Chronic total occlusion (CTO) in a non–infarct-related artery (IRA) is an independent predictor of clinical outcomes in patients with acute myocardial infarction (AMI). This study evaluated the impact of successful percutaneous coronary intervention (PCI) for CTO of a non-IRA on the long-term clinical outcomes in patients with AMI. A total of 4,748 patients with AMI were consecutively enrolled in the Convergent Registry of Catholic and Chonnam University for AMI registry from January 2004 to December 2009. We enrolled 324 patients with CTO in a non-IRA. To adjust for baseline differences, propensity matching (96 matched pairs) was used to compare successful PCI and occluded CTO for the treatment of CTO in non-IRA. The primary clinical end points were all-cause mortality and a composite of the major adverse cardiac events, including cardiac death, MI, stroke, and any revascularization during the 5-year follow-up. Patients who received successful PCI for CTO of non-IRA had lower rates of all-cause mortality (16.7% vs 32.3%, hazard ratio 0.459, 95% CI 0.251 to 0.841, p = 0.012) and major adverse cardiac events (21.9% vs 55.2%, hazard ratio 0.311, 95% CI 0.187 to 0.516, p <0.001) compared with occluded CTO group. Subgroup analyses revealed that successful PCI resulted in a better mortality rate in patients with normal renal function compared to patients with chronic kidney disease (p = 0.010). In conclusion, successful PCI for CTO of non-IRA is associated with improved long-term clinical outcomes in patients with AMI.
Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality worldwide. Early restoration of blood flow in the infarct-related artery (IRA) is the primary treatment aim of AMI. Of patients with AMI, approximately 40% to 60% of those with AMI have multivessel disease (MVD), and 10% of patients with AMI have MVD with chronic total occlusion (CTO) in non-IRA. MVD with CTO is an independent predictor of mortality. Successful percutaneous coronary intervention (PCI) for CTO reduces long-term, adverse clinical outcomes and mortality. However, there is a paucity of data on the clinical impact of PCI for CTO of non-IRA in patients with AMI. Thus, we hypothesized that successful PCI of CTO in non-IRA might improve long-term clinical outcomes. To address this hypothesis, we compared the long-term clinical outcomes of patients who underwent successful PCI versus medical treatment for CTO of non-IRA in patients with AMI.
Methods
The Convergent Registry of Catholic and Chonnam University for AMI is a Korean, retrospective, multicenter registry designed to investigate the real-world outcomes of patients with AMI, including ST-elevation MI (STEMI) and non-STEMI (NSTEMI). All consecutive patients diagnosed with AMI from January 2004 to December 2009 in 9 major cardiovascular centers were retrospectively included in this registry. The participating centers are located throughout the country, and all centers perform a large number of PCIs each year (>500 PCI/year). This large observational registry includes demographic, clinical, and angiographic data, as well as short- and long-term clinical outcome data. A total of 4,748 patients with AMI who successfully underwent PCI for IRA were included in this registry. Patients who underwent bypass surgery (n = 14, 0.3%) or received only medical therapy (n = 16, 0.3%) were excluded. In this sample, 2,828 patients (59.6%) had single vessel disease; 1,566 patients (33.0%) had MVD without CTO of non-IRA; and 324 patients (6.4%) were diagnosed with a CTO lesion in a non-IRA. The culprit artery was identified through echocardiographic, angiographic, and electrocardiographic (ECG) findings by physicians.
The clinical outcome data were collected by independent research personnel. All the outcomes of interest were confirmed by a source document and were centrally adjudicated by the local events committee of Seoul St. Mary’s Hospital, Seoul, Korea, whose members were unaware of the patients’ statuses. To validate the follow-up data, information on the censored survival data and the causes of death were obtained on July 31, 2013, from the Office of Statistics Korea with the use of unique identification numbers. This study complied with the Declaration of Helsinki regarding human experiments, and written informed consent was obtained from each patient before enrollment. There was no industry involvement in the design, conduct, or analysis of the study. The study protocol was approved by the institutional review board at each participating hospital. This registry has been registered on ClinicalTrial.gov (study ID: NCT02385682 ).
