Abstract: Background. The impact of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) on angina and subsequent incidence of major adverse cardiovascular event (MACE) rate remains controversial. Methods. We compared patient-reported angina change and the incidence of MACE (defined as death, myocardial infarction [MI], target-vessel revascularization) between successful vs failed CTO-PCI in 1612 patients participating in a large, multicenter registry. Results. CTO-PCI was successful in 1387 patients (86%). Compared with failed CTO-PCI, successful CTO-PCI patients were less likely to have history of heart failure (33% vs 41%; P=.02), prior MI (49% vs 62%; P<.01), or prior coronary revascularization (63% vs 71% [P=.03] for PCI and 30% vs 40% [P<.01] for coronary artery bypass graft surgery). Patients in the successful CTO-PCI group had lower J-CTO scores (2.4 ± 1.3 vs 3.1 ± 1.1; P<.01) and lower PROGRESS-CTO Complications scores (1.1 ± 1.0 vs 1.6 ± 1.0; P<.01). After a mean follow-up of 181 ± 153 days, patients with successful PCI were more likely to have angina improvement (83% vs 38%; P<.01) and had lower incidence of 1-year MACE (8% vs 15%; P<.01), death (3% vs 7%; P<.01), and MI (2% vs 4%; P=.02). On multivariable analysis, however, CTO-PCI success was not independently associated with MACE. Conclusion. Compared with failed CTO-PCI, successful CTO-PCI is associated with better angina improvement and lower incidence of MACE (on univariable analysis) during follow-up.
J INVASIVE CARDIOL 2020 June 22 (Epub Ahead of Print).
Key words: chronic total occlusion, follow-up, major adverse cardiovascular events, percutaneous coronary intervention, symptom improvement
Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has 49%-59% technical success at less-experienced centers vs 86%-91% at experienced centers, which is lower than success of non-CTO PCI.1-9 CTO-PCI carries risk of complications, and should be attempted when the anticipated benefits exceed the potential risks. According to a recently published global expert consensus, the primary indication for CTO-PCI is symptom improvement,10 as is true for PCI in all patients with stable coronary artery disease. Whether CTO-PCI can reduce the risk for a subsequent major adverse cardiovascular event (MACE) remains controversial. We analyzed a large, multicenter, CTO-PCI registry to determine the impact of successful CTO-PCI on patient-reported angina and mid-term MACE rate.
We evaluated 1612 patients who underwent 1615 CTO-PCIs and were included in the PROGRESS-CTO registry (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention; NCT02061436) between January 2012 and November 2019 and had clinical follow-up. Follow-up was performed as per standard of clinical care at each center participating in the PROGRESS-CTO registry. Patients who underwent more than 1 CTO-PCI during the same procedure with discordant outcome for each lesion were excluded. We compared the clinical, technical, and procedural characteristics, as well as patient-reported angina change and the composite endpoint of death, myocardial infarction (MI), and coronary revascularization at 1 year between patients with technically successful vs failed CTO-PCI.
Coronary CTOs were defined as coronary lesions with Thrombolysis in Myocardial Infarction (TIMI) grade 0 flow of at least 3-month duration. Estimation of the duration of occlusion was clinical, based on the first onset of angina, prior history of MI in the target-vessel territory, or comparison with a prior angiogram. Calcification was assessed by angiography as mild (spots), moderate (involving ≤50% of the reference lesion diameter), and severe (involving >50% of the reference lesion diameter). Moderate proximal vessel tortuosity was defined as the presence of at least 2 bends >70° or 1 bend >90° and severe tortuosity as 2 bends >90° or 1 bend >120° in the CTO vessel. Proximal cap ambiguity was defined as the inability to determine the exact location of the proximal cap of the occlusion due to the presence of obscuring side branches or overlapping branches that could not be resolved despite multiple angiographic projections or by flush ostial occlusion. Interventional collaterals were defined as collaterals considered amenable to crossing by a guidewire and a microcatheter by the operator. Antegrade wire escalation (AWE) was defined as antegrade PCI during which the guidewire crossed the lesion from “true to true” lumen. A procedure was defined as retrograde if an attempt was made to cross the lesion through a collateral vessel or bypass graft supplying the target vessel distal to the lesion. Antegrade dissection/re-entry (ADR) was defined as antegrade PCI during which a guidewire was intentionally introduced into the subintimal space proximal to the lesion, or re-entry into the distal true lumen was attempted following intentional or inadvertent subintimal guidewire or device crossing.
