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CDRH Panel Meeting
June 22, 2005
Ileana L. Piña, M.D.
Professor of Medicine
Case Western Reserve University
Director Heart Failure/Transplantation
Julie Swain, M.D.
Cardiovascular Surgeon
Consultants
Clinical Reviewers for PMA P040049
Panel Presenation FDA Clinical Review 1
Intended Use of the CorCap
“…provides beneficial changes in cardiac structure
associated with a reverse remodeling effect as
defined by a reduction in LV size, an increase in
EF and a change to a more elliptical shape.
…provides a decrease in the need for additional
major cardiac procedures associated with the
progression of HF and an overall improvement
in QOL.”
Panel Presenation FDA Clinical Review 2
CorCap Clinical Trial
• Prospective
• Randomized
• Controlled
• 2-arm trial (heart failure patients either with
mitral insufficiency requiring MVR or
without mitral insufficiency) stratified by
MVR
Panel Presenation FDA Clinical Review 3
CorCap Clinical Trial
• Hypothesis:
The CorCap would improve patient
functional status as measured by a clinical
composite consisting of
mortality
major cardiac procedure for worsening
heart failure (MCP)
change in NYHA Class
Panel Presenation FDA Clinical Review 4
CorCap Clinical Trial
• Primary Objective:
To compare the functional status after a minimum of 12
months of follow-up for patients randomly assigned to
Treatment (CorCap) or Control (no CorCap).
• Secondary Objective:
To determine the rate of death and other SAE’s
experienced by patients randomized to CorCap implant
and to compare this rate with that for patients assigned to
the control group.
To compare patient functional status and structural
changes in the heart for the Treatment and the Control
groups.
Panel Presenation FDA Clinical Review 5
CorCap Clinical Trial
• Primary Composite Efficacy Endpoint:
Composite endpoint of :
• all-cause mortality
• NYHA class as per core lab
• Major Cardiac Procedures (MCP)
indicative of progression of HF.
Panel Presenation FDA Clinical Review 6
CorCap Clinical Trial
• Secondary Efficacy Endpoints:
Reduction in LV size, LV function and re-shape of the LV
Functional status: Improvement in QOL at 6 and 12 months (MLWHF,
SF36), exercise status 6 and 12 months (6 min walk, CPX testing ) and
site-determined NYHA
Changes in CPX , Peak VO2, VT, and exercise time at 6 and 12 mo
Changes in BNP
All cause mortality and hospitalizations
Incidence of Major Cardiac Procedures
Safety: hospitalization, adverse events, major cardiac procedures and
mortality
# of hospitalizations, hospital days and ICU days
Panel Presenation FDA Clinical Review 7
Baseline Characteristics
Parameter Value
Age 52.5 years
Men 55.3%
Caucasian 65%
Etiology : Ischemic 10%
Non-ischemic (dilated) 81.6%
Valvular 11.3%
EF 27.4%
LVEDD 7.2 cm
Peak VO2 15.0 ml/min/kg
6 min walk 340.9 m
MLWHF 59.3
Panel Presenation FDA Clinical Review 8
Missing Data
• Missing tests occurred in
50 47% of patients.
45
40
35 • In the Treatment arm,
30 MLWHF 59% of patients did not
%
25 SF36 have a baseline CoreLab
Missing
follow-up 20 Peak VO2 NYHA assessment.
data 15 6' walk
10
5
• In the Control arm, 57%
0
of the patients did not
Treatment Control have a baseline CoreLab
NYHA assessment.
