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Comparison of Five-Year Outcomes of Patients With and Without Chronic Total Occlusion of Noninfarct Coronary Artery After Primary Coronary Intervention for ST-Segment Elevation Acute Myocardial Infarction
Comparison of Five-Year Outcomes of Patients With and Without Chronic Total Occlusion of Noninfarct Coronary Artery After Primary Coronary Intervention for ST-Segment Elevation Acute Myocardial Infarction Mateusz Tajstra, MDa,*, Mariusz Gasior, MD, PhDa, Marek Gierlotka, MDa, Damian Pres, MDa, Michał Hawranek, MDa, Przemysław Trzeciak, MDa, Andrzej Lekston, MD, PhDa, Lech Polonski, MD, PhDa, and Marian Zembala, MD, PhDb The aim of the present study was to evaluate the effect of concurrent chronic total occlusion (CTO) in a noninfarct-related artery (IRA) on the long-term prognosis in patients with ST-segment elevation myocardial infarction and multivessel coronary disease. Of 1,658 consecutive patients with ST-segment elevation myocardial infarction, 666 with multivessel coronary disease who underwent percutaneous coronary intervention from 1999 to 2004 were included in the present analysis. The patients were divided into 2 groups: no CTO and CTO. The first group included 462 patients without CTO (69%) and the second group included 204 patients with CTO in a non-IRA (31%). The in-hospital mortality rate was 6.3% and 21.1% (p < 0.0001) and the 5-year mortality rate was 22.5% and 40.2% (p < 0.0001) for the no-CTO and CTO patients, respectively. Multivariate analysis revealed that after correction for baseline differences CTO in a non-IRA was a strong, independent predictor of 5-year mortality in patients undergoing percutaneous coronary intervention (hazard ratio 1.85; 95% confidence interval 1.35 to 2.53; p ⴝ 0.0001). In conclusion, the presence of CTO in a non-IRA in patients with ST-segment elevation myocardial infarction and multivessel coronary disease is a strong and independent risk factor for greater 5-year mortality. © 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;109:208 –213) The objective of the present investigation, given that the available data are limited, was to evaluate the effect of chronic total occlusion (CTO) in a noninfarct-related artery (IRA) on the clinical outcomes. We studied the in-hospital and long-term follow-up outcomes of patients with STsegment elevation myocardial infarction (STEMI) and multivessel coronary disease (MVD) who underwent percutaneous coronary intervention (PCI) limited to the IRA. Using the findings from a large interventional cardiology center, we hoped to identify the differences in patient characteristics and clinical course of patients with and without CTO. Also, an analysis of the factors that affect the long-term prognosis was conducted, and an additional multifactorial analysis was undertaken in patients with MVD and CTO. Methods From January 1999 to December 2004, 1,658 consecutive patients with STEMI underwent PCI at our center. In this cohort of patients, we conducted a single-center analysis of 666 patients with MVD. Of the 666 patients with
a
Third Department of Cardiology and bDepartment of Cardiac Surgery and Transplantology, Silesian Centre for Heart Diseases, Medical University of Silesia, Zabrze, Poland. Manuscript received June 25, 2011; revised manuscript received and accepted August 30, 2011. *Corresponding author: Tel: (⫹48) 32-373-3674; fax: (⫹48) 32-2732679. E-mail address: [email protected] (M. Tajstra). 0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.08.026
MVD, we found MVD without CTO in non-IRA segments in 462 (69%; no-CTO group) and MVD with CTO in 204 (31%; CTO group). MVD was defined as ⬎70% diameter stenosis of ⱖ1 major epicardial coronary artery or its major branch, remote from the IRA, as determined by visual assessment. CTO was defined as a non-IRA with 100% luminal narrowing before PCI without anterograde flow or with anterograde or retrograde filling through collateral vessels. The differentiation between CTO and acute occlusion was determined by the compilation among the morphology of the occlusion (presence of fresh thrombus, bridge, or ipsior contralateral collaterals), electrocardiographic recording, and a possible history of previously documented acute coronary events in the same territory. The patients with STEMI after coronary artery bypass grafting were excluded from the present analysis. The patients with cardiogenic shock on admission— defined clinically as symptoms of shock or peripheral hypoperfusion and hemodynamically as systemic systolic pressure ⬍90 mm Hg or systemic systolic pressure 90 to 110 mm Hg during intra-aortic balloon pumping or while using inotropic drugs—were included in the present analysis. The clinical data from all patients with STEMI were prospectively recorded in a computerized database as a part of a single-center acute coronary syndromes registry. Follow-up information was obtained by direct telephone interviews and outpatient visits and from the National Health Fund database. At our center, an interventional cardiologist is on duty 24 hr/day. All patients with acute STEMI were treated with 300 www.ajconline.org
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Table 1 Patient characteristics Variable
Age (years) Men Duration of pain (hours) Thrombolysis before percutaneous coronary intervention Anterior wall myocardial infarction Arterial hypertension* Diabetes mellitus Hyperlipidemia† Current smoker Previous myocardial infarction Cardiogenic shock on admission Infarct-related artery Left anterior descending artery Right coronary artery Left circumflex artery Baseline Thrombolysis In Myocardial Infarction flow grade 0–1 Stent implantation Glycoprotein IIb/IIIa blocker Final Thrombolysis In Myocardial Infarction flow grade 0–2 Angiographic success 5-Year mortality
No. of Narrowed Coronary Arteries 1 (n ⫽ 992; 60%)
⬎1 (n ⫽ 666; 40%)
56 ⫾ 10 738 (74%) 4.8 ⫾ 4 234 (24%) 422 (43%) 478 (48%) 158 (16%) 579 (59%) 664 (62%) 120 (12%) 59 (6%)
61 ⫾ 11 479 (72%) 5.6 ⫾ 5 120 (18%) 256 (38%) 396 (60%) 163 (25%) 399 (60%) 368 (56%) 202 (30%) 97 (15%)
438 (44%) 394 (40%) 153 (15%) 692 (70%) 751 (76%) 43 (4%) 96 (10%) 892 (90%) 134 (13%)
250 (38%) 292 (44%) 111 (17%) 585 (88%) 461 (69%) 32 (5%) 109 (16%) 556 (84%) 186 (28%)
p Value
⬍0.0001 NS 0.001 0.006 NS ⬍0.0001 ⬍0.001 NS 0.001 ⬍0.0001 ⬍0.0001 NS
⬍0.0001 0.003 NS ⬍0.001 ⬍0.001 ⬍0.0001
Data are presented as mean ⫾ SD or n (%). NS ⫽ not significant. * Defined as history of hypertension diagnosed and treated with medication, diet, and/or exercise, blood pressure ⬎140 mm Hg systolic or ⬎90 mm Hg diastolic on ⱖ2 occasions, or currently taking antihypertensive pharmacologic therapy. † Hyperlipidemia defined as history of hyperlipidemia diagnosed and/or treated by physician, documentation of total cholesterol ⬎200 mg/dl, low-density lipoprotein ⱖ130 mg/dl, high-density lipoprotein ⬍30 mg/dl, admission cholesterol ⬎200 mg/dl, or triglycerides ⬎150 mg/dl. Table 2 Baseline clinical and angiographic characteristics Variable
Age (years) Men Duration of pain (hours) Thrombolysis before percutaneous coronary intervention Anterior wall myocardial infarction Arterial hypertension Diabetes mellitus Hyperlipidemia Current smoker Previous myocardial infarction Cardiogenic shock on admission Infarct-related artery Left anterior descending artery Right coronary artery Left circumflex artery Baseline Thrombolysis In Myocardial Infarction flow grade 0–1 Stent implantation Glycoprotein IIb/IIIa blocker Final Thrombolysis in Myocardial Infarction flow grade 0–2 Angiographic success Data are presented as mean ⫾ SD or n (%). Abbreviation as in Table 1.
