CLINICAL DOSSIER Protected PCI

Transcription

1 CLINICAL DOSSIER Protected PCI with the Impella Heart Pump

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3 Executive Summary Protected PCI with the Impella On March 23, 2015, the Impella 2.5 received PMA approval from the U.S. FDA* and on December 2, 2016 the Impella CP received PMA approval from the U.S. FDA for the indication of Protected PCI. The clinical data demonstrating the Impella heart pump s safety and effectiveness includes > 1,600 patients from an FDArandomized, controlled trial and a U.S. multi-center registry, as well as over 200 peer-reviewed publications in the high-risk PCI setting. Impella 2.5 and Impella CP maintain patient hemodynamic status during planned temporary coronary occlusions by maintaining mean arterial pressure (MAP), which may allow for a more thorough procedure and a more complete revascularization in a single session. Mean arterial pressure29 Procedural decrease in arterial pressure from baseline27 Mean Arterial Pressure n=543; p< ±18 IABP 2 Vessels Treated 3 Vessels Treated -2.7% IABP -8.5% Impella 22% Pre Impella 1 Vessel Treated 101±20 N= % p=<0.001 On Impella -7.6% Baseline Protected PCI -14.9% p= % Impella p=0.026 MACCE10 Clinical outcomes of the Protect II randomized controlled trial demonstrated a 29% reduction in MACCE at 90 days.10 Extensive revascularization was also associated with the largest reduction of adverse events.33 Readmissions from 31 repeat revascularization Cost effectiveness of Impella Heart pumps has been demonstrated through a randomized controlled trial, all-payer population based studies, and a systemic review of reduced length of stay. Study observations include fewer readmissions, less days in the hospital, and a better of quality of life through reduced heart failure symptoms, after a Protected PCI. 12% 52% Reduction in repeat revascularization N=427; p=0.024 Reduced length of stay Total days in hospital 31 NYHA class improvement post PCI NYHA class improvement post procedure 6 Total Days in Hospital p= p< days or 22% 7.0 6% 8% 58% Reduction in Class III, IV 17% 18% NYHA Class of heart failure Class IV 45% 30% Class III Class II IABP Impella 90 DAYS N=211 N=216 IABP Impella Median days in hospital; index stay through 90 days, N=427, Readmissions N=208 Class I 31% 44% 7% Baseline 90 days N=223 patients from both arms of Protect II trial with NYHA measurements available at baseline and 90 days PROTECT II STUDY Seven society clinical guidelines now reference Impella including ACC/AHA/SCAI/ISHLT/HFSA * The The Impella 2.5 and Impella CP Systems are temporary ( 6 hours) ventricular support devices indicated for use during high-risk percutaneous coronary interventions (PCI) performed in elective or urgent, hemodynamically stable patients with severe coronary artery disease when a heart team, including a cardiac surgeon, has determined high-risk PCI is the appropriate therapeutic option. Use of the Impella 2.5 and Impella CP Systems in these patients may prevent hemodynamic instability, which can result from repeat episodes of reversible myocardial ischemia that occur during planned temporary coronary occlusions and may reduce peri- and post-procedural adverse events. 3

4 Device Description and Hemodynamic Characteristics The Impella 2.5 and Impella CP Heart Pumps are the smallest and least invasive percutaneous ventricular support blood pumps available on the market. The device directly unloads the left ventricle (LV) and propels blood forward, from the left ventricle into the aorta, in a manner consistent with normal physiology. Impella Heart Pumps provide both an active forward flow 1,5,14 and systemic aortic pressure (AOP) contribution, 1,2,4 leading to an effective increase in mean arterial pressure (MAP) and overall cardiac power output (CPO). 1,3,6 Combined with LV unloading, Impella support reduces end-diastolic volume and pressure (EDV, EDP) and augments peak coronary flow, 1,2,15,16 leading to a favorable alteration of the balance of myocardial oxygen supply and demand. This cascade of hemodynamic effects has been described in the literature 1,21 and validated in computational modeling and a variety of pre-clinical and clinical studies. 1-6,14-21 Current Clinical Experience Impella devices are routinely used in clinical practice in a variety of clinical scenarios to support patients with anticipated hemodynamic instability in connection with elective or urgent coronary interventions. Since the U.S. market introduction of Impella in 2008, more than 1200 hospitals have supported over 65,000 patients. The device is approved in Europe (2004), Canada (2007), Latin and South Americas ( ) and recently in China (2013) and India (2017) for a variety of indications, including high risk percutaneous coronary intervention (PCI). In the United States, the device has been used since 2006, beginning with the Protect I FDA approved trial for high-risk PCI. It has been used commercially since 2008, under a 510(k) clearance. In 2015, the Impella 2.5 heart pump was granted Pre-Market Approval (PMA) as a safe and effective ventricular support device, For Protected PCI as the PMA indication states, the Impella s intended use includes the treatment of elective or urgent, hemodynamically stable patients with severe coronary artery disease and depressed LVEF. The FDA has determined that the use of the Impella in connection with these patients may result in a reduction of peri- and post procedural adverse events typically accompanying such procedure. the past decade, a relatively large body of evidence has been generated through prospective clinical trials registry and case series investigations and nearly 400 peer-reviewed publications, making Impella the most studied circulatory support device on the market 5. 4

