Benefit of Percutaneous Coronary Intervention in Early Latecomers With Acute ST-Segment Elevation Myocardial Infarction

Benefit of Percutaneous Coronary Intervention in Early Latecomers With Acute ST-Segment Elevation Myocardial Infarction Doo Sun Sim, MD, PhDa, Myung-Ho Jeong, MD, PhDa,*, Youngkeun Ahn, MD, PhDa, Young Jo Kim, MD, PhDb, Shung Chull Chae, MD, PhDc, Taek Jong Hong, MD, PhDd, In Whan Seong, MD, PhDe, Jei Keon Chae, MD, PhDf, Chong Jin Kim, MD, PhDg, Myeong Chan Cho, MD, PhDh, Seung-Woon Rha, MD, PhDi, Jang Ho Bae, MD, PhDj, Ki Bae Seung, MD, PhDk, and Seung Jung Park, MD, PhDl; Other Korea Acute Myocardial Infarction Registry (KAMIR) Investigators The clinical benefit of percutaneous coronary intervention (PCI) is controversial in stable early latecomers with ST-segment elevation myocardial infarction (STEMI). We evaluated the efficacy of PCI in 2,344 stable patients with STEMI presenting 12 to 72 hours after symptom onset. Patients who had impaired hemodynamics or who had undergone fibrinolysis or immediate or urgent PCI were excluded. The patients were divided into the PCI group (n ⴝ 1,889) and medical treatment group (n ⴝ 455). The 12-month clinical outcome was compared between the 2 groups. After adjustment using propensity score stratification, the PCI group had lower mortality (3.1% vs 10.1%; hazard ratio 0.31; 95% confidence interval 0.20 to 0.47; p <0.001) and a lower incidence of composite death/myocardial infarction (3.8% vs 11.2%; hazard ratio 0.36; 95% confidence interval 0.25 to 0.53; p < 0.001) at 12 months. The benefit of PCI was consistent across all subgroups, including patients presenting without chest pain. In conclusion, in stable patients with STEMI presenting 12 to 72 hours after symptom onset, PCI was associated with significant improvement in the 12-month clinical outcome. © 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:1275–1281) The clinical benefit of reperfusion is controversial for stable patients with ST-segment elevation myocardial infarction (STEMI) presenting ⬎12 to 24 hours after the onset of symptoms and largely unrelated to myocardial salvage.1,2 However, viable myocardium can be found even after ischemia of ⬎12 hours3,4 and the period to salvage viable myocardium can extend to several days.5 The accepted

a

Chonnam National University Hospital, Gwangju, Republic of Korea; Yeungnam University Hospital, Daegu, Republic of Korea; cKyungpuk National University Hospital, Daegu, Republic of Korea; dBusan National University Hospital, Busan, Republic of Korea; eChungnam National University Hospital, Daejon, Republic of Korea; fChunbuk National University Hospital, Jeonju, Republic of Korea; gKyung Hee University Hospital at Gangdong, Seoul, Republic of Korea; hChungbuk National University Hospital, Cheongju, Republic of Korea; iKorea University Guro Hospital, Seoul, Republic of Korea; jKonyang University Hospital, Daejon, Republic of Korea; kCatholic University Seoul St. Mary’s Hospital, Seoul, Republic of Korea; and lAsan Medical Center, Seoul, Republic of Korea. Manuscript received April 23, 2012; revised manuscript received and accepted June 20, 2012. This study was performed with the support of the Korean Circulation Society, Seoul, Republic of Korea in commemoration of its 50th Anniversary and grant A084869 from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea. *Corresponding author: Tel: (⫹82) 62-220-6243; fax: (⫹82) 62-2287174. E-mail address: [email protected] (M.-H. Jeong). b

