Chronic Total Coronary Occlusions: Rationale, Technique, and Clinical Outcomes

Introduction

Despite remarkable advances in the procedural and clinical outcomes of percutaneous revascularization, chronically occluded coronary arteries represent persistent technical challenges and unresolved clinical dilemmas in interventional cardiology. Although a coronary chronic total occlusion (CTO) is identified in approximately one in every three to five diagnostic cardiac catheterizations, revascularization is attempted in fewer than 10% of instances and overall accounts for less than 8% of all percutaneous coronary interventions (PCI) ( Figure 9-1 ). Such a disparity between their frequency and treatment not only underscores the technical and procedural frustrations associated with these complex lesions but also the clinical uncertainties regarding which patients may benefit from CTO revascularization. Chronic occlusions remain the single most important reason not to attempt PCI in favor of bypass surgery or medical treatment. As an example, in the multivessel PCI versus coronary artery bypass graft (CABG) surgery SYNTAX (SYNergy Between PCI with TAXUS and Cardiac Surgery) study, the prevalence of CTO in the randomized arm was only 10%, yet it was 40% in the CABG registry arm.

FIGURE 9-1, Prevalence of and variability in treatment of coronary CTOs.

Unlike catheter-based revascularization of nonocclusive coronary disease, much of our understanding regarding total occlusions has been further limited by relatively few studies describing the procedural and clinical outcomes among patients undergoing attempted revascularization. Moreover, these investigations are limited by their retrospective, observational design, variability in operator skills, inconsistencies regarding the definition of total occlusions, and bias regarding patient selection. Since the duration of an occluded artery is an independent predictor of procedural outcome, an inability to date these lesions, in addition to their heterogeneous composition, have restricted the evaluation of novel revascularization technologies. Until recently, many of the technologies promoted for the treatment of total occlusions were simply modeled after devices applied to nonocclusive disease, erroneously assuming that the pathophysiology between these lesion subsets was similar.

Anatomic Considerations

The definition of a coronary CTO is reflective of the degree of lumen stenosis, the extent of antegrade blood flow, and the age of the occlusion. In general, a CTO is defined as a high-grade coronary occlusion with reduced antegrade flow (Thrombolysis in Myocardial Infarction [TIMI] grade 0 or 1 flow) with estimated duration of at least 3 months. Without serial angiograms, however, the duration of coronary occlusion is difficult to specify with any certainty and must be estimated from available clinical information related to the timing of the event that caused the occlusion, for example, clinical history of myocardial infarction or a sudden change in angina pattern with electrocardiographic changes consistent with the location of the occlusion. In addition, despite presenting with such advanced disease, less than half of the patients demonstrate a clinical history or electrocardiogram suggestive of prior myocardial infarction. In most patients, the age of the CTO cannot be determined with confidence. Furthermore, the temporal criterion used to define a CTO has varied among registries, trials, and databases, ranging from >2 weeks to >3 months, which in part explains interstudy differences in lesion characteristics and procedural success.

Histopathology of CTOs

Chronic coronary occlusions most often arise from thrombotic occlusion, followed by thrombus organization and tissue aging. Particularly relevant to PCI strategies for CTO recanalization is the histological finding that approximately half of all CTOs are <99% stenotic when observed by histopathology, despite the angiographic appearance of total occlusion with TIMI grade 0 antegrade flow. Moreover, little to no relationship exists between the severity of the histopathological lumen stenosis and either plaque composition or lesion age.

The typical atherosclerotic plaque of a CTO consists of intracellular and extracellular lipids, smooth muscle cells, extracellular matrix, and calcium. Collagens are the major structural components of the extracellular matrix, with predominance of types I and III (and minor amounts of IV, V, and VI) in the fibrous stroma of atherosclerotic plaques. The concentration of collagen-rich fibrous tissue is particularly dense at the proximal and distal ends of the lesion, contributing to a column-like lesion of calcified, resistant fibrous tissue surrounding a softer core of organized thrombus and lipids.

Key histopathological attributes of CTOs include calcification extent, inflammation, and neovascularization. The typical CTO may be classified as “soft,” “hard,” or a mixture of both. Soft plaque consists of cholesterol-laden cells and foam cells with loose fibrous tissue and neovascular channels and is more frequent in younger occlusions (<1 year old). Soft plaque is more likely to allow wire passage either directly through tissue planes or via neovascular channels into the distal lumen. Conversely, hard plaque is characterized by dense fibrous tissue and often contains large fibrocalcific regions without neovascular channels. During percutaneous revascularization, these occlusions are thus more likely to deflect coronary guidewires into the subintimal area, thereby creating dissection planes. Hard plaque is more prevalent with increasing CTO age (>1 year old). Of note, however, areas of calcification frequently occur even in CTOs <3 months of age, although the extent and severity of calcification increase with occlusion duration. This age-related increase in calcium and collagen content of CTOs in part underlies the progressive difficulty during PCI in crossing older occlusions.

