1. BLOCK HF Study Biventricular versus Right Ventricular Pacing in Patients with Left Ventricular Dysfunction and Atrioventricular Block – Preliminary Results
Anne B. Curtis, Buffalo, NY
Seth J. Worley, Lancaster, PA
Philip B. Adamson, Oklahoma City, OK
Eugene S. Chung, Cincinnati, Ohio
Imran Niazi, Milwaukee, WI
Lou Sherfesee, Minneapolis, MN
Timothy S. Shinn, Ann Arbor, MI
Martin St. John Sutton, Philadelphia, PA
On behalf of the BLOCK HF Trial Investigators and Coordinators

2. Acknowledgments BLOCK HF Steering Committee
Curtis AB (Principal Investigator), Adamson PB , Chung ES, St. John Sutton MG, Worley SJ
Echo Core Lab
St. John Sutton MG, Plappert T
Adverse Events Advisory Committee
Boehmer JP, Meyer TE(Chair), Smith AL, De Lurgio DB
Data Monitoring Committee
Steinberg JS (Chair), DeMarco T, Elkayam U, Louis TA (Statistician)
Investigators
Canada: Rinne C, Thibault B
United 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
Sponsor
Medtronic Inc.
Clinical Trials.gov Identifier: NCT
Caution: Use of CRT devices for AV block and systolic dysfunction patients without ventricular dyssynchrony is not an approved use in the United States.
You may want to lead into the presentation to your fellow investigators with a summary of the August 2012 DMC meeting and what has led everyone to this meeting.
BLOCK HF

3. Background
Clinical 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 prevent progression of heart failure and its clinical and economic consequences in AV block?
BLOCK HF

4. Study Design BLOCK HF AV block necessitating pacing
ELIGIBILITY 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
Implant
(CRT-P/D)
Establish OMT
(30-60 days)
Randomize 1:1
Control:
RV pacing
Treatment:
BiV pacing
You might want to comment that a brief summary of why a Bayesian approach was chosen and how to interpret the data via Bayesian methods will be described in an upcoming slide.
Double-Blind
OMT=optimal medical therapy
CRT-P=cardiac resynchronization therapy pacemaker
CRT-D=CRT defibrillator
Follow-up
Every 3 months
Follow-up
Every 3 months
BLOCK HF

5. Study Purpose and Objectives
Purpose: Biventricular pacing is superior to RV apical pacing in patients with AV block and LVEF <50% who require ventricular pacing
Endpoints:
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: All-cause mortality,
All-cause mortality/HF hospitalization,
HF hospitalization
1. Describe the difference between the primary HF morbidity objective and the secondary HF hospitalization in that for the primary, the patient must have presented with HF symptoms in which IV diuretics or in which was classified as meeting the primary objective even if HF wasn’t the primary reason for the hospitalization, but later developed HF and given IV diuretics while being hospitalized. The secondary objective hospitalization was met if the patient was admitted for HF and may or may not have received IV therapies
BLOCK HF

6. Study Success Criteria
Methods
Study featured:
Adaptive sample size
Pre-specified interim analyses
Stopping rules for success, safety, futility
Analysis: Intention-to-treat Bayesian survival analysis using time to first event
Parameter of interest for each endpoint: BiV to RV hazard ratio (HR)
Metric: Probability that HR < 1
BLOCK HF utilized a Bayesian statistical design which is an adaptive type of design in terms of sample size, which allows only enough subjects to be randomized in the trial to conclude enrollments and possibly reach a successful study outcome. Had the design not been adaptive in nature, a pre-specified sample size may have produced a negative or non-significant result if too small, or if too large, would have taken longer to enroll. (Keep in mind, that it took almost 8 years to enroll 918 patients.)
The metric for passing the objective in Bayesian statistics does not make use of P-values. Instead the probability that BiV is superior to RV (represented by a Hazard Ratio less than 1) is determined through a combination of pre-trial assumptions and accumulated trial data. For this to be concluded, the probability that the hazard ratio is less than 1 must exceed the pre-specified threshold seen in the table. So for the primary objective, the probability of the hazard ratio being less than 1 must be at least and for the secondary objectives the probability must be at least 0.95.
Endpoint
Study Success Criteria
Primary Endpoint (Mortality, HF Urgent Care, LVESVI)
Probability of (HR <1) >
Secondary Endpoints
All-cause Mortality
All-cause Mortality/HF Hospitalization
HF Hospitalization
Probability of (HR <1) > 0.95
BLOCK HF

7. 918 Assessed for eligibility
Study Flow Diagram
Enrollment
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
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
Follow-up
52 Exited/lost to follow-up
75 Deaths
13 Crossed over to Right Ventricular Pacing
3 Met primary endpoint prior to crossover
50 Exited/lost to follow-up
90 Deaths
84 Crossed over to Biventricular Pacing
50 Met primary endpoint prior to crossover
Analysis
Implanted subject not randomized (n =67)
Implanted subject exited prior to randomization (n=21)
Implanted subject died prior to randomization (n=16)
Programmed to BiV pacing prior to randomization (n = 10)
Randomization visit missed (n = 10)
LV lead complication (n = 6)
Subject did not meet inclusion/exclusion criteria (n = 4)
349 Analyzed
83 Censored for primary endpoint due to missing LVESVI data
342 Analyzed
71 Censored for primary endpoint due to missing LVESVI data
BLOCK HF