0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.06.028

definition of “early latecomers” refers to patients with STEMI presenting ⬎12 to 72 hours after the onset of symptoms.6 Several recent studies evaluating the efficacy of percutaneous coronary intervention (PCI) in early latecomers have shown conflicting results.7–12 In the present study, we sought to assess the benefit of PCI in stable, early latecomers with STEMI using the database of the Korea Acute Myocardial Infarction Registry. Methods The Korea Acute Myocardial Infarction Registry is the first nationwide, population-based, multicenter data collection registry in Korea designed to track the outcomes of patients presenting with acute myocardial infarction (MI).13,14 The diagnosis of acute MI was determined by a typical increase and decrease in biochemical markers of myocardial necrosis (including creatine kinase-MB and troponin I and T), with ⱖ1 of the following: ischemic symptoms, electrocardiographic changes indicative of ischemia (ST-segment elevation or depression), and the development of pathologic Q waves on the electrocardiogram. The study population was derived from patients in the Korea Acute Myocardial Infarction Registry enrolled from November 2005 to January 2008. We included patients (aged ⱖ18 years) with persistent ST-segment elevation ⬎0.1 mV in ⱖ2 contiguous precordial leads or ⱖ2 adjacent limb leads or new or presumably new left bundle branch block. From this population, we excluded patients with cardiac arrest, venwww.ajconline.org

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Table 1 Baseline clinical characteristics between percutaneous coronary intervention (PCI) and medical therapy groups Variable Age (years) Men Smoker Hypertension Diabetes mellitus Dyslipidemia Chronic kidney disease Myocardial infarction Angina pectoris Percutaneous coronary intervention Coronary bypass Heart failure Stroke Peripheral artery disease Presentation data Interval from symptom onset (hours) Chest pain Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min) Killip class I II Preinfarct angina pectoris Q waves Left bundle branch block Anterior myocardial infarction Left ventricular ejection fraction (%) Laboratory findings Total cholesterol (mg/dl) Low-density lipoprotein cholesterol (mg/dl) High-density lipoprotein cholesterol (mg/dl) Triglycerides (mg/dl) Creatinine (mg/dl) Peak troponin I (ng/ml) Glucose at admission (mg/dl) High-sensitivity C-reactive protein at admission (mg/dl) N-terminal pro-B-type natriuretic peptide at admission (pg/ml)

PCI (n ⫽ 1,889)

Medical Therapy (n ⫽ 455)

p Value

66 (55–73) 1,314 (69.6%) 1,078 (57.1%) 1,021 (54.0%) 506 (26.8%) 193 (10.2%) 35 (1.9%) 86 (4.6%) 87 (4.6%) 75 (4.0%) 10 (0.5%) 18 (1.0%) 129 (6.8%) 17 (0.9%)

69 (57–76) 269 (59.1%) 221 (48.6%) 236 (51.9%) 129 (28.4%) 42 (9.2%) 24 (5.3%) 46 (10.1%) 41 (9.0%) 34 (7.5%) 4 (0.9%) 32 (7.0%) 54 (11.9%) 12 (2.6%)

⬍0.001 ⬍0.001 0.001 0.40 0.50 0.53 ⬍0.001 ⬍0.001 ⬍0.001 0.001 0.49 ⬍0.001 ⬍0.001 0.003

22 (15–34) 1,521 (80.5%) 130 (110–146) 80 (70–90) 76 (66–86)

23 (16–35) 312 (68.6%) 130 (110–150) 80 (70–87) 78 (68–92)

0.84 ⬍0.001 0.57 0.50 ⬍0.001 ⬍0.001

1,555 (82.3%) 334 (17.7%) 876 (46.4%) 372 (19.7%) 12 (0.6%) 830 (43.9%) 53 (46–60)

338 (74.3%) 117 (25.7%) 199 (43.7%) 74 (16.3%) 8 (1.8%) 166 (36.5%) 53 (44–60)

182 (157–211) 114 (95–141) 43 (37–51) 104 (76–152) 0.9 (0.8–1.1) 15 (5–39) 130 (109–168) 1.2 (0.4–3.9) 1,020 (683–1,291)

171 (143–202) 108 (80–128) 43 (36–53) 102 (69–132) 1.0 (0.8–1.3) 8 (2–17) 131 (108–169) 1.2 (0.4–3.7) 1,020 (857–1,854)