5 The Clinical Need for Impella Support in HRPCI Impella device support is utilized as an adjunct to PCI to protect against hemodynamic instablility, which can result from periods of myocardial ischemia that occur during procedure-related temporary coronary occlusions. In hemodynamically stable patients with severe coronary artery disease and a depressed left ventricular ejection fraction undergoing appropriate elective or urgent high-risk PCI, the strategy of Protected PCI may reduce peri and post-procedural adverse events. The 2011 ACC/AHA/SCAI PCI guidelines considered the use of hemodynamic support devices as an adjunct to PCI to be reasonable in carefully selected high-risk patients as a category IIb (i.e., benefit risk) for high-risk PCI This recommendation was made prior to the availability of most of the data referenced in this dossier. Overall, Impella is now incorporated into seven medical guideline publications, ranging from Class I to Class IIb for multiple indications, including high-risk PCI. Clinical Evidence of Safety & Effectiveness for Impella Protected PCI The data supporting the safety and effectiveness of Impella in Protected PCI settings includes prospective, randomized and non-randomized clinical trial data, as well as registry data and published literature review (see Appendix) with a total of 1,638 patients. Table 1: Scientific evidence used to support the PMA indication for Impella 2.5 in Protected PCI SUPPORTED Total number of patients for Impella 2.5 publications all indications 2. Reported total number of patients supported with Impella 2.5 all indications 5

6 Protect I Protect I was a prospective, single arm, multi-center feasibility study designed under FDA guidance to examine the safety and feasibility of the Impella device in patients undergoing high-risk angioplasty procedures. Patients presenting with a left ventricular ejection fraction (LVEF) 35% and scheduled to undergo PCI on an unprotected left main lesion or last patent conduit were considered for enrollment. The study showed an excellent safety profile of the device when used in this setting. FDA reviewed this data and approved the start of the Protect II trial based on Protect I meeting its primary and secondary endpoints. Data from this study was published by Dixon, et al. in the Journal of American College of Cardiology: Cardiovascular Interventions 5. Protect II Protect II was a prospective, multicenter, randomized trial comparing outcomes between Impella 2.5 and the IABP in patients deemed to require hemodynamic support during elective or urgent high-risk PCI. Beyond the goal of establishing a reasonable assurance for safety and effectiveness, the objective of the study was to demonstrate that prophylactic use of Impella 2.5 is superior to the IABP in preventing periand post-procedural major adverse events (MAE) in this patient population. The study enrolled 452 patients at 112 sites. The primary efficacy endpoint was a composite of ten major adverse events: death, stroke/tia, myocardial infarction, repeat revascularization, need for cardiac or vascular operation, acute renal dysfunction, cardiopulmonary resuscitation or ventricular arrhythmia requiring cardioversion, increase in aortic insufficiency by more than one grade, severe hypotension, and failure to achieve angiographic success. The multiple safety endpoints comprising this primary endpoint allowed for a comprehensive evaluation of the safety profile of this device 30 days with a follow up analysis at 90 days (both prespecified). The enrolled population consisted of patients undergoing elective or urgent hemodynamically-supported high risk PCI on an unprotected left main or last patent conduit, with an LVEF 35%, or patients who had three-vessel disease and an LVEF 30%. Investigators identified target lesions prior to randomization and then aimed for the most complete revascularization of the myocardium at jeopardy in the index procedure. The randomization was 1:1 between the two study arms (Impella vs. IABP). 6