Inflammatory cell infiltrates in CTOs consist of macrophages, foam cells, and lymphocytes. Inflammation may exist in the intima, media, and adventitia of CTOs, although it is most predominant in the intima. As fibrotic CTO lesions age, the vessels typically undergo negative remodeling with a decreasing dimension of the external elastic membrane, a phenomenon due to adventitial vascular responses. Less commonly, plaque hemorrhage and inflammation may result in positive remodeling. Notably, although negative remodeling may be initially observed following successful CTO recanalization, serial angiographic surveillance may reveal temporal recovery of normal vessel dimensions.

Another observation common to CTOs is the presence of extensive neovascularization that occurs throughout the extent of the vessel wall. Capillary density and angiogenesis increase with increasing occlusion age. In CTOs <1 year old, new capillary formation is greatest in the adventitia. In CTOs of more advanced duration, the number and size of capillaries in the intima have increased to a similar or greater extent than those present in the adventitia. Relatively large (>250 µm) capillaries are frequently present throughout the CTO vessel wall, even in young occlusions, suggesting that angiogenesis within the CTO is an early event. Frequent co-localization of inflammation and neovascularization within the intimal plaque and adventitia suggests that these findings are closely related, although it is unclear whether inflammation is a cause or an effect of neovascularization in CTOs.

A rich neovasculature network often traverses the CTO vessel wall, arising from the adventitial vasa vasorum across the media and into the lesion intima, suggesting that vessel in-growth proceeds from the adventitia in younger lesions. An autopsy study of subtotal atherosclerotic lesions demonstrated that new intimal vessels originate in the adventitial vasa vasorum of lesions with >70% stenosis but rarely from the coronary lumen. Such microchannels, which can recanalize the distal lumen, may result from thrombus-derived angiogenic stimuli and are suggested on an angiogram of an old CTO without a well-defined proximal cap or stump. In this regard, the distinction should be made between ipsilateral epicardial angiographic “bridging” collateral vessels and true microvascular collaterals. Neochannels may also develop with organization of thrombus, connecting the proximal and distal lumens; this is suggested by a tapered CTO proximal cap on an angiogram. Such channels may serve as a route for a guidewire to reach the distal vessel and hence may have therapeutic value.

Collaterals and CTOs

Collaterals preserve myocardial function and avoid cardiac myocyte death in the distribution of the occluded artery. The most widely used angiographic grading system for collaterals described by Rentrop does not actually characterize the collaterals themselves but rather their contribution to filling the occluded arterial segment. Recently, a grading of collateral connections was introduced specifically for CTOs that may assist in interventional decision making regarding retrograde strategies ( Figure 9-2 ).

FIGURE 9-2, Coronary collateral circulation to CTOs.

Importantly, a common misperception is the unawareness that even well-developed collaterals do not prevent ischemia during exercise. A total occlusion that is well collateralized is functionally equivalent to a 90% stenosis in a non-CTO vessel. When FFR is performed following initial CTO recanalization, the FFR value is persistently ischemic (Pd/Pa < 0.80), and resting ischemia was present in 78% of instances. Ischemia was demonstrated in all CTO cases independent of collateral development or presence of severe regional left ventricular dysfunction. The myocardium remains viable but produces ischemia during periods of increased oxygen demand, and thus patients with these lesions are likely to have exertional angina. Although the risk of a spontaneous acute coronary syndrome due to a chronically occluded lesion is unlikely, infarction in distribution of the CTO may result during instances of increased demand or if the arteries supplying the collaterals become compromised in any way.

