Coronary Intervention in Acute Myocardial Infarction

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ISSN: 1941-7632

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Circulation: Cardiovascular Interventions is published by the American Heart Association. 7272DOI:10.1161/CIRCINTERVENTIONS.108.840066

2009;2;366-375; originally published online Sep 15, 2009;Circ Cardiovasc IntervMartin Fahy, W. John Boscardin and for the AMIHOT-II Trial Investigators

Barbara S. Lindsay, Bonnie H. Weiner, Alexandra J. Lansky, Mitchell W. Krucoff,Bramucci, James C. Blankenship, D. Christopher Metzger, Raymond J. Gibbons,Gregg W. Stone, Jack L. Martin, Menko-Jan de Boer, Massimo Margheri, Ezio

Coronary Intervention in Acute Myocardial InfarctionEffect of Supersaturated Oxygen Delivery on Infarct Size After Percutaneous

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Data Supplement (unedited) at:

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Original Articles

Effect of Supersaturated Oxygen Delivery on Infarct SizeAfter Percutaneous Coronary Intervention in Acute

Myocardial Infarction

Gregg W. Stone, MD; Jack L. Martin, MD; Menko-Jan de Boer, MD; Massimo Margheri, MD;Ezio Bramucci, MD; James C. Blankenship, MD; D. Christopher Metzger, MD;

Raymond J. Gibbons, MD; Barbara S. Lindsay, RN; Bonnie H. Weiner, MD;Alexandra J. Lansky, MD; Mitchell W. Krucoff, MD; Martin Fahy, MSc; W. John Boscardin, PhD;

for the AMIHOT-II Trial Investigators

BackgroundMyocardial salvage is often suboptimal after percutaneous coronary intervention in ST-segment elevation

myocardial infarction. Posthoc subgroup analysis from a previous trial (AMIHOT I) suggested that intracoronary

delivery of supersaturated oxygen (SSO2) may reduce infarct size in patients with large ST-segment elevation

myocardial infarction treated early.

Methods and ResultsA prospective, multicenter trial was performed in which 301 patients with anterior ST-segment

elevation myocardial infarction undergoing percutaneous coronary intervention within 6 hours of symptom onset wererandomized to a 90-minute intracoronary SSO2 infusion in the left anterior descending artery infarct territory (n222)

or control (n79). The primary efficacy measure was infarct size in the intention-to-treat population (powered for

superiority), and the primary safety measure was composite major adverse cardiovascular events at 30 days in the

intention-to-treat and per-protocol populations (powered for noninferiority), with Bayesian hierarchical modeling used

to allow partial pooling of evidence from AMIHOT I. Among 281 randomized patients with tc-99m-sestamibi

single-photon emission computed tomography data in AMIHOT II, median (interquartile range) infarct size was 26.5%

(8.5%, 44%) with control compared with 20% (6%, 37%) after SSO2. The pooled adjusted infarct size was 25% (7%,

42%) with control compared with 18.5% (3.5%, 34.5%) after SSO2 (PWilcoxon0.02; Bayesian posterior probability of

superiority, 96.9%). The Bayesian pooled 30-day mean (SE) rates of major adverse cardiovascular events were

5.01.4% for control and 5.91.4% for SSO2 by intention-to-treat, and 5.11.5% for control and 4.71.5% for SSO2by per-protocol analysis (posterior probability of noninferiority, 99.5% and 99.9%, respectively).

ConclusionsAmong patients with anterior ST-segment elevation myocardial infarction undergoing percutaneouscoronary intervention within 6 hours of symptom onset, infusion of SSO2 into the left anterior descending artery infarct

territory results in a significant reduction in infarct size with noninferior rates of major adverse cardiovascular events

at 30 days.

Clinical Trial Registration clinicaltrials.gov Identifier: NCT00175058 (Circ Cardiovasc Intervent. 2009;2:366-375.)

Key Words: myocardial infarction infarct size angioplasty reperfusion

Myocardial salvage is frequently suboptimal despitesuccessful reperfusion in ST-segment elevation myo-cardial infarction (STEMI), resulting in left ventricular dys-

function and increased mortality.1,2 Although delays to reper-

fusion contribute to irreversible myonecrosis,3 additional

causal mechanisms include microcirculatory dysfunction and

reperfusion injury.4,5 Most prior studies of pharmacological

and mechanical interventions to reduce infarct size after

fibrinolysis and primary percutaneous coronary intervention

(PCI) have been negative.6,7 The delivery of supersaturated

Received December 1, 2008; accepted July 30, 2009.From the Columbia University Medical Center (G.W.S., A.J.L., M.F.), New York-Presbyterian Hospital and the Cardiovascular Research Foundation,

New York, NY; Sharpe-Strumia Research Foundation of the Bryn Mawr Hospital (J.L.M.), Main Line Health, Bryn Mawr, Pa; Isala ClinicsWeezenlanden (M.J.D.), Zwolle, the Netherland; Universitaria di Careggi (M.M.), Florence, Italy; Policlinico San Matteo (E.B.), Pavia, Italy; Geisinger

Medical Center (J.C.B.), Danville, Pa; Wellmont Holston Med Center (D.C.M.), Kingsport, Tenn; Mayo Clinic Foundation (R.J.G.), Rochester, Minn;TherOx, Inc. (B.S.L.), Irvine, Calif; Worcester Medical Center (B.H.W.), Worcester, Mass; Duke Clinical Research Institute (M.W.K.), Durham, NC; andUniversity of California (W.J.B.), San Francisco, San Francisco, Calif.

The online-only Data Supplement is available at http://circinterventions.ahajournals.org/cgi/content/full/CIRCINTERVENTIONS.108.840066/

DC1.Correspondence to Gregg W. Stone, MD, Columbia University Medical Center, New York-Presbyterian Hospital, the Cardiovascular Research

Foundation, 111 E 59th St, 11th Floor, New York, NY 10022. E-mail [email protected] 2009 American Heart Association, Inc.

Circ Cardiovasc Intervent is available at http://circinterventions.ahajournals.org DOI: 10.1161/CIRCINTERVENTIONS.108.840066

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oxygen (SSO2) with a PaO2 of 760 to 1000 mm Hg in the

infarct-related artery immediately after successful reperfusion

markedly reduces infarct size in porcine coronary occlusion

models,8 possibly by decreasing capillary endothelial cell

swelling, reducing formation of lipid peroxide radicals, alter-

ing nitric oxide synthase expression, and/or inhibiting leuko-

cyte activation and adherence.913 Following promising pilot

study results,1416 269 patients with anterior or large inferior

STEMI undergoing successful PCI within 24 hours of symp-

tom onset (the preclinical parameters for which SSO2 suc-

cessfully reduced infarct size) were randomly assigned to

SSO2 or control in the Acute Myocardial Infarction With

Hyperoxemic Therapy (AMIHOT)-I trial. In this study, in-

farct size measured by technetium (tc)-99m-sestamibi single-

photon emission computed tomography (SPECT) imaging at

14 days was not significantly different between the 2 treat-

ment groups.17 However, the 105 patients with anterior

infarction reperfused within 6 hours assigned to SSO2 had a

smaller median infarct size, less post-PCI residual ischemic

burden measured by ST-segment Holter monitoring, and im-proved echocardiographic regional wall motion at 3 months.17

Editorial see p 363Clinical Perspective on p 375

As a post hoc subgroup analysis, these findings from the

AMIHOT-I trial are not definitive. We therefore performed a

second, prospective, randomized trial of SSO2 therapy, this

time confined to patients with large anterior infarction under-

going PCI within 6 hours of symptom onset (AMIHOT II).

The study was powered with a Bayesian approach using

hierarchical modeling to allow partial borrowing of evidence

from the AMIHOT-I trial.

