in at least 50% of patients due to high surgical risk or comorbidities, including frailty78910. Ineligibility for CABG is not accounted for in non-randomised comparisons of PCI versus CABG, limiting their utility. In patients with HFrEF and limited myocardial reserve, PCI may result in haemodynamic decompensation, including the development of cardiogenic shock or the need for resuscitation, which can lead to adverse procedural events. Moreover, even lesser degrees of haemodynamic instability may lead to a hurried procedure, resulting in suboptimal lesion selection (e.g., less use of intracoronary physiology assessment), inadequate lesion preparation and stent implantation (e.g., less use of intracoronary imaging), and a higher incidence of incomplete revascularisation, all of which are important predictors of early and late prognosis11. Approximately half of patients undergoing high-risk PCI experience loss of pulse pressure during the procedure12. Use of a mechanical circulatory support (MCS) device during PCI may afford greater haemodynamic stability and thus potentially improve early and late outcomes by preventing procedural complications and enabling more appropriate lesion preparation, optimal stent implantation and achievement of complete revascularisation (CR). Two randomised controlled trials of MCS have been conducted in this setting to date: the Balloon Pump-Assisted Coronary Intervention Study (BCIS-1)13 and A Prospective, Multi-center, Randomized Controlled Trial of the IMPELLA RECOVER LP 2.5 System Versus Intra Aortic Balloon Pump (IABP) in Patients Undergoing Non Emergent High Risk PCI (PROTECT II)14. In the BCIS-1 trial (n=301), IABP support during elective complex PCI in patients with LVEF ≤30% did not significantly reduce major adverse cardiac or cerebrovascular events (MACCE) at discharge (15.2% vs 16.0% with no planned IABP; p=0.85)13. However, an exploratory long-term analysis showed a reduction in all-cause mortality at a median 51-month follow-up in the IABP group (hazard ratio 0.66, 95% confidence interval [CI]: 0.44-0.98; p=0.039)15. In the PROTECT II trial (n=448), patients with LVEF ≤35% and complex CAD randomised to Impella 2.5 (Abiomed, J&J MedTech Heart Recovery)-supported versus IABP-supported PCI had similar major adverse events (MAE) rates at 30 days (35.1% vs 40.1%; p=0.227)14. At 90 days, in a prespecified per-protocol analysis, the MAE rate was lower in the Impella cohort (40.0% vs 51.0%; p=0.023). In addition, when major adverse cardiac events (MACE) and periprocedural MI were readjudicated according to more contemporary definitions, Impella use resulted in a relative 29% reduction in MACE compared with IABP at 90-day follow-up (p=0.042)16. These results ultimately led to U.S. Food and Drug Authority (FDA) premarket approval of the Impella CP (Abiomed, J&J MedTech Heart Recovery) for high-risk PCI patients as defined in the PROTECT II trial. However, the clinical community has continued to debate the results given that PROTECT II was stopped for futility before enrolment of the 654 planned patients was completed and because the study missed its 30-day primary intention-to-treat endpoint. Compared with the Impella 2.5 device tested in PROTECT II, the Impella CP device offers substantially greater haemodynamic support17. A recent analysis compared the patient characteristics and outcomes of 504 “PROTECT II-like” patients enrolled in the prospective, observational PROTECT III post-approval study with patients treated by Impella support and enrolled in the PROTECT II trial17. In PROTECT III, contemporary patients undergoing high-risk PCI were older and had more complex CAD than in PROTECT II. Impella CP and Impella 2.5 were used in 68% and 32% of the PROTECT II-like patients, respectively. After propensity score matching, the more contemporary cohort had important differences in revascularisation technique, including the treatment of more lesions, more frequent use of atherectomy, and a longer duration of Impella support. These differences were associated with a greater reduction in SYNTAX score (more CR). Propensity-matched patients in PROTECT III experienced less hypotension during support (2.2% vs 10.2%; p<0.001) and less frequently developed malignant ventricular arrhythmias or required cardiopulmonary resuscitation (1.6% vs 6.9%; p<0.001) compared with those in PROTECT II. Despite the use of the larger-bore Impella CP device, the PROTECT III group also had fewer major bleeding events requiring blood transfusion (1.2% vs 9.4%; p<0.001). Even after excluding procedural events within the first 72 hours, propensity-matched PROTECT III patients experienced fewer MACCE between 3 and 90 days compared with those in PROTECT II (10.4% vs 16.9%; p=0.048). This study illustrates the improving outcomes of high-risk PCI with Impella support over the past decade but does not prove that MCS-assisted high-risk PCI is superior to high-risk PCI without MCS. Further data on MCS-assisted high-risk PCI have been reported from single-arm observational studies and claims database analyses (Table 1)1314151718192021222324. The use of MCS devices in these studies has been associated with mixed outcomes. In several studies, haemodynamic support during high-risk PCI led to a safer procedure and showed a possible benefit compared with an IABP1820. Conversely, other studies have raised concerns about greater costs and potential harm with MCS, including increased bleeding, vascular complications, and even higher mortality in certain patient cohorts2123. On the basis of these studies (in particular the two randomised trials), the most recent 2021 ACC/AHA/SCAI guidelines for myocardial revascularisation provide a Class IIb, Level of Evidence B recommendation for elective MCS use during PCI in certain high-risk patients, without favouring one device over the other (albeit noting that Impella provides greater haemodynamic support than an IABP)25. The 2024 ESC Guidelines for the management of chronic coronary syndromes provide a Class IIb, Level of Evidence C recommendation that in selected patients with HFrEF undergoing high-risk PCI for complex CAD, the use of a microaxial flow pump may be considered in experienced centres (IABP use as an option is not mentioned)26. Thus, there is currently equipoise regarding the risk-benefit ratio of routine use of MCS in general, and Impella CP in particular, in high-risk patients with LV dysfunction undergoing elective complex PCI. This evidence gap prompted the PROTECT IV trial, a multicentre, randomised, parallel-controlled, open-label study to assess the utility of routine Impella CP use during elective high-risk PCI in patients with complex CAD and LVEF ≤40%.