0.31 0.09 0.04 0.004 0.13 ⬍0.001 ⬍0.001 0.51 0.002 0.001 ⬍0.001 0.84 0.91 0.002

Continuous variables are presented as the median (interquartile range) and other data as n (%).

tricular arrhythmia, advanced atrioventricular block, systolic blood pressure ⬍90 mm Hg, heart rate ⬎100 beats/ min, or Killip class III-IV at presentation. We also excluded patients who had undergone fibrinolysis. Of the 7,885 patients who presented within 72 hours after symptom onset, 2,640 patients presenting ⬎12 to 72 hours were selected: 2,185 underwent PCI and 455 received conservative medical treatment. Of the 2,185 patients in the invasive cohort, 236 underwent immediate PCI (median interval from arrival 59 minutes), 60 underwent urgent PCI during conservative treatment (median interval from arrival 68 hours), and 1,889 underwent elective PCI (median interval from arrival 23 hours). Because it was difficult to capture the fluctuation of chest pain and/or ST-segment elevation from our registry—to compensate for the potential selection bias associated with this—we excluded patients receiving immediate and urgent PCI, and compared the 12-month clinical out-

comes of patients who underwent elective PCI (n ⫽ 1,889) versus those who received medical therapy (n ⫽ 455). The median interval from arrival to PCI was 23 hours (range 13 to 47). The present study was conducted according to the Declaration of Helsinki. The institutional review board of all participating centers approved the study protocol (approval no. 05-49 of Chonnam National University Hospital). All the participating patients provided written informed consent. The primary end point was the occurrence of death or recurrent MI at 12 months between the PCI and medical therapy groups. Death was defined as death from any cause. Recurrent MI was defined as the recurrence of symptoms or the presence of electrocardiographic changes in association with an increase in the cardiac biomarker levels greater than the upper limit of normal. The baseline differences between the 2 groups were compared using the Mann–Whitney U test for continuous

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Table 2 Characteristics of procedures, complications, and medical treatment during hospitalization between percutaneous coronary intervention (PCI) and medical therapy groups Variable Procedure Coronary angiography Infarct-related artery Left main Left anterior descending Left circumflex Right coronary Prepercutaneous coronary intervention Thrombolysis In Myocardial Infarction flow 0 1 2 3 Complications during hospitalization Cardiogenic shock Atrial fibrillation Ventricular tachycardia/fibrillation Advanced atrioventricular block Cardiovascular resuscitation Intra-aortic balloon counterpulsation Mechanical ventilation Temporary cardiac pacing Acute kidney injury Major bleeding Acute stroke Medical treatment during hospitalization Unfractionated heparin Low-molecular-weight heparin Aspirin Clopidogrel Cilostazol ␤ Blockers Calcium channel blockers Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker Diuretics Long-acting nitrates Statin

PCI (n ⫽ 1,889)

Medical Therapy (n ⫽ 455)

p Value

1,889 (100%)

132 (29.0%)

⬍0.001 0.39

43 (2.3%) 883 (46.7%) 387 (20.5%) 576 (30.5%)

6 (4.5%) 63 (47.7%) 24 (18.2%) 39 (29.5%)

808 (42.8%) 242 (12.8%) 296 (15.7%) 543 (28.7%)

35 (26.5%) 15 (11.4%) 20 (15.2%) 62 (47.0%)

30 (1.6%) 6 (0.3%) 20 (1.1%) 21 (1.1%) 15 (0.8%) 36 (1.9%) 23 (1.2%) 33 (1.7%) 6 (0.3%) 5 (0.3%) 3 (0.2%)

14 (3.1%) 2 (0.4%) 10 (2.2%) 1 (0.2%) 12 (2.6%) 2 (0.4%) 14 (3.1%) 1 (0.2%) 5 (1.1%) 2 (0.4%) 4 (0.9%)