Methods

The AMIHOT-I TrialThe AMIHOT-II protocol intentionally preserved core design ele-ments from AMIHOT I, the details of which have been previously

described.17 In brief, from January 2002 to December 2003, 269

patients with anterior or large inferior STEMI and baseline Throm-bolysis In Myocardial Infarction (TIMI) 0 to 2 flow undergoingprimary or rescue PCI within 24 hours after symptom onset wereenrolled in AMIHOT I. Patients in whom TIMI 2 to 3 flow wasachieved were randomly assigned to receive a 90-minute infusion ofSSO2 in the infarct artery versus control (standard of care withoutintracoronary infusion). Three primary efficacy end points wereprespecified: infarct size at 14 days measured by tc-99m-sestamibi

SPECT; total ischemic burden within 3 hours after reperfusionmeasured by continuous Holter monitoring as the area under theST-segment level versus time curve (an end point distinct fromST-segment resolution); and echocardiographic infarct zone regionalwall motion at 3 months. The primary safety end point was thecomposite incidence of major adverse cardiovascular events(MACE), defined as death, reinfarction, target vessel revasculariza-tion, or stroke at 30 days. The baseline characteristics and outcomesin the treatment groups have been previously reported.17 The trialprespecified examination of subgroups based on infarct location(anterior versus nonanterior) and by time to reperfusion (less than orgreater than 6 hours).

The AMIHOT-II Trial, Study PopulationPatients aged 18 years or older with anterior MI (ST-segment

elevation1 mm in2 contiguous precordial leads [V1V4] or newleft bundle-branch block with confirmation of left anterior descend-

ing coronary artery occlusion) and symptom onset within 6 hours

were considered for enrollment. Also for eligibility, angiographic

documentation of baseline TIMI 0 to 2 flow in a native coronary

artery and intended intracoronary stent placement were required.

Principal clinical and angiographic exclusion criteria included abso-

lute contraindications to anticoagulant therapy; hemorrhagic stroke

within 6 months; intra-aortic balloon pump counterpulsation or

cardiogenic shock; coronary artery bypass graft surgery within 30

days; severe valvular stenosis or insufficiency, pericardial disease,nonischemic cardiomyopathy, ventricular septal defect, pseudoaneu-

rysm, or papillary muscle rupture; cardiopulmonary resuscitation for

10 minutes; expected survival 6 months due to noncardiac

comorbidities; current participation in other investigational device or

drug trials; inability or unwillingness to provide informed consent or

to agree to all follow-up study procedures; systemic arterial PO280 mm Hg despite supplemental oxygen; severe target vessel

calcification or tortuosity; coronary stenosis 40% proximal to the

infarct lesion, unprotected left main stenosis 60%, or a significant

nonstented coronary dissection; total symptom-to-balloon time of6 hours, or TIMI 0 to 1 flow at the end of procedure; or surgery or

additional PCI planned within 30 days after procedure. A screening

log was kept at all participating sites to document reasons for patient

ineligibility. The study was approved by the institutional review

board at each participating center, and consecutive eligible patientssigned informed written consent.

AMIHOT-II Protocol Proceduresand RandomizationBefore angiography, an ECG was performed, a 24-hour 12-lead

continuous digital electrocardiographic monitor (180, Northeast

Monitoring, Maynard, Mass) was placed, cardiac biomarkers were

drawn (creatine phosphokinase [CK], CK MB fraction [CK-MB] or

troponin), and 325 mg of aspirin was administered. A clopidogrel

loading dose of 300 or 600 mg was recommended before procedure,

but in no case 4 hours after the procedure. Left ventriculography,

coronary arteriography, and PCI were performed with standard

techniques and commercially available devices. Anticoagulation

during PCI was achieved with intravenous unfractionated heparin.Glycoprotein IIb/IIIa inhibitor and stent selection decisions were per

investigators discretion. After PCI, cardiac biomarkers were drawn

every 8 to 12 hours, aspirin was continued indefinitely, and 75 mg of

clopidogrel was administered daily for at least 1 month depending on

the stent type.

Eligible patients were randomized at the completion of the PCI

procedure in an open-label and unbalanced fashion (as described

later) to either an intracoronary infusion of SSO2 or standard of care

without infusion. Randomization was performed using an automated

voice response system, in blocks of 19 (14 SSO2 patients for each 5

control patients2.8:1) stratified by time to reperfusion (0 to 3 hours

or 3 to 6 hours) and lesion location (proximal or nonproximal left

anterior descending), accomplished using an adaptive scheme with a

biased coin randomization.18

Device Description and Study ProceduresSSO2 was delivered for 90 minutes using an extracorporeal circuit

(TherOx, Inc, Irvine, Calif), as previously described.14,17 Blood is

withdrawn either from the side port of a single femoral sheath sized

2F larger than the PCI guide catheter (coaxial configuration), or

alternatively through a second 5F sheath placed in the contralateral

femoral artery and is oxygenated in a polycarbonate chamber to

achieve a PO2 of 760 to 1000 mm Hg. Hyperoxemic blood is then

returned to the patient at 75 mL/min for 90 minutes through an

intracoronary infusion catheter placed in the infarct artery proximal

to the stent, during which the guide catheter is disengaged from the

left main coronary ostium. At the beginning of the protocol, the only

infusion catheter available was the 5.3F Tracker-38 (Target Thera-

peutics, Fremont, Calif), which in the coaxial configuration required

a 7F guide catheter and 9F sheath. During the latter phases ofenrollment the lower profile 4.6F MI-Cath infusion catheter

Stone et al Supersaturated Oxygen and Infarct Size 367

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(TherOx, Inc) was introduced, which required a 6F guide catheterand 8F sheath, allowing for a smaller arteriotomy.

The SSO2 infusion was initiated in all patients in the cardiaccatheterization laboratory immediately after the final coronary an-giogram, after which the patient could remain in this setting or betransferred either to a holding area or the coronary care unit forcompletion of the infusion. The systemic arterial PO2 was measuredevery 30 minutes during the 90-minute infusion, and nasal oxygen

adjusted to maintain the PO2 80 mm Hg. The activated clottingtime was checked every 30 minutes and supplemental heparinboluses administered as necessary to maintain the activated clottingtime 250 seconds during the active infusion.

Data ManagementIndependent study monitors verified 100% of case report form dataonsite. All adverse cardiac events were adjudicated by an indepen-dent committee blinded to treatment allocation after review oforiginal source documentation. A data safety and monitoring com-mittee periodically reviewed blinded safety data, each time recom-mending the study continue without modification. Independent corenuclear, electrocardiographic and angiographic laboratory analyses wereperformed by technicians blinded to treatment assignment and clinicaloutcomes using validated methods as previously described.1921

Endpoints and DefinitionsThe primary efficacy end point was infarct size measured bytc-99m-sestamibi SPECT at 14 days, powered for superiority. Theprimary safety measure was composite MACE (as defined inAMIHOT I), measured at 30 days, powered for noninferiority. Deathwas defined as all-cause death. Reinfarction was defined as recurrentischemic symptoms lasting 20 minutes with new ST-segmentelevation and/or CK-MB re-elevation if occurring 96 hours afterthe index event. Target vessel revascularization was defined as anyrepeat PCI or bypass graft surgery of the study coronary artery.

Stroke was defined as a neurologic deficit lasting24 hours, or24hours with a brain imaging study showing infarction.