7 A High-Risk Profile of the Protect II Patient Population The Protect II population was the sickest elective and urgent PCI population ever studied in a RCT in cardiovascular medicine. Patients were symptomatic and presented with high-risk features including complex coronary anatomy (mean SYNTAX score=30±13), depressed left ventricular ejection fraction (mean LVEF=24±6%) and other comorbidities including prior procedures, making most patients (64%) ineligible for surgical revascularization (average Society of Thoracic Surgery (STS) score=6±6%) (See Figure 1 and Table 2). Figure 1: Revascularization Strategy by Risk Category Table 2: Comparison of SYNTAX trial and SYNTAX Registry populations (PCI arm) to Protect II ** 25 PCI arm in SYNTAX trial, Serruys et al. N Engl J Med. 2009;360: PCI arm in SYNTAX Registry Head et al JACC Cardiovasc Interv. 2012;5: O Neill et al.; Circulation. 2012;126(14): * SYNTAX does not incorporate prior CABG into Risk Stratification ** 34% of patients in Protect II had prior CABG 7

8 Benefits of Protected PCI in Protect II Hemodynamic Effects: Impella patients had fewer hypotensive events compared to the IABP during the procedures (0.45±1.37 vs. 0.96±2.05 event/patient, p=0.001) 6. Impella also provided superior hemodynamic support for the patients compared to the IABP (maximal decrease in cardiac power CPO -0.04±0.24 vs ±0.27 Watts, p=0.001, secondary endpoint) 6. Consistent with this, longer support time post procedure was required for the IABP patients (p<0.001) 6 and the proportion of patients discharged from the catheterization laboratory on device support was lower in the Impella group compared to the IABP group (5.9% vs. 36.7%, p<0.001) 6. Clinical Outcomes: There was a significant reduction in major adverse events at 90 days in favor of Impella 6 (See also Figure 2). Composite Primary Endpoint of Major Adverse Events at 90 Days 6 Figure 2: Kaplan-Meier curves for major adverse events. Composite of the Primary Endpoint up to 90 days 55 MAJOR ADVERSE EVENTS RATE (%) IABP IMPELLA 2.5 LOG RANK TEST, p= TIME POST INDEX PROCEDURE (DAYS) 8

9 Pre-specified Subgroup Analyses of the Primary Endpoint Learning Curve: There was a significant learning curve in the trial. Patients in the Impella arm had significantly fewer MAE at 90 days compared to the IABP when the first subject enrolled at each site was excluded from the analysis to account for the learning curve 7. In recognition of this learning curve effect, current Impella instructions for use contain information and caution pertaining to the need for proper training. Composite Primary Endpoint of Major Adverse Events at 90 Days with First Subject Enrolled at Each Site Excluded (N=373) 7 The learning curve was also observed over time. Figure 3 shows the outcomes of the trial by the year of enrollment 6,7. Unlike the pre-specified learning curve analysis presented above, this over time analysis presented in Figure 3 was not pre-specified for assessing the learning curve, but is presented here as it complements the pre-specified analysis, and has been published by Henriques, et al. in the American Heart Journal. 7 Figure 3: 90-day MAE rates over the course of the study 6 Combined Calendar Year 9

