Reduced immediate ischemic events with cangrelor in PCI: A pooled analysis of the CHAMPION trials using the universal definition of myocardial infarction

Reduced immediate ischemic events with cangrelor in PCI: A pooled analysis of the CHAMPION trials using the universal definition of myocardial infarction Harvey D. White, DSc, a Derek P. Chew, MBBS, MPH, b Harold L. Dauerman, MD, c Kenneth W. Mahaffey, MD, d C. Michael Gibson, MS, MD, e Gregg W. Stone, MD, f Luis Gruberg, MD, g Robert A. Harrington, MD, d and Deepak L. Bhatt, MD, MPH h Auckland, New Zealand; Adelaide, Australia; Burlington, VT; Durham, NC; Boston, MA; and New York, NY

Background There is a clinical need for an intravenous P2Y12 inhibitor in patients with acute coronary syndromes (ACS) for patients who are unable to take oral medications or might benefit from a rapidly reversible compound. As the time from admission to percutaneous coronary intervention (PCI) shortens, establishing the benefit of novel therapies impacting ischemic events is increasingly challenging. Cangrelor, an intravenous potent rapidly acting P2Y12 inhibitor, bolus 30 μg/Kg plus infusion of 4 μg/Kg/min, was compared to a 600-mg loading dose of clopidogrel either before or early after PCI in patients with ACS undergoing PCI in The CHAMPION (Cangrelor versus standard tHerapy to Achieve optimal Management of Platelet InhibitiON) PLATFORM and PCI studies. Methods As both CHAMPION studies used similar inclusion/exclusion criteria and death, myocardial infarction, or ischemiadriven revascularization (including stent thrombosis) at 48 hours as their primary end points, the studies were pooled. The clinical events committee adjudicated myocardial infarction. The universal definition was used to define myocardial infarction. Results

A total of 13 049 patients were included. Cangrelor had no effect on the primary end point with the original MI definition (P = .646). With the use of the universal definition, the primary end point was decreased with cangrelor (odds ratio 0.82, 95% confidence interval 0.68-0.99, P = .037). Stent thrombosis was reduced from 0.4% to 0.2% (odds ratio 0.44, 95% confidence interval 0.22-0.87, P = .018). Thrombolysis in Myocardial Infarction major bleeding and transfusions were not increased with cangrelor.

Conclusion With the use of the universal definition of myocardial infarction, cangrelor was associated with a significant reduction in early ischemic events when compared with clopidogrel in patients with non–ST-elevation ACS undergoing PCI. (Am Heart J 2012;163:182-190.e4.)

After percutaneous coronary intervention (PCI) ischemic complications such as myocardial infarction (MI), recurrent ischemia necessitating urgent revascularization and death may occur. These complications are From the aGreen Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand, bDepartment of Cardiovascular Medicine, Flinders University, Adelaide, Australia, cUniversity of Vermont, Burlington, VT, dDuke Clinical Research Institute, Durham, NC, eBeth Israel Hospital, Boston, MA, fColumbia University Medical Center and The Cardiovascular Research Foundation, New York, NY, gStony Brook University Medical Center, New York, NY, and hVA Boston Healthcare System & Brigham and Women's Hospital, Boston, MA. CHAMPION PLATFORM is registered at clinicaltrials.gov: NCT00385138. CHAMPION PCI is registered at clinicaltrials.gov: NCT00305162. Charles J. Davidson, MD, served as guest editor for this article. Submitted September 2, 2011; accepted November 4, 2011. Reprint requests: Harvey White, DSc, Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92024, Victoria St, West Auckland 1142, New Zealand. E-mails: [email protected], [email protected] 0002-8703/$ - see front matter © 2012, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2011.11.001

usually related to thrombus formation either at the site of the PCI or as a result of embolism downstream. Platelets play an integral part in the initiation and propagation of the thrombus. Several oral inhibitors of the platelet P2Y12 receptor which reduce platelet activation and aggregation are available. Clopidogrel only partially inhibits adenosine diphosphate–induced platelet aggregation, has a delayed onset of activation, and up to 50% of patients 1 may be resistant to the antiplatelet effects owing to polymorphisms. 2 Prasugrel is more potent and has been shown to reduce the risk of ischemic events after PCI as compared to clopidogrel, but is associated with increased bleeding, particularly in patients who require coronary artery bypass grafting (CABG). The antiplatelet effects of both clopidogrel and prasugrel are delayed and nonreversible and last for the life of the platelets. 3 Ticagrelor is a potent reversible oral P2Y12 inhibitor that has been shown to reduce ischemic events as well as mortality,

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Figure 1

Design of the CHAMPION PCI and CHAMPION PLATFORM trials.

but with increased non-CABG major bleeding. 4 However, the effects of ticagrelor on platelet function persist for N48 hours after drug cessation. 5 Many patients with acute coronary syndromes (ACS) experience nausea or vomiting, and may have poor gastrointestinal blood flow. Similarly, because of severe respiratory or hemodynamic compromise some will be intubated. These factors affect the administration and absorption of oral agents. Thus there is a rationale for an intravenous formulation of a P2Y12 inhibitor that acts rapidly combined with rapid reversibility because of the requirement for emergency or early CABG in some patients with the associated increased risk of bleeding. 6 Cangrelor is a parenteral P2Y12 inhibitor, which directly and reversibly blocks platelet activation and aggregation with an immediate onset of activation. The plasma half-life is 3 to 6 minutes, and platelet function returns to normal 30 to 60 minutes after discontinuation. The CHAMPION PLATFORM and CHAMPION PCI studies were 2 phase 3 studies comparing cangrelor bolus 30 μg/kg plus infusion of 4 μg/kg/min for the duration of the PCI procedure, with a minimum infusion duration of 2 hours and a maximum of 4 hours, with clopidogrel 600-mg in patients undergoing PCI (Figure 1). 7,8 Cangrelor was neither superior to clopidogrel in CHAMPION PLATFORM nor superior to clopidogrel in CHAMPION PCI in reducing the primary end points of death, MI, or ischemia-driven revascularization (IDR) at 48 hours. The primary end point in the CHAMPION trials was driven by the occurrence of MI. However, MI is difficult to ascertain post-PCI particularly when patients have elevated

baseline cardiac biomarkers before the procedure. It is also difficult to distinguish MI occurring before from that occurring after randomization when the time from hospital admission to PCI is short as in the CHAMPION trials (6.3 [interquartile range 2.6-23.7 hours in PCI] and 7.9 [interquartile range 3.3-24.1 hours] in PLATFORM). The universal definition of MI 9 defines MI associated with PCI (type 4a) as elevation of biomarkers N3 times the 99th percentile upper limit of normal. The guideline also states that if biomarkers are elevated before the procedure and not stable for at least 2 samples 6 hours apart, there are insufficient data to recommend biomarker criteria for the diagnosis of peri-procedural MI. Thus we performed a prespecified pooled analysis of data from CHAMPION PCI and CHAMPION PLATFORM trials and utilized the universal definition to define MI to explore the effect of cangrelor on ischemic events.