Power and Statistical AnalysisA prespecified Bayesian hierarchical modeling approach was usedfor analysis of the primary end points to allow partial borrowing ofevidence from the previously performed AMIHOT-I trial. Directspecification of a previous distribution using the favorable results ofthe AMIHOT-I trial would have inflated frequentist type I errorbeyond acceptable levels.22 The hierarchical Bayesian approachallows inference for the AMIHOT-II trial to borrow a certain amountof evidence from the AMIHOT-I trial, with the amount of borrowingdetermined by the similarity of the data between the 2 trials.23 Thismay be conceptualized as precision weighted averages of the variousinformation sources for the parameter where the weights are data-determined. Estimates are pulled in varying degrees toward theoverall mean, a behavior known as shrinkage.24 Moreover, the modelwas tuned such that the AMIHOT-II trial would have frequentist typeI error of no 5% level on the boundaries of the null hypotheses for

the primary end points.25 A posterior probability of95% for bothend points was required for success. The treatment versus controleffect differences for the primary efficacy end point were determined

using a pooled analysis adjusted for the study-specific medians.Probability statements as to the strength of evidence for the efficacyend point are made with respect to the Bayesian model, however.Unbalanced randomization (2.8:1) was used to maximize power forthe safety end point for a given sample size; power gains forunbalanced randomization in standalone noninferiority designs canbe substantial,26 and the advantage is amplified in the Bayesianhierarchical design. Further details of the power calculations andBayesian modeling for the primary efficacy and safety end points areprovided in the online-only Data Supplement.

Regarding the primary efficacy end point, assuming an absolutereduction in infarct size of 5% of the left ventricle, randomizing 304

patients in a 2.8:1 ratio between SSO2 and control in AMIHOT IIusing Bayesian hierarchical modeling to incorporate the AMIHOT-I

findings, provided 85.4% power to demonstrate superiority of SSO2.Regarding the primary safety end point, assuming 30-day rates ofMACE of 7% in both randomized arms, with a noninferiority of6% (a margin agreed on with the Food and Drug Administration),

80.7% power was present to declare noninferiority between the2 groups. This approach is distinctly different from simple pooling ofthe AMIHOT-I subgroup data in patients with anterior MI reperfused

within 6 hours with the AMIHOT-II results. Simple pooling (which

greatly inflates type I error) would have provided significantlygreater power for the primary efficacy and safety end points (93%

and 86%, respectively). Conversely, it is also important to note thatAMIHOT II was intentionally underpowered as a standalone studyfor the primary efficacy and safety end points (73% and 64% power,

respectively); statistical testing of AMIHOT II alone was thereforenot prespecified for primary end point analysis. Rather, some degreeof borrowing from the AMIHOT-I data would be necessary for eitherprimary end point to be satisfied (with the degree of borrowing

depending on the similarity of the datasets), with the principalstatistical analysis planned only on the blended Bayesian dataset.

Use of Bayesian analysis was restricted to assessment of the

primary end points. Secondary and subgroup analyses were con-ducted using standard (frequentist) methods. Categorical variableswere compared by Fisher exact test. Continuous variables are

presented as meanSD or median (interquartile range), and werecompared by the nonparametric Wilcoxon rank-sum test. ExactWilcoxon 2-sample tests were used to compare infarct size data

between the SSO2 and control groups. Linear regression analysis wasused to adjust for differences between the groups in age, gender,

prior MI, diabetes, infarct location, time to reperfusion, post-PCIST-segment resolution prerandomization, and major bleeding. Allprimary and secondary analyses were performed in the intent-to-treat

population. A per-protocol subset was used as a coprimary analysisfor the primary (noninferiority) safety end point, consisting ofrandomized patients not excluded due to a major protocol deviation

likely to impact the primary safety end point. Formal interactiontesting was used to assess the impact of baseline left ventricularejection fraction (LVEF) on the relative reduction in infarct size withSSO2. Smoothed medians of infarct size distributions were computed

by kernel density estimation to de-emphasize the effects of discrete-ness in smaller subgroups. Statistical evaluations using frequentistmethods in the AMIHOT-II study patients were performed using a2-sided significance level of 0.05. Non-Bayesian statistical analyses

were performed by SAS version 9.1.3, Cary, NC. Bayesian inferencewas conducted using Markov chain Monte Carlo computation by theR2WinBUGS interface to WinBUGS 1.4.1 (Data Supplement).

Results

PatientsBetween September 13, 2005, and May 26, 2007, a total of

2517 consecutive patients with STEMI were screened at 20

sites in 4 countries for enrollment in AMIHOT II, of whom

317 (12.6%) were enrolled (Figure 1). Of the 2200 excluded

patients, 1244 (56.5%) had a nonanterior MI and 388 (15.4%)

presented6 hours after symptom onset. Among the remain-

ing 934 patients with anterior STEMI presenting within 6

hours of symptom onset, 617 (66.1%) were not eligible for

randomization, the most common reasons being cardiogenic

shock or intra-aortic balloon counterpulsation use, baseline

TIMI-3 flow, procedural complications, inability to obtain

consent, or physician discretion (Figure 1). Of the 317

eligible patients who provided informed consent, 13 received

SSO2 as part of a nonrandomized training cohort, and 3

patients who were prematurely randomized in error were

subsequently deregistered before any treatment was delivered

after it was recognized that major exclusion criteria werepresent (ventricular septal defect in 1 patient, prolonged

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cardiopulmonary resuscitation in 1 patient, and cardiogenicshock in 1 patient). Thus, the intention-to-treat study cohort

consisted of 301 randomized patients, 222 of whom were

assigned to SSO2 and 79 to control. Of the 301 randomized

patients, tc-99m-sestamibi SPECT infarct size assessment

was completed in 281 patients (93.4%), and no patient was

lost to follow-up at 30 days.

The baseline characteristics of the randomized AMIHOT-II

groups were well matched (Table 1). The enrolled

AMIHOT-II patients were also comparable with the cohort of

AMIHOT-I patients with anterior STEMI reperfused within 6

hours of symptom onset, except that the AMIHOT-I patients

were less likely to have hypertension and baseline TIMI-2

flow, had a lower baseline LVEF, were more likely to receive

glycoprotein IIb/IIIa inhibitors but less likely to undergo

thrombectomy (Table 1). Drug-eluting stents were also not

available during AMIHOT I.

AMIHOT-II SSO2

ProcedureAmong patients randomized to SSO2, the coaxial approach

was most commonly used, which required a 9F sheath to

accommodate the Tracker-38 infusion catheter (Table 2). To

avoid the 9F sheath, contralateral femoral arterial access was

used for the draw sheath in 40.1% of patients in whom the

Tracker-38 was used. In contrast, the coaxial (single sheath)

approach was used in almost all cases when the smallerMI-Cath infusion catheter became available (Table 2).

A 90-minute or longer SSO2 infusion was delivered in

84.7% of patients (Table 2). The infusion most commonly

took place in the cardiac catheterization laboratory, though

30% of patients received the infusion in other settings. Vital

signs and arterial blood gas measurements (assessed every 30

minutes) were stable during the infusion; neither the systemic

arterial PO2 (140 mm Hg on supplemental low-flow nasal

cannula oxygen) nor oxygen saturation (98%) changed

during intracoronary SSO2 infusion (data not shown).

Infarct Size

As shown in Figure 2, among 101 patients with anteriorSTEMI reperfused within 6 hours in AMIHOT I in whom

infarct size was measured, the median (interquartile range)infarct size (measured as the percentage of the left ventricle)

was 23% (5%, 37%) with control therapy compared with 9%

(0%, 30%) after SSO2 (smoothed medians, 24% versus

17.5%, respectively). Among 281 randomized patients with

tc-99m-sestamibi SPECT data in AMIHOT II, infarct size

was 26.5% (8.5%, 44%) with control therapy compared with

20% (6%, 37%) after SSO2 (unadjusted P0.10, adjusted

P0.03). The pooled study-level adjusted infarct size from

the AMIHOT I and II trials was 25% (7%, 42%) with control

therapy compared with 18.5% (3.5%, 34.5%) after SSO2(PWilcoxon0.02; Bayesian posterior probability of superior-

ity, 96.9%). Figure 3 depicts the histogram of infarct sizes inthe pooled treatment and control cohorts, demonstrating a

shift to smaller infarcts across the range of the skewed

distribution. Among 154 patients with a baseline LVEF of

40%, infarct size was reduced from 33.5% (17.5%, 43.5%)

with control to 23.5% (7.5%, 38.5%) with SSO2, an absolute

reduction of 10% (0%, 14%), whereas the absolute decrease

in infarct size was less marked in the 196 patients with an

LVEF of40% (16.5% [4.5%, 31.5%] with control versus

12.5% [2.5%, 30.5%] with SSO2, a reduction of 4% [1%,

7%], P for interaction, 0.60).