CTO
p Value
No (n ⫽ 462; 69%)
Yes (n ⫽ 204; 31%)
61 ⫾ 11 325 (70%) 5.5 ⫾ 3 92 (20%) 171 (37%) 279 (61%) 108 (23%) 271 (59%) 252 (55%) 112 (24%) 52 (11%)
61 ⫾ 10 154 (75%) 5.7 ⫾ 4 28 (14%) 85 (42%) 117 (58%) 55 (27%) 128 (64%) 116 (59%) 89 (44%) 45 (22%)
169 (37%) 212 (45%) 81 (17%) 393 (85%) 324 (70%) 20 (4%) 65 (14%) 396 (86%)
81 (40%) 80 (40%) 43 (20%) 192 (94%) 137 (67%) 10 (5%) 44 (22%) 160 (78%)
NS NS NS 0.06 NS NS 0.04 NS NS ⬍0.0001 0.0027 NS
0.0001 NS NS 0.016 0.016
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Table 3 In-hospital outcomes Variable
CTO
Maximum creatinine kinase (IU) Left ventricular ejection fraction (%) Glomerular filtration rate (Modification of Diet in Renal Disease) Re-occlusion angiographically confirmed (urgent percutaneous coronary intervention required) Gastrointestinal bleeding Coronary artery bypass grafting during hospitalization Coronary artery bypass grafting arranged after discharge Elective percutaneous coronary intervention in non–infarctrelated artery vessel during hospitalization Hospital stay (days)
p Value
No (n ⫽ 462; 69%)
Yes (n ⫽ 204; 31%)
2,190 ⫾ 2,077 44 ⫾ 8 76 ⫾ 8 32 (7%)
2,195.5 ⫾ 2,350 39 ⫾ 9 72 ⫾ 9 24 (12%)
NS ⬍0.0001 NS 0.038
4 (1%) 13 (3%) 46 (10%) 98 (21%)
9 (4%) 8 (4%) 14 (7%) 13 (6%)
0.02 NS NS ⬍0.0001
9⫾5
8⫾5
NS
Data are presented as mean ⫾ SD or n (%). Abbreviation as in Table 1. Table 4 In-hospital, 12-month, and 5-year mortality Mortality
In-hospital At 12 months At 5 years
CTO
p Value
No (n ⫽ 462; 69%)
Yes (n ⫽ 204; 31%)
29 (6.3%) 51 (11%) 104 (22%)
43 (21%) 51 (25%) 82 (40%)
Table 5 Predictors of 5-year mortality for entire population (Cox proportional hazards model results) Variable
⬍0.0001 ⬍0.0001 ⬍0.0001
Data are presented as n (%).
to 500 mg aspirin, 300 mg clopidogrel (since 2001), with 75 mg/day thereafter or ticlopidine 250 mg twice daily for ⱖ8 weeks, 5,000 to 10.000 U unfractionated heparin, and 2.5 to 5 mg of morphine intravenously. Acute STEMI was defined as stenocardial pain lasting ⱖ30 minutes, with electrocardiographic features of an evolving myocardial infarction (i.e., ST-segment elevation ⱖ0.1 mV in ⱖ2 limb leads or ⱖ0.2 mV in ⱖ2 precardial leads or new-onset left bundle branch block, with the interval since onset not ⬎12 hours or, in the case of cardiogenic shock, 18 to 24 hours). Depending on the patient’s condition, other medications were also used. The patients were then referred for urgent coronary angiography. Standard guidewires, balloon catheters, and coronary stents were used in these procedures. In some patients with myocardial infarction complicated by cardiogenic shock, depending on their clinical status, intra-aortic balloon pumping was performed. Vascular sheaths were removed at normalization of the blood coagulation parameters (i.e., activated partial thromboplastin time). After intervention, in addition to thienopiridynes, all patients received 150 mg/day of aspirin indefinitely. They also received  blockers, angiotensin-converting enzyme inhibitors, and statins, if these agents were not otherwise contraindicated. The 12-month and 5-year mortality were assessed. The angiographic success of IRA angioplasty was defined as Thrombolysis In Myocardial Infarction grade 3 flow and ⬍30% residual stenosis. Continuous parameters with a normal distribution are presented as the mean ⫾ SD. The significance of differences between the mean values was tested using Student’s t test. Qualitative parameters were analyzed using a chi-square
Shock on admission Age (per 1-year increase) Chronic total occlusion Left ventricle ejection fraction (per 1% increase) Final Thrombolysis In Myocardial Infarction flow grade 3 Initial Thrombolysis In Myocardial Infarction flow grade 1–2 Diabetes Men Anterior myocardial infarction Stent implantation Arterial hypertension Smoker Hypercholesterolemia Previous myocardial infarction
HR
95% CI
p Value
3.53 1.055 1.85 0.97
2.57–4.83 1.054–1.056 1.35–2.53 0.95–0.98
⬍0.0001 ⬍0.0001 0.0001 0.0002
0.6
0.43–0.84
0.003
1.55
1.07–2.23
0.017
1.43 0.71 1.29 0.6 1.22 1.09 0.92 1.08
1.06–1.93 0.52–0.98 0.97–1.71 0.43–0.84 0.9–1.63 0.82–1.45 0.7–1.2 0.8–1.44
0.017 0.04 0.07 0.1 0.17 0.54 0.55 0.6
CI ⫽ confidence interval; HR ⫽ hazard ratio.