Methods Patients undergoing PCI with or without stent implantation and non–ST-elevation acute coronary syndromes were eligible. Patients with stable angina (n = 1620) were randomized at the very beginning of the trials before a protocol amendment. The inclusion and exclusion criteria were similar in both trials, except in CHAMPION PLATFORM, 7 where the exclusion criteria included prior thienopyridine use in the past 7 days, whereas in CHAMPION PCI clopidogrel N75 mg/d at any time in the prior 5 days was an exclusion. 8 The primary analyses for both trials were performed on a modified intent-to-treat population (mITT) (randomized patients who received any drug and underwent PCI). Secondary end points were the individual rates of death, MI, new Q-wave MI, IDR, or stroke at 48 hours.

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Table I. Baseline clinical and procedural characteristics

Baseline characteristics Age, y Sex, n (%) Male Female Race, n (%) White Asian Black Hispanic Other Weight, kg Height, cm Stable angina, n (%) Unstable angina, n (%) Non–ST-segment elevation MI, n (%) Medical history, n (%) Diabetes Current smoker Hypertension Hyperlipidemia Stroke/TIA Family history of CAD MI PCI CABG Congestive HF PAD PCI Number of target vessels, n (%) 1 2 3 Drug-eluting stent, n (%) Bare metal stent, n (%)

Cangrelor (n = 6639)

Clopidogrel (n = 6604)

63.0 (54, 71)

62.0 (54, 71)

4829 (72.7) 1810 (27.3)

4708 (71.3) 1896 (28.7)

5268 776 270 272 39 82.0 170.2 813 2046 3780

(79.3) (11.7) (4.1) (4.1) (0.6) (71, 95) (164, 178) (12.3) (30.8) (56.9)

5208 776 281 289 39 82.0 170.0 807 2006 3791

(78.9) (11.8) (4.3) (4.4) (0.6) (71, 95) (164, 178) (12.2) (30.4) (57.4)

2076 1885 4894 3932 370 2574 1648 1574 744 529 420

(31.3) (28.7) (74.0) (62.5) (5.6) (42.1) (25.1) (23.8) (11.2) (8.0) (6.5)

2131 1882 4818 3883 365 2587 1690 1609 755 514 433

(32.3) (28.7) (73.3) (62.0) (5.5) (42.6) (25.8) (24.5) (11.4) (7.8) (6.7)

5637 871 57 3459 2881

(85.8) (13.3) (0.9) (52.7) (43.9)

5571 900 64 3406 2895

(85.2) (13.8) (1.0) (52.0) (44.3)

Table II. Numbers of myocardial infarctions with the universal definition compared to the CHAMPION definition CHAMPION

Universal

Cangrelor Placebo Cangrelor Placebo

Values are presented as median (25th, 75th) unless otherwise indicated. MI, Myocardial infarction; TIA, transient ischemic attack; CAD, coronary artery disease; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft surgery; HF, heart failure; PAD, peripheral artery disease.

Myocardial infarction was defined in the trials as the appearance of new Q waves (duration N0.03 seconds) in 2 contiguous electrocardiographic leads or cardiac biomarkers ≥3 times the local upper limit of normal, as well as a rise N50% above the baseline when biomarkers were initially elevated. With the use of the universal definition of MI, 9 new or recurrent MI was defined as the clinical events committee (CEC)–adjudicated MI when the patient had normal baseline or unknown baseline troponin levels. The same criteria as used by the CEC for elevation of CK-MB or CK were used for the universal definition. If baseline troponin levels were abnormal, only Q-wave MIs were included. The CEC adjudicated IDR, stroke, and stent thrombosis defined as angiographic thrombus or subacute closure or re-narrowing within the treated vessel at the time of a clinically driven restudy for ischemia. The universal definition of MI was not readjudicated.

MI (%) MI with unknown or stable baseline troponins (%) MI with abnormal baseline troponins (%) Q-wave MI only (%) Q-wave MI with unknown or stable baseline troponins (%) Q-wave MI with abnormal baseline troponins (%)

455 (7.0) 166 (5.8)

447 (6.9) 185 (6.6)

171 (2.6) 166 (5.8)

194 (3.0) 185 (6.6)

289 (7.8)

262 (7.1)

5 (0.1)

9 (0.2)

8 (0.1) 3 (0.1)

18 (0.3) 9 (0.4)

8 (0.1) 3 (0.1)

18 (0.3) 9 (0.4)

5 (0.1)

9 (0.2)

5 (0.1)

9 (0.2)

Safety end points Assessments of bleeding were performed up to 48 hours after PCI using both clinical and laboratory definitions. 10-12

Statistical analyses All statistical tests were 2-tailed using a level of significance of .05. Heterogeneity between the trials was examined using the Breslow-Day test. The primary end-point comparisons were performed by calculating odds ratio (OR) with accompanying 95% confidence intervals (CI) using logistic regression which was also used to analyze the majority of the secondary end points. Heterogeneity of the ORs within subgroup interactions was examined using the Breslow-Day test. Kaplan-Meier curves were generated to compare time-to-event profiles for the primary end point over 48 hours between the treatment groups with the log-rank test. The authors are solely responsible for the design and conduct of this study, the drafting and editing of the paper and its final contents. Analyses were performed by the Medicines Company and confirmed independently by the authors. All patients gave informed consent to participate.

Results This analysis included the pooled ITT population of 14 239 patients, with the 996 patients with ST-elevation myocardial infarction (STEMI) excluded from the efficacy analysis. From the remaining 13 243 ITT patients, 194 were excluded from the mITT analysis population resulting in an mITT population of 13 049 (6543 in cangrelor and 6506 in clopidogrel). There was no significant heterogeneity between the trials (P = .283 for death/MI/IDR). Baseline characteristics were similar in both groups (Table I). The median time from hospital admission to randomization was 7.8 hours (Q1 2.8, Q3 24.2) and from randomization to PCI was 15 minutes (Q1 9, Q3 23).