10 Atherectomy/Non-atherectomy: The superior hemodynamic support with Impella was associated with more frequent (~2x) and more vigorous use of rotational atherectomy with more passes per lesion (p<0.001) and longer runs compared to the IABP (p<0.004) 6, which was possible because of more stability in blood pressure in the Impella arm. For the atherectomy patients (12% of population), there was no significant difference in the composite MAE. There was also no difference in mortality between the two study arms for patients receiving rotational atherectomy (4% Impella vs. 7.7% IABP, p=0.6 at 30 days and 12% vs. 15.4%, p=0.8 at 90 days respectively) 12. There were, however, significant differences in the two study arms between MI (cardiac biomarker increased values of 3x upper limit of normal) and repeat revascularization with a higher rate of peri-procedural MI and lower rate of repeat revascularization for Impella vs. IABP, respectively. All patients with a post-procedural MI were discharged post procedure. There was no evidence of a functional impact on these patients 12. Less repeat revascularization procedures were observed in the Impella arm compared to the IABP (at 90 days, 4/13 (30.8%) IABP vs. 1/25 (4.0%) for Impella, p=0.021) 12. This data was published by Cohen, et al. in Catheterization Cardiovascular Interventions 12. ABIOMED issued a technical bulletin to all Impella sites informing them of the potential risks of peri-procedural MI (based on the 2007 definition of MI of 3x ULN) 9 associated with the use of rotational atherectomy. A warning has also been added to the device s IFU. The differences in outcomes in favor of Impella were greater in the group of patients who did not undergo rotational atherectomy (88% of the patient population). At 90 days (N=375), there was a statistically significant reduction in MAE rate for the Impella arm 6. Composite Primary Endpoint of Major Adverse Events at 90 Days for Patients that did not Undergo Rotational Atherectomy (N=375) 6 Figure 4 depicts the Kaplan-Meier results out to 90 days for the same group. Figure 4: Pre-specified analysis of the primary endpoint for patients not undergoing rotational atherectomy in Protect II per protocol (88% of the population) 12 55% 50% 45% IABP MACCE(%) 40% 35% 30% IMPELLA 25% 20% LOG RANK TEST, p= TIME AFTER INITIAL PROCEDURE (DAYS)

11 Coronary Anatomy Complexity: The differences in favor of Impella were also greater in the subgroup of patients with three vessel disease (76% of population) compared to the IABP at 90 days, and was published by Kovacic, et al. in The Journal of Interventional Cardiology 27. Composite Primary Endpoint of Major Adverse Events at 90 Days of Patients with 3-vessel Disease (N=325) 27 Outcomes as a Function of Morbidity: STS mortality score To assess the subgroup of patients studied in Protect II with different burdens of comorbidities, patients above and below an STS of 10 were evaluated. Outcome differences in favor of Impella were greater in the group of patients with an STS<10 (83% of the population) at 90 days 6. Composite Primary Endpoint of Major Adverse Events at 90 for patients with STS<10 (N=355) 6,12 11

12 Post-hoc Analyses Conducted on the Primary Endpoint Use of prognostically relevant definition of peri-procedural myocardial infarction: The 2007 universal definition of MI used in the trial has since changed to reflect current knowledge. This post-hoc analysis incorporates the identical data from Protect II but was conducted using an 8x Upper Limit of Normal (ULN) threshold for peri-procedural MI to reflect a contemporary and prognostically relevant definition of MI (Stone, et al. in Circulation 8 ) compared to the 3x ULN used in the 2007 definition of MI in the Protect II trial. This analysis of the Protect II data was published by Dangas, et al. in American Journal of Cardiology 10. The Society of Cardiovascular Angiography and Intervention (SCAI) consensus document 11 authored by Moussa, et al., recommends using a 10x ULN threshold for the definition of peri-procedural MI, and more recent the EXCEL PCI trial utilized a 10x ULN definition. At 90 days, significantly lower MACCE rates defined as the composite of death, stroke, clinically significant MI ( 8x ULN) and repeat revascularization, were observed in the Impella group compared to the IABP 10. Composite Primary Endpoint of Major Adverse Cardiac and Cerebral Events (MACCE) at 90 Days (N=427) 10 Figure 5 depicts the composite MACCE rates to 90 days when a prognostically relevant and more contemporary definition of peri-procedural MI is used (8x ULN). Figure 5: Post-hoc analysis of the composite MACCE rates using a meaningful, contemporary definition for peri-procedural MI (8x ULN) 10 35% CUMULATIVE INCIDENCE OF MACCE 30% 25% 20% 15% 10% 5% IABP IMPELLA LOG RANK TEST, p= TIME AFTER INITIAL PROCEDURE (DAYS) Moreover, the use of Impella in this analysis was an independent predictor as a protector against MACCE events (Odds Ratio=0.77, p=0.02)

