Transcript The Detrimental Impact of Chronic Renal Insufficiency

A Prospective, Randomized Evaluation
of Supersaturated Oxygen Therapy After
Percutaneous Coronary Intervention in
Acute Anterior Myocardial Infarction
Gregg W. Stone MD
For the AMIHOT II Investigators
Disclosures
• Gregg W. Stone MD
 Research support from TherOx Inc.
Background
• Despite successful reperfusion in AMI, myocardial
recovery is often suboptimal, resulting in
extensive infarction.
• In experimental infarct models, hyperbaric oxygen
reduces myocardial tissue damage, in part by
reducing reperfusion injury and improving
microcirculatory perfusion.
• Regional hyperoxemia in the infarct zone can be
achieved by infusion of supersaturated blood into
the infarct artery after successful primary PCI.
• This concept was tested in the AMIHOT I trial.
The AMIHOT I Trial
269 pts with anterior or large inferior AMI and TIMI 0-2
flow undergoing primary or rescue PCI within 24 hours
from symptom onset were randomized after successful
PCI to intracoronary supersaturated oxygen therapy
(SSO2; PO2 760-1000 mmHg) for 90’ versus control.
Therox, Inc.
AMIHOT I Results
3 Co-Primary Efficacy Endpoints
Control
N=135
SSO2
N=134
P value
Infarct size (tc-99msestamibi at 14 days; %LV)
13 [3, 28.5]
11 [2, 29]
0.30
ST resolution (Holter; AUC
from 0-3 hrs post PCI)
57%
55%
NS
0.57±0.48
0.62±0.53
0.24
N=53
N=52
23 [5, 37]
9 [0, 30]
0.04
Complete ST resolution
37%
59%
<0.05
Improvement in RWMSI
0.54±0.49
0.75±0.57
0.03
All patients
Improvement in echo RWMSI
from baseline to 3 months
Anterior MI, reperfused <6h
Infarct size
O’Neill WW et al. JACC 2007;50:397-405.
(one sided)
AMIHOT II Trial Design
Anterior AMI* with TIMI 0-2 flow
reperfused by PCI with stenting within 6 hrs
TIMI 2-3 flow achieved
Randomize**
Standard therapy
SSO2 for 90 mins
2 Primary Endpoints
Efficacy: Infarct size (superiority)
(tc=99m sestamibi SPECT @14 days)
Safety: 30 day MACE (noninferiority)
*STE ≥1 mm in ≥2 contiguous leads V1-V4 or LBBB with LAD infarct
**Stratified by time to reperfusion (<3 vs. 3-6 hrs) and prox vs. non prox lesion
Endpoints and Statistical Methodology
• Objective 1 - Efficacy: To demonstrate that compared to
control, SSO2 results in reduced infarct size as measured
by tc-99m-sestamibi SPECT imaging at 14 (±7) days in pts
with anterior MI reperfused within 6 hours
• Objective 2 - Safety: To demonstrate that compared to
control, SSO2 has noninferior rates of major adverse
cardiac events (MACE – death, reinfarction, TVR or stroke)
at 30 days
• Bayesian hierarchical modeling: To allow pooling of data
from AMIHOT I, with the amount of pooling determined by
the similarity of the AMIHOT II results to the AMIHOT I data,
while still preserving type I error to <5% (as per FDA “Draft
Guidance for the Use of Bayesian Statistics in Medical
Device Clinical Trials”)*
*http://www.fda.gov/cdrh/osb/guidance/1601.pdf
Patient Enrollment
304 patients randomized at 20 sites in 4 countries
(US, Canada, Netherlands, Italy) between
September 13, 2005 and May 26, 2007
3 randomization errors
301 ITT patients
Randomize 2.8:1
SSO2
N=222
Control
N=79
SPECT
endpoint
N=175
(78.8%)
N=69
(87.3%)
30 day FU
complete
N=222
(100%)
N=79
(100%)
Primary Efficacy Endpoint
Infarct size, %LV
Infarct Size by Tc-99m-sestamibi SPECT
70
Pooled, adjusted
60
N=382
Difference
of medians
-6.5%
P
=0.023
50
Wilcoxon
40

30
20
10
0
Control
SSO2
N=124
N=258
Median [IQR]
Median [IQR]
25 [7, 42] 18.5 [3.5, 34.5]
Bayesian
Posterior
Probability =
98.0%*
*Imputed;
95.6% using only
non imputed data
Proportion with “0% LV” infarcts (%)
Immeasurable Infarcts
P = 0.11
RR [95%CI] =
1.76 (1.04, 3.00)
P = 0.03
P = 0.20
Primary Safety Endpoint: 30 Day MACE
AMIHOT I
Control
SSO2
Difference [95%CI]
Psup
MACE, all pts
7/135 (5.2%)
9/134 (6.7%)
1.5% [-4.5, 7.8]
0.62
MACE, ant <6
2/53 (3.8%)
3/52 (5.8%)
2.0% [-7.8, 12.4] 0.68
N=79
N=222
3 (3.8%)
12 (5.4%)
0 (0%)
4 (1.8%)
0.58
- Reinfarction
2 (2.5%)
4 (1.8%)
0.65
- TVR
3 (3.8%)
8 (3.6%)
1.0
0 (0%)
0 (0%)
-
AMIHOT II
MACE
- Death
- Stroke
1.6% [-5.5, 6.3]
0.77
MACE pooled1
10/214 (4.7%) 21/356 (5.9%)
1.2% [-3.0, 4.9]
0.57
MACE pooled2
5/132 (3.8%)
1.7% [-3.5, 5.8]
0.48

15/274 (5.5%)
Bayesian Posterior ProbNI = 99.8%
1 = using all pts from AMIHOT I
2 = using only anterior MI reperfused <6 from AMIHOT I
Conclusion
Among high risk patients with
acute anterior MI undergoing
successful PCI within 6 hours of
symptom onset, infusion of
SSO2 into the myocardial infarct
territory results in a significant
reduction in infarct size