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Prevalence, predictors and clinical impact of unique and multiple chronic total occlusion in non-infarct-related artery in patients presenting with ST-elevation myocardial infarction
  1. Yoann Bataille,
  2. Jean-Pierre Déry,
  3. Éric Larose,
  4. Ugo Déry,
  5. Olivier Costerousse,
  6. Josep Rodés-Cabau,
  7. Stéphane Rinfret,
  8. Robert De Larochellière,
  9. Eltigani Abdelaal,
  10. Jimmy Machaalany,
  11. Gérald Barbeau,
  12. Louis Roy,
  13. Olivier F Bertrand
  1. Quebec Heart-Lung Institute, Quebec, Canada
  1. Correspondence to Dr Olivier F Bertrand, Interventional Cardiology, Quebec Heart-Lung Institute, 2725, chemin Ste Foy, Quebec City, Canada; olivier.bertrand{at}crhl.ulaval.ca

Abstract

Objectives To investigate the predictors and impact on long-term survival of one chronic total occlusion (CTO) or multiple CTOs in patients presenting with ST-elevation myocardial infarction (STEMI).

Design Single-centre retrospective observational study.

Setting University-based tertiary referral centre.

Patients Between 2006 and 2011, a total of 2020 consecutive patients referred with STEMI were categorised into single vessel disease, multivessel disease (MVD) without CTO, with one CTO or with multiple CTOs.

Intervention Primary percutaneous coronary intervention.

Main outcome measure The primary end-point was the 1-year mortality.

Results The prevalence of single vessel disease, MVD without CTO, with one CTO or with multiple CTOs was 70%, 22%, 7.2% and 0.8%, respectively. Independent clinical predictors for the presence of CTO were cardiogenic shock (OR 5.05; 95% CI 3.29 to 7.64), prior myocardial infarction (OR 2.06; 95% CI 1.35 to 3.09), age >65 years (OR 1.94; 95% CI 1.40 to 2.71) and history of angina (OR 1.94; 95% CI 1.29 to 2.87). Mortality was worse in patients with multiple CTOs (76.5%) compared with those with one CTO (28.1%) or without CTO (7.3%) (p<0.0001). After adjustment for left ventricular ejection fraction and renal function, MVD was an independent predictor for 1-year mortality (HR: 1.81; 95% CI 1.18 to 2.77, p=0.007), but CTO was not (HR: 1.07; 95% CI 0.66 to 1.73, p=0.78).

Conclusions Simple clinical factors are associated with the presence of CTO in non-infarct-related artery in patients presenting with STEMI. In these patients, long-term survival was independently associated with MVD, left ventricular ejection fraction and renal function, but not with CTO per se.

  • Myocardial infarction
  • primary
  • percutaneous coronary intervention
  • multivessel disease
  • chronic total occlusion
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Introduction

Successful and timely primary percutaneous coronary intervention has become the treatment of choice for patients presenting with ST-elevation myocardial infarction (STEMI). This strategy has been found to be superior to thrombolytic therapy in improving morbidity and mortality.1 In patients presenting with STEMI, multivessel disease (MVD) is found in 41%–67% of patients depending upon the baseline characteristics of the population studied,2–4 and has been associated with a worse prognosis.5 ,6 Yet, predictors of MVD or chronic total occlusion (CTO) in non-infarct-related artery in patients presenting with STEMI has not been described. Furthermore, a few studies have recently suggested that the effect of MVD on mortality was essentially due to the presence of a CTO in a non-infarct-related artery7–10 especially in the high-risk subset of STEMI patients with diabetes.11 However, most of these studies involved either selected patients from randomised trials, or did not include the presence of MVD, left ventricular ejection fraction, or baseline renal function in their multivariate analysis. Moreover, the impact of multiple CTOs in non-infarct-related arteries has not been previously assessed. Our objectives were to evaluate in unselected patients presenting with STEMI (1) the prevalence and the predictors of CTO in non-infarct-related artery and (2) the impact of the presence of one CTO or multiple CTOs in non-infarct-related artery on long-term survival.

Methods

This study was conducted according to the STROBE guidelines for Reporting Observational Studies.12 Study participation required written informed patient consent before enrolment.