13 Outcomes as a Function of the Extent of Revascularization: The benefit of hemodynamic support was evaluated as a function of the extent of revascularization. In aggregate, more extensive revascularization was associated with improved 90 day outcomes in terms of MACCE events compared to a limited revascularization (p<0.01) 28. Moreover, the use of Impella was associated with improved clinical outcomes compared to the IABP when extensive revascularization was performed 28. Composite Primary Endpoint of Major Adverse Cardiac and Cerebral Events (MACCE) at 90 Days when Extensive Revascularization was Performed (N=270) 28 Other Relevant Analyses Out of Hospital Course and Re-hospitalization: Significantly fewer out of hospital irreversible MAE (composite of death/stroke/mi, 7.0% vs. 12.9%, p=0.042, 46% relative reduction) 6 and fewer re-admissions for repeat revascularization (6.0% vs. 12.4%, p=0.024) 6 were observed in the Impella arm compared to the IABP at 90 days, respectively. The overall median length of stay for the entire episode of care of the study duration was shorter for Impella compared to the IABP: (7 days vs. 9 days, p=0.026, 22% relative reduction) 13, driven primarily by more re-admissions days for the IABP. The out of hospital follow-up to 90 days provides a more comprehensive and sustained view of patient outcomes. Functional Status and Quality of Life: In aggregate, patient cardiac function and functional status improved significantly post-revascularization, confirming the benefit of the PCI in this high-risk population (average 22% increase in LVEF, p<0.001) and a 58% reduction in the percent of patients remaining in NYHA functional Class III/IV, p<0.001) at 90 days

14 cvad Registry Data Supporting Safety and Effectiveness The cvad (Catheter based ventricular assist devices) Registry is an ongoing multicenter, prospective registry with data from 49 sites in U.S., Europe and Canada. The data collection from the registry includes IRB approval, data monitoring, adverse event definition per prior ABIOMED/FDA approved clinical trials and CEC adjudication., Data has been collected in the Registry for over 3,000 patients implanted with the Impella family of devices in CVAD, consecutive non-randomized HRPCI data (N=637) provided further support of the safety and effectiveness of Impella. The cvad Registry data is consistent with prior analyses and shows: Patients undergoing high-risk PCI in clinical practice are similar to Protect II patients with high risk features, including a depressed LV function (mean LVEF=30±16%) and complex coronary anatomy and high risk for surgical revascularization. (mean STS=6±6%). The use of Impella during high-risk PCI provides adequate hemodynamic support during these interventions with a significant increase in mean arterial pressure from baseline (p<0.001) 29. Patients benefit from Impella supported percutaneous revascularization. There was an increase in the LVEF (LVEF: 31±15 vs. 36±14, p<0.0001) and a 52% reduction of NYHA Class III/IV symptoms post discharge 29 The use of Impella is safe in high-risk PCI. The adverse events were low and consistent with the Protect II results 29. In 2017, an updated cvad study was initiated at 37 sites with plans to expand this version globally. This was a prospective design with nested data collection by indication and includes angiographic and echocardiographic core cases. Patients providing consent will be followed to one year. In 2017, the FDA permitted the cvad Registry as a vehicle for four Impella post approval studies. Cost Effectiveness Cardiovascular diseases are the most prevalent and costly disease categories, with over US $300 billion in direct and indirect costs, in the US, according to the American Heart Association. Heart failure is the leading cause for medical readmissions among the Medicare population. One of every four acute heart failure patients is readmitted within 90 days of initial admission. Impella therapy has demonstrated significant cost savings and cost-effectiveness, both for payers and providers in multiple studies and economic models, namely in reduced length of stay and reduced readmissions from repeat procedures 13, By providing support to the failing heart sooner with the minimally-invasive Impella devices, clinicians are able to provide patients with better outcomes, and providers and payers may remove longer-term costs associated with resource-intensive therapies and open heart procedures

15 The Protect II Economic Study 13 concluded that for patients with severe LV dysfunction and complex anatomy, Impella-assisted PCI significantly reduced major adverse events at an incremental cost per quality-adjusted life year (ICER) considered to be cost-effective for advanced cardiovascular technologies ($39,000/QALY). In the 90 days following initial hospitalization, Impella patients experienced: Two fewer days in the hospital (p=0.001) 13 A 52% reduction in hospitalizations due to repeat revascularization (p=0.024) 13 50% lower re-hospitalization costs compared to the IABP (p=0.023) 13 The national trends in the utilization of pvads and other short term mechanical support reported by Stretch, et al. of Yale University 30 observed a correlation between increased utilization of pvads and decreased costs. A systemic review by Maini, et al. 31, reported the findings of six cost effectiveness studies of pvads. Length of stay reductions were observed in all studies, with a clinically relevant observation of fewer days in the intensive care unit, fewer days from readmissions, and two less days in the hospital over 90 days. Figure 6: Length of Stay (LOS) reductions observed in Protect II randomized controlled trial13 (left panel) and Optum population-based study (right panel)31,