Cardiac Biomarker and ST-Segment Assessment

Among patients randomized in AMIHOT II to SSO2 versus

control, there were no significant differences in the post-PCI

peak levels of CK-MB (299257 versus 289175 IU/L

respectively, P0.39) or troponin (96136 versus 128161

ng/mL respectively, P0.27). Nor were there significant

differences between the groups in post-PCI total ischemic

burden measured by the Holter monitor cumulative ST-

elevation time trend curve area at 3 hours (11782596 versus

13693684 V min, respectively, P0.69).

Clinical OutcomesAs shown in Table 3, by intention-to-treat analysis, the

Bayesian pooled 30-day mean (

SE) rates of MACE were5.01.4% for control and 5.91.4% for SSO2 (posterior

Figure 1. Patient flow and follow-up in theAMIHOT-II trial. See text for details. IABPindicates intra-aortic balloon pump.




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probability of noninferiority, 99.5%). By per-protocol analy-

sis, the Bayesian pooled 30-day rates of MACE were

5.11.5% for control and 4.71.5% for SSO2 (posterior

probability of noninferiority99.9%).

Other adverse events in AMIHOT II appear in Table 4.Hemorrhagic complications and access site-related events,

mostly hematomas, were more frequent in patients random-

ized to SSO2. Among SSO2 patients, use of the smaller

MI-Cath infusion catheter compared with the Tracker-38 was

associated with a reduction in access site-related adverse

events (from 27.2% to 13.3%, P

0.03), due mainly to feweraccess site reacted complications in the SSO2 group with use

Table 1. Baseline Characteristics of the AMIHOT-I and AMIHOT-II Study Populations and Procedural Results Before Randomization

AMIHOT I

Anterior MI,

6 hours* (N105)

AMIHOT II

All patients

(N301) P

AMIHOT II

SSO2 (N222) Control (N79)

Age, y 58.412.3 60.412.0 0.15 60.912.2 59.211.3

Male 80 (76.2) 242 (80.4) 0.40 173 (77.9) 69 (87.3)

Diabetes mellitus 10 (9.5) 47 (15.6) 0.14 36 (16.2) 11 (13.9)

Hypertension 33 (31.4) 140 (46.5) 0.008 104 (46.8) 36 (45.6)

Hyperlipidemia 36 (34.3) 134 (44.5) 0.09 100 (45.0) 34 (43.0)

Current smoking 50 (47.6) 119 (39.5) 0.17 85 (38.3) 34 (43.0)

Prior MI 9 (8.6) 27 (9.0) 1.0 20 (9.0) 7 (8.9)

Rescue PCI 4 (3.8) 18 (6.0) 0.47 11 (5.0) 7 (8.9)

Serum creatinine 1.5 mg/dL 3 (2.9) 8 (2.7) 1.0 6 (2.7) 2 (2.5)

Symptom onset to PCI, min 20373 20876 0.81 20974 20584

LVEF, % 37.810.9 40.58.7 0.005 40.28.6 41.39.1

Infarct artery location

Proximal LAD N/A 143 (47.5) 106 (47.7) 37 (46.8)

Mid-LAD N/A 150 (49.8) 109 (49.1) 41 (51.9)Distal LAD N/A 5 (1.7) 5 (2.3) 0 (0.0)

Diagonal N/A 3 (1.0) 2 (0.9) 1 (1.3)

Initial TIMI flow grade (pre-PCI), site

0 73 (69.6) 206 (68.4) 155 (69.8) 51 (64.6)

1 18 (17.1) 25 (8.3) 0.008 19 (8.6) 6 (7.6)

2 14 (13.3) 70 (23.3) 48 (21.6) 22 (27.9)

Initial TIMI flow grade (pre-PCI), core lab

0/1 N/A 214/289 (74.0) 163/216 (75.5) 51/73 (69.9)

2 N/A 47/289 (16.3) 37/216 (17.1) 10/73 (13.7)

3 N/A 28/289 (9.7) 16/216 (7.4) 12/73 (16.4)

PCI performed 105 (100.0) 301 (100.0) 1.0 222 (100) 79 (100)

Stent implanted 105 (100.0) 297 (98.7) 0.36 220 (99.1) 77 (97.5)

Bare metal stent 105 (100.0) 134/297 (45.1) 0.0001 97/220 (44.1) 37/77 (48.0)

Drug-eluting stent 0 (0) 163/297 (54.9) 123/220 (55.9) 40/77 (52.0)

Thrombectomy 3 (2.9) 67 (22.3) 0.0001 50 (22.5) 17 (21.5)

Glycoprotein IIb/IIIa inhibitor used 100 (95.2) 202 (67.1) 0.0001 151 (68.0) 51 (64.6)

Final TIMI flow grade (post-PCI), site

2 7 (6.6) 17 (5.7) 0.81 11 (5.0) 6 (7.6)

3 98 (93.3) 284 (94.3) 211 (95.0) 73 (92.4)

Final TIMI flow grade (post-PCI), core lab

0/1 N/A 5/286 (1.7) 3/215 (1.4) 2/71 (2.8)

2 N/A 25/286 (8.7) 22/215 (10.2) 3/71 (4.2)

3 N/A 256/286 (89.5) 190/215 (88.4) 66/71 (93.0)

ST-segment resolution post-PCI, % N/A 59.025.1 65.225.3

Discharge medications

Aspirin 98 (93.3) 284 (94.4) 0.81 209 (94.1) 75 (94.9)

Thienopyridine 102 (97.1) 296 (98.3) 0.43 217 (97.8) 79 (100.0)

Data are presented as meanSD or n (%). LAD indicates left anterior descending; N/A, not available.

*Subgroup of patents in the AMIHOT-I trial with anterior MI reperfused within 6 hours of symptom onset.




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of a single unilateral compared with dual bilateral femoral

artery sheaths (from 45.2% versus 13.8%, P0.0001).

DiscussionThe principal finding of this study, representing the net

results of a prespecified Bayesian analysis from 2 consecutive

randomized trials, is that in patients with anterior STEMI

undergoing successful PCI within 6 hours of symptom onset,

a 90-minute post-PCI infusion of SSO2 significantly reduces

infarct size, with noninferior rates of MACE at 30 days. As

such, SSO2 represents the first adjunctive therapy demon-

strated in a pivotal trial to reduce infarct size when used in

concert with a mechanical reperfusion strategy in STEMI.

SPECT imaging using tc-99m-sestamibi is the most widely

studied technique to evaluate myocardial salvage and infarct

size, having been shown to correlate with global and regional

left ventricular function and volumes after STEMI,2731 clin-

ical outcomes after reperfusion therapy (including early and

late mortality and heart failure),3136 and pathologically with

the extent of fibrosis in human hearts.32,37 In this study, the

absolute reduction in infarct size with SSO2 was greatest in

patients with the greatest clinical needthose with the largestinfarctions in whom the prognosis is known to be poor

despite successful PCI.2,38 Although the median reduction in

infarct size with SSO2 was 6.5% in the entire study popula-

tion, the median infarct size in patients with a baseline LVEF

of40% was decreased from a median of 33.5% with control

to 23.5% with SSO2, representing incremental salvage of

10% of the left ventricular myocardium. Although the abso-

lute reduction in infarct size was less in smaller anterior

infarcts (a median 4% decrease in infarct size), the relative

reduction was comparable, as evidenced by the negative

interaction effect. Moreover, as the SSO2 infusion is not

initiated until after PCI is completed, no delays to reperfusionare required to deliver this therapy, representing a procedure

that can readily be incorporated into current reperfusion

treatment pathways in which minimizing door-to-balloon

time is an imperative.39

Although this study was not designed to address the

mechanisms underlying the decrease in infarct size with

SSO2, neither post-PCI ischemic burden (representing resid-

ual or recurrent ischemia),20 nor peak cardiac biomarker

Figure 2. Infarct size among patients with acute anterior myo-cardial infarction in whom PCI was performed within 6 hours ofsymptom onset randomized to SSO

2versus control in the

AMIHOT-I and AMIHOT-II trials, with the adjusted pooled infarctsize estimates shown. Compared with control, SSO2 was asso-ciated with a significant reduction in infarct size, as evidencedby the Bayesian posterior probability of 95%. The thick blacklines represent the median, with the vertical limits of the boxes

representing the interquartile (25% to 75%) ranges. The limitlines represent the 95% CIs. LV indicates left ventricle.