The study population included all consecutive 2144 STEMI patients who were referred to our centre for primary percutaneous coronary intervention within 12 h after symptom onset between January 2006 and January 2011. The inclusion criteria were: chest pain lasting >30 min, ST-segment elevation ≥1 mm in ≥2 adjacent ECG leads, new left bundle branch block (LBBB) or true posterior myocardial infarction. All STEMI patients were pretreated with aspirin, clopidogrel and heparin. Cardiac catheterisation was performed via radial approach using 6Fr-guiding catheters in the majority of patients. Adjunctive pharmacotherapy, such as bivalirudin or glycoprotein IIb/IIIa inhibitors was left to the operator's discretion. If the coronary anatomy was suitable for primary percutaneous coronary intervention, the procedure was performed with standard techniques. For the purpose of this study, all angiograms were prospectively reviewed by two independent readers with discrepancies resolved by a third reader and consensus. MVD was defined by visual assessment as any stenosis >70% of the coronary lumen diameter in ≥1 of the non-infarct-related artery, or left main stenosis ≥50%.7 A CTO was defined as a total occlusion in a non-infract-related artery without anterograde flow, or with antegrade or retrograde filling through collateral vessels.7 Furthermore, only CTOs of major epicardial coronary arteries, or a major side branch with ≥2 mm in diameter and judged to be (1) amenable to percutaneous coronary intervention and (2) subtending significant myocardial territory were evaluated. The differentiation between CTO and subacute or acute occlusions was made based on morphology of the occlusion (absence of fresh thrombus, presence of bridge, epicardial or septal collaterals) and a possible history of prior MI dated. The initial STEMI ECG was analysed among patients with CTO to evaluate the presence of pathologic Q waves13 in leads corresponding to the CTO. Myocardial blush grade was assessed for the infarct-related artery as previously described.14

Patients with previous coronary artery bypass graft (n=73), as well as STEMI patients without significant coronary lesion (n=51), were excluded from the study. Baseline in-hospital data of the 2020 included patients were obtained from a computerised database of prospectively recorded demographic, clinical and procedural information. The left ventricular ejection fraction was assessed within 3 days after the index event. Clinical follow-up information was obtained from the referring physicians or by phone contact with patients. Finally, information on vital status at 1 year for those who were lost to follow-up was collected from the Quebec death registry ‘Directeur de l'Etat Civil’ Quebec service counter.

Statistical analysis

Categorical variables are presented as numbers and percentages, and continuous variables as the mean±SD or medians (IQR). The baseline and procedural characteristics were compared using Fischer's exact test or χ2 test for categorical variables, and one-way ANOVA, or Kruskal–Wallis, for continuous variables. Potential predictors of CTO were selected with stepwise, backward and forward procedures with logistic regression analyses. Survival curves were constructed using Kaplan–Meier techniques, and comparisons between groups were done using the log-rank test. The Cox proportional hazard model was used to identify the independent predictors of 1-year mortality. Stepwise selection was used to identify potential predictors of death at 1 year, which were entered into the model at p<0.10 and retained at p<0.10. p Values <0.05 were considered significant. The area under the curve for each multivariate model was calculated, and C-indexes are provided in each case. To identify optimal age, CK-MB, and troponin threshold values for predicting death, receiver operating characteristic (ROC) curve analysis was performed by computing sensitivity and specificity. The calculations and statistical analysis were performed using JMP statistical software, V.9.0.0 (SAS Institute).

Results

Clinical follow-up was complete for 100% of patients with a duration of ≥1 year (median 573, 387–952 days). Among the 2020 patients, 1411 patients (70%) had single vessel disease, 447 patients (22%) had MVD without CTO, 145 patients (7.2%) had MVD with one CTO, and 17 patients (0.8%) had MVD with multiple CTOs in non-infarct-related artery (table 1). In the two latter groups, the CTO was in the left anterior descending artery, left circumflex artery, and right coronary artery in 23%, 24% and 53% of the patients, respectively. Patients with one CTO and multiple CTOs were older, had more diabetes, more hypertension, involved more smokers, had more often dyslipidemia, and a prior history of angina and myocardial infarction. Patients with one CTO and multiple CTOs presented more often in cardiogenic shock and with renal failure than patients without CTO (p<0.0001). Of the 162 patients with a CTO, eight patients exhibited a LBBB. In the 154 remaining patients, 41 patients (27%) demonstrated pathologic Q waves in leads corresponding to the CTO. In these 41 patients, the CTO was located as follows: in the LAD (37%), in the Cx (15%), in the RCA (49%).