Table 1. Large-scale studies of haemodynamically supported high-risk percutaneous coronary intervention published between 2010 and 2022.
| Study | Year published | Enrolment periods | Trial design | No. of sites | Patient population | No. of patients | Group I | Group II | Primary endpoint | Key findings (group I vs group II) |
|---|---|---|---|---|---|---|---|---|---|---|
| BCIS-I13 | 2010 | 2005-2009 | RCT in the United Kingdom | 17 | Patients undergoing high-risk PCI with IABP or no support | 301 | IABP (n=151) | No planned IABP (n=150) | MACCE (death, MI, cerebrovascular event, or further revascularisation at hospital discharge [capped at 28 days]) | No difference in in-hospital MACCE rateMACCE15.2% vs 16.0%; p=0.85; OR 0.94 (95% CI: 0.51-1.76)Major complications*1.3% vs 10.7%; p<0.001; OR 0.11 (95% CI: 0.01-0.49)All-cause mortality at 6 months (secondary endpoint)4.6% vs 7.4%; p=0.32; OR 0.61 (95% CI: 0.24-1.62) |
| PROTECT II14 | 2012 | 2007-2010 | RCT in the USA, Canada, and the EU | 112 | Patients undergoing high-risk PCI with Impella 2.5 or IABP support | 448 | Impella 2.5 (n=225) | IABP (n=223) | MAE at discharge or 30-day follow-up: all-cause death, Q-wave or non-Q-wave MI, stroke, or transient ischaemic attack, any repeat revascularisation procedure, need for a cardiac or a vascular operation, acute renal insufficiency, severe intraprocedural hypotension requiring therapy, cardiopulmonary resuscitation or ventricular tachycardia requiring cardioversion, aortic insufficiency, and angiographic failure of PCI | No difference in 30-day MAE rate (primary endpoint); however, 90-day MAE rate (secondary endpoint) was significantly lower in the Impella per-protocol armMAE at 30 days (intention-to-treat)35.1% vs 40.1%; p=0.277MAE at 90 days (intention-to-treat, secondary endpoint)40.6% vs 49.2%; p=0.066Prespecified per-protocol analysis for 30-day and 90-day MAE34.3% vs 42.2%; p=0.09240.0% vs 51.0%; p=0.023 |
| Zeitouni et al24 | 2022 | 2009-2018 | Prospective CathPCI registry, retrospective analysis | 514 (using MCS) | Patients with stable CAD undergoing elective PCI with Impella, ECMO, IABP, or no support (CS, CA, and NYHA IV excluded) | 6,905 | IABP (n=2,035) | Other MCS (presumably Impella in the majority of cases; n=4,870) | MACE (death, cardiogenic shock, or new heart failure)Safety (stroke, tamponade, major bleeding, or vascular complications) | Use of IABP was associated with lower effectiveness than other MCS devices to prevent the composite of death, cardiogenic shock, or heart failureMACE9.6% vs 6.0%; p≤0.0001, aOR 1.59 (95% CI: 1.32-1.91)Safety18.2% vs 19.1%; p=0.0557, aOR 0.88 (95% CI: 0.77-0.99) |
| Bjarnason et al23 | 2022 | 2013-2019 | Medicare database analysis | 306 | Patients undergoing PCI with PVAD (Impella or TandemHeart) or IABP support (undifferentiated high-risk PCI/CS population) | 79,176 | n.a. | n.a. | 30-day mortality | Use of PVADs for PCI was not associated with lower in-hospital mortalityRisk-adjusted 30-day mortalityThis was assessed according to quartiles based on the proportion of all PCIs that were performed with a PVAD (<17%, 17-28%, 28-38%, >38%)31.5% vs 31.2% vs 31.3% vs 31%; p=0.074 |
| J-PCI22 | 2022 | 2018 | Prospective Japanese registry, retrospective analysis | 551 | Patients undergoing non-emergent PCI with Impella, ECMO+IABP, or IABP alone | 1,627 | IABP (n=1,402) | Impella (n=69), ECMO (n=156) | Primary endpoint: in-hospital mortalitySecondary outcome: procedural complications (periprocedural MI, cardiac tamponade, heart failure or shock, definite stent thrombosis according to the ARC definition, emergency surgery, and major bleeding requiring blood transfusion) | VA-ECMO was associated with a higher incidence of procedural complications, and major bleeding was more frequently observed in patients receiving VA-ECMO or Impella than IABPIABP vs Impella vs ECMOIn-hospital mortality5.3% vs 7.2% vs 34.6%; p<0.01Procedural complications22.0% vs 27.5% vs 55.8%; p<0.01 |
| Amin et al21 | 2020 | 2004-2016 | Premier database analysis | 432 | Patients undergoing PCI with Impella or IABP support (undifferentiated high-risk PCI/CS population) | 48,306 | Impella (type not differentiated; n=4,782) | IABP (n=43,524) | Death, bleeding requiring transfusion, AKI, and stroke | Impella use was associated with higher rates of in-hospital adverse events and costs than IABPIndividual patient comparative effectiveness analysesDeathOR 1.24 (95% CI: 1.13-1.36)BleedingOR 1.10 (95% CI: 1.00-1.21)AKIOR 1.08 (95% CI: 1.00-1.17)StrokeOR 1.34 (95% CI: 1.18-1.53) |
| Al-Khadra et al20 | 2020 | 2005-2014 | NIS database analysis | n.a. | Patients undergoing PCI with PVAD or IABP support (CS, ACS, and AMI excluded) | 21,848 | PVAD (n=4,578) | IABP (n=17,270) | In-hospital mortalityVascular complicationsCardiac complicationsRespiratory complications | PVAD patients had lower in-hospital mortality and vascular, cardiac, and respiratory complications than IABP patientsIn-hospital mortality6.1% vs 8.8%, aOR 0.62 (95% CI: 0.51-0.77)Vascular complications4.3% vs 7.5%, aOR 0.78 (95% CI: 0.62-0.99)Cardiac complications5.6% vs 14.5%, aOR 0.29 (95% CI: 0.24-0.36)Respiratory complications3.8% vs 9.8%, aOR 0.37 (95% CI: 0.28-0.48) |
| Lansky et al18 | 2022 | 2016-2019 | Premier database analysis | 304 | Patients undergoing non-emergent PCI with Impella or IABP support (CS and STEMI excluded) | 2,156 | Impella (n=1,447) | IABP (n=709) | In-hospital survivalIn-hospital MIIn-hospital CS | Use of Impella was associated with improved in-hospital survival and reduced in-hospital MI and CSIn-hospital survival95.3% vs 91.0%; p=0.0002, aOR 1.55 (95% CI: 1.02-2.36)In-hospital MI2.5% vs 11.9%; p<0.0001, aOR 0.29 (95% CI: 0.18-0.46)In-hospital CS8.3% vs 18.9%; p<0.0001, aOR 0.54 (95% CI: 0.39-0.74) |
| PROTECT III17 | 2022 | 2017-2020 | Prospective, single-arm, observational, FDA-audited PAS† | 45 | Patients undergoing high-risk PCI with Impella 2.5 or CP support (and deemed PROTECT II like) | 504 | PROTECT III(68.1% Impella CP, 31.9% Impella 2.5) | PROTECT II (100% Impella 2.5) | MACCE at 90 days (death, MI, stroke/TIA, and any repeat revascularisation) | PIII patients had significantly lower 90-day MACCE rates (in unmatched and propensity score-matched populations) compared to PII patients†MACCE (matched population)14.2% vs 22.3%; p=0.045 |
| RESTORE-EF19 | 2022 | 2019-2021 | Retrospective analysis of prospectively collected, observational US dataset, single arm | 22 | Patients undergoing high-risk PCI with Impella 2.5 or CP support and 90-day FU available | 406 | n.a. | n.a. | Change in LVEF within 90 days | LVEF improved significantly (primary endpoint), with a significantly greater LVEF improvement in patients with a residual SYNTAX score of 0LVEF change within 90 days35±15% to 45±14% (n=251; p<0.0001) |