Figure 3. Histogram of infarct sizes (each vertical bar represent-ing a 5% increment) in the pooled AMIHOT-I and AMIHOT-IItreatment and control cohorts, demonstrating a reduction ininfarct size with SSO2 across the naturally skewed distribution

of infarct size. LV indicates left ventricle; IQR, interquartilerange.

Table 2. SSO2

Procedure in 222 Randomized AMIHOT-II

Patients

Largest sheath size

7F 55 (24.8)

8F 48 (21.6)

9F 118 (53.2)

10F 1 (0.5)

Draw sheath approach

Coaxial 160 (72.1)

Contralateral femoral artery 62 (27.9)

Sheath size

5F 30 (13.5)

6F 32 (14.4)

Infusion catheter

Tracker-38 147 (66.2)

Coaxial draw sheath configuration 88/147 (59.9)

Contralateral femoral draw sheath 59/147 (40.1)

MI-cath (INCA-1) 75 (33.8)Coaxial draw sheath configuration 72/75 (96.0)

Contralateral femoral draw sheath 3/75 (4.0)

SSO2 infusion duration, min 81.225.5

60 min 25 (11.3)

6089 min 9 (4.1)

90 min 165 (74.3)

90 min 23 (10.4)

SSO2 therapy delivery location

Catheterization laboratory 152/216 (70.4)

Holding area 5/216 (2.3)

Coronary care unit 53/216 (24.5)Other 6/216 (2.8)

Data are presented as m (%) or meanSD.




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levels (an important prognostic signal after primary PCI)40

were improved with SSO2. However, recurrent ischemia wasuncommon in both groups, and varying biomarkers were

collected at different hospitals, assessed infrequently (every 8

to 12 hours), and not measured by a central core laboratory,

precluding reliable quantification. In experimental models,

improved microcirculatory function and reduction in reper-

fusion injury has been hypothesized to underlie many of the

beneficial effects of SSO2.813 Conceptually, these findings

also suggest that reperfusion injury continues to have animportant reversible component after epicardial flow restora-

tion, making possible beneficial therapies such as SSO2,which can be implemented without necessitating delay to

reperfusion.

Randomization to SSO2 was associated with an increase in

hemorrhage-related adverse events, mostly access site hema-

Table 3. MACE Through 30 Days

SSO2

Control P

Posterior Probability

of Noninferiority*

Intention-to-treat population

AMIHOT-I N134 N135

MACE, n (%) 9 (6.7) 7 (5.2) 0.62

AMIHOT-II N222 N79

MACE, n (%) 12 (5.4) 3 (3.8) 0.77

Death 4 (1.8) 0 (0) 0.58

Reinfarction 4 (1.8) 2 (2.5) 0.65

Target vessel revascularization 8 (3.6) 3 (3.8) 1.0

Stroke 0 (0) 0 (0)

MACE blended, adjusted Bayesian

meanSE

5.91.4% 5.01.4% 99.5%

Per-protocol population

AMIHOT-I N119 N124

MACE, n (%) 9 (7.6) 7 (5.6) 0.61

AMIHOT-II N

186 N

78MACE, n (%) 7 (3.8) 3 (3.8) 1.0

Death 2 (1.1) 0 (0) 1.0

Reinfarction 3 (1.6) 2 (2.6) 0.63

Target vessel revascularization 5 (2.7) 3 (3.8) 0.70

Stroke 0 (0) 0 (0)

MACE blended, adjusted Bayesian

meanSE

4.71.5% 5.11.5% 99.9%

*Posterior probability that the SSO2 therapy group MACE rate is not more than 6% greater than the control group

rate.

Table 4. Other Adverse Events Among Randomized Patients in AMIHOT-II

SSO2

(N222) Control (N79) P

Stent thrombosis 9 (4.1) 2 (2.5) 0.73

Any access site related adverse event 50 (22.5) 10 (12.7) 0.07

Hematoma 39 (17.6) 8 (10.1) 0.15

Any hemorrhagic adverse event 55 (24.8) 10 (12.7) 0.03

Access site related* 41 (18.5) 9 (11.4) 0.16

Mild 34 (15.3) 8 (10.1) 0.34

Moderate 6 (2.7) 0 (0) 0.35

Severe 1 (0.5) 1 (1.3) 0.46

Nonaccess site related 16 (7.2) 1 (1.3) 0.05

Hemoglobin baseline, g/dL 14.3 (13.4, 15.5) 14.7 (13.7, 15.5) 0.27

Hemoglobin 24 hours, g/dL 12.9 (12.0, 13.8) 13.6 (12.6, 14.6) 0.0005

Transfusion 14 (6.3) 1 (1.3) 0.13

Data are presented as n (%) or median (interquartile range).

*Mild, does not require transfusion or result in hemodynamic compromise; moderate, requires transfusion; *Severe,intracranial bleed or hemodynamic compromise requiring treatment.




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tomas due to use of contralateral femoral artery access to

avoid the 9F sheath required for the Tracker-38 infusion

catheter. The rates of access site-related complications and

bleeding were reduced to control levels with the introduction

of the lower profile MI-Cath infusion catheter, which facili-

tated use of a single smaller sheath, thus obviating contralat-

eral femoral artery access. As major bleeding can increase

mortality in STEMI,41 minimizing hemorrhagic complica-

tions is essential if the benefits of infarct size reduction with

SSO2 are to be realized.

A novel aspect of this investigation was specification of the

primary end point based on Bayesian hierarchical analysis,

allowing partial pooling of data from 2 consecutive random-

ized trials. Such methodology is well established,4244 in-

creasingly used for randomized trials,45,46 and described by

the Food and Drug Administration as an underutilized ap-

proach to reduce sample size, allowing pivotal trials to be

completed more rapidly and efficiently.22 This study was

planned in concert with the Food and Drug Administration as

the US approval trial for SSO2 in patients with anteriorSTEMI undergoing PCI within 6 hours of symptom onset,

including selection of the primary efficacy and safety end

points. Bayesian hierarchical modeling allow data to be

borrowed from prior studies, with the extent of borrowing

depending on how closely the results from the new study

reflect the previous experience. Thus, if the results of AMIHOT II

varied greatly from AMIHOT I, little evidence would be

borrowed from the prior experience and the AMIHOT-II

results would be minimally changed (or could even be

adversely affected). The present Bayesian model avoids bias

from knowledge of the prior subgroup by ensuring that type

I conditional error is 5%, exactly the same type I error that

a standalone frequentist trial would have. In this study, areduction in infarct size was present in both trials in patients

with anterior STEMI reperfused within 6 hours of symptom

onset, allowing sufficient borrowing such that the pooled

Bayesian posterior probability for superiority was 96.9%,

signifying a significant reduction in infarct size with SSO2compared with control. Of note, the smoothed median differ-

ences in infarct size were similar in both AMIHOT I and

AMIHOT II. Thus, the finding of efficacy in the AMIHOT II

Bayesian model does not represent regression to the mean

had regression to the mean been present to a significant

degree, the posterior probability would not have been 95%.

