BLOCK HF StudyBLOCK HF Study

Biventricular versus Right Ventricular Biventricular versus Right Ventricular Pacing in Patients with Left Ventricular Pacing in Patients with Left Ventricular

Dysfunction and Atrioventricular Block – Dysfunction and Atrioventricular Block – Preliminary ResultsPreliminary Results

Anne B. Curtis, Buffalo, NYSeth J. Worley, Lancaster, PA

Philip B. Adamson, Oklahoma City, OKEugene S. Chung, Cincinnati, Ohio

Imran Niazi, Milwaukee, WILou Sherfesee, Minneapolis, MNTimothy S. Shinn, Ann Arbor, MI

Martin St. John Sutton, Philadelphia, PA

On behalf of the BLOCK HF Trial Investigators and Coordinators

AcknowledgmentsSteering CommitteeSteering Committee

Curtis AB (Principal Investigator), Adamson PB , Chung ES, St. John Sutton MG, Worley SJ

Echo Core LabEcho Core LabSt. John Sutton MG, Plappert T

Adverse Events Advisory CommitteeAdverse Events Advisory Committee Boehmer JP, Meyer TE(Chair), Smith AL, De Lurgio DB

Data Monitoring CommitteeData Monitoring CommitteeSteinberg JS (Chair), DeMarco T, Elkayam U, Louis TA (Statistician)

InvestigatorsInvestigatorsCanada: Rinne C, Thibault BUnited States: Adamson PB, Al-Sheikh T, Andriulli J, Barber MJ, Beau S, Bell M, Borgatta L, Brodine W, Canosa R, Chung ES, Compton S, Curtis AB, Ellison K, Evonich R, Faddis M, Foreman B, Murray C, Guerrero M, Herre J, Hodgkin D, Huang D, Keim S, Kocovic D, Kusmirek SL, Lessmeier T, Levanovich P, Lobban JH, Mackall JA, Manaris A, McBride W, McKenzie J, Mela T, Merliss A, Mitrani R, Mittal S, Mounsey P, Navone A, Niazi I, Obel O, Oren J, Patel P, Patel V, Pickett A, Rao A, Rist K, Rosenblum A, Saba S, Sakaguchi S, Sandler D, Sangrigoli R, Shinn TS, Simmons T, Simonson J, Smith JE, Telfer EA, Tobias S, Tomassoni G, Worley SJ

SponsorSponsorMedtronic Inc.

Clinical Trials.gov Identifier:Clinical Trials.gov Identifier: NCT00267098

Caution: Use of CRT devices for AV block and systolic dysfunction patients without ventricular dyssynchrony is not an approved use in the United States.

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BackgroundCLINICAL IMPORTANCECLINICAL IMPORTANCE

• Over 1 million people world-wide and 819,000 people in the US have atrioventricular (AV) block

• Currently treated with standard pacemaker (i.e. right ventricular (RV pacing)) therapy

• Approximately 6 million in the US are currently diagnosed with heart failure (HF) and approximately 670,000 new cases confirmed each year

• According to AHA 2012 statistics, this costs the US approximately $20 to $56 billion annually

• DAVID and MOST Trial results have shown that RV pacing may have long-term deleterious effects

• Can biventricular (BiV) pacing Can biventricular (BiV) pacing preventprevent progression of heart failure progression of heart failure and its clinical and economic consequences in AV block?and its clinical and economic consequences in AV block?

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Study Design

Implant(CRT-P/D)

Establish OMT(30-60 days)

Establish OMT(30-60 days)

Randomize 1:1

Control:RV pacing

Treatment:BiV pacing

Double-Blind

Double-Blind

Follow-upEvery 3 months

Follow-upEvery 3 months

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ELIGIBILITY CRITERIAELIGIBILITY CRITERIA

• AV block necessitating pacing

• Left ventricular ejection fraction (LVEF) < 50%

• NYHA functional class I, II or III

• Absence of a Class I indication for resynchronization therapy

• No previous pacemaker or implantable cardioverter defibrillator (ICD)

•Echocardiography performed at Randomization, 6, 12, 18 and 24 months

OMT=optimal medical therapy CRT-P=cardiac resynchronization therapy pacemaker CRT-D=CRT defibrillator

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Study Purpose and ObjectivesPurpose:Purpose: Biventricular pacing is superior to RV apical pacing in patients with AV block and LVEF <50% who require ventricular pacing

