R elaxin ( mcg / kg / d )

CHF State-of-theArt:
Optimizing Drugs and Devices
The Latest for 2009
Hani N. Sabbah, Ph.D., FACC, FCCP, FAHA
Professor of Medicine
Wayne State University &
Director of Cardiovascular Research
Henry Ford Health System
5.0 million patients with CHF
450,000 new cases a year
250,000 death
Mild to ModerateHeart Failure
One year mortality
Five year mortality
12%
50%
SevereHeart Failure
One year mortality
50%
Despite all our efforts and all our expenditures
we are not keeping pace with the heart failure epidemic
Surgical Treatment for Ischemic
Heart Failure (STICH) Trial:
CABG versus CABG + SVR
Robert H. Jones, M.D.
ACC’09
 1000
patients
 96
clinical sites
 23
countries
 1231
days
Hypothesis 2
• Surgical ventricular reconstruction (SVR)
combined with CABG and evidence-based
medical therapy (MED) decreases death or
cardiac hospitalization compared to CABG and
MED without SVR.
Baseline Clinical
Characteristics
Characteristic
Age
Female
White
Diabetes
2
ESVI (mL/m
)
(
EF (%)
CABG
N = 499
CABG +
SVR
N = 501
62 (54, 66) 62 (56, 69)
78 (16%)
90%
35%
82
28
69 (14%)
92%
34%
82
28
Baseline and Four Month End-Systolic Volume Index
(ESVI) in 373 Hypothesis 2 Patients With Quantitative
Echocardiogram at Both Intervals
80
P<0.001
P<0.001
60
ESVI
40
82
ml/m2
77
ml/m2
83
ml/m2
67
ml/m2
20
0
Baseline
4 Months
CABG
(N = 212)
Baseline
4 Months
CABG+SVR
(N = 161)
Canadian Cardiovascular Society Angina Class in
Hypothesis 2 Patients at Baseline and Latest Follow-up
CABG
CCS Angina Class
CABG+SVR
CCS Angina Class
No Angina
121
No Angina
128
Class I- II
130
Class I- II
129
500
400
300
Patients
200
100
0
No Angina
339
Class III- IV
248
Class III- IV
244
Class I- II
88
Baseline
(N = 499)
No Angina
339
Latest
Follow-up
(N = 435)
Class I- II
83
ClassIII- IV
8
Baseline
(N = 501)
Angina symptoms improved by an averageof 1.7 classes
in both cohorts (P=0.84).
Latest
Follow-up
(N = 428)
ClassIII- IV
6
New York Heart Association Heart Failure Class in
Hypothesis 2 Patients at Baseline and Latest Followup
CABG
CABG+SVR
NYHA HF Class
500
Class I 36
400
300
Patients
Class II
222
200
100
0
Class III- IV
241
NYHA HF Class
Class I 50
Class I
165
Class II
190
Class II
207
Class III- IV
244
Class III- IV
80
Baseline
(N = 499)
Latest
Follow-up
(N = 436)
Class I
179
Class II
188
Class III- IV
62
Baseline
(N = 501)
Heart failuresymptoms improved by an averageof oneclass
in both cohorts (P = 0.70).
Latest
Follow-up
(N = 435)
Baseline and Four Month 6-Minute Walk in 693
Hypothesis 2 Patients with Baseline
Assessment
Patients
Primary Endpoint: Death or Cardiac
Hospitalization
Kaplan-Meier Estimates
0.7
Event Rate
0.6
HR 0.99 (95% CI: 0.84, 1.17), P=0.90
0.5
0.4
0.3
0.2
CABG
292 events
0.1
CABG+SVR
289 events
0
0
1
No. at Risk
CABG
499
CABG+SVR 501
319
319
2
3
4
Years from Randomization
270
275
220
216
99
11
5
23
23
Conclusions
• The STICH trial definitively
shows adding SVR to CABG
provides no clinical benefit
beyond that of CABG alone in
the study population.