test (when the numbers were anticipated to be ⬍5, Yates’ correction for continuity was implemented). Mortality curves ⱕ5 years after STEMI were constructed using the Kaplan-Meier method and were compared using the log– rank test. To assess the effect of particular parameters on mortality, multivariate analysis was performed using stepdown Cox proportional hazards regression modeling and expressed as the hazard ratio, with the 95% confidence interval. All clinical and angiographic variables were used in the risk-adjusted models. The level of statistical significance was p ⬍ 0.05 (2-tailed). The calculations and statistical analyses were performed using Statistica, version 7.0 (StatSoft, Tulsa, Oklahoma). Results The characteristics of the 1658 patients with STEMI, with and without MVD, who underwent PCI in the analyzed
Coronary Artery Disease/Chronic Total Occlusion in Myocardial Infarction Table 6 Predictors of 5-year mortality in chronic total occlusion (CTO) group (Cox proportional hazards model results) Variable
HR
95% CI
P Value
Shock on admission Age (per 1-year increase) Left ventricle ejection fraction (per 1% increase) Men Smoker Hypercholesterolemia Diabetes Anterior myocardial infarction Initial Thrombolysis In Myocardial Infarction flow grade 1–2 Arterial hypertension Final Thrombolysis In Myocardial Infarction flow grade 3 Previous myocardial infarction
6.8 1.05
3.9–11.9 1.025–1.078
⬍0.0001 ⬍0.0001
0.96
0.94–0.99
0.02
0.57 0.66 1.5 1.41 0.72
0.32–1.03 0.41–1.09 0.9–2.5 0.83–1.42 0.42–1.22
0.06 0.1 0.12 0.2 0.23
2.24
0.5–9.4
0.27
0.83 0.84
0.5–1.4 0.43–1.53
0.5 0.6
0.9
0.54–1.5
0.7
Abbreviations as in Table 5.
period are listed in Table 1. The baseline clinical and angiographic characteristics of the study groups are listed in Table 2. Patients with CTO had a greater prevalence of diabetes, previous myocardial infarction, and cardiogenic shock on admission than did the patients without CTO. The in-hospital parameters differed significantly between the 2 groups. The patients with CTO had a lower left ventricular ejection fraction and more frequently had angiographically confirmed reocclusion and gastrointestinal bleeding and underwent elective PCI in non-IRA vessels. Detailed data concerning the in-hospital period are listed in Table 3. The in-hospital, 12-month, and 5-year mortality rates in the analyzed groups are listed in Table 4. Of the patients, 6.3% of the no-CTO and 21.1% of the CTO group (p ⬍ 0.0001) died during hospitalization. The significant difference in the mortality rate was maintained during the 5-year follow-up period, with 22.5% of the no-CTO group and 40.2% of the CTO group (p ⬍ 0.0001) dying within that period. In the multifactorial analysis of the entire study population, the presence of CTO was an independent and strong factor affecting the 5-year mortality risk (hazard ratio 1.29, 95% confidence interval 0.98 to 1.71; p ⫽ 0.0001; Table 5). Additional multifactorial analysis of the MVD with CTO subpopulation identified cardiogenic shock on admission, older age, and lower left ventricular ejection fraction as independent predictors of death during the 5-year follow-up period in this group of patients (Table 6).
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Discussion The aim of the present study was to compare the early and long-term treatment results of patients with MVD who underwent PCI for STEMI without and with CTO in nonIRAs and to evaluate the effect of CTO on the prognosis during long-term follow-up. The principal findings from our investigation were as follows. First, the presence of CTO in vessels remote from the IRA in patients with STEMI and MVD increased the early and long-term mortality. Second, after adjustment for differences in the baseline clinical characteristics, the presence of CTO remained a powerful independent predictor of greater mortality. Finally, in the CTO subpopulation, those patients who were in cardiogenic shock on admission, who were older, and who had a lower left ventricular ejection fraction had a worse long-term prognosis. The presence of MVD has been associated with poorer clinical outcomes.1–3 This population of patients with STEMI has more risk factors and more co-morbidities, a worse left ventricular ejection fraction, and a greater rate of ischemia before myocardial infarction. All of these factors could contribute to the poor prognosis.4 However, the direct, unambiguous mechanism by which MVD so seriously worsens the prognosis is unknown and has been widely discussed. CTO has been reported in approximately 30% of patients with STEMI and MVD— consistent with the data obtained in our investigation.5 This subpopulation of patients with STEMI is truly at risk after primary PCI. Investigators have reported that the greater mortality in this group is mainly determined by the presence of CTO in non-IRA segments. Additionally, CTO was associated with a reduction in the left ventricular ejection fraction during a 12-month period, although only 1 study reported on a follow-up period as long as in our investigation.5–7 Recently, Lexis et al8 have demonstrated that the presence of CTO in a non-IRA after STEMI is associated with worse reperfusion markers and larger enzymatic infarct size. The reason concurrent CTO affects the prognosis so adversely in patients with STEMI and MVD can be partly explained by the greater risk profile of those with CTO. These patients tend to have diabetes and previous myocardial infarction, lower left ventricular ejection fraction, lower baseline Thrombolysis In Myocardial Infarction flow grades, and cardiogenic shock on admission more often than patients without CTO. However, after adjustment for these differences in the baseline characteristics on multivariate Cox regression analysis, CTO remained an independent predictor of greater 5-year mortality. Another explanation of the underlying mechanism for the increased mortality in patients with STEMI with concurrent CTO could be that in patients with CTO, PCI was less successful. A final Thrombolysis In Myocardial Infarction flow grade ⬍3 is strongly associated with a worse prognosis.9 In our investigation, it was more frequently present in the CTO group. Nevertheless, an additional multifactorial analysis of MVD in the CTO subpopulation only identified cardiogenic shock on admission, older age, and lower left ventricular ejection fraction as independent pre-
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Figure 1. Five-year mortality rate of patients undergoing PCI for STEMI (p ⬍ 0.0001, log-rank for single-vessel disease [SVD] vs MVD without CTO, SVD vs MVD with CTO, and MVD without CTO vs MVD with CTO).
