EXPEDITED PUBLICATION: EDITORIAL COMMENT
Revascularization of the Infarct-Related ArteryNever Too Late to Do Well*
Manel Sabaté, MD, PhD, FESC*
Interventional Cardiology Unit, Cardiology Department, Saint Paul University Hospital, Barcelona, Spain.
* Reprint requests and correspondence: Dr. Manel Sabaté, Interventional Cardiology Unit, Cardiology Department, Saint Paul University Hospital, Barcelona, Spain. (Email: msabatet{at}santpau.es).
Revascularization of the infarct-related artery (IRA) has been evaluated since the understanding that an occlusive thrombus in a coronary artery could be managed either by thrombolytic therapy or mechanically by means of percutaneous coronary interventions (PCIs). However, after acute myocardial infarction (MI), different scenarios may be defined according to the duration of the occlusion (Table 1). During the early phase of an MI, current consensus is the reperfusion of the IRA as soon as possible. The main goal in this phase is myocardial salvage, which is critically time-dependent. Prompt restoration of blood flow reduces infarct size, preserves global left ventricular function, and improves patient survival. Current guidelines support primary PCI as the treatment of choice (as opposed to thrombolytic therapy) when delivered rapidly and in high-volume centers by experienced teams specifically when the time from the onset of symptoms is lower than 12 h. Besides, this technique has to be performed in a period no longer than 90 min from patients’ first medical contact (1). Main evidence impacting this decision comes from a meta-analysis of 23 randomized trials (2), which together assigned 7,739 thrombolytic-eligible patients with ST-segment elevation MI to either primary PCI or thrombolytic medication. Primary PCI was better than thrombolytic therapy at reducing overall short-term (defined as 4 to 6 weeks) death (9.3% vs. 7.0%, p = 0.0002), nonfatal reinfarction (6.8% vs. 2.5%, p < 0.0001), total stroke (2.0% vs. 1.0%, p = 0.0004), and the combined end point of death, nonfatal reinfarction, and stroke (14.5% vs. 8.2%, p < 0.0001). During long-term follow-up (6 to 18 months), the results seen with primary PCI remained better than those seen with thrombolytic therapy with 12.8% versus 9.6% for death, 10.0% versus 4.8% for nonfatal MI, and 19% versus 12% for the combined end point of death, nonfatal reinfarction, and stroke. The most impressive difference between thrombolysis and primary PCI was the significant reduction of recurrent ischemia from 21% with thrombolysis to 6% after primary PCI during short-term (p < 0.0001), and also during long-term follow-up (39% vs. 22%, p < 0.0001).
At the other side of the spectrum reside patients with a chronic total occlusion (CTO), defined as a complete occlusion at least 3 months old (3) (Table 1). In this setting, the benefit from recanalization is time-independent and is based on relieving symptomatic ischemia and angina, enhancing left ventricular function, reducing predisposition to ventricular arrhythmias, and improving tolerance of contralateral coronary occlusion. From a clinical standpoint, CTO recanalization is usually attempted in symptomatic patients or in patients with evidence of silent ischemia in a large territory at risk and/or with the presence of viable myocardium. In this regard, contrast and adenosine stress magnetic resonance imaging may identify viable and ischemic myocardium subtended by a CTO that may benefit from revascularization (4). Several retrospective observational studies have reported the clinical impact of successful percutaneous CTO revascularization on long-term survival. In a consecutive series of 2,007 patients undergoing intended PCI of a nonacute coronary occlusion at the Mid America Heart Institute between 1980 and 1999 (5), technical success was achieved in 74.4%. Compared with those patients in whom the procedure was successful, the in-hospital occurrence of major adverse cardiac events was significantly higher among patients with procedural failure (3.2% vs. 5.4%; p = 0.02). Long-term survival was similar in patients with successful CTO recanalization compared with that seen in a matched cohort of patients undergoing successful angioplasty of nonoccluded lesions and significantly greater than in patients in whom attempted CTO revascularization failed (10-year survival 73.5% with CTO success vs. 65.0% with CTO failure, p = 0.001). By multivariate analysis, failure to successfully recanalize the CTO was an independent predictor of reduced survival (hazard ratio 1.4 [95% confidence interval (CI) 1.25 to 2.0], p < 0.0003). In the prospective TOAST-GISE (Total Occlusion Angioplasty Study–Società Italiana di Cardiologia Invasiva) (6), successful PCI of a CTO (attempted in 390 lesions in 369 patients) was associated with a reduced 12-month incidence of cardiac death or MI (1.1% vs. 7.2%; p = 0.005), a reduced need for coronary artery bypass surgery (2.5% vs. 15.7%; p < 0.0001), and greater freedom from angina (88.7% vs. 75.0%; p = 0.008). In the overall study population, the only factor associated with enhanced 1-year event-free survival was successful CTO recanalization (odds ratio [OR] 0.24 [95% CI 0.07 to 0.80], p = 0.018). Finally, a total of 874 consecutive patients were treated for 885 CTO lesions at the Thoraxcenter between 1992 and 2002. Mean follow-up time was 4.47 ± 2.69 years (median 4.10 years). At 5 years, survival was significantly higher in those patients with a successful revascularization (93.5% vs. 88.0%, p = 0.02). Independent predictors for survival were successful revascularization, lower age, and the absence of diabetes mellitus and multivessel disease (7).