Multicenter Randomized Controlled
Trial of Cardiac Contractility
Modulation (CCM) in Patients with
Advanced Heart Failure
The FIX-HF5 Trial
William T. Abraham MD
ACC’09
The Concept Behind Cardiac Contractility
Modulation (CCM)
n
io
t
y
a
ra
el
u
D
D
Amplitude
CCM
Muscle
Force
Apply electric signal
during absolute refractory
period
Detect local
activation
Optimizer System
IPG
Millar
(dP/dtmax)
Atrial Lead
ICD Lead
CCM Leads
FIX-HF-5 Trial
• Multi-center, unblinded, randomized,
parallel- controlled clinical trial
– 50 participating centers (all US)
– 6-month efficacy endpoint
• First US randomization occurred on
April 8, 2005 and the last on June 12,
2007
• Last follow-up completed June 2008
FIX-HF-5: Study Schematic
Informed Consent
Baseline Testing
Eligibility Determination
Group 1
Group 2
Device Implantation
2 week Run-In
12 Months
Medical
Control
12 Months
CCM 5 hr/day
Study visits at: Baseline, 12Wk, 24Wk and 50Wk
FIX-HF-5: Study Endpoints
• Primary Safety Endpoint: Composite of all-cause
mortality and all-cause hospitalization assessed by noninferiority analysis (active versus control group with
12.5% allowable delta)
• Primary Efficacy Endpoint: Anaerobic Threshold (AT)
assessed by responders analysis (≥20% increase in AT
= responder)
• Secondary Efficacy Endpoints:
– Peak VO2
– Minnesota Living with Heart Failure Questionnaire
• Other Efficacy Endpoints
– NYHA Functional Class Ranking
– 6-Minute Hall Walk Distance
FIX- HF- 5: BaselineCharacteristics
Variable
Control (n=213)
Mean (SD) or n (%)
Treatment (n=215)
Mean (SD) or n (%)
P- value
Age(yrs)
58.55 (12.23)
58.09 (12.79)
0.51091
151 (70.9%)
158 (73.5%)
0.59012
White
142 (66.7%)
154 (71.6%)
0.50263
Black
45 (21.1%)
36 (16.7%)
Other
26 (12.2%)
25 (11.7%)
93.30 (22.16)
91.17 (23.27)
0.16321
26.09 (6.54)
25.74 (6.60)
0.56411
73.74 (12.19)
73.98 (13.13)
0.96811
115.61 (17.61)
116.65 (19.48)
0.86951
Ischemic
142 (66.7%)
139 (64.7%)
0.64653
Idiopathic
48 (22.5%)
58 (27.0%)
Other
23 (10.8%)
18 (8.3%)
Class I
0 (0%)
0 (0%)
Class II
1 (0.47%)
0 (0%)
Class III
183 (85.92%)
196 (91.16%)
Class IV
29 (13.62%)
19 (8.84%)
Male
Ethnicity
Weight (kg)
EF (%)
Resting HR (bpm)
SBP (mmHg)
CHF Etiology
NYHA
0.17203
Primary Efficacy Endpoint
Anaerobic Threshold Comparison of Mean Change
DAnaerobic Threshold
(ml/kg/min)
0.1
0.0
-0.1
-0.2
-0.3
Control
Treatment Difference
p=ns
Secondary Efficacy Endpoint
Peak VO2 Comparison of Mean Change
0.75
p=0.024
DPeak VO 2
(ml/kg/min)
0.50
0.25
0.00
-0.25
-0.50
-0.75
Control
Treatment Difference
Secondary Efficacy Endpoint
Quality of Life Comparison of Mean Change
D MLWHFQ
0
Control
Treatment Difference
-5
-10
-15
-20
p<0.0001
Other Efficacy Endpoint
Change in NYHA Functional Class
NYHA
%
( Patients with ≥ 1