dictors of death at 5 years of follow-up in this group of patients (Table 6). Other factors that might contribute to the adverse outcomes in patients with CTO include the lack of a compensation mechanism for the decrease in the left ventricular ejection fraction in acute myocardial infarction. Patients with MVD and concomitant CTO have a lower residual left ventricular ejection fraction and less improvement in left ventricular systolic function, strongly influencing survival.5 Although enzymatic infarct size did not differ between the 2 groups in our investigation, with a lower residual left ventricular ejection fraction, it is likely that the patients with STEMI and CTO had left ventricular dysfunction before myocardial infarction because of the greater extent of their coronary artery disease. However, ⬎1/2 of the patients in the CTO group had not had a documented myocardial infarction. Goldstein et al10 have shown that the pathologic process in STEMI involves the entire coronary tree and can lead to the destabilization and rupture of multiple atherosclerotic plaques, resulting in a significantly increased risk of death and repeated ischemic events. The dynamics of this specific inflammatory process are greatest in the first month after acute myocardial infarction,11 possibly explaining the increase in mortality in the first 30 days observed in our investigation (Figure 1). Owing to the paucity of data regarding the optimal treatment of patients with STEMI and MVD, the need for, and timing of, subsequent revascularization of diseased nonIRA vessels remains controversial. Current practice guidelines in the acute setting recommend revascularization of diseased non-IRA vessels only in the presence of hemodynamic or electrical instability.12 A number of observational studies investigating multivessel PCI during the index event were hampered by selection bias and have reported inconclusive results.13–15 The lack of benefit observed in trials studying multivessel PCI for STEMI might have been because approximately 30% of the patients with STEMI and MVD had concurrent CTO. The presence of CTO in a
non-IRA was the main factor affecting greater early and long-term mortality in this group of patients. Another reason for the lack of benefit observed was the patients with CTO were excluded from previous studies reporting multivessel PCI. Accordingly, a complete analysis of each case with regard to total revascularization, especially in patients with CTO, is warranted. The evaluation of the effectiveness of such conduct requires additional prospective, randomized trials. It is likely that the ongoing Evaluating XIENCE V and left ventricular function in PCI on Occlusions after STEMI (EXPLORE) trial will show whether recanalization of CTO in patients with STEMI improves the outcomes in this high-risk subgroup of patients with STEMI.16 1. Lekston A, Tajstra M, Ga˛sior M, Gierlotka M, Pres D, Hudzik B, Trzeciak P, Kalarus Z, Polon´ski L, Zembala M. Impact of multivessel coronary disease on one-year clinical outcomes and five-year mortality in patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention. Kardiol Pol 2011;69:336 –343. 2. Sorajja S, Gersh BJ, Cox DA, McLaughlin MG, Zimetbaum P, Costatini C, Stuckey T, Tcheng JE, Mehran R, Lansky AJ, Grines CL, Stone GW. Impact of multivessel disease on reperfusion success and clinical outcomes in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction. Eur Heart J 2007;28:1709 –1716. 3. Tarantini G, Napodano M, Gasparetto N, Favaretto E, Marra MP, Cacciavillani L, Bilato C, Osto E, Cademartiri F, Musumeci G, Corbetti F, Razzolini R, Iliceto S. Impact of multivessel coronary artery disease on early ischemic injury, late clinical outcome, and remodeling in patients with acute myocardial infarction treated by primary coronary angioplasty. Coron Artery Dis 2010;21:78 – 86. 4. DeGeare VS, Stone GW, Grines L, Grines L, Brodie BR, Cox DA, Garcia E, Wharton TP, Boura JA, O’Neill WW, Grines CL. Angiographic and clinical characteristics associated with increased in-hospital mortality in elderly patients with acute myocardial infarction undergoing percutaneous intervention (a pooled analysis of the primary angioplasty in myocardial infarction trial). Am J Cardiol 2000; 86:30 –34. 5. Claessen BEPM, van der Schaaf RJ, Verouden NJ, Stegenga NK, Engstrom AE, Sjauw KD, Kikkert WJ, Vis MM, Baan J, Koch KT, de Winter RJ, Tijssen JG, Piek JJ, Henriques JP. Evaluation of the effect of a concurrent chronic total occlusion on long-term mortality and left ventricular function in patients after primary percutaneous coronary intervention. JACC Cardiovasc Interv 2009;2:1128 –1134.
Coronary Artery Disease/Chronic Total Occlusion in Myocardial Infarction 6. Moreno R, Conde C, Perez-Vizcayno MJ, Villarreal S, HernandezAntolin R, Alfonso F, Bañuelos C, Angiolillo DJ, Escaned J, Fernandez-Ortiz A, Macaya C. Prognostic impact of a chronic occlusion in a noninfarct vessel in patients with acute myocardial infarction and multivessel disease undergoing primary percutaneous coronary intervention. J Invasive Cardiol 2006;18:16 –19. 7. van der Schaaf RJ, Vis MM, Sjauw KD, Koch KT, Baan J Jr, Tijssen JG, de Winter RJ, Piek JJ, Henriques JP. Impact of multivessel coronary disease on long-term mortality in patients with ST-elevation myocardial infarction is due to the presence of a chronic total occlusion. Am J Cardiol 2006;98:1165–1169. 8. Lexis CP, van der Horst IC, Rahel BM, Lexis MA, Kampinga MA, Gu YL, de Smet BJ, Zijlstra F. Impact of chronic total occlusions on markers of reperfusion, infarct size, and long-term mortality: a substudy from the TAPAS trial. Catheter Cardiovasc Interv 2011;77: 484 – 491. 9. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993;329:1615–1622; erratum in N Engl J Med 1994; 330:516. 10. Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfeh M, O’Neil WW. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2000;343:915–922. 11. Guazzi MD, Bussotti M, Grancini L, De Cesare N, Guazzi M, Pera IL, Loaldi A. Evidence of multifocal activity of coronary disease in patients with acute myocardial infarction. Circulation 1997;96: 1145–1151. 12. Wijns W, Kolh P, Danchin N, Di Mario C, Falk V, Folliguet T, Garg S, Huber K, James S, Knuuti J, Lopez-Sendon J, Marco J, Menicanti L, Ostojic M, Piepoli MF, Pirlet C, Pomar JL, Reifart N, Ribichini FL, Schalij MJ, Sergeant P, Serruys PW, Silber S, Sousa Uva M, Taggart D, ESC Committee for Practice Guidelines, Vahanian A, Auricchio A, Bax J, Ceconi C, Deans V, Filippatos G, Funck-Brentano C, Hobbs R, Kearney P, McDonagh T, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas PE, Widimsky P, EACTS Clinical Guidelines
13.
