Clinical Outcome of Successful Percutaneous Coronary Intervention for Chronic Total Occlusion: Results From the Multicenter Korean Chronic Total Occlusion (K-CTO) Registry

Abstract: Objectives. To investigate the impact of the success or failure of chronic total occlusion (CTO) interventions on the clinical outcomes in the current drug-eluting stent (DES) era. Background. The impact of the successful CTO intervention on long-term clinical outcomes still remains unclear. Methods. Between 2007 and 2009, a total of 2568 patients with CTO were followed in a multicenter Korean CTO registry. Of these, successful recanalization with DESs occurred in 2045 patients (successful CTO group), whereas failure occurred in 523 patients (failed CTO group). Results. The occurrence of the composite of cardiac death and myocardial infarction (MI) was compared between the successful CTO and failed CTO groups. During follow-up (median duration, 729 days), the occurrence of cardiac death or MI was significantly lower in the successful CTO group than in the failed CTO group (1.7% vs 3.3%; hazard ratio, 0.50; 95% confidence interval, 0.28-0.91; P=.02) and the cumulative occurrence in the successful CTO group was also significantly lower than in the failed CTO group (1.7% vs 3.0%; P=.03) by the Kaplan-Meier method. The successful CTO group had a significantly lower need for bypass surgery than the failed CTO group (0.2% vs 2.5%; P<.001). In multivariate analysis, procedural success of CTO (odds ratio, 0.51; 95% CI, 0.29-0.92) was significantly predictive of the occurrence of cardiac death or MI, together with age and left ventricular ejection fraction <40%. Conclusion. This registry study demonstrated that successful CTO intervention with DESs compared to failed CTO intervention was associated with lower event rates during follow-up.

J INVASIVE CARDIOL 2014;26(6):255-259

Key words: coronary occlusion, drug-eluting stents, clinical outcomes

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Percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) remains challenging. However, due to improvements in the technologies and techniques used for PCIs for CTO, the rate of procedural success is increasing.^1-3 In addition, with the introduction of drug-eluting stent (DES) implantation, which effectively suppresses neointimal growth and exhibits effectiveness in high-risk patients, ie, those with diabetes or acute coronary syndrome as well as those with complex lesions such as small-vessel diseases or diffuse long lesions, a better clinical outcome via the successful recanalization of CTOs could be expected.^4-7 However, as the use of DESs in complex lesions including CTO increased, safety concerns regarding DESs have been raised.^8-10 Recently, data regarding the successful recanalization of CTOs were reported.^11-13 However, the long-term clinical benefits of successful PCIs for CTO remain unclear, and additional research with larger populations and different ethnic groups is needed. Therefore, we sought to investigate the impact of the success or failure of CTO interventions on long-term clinical outcomes for a large cohort of Korean patients undergoing CTO interventions in the era of DES implantation. 

Methods

From January 2007 to December 2009, a total of 2568 patients who underwent PCI for CTO in the 26-center Korean CTO (K-CTO) registry and who met the criteria of this study were enrolled and finally analyzed. True CTO was defined as an obstruction of a native coronary artery with Thrombolysis In Myocardial Infarction (TIMI) flow 0 and an estimated duration of occlusion of at least 3 months based on the patient’s clinical history or a previous coronary angiogram.^14,15 The duration of CTO was determined by the interval from the last episode of acute coronary syndrome or from the first episode of effort angina consistent with the location of the occlusion in patients without histories of acute coronary syndrome.^11,16 All patients had a typical symptomatic angina or a positive test in various functional studies evaluating ischemia. Exclusion criteria were: presentation with acute myocardial infarction (MI) or cardiogenic shock; undergoing only bare-metal stent (BMS) implantation or balloon angioplasty without DES implantation; CTO lesions with DES restenosis, graft vessel occlusion, or culprit lesion of acute coronary syndrome within 4 weeks; severe hepatic dysfunction (≥3 times normal reference values); life expectancy <3 years; or contraindication to antiplatelet agents. All patients provided written informed consent, and the institutional review boards at each center approved this study. 