Technical success was defined as successful CTO revascularization with achievement of <30% residual diameter stenosis within the treated segment and restoration of TIMI grade 3 antegrade flow. In-hospital MACE included any of the following adverse events prior to hospital discharge: death, myocardial infarction (MI), recurrent symptoms requiring urgent repeat target-vessel revascularization with PCI or coronary artery bypass graft (CABG) surgery, tamponade requiring either pericardiocentesis or surgery, and stroke. MI was defined using the Third Universal Definition of Myocardial Infarction.11 One-year MACE was defined as the composite of death, MI, and target-vessel revascularization. The Japan-Chronic Total Occlusion (J-CTO) score was calculated as described by Morino et al,12 the PROGRESS-CTO score as described by Christopoulos et al,13 and the PROGRESS-CTO Complications score as described by Danek et al.14
Statistical analysis. Categorical variables were expressed as percentages and were compared using Pearson’s Chi-square test or 2-tailed Fisher’s exact test. Continuous variables were presented as mean ± standard deviation or median with interquartile range (IQR) and were compared using the t-test or Wilcoxon rank-sum test, as appropriate. The incidence of clinical events during follow-up was calculated using the Kaplan-Meier method, and between-group comparisons were done using the log-rank test. Cox proportional hazards analysis was used to examine the association between technical success and the composite endpoint of death, MI, and revascularization at 1 year after adjusting for confounding variables selected on univariable association (P<.10). All statistical analyses were performed with JMP, version 14.0 (SAS Institute). A two-sided P-value of .05 was considered statistically significant.
The clinical characteristics of the study patients are described in Table 1. Patients who had successful CTO-PCI were less likely to have a history of heart failure (33% vs 41%; P=.02), MI (49% vs 62%; P<.01), or coronary revascularization (63% vs 71% [P=.03] for PCI and 30% vs 40% [P<.01]) for CABG. There was no difference in antianginal medication use between the two groups.
Angiographic and technical characteristics are shown in Table 2. Patients who had successful CTO-PCI had lower J-CTO scores (2.4 ± 1.3 vs 3.1 ± 1.1; P<.01), PROGRESS-CTO scores (1.1 ± 1.0 vs 1.6 ± 1.0; P<.01), and PROGRESS-CTO Complications scores (2.8 ± 2.0 vs 3.4 ± 2.0; P<.01). ADR (24% vs 39%; P<.01) and the retrograde approach (31% vs 54%; P<.01) were used more often in patients with failed CTO-PCI, while intravascular ultrasound was used more frequently in patients who had successful CTO-PCI.
Procedural outcomes are presented in Table 3. The incidence of perforation (0.9% vs 3.1%; P<.01) and in-hospital MACE (2.4% vs 8%; P<.01) was lower in patients with technical success.
After a mean follow-up of 181 ± 153 days, patient-reported angina improved more often in the patients in whom CTO-PCI was successful (Figure 1). The 1-year incidence of MACE (8% vs 15%; P<.01), death (3% vs 7%; P<.01), and MI (2% vs 4%, P=.02) was lower in the technical success group, while there was no difference in coronary revascularization (4% vs 2%; P=.49) (Figure 2). Οn multivariable analysis, diabetes mellitus (hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.17-2.34) and the PROGRESS-CTO Complications score (HR, 1.20; 95% CI, 1.09-1.31) were independently associated with higher incidence of the composite endpoint (Figure 3). In contrast, technical success was not independently associated with MACE (HR, 0.66; 95% CI, 0.44-1.03).
The main findings of our study are that successful CTO-PCI is associated with angina improvement and lower incidence of MACE during follow-up. Moreover, the PROGRESS-CTO Complications score is independently associated with a higher incidence of MACE during 1-year follow-up.
