Published online before print September 15, 2009, doi: 10.1161/CIRCINTERVENTIONS.108.840066
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Original Articles |
Effect of Supersaturated Oxygen Delivery on Infarct Size After Percutaneous Coronary Intervention in Acute Myocardial Infarction
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 Clinics Weezenlanden (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; and University of California (W.J.B.), San Francisco, San Francisco, Calif.
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 gs2184{at}columbia.edu
Received December 1, 2008; accepted July 30, 2009.
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Abstract |
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Background— Myocardial 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 Results— A 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 were randomized to a 90-minute intracoronary SSO2 infusion in the left anterior descending artery infarct territory (n=222) or control (n=79). 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 (PWilcoxon=0.02; Bayesian posterior probability of superiority, 96.9%). The Bayesian pooled 30-day mean (±SE) rates of major adverse cardiovascular events were 5.0±1.4% for control and 5.9±1.4% for SSO2 by intention-to-treat, and 5.1±1.5% for control and 4.7±1.5% for SSO2 by per-protocol analysis (posterior probability of noninferiority, 99.5% and 99.9%, respectively).
Conclusions— Among patients with anterior ST-segment elevation myocardial infarction undergoing percutaneous coronary 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
Key Words: myocardial infarction • infarct size • angioplasty • reperfusion
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Introduction |
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Myocardial salvage is frequently suboptimal despite successful reperfusion in ST-segment elevation myocardial infarction (STEMI), resulting in left ventricular dysfunction and increased mortality.1,2 Although delays to reperfusion 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 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, altering nitric oxide synthase expression, and/or inhibiting leukocyte activation and adherence.9–13 Following promising pilot study results,14–16 269 patients with anterior or large inferior STEMI undergoing successful PCI within 24 hours of symptom onset (the preclinical parameters for which SSO2 successfully reduced infarct size) were randomly assigned to SSO2 or control in the Acute Myocardial Infarction With Hyperoxemic Therapy (AMIHOT)-I trial. In this study, infarct size measured by technetium (tc)-99m-sestamibi single-photon emission computed tomography (SPECT) imaging at 14 days was not significantly different between the 2 treatment 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 improved echocardiographic regional wall motion at 3 months.17
Editorial see p 363
Clinical Perspective on p 366
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 undergoing 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.
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Methods |
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The AMIHOT-I Trial
The AMIHOT-II protocol intentionally preserved core design elements 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 Thrombolysis In Myocardial Infarction (TIMI) 0 to 2 flow undergoing primary or rescue PCI within 24 hours after symptom onset were enrolled in AMIHOT I. Patients in whom TIMI 2 to 3 flow was achieved were randomly assigned to receive a 90-minute infusion of SSO2 in the infarct artery versus control (standard of care without intracoronary infusion). Three primary efficacy end points were prespecified: infarct size at 14 days measured by tc-99m-sestamibi SPECT; total ischemic burden within 3 hours after reperfusion measured by continuous Holter monitoring as the area under the ST-segment level versus time curve (an end point distinct from ST-segment resolution); and echocardiographic infarct zone regional wall motion at 3 months. The primary safety end point was the composite incidence of major adverse cardiovascular events (MACE), defined as death, reinfarction, target vessel revascularization, or stroke at 30 days. The baseline characteristics and outcomes in the treatment groups have been previously reported.17 The trial prespecified examination of subgroups based on infarct location (anterior versus nonanterior) and by time to reperfusion (less than or greater than 6 hours).
The AMIHOT-II Trial, Study Population
Patients aged 18 years or older with anterior MI (ST-segment elevation >1 mm in 
2 contiguous precordial leads [V1–V4] or new left bundle-branch block with confirmation of left anterior descending 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 absolute 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, pseudoaneurysm, 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 PO2 <80 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 of >6 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 patients signed informed written consent.
AMIHOT-II Protocol Procedures and Randomization
Before 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 investigator’s 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 patients=2.8:1) 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 Procedures
SSO2 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 Therapeutics, Fremont, Calif), which in the coaxial configuration required a 7F guide catheter and 9F sheath. During the latter phases of enrollment the lower profile 4.6F MI-Cath infusion catheter (TherOx, Inc) was introduced, which required a 6F guide catheter and 8F sheath, allowing for a smaller arteriotomy.
The SSO2 infusion was initiated in all patients in the cardiac catheterization laboratory immediately after the final coronary angiogram, after which the patient could remain in this setting or be transferred either to a holding area or the coronary care unit for completion of the infusion. The systemic arterial PO2 was measured every 30 minutes during the 90-minute infusion, and nasal oxygen adjusted to maintain the PO280 mm Hg. The activated clotting time was checked every 30 minutes and supplemental heparin boluses administered as necessary to maintain the activated clotting time 250 seconds during the active infusion.
