Cardiac Resynchronization Therapy with Implantable Cardioverter Defibrillator (CRT-D) for Mildly Symptomatic Heart Failure

Medtronic CRT FDA-Approved Labeling* NYHA III/IV**NYHA II QRS DurationProlongedLBBB***, QRS ≥ 130 ms LVEF≤ 35%≤ 30% Optimal Medical TherapyYes Approved Device(s)CRT-P, CRT-DCRT-D only *See for complete labeling 7. This is the “expanded indication” population approved for Medtronic in April, **NYHA Class IV patients should be ambulatory with no admissions for HF in the last month and have a reasonable expectation of survival. ***LBBB = Left bundle branch block 2

3 Recent Medtronic Studies Supporting CRT-D Expansion 1 Linde C, et al. JACC. 2008;52: Tang A, et al. N Engl J Med. 2010;363: REVERSE 1 RAFT 2 Study Design Randomized 2:1; CRT±D ON vs. OFF; Double-blinded Randomized 1:1; CRT-D vs. ICD; Double-blinded Size610 randomized1,798 randomized Randomized Duration12 months 18 months minimum; Mean 40 months Primary EndpointHF Clinical Composite Total mortality + HF hospitalization NYHA ClassI and IIII and III

REVERSE 1 : REsynchronization ReVErses Remodeling in Systolic Left VEntricular Dysfunction 1 Linde, C, Abraham, WT, Gold, MR, et al., JACC, Dec 2, 2008; 52 (23): Linde C, et al. JACC. 2008;52:

Prospective, randomized, double-blind, multicenter –73 international centers 37 US, 35 Europe, 1 Canada –610 randomized 2:1 (CRT ON : CRT OFF) Enrollment –September 2004 through September 2006 Follow-up –40 ± 5 months REVERSE: Study Design 5

Inclusion NYHA Class II or I (ACC/AHA Stage C) QRS  120 ms LVEF  40%; LVEDD  55 mm Optimal medical therapy Without permanent cardiac pacing With or without an ICD indication Exclusion NYHA Class III or IV within 90 days prior to enrollment HF hospitalization within 90 days prior to enrollment ACS, acute MI, CABG, or PCI within 90 days prior to enrollment Persistent or permanent atrial arrhythmias REVERSE: Key Inclusion/Exclusion Criteria 82% NYHA Class II 83% received CRT-D 6

Patient classified as worsened Definition: Clinical Composite Response Answer YES to Any Answer NO to ALL Patient classified as unchanged Patient classified as improved Did the patient die? Hospitalized for worsening HF? Crossover due to worsening HF? Worsening NYHA Classification? Moderately or markedly worse on Patient Global Assessment? Improved NYHA Classification? Moderately or markedly improved on Patient Global Assessment? Answer NO to ALL Answer YES to Any 7

Baseline Assessment (n = 684) Successful CRT Implant (n = 621) Randomization 2:1 (n = 610) CRT ON (OMT ± ICD) (n = 419) CRT OFF (OMT  ICD) (n = 191) 12 Months – North American Randomization complete (US n = 343; Canada n = 5) 24 Months – European Randomization complete (Europe n = 262) 42 ineligible or withdrew 97% successful implants 11 exits after implant 99% follow-up compliance at 12 months 8

Primary Endpoint: Clinical Composite Response (CCR) Full Cohort % Worsened at 12 Months 1 and Full Distribution* 1 Linde C, et al. JACC. 2008;52: * Post-hoc analysis. 9 9 CRT OFF (n = 191) CRT ON (n = 419)

Primary Endpoint: Clinical Composite Response (CCR) Expanded Indication* % Worsened at 12 Months** *FDA-approved cohort. **Post-hoc analysis. 10 CRT OFF (n = 60) CRT ON (n = 119)

Secondary Endpoint: Significant Reduction in LV End Systolic Volume Index (LVESVi) 1 – Full Cohort 1 Linde C, et al. JACC. 2008;52:

Significant Reduction in HF Hospitalization or All-Cause Death – Full Cohort and Expanded Indication Population* Yellow = All patients (n = 610); RRR = 51% Blue = Expanded indication cohort (n = 179); RRR = 73% * Post-hoc analysis. 12

All Patients Ischemic Non-ischemic CRT-P CRT-D NYHA I NYHA II Male Female < 65 years ≥ 65 years Non-white White LBBB non-LBBB QRS duration (ms) ≥ 150 Worsened Clinical Composite Response Odds Ratio CRT ON BetterCRT OFF Better REVERSE Clinical Composite Response Worsened Subgroup Analysis – Full Cohort* * Post-hoc analysis. 13

REVERSE Safety: Left Ventricular Lead Complication Rate Similar to Previous Trials 14

REVERSE: Conclusions Primary endpoint not met at 12 months in full cohort (p = 0.10) However… Primary endpoint met at 12 months in expanded indication* cohort (p = 0.004) Totality of data demonstrates CRT-D can safely improve patient outcomes in expanded indication population: –Clinical composite response* –LV structural changes (LVESVi) –Time to first HF hospitalization or all-cause death* * Post-hoc analysis. 15

RAFT 2 : Resynchronization/Defibrillation for Ambulatory Heart Failure Trial 2 Tang A, et al., N Engl J Med. 2010;363:

Prospective, randomized, double-blind, multicenter –1,798 enrolled and randomized patients –34 international centers 24 Canada, 8 Western Europe/Turkey, 2 Australia –Randomization 1:1 (ICD:CRT-D) Enrollment –January 2003 through February 2009 Follow-up –40 ± 20 months RAFT: Study Design 17

RAFT: Key Inclusion/Exclusion Criteria Inclusion Criteria NYHA Class II or III (changed to NYHA Class II only as of February 2006) QRS  120 ms or Paced QRS  200 ms LVEF  30% Optimal medical therapy ICD indication With or without persistent atrial tachycardia Exclusion Criteria NYHA Class I or IV Existing ICD 18

RAFT: Endpoints Primary Endpoint –HF hospitalization or all-cause mortality Key Secondary Endpoint –Mortality 19

Enrollment (n = 1,798) Randomization 1:1 (ICD n = 904; CRT-D n = 894) Device Implant ICD or CRT-D ICD (n = 899) CRT-D (n = 888) 18-month Minimum Follow-Up Mean follow-up 40 months ± 20 months All patients included in the primary analysis 95% successful LV implants (n = 841) 20

Primary Endpoint: Significant Reduction in HF Hospitalization or All-cause Death 7 (Full Cohort) * Adjusted p-value. 21

Primary Endpoint: Significant Reduction in HF Hospitalization or All-Cause Death – NYHA II vs. Expanded Indication Population* Yellow = NYHA II cohort (n = 1,438); RRR = 27% Blue = Expanded indication cohort (n = 850); RRR = 42% * Post-hoc analysis. 22

Secondary Endpoint: Significant Reduction in Mortality – NYHA II vs. Expanded Indication Population* Yellow = NYHA II cohort (n = 1,438); RRR = 29% Blue = Expanded indication cohort (n = 850); RRR = 42% * Post-hoc analysis. 23

RAFT Conclusions Among ICD-indicated patients with mildly symptomatic HF/systolic dysfunction/QRS prolongation, CRT-D: –Reduces heart failure hospitalization or all-cause mortality –Reduces mortality alone Consistently strong evidence in full cohort, NYHA II cohort, and expanded indication population Findings support expanded use of CRT-D in mildly symptomatic heart failure 24

Medtronic Experience with CRT Late 1990s MIRACLE and MIRACLE ICD Clinical Studies FDA Approval CRT and CRT-D CARE-HF 2012 FDA Approval For REVERSE and RAFT 25