Similarly, the posterior probability of noninferiority for

safety (30-day MACE) with SSO2 compared with control was

99.5% and 99.9% in the intention-to-treat and per-protocol

populations, respectively, both highly statistically significant.

Use of Bayesian methodology in this investigation thus

allowed statistically valid study conclusions to be reached

with randomization of only 304 patients in AMIHOT II,

whereas 458 patients would have been required for 80%

power had traditional frequentist statistics been used. The

Bayesian approach is thus consistent with the US statutory

least burdensome pathway for clinical investigation and

device approval.22

Several limitations of this investigation should be acknowl-

edged. No significant differences in survival at 30 daysbetween the control and treatment groups were present.

However, although the 6.5% median (4.5% mean) reduction

in infarct size with SSO2 represents a greater improvement in

myocardial recovery than with tPA compared with streptoki-

nase,47 or with primary PCI compared with tPA,34 much

larger studies than AMIHOT II would be required to detect an

improvement in survival given the currently achieved low

mortality rates with contemporary primary PCI. The current

trial was also underpowered for a robust analysis of sub-

groups. The for noninferiority for the safety end point may

also be considered broad, although such a safety margin is

typical for regulatory device approval trials, and the Bayesian

estimates for noninferiority between SSO2 and control were

highly significant by both intention-to-treat and per-protocol

analyses. Serial echocardiographic measures of regional wall

motion recovery, which correlate closely with tc-99m-

sestamibi infarct size and which improved in AMIHOT 1

with SSO2, were not measured in AMIHOT II as they are

more load dependent and technique sensitive than infarct size,

requiring a larger sample size. Finally, the safety and efficacy

results demonstrated for SSO2 in the present study apply onlyto those patients enrolled in AMIHOT II, and should not be

extrapolated to other patient cohorts, such as those with

nonanterior STEMI, patients reperfused beyond 6 hours after

symptom onset and those in cardiogenic shock.

In summary, in patients with anterior STEMI undergoing

successful PCI within 6 hours of symptom onset, a post-PCI

infusion of SSO2 for 90 minutes safely reduces infarct size,

an effect which is most pronounced in patients with the

greatest amount of myocardium at risk, with noninferior rates

of MACE at 30 days.

Appendix

For AMIHOT-I trial organization and list of participating investiga-tors, see reference 17.

AMIHOT-II Trial Organization and List ofParticipating InvestigatorsPrincipal Investigator: G.W. Stone, Columbia University MedicalCenter, New York Presbyterian Hospital and the CardiovascularResearch Foundation, New York City, NY.

Co-Principal Investigator: J.L. Martin, Sharpe-Strumia ResearchFoundation of the Bryn Mawr Hospital, Main Line Health, BrynMawr, Pa.

Bayesian Statistician: W.J. Boscardin, University of California,San Francisco, San Francisco, Calif.

Study Sponsor: TherOx, Inc, Irvine, Calif; B.S. Lindsay (VicePresident, Clinical Programs).

Site and Data Monitoring: TherOx, Inc, Irvine, Calif.Data Management and Biostatistical Analysis: Boston Biomedical

Associates, Northborough, Mass.Clinical Events Adjudication Committee: B.W. Weiner (Chair),

M.J. Schweiger, and S. Waxman.Data and Safety Monitoring Board: D.W. Holmes (Chair), E.

Bates, J. Ferguson, W. Gaasch, and K. Freeman.Nuclear Core Laboratory: The Mayo Clinic Nuclear Cardiology

Laboratory, Rochester, Minn; R.J. Gibbons (Co-Director), T. Miller,P. Chareonthaitawee, and A. Lapeyre.

Angiographic Core Laboratory: The Cardiovascular ResearchFoundation, New York, NY: A.J. Lansky (Director) and E. Cristea.

ECG and Holter Core Laboratory: Duke Clinical Research Insti-tute, Durham, NC; M.W. Krucoff (Director) and C. Green.

Study Sites, Principal Investigators, and Primary Study Coordina-

tors: Saint Paul Hospital, Vancouver, BC: J.G. Webb, E. Grieve;Mercy Heart Institute, Sacramento, Calif: M. Chang, W. Marquardt,




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S. Bordash; Saint Agnes Hospital, Fresno, Calif: R. Plenys, C.

Okamoto; Mercy Hospital, Miami, Fla: M. Mayor, I. Mariota; Mercy

Medical Center, Des Moines, Iowa: M.A. Tannenbaum, C. Noyes;

Spedali Civili, Brescia, Italy: F. Ettori, C. Fiorina; Ospedaliera

Universitaria di Careggi, Florence, Italy: R. Margheri, G. Spaziani;

Policlinico San Matteo, Pavia, Italy: E. Bramucci, B. Marinoni, U.

Canosi; Harper University Hospital, Detroit, Mich: R. Spears, M.

Fathy; Henry Ford Health System, Detroit, Mich: A. Kugelmass, J.

Longlade; William Beaumont Hospital; Royal Oak, Mich, S. Dixon,D. Richardson; Isala Klinieken Weezenlanden, Zwolle, Netherlands:

M.J. De Boer, D. Beuving; Allegheny General Hospital, Pittsburgh,

Pa: D. Lasorda, C. Harter; Geisinger Medical Center, Danville, Pa: J.

Blankenship, K. Skelding, D. Zimmerman; Sharpe-Strumia Research

Foundation of the Bryn Mawr Hospital, Main Line Health, Bryn

Mawr, Pa: J.L. Martin, A. Pratsos, C. Pensyl; Tri-State Medical

Center, Beaver, Pa: J. Rich, M. Kilhof; Jackson-Madison County

Medical Hospital, Jackson, Tenn: H.K. Lui, A. Hysmith; Wellmont

Holston Valley Medical Center, Kingsport, Tenn: C. Metzger, A.

Armstrong; Scott and white Hospital, Temple, Tex: S. Gantt, J. Asea;

East Texas Medical Center, Tyler, Tex: S.M. Lieberman, J. Crump.

Sources of FundingThe study was sponsored and funded by TherOx, Inc. The sponsor

was involved in study design and in data collection, analysis, and

interpretation, along with the principal investigators. The corre-

sponding author had full access to all the data in the study. The

manuscript was prepared by the corresponding author and revised by

all coauthors. The authors controlled the decision to submit the

manuscript for publication. The sponsor was provided the opportu-

nity for a nonbinding review of the manuscript before its submission.

DisclosuresDr Stone reports having received research support from TherOx,

Abbott Vascular, Boston Scientific, and The Medicines Company.

Dr Martin reports having equity interests and serving as a consultant

to TherOx. Dr Blankenship reports serving on a speakers bureau for

Sanofi-Aventis. Dr Gibbons reports having received research support

from TherOx. Ms Lindsay is a full-time employee of and ownsequity in TherOx. Dr Weiner reports serving as a consultant to

TherOx and having received research support from Medtronic,

Boston Scientific, and Abbott Vascular. Dr Krucoff reports having

served as a consultant to and received research grants and consul-

tancy fees from TherOx. Dr Boscardin reports having served as a

consultant to TherOx. Drs de Boer, Margheri, Bramucci, Metzger,

Lansky, and Fahy report no conflicts of interest.