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Table III. Endpoints at 48 h using the universal definition of MI

Death/MI universal definition/IDR, n (%) Death, n (%) MI Universal definition, n (%) Q-wave only, n (%) Ischemia-driven revascularization, n (%) Stent thrombosis, n (%) Stroke, n (%) Death/MI universal definition/stent thrombosis, n (%) Death/QMI/IDR, n (%)

Cangrelor (n = 6543)

Clopidogrel (n = 6506)

Odds ratio (95% CI)

P

202 /6543 (3.1) 14/6543 (0.2)

244/6506 (3.8) 23/6506 (0.4)

0.82 (0.68-0.99) 0.60 (0.31-1.18)

.0374 .1380

171/6543 (2.6) 8/6543 (0.1) 32/6543 (0.5) 12/6543 (0.2) 13/6543 (0.2) 189 6543 (2.9) 46/6543 (0.7)

194/6506 (3.0) 18/6506 (0.3) 47/6506 (0.7) 27/6506 (0.4) 12/6506 (0.2) 228/6506 (3.5) 75/6506 (1.2)

0.87 0.44 0.68 0.44 1.08 0.82 0.61

.2023 .0544 .0878 .0184 .8525 .0458 .0080

(0.71-1.08) (0.19-1.02) (0.43-1.06) (0.22-0.87) (0.49-2.36) (0.67-1.00) (0.42-0.88)

QMI, Q-wave myocardial infarction; IDR, ischemia-driven revascularization.

During PCI, 58.6% received unfractionated heparin, 27.4% received bivalirudin, and 17.7% received glycoprotein IIb/IIIa antagonists. Drug-eluting stents were implanted in 52.3% and bare-metal stents in 44.0% of patients.

Efficacy At 48 hours, with the CHAMPION definitions, there was no effect of cangrelor on the primary end point of death, MI, and IDR (7.3% vs 7.5%; OR 0.97 [95% CI 0.851.111], P = .6455). There was no effect either on MI (7.0% cangrelor vs 6.9% placebo; OR 1.01 [95% CI 0.881.16], P = .8510). Table II shows the number of MIs with the universal definition compared to the CHAMPION definition. When the universal definition was applied, 59.5% of events, originally defined by the CEC, were removed from the analysis. Table III shows the 48-hour event rates using the universal definition. Cangrelor significantly reduced the primary end point (3.1% cangrelor vs 3.8% clopidogrel; OR 0.82 [95% CI 0.68–0.99], P = .037). There was no statistical reduction in the MI end point (OR 0.87 [95% CI 0.71-1.08], P = .202). Figure 2 shows the Kaplan-Meier curve for the primary end point to 48 hours, with the event curves beginning to separate at about 1 hour. The secondary composite of death, Q-wave MI, or IDR was also significantly reduced (0.7% cangrelor vs 1.2% clopidogrel; OR 0.61 [95% CI 0.42-0.88], P = .008) (Table II and Figure 3, A). There was a significant reduction in stent thrombosis from 0.4% to 0.2% (OR 0.44 [95% CI 0.22-0.87], P = .018) with cangrelor. The OR for stent thrombosis was 0.81 (95% CI 0.33-1.95) for drug-eluting stents and 0.13 (95% CI 0.03-0.55) for bare-metal stents with a significant interaction (P b .05). For patients not receiving clopidogrel before randomization (ie, naive), there was a trend for the primary end point to be reduced (3.0% cangrelor vs 3.6% clopidogrel; OR 0.84 [95% CI 0.67-1.04], P = .106). The composite of death, Q-wave MI, or IDR was significantly

reduced (P = .008) (Figure 3, B). Mortality was reduced from 0.4% to 0.2% with cangrelor (OR 0.45 [95% CI 0.20-0.98], P = .045). There were no differences in effects in other predefined subgroups including patients with troponin elevations at baseline, diabetes, renal impairment, or aged ≥75 years (Figure 3, A, and Figure 4). At 30 days, the absolute difference in the primary end point was similar to that at 48 hours (0.6% vs 0.7%), but was no longer statistically significant (P = .100). There was a significant reduction in the incidence of Q-wave MIs (0.2% cangrelor vs 0.4% clopidogrel; OR 0.51 [95% CI 0.27-0.96], P = .036). The P values for testing heterogeneity of ORs between the trials for all end points except mortality were all N.100. The P value for death was .028, as mortality was significantly reduced with cangrelor (0.2% vs 0.7%; OR 0.33 [95% CI 0.13-0.83]) in CHAMPION PLATFORM, whereas mortality was nonsignificantly increased with cangrelor (0.2% vs 0.1%; OR 1.59 [95% CI 0.52-4.87]) in CHAMPION PCI.

Safety Bleeding events are shown in Table IV. Major Thrombolysis in Myocardial Infarction (TIMI) or Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) bleeding and transfusions were not increased with cangrelor, but clinically significant bleeding was increased (4.3% cangrelor vs 3.1% clopidogrel; P = .0002). A similar increase was seen for groin hematomas (2.8% cangrelor vs 2.1% clopidogrel; P = .0045). Minor bleeding was also increased with cangrelor.

Discussion This analysis using the universal definition of MI to ascertain the occurrence of MI shows that cangrelor reduced the primary end point at 48 hours of death, MI, or IDR as compared to a 600-mg loading dose of clopidogrel given either before or early after PCI in a

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186 White et al

Figure 2

Kaplan-Meier curves for the primary end points of the combined CHAMPION trials at 48 hours.

population mostly with ACS. Stent thrombosis was reduced by N50%. The pooling of the CHAMPION trials was prespecified based on the CHAMPION program, with the 2 trials being undertaken at the same time, with the same end points, and CEC adjudication. The findings suggest a potential role for cangrelor as an intravenous alternative to the currently available oral antiplatelet agents. Prasugrel and ticagrelor have faster and more effective platelet inhibition than clopidogrel. In the TRITON-TIMI 38 trial, 13 prasugrel reduced cardiovascular death, MI, and stroke by 19% as compared to clopidogrel with a 300mg loading dose. In the PLATO trial, 4 ticagrelor reduced the same composite end point by 16% with 19.6% of patients randomized to clopidogrel receiving a 600-mg loading dose of clopidogrel within 24 hours before or after randomization. Ticagrelor also reduced total mortality. Both prasugrel and ticagrelor reduced definite or probable stent thrombosis by 52% and 25%, respectively, compared with clopidogrel. In the current study, augmenting platelet inhibition with cangrelor was associated with an 18% reduction in early ischemic events and reduced rates of stent thrombosis. These relative benefits are comparable to those seen with prasugrel 13 and ticagrelor. 4 The effect of cangrelor on the primary composite end point was not greater in clopidogrel-naive patients, but in this group of

