Transcript Curtis_BLOCK HF AHA Presentation Final

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
Acknowledgments
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: 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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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?
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Study Design
ELIGIBILITY CRITERIA
•
AV block necessitating pacing
(CRT-P/D)
•
Establish OMT
(30-60 days)
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)
Implant
Randomize
1:1
Control:
Treatment:
RV pacing
BiV pacing
DoubleBlind
Follow-up
Follow-up
Every 3 months
Every 3 months
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• 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 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
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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
Endpoint
Primary Endpoint (Mortality, HF Urgent Care, LVESVI)
Secondary Endpoints
All-cause Mortality
All-cause Mortality/HF Hospitalization
HF Hospitalization
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Study Success Criteria
Probability of (HR <1) > 0.9775
Probability of (HR <1) > 0.95
Probability of (HR <1) > 0.95
Probability of (HR <1) > 0.95
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Study Flow Diagram
Enrollment
918 Assessed for eligibility
691 Randomized 1:1
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
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
349 Analyzed
83 Censored for primary endpoint due to
missing LVESVI data
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342 Analyzed
71 Censored for primary endpoint due to
missing LVESVI data
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Follow-Up Experience
Average Follow-up (months)
Follow-up Compliance (% of visits)
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BiV (N=349)
RV (N=342)
36.3 ± 23.1
37.9 ± 23.5
94.6%
93.8%
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Baseline Demographics
CRT-P
CRT-D
BiV (N=243)
RV (N=241)
BiV (N=106)
RV (N=101)
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 I
NYHA II
NYHA 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 Block
2nd Degree AV Block
3rd 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%
% Male
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Primary Endpoint Results: Mortality/HF Urgent
Care/LVESVI
100
Event-Free Rate (%)
80
60
40
BiV Arm
RV Arm
20
0
0
12
24
161
126
87
59
Cohort
All Randomized Subjects
CRT-P Only
CRT-D Only
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48
60
72
38
28
17
18
3
10
Number of Months
Number at Risk
BiV: 349
RV: 342
36
62
39
Estimated HR (95% CI)
0.74 (0.60, 0.90)
Probability HR < 1
0.9978
Threshold
0.9775
0.73 (0.58, 0.91)
0.75 (0.57, 1.02)
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Clinical Components of Primary Endpoint:
Mortality/HF Urgent Care Visits
100
Event-Free Rate (%)
80
60
40
BiV Arm
RV Arm
20
0
0
12
24
271
248
195
180
Cohort
All Randomized Subjects
CRT-P Only
CRT-D Only
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48
60
72
91
88
52
54
17
22
Number of Months
Number at Risk
BiV: 349
RV: 342
36
134
121
Estimated HR (95% CI)
0.73 (0.57, 0.92)
Probability HR < 1
0.997
Threshold
N/A
0.73 (0.56, 0.94)
0.73 (0.53, 1.02)
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Secondary Endpoint: Mortality/HF Hospitalization
100
Event-Free Rate (%)
80
60
40
BiV Arm
RV Arm
20
0
0
12
24
36
Number at Risk
BiV: 349
RV: 342
270
258
Cohort
All Randomized Subjects
CRT-P Only
CRT-D Only
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48
60
72
93
94
54
55
17
21
Number of Months
198
193
137
128
Estimated HR (95% CI)
0.78 (0.61, 0.99)
Probability HR < 1
0.9802
Threshold
0.95
0.77 (0.58, 1.00)
0.80 (0.58, 1.13)
12
100
100
80
80
Event-Free Rate (%)
Event-Free Rate (%)
Secondary Objective Results: HF Hospitalization
and Mortality
60
40
BiV Arm
RV Arm
20
60
40
BiV Arm
RV Arm
20
HF Hospitalization
0
Mortality
0
0
Number at Risk
12
24
BiV: 349
RV: 342
270
258
198
193
36
48
Number of Months
Cohort
All Randomized Subjects
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137
128
93
94
60
72
0
Number at Risk
12
24
54
55
17
21
BiV: 349
RV: 342
290
290
222
228
HF Hospitalization
Estimated HR (95% CI) Probability
HR < 1
0.70 (0.52, 0.93)
0.9922
36
48
Number of Months
Mortality
Estimated HR (95% CI)
0.83 (0.61, 1.14)
152
168
111
123
60
72
68
72
25
31
Threshold
Probability
HR < 1
0.8588
0.95
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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%)
* Subcategories for other system-related complications such as RA or RV-related complications not included
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Strengths and Limitations
• 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:
• 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
• 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 allcause mortality
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Back-up Slides
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Post-randomization Cross-overs
Device Group
CRT-P
RV to BiV
60 (24.9%)
BiV to RV
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
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