Panel Presenation FDA Clinical Review 9
Results: Primary Composite Endpoint
Odds Ratio
Treatment Control
T/C P-value
(Average %) (Average %)
(95% CI)
Improved 37.7 27.3
1.73 (1.07-
Same 25.1 27.7 0.024
2.79)
Worsened 37.2 45.1
Panel Presenation FDA Clinical Review 10
Mortality
(as of April 15, 2005)
25 23 24
21 20 22
20 18
% of patients
15
10
5
0
NO NO MVR MVR Tot Tot
treat con treat con treat con
Panel Presenation FDA Clinical Review 11
30 Day Operative Mortality by Year
NoMVR Stratum
20
15
% of patients
10
5
0
2000-1 2002 2003
Panel Presenation FDA Clinical Review 12
Hospitalized Patients for HF
REMATCH
VMAC OPT FIRST OMM ESCAPE CorCap
Control
SBP 121 120 107 103 106 111
LVEF 26% 24% 19% 17% <30% 27.3
Na 138 138 135 136.7
6 mo 23% 10% 37% 48% 19% 7.7%
Mortality
Adapted from LW Stevenson, presentation for REMATCH
Panel Presenation FDA Clinical Review 13
1 year Mortality
Study Control vs Tx
SOLVD 14 vs 11
(ACE Inhibitor)
CONSENSUS 62 vs 45
(ACE Inhibitor)
COPERNICUS 18.5 vs 11
(Beta Blocker)
RALES 25 vs 17
(Spironolactone)
REMATCH 76 vs 49
(LVAD)
ESCAPE 17.4 vs. 20.9
(6 mos)
CorCap 14 vs. 13
Panel Presenation FDA Clinical Review 14
Adapted from LW Stevenson, presentation for REMATCH
Concerns
• There are remaining concerns regarding:
Disagreement with CERC Adjudication of
several MCP’s
Bias against re-op of pts with CorCap
NYHA Class for Status II Transplant patients
Reverse remodeling
Significance of BNP
Clinical relevance of MLWHF differences
Panel Presenation FDA Clinical Review 15
Major Cardiac Procedures
• Major Cardiac Procedures (MCP) were defined as
surgical interventions for worsening heart failure
including CABG, MVR, TVR and BiV pacing.
• Progression of heart failure
Hx and P.E.
Decreased exercise tolerance, JVD, rales
CXR
Laboratory Studies
Right Heart Cath
Lack of Clinical Response to Conservative Rx
Panel Presenation FDA Clinical Review 16
Major Cardiac Procedures: MVR Stratum
Treatment Control
(n=91) (n=102)
# Pts # Events Rate # Pts # Events Rate HR (T/C) p-value
(95% CI)
Cardiac 6 6 3.8 10 12 6.2 0.63 0.37
Transplant (0.23, 1.74)
LVAD 3 3 1.9 6 7 3.6 0.57 0.43
(0.14, 2.28)
MVR 1 1 0.6 3 3 1.8 NA NA
Bi-Ventricular 6 6 3.8 7 8 4.3 0.75 0.62
Pacing (0.24, 2.36)
TVR 0 0 0.0 2 2 1.2 NA NA
Any of above 14 16 9.3 21 32 14.2 0.57 0.12
procedures (0.28, 1.16)
Panel Presenation FDA Clinical Review 17
Major Cardiac Procedures:
NoMVR Stratum
Treatment Control
# patients # events Rate # patients # events Rate p value
Cardiac 1 1 1.1 6 6 7.5 0.06
Transplant
LVAD 0 0 0 2 2 2.4 NA
MVR 0 0 0 0 0 0 NA
Bi-Ventricular 4 4 4.0 7 8 9.2 0.24
Pacing
TVR 0 0 0 0 0 0 NA
Any of above 5 5 5.8 12 10 16.8 0.03
procedures
Panel Presenation FDA Clinical Review 18
CRT (BiV Pacing) and Open
Procedures by Group
30 Open
CRT
25
20
% of patients
15
10
5
0
NO NO MVR MVR Total Total
treat con treat con treat con
Panel Presenation FDA Clinical Review 19
Cardiac Transplant Status
Group NoMVR MVR MVR
Control Control Treatment
UNOS Status Ib II II Ib
Months 8 13 6 9
enrollment to
transplant
Panel Presenation FDA Clinical Review 20
LVAD as MCP
• None of the 11 patients who received an LVAD
were listed for transplantation prior to enrollment
• 6 were listed prior to LVAD insertion as a bridge
to transplant
• 3 patients were not on the transplant list
• 2 were listed after the LVAD was placed
• 3 patients who received LVAD’s were never listed
for transplant
Panel Presenation FDA Clinical Review 21
Functional Measures
• Placebo effect possible in less objective
measures
QOL
NYHA, site assessed
• Placebo effect less likely in objective measures
of function
VO2
6 min walk
Panel Presenation FDA Clinical Review 22
NYHA by Core Lab
60
50
40
% of patients
with CoreLab 30 Improved
NYHA Same
20 Worsened
10
0
No MVR No MVR MVR MVR
Treatment Control Treatment Control
Panel Presenation FDA Clinical Review 23
NYHA-Site Assessed
70
60
50
% pa t ie nt s wit h 4 0 Im pro v e d
N Y H A - S it e 30 Same
Wo rs e
20
10
0
NoMVR T NoMVR C MVR T MVR C
Panel Presenation FDA Clinical Review 24
QOL by MLWHF
NoMVR Treatment Control
Stratum (n=57) (n=50)
Mean Change Mean Change
# Patients (95% CI) # Patients (95% CI)
12 Months 45 -11.3 42 -6.4
(-17.1, -5.5) (-12.4, -0.3)
MVR Treatment Control
Stratum (n=91) (n=102)
Mean Change Mean Change
# Patients (95% CI) # Patients (95% CI)
12 Months 80 -21.9 77 -18.3
(-26.9, -16.9) (-23.3, -13.3)
Panel Presenation FDA Clinical Review 25
6 minute walk
70
60
50
% of patients No Control
with 12 mos 40 No+ treatment
data 30
MVR+control
20
MVR+treatment
10
0
Decreased >65 m 0-65 m
or dead
Panel Presenation FDA Clinical Review 26
CPX data, peak VO2
50
45 No Control
40 No Treatment
35 MVR Control
% of patients 30 MVR Treatment
with 12 mos 25
data 20
15
10
5
0
<-1.7 or >0.7 -1.7 to
dead 0.6
Panel Presenation FDA Clinical Review 27
Functional Summary
• Placebo effects are most likely in subjective
testing, such as QOL and NYHA Class.