16 Summary and Conclusion The safety and effectiveness of Impella hemodynamic support for Protected PCI has been validated by FDA PMA indications for both the Impella 2.5 and Impella CP. This dossier contains literature review of Impella 2.5 in the setting of HRPCI in PROTECT I, PROTECT II and the cvad Registry, and is further supported by eight years of U.S. clinical experience, medical society guidelines, and other FDA approved studies and publications. Higher risk patients, especially those at high risk for surgical revascularization, have limited options, and Impella Heart Pumps are the only hemodynamic support devices proven safe and effective at reducing peri-procedural and post-procedural adverse events in these elective and urgent Protected PCI procedures. Post revascularization, these patients experience significant improvement of their symptoms, as well as improvement in cardiac function and functional status. 16

17 Appendix A Figure A1 - Literature Review Summary 17

18 Appendix B Figure B1- Protected PCI Protocol Sample University Hospital: High-Risk Protected PCI Decision Tree High Risk PCI Decision Tree Heart Team Review Revascularization? YES NO Surgery PCI Hybrid Yes No Conventional PCI Protected PCI OR CABG with Impella support Post PCI Hemodynamic Support with Impella Hemodynamic Compromise Myocardial Recovery with STEMI/NSTEMI No Reflow for Recovery Dissection / Perforation Indications 1) HEMODYNAMIC COMPROMISE Decreased EF/LV Dysfunction CHF Abnormal Right Heart Pressures 2) COMPLEX CORONARY ANATOMY Heavy Calcification Requiring PTCRA/ Orbital Atherectomy LMCA Dx Multivessel CAD Complex Bifurcation Disease With Large Area of Myocardium at Risk Complex CTO Last Remaining Conduit Complex Bypass Graft Disease Treated Vessel Supplies Collaterals to Occluded 2 nd Vessel 3) COMORBIDITIES CHF STEMI NSTEMI Advanced Age Valvular Heart Disease Surgical Ineligibility WEANING Stable Hemodynamics Low Dose Inotropic/Pressor Requirement High Dose Inotropic/Pressor Requirement Stunning of Large Area of Wean/Explant in Lab Support 6-24 Hours in CCU Myocardium Following PCI/PTCRA Valvular Heart Disease Support to Wean of Inotropic/Pressors 18 Patrick Hall, MD Les Walters, MD Kraig Wangsnes, MD Patrick Hall, MD Les Walters, MD Kraig Wangsnes, MD Stable Hemodynamics Unable to Wean Escalate to Impella 5.0

