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 Duration Prolonged LBBB***, QRS ≥ 130 ms

LVEF ≤ 35% ≤ 30%

Optimal Medical Therapy Yes Yes

Approved Device(s) CRT-P, CRT-D CRT-D only

* See www.manuals.medtronic.com for complete labeling7. This is the “expanded indication” population approved for Medtronic in April, 2012.

** 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;52:1834-1843. 2 Tang A, et al. N Engl J Med. 2010;363:2385-2395.

3

REVERSE1 RAFT2

Study DesignRandomized 2:1;

CRT±D ON vs. OFF; Double-blinded

Randomized 1:1; CRT-D vs. ICD; Double-blinded

Size 610 randomized 1,798 randomized

Randomized Duration 12 months18 months minimum;

Mean 40 months

Primary Endpoint HF Clinical CompositeTotal mortality + HF

hospitalization

NYHA Class I and II II and III

REVERSE1: REsynchronization ReVErses Remodeling in Systolic Left

VEntricular Dysfunction

1 Linde, C, Abraham, WT, Gold, MR, et al., JACC, Dec 2, 2008; 52 (23): 1834-1843.4

1 Linde C, et al. JACC. 2008;52:1834-1843.

• 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 classifiedas worsened

Definition: Clinical Composite Response

Answer YES to Any

Answer NOto ALL

Patient classified as unchanged

Patient classifiedas 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 NOto 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% successfulimplants

11 exits after implant

99% follow-up compliance at

12 months

8

Primary Endpoint: Clinical Composite Response (CCR) Full Cohort % Worsened at 12 Months1 and Full Distribution*

40% 39%

21%

54%

30%

16%

Improved Unchanged Worsened

p = 0.10

p = 0.004

1 Linde C, et al. JACC. 2008;52:1834-1843. * Post-hoc analysis.

99

CRT OFF (n = 191) CRT ON (n = 419)

Primary Endpoint: Clinical Composite Response (CCR) Expanded Indication* % Worsened at 12 Months**

47%

35%

18%

65%

30%

5%

Improved Unchanged Worsened

p = 0.004

* FDA-approved cohort.**Post-hoc analysis.

1010

CRT OFF (n = 60) CRT ON (n = 119)

Secondary Endpoint: Significant Reduction in LV End Systolic Volume Index (LVESVi)1 – Full Cohort

60

70

80

90

100

110

Pre-Implant Baseline 12 Months

LV

ES

Vi (

ml/m

2)

CRT OffAcutely

Delta:-18.2 � 29.4

Delta:-1.6 � 23.4

CRT OFF(n = 165)

CRT ON(n = 328)

p < 0.0001

1 Linde C, et al. JACC. 2008;52:1834-1843.

11

Significant Reduction in HF Hospitalization or All-Cause Death – Full Cohort and Expanded Indication Population*

0%

5%

10%

15%

20%

25%

30%

0 6 12 18 24

Months Since Randomization

% w

ith

HF

Ho

sp

italizati

on

or

Death

CRT ON

CRT OFF

 Yellow = All patients (n = 610); RRR = 51%Blue = Expanded indication cohort (n = 179); RRR = 73% * Post-hoc analysis.

12

0.1 1 10

All Patients  IschemicNon-ischemic  CRT-PCRT-D  NYHA INYHA II  MaleFemale  < 65 years≥  65 years  Non-whiteWhite  LBBBnon-LBBB  QRS duration (ms)120-129130-149≥  150  

Worsened Clinical Composite Response Odds Ratio

CRT ON Better CRT 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

RAFT2: Resynchronization/Defibrillation

for Ambulatory Heart Failure Trial

2 Tang A, et al., N Engl J Med. 2010;363:2385-2395.

16

• 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 ImplantICD 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)

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Primary Endpoint: Significant Reduction in HF Hospitalization or All-cause Death7 (Full Cohort)

0%

10%

20%

30%

40%

50%

60%

0 12 24 36 48 60

Months Since Randomization

HF

Ho

sp

ita

liza

tio

n o

r A

ll-c

au

se

De

ath

Number 904 770 572 384 214 101 remaining 894 779 615 429 278 130

ICD

CRT-D

P = 0.014*HR = 0.75 (0.67-0.96)

* Adjusted p-value.