• Neither 6 min walk nor CPX testing showed
clinically significant improvements in the
CorCap group.
Panel Presenation FDA Clinical Review 28
Structural Endpoints (at 12 mos)
Treatment Control
(n=132) (n=134)
LVEDV(ml) -32.7(n=97) -17.2 (n=88)
LVESV(ml) -25.9(n=97) -8.2 (n=88)
LV EF(%) 3.7 0.2
Sphericity 0.10 0.03
LV mass gm/m2 -14.9 (n=50) -13.6 (n=53)
LVEDD(mm) -5.8 (n=114) -3.6 (n=107)
LVESD(mm) -4.8 (n=114) -2.5 (n=105)
Panel Presenation FDA Clinical Review 29
Structural Endpoints (at 12 mos)
0
-5
-10
-15 LVEDV (ml)
-20
LV mass
-25 (g/m2)
-30
-35
-40
MVR T MVR C noMVR T noMVR C
(n=64/91) (n=60/102) (n=33/57) (n=28/50)
Panel Presenation FDA Clinical Review 30
Reverse Remodeling?
100
80
60
Treatment
40 At 6 mos, 30% pts with no data
LV Volume
20
0
LVEDD T At 12 mos, 34% pts with no data
LVEDD C
-20
-40
-60
-80
-100 100
Change in LV Systolic Volume
Baseline 3 mos 6 mos 12 mos 80
Follow up Month 60
40
20
LVESV T
0
LVESV C
-20
-40
Control -60
At 6 mos, 37% pts with no data -80
-100
At 12 mos, 42% pts with no data
os
e
os
os
lin
m
m
m
se
12
3
6
ba
Panel Presenation FDA Clinical Review 31
Follow up Month
Reverse Remodeling?
• Data are missing—not at
random with more data 0.3
missing in the Control group
• Remodeling is a time related 0.2
process
• Should be linked to 0.1
favorable outcome Sphericity
• No difference in mortality 0 Index T
• Most changes occur early -0.1
Sphericity
Index C
post CorCap application
• Less likely to be true reverse -0.2
remodeling
• Most of the LV mass -0.3
decrease is accounted for by 0 3 6 12
the MVR procedure
Panel Presenation FDA Clinical Review 32
Previous Clinical Experience
(not published) (Charité)
• Single center, non randomized
• 29 patients
17 with other valve surgery
12 with CorCap only
• Baseline imbalances in sickness severity
(duration of HF, beta blocker, #hospitalizations)
• 4 in-hospital deaths
Panel Presenation FDA Clinical Review 33
Clinical Experience (Charité)
80
70
60
50 10 baseline
40
10 10 6 mos
30
9 12 mos
20 8 10 3
10
0 2.5
LVEDD(valve) LVEDD(CorCap)
11 10
2
11
baseline
1.5
6 mos
Values are averages 1 8
10 12 mos
10
0.5
Panel Presenation 0
FDA Clinical Review 34
NYHA(valve) NYHA(CorCap)
Clinical Experience (Charité)
Changes in LVEDD and EF for 6 patients with
followup complete data
80
70
LVEDD(mm)
60
LVEF(%)
50
40 LVEDD(mm)
30 LVEF(%)
20
10
0
0 3 6 12 24 36 48
Duration(months)
Panel Presenation FDA Clinical Review 35
Brain Natriuretic Peptide (BNP)
250
200
150
pg/dl Baseline
100 6 months
50 n-71 n=106 n=80 n=104
0
Treatment Control
Panel Presenation FDA Clinical Review 36
Structural Summary
• Structural Changes support most of the benefit in LV mass
reduction due to MVR and not to the CorCap + MVR.
