A Prospective, Randomized Evaluation A Prospective, Randomized Evaluation of Supersaturated Oxygen Therapy After of Supersaturated Oxygen Therapy After Percutaneous Coronary Intervention in Percutaneous Coronary Intervention in

Acute Anterior Myocardial InfarctionAcute Anterior Myocardial Infarction

Gregg W. Stone MDGregg W. Stone MD

For the AMIHOT II InvestigatorsFor the AMIHOT II Investigators

DisclosuresDisclosures

• Gregg W. Stone MDGregg W. Stone MD Research support from TherOx Inc.Research support from TherOx Inc.

BackgroundBackground• Despite successful reperfusion in AMI, myocardial recovery Despite successful reperfusion in AMI, myocardial recovery

is often suboptimal, resulting in extensive infarction.is often suboptimal, resulting in extensive infarction.

• In experimental infarct models, hyperbaric oxygen reduces In experimental infarct models, hyperbaric oxygen reduces myocardial tissue damage, in part by reducing reperfusion myocardial tissue damage, in part by reducing reperfusion injury and improving microcirculatory perfusion.injury and improving microcirculatory perfusion.

• Regional hyperoxemia in the infarct zone can be achieved Regional hyperoxemia in the infarct zone can be achieved by infusion of supersaturated blood into the infarct artery by infusion of supersaturated blood into the infarct artery after successful primary PCI.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 TrialThe AMIHOT I Trial269 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; PaO; PaO22 760-1000 mmHg 760-1000 mmHg) for 90’ versus

control. Therox, Inc.

AMIHOT I ResultsAMIHOT I Results3 Co-Primary Efficacy Endpoints3 Co-Primary Efficacy Endpoints

All patientsControlN=135

SSO2

N=134P 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±0.48 0.62±0.53 0.24

Anterior MI, reperfused <6h N=53 N=52

Infarct size 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

O’Neill WW et al. JACC 2007;50:397-405.O’Neill WW et al. JACC 2007;50:397-405.

AMIHOT II Trial DesignAMIHOT II Trial Design

2 Primary Endpoints2 Primary EndpointsEfficacy: Efficacy: Infarct size Infarct size (superiority)(superiority)(tc=99m sestamibi SPECT @14 days)(tc=99m sestamibi SPECT @14 days)

Safety: Safety: 30 day MACE 30 day MACE (noninferiority)(noninferiority)

Anterior AMI* with TIMI 0-2 flowAnterior AMI* with TIMI 0-2 flowreperfused by PCI with stenting within 6 hrsreperfused by PCI with stenting within 6 hrs

TIMI 2-3 flow achievedTIMI 2-3 flow achieved

Standard therapyStandard therapy SSOSSO22 for 90 mins for 90 mins

Randomize**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

Principal Exclusion CriteriaPrincipal Exclusion Criteria Cardiogenic shock, CPR for >10’, or IABP

Hemorrhagic diathesis, thrombocytopenia, or hemorrhagic stroke Hemorrhagic diathesis, thrombocytopenia, or hemorrhagic stroke within 6 monthswithin 6 months

Severe valvular stenosis or insufficiency, pericardial disease, non-Severe valvular stenosis or insufficiency, pericardial disease, non-ischemic cardiomyopathy, recent CABGischemic cardiomyopathy, recent CABG

Unsuccessful or complicated PCI: DS% in infarct lesion >50%, or final TIMI 0-1 flow, or major procedural complications such as perforation or shock

Other angiographic: severe calcification or tortuosity, SVG infarct Other angiographic: severe calcification or tortuosity, SVG infarct artery, LM >60%, proximal stenosis >40%, unstented dissection, MVD artery, LM >60%, proximal stenosis >40%, unstented dissection, MVD with likelihood for CABGwith likelihood for CABG

Systemic POSystemic PO22 <80 mmHg despite supplemental oxygen <80 mmHg despite supplemental oxygen

Study ProceduresStudy Procedures• Consent Consent beforebefore cath; randomize cath; randomize afterafter successful PCI successful PCI

• ASA 325 mg, clopidogrel 300-600 mg, UFH ± optional GPIASA 325 mg, clopidogrel 300-600 mg, UFH ± optional GPI

