PCI using LV Support. Jason Kovacic, MD, PhD, FRACP, FACC, FAHA, FSCAI

PCI using LV Support Jason Kovacic, MD, PhD, FRACP, FACC, FAHA, FSCAI

A GROWING POPULATION APPROPRIATE FOR PCI 2 Heart failure, diabetes, advanced age, peripheral vascular disease, complex lesions, history of angina, prior surgery Patient Comorbidities Protected PCI Patients Complex Coronary Artery Disease Multi-vessel disease, Left Main disease Hemodynamic Compromise Protected PCI with Impella 2.5 Now found Safe & Effective by FDA for High Risk PCI in hemodynamically stable patients Stable but depressed ejection fraction (LVEF<35%)

3 TREATMENT OF HIGHER RISK PATIENTS PROTECTED PCI WITH IMPELLA 2.5 HCS-PMA-PP00915-000 rb

Symptoms Symptoms PATIENTS MOST APPROPRIATE FOR REVASCULARIZATION 4 Coronary Revascularization Appropriateness Guidelines ACCF/SCAI/STS/AATS/AHA/ASNC/HFSA/SCCT 1 Heart Failure Angina High Risk Findings on Noninvasive Study CCS Class III or IV Angina Symptoms Med. Rx Class III or IV Max Rx A A A A A Class I or II Max Rx A A A A A Asymptomati c Max Rx U A A A A Class III or IV No/min Rx A A A A A Class I or II No/min Rx U A A A A Asymptomati c No/min Rx U U A A A Protected PCI Patients = More Heart Failure More Angina More Complex = More likely to be appropriate Stress Test Med. Rx High Risk Max Rx A A A A A High Risk No/min Rx A A A A A Int. Risk Max Rx A A A A A Int. Risk No/min Rx U U A A A Low Risk Max Rx U A A A A Low Risk No/min Rx I U A A A Coronary Anatomy CTO of 1 vz.; no other disease 1-2 vz. disease; no Prox. LAD 1 vz. disease of Prox. LAD 2 vz. disease with Prox. LAD 3 vz. disease; no Left Main Coronary Anatomy CTO of 1-vz; no other disease 1-2-vz. disease; no prox. LAD 1-vz. disease of prox. LAD 2-vz. disease with prox. LAD 3-vz. disease; no left main A = Appropriate, U = Uncertain, I= Inappropriate A = Appropriate, U = Uncertain, I= Inappropriate Complexity Complexity 1. Patel MR, et al, J AM Coll Cardiol. 2012;59(9); 857-881

FDA APPROVES IMPELLA 2.5 FOR HIGH RISK PCI 5 Impella is the only hemodynamic support device proven safe and effective in elective and urgent High Risk PCI patients Impella is designed to protect the patient hemodynamically during a high risk procedure

Impella 2.5

HEMODYNAMICS OF PROTECTED PCI 7 Case Example* 66 yo male 85% SVG Last patent conduit EF = 30% NYHA Class IV Prior CABG Prior PCI Hemodynamically stable Not Surgical Candidate MAP 110 mmhg MAP 86 mmhg Impella 2.5 On No Impella Simulated Arterial Pressure Tracings 1-8% -10% -12% 97 mmhg -15% -23% -51% 42 mmhg Case Start Balloon Inflation 1. Physiologic computational modeling, Am J Physiol 1991;260 (HCP 29): H146-H157 * Not all patients will experience the same clinical outcomes or hemodynamic responses 15 sec 30 sec 45 sec

DATA SUPPORTING PROTECTED PCI INDICATION 8 Scientific Evidence to Support PMA Application Total Number of Patients in the Cohort Number of Impella 2.5 Protected PCI Patients Protect I 20 20 Protect II 452 225 U.S. Impella Registry 1,322 637 Literature review 2,537 756 Total 4,331 1,638

9 PROTECTED PCI WITH IMPELLA 2.5 CLINICAL DATA & GUIDELINES

PROTECT II TRIAL DESIGN 11 Patients Requiring Prophylactic Hemodynamic Support During Non-Emergent High Risk PCI on Unprotected LM/Last Patent Conduit and LVEF 35% OR 3 Vessel Disease and LVEF 30% IABP + PCI R 1:1 IMPELLA 2.5 + PCI Primary Endpoint = 30-day Composite MAE* rate Follow-up of the Composite MAE* rate at 90 days *Major Adverse Events (MAE) : Death, MI (>3xULN CK-MB or Troponin), Stroke/TIA, Repeat Revasc, Cardiac or Vascular Operation or Vasc. Operation for limb ischemia, Acute Renal Dysfunction, Increase in Aortic insufficiency, Severe Hypotension, CPR/VT, Angio Failure O Neill et al, Circulation. 2012;126(14):1717-27