PCI was performed according to current guidelines using conventional techniques. All patients received at least 75 mg of aspirin before PCI. The administration of a loading dose of 300 mg of clopidogrel at least 12 h before the procedure or a maintenance dose of 75 mg of clopidogrel for >5 days was performed before PCI. The use of intravascular ultrasound, glycoprotein IIb/IIIa inhibitors, and postadjuvant balloon dilation, as well as the approach and devices used for CTO, were left to the operator’s discretion. After PCI, dual-antiplatelet therapy with aspirin and clopidogrel was used for at least 12 months. Regardless of the success of the CTO intervention, the use of statins was strongly recommended.

The successful CTO group was defined as the patients with a final TIMI flow grade ≥2 and ≤30% residual stenosis on visual estimation after successful recanalization of at least one CTO with DES implantation. Patients lacking these findings comprised the failed CTO group. Patients were included in the successful CTO or failed CTO group depending on whether the CTO PCI was successful or unsuccessful at the time of registration in our registry. Patients undergoing an initial failed procedure but undergoing a subsequent successful attempt were included the successful CTO group. 

The primary endpoint of this study was the occurrence of cardiac death or MI during follow-up. Death due to any cause, the incidence of repeat revascularization, and the need for bypass surgery were also assessed between the groups. All deaths were considered cardiac unless a definite non-cardiac cause could be established. Myocardial infarction was defined as the presence of clinical symptoms, electrocardiographic changes, or abnormal imaging findings of MI combined with an increase in the creatine kinase myocardial band fraction to greater than 3x the upper reference or troponin T/troponin I levels greater than the 99th percentile of the upper normal limit, unrelated to an interventional procedure.¹⁷ Stent thrombosis was assessed according to the Academic Research Consortium (ARC) definitions.¹⁸ Repeat revascularization included all kinds of revascularization methods, including PCI or bypass surgery following index procedures. All data was collected by web-based system and clinical follow-up was performed at 1, 3, 6, 9, and 12 months after the index procedure, and then annually thereafter. 

All data are expressed as number (percentage) or mean ± standard deviation. Continuous variables were compared using an independent T-test, whereas categorical variables were compared by the chi-square test or Fisher’s exact test. Cumulative incidences were calculated using the Kaplan-Meier method and compared using the log-rank test. Cox’s proportional hazard model was used for calculating hazard ratios and determining the predictors of clinical events. To identify the predictors of the occurrence of endpoints, multivariate analysis was performed. In the multivariate analysis, variables displaying significant relationships with hard endpoint in previous DES studies and those with P-values <.10 in univariate analysis were included in the model. P-values <.05 were considered statistically significant. Statistical Package for the Social Sciences (SPSS, version 19; IBM) and R version 2.10 (R Development Core Team) were used for these analyses.

Results

Among the patients enrolled in the K-CTO registry study (n = 2568), a total of 2045 patients (80%) who underwent successful CTO PCI with DESs were included in the successful CTO group, whereas the remaining 523 patients (20%) were included in the failed CTO group. The baseline characteristics of both groups are presented in Table 1. Compared with the failed CTO group, the successful CTO group was significantly younger, and this group had lower incidences of previous MI, PCIs, bypass surgery, and multivessel diseases. Concerning the lesion characteristics, the successful CTO group was more likely to have a shorter CTO length, a higher frequency of CTO at left anterior descending artery, and a lower incidence of unfavorable CTO characteristics, such as blunt stump, occlusion at side branch, or presence of bridging collaterals, than the failed CTO group. 

During follow-up (median duration, 729 days; interquartile range, 650-757 days), the successful CTO group exhibited a significantly lower occurrence of the primary endpoint than the failed CTO group (1.7% vs 3.3%; hazard ratio, 0.50; 95% confidence interval, 0.28-0.91; P=.02) (Table 2). In the Kaplan-Meier analysis, the cumulative incidence of the primary endpoint was significantly lower in the successful CTO group than in the failed CTO group (1.7% vs 3.0%; P=.03, log-rank test) (Figure 1A). The 12- and 24-month cumulative incidences of the primary endpoint were significantly lower in the successful CTO group than in the failed CTO group (12-month cumulative incidence: 1.3% vs 2.8%, P=.01; 24-month cumulative incidence: 1.6% vs 3.0%, P=.02). The composite rate of cardiac death, MI, and repeat revascularization was not significantly different between the successful CTO and failed CTO groups (Table 2, Figure 1B). In the comparison of each component, the successful CTO group showed the significantly lower occurrences of cardiac death (1.2% vs 2.7%; P=.02) and the need for bypass surgery (0.2% vs 2.5%; P<.001) without a significant increase in the stent thrombosis or repeat revascularization rate (Table 2).

