Peri-infarct Zone Pacing to Prevent Adverse Left Ventricular Remodeling in Patients with Large Myocardial Infarction

1
Peri-infarct Zone Pacing to Prevent Adverse Left
Ventricular Remodeling in Patients with Large
Myocardial Infarction
Results from the PRomPT Trial

• Gregg W. Stone, MD
• Eugene S. Chung, Branislav Stancak,
  Jesper H. Svendsen, Trent
  M. Fischer, Fred Kueffer, Thomas Ryan, Jeroen
  Bax, and Angel Leon,
  for the Post-Myocardial Infarction Remodeling
  Prevention Therapy (PRomPT)
  Trial Investigators

2
Presenter Disclosures

• None

3
PRomPT Background

• Patients with large MI have high rates of death
  and hospitalization for heart failure (HF), which
  markedly affects quality of life (QoL) and
  increases healthcare costs
• Delayed contractile activation in the infarct and
  peri-infarct regions may increase local wall
  stress and workload, resulting in infarct
  expansion, wall thinning and LV remodeling
• LV pacing in the peri-infarct zone reduces local
  stroke work, and may attenuate post-MI increase
  in LV end-diastolic volume (LVEDV), preventing
  ventricular remodeling and improving prognosis

4
PRomPT Design
Up to 250 patients with large first MI (CPK gt3000
U/L) and QRS duration
lt120 msec within 10 days of symptom onset
Baseline 2D echo, NYHA, MLWHF, EQ-5D
Follow-up visits and evaluations 2D echo, NYHA,
MLWHF, EQ-5D, 6MWT at 1, 3, 6, 12, and 18 months
5
Target (green) and acceptable (yellow) lead
implantation sites
Anterior infarcts
Inferior and lateral infarcts
A lateral (circumflex) infarct generally
comprises segments 5, 6, 11, 12, and 16, while an
inferior (right coronary artery) infarct
typically comprises segments 3, 4, 9, 10, and 15.
A LV lead in this location will be in the
peri-infarct zone of either infarct.
Anterior (i.e. left anterior descending) infarcts
generally comprise segments 1, 2, 7, 8, 13, 14,
and 17. The target location in green is in the
lateral peri-infarct region, segment 12, with
other acceptable regions adjacent (yellow).
6
PRomPT Primary endpoint

• Change in LVEDV in the echocardiographic apical
  4-chamber view from baseline to 18
  months between the pooled pacing therapy groups
  and the control group (?LVEDV)
• Primary analysis is performed in the as-treated
  cohort, including all randomized subjects, but
  requiring successful CRT-D implantation in the
  device arms
• Analyzed by analysis of covariance (ANCOVA) with
  baseline LVEDV as a covariate

7
PRomPT Power analysis / sample size

• Assumptions
• Baseline mean LVEDV 130 mL in each group
• 15 greater increase in mean LVEDV from baseline
  to 18 months in control patients compared to the
  pooled pacing therapy group (e.g. 19.5 mL vs. 0
  mL)
• Standard deviation of ?LVEDV from baseline to
  follow-up of 35 mL in the randomized groups
• ? 156 evaluable echocardiograms would provide
  90 power at a 2-sided alpha of 0.05 to
  demonstrate superiority of peri-infarct pacing

8
PRomPT Organization / quality control

• Principal Investigator Gregg W. Stone, Columbia
  University
• Co-principal Investigator Angel Leon, Emory
  University
• Steering Committee Eugene S. Chung, Inder S.
  Anand, Jeroen J. Bax, Michael R. Gold,
  Robert Gorman, MD, Heinz
  Theres, James Udelson, Mark Pfeffer
• Clinical Events Adjudication Committee John
  Herre (Chair), Michael Dickinson, Ayesha Hasan,
  Mark Kremers
• Echocardiography Core Laboratory Thomas Ryan,
  Ohio State University
• Implant Lead Adjudication Committee Jose Dizon,
  Jagmeet Singh, Oussama Wazni
• Data Safety and Monitoring Board Dwight W.
  Reynolds (Chair), Juan Aranda, Tim Church
• Trial and Site Management, Data Monitoring,
  Management and Analysis and Sponsor Medtronic,
  plc

9
PRomPT Enrollment

• Given difficult recruitment and the goal of the
  present trial to inform a pivotal trial design,
  it was determined during enrollment, while the
  study leadership was still blinded, to accept
  80 power and an alpha of 0.10, requiring
  96 evaluable echocardiograms
• Assuming 20 of subjects would not have data
  available at the 18-month visit due to early
  study exit, death, or non-evaluable
  echocardiograms, a sample size of 120 as-treated
  patients was required (40 per group)

