Chronic Total Occlusions: Patient Selection and Overview of Advanced Techniques
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- Garcia, S., Abdullah, S., Banerjee, S. et al. Curr Cardiol Rep (2013) 15: 334. doi:10.1007/s11886-012-0334-2
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Percutaneous treatment of coronary chronic total occlusions (CTOs) remains challenging, mainly due to difficulty in crossing the lesion. However tremendous progress has been achieved recently with expanded use of the retrograde approach and advanced dissection re-entry techniques. The development of the “hybrid” approach from North American operators has provided practical recommendations on how to select initial and subsequent CTO crossing strategies. Moreover, additional information has emerged on the frequency of CTOs among patients undergoing cardiac catheterization and on the adverse prognostic impact of CTOs on clinical outcomes of patients with ischemic cardiomyopathy who have implantable cardioverter defibrillators. Overall, CTO interventions remain a dynamic area with multiple novel technical and clinical developments.
KeywordsChronic total occlusionCoronary revascularizationPercutaneous coronary intervention
Coronary chronic total occlusions (CTOs) are defined as the presence of TIMI 0 (Thrombolysis in Myocardial Infarction) flow within the occluded segment with an estimated or known occlusion duration of ≥ 3 months . Occluded arteries within 30 days of a myocardial infarction, such as those included in the Open Artery Trial (OAT), do not constitute a CTO .
CTO percutaneous coronary interventions (PCI) are challenging, however tremendous progress has been achieved in recent years with the development and widespread application of novel techniques and equipment, which are summarized in the present review.
Prevalence and Current Approaches to Coronary CTOs
In an important study published in 2012, Fefer et al.  reported the prevalence of coronary CTO in three centers in Canada. Among 14,439 patients undergoing coronary angiography at least one coronary CTO was present in 14.7 %. The prevalence of CTO was higher among prior coronary artery bypass graft (CABG) surgery patients (54 %) and lower among patients undergoing primary PCI for acute ST-segment elevation myocardial infarction (10 %). Left ventricular function was normal in >50 % of patients with CTO and half of the CTOs were located in the right coronary artery.
Patient Selection and Benefits of CTO Recanalization
The goal of CTO-PCI is to improve symptoms, left ventricular function and subsequent clinical outcomes. In the 2011 American College of Cardiology/American Heart Association PCI guidelines CTO PCI carries a class IIA recommendation: “PCI of a CTO in patients with appropriate clinical indications and suitable anatomy is reasonable when performed by operators with appropriate expertise” . Current indications and potential benefits of CTO PCI are as follows:
Improving angina is the main reason currently for performing CTO PCI. Angina improvement after CTO PCI has been demonstrated in multiple published studies that were summarized in a meta-analysis by Joyal et al. [5••]. Compared to patients in whom CTO PCI failed, those in whom CTO PCI was successful had significant reduction in recurrent angina during a 6-year follow-up (odds ratio, 0.45; 95 % confidence interval, 0.30 to 0.67) [5••].
Improve Left Ventricular Function
Reduce the Risk for Ventricular Arrhythmias
The “ventricular arrhythmias among implantable cardioverter defibrillator recipients for primary prevention” (VACTO) study examined 162 patients with ischemic cardiomyopathy who had received an implantable cardioverter defibrillator. During a median follow-up of 26 months presence of a CTO (which was found in 44 % of the patients) was associated with higher risk for ventricular arrhythmias and death (p <0.01) [15•]. Whether successful CTO PCI reduces the risk for ventricular arrhythmias (and other adverse clinical outcomes) in ischemic cardiomyopathy patients has not yet been studied.
Improve Tolerance of a Future Acute Coronary Syndrome
Patients with a CTO who develop an acute coronary syndrome have high risk for adverse events . Claessen et al. reported that 8.6 % of 3283 patients participating in the HORIZONS-AMI study had a CTO in a non-infarct related artery , which was independently associated with 30-day [hazard ratio (HR) 2.88, 95 % confidence interval (CI) 1.41-5.88, P = 0.004] and 3-year mortality (HR 1.98, 95 % CI 1.19-3.29, P = 0.009). Multivessel disease without a CTO was a significant predictor of 30-day mortality (HR 2.20, 95 % CI 1.00-3.06, P = 0.049) but not of late (30-days to 3 years) mortality .
