Transcript Mann_AUGMENTHF - Clinical Trial Results

One Year Follow-Up Results from AUGMENT-HF:
A Multicenter Randomized Controlled Clinical Trial of
the Efficacy of Left Ventricular Augmentation with
Algisyl-LVR in the Treatment of Heart Failure*
Douglas L. Mann, Randall J. Lee, Andrew J.S. Coats, Gheorghe Neagoe, Dinu Dragomir,
Enrico Pusineri, Massimo Piredda, Luca Bettari, Bridget-Anne Kirwan, Robert Dowling,
Maurizio Volterrani, Scott D. Solomon, Hani N. Sabbah, Andy Hinson, Stefan D. Anker
on behalf of the AUGMENT-HF Investigators
* These data will be published online in European Journal of Heart Failure following this
presentation
Disclosures:
Scientific Advisory Board - Lone Star Heart, miRagen therapeutics, Lilly Corporation
Consultant – Bio Control Medical, Cardioxyl, Medtronic
Grant Support – NIH
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Background
• Therapeutic options are limited for patients with advanced heart failure
who become refractory to conventional pharmacological therapies
• The injection of biomaterials into diseased myocardium has been
shown to reduce myofiber stress, LV wall stress, restore LV geometry
and improve LV function1,2
• Algisyl® is a medical device that consists of an alginate hydrogel that is
injected into the midwall of the LV, where it remains as a permanent
implant that is intended to reduce LV wall stress and prevent or reverse
the progression of HF
• Results of the AUGMENT-HF 6-month primary endpoint analysis were
presented at this meeting in 2014 and published earlier this summer3
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Sabbah HN, et. al., JACC Heart Fail. 2013;1(3):252-8.
Lee RJ, et. al, Int J Cardiol. 2015 Jul 2;199:18-24.
3 Anker, SD, et. al. Eur Heart J. 2015 Sep 7;36(34):2297-309
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LV Restoration & Laplace’s Law
Mechanism of Action of Algisyl
R
R
h
Dilated
s
=
h
Modified (LVR)
PxR
2h
s
=
PxR
2h
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LV Restoration with Algisyl
Placement of Alginate Hydrogel via a Limited Thoracotomy
Mean procedure duration 80.5 (±24.9) minutes
Mean number of implants 15.5 (±2.0)
Mean total volume of Alginate-hydrogel 4.6 (±0.6) mL
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AUGMENT-HF Study Design & Objectives
• Multicenter prospective randomized clinical trial
• 78 Patients with moderate to severe HF that had been treated
with optimal medical and/or device therapy, randomized 1:1
− 40 patients randomized to Algisyl implant procedure + optimal
standard medical therapy (SMT)
− 38 patients randomized to optimal standard medical therapy alone
• 15 centers in Australia, Italy, Romania, Netherlands & Germany
• Primary Efficacy Endpoint: peak VO2 assessed by a blinded core
lab at 6 months
• Secondary Endpoints: peak VO2, 6MWT, Symptoms, QOL and
measures of LV remodeling (echo) at 12, 18 and 24 months
• Safety: clinical outcomes (MACE) adjudicated by blinded CEC
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AUGMENT-HF Key Inclusion & Exclusion Criteria
• Inclusion criteria
− Written informed consent
− ischemic or non-ischemic HF patients who are symptomatic
despite optimal evidence-based therapies for HF
− LVEF ≤ 35%
− Peak VO2 of 9.0 - 14.5 mL/min/kg
− LVEDDi 30 to 40mm/m2 (LVEDD/BSA)
− Stable, evidence-based therapy for heart failure
 Previously reported high compliance: diuretics (99%) Beta Blockers
(95%), ARBs/ACE-enzyme inhibitors (89%) and MRAs (69%)
• Exclusion criteria
− renal, hepatic, stroke and MI status
− LV wall thickness < 8 mm required for implant
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AUGMENT-HF Baseline Demographics
Patients Completing 1-year follow-up
All Patients
(n=73)*
All
(n=59)**
Control
(n=33)
Algisyl
(n=26)
Age (years)
62.6 ± 9.6
63.2 ± 9.1
63.0  9.3
63.5  9.0
Ischemic HF
42 (58%)
35 (59%)
20 (61%)
15 (58%)
Non-ischemic HF
31 (42%)
24 (41%)
13 (39%)
11 (42%)
NYHA Class III/IV
81%
79%
76%
81%
LVEF (%)
25.5  5.1
26.0  5.0
25.9  5.1
26.1  5.0
Peak VO2 (mL/min/kg)
12.2  1.8
12.4  1.7
12.4  1.7
12.3  1.8
6MWT distance (m)
293  84
292  88
306  81
275  95
Mitral regurgitation 3+
37 (51%)
27 (46%)
18 (55%)
9 (35%)
Hypertension
43 (59%)
37 (63%)
20 (61%)
17 (65%)
Diabetes
29 (40%)
25 (42%)
15 (46%)
10 (39%)
Previous PCI or CABG
20 (27%)
17 (29%)
9 (27%)
8 (31%)
* Modified Intention-to-Treat (mITT) population; ** 1 patient assessed by telephone only
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Peak VO2 - Mean Change from Baseline
(a)
Peak VO2 (mL/min/kg)
Mean change from baseline (SE)
2.5
P=0.014
P<0.001
2
1.5
1
0.5
0
-0.5
-1
-1.5
0
3
6
9
12
Time since randomisation (months)
Control
Algisyl
# of available values
Control
37
33
30
29
Algisyl
34
27
26
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Algisyl was superior to SMT at 12 months with a mean treatment effect of 2.10
mL/kg/min (CI 0.96–3.24). Algisyl patients completed the 1 year follow-up with a
mean peak VO2 of 14.0 (±3.1) mL/min/kg
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Anaerobic Threshold – Mean Change from Baseline
VO2 at AT (mL/min/kg)
Mean change from baseline (SE)
(b)
2.5
P=0.235
P<0.001
2
1.5
1
0.5
0
-0.5
-1
-1.5
-2
0
3
6
9
12
Time since randomisation (months)
Control
Algisyl
# of available values
Control
32
22
20
12
Algisyl
23
14
14
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AT is independent of patient motivation or effort. Algisyl was superior to SMT with a mean
treatment effect of 2.34 mL/kg/min (CI 1.35–3.32) at 12 months (p<0.001).
