Chronic total occlusions (CTO) of the coronary arteries are common among patients presenting to the cardiac catheterization laboratory, and data suggests a worse overall prognosis in patients with CTOs. Percutaneous coronary intervention (PCI) of CTOs has been shown to improve anginal symptoms in observational studies and in a limited number of randomized trials. However, CTO PCI has not been shown to lead to a reduction in other important end points such as myocardial infarction or death. Furthermore, despite recent advances in the field, CTO PCI still carries higher risks and a lower likelihood of success compared with non-CTO PCI. Thus, determining which patients may be appropriate for CTO PCI is challenging and must involve a comprehensive risk-benefit analysis and discussion with the patient. Therefore, we review the currently available data regarding CTO PCI, including the clinical outcomes, the role of preprocedural ischemia testing, and various procedural success and risk stratification scores. Finally, we present our approach to the patient referred for CTO PCI.
Chronic total occlusions (CTOs), defined by the Chronic Total Occlusion Academic Research Consortium as coronary lesions with the absence of anterograde flow (i.e., thrombolysis in myocardial infarction [TIMI] grade 0 flow) with a presumed or documented duration of at least 3 months, are present in 12% to 37% of all-comers to the cardiac catheterization laboratory and 18% to 46% of patients with coronary artery disease (CAD) depending on the population studied. The presence of a CTO has significant prognostic implications, although the benefits of CTO percutaneous coronary intervention (PCI) remain less clear.
In recent years, the development of specialized devices, novel techniques, and dedicated training programs has led to improvement in procedural success rates for CTO PCI. , Therefore, there has been a concomitant increase in the relative percentage of CTO PCI among all PCIs performed, growing from 3% in 2010 to 4% in 2014 (p for trend <0.001). Despite this growth and advancement of the field, CTO recanalization remains among the most challenging procedures for interventional cardiologists, given the inherently high procedural and patient complexity.
Given the clinical equipoise of CTO PCI with regard to many outcomes and the challenges and potential complications of the procedure, operators must be able to critically evaluate which patients may be appropriate for CTO PCI. In the present article, we offer the data that we consider relevant to this goal, including the prognostic implications of CTO, potential benefits of CTO PCI, contemporary complication rates, and pertinent preprocedural planning, including viability testing and risk stratification. Finally, we present our approach to the patient who presents for consideration of CTO PCI as informed by the currently available data.
Prognostic Implications of CTO
CTOs are commonly identified among patients who underwent coronary angiography and have been associated with a greater burden of co-morbidities and poor short- and long-term prognosis. A retrospective study conducted at a Veterans Affairs tertiary referral center analyzed 1,699 patients who underwent coronary angiography and demonstrated that patients with at least 1 CTO were more likely to have co-morbidities and to be referred for coronary artery bypass grafting (CABG). In another large registry, CTOs were associated with lower left ventricular (LV) ejection fraction and a higher prevalence of multivessel coronary disease. Multiple studies have demonstrated that patients with CTOs and incomplete revascularization have significantly greater rates of major adverse cardiovascular events (MACEs) compared with those who underwent complete revascularization. ,
In several studies, the presence of a CTO was associated with higher mortality. A 2016 analysis using the single-center Contemporary Management in Treatment of Heart Failure (COMMIT-HF) registry found that the presence of a CTO was associated with higher 12-month mortality even after multivariable adjustment. Similarly, a subgroup analysis of 3,283 patients enrolled in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial who underwent primary PCI for ST-elevation myocardial infarction (MI) found that CTOs in a non-infarct-related artery were independently associated with both early (0 to 30-day) and late (30-day to 3-year) mortality. Another large registry of 89,872 patients from the Swedish Coronary Angiography and Angioplasty Registry, of whom 14,441 had CTOs, found that CTOs were associated with higher mortality, with the strongest association in patients younger than 60 years.