PATIENT CHARACTERISTICS OF HIGH RISK 12 REVASCULARIZAT ION STUDY SYNTAX 1 Stent vs. CABG (n=903) HIGH RISK PCI STUDY PROTECT II 2,3 Impella 2.5 vs. IABP (n=427) LVEF 35% (%) ~2 100 CHF (%) 4 87 Unstable Angina 29 40 Diabetes (%) 26 51 Prior MI (%) 32 68 Prior PCI 0 40 Prior CABG 0 34 Age (Mean±SD) 65±10 67±11 Not Surgical Candidates (%) 0 64 * * 64% of patients determined inoperable by surgical consult or refused surgery. Remaining 36% determined not surgical candidate by treating physician. 1.Serruys PW et al., N Engi J Med. 2009;360:961-972 2.Dangas et al., Am. Journ of Cardiol. 2014: 113(2):222-8 3.Pershad, et al., Am J Cardiol. 2014 Sep 1;114(5):657-64

PROTECT II PROCEDURAL CHARACTERISTICS 13 Procedural Characteristics IABP (N=211) Impella (N=216) p-value Use of Heparin 82.4% 93.5% <0.001 IIb/IIIa Inhibitors 26.5% 13.4% <0.001 Total Contrast Media (cc) 241±115 267±141 0.035 Rotational Atherectomy (RA) 9.0% 14.2% 0.083 Median # of RA Passes/lesion (IQ range) 1 (1-2) 3 (2-5) 0.001 Median # of RA passes/pt (IQ range) 2.0 (2.0-4.0) 5.0 (3.5-8.5) 0.003 Median RA time/lesion (IQ range sec) 40 (20-47) 60 (40-97) 0.004 RA of Left Main Artery 3.1% 8.0% 0.024 Total Support Time (hours) 8.23±21.0 1.86±2.7 <0.001 Discharge from Cath Lab on device 37.7% 5.6% <0.001 O Neill et al, Circulation. 2012;126(14):1717-27

Major Adverse Events Rate (%) IMPELLA REDUCES MAJOR ADVERSE EVENTS 14 Per Protocol (N=427) 30 Day MAE 90 Day MAE 50 IABP 51.0% 22% reduction 45 42.2% p=0.092 p=0.023 40.0% 40 35 Impella 34.3% 30 25 N=211 N=216 N=210 N=215 IABP Impella IABP Impella Log rank test, p=0.048 20 0 10 20 30 40 50 60 70 80 90 Time post index procedure (days) MAE= Major Adverse Event Rate O Neill et al, Circulation. 2012;126(14):1717-27

HEMODYNAMIC SUPPORT EFFECTIVENESS 15 Cardiac Power Output Secondary Endpoint Maximal Decrease in CPO on device Support from Baseline (in x0.01 Watts) IABP Impella N=138 N=141-4.2 ± 24 p=0.001-14.2 ± 27 O Neill et al, Circulation. 2012;126(14):1717-27

PRE-SPECIFIED SUB-GROUP ANALYSIS 16 90 day MAE Relative Risk [95% CI] Relative Risk [95% CI] Group p-value Interaction p-value Overall Per Protocol (n=425) 0.79 [0.64, 0.97] 0.023 PCI Procedure Without Atherectomy (n=373) With Atherectomy (n=52) 0.70 [0.55, 0.89] 0.003 1.19 [0.75, 1.91] 0.444 0.087 Anatomy ULM / Last conduit (n=101) 0.82 [0.53, 1.25] 0.351 0.845 3VD (n=324) 0.78 [0.61, 0.99] 0.039 STS Mortality Score STS 10 (n=71) STS < 10 (n=354) 1.14 [0.75, 1.71] 0.540 0.71 [0.56, 0.91] 0.006 0.092 Roll in subject 1 st Impella/IABP Pt per site (n=116) After 1 st Impella/IABP Pt (n=309) 0.92 [0.62, 1.38] 0.697 0.74 [0.58, 0.95] 0.016 0.348 O Neill et al, Circulation. 2012;126(14):1717-27 0.0 0.5 1.0 1.5 2.0 Impella better IABP better Per Protocol