Multivariate analysis was performed to determine the predictors of the occurrence of the primary endpoint. In the analysis, procedural success for CTO, age, and left ventricular ejection fraction <40% were identified as significant predictors of the occurrence of cardiac death or MI (Table 3).

Discussion

This CTO study conducted using the K-CTO registry demonstrated that successful CTO intervention using DESs compared to failed CTO intervention was significantly associated with lower occurrences of the composite of cardiac death and MI or cardiac mortality during follow-up. In addition, successful CTO intervention showed a significant association with the lower rate of need for bypass surgery. In multivariate analysis, procedural success for CTO was one of the significant predictors of the occurrence of the composite of cardiac death or MI. As for the efficacy and safety concerns of DESs in the successful CTO group, no significant difference in the rate of repeat revascularization was noted between the groups. The rate of stent thrombosis in the successful CTO group was not high, suggesting that the use of DESs in CTO interventions was effective and safe. 

Although several studies recently compared clinical outcomes after successful and failed CTO interventions, conflicting findings were reported.^{11-13,16,19-22} According to a meta-analysis incorporating 7288 patients across 13 observational studies, successful PCIs for CTO were significantly associated with a reduced the risk of mortality during a 6-year follow-up period by 44%.¹⁹ Other retrospective studies also reported that successful PCIs for CTO were associated with reduced cardiac mortality, need for CABG, and the composite occurrence of death, MI, and repeat revascularization.^12,13,16 In a more recent meta-analysis, it was reported that successful PCIs for CTO were associated with improved clinical outcomes, including a reduction in the rate of all-cause mortality.²² Contrary to these positive findings, other studies did not confirm these results.^11,20 In a study of 346 patients with CTO who were monitored for 5 years, successful CTO revascularization was not associated with a reduction in the occurrences of death or rehospitalization for cardiovascular causes.²⁰ Similar findings regarding the lack of a clinical effect of successful PCIs for CTO on mortality have been reported.^11,21

Prior CTO studies had some limitations, such as: (1) small number of enrolled patients with CTO; (2) inclusion of patients with bare-metal stent implantation or balloon angioplasty without stent implantation, resulting in efficacy issues; and (3) a lack of data on Asian patients.^{11-13,16,19-22} Unlike these studies, our study included a relatively large number of Asian patients (2568 patients) who underwent both failed and successful CTO interventions using DESs and enrolled patients treated in a relatively short period (2007-2009), which might better reflect the current technique and technology for CTO interventions and recent trends in the use of medication. In particular, all patients in the successful CTO group in the K-CTO registry were treated using DESs, and new-generation DESs, modified stent platforms, and drug-carrying systems with different drugs were used in some patients. Under these conditions, our CTO study revealed positive clinical outcomes following successful CTO interventions, including the significant association with a reduction in cardiac mortality. These findings may support the advantages of the successful revascularization of CTOs and long-term safety of DES use in CTO interventions. However, because first-generation DESs might cause poor long-term outcomes due to very late DES thrombosis despite their proven efficacy, a longer follow-up is needed for a definitive conclusion.²³

Successful CTO revascularization has many potential benefits. First, as demonstrated by our results, successful CTO revascularization could bring the reduction of the need for bypass surgery. Second, successful CTO revascularization may improve left ventricular function and wall motion, prevent further ventricular remodeling, decrease electrical instability, increase the tolerance of future coronary occlusion events, and decrease the risk of fatal arrhythmic events and mortality.^16,24-26 It has also been reported that patients with acute MI have a higher 1-year mortality rate, primarily due to the presence of CTO in a non-infarct related artery, meaning that untreated CTO can influence the occurrence of fatal complications irrespective of culprit lesions.²⁷ Third, while failed CTO interventions were related to incomplete revascularization and associated with a higher mortality rate during follow-up, successful CTO revascularization could cause complete revascularization, known as one of the most important strategies for patients with multivessel diseases, and improve long-term clinical outcomes.^28,29