Clinical Benefits of CTO PCI
Although the presence of CTO has been associated with poor overall prognosis and higher mortality, data linking CTO revascularization to improved outcomes is mixed. Much of the data comes from registries and observational studies. Data from the Outcomes, Patient Health Status, and Efficiency in Chronic Total Occlusion Hybrid Procedures (OPEN-CTO) registry, a multicenter registry of 1,000 consecutive patients who underwent CTO PCI, showed improvements in quality of life, dyspnea, and depression as soon as 1 month after CTO PCI. A number of observational studies also found lower rates of MACE, mortality, cardiac death, acute MI, rehospitalization, and CABG among patients who underwent successful compared with failed CTO PCI or medical therapy. , , Other studies, however, have failed to show any association of successful CTO PCI with lower long-term mortality. ,
Contrary to the abundance of observational data, there are few contemporary randomized trials evaluating CTO PCI ( Table 1 ). These studies had contradictory results with regard to symptom relief but have consistently failed to demonstrate an impact of CTO PCI on MACE, mortality, and LV ejection fraction.
| Study | N | Pertinent Inclusion Criteria | Pertinent Exclusion Criteria | CTO PCI Success Rate | Notable Findings | Limitations |
|---|---|---|---|---|---|---|
| EUROCTO (2018) | 396 |
|
| 86.6% |
|
|
| DECISION-CTO (2019) | 834 |
|
| 90.6% |
|
|
| COMET-CTO (2021) | 100 |
|
| 94% |
|
|
| EXPLORE (2016) | 304 |
|
| 73% |
|
|
| REVASC (2018) | 205 |
|
| 97% |
|
|
| IMPACTOR-CTO (2018) | 94 |
|
| 83% |
|
|
The Randomized Multicentre Trial to Compare Revascularization with Optimal Medical Therapy for the Treatment of Chronic Total Occlusions (EuroCTO) trial, a randomized, multicenter, open-label, controlled trial, randomized 396 patients with stable angina pectoris to either CTO PCI or optimal medical therapy (OMT) >4 weeks after PCI of non-CTO lesions, if present. At 12 months, patients who were randomized to PCI (vs OMT) experienced greater improvement in Seattle Angina Questionnaire (SAQ) subscales (including angina frequency [86.8 vs 92.0, p = 0.003] and quality of life [70.5 vs 77.1, p = 0.007]) and freedom from angina (71.6% vs 57.8%, p = 0.008). However, the incidence of MACE (defined as cardiac death, nonfatal MI, and ischemia-driven premature target lesion revascularization during follow-up) was similar between the 2 groups at 12 months and lower in the PCI group at 3 years. EuroCTO has several limitations. First, the open-label design may have influenced patient-reported symptoms, including SAQ scores through the placebo effect. Second, given funding limitations and slow enrollment, only 396 of the target 600 patients were enrolled. Third, the 2 groups differed significantly in the number of diseased arteries (more 3-vessel patients in the PCI group compared with the OMT group) and proportion of post-CABG patients. Fourth, medical therapy between the 2 groups differed significantly, with antianginals being prescribed more often in the OMT group both at discharge and at follow-up. Within these limitations, the results of the EuroCTO trial remain the best randomized data evaluating CTO PCI to date and suggest that patients who underwent CTO PCI may experience better symptom relief and quality of life than those receiving OMT alone.
The Randomized Trial Evaluating Percutaneous Coronary Intervention for the Treatment of Chronic Total Occlusion (DECISION-CTO) trial, another open-label, multicenter, randomized trial, enrolled patients with silent ischemia, stable angina, or acute coronary syndrome and randomized them to either CTO PCI or non-CTO PCI. Unlike the EuroCTO trial, PCI of other co-existing non-CTO lesions was left to the discretion of the operator. At a median follow-up of 4 years, investigators found no significant difference between the 2 groups in the primary composite outcome of death, MI, stroke, or any revascularization (22.3% in the CTO PCI group and 22.4% in the non-CTO PCI group, p = 0.86) or any of the individual components. Quality-of-life scores increased substantially from baseline in both groups without any significant between-group differences. Despite the negative results of this trial, several limitations must be highlighted. First, similar to EuroCTO, enrollment was stopped short of the planned >1,200 patients secondary to slow enrollment. Second, nearly 20% of patients initially assigned to the non-CTO PCI strategy crossed over and underwent CTO PCI within 3 days of randomization, which by the trial design was considered a protocol deviation rather than an outcome event. Third, about half of the patients in each group underwent PCI of non-CTO lesions, which makes isolating the incremental benefit of CTO PCI on patient symptoms challenging. Fourth, patients enrolled in DECISION-CTO were generally low risk (25% having single vessel disease, overall Synergy between PCI with taxus and Cardiac Surgery (SYNTAX) and Japanese Chronic Total Occlusion (J-CTO) scores were relatively low, and LV ejection fractions were mostly normal). Ultimately, DECISION-CTO found that despite achieving nearly 91% procedural success with low complication rates, CTO PCI conferred no benefit with regard to MACE, any of its individual components, or disease-specific health status and quality of life compared with non-CTO PCI among low-risk patients with generally low-complexity CAD.