• 24 hour Holter placed in ER or cath lab (ST res; 224 hour Holter placed in ER or cath lab (ST res; 2 EP) EP)

• Supplemental oxygen to keep PaOSupplemental oxygen to keep PaO22 >80 mmHg >80 mmHg

• SSOSSO22 procedures procedures

Begin immediate post successful PCIBegin immediate post successful PCI Draw line from sheath sideport (≥8F) or contralateral FADraw line from sheath sideport (≥8F) or contralateral FA

SSOSSO22 delivery via a Tracker-38 or INCA-1 infusion catheter delivery via a Tracker-38 or INCA-1 infusion catheter

90' target infusion either in cath lab, holding area or CCU90' target infusion either in cath lab, holding area or CCU

Infusion at 75 cc/min; Infusion at 75 cc/min; ACT (≥250 secs during SSO2), HR, BP, PaOACT (≥250 secs during SSO2), HR, BP, PaO22

checked every 30' during infusionchecked every 30' during infusion

• CK, CK-MB, troponins at baseline and Q8CK, CK-MB, troponins at baseline and Q8 x3 x3

Endpoints and Statistical MethodologyEndpoints and Statistical Methodology• Objective 1 - Efficacy: Objective 1 - Efficacy: To demonstrate that compared to control, To demonstrate that compared to control,

SSOSSO22 results in reduced infarct size as measured by tc-99m- results in reduced infarct size as measured by tc-99m-

sestamibi SPECT imaging at 14 (±7) days in pts with anterior MI sestamibi SPECT imaging at 14 (±7) days in pts with anterior MI reperfused within 6 hoursreperfused within 6 hours

• Objective 2 - Safety: Objective 2 - Safety: To demonstrate that compared to control, SSOTo demonstrate that compared to control, SSO22

has noninferior rates of major adverse cardiac events (MACE – has noninferior rates of major adverse cardiac events (MACE – death, reinfarction, TVR or stroke) at 30 days death, reinfarction, TVR or stroke) at 30 days

• Bayesian hierarchical modeling: Bayesian hierarchical modeling: To allow pooling of data from To allow pooling of data from AMIHOT I, with the amount of pooling determined by the similarity of AMIHOT I, with the amount of pooling determined by the similarity of the AMIHOT II results to the AMIHOT I data, while still preserving 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 type I error to <5% (as per FDA “Draft Guidance for the Use of Bayesian Statistics in Medical Device Clinical Trials”)*Bayesian Statistics in Medical Device Clinical Trials”)*

*http://www.fda.gov/cdrh/osb/guidance/1601.pdf

Power AnalysisPower AnalysisAssumed rates:Assumed rates:

- Efficacy (median infarct size): - Efficacy (median infarct size): The absolute difference The absolute difference in in imputed infarct size* between control and SSOimputed infarct size* between control and SSO22 will be >5%** will be >5%**

- Safety (30 day MACE): - Safety (30 day MACE): Control and SSOControl and SSO22 = 7%, with a = 7%, with a

noninferiority margin (delta) = 6% noninferiority margin (delta) = 6%

Randomizing 304 pts in a 2.8:1 ratio Randomizing 304 pts in a 2.8:1 ratio between SSObetween SSO22 and and

control in AMIHOT II, utilizing Bayesian hierarchical control in AMIHOT II, utilizing Bayesian hierarchical modeling to pool data from AMIHOT I, provides (with modeling to pool data from AMIHOT I, provides (with type I error <0.05):type I error <0.05):

1.1. 85.4% power 85.4% power to demonstrate superiority (smaller infarct size to demonstrate superiority (smaller infarct size with SSOwith SSO22 than control) with a posterior probability of >95% than control) with a posterior probability of >95%

2.2. 80.7% power 80.7% power to declare noninferiority between the to declare noninferiority between the 2 groups with a posterior probability of >95% 2 groups with a posterior probability of >95%

*Missing values imputed for treatment, study, MI location, time to reperfusion, age and gender; **Consistent with a 17.6% reduction in 6 month mortality(Burns RJ et al. JACC 2002;39:30-6)