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CLINICAL PERSPECTIVEPrimary percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction has

become widely accepted as the preferred reperfusion modality because of its high success rate in restoring patency of the

occluded infarct artery, with resultant low rates of death, reinfarction, recurrent ischemia, and stroke. Nonetheless,

myocardial salvage is often suboptimal in many patients after primary PCI, in part because of late presentation and also

because of microcirculatory dysfunction and reperfusion injury. The intracoronary delivery of supersaturated oxygen with

a PaO2 of 760 to 1000 mm Hg into the coronary artery supplying the myocardial infarct zone for 90 minutes after

successful primary PCI has been shown in preclinical models to markedly enhance myocardial recovery. In the randomized

AMIHOT-I and AMIHOT-II trials, this therapy was compared with primary PCI without intracoronary infusion in a total

of 406 patients with anterior ST-segment elevation myocardial infarction reperfused by successful PCI within 6 hours of

symptom onset. Compared with control, SSO2 resulted in a significantly smaller infarct size at 14 days as measured by

tc-99m-sestamibi single-photon emission computed tomography imaging, with noninferior rates of major adversecardiovascular events at 30 days. The benefit in terms of infarct size reduction was particularly profound in patients with

the largest infarctions (baseline left ventricular ejection fraction 40%), in whom an incremental 10% salvage of the left

ventricular myocardium was noted. As such, supersaturated oxygen represents the first adjunctive therapy demonstrated in

a pivotal trial to reduce infarct size when used in concert with a mechanical reperfusion strategy in ST-segment elevation

myocardial infarction.




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Supplemental Material

Bayesian methodology

PRIMARY EFFECTIVENESS ENDPOINT ANALYSIS

The AMIHOT and AMIHOT-II effectiveness data were analyzed jointly in a hierarchical Bayesian

model. Primary effectiveness analysis was performed on an intent-to-treat basis.

It was necessary to develop a transformation of the primary endpoint infarct size that would, to a degree,

remove the skewness of the data (which includes a number of exactly zero values). Transformations of

the form Y=log(X + c) were considered, where log denotes the natural logarithm. Consideration of a

wide variety of choices for c gave reasonable approximations of normality, and extremely similar

statistical inference, and a value of c=10 was chosen based on the distribution of the AMIHOT-I data in

designing the AMIHOT-II trial. Using this transformation in the subgroup of patients with anteriorSTEMI undergoing PCI in less than 6 hours (the anterior/LT6 subgroup), the mean (SD) for Control

subjects was 3.30 (0.66), and for SSO2 subjects the mean (SD) was 3.06 (0.72). Thus, a difference of

almost one quarter of a log in these groups was observed. The data distributions are not exactly normal

after transformation, and the use of smearing4 could be used to describe the treatment versus control

differences in medians on the original scale. More directly, the treatment effect has been reported using a

pooled analysis for the subgroup of interest adjusted for the study-specific medians.

As noted, the current randomized trial was entirely based on anterior patients with times to reperfusion of

less than or equal to 6 hours (LT6). Of the 269 patients randomized into the completed AMIHOT trial,

240 subjects had both infarct size data and time to reperfusion recorded. The anterior LT6 subgroup

represented a total of 101 patients. Thus, the original study can be regarded as being composed of 4

mutually exclusive subgroups: anterior/LT6, anterior/greater than (GT)6, non-anterior/LT6, non-anterior/GT6. The Bayesian hierarchical model was used to analyze the AMIHOT data and the results

from the current study. In this model, the posterior mean effect size in any particular subgroup is shrunk

towards the overall mean. This procedure gives a formal methodology to account for the reduction of the

target population. The model also includes random study effects. As a result, if the difference between

the SSO2 Therapy and Control means for the proposed study was different from that seen in the

AMIHOT trial, the analysis would not permit a high degree of borrowing. This allows the type I error to

be kept to a reasonable level even though the prior information is centered over a favorable outcome. In

particular, the following model was assumed. The log-transformed values (as discussed above) in each

subgroup were assumed to be normally distributed with a mean and standard deviation specific to the

subgroup-treatment (SSO2 Therapy versus Control) combination.

The mean values for study i=1,2 (1=AMIHOT, 2=proposed study) and subgroupj(j=1,2,3,4 in study i=1 andj=1 only for study i=2) are parameterized as:

Cij=Mean Control grouP=Cj +

Ci

Tij=Mean SSO2 Therapy grouP=C

ij + 0+ Tj +

Ti,

where 0 is the grand mean for the Control group, 0 describes the overall SSO2 Therapy versus Control

difference, Cj represents the subgroup effect and C

i describes the study effect in the Control arm, and

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Tj represents the subgroup effect and T

i describes the study effect in the SSO2 Therapy minus Cont

differences.

rol

i

The full model is written as

yCijk~ N (C

ij , C2)

yTijk~ N (Tij , T2)

Cij=Cj +

Ci

Tij=C

ij + 0+ Tj +

T

Cj ~ N(0,

2); Ci ~ N(0, 2)

Tj ~ N(0, 2); Ti ~ N(0,

2)

~ U(0.01, 0.67); ~ U(0.01, 0.10)

~ U(0.01, 0.67); ~ U(0.01, 0.10)

C ~ U(0.01, 2.0); T ~ U(0.01, 2.0)

0 ~ N(3.2, 0.72); 0 ~ N(0, 0.7

2)

where yCijk denotes the response of the kth Control subject in study i subgroup j (k runs from 1 to nC

ij),

and, similarly, yT

ijk denotes the response of the kth SSO 2 Therapy subject in study i subgroup j (k runsfrom 1 to nTij). Specific choices of prior distributions were made to balance three goals: (i) be as non-

informative as possible, (ii) capture first-order substantive considerations, and (iii) allow the model to

have acceptable frequentist type I error in the case of no treatment effect. Some specific considerations

were as follows:

(i) The transformed response, log(y+10), is constrained to lie in the interval 2.3 to 4.7. Thus,standard deviations of 0.5 or 1.0 are quite large relative to this range, and a standard

deviation of 2.0 is essentially non-informative.

(ii) The grand mean for Control infarct size () is centered around a prior mean thatcorresponds to 15 on the original scale. The standard deviation of 0.7 then gives a 99.7%

prior probability that the grand mean can be between 0 and 100, a very broad range on the

original scale.(iii) The overall mean for the SSO2 Therapy minus Control difference (0) can be anywhere

from 0 to 100 on the original scale.

(iv) ~ U(0.01, 0.67); ~ U(0.01, 0.10). This is an extremely vague prior for the subgroupeffects in the Control group (which can easily span the full range of the data). Study

random effects for the Control group have a standard deviation no larger than 0.10 on the

log scale. This suggests that if the mean in a particular Control subgroup is 15 on the

original scale, then study-specific means for that subgroup could possibly vary from 8 to23. The stronger prior on study effects is used to combat the problem of having only two

study effects for which we are attempting to estimate a variance component.

(v) ~ U(0.01, 0.67); ~ U(0.01, 0.10). The same comments noted above for the Controlrandom effects standard deviations, except that in the treatment case, the parameters refer

to differences between the SSO2 Therapy and Control means.(vi) C ~ U(0.01, 2.0); T ~ U(0.01, 2.0). The Control and SSO2 Therapy group standard

deviations for individual measurements should be very precisely determined by the data,

and thus we specify only that these values are certain to be less than 2.0 on the logarithmic

scale.

Inference is based on the posterior distribution of the SSO2 Therapy minus Control mean difference in

study 2, subgroup1, i.e. (T21 C

21)=0+ T2 +

T1 given the previous and current study data.



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Consideration is given to the posterior probability that this combination of parameters is less than zero,

indicating that the SSO2 Therapy group tends to have lower infarct sizes. Should this posterior

probability be 95% or higher, the effectiveness endpoint would have been fulfilled. That is, the

effectiveness endpoint would be satisfied if P(T21 C

21 < 0 | data from all subgroups in both trials) >

0.95. Inference was conducted using Markov chain Monte Carlo using an R front end1 to WinBUGS

1.4.12 (called R2WinBUGS3). Sufficient run lengths were generated to ensure the accuracy of all decimals

reported in the Bayesian model results tables (more detail is given later in this section).