Table 1

Baseline clinical characteristics

In patients with MVD, the prevalence of three-vessel disease was higher in patients with one CTO (37%), and with multiple CTOs (100%) compared with those without CTO (24%) (p<0.0001) (table 2). Patients with one CTO and multiple CTOs had more often left anterior descending artery-related myocardial infarction (p<0.0001). The ischaemic time was also significantly longer in patients with one CTO, or with multiple CTOs, compared with patients with single vessel disease or MVD without CTO. A postprimary percutaneous coronary intervention abnormal epicardial or myocardial flow in infarct-related artery (TIMI flow grade 0 or 1, and a MBG 0 or 1) occurred more frequently in patients with one CTO or with multiple CTOs compared with patients with single vessel disease or MVD without CTO (p<0.0001). Of note, there were less stents implanted in patients with one CTO or with multiple CTOs compared with patients without CTO (p<0.0001). The myocardial infarction size was larger in patients with one CTO or with multiple CTOs compared with patients with single vessel disease or MVD without CTO (p=0.0059). Accordingly, the residual left ventricular ejection fraction was lower in patients with one CTO or with multiple CTOs (SVD vs CTO P <0.0001 and MVD-CTO vs CTO p<0.0001). A total of 36 (22%) patients with CTO underwent further attempted revascularisation of their CTO (19 with PCI and 17 with CABG) during long-term follow-up. Of note, 10 out of 19 patients (53%) had a successful percutaneous recanalisation of CTO, whereas, 15 out of 17 patients (88%) had coronary artery bypass graft surgery.

Table 2

Angiographic characteristics

By multivariable analysis, the independent clinical predictors of CTO in non-infarct-related artery included cardiogenic shock (OR 5.05; 95% CI 3.29 to 7.64, p<0.0001), prior myocardial infarction (OR 2.06 ; 95% CI 1.35 to 3.09, p=0.001), age >65 years (OR 1.94 ; 95% CI 1.40 to 2.71, p<0.0001), and history of angina (OR 1.94 ; 95% CI 1.29 to 2.87, p=0.0016). The C-index for the model was 0.72. Hence, the incidence of CTO in non-infarct-related artery varied from 8% in the whole population, to 17% in patients with prior MI, to 23% in those with prior MI and >65 years old, and to 24% in those with prior MI and angina and >65 years old. In patients presenting with cardiogenic shock on admission, the prevalence of CTO in non- infarct-related artery was 28%. By contrast, independent predictors of MVD without CTO included creatinine clearance <60 ml/min (OR 2.12; 95% CI 1.51 to 2.96, p<0.0001), males (OR 2.07; 95% CI 1.52 to 2.86, p<0.0001), prior myocardial infarction (OR 1.52; 95% CI 1.07 to 2.14, P=0.02), age >65 years (OR 1.44; 95% CI 1.08 to 1.90, p=0.012), and hypertension (OR 1.35; 95% CI 1.06 to 1.72, P=0.015). The C-index was 0.63.

Figure 1 shows the cumulative mortality curves for patients with single vessel disease, MVD without CTO and MVD with CTO during long-term follow-up. Kaplan–Meier estimates for late death were 5.8% in the single vessel disease group, 12.1% in the MVD without CTO group, and 34.1% in the MVD with CTO (p<0.0001). Figure 2 shows the cumulative mortality curves for patients with no CTO, one CTO and multiple CTOs during follow-up. Overall, the late mortality was significantly worse in patients with multiple CTOs (76.5%) compared with those with one CTO (28.1%) or without CTO (7.3%) (p<0.0001).

Figure 1

Survival Curve of Patients After Primary Percutaneous Coronary Intervention According to the Extent of Coronary Artery Disease. Mortality in patients with STEMI after Primary Percutaneous Coronary Intervention for patients with Single vessel disease, MVD without CTO and with CTO.