Primary Bayesian AnalysisPrimary Bayesian Analysis• AMIHOT II AMIHOT II was not was not powered as a stand alone trial, powered as a stand alone trial,

instead relying on Bayesian hierarchical modeling instead relying on Bayesian hierarchical modeling to allow partial pooling with AMIHOT I datato allow partial pooling with AMIHOT I data

Trial Power

EndpointFrequentist power (AMIHOT II alone)

Simple pooling (AMIHOT I + II)

Bayesian posterior power*

Efficacy 73% 93% 85.4%

Safety 64% 86% 80.7%

*Posterior Probability of >95% Success

Study OrganizationStudy Organization Principal Investigator:Principal Investigator: Gregg W. StoneGregg W. Stone

Co-Principal Investigator:Co-Principal Investigator: Jack L. MartinJack L. Martin

Bayesian Statistician:Bayesian Statistician: W. John BoscardinW. John Boscardin

Data ManagementData Management:: Boston Biomedical AssociatesBoston Biomedical Associates

Site and Data Monitoring:Site and Data Monitoring: TherOx, Inc.TherOx, Inc.

Clinical Events Committee:Clinical Events Committee: Bonnie H. Weiner (Chair)Bonnie H. Weiner (Chair)

SPECT Core Lab:SPECT Core Lab: Mayo Clinic, Ray J. Gibbons (Director)Mayo Clinic, Ray J. Gibbons (Director)

Angiographic Core Lab:Angiographic Core Lab: Cardiovascular Research Foundation, Cardiovascular Research Foundation, Alexandra J. Lansky (Director) Alexandra J. Lansky (Director)

ECG/Holter Core Lab:ECG/Holter Core Lab: Duke Clinical Research Institute, Duke Clinical Research Institute, Mitchell W. Krucoff (Director)Mitchell W. Krucoff (Director)

DSMB:DSMB: David Holmes (Chair), E. Bates, David Holmes (Chair), E. Bates, J. Ferguson, W. Gaasch, K. FreemanJ. Ferguson, W. Gaasch, K. Freeman

Sponsor:Sponsor: TherOx, Inc.TherOx, Inc.

Top Enrolling SitesTop Enrolling Sites

1. Menko-Jan deBoer, Isala Clinics Weezenlanden, Zwolle, NL

2. Massimo Margheri, Universitaria di Careggi, Florence, Italy

3. Ezio Bramucci, Policlinico San Matteo, Pavia, Italy

4. James Blankenship, Geisinger Clinic, Danville, PA

5. Jack L. Martin, Main Line Health, Bryn Mawr, PA

6. D. Christopher Metzger, Wellmont Holston Med Cntr, Kingsport, TN

7. Michael Chang, Mercy Heart Institute, Sacramento, CA

8. Aaron Kugelmass, Henry Ford Health System, Detroit, MI

Patient EnrollmentPatient Enrollment

304 patients randomized at 20 sites in 4 countries304 patients randomized at 20 sites in 4 countries((US, Canada, Netherlands, Italy) between between

September 13, 2005 and May 26, 2007

3 randomization errors3 randomization errors

301 ITT patients301 ITT patients

SSOSSO22

N=222N=222ControlControl

N=79N=79

30 day FU30 day FUcompletecomplete

N=222N=222(100%)(100%)

N=79N=79(100%)(100%)

SPECTSPECTendpointendpoint

N=209N=209(94.1%)(94.1%)

N=72N=72(91.1%)(91.1%)

Randomize 2.8:1Randomize 2.8:1

Baseline CharacteristicsBaseline Characteristics

ControlControl(N=79)(N=79)

SSOSSO22

(N=222)(N=222)

Age (years)Age (years) 59.3 [50.1, 69.6]59.3 [50.1, 69.6] 60.5 [51.7, 71.3]60.5 [51.7, 71.3]

MaleMale 87.3%87.3% 77.9%77.9%

DiabetesDiabetes 13.9%13.9% 16.2%16.2%

HypertensionHypertension 45.6%45.6% 46.9%46.9%

HyperlipidemiaHyperlipidemia 43.0%43.0% 45.1%45.1%

Current smokingCurrent smoking 43.0%43.0% 38.2%38.2%

Prior MIPrior MI 8.9%8.9% 9.0%9.0%

Prior PCI of TVPrior PCI of TV 10.1%10.1% 5.9%5.9%

CrCl <60 ml/minCrCl <60 ml/min 12.0%12.0% 18.8%18.8%

P=NS for all comparisons

Procedural ResultsProcedural ResultsControlControl(N=79)(N=79)