19 References: 1. Burkhoff D, Naidu SS. The science behind percutaneous hemodynamic support: A review and comparison of support strategies. Catheter Cardiovasc Interv. 2012;80(5): Remmelink M, Sjauw KD, Henriques JP, et al. Effects of left ventricular unloading by Impella Recover LP 2.5 on coronary hemodynamics. Catheter Cardiovasc Interv. 2007;70(4): O Neill WW, Schreiber T, Wohns DHW, et al. The Current Use of Impella 2.5 in Acute Myocardial Infarction Complicated by Cardiogenic Shock: Results from the cvad Registry. J Interv Cardiol. 2014;27(1): Seyfarth M, Sibbing D, Bauer I, et al. A randomized clinical trial to evaluate the safety and efficacy of a percutaneous left ventricular assist device versus intra-aortic balloon pumping for treatment of cardiogenic shock caused by myocardial infarction. J Am Coll Cardiol. 2008;52(19): Dixon SR, Henriques JP, Mauri L, et al. A prospective feasibility trial investigating the use of the Impella 2.5 system in patients undergoing high-risk percutaneous coronary intervention (The PROTECT I Trial): initial U.S. experience. JACC Cardiovasc Interv. 2009;2(2): O Neill WW, Kleiman NS, Moses J, et al. A prospective, randomized clinical trial of hemodynamic support with Impella 2.5 versus intra-aortic balloon pump in patients undergoing high-risk percutaneous coronary intervention: the PROTECT II study. Circulation. 2012;126(14): Henriques JPS, Ouweneel DM, Naidu SS, et al. Evaluating the learning curve in a clinical trial using a new percutaneous left ventricular support system. Observations from the PROTECT II Trial. Am Heart J doi: /j.ahj Stone GW, Mehran R, Dangas G, et al. Differential impact on survival of electrocardiographic Q-wave versus enzymatic myocardial infarction after percutaneous intervention: a device-specific analysis of 7147 patients. Circulation. 2001;104(6): Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction. Circulation. 2007;116(22): Dangas GD, Kini AS, Sharma SK, et al. Impact of hemodynamic support with Impella 2.5 versus intra-aortic balloon pump on prognostically important clinical outcomes in patients undergoing high-risk percutaneous coronary intervention (from the PROTECT II randomized trial). Am J Cardiol. 2014;113(2): Moussa ID, Klein LW, Shah B, et al. Consideration of a new definition of clinically relevant myocardial infarction after coronary revascularization: an expert consensus document from the Society for Cardiovascular Angiography and Interventions (SCAI). J Am Coll Cardiol. 2013;62(17): Cohen MG, Ghatak A, Kleiman NS, et al. Optimizing rotational atherectomy in high-risk percutaneous coronary interventions: Insights from the PROTECT study. Catheter Cardiovasc Interv doi: /ccd Gregory D, Scotti DJ, de Lissovoy G, et al. A Value-Based Analysis of Hemodynamic Support Strategies for High-Risk Heart Failure Patients Undergoing a Percutaneous Coronary Intervention. Am Health Drug Benefits. 2013;6(2): Burzotta F, Paloscia L, Trani C, et al. Feasibility and long-term safety of elective Impella-assisted high risk percutaneous coronary intervention: a pilot two-centre study. J Cardiovasc Med. 2008;9(10): Sauren LD, Accord RE, Hamzeh K, et al. Combined Impella and Intra-Aortic Balloon Pump Support to Improve Both Ventricular Unloading and Coronary Blood Flow for Myocardial Recovery: An Experimental Study. Artificial Organs. 2007;31(11): Reesink KD, Dekker AL, van Ommen V, et al. Miniature intracardiac assist device provides more effective cardiac unloading and circulatory support during severe left heart failure than intraaortic balloon pumping. CHEST Journal. 2004;126(3): Valgimigli M, Steendijk P, Sianos G, et al. Left ventricular unloading and concomitant total cardiac output increase by the use of percutaneous Impella Recover LP 2.5 assist device during high-risk coronary intervention. Catheter Cardiovasc Interv. 2005;65(2): Remmelink M, Sjauw KD, Henriques JP, et al. Effects of mechanical left ventricular unloading by Impella on left ventricular dynamics in high-risk and primary percutaneous coronary intervention patients. Catheter Cardiovasc Interv. 2010;75(2): Kawashima D, Gojo S, Nishimura T, et al. Left ventricular mechanical support with Impella provides more ventricular unloading in heart failure than extracorporeal membrane oxygenation. ASAIO J. 2011;57(3):

