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 MDGregg W. Stone MD  Research support from TherOx Inc.

Background Despite successful reperfusion in AMI, myocardial recovery is often suboptimal, resulting in extensive infarction.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.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.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.This concept was tested in the AMIHOT I trial.

The AMIHOT I Trial ; PO mmHg 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 (SSO 2 ; PO mmHg) for 90’ versus control. Therox, Inc.

AMIHOT I Results 3 Co-Primary Efficacy Endpoints All patients Control N=135 SSO 2 N=134 P value (one sided) Infarct size (tc-99m- sestamibi 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 Improvement in echo RWMSI from baseline to 3 months 0.57± ± Anterior MI, reperfused <6hN=53N=52 Infarct size23 [5, 37]9 [0, 30]0.04 Complete ST resolution37%59%<0.05 Improvement in RWMSI0.54± ± O’Neill WW et al. JACC 2007;50:

AMIHOT II Trial Design 2 Primary Endpoints Efficacy: Infarct size (superiority) (tc=99m sestamibi days) Safety: 30 day MACE (noninferiority) Anterior AMI* with TIMI 0-2 flow reperfused by PCI with stenting within 6 hrs TIMI 2-3 flow achieved Standard therapy SSO 2 for 90 mins Randomize** *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 hoursObjective 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 daysObjective 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”)*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”)* *

Patient Enrollment 304 patients randomized at 20 sites in 4 countries (between (US, Canada, Netherlands, Italy) between September 13, 2005 and May 26, randomization errors 301 ITT patients SSO2N=222ControlN=79 30 day FU completeN=222(100%)N=79(100%) SPECTendpointN=175(78.8%)N=69(87.3%) Randomize 2.8:1

Control N=124 Median [IQR] 25 [7, 42] SSO2 N=258 Median [IQR] 18.5 [3.5, 34.5] Pooled, adjusted N=382 Primary Efficacy Endpoint Infarct Size by Tc-99m-sestamibi SPECT Infarct size, %LV Difference of medians -6.5% P Wilcoxon =0.023  Bayesian Posterior Probability = 98.0%* *Imputed; 95.6% using only non imputed data

Immeasurable Infarcts RR [95%CI] = 1.76 (1.04, 3.00) P = 0.03 P = 0.20 P = 0.11 Proportion with “0% LV” infarcts (%)

Primary Safety Endpoint: 30 Day MACE AMIHOT I Control SSO 2 Difference [95%CI] P sup 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] 2.0% [-7.8, 12.4]0.68 AMIHOT II N=79N=222 MACE 3 (3.8%) 12 (5.4%) 1.6% [-5.5, 6.3] Death - Death 0 (0%) 4 (1.8%) Reinfarction - Reinfarction 2 (2.5%) 4 (1.8%) TVR - TVR 3 (3.8%) 8 (3.6%) Stroke - Stroke 0 (0%) - MACE pooled 1 10/214 (4.7%) 21/356 (5.9%) 1.2% [-3.0, 4.9] 0.57 MACE pooled 2 5/132 (3.8%) 15/274 (5.5%) 1.7% [-3.5, 5.8] 0.48 Bayesian Posterior Prob NI = 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