Aqueous Oxygen Therapy Improves
ST –Segment Resolution in Anterior
Myocardial Infarction
AMIHOT Phase II Clinical Study
J. L. Martin, B.S. Lindsay, P.V. Oemrwasingh, D.A. Atsma,
M.W. Krucoff, S.R. Dixon, A.L. Bartorelli, W.W. O’Neill,
for the AMIHOT Investigators
Main Line Health
TCT 2004
Washington DC, September 27- October 1, 2004
Supersaturated Oxygen
Aqueous Oxygen (AO)
• Solution of saline and hyperbaric levels (pO2~30,000 mmHg)
of dissolved oxygen (1 ml O2/ml saline)
• Remarkable stability (no bubble
formation) despite high level of O2
saturation due to the controlled delivery
from high pressure (40 atm) to ambient blood
• AO is mixed with the patient’s arterial blood at a ratio
of 25 parts blood to 1 part AO (pO2>760 mmHg), and
carried to the myocardial tissue via the plasma
Infarct Size after AO Therapy
Pig Model
Area of necrosis
Area of risk
18
* p< 0.01 (vs. Auto RP)
16
14
12
Auto RP
10
8
6
4
2
0
Auto RP
(n=6)
AO RP
(n=6)
AORP= Treatment group with 90’ AO hyperoxemic perfusion
Auto RP= Control group with normoxemic reperfusion
AO RP
Spears et al. 1999
TherOx Pilot Study
LV Function Recovery (WMSI)
Infarct zone
Non-infarct zone
2.6
†
WMSI
2.2
*
1.8
*
*
1.4
1
0.6
Baseline
Post AO
24-hrs
1-mo
3-mo
*p<0.01 vs.baseline, † p=0.01
Dixon SR. J Am Coll Cardiol 2002;39:387-92
OYSTER-AMI
AO in Anterior AMI
AO Treated vs. Controls
Ejection fraction (%)
55
50
28% mean relative improvement
45
40
2.5% mean relative improvement
35
30
AO Infusion (n=21)
25
Controls (n=20)
20
Baseline
Bartorelli A. TCT 2002
24 hours
7 days
1 month
3 months
6 months
Centro Cardiologico Monzino, Milan, Italy
AO Therapy Benefits
 AO is believed to salvage myocardium by
• Increasing O2 diffusion distance 3 to 4 times and O2
penetration into ischemic myocardium
• Reducing interstitial/endothelial edema
• Reducing leukocyte activation (decreased myeloperoxidase
levels)
• Improving capillary blood flow in the IRA microcirculation
AMIHOT
Study Objective
• To evaluate
– the safety of intra-coronary hyperoxemic
therapy after primary PCI for AMI
– the efficacy of hyperoxemic reperfusion to
enhance ST-segment elevation recovery,
improve convalescent left ventricular function
and reduce infarct size
Study Organization
•Principal Investigator: William W. O’Neill, MD
•Sponsor: TherOx® Inc., Irvine, California
•Core Laboratories
-Echo - Mayo Clinic, (Jae Oh, MD)
-Nuclear - Mayo Clinic, (Raymond J. Gibbons, MD)
-ECG - DCRI, (Mitchell W. Krucoff, MD)
•DSMB: Magnus Ohman, MD (Chairman)
Top Ten Enrollers
• Jack L. Martin MD, Main Line Health System
• Pranobe V. Oemrawsingh MD, Douwe Atsma, MD Leiden University Medical
Center
• William W. O’Neill MD, Simon R. Dixon MD, William Beaumont Hospital
• Michael Chang, MD, William Marquardt MD, Mercy General Hospital
• Shukri David, MD, Providence Hospital
• Antonio L. Bartorelli, MD, Daniela Trabattoni, MD, Centro Cardiologico
Monzino
• James B. Hermiller, MD, Saint Vincent Hospital
• Peter S. Fail, MD, Terrebonne General Hospital
• Rimvydas Plenys, MD, Saint Agnes Medical Center
• Habib Samady, MD, Michael Ragosta, MD, University Of Virginia Health
System
AMIHOT
Trial Algorithm
Major exclusion:
•Cardiogenic shock
•Need for IABP
•Systemic pO2
<80mmHg
AMI  24-hrs
(Primary or Rescue) n=269
Successful PCI