10
PRomPT Enrollment
Between December 2010 and October 2013,
126 patients were randomized at 27
sites in Europe, the Middle East, and the United
States
Randomized 111
LV and RV pacing (n41)
LV pacing only (n40)
No implant (n45)
1 withdrew 1 withdrawn
1 withdrew 1 withdrawn
5 withdrew 3 lost to FU 1 missed 18-mo FU
Successful implant (n37)
Successful implant (n38)
1 withdrew
2 lost to FU
18-month FU (n38) As-treated (n37) ITT (n41)
18-month FU (n36) As-treated (n38) ITT (n40)
18-month FU (n36) As-treated (n45) ITT (n45)
11
PRomPT Top 5 Enrolling Sites

1. East-Slovak Institute of Cardiovascular Diseases,
   Kosice, Slovakia (20) B. Stancak, J. Ignac, M.
   Jankajova,
   E. Komanova
2. The Lindner Research Center, Cincinnati, OH, USA
   (17) E. Chung, T.
   Waller, S. Menon, M. Gupta, K. Bailey,
   E. Schloss, D.
   Kereiakes, D. Wahl
3. Rigshospitalet, Copenhagen, Denmark (11)
   J.
   Svendsen, J. Bro-Jeppesen
4. Emory University Hospital Midtown, Atlanta, GA,
   USA (9) A.
   Leon, M. El-Chami, M. Lloyd, M. Hoskins, J.
   Langberg, D.
   DeLurgio
5. University of Pennsylvania, Philadelphia, PA, USA
   (7) W. Matthai, W.
   Groh, R. Li, J. Stern, J. Bullinga, G. Chang,
   C. Frankil, C. Gasperetti, C.
   Leng, A. Moak

12
PRomPT Baseline features
  Pooled pacing (n75) Control (n45)
Age (yrs) 59 11 54 11
Gender (male) 73.3 73.3
Body mass index (kg/m2) 29 6 29 4
Hypertension 56.0 55.6
Hyperlipidemia 40.0 46.7
Diabetes mellitus 20.0 22.2
Current smoking 45.3 42.2
MI location    
Anterior 76.0 77.8
Non-anterior 24.0 22.2
PCI performed 96.0 97.8
Symptom onset to PCI (hrs) 7.6 8.2 9.0 12.7
Peak CPK (U/L) 4513 1316 5248 2832
P0.02 otherwise there were no significant
differences between groups
13
PRomPT Implant performance

• Pooled pacing groups
• Devices were successfully implanted in 75/76
  attempts (98.7) at 7.0 2.3 days after MI
• The LV lead was successfully placed within the
  echocardiographic peri-infarct zone in 95.5 of
  patients, and in the pre-specified target zone in
  62.7 of patients
• The median (25, 75) percent LV pacing during
  follow-up was 98.9 (97.9, 99.0)