Endpoints:Endpoints:

Primary:Primary: Composite of:

•All-cause mortality,

•HF-related urgent care, defined as

•HF hospitalization requiring IV therapy, or

•Any unplanned visit requiring intravenous HF therapy, and

•Increase in left ventricular end systolic volume index (LVESVI) >15%

Key Secondary: Key Secondary: All-cause mortality,

All-cause mortality/HF hospitalization,

HF hospitalization

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MethodsStudy featured:Study featured:•Adaptive sample size

•Pre-specified interim analyses

•Stopping rules for success, safety, futility

Analysis: Analysis: Intention-to-treat Bayesian survival analysis using time to first event

Parameter of interest for each endpoint: Parameter of interest for each endpoint: BiV to RV hazard ratio (HR)

Metric: Metric: Probability that HR < 1

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Endpoint Study Success Criteria

Primary Endpoint (Mortality, HF Urgent Care, LVESVI) Probability of (HR <1) > 0.9775

Secondary Endpoints All-cause Mortality All-cause Mortality/HF Hospitalization HF Hospitalization

Probability of (HR <1) > 0.95Probability of (HR <1) > 0.95Probability of (HR <1) > 0.95

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Study Flow Diagram

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Enrollment

918 Assessed for eligibility

691 Randomized 1:1

Allocation

349 Allocated to Biventricular Pacing 346 Received allocated intervention 3 Did not receive allocated intervention

342 Allocated to Right Ventricular Pacing 342 Received allocated intervention

52 Exited/lost to follow-up75 Deaths13 Crossed over to Right Ventricular Pacing 3 Met primary endpoint prior to crossover

50 Exited/lost to follow-up90 Deaths84 Crossed over to Biventricular Pacing 50 Met primary endpoint prior to crossover

349 Analyzed 83 Censored for primary endpoint due to missing LVESVI data

342 Analyzed 71 Censored for primary endpoint due to missing LVESVI data

Follow-up

Analysis

227 Subjects not randomized: 95 Subjects for which AV conduction testing criteria not met prior to implant 14 Subject withdrawals prior to implant 51 Unsuccessful implants 67 Implanted subjects not randomized

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Follow-Up ExperienceBiV (N=349) RV (N=342)

Average Follow-up (months) 36.3 ± 23.1 37.9 ± 23.5

Follow-up Compliance (% of visits) 94.6% 93.8%

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Baseline DemographicsCRT-P CRT-D

BiV (N=243) RV (N=241) BiV (N=106) RV (N=101)

% Male 75% 70% 82% 80%

Age, years 74 ± 10 74 ± 11 72 ± 9 71 ± 10

LVEF, % 43 ± 7 43 ± 7 33 ± 8 33 ± 8

Heart Rate, beats/min 69 ± 23 69 ± 24 68 ± 17 69 ± 17

QRS Duration, ms 125 ± 33 125 ± 31 123 ± 30 119 ± 30

NYHA INYHA IINYHA III

14%58%27%

20%52%28%

10%63%26%

16%57%27%

Left Bundle Branch Block 35% 31% 35% 27%

Ischemic Heart Disease 39% 38% 63% 58%

1st Degree AV Block2nd Degree AV Block3rd Degree AV Block

17%33%49%

15%29%56%

27%33%40%

31%38%32%

ACE Inhibitor/ARB at Randomization 71% 74% 83% 88%

Beta Blocker at Randomization 75% 78% 92% 92%

Diuretics at Randomization 64% 66% 72% 70%

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Primary Endpoint Results: Mortality/HF Urgent Care/LVESVI

Cohort Estimated HR (95% CI) Probability HR < 1 ThresholdAll Randomized Subjects 0.74 (0.60, 0.90) 0.9978 0.9775

CRT-P Only CRT-D Only

0.73 (0.58, 0.91)0.75 (0.57, 1.02)

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Eve

nt-

Fre

e R

ate

(%

)

BiV ArmRV Arm

0

20

40

60

80

100

0 12 24 36 48 60 72

Number of MonthsNumber at RiskBiV: 349 161 87 62 38 17 3RV: 342 126 59 39 28 18 10

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Clinical Components of Primary Endpoint: Mortality/HF Urgent Care Visits