ADDITIONAL IMPELLA SAFETY ENDPOINTS 1 17 IABP Control Arm (n=210) Impella Protected PCI (n=215) p- value Aortic Valve Damage 0 0 NA Vascular Complications 2 1.9% 1.4% 0.680 Acute Renal Dysfunction 4.8% 4.2% 0.774 (Total Contrast media) 3 (241 ml) (267 ml) (0.036) 1. O Neill WW et al. Circulation. 2012 Oct 2:126(14):1717-27 2. Vascular complications from Protect II RCT = Cardiac, thoracic, or abdominal operation, or vascular operation for limb ischemia. 3. Acute renal dysfunction was numerically lower even with additional contrast media in the Protected PCI with Impella arm of Protect II RCT

REDUCED MAE IN 3-VESSEL SUBGROUP 18 Kovacic, et al. J Interv Cardiol. 2015 Feb;28(1):32-40 FDA Approved Randomized Controlled Trial Protect II

IMPELLA MAINTAINS PATIENT HEMODYNAMICS ALLOWING FOR MORE COMPLETE REVASCULARIZATION 19 Procedural Decrease in Arterial Pressure from Baseline 1 Vessel Treated 2 Vessels Treated 3 Vessels Treated Baseline IABP Impella N = 325-2.7% Protected PCI -8.5% -7.6% p <0.001 p =0.007 p =0.026-13.1% -14.9% Kovacic, et al. J Interv Cardiol. 2015 Feb;28(1):32-40 -18.8% FDA Approved Randomized Controlled Trial Protect II

MACCE (%) IMPELLA REDUCES PERI & POST PROCEDURAL MACCE (MAJOR ADVERSE CARDIAC AND CEREBROVASCULAR EVENTS) 20 30 25 MACCE = Death, Stroke, MI, Repeat revasc. IABP 29% reduction In MACCE 20 N=211 15 Impella N=216 10 p=0.042 0 10 20 30 40 50 60 70 80 90 Time Post Procedure (day) Dangas et al, Am. Journ of Cardiol. 2014: 113(2):222-8 FDA Approved Randomized Controlled Trial Protect II

IMPELLA SUPPORT INCREASES ARTERIAL PRESSURE 21 U.S. Impella Registry Data 1 N=148 Systolic Pressure p<0.0001 139±27 119±25 Diastolic Pressure p<0.0001 81±19 Mean Pressure p<0.0001 101±20 17% 83±18 64±15 26% 22% Pre- Impella On Impella Pre- Impella On Impella Pre- Impella On Impella 1. Maini et al,.catheter Cardiovasc Interv. 2012 Nov 1;80(5):717-25

Cumulative Incidence of MAE SIMILAR RATES OF MAJOR ADVERSE EVENTS TO 90 DAYS FOR PATIENTS 80 YEARS VS. < 80 YEARS OLD 22 55% 50% 45% 40% 35% 30% 25% 20% 15% Patients 80 years old (N=59) Patients <80 years old (N=368) 10% 5% 0% Log rank test p=0.957 0 30 60 90 Time after Initial Procedure (days) Pershad et. al. AJC. 2014 Sep 1;114(5):657-64

IMPELLA 2.5: INDEPENDENT PREDICTORS OF FAVORABLE OUTCOMES TO 90 DAYS 23 Variable OR Estimate 95% Conf. Interval p value Device: Impella 2.5 0.601 [0.391, 0.923] 0.020 Age 80 years 1.031 [0.459, 2.315] 0.941 Diabetes Mellitus 1.126 [0.747, 1.698] 0.571 Acute Myocardial Infarction 1.424 [0.747, 2.712] 0.283 Renal Insufficiency 1.921 [1.177, 3.137] 0.009 Hemoglobin (g/dl) 0.902 [0.804, 1.013] 0.082 Impella 2.5 * age 80 years 2.174 [0.683, 6.922] 0.189 Pershad et. al. AJC. 2014;114(5):657-64