There were no significant differences between
single and dual lead groups
14
PRomPT Primary endpoint - ?LVEDV
Paired echocardiographic results between the
baseline and 18-month follow-up visits
LVEDV (mL)  n Baseline 18-month Adj mean change (95 CI) Difference (95CI) P
Control 34 118.6 29.4 133.9 38.9 15.8 (5.5, 26.2) 0.6 (-12.3, 13.5) 0.92
Pooled pacing 64 106.1 27.6 122.8 40.4 16.4 (8.9, 23.9) 0.6 (-12.3, 13.5) 0.92
15
PRomPT Primary Endpoint ?LVEDV
Paired echocardiographic results between the
baseline and 18-month follow-up visits
100
Control
Single Site
Dual Site
75
50
Mean ?LVEDV (mL)
25
0
-25
-50
0
1
3
6
12
18
Months after randomization
N with data
31 33 34
29 25 31
27 28 33
27 34 34
32 33 34
37 37 44
Single-site Dual-site Control
16
PRomPT ?LVEDV - Subgroup analysis
?LVEDV (Intervention Control) Mean (95 CI)
Interaction P value
?LVEDV (Intervention Control)
Variable
Patients
ALL patients
98
0.6 (-12.3, 13.5)
Age ltmedian (58 years) median (58 years)
48 50
3.3 (-14.1, 20.7) 1.2 (-18, 20.4)
0.87
Gender Female Male
27 71
8.2 (-15.7, 32) -3.2 (-18.6, 12.2)
0.42
Hypertension No Yes
42 56
-2.2 (-21.2, 16.8) 2.3 (-15.2, 19.8)
0.73
Hyperlipidemia No Yes
59 39
6.2 (-10, 22.3) -9.6 (-30.1, 10.9)
0.23
Diabetes No Yes
81 17
-3.6 (-17.6, 10.4) 20.7 (-13.2, 54.7)
0.19
Infarct Location Anterior Non-anterior
78 20
3.6 (-10.6, 17.8) -12.1 (-41.4, 17.3)
0.34
Peak CPK ltmedian (4447 U/L) median (4447 U/L)
44 45
0.5 (-19.1, 20.1) 8.7 (-9, 26.4)
0.54
Baseline LVEDV ltmedian (105.8 mL) median
(105.8 mL)
49 49
6.5 (-12.9, 25.9) -4 (-21.5, 13.4)
0.42
Baseline LVEF ltmedian (43.1) median (43.1)
49 49
9.9 (-8.2, 27.9) -11.5 (-28.6, 5.5)
0.09
?LVEDV was not significantly different in pts in
whom the LV lead was vs. was not implanted in
the pre-specified target location (adjusted
mean diff (95CI) -4.3 (-20.4, 11.8) mL, P0.60)
17
PRomPT Secondary echo endpoints
Paired echocardiographic results between the
baseline and 18-month follow-up visits
n Baseline 18-month Adj mean change Difference P
LVESV (mL) LVESV (mL) (95 CI) (95 CI)
Control 34 67.7 24.9 81.5 32.5 14.0 (5.4, 22.7) -2.8 (-13.5, 7.9) 0.61
Pooled pacing 64 61.8 21.2 73.1 33.1 11.2 (5.0, 17.5) -2.8 (-13.5, 7.9) 0.61
LVEF () LVEF ()
Control 34 43.8 9.1 40.5 10.1 -3.0 (-5.8, -0.2) 2.3 (-1.2, 5.7) 0.20
Pooled pacing 64 42.5 8.9 41.9 10.0 -0.8 (-2.8, 1.3) 2.3 (-1.2, 5.7) 0.20
18
PRomPT Secondary endpoint 6MWT
Paired 6 minute walk test results between the
1-month and 18-month follow-up visits
6MWT (meters) n Baseline 18-month Adj mean change (95 CI) Difference (95CI) P
Control 28 399.6 155.0 410.3 151.8 15.6 (-32.1, 63.2) 22.0 (-35.3, 79.3) 0.45
Pooled pacing 63 384.2 134.8 424.0 145.6 37.6 (5.8, 69.3) 22.0 (-35.3, 79.3) 0.45
19
PRomPT Secondary endpoints - QoL
Paired Minnesota Living with Heart Failure and
EQ-5D results between the baseline and 18-month
follow-up visits
n Baseline 18-month Adj mean change Difference P
MLWHF score MLWHF score MLWHF score (95 CI) (95 CI)
Control 32 29.6 29.7 26.8 25.4 -0.1 (-8.5, 8.3) 0.5 (-9.6, 10.7) 0.92
Pooled pacing 69 24.6 24.5 26.2 24.2 0.4 (-5.3, 6.1) 0.5 (-9.6, 10.7) 0.92
EQ-5D score EQ-5D score EQ-5D score
Control 33 0.8 0.2 0.8 0.2 0.1 (0.0, 0.1) -0.0 (-0.1, 0.1) 0.99
Pooled pacing 69 0.8 0.2 0.8 0.2 0.1 (0.0, 0.1) -0.0 (-0.1, 0.1) 0.99
20
PRomPT Secondary endpoints - NYHA
Paired NYHA classification between the baseline
and 18-month follow-up visits
P0.67
NYHA class
Proportion
21
PRomPT Death or HF Hospitalization
1.0
82.6
0.8
78.3
Pooled Pacing (n75) Control (n45)
0.6
Freedom from Death or HF Hospitalization
Pooled Pacing vs. Control HR 0.79 (0.34, 1.86) P
0.59
0.4
0.2
0.0
0
50
100
150
200
250
300
350
400
450
500
Month 18
Days after Randomization
Number at Risk
75 45
Pooled Pacing Control
67 38
66 35
63 34
62 32
61 32
61 32
61 31
61 31
60 30
59 30
58 25
22
PRomPT Adverse events during FU
  Pooled pacing (n75) Control (n45) HR (95 CI) P value
Death 3 (4.0) 2 (4.7) 0.83 (0.14, 4.98) 0.84
- Cardiac death 3 (4.0) 1 (2.4) 1.64 (0.17, 15.82) 0.66
- Sudden death 1 (1.4) 1 (2.4) 0.56 (0.03, 9.03) 0.68
- Non-cardiac death 0 (0.0) 1 (2.3) - 0.19
Hospitalization, all 29 (39.9) 18 (44.7) 0.81 (0.45, 1.46) 0.48
- For heart failure 11 (15.0) 8 (19.6) 0.75 (0.30, 1.87) 0.54
Death or hosp 31 (41.5) 19 (46.3) 0.82 (0.46, 1.46) 0.50
Death or HF hosp 13 (17.4) 9 (21.7) 0.79 (0.34, 1.86) 0.59
Data are time to event Kaplan-Meier estimates,
compared by log rank
23
PRomPT Limitations

• Sample size reduced to 120 as-treated patients
• Nonetheless, the largest trial of its type to
  date
• With 95 confidence we can exclude
  a gt12.3 mL reduction in ?LVEDV with
  successful peri-infarct pacing
• The study was not powered to assess most
  secondary endpoints, or compare outcomes between
  the individual pacing groups
• Cannot exclude benefit in subgroups that the
  trial was under-powered to detect

24
PRomPT Conclusions

• In the present multicenter, randomized trial,
  peri-infarct pacing did not prevent LV remodeling
  or improve functional or clinical outcomes during
  18 months of follow-up in patients with large
  first MI