patients with a more specific MI definition using the development of Q waves and a composite with death and IDR, there was a significant benefit with cangrelor. Thrombolysis in Myocardial Infarction major non-CABG bleeding was increased by 25% with prasugrel in TRITON and 27% with ticagrelor in PLATO as compared to clopidogrel. In the CHAMPION trials, there was no increase in blood transfusions or major bleeding using the TIMI or GUSTO bleeding scales with cangrelor as compared with clopidogrel. However, there was an increase in clinically significant major bleeding using the more sensitive ACUITY scale with cangrelor mainly because of the increased groin hematomas. Groin hematomas have been shown not to be important prognostically, 15 and the absolute difference in clinically significant bleeding when groin hematomas were removed was 0.5%. Although prasugrel 3 and ticagrelor 4 act more quickly than clopidogrel, there remains a need for an intravenous formulation of a P2Y12 inhibitor in patients who cannot tolerate or who may not fully absorb oral drugs such as patients with cardiogenic shock or those who are heavily sedated, nauseated, or vomiting. It is also important to have agents that are truly rapidly reversible as an important minority of patients will require same-day cardiac or noncardiac surgical procedures. In the USA, surgery is not recommended within 5 days of cessation of clopidogrel

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Figure 3

A, Pooled data from CHAMPION PCI and CHAMPION PLATFORM for efficacy end points. MI, Universal definition of MI; IDR, ischemia-driven revascularization. B, Pooled data from CHAMPION PCI and CHAMPION PLATFORM for efficacy end points in clopidogrel-naive patients.

and within 7 days of cessation of prasugrel. For ticagrelor, the European guidelines state that 7 days and the US guidelines state that 5 days should be the waiting time after discontinuing ticagrelor before performing surgery. Surgery after cangrelor could potentially be performed much sooner, with restoration of platelet function observed within 60 minutes of drug discontinuation. Hence, cangrelor represents an appropriate potential choice when the coronary anatomy has not been defined and the mode of revascularization is uncertain. Although genetic factors have been shown to influence clopidogrel dosing, recent meta-analyses have shown the impact of this to be relatively small. 14 Limited efficacy associated with the late use of clopidogrel in the CHAMPION trials would tend to increase events in both arms and potentially obscure the early benefits observed with cangrelor. Hence, the finding of benefit using the universal definition of MI within 48 hours is reassuring.

Determination of myocardial infarction As clinical practice has evolved, the time from admission to PCI has become shorter. In the ACUITY

trial, the time from admission to angiography was 19.7 hours, 11 and in the EARLY ACS trial, it was 27.4 hours. 16 In the recent ACTION registry, the time from hospital presentation to PCI varied from 17 to 26 hours depending on the antithrombotic treatment. 17 The rapid time from presentation to PCI is challenging for clinical trials evaluating therapies before PCI especially when periprocedural MI is part of the primary end point. Cardiac biomarkers are released within several hours after the onset of prolonged ischemia, and when baseline levels are rising such as with non-STEMI it is not possible to ascertain whether additional release of biomarkers has occurred in association with PCI-related complications. To determine the stability of the baseline biomarker, 2 levels 6 hours apart are required. Therefore, in many patients it may not be possible to determine whether biomarker levels are stable, rising, or falling before administration of novel pharmacotherapy and PCI. Similarly, ascertainment of MI is difficult in patients with STEMI as biomarker levels are usually elevated and rising. Therefore, in this analysis, patients with STEMI, who were included in the safety population, were excluded from the efficacy analysis.

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Figure 4

Prespecified individual and composite efficacy end points for CHAMPION PCI and CHAMPION PLATFORM using the universal definition of MI for subgroups.

When the CHAMPION trials were designed, it was not anticipated that the time from randomization to PCI would be b8 hours. The CEC carefully adjudicated the occurrence of MI given the protocol definition. To overcome some of the challenges of adjudication of MI based on our protocol definition, we implemented the universal definition of MI to ensure greater specificity for MI and only included patients with stable or falling biomarker levels. We also used a conservative 50% reelevation of levels to define an MI. Determination of the development of Q waves is not affected by rapid triage to PCI and it is notable that, in the small number of patients who developed Q waves, the incidence was reduced by almost 50% by cangrelor. The difficulty with discerning recurrent MI resulting from PCI with temporal proximity to the index event raises the question as to whether suppression of such events remains clinically relevant. Supplementary myocardial damage that is difficult to observe with established definitions may still contribute to mortality and left ventricular dysfunction. Evidence for this resides in the nonsignificant 40% reduction in mortality observed with

cangrelor despite the marginal difference in MI observed using the original CHAMPION definition. Given these data, the PHOENIX trial is comparing cangrelor to clopidogrel in patients undergoing PCI and who are clopidogrel naive. The primary end point is mortality, MI, IDR, and stent thrombosis assessed at 48 hours. Myocardial infarction will be determined using the universal definition of MI. Future clinical trials, potentially using other modalities such as cardiac magnetic resonance imaging, 18 may be of value in the detection of clinically relevant re-MI among patients undergoing PCI close to the index presenting event.

Limitations Although pooling of the 2 CHAMPION studies was planned, using the universal definition of MI was not prespecified. The universal definition represents a standardized definition that is being used in ongoing trials, and reporting these results enables comparison to trials testing other novel therapies. No adjustments were made for multiple comparisons. Also, subgroup analyses

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Table IV. Bleeding events at 48 h Cangrelor (n = 7036) ACUITY 11 Criteria Clinically significant bleeding n (%) Hematomas n (%) Clinically significant bleeding without hematomas n (%) Minor bleeding n (%) GUSTO 12 criteria Mild bleeding n (%) Moderate bleeding n (%) Severe/life-threatening bleeding n (%) TIMI 10 criteria Minor bleeding n (%) Major bleeding n (%) Any transfusion n (%)

305 200 105 1088

(4.3) (2.8) (1.5) (15.5)

Clopidogrel (n = 7015)

219 147 72 909

(3.1) (2.1) (1.0) (13.0)

Odds ratio (95% CI)

1.41 1.37 1.46 1.23

P

(1.18-1.68) (1.10-1.70) (1.08-1.98) (1.12-1.35)

.0002 .0045 .0133 b.0001

1285 (18.3) 61 (0.9) 19 (0.3)

1049 (15.0) 47 (0.7) 17 (0.2)

1.27 (1.16-1.39) 1.30 (0.89-1.90) 1.11 (0.58-2.15)

b.0001 .1825 .7455

58 (0.8) 23 (0.3) 72 (1.0)

42 (0.6) 23 (0.3) 58 (0.8)

1.38 (0.93-2.06) 1.00 (0.56-1.78) 1.24 (0.88-1.76)

.1132 .9919 .2247

The bleeding options under each criterion are not mutually exclusive. ACUITY, Acute Catheterization and Urgent Intervention Triage Strategy; TIMI, Thrombolysis in Myocardial Infarction; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries.

of randomized studies can result in chance findings and these results should be interpreted with caution.