Yang et al. recently performed a retrospective study of 136 patients with STEMI and non-infarct related artery CTO. Successful staged PCI of the CTO (which was accomplished in 64 % of the patients) was associated with lower 2-year cardiac mortality and major adverse cardiac events compared to failed CTO PCI attempt . The ongoing Evaluating Xience V and left ventricular function in Percutaneous coronary intervention on occLusiOns afteR ST-Elevation myocardial infarction (EXPLORE, trialregister.nl NTR1108) trial is evaluating whether PCI of a CTO in a non-infarct related artery within 1 week after primary PCI can improve LV dimensions and function .
Whether CTO PCI can improve survival remains controversial. Several observational studies have consistently shown improved survival among patients who underwent successful vs. failed CTO PCI [5••]. In a single-center retrospective study, mortality benefit was only observed when the CTO target vessel was the left anterior descending artery but not the right coronary artery or the circumflex .
Ongoing Randomized-Controlled Trials
A major limitation of CTO PCI is that no randomized-controlled trial comparing CTO PCI with medical therapy or with coronary artery bypass graft surgery has been performed to date. However, two such studies are currently ongoing. The first is the Drug-Eluting Stent Implantation Versus Optimal Medical Treatment in Patients With Chronic Total Occlusion (DECISION-CTO, NCT01078051), which is evaluating whether, compared to optimal medical therapy, CTO PCI will reduce the composite endpoint of all cause death, myocardial infarction, stroke, and any revascularization at 3 years after randomization. The second is the European Study on the Utilization of Revascularization versus Optimal Medical Therapy for the Treatment of Chronic Total Coronary Occlusions (EURO-CTO) trial, which has a primary endpoint of death or non-fatal myocardial infarction during a follow-up of 36 months. However, neither study is anticipated to have results before 2018.
Overview of Advanced Techniques
Patients with coronary CTOs are often treated medically or referred for coronary artery bypass graft surgery. Fefer et al.  reported that among 1697 patients with a coronary CTO, medical therapy alone was used in 44 %, coronary bypass graft surgery in 26 %, and PCI in 30 %, however CTO PCI was only done in 10 % of patients. This is similar to what has been observed in other patient populations [20–22].
A major reason for the low utilization of CTO PCI is high procedural complexity and low success rates. However, with use of advanced contemporary techniques high success rates (>80 % and sometimes >90 %) can be achieved by experienced operators in experienced centers. In the following sections we will summarize some of the state-of-the-art strategies and techniques.
Basics of CTO PCI
The simplest, yet probably most important technique for increasing the CTO PCI success rates is use of dual injection, which is performed by simultaneously injecting contrast both in the CTO PCI target vessel and in another vessel (the contralateral coronary artery or a bypass graft) that provides collaterals to the distal target vessel. Dual injection should be used in nearly all cases for accurate determination of the proximal cap, lesion length, and size and location of the distal target vessel.
Dual injection also allows assessment of the size and suitability of collateral vessels to determine whether the retrograde approach is feasible. Dual injection is best performed at low magnification with prolonged imaging exposure and without table panning. Prolonged and detailed review of the angiogram is critical to determine possible treatment options should early crossing attempts fail.
Use of long sheaths (35 to 45 cm) and large-bore guide catheters (7- to 8-F) are preferred to provide optimal support and allow for a seamless transition in interventional strategies (see algorithm for CTO crossing). We prefer use of bilateral femoral access for CTO PCI, although some operators have reported successful results using biradial access .