Major Adverse Events Rate (%) IMPELLA REDUCES MAJOR ADVERSE EVENTS 24 Pre-specified High Risk PCI Without Atherectomy Group (N=375) 30 Day MAE 50.5% 90 Day MAE 29% reduction 50 45 IABP 40 41.9% p=0.003 35 p=0.01 35.5% 30 Impella 29.3% N=191 N=184 N=191 N=184 IABP Impella IABP Impella 25 Log rank test, p=0.005 20 0 10 20 30 40 50 60 70 80 90 Time from index procedure (days) MAE= Major Adverse Event Rate Cohen et al, Catheter Cardiovasc Interv. 2014 Jun 1;83(7):1057-64

COST EFFECTIVENESS OF PROTECTED PCI 25 Reduced Length of Stay Total Days in Hospital 1,3 Economic Study Less Readmissions from Repeat Procedures 9.0 p=0.008 2 days or 22% 12.4% p=0.024 52% Reduction 7.0 6.0% N=211 N=216 N=211 N=216 IABP Impella IABP Impella Median days in hospital; index stay through 90 days, N=427, Readmissions N=208 1. Gregory, O Neill, et al. American Health & Drug Benefits 2013 Mar;6(2):88-99 2. Gregory, et al. Managed Care Medicine, Feb 2013 3. Maini, et al. Expert Rev Pharmacoecon Outcomes Res. 2014 Jun;14(3):403-16

HIGH RISK PATIENTS MAY BENEFIT FROM PROTECTED PCI 26 LVEF Improvement Post Protected PCI 2 Italian Ctrs Study 1 (n=10) 41±13 Protect I 2 (n=16) 31±7 32% p=0.02 26±6 34±11 p=0.003 31% Pre-PCI Follow-up Pre-PCI Follow-up U.S. Impella Registry 3 (n=175) 35±15 30±15 17% p<0.0001 27±9 Protect II 4 (n=175) 22% 33±11 p<0.001 Pre-PCI Follow-up Pre-PCI Follow-up 1. Burzotta et al. Cardiovasc Med 2008 Oct;9(10):1004-10.; 2. Dixon et al. JACC Cardiovasc Interv. 2009 Feb;2(2):91-6; 3. Maini et al,.catheter Cardiovasc Interv. 2012 Nov 1;80(5):717-25.; 4.O Neill et al. Circulation. 2012 Oct 2:126(14):1717-27

IMPELLA 2.5 LABELING 27 Indication for Use The Impella 2.5 System is a temporary (< 6 hours) ventricular support device indicated for use during high risk PCI in elective or urgent, hemodynamically stable patients with severe CAD and depressed LVEF, when a heart team, including a cardiac surgeon, has determined high risk PCI is the appropriate therapeutic option. Use of the Impella 2.5 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 periand post-procedural adverse events.

IMPELLA 2.5 LABELING 28 Warnings and Contraindications The Impella 2.5 is contraindicated for use : (1) mural thrombus in the left ventricle; (2) Mechanical aortic valve or heart constrictive device; (3) Aortic valve stenosis/calcification (equivalent to an orifice of 0.6 cm2 or less); (4) Moderate to severe aortic insufficiency (echocardiographic assessment of aortic insufficiency graded as +2); and (5) Severe peripheral arterial disease that precludes the placement of the Impella 2.5 Additionally, potential for the following risks has been found to exist with use of the Impella 2.5: Acute renal dysfunction; Aortic insufficiency; Aortic valve injury; Atrial fibrillation; Bleeding; Cardiogenic shock; Cardiac tamponade; Cardiopulmonary resuscitation; Cerebral vascular accident/stroke; Death; Device malfunction; Failure to achieve angiographic success; Hemolysis; Hepatic failure; Insertion site infection; Limb ischemia; Myocardial infarction; Need for cardiac, thoracic or abdominal operation; Perforation; Renal failure; Repeat revascularization; Respiratory dysfunction; Sepsis; Severe hypotension; Thrombocytopenia; Thrombotic vascular (non-cns) complication; Transient ischemic attack; Vascular injury; Ventricular arrhythmia, fibrillation or tachycardia The Impella 2.5 s product labeling allows for the clinical decision to leave Impella 2.5 in place beyond the intended duration of <6 hours due to unforeseen circumstances.