Study limitations. There are several limitations to this study. First, this was a retrospective, non-randomized registry study. Second, although a relatively large number of patients with CTO were enrolled in the K-CTO registry study, some concerns regarding the statistical power related to the sample size and statistical methods used to compare the two groups could be raised. In addition, because the baseline characteristics were quite different between the successful CTO group and the failed CTO group, a statistical method like propensity-matching analysis could be needed for balancing the different baseline characteristics between the groups. However, this method could cause other potential problems such as statistical underpowering by the unbalanced ratio between the two groups. Also, because the success or failed CTO was the final determined result rather than a selectable variable, the crude analysis of the entire population and final multivariate analysis as performed in this study could be better. Third, the median follow-up duration in this CTO study was 2 years, thus necessitating a study with longer-term follow-up. Fourth, because this was a registry study using only restrictive data, there was a paucity of information on the exact use of medication and its duration, especially drugs affecting long-term clinical outcomes, detailed angiographic parameters or data regarding ischemic burdens, use of cardiodefibrillators, and changes in the laboratory data. In addition, there were no data on the questionnaire regarding symptom improvement or aggravation during follow-up and no analyses of the detailed reasons for the patients with repeat revascularization. Finally, this study compared outcomes between successful and failed CTO interventions, but not between PCI and medical therapy for CTO. Therefore, the applicability of our findings is confined to patients undergoing PCIs for CTO. 

Conclusion

This registry study demonstrated that successful revascularization with DESs compared to failed revascularization was associated with a lower occurrence of the composite of cardiac death and MI, cardiac death, and the need for bypass surgery in patients with CTO, and successful revascularization was one of the significant predictors of the occurrence of the composite endpoint. However, for a definitive conclusion regarding the role of PCI for patients with CTO, a prospective, randomized study comparing PCIs for CTO with medical therapy will be needed in the future. 