Selected guidewires, microcatheters and dissection/re-entry devices for CTO crossing
Tip stiffness and style
1.2 g/ tapered, polymer jacketed
Frontline wire for antegrade crossing
1.6 g, polymer jacketed
Collateral crossing during retrograde crossing attempts
4.1 g, polymer jacketed
Antegrade crossing when vessel course is not known
“Knuckle-wire” formation and re-entry into true lumen
Confianza Pro 12
12.4 g/tapered, hydrophilic coating
Antegrade crossing when vessel course is known
3.6 grs/335 cm in length
Wire externalization in the retrograde approach
130 and 150 cm in length (we always use the 150 cm length in our laboratory), 2.8 French outer diameter with lubricious outer coating and bidirectional wire braiding for torque transmission
Collateral channel crossing (septal and epicardial)
130 and 150 cm in length, tapers from 2.6 to 1.8 French distally, hydrophilic coating
Smallest available microcatheter with excellent flexibility and support
2.4 French over the wire microcatheter with a rounded tip to prevent vessel exit. Can be advanced forward through the CTO without a wire.
Antegrade crossing especially when lesion length is > 20 mm
Highly effective for in-stent restenosis CTOs 
Stingray balloon and wire
1-mm flat balloon with 3 exit ports, 2 of which are 180° opposed so when inflated one is facing the true lumen and the other the adventitia. The Stingray guidewire is a high-gram force wire with a tapered distal probe (0.003 inch) designed to grab tissue
Antegrade re-entry after subintimal crossing
CTO Crossing Techniques
Crossing the lesion is the most challenging step of CTO PCI. The currently utilized crossing techniques can be categorized in three groups: antegrade wire escalation, antegrade dissection/re-entry, and retrograde.
Antegrade Wire Escalation
Antegrade wire escalation is the most commonly utilized crossing strategy and also the simplest. Attempts to cross the lesion are done using wires of increasing stiffness through an over-the-wire balloon (OTW) or through a microcatheter. We prefer using microcatheters, such as the Finecross (Terumo, Somerset, New Jersey) over OTW balloons because they are more flexible and the distal tip is marked for optimal visualization. In contrast the 1.5 mm or smaller balloons have a single marker in the middle of the balloon, and hence the exact position of the balloon tip may be difficult to determine.
Rapid escalation in wire stiffness is currently advocated by most North American operators: initially crossing is attempted using a polymer-jacketed tapered guidewire, such as the Fielder XT (Asahi Intecc, Nagoya, Japan). If this fails, then a stiff polymer jacketed wire, such as the Pilot 200 (Abbott Vascular, Santa Clara, California) is used if the course of the occluded vessel is unclear. If the course of the occluded vessel is well understood, then a stiff, tapered, high-gram wire, such as the Confianza Pro 12 (Asahi Intecc) is preferred.
The fundamental principle in dissection/re-entry is to bypass the CTO using the subintimal space as a conduit with the intention to regain access to the true lumen distal to the occlusion. This can be achieved by a “knuckle wire”, which is formed by advancing a polymer-jacketed wire, such as the Fielder XT (Asahi Intecc) or the Pilot 200 (Abbott Vascular) to form a loop. It is best to limit the loop diameter to limit the extent of dissection and facilitate re-entry. Alternatively, a blunt-tipped microcatheter (CrossBoss, BridgePoint Medical, Plymouth, Minnesota) can be used. If the knuckle wire or the CrossBoss catheter reaches the subintimal space around the distal true lumen, re-entry can be accomplished using either a guidewire or the Stingray balloon (BridgePoint Medical).
Guidewire-based re-entry can be achieved by advancing the knuckled guidewire distally until it spontaneously enters the true lumen (Subintimal Tracking And Re-entry or “STAR”) . To minimize the length of subintimal crossing, the “mini-STAR”  or the Limited Antegrade Subintimal Tracking (LAST) technique were developed. A Fielder FC or XT guidewire is used in “mini-STAR” and a Pilot 200 (Abbott Vascular) or Confianza Pro 12 (Asahi Intecc) guidewire with an acute distal bend are used in LAST. The Venture deflectable-tip catheter (Vascular Solutions, Minneapolis, Minnesota) can assist in distal true lumen re-entry [26, 27].