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Six Minute Walk Test - Change from Baseline
6MWT Distance (m)
Median change [25% - 75% range]
220
P<0.001*
P<0.001*
180
140
100
60
20
-20
-60
0
3
6
9
12
Time since randomisation (months)
Control
Algisyl
# of available values
Control
38
34
34
31
Algisyl
35
29
29
26
Treatment effect (vs. SMT) of 101 meters for median 6MWT distance
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NYHA Functional Class at 12 months
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Control (n=32)
Algisyl (n=26)
Odds Ratio: 31.90 (CI 7.6–133.4); P < 0.001
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No. of Patients
20
15
10
5
0
Control (n=32)
Algisyl (n=26)
Class I
0
8
Class II
8
14
Class III
24
4
Class IV
0
0
At 12 months, 85% of patients in the Algisyl group were NYHA functional class I or II
compared to 25% of patients on SMT. Only 4 patients in the Algisyl group remained in NYHA
class III at 12 months. These differences were highly statistically significant. The odds ratio
favoring improvement by one class for Algisyl was 31.90 (CI 7.6–133.4); P < 0.001
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AUGMENT-HF – Summary of 12 Month Outcomes
Mean Difference
Algisyl vs. Standard
Medical Therapy
P Value
Algisyl vs. Standard
Medical Therapy
Peak VO2 (mL/kg/min)
2.10
< 0.001
Anaerobic Threshold (mL/kg/min)
2.34
< 0.001
Peak Watts
11.9
0.003
Total Exercise Time (min)
1.52
0.002
6-min walk test distance (m)a
101a
< 0.001
NYHA class
- 1.0
< 0.001
KCCQ Overall Summary score
13.4
0.016
KCCQ quality of life score
12.5
0.04
Outcomes
a non-parametric
test
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All Adverse Events at 12 months
SMT
(N=38)
Safety population
Algisyl-LVR
(N=40)
# of patients
# of patients
Total #
Total #
with events
with events
of events
of events
(%)
(%)
P
All adverse events
98
25 (66)
144
34 (85)
<0.001#
Serious adverse
events
44
18 (47)
50
21 (53)
0.186#
#
p-value calculated by the log-rank test of the hazard ratio (hazard rate per 100 patient years at risk)
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MACE and Mortality – Blinded CEC Adjudication
SMT
(N=38)
Safety population
Event
Death
Algisyl-LVR
(N=40)
Total # # of patients Total #
# of
of events
(%)
of events patients (%)
4
4 (10.5%)
9
9 (22.5%)
Cardiovascular death
4
4 (10.5%)
8
8 (20.0%)
Non-cardiovascular death
0
0 (0.0%)
1
1 (2.5%)
38
15 (39.5%)
19
10 (25.0%)
Cardiovascular death
4
4 (10.5%)
6
6 (15.0%)
Cardiac arrest
3
3 (7.9%)
2
2 (5.0%)
Worsening heart failure
23
13 (34.2%)
11
6 (15.0%)
Sustained ventricular arrhythmias
8
5 (13.2%)
1
1 (2.5%)
MACE events (excludes index procedure)
The study was not powered to detect differences in event rates and there were no statistically
significant differences between groups for any of these event categories
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The Future of Algisyl
AUGMENT-HF II – Large US PMA Study (recent FDA cleared IDE)
•Sample size of 240 patients, randomized 1:1 versus usual care
•Endpoints essentially identical to the prior AUGMENT-HF study
•Peak VO2 and Combined HF hospitalization and mortality
Algisyl as a Percutaneous Intervention
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Conclusions
•
We previously reported that Algisyl injections can be administered safely in
patients with advanced HF, with an acceptable 30 day post-operative morbidity &
mortality.
•
These one-year follow-up results from AUGMENT-HF demonstrate continued long
term benefits of the Algisyl implant procedure in patients with advanced HF.
•
Algisyl combined with SMT provided substantial improvements in functional
capacity & HF symptoms compared to patients on SMT alone at 1 year post
treatment.
•
The 1 year MACE suggest a potential favorable reduction in HF hospitalization in
patients treated with Algisyl. However there was a trend towards higher CV
mortality and overall mortality at 1 year for patients receiving Algisyl.
•
Longer term observations for this patient cohort and larger studies will provide
insights into important clinical outcomes such as HF hospitalizations and CV
mortality
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