Figure 2

Survival Curve of Patients After Primary Percutaneous Coronary Intervention According to the Presence of CTO. Mortality in patients with STEMI after primary Percutaneous Coronary Intervention for patients with NO CTO, 1 CTO or >1 CTO.

Patients who died within 1 year were older, involved more women, and those patients had more often diabetes, a prior history of angina and myocardial infarction. They also presented more frequently in cardiogenic shock and with renal failure (table 3). Among CTO patients, there were no significant differences in 1-year mortality between patients with (37%) or without a Q wave (25%) in leads corresponding to CTO (p=0.16). Among patients with CTO, mortality rate at 1 year was not significantly different among those who were successfully revascularised (24%) compared with those who were not (31%) (p=0.63).

Table 3

One-year mortality and multivariate predictors

Independent predictors of 1-year mortality were assessed using two different multivariate models. In the first model excluding left ventricular ejection fraction and renal function (C-index = 0.88), MVD (HR 1.65; 95% CI 1.12 to 2.43, p=0.012) and CTO (HR 1.84; 95% CI 1.21 to 2.82, p=0.005) were identified as independent predictors. However, in the second model, which included left ventricular ejection fraction and renal function (C-index 0.92), MVD remained an independent predictor (HR 1.81; 95% CI 1.18 to 2.77, p=0.007), but CTO per se was no longer an independent predictor of mortality (HR 1.07; 95% CI 0.66 to 1.73, p=0.78.

CTO was also an independent predictor of left ventricular ejection fraction <40% (OR 2.51; 95% CI 1.53 to 4.10, p=0.0003), together with left anterior descending artery-related myocardial infarction (OR 4.65; 95% CI 3.47 to 6.30, p<0.0001), cardiogenic shock (OR 4.11; 95% CI 2.57 to 6.63, p<0.0001), peak troponin >5.6 μg/l (OR 2.71; 95% CI 1.93 to 3.82, p<0.0001), creatinine clearance <60 ml/min (OR 2.34; 95% CI 1.65 to 3.30, p<0.0001), prior myocardial infarction (OR 2.03; 95% CI 1.33 to 3.09, p=0.0011), peak CK-MB >100 μg/l (OR 1.70; 95% CI 1.13 to 2.56, p=0.0098) and total ischaemic time >7 h (OR 1.67; 95% CI 1.22 to 2.28, p=0.0013). The C-index was 0.82.

Discussion

In this study involving unselected patients presenting with acute STEMI, we found that (1) the prevalence of CTO in non-infarct-related artery was 7.2% for one CTO, and 0.8% for multiple CTOs; (2) simple clinical criteria permitted to suspect the presence of CTO in non-infarct-related artery before proceeding to primary percutaneous coronary intervention; (3) the presence of one CTO or multiple CTOs in non-infarct-related artery confers a worse prognosis, but after adjustment for left ventricular ejection fraction and renal function, 1-year survival was independently associated with the presence of MVD with or without CTO, but not CTO per se.

In our investigation, the prevalence of a CTO was 8% in the whole population and 27% in the patients with MVD. This is concordant with data obtained in previous studies with STEMI patients.7–10 ,15 ,16 The prevalence of CTO can even reach >20% in STEMI patients with diabetes,11 or with cardiogenic shock on admission.17 ,18 For the first time, we also identified that among patients with MVD and CTO, 10% have multiple CTOs in non-infarct-related artery.

In unselected patients referred for diagnostic coronary angiography, Christofferson et al 19 found one CTO in 24% of patients and in 52% of patients with MVD. They also reported 23% with multiple CTOs. More recently, Fefer et al 20 described a prevalence of 18.4% of CTO in patients undergoing non-urgent angiography, including 17% of multiple CTOs. From a clinician's perspective, it is important to suspect the presence of CTO in non-infarct-related artery before proceeding to angiography in patients presenting with STEMI. We identified several simple clinical predictors of the presence of CTO in non-infarct-related artery. Although some were also independent predictors of both CTO and MVD without CTO, we found that presentation in cardiogenic shock and a history of angina were specifically associated with the presence of one or multiple CTOs.