The Stingray is a flat 1-mm balloon with three exit ports connected to a common lumen. The distal port is used to place the balloon in position. The other two ports, one proximal and one distal, are 180° opposed so that when the balloon is inflated one is facing the true lumen and the other the adventitia. The Stingray guidewire is an angled, high-gram force wire with a distal tapered probe designed to grab tissue as the operator (guided by fluoroscopy and dual injections) advances it through the port facing the true lumen. Most operators exchange for a more steerable guidewire (such as Pilot 200) after gaining access to the distal vessel (stick and switch technique). In the FAST-CTOs (Facilitated Antegrade Steering Technique in Chronic Total Occlusions) trial, use of the Bridgepoint system, among patients with CTOs in which conventional techniques had failed to cross, resulted in 77 % technical success rate. In about a third of patients the CrossBoss catheter crossed into the distal true lumen [28•].
Although dissection/re-entry strategies can enhance the success rate and efficiency of CTO crossing and carry low risk for procedural complications, they have however been associated with high restenosis rates in small studies  and require further evaluation of their long-term outcomes .
The Retrograde Approach
The retrograde approach has been established as an important strategy for crossing challenging CTOs. Although Japanese operators have been at the forefront of the retrograde technique development , the technique is now used successfully worldwide. Karmapaliotis et al. recently published procedural outcomes of 462 retrograde CTO-PCIs in 3 high-volume CTO centers in the United States  showing 80 % procedural success and 2.6 % complication rate. Moreover, early in 2012, two detailed descriptions and critique of the technique were published, providing step-by-step guidance for both beginning and expert operators [33•, 34•].
Collateral crossing is usually achieved using a soft polymer jacketed guidewire (Fielder FC or Pilot 50) or the Sion guidewire (Asahi Intecc) with a 1 mm 45° bend at its distal tip inserted over a Corsair® catheter (Asahi Intecc). The Corsair catheter, with its hydrophilic coating and stainless steel braiding design, not only provides wire support but also serves as collateral channel dilator.
Once the retrograde wire has been advanced to the distal cap, the CTO can be crossed by using a wire escalation or dissection re-entry technique, similar to the antegrade approach. Retrograde true lumen puncture is only achieved in 40 % of cases [33••]. Occasionally, crossing is successful antegradely with the retrograde wire serving as distal true lumen marker. However, most commonly crossing is completed using a dissection and re-entry technique, using a knuckle wire for dissection and the reverse controlled antegrade and retrograde subintimal tracking (reverse CART) for re-entry. In reverse CART a balloon is advanced over the antegrade wire and inflated in the subintimal space to enlarge it, while the retrograde guidewire is advanced into the newly created space. Using large balloons (often with IVUS guidance) can facilitate re-entry. In the classic CART technique, the subintimal space is enlarged using a retrograde balloon while an antegrade wire is aimed at the space created. Since the introduction of the Corsair catheter the classic CART is rarely performed [34•] because exchanging the Corsair catheter for an OTW balloon is time consuming and leaves the distal wire uncovered, which may lead to collateral vessel injury.
After reverse CART succeeds, the retrograde wire is advanced into the antegrade guide catheter, where it is “trapped” allowing advancement of the microcatheter into the guide catheter and exchange of the wire for a long guidewire that can be externalized. Because of its length, support and ease to advance through the Corsair catheter the 335 cm Viper Advance wire (Cardiovascular Systems Inc., Saint Paul, Minnesota) is preferred for externalization in the US, whereas the RG3 wire (Asahi Intecc) is the wire of choice in Japan. Occasionally, instead of externalizing the retrograde guidewire, retrograde balloon dilation can be performed followed by antegrade CTO crossing. When wire externalization is performed extreme care should be taken to prevent injury of the target and donor coronary artery by movement of the guide catheters.