SSOSSO22

(N=222)(N=222)

Symptom to ER (mins)Symptom to ER (mins) 90 [60, 150]90 [60, 150] 109 [60, 170]109 [60, 170]

Door to balloon (mins)Door to balloon (mins) 75 [45, 117]75 [45, 117] 77 [47, 116]77 [47, 116]

Symptom to reperfusion (mins)Symptom to reperfusion (mins) 171 [143, 290]171 [143, 290] 194.5 [154, 265]194.5 [154, 265]

Infarct lesionInfarct lesion

- Proximal LAD- Proximal LAD 46.8%46.8% 47.8%47.8%

- Mid LAD- Mid LAD 51.9%51.9% 49.1%49.1%

- Distal LAD- Distal LAD 0%0% 2.3%2.3%

- Diagonal- Diagonal 1.3%1.3% 0.9%0.9%

LVEF % (site) LVEF % (site) 40 [35, 45]40 [35, 45] 40 [35, 45]40 [35, 45]

P=NS for all comparisons

Procedural ResultsProcedural ResultsControlControl(N=79)(N=79)

SSOSSO22

(N=222)(N=222)

Stent implantedStent implanted 97.5%97.5% 99.1%99.1%

GP IIb/IIIa usedGP IIb/IIIa used 64.6%64.6% 68.0%68.0%

Rescue PCI (failed lytic)Rescue PCI (failed lytic) 8.9%8.9% 5.0%5.0%

TIMI flow pre (core lab)TIMI flow pre (core lab)

- 0/1- 0/1 69.9%69.9% 75.5%75.5%

- 2- 2 13.7%13.7% 17.1%17.1%

- 3- 3 16.4%16.4% 7.4%*7.4%*

TIMI flow post (core lab) – pre randomizationTIMI flow post (core lab) – pre randomization

- 0/1- 0/1 2.8%2.8% 1.4%1.4%

- 2- 2 4.2%4.2% 10.2%10.2%

- 3- 3 93.0%93.0% 88.4%88.4%

*P=0.02; otherwise P = NS for all comparisons

Primary Efficacy EndpointPrimary Efficacy EndpointInfarct Size by Tc-99m-sestamibi SPECTInfarct Size by Tc-99m-sestamibi SPECT

ControlN=52

Median [IQR]

23 [5, 37]

SSO2N=49

Median [IQR]

9 [0, 30]

ControlN=72

Median [IQR]

26.5 [8.5, 44]

SSO2N=209

Median [IQR]

20 [6, 37]

AMIHOT I AMIHOT II

Infa

rct

siz

e, %

LV

P=0.07(2-sided)

P=0.10(2-sided)

ControlN=124

Median [IQR]

25 [7, 42]

SSO2N=258

Median [IQR]

18.5 [3.5, 34.5]

Pooled, adjustedN=382

Primary Efficacy EndpointPrimary Efficacy EndpointInfarct Size by Tc-99m-sestamibi SPECTInfarct Size by Tc-99m-sestamibi SPECT

Infa

rct

siz

e, %

LV

Differenceof medians

-6.5%PWilcoxon=0.023

BayesianPosterior

Probability = 98.0%*

*Imputed infarct size;95.6% using onlynon imputed data

Infarct Size DistributionInfarct Size Distribution

Proportion

Infarct size in 5% increments Infarct size in 5% increments

Pooled, adjustedControl(n=124)

Pooled, adjustedSSO2

(n=258)Median [IQR] =

25 [7, 42]Median [IQR] =

18.5 [3.5, 34.5]

0-5% 0-5%

Immeasurable InfarctsImmeasurable Infarcts

RR [95%CI] = 1.76 (1.04, 3.00)

P = 0.03P = 0.03P = 0.20P = 0.20

P = 0.11P = 0.11

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infa

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(%

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0.0

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2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