With contradictory findings from the EuroCTO and DECISION-CTO trials, the Randomized Controlled Comparison of Optimal Medical Therapy with Percutaneous Recanalization of Chronic Total Occlusion (COMET-CTO) trial was designed to explicitly test whether CTO PCI improved quality-of-life as determined by SAQ and overall well-being compared with OMT alone. Investigators randomized 100 patients with stable angina, myocardial ischemia, and/or myocardial viability in regions supplied by the CTO without other angiographically significant coronary artery stenoses. CTO PCI’s success rate was 94%. After a mean follow-up of 275 days, patients who were randomized to CTO PCI reported lower physical activity limitations (72.7 vs 60.5, p = 0.014), less frequent angina episodes (76.8 vs 89.8, p = 0.006), better quality of life (62.5 vs 79.9, p = 0.001), and greater treatment satisfaction (81.4 vs 91.2, p = 0.003) compared with those who were randomized to OMT alone. The COMET-CTO trial, however, was a relatively small study (100 patients randomized) and was not powered to assess MACE or other hard end points. Further, the CTOs addressed in this trial were of limited complexity based on preprocedural stratification scores and intraprocedural features. Finally, and most notably, patients were not blinded to the study allocation or to the success of the PCI, again subjecting the results to bias by the placebo effect. Acknowledging these limitations, the results of the COMET-CTO trial suggest that patients who underwent successful CTO PCI with OMT experienced significantly improved quality of life compared with those randomized to OMT alone.
The effect of CTO revascularization on 10-year mortality was also examined in the Synergy Between PCI with Taxus and Cardiac Surgery Extended Survival (SYNTAXES) study. In this subanalysis of patients with 3-vessel CAD or left main coronary artery disease who underwent either PCI or CABG, authors found that roughly 25% of patients had a total occlusion and that there was no significant difference in 10-year all-cause mortality between patients who underwent successful revascularization of the CTO compared with those who did not, whether by PCI (29.9% among PCI patients who had CTO revascularized vs 29.4% among PCI patients with no CTO PCI, p = 0.982) or CABG (28.0% among CABG patients with CTO grafting vs 21.4% among CABG patients without CTO grafting, p = 0.330). These results did not differ by total occlusion location or indication for revascularization (3-vessel CAD or left main coronary artery disease). However, revascularization of the total occlusion was associated with improvement in angina frequency.
The Impact on Inducible Myocardial Ischemia of Percutaneous Coronary Intervention versus Optimal Medical Therapy in Patients with Right Coronary Artery Chronic Total Occlusion (IMPACTOR-CTO) trial evaluated the impact of CTO PCI on inducible ischemia burden of the LV. Ninety-four patients with isolated right coronary artery CTO were randomized to CTO PCI with OMT versus OMT alone. Myocardial ischemia burden, as determined by adenosine stress cardiac magnetic resonance, was evaluated at baseline and at 2 and 12 months. Patients who underwent successful CTO PCI had a greater reduction in their myocardial ischemia burden at 12 months compared with those randomized to OMT alone (13.9 ± 6.1% vs 0.3 ± 4.2%, p <0.01). Patients in the CTO PCI arm also achieved increased 6-minute walk distance and higher quality-of-life scores compared with those in the OMT arm.