| The minimum study population size for inclusion in the above table was 250 patients. *Major procedural complications include prolonged hypotension, ventricular tachycardia/fibrillation requiring defibrillation, or cardiorespiratory arrest requiring assisted ventilation. †The analysis of the PROTECT III study compares a PROTECT III cohort to a PROTECT II cohort; however, the PROTECT III study itself was a single-arm, observational study. ACS: acute coronary syndrome; AKI: acute kidney injury; AMI: acute myocardial infarction; aOR: adjusted odds ratio; ARC: Academic Research Consortium; CA: cardiac arrest; CAD: coronary artery disease; CI: confidence interval; CS: cardiogenic shock; ECMO: extracorporeal membrane oxygenation; FDA: U.S. Food and Drug Administration; FU: follow-up; IABP: intra-aortic balloon pump; LVEF: left ventricular ejection fraction; MACCE: major adverse cardiac and cerebrovascular events; MACE: major adverse cardiac events; MAE: major adverse events; MCS: mechanical circulatory support; MI: myocardial infarction; n.a.: not available; NIS: National Inpatient Sample; NYHA: New York Heart Association; OR: odds ratio; PAS: post-approval study; PCI: percutaneous coronary intervention; PII: PROTECT II; PIII: PROTECT III; PVAD: peripheral ventricular assist device; RCT: randomised controlled trial; STEMI: ST-segment elevation myocardial infarction; TIA: transient ischaemic attack; VA-ECMO: venoarterial extracorporeal membrane oxygenation | ||||||||||
Methods
Trial population and design
The Impella-Supported PCI in High-Risk Patients With Complex Coronary Artery Disease and Reduced Left Ventricular Function (PROTECT IV) trial will enrol 1,252 patients aged 18-90 years with complex CAD, LV dysfunction (defined as LVEF ≤40% in those with chronic coronary syndrome [CCS] or non-ST-segment elevation MI [NSTEMI], or LVEF ≤30% in those with ST-segment elevation MI [STEMI] ≥24 hours and <30 days after symptom onset), for whom the local Heart Team (interventional cardiologist and heart surgeon) deem that PCI is the most appropriate revascularisation option due to excessive surgical risk. Full inclusion/exclusion criteria and the requirements defining complex CAD for PCI are presented in Table 2 and Table 3, respectively. PROTECT IV is sponsored and funded by Abiomed, J&J MedTech Heart Recovery. Briefly, complex PCI is defined as either (a) triple-vessel disease, with PCI planned in at least two of the three major epicardial vessels in the proximal or mid-segments (not branch vessels); or (b) left main (LM) disease involving the distal bifurcation or trifurcation, with planned LM intervention in the ostial left anterior descending artery (LAD) and ostial left circumflex artery (LCx; ramus); or (c) LM equivalent disease with similar planned ostial LAD and ostial LCx (ramus) treatment; or (d) intervention of the last remaining vessel (native coronary artery or bypass graft); or (e) multivessel disease with PCI planned in at least two separate, complex lesions (i.e., long lesions ≥28 mm, severe calcification, chronic total occlusion [CTO], giant thrombus, etc.) in different epicardial territories. Regarding the LVEF inclusion criterion, patients may qualify if the site-read quantified LVEF is ≤30%. If the site-read LVEF is >30% and ≤40% or not quantified, the LVEF must be confirmed to be ≤40% by the independent study echocardiographic laboratory (ECL). Enrolment will take place at up to 120 centres in the USA, Canada, and Europe. The trial is being conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The trial is registered on ClinicalTrials.gov: NCT04763200. Written informed consent is obtained in all patients prior to any study-related procedures. Patients will be randomised in a 1:1 ratio to either Impella CP-assisted high-risk PCI (treatment group) or high-risk PCI with or without pre-PCI IABP (control group). Randomisation takes place in the cardiac catheterisation laboratory, immediately prior to the planned PCI procedure, and is stratified by site, LVEF ≤25%, and intended IABP use if randomised to the control group. Allowing IABP in the control group is justified by the long-term analysis of BCIS-1, which showed a reduction in all-cause mortality at the 51-month median follow-up in the IABP group15. In addition, the design of an international trial should reflect common practice, and IABP use remains frequent during high-risk PCI in the USA. Stratifying randomisation by intended IABP use in the control group will enable us to examine the impact of this strategy compared with Impella MCS. The study flow is detailed in Figure 1 and the Central illustration. Follow-up visits are required for all patients at 30 days after discharge, and after randomisation at 60 days, 90 days, and 6 months, and at 1, 2, and 3 years. The first patient was randomised in April 2021 and enrolment will conclude in 2025.
Table 2. Full inclusion criteria.
| Subjects must meet all of the following inclusion criteria to participate in the trial: |
|---|
| 1. Age ≥18 years and ≤90 years |
| 2. Clinical presentation and baseline left ventricular function are as follows: either 2A or 2B must be present |
| A. Subject has CCS or NSTEMI with an LVEF ≤40%*orB. Subject has STEMI ≥24 hours and <30 days after symptom onset with an LVEF ≤30%† |
| 3. Local Heart Team (interventional cardiologist and cardiac surgeon) has determined that PCI is indicated and is the most appropriate management for the patient |
| 4. Complex PCI will be performed: either 4A or 4B must be met |
| A. One of the following must be present: |
| i. Triple-vessel disease (visually-assessed angiographic DS ≥80% [or ≥40% if there is non-invasive evidence of ischaemia on a localising stress test or invasive evidence of ischaemia {FFR ≤0.80 or iFR ≤0.89}] in all 3 epicardial coronary artery distributions in a main vessel or branch with a visually-assessed reference vessel diameter ≥2.5 mm) with PCI planned in ≥2 of these vessels in the proximal or mid-LAD, proximal or mid-LCx or proximal, mid- or distal RCA (i.e., not a branch vessel) orii. Left main distal bifurcation or trifurcation disease (visually assessed DS ≥50% [or DS ≥30% if there is non-invasive evidence of ischaemia in both the anterior and posterolateral distributions or left main IVUS MLA ≤6.0 mm2 or FFR ≤0.80 or iFR ≤0.89]) with planned intervention of the left main plus at least 2 branch vessels (i.e., the ostial LAD, ostial LCx or ostial ramus) oriii. Left main equivalent disease with both the ostial LAD and ostial LCx having visually angiographic DS ≥80% (or ≥40% if there is non-invasive evidence of ischaemia on a localising stress test or invasive evidence of ischaemia [FFR ≤0.80 or iFR ≤0.89]) and requiring intervention in both branches oriv. Intervention of the last remaining vessel (native coronary artery or bypass grafting) or |
| B. Multivessel disease is present (visually assessed angiographic DS ≥80% [or ≥40% if non-invasive or invasive evidence of ischaemia is present] in ≥2 of the 3 epicardial coronary artery distributions in a main vessel or branch with visually assessed reference vessel diameter ≥2.5 mm) and PCI is planned for at least 2 separate complex lesions in main vessels or branch vessels, each having one or more of the following characteristics‡: |
| i. Long lesion (≥28 mm visually assessed) requiring ≥30 mm stent length (single or multiple)ii. Severe angiographic calcification (see protocol definition) or requiring atheroablationiii. Any left main morphology not in criterion A requiring intervention (e.g., isolated ostial or mid-shaft left main lesion or distal left main bifurcation lesion with a planned single provisional stent technique)iv. Non-left main bifurcation lesion requiring intervention in both the main branch and side branchv. CTO (TIMI 0 flow)vi. Giant thrombus (length ≥3x vessel diameter)vii. SVG (other than focal [<5 mm] disease of the proximal or distal anastomosis or in-stent restenosis) |
