Impella®-Supported PCI in High-Risk Patients With Complex Coronary Artery Disease and Reduced Left Ventricular Function

Inclusion Criteria:

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% NOTE: The LVEF must be quantitativelymeasured as ≤40% by echo within 30 days assuming no change in clinical condition. Ifmultiple echos have been performed within 30-days, the most recent test must be usedto qualify the patient. NOTE: Subject qualifies if the quantitative site read LVEFis ≤30%; if the quantitative site read is >30% - ≤40% the Echo Core Lab must confirmthe LVEF is ≤40% before subject enrollment (Core Lab will provide <48-hourturnaround). Similarly, if the site read is qualitative only (i.e., only providesbroad ranges without detailed LVEF quantification), the Echo Core Lab must confirmthe LVEF is ≤40% before subject enrollment. OR B. Subject has STEMI ≥24 hours and <30 days after symptom onset with an LVEF ≤30%NOTE: 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 randomization. If primary PCI was notperformed, the qualifying echocardiogram will be the one taken during the indexhospitalization closest to the index procedure. If the site read is qualitative only (i.e., only provides broad ranges without detailed LVEF quantification), the EchoCore Lab must confirm the LVEF is ≤30% before subject enrollment.

3. Local heart team (interventional cardiologist and cardiac surgeon) has determinedthat 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 is present (visually-assessed angiographic DS ≥80% [or ≥40%if non-invasive evidence of ischemia on a localizing stress test or invasiveevidence of ischemia (FFR ≤0.80 or iFR ≤0.89)] is present in all 3 epicardialcoronary artery distributions in a main vessel or branch with visually-assessedreference vessel diameter ≥2.5 mm) with PCI planned in ≥2 of these vessels in theproximal or mid LAD, proximal or mid-LCX or proximal, mid- or distal RCA [i.e., nota branch vessel]) OR ii. Left main distal bifurcation or trifurcation disease (visually-assessed DS ≥50% [or DS ≥30% if non-invasive evidence of ischemia in both the anterior andposterolateral distributions or left main IVUS MLA ≤6.0 mm2 or FFR ≤0.80 or iFR ≤0.89] is present) with planned intervention of the left main plus at least 2 branchvessels (i.e., the ostial LAD, ostial LCX or ostial ramus) OR iii. Left main equivalent disease with both ostial LAD and ostial LCX havingvisually-assessed angiographic DS ≥80% [or ≥40% if non-invasive evidence of ischemiaon a localizing stress test or invasive evidence of ischemia (FFR ≤0.80 or iFR ≤0.89] and requiring intervention in both branches OR iv. Intervention of the last remaining vessel (native coronary artery or bypassgraft) OR B. Multivessel disease is present (visually-assessed angiographic DS ≥80% [or ≥40%if non-invasive or invasive evidence of ischemia is present] in ≥2 of the 3epicardial coronary artery distributions in a main vessel or branch withvisually-assessed reference vessel diameter ≥2.5 mm) and PCI is planned of at least 2 separate complex lesions in main vessels or branch vessels each having one or moreof the following characteristics: i. Long lesion (≥28 mm visually assessed) requiring ≥30 mm stent length (single ormultiple) ii. Severe angiographic calcification (see Protocol definition) or requiringatheroablation iii. 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 lesionwith a planned single provisional stent technique) iv. Non-left main bifurcation lesion requiring intervention in both the main branchand side branch v. 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 orin-stent restenosis) NOTES:

5. The 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 abovecharacteristics

6. PCI may be performed on additional non-qualifying lesions (i.e., without 1 ormore of the above high-risk characteristics) as long as there are at least twolesions also undergoing PCI with each having 1 or more of the abovecharacteristics)

7. There are 2 exceptions to the rule that each separate lesion must have one ormore of the above characteristics (as in Inclusion Criterion 4B above): Thesubject may qualify if undergoing complex PCI of a single lesion that has 2 ormore of the above complex characteristics (as in Inclusion Criterion 4B above)if also: i. There is a CTO of a proximal or mid-LAD, proximal or mid-LCX or proximal, mid- ordistal 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 isplanned in a non-infarct vessel (i.e., a complex PCI in the infarct vessel does notqualify)

8. Subject or legal guardian (permitted at US sites only) agrees to randomization andto follow all study procedures and provides informed, written consent

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 ischemic symptoms or at any time if mechanicalcomplications of transmural infarction are present (e.g., VSD, papillary musclerupture, etc.)

