Management of Chronic Total Occlusion of Coronary Artery

Abstract

Chronic total occlusion (CTO) of a coronary artery is typically defined as a completely occluded artery without any antegrade flow and a duration of at least 3 months. We reviewed the current literature describing the optimal management of CTO including the role of revascularization and choice of modality, i.e., percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery. Databases (PubMed, the Cochrane Library, Embase, EBSCO, Web of Science, and CINAHL) were searched and relevant studies of patients with CTO were selected for review. The prevalence of coronary artery CTOs is approximately 25% among patients undergoing coronary angiography for angina. Available data suggests that PCI of CTO can be a technically complex procedure with relatively lower success rates compared with non-CTO PCI and typically associated with a higher complication rate especially at nonspecialized centers. Furthermore, successful CTO-PCI is associated with symptomatic improvement but does not appear to improve mortality, myocardial infarction, stroke, and repeat revascularization rates. Based on contemporary data, PCI of CTO lesions may be considered in patients with incapacitating angina despite treatment with optimal guideline-directed medical therapy and in whom based on coronary anatomy there is a reasonable chance of technical success with an acceptable risk.

A coronary artery chronic total occlusion (CTO) is defined as a completely occluded coronary artery without any anterograde blood flow (thrombolysis in myocardial infarction score of 0) for more than 3 months. ¹ The reported prevalence of CTO varies in different populations and a Multicenter Canadian registry of CTOs reported CTO rates of 54 and 18% in patients with and without prior coronary artery bypass surgery (CABG), respectively. ² Another contemporary study reported that approximately 25% of the patients with obstructive coronary artery disease (CAD) on coronary angiography had CTOs. ³

All patients with CTO should receive optimal guideline-directed medical therapy (GDMT) and revascularization should be considered only in those with debilitating angina despite medical therapy and in whom benefits exceed potential risk of procedure. In recent years with advances in interventional technology, there has been considerable interest in percutaneous coronary intervention (PCI) of CTO lesions. However, these procedures are technically complex with higher complication rates compared with non-CTO PCI. Furthermore, CTO interventions typically require longer procedure times, increased iodinated contrast administration, increased radiation exposure, and are associated with higher complication rates compared with non-CTO PCIs. ^{1 4}

We examine contemporary optimal management of CTO and assess clinical outcomes and role of contemporary revascularization techniques.

Guideline-Directed Medical Therapy

GDMT is the foundation ^{5 6} of the management of individuals with significant CAD, including those with CTOs. ⁷ Medical therapies are targeted to improve symptoms, i.e., reduce angina, improve quality of life, improve survival, and reduce major cardiovascular events. ⁸ Key therapeutic agents to relieve angina are β-blockers, calcium channel blockers, nitrates, and ranolazine. ⁴ Beta-blockers reduce myocardial oxygen demand by lowering heart rate, blood pressure, and myocardial contractility. Calcium channel blockers relax smooth muscle in the systemic blood vessels and coronary arteries leading to increased coronary blood flow by vasodilation, and reduced afterload which lowers myocardial oxygen demand. ⁴ The nondihydropyridine calcium channel blockers diltiazem and verapamil, have a negative inotropic effect and reduce heart rate, thereby further lowering myocardial oxygen demand. Nitrates primarily work by venodilation lowering preload and myocardial cardiac demand. At higher doses, nitrates have a direct effect on arteries and reduce blood pressure and afterload. ⁹ Finally, ranolazine works by preventing intracellular calcium overload that has detrimental electrical and mechanical effects. ¹⁰ It has no significant effect on heart rate or blood pressure and may be used in combination with other antianginal medications if needed. In addition to symptom alleviation, patients with CTO should be targeted for improving long-term cardiovascular outcomes. Every patient with CTO should be on a statin and an antiplatelet agent to improve cardiovascular outcomes. ^{4 5 6}

Revascularization

Consideration of revascularization with PCI or CABG is reasonable for patients with CTOs with debilitating symptoms on GDMT. ¹¹ In general, PCI is preferred in patients who have single-vessel CTO of the right coronary artery or the left circumflex coronary artery, and in those with prior CABG and a patent left internal mammary graft (LIMA). Left anterior descending artery (LAD) CTO may be better served with CABG given the durability of the LIMA graft compared with CTO-PCI. A multidisciplinary team that assesses the degree of the patient's symptoms, coronary anatomy, likelihood of procedural success, risk for complications, and patient preferences should ideally make the decision regarding revascularization modality for CTOs.