Although the previously mentioned trials investigated the role of CTO PCI in improving symptoms and mortality, the Randomized Trial to Assess Regional Left Ventricular Function After Stent Implantation in Chronic Total Occlusion (REVASC) trial and the Percutaneous Intervention for Concurrent Chronic Total Occlusions in Patients with STEMI (EXPLORE) trial investigated its effect on LV function. The REVASC trial enrolled patients with CTO to either PCI or no PCI and found no difference in LV segmental wall thickening (SWT) in the CTO territory, regional wall motion, LV volume, or ejection fraction at 6 months. However, subgroup analysis suggested that among patients without major non-CTO obstruction, CTO PCI resulted in improved SWT. The EXPLORE trial similarly found a lack of difference in LV ejection fraction and LV end-diastolic volume among patients who underwent PCI of a non-infarct-related artery CTO within 1 week after successful primary PCI for ST-elevation MI. Subgroup analysis suggested that patients with CTO of the left anterior descending artery may achieve higher LV ejection fraction after CTO PCI.
In sum, observational data, whereas mixed, suggests a possible benefit of CTO PCI in quality-of-life, dyspnea, depression, MACE, mortality, cardiac death, acute MI, rehospitalization, and CABG. More rigorous randomized clinical trial data, however, has failed to demonstrate a consistent relation between successful CTO PCI and improvement in MACE and LV function. To date, the strongest evidence in favor of CTO PCI remains symptom alleviation and improved quality of life. Therefore, the 2021 American College of Cardiology/American Heart Association/Society for the Cardiovascular Angiography and Interventions Guideline for coronary artery revascularization reflects these uncertainties and gives CTO PCI a 2b recommendation in patients with suitable anatomy and angina refractory to medical therapy.
The Role of Viability Testing Before CTO PCI
Given the failure of randomized clinical trials to demonstrate an improvement in MACE and LV function, many have postulated that the presence or absence of myocardial viability in the CTO territory may affect outcomes after CTO PCI. A retrospective cohort study from China found that patients who underwent CTO PCI of nonviable myocardium as defined by fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging were nearly twice as likely to experience death or MI at 5 years than those who underwent CTO PCI of viable myocardium even after adjusting for anatomic complexity, LV function, completeness of revascularization, and technical success. Furthermore, in a substudy of the EXPLORE trial, viable myocardial segments in the CTO territory were more likely to recover function as determined by SWT on cardiac magnetic resonance imaging than nonviable myocardial segments and segments outside the CTO territory. Similarly, a small prospective study of 50 consecutive patients with CTO demonstrated a significant improvement in ischemia burden and LV systolic function after successful CTO PCI of viable myocardial segments.
Although the previously mentioned studies lend some evidence to a potential interaction between CTO-territory myocardial viability and improvement in MACE and LV systolic function, they are either observational in design or subanalyses of larger studies and, therefore, remain hypothesis-generating only. Furthermore, subgroup analysis from the REVASC trial showed no change in LV SWT between patients who underwent CTO PCI and no PCI even among patients with cardiac magnetic resonance confirmed viability of the CTO territory. Randomized clinical trials specifically investigating this interaction are warranted. For now, operators may consider performing preprocedural myocardial viability testing to help identify patients that may be more likely to benefit from CTO PCI, although this remains an area with limited supportive data.
Predicting Procedural Success and Complications in CTO PCI
When considering a patient for CTO PCI, clinicians must weigh the potential clinical benefits of CTO PCI against the likelihood of procedural success and the possibility of a complication. Although early CTO PCI success rates were only about 50% to 70%, more contemporary data shows an increase in technical and procedural success. In the Prospective Global Registry for the Study of Chronic Total Occlusion Intevention (PROGRESS-CTO) registry, for instance, technical success increased from 81.6% in 2016 to 88.1% in 2021. Similar improvement was seen in the European Registry of CTO, with success rates increasing from 79.7% in 2008 to 89.3% in 2015. In the randomized trials previously mentioned, success rates ranged from 83.1% to 94%. , , This overall increase in procedural success is likely because of a combination of factors, including the development of new crossing techniques, CTO-specific devices, dedicated high-volume centers, and the advent of dedicated training programs.
This increase in procedural success has been coupled with a concomitant decrease in complications rates. Although early periprocedural MACE rates were almost 4%, contemporary data suggests that this rate is now <2%, nearing that of non-CTO interventions. , , , In the NCDR, for example, MACE rate trended down from 1.9% in 2009 to 1.3% in 2013. Rates of other complications of CTO PCI, including perforation, tamponade, contrast nephropathy, and vascular access site complications, have also decreased over time. Furthermore, the increase in radial-only access CTO PCI has been associated with a significant reduction in major bleeding. However, it is important to acknowledge that despite these improvements, 30-day mortality after CTO PCI was >1% in a rigorously conducted registry of highly experienced operators.
