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Aqueous Oxygen Therapy Improves ST –Segment Resolution in Anterior Myocardial Infarction

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.

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Aqueous Oxygen Therapy Improves ST –Segment Resolution in Anterior Myocardial Infarction

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  1. 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

  2. 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

  3. Infarct Size after AO Therapy Pig Model Area of necrosis Area of risk * p< 0.01 (vs. Auto RP) Auto RP % Left Ventricle (n=6) (n=6) AO RP AORP= Treatment group with 90’ AO hyperoxemic perfusion Auto RP= Control group with normoxemic reperfusion Spears et al. 1999

  4. TherOx Pilot Study LV Function Recovery (WMSI) *p<0.01 vs.baseline, † p=0.01 Dixon SR. J Am Coll Cardiol 2002;39:387-92

  5. Centro Cardiologico Monzino, Milan, Italy OYSTER-AMI AO in Anterior AMI AO Treated vs. Controls 28% mean relative improvement 2.5% mean relative improvement Bartorelli A. TCT 2002

  6. AO Therapy Benefits • Increasing O2 diffusion distance 3 to 4 timesand O2 penetration into ischemic myocardium • Reducing interstitial/endothelial edema • Reducing leukocyte activation (decreased myeloperoxidase levels) • Improving capillary blood flow in the IRA microcirculation • AO is believed to salvage myocardium by

  7. 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

  8. 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)

  9. Top Ten Enrollers • Jack L. Martin MD, Main Line Health System • Pranobe V. Oemrawsingh MD, Douwe Atsma, MDLeiden 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

  10. AMIHOT Trial Algorithm • Major exclusion: • Cardiogenic shock • Need for IABP • Systemic pO2 • <80mmHg Anterior MI or Inferior MI withanterior ST AMI  24-hrs (Primary or Rescue) n=269 Successful PCI Initial TIMI flow  2 Hyperoxemic Reperfusion with AO for 90-minutes Normoxemic Reperfusion (Standard Therapy) ST-Monitor 24-hours Enrollment in 20 US and European sites Jan 2002 – Dec 2003 SPECT Scan 14-days Contrast Echo 1 month Contrast Echo 3 months

  11. 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

  12. Control (n=135) AO (n=134) Age (yrs) 60.0 60 Female 27% 27% Diabetes 11% 13% Hypertension 49% 53% Dyslipidemia 41% 49% Smoker 42% 43% Previous MI 10% 13% Previous PCI 7% 12% Previous CABG 1.5% 1% Time to Reperfusion (hours) 5.45 6.23 Door to Balloon (hours) Rescue PCI 2.23 16% 1.88 11% Anterior MI 56% 60% AMIHOT Trial Clinical Characteristics

  13. Control (n=135) AO (n=134) Infarct related artery LAD 56% 60% RCA 36% 31% Circumflex Other 6% 2% 8% 1% Initial TIMI flow grade 0/1 90% 87% 2 10% 13% 3 0% 0% Stent 100% 100% IIb/IIIa inhibitor 84% 90% Final TIMI flow grade 0/1 0% 0% 2 8% 4% 3 92% 96% AMIHOT Trial Angiographic Characteristics

  14. AO system & Delivery

  15. Primary Safety Endpoint 6.0 % 4.4 3.0 2.2 2.2 1.5 1.5 1.5 1.5 0.7 Death Re-Infarct TVR Stroke Composite Treat (n=134) Control (n=135) AMIHOT Trial - 30-day MACE p=ns

  16. All Patients (Area under the Curve) 2200 Tx (n = 106) Ctr (n = 116) 2000 1800 Area Under the Curve Mean ST-elevation 1600 1400 1200 p = ns at 3, 4, 6 hrs 1000 3 4 5 6 t (hr) AMIHOT ST-Elevation Reduction in AO Therapy vs. Controls

  17. AMIHOT ST-Elevation Reduction in AO Therapy vs. Controls Anterior Patients (Area under the Curve) 3500 Tx (n = 65) Ctr (n = 64) 3000 2500 Area Under the Curve Mean ST-elevation 2000 1500 p = 0.04 @ 3 hrs p = 0.03 @ 4 hrs p = 0.02 @ 6 hrs 1000 3 4 5 6 t (hr)

  18. Regional Wall Motion & Infarct Size Primary Endpoints Infarct Size Regional Wall Motion P=0.16 P=NS N=119 N=101 N=112 N=103

  19. Time to Reperfusion <6 hrs All Patients Infarct Size Regional Wall Motion P=0.04 P=0.05 N=84 N=69 N=82 N=69

  20. Regional Wall Motion Anterior MI Patients P=0.049 P=0.01 N=68 N=61 N=49 N=42

  21. 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

  22. AMIHOT Trial Conclusions - continued • Early indicators of relief of myocardial ischemia (i.e ST-Segment 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.

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