⬍0.001

1,134 (60.0%) 656 (34.7%) 1,877 (99.4%) 1,862 (98.6%) 596 (31.6%) 1,491 (78.9%) 222 (11.8%) 1,600 (84.7%) 471 (24.9%) 1,315 (69.6%) 1,493 (79.0%)

0.04 0.66 0.05 0.10 0.001 0.03 0.004 0.01 0.05 0.63 0.03

258 (56.7%) 135 (29.7%) 431 (94.7%) 405 (89.0%) 27 (5.9%) 300 (65.9%) 97 (21.3%) 344 (75.6%) 187 (41.1%) 325 (71.4%) 277 (60.9%)

0.19 0.04 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.45 ⬍0.001

Data are presented as n (%).

Table 3 Unadjusted and adjusted clinical outcomes between percutaneous coronary intervention and medical therapy groups Variable

In-hospital Death At 30 days Death Death/myocardial infarction At 6 mo Death Death/myocardial infarction At 12 mo Death Death/myocardial infarction

PCI (n ⫽ 1,889)

Medical Therapy (n ⫽ 455)

32 (1.7%)

Unadjusted

Adjusted*

HR (95% CI)

p Value

HR (95% CI)

24 (5.3%)

0.31 (0.18–0.53)

⬍0.001

0.39 (0.22–0.70)

0.002

40 (2.1%) 43 (2.3%)

37 (8.1%) 39 (8.6%)

0.26 (0.17–0.41) 0.27 (0.17–0.41)

⬍0.001 ⬍0.001

0.29 (0.18–0.47) 0.30 (0.19–0.48)

⬍0.001 ⬍0.001

50 (2.6%) 58 (3.1%)

43 (9.5%) 47 (10.3%)

0.27 (0.18–0.41) 0.29 (0.20–0.43)

⬍0.001 ⬍0.001

0.29 (0.19–0.45) 0.31 (0.21–0.48)

⬍0.001 ⬍0.001

58 (3.1%) 72 (3.8%)

46 (10.1%) 51 (11.2%)

0.29 (0.20–0.43) 0.33 (0.23–0.47)

⬍0.001 ⬍0.001

0.31 (0.20–0.47) 0.36 (0.25–0.53)

⬍0.001 ⬍0.001

* Stratified by the propensity score. CI ⫽ confidence interval; HR ⫽ hazard ratio.

p Value

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Figure 1. PCI versus medical therapy and rates of death and MI at 12 months before and after adjustment by stratification by the propensity score. *Test for heterogeneity, p ⫽ 0.885. CI ⫽ confidence interval; PS ⫽ propensity score.

variables and the chi-square test or Fisher’s exact test for categorical variables. Unadjusted hazard ratios and their 95% confidence intervals were calculated for the outcome variables. To adjust for the bias inherent in the decision of choosing PCI or medical therapy, propensity scores were used.15,16 The propensity scores were estimated for the likelihood of receiving PCI using a multiple logistic regression model that contained all covariates listed in Tables 1 and 2, except for diastolic blood pressure, total cholesterol, and procedures. Model discrimination was measured by the c-statistic, and calibration was assessed using the Hosmer– Lemeshow goodness-of-fit test (c-statistic 0.82, Hosmer– Lemeshow, p ⫽ 0.68). The propensity scores were divided into quintiles to eliminate bias due to an imbalance in the measured covariates between the 2 groups.17 The degree to which the propensity score balanced the measured covariates was assessed by comparing the standardized differences in the mean values of each covariate. After adjustment by stratification on the propensity score, the standardized differences of all covariates were ⬍0.25, suggesting that all the measured covariates were well balanced between the 2 groups.18 The treatment effect was estimated separately within each quintile, and a pooled average treatment effect was obtained by combining the estimates across the quintiles. Statistical analyses were conducted using SPSS, version 18.0 (SPSS, Chicago, Illinois) and R, version 2.13.1 (R Foundation for Statistical Computing, Vienna, Austria). All statistical tests were 2-sided, with a significance level of p ⬍0.05. Results The baseline characteristics, in-hospital treatments, and outcomes of the 2,344 early latecomers with STEMI are listed in Tables 1 and 2. The patients undergoing PCI were younger, more often men and smokers, and more likely to have chest pain at presentation, anterior MI, elevated levels of cholesterols and troponins, and to receive adequate med-