Cohort Estimated HR (95% CI) Probability HR < 1 ThresholdAll Randomized Subjects 0.73 (0.57, 0.92) 0.997 N/A

CRT-P Only CRT-D Only

0.73 (0.56, 0.94)0.73 (0.53, 1.02)

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Eve

nt-F

ree

Rat

e (%

)

BiV ArmRV Arm

0

20

40

60

80

100

0 12 24 36 48 60 72

Number of MonthsNumber at RiskBiV: 349 271 195 134 91 52 17RV: 342 248 180 121 88 54 22

Secondary Endpoint: Mortality/HF Hospitalization

Cohort Estimated HR (95% CI) Probability HR < 1 ThresholdAll Randomized Subjects 0.78 (0.61, 0.99) 0.9802 0.95

CRT-P Only CRT-D Only

0.77 (0.58, 1.00)0.80 (0.58, 1.13)

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Eve

nt-

Fre

e R

ate

(%

)

BiV ArmRV Arm

0

20

40

60

80

100

0 12 24 36 48 60 72

Number of MonthsNumber at RiskBiV: 349 270 198 137 93 54 17RV: 342 258 193 128 94 55 21

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Secondary Objective Results: HF Hospitalization and Mortality

Cohort HF Hospitalization Mortality ThresholdEstimated HR (95% CI) Probability

HR < 1Estimated HR (95% CI) Probability

HR < 1All Randomized Subjects 0.70 (0.52, 0.93) 0.9922 0.83 (0.61, 1.14) 0.8588 0.95

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HF Hospitalization Mortality

Eve

nt-F

ree

Rat

e (%

)

BiV ArmRV Arm

0

20

40

60

80

100

0 12 24 36 48 60 72Number of MonthsNumber at Risk

BiV: 349 270 198 137 93 54 17RV: 342 258 193 128 94 55 21

Eve

nt-F

ree

Rat

e (%

)

BiV ArmRV Arm

0

20

40

60

80

100

0 12 24 36 48 60 72Number of MonthsNumber at Risk

BiV: 349 290 222 152 111 68 25RV: 342 290 228 168 123 72 31

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Adverse Events

Note: Table below includes pre-randomization AE’s

Number of Adverse Events (N, % of Subjects)

CRT-P CRT-D

BiV (N=243) RV (N=241) BiV (N=106) RV (N=101)

Procedure-related Complications 50 (41, 17%) 32 (25, 10%) 18 (18, 17%) 21 (16, 16%)

System-related Complications* Generator-related LV lead-related

41 (36, 15%)10 (10, 4%)16(15, 6%)

37 (31, 13%)11 (11, 5%)13 (13, 5%)

48 (40, 38%)32 (32, 30%)

6 (6, 6%)

34 (24, 24%)13 (12, 12%)

10 (9, 9%)

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* Subcategories for other system-related complications such as RA or RV-related complications not included

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Strengths and Limitations

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• STRENGTHS:STRENGTHS:• Prospective, randomized, double-blind control design• Largest, longest follow-up trial to date• First to show difference in outcomes in AV block and LV

systolic dysfunction patients with BiV vs. RV pacing

• LIMITATIONS:LIMITATIONS:• Long enrollment duration• Censoring due to missing LVESVI in primary objective• Crossover imbalance between arms:

• 24.6% crossed over from RV to BiV• 4.6% crossed over from BiV to RV

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Conclusions

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• In patients with AV block and LV systolic dysfunction In patients with AV block and LV systolic dysfunction (LVEF < 50%), BiV pacing compared to RV pacing leads to (LVEF < 50%), BiV pacing compared to RV pacing leads to a significant 26% reduction in the combined endpoint of a significant 26% reduction in the combined endpoint of mortality, heart-failure related urgent care, and increase in mortality, heart-failure related urgent care, and increase in LVESVI.LVESVI.

• Furthermore, there is a 27% relative risk reduction in the Furthermore, there is a 27% relative risk reduction in the composite endpoint of heart-failure urgent care and all-composite endpoint of heart-failure urgent care and all-cause mortality cause mortality

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Back-up Slides

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Post-randomization Cross-overs

Device Group RV to BiV BiV to RVCRT-P 60 (24.9%) 9 (3.7%)

CRT-D 24 (23.8%) 7 (6.6%)

Total 84 (24.6%) 16 (4.6%)

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* Percentages reflect percentage of subjects randomized subjects

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