Symptoms. Observational studies and randomized clinical trials have shown symptom improvement after successful CTO-PCI. Sapontis et al reported that quality of life, captured by the Seattle Angina Questionnaire (SAQ) score, the Rose Dyspnea Scale, and the Patient Health Questionnaire 8, improved significantly after CTO-PCI.4 The multicenter EURO-CTO trial randomized 396 patients to either optimal medical therapy (OMT) or CTO-PCI and used the Seattle Angina Questionnaire to assess the change in quality of life between baseline and 12-month follow-up.15 At 12 months, patients in the CTO-PCI arm had greater improvement in angina frequency (HR, 5.23; 95% CI, 1.75-8.71; P<.01), and quality of life (HR, 6.62; 95% CI 1.78-11.46; P<.01). The IMPACTOR-CTO (Impact on Inducible Myocardial Ischemia of PercutAneous Coronary InTervention versus Optimal Medical TheRapy in Patients with Right Coronary Artery Chronic Total Occlusion) single-center trial randomized 94 patients with right coronary artery CTO to either PCI or OMT.16 Patients assigned to the CTO-PCI group experienced improvement in quality of life as assessed by the Short Form-36 Health Survey. In contrast, the randomized DECISION-CTO (Drug-Eluting Stent Implantation Versus Optimal Medical Treatment in Patients With Chronic Total Occlusion) trial showed no difference between the CTO-PCI and no CTO-PCI group in subsequent quality of life.17 DECISION CTO, however, enrolled patients with mild baseline symptoms and had high crossover rates (21% crossed over from the no-CTO PCI arm to the CTO-PCI arm immediately after randomization).18
In our study, angina improvement was more frequent in patients with technical success compared with patients with technical failure. In addition to relief of ischemia, angina improvement could be partially related to the placebo effect of PCI, partial flow restoration that is achieved in subintimal plaque modification procedures in the failed CTO-PCI group, and to antianginal medication intensification.19
MACE rates. Multiple observational studies have demonstrated an association between successful CTO-PCI and higher survival and lower mid- and long-term MACE rates.20-23 In a meta-analysis of 25 observational studies, successful CTO-PCI was associated with lower risk for death (odds ratio [OR], 0.52; 95% CI, 0.43-0.63) and MACE (OR 0.59; 95% CI, 0.44-0.79), but not target-vessel revascularization (OR, 0.66; 95% CI, 0.36-1.23) or MI (OR, 0.73; 95% CI, 0.52-1.03) compared with failed CTO-PCI, during a median follow-up of 3 years.20 In the RECHARGE (REgistry of Crossboss and Hybrid procedures in FrAnce, the NetheRlands, BelGium and UnitEd Kingdom) registry that enrolled 1165 patients, the 1-year MACE-free survival (defined as the composite endpoint of death, MI, target-vessel and target-lesion revascularization) was significantly higher after successful vs failed CTO-PCI (8% vs 13%; P=.04),24 even after adjustment for baseline differences (HR, 0.59; P=.04). Similar to our study, in a recent prospective trial of 145 patients (137 with available 12-month follow-up data) by Wu et al, 1-year mortality (HR, 0.49; 95% CI, 0.003-0.817) and MACE rate, defined as the composite of death, MI, and target-vessel revascularization (HR, 0.026; 95% CI, 0.004-0.176; P<.001) were both significantly lower in patients with successful revascularization.25 In contrast to our study, technical success was independently associated with lower 1-year MACE on multivariable analysis in the RECHARGE and Wu et al trials. 24,25
Studies by Yamamoto et al26 and Lee et al27 did not show a difference in survival of patients with successful CTO-PCI at 3-year and 4.6-year follow-up, respectively. In both trials, however, target-vessel revascularization after failed CTO-PCI was high (approximately 20%), which indicates that a significant percentage of patients with an initial “unsuccessful” procedure were likely successfully revascularized. Studies comparing successful vs failed CTO-PCI published between 2015 to 2019 are shown in Table 4.
The PROGRESS-CTO Complications score was introduced by Danek et al in 2016.14 It incorporates patient (age), angiographic (lesion length), and technical characteristics (use of retrograde crossing strategy) to predict the risk of in-hospital MACE in patients undergoing CTO-PCI. Our study demonstrated that higher PROGRESS-CTO Complications score was also associated with higher risk of 1-year MACE, which may reflect the contribution of older age and more complex CTO characteristics to subsequent outcomes.
Observational studies are subject to bias. It is likely that the higher complication rates related with failed interventions contributed to higher MACE rates. In addition, failed PCI might be a marker of advanced coronary artery disease and other comorbidities that may lead to worse outcomes. Determining whether successful CTO-PCI may improve survival requires large, well-designed, randomized trials. Two such trials are currently ongoing — the NOBLE-CTO trial (Nordic-Baltic Randomized Registry Study for Evaluation of PCI in Chronic Total Coronary Occlusion; NCT03392415) and the ISCHEMIA-CTO trial (International Randomized Trial on the Effect of Revascularization or Optimal Medical Therapy of Chronic Total Coronary Occlusions With Myocardial Ischemia; NCT03563417).