| 5. Subject or legal guardian (permitted at US sites only) agrees to randomisation and to follow all study procedures and provides informed written consent |
| *The LVEF must be quantitatively measured as ≤40% by echo within 30 days assuming no change in clinical condition. If multiple echos have been performed within 30 days, the most recent test must be used to qualify the patient. The subject qualifies if the quantitative site-read LVEF is ≤30%; if the quantitative site-read LVEF is >30% and ≤40%, the echo core lab must confirm the LVEF is ≤40% before subject enrolment (core lab will provide <48-hour turnaround). Similarly, if the site read is qualitative only (i.e., only provides broad ranges without detailed LVEF quantification), the echo core lab must confirm the LVEF is ≤40% before subject enrolment. †In patients qualifying with recent STEMI, the LVEF must be demonstrated to be ≤30% by quantitative echocardiography after the primary PCI procedure (if performed) and within 72 hours prior to the planned randomisation. If primary PCI was not performed, the qualifying echocardiogram will be the one taken during the index hospitalisation closest to the index procedure. If the site read is qualitative only (i.e., only provides broad ranges without detailed LVEF quantification), the echo core lab must confirm the LVEF is ≤30% before subject enrolment. ‡a. Multiple lesions can be in the same vessel if separated by ≥10 mm; however, each separate lesion has to have one or more of the above characteristics. b. PCI may be performed on additional non-qualifying lesions (i.e., without 1 or more of the above high-risk characteristics) as long as there are at least 2 lesions also undergoing PCI with each having 1 or more of the above characteristics). c. There are 2 exceptions to the rule that each separate lesion must have 1 or more of the above characteristics (as in inclusion criterion 4B above): the subject may qualify if undergoing complex PCI of a single lesion that has 2 or more of the above complex characteristics (as in inclusion criterion 4B) if also (i) there is a CTO of a proximal or mid-LAD, proximal or mid-LCx or proximal, mid- or distal RCA (i.e., not a branch vessel) that will not be treated; or (ii) the subject qualifies with recent STEMI with an LVEF ≤30%, and the complex PCI is planned in a non-infarct vessel (i.e., a complex PCI in the infarct vessel does not qualify). CCS: chronic coronary syndrome; CTO: chronic total obstruction; DS: diameter stenosis; FFR: fractional flow reserve; iFR: instantaneous wave-free ratio; IVUS: intravascular ultrasound; LAD: left anterior descending artery; LCx: left circumflex artery; LVEF: left ventricular ejection fraction; MLA: minimal lumen area; NSTEMI: non-ST-segment elevation myocardial infarction; RCA: right coronary artery; STEMI: ST-segment elevation myocardial infarction; SVG: saphenous vein graft; TIMI: Thrombolysis in Myocardial Infarction |
Table 3. Full exclusion criteria.
| Subjects must not meet any of the following exclusion criteria to participate in the trial: |
|---|
| 1. STEMI ≤24 hours from the onset of ischaemic symptoms or at any time if mechanical complications of transmural infarction are present (e.g., VSD, papillary muscle rupture, etc.) |
| 2. Cardiogenic shock (SBP <80 mmHg for ≥30 mins and not responsive to intravenous fluids or haemodynamic deterioration for any duration requiring pressors or mechanical circulatory support, including IABP) |
| 3. Subject is presently or recently intubated for the current admission* |
| 4. Cardiorespiratory arrest related to the current admission unless subject is extubated for >24 hours with full neurological recovery and haemodynamically stable |
| 5. Any contraindication or inability to Impella placement in either the left or right common femoral artery based on clinical or imaging findings, including iliofemoral artery diameter <5 mm, tortuous vascular anatomy or severe bilateral peripheral vascular disease of the iliac or femoral arteries that cannot be adequately treated (e.g., with intravascular lithotripsy)† |
| 6. Iliofemoral stents placed within 6 months of enrolment with planned vascular access through these vascular segments |
| 7. Vascular access for Impella is required in any location other than the left or right common femoral artery (i.e., axillary access, transcaval access, etc., are not permitted for Impella) |
| 8. Known left ventricular thrombus |
| 9. Incessant ventricular arrhythmias that would likely preclude stable Impella positioning |
| 10. Severe aortic stenosis or severe aortic insufficiency |
| 11. Prior mechanical valve or self-expanding TAVI‡ |
| 12. Prior CABG within 3 months or successful prior PCI of at least one attempted lesion within 12 months (including during the index hospitalisation prior to randomisation) that has not experienced stent thrombosis or restenosis during that 12-month period; the one exception is that patients may be enrolled if a primary PCI for STEMI was performed during the index hospitalisation without MCS and that was ≥24 hours and <30 days prior to randomisation§ |
| 13. Prior placement of IABP, Impella, or any other MCS device for any reason during the index admission, prior to randomisation |
| 14. Known severe pulmonary hypertension (right ventricular systolic pressure on echo or pulmonary artery systolic pressure on right heart catheterisation) >70 mmHg unless active vasodilator therapy in the cath lab is able to reduce the pulmonary vascular resistance to <3 Wood units or between 3 and 4.5 Wood units with a V wave less than twice the mean of the pulmonary capillary wedge pressure |
| 15. Symptoms or signs of severe RV dysfunction, such as anasarca¶ |
| 16. Severe tricuspid insufficiency |
| 17. Platelet count <75,000 cells/mm3, bleeding diathesis or active bleeding, coagulopathy, or unwilling to receive blood transfusions |
| 18. On dialysis |
| 19. Prior stroke with any permanent neurological deficit within the previous 3 months or any prior intracranial haemorrhage or any prior subdural haematoma or known intracranial pathology predisposing to intracranial bleeding, such as an arteriovenous malformation or mass |
| 20. Taking a chronic oral anticoagulant that cannot be safely discontinued for at least 72 hours before and 72 hours after the index procedure (if a vitamin K antagonist) or that cannot be safely discontinued for at least 48 hours before and 48 hours after the index procedure (for a direct acting oral anticoagulant) |
| 21. Plan for any surgery within 6 months necessitating discontinuing antiplatelet agents |
| 22. Pregnant or childbearing potential unless negative pregnancy test within 1 week |
| 23. Participation in the active treatment or follow-up phase of another clinical study of an investigational drug or device that has not reached its primary endpoint |
| 24. Any medical or psychiatric condition such as dementia, alcoholism, or substance abuse which may preclude informed consent or interfere with any of the study procedures, including follow-up visits |