20 20. Meyns B, Stolinski J, Leunens V, et al. Left ventricular support by catheter-mounted axial flow pump reduces infarct size. J Am Coll Cardiol. 2003;41(7): Naidu S. Novel percutaneous cardiac assist devices: the science of and indications for hemodynamic support. Circulation. 2011;123(5): Fincke R, Hochman JS, Lowe AM, et al; SHOCK Investigators. Cardiac power is thestrongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry. J Am Coll Cardiol. 2004;44: Torgerson C, Schmittinger CA, Wagner S, et al. Hemodynamic variables and mortality in cardiogenic shock: a prospective cohort study. Critical Care. 2009;13:R Mendoza DD, Cooper HA, Panza JA. Cardiac power output predicts mortality across a broad spectrum of patients with acute cardiac disease. Am Heart J. 2007;153: Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, Ståhle E, Feldman TE, van den Brand M, Bass EJ, Van Dyck N, Leadley K, Dawkins KD, Mohr FW; SYNTAX Investigators. Percutaneous coronary intervention versus coronary artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009;360: Head SJ, Holmes DR Jr, Mack MJ, Serruys PW, Mohr FW, Morice MC, Colombo A,Kappetein AP; SYNTAX Investigators. Risk profile and 3-year outcomes from the SYNTAX percutaneous coronary intervention and coronary artery bypass grafting nested registries. JACC Cardiovasc Interv. 2012;5: Kovacic JC, Kini A, Banerjee S, et al. Patients with 3-Vessel Coronary Artery Disease and Impaired Ventricular Function Undergoing PCI with Impella 2.5 Hemodynamic Support Have Improved 90-Day Outcomes Compared to Intra-Aortic Balloon Pump: A Sub-Study of the PROTECT II Trial. J Interven Cardiol 2015;28: Data submitted for FDA Pre-Market Approval (PMA) of Impella 2.5 High risk PCI indication. 29. Maini B, Naidu SS, Mulukutla S, et al. Real-World Use of the Impella 2.5 Circulatory Support System in Complex High-Risk Percutaneous Coronary Intervention: The cvad Registry. Catheter Cardiovasc Interv 2012;80: Stretch R, Sauer DM, Yuh DD, et al. National Trends in the Utilization of Short-Term Mechanical Circulatory Support. Incidence, Outcomes and Cost Analysis. J Am Coll Cardiol 2014;64(14): Gregory D, Scotti DJ. A Budget Impact Model to Estimate the Cost Dynamics of Treating High-Risk Heart Failure Patients with Advanced Percutaneous Cardiac Assist Devices: The Payer Perspective. J Manag Care Med 2013;16(1); Maini B, Scotti DJ, Gregory D. Health economics of percutaneous hemodynamic support in the treatment of high-risk cardiac patients: a systematic appraisal of the literature. Expert Rev Pharmacoecon Outcomes Res 2014 Jun;14(3): O Neill, PROTECT II Abstract, Presented at Transcatheter Cardiovascular Therapeutics 2013 INDICATIONS FOR USE Protected PCI The Impella 2.5 and Impella CP Systems are temporary ( 6 hours) ventricular support devices indicated for use during high-risk percutaneous coronary interventions (PCI) performed in elective or urgent, hemodynamically stable patients with severe coronary artery disease, when a heart team, including a cardiac surgeon, has determined high-risk PCI is the appropriate therapeutic option. Use of the Impella 2.5 and Impella CP Systems in these patients may prevent hemodynamic instability, which can result from repeat episodes of reversible myocardial ischemia that occur during planned temporary coronary occlusions and may reduce peri- and post-procedural adverse events. Cardiogenic Shock The Impella 2.5, Impella CP, Impella 5.0, and Impella LD Catheters, in conjunction with the Automated Impella Controller (collectively, Impella System Therapy ), are temporary ventricular support devices intended for short term use ( 4 days for the Impella 2.5 and Impella CP, and 6 days for the Impella 5.0, and Impella LD) and indicated for the treatment of ongoing cardiogenic shock that occurs immediately (< 48 hours) following acute myocardial infarction or open heart surgery or in the setting of cardiomyopathy, including peripartum cardiomyopathy, or myocarditis as a result of isolated left ventricular failure that is not responsive to optimal medical management and conventional treatment measures (including volume loading and use of pressors and inotropes, with or without IABP). The intent of Impella System Therapy is to reduce ventricular work and to provide the circulatory support necessary to allow heart recovery and early assessment of residual myocardial function. Important Risk Information for Impella devices CONTRAINDICATIONS The Impella 2.5, Impella CP, Impella 5.0 and Impella LD are contraindicated for use with patients experiencing any of the following conditions: Mural thrombus in the left ventricle; Presence of a mechanical aortic valve or heart constrictive device; Aortic valve stenosis/calcification (equivalent to an orifice area of 0.6 cm2 or less); Moderate to severe aortic insufficiency (echocardiographic assessment graded as +2); Severe peripheral arterial disease precluding placement of the Impella System; Significant right heart failure*; Combined cardiorespiratory failure*; Presence of an Atrial or Ventricular Septal Defect (including post-infarct VSD)*; Left ventricular rupture*; Cardiac tamponade* * This condition is a contraindication for the cardiogenic shock indication only. POTENTIAL ADVERSE EVENTS Acute renal dysfunction, Aortic valve injury, Bleeding, Cardiogenic shock, Cerebral vascular accident/stroke, Death, Hemolysis, Limb ischemia, Myocardial infarction, Renal failure, Thrombocytopenia and Vascular injury In addition to the risks above, there are other WARNINGS and PRECAUTIONS associated with Impella devices. To learn more visit IM V3