• Structural changes occur by 3 mos suggestive of an early
effect and not reverse remodeling which should occur and
improve with time (beyond 3 months).
• The BNP measures do not support an improvement in
filling pressures in the T arm.
• Correlations between structural and functional changes are
difficult to interpret due to large amounts of missing data
particularly in CPX testing and 6’ walk. Missing data may
not be at random.
Panel Presenation FDA Clinical Review 37
Adverse Events Related to
Hemodynamic Compromise
90
80 p =0.053 p =0.14
70
60
50 AE-Hemodynamic
40 compromise
30 SAE-Hemodynamic
20 compromise
10
Treatment group n=148
0 Control group n=152
Treatment % Control # %
#
Panel Presenation FDA Clinical Review 38
<30 days SAE’s
NoMVR MVR
Control Treat p Control Treat p
Hemodynamic
5 18 0.007 24 21 0.95
compromise
Infection 0 6 0.03 13 18 0.23
Neurologic
0 1 1.0 2 5 0.23
deficit
Pulmonary
0 7 0.01 12 17 0.19
Compromise
Any
7 31 0.0001 54 51 0.74
SAE/Death
Panel Presenation FDA Clinical Review 39
Constrictive Physiology
• 252 patients had echo data
• 18 patients in the Treatment arm and 30 in the Control arm
without follow-up echo.
• 43 patients (33%) in the Treatment group and 16 patients (13%)
in the Control group with at least 1 echo with possible or
suggestion of constriction (p=0.0002).
• No patient had any action taken nor are there any AE’s related to
constriction.
• There is more early hemodynamic compromise in the Treatment
group when compared to Control, but no evidence of
constriction at 18 months
Panel Presenation FDA Clinical Review 40
Clinical Summary
• The Sponsor has met the primary endpoint.
The only component contribution of the
primary endpoint that is significant is the MCP.
• There are no differences in mortality or
rehospitalizations.
• There are large amounts of missing data
which may not be at random, including
baseline core lab NYHA Class.
Panel Presenation FDA Clinical Review 41
Clinical Summary (cont)
• Unblinded trial with potential problems of
known and unknown treatment and
assessment bias.
• Upfront mortality cost to the device, with
modest long term benefit.
• Only 10% of the patients tested had an
ischemic etiology for HF.
Panel Presenation FDA Clinical Review 42
Panel Presenation FDA Clinical Review 43
Structural Endpoints (at 12 mos)
MVR noMVR
Treatment Control Treatment Control
(n=91) (n=102) (n=57) (n=50)
LVEDV -39.9(n=64) -25 (n=60) -25.9 (n=33) -12.4 (n=28)
LVESV 0.1(n=64) 0 (n=60) -23.6 (n=33) -6.0 (n=28)
LV EF 2.9 (n=64) -1.2 (n=60) 4.4 (n=33) 1.5 (n=28)
Sphericity 0.12 (n=63) 0.03 (n=58) 0.08 (n=34) 0.04 (n=29)
LV mass -20.8(n=64) -18.4 (n=60) -8.2 (n=33) -9.3 (n=28)
LVEDD -7.1 (n=62) -4.8 (n=53) -5.0 (n=27) -2.5 (n=26)
LVESD -5.4 (n=60) -3.4 (n=53) -5.1 (n=27) -1.3 (n=26)
Panel Presenation FDA Clinical Review 44
Brain Natriuretic Peptide (BNP)
Treatment Control
# Mean + SD # Mean + SD
71 176.0 + 229.9 80 184.0 + 284.7
106 238.3 + 307.6 104 176.7 + 211.4
Panel Presenation FDA Clinical Review 45
Adverse Events Related to
Hemodynamic Compromise
Any Adverse Event
Treatment Control (n=152)
(n=148)
# Pts % of #Pts % of p-value
148 152
Hemodynamic 90 60.8 75 49.3 0.05
Compromise
Any Serious Adverse Event
Treatment Control (n=152)
(n=148)
# Pts % of #Pts % of p-value
148 152
Hemodynamic
Panel Presenation
90 60.8
FDA Clinical Review
74 48.7 0.14 46
Compromise