Coronary interventions were performed according to the current standard techniques. The treatment strategy, stent type, predilation, poststenting adjunctive balloon inflation, and the use of intravascular ultrasound or glycoprotein IIb/IIIa inhibitors were chosen at the discretion of the operators. All patients received a 300 mg loading dose of aspirin and 300 to 600 mg of clopidogrel (unless these antiplatelet medications had been previously administered). The postprocedural antiplatelet therapy consisted of 100 mg of aspirin (once daily indefinitely) and 75 mg of clopidogrel (once daily for at least 1 year). During the procedure, anticoagulation was maintained through unfractionated heparin administration (5,000 IU or 70 to 100 IU per kilogram body weight) according to the standard protocols.
AMI was diagnosed according to characteristic clinical symptoms, serial changes on electrocardiograms consistent with infarction, or increased cardiac enzyme values. The AMI diagnosis was confirmed through coronary angiography in all patients. A CTO in a non-IRA was defined as the presence of Thrombolysis In Myocardial Infarction flow 0 grade with or without anterograde or retrograde filling through collateral vessels. All deaths were considered to be cardiac-related unless a definite noncardiac cause could be established. AMI was defined as an increase in the creatinine kinase-MB isoenzyme or troponin value to ≥2 times the upper limit of normal and either symptoms consistent with AMI or ECG changes in at least 2 contiguous leads (pathologic Q waves, persistent ST-segment elevation, or ST-segment depression >0.1 mV). We did not include patients with periprocedural MIs. Any revascularization was defined as a clinically driven percutaneous revascularization or bypass of any segment of the epicardial coronary artery containing the target lesion. Patients with successful PCI were identified as having a Thrombolysis In Myocardial Infarction ≥2 final flow and residual stenosis <30%. The occluded CTO group consisted of patients with failed PCI or initial medical therapy for non-IRA. All clinical outcomes of interest were confirmed by source documents and were centrally adjudicated by a local events committee at the Cardiovascular Center of Seoul St. Mary’s Hospital and by an independent group of clinicians who were unaware of the patients’ statuses. Information regarding death was matched with records from the National Population Registry of the Korea National Statistical Office with a unique personal identification number to validate the mortality follow-up data. The primary clinical end points were all-cause mortality and a composite score consisting of cardiac death, nonfatal MI, stroke, and any revascularization (PCI or coronary artery bypass graft surgery). The secondary clinical end points were cardiac death, nonfatal MI, stroke, and any revascularization.
All analyses were 2-tailed, and clinical significance was defined as a p value <0.05. Statistical analyses were performed using SAS software, version 9.2 (SAS Institute, Cary, North Carolina), and the R programming language was used for the statistical analyses.
Baseline characteristics were analyzed for differences between patients with and without successful PCI through the Student t tests or Mann–Whitney U tests for continuous variables (after testing for normality) and the chi-square or Fisher’s exact tests for categorical variables as appropriate. Survival curves were constructed with Kaplan–Meier estimates and compared using the log-rank test. Available information was included on statistical analyses without the distortion resulting from using imputed values to missing data.
To reduce the impact of treatment selection bias and the potential confounding factors in this observational study, we calculated a propensity score to predict the probability of performing PCI in each patient. The propensity scores were estimated without considering the outcomes using a multiple logistic regression analysis. Adjusted covariates, including age, gender, body mass index, hypertension, diabetes, smoking, dyslipidemia, chronic kidney disease, stroke, a family history of coronary artery disease, a history of MI, a history of PCI, diagnosis (STEMI vs NSTEMI), Killip’s class, IRA, stent type (bare-metal vs drug-eluting stent) of IRA, non-IRA CTO vessel, glycoprotein IIb/IIIa inhibitor, no reflow after PCI of an IRA, left ventricular (LV) ejection fraction, hemoglobin, HbA1c, estimated glomerular filtration rate, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, high-sensitivity C-reactive protein, β blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and statins were used to generate the propensity scores.