2. Cardiogenic shock (SBP <80 mmHg for ≥30 mins and not responsive to intravenousfluids or hemodynamic deterioration for any duration requiring pressors ormechanical circulatory support, including IABP)

3. Subject is presently or recently intubated for the current admission (NOTE: recentlyintubated patients must be extubated for >24 hours with full neurologic recovery)

4. Cardiorespiratory arrest related to the current admission unless subject isextubated for >24 hours with full neurologic recovery and hemodynamically stable

5. Any contraindication or inability to Impella placement in both the left and rightcommon femoral artery based on clinical or imaging findings, including iliofemoralartery diameter <5 mm, tortuous vascular anatomy or severe bilateral peripheralvascular disease of the iliac or femoral arteries that can't be adequately treated (e.g., with intravascular lithotripsy) NOTES:

6. Computed tomography (CT), magnetic resonance angiography (MRA) or contrastangiography to assess the aorta and iliofemoral vasculature to ensure Impellacompatibility must be performed within 90 days prior to randomization. It isrecommended that this evaluation be performed prior to the index procedure.Absent a qualifying pre-procedure imaging study, contrast angiography of thepotential Impella access vessel(s) must be performed in the Cath Lab before theplanned enrollment after which the subject may be randomized if he/she stillqualifies. Of note, if pre-procedure imaging was performed and after this testbut before randomization there was a worsening in PVD symptoms, repeat imagingmust be performed prior to randomization.

7. If iliofemoral peripheral vascular disease is present precluding Impella usethat can be adequately treated with angioplasty, atherectomy or lithotripsy (without a stent), the subject can be enrolled if such treatment is undertakenand is successful and uncomplicated - randomization must not be performed untilsuch successful and uncomplicated treatment

8. Iliofemoral stents placed within 6 months of enrollment with planned vascular accessthrough these vascular segments

9. Vascular access for Impella is required in any location other than the left or rightcommon femoral artery (i.e., axillary access, transcaval access, etc., for Impellaaccess are not permitted)

10. Known left ventricular thrombus

11. Incessant ventricular arrhythmias that would likely preclude stable Impellapositioning

12. Severe aortic stenosis or severe aortic insufficiency

13. Prior mechanical valve or self-expanding TAVR (NOTE: prior bioprosthetic surgicalvalve or balloon expandable TAVR implanted >24 hours pre-procedure is acceptable)

14. Prior CABG within three (3) months or successful prior PCI of at least one (1)attempted lesion within 12 months (including during the index hospitalization priorto randomization), that has not experienced stent thrombosis or restenosis duringthat 12-month period; the one (1) exception is that patients may be enrolled if aprimary PCI for STEMI was performed during the index hospitalization without MCS andthat was ≥24 hours and <30 days prior to randomization. NOTE: Successful PCI for this exclusion criterion is defined as a visually-assessedangiographic DS ≤50% in at least one (1) attempted lesion.

15. Prior placement of IABP, Impella or any other MCS device for any reason during theindex admission, prior to randomization

16. Known severe pulmonary hypertension (right ventricular systolic pressure (RVSP) onecho or pulmonary artery systolic pressure (PASP) on right heart catheterization) >70 mm Hg unless active vasodilator therapy in the Cath Lab is able to reduce thepulmonary vascular resistance (PVR) to <3 Wood Units or between 3 and 4.5 Wood Unitswith v-wave less than twice the mean of the pulmonary capillary wedge pressure

17. Symptoms or signs of severe RV dysfunction, such as anasarca (NOTE: Leg edema alonedoes not necessarily indicate severe RV dysfunction if the investigator believes itis due to LV dysfunction)

18. Severe tricuspid insufficiency

19. Platelet count <75,000 cells/mm3, bleeding diathesis or active bleeding,coagulopathy or unwilling to receive blood transfusions

20. On dialysis

21. Prior stroke with any permanent neurologic deficit within the previous three (3)months, or any prior intracranial hemorrhage or any prior subdural hematoma or knownintracranial pathology pre-disposing to intracranial bleeding, such as anarteriovenous malformation or mass

22. 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 hoursafter the index procedure (for a direct acting oral anticoagulant)

23. Plan for any surgery within 6 months necessitating discontinuing antiplatelet agents

24. Pregnant or child-bearing potential unless negative pregnancy test within 1 week

25. Participation in the active treatment or follow-up phase of another clinical studyof an investigational drug or device that has not reached its primary endpoint

26. Any medical or psychiatric condition such as dementia, alcoholism or substance abusewhich may preclude informed consent or interfere with any of the study procedures,including follow-up visits

27. Any non-cardiac condition with life expectancy <3 years (e.g., cirrhosis, oxygen ororal steroid dependent COPD, cancer not in remission, etc.)

28. Subject is currently hospitalized for definite or suspected COVID-19

29. Subject has previously been symptomatic with or hospitalized for COVID-19 unlesshe/she has been discharged (if hospitalized) and asymptomatic for ≥4 weeks and hasreturned to his/her prior baseline (pre-COVID) clinical condition

30. Subject is asymptomatic (never ill) and COVID-19 PCR/antigen test is positive withinthe prior four (4) weeks unless a) subject remains asymptomatic for ≥2 weeks afterthe last positive test or b) the positive test occurred within six (6) months afterthe subject received a COVID vaccine

31. Subject belongs to a vulnerable population (defined as individuals with mentaldisability, impoverished persons, homeless persons, nomads, refugees and thosepermanently incapable of giving informed consent; vulnerable populations also mayinclude members of a group with a hierarchical structure such as universitystudents, subordinate hospital and laboratory personnel, employees of the Sponsor,members of the armed forces and persons kept in detention)