Conclusion In a pooled analysis of the 2 large CHAMPION trials, with the use of the universal definition of MI, cangrelor reduced ischemic events compared with clopidogrel. There was no increase in major bleeding, but there was an increase in clinically significant and minor bleeding. Further appropriately designed trials, able to accurately ascertain ischemic end points, particularly the occurrence of periprocedural MI, are required to confirm the potential role of cangrelor in managing patients with ACS undergoing PCI. (See online Appendix.)

Acknowledgements We would like to thank the patients and investigators who participated in the CHAMPION trials. We would also like to thank Charlene Nell, team support administrator, Green Lane Cardiovascular Research Unit, for excellent secretarial assistance.

Disclosures Harvey White — Research grants: Sanofi Aventis; Eli Lilly; Medicines Company; NIH; Pfizer; Roche; Johnson & Johnson; Schering Plough; Merck Sharpe & Dohme; Astra Zeneca; GlaxoSmithKline; Daiichi Sankyo Pharma Development; Bristol-Myers Squibb; Consulting: Regado Biosciences. Dr Chew — Research grants: Astra-Zeneca Australia, and Sanofi-Aventis Australia. Dr Dauerman — Research grants: Abbott Vascular, Medtronic, MDS Scientific; Consulting: Abbott Vascular, Medtronic, The Medicines Company, MDS Scientific.

Dr Mahaffey — Consulting: AstraZeneca, Eli Lilly, Johnson & Johnson, and Schering- Plough; Lecture fees: Bayer, Bristol-Myers Squibb, Daiichi Sankyo, SanofiAventis, and Schering-Plough; Travel support: Bayer, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Schering-Plough, and Sanofi-Aventis. Dr Gibson — Research grant: The Medicines Company; Consulting: The Medicines Company; Speaker: The Medicines Company. Dr Stone — Lecture fees: The Medicines Company, Boston Scientific, Nycomed, Guidant, Medtronic, and Abbott; Consulting: The Medicines Company, Boston Scientific, Guidant, Abbott, Volcano, St. Jude, and BMS. Dr Gruberg — Lecture fees: Lilly-Daiichi Sankyo, Abbott; Consulting: Abbott. Dr Harrington — Research grants: The Medicines Company, BMS, Sanofi-Aventis, AstraZeneca, Eli Lilly, Novartis, Portola, Merck Sharpe & Dohme; Consulting: BMS, AstraZeneca, Novartis, Merck Sharpe & Dohme. Dr Bhatt — Research grants: Astra Zeneca, BristolMyers Squibb, Eisai, Ethicon, Heartscape, Sanofi Aventis, The Medicines Company. CHAMPION PLATFORM was funded by The Medicines Company, Parsippany, NJ. CHAMPION PCI was funded by The Medicines Company, Parsippany, NJ. Funding for MPION PCI and PLATFORM was provided by The Medicines Company, Parsippany, NJ.

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percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009;54:2205-41. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361: 1045-57. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009;120: 2577-85. Fox KA, Mehta SR, Peters R, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial. Circulation 2004;110:1202-8. Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009;361:2330-41. Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009;361: 2318-29. Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction. Circulation 2007;116:2634-53. Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis in Myocardial Infarction (TIMI) trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase: clinical findings through hospital discharge. Circulation 1987;76:142-54.

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11. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203-16. 12. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673-82. 13. Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009;373: 723-31. 14. Bauer T, Bouman HJ, van Werkum JW, et al. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ 2011:343. 15. White HD, Aylward PE, Gallo R, et al. Hematomas of at least 5 cm and outcomes in patients undergoing elective percutaneous coronary intervention: insights from the SafeTy and Efficacy of Enoxaparin in PCI patients, an internationaL randomized Evaluation (STEEPLE) trial. Am Heart J 2010;159:110-6. 16. Giugliano RP, White JA, Bode C, et al. Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med 2009;360:2176-90. 17. Lopes RD, Peterson ED, Chen AY, et al. Antithrombotic strategy in non-ST-segment elevation myocardial infarction patients undergoing percutaneous coronary intervention: insights from the ACTION (Acute Coronary Treatment and Intervention Outcomes Network) Registry. JACC Cardiovasc Interv 2010;3:669-77. 18. Schoenhagen P, White HD. Magnetic resonance imaging and troponin elevation following percutaneous coronary intervention: new insights into myocyte necrosis and scar formation. JACC Cardiovasc Interv 2010;3:959-62.

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Appendix CHAMPION Executive committee D.L. Bhatt (co-principal investigator), VA Boston Healthcare System and Brigham and Women's Hospital, Boston, MA; R.A. Harrington (co-principal investigator), Duke Clinical Research Institute, Duke University Medical Center, Durham, NC; A.M. Lincoff, Cleveland Clinic Foundation, Cleveland, OH; C.V. Pollack, Jr, Pennsylvania Hospital, University of Pennsylvania, Philadelphia, PA; C.M. Gibson, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; G.W. Stone, Columbia University Medical Center and The Cardiovascular Research Foundation, New York, NY; K.W. Mahaffey, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC; N.S. Kleiman, Methodist DeBakey Heart Center, The Methodist Hospital, Houston, TX; G. Montalescot, Institut de Cardiologie, Pitié-Salpêtrière Hospital, Paris, France; H.D. White, Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand; S.G. Goodman, Terrence Donnelly Heart Centre, Division of Cardiology, St. Michael's Hospital and the Canadian Heart Research Centre, Toronto, Ontario, Canada. CHAMPION Steering committee A. Greenbaum, Henry Ford Hospital, Detroit, MI; D. Simon, University Hospitals Case Medical Center, Cleveland, OH; D. Lee, Stanford Interventional Cardiology, Stanford, CA; F. Feit, New York University Hospital, NY, NY; H. Dauerman, The University of Vermont Fletcher Allen Medical Center, Burlington, VT; P. Gurbel, Sinai Hospital, Baltimore, MD; P. Berger, Geisinger Center for Clinical Studies, Danville, PA; R. Makkar, Cedar's-Sinai Heart Center, Los Angeles, CA; R.C. Becker, Duke Clinical Research Institute, Durham, NC; S. Manoukian, Centennial Heart Cardiovascular Center, Nashville, TN; J. Jorgova, UNSHAT (St. Ekatherina), Sofia, Bulgaria; D.P. Chew, Flinders University/Flinders Medical Centre, Adelaide, SA, Australia; R. Storey, Northern General Hospital, Sheffield, UK; W. Desmet, University Hospital Gasthuisberg, Leuven, Belgium; F. Cura, Insituto Cardiovascular de Buenos Aires, Buenos Aires, Argentina; H. Herrmann, University of Pennsylvania Hospital Center, Philadelphia, PA;