14.
15.
16.
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Committee, Kolh P, Alfieri O, Dunning J, Elia S, Kappetein P, Lockowandt U, Sarris G, Vouhe P, Kearney P, von Segesser L, Agewall S, Aladashvili A, Alexopoulos D, Antunes MJ, Atalar E, Brutel de la Riviere A, Doganov A, Eha J, Fajadet J, Ferreira R, Garot J, Halcox J, Hasin Y, Janssens S, Kervinen K, Laufer G, Legrand V, Nashef SA, Neumann FJ, Niemela K, Nihoyannopoulos P, Noc M, Piek JJ, Pirk J, Rozenman Y, Sabate M, Starc R, Thielmann M, Wheatley DJ, Windecker S, Zembala M. Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS), European Association for Percutaneous Cardiovascular Interventions. Eur Heart J 2010;31: 2501–2555. Kalarus Z, Lenarczyk R, Kowalczyk J, Kowalski O, Ga˛sior M, Wa˛s T, Zebik T, Krupa H, Chodór P, Polon´ski L, Zembala M. Importance of complete revascularization in patients with acute myocardial infarction treated with percutaneous coronary intervention. Am Heart J 2007; 153:304 –312. Chen LY, Lennon RJ, Grantham JA, Berger PB, Mathew V, Singh M, Holmes DR Jr, Rihal CS. In-hospital and long-term outcomes of multivessel percutaneous coronary revascularization after acute myocardial infarction. Am J Cardiol 2005;95:349 –354. Corpus RA, House JA, Marso SP, Grantham JA, Huber KC Jr, Laster SB, Johnson WL, Daniels WC, Barth CW, Giorgi LV, Rutherford BD. Multivessel percutaneous coronary intervention in patients with multivessel disease and acute myocardial infarction. Am Heart J 2004; 148:493–500. van der Schaaf RJ, Claessen BE, Hoebers LP, Verouden NJ, Koolen JJ, Suttorp MJ, Barbato E, Bax M, Strauss BH, Olivecrona GK, Tuseth V, Glogar D, Råmunddal T, Tijssen JG, Piek JJ, Henriques JP; EXPLORE investigators. Rationale and design of EXPLORE: a randomized, prospective, multicenter trial investigating the impact of recanalization of a chronic total occlusion on left ventricular function in patients after primary percutaneous coronary intervention for acute ST-elevation myocardial infarction. Trials 2010;11:89.
a
Third Department of Cardiology and bDepartment of Cardiac Surgery and Transplantology, Silesian Centre for Heart Diseases, Medical University of Silesia, Zabrze, Poland. Manuscript received June 25, 2011; revised manuscript received and accepted August 30, 2011. *Corresponding author: Tel: (⫹48) 32-373-3674; fax: (⫹48) 32-2732679. E-mail address: [email protected] (M. Tajstra). 0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.08.026
MVD, we found MVD without CTO in non-IRA segments in 462 (69%; no-CTO group) and MVD with CTO in 204 (31%; CTO group). MVD was defined as ⬎70% diameter stenosis of ⱖ1 major epicardial coronary artery or its major branch, remote from the IRA, as determined by visual assessment. CTO was defined as a non-IRA with 100% luminal narrowing before PCI without anterograde flow or with anterograde or retrograde filling through collateral vessels. The differentiation between CTO and acute occlusion was determined by the compilation among the morphology of the occlusion (presence of fresh thrombus, bridge, or ipsior contralateral collaterals), electrocardiographic recording, and a possible history of previously documented acute coronary events in the same territory. The patients with STEMI after coronary artery bypass grafting were excluded from the present analysis. The patients with cardiogenic shock on admission— defined clinically as symptoms of shock or peripheral hypoperfusion and hemodynamically as systemic systolic pressure ⬍90 mm Hg or systemic systolic pressure 90 to 110 mm Hg during intra-aortic balloon pumping or while using inotropic drugs—were included in the present analysis. The clinical data from all patients with STEMI were prospectively recorded in a computerized database as a part of a single-center acute coronary syndromes registry. Follow-up information was obtained by direct telephone interviews and outpatient visits and from the National Health Fund database. At our center, an interventional cardiologist is on duty 24 hr/day. All patients with acute STEMI were treated with 300 www.ajconline.org
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Table 1 Patient characteristics Variable
Age (years) Men Duration of pain (hours) Thrombolysis before percutaneous coronary intervention Anterior wall myocardial infarction Arterial hypertension* Diabetes mellitus Hyperlipidemia† Current smoker Previous myocardial infarction Cardiogenic shock on admission Infarct-related artery Left anterior descending artery Right coronary artery Left circumflex artery Baseline Thrombolysis In Myocardial Infarction flow grade 0–1 Stent implantation Glycoprotein IIb/IIIa blocker Final Thrombolysis In Myocardial Infarction flow grade 0–2 Angiographic success 5-Year mortality
No. of Narrowed Coronary Arteries 1 (n ⫽ 992; 60%)
⬎1 (n ⫽ 666; 40%)
56 ⫾ 10 738 (74%) 4.8 ⫾ 4 234 (24%) 422 (43%) 478 (48%) 158 (16%) 579 (59%) 664 (62%) 120 (12%) 59 (6%)
61 ⫾ 11 479 (72%) 5.6 ⫾ 5 120 (18%) 256 (38%) 396 (60%) 163 (25%) 399 (60%) 368 (56%) 202 (30%) 97 (15%)
438 (44%) 394 (40%) 153 (15%) 692 (70%) 751 (76%) 43 (4%) 96 (10%) 892 (90%) 134 (13%)
250 (38%) 292 (44%) 111 (17%) 585 (88%) 461 (69%) 32 (5%) 109 (16%) 556 (84%) 186 (28%)
p Value
⬍0.0001 NS 0.001 0.006 NS ⬍0.0001 ⬍0.001 NS 0.001 ⬍0.0001 ⬍0.0001 NS
⬍0.0001 0.003 NS ⬍0.001 ⬍0.001 ⬍0.0001
Data are presented as mean ⫾ SD or n (%). NS ⫽ not significant. * Defined as history of hypertension diagnosed and treated with medication, diet, and/or exercise, blood pressure ⬎140 mm Hg systolic or ⬎90 mm Hg diastolic on ⱖ2 occasions, or currently taking antihypertensive pharmacologic therapy. † Hyperlipidemia defined as history of hyperlipidemia diagnosed and/or treated by physician, documentation of total cholesterol ⬎200 mg/dl, low-density lipoprotein ⱖ130 mg/dl, high-density lipoprotein ⬍30 mg/dl, admission cholesterol ⬎200 mg/dl, or triglycerides ⬎150 mg/dl. Table 2 Baseline clinical and angiographic characteristics Variable
Age (years) Men Duration of pain (hours) Thrombolysis before percutaneous coronary intervention Anterior wall myocardial infarction Arterial hypertension Diabetes mellitus Hyperlipidemia Current smoker Previous myocardial infarction Cardiogenic shock on admission Infarct-related artery Left anterior descending artery Right coronary artery Left circumflex artery Baseline Thrombolysis In Myocardial Infarction flow grade 0–1 Stent implantation Glycoprotein IIb/IIIa blocker Final Thrombolysis in Myocardial Infarction flow grade 0–2 Angiographic success Data are presented as mean ⫾ SD or n (%). Abbreviation as in Table 1.