| 25. Any non-cardiac condition with life expectancy <3 years (e.g., cirrhosis, oxygen- or oral steroid-dependent COPD, cancer not in remission, etc.) |
| 26. Subject is currently hospitalised for definite or suspected COVID-19 |
| 27. The subject has previously been symptomatic with or hospitalised for COVID-19 unless they have been discharged (if hospitalised) and asymptomatic for ≥4 weeks and have returned to their prior baseline (pre-COVID) clinical condition |
| 28. Subject is asymptomatic with a positive COVID-19 PCR/antigen test within the prior 4 weeks unless (a) the subject remains asymptomatic for ≥4 weeks after the last positive test; or (b) the positive test occurred within 6 months after the subject received a COVID vaccine |
| 29. Subject belongs to a vulnerable population (defined as individuals with mental disability, impoverished persons, homeless persons, nomads, refugees, and those permanently incapable of giving informed consent; vulnerable populations may also include members of a group with a hierarchical structure such as university students, subordinate hospital and laboratory personnel, employees of the sponsor, members of the armed forces, and those kept in detention) |
| *Recently intubated patients must be extubated for >24 hours with full neurological recovery. †a. Computed tomography, magnetic resonance angiography, or contrast angiography to assess the aorta and iliofemoral vasculature to ensure Impella compatibility must be performed within 90 days prior to randomisation. It is recommended that this evaluation be performed prior to the index procedure. Without a qualifying preprocedural imaging study, contrast angiography of the potential Impella access vessel(s) must be performed in the cath lab before the planned enrolment, after which the subject may be randomised if he/she still qualifies. Of note, if preprocedural imaging was performed and, after this test but before randomisation, there was a worsening in PVD symptoms, repeat imaging must be performed prior to randomisation. b. If iliofemoral peripheral vascular disease is present, precluding Impella use that can be adequately treated with angioplasty, atherectomy, or lithotripsy (without a stent), the subject can be enrolled if such treatment is undertaken and is successful and uncomplicated – randomisation must not be performed until such successful and uncomplicated treatment has taken place. ‡Prior bioprosthetic surgical valve or balloon-expandable TAVI implanted >24 hours preprocedure is acceptable. §Successful PCI is defined as a visually assessed angiographic DS ≤50% in at least one attempted lesion. ¶Leg oedema alone may not necessarily indicate severe RV dysfunction, particularly if the investigator believes it is due to LV dysfunction. CABG: coronary artery bypass grafting; COPD: chronic obstructive pulmonary disease; DS: diameter stenosis; IABP: intra-aortic balloon pump; LV: left ventricular; MCS: mechanical circulatory support; PCI: percutaneous coronary intervention; PCR: polymerase chain reaction; PVD: peripheral vascular disease; RV: right ventricular; SBP: systolic blood pressure; STEMI: ST-segment elevation myocardial infarction; TAVI: transcatheter aortic valve implantation; VSD: ventricular septal defect |
Figure 1. Study flowchart. *Impella CP is the default device in the Impella arm, except in special circumstances, in which case the Impella 2.5 may be used. See Table 2 for a description of inclusion criteria #2 and #4. 6MWD: six-minute walk distance; CABG: coronary artery bypass grafting; CCS: chronic coronary syndrome; GDMT: guideline-directed medical therapy; IABP: intra-aortic balloon pump; LVEF: left ventricular ejection fraction; NSTEMI: non-ST-segment elevation myocardial infarction; PCI: percutaneous coronary intervention; QoL: quality of life; RHC: right heart catheterisation; STEMI: ST-segment elevation myocardial infarction 
Central illustration. Design and rationale of the PROTECT IV trial. CAD: coronary artery disease; CCS: chronic coronary syndrome; CR: complete revascularisation; GDMT: guideline-directed medical therapy; HF: heart failure; HFrEF: heart failure with reduced ejection fraction; IABP: intra-aortic balloon pump; LVAD: left ventricular assist device; LVEF: left ventricular ejection fraction; MI: myocardial infarction; NSTEMI: non-ST-segment elevation myocardial infarction; PCI: percutaneous coronary intervention; STEMI: ST-segment elevation myocardial infarction
Trial hypothesis and endpoints
The primary objective of PROTECT IV is to assess the effectiveness of haemodynamic support with Impella CP in high-risk patients with LVEF ≤40% and complex CAD undergoing PCI. The study aims to demonstrate that PCI with Impella CP is superior to PCI without it in reducing the primary composite endpoint of all-cause death, stroke, MI, unplanned clinically driven revascularisation, durable LV assist device (LVAD) implant or heart transplant, or other hospitalisation for cardiovascular causes during 3-year follow-up. The primary endpoint will be assessed as a time-to-first event analysis. Eight secondary endpoints are powered for statistical testing (Table 4). Additional non-powered, secondary endpoints include numerous clinical and safety outcomes, and changes in quality of life (QoL), functional capacity, and LV function during follow-up (Table 5). An independent clinical events committee will be responsible for adjudicating protocol-defined clinical events, including but not limited to the primary endpoint, using original source documents. Prespecified subgroups for analysis are presented in Supplementary Table 1. Substudies and the accompanying PROTECT IV registry are described in Supplementary Appendix 1 and Supplementary Table 2.
Table 4. Primary and powered secondary endpoints.
| Endpoint | Definition | Timepoint |
|---|---|---|
| Primary endpoint | The composite of all-cause death, stroke, MI, unplanned clinically driven revascularisation, durable LVAD implant or heart transplant, or other hospitalisation for cardiovascular causes. | At 3 years, assessed when the last randomised patient has reached 1-year follow-up |
| Powered secondary endpoints (in hierarchical order of testing) | Death, or NYHA Class III or IV | 1 year |
| Improvement in KCCQ from baseline | 6 months | |
| 6MWD | 6 months | |
| All CV hospitalisations | 3 years | |
| Composite of CV death, stroke, MI, unplanned clinically driven revascularisation, durable LVAD implant or heart transplant, or other hospitalisation for a cardiovascular cause | 3 years | |
| CV death or HF hospitalisations | 3 years | |
| Improvement in LVEF from baseline | 6 months | |
| Achievement of complete anatomical revascularisation after the index and planned staged procedures | Immediately post-procedure(s) | |
| The individual power is >80% for each of the powered hierarchical secondary endpoints. 6MWD: 6-minute walk distance; CV: cardiovascular; HF: heart failure; KCCQ: Kansas City Cardiomyopathy Questionnaire; LVAD: left ventricular assist device; LVEF: left ventricular ejection fraction; MI: myocardial infarction; NYHA: New York Heart Association | ||
Table 5. Other secondary endpoints.