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D. Rizik, Scottsdale Healthcare, Scottsdale, AZ; S. DeServi, Azienda Ospedaliera di Legnano, Legnano, Italy; K. Huber, Wilhelminenhospital, Vienna, Austria; W.J. Jukema, Leiden University Medical Center, Leiden, The Netherlands; W. Knopf, St. Joseph's Hospital, Atlanta, GA; P.G. Steg, Hôpital Bichat-Claude Bernard, Paris, France; H. Schunkert, Universitaetsklinikum Schleswig-Holstein Campus Lübeck, Lübeck, Germany; P. Widimsky, Charles University, Prague, Czech Republic; A. Betriu, University of Barcelona, Barcelona, Spain

CHAMPION National Coordinators Australia: P. Aylward, Flinders University/Flinders Medical Centre, Adelaide, SA, Australia; Belarus: L. Polonestsky, Republican Research and Practical Centre Cardiology of The Ministry of Health of Republic of Belarus; Brazil: V. Lima, Universidade Federal do Estado de São Paulo, Hospital São Paulo; Bulgaria: J. Jorgova, UNSHAT, St. Ekatherina; Czech Republic: P. Widimsky, Charles University; Georgia: B. Kobulia, Clinic of Angiocardiology, ADAPTI; Lithuania: R. Navickas, Kaunas Medical University Hospital, Cardiology Department; Poland: Z. Gasior, Slaskiego Uniwersytetu Medycznego Katowicach, Gornoslaskie Centrum Medyczne, II Oddzial Kardiologii; Russia: E. Vasilieva, Cardiology, City Hospital #23; South Africa: J.M. Bennett, Life Wilgers Hospital; Ukraine: I. Kraiz, State Treatment and Prevention Institution, Central Clinical Hospital of Ukrainian Railway, Department of Cardiology. CHAMPION Data safety monitoring board F. Van de Werf (chair), Leuven Clinical Coordinating Center; University Hospital Gasthuisberg, Leuven, Belgium; D. Faxon, Brigham and Women's Hospital, Boston, MA; E.M. Ohman, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC; J.G.P. Tijssen, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; F. Verheugt, University Medical Center; Amsterdam, the Netherlands W.D. Weaver, Henry Ford Hospital, Detroit, MI CHAMPION Independent analysis review committee R.M. Califf (chair), Duke Translational Medicine Institute, Durham, NC; C. Mehta, Cytel Software Corporation, Cambridge, MA; C.W. Hamm, Kerckhoff Heart Center, Bad Nauheim, Germany; C.J. Pepine, University of Florida, Gainesville, FL;

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J. Ware, Harvard School of Public Health, Cambridge, MA

CHAMPION Clinical events committee K.W. Mahaffey (chair); M. Wilson (lead CEC CTC); C. Gorham (lead CEC CDA); A. Maran; S. McNulty; D. Fasteson; G. Ryan; J. Bradsher; P. Connolly; R. Mehta; S. Leonardi; M. Brennan; M. Patel; J. Petersen; C. Bushnel; M. Jolicoeur; M. Chan; L. Dowd; P. Skinner; G. Lawrence; M. Jordon; S. Dickerson; M. Meyer; S. Hartford, Duke Clinical Research Institute, Durham, NC CHAMPION PLATFORM Investigators Participating countries (with total enrollment), principal investigators, and hospitals. Argentina: Fernando Cura, Instituto Cardiovascular de Buenos Aires; Alejandro Garcia Escudero, Sanatorio Junin; Carlos Poy, Sanatorio Parque; Miguel Miceli, Hospital Ramon Carrillo; Antonio Pocovi, Sanatorio de la Trinidad Mitre; Hugo Londero, Sanatorio Allende; Jorge Baccaro, Instituto Cardiovascular de Corrientes Belarus: Leonid Polonetsky, Republican Research and Practical Centre Cardiology of The Ministry of Health of Rep of Belarus; Aliaksey Karotkin, 1st Minsk City Clinical Hospital; Leanid Shubau, Gomel Regional Clinical Cardiology Dispensary Brazil: Eduardo Maffini, Universidade de Caxias do Sul, Caxias do Sul-RS; Bruno Machado, Centro Integrado de Atenção à Saúde, Vitória-ES; José Airton, Hospital Meridional, Cariacica-ES; Valter Lima, Universidade Federal do Estado de São Paulo-Hospital São Paulo, São Paulo-SP; Eulogio Martinez Filho, Faculdade de Medicina da USPINCOR, São Paulo-SP; Arthur Herdy, Instituto de Cardiologia-Hospital Regional de São José, Florianópolis-SC; Rogerio Tumelero, Hospital São Vicente de Paulo, Passo Fundo-RS; Dalton Precoma, Sociedade Hospitalar Angelina Caron, Campina Grande do Sul-PR; Roberto Botelho, Instituto do Coração do Triângulo Mineiro, UberlândiaMG; Jamil Saad, Hospital Felicio Rocho, Belo HorizonteMG; Jose Jatene, Hospital Lúcio Rebelo, Goiânia-GO; Fabio Vilas-Boas, Hospital Espanhol, Salvador-BA; Antonio Godinho, Fundação Bahiana de Cardiologia, Salvador-BA; Marco Perin, Casa de Saúde Santa Marcelina, São Paulo-SP; Paulo Caramori, Hospital São Lucas da PUCRS, Porto Alegre- RS; Iran Castro, Instituto de Cardiologia do Rio Grande do Sul, Porto Alegre-RS; Bulgaria: Ivan Manukov, Clinic of Invasive Cardilogy, UMHAT Sveti Georgi EAD-Plovdiv; Mladen Grigorov, SHAT of Cardiology; Plamen Milkov, Cardiology Clinic, 2nd MHAT-Sofia; Julia Jorgova, Cardiology Clinic, UNSHAT St. Ekatherina; Svetoslav Georgiev, 2nd Clinic of Cardiology, MHAT Sveta Marina; Nizar Rifai, Clinic of Cardiology, UMHAT Sv. Anna; Alexander Doganov, Clinic of Cardiology, National Cardiology Hospital; Ivo Petrov, Department of Cardiology, Tokuda Hospital