Given the important need to evaluate the risks and benefits of CTO PCI for individual patients to help guide clinical decision-making, several risk scores have been developed to aid clinicians in estimating the crossing difficulty, procedural success, complication risk, and potential clinical benefit of CTO PCI. The J-CTO score was created using the Multicenter CTO Registry of Japan and estimates the likelihood of successful anterograde guidewire crossing within 30 minutes based on anatomic features and a history of previously failed CTO PCI attempts. The probability of crossing the lesion within 30 minutes decreases with increasing J-CTO score, from 90% in lesions with a score of 0% to <25% in lesions with a score ≥3. Similarly, the probability of procedural success also decreases with increasing J-CTO score, from 97.8% in lesions with a score of 0% to 73.3% in lesions with a score ≥3.
In a similar fashion, the PROGRESS-CTO score attributes 1 point to each of 4 factors (proximal cap ambiguity, moderate/severe tortuosity, circumflex artery CTO, and absence of interventional collaterals) to predict the likelihood of technical success. Again, the likelihood of technical success is inversely related to the PROGRESS-CTO score, with success rates ranging from 95.6% in lesions with a PROGRESS-CTO score of 0% to 76.5% in lesions with a PROGRESS-CTO score of 4. Although the J-CTO and PROGRESS-CTO scores are slightly different in the factors they include and the outcome they model, both scores are informative for clinicians and patients considering CTO PCI.
To further help clinicians and patients weigh the potential risks and benefits of CTO PCI, the PROGRESS-CTO complications score estimates the risk for periprocedural complications, including death, MI, target vessel revascularization, tamponade requiring pericardiocentesis or surgery, and stroke. The score was updated in 2022 as the PROGRESS-CTO MACE score and attributes points for age ≥65 years (1 point), female sex (2 points), moderate to severe calcification (1 point), blunt stump (1 point), anterograde dissection and re-entry (1 point), and retrograde approach (2 points). Procedures scoring 0 to 3 points carry a <2% risk of complications, whereas those scoring 6 to 7 points carry a risk of >5%.
To identify patients with the most to gain from CTO PCI, the Outcomes, Patient Health Status, and Efficiency in Chronic Total Occlusion Hybrid Procedures Angina Prediction (OPEN-AP) score was recently developed to help identify patients that were more versus less likely to experience symptom improvement after CTO intervention. The score was developed from the OPEN-CTO registry and identified 7 variables that help predict residual angina after CTO PCI. These factors include baseline angina frequency, nitroglycerin use frequency, dyspnea symptoms, depressive symptoms, number of antianginal medications, PCI indication, and presence of multiple CTO lesions. The utility of the OPEN-AP score lies in its ability to predict angina relief from CTO PCI based on variables typically available to interventional cardiologists at the time of the initial consultation.
The previously mentioned scores help estimate procedural efficiency, likelihood of success, rates of complication, and potential benefit of CTO PCI for a given patient. They are instrumental in informing the risk-benefit discussion between clinicians and patients considering CTO PCI.
Our Approach to the Patient Referred for CTO PCI
Our approach to the patient referred for CTO PCI is informed by the previously mentioned data and our clinical experience ( Figure 1 ). The initial step in evaluating a patient for CTO PCI is assessing the likelihood that the anginal symptoms may be attributable to the CTO. This evaluation is both challenging and of critical importance and should include, at minimum, assessing the extent to which classic symptoms of exertional angina are present and reviewing available angiograms to determine whether other obstructive epicardial coronary disease may be contributory. It may be further corroborated by the reproduction of symptoms during an exercise stress test and presence of ischemia in the subtended territory. Furthermore, to provide patients with the highest likelihood of symptom improvement after CTO PCI, clinicians should consider the potential effect of concomitant diseases, for example, the possibility of chronic obstructive pulmonary disease or anemia in the patient complaining of dyspnea or of hypothyroidism or depression in the patient complaining of fatigue. Clinicians may also consider exonerating microvascular dysfunction as the etiology for symptoms in patients with CTO. Although current data examining the role of microvascular dysfunction before PCI in patients with CTO is limited, it represents an area of future research.