| Prespecified, non-powered, exploratory endpoints assessed at 30 days, 6 months and 1, 2, and 3 years after randomisation unless otherwise listed in the primary or secondary powered endpoint hierarchy |
|---|
| Primary composite endpoint |
| All-cause mortality |
| CV death |
| Non-CV death |
| MI (all, procedural and non-procedural, target vessel and non-target vessel) |
| Hospitalisations (CV, HF-related, non-HF-related, non-CV) |
| Cardiac arrest requiring CPR or intubation |
| Cerebrovascular events (all stroke and TIA) |
| Composite death or stroke |
| Composite CV death or stroke |
| Composite of death or MI |
| Composite of CV death or MI |
| Composite of death, stroke, or MI |
| Composite of CV death, stroke, or MI |
| Ability to complete the intended revascularisation plan (angiographic core lab-assessed) |
| Achievement of complete angiographic and functional revascularisation and their relationship to outcomes (angiographic core lab-assessed according to a prespecified definition) |
| In-hospital acute kidney injury and change in renal function and/or the need for dialysis at 30 days, 6 months, 1 year, and 3 years |
| New onset atrial fibrillation or atrial flutter |
| Major bleeding (BARC 3 to 5) |
| Any medically actionable bleeding (BARC 2 to 5) |
| Vascular complications (VARC-3 definition) |
| Unplanned clinically driven revascularisation |
| Stent thrombosis (ARC-2 definite or probable) |
| New ICD or CRT implant |
| Durable LVAD, OHT, or OHT listing |
| Mitral, tricuspid and/or aortic valve repair or replacement |
| Failure to explant an Impella or IABP device placed during the index or planned staged procedure(s), at the end of the procedure and within 48 hours after its placement |
| Escalation (bailout use) of MCS device usage beyond Impella CP in the Impella arm or beyond IABP in the control arm |
| The rate of unplanned Impella 2.5 or Impella CP use in the Impella arm (e.g., if starting with an Impella 2.5 device or starting without support in a staged procedure) or unplanned IABP use in the control arm (both of which are not considered device escalations) |
| Length of hospital stay post-randomisation |
| NYHA Class |
| Absolute measures and improvement in QoL (KCCQ and EQ-5D) and 6MWD from baseline to 30 days, 1 year, and 3 years |
| Percentage of patients with ≥5 point change in KCCQ from baseline to 30 days, 1 year, and 3 years |
| BNP or NT-proBNP levels at 30 days, 6 months, and 1 year |
| Absolute measures and change in LV dimensions (LVEF, GLS, LV regional wall motion), RV function (RVFAC, TAPSE, GLS), valvular function and RVSP from baseline to 6 months, 1 year and 3 years (echocardiographic core lab-assessed) |
| Costs and cost-effectiveness during follow-up |
| All 2-year and 3-year outcome measures will be reported when all subjects have reached 2-year and 3-year follow-up. Some of these outcomes (e.g., the components of the primary composite outcome) may also selectively be reported at the time of the principal reporting of the primary endpoint, i.e., when all subjects have reached 1-year follow-up but only a proportion have reached 2-year or 3-year follow-up. 6MWD: 6-minute walk distance; ARC: Academic Research Consortium; BARC: Bleeding Academic Research Consortium; BNP: brain natriuretic peptide; CPR: cardiopulmonary resuscitation; CRT: cardiac resynchronisation therapy; CV: cardiovascular; EQ-5D: EuroQol 5-Dimension; GLS: global longitudinal strain; HF: heart failure; IABP: intra-aortic balloon pump; ICD: implantable cardioverter-defibrillator; KCCQ: Kansas City Cardiomyopathy Questionnaire; LV: left ventricular; LVAD: left ventricular assist device; LVEF: left ventricular ejection fraction; MCS: mechanical circulatory support; MI: myocardial infarction; NT-proBNP: N-terminal pro-B-type natriuretic peptide; NYHA: New York Heart Association; OHT: orthotopic heart transplant; QoL: quality of life; RV: right ventricular; RVFAC: right ventricular fractional area change; RVSP: right ventricular systolic pressure; TAPSE: tricuspid annular plane systolic excursion; TIA: transient ischaemic attack; VARC: Valve Academic Research Consortium |
Treatment strategy
Prior to randomisation, computed tomography (CT), magnetic resonance angiography (MRA), or contrast angiography must be performed to ensure that at least one iliofemoral system can safely accommodate the Impella CP. In the cath lab, prior to randomisation, the investigator will declare their intended revascularisation plan, including the vessels and lesions to be treated, and whether staged revascularisation procedures are expected. They will also affirm whether they intend to use IABP support if the patient is randomised to the control arm, and any planned use of right heart catheterisation (RHC), either within or outside the formal RHC substudy. Randomisation is performed in the cath lab immediately prior to the index procedure. Initiation of any PCI procedure or insertion of any MCS device is not permitted prior to randomisation. After randomisation, MCS (whether Impella or IABP in the control arm if so declared) is initiated prior to the PCI procedure, with the Impella CP being the default device for all subjects in the Impella arm, unless special circumstances warrant use of the Impella 2.5 device (i.e., small vasculature or body weight). Ultrasound-guided arterial puncture with fluoroscopic guidance and angiographic confirmation of the puncture site location is mandated in all cases, in both trial arms. Micropuncture femoral artery access is strongly recommended for all operators familiar with the technique. PCI is performed with a goal of achieving at least ischaemic CR in both trial arms. Post-PCI, if the original staging plan changes (i.e., planned staging is now necessary or is no longer needed), the new staging plan must be declared within 4 hours of the index PCI procedure. The planned staged PCI must then be performed within 6 weeks of the index procedure (or 12 weeks for a failed CTO procedure). In most cases, only one planned staged procedure should be performed.
Complex PCI techniques
The trial protocol recommends consideration of specific techniques and adjuncts as prescribed by the PROTECT IV Technique Committee, consisting of investigators with proven expertise in the fields of complex PCI and MCS (Supplementary Figure 1). Strategy recommendations include pressure wire-based physiological lesion assessment for lesion selection and the routine use of intravascular imaging for stent optimisation, which is mandatory to guide left main PCI. For CTO PCI, investigators are strongly encouraged to use microcatheters and distal vessel visualisation, applying all four lesion-crossing strategies (antegrade wire escalation, anterograde dissection re-entry, retrograde wire escalation, and retrograde dissection re-entry) as appropriate. The use of embolic protection devices is strongly recommended for saphenous vein graft interventions. To reduce the risk of acute kidney injury (AKI), intravascular volume administration of normal saline guided by invasively measured filling pressures is strongly recommended, minimising the contrast volume-to-estimated glomerular filtration rate ratio to ≤2.0-3.7. The protocol also advises on mandatory or highly recommended aspects related to periprocedural anticoagulation, pretreatment with aspirin and P2Y12 inhibitors, and choice and duration of dual antiplatelet therapy in patients with or without an indication for chronic oral anticoagulation.