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Canada: William Hui, Royal Alexandra Hospital; Charles Lazzam, Trillium Health Centre; Francois Reeves, Hôpital Notre-Dame du CHUM; Jean-Francois Tanguay, Montreal Heart Hospital; Czech Republic: Marek Richter, Faculty Hospital Olomouc, 1st Internal Clinic; Frantisek Tousek, Hospital Ceske Budejovice, Cardiocenter-Cardiology; Zdenek Klimsa, Hospital Jihlava and Cardiocenter Vysocina CZ; Michal Padour, Regional Hospital Karlovy Vary, Department of Interventional Cardiology; Jan Mrozek, 2nd Internal-Cardiovascular Department of Municipal Hospital Ostrava; Marian Branny, Hospital Podlesi, Cardiocenter; Zdenek Coufal, Bata Regional Hospital Inc., Internal Clinic; Stanislav Simek, General Faculty Hospital, 2nd Internal Clinic; Vladimir Rozsival, Hospital Pardubice, Internal Clinic, Cardiology; Leos Pleva, Faculty Hospital Ostrava, Internal Clinic, Department of Invasive Cardiology; Josef Stasek, Faculty Hospital Hradec Kralove, Internal Clinic-Department of Invasive Cardiology; Petr Kala, Faculty Hospital Brno, Internal and Cardiological Department; Ladislav Groch, Faculty Hospital, Anny Brno, 1st Internal-Cardioangiological Department; Viktor Kocka, Faculty Hospital Kralovske Vinohrady 3rd Internal Cardiology Clinic; Georgia: Tamaz Shaburishvili, Diagnostic Services Clinic; Irakli Khintibidze, Tbilisi State Medical University Alexandre Aladashvili University Clinic; Gulnara Chapidze, Emergency Cardiology Centre; Merab Mamatsashvili, Clinic of Angiocardiology ADAPTI; India: Padinhare Mohanan, West Fort Hi-Tech Hospital Ltd; Rajesh Jain, CHL-Apollo Hospitals; Keyur Parikh, S.A.L. Hospital; Tejas Patel, Krishna Heart and Super Speciality Institute; Sampath Kumar, Osmania Hospital; Ashwani Mehta, Dharma Vira Heart Centre; Darshan Banker, Bankers Heart Institute; Lanka Krishna, Nizam's Institute of Medical Sciences; Milind Gadkari, KEM Hospital and Research Center; Hasit Joshi, Apollo Hospitals International Ltd; Jaspal Arneja, Arneja Heart Institute; Shirish Hiremath, Grant Medical Foundation; Lithuania: Virgilijus Grinius, Kaunas Medical University Hospital, Cardiology Department; Sigute Norkiene, Klaipeda Seamen's Hospital, 3rd Cardiology Department; Birute Petrauskiene, Vilnius University Hospital Santariskiu Klinikos, Centre of Cardiology and Angiology; Netherlands: Rolf Michels, Catharina Hospital Department R&D, Cardiology; Melvin Tjon, Rijnstate Hospital Arnhem; Hans de Swart, Medisch Centrum Alkmaar; Robbert de Winter, Academic Medical Center Amsterdam; New Zealand: Harvey White, Auckland City Hospital; Gerard Devlin, Waikato Hospital; Malcolm Abernethey, Wakefield; Russia: Alexander Osiev, FSI Novosibirsk Research Institute of Circulation Pathology; Kirill Linev, Territorial State Healthcare Institution, Territorial Clinical Hospital; Svetlana Kalinina, Cardiology, Clinical Centre Cardiology;

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Svetlana Baum, Railway Clinical Hospital of RZhD on the Station Novosibirsk-Glavny; Elena Kosmachova, Territorial Clinical Hospital #1; Zaur Shogenov, City Clinical Hospital #81; Valentin Markov, Coronary Care Unite, Cardiology Research Institute; Svetlana Boldueva, Department of Cardiology, St. Petersburg State Medical Academy n.a. I.I. Mechnikov; Olga Barbarash, Cardiology and Cardiosurgery, Kemerovo Cardiology Dispensary; Victor Kostenko, AMI, Research Institute of Emergency Medical Care; Elena Vasilieva, Cardiology, City Hospital #23; Aleksey Gruzdev, Cardiology, Central Clinical Hospital; Victor Lusov, Cardiology, City Hospital #15; Pavel Dovgalevsky, Cardiology, Saratov Institute of Cardiology; Oleg Azarin, Cardiology, Voronezh Regional Hospital; Sergey Chernov, FSI Main Military Hospital na Burdenko; Olga Smolenskaya, Cardiology, Ural SMA b.o. City Clinical Hospital #41; Alexey Duda, Altay Regional Cardiology Dispensary; Slovakia: Viliam Fridrich, Národný, Oddelenie Intervenčnej Kardiológie; Marian Hranai, Kardiocentrum Nitra; Martin Studenčan, Východoslovenský, Kardiologické Oddelenie; Peter Kurray, Stredoslovenský, Oddelenie Koronárnej Jednotky; South Africa: John Bennett, Life Wilgers Hospital; Pieter Blomerus, Unitas Hospital; Laurence Disler, Linksfield Park Clinic; Johannes Engelbrecht, Vergelegen Medi Clinic; Eric Klug, Sunninghill Hospital; Robert Routier, Olivedale Clinic; Tjaart Venter, Union Hospital; Eric Klug, Sunward Park Hospital; Nico Van Der Merwe, Bloemfontein Medi-Clinic; Anthony Becker, Morningside Clinic; South Korea: Kwang-Soo Cha, Dong-A University Hospital; Seung-Hwan Lee, Wonju Christian Hospital, Yonsei University Wonju College of Medicine; Sang-Jin Han, Chuncheon Sacred Heart Hospital, Hallym University Medical Center; Tae Jin Youn, Seoul National University Bundang Hospital; Seung-Ho Hur, Keimyung University Dongsan Medical Center; Hong Seog Seo, Korea University Guro Hospital; Hun-Sik Park, Kyungpook National University Hospital; Chong-Yun Rhim, Hallym Universit Sacred Heart Hospital; Wook-Bum Pyun, Ewha Woman's University Dongdaemun Hospital; Hyunmin Choe, Inje University Ilsan Paik Hospital; Myung-Ho Jeong, Chunnam National University Hospital; Jong-Seon Park, Yeungnam University Hospital; Eak-Kyun Shin, Gachon Medical School, Gil Medical Center; Spain: Felipe Hernández, Hospital 12 de Octubre; Jaume Figueras, Hospital Vall D'Hebrón; Rosana Hernández, Hospital Clinico San Carlos; José Ramón LópezMinguez, Hospital Infanta Cristina; José Ramón González Juanatey, Hospital Clinico Universitario Santiago; Ramón López Palop, Hospital San Juan de Alicante; Guillermo Galeote, Hospital La Paz; Thailand: Noppadol Chamnarnphol, Songklanagarind Hospital; Wacin Buddhari, King Chulalongkorn Memorial Hospital; Nakarin Sansanayudh, Phramongkutklao Hospital; Srun Kuanprasert, Maharaj Nakorn Chiang Mai Hospital;