Thus, the current evidence supports recanalization of the IRA not only acutely after MI (<12 h) but also in the chronic phase (>3 months) if symptoms, ischemia, or viability of the occluded vessel are present. It is, therefore, questioned whether an invasive strategy may also be indicated on a continuum for latecomers after MI (>12 h but <3 months). The most recently published update of the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography Interventions (ACC/AHA/SCAI) guidelines (8) for PCI refers to this issue. Specifically, it is recommended (Class I, Level of Evidence: A) to perform PCI after successful fibrinolysis or in patients not undergoing primary reperfusion within the first 12 h, in patients with any of the following: objective evidence of recurrent MI, presence of moderate or severe spontaneous or induced ischemia after the MI, and in cardiogenic shock or hemodynamic instability. Besides, it is reasonable to perform routine late PCI after an MI (Class IIa) in patients with left ventricular ejection fraction  0.40, heart failure, or serious ventricular arrhythmias. However, PCI of a totally occluded IRA >24 h after an ST-segment elevation MI is not recommended (Class III, Level of Evidence: B) in asymptomatic patients with 1- or 2-vessel disease if they are hemodynamically and electrically stable and do not have evidence of severe ischemia. For those patients having received thrombolysis before 24 h, these guidelines do not express any recommendation. However, the European Society of Cardiology (ESC) guidelines (1) recommend routine coronary angiography and, if applicable, PCI early after effective thrombolysis (Class I, Level of Evidence: A) up to 24 h after thrombolysis independent from angina and/or ischemia. For those patients not having received reperfusion (latecomers), the ESC guidelines do not express any recommendation due to inconsistent data at the time of the publication.
Taken together both guidelines are to some extent complementary but somewhat insufficient as they do not cover all possible scenarios and clinical situations in this time frame (Table 2). In this regard in this issue of the Journal, Abbate et al. (9) should be commended for their meta-analysis that has contributed to shed light on this controversial topic. The authors retrieved 10 studies enrolling 3,560 patients that were randomized to either late PCI of the IRA (range 1 to 26 days after the MI) or optimal medical treatment. The primary end point of this meta-analysis was all-cause mortality. In addition, left cardiac remodeling was also assessed in those studies with echocardiographic analyses. Randomization allocated 1,779 subjects to PCI and 1,781 to medical treatment. As a result, late PCI improved survival as compared with medical treatment (OR 0.49 [95% CI 0.26 to 0.94], p = 0.030) during a follow-up period of 2.8 years (42 days to 10 years). This beneficial effect in all-cause mortality reduction was associated with favorable effects on cardiac function and remodeling, as late PCI demonstrated significant greater improvement in left ventricular ejection fraction and left ventricular end diastolic and end systolic volume indexes. This meta-analysis fully addressed the open artery hypothesis with an adequate final sample size and a long enough clinical follow-up. This hypothesis suggests that survival after MI depends on the effect of mechanical recanalization to improve left ventricular remodeling and healing, to enhance electrical stability, and to cause myocardial perfusion rather than to reduce the infarct size (that is, myocardial salvage). Interestingly, this meta-analysis did not include those trials aimed to determine whether performing routine PCI within the first 24 h after successful thrombolysis is beneficial as compared with conventional medical treatment (10–13). As reflected in Table 2, the ESC guidelines gave, in this scenario, a Class I, Level of Evidence: A recommendation on the basis of the 4 randomized studies that addressed this issue: SIAM III (Southwest German Interventional Study in Acute Myocardial Infarction) (10), GRACIA-1 (Randomized Trial Comparing Stenting Within 24 Hours of Thrombolysis Versus Ischemia-Guided Approach to Thrombolysed Acute Myocardial Infarction With ST Elevation) (11), CAPITAL-AMI (Combined Angioplasty and Pharmacological Intervention Versus Thrombolysis Alone in Acute Myocardial Infarction) (12), and the Leipzig Prehospital Lysis study (13). On the contrary, the most recently updated ACC/AHA/SCAI guidelines do not mention this clinical situation. Probably, routine angiography post-effective thrombolysis does not reflect the paradigm of the open artery hypothesis, as by definition most IRAs will be certainly open at the time of PCI. Then, to whom does this meta-analysis apply? Most of patients included in the analysis (84%) showed total IRA occlusion, and the presence of relevant ischemia was an exclusion criterion in 6 of 10 studies. Besides, the degree of angiographic success was variable (range 72% to 100%) as were both the rates of stent implantation (range 0% to 100%) and the glycoprotein IIb/IIIa inhibitor usage. In this heterogeneous scenario, poorly representative of current PCI technology and outcomes, late PCI was still able to significantly reduce the all-cause mortality rate. Another interesting finding was the fact that the benefit was more obvious in those trials with a median follow-up of >4 years. This goes in line with the hypothesis that restoration of antegrade blood flow to the peri-infarct area may interrupt the progression to apoptosis of the hibernating myocardium and prevent the development of cardiomyopathy (14,15).