Hazard ratios of a composite outcome were calculated with Cox proportional hazards models. We performed prespecified analyses stratified according to the following variables: age, gender, diabetes, chronic kidney disease, diagnosis, and LV ejection fraction.
Results
A total of 324 patients were categorized into 2 groups: successful PCI (n = 170, 52.5%) or occluded CTO (n = 154, 47.5%). The crude and propensity score–matched baseline and angiographic characteristics of the patients are listed in Table 1 . The patients with occluded CTO were older, more likely to be in a higher Killip’s class, and had higher high-sensitivity C-reactive protein levels. Furthermore, a smaller proportion of patients with occluded CTO received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and drug-eluting stents ( Table 1 , left). These phenomena reflect the real-world management of patients with CTO and AMI. However, the baseline and procedural characteristics of the 2 propensity-matched groups (96 pairs, total n = 192) were completely balanced in most of the measured characteristics after propensity score matching ( Table 1 , right).
| Variables | Unmatched | Propensity-matched | ||||
|---|---|---|---|---|---|---|
| Occluded CTO (n=154) | Successful PCI (n=170) | p | Occluded CTO (n=96) | Successful PCI (n=96) | p | |
| Age (years) | 67.5±11.2 | 62.7±12.9 | 0.004 | 64.9±10.9 | 64.7±12.1 | 0.915 |
| Men | 102 (66.2%) | 118 (69.4%) | 0.541 | 70 (73%) | 65 (68%) | 0.430 |
| Body mass index (Kg/m 2 ) | 23.8±3.0 | 23.8±3.0 | 0.914 | 23.8±3.0 | 23.7±3.1 | 0.931 |
| Killip class ≥ 3 | 37 (24.0%) | 21 (12.3%) | 0.006 | 17 (18%) | 16 (17%) | 0.848 |
| Hypertension | 88 (57.1%) | 93 (54.7%) | 0.659 | 50 (52%) | 55 (57%) | 0.469 |
| Diabetes mellitus | 53 (34.4%) | 56 (32.9%) | 0.779 | 31 (32%) | 31 (32%) | 0.999 |
| Smoker | 54 (35.1%) | 59 (34.7%) | 0.946 | 38 (40%) | 35 (37%) | 0.656 |
| Family history of coronary artery disease | 5 (3.3%) | 13 (7.7%) | 0.084 | 5 (5%) | 4 (4%) | 0.999 |
| Chronic kidney disease | 15 (9.7%) | 9 (5.3%) | 0.127 | 7 (7%) | 6 (6%) | 0.774 |
| Dyslipidemia | 99 (64.3%) | 107 (62.9%) | 0.802 | 60 (63%) | 62 (65%) | 0.764 |
| Stroke | 7 (4.6%) | 8 (4.7%) | 0.945 | 5 (5%) | 5 (5%) | 0.999 |
| Prior myocardial infarction | 6 (3.9%) | 9 (5.3%) | 0.550 | 3 (3%) | 6 (6%) | 0.497 |
| Prior percutaneous coronary intervention | 8 (5.2%) | 10 (5.9%) | 0.787 | 6 (6%) | 7 (7%) | 0.774 |
| ST elevation myocardial infarction | 90 (58.4%) | 97 (57.1%) | 0.801 | 58 (60%) | 64 (67%) | 0.368 |
| Creatinine (mg/dL) | 1.2±1.3 | 1.2±1.1 | 0.565 | 1.1±0.9 | 1.1±0.8 | 0.985 |
| Total cholesterol (mg/dL) | 174.8±44.5 | 181.5±45.4 | 0.188 | 180.3±42.4 | 175.1±47.7 | 0.425 |
| Triglyceride (mg/dL) | 107.8±52.3 | 115.6±76.4 | 0.303 | 107.2±53.7 | 112.4±51.6 | 0.498 |
| HDL cholesterol (mg/dL) | 43.1±12.4 | 43.2±10.9 | 0.923 | 42.9±12.1 | 42.5±10.5 | 0.766 |