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United States: William Penny, San Diego VA Medical Center, CA; Charles Lui, UT-Galveston, TX; Garfield Grimmett, Dakota Clinic, Innovis Health, ND; Venkatraman Srinivasan, Western PA Hospital, PA; Kevin Ariani, Northridge Hospital, CA; Waqor Khan, Tomball Regional Hospital, TX; James Blankenship, Geisinger Medical Center, PA; Louis Cannon, Northern Michigan Hospital, MI; Steven Eisenberg, St. Joseph's Hospital of Atlanta, GA; M. Zubair Jafar, Hudson Valley Heart Center/Vassar Brothers Medical Center, NY; Brent McLaurin, Anderson Area Medical Center, SC; Paul Mahoney, Sentara Norfolk General Hospital, VA; Jerry Greenberg, Medical Center of Aurora, CO; Jeffrey Breall, Clarian Health Partners, IN; Harish Chandna, Detar Hospital, TX; Eric Hockstad, Kansas City Heart Foundation, MO; Paul Tolerico, York Hospital, PA; John Kao, Jesse Brown VAMC, IL; Adhir Shroff, University of Illinois at Chicago Medical Center, IL; Georges Nseir, Chandler Regional Hospital, AZ; Adam Greenbaum, Henry Ford Hospital, MI; Joel Cohn, Ingham Regional Medical Center, MI; Harinder Gogia, Anaheim Memorial Medical Center, CA; Ahed Nahhas, Toledo Hospital, OH; Pierre Istfan, Wellmont Bristol Regional Medical Center, TN; Steve Orlow, Lutheran Hospital of Indiana, IN; Douglas Spriggs, Clearwater Cardiovascular & Interventional Consultant, FL; Joel Sklar, Marin General Hospital, CA; Richard Paulus, King's Daughters Medical Center, KY; David Cochran, St. John's Hospital, MO; Robert Smith, Trinity Mother Francis Hospital, East Texas Med Center, TX; L. Norman Ferrier, Rapid City Regional Hospital, SD; J. Christopher Scott, University of Tennessee Medical Center, TN; Nicholaos Xenopoulos, Jewish Hospital, KY; Mahesh Mulumudi, Providence Everett Medical Center, WA; James Hoback, Chattanooga Heart Institute, TN; Wilson Ginete, St. Mary's Medical Center, Duluth Clinic, MN; William Ballard, Piedmont Hospital/Fuqua Heart Center of Atlanta, GA; Joseph Stella, St. Francis Hospital, IL; Michele Voeltz, Emory University Hospital Midtown, GA; Cezar Staniloae, St. Vincent Catholic Medical Center, NY; Gregory Eaton, MedCentral Health System, OH; John Griffin, Cardiovascular Associates, Sentara Virginia Beach General, VA; Krishna Kumar, The Wisconsin Heart Hospital, WI; Ramin Ebrahimi, VAMC-GLAHS, CA; Charles O'Shaughnessy, DMH Regional Medical Center, OH; Robert Lundstrom, Kaiser Permanente Medical Center, CA; Dogan Temizer, Good Samaritan Hospital, OH; Kenneth Tam, Providence Holy Cross Medical Center, CA; Jose Suarez, University Cardiology Group, TX; Amish Raval, University of Wisconsin School of Medicine and Public Health, WI; Jay Kaufman, Maricopa Integrated Health Systems, AZ; Emmanouil Brilakis, Dallas VA Medical Center, TX; Michael Stillabower, Christiana Care Health Services, DE; Kathleen Quealy, Metro Health Medical Center, OH; Boris Nunez, Winter Haven Hospital, FL; Thomas Pow, Lakeland Hospital St. Joseph, MI; Bruce Samuels, Cedars-Sinai Medical Center/CVIC, CA; Agustin Argenal, John Muir Hospital, CA; Vankeepuram Srinivas,

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Jack D. Weiler Hospital, NY; Andrew Rosenthal, The Heart and Vascular Institute of Florida, FL; Pradyumna Tummala, Northeast Georgia Medical Center, GA; Paul Myers, Centennial Medical Center, TN; Georges Nseir, Mercy Gilbert Medical Center, AZ; Nelson LaMarche, Jersey Shore Medical Center, NJ; Michael Chan, St. Joseph Hospital, CA; Harinder Gogia, Western Medical Center Santa Ana, CA; Richard Bach, Washington University/Barnes-Jewish Hospital, MO; Daniel Simon, University Hospital of Cleveland, OH; Richard Kettelkamp, Mercy Hospital, IA; Tarek Helmy, University Hospital, OH; Gary Schaer, Rush University Medical Center, IL; Edward Kosinski, Connecticut Clinical Research, LLC, CT; Maurice Buchbinder, Foundation for Cardiovascular Medicine, CA; Mukesh Sharma, Parkway Cardiology Associates, PC/Methodist Medical Center, TN;

American Heart Journal February 2012

Mark Goodwin, Edward Hospital, IL; Phillip Horwitz, University of Iowa Hospital, IA; J. Tift Mann, III, Wake Heart Research, NC; David Holmes, Jr., Mayo Clinic-Rochester, MN; Dominick Angiolillo, University of Florida Health Science Center, FL; Sunil Rao, Duke University Medical Center, NC; Michael Azrin, University of CT Health Center, CT; Roger Gammon, The Heart Hospital of Austin, TX; Kreton Mavromatis, Atlanta VA Medical Center, GA; Abdel Ahmed, Altru Health System, ND; Kenneth Kent, Suburban Hospital, MD; Marcel Zughaib, Providence Hospital, MI; R. Jeffrey Westcott, Swedish Heart & Vascular Institute, WA; Ash Jain, Washington Hospital, CA; Luis Gruberg, Stony Brook University Hospital, NY; Thomas LeGalley, Upper Michigan Cardiovascular Associates (Marquette General Health System), MI.