Target Vessel

Very little data exist regarding the potential for differential benefit of CTO recanalization depending on the target vessel (e.g., left anterior descending [LAD], left circumflex [LCX], or right coronary artery [RCA]). In a large, single-center registry, PCI for CTO of the LAD, but not LCX or RCA, was associated with improved long-term survival. There were 2608 patients included, and the LAD was the target vessel in 936 (36%), the LCX in 682 (26%), and the RCA in 990 (38%) patients. The angiographic success rates were similar across coronary artery distributions (LAD, 77%; LCX, 76%; RCA, 72%). Procedural success compared with failure was associated with improved 5-year survival in the LAD (88.9% vs. 80.2%, p < 0.001) group but not in the LCX (86.1% vs. 82.1%, p = 0.21) and RCA (87.7% vs. 84.9%, p = 0.23) groups. In multivariable analysis, CTO PCI success in the LAD group remained associated with decreased mortality risk (hazard ratio [HR] 0.61; 95% confidence interval [CI], 0.42 to 0.89). In addition to other clinical characteristics, this information may assist in selecting patients for attempted CTO PCI.

Indications

In general, when the CTO represents the only significant lesion in the coronary tree, PCI is warranted when the following three conditions are all present: (1) the occluded vessel is responsible for the patient's symptoms of chest pain or heart failure, or the vessel is responsible for a reduced ventricular function (PCI may also be considered in selected cases of silent ischemia if a large myocardial territory at risk is demonstrable); (2) the myocardial territory supplanted by the occluded artery is viable; and (3) the likelihood of success is moderate to high (>60%), with an anticipated major complication rate of death <1% and myocardial infarction <5%. If the PCI attempt is unsuccessful, further management will depend on the symptomatic status and the extent of jeopardized ischemic myocardium. Repeated PCI following initial failure (typically with an allowance of several weeks for vessel healing in the case of dissection) or surgical revascularization may be warranted if a large myocardial territory is ischemic or the patient is very symptomatic. Alternatively, conservative therapy may be appropriate if repeated PCI is unlikely to be successful and the patient's symptoms can be controlled with antianginal medications.

Despite the intuitive benefit of an open artery, the rationale for CTO PCI is mistakenly challenged by a singular trial demonstrating no clinical benefit with revascularization of subacute total occlusions following recent myocardial infarction. Differences in the indication and pathophysiology notwithstanding, it is noteworthy that unlike the clinical characteristics of patients included in the Occluded Artery Trial (OAT), CTO patients selected for attempted PCI often represent a very different patient population characterized by features systematically excluded from the OAT trial, including symptoms refractory to medical therapy, abnormal left ventricular function, multivessel coronary disease, and/or extensive ischemia demonstrated by noninvasive testing. Performance of CTO revascularization based on these indications is also in accord with recent multidisciplinary committee recommendations regarding appropriateness of PCI in specific patient and lesion subsets.

Recently, consensus recommendations regarding appropriateness of PCI in general have highlighted disparate conclusions related to percutaneous revascularization depending on the stenosis severity. The 2011 American College of Cardiology/American Heart Association PCI guidelines endorse CTO PCI with a class IIA recommendation, citing that PCI of a CTO in patients with appropriate clinical indications and suitable anatomy is reasonable when performed by operators with appropriate expertise. Similarly, the 2010 European Society of Cardiology states that similar to nonchronically occluded vessels, revascularization of a CTO may be considered in the presence of angina or ischemia related to the corresponding territory. In contrast, the 2012 statement on Appropriate Use Criteria for Coronary Revascularization provided a lower level recommendation for CTO PCI compared with patients having one- or two-vessel coronary disease and without a CTO in 10 of 36 clinical scenarios assessed. In particular, for both symptomatic and asymptomatic patients, several instances exist for which PCI may be considered “appropriate” or “uncertain” for a non-CTO lesion but downgraded for the same respective indications to “uncertain” or “inappropriate” for a CTO lesion. Although it is likely that such endorsements are based on both evidence and opinion, the reasons for differing recommendations are not provided. Further, establishing unconditional treatment recommendations regarding CTO revascularization for any individual patient is especially challenging given that the risk/benefit balance may vary considerably depending on the symptoms, the extent of ischemia or left ventricular dysfunction, the presence of multivessel disease, or additional comorbidities that increase procedural risk (e.g., chronic kidney disease). Therefore, for consideration of CTO PCI, the document should be considered a guideline for treatment rather than an absolute standard, and the presence of a CTO should not have an impact on revascularization decision making with the caveat that appropriate expertise in CTO PCI is locally available.