The post-PCI abnormal epicardial or myocardial flow in infarct-related artery which occurred more frequently in patients with one CTO or with multiple CTOs, could be partly explained by the longer total ischaemic time in those patients compared with patients without CTO. Moreover, patients with CTO in one epicardial coronary artery lost one of two possible collateral supports resulting in less blood supply to the infarct-related artery.9

The association between CTO in non-infarct-related artery and survival remains controversial. A few studies have found that CTO in non-infarct-related artery were independent predictors of early or late mortality,7–10 ,16 whereas, other reports have not found such relationship.15 In one of our multivariate models, without taking into account the postprimary percutaneous coronary intervention, left ventricular ejection fraction, or baseline renal function, MVD and CTO were identified as independent predictors of mortality. However, when adjustment for the renal function and postprimary percutaneous coronary intervention left ventricular function was made, MVD remained independently associated with 1-year mortality, but CTO per se was no longer an independent predictor. Studies, which previously identified the presence of CTO as independent predictors of mortality did not include left ventricular ejection fraction, renal function or MVD in their models.7–10 ,16 Our C-index values >0.85 indicate that both our models are very robust. Moreover, in our study, all cine-films were prospectively reviewed and the cut-off values for lesion severity were set at 70% instead of 50%, such as in some previous studies.7 ,10 This is important, as 50% lesions might represent physiologically non-significant lesions.

Yet, we believe that CTO is still a marker of disease severity, as CTO was an independent predictor of lower left ventricular ejection fraction after the index STEMI. For the first time, we also report that the risk of mortality in patients with multiple CTOs in non-infarct-related arteries is exceedingly high. It is important to realise that most patients with CTO in non-infarct-related artery die very early after primary percutaneous coronary intervention of the culprit vessel. Given the frequent association of cardiogenic shock and the presence of one and particularly multiple CTOs, it is likely that a significant number of those patients even die prior to undergoing primary percutaneous coronary intervention.

Recently, a small study has suggested better outcomes in patients undergoing successful early CTO recanalisation after STEMI.21 In patients who have survived the acute phase, the EXPLORE (The Evaluating Xience V and left ventricular function in Percutaneous coronary intervention on occLusiOns afteR ST-Elevation myocardial infarction) randomised trial (trialregister.nl:NTR1108) will evaluate whether CTO recanalisation within 7 days may improve left ventricular ejection fraction and clinical outcomes.22 Conversely, with the advancement of CTO techniques and better results associated with primary percutaneous coronary intervention of CTO,23 ,24 it is tempting to speculate that earlier CTO revascularisation could perhaps influence clinical outcomes in patients presenting later with STEMI. Properly conducted randomised trials with clinical end-points and long-term follow-up will be required in the future.

Study limitations

Our study included patients from a single centre. In many patients, the age of the CTO cannot be determined with confidence, but was assumed after careful examination of the lesion morphology to be ≥3 months old and, consequently, considered as true CTO.25 By excluding patients with history of CABG, we excluded a number of patients with CTO. Nonetheless, patients with previous CABG and AMI remain at high risk for early and late mortality26 ,27 and, therefore, it could be difficult to appreciate the prognosis of CTO in the setting of STEMI in those patients.

Conclusion

In unselected patients with STEMI referred for primary percutaneous coronary intervention, the presence of one CTO or multiple CTOs in non-infarct-related artery is not rare. Importantly, a few simple clinical factors may permit to suspect the presence of CTO in non-infarct-related artery upon STEMI presentation. Mortality in patients with CTO in non-infarct-related artery is higher than in patients with MVD without CTO. However, after adjustment for left ventricular ejection fraction and renal function, MVD remains an independent predictor of 1-year mortality, but not CTO.

Acknowledgments

OF Bertrand, E Larose and S Rinfret are research scholars of the Quebec Foundation for Health Research. We thank Micheline Charron for her contribution to data collection.

References

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Footnotes

  • Funding Y Bataille received a fellowship grant from the Centre Hospitalier Régional ‘Citadelle’, Liège, Belgium, and a research fellowship grant from the ‘Fonds Léon Fredericq’ at University of Liège, Belgium.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was obtained from Laval Hospital Ethics Review Board, Quebec City, Canada, Quebec Heart-Lung Institute IRB.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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