Data Management
Independent study monitors verified 100% of case report form data onsite. All adverse cardiac events were adjudicated by an independent committee blinded to treatment allocation after review of original source documentation. A data safety and monitoring committee periodically reviewed blinded safety data, each time recommending the study continue without modification. Independent core nuclear, electrocardiographic and angiographic laboratory analyses were performed by technicians blinded to treatment assignment and clinical outcomes using validated methods as previously described.19–21
Endpoints and Definitions
The primary efficacy end point was infarct size measured by tc-99m-sestamibi SPECT at 14 days, powered for superiority. The primary safety measure was composite MACE (as defined in AMIHOT I), measured at 30 days, powered for noninferiority. Death was defined as all-cause death. Reinfarction was defined as recurrent ischemic symptoms lasting >20 minutes with new ST-segment elevation and/or CK-MB re-elevation if occurring >96 hours after the index event. Target vessel revascularization was defined as any repeat PCI or bypass graft surgery of the study coronary artery. Stroke was defined as a neurologic deficit lasting 24 hours, or <24 hours with a brain imaging study showing infarction.
Power and Statistical Analysis
A prespecified Bayesian hierarchical modeling approach was used for analysis of the primary end points to allow partial borrowing of evidence from the previously performed AMIHOT-I trial. Direct specification of a previous distribution using the favorable results of the AMIHOT-I trial would have inflated frequentist type I error beyond acceptable levels.22 The hierarchical Bayesian approach allows inference for the AMIHOT-II trial to borrow a certain amount of evidence from the AMIHOT-I trial, with the amount of borrowing determined by the similarity of the data between the 2 trials.23 This may be conceptualized as precision weighted averages of the various information sources for the parameter where the weights are data-determined. Estimates are pulled in varying degrees toward the overall mean, a behavior known as shrinkage.24 Moreover, the model was tuned such that the AMIHOT-II trial would have frequentist type I error of no >5% level on the boundaries of the null hypotheses for the primary end points.25 A posterior probability of >95% for both end points was required for success. The treatment versus control effect 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 efficacy end point are made with respect to the Bayesian model, however. Unbalanced randomization (2.8:1) was used to maximize power for the safety end point for a given sample size; power gains for unbalanced randomization in standalone noninferiority designs can be substantial,26 and the advantage is amplified in the Bayesian hierarchical design. Further details of the power calculations and Bayesian modeling for the primary efficacy and safety end points are provided in the online-only Data Supplement.
Regarding the primary efficacy end point, assuming an absolute reduction in infarct size of 5% of the left ventricle, randomizing 304 patients in a 2.8:1 ratio between SSO2 and control in AMIHOT II using 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 of MACE of 7% in both randomized arms, with a noninferiority 
of 6% (a margin agreed on with the Food and Drug Administration), 80.7% power was present to declare noninferiority between the 2 groups. This approach is distinctly different from simple pooling of the 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 significantly greater power for the primary efficacy and safety end points (93% and 86%, respectively). Conversely, it is also important to note that AMIHOT II was intentionally underpowered as a standalone study for the primary efficacy and safety end points (73% and 64% power, respectively); statistical testing of AMIHOT II alone was therefore not prespecified for primary end point analysis. Rather, some degree of borrowing from the AMIHOT-I data would be necessary for either primary end point to be satisfied (with the degree of borrowing depending on the similarity of the datasets), with the principal statistical 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 conducted using standard (frequentist) methods. Categorical variables were compared by Fisher exact test. Continuous variables are presented as mean±SD or median (interquartile range), and were compared by the nonparametric Wilcoxon rank-sum test. Exact Wilcoxon 2-sample tests were used to compare infarct size data between the SSO2 and control groups. Linear regression analysis was used to adjust for differences between the groups in age, gender, prior MI, diabetes, infarct location, time to reperfusion, post-PCI ST-segment resolution prerandomization, and major bleeding. All primary and secondary analyses were performed in the intent-to-treat population. A per-protocol subset was used as a coprimary analysis for the primary (noninferiority) safety end point, consisting of randomized patients not excluded due to a major protocol deviation likely to impact the primary safety end point. Formal interaction testing was used to assess the impact of baseline left ventricular ejection fraction (LVEF) on the relative reduction in infarct size with SSO2. Smoothed medians of infarct size distributions were computed by kernel density estimation to de-emphasize the effects of discreteness in smaller subgroups. Statistical evaluations using frequentist methods in the AMIHOT-II study patients were performed using a 2-sided significance level of 0.05. Non-Bayesian statistical analyses were performed by SAS version 9.1.3, Cary, NC. Bayesian inference was conducted using Markov chain Monte Carlo computation by the R2WinBUGS interface to WinBUGS 1.4.1 (Data Supplement).