PRIMARY SAFETY ENDPOINT ANALYSIS

A hierarchical Bayesian model was also be used to evaluate the major adverse cardiovascular events

(MACE) rates in the two studies using the intention to treat population. The following set-up of the

model is assumed (similar to Warn, Thompson, and Spiegelhalter, 20025). As above the study numbers

are i=1,2 (i=1 is AMIHOT, i=2 is proposed incremental study), the subgroup numbers are j=1,2,3,4 (j=1

is anterior/LT6, j=2 is anterior/GT6, j=3 is non-anterior/LT6, j=4 is non-anterior/GT6). For study 2, j=1

only. Then we denote rCij /nC

ij=# of Control MACE events/# of Control subjects in study i, subgroup j,

and rTij/nT

ij=# of SSO2 Therapy MACE events/# of SSO2 Therapy subjects in study i, subgroup j. The

full model is specified as follows:

rCij ~ Bin (nC

ij , C

ij)

rTij ~ Bin (nT

ij , T

ij)

logit(Cij)=C

ij

Cij=0 + Cj +

Ci

Tij=C

ij + 0 + Tj +

Ti (truncated to [0,1])

Cj ~ N(0, 2); Ci ~ N(0,

2)

Tj ~ N(0, 2); Ti ~ N(0,

2)

~ U(0.01, 0.30); ~ U(0.01, 0.30)

~ U(0.001, 0.10); ~ U(0.001, 0.033)

0 ~ N(-2.6, 0.5

2

); 0 ~ N(0, 0.2

2

);

where 0 is the grand mean of MACE rates in the Control group (on logit scale), is the overall SSO2

Therapy versus Control difference in safety rates (i.e. on risk difference scale), Cj represents the

subgroup effect and Ci describes the study effect in the Control arm (these parameters are both on the

logit scale), and Tj represents the subgroup effect and T

i describes the study effect in the SSO2 Therapy

minus Control differences (these parameters are both on the risk difference scale). The basis for the

Bayesian model of these various parameters is as follows:

Treatment rates are modeled as an additive deviation from the Control rate in order to maximize

efficiency in testing risk differences.

(i) 0 ~ N(-2.6, 0.52). The grand mean of MACE rates in the Control group should be on theorder of 7%; the logit of 0.07 is equal to -2.6. The choice of standard deviation gives a 99.7%prior probability that the average Control MACE rate is between 0% and 25%.

(ii) 0 ~ N(0, 0.22). The overall SSO2 Therapy versus Control difference in safety rates isassumed to be normally distributed around zero with a standard deviation of 20 percentage

points. This is an extremely vague prior.

(iii) ~ U(0.01, 0.30); ~ U(0.01, 0.30). The random effects standard deviations for the logitof Control rates between subgroups and between studies are assumed to be no larger than

0.30. If the mean rate is 7%, this translates into a 99.7% prior probability that subgroup or



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of a trial.

n

ons.

(iv) ~ U(0.001, 0.10); ~ U(0.001, 0.033). The random effects standard deviations in thedifferences between SSO2 Therapy and Control means among the subgroups and between

studies are assumed to be no larger than 10 percentage points and 3.3 percentage points,

respectively. This in turn suggests that these differences between subgroups could vary asmuch as 30 percentage points around the mean, and differences between the two studies

could be as large as 10 percentage points.

A second analysis similar to that described above for the intention to treat analysis (ITT) was performed

using the per protocol (PP) safety sample. Because it is unclear for a non-inferiority hypothesis whether

the ITT or PP subset is more conservative, both were considered primary for the primary safety endpoint

analysis. Again, the same Bayesian hierarchical model was employed with the original AMIHOT trial

data limited to the PP patient sample using the same limiting criteria as was used for the AMIHOT-II PP

patient sample.

EFFECTIVENESS BASED SAMPLE SIZE CALCULATION

The power of the current study with nT21=224 patients in the SSO2 Therapy arm and nC

21=80 in the

Control arm was calculated using the defined Bayesian hierarchical model. Computations were based o

2000 simulated data sets, with each data set analyzed by MCMC with 20,000 iterati

Table 1. Power to reach the conclusion of effectiveness for various true SSO2 Therapy versus Control

differences.

(Transformed

Scale)

Original

Scale

Posterior

Power

Frequentist

Power

Complete

Pooling0.00 0.0% 5.0% 5% 17%

-0.20 -5.0% 85.4% 73% 93%

-0.25 -6.5% 96.0% 88% 97%

Prior Predictive 64.0%

The middle two lines in Table 1 demonstrate that there is 85.4% power to detect an effect size of 5.0%

infarct size reduction, and 96% power to detect a difference similar to that seen in the AMIHOT-I trial of

6.5%. In the other direction, as shown by the first line of the table, we found that the hierarchical model

was able to achieve an appropriate type I error rate when, in fact, the SSO 2 Therapy mean and the Control

mean are both equal. Finally, the bottom line of the table gives the prior predictive power for the study as

64%.

SAFETY BASED SAMPLE SIZE CALCULATION

The power of the current study with nT21=224 patients in the treatment arm and nC

21=80 in the Control arm

was calculated using the defined Bayesian hierarchical model. Computations were performed using

MCMC (with 15000 iterations) for the full grid of possible pairs of MACE counts in the two arms of the

new trial.



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In addition, for comparison, the frequentist power was calculated using the program PASS 2002 (Number

Cruncher Statistical Systems, Kaysville, Utah, 2002) and assumed no use of the AMIHOT-I data.

Table 2. Power table and Type I error calculations for the MACE safety endpoint.

C21 T

21 nC

21 =80, nT

21 =224

Posterior Power Frequentist Power Complete Pooling

0.05 0.05 96.3% 75% 97%

0.06 0.06 89.8% 69% 92%

0.07 0.07 80.7% 64% 86%

0.08 0.08 70.5% 60% 79%

0.09 0.09 59.8% 56% 72%

0.07 0.13 4.7% 5% 8%

0.07 0.14 2.5% 2% 4%

0.07 0.15 2.0% 1.5% 2%

Prior Predictive 61.2%

Type I error calculations are shown in italics for a true Control rate of 0.07 and true SSO2 Therapy rates

that are bigger than this rate by d=0.06 or more.

At the expected MACE rate of 0.07, it is evident that the proposed sample size of 80 Control and 224

SSO2 Therapy patients would have achieved adequate power to conclude equivalence using the Bayesian

hierarchical model.

RUN LENGTHS FOR MCMC ANALYSIS OF PRIMARY EFFICACY ENDPOINT

We generated enough posterior simulations using the MCMC technique discussed above to ensure that

the first decimal point in the posterior probability of satisfying the efficacy or safety endpoints is correct.We generated three chains, each with 2,000,000 iterations. The first 400,000 simulations were regarded

as burn-in and the resulting 1,600,000 simulations for each of the three chains were thinned, saving only

every 5th iteration. The resulting set of posterior simulations for analysis is thus of size 3 x

320,000=960,000. Convergence diagnostics indicated that the autocorrelation in this thinned set was

extremely low, but we conservatively regard this as an effective sample size of Neff=480,000. The Monte

Carlo standard error for estimating a probability of 95.0% is thus sqrt(0.950 * 0.005 / 480000)=0.0001,

ensuring that the first decimal place is correct with almost 100% confidence.

BAYESIAN SENSITIVITY ANALYSES FOR PRIMARY EFFICACY ENDPOINT

A secondary analysis similar to that described above for the ITT analysis was performed for the PPanalysis. The same Bayesian hierarchical model was employed with the original AMIHOT trial data

limited to the PP patient sample using the same criteria used for the AMIHOT-II PP patient sample.

Sensitivity analyses on the Bayesian primary effectiveness endpoint evaluation in both the ITT and PP

analyses were conducted by varying two of the assumptions for prior distributions on the

hyperparameters. The first model of these alternative models (M2) changes the prior distribution for the

standard deviation of the study random effects in the Control group from ~ U(0.01, 0.10) to ~

U(0.01, 0.20). This change allows the average Control infarct size to be more variable between



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Coronary Intervention in Acute Myocardial Infarction

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