Figure 2. Death/MI-free survival at 12 months between PCI and medical therapy groups after adjustment by stratification by the propensity score. CI ⫽ confidence interval; HR ⫽ hazard ratio.

ical treatment during hospitalization. Unadjusted in-hospital mortality was lower in the PCI group (1.7% vs 5.3%, p ⬍0.001; Table 3). The rates of death or MI at 12 months were also lower in the PCI group (3.8% vs 11.2%, p ⬍0.001). After adjustment, PCI was still associated with lower in-hospital mortality (hazard ratio 0.39, 95% confidence interval 0.22 to 0.70; p ⫽ 0.002). The 12-month death/MI rates remained significantly lower in the PCI group (hazard ratio 0.48, 95% confidence interval 0.33 to 0.70; p ⬍0.001; Table 3 and Figures 1 and 2). In each quintile of propensity for PCI, the 12-month death/MI rates were lower for patients who underwent PCI than for those who did not, with a hazard ratio of 0.30 to 0.64 (test for heterogeneity, p ⫽ 0.885), indicating that patients with the same likelihood of undergoing PCI were more likely to benefit if they actually underwent PCI (Figure 1). Additional analysis revealed that the favorable outcomes associ-

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Figure 3. Subgroup analysis of 12-month death/MI. CI ⫽ confidence interval; HR ⫽ hazard ratio; TIMI ⫽ Thrombolysis In Myocardial Infarction.

ated with PCI applied to all subgroups, including patients presenting without chest pain (Figure 3). Discussion The present study has shown that in patients with stable STEMI presenting 12 to 72 hours after symptom onset, PCI is associated with significantly lower rates of 12-month death/MI than conservative medical treatment. Currently, it is thought that for stable patients with STEMI presenting ⬎12 to 24 hours after the symptom onset, the clinical benefit of reperfusion is controversial and largely unrelated to myocardial salvage.1,2 However, it has been suggested that viable myocardium can be found even after ischemia of ⬎12 hours,3,4 and preserved residual flow in the infarctrelated artery (IRA) is associated with reduced infarct size, better left ventricular function, and improved clinical outcomes compared to a totally occluded IRA.4,19 –21 Residual anterograde coronary flow and collateral circulation can ensure stunned or hibernated myocardium within the area at risk and the interval to salvage viable myocardium can extend to several days.5 The accepted definition of “early latecomers” refers to patients with STEMI presenting ⬎12 to 72 hours after the onset of symptoms.6 Recent studies evaluating the efficacy of PCI in early latecomers have shown conflicting results.7,9 –12 The Beyond 12 hours Reperfusion AlternatiVe

Evaluation (BRAVE-2) trial7 included 365 patients—57% with Thrombolysis in Myocardial Infarction 0-1 flow— without persistent symptoms, who presented 12 to 48 hours after the onset of STEMI. The main result was a significant infarct size reduction in patients treated with PCI compared to patients treated conservatively (8% vs 13%, p ⬍0.001). The Occluded Artery Trial (OAT)8 randomized 2,166 stable late presenters (⬎24 hours from symptom onset) undergoing coronary angiography 3 to 28 days after acute MI to PCI (n ⫽ 1,082) or conservative medical therapy (n ⫽ 1,084). Routine PCI for a totally occluded IRA failed to reduce the incidence of major cardiovascular events during 4 years of follow-up. The lack of clinical benefit of PCI remained consistent in the OAT substudy of 331 patients enrolled 24 to 72 hours after the onset of acute MI.9 The discrepancy between these 2 randomized trials might be related to the differences in the patients enrolled.6 Of the patients in the invasive arm of the BRAVE-2 trial,7 43% had a patent IRA and patients with severe inducible ischemia were not excluded. In contrast, all the patients in the OAT had a totally occluded IRA and patients with severe inducible ischemia were excluded. This finding might suggest a role for the patency of the IRA in the salvage of myocardium at risk in early latecomers undergoing PCI. Busk et al10 investigated the relationship of IRA patency to myocardial salvage and left ventricular remodeling after primary PCI in 396 patients with STEMI: 341 patients presenting ⬍12 hours and 55