More than a Decade of Experience With CRT in Mild Heart Failure 2003: CONTAK CD 6 mos; n = : MICD II 6 mos; n = : REVERSE 12 mos, n = 610; 24 mos, n = : MADIT CRT Average 29 mos, n = 1, : RAFT Average 40 mos, n = 1,438 26

More than a Decade of Experience With CRT in Mild Heart Failure Mortality benefit Mortality benefit in LBBB population* * Post-hoc analysis. 1 Linde C, et al. JACC. 2008;52: Tang A, et al. N Engl J Med. 2010;363: Moss AJ, et al. N Engl J Med. 2009;361: Young JB, et al. JAMA. 2003;289: Higgins S, et al. JACC. 2003;42: : CONTAK CD 6 6 mos; n = : MICD II 5 6 mos; n = : REVERSE 1 12 mos, n = 610; 24 mos, n = : MADIT CRT 4 Average 29 mos, n = 1, : RAFT 2 Average 40 mos, n = 1,438 27

More than a Decade of Experience With CRT in Mild Heart Failure Mortality benefit Reduced HF hospitalizations Mortality benefit in LBBB population* Reduced HF hospitalizations * Post-hoc analysis. Improved CCR Reduced HF hospitalizations* Improved CCR* 2003: CONTAK CD 6 mos; n = : MICD II 6 mos; n = : REVERSE 12 mos, n = 610; 24 mos, n = : MADIT CRT Average 29 mos, n = 1, : RAFT Average 40 mos, n = 1,438 28

More than a Decade of Experience With CRT in Mild Heart Failure Mortality benefit Reduced HF hospitalizations Mortality benefit in LBBB population* Reduced HF hospitalizations Improved cardiac function* * Post-hoc analysis. Improved CCR Improved cardiac function Reduced HF hospitalizations* Improved CCR* Improved cardiac function 2003: CONTAK CD 6 mos; n = : MICD II 6 mos; n = : REVERSE 12 mos, n = 610; 24 mos, n = : MADIT CRT Average 29 mos, n = 1, : RAFT Average 40 mos, n = 1,438 Improved cardiac function 29

CRT Shown to Slow HF Progression in Mild or Moderate/Severe HF MortalityHF or CV Hospitalizations Cardiac Function/ Structure CARE-HF 1,2 +++ COMPANION 3 ++Not collected MIRACLE 4 Not powered for mortality or hospitalization + Not powered MIRACLE ICD 5 REVERSE 6 Not powered+*+ RAFT 7 ++Not collected MADIT CRT 8 +*+ 1 Cleland J, et al. N Engl J Med. 2005;352: Cleland J, et al. Eur Heart J. 2006;27: Bristow M, et al. J Card Fail. 2000;6: Abraham W, et al. N Engl J Med. 2002;346: Young J, et al. JAMA. 2003;289: Linde C, et al. JACC. 2008;52: Tang A, et al. N Engl J Med. 2010;363: Moss A, et al. N Engl J Med. 2009;361: * Post-hoc analysis. 30

Similar Results for CRT in Patients with Mild Symptoms REVERSE: Linde C, et al. JACC. 2008;52: RAFT: Tang A, et al. N Engl J Med. 2010;363: MADIT-CRT: Moss A, et al. N Engl J Med. 2009;361:

32 Consistent Benefit of CRT for Patients with LBBB within Study Cohorts* * Post-hoc analysis for all 3 trials. REVERSE: Linde C, et al. JACC. 2008;52: RAFT: Tang A, et al. N Engl J Med. 2010;363: MADIT-CRT: Cognis 100-D Physician’s Technical Manual, Boston Scientific, Inc. Retrieved from 32 Death or Heart Failure Hospitalization/Event LBBB: REVERSE RAFT Class II MADIT-CRT Non-LBBB: REVERSE RAFT Class II MADIT-CRT CRT-D Better Odds Ratio with 95% CI

Totality of Evidence: Conclusion In the expanded indication patient population, CRT-D: Reduces mortality Reduces heart failure hospitalization Improves cardiac function 33