8. Follow-Up Experience BLOCK HF BiV (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%
BLOCK HF

9. Baseline Demographics
CRT-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
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 I
NYHA II
NYHA III
14%
58%
27%
20%
52%
28%
10%
63%
26%
16%
57%
Left Bundle Branch Block
35%
31%
Ischemic Heart Disease
39%
38%
1st Degree AV Block
2nd Degree AV Block
3rd Degree AV Block
17%
33%
49%
15%
29%
56%
40%
32%
ACE Inhibitor/ARB at Randomization
71%
74%
83%
88%
Beta Blocker at Randomization
78%
92%
Diuretics at Randomization
64%
66%
72%
DMC recommended trial be continued at least through October 15; Data in presentation is data through September 24, 2012 (data cleaned and frozen on Oct 15).
The medications are bolded showing consistency across both groups at Randomization versus at Baseline.
BLOCK HF

10. All Randomized Subjects
Primary Endpoint Results: Mortality/HF Urgent Care/LVESVI
Key Take-Away: There was demonstrated to be at least a 10% relative reduction in risk (95% upper bound for HR is 0.9) and an estimated 26% relative reduction (estimated HR is 0.74) in mortality/HF urgent care risk and significant increase in left ventricular volume in the BiV arm versus the RV arm. This finding holds up in the CRT-P subjects alone as well. In the CRT-D subjects, the HR estimate was comparable to that of the CRT-P subjects, as were the BiV and RV event rates themselves (see next slide).
Cohort
Estimated HR (95% CI)
Probability HR < 1
Threshold
All 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)
BLOCK HF

11. Clinical Components of Primary Endpoint: Mortality/HF Urgent Care Visits
Graphs show the composite primary objective without the echo endpoint for both types of devices. Even without LVESVi, we passed. These results demonstrate at least a 19% relative reduction in mortality/HF urgent care (upper 95% confidence bound was 0.81), and an estimated 38% relative reduction in risk of events (estimate for HR was 0.62). In both device groups the confidence bounds fell below 1, showing evidence of a significant reduction.
Cohort
Estimated HR (95% CI)
Probability HR < 1
Threshold
All 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)
BLOCK HF

12. Secondary Endpoint: Mortality/HF Hospitalization
Graph shows secondary endpoint of mortality and the HF hospitalization endpoint in combination. However, the difference between this endpoint and the primary endpoint is that a HF hospitalization is a Cardiovascular-related hospitalization in which the primary reason for admission is a heart failure-related adverse event as previously defined (for the primary endpoint, the hospitalization need not have HF as the primary reason for admission, as long as the patient presents with signs or symptoms consistent with HF and receives IV therapy for HF during the hospitalization). IV therapy was not a requirement for this secondary endpoint.
The probability that HR <1 was , exceeding the pre-specified threshold of Thus, the objective was met and demonstrates a significant relative reduction in risk of mortality/HF hospitalization. The estimated relative reduction was 22% (estimated HR was 0.78).
Note: Medtronic can provide a specific example for you.
Cohort
Estimated HR (95% CI)
Probability HR < 1
Threshold
All 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)
BLOCK HF

13. Secondary Objective Results: HF Hospitalization and Mortality
If we have two many slides in the main body, maybe we can consolidate the mortality & HF hospitalization objective results into one slide.
For Hospitalization alone: The probability that HR < 1 was , exceeding the pre-specified threshold of Thus, since there is a greater than 95% chance of the HR being less than 1, the objective is met. Graphs show that HF hospitalizations are reduced in the BiV arm when looking at all subjects and is the driver in the combined mortality/morbidity objective. The estimated relative reductio was 30% (estimated HR was 0.7), and the HR estimates were comparable between the two device groups (0.69 vs. 0.73).
For Mortality alone: The probability that the HR <1 was found to be , which is below the pre-specified cutoff of Thus, since there was not a 95% or greater chance of the HR being less than 1, the objective was not met.
Possible Rationale for not passing Mortality alone: Whether this was impacted by the imbalance in crossovers (predominately from RV to BiV) between the arms is not known. The curves do not separate until after 48 months in the CRT-P group, while in the CRT-D group there was some very modest separation earlier.
Cohort
HF Hospitalization
Mortality
Threshold
Estimated HR (95% CI)
Probability HR < 1
All Randomized Subjects
0.70 (0.52, 0.93)
0.9922
0.83 (0.61, 1.14)
0.8588
0.95
BLOCK HF

14. Number of Adverse Events (N, % of Subjects)
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%)
Many of the generator-related complications were changeouts (54 of the 66 generator-related compls), and most of these 66 comps occurred at least 2.5 years after the initial implant attempt.
20 of the 23 generator-related complications for subjects randomized to RV occurred post-randomization, and 19 of those 20 occurred more than 1 year post-randomization.
40 of the 42 generator-related complications for subjects randomized to BiV occurred post-randomization, and 39 of those 40 occurred more than 11 months post-randomization.
14 of the 23 LV lead-related comps among subjects randomized to RV occurred prior to randomization.
8 of the 22 LV lead-related comps among subjects randomized to BiV occurred prior to randomization.
* Subcategories for other system-related complications such as RA or RV-related complications not included
BLOCK HF

15. Strengths and Limitations
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:
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
BLOCK HF

16. Conclusions
In patients with AV block and LV systolic dysfunction (LVEF < 50%), BiV pacing compared to RV pacing leads to a significant 26% reduction in the combined endpoint of mortality, heart-failure related urgent care, and increase in LVESVI.
Furthermore, there is a 27% relative risk reduction in the composite endpoint of heart-failure urgent care and all-cause mortality
BLOCK HF

17. Back-up Slides

18. Post-randomization Cross-overs
Device Group
RV to BiV
BiV to RV
CRT-P
60 (24.9%)
9 (3.7%)
CRT-D
24 (23.8%)
7 (6.6%)
Total
84 (24.6%)
16 (4.6%)
* Percentages reflect percentage of subjects randomized subjects
BLOCK HF