10.0

0 5 10 15 20 25 30

Time to MACE Events (days)

Cu

mu

lati

ve M

AC

E r

ate

No. at RiskSSO2 222 217 213 211 211 206 195

Control 79 77 77 77 77 74 63

ControlSSO2

Plog rank = 0.58

5.4%

3.8%

Primary Safety Endpoint: Primary Safety Endpoint: 30 Day MACE30 Day MACE

Primary Safety Endpoint: Primary Safety Endpoint: 30 Day MACE30 Day MACEAMIHOT IAMIHOT I ControlControl SSOSSO22 Difference Difference [95%CI][95%CI] PPsupsup

MACE, all ptsMACE, all pts 7/135 (5.2%)7/135 (5.2%) 9/134 (6.7%)9/134 (6.7%) 1.5% [-4.5, 7.8]1.5% [-4.5, 7.8] 0.620.62

MACE, ant <6MACE, ant <6 2/53 (3.8%)2/53 (3.8%) 3/52 (5.8%)3/52 (5.8%) 2.0% [-7.8, 12.4]2.0% [-7.8, 12.4] 0.680.68

AMIHOT IIAMIHOT II N=79N=79 N=222N=222

MACEMACE 3 (3.8%)3 (3.8%) 12 (5.4%)12 (5.4%) 1.6% [-5.5, 6.3]1.6% [-5.5, 6.3] 0.770.77

- Death- Death 0 (0%)0 (0%) 4 (1.8%)4 (1.8%) 0.580.58

- Reinfarction- Reinfarction 2 (2.5%)2 (2.5%) 4 (1.8%)4 (1.8%) 0.650.65

- TVR- TVR 3 (3.8%)3 (3.8%) 8 (3.6%)8 (3.6%) 1.01.0

- Stroke- Stroke 0 (0%)0 (0%) 0 (0%)0 (0%) --

MACE pooledMACE pooled11 10/214 (4.7%)10/214 (4.7%) 21/356 (5.9%)21/356 (5.9%) 1.2% [-3.0, 4.9]1.2% [-3.0, 4.9] 0.570.57

MACE pooledMACE pooled22 5/132 (3.8%)5/132 (3.8%) 15/274 (5.5%)15/274 (5.5%) 1.7% [-3.5, 5.8]1.7% [-3.5, 5.8] 0.480.48

Bayesian Posterior ProbNI = 99.8%1 = using all pts from AMIHOT I2 = using only anterior MI reperfused <6 from AMIHOT I

Other Adverse Events at 30 DaysOther Adverse Events at 30 DaysControl SSO2 P

N=79 N=222

Stent thrombosis 2 (2.5%) 9 (4.1%) 0.73

Any access site AE 10 (12.7%) 50 (22.5%) 0.07

- Hematoma 8 (10.1%) 39 (17.6%) 0.15

Any bleeding AE 10 (12.7%) 54 (24.3%) 0.04

- Access site related 9 (11.4%) 41 (18.5) 0.16

- Non access site related 1 (1.3%) 15 (6.8%) 0.08

- Hemoglobin baseline 14.7 [13.7, 15.5] 14.3 [13.4, 15.5] 0.27

- Hemoglobin 24 hours 13.6 [12.6, 14.6] 12.9 [12.0, 13.8] 0.0005

- Transfusion 1 (1.3%) 14 (6.3%) 0.13

LimitationsLimitations• The AMIHOT II trial The AMIHOT II trial per se per se was (intentionally) was (intentionally)

underpowered for a stand alone determination of underpowered for a stand alone determination of safety or efficacysafety or efficacy

• A broad delta for safety was utilized; as such, lesser A broad delta for safety was utilized; as such, lesser differences in safety measures cannot be excludeddifferences in safety measures cannot be excluded

• The trial was also underpowered for mortality; longer The trial was also underpowered for mortality; longer term follow-up (ongoing to 1-year) will reveal whether term follow-up (ongoing to 1-year) will reveal whether the reduction in infarct size with SSOthe reduction in infarct size with SSO22 results in results in

directionally enhanced survival or reduced heart directionally enhanced survival or reduced heart failurefailure

ConclusionConclusion

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