References 1 REVERSE: Linde C, Abraham WT, Gold MR, et al. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. JACC. Dec 2, 2008;52(23): RAFT: Tang A, Wells GA, Talajic M, et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med. Dec 16, 2010;363(25): COMPANION: Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004:350: MADIT CRT: Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. October 1, 2009; 361(14): MIRACLE ICD: Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA. May 28, 2003; 289(20): CONTAK CD: Higgins S, Hummel J, et al. Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. JACC. 2003;42: REVERSE and RAFT Clinical Studies: Summary of Clinical Results. See 34

Brief Statement Medtronic CRT-D Systems Indications: Medtronic Cardiac Resynchronization Therapy Implantable Cardioverter-Defibrillators (CRT-Ds) are indicated for ventricular antitachycardia pacing and ventricular defibrillation for automated treatment of life-threatening ventricular arrhythmias and for providing cardiac resynchronization therapy in heart failure patients who remain symptomatic despite optimal medical therapy, and meet any of the following classifications: New York Heart Association (NYHA) Functional Class III or IV and who have a left ventricular ejection fraction ≤ 35% and a prolonged QRS duration, Left bundle branch block (LBBB) with a QRS duration ≥ 130 ms, left ventricular ejection fraction ≤ 30%, and NYHA Functional Class II Contraindications: CRT-Ds are contraindicated in patients whose ventricular tachyarrhythmias may have transient or reversible causes; patients with incessant VT or VF; patients who have a unipolar pacemaker. The leads are contraindicated for patients with coronary venous vasculature that is inadequate for lead placement, as indicated by venogram. The lead is also contraindicated in patients for whom a single dose of 1.0 mg of dexamethasone acetate and/or dexamethasone sodium phosphate may be contraindicated. Warnings and Precautions: For the CRT-Ds, changes in a patient’s disease and/or medications may alter the efficacy of the device’s programmed parameters. Patients should avoid sources of magnetic and electromagnetic radiation to avoid possible underdetection, inappropriate sensing and/or therapy delivery, tissue damage, induction of an arrhythmia, device electrical reset, or device damage. Do not place transthoracic defibrillation paddles directly over the device. Certain programming and device operations may not provide cardiac resynchronization. For the leads, people with metal implants such as pacemakers, ICDs, and accompanying leads should not receive diathermy treatment. The interaction between the implant and diathermy can cause tissue damage, fibrillation, or damage to the device components, which could result in serious injury, loss of therapy, or the need to reprogram or replace the device. Potential Complications: Potential complications include, but are not limited to, acceleration of ventricular tachycardia, air embolism, bleeding, body rejection phenomena which includes local tissue reaction, cardiac dissection, cardiac perforation, cardiac tamponade, chronic nerve damage, constrictive pericarditis, death, device migration, endocarditis, erosion, excessive fibrotic tissue growth, extrusion, fibrillation or other arrhythmias, fluid accumulation, formation of hematomas/ seromas or cysts, heart block, heart wall or vein wall rupture, hemothorax, infection, keloid formation, lead abrasion and discontinuity, lead migration/ dislodgement, mortality due to inability to deliver therapy, muscle and/or nerve stimulation, myocardial damage, myocardial irritability, myopotential sensing, pericardial effusion, pericardial rub, pneumothorax, poor connection of the lead to the device, which may lead to oversensing, undersensing, or a loss of therapy, threshold elevation, thrombosis, thrombotic embolism, tissue necrosis, valve damage (particularly in fragile hearts), venous occlusion, venous perforation, lead insulation failure, or conductor or electrode fracture. See the device manual for detailed information regarding the implant procedure, indications, contraindications, warnings, precautions, and potential complications/adverse events. For further information, please call Medtronic at 1 (800) and/or consult Medtronic’s website at Caution: Federal law (USA) restricts these devices to sale by or on the order of a physician. 35

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