Bailout device usage in both arms
In patients who become haemodynamically unstable during or after index PCI, the use of other MCS such as extracorporeal membrane oxygenation (ECMO), TandemHeart (LivaNova), or ProtekDuo (also LivaNova) is allowed in both arms during or after PCI and is considered “bailout MCS use”. However, the use of Impella devices is not allowed in the control arm, and IABPs are not allowed in the Impella arm, unless their use is deemed lifesaving. In the control arm, if PCI is initiated with no support and an IABP is subsequently required, this will be considered “unplanned IABP use”. In the Impella arm, if PCI is initiated with an Impella 2.5 and then upgraded to an Impella CP, this will be considered “unplanned Impella use”. Use of the Impella 5.0, 5.5, or RP (all Abiomed J&J MedTech Heart Recovery) in the Impella arm is considered bailout MCS use.
Heart failure specialist and GDMT-HF committee
A key component of the PROTECT IV trial design is to ensure that all enrolled patients, regardless of treatment arm, are receiving optimal HF-related medical therapies according to societal guidelines27282930. Each site will assign an HF specialist to direct the appropriate utilisation of all HF therapies including GDMT, cardiac resynchronisation therapy (CRT) and implantable cardioverter-defibrillators (ICDs). The HF specialist must see the patient, either in person or via a tele-visit, during the index hospitalisation and any planned staged hospitalisations. At this time, they will assess the patient’s New York Heart Association Class (independent of the study investigator) in order to guide GDMT. The HF specialist will also see the patient in person or via a tele-visit at the 30-day, 60-day, and 90-day follow-up visits. After 90 days, continued visits with the HF specialist are strongly recommended throughout the 3-year follow-up period. The HF specialist will ensure that maximally tolerated doses of all Class I-recommended GDMT are administered in all enrolled patients as soon as possible after randomisation, but in all cases within 90 days after randomisation. These and all subsequent adjustments must be made independently of randomisation assignment, dictated only by the patient’s clinical status. Since all patients enrolled in this trial have an LVEF ≤40% (HFrEF), these recommendations apply to all study participants. The GDMT regimen should not be reduced during follow-up, even if serial LVEF measurements improve. A GDMT-HF committee comprised of HF experts will provide oversight of these issues (Supplementary Figure 1). This entails evaluating and approving all onsite HF specialists and reviewing HF medications and CRT/ICD device therapies for all enrolled subjects following randomisation, with site feedback as necessary.
Statistical analysis and sample size determination
Unless revised by the results of an interim adaptive design, approximately 1,252 subjects will be enrolled and randomised in a 1:1 ratio to intervention versus control. All subjects will undergo a minimum of 1 year and a maximum of 3 years of follow-up. The study will be unblinded for the primary data analysis once the last enrolled subject completes their 1-year follow-up. The null hypothesis that there is no difference in the risk of the composite primary endpoint after Impella-assisted high-risk PCI compared with high-risk PCI±IABP will be assessed using covariate-adjusted Cox proportional hazards regression at a two-sided 0.05 significance level. This analysis will be conducted in the intention-to-treat population, which includes all randomised patients regardless of MCS device use or crossover and whether the procedure was successful. Baseline covariates for adjustment are the intention to use versus not use an IABP if randomised to control (declared before randomisation); LVEF determined by the ECL, diabetes, age, sex, clinical syndrome presentation, chronic kidney disease, and angiographic core laboratory-determined SYNTAX score (Supplementary Appendix 1). For the principal analysis of the primary endpoint, missing data, either at baseline or during follow-up, will not be replaced. As a sensitivity analysis, multiple imputation will be used to account for missing baseline and follow-up data. Primary endpoint event rates in the control arm of 25%, 50%, and 75% are anticipated at 1 year, 2 years, and 3 years, respectively. A sample size of 1,252 randomised patients (approximately 626 in each arm) and 516 total primary endpoint events provides 90.4% power to detect a hazard rate reduction of 25% in the Impella group compared with the control group at a two-sided alpha level of 0.05. If the primary endpoint passes the test for statistical significance, the powered secondary endpoints will be tested sequentially at a two-sided alpha level of 0.05. An unblinded Bayesian interim analysis will be conducted by an independent adaptive design committee after enrolment of ~85% of the planned 1,252 subjects (Supplementary Appendix 1). Recommendations from this committee may include increasing the sample size to a maximum of 2,500 patients, prolonging the minimum follow-up in all patients (maximum follow-up remains 3 years), a combination of both, or no change.
Discussion
The PROTECT IV trial is, to our knowledge, the first adequately powered randomised comparison to test the hypothesis that haemodynamic support with Impella CP in patients with complex CAD and reduced LVEF undergoing elective high-risk PCI will facilitate a safer procedure with higher rates of optimal and complete revascularisation, leading to improved long-term event-free survival, QoL, and functional outcomes during 3-year follow-up. Large-scale database analyses examining the results of Impella-supported elective PCI have reported conflicting findings18202123: some studies have reported higher costs and no improvement in clinical outcomes (or increased complications) with Impella2123, while others have noted improved outcomes with Impella support1820. The randomised PROTECT II trial had a complex 10-component primary composite endpoint of efficacy and safety and was terminated early because of futility. However, in this study MAE were comparable at 30 days but diverged by 90 days in favour of patients who received an Impella 2.514. In PROTECT II, Impella preserved patient haemodynamics to a greater degree than an IABP, resulting in more CR31, which was associated with improved clinical outcomes32. These findings were confirmed and extended by the prospective PROTECT III registry, which reported fewer procedural complications, higher rates of CR, and improved 90-day clinical outcomes after Impella-supported high-risk PCI compared with PROTECT II17. Collectively, these findings support the hypothesis that haemodynamic support may facilitate not only procedural safety but also enable CR, which has been associated with improvements in LV function19 and prognosis33. In addition, the haemodynamic stability afforded by Impella may enable greater use of high-quality PCI techniques including physiological lesion assessment34 and intravascular imaging35, which have been associated with improved outcomes. PROTECT IV is enrolling patients with complex CAD in need of revascularisation for progressive or unstable ischaemic and/or HF symptoms and reduced LVEF whom the local Heart Team has deemed to be at excessive risk or ineligible for cardiac surgery, necessitating PCI. The primary endpoint of PROTECT IV − the 3-year rate of all-cause death, stroke, MI, unplanned clinically driven revascularisation, durable LVAD implant or heart transplant, or other hospitalisation for cardiovascular causes − is of clinical importance in this high-risk population in whom both HF-related and ischaemic events are common. Secondarily, PROTECT IV will determine whether Impella support during high-risk PCI improves long-term QoL, exercise and functional capacity, LV volumes and function, and renal function. Assessing the safety of Impella for this application in this study is also critical, with the protocol implementing best practices for vascular access, Impella weaning and closure to minimise complications. Finally, the critical importance of medical therapy in HFrEF patients is addressed by the involvement of HF specialists at each site to optimise the rapid titration of class I HF therapies and to provide long-term HF follow-up, as overseen by a GDMT-HF committee comprised of globally recognised HF experts.