SUMMARY OF PROTECT II 29 1. Candidates are hemodynamically stable, higher risk patients that have depressed LVEF, complex CAD, & co-morbidities 2. Higher risk patients are appropriate for revascularization according to AUC criteria; a heart team should determine PCI or CABG 3. Impella is the only hemodynamic support device proven safe and effective in elective and urgent High Risk PCI patients 4. Benefits from a Protected PCI may include: More complete revascularization with reduction in MACCE Reduction in symptoms and class of heart failure Improvement in LVEF post procedure Reduction in days in the hospital Reduction in readmissions due to fewer repeat procedures 5. Clinical guidelines and the FDA approval support the use of Impella 2.5 for Protected PCI in this higher risk patient population

The TandemHeart System Percutaneous extracorporeal platform for temporary circulatory support 5.0 L/min of percutaneous cardiac output augmentation Centrifugal pump capable of full pressure support 5.0 L/min percutaneous (8.0 L/min surgical)

How the System Works: TandemHeart Transseptal Cannula Withdraws oxygenated blood from the left atrium to bypass the left ventricle. 21Fr cannula available in 62cm and 72cm lengths. TandemHeart Transseptal Cannula

How the System Works: TandemHeart Centrifugal Pump Centrifugal pump provides up to 5 liters per minute of forward flow in a percutaneous configuration. Provides uniform flow and full pressure support. TandemHeart Centrifugal Pump

Kovacic et al. CCI; 2013 Baber et al. Thromb Haemost. 2013 Jul 1;110(1):118-23

Impella 2.5 vs. TandemHeart for High-Risk PCI Demographics 68 patients (36 Impella, 32 TH); 72% males 4/2005 6/2010 Mean age: 71.1 ± 12.1 yrs Diabetes: 47% LVEF: 31.0 ± 13% Number diseased vessels: 2.5 ± 0.7 STS mortality: 4.2 ± 3.7% STS morbidity and mortality: 23.3 ± 13.4 Kovacic et al. CCI; 2013

Impella 2.5 vs. TandemHeart for High-Risk PCI Lesion Details Kovacic et al. CCI; 2013

Impella 2.5 vs. TandemHeart for High-Risk PCI Procedural Details ocd. Time: 67.0 ± 39.1 vs. 41.7 ± 38.7 mins (p = 0.009 TH v Impella) Kovacic et al. CCI; 2013

Impella 2.5 vs. TandemHeart for High-Risk PCI Periprocedural and In-Hosp Outcomes Kovacic et al. CCI; 2013

Impella 2.5 vs. TandemHeart for High-Risk PCI Event Free Survival Kovacic et al. CCI; 2013

Impella 2.5 vs. TandemHeart for High-Risk PCI Conclusions Both Impella and TandemHeart are feasible, safe effective during elective high-risk PCI No difference in acute or intermediate-term complications or outcomes when used for hemodynamic support during high-risk PCI Kovacic et al. CCI; 2013

Absolute Reasons to use TandemHeart over Impella LV thrombus Significant native aortic valve disease AS or AI Metallic aortic valve prosthesis Support during TAVR (?) Severe aortic pathology Pedunculated atheromatous disease etc Kovacic et al. CCI; 2013

Objectives for Circulatory Support TandemHeart is designed to meet two objectives for circulatory support: Augment the flow of oxygenated blood to vital organs Decompress the left ventricle to reduce cardiac work W = V f pdv V i Work is a function of both Pressure and Volume Different cannulation & pump types have different performance profiles.

Average Flow (L/min) TandemHeart vs. LV-Axial Support TandemHeart operates at 90 mmhg pressure, similar to a healthy native heart All LV-axial devices operate at lower pressures (60 mmhg) Performance is defined by a combination of pressure and flow Pressure (mmhg) Flow (L/min) Power (Watts) Healthy Left Ventricle 90 5.0 1.00 TandemHeart @ 7,500 rpm 90 4.4 0.88 21 Fr Axial @ P9 60 4.4 0.59 14 Fr Axial @ P8 60 3.3 0.44 12 Fr Axial @ P8 60 2.1 0.28 6.0 5.0 4.0 3.0 2.0 Power Output (Watts) 0.59 0.44 0.28 1.00 0.88 Healthy Left Ventricle TandemHeart @ 7,500 rpm 21 Fr Axial @ P9 14 Fr Axial @ P8 12 Fr Axial @ P8 1.0 50 60 70 80 90 100 Average Pressure (mmhg)