Point Reduction )
50
40
30
20
p=0.0026
10
0
Control Treatment Difference
Other Efficacy Endpoint
Six Minute Walk (m)
6-Minute Hall Walk Distance Comparison of
Mean Change
30
20
p=0.108
10
0
Control
Treatment Difference
Relaxin, A Novel
Treatment for Acute Heart
Failure
The Pre-RELAX-AHF Study
John R. Teerlink, MD
ACC’09
Relaxin
Relaxin
• Peptide hormone
• Similar in size and shape to insulin
(MW 5963)
• Found in men and women
• Normal hormone of pregnancy
• Women “exposed” for 9 months to
increased plasma concentrations:
0.8-1.6 ng/ml pregnancy*
• Benign safety profile
Vasodilator effect of Relaxin
P
0
R
e
L 1
0 3
l a
0 1
x
0 20
i n
5
( m
0
- 2
•
- 4
- 6
•
- 8
- 1
0
- 1
2
- 1
4
- 1
6
- 1
8
- 2
0
•
•
c g
/ k g effect
/ d
) of
Vasodilator
Relaxin effect partially
balanced by:
Increased NTG and
diuretics in Placebo
Stopping rules for BP
reduction to avoid
Hypotension
Selective vasodilation
by Relaxin
U-shaped doseresponse of Relaxin
Pre-RELAX-AHF:
Phase II Study Objective
• Evaluate the impact of IV relaxin
compared to placebo on symptom relief
and other clinical endpoints in patients
with AHF and normal or elevated blood
pressure.
Inclusion Criteria
• Admitted for Acute heart failure (all):
– Dyspnea at rest or with minimal exertion
– Congestion on chest-X-ray
– BNP ≥ 350 or NT-pro-BNP ≥ 1400 pg/mL
•
•
•
•
Baseline BP > 125 mmHg
Renal dysfunction (CrCl 30-75 mL/min)
Randomized within 16h of presentation
Received at least 40 mg iv Furosemide
prior to screening
Pre-RELAX-AHF Endpoints
• Dyspnea relief: Patient-reported
• Post-discharge
– Day 60: Days alive and out-of-hospital
– Day 60: Cardiovascular mortality and
rehospitalization due to heart or renal failure
– Day 180: Cardiovascular death
Dyspnea Improvement
through 24 hours (Likert Scale)
Proportion of Patients with Moderate/Marked
Improvement in Dyspnea at 6, 12 and 24 hr
p
5 0
=
0 . 0 4
4 5
P a tie n ts (% )
4 0
3 5
3 0
2 5
2 0
1 5
1 0
5
0
P
l a c e b o1 0
3 0
R
e la x in
1 0 0
( m
2 5 0
c g /k g /d )
Sustained Dyspnea Improvement
Through Day 14 (Visual Analog Scale)
D y s p n e a (A U C ; m m *h r)
1
0
0
0
9
0
0
0
8
0
0
0
7
0
0
0
6
0
0
0
5
0
0
0
4
0
0
0
3
0
0
0
2
0
0
0
1
0
0
0
0
p = 0 . 0 6
p = 0 . 0 5
0
p =
0 . 1 6
p = 0 . 1 1
0 . 1p5= 0 . 1 6
p =
P l a c e 1b 0o
R
3 0
1 0 0
e l a x i n
D
a y
2 5 0
( m
5
P l a c e 1b 0o
c g / k g / d )
R
3 0
1 0 0
e l a x i n
D
a y
2 5 0
( m
1 4
c g / k g / d )
Days Alive and
Out of Hospital to Day 60
D ays
5
0
4
9
4
8
4
7
4
6
4
5
4
4
4
3
4
2
4
1
4
0
p
P
l a c e b o
1 0
=
0
. 1 6
3 0
1 0 0
R e l a x i n ( m
p
=
0
. 0
5
2 5 0
c g / k g / d )
CV Death or Heart/Renal Failure
Re-hospitalizations to Day 60
1
. 9
0
0
0
. 8
0
m
R
e
l a
x
i n
2
5
0
R
e
l a
x
i n
1
0
0
R
e
l a
x
i n
1
0
P
l a
c
e
b
c
g
/ k
g
/ d
m
c
g