Percutaneous Revascularization

Several observational studies have shown benefits in hard clinical outcomes with CTO revascularization. George et al analyzed the United Kingdom Central Cardiac Audit Database for all CTO PCI cases performed in England and Wales between January 1, 2005, and December 31, 2009 and reported that successful CTO PCI was associated with improved long-term survival with the greatest improvement in patients when complete revascularization was achieved. ¹² Complete revascularization in this analysis was associated with improved survival compared with partial revascularization (hazard ratio [HR]: 0.70; 95% confidence interval [CI]: 0.56–0.87; p  = 0.002) or failed revascularization (HR: 0.61; 95% CI: 0.50–0.74; p  < 0.001). Tomasello et al, investigated the data on prevalence, characteristics, and outcome of CTO patients according to the management strategy in the Italian Registry of Chronic Total Occlusions. ¹³ They reported that CTO PCI might significantly improve the survival and decrease major adverse cardiac and cerebrovascular events occurrence at 1-year follow-up in comparison with medical therapy. Christakopoulos et al performed a meta-analysis of the long-term outcomes of successful versus failed CTO PCI in 28,486 patients (29,315 CTO PCI procedures) from 25 studies. ¹⁴ The authors reported that compared with failed procedures, successful CTO PCIs are associated with a lower risk of death, stroke, and coronary artery bypass grafting and less recurrent angina pectoris. However, the nonrandomized nature of these studies cannot completely exclude all selection and publication bias and there is a need for randomized clinical trials to assess true benefits and risk of CTO PCI. The conclusive proof of a beneficial effect of successful CTO PCI can only be furnished by adequately powered, prospective, randomized controlled clinical trials preferably with sham controls.

Need for Complete Revascularization

Complete revascularization defined as restoration of blood flow, via PCI or CABG, to all major epicardial coronary arteries is currently recommended to optimize outcomes in individuals with CAD. ¹⁵ In fact, several studies have attributed the superiority of CABG over multivessel PCI for better cardiovascular outcomes due to the completeness of revascularization achieved by CABG. A substudy of the Coronary Angioplasty Versus Bypass Revascularization Investigation (CABRI) trial included 223 patients with CTOs, 121 were randomized to PCI and 102 to CABG, ¹⁶ reported better outcomes with CABG likely due to completeness of revascularization. In the SYNTAX trials, presence of a CTO made incomplete revascularization more than twice as likely with PCI (odds ratio, 2.46; 95% CI, 1.66–3.64; p  < 0.001), which translated to higher event rates in the PCI group as compared with CABG (HR, 1.55; 95% CI, 1.15–2.08; p  = 0.004). ¹⁷ Another post-hoc analysis of the SYNTAX trial reported that only half of patients undergoing PCI had complete revascularization versus more than two-thirds undergoing CABG, and the presence of a CTO was the strongest predictor for incomplete revascularization with PCI (HR, 2.70; 95% CI, 1.98–3.67; p < 0.001). ¹⁸ Based on available data, among patients with CTOs, the presence of left main disease, anatomically complex multivessel disease, especially in patients with diabetes, severe left ventricular dysfunction, or chronic kidney disease, occluded proximal LAD that supplies a large territory of the anterior wall, and presence of multiple CTOs favor CABG over PCI as revascularization modality.

Randomized Controlled Trials

There is minimal data from randomized controlled trials comparing CTO-PCI with medical therapy. Majority of the studies assessing PCI of CTO on outcomes are either observational single-center or multicenter registries. The EXPLORE trial randomized 304 patients with STEMI and a CTO in a nonculprit artery to undergo CTO-PCI (154) versus medical therapy (154), after primary PCI, to assess improvement in left ventricular ejection fraction (LVEF) and left ventricular end diastolic volume (LVEDV) by magnetic resonance imaging at 4 months. ¹⁹ The primary end points of LVEF (44.1 ± 12.2% vs. 44.8 ± 11.9%; p  = 0.597) and LVEDV (215.6 ± 62.5 mL vs. 212.8 ± 60.3 mL; p  = 0.703) and cardiovascular events were not improved with CTO-PCI at 4 months. The DECISION-CTO trial was an open-label, multicenter, randomized, noninferiority trial, that treated patients with CTO with either PCI with optimal medical therapy (OMT) ( n  = 417) or OMT alone ( n  = 398). ²⁰ The study reported no difference in the incidence of major adverse cardiovascular events with CTO-PCI versus medical therapy. ²⁰ The EUROCTO-trial assessed health status of patients with at least one CTO. ²¹ This study reported a significant improvement of the health status in patients with stable angina and a CTO as compared with medical therapy alone. However, major adverse cardiac events were comparable between the two groups with no improvement with PCI. ²¹ The randomized trials reported to date have not shown benefit in hard clinical end points with CTO PCI in contrast to such benefits noted in observational studies. Two ongoing clinical trials, the NOrdic-Baltic Randomized Registry Study for Evaluation of PCI in chronic total coronary occlusion (NOBLE-CTO) and the revascularization or OMT of CTO (ISCHEMIA-CTO) will provide additional insight on risks versus benefits with CTO PCI.