CTO
p Value
No (n ⫽ 462; 69%)
Yes (n ⫽ 204; 31%)
61 ⫾ 11 325 (70%) 5.5 ⫾ 3 92 (20%) 171 (37%) 279 (61%) 108 (23%) 271 (59%) 252 (55%) 112 (24%) 52 (11%)
61 ⫾ 10 154 (75%) 5.7 ⫾ 4 28 (14%) 85 (42%) 117 (58%) 55 (27%) 128 (64%) 116 (59%) 89 (44%) 45 (22%)
169 (37%) 212 (45%) 81 (17%) 393 (85%) 324 (70%) 20 (4%) 65 (14%) 396 (86%)
81 (40%) 80 (40%) 43 (20%) 192 (94%) 137 (67%) 10 (5%) 44 (22%) 160 (78%)
NS NS NS 0.06 NS NS 0.04 NS NS ⬍0.0001 0.0027 NS
0.0001 NS NS 0.016 0.016
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Table 3 In-hospital outcomes Variable
CTO
Maximum creatinine kinase (IU) Left ventricular ejection fraction (%) Glomerular filtration rate (Modification of Diet in Renal Disease) Re-occlusion angiographically confirmed (urgent percutaneous coronary intervention required) Gastrointestinal bleeding Coronary artery bypass grafting during hospitalization Coronary artery bypass grafting arranged after discharge Elective percutaneous coronary intervention in non–infarctrelated artery vessel during hospitalization Hospital stay (days)
p Value
No (n ⫽ 462; 69%)
Yes (n ⫽ 204; 31%)
2,190 ⫾ 2,077 44 ⫾ 8 76 ⫾ 8 32 (7%)
2,195.5 ⫾ 2,350 39 ⫾ 9 72 ⫾ 9 24 (12%)
NS ⬍0.0001 NS 0.038
4 (1%) 13 (3%) 46 (10%) 98 (21%)
9 (4%) 8 (4%) 14 (7%) 13 (6%)
0.02 NS NS ⬍0.0001
9⫾5
8⫾5
NS
Data are presented as mean ⫾ SD or n (%). Abbreviation as in Table 1. Table 4 In-hospital, 12-month, and 5-year mortality Mortality
In-hospital At 12 months At 5 years
CTO
p Value
No (n ⫽ 462; 69%)
Yes (n ⫽ 204; 31%)
29 (6.3%) 51 (11%) 104 (22%)
43 (21%) 51 (25%) 82 (40%)
Table 5 Predictors of 5-year mortality for entire population (Cox proportional hazards model results) Variable
⬍0.0001 ⬍0.0001 ⬍0.0001
Data are presented as n (%).
to 500 mg aspirin, 300 mg clopidogrel (since 2001), with 75 mg/day thereafter or ticlopidine 250 mg twice daily for ⱖ8 weeks, 5,000 to 10.000 U unfractionated heparin, and 2.5 to 5 mg of morphine intravenously. Acute STEMI was defined as stenocardial pain lasting ⱖ30 minutes, with electrocardiographic features of an evolving myocardial infarction (i.e., ST-segment elevation ⱖ0.1 mV in ⱖ2 limb leads or ⱖ0.2 mV in ⱖ2 precardial leads or new-onset left bundle branch block, with the interval since onset not ⬎12 hours or, in the case of cardiogenic shock, 18 to 24 hours). Depending on the patient’s condition, other medications were also used. The patients were then referred for urgent coronary angiography. Standard guidewires, balloon catheters, and coronary stents were used in these procedures. In some patients with myocardial infarction complicated by cardiogenic shock, depending on their clinical status, intra-aortic balloon pumping was performed. Vascular sheaths were removed at normalization of the blood coagulation parameters (i.e., activated partial thromboplastin time). After intervention, in addition to thienopiridynes, all patients received 150 mg/day of aspirin indefinitely. They also received  blockers, angiotensin-converting enzyme inhibitors, and statins, if these agents were not otherwise contraindicated. The 12-month and 5-year mortality were assessed. The angiographic success of IRA angioplasty was defined as Thrombolysis In Myocardial Infarction grade 3 flow and ⬍30% residual stenosis. Continuous parameters with a normal distribution are presented as the mean ⫾ SD. The significance of differences between the mean values was tested using Student’s t test. Qualitative parameters were analyzed using a chi-square
Shock on admission Age (per 1-year increase) Chronic total occlusion Left ventricle ejection fraction (per 1% increase) Final Thrombolysis In Myocardial Infarction flow grade 3 Initial Thrombolysis In Myocardial Infarction flow grade 1–2 Diabetes Men Anterior myocardial infarction Stent implantation Arterial hypertension Smoker Hypercholesterolemia Previous myocardial infarction
HR
95% CI
p Value
3.53 1.055 1.85 0.97
2.57–4.83 1.054–1.056 1.35–2.53 0.95–0.98
⬍0.0001 ⬍0.0001 0.0001 0.0002
0.6
0.43–0.84
0.003
1.55
1.07–2.23
0.017
1.43 0.71 1.29 0.6 1.22 1.09 0.92 1.08
1.06–1.93 0.52–0.98 0.97–1.71 0.43–0.84 0.9–1.63 0.82–1.45 0.7–1.2 0.8–1.44
0.017 0.04 0.07 0.1 0.17 0.54 0.55 0.6
CI ⫽ confidence interval; HR ⫽ hazard ratio.