| LDL cholesterol (mg/dL) | 112.8±39.6 | 116.3±40.6 | 0.440 | 115.7±38.2 | 110.8±41.2 | 0.399 |
| High-sensitivity C-reactive protein (mg/L) | 32.8±45.1 | 21.5±34.4 | 0.015 | 27.7±33.4 | 27.3±43.0 | 0.945 |
| Hemoglobin A1C (%) | 6.6±1.6 | 6.6±1.5 | 0.853 | 6.6±1.7 | 6.6±1.6 | 0.862 |
| Hemoglobin (g/dL) | 12.7±2.3 | 12.9±2.5 | 0.358 | 12.8±2.2 | 12.7±2.5 | 0.702 |
| Medications | ||||||
| Beta-blockers | 118 (76.6%) | 125 (73.5%) | 0.521 | 72 (75%) | 79 (82%) | 0.218 |
| Renin-Angiotensin System inhibitors | 108 (70.1%) | 138 (81.2%) | 0.020 | 72 (75%) | 74 (77%) | 0.735 |
| Statins | 123 (79.9%) | 146 (85.9%) | 0.150 | 80 (83%) | 81 (84%) | 0.845 |
| Ejection fraction (%) | 49.6±14.2 | 51.2±13.0 | 0.306 | 49.8±14.3 | 50.9±13.7 | 0.610 |
The median follow-up duration was 42.5 months (interquartile range 26.1 to 59.8). Clinical outcomes are presented in Table 2 . In the overall and propensity-matched cohort, patients who underwent a successful PCI had significantly lower incidences of all-cause death and major adverse cardiac events (MACE) than patients with occluded CTO over the 5-year follow-up ( Table 3 ). Furthermore, the incidence of cardiac death and any revascularization were significantly lower in the successful PCI group than the occluded CTO group. Among the 96 propensity-matched pairs, 31 patients with occluded CTO (32.3%) and 16 patients receiving successful PCI (16.7%) died during the 5-year follow-up (hazard ratio 0.459, 95% CI 0.251 to 0.841, p = 0.012). Figure 1 shows the Kaplan–Meier curves for all-cause mortality and MACE up to 5 years in the overall cohort. Figure 2 shows the Kaplan–Meier curves for cardiac death, nonfatal MI, stroke, and any revascularization.
| Variables | Unmatched | Propensity-matched | ||||
|---|---|---|---|---|---|---|
| Medical therapy (n=154) | PCI (n=170) | p | Medical therapy (n=96) | PCI (n=96) | p | |
| Infarct-related artery | 0.725 | 0.999 | ||||
| Left anterior descending | 70 (45.4%) | 67 (39.4%) | 46 (48%) | 45 (47%) | ||
| Left circumflex | 31 (20.1%) | 36 (21.2%) | 19 (20%) | 18 (19%) | ||
| Right | 48 (31.2%) | 60 (35.3%) | 28 (29%) | 29 (30%) | ||
| Left main | 5 (3.3%) | 7 (4.1%) | 3 (3%) | 4 (4%) | ||
| Stent type of culprit artery | <0.0001 | 0.830 | ||||
| Bare metal stent | 44 (28.6%) | 14 (8.2%) | 13 (14%) | 12 (13%) | ||
| Drug-eluting stent | 110 (71.4%) | 156 (91.8%) | 83 (87%) | 84 (88%) | ||
| Non-infarct-related artery | 0.161 | 0.949 | ||||
| Left anterior descending | 39 (25.6%) | 57 (33.5%) | 28 (29%) | 25 (26%) | ||
| Left circumflex | 63 (40.9%) | 56 (32.9%) | 35 (37%) | 37 (39%) | ||
| Right | 52 (33.8%) | 57 (33.5%) | 33 (34%) | 34 (35%) | ||
| Glycoprotein IIb/IIIa inhibitor | 37 (24.0%) | 34 (20.0%) | 0.382 | 17 (18%) | 21 (22%) | 0.469 |
| No reflow | 13 (8.4) | 15 (8.8) | 0.903 | 8 (8%) | 8 (8%) | 0.999 |
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