Technical Aspects of CTO PCI

While a detailed description of all the techniques and devices available for CTO PCI is beyond the scope of this review, certain key principles are discussed here. In general, diagnostic coronary angiogram should be carefully evaluated to assess the characteristics of the proximal cap of the occlusion, the true length of the CTO segment, the quality of the distal vessel, presence and location of side branches, and the size and course of collateral vessels. Two arterial access sites are typically used to enable simultaneous injections of the occluded vessel and the collateral supplying vessel. A microcatheter is used for optimal guidewire manipulation and exchange in most cases with antegrade wire escalation and antegrade dissection re-entry if needed. Microcatheters (such as the Corsair and Caravel microcatheter [Asahi Intecc], the Turnpike [Vascular Solutions Inc, MN], CrossBoss catheter [Boston Scientific] and the Finecross [Terumo, Japan]) etc., facilitate CTO crossing. In addition, guide catheter extensions (GuideLiner [6–8 Fr] [Teleflex], Guidezilla [6 Fr] [Boston Scientific]) and side-branch anchoring may be needed during CTO PCI. In patients with robust collaterals, retrograde approach would be the next step if antegrade approach fails. Retrograde dissection reentry may be used when retrograde wires are not able to cross the occlusion. Controlled antegrade and retrograde tracking (CART) is performed using a balloon to enlarge the false lumen so that antegrade and retrograde wires can meet. ²² Typically, “reverse CART” is performed in which a balloon is inflated over a wire that passes from the proximal true lumen and into the subintimal space within the CTO and a retrograde wire in the common subintimal space is then advanced following the pathway created by the antegrade balloon inflation, and into the antegrade guide catheter. The retrograde wire can be externalized out of the body through the antegrade guide, and CTO PCI can then be performed over this wire. Of note, retrograde techniques are associated with a higher rate of complications. Some examples of specialized guidewires used for CTO PCI include the Fielder XT-A, XT, or XT-R (Asahi), Pilot 200 (Abbott), Confianza Pro 12 (Asahi), Hornet 14 (Boston Scientific), and the Gaia series (Asahi) wire.

The hybrid approach with dual angiography is based on assessment of four anatomical features (proximal cap characteristic, distal target vessel, suitable collaterals, and lesion length) to determine the initial crossing strategy. Setting up for all potential strategies including retrograde techniques increases the change of a successful outcome and reduces the need for multiple procedures.

Clinical Indications for CTO-PCI

The decision-making process for CTO-PCI should be made by a multidisciplinary team factoring in the severity of symptoms, amount of myocardium at jeopardy, possible demonstration of viability and ischemia on noninvasive testing, potential likelihood of success, risks of procedure, and patient preference. In general, refractory or debilitating symptoms despite maximally tolerated GDMT are the most common rationale for CTO-PCI. There should be a discussion with the patient and the family regarding the perceived need for the procedure, the substantial risks associated with it, likelihood of success, need for emergent CABG, stroke, pericardial tamponade, and possibility of a fatal outcome. ¹ CTO-PCI should not be performed as an ad hoc procedure as careful planning is indicated. Finally, the 2019 expert consensus document on guiding principles for CTO PCI recommended that ischemic symptom improvement remains the primary indication for CTO-PCI as improvement in hard clinical outcomes has not been reported in randomized, controlled clinical trials. ²³

Risk Prediction Scoring Systems for CTO-PCI

While several scoring systems have been developed for predicting the success of CTO-PCI, the J-CTO score and the PROGRESS-CTO scores are more widely used. The J-CTO score predicts the likelihood of lesion crossing within 30 minutes, and uses five variables (occlusion length >20 mm, blunt stump, CTO calcification, CTO tortuosity, and prior failed attempt) with a higher score associated with lower likelihood of success. ²⁴ Similarly, the Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS-CTO) scores based on four variables (proximal cap ambiguity, vessel tortuosity, left circumflex artery CTO, and absence of adequate collaterals for retrograde access) predict successful PCI with higher scores associated with lower success. ²⁵

Complications

Major complication rates reported in the trials have been higher with CTO-PCI as compared with non-CTO PCI and include dissections, side branch occlusion, cardiac tamponade, significant arrhythmias, periprocedural myocardial infarction, perforations, need for emergent CABG, strokes, contrast-induced nephropathy and death. Complication rates tend to be lower with experienced operators or a dedicated team of interventionalists highly skilled in CTO-PCI. ^{26 27}

Conclusion

While GDMT remains the foundation of management of patients with CTO similar to those with established CAD, revascularization is reasonable in those with refractory symptoms despite maximal therapy. The 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention recommends PCI for CTO in patients with clinical indications and suitable anatomy when performed by operators with appropriate expertise (Class IIa, level of evidence [LOE] B). ²⁸ The 2014 European Society of Cardiology (ESC) and European Association for Cardio-Thoracic Surgery guidelines on myocardial revascularization recommend PCI to be considered in patients with CTO with expected ischemia reduction in a correlated myocardial territory and/or angina relief (Class IIa, LOE B). ²⁹ Finally, the American College of Cardiology 2017 Appropriate Use Criteria for Coronary Revascularization in Patients With Stable Ischemic Heart Disease got rid of the separate criteria for CTO lesions as was the case in the earlier 2012 guidelines. ³⁰ In this guideline, indications for revascularization in stable ischemic heart disease are determined irrespective of whether the lesion is a CTO and is based on symptoms, adequacy of antianginal medications, and the risk of ischemia. ³⁰

We agree with the national guidelines suggesting that CTO-PCI be considered only if the occluded vessel is responsible for symptoms and patient has debilitating angina despite optimal GDMT. Ongoing clinical trials of CTO PCI will provide additional insight.