test (when the numbers were anticipated to be ⬍5, Yates’ correction for continuity was implemented). Mortality curves ⱕ5 years after STEMI were constructed using the Kaplan-Meier method and were compared using the log– rank test. To assess the effect of particular parameters on mortality, multivariate analysis was performed using stepdown Cox proportional hazards regression modeling and expressed as the hazard ratio, with the 95% confidence interval. All clinical and angiographic variables were used in the risk-adjusted models. The level of statistical significance was p ⬍ 0.05 (2-tailed). The calculations and statistical analyses were performed using Statistica, version 7.0 (StatSoft, Tulsa, Oklahoma). Results The characteristics of the 1658 patients with STEMI, with and without MVD, who underwent PCI in the analyzed
Coronary Artery Disease/Chronic Total Occlusion in Myocardial Infarction Table 6 Predictors of 5-year mortality in chronic total occlusion (CTO) group (Cox proportional hazards model results) Variable
HR
95% CI
P Value
Shock on admission Age (per 1-year increase) Left ventricle ejection fraction (per 1% increase) Men Smoker Hypercholesterolemia Diabetes Anterior myocardial infarction Initial Thrombolysis In Myocardial Infarction flow grade 1–2 Arterial hypertension Final Thrombolysis In Myocardial Infarction flow grade 3 Previous myocardial infarction
6.8 1.05
3.9–11.9 1.025–1.078
⬍0.0001 ⬍0.0001
0.96
0.94–0.99
0.02
0.57 0.66 1.5 1.41 0.72
0.32–1.03 0.41–1.09 0.9–2.5 0.83–1.42 0.42–1.22
0.06 0.1 0.12 0.2 0.23
2.24
0.5–9.4
0.27
0.83 0.84
0.5–1.4 0.43–1.53
0.5 0.6
0.9
0.54–1.5
0.7
Abbreviations as in Table 5.
period are listed in Table 1. The baseline clinical and angiographic characteristics of the study groups are listed in Table 2. Patients with CTO had a greater prevalence of diabetes, previous myocardial infarction, and cardiogenic shock on admission than did the patients without CTO. The in-hospital parameters differed significantly between the 2 groups. The patients with CTO had a lower left ventricular ejection fraction and more frequently had angiographically confirmed reocclusion and gastrointestinal bleeding and underwent elective PCI in non-IRA vessels. Detailed data concerning the in-hospital period are listed in Table 3. The in-hospital, 12-month, and 5-year mortality rates in the analyzed groups are listed in Table 4. Of the patients, 6.3% of the no-CTO and 21.1% of the CTO group (p ⬍ 0.0001) died during hospitalization. The significant difference in the mortality rate was maintained during the 5-year follow-up period, with 22.5% of the no-CTO group and 40.2% of the CTO group (p ⬍ 0.0001) dying within that period. In the multifactorial analysis of the entire study population, the presence of CTO was an independent and strong factor affecting the 5-year mortality risk (hazard ratio 1.29, 95% confidence interval 0.98 to 1.71; p ⫽ 0.0001; Table 5). Additional multifactorial analysis of the MVD with CTO subpopulation identified cardiogenic shock on admission, older age, and lower left ventricular ejection fraction as independent predictors of death during the 5-year follow-up period in this group of patients (Table 6).
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Discussion The aim of the present study was to compare the early and long-term treatment results of patients with MVD who underwent PCI for STEMI without and with CTO in nonIRAs and to evaluate the effect of CTO on the prognosis during long-term follow-up. The principal findings from our investigation were as follows. First, the presence of CTO in vessels remote from the IRA in patients with STEMI and MVD increased the early and long-term mortality. Second, after adjustment for differences in the baseline clinical characteristics, the presence of CTO remained a powerful independent predictor of greater mortality. Finally, in the CTO subpopulation, those patients who were in cardiogenic shock on admission, who were older, and who had a lower left ventricular ejection fraction had a worse long-term prognosis. The presence of MVD has been associated with poorer clinical outcomes.1–3 This population of patients with STEMI has more risk factors and more co-morbidities, a worse left ventricular ejection fraction, and a greater rate of ischemia before myocardial infarction. All of these factors could contribute to the poor prognosis.4 However, the direct, unambiguous mechanism by which MVD so seriously worsens the prognosis is unknown and has been widely discussed. CTO has been reported in approximately 30% of patients with STEMI and MVD— consistent with the data obtained in our investigation.5 This subpopulation of patients with STEMI is truly at risk after primary PCI. Investigators have reported that the greater mortality in this group is mainly determined by the presence of CTO in non-IRA segments. Additionally, CTO was associated with a reduction in the left ventricular ejection fraction during a 12-month period, although only 1 study reported on a follow-up period as long as in our investigation.5–7 Recently, Lexis et al8 have demonstrated that the presence of CTO in a non-IRA after STEMI is associated with worse reperfusion markers and larger enzymatic infarct size. The reason concurrent CTO affects the prognosis so adversely in patients with STEMI and MVD can be partly explained by the greater risk profile of those with CTO. These patients tend to have diabetes and previous myocardial infarction, lower left ventricular ejection fraction, lower baseline Thrombolysis In Myocardial Infarction flow grades, and cardiogenic shock on admission more often than patients without CTO. However, after adjustment for these differences in the baseline characteristics on multivariate Cox regression analysis, CTO remained an independent predictor of greater 5-year mortality. Another explanation of the underlying mechanism for the increased mortality in patients with STEMI with concurrent CTO could be that in patients with CTO, PCI was less successful. A final Thrombolysis In Myocardial Infarction flow grade ⬍3 is strongly associated with a worse prognosis.9 In our investigation, it was more frequently present in the CTO group. Nevertheless, an additional multifactorial analysis of MVD in the CTO subpopulation only identified cardiogenic shock on admission, older age, and lower left ventricular ejection fraction as independent pre-
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Figure 1. Five-year mortality rate of patients undergoing PCI for STEMI (p ⬍ 0.0001, log-rank for single-vessel disease [SVD] vs MVD without CTO, SVD vs MVD with CTO, and MVD without CTO vs MVD with CTO).