/ k
g
/ d
m
c
g
/ k
g
/ d
g
/ k
5
. 9
. 8
0
m
c
g
/ d
5
1
0
2
0
3
D
0
4
a
y
0
s
5
0
6
0
K a p la n - M e ie r E v e n t- fr e e S u r v iv a l ( % )
0
R e l a x i n
3
( p = 0 · 0 5 )
o
Cardiovascular Deaths to Day 180
1
0
. 9
0
0
x i n
. 0 5
3
0
R
R
e
e
l a
l a
x
x
R
e
l a
P
l a
c
. 8
0
8
0
m
i n
i n
1
1
0
0
0
x
i n
2
5
0
e
b
)
m
5
. 9
. 8
0
R e l a
( p < 0
5
3
0
6
0
9
D
0
1
a
2
y
0 1
s
5
0 1
o
Conclusions
• In selected patients with AHF, early
treatment with relaxin for 48 h produced
consistently favorable trends in multiple
AHF endpoints, including:
– Symptom relief: VAS and Likert Scales
– In-hospital measures of AHF signs and
symptoms
– Post-discharge clinical outcomes to Day
60/180
RELAX-AHF-1: An international Phase 3
HYPOTHESIS (BL-1040)
Injection of a resorbable biomaterial (BL-1040)
into the infarct can provide a temporary structural
support to prevent infarct expansion and
subsequent left ventricular dilation and the
development of CHF.
BL-1040 Prevents LV
Dysfunction
Prevents end systolic volume dilation
46
50
46
42
38
34
30
BL-1040
*
control
38
34
*
30
post
2M
AMI
4M
BL-1040
control
*
EF (%)
ESV (mm)
42
Prevents LV dysfunction
6M
* P<0.05
*
post
AMI
2M
Beneficial effects are maintained after BL-1040
res orption
Dog AMI model (N=30)
4M
6M
* P<0.05
9 Active Sites in
Europe
Preliminary Data
First 5 Patients
LV ejection fraction
LV diastolic volume
LV systolic volume
Pro BNP (pg/ml)
Baseline
47 ± 9%
132 ± 20 ml
67 ± 11 ml
830 ± 580
90 days
49 ± 7%
122 ± 24 ml
62 ± 8 ml
480 ± 414
First Proof of Long Term Hemodynamic
Benefits of Partial Ventricular Support in
Patients with Severe Heart Failure
The Synergy® Micro-Pump
Addressing Limitations of Existing LVADs
Outflow
Cannula
Inflow
Cannula
~ 3 liters/min
Right Mini Thoracotomy
Inflow = Subclavian Artery
Pump
Outlow = Left Atrium
Trans-Septal
Controller Wire
With
Quick Connect
Baseline Hemodynamics (n=16)
Mean
Range
LV Ejection Fraction (%)
20
10-32
LV End Diastolic Dimension (cm)
6.9
5.4-9.2
Heart Rate (bpm)
80
50-112
Mean Blood Pressure (mmHg)
72
61-81
Mean Pulmonary Artery Pressure (mmHg)
38
28-53
Pulmonary Capillary Wedge Pressure (mmHg)
29
21-43
Pulmonary Vascular Resistance (W)
2.3
1.3-3.6
Cardiac Index (L/min/m2)
1.9
1.3-2.6
2
p=0.001
Cardiac Index (L/min/M )
Long Term Hemodynamic Effects
10 ± 6 weeks (n=9)
p=0.005
5
4
3
2
1
Baseline
Pump Flow= 2.8± 0.4 L/min
24Hr
Chronic
Follow Up
Other Clinical Effects
• BNP (n=9)
– Baseline: 6856±1952 pg/ml
– Follow up: 2381±675 pg/ml
– Change: 4475±1389 pg/ml (p=0.02)
• Peak VO2 (n=5)
– Baseline: 9.6±2.0 ml/kg/min
– Follow up: 14.1±1.6 ml/kg/min
– Change: 4.5±2.0 ml/kg/min (p=0.01)
Why all the Failure
in CHF Clinical Trials ?
Bad Drugs and Devices
Trial Design
Study Population
Regulatory Issues