Greater LV unloading with TandemHeart in porcine models Kapur et al. ESC; 2013

Summary of Device Performance TandemHeart Transseptal Support Physiologic pressure (90 mmhg) and flow (4-5 L/min) Maximum left ventricular unloading, up to 80-90% More complex insertion requiring trans-septal puncture LV-Axial Circulatory Support (e.g., Impella) Comparable flow to TH only with largest device Lower pressure capability (60 mmhg) Ease of use; no trans-septal puncture; only needs arterial access Percutaneous Cardiopulmonary Bypass (i.e., VA ECMO) Physiologic pressure & flow, but Significant increase in left ventricular pressure, volume & strain

Role of the Tandem Heart Device(s) in Contemporary Practice Complex PCI when axial device contraindicated Acute cardiac failure Right heart failure Surgical support Other

The use of IABP did not reduce 30- day mortality in patients with cardiogenic shock complicating AMI for whom early revasc was planned.

IABP SHOCK II Patient Characteristics

IABP SHOCK II Patient Characteristics

IABP SHOCK II Patient Anatomy

IABP SHOCK II Outcomes

IABP SHOCK II Outcomes

IABP SHOCK II Outcomes by sub-group

IABP SHOCK II 12 month mortality

IABP SHOCK II Failed to show any benefit of IABP use in patients with AMI complicated by cardiogenic shock undergoing PCI

2013 ACCF/AHA Guidelines for Management of STEMI

2014 ACC/AHA Guidelines for Management of NSTEMI

Good Luck

MORE COMPLETE REVASCULARIZATION LEADS TO REDUCED ADVERSE EVENTS 60 MACCE at 90 Days Protect II, Both IABP and Impella Arms, All Patients 33.8% p=0.019 23.3% 17.0% N=157 N=215 N=53 1 Vessel Treated 2 Vessels Treated 3 Vessels Treated O'Neill, PROTECT II Abstract, Presented at Transcatheter Cardiovascular Therapeutics 2013 FDA Approved Randomized Controlled Trial Protect II

Major Adverse Events Rate (%) STUDY DEVICE LEARNING CURVE EFFECT 61 Pre-specified High Risk PCI Without First Enrolled Patient (N=374) 30 Day MAE 90 Day MAE 55% 42.1 p=0.066 52.0 38.5-22% p=0.017 50% 45% 40% 1 st Patient IABP 32.1 35% Impella 30% 25% Log-rank test, remaining IABP vs. remaining Impella patients, p=0.058 N=152 N=162 N=152 N=161 IABP Impella IABP Impella 20% 0 30 60 Time post index procedure (days) 90 MAE= Major Adverse Event Rate Henriques et al, Am Heart J. 2014 Apr;167(4):472-479

IMPROVEMENT IN QUALITY OF LIFE POST PCI 62 NYHA Class Improvement Post Procedure p<0.001 17% 58% Reduction in Class III,IV 8% 18% Class IV 45% 30% Class III Class II 31% 44% Class I 7% Baseline 90 days N=223 patients from Both Arms of Protected II Trial with NYHA measurements available at baseline and 90 days 1 O Neill WW et al. Circulation. 2012 Oct 2:126(14):1717-27 FDA Approved Randomized Controlled Trial Protect II

Incremental cost per life year or QALY ($thousands) IMPELLA IS COST-EFFECTIVE 63 $274k $175 $199k $150 $125 $100 <$100,000 Threshold (US) $75 $50 $25 $0 1 Aspirin MI Impella Emergent -$135k 2 3 4 5 6 7 8 9 10 8 11 12 13 CRT-P C-reactive Protein Clopidogrel Impella PROTECT II CRT-D Impella US Registry TAVR (LYG) AF ablation Impella EU Registry Dialysis (LYG) LVAD 1 DT(LYG) LVAD 2 DT(LYG) 1. Maini, et al. CCI, 2014 2. Earnshaw, et al. Arch. of Intern Med., 2011. 3. Feldman, et al. JACC, 2005. COMPANION 4. Choudhry, et al. JACC, 2011. JUPITER 5. Chen, et al. ISPOR, 2009.CHARISMA 6. Gregory, et al. Am Health & Drug Ben, 2013 7. Feldman, et al. JACC, 2005. COMPANION 8. Roos, et al. J Med Econ, 2013 9. Reynolds, et al. ACC, 2011. 10. Reynolds, et al. Circ Arrhythm Electrophysiol, 2009 11. Winkelmayer, et al. Medical Decision Making, 2002. 12. Slaughter, et al. AHA, 2011. 13. Russo, et al. ACC 2010.

Kovacic Lab Mount Sinai