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Results |
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Patients
Between 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%) presented >6 hours after symptom onset. Among the remaining 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 were present (ventricular septal defect in 1 patient, prolonged cardiopulmonary resuscitation in 1 patient, and cardiogenic shock 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.
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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.
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AMIHOT-II SSO2 Procedure
Among 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 smaller MI-Cath infusion catheter became available (Table 2).
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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 anterior STEMI 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 P=0.10, adjusted P=0.03). 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 (PWilcoxon=0.02; Bayesian posterior probability of superiority, 96.9%). Figure 3 depicts the histogram of infarct sizes in the 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 of 40% (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).
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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 (299±257 versus 289±175 IU/L respectively, P=0.39) or troponin (96±136 versus 128±161 ng/mL respectively, P=0.27). 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 (1178±2596 versus 1369±3684 µV · min, respectively, P=0.69).
Clinical Outcomes
As shown in Table 3, by intention-to-treat analysis, the Bayesian pooled 30-day mean (±SE) rates of MACE were 5.0±1.4% for control and 5.9±1.4% for SSO2 (posterior probability of noninferiority, 99.5%). By per-protocol analysis, the Bayesian pooled 30-day rates of MACE were 5.1±1.5% for control and 4.7±1.5% for SSO2 (posterior probability of noninferiority=99.9%).
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Other adverse events in AMIHOT II appear in Table 4. Hemorrhagic complications and access site-related events, mostly hematomas, were more frequent in patients randomized 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 fewer access site reacted complications in the SSO2 group with use of a single unilateral compared with dual bilateral femoral artery sheaths (from 45.2% versus 13.8%, P<0.0001).
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Discussion |
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The 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 demonstrated 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,27–31 clinical outcomes after reperfusion therapy (including early and late mortality and heart failure),31–36 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 need—those with the largest infarctions 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 population, the median infarct size in patients with a baseline LVEF of <40% 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 absolute 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 reperfusion are 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 residual or recurrent ischemia),20 nor peak cardiac biomarker levels (an important prognostic signal after primary PCI)40 were improved with SSO2. However, recurrent ischemia was uncommon 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 reperfusion injury has been hypothesized to underlie many of the beneficial effects of SSO2.8–13 Conceptually, these findings also suggest that reperfusion injury continues to have an important reversible component after epicardial flow restoration, 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 hematomas 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 facilitated use of a single smaller sheath, thus obviating contralateral femoral artery access. As major bleeding can increase mortality in STEMI,41 minimizing hemorrhagic complications 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 randomized trials. Such methodology is well established,42–44 increasingly used for randomized trials,45,46 and described by the Food and Drug Administration as an underutilized approach 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 anterior STEMI 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, a reduction 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 SSO2 compared with control. Of note, the smoothed median differences 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 acknowledged. No significant differences in survival at 30 days between 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 streptokinase,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 subgroups. 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 only to 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.
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For AMIHOT-I trial organization and list of participating investigators, see reference 17.
AMIHOT-II Trial Organization and List of Participating Investigators
Principal Investigator: G.W. Stone, Columbia University Medical Center, New York Presbyterian Hospital and the Cardiovascular Research Foundation, New York City, NY.
Co-Principal Investigator: J.L. Martin, Sharpe-Strumia Research Foundation of the Bryn Mawr Hospital, Main Line Health, Bryn Mawr, Pa.
Bayesian Statistician: W.J. Boscardin, University of California, San Francisco, San Francisco, Calif.
Study Sponsor: TherOx, Inc, Irvine, Calif; B.S. Lindsay (Vice President, 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 Research Foundation, New York, NY: A.J. Lansky (Director) and E. Cristea.
ECG and Holter Core Laboratory: Duke Clinical Research Institute, Durham, NC; M.W. Krucoff (Director) and C. Green.
Study Sites, Principal Investigators, and Primary Study Coordinators: Saint Paul Hospital, Vancouver, BC: J.G. Webb, E. Grieve; Mercy Heart Institute, Sacramento, Calif: M. Chang, W. Marquardt, 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.
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Acknowledgments |
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Sources of Funding
The 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 corresponding 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 opportunity for a nonbinding review of the manuscript before its submission.
Disclosures
Dr 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 speaker’s bureau for Sanofi-Aventis. Dr Gibbons reports having received research support from TherOx. Ms Lindsay is a full-time employee of and owns equity 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 consultancy 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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The online-only Data Supplement is available at http://circinterventions.ahajournals.org/cgi/content/full/CIRCINTERVENTIONS.108.840066/DC1.
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