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presenting 12 to 72 hours from symptom onset. Latecomers (12 to 72 hours after symptom onset) with a totally occluded IRA had a larger infarct size, lower salvage index (percentage of noninfarcted area at risk), and a lower left ventricular ejection fraction compared with the early presenters. Late presenters with a patent IRA had a larger infarct size but the salvage index and left ventricular ejection fraction did not differ compared to the early presenters, indicating a larger amount of ischemic myocardium can be salvaged even in late presenters if the IRA is patent. These findings might support the importance of IRA patency in planning the optimal timing to perform PCI in late presenters. Although no period has been established for reperfusion in late presenters with STEMI, the findings from these 3 trials might indicate that PCI within 48 to 72 hours after symptom onset is reasonable for an occluded IRA and that reperfusion of a patent IRA could be beneficial even later.10 It should be noted, however, that the lack of clinical benefit of PCI in any of these trials should be interpreted in light of the study designs selected. The BRAVE-2 trial7 and the study by Busk et al10 were not designed to assess differences in clinical end points. In the OAT, PCI 3 to 28 days (median 8) after acute MI seems too late for a beneficial clinical effect, given that all enrollees had a totally occluded IRA without severe inducible ischemia. In addition, the OAT substudy of early latecomers (n ⫽ 331) was underpowered to detect a benefit for PCI strategy. In contrast, in the recent meta-analysis of late PCI for acute MI (⬎12 hours after symptom onset, median symptom duration 12 days, 74% totally occluded IRA), PCI improved cardiac function and survival.11 The benefits of PCI in terms of mortality reduction were greater when patients with a patent IRA were also included. Similarly, in the present study (12 to 72 hours after symptom onset, median symptom duration 22 hours; 47% with a totally occluded IRA), late PCI improved 12month clinical outcome, and the benefit was consistent regardless of IRA patency. Taken together, these findings support the value of timely PCI in stable early latecomers with STEMI, particularly those with a totally occluded IRA, although additional studies are warranted to evaluate the efficacy and optimal timing of PCI in this patient population. The present study had limitations. Although these results came from a large cohort and adjustment was performed using propensity score analysis for a large number of confounding variables, a registry study cannot replace a randomized controlled trial, and unmeasurable factors could still exist. In addition, some important measures of patient outcome were not collected or available for the present analysis. These included the status of collateral circulation and myocardial viability, amount and fluctuation of STsegment elevation and chest pain, and the use of newer therapeutic modalities such as thrombus aspiration devices. Acknowledgment: Korea Acute Myocardial Infarction (KAMIR) Investigators: Myung Ho Jeong, MD, Young Keun Ahn, MD, Shung Chull Chae, MD, Jong Hyun Kim, MD, Seung Ho Hur, MD, Young Jo Kim, MD, In Whan Seong, MD, Dong Hoon Choi, MD, Jei Keon Chae, MD, Taek Jong Hong, MD, Jae Young Rhew, MD, Doo Il Kim,