Angina and Quality of Life

Stress-induced ischemia can typically be elicited in patients with a CTO, especially in the absence of a history of prior myocardial infarction and irrespective of collateral development. The temporal changes in contractility and hyperemic and resting myocardial blood flow in dependent and remote myocardium after PCI of CTOs have been further characterized using cardiovascular magnetic resonance imaging. Three groups were prospectively studied: 17 patients scheduled for CTO PCI, 17 scheduled for PCI of a stenosed but nonoccluded coronary artery (non-CTO), and 6 patients with CTO who were not scheduled for revascularization. Contractility in treated segments was improved at 24 hours and 6 months after CTO PCI but only at 6 months after non-CTO PCI. In both intervention groups, treated segments no longer had reduced myocardial blood flow or contractility compared with remote segments ( Figure 9-3A ). In patients with nonrevascularized CTO segments and treated with medical therapy alone, myocardial blood flow and wall thickening did not improve at follow-up ( Figure 9-3B ).

FIGURE 9-3, Impact of CTO revascularization on regional myocardial blood flow.

The majority of patients undergoing CTO PCI have stable or progressive angina, whereas many asymptomatic patients with CTO and minimal or no ischemia by noninvasive imaging are managed medically. In several large databases, only 10% to 15% of patients undergoing angioplasty for CTO were asymptomatic. Conversely, the proportion of patients presenting with unstable angina due to a CTO is also fairly low and of similar prevalence to asymptomatic patients. Patients with medically refractory angina or a moderate to large ischemic burden deserve consideration for percutaneous revascularization, particularly if the symptoms or territory are enough to warrant surgical revascularization as an option. The presence of moderate or severe ischemia is associated with worse clinical outcomes in patients with CTO. In a study of 301 patients who underwent myocardial perfusion imaging before and after CTO PCI, a baseline ischemic burden of >12.5% identified patients most likely to have a significant decrease in ischemic burden post-CTO PCI, indicating that the highest benefit of CTO revascularization is likely to be achieved in patients with a significant baseline ischemic burden.

In a metaanalysis of six observational studies evaluating angina following CTO PCI, patients undergoing successful revascularization experienced a significant reduction in recurrent angina during a 6-year follow-up compared with patients undergoing unsuccessful PCI (odds ratio [OR], 0.45; 95% CI, 0.30 to 0.67). In the Flowcardia's Approach to Chronic Total Occlusion Recanalization (FACTOR) trial, among patients referred for the CTO PCI (which per protocol required symptoms and/or abnormal stress testing), two thirds of the patients had angina, and one third had no angina. Presence of angina was objectively assessed using the Seattle Angina Questionnaire (SAQ) and defined as angina frequency scores of less than 90. Among those with angina at baseline, the impairment in angina-associated quality of life was significant, and CTO PCI was associated with significant improvement in self-reported angina measures.

The first assessment of the most common angina equivalent (dyspnea) among patients with CTO was reported by Safley and colleagues. In this study, 98 patients with single-vessel CTO were matched with 687 patients undergoing non-CTO PCI. Baseline and post-PCI SAQ and Rose dyspnea scale scores were compared. Dyspnea was present among both CTO and non-CTO patients as reflected in baseline Rose dyspnea scale scores of 1.9 versus 1.7, p = 0.21 (higher scores indicating more dyspnea), in the CTO and non-CTO groups, respectively. Percutaneous CTO revascularization was statistically noninferior to non-CTO PCI in alleviating both dyspnea and angina (p < 0.02 for all domains), suggesting that the clinical benefit was of at least a similar magnitude for both CTO and non-CTO PCI.

Improvement in Left Ventricular Dysfunction

Regional left ventricular systolic function has been demonstrated to improve after CTO PCI. The degree of improvement is especially evident in patients with decreased left ventricular systolic function at baseline, while no change in ejection fraction can be expected when the baseline function is normal. Improvement in left ventricular function is not predicted by a history of myocardial infarction or the duration of occlusion. Further, recovery of impaired ventricular function after revascularization of a CTO is not directly related to the quality of collateral function, as collateral development does not appear to require the presence of viable myocardium. Left ventricular function improvement is dependent on maintenance of CTO target vessel patency and on viability of the perfused myocardial territory.

Reduction in Arrhythmic Events

Although no study has documented a reduction in ventricular arrhythmic events with CTO PCI, the contribution of CTOs to either ischemia-driven or scar-related arrhythmic events has been recently characterized. In the Ventricular Arrhythmia Chronic Total Occlusion (VACTO) study, among 162 patients with ischemic cardiomyopathy who received an implantable cardioverter defibrillator, 44% had at least one CTO. During a median follow-up of 26 months, the presence of CTO was associated with higher ventricular arrhythmia and mortality rates compared with patients without a CTO. In particular, the occurrence of appropriate defibrillator therapy was significantly more common in comparison with patients having multivessel disease but without a CTO.

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