dictors of death at 5 years of follow-up in this group of patients (Table 6). Other factors that might contribute to the adverse outcomes in patients with CTO include the lack of a compensation mechanism for the decrease in the left ventricular ejection fraction in acute myocardial infarction. Patients with MVD and concomitant CTO have a lower residual left ventricular ejection fraction and less improvement in left ventricular systolic function, strongly influencing survival.5 Although enzymatic infarct size did not differ between the 2 groups in our investigation, with a lower residual left ventricular ejection fraction, it is likely that the patients with STEMI and CTO had left ventricular dysfunction before myocardial infarction because of the greater extent of their coronary artery disease. However, ⬎1/2 of the patients in the CTO group had not had a documented myocardial infarction. Goldstein et al10 have shown that the pathologic process in STEMI involves the entire coronary tree and can lead to the destabilization and rupture of multiple atherosclerotic plaques, resulting in a significantly increased risk of death and repeated ischemic events. The dynamics of this specific inflammatory process are greatest in the first month after acute myocardial infarction,11 possibly explaining the increase in mortality in the first 30 days observed in our investigation (Figure 1). Owing to the paucity of data regarding the optimal treatment of patients with STEMI and MVD, the need for, and timing of, subsequent revascularization of diseased nonIRA vessels remains controversial. Current practice guidelines in the acute setting recommend revascularization of diseased non-IRA vessels only in the presence of hemodynamic or electrical instability.12 A number of observational studies investigating multivessel PCI during the index event were hampered by selection bias and have reported inconclusive results.13–15 The lack of benefit observed in trials studying multivessel PCI for STEMI might have been because approximately 30% of the patients with STEMI and MVD had concurrent CTO. The presence of CTO in a
non-IRA was the main factor affecting greater early and long-term mortality in this group of patients. Another reason for the lack of benefit observed was the patients with CTO were excluded from previous studies reporting multivessel PCI. Accordingly, a complete analysis of each case with regard to total revascularization, especially in patients with CTO, is warranted. The evaluation of the effectiveness of such conduct requires additional prospective, randomized trials. It is likely that the ongoing Evaluating XIENCE V and left ventricular function in PCI on Occlusions after STEMI (EXPLORE) trial will show whether recanalization of CTO in patients with STEMI improves the outcomes in this high-risk subgroup of patients with STEMI.16 1. Lekston A, Tajstra M, Ga˛sior M, Gierlotka M, Pres D, Hudzik B, Trzeciak P, Kalarus Z, Polon´ski L, Zembala M. Impact of multivessel coronary disease on one-year clinical outcomes and five-year mortality in patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention. Kardiol Pol 2011;69:336 –343. 2. Sorajja S, Gersh BJ, Cox DA, McLaughlin MG, Zimetbaum P, Costatini C, Stuckey T, Tcheng JE, Mehran R, Lansky AJ, Grines CL, Stone GW. Impact of multivessel disease on reperfusion success and clinical outcomes in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction. Eur Heart J 2007;28:1709 –1716. 3. Tarantini G, Napodano M, Gasparetto N, Favaretto E, Marra MP, Cacciavillani L, Bilato C, Osto E, Cademartiri F, Musumeci G, Corbetti F, Razzolini R, Iliceto S. Impact of multivessel coronary artery disease on early ischemic injury, late clinical outcome, and remodeling in patients with acute myocardial infarction treated by primary coronary angioplasty. Coron Artery Dis 2010;21:78 – 86. 4. DeGeare VS, Stone GW, Grines L, Grines L, Brodie BR, Cox DA, Garcia E, Wharton TP, Boura JA, O’Neill WW, Grines CL. Angiographic and clinical characteristics associated with increased in-hospital mortality in elderly patients with acute myocardial infarction undergoing percutaneous intervention (a pooled analysis of the primary angioplasty in myocardial infarction trial). Am J Cardiol 2000; 86:30 –34. 5. Claessen BEPM, van der Schaaf RJ, Verouden NJ, Stegenga NK, Engstrom AE, Sjauw KD, Kikkert WJ, Vis MM, Baan J, Koch KT, de Winter RJ, Tijssen JG, Piek JJ, Henriques JP. Evaluation of the effect of a concurrent chronic total occlusion on long-term mortality and left ventricular function in patients after primary percutaneous coronary intervention. JACC Cardiovasc Interv 2009;2:1128 –1134.
Coronary Artery Disease/Chronic Total Occlusion in Myocardial Infarction 6. Moreno R, Conde C, Perez-Vizcayno MJ, Villarreal S, HernandezAntolin R, Alfonso F, Bañuelos C, Angiolillo DJ, Escaned J, Fernandez-Ortiz A, Macaya C. Prognostic impact of a chronic occlusion in a noninfarct vessel in patients with acute myocardial infarction and multivessel disease undergoing primary percutaneous coronary intervention. J Invasive Cardiol 2006;18:16 –19. 7. van der Schaaf RJ, Vis MM, Sjauw KD, Koch KT, Baan J Jr, Tijssen JG, de Winter RJ, Piek JJ, Henriques JP. Impact of multivessel coronary disease on long-term mortality in patients with ST-elevation myocardial infarction is due to the presence of a chronic total occlusion. Am J Cardiol 2006;98:1165–1169. 8. Lexis CP, van der Horst IC, Rahel BM, Lexis MA, Kampinga MA, Gu YL, de Smet BJ, Zijlstra F. Impact of chronic total occlusions on markers of reperfusion, infarct size, and long-term mortality: a substudy from the TAPAS trial. Catheter Cardiovasc Interv 2011;77: 484 – 491. 9. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993;329:1615–1622; erratum in N Engl J Med 1994; 330:516. 10. Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfeh M, O’Neil WW. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2000;343:915–922. 11. Guazzi MD, Bussotti M, Grancini L, De Cesare N, Guazzi M, Pera IL, Loaldi A. Evidence of multifocal activity of coronary disease in patients with acute myocardial infarction. Circulation 1997;96: 1145–1151. 12. Wijns W, Kolh P, Danchin N, Di Mario C, Falk V, Folliguet T, Garg S, Huber K, James S, Knuuti J, Lopez-Sendon J, Marco J, Menicanti L, Ostojic M, Piepoli MF, Pirlet C, Pomar JL, Reifart N, Ribichini FL, Schalij MJ, Sergeant P, Serruys PW, Silber S, Sousa Uva M, Taggart D, ESC Committee for Practice Guidelines, Vahanian A, Auricchio A, Bax J, Ceconi C, Deans V, Filippatos G, Funck-Brentano C, Hobbs R, Kearney P, McDonagh T, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas PE, Widimsky P, EACTS Clinical Guidelines
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