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Table 2 ACC/AHA/SCAI and ESC Guidelines for Patients After Successful Fibrinolysis and for Patients Not Undergoing Primary Reperfusion (Latecomers)
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Abbate et al. (9) have provided us with the last remaining piece of evidence in the field of total occluded IRA. Finally, all gaps can be filled in (Table 2) by a homogenous recommendation and level of evidence. Successful PCI of the nonreperfused IRA (beyond 12 h after the onset of symptoms) with or without the presence of ischemia is associated with improved long-term survival and improved cardiac function and remodeling parameters.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Silber S, Albertsson P, Fernandez-Avilés F, et al. Guidelines for Percutaneous Coronary Interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J 2005;26:804-847.[Free Full Text]2. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials Lancet 2003;361:13-20.[CrossRef][Web of Science][Medline] 3. Stone GW, Kandzari DE, Mehran R, et al. Percutaneous recanalization of chronically occluded coronary arteries. A Consensus Document Part I. Circulation 2005;112;:2364-2372.[Free Full Text] 4. Kim RJ, Wu E, Rafael A, et al. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction N Engl J Med 2000;343:1445-1453.[Abstract/Free Full Text] 5. Suero JA, Marso SP, Jones PG, et al. Procedural outcomes and long-term survival among patients undergoing percutaneous coronary intervention of a chronic total occlusion in native coronary arteries: a 20-year experience J Am Coll Cardiol 2001;38:409-414.[Abstract/Free Full Text] 6. Olivari Z, Rubartelli P, Piscione F, et al. TOAST-GISE Investigators Immediate results and one-year clinical outcome after percutaneous coronary interventions in chronic total occlusions: data from a multicenter, prospective, observational study (TOAST-GISE) J Am Coll Cardiol 2003;41:1672-1678.[Abstract/Free Full Text] 7. Hoye A, van Domburg RT, Sonnenschein K, Serruys PW. Percutaneous coronary intervention for chronic total occlusions: the Thoraxcenter experience 1992–2002 Eur Heart J 2005;26:2630-2636.[Abstract/Free Full Text] 8. King III SB, Smith Jr. SC, Hirshfeld Jr. JW, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (2007 Writing Group to Review New Evidence and Update the 2005 ACC/AHA/SCAI Guideline Update for Percutaneous Coronary Intervention) J Am Coll Cardiol 2008;51:172-209.[Free Full Text] 9. Abbate A, Biondi-Zoccai GGL, Appleton DL, et al. Survival and cardiac remodeling benefits in patients undergoing late percutaneous coronary intervention of the infarct-related artery: evidence from a meta-analysis of randomized controlled trials J Am Coll Cardiol 2008;51:956-964.[Abstract/Free Full Text] 10. Scheller B, Hennen B, Hammer B, et al. Beneficial effects of immediate stenting after thrombolysis in acute myocardial infarction J Am Coll Cardiol 2003;42:634-641.[Abstract/Free Full Text] 11. Fernandez-Aviles F, Alonso JJ, Castro-Beiras A, et al. Routine invasive strategy within 24 hours of thrombolysis versus ischaemia-guided conservative approach for acute myocardial infarction with ST-segment elevation (GRACIA-1): a randomised controlled trial Lancet 2004;364:1045-1053.[CrossRef][Web of Science][Medline] 12. Le May MR, Wells GA, Labinaz M, et al. Combined Angioplasty and Pharmacological Intervention versus Thrombolysis Alone in Acute Myocardial Infarction (CAPITAL AMI Study) J Am Coll Cardiol 2005;46:417-424.[Abstract/Free Full Text] 13. Thiele H, Engelmann L, Elsner K, et al. Comparison of prehospital fibrinolytic/abciximab therapy with prehospital initiated facilitated percutaneous coronary intervention in acute myocardial infarction Eur Heart J 2005;26:1956-1963.[Abstract/Free Full Text] 14. Abbate A, Bussani R, Biondi-Zoccai GG, et al. Persistent infarct-related artery occlusion is associated with an increased myocardial apoptosis at postmortem examination in humans late after an acute myocardial infarction Circulation 2002;106:1051-1054.[Abstract/Free Full Text] 15. Abbate A, Bussani R, Biondi-Zoccai GG, et al. Infarct-related artery occlusion, tissue markers of ischaemia, and increased apoptosis in the peri-infarct viable myocardium Eur Heart J 2005;26:2039-2045.[Abstract/Free Full Text]
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