Normoxemic
Reperfusion
(Standard Therapy)
Initial TIMI flow  2
Hyperoxemic
Reperfusion with AO
for 90-minutes
ST-Monitor 24-hours
Enrollment in 20 US
and European sites
Jan 2002 – Dec 2003
Anterior MI or
Inferior MI with
anterior ST
SPECT Scan 14-days
Contrast Echo 1 month
Contrast Echo 3 months
AMIHOT Trial
Endpoints
 Primary Safety Endpoint
- Composite of death, reinfarction, TVR and stroke at 30 days
 Primary Efficacy Endpoints
- Regional wall motion score index (WMSI) at 3 months
(16-segment model*)
- Infarct size at 14-days (SPECT imaging)
- ST-Segment resolution (continuous ST-monitoring)
*Schiller et al. J Am Soc Echo1989; 2: 358-367
AMIHOT Trial
Clinical Characteristics
Age (yrs)
Female
Diabetes
Hypertension
Dyslipidemia
Smoker
Previous MI
Previous PCI
Previous CABG
Time to Reperfusion (hours)
Door to Balloon (hours)
Rescue PCI
Anterior MI
Control (n=135)
60.0
27%
11%
49%
41%
42%
10%
7%
1.5%
5.45
2.23
16%
56%
AO (n=134)
60
27%
13%
53%
49%
43%
13%
12%
1%
6.23
1.88
11%
60%
AMIHOT Trial
Angiographic Characteristics
Control (n=135)
AO (n=134)
LAD
RCA
Circumflex
Other
Initial TIMI flow grade
0/1
2
56%
36%
6%
2%
60%
31%
8%
1%
90%
10%
87%
13%
3
Stent
IIb/IIIa inhibitor
Final TIMI flow grade
0/1
0%
100%
84%
0%
100%
90%
0%
0%
2
8%
4%
3
92%
96%
Infarct related artery
AO system & Delivery
AMIHOT Trial - 30-day MACE
Primary Safety Endpoint
p=ns
6.0
%
4.4
3.0
2.2
2.2
1.5
1.5
1.5
1.5
0.7
Death
Re-Infarct
TVR
Treat (n=134)
Stroke
Control (n=135)
Composite
15
AMIHOT ST-Elevation Reduction in
AO Therapy vs. Controls
All Patients (Area under the Curve)
2200
2000
Tx (n = 106)
Ctr (n = 116)
1800
1600
1400
1200
p = ns at 3, 4, 6 hrs
1000
3
4
5
t (hr)
6
AMIHOT ST-Elevation Reduction
in AO Therapy vs. Controls
Anterior Patients (Area under the Curve)
3500
Tx (n = 65)
Ctr (n = 64)
3000
2500
2000
1500
p = 0.04 @ 3 hrs
p = 0.03 @ 4 hrs
p = 0.02 @ 6 hrs
1000
3
4
t (hr)
5
6
Regional Wall Motion & Infarct Size
Primary Endpoints
Infarct Size
Regional Wall Motion
1
20
17.3
P=NS
10
0
16.3
N=112
N=103
Control
AO
Change in RWM Score
% of Left Ventricle
30
0.8
0.65
0.6
0.55
0.4
P=0.16
0.2
0
N=119
N=101
Control
AO
Time to Reperfusion <6 hrs
All Patients
Infarct Size
Regional Wall Motion
1
P=0.04
20
18.1
14.3
10
0
N=82
N=69
Control
AO
Change in RWM Score
% of Left Ventricle
30
P=0.05
0.8
0.6
0.7
0.55
0.4
0.2
0
N=84
N=69
Control
AO
Regional Wall Motion
Anterior MI Patients
1
Change in RWM score
Control
Aqueous Oxygen
0.8
0.6
0.8
0.7
0.55
0.55
P=0.049
P=0.01
0.4
0.2
N=68
N=61
N=49
N=42
0
All Patients
<6-hours
AMIHOT Trial
Conclusions
gg
• Hyperoxemic reperfusion with Aqueous Oxygen is safe
and well tolerated after primary PCI for AMI
• ST segment resolution is significantly better in the anterior
MI group with a favorable trend in the entire cohort
• Infarct size as determined by Sestamibi Scan shows a
favorable trend in the entire cohort with a significant
reduction in infarct size in patients treated within 6 hours
of symptom onset
AMIHOT Trial
Conclusions - continued
• Early indicators of relief of myocardial ischemia (i.e STSegment resolution) lead to later functional recovery (i.e.
RWMSI improvement at 3 months).
• The AMIHOT study is the first adjunctive device study to
demonstrate significance in multiple endpoints in AMI.