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Primary Endpoint: Significant Reduction in HF Hospitalization or All-Cause Death – NYHA II vs. Expanded Indication Population*

0%

10%

20%

30%

40%

50%

0 12 24 36 48 60

Months Since Randomization

% w

ith

HF

Ho

sp

itali

zati

on

or

Death

CRT-D

ICD

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*

0%

10%

20%

30%

40%

0 12 24 36 48 60

Months Since Randomization

% M

ort

ali

ty

CRT-D

ICD

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

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Medtronic Experience with CRT

Late 1990s 2001 2002 2005

MIRACLE andMIRACLE ICDClinical Studies

FDA ApprovalCRT and CRT-D

CARE-HF

2012

FDA ApprovalFor REVERSE

and RAFT

25

More than a Decade of Experience With CRT in Mild Heart Failure

2003: CONTAK CD6 mos; n = 263

2004: MICD II6 mos; n = 186

2008: REVERSE12 mos, n = 610; 24 mos, n = 262

2009: MADIT CRTAverage 29 mos, n = 1,820

2010: RAFTAverage 40 mos, n = 1,438

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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;52:1834-1843.2 Tang A, et al. N Engl J Med. 2010;363:2385-2395.3 Moss AJ, et al. N Engl J Med. 2009;361:1329-1338.4 Young JB, et al. JAMA. 2003;289:2685-2694.5 Higgins S, et al. JACC. 2003;42:1454-1459.

2003: CONTAK CD6

6 mos; n = 263

2004: MICD II5

6 mos; n = 186

2008: REVERSE1

12 mos, n = 610; 24 mos, n = 262

2009: MADIT CRT4

Average 29 mos, n = 1,820

2010: RAFT2

Average 40 mos, n = 1,438

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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 = 263

2004: MICD II6 mos; n = 186

2008: REVERSE12 mos, n = 610; 24 mos, n = 262

2009: MADIT CRTAverage 29 mos, n = 1,820

2010: RAFTAverage 40 mos, n = 1,438

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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 CD6 mos; n = 263

2004: MICD II6 mos; n = 186

2008: REVERSE12 mos, n = 610; 24 mos, n = 262

2009: MADIT CRTAverage 29 mos, n = 1,820

2010: RAFTAverage 40 mos, n = 1,438

• Improved cardiac function

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CRT Shown to Slow HF Progression in Mild or Moderate/Severe HF

Mortality HF or CV HospitalizationsCardiac Function/

Structure

CARE-HF1,2 + + +

COMPANION3 + + Not collected

MIRACLE4 Not powered formortality or hospitalization

+

Not poweredMIRACLE ICD5

REVERSE6 Not powered +* +

RAFT7 + + Not collected

MADIT CRT8 +* + +*

1 Cleland J, et al. N Engl J Med. 2005;352:1539-1549.2 Cleland J, et al. Eur Heart J. 2006;27:1928-1932.3 Bristow M, et al. J Card Fail. 2000;6:276-285.

4 Abraham W, et al. N Engl J Med. 2002;346:1845-1853.5 Young J, et al. JAMA. 2003;289:2685-2694.6 Linde C, et al. JACC. 2008;52:1834-1843.

7 Tang A, et al. N Engl J Med. 2010;363:2385-2395. 8 Moss A, et al. N Engl J Med. 2009;361:1329-1338.

* Post-hoc analysis.

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Similar Results for CRT in Patients with Mild Symptoms

REVERSE: Linde C, et al. JACC. 2008;52:1834-1843.RAFT: Tang A, et al. N Engl J Med. 2010;363: 2385-2395.MADIT-CRT: Moss A, et al. N Engl J Med. 2009;361:1329-1338.

31

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;52:1834-1843.RAFT: Tang A, et al. N Engl J Med. 2010;363:2385-2395.MADIT-CRT: Cognis 100-D Physician’s Technical Manual, Boston Scientific, Inc. Retrieved from http://www.accessdata.fda.gov/cdrh_docs/pdf/P010012S230c.pdf

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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

0.1 1 10

1.32

1.10

0.53

0.43

0.63

0.48

Totality of Evidence: Conclusion

In the expanded indication patient population, CRT-D:

• Reduces mortality

• Reduces heart failure hospitalization

• Improves cardiac function

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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):1834-1843.

2 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):2385-2395.

3 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. 2004:350:2140-2150.

4 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):1329-1338.

5 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):2685-2694.

6 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;42:1454-1459.

7 REVERSE and RAFT Clinical Studies: Summary of Clinical Results. See www.manuals.medtronic.com.

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Brief StatementMedtronic 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) 328-2518 and/or consult Medtronic’s website at www.medtronic.com.

Caution: Federal law (USA) restricts these devices to sale by or on the order of a physician.

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www.medtronic.com

 World HeadquartersMedtronic, Inc.710 Medtronic ParkwayMinneapolis, MN 55432-5604USATel: (763) 514-4000Fax: (763) 514-4879

Medtronic USA, Inc.Toll-free: 1 (800) 328-2518(24-hour technical support for physicians and medical professionals)