Study limitations. Our study has limitations. Lower incidence of MACE did not hold up on multivariable analysis and should therefore be interpreted cautiously. PROGRESS-CTO is an observational, retrospective study without core laboratory assessment of the study angiograms or clinical event adjudication. Follow-up was not available in all registry patients. The procedures were performed in dedicated, high-volume CTO centers by experienced operators, limiting extrapolation to less-experienced operators and lower-volume centers. Finally, symptom improvement was not evaluated by a standardized questionnaire.
Successful CTO-PCI is associated with higher likelihood of angina improvement and lower incidence of 1-year-MACE. Prospective, randomized trials are needed to confirm these findings.
Acknowledgments. Study data were collected and managed using Research Electronic Data Capture (REDCap) electronic data capture tools hosted at the Minneapolis Heart Institute Foundation (MHIF), Minneapolis, Minnesota. REDCap is a secure, web-based application designed to support data capture for research studies, providing: (1) an intuitive interface for validated data entry; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for importing data from external sources.
From the 1Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, Abbott Northwestern Hospital, Minneapolis, Minnesota; 2Meshalkin Novosibrisk Research Institute, Novosibirsk, Russia; 3Cleveland Clinic, Cleveland, Ohio; 4Medical Center of the Rockies, Loveland, Colorado; 5Henry Ford Hospital, Detroit, Michigan; 6University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 7Wellstar Health System, Marietta, Georgia; 8Massachusetts General Hospital, Boston, Massachusetts; 9Tristar Centennial Medical Center, Nashville, Tennessee; 10Oklahoma Heart Institute, Tulsa, Oklahoma; 11Emory University Hospital Midtown, Atlanta, Georgia; 12VA San Diego Healthcare System and University of California San Diego, La Jolla, California; 13Baylor Heart and Vascular Hospital, Dallas, Texas; 14Red Cross Hospital of Athens, Athens, Greece; 15VA North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, Texas; and 16Columbia University, New York, New York.
Funding: Abbott Northwestern Hospital Foundation Innovation Grant and Gift from Joseph F. and Mary M. Fleischhacker Foundation.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Khatri reports speaker/proctor fees from Asahi Intecc and Abbott Vascular. Dr Alaswaad reports consulting fees from Terumo and Boston Scientific; consultant, non-financial, for Abbott Laboratories. Dr Jaffer reports consultant fees from Abbott Vascular, Boston Scientific, and Siemens; grant support from Canon, Siemens, and the National Institutes of Health. Dr Jaber reports personal fees from Abbott Vascular and Medtronic. Dr Jefferson reports honoraria/consulting/speaking fees from Abbott, Boston Scientific, CSI, and Medtronic. Dr M. Patel reports speakers’ bureau fees from Astra Zeneca. Dr Mahmud reports consulting fees from Medtronic and Corindus; speaker’s fees from Medtronic, Corindus, and Abbott Vascular; educational program fees from Abbott Vascular; and clinical events committee fees from St. Jude. Dr Rangan reports grant support from InfraReDx and Spectranetics. Dr Garcia reports consulting fees from Medtronic. Dr Banerjee reports grant support from Gilead and The Medicines Company; consultant/speaker honoraria from Covidien and Medtronic; ownership in MDCare Global (spouse); intellectual property in HygeiaTel. Dr Burke reports shareholder income from MHI Ventures and Egg Medical. Dr Brilakis reports consulting/speaker honoraria from Abbott Vascular, American Heart Association (associate editor, Circulation), Biotronik, Boston Scientific, Cardiovascular Innovations Foundation (Board of Directors), CSI, Elsevier, InfraRedx, GE Healthcare, Siemens, Teleflex and Medtronic; research support from Siemens, Regeneron, and Osprey; shareholder in MHI Ventures. Dr Karmpaliotis reports speaker honoraria from Abbott Vascular, Boston Scientific, Medtronic, and Vascular Solutions. The remaining authors report no conflicts of interest regarding the content herein.
Manuscript submitted February 3, 2020, provisional acceptance given February 5, 2020, final version accepted February 10, 2020.
Address for correspondence: Emmanouil S. Brilakis, MD, PhD, Minneapolis Heart Institute, 920 E 28th Street #300, Minneapolis, Minnesota 55407. Email: firstname.lastname@example.org.
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