References

1. Suero J, 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(2):409-414.
2. Werner GS, Krack A, Schwarz G, et al. Prevention of lesion recurrence in chronic total coronary occlusions by paclitaxel-eluting stents. J Am Coll Cardiol. 2004;44(12):2301-2306.
3. Rathore S, Katoh O, Matsuo H, et al. Retrograde percutaneous recanalization of chronic total occlusion of the coronary arteries: procedural outcomes and predictors of success in contemporary practice. Circ Cardiovasc Interv. 2009;2(2):124-132.
4. Schofer J, Schlüter M, Gershlick AH, et al. Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: double blind randomized controlled trial (E-SIRIUS). Lancet. 2003;362(9390):1093-1099.
5. Scheen AJ, Warzee F, Legrand VM. Drug-eluting stents: meta-analysis in diabetic patients. Eur Heart J. 2004;25(23):2167-2168.
6. Suttorp MJ, Laarman GJ, Rahel BM, et al. Primary stenting of totally occluded native coronary arteries II (PRISON II): a randomized comparison of bare metal stent implantation with sirolimus-eluting stent implantation for the treatment of total coronary occlusions. Circulation. 2006;114(9):921-928.
7. Hannan EL, Racz M, Walford G, et al. Drug-eluting versus bare-metal stents in the treatment of patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Interv. 2008;1(2):129-135.
8. Moreno R, Fernández C, Hernández R, et al. Drug-eluting stent thrombosis. J Am Coll Cardiol. 2005;45(6):954-959.
9. Beohar N, Davidson CJ, Kip KE, et al. Outcomes and complications associated with off-label and untested use of drug-eluting stents. JAMA. 2007;297(18):1992-2000.
10. Tommaso CL. Long stents as a risk factor for late stent thrombosis. JACC Cardiovasc Interv. 2010;3(4):390-391.
11. Lee SW, Lee JY, Park DW, et al. Long-term clinical outcomes of successful versus unsuccessful revascularization with drug-eluting stents for true chronic total occlusion. Catheter Cardiovasc Interv. 2011;78(3):346-353.
12. Mehran R, Claessen BE, Godino C, et al. Long-term outcome of percutaneous coronary intervention for chronic total occlusions. JACC Cardiovasc Interv. 2011;4(9):952-961.
13. Jones DA, Weerackody R, Rathod K, et al. Successful recanalization of chronic total occlusions is associated with improved long-term survival. JACC Cardiovasc Interv. 2012;5(4):380-388.
14. Stone GW, Kandzari DE, Mehran R, et al. Percutaneous recanalization of chronically occluded coronary arteries: a consensus document: part I. Circulation. 2005;112(15):2364-2372.
15. 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(24):2630-2636.  
16. Niccoli G, De Felice F, Belloni F, et al. Late (3 years) follow-up of successful versus unsuccessful revascularization in chronic total coronary occlusions treated by drug eluting stent. Am J Cardiol. 2012;110(7):948-953.
17. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115(17):2344-2351.
18. Laskey WK, Yancy CW, Maisel WH. Thrombosis in coronary drug-eluting stents: report from the meeting of the Circulatory System Medical Devices Advisory Panel of the Food and Drug Administration Center for Devices and Radiologic Health, December 7-8, 2006. Circulation. 2007;115(17):2352-2357.
19. Joyal D, Afilalo J, Rinfret S. Effectiveness of recanalization of chronic total occlusions: a systematic review and meta-analysis. Am Heart J. 2010;160(1):179-187.
20. Jolicoeur EM, Sketch MJ, Wojdyla DM, et al. Percutaneous coronary interventions and cardiovascular outcomes for patients with chronic total occlusions. Catheter Cardiovasc Interv. 2012;79(4):603-612.
21. de Labriolle A, Bonello L, Roy P, et al. Comparison of safety, efficacy, and outcome of successful versus unsuccessful percutaneous coronary intervention in “true” chronic total occlusions. Am J Cardiol. 2008;102(9):1175-1181.
22. Khan MF, Wendel CS, Thai HM, Movahed MR. Effects of percutaneous revascularization of chronic total occlusions on clinical outcomes: a meta-analysis comparing successful versus failed percutaneous intervention for chronic total occlusion. Catheter Cardiovasc Interv. 2013;82(1):95-107.
23. Sarno G, Lagerqvist B, Fröbert O, et al. Lower risk of stent thrombosis and restenosis with unrestricted use of ‘new-generation’ drug-eluting stents: a report from the nationwide Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Eur Heart J. 2012;33(5):606-613.
24. Sirnes PA, Myreng Y, Mølstad P, et al. Improvement in left ventricular ejection fraction and wall motion after successful recanalization of chronic coronary occlusions. Eur Heart J. 1998;19(2):273-281.
25. Silva JC, Rochitte CE, Junior JS, et al. Late coronary artery recanalization effects on left ventricular remodeling and contractility by magnetic resonance imaging. Eur Heart J. 2005;26(1):36-43. 
26. Yang ZK, Zhang RY, Hu J, et al. Impact of successful staged revascularization of a chronic total occlusion in the non-infarct-related artery on long-term outcome in patients with acute ST-segment elevation myocardial infarction. Int J Cardiol. 2013;165(1):76-79.
27. van der Schaaf RJ, Vis MM, Sjauw KD, et al. 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(9):1165-1169.
28. Hannan EL, Racz M, Holmes DR, et al. Impact of completeness of percutaneous coronary intervention revascularization on long-term outcomes in the stent era. Circulation. 2006;113(20):2406-2412. 
29. Vieira RD, Hueb W, Gersh BJ, et al. Effect of complete revascularization on 10-year survival of patients with stable multivessel coronary artery disease: MASS II trial. Circulation. 2012;126(11 Suppl 1):S158-S163.

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*Joint first authors. 

From the ¹Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea; ²Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; ³Seoul National University Hospital, Seoul, South Korea; ⁴Sejong General Hospital, Gyeonggi-do, South Korea; ⁵Kyungpook National University Hospital, Daegu, South Korea; ⁶Korea University Guro Hospital, Seoul, South Korea; ⁷Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Seoul, South Korea; ⁸Dong-A University Hospital, Busan, South Korea; and ⁹Keimyung University Dongsan Medical Center, Daegu, South Korea.

Funding: This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare, Republic of Korea (No. A085012).

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted December 10, 2013, provisional acceptance given December 16, 2013, final version accepted January 29, 2014.

Address for correspondence: Prof Yangsoo Jang, Yonsei Cardiovascular Center, Yonsei University College of Medicine, Division of Cardiology of Yonsei Cardiovascular Center, Seodaemun-gu, Shinchondong, Shinchon Severance Hospital, Seoul 120-752, South Korea. Email: Jangys1212@yuhs.ac