MD, In Ho Chae, MD, Jung Han Yoon, MD, Bon Kwon Koo, MD, Byung OK Kim, MD, Myoung Yong Lee, MD, KeeSik Kim, MD, Jin Yong Hwang, MD, Myeong Chan Cho, MD, Seok Kyu Oh, MD, Nae Hee Lee, MD, Kyoung Tae Jeong, MD, Seung Jea Tahk, MD, Jang Ho Bae, MD, Seung-Woon Rha, MD, Keum Soo Park, MD, Chong Jin Kim, MD, Kyoo Rok Han, MD, Tae Hoon Ahn, MD, Moo Hyun Kim, MD, Ki Bae Seung, MD, Wook Sung Chung, MD, Ju Young Yang, MD, Chong Yun Rhim, MD, Hyeon Cheol Gwon, MD, Seong Wook Park, MD, Young Youp Koh, MD, Seung Jae Joo, MD, Soo Joong Kim, MD, Dong Kyu Jin, MD, Jin Man Cho, MD, Yang Soo Jang, MD, Jeong Gwan Cho, MD, and Seung Jung Park, MD. 1. Kushner FG, Hand M, Smith SC Jr, King SB III, Anderson JL, Antman EM, Bailey SR, Bates ER, Blankenship JC, Casey DE Jr, Green LA, Hochman JS, Jacobs AK, Krumholz HM, Morrison DA, Ornato JP, Pearle DL, Peterson ED, Sloan MA, Whitlow PL, Williams DO. 2009 Focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on 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;54:2205–2241. 2. Van de Werf F, Bax J, Betriu A, Blomstrom-Lundqvist C, Crea F, Falk V, Filippatos G, Fox K, Huber K, Kastrati A, Rosengren A, Steg PG, Tubaro M, Verheugt F, Weidinger F, Weis M; ESC Committee for Practice Guidelines (CPG). Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2008;29:2909 –2945. 3. Milavetz JJ, Giebel DW, Christian TF, Schwartz RS, Holmes DR Jr, Gibbons RJ. Time to therapy and salvage in myocardial infarction. J Am Coll Cardiol 1998;31:1246 –1251. 4. Sabia PJ, Powers ER, Ragosta M, Sarembock IJ, Burwell LR, Kaul S. An association between collateral blood flow and myocardial viability in patients with recent myocardial infarction. N Engl J Med 1992;327: 1825–1831. 5. Sawyer DB, Loscalzo J. Myocardial hibernation: restorative or preterminal sleep? Circulation 2002;105:1517–1519. 6. Fontanelli A, Bonanno C. Primary percutaneous coronary intervention in “early” latecomers with ST-segment elevation acute myocardial infarction: the role of the infarct-related artery status. J Cardiovasc Med (Hagerstown) 2011;12:13–18. 7. Schömig A, Mehilli J, Antoniucci D, Ndrepepa G, Markwardt C, Di Pede F, Nekolla SG, Schlotterbeck K, Schühlen H, Pache J, Seyfarth M, Martinoff S, Benzer W, Schmitt C, Dirschinger J, Schwaiger M, Kastrati A; Beyond 12 hours Reperfusion AlternatiVe Evaluation (BRAVE-2) Trial Investigators. Mechanical reperfusion in patients with acute myocardial infarction presenting more than 12 hours from symptom onset: a randomized controlled trial. JAMA 2005;293:2865– 2872. 8. Hochman JS, Lamas GA, Buller CE, Dzavik V, Reynolds HR, Abramsky SJ, Forman S, Ruzyllo W, Maggioni AP, White H, Sadowski Z, Carvalho AC, Rankin JM, Renkin JP, Steg PG, Mascette AM, Sopko G, Pfisterer ME, Leor J, Fridrich V, Mark DB, Knatterud GL; Occluded Artery Trial Investigators. Coronary intervention for persistent occlusion after myocardial infarction. N Engl J Med 2006;355:2395– 2407. 9. Menon V, Pearte CA, Buller CE, Steg PG, Forman SA, White HD, Marino PN, Katritsis DG, Caramori P, Lasevitch R, Loboz-Grudzien K, Zurakowski A, Lamas GA, Hochman JS. Lack of benefit from percutaneous intervention of persistently occluded infarct arteries after the acute phase of myocardial infarction is time independent: insights from occluded artery trial. Eur Heart J 2009;30:183–191. 10. Busk M, Kaltoft A, Nielsen SS, Bøttcher M, Rehling M, Thuesen L, Bøtker HE, Lassen JF, Christiansen EH, Krusell LR, Andersen HR, Nielsen TT, Kristensen SD. Infarct size and myocardial salvage after

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