Conclusions
The randomised PROTECT IV trial will provide high-quality evidence to conclude whether Impella CP-assisted PCI is superior to PCI±IABP in patients with complex CAD and reduced LVEF (≤40%) for the composite rate of all-cause death, stroke, MI, unplanned clinically driven revascularisation, permanent LVAD implantation or heart transplantation, or other hospitalisation for cardiovascular causes at 3-year follow-up.
Acknowledgements
The authors and sponsor dedicate this work to Dimitri I. Karmpaliotis, MD, who died after completion of this manuscript. Dr Karmpaliotis served as a US regional lead for PROTECT IV and was a member of the Technique Committee and a high enroller in the study. PROTECT IV would not have been possible without his dedication, inspiration, and insights into high-risk PCI and patient care. The authors would also like to thank Carie Facemire, PhD, for her role in the substudy design.
Funding
The trial is sponsored and funded by Abiomed, J&J MedTech Heart Recovery, the manufacturer of the Impella device.
Conflict of interest statement
N. Mangner received a research and an educational grant from Abiomed, Johnson & Johnson MedTech Heart Recovery, to his institution, outside the submitted work; an educational grant from Boston Scientific to his institution, outside the submitted work; and received personal fees from Abbott, Abiomed, Johnson & Johnson MedTech Heart Recovery, Amgen, AstraZeneca, B. Braun, Biotronik, BMS/Pfizer, Boston Scientific, Daiichi Sankyo, Edwards Lifesciences, Medtronic, Novartis, Sanofi Genzyme, and Shockwave Medical, outside the submitted work. C. O’Connor has received consulting fees from Abiomed, Johnson & Johnson MedTech Heart Recovery, and Merck. A. Kaki receives speaker honoraria from Abbott, Abiomed, Johnson & Johnson MedTech Heart Recovery, CathWorks, Medtronic, Recor Medical, and Terumo. E. Mahmud is a consultant for Abiomed, Johnson & Johnson MedTech Heart Recovery (PROTECT IV Steering Committee) and MicroPort (Co-PI Target IV); and receives DSMB fees from CRF and Baim Cardiovascular. S.J. Pocock is a consultant with Medtronic and Edwards Lifesciences. W.W. O’Neill has consulting and research funding from Abiomed, Johnson & Johnson MedTech Heart Recovery, Edwards Lifesciences, Abbott, and BSCI. A.J. Lansky has received institutional research support and consulting fees from Abiomed, Johnson & Johnson MedTech Heart Recovery. J.R. Wollmuth has received speaker honoraria and consulting fees from Abiomed, Johnson & Johnson MedTech Heart Recovery, Abbott, Asahi Intecc, Boston Scientific, and Shockwave Medical. H.A. Faraz receives speaker honoraria from Abiomed, Johnson & Johnson MedTech Heart Recovery and Shockwave Medical (J&J MedTech). M.B. Basir is a consultant for Abiomed, Johnson & Johnson MedTech Heart Recovery, Boston Scientific, Chiesi, and Zoll. A.S. Bharadwaj has received speaker honoraria and consulting fees from Abiomed, Johnson & Johnson MedTech Heart Recovery, Shockwave Medical, and Abbott/CSI. Z.A. Ali reports institutional grant support from Abbott, Abiomed, Johnson & Johnson MedTech Heart Recovery, ACIST, Amgen, Boston Scientific, CathWorks, Canon, Conavi, Chiesi, HeartFlow, Inari, Medtronic, National Institute of Health, Nipro, Opsens Medical, Medis Medical Imaging, Philips, Shockwave Medical, Siemens, SpectraWAVE, and Teleflex; consulting fees from Abiomed, Johnson & Johnson MedTech Heart Recovery, AstraZeneca, Boston Scientific, CathWorks, HeartFlow, Opsens Medical, Philips, and Shockwave Medical; and equity with Elucid, Lifelink, SpectraWAVE, Shockwave Medical, and VitalConnect. C. Simonton, S.D. Bilazarian, N.K. Kapur, R.C. Chapman, and D. Bentley are employees of the trial sponsor, Abiomed, Johnson & Johnson MedTech Heart Recovery. J.J. Popma was a former employee of Medtronic (<24 months) and has non-vested equity. A. Maehara serves as an advisory board member for SpectraWAVE and Canon; and as a consultant for Amgen and Boston Scientific. S. Windecker reports research, travel and/or educational grants to the institution from Abbott, Abiomed, Johnson & Johnson MedTech Heart Recovery, Alnylam, Amicus Therapeutics, Amgen, AstraZeneca, Bayer, B. Braun, Bioanalytica, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cordis Medical, CorFlow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Fumedica, GE HealthCare, Guerbet, IACULIS, Inari Medical, Janssen AI, Johnson & Johnson, Medalliance, Medtronic, Merck Sharp & Dohme, Neovii Pharmaceuticals, Neutromedics AG, Novartis, Novo Nordisk, OM Pharma, Optimapharm, Orchestra BioMed, Pfizer, Philips AG, Sanofi-Aventis, Servier, Shockwave Medical, Siemens Healthineers, Sinomed, Sahajanand Medical Technologies, Vascular Medical, and V-Wave; serves as an advisory board member and/or member of the steering/executive group of trials funded by Abbott, Amgen, Abiomed, Johnson & Johnson MedTech Heart Recovery, Edwards Lifesciences, InCarda Inc., Medtronic, Novartis, and Sinomed, with payments to the institution but no personal payments; and he is also a member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. G.W. Stone has received speaker honoraria from Medtronic, Amgen, and Boehringer Ingelheim; has served as a consultant to Robocath, Daiichi Sankyo, Vectorious, Miracor, Apollo Therapeutics, Cardiac Success, Occlutech, Millennia Biopharma, Ablative Solutions, Oxitope, Elixir, Impulse Dynamics, Asceneuron, Myochron, Remote Cardiac Enablement, Valfix, Zoll, HeartFlow, Shockwave Medical, Adona Medical, Abbott, HighLife, Elucid Bio, Aria, Alleviant, FBR Medical, Colibri, Bioventrix, and MedHub; and has equity/options from Cardiac Success, Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWAVE, Orchestra Biomed, Aria, Valfix, and Xenter; his employer, Mount Sinai Hospital, receives research grants from Shockwave Medical, Biosense Webster, Bioventrix, Abbott, Abiomed, Johnson & Johnson MedTech Heart Recovery, Cardiovascular Systems Inc, Philips, Vascular Dynamics, Pulnovo, V-wave, and PCORI (via the Weill Cornell Medical Center). The other authors have no relevant conflicts of interest to declare.
Supplementary data
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