Algorithm for CTO Crossing
The first step is a detailed assessment of four coronary angiography parameters using dual injection (Fig. 2, box 2), which will determine the primary interventional strategy (antegrade vs. retrograde). Four key parameters are assessed: 1) proximal cap (ambiguous vs. identifiable), 2) length of the occlusion (> or < 20 mm), 3) size and location of distal vessel relative to secondary branches (> 2 mm vessel with no disease or side branches being a good distal target), and 4) presence of interventional collaterals (large collaterals with minimal tortuosity being ideal). Based on these parameters an initial crossing strategy is selected, which can be modified based on the progress made during the procedure. Prolonged crossing attempts using the same strategy should be avoided if no progress is made and alternative strategies should be attempted. This is at the core of the “hybrid approach” that advocates pursuing crossing of the CTO using all available techniques in the most safe and efficient manner [37••].
Given the long stent length in CTO PCI and high restenosis rates with bare metal stents, drug-eluting stents are preferred as they significantly reduce restenosis [38, 39]. In a recent multicenter US retrograde CTO PCI registry the average stent length was 72 ± 35 mm with 96 % of patients receiving a drug-eluting stent . High fracture rates were seen in the past with implantation of the sirolimus-eluting stent, which is no longer commercially available .
The non-acute Coronary occlusIon treated By EveroLimus- Eluting Stent (CIBELES) trial (presented at EuroPCR in 2012) showed similar angiographic late loss at 9 months among the sirolimus and the everolimus-eluting stent. Several ongoing studies, such as the AngiographiC Evaluation of the Everolimus-Eluting Stent in Chronic Total Occlusions (ACE-CTO, NCT01012869) and the Evaluation of the XIENCE Coronary Stent, Performance, and Technique in Chronic Total Occlusions (EXPERT-CTO, NCT01435031) are currently evaluating the outcomes after implantation of the everolimus-eluting stent in CTOs.
Complications of CTO-PCI
Contrary to what many believe, the overall risk of CTO-PCI in specialty centers may be comparable to that on non-CTO-PCI [1, 20, 41•]. A matched-cohort study involving 4014 patients from Mid-America Heart Institute in Kansas City, MO reported similar rates of death (1.3 % vs. 0.8 %, p = 0.13), Q-wave myocardial infarction (0.5 % vs. 0.6 %, p = 0.67), urgent CABG (0.7 % vs. 1.1 %, p = 0.25) and combined major adverse cardiac events (3.8 % vs. 3.7 %, p = 0.90) in CTO-PCI vs. non-CTO-PCI, respectively . However, CTO PCI does carry risk for complications and requires advanced planning for successful treatment of those complications, as reviewed in detail recently [41•]. Specifically, covered stents and coils should be available for the treatment of perforations.
To minimize the risk for radiation skin injury, collimation, fluoroscopy at 7.5 rather than 15 or 30 frames per second, frequent changes in angiographic views, maximization of the distance between X-ray source and patient, minimization of the distance between the patient and the image intensifier and shielding (for example by using the RadPad (Worldwide Innovations & Technologies, Inc., Kansas City, MO) should be used. Careful attention should be paid to the fluoroscopy dose used throughout the case. In general the procedure should be stopped if crossing has not occurred at 8 Grays air kerma dose.
In summary, CTOs are frequently encountered in clinical practice but only a minority undergoes percutaneous revascularization. In specialized centers, success rates of 80-90 % with major complications rates similar to non-CTO-PCI can be achieved using a combination of antegrade wire escalation, antegrade dissection/re-entry and retrograde crossing strategies. Successful CTO-PCI can relieve angina, and may also improve left ventricular dysfunction, decrease the risk for arrhythmias, and improve tolerance of future acute coronary syndromes. Ongoing studies are evaluating the role of CTO PCI compared to optimal medical therapy in improving hard clinical outcomes.
Conflicts of interest: S. Garcia: is a recipient of a career development award (1IK2CX000699-01) from the VA Office of Research and Development; S. Abdullah: none; S. Banerjee: has served on the Speakers’ Bureau for St. Jude Medical Center, Medtronic Corp., and Johnson & Johnson and has received a research grant from Boston Scientific; has received grant support from Gilead Medicine Company; and spouse has received honoraria from Abbott; he has ownership interest in Hygeia Tel and spouse has ownership interest in Mdcare Global; E.S. Brilakis: has received speaker honoraria from St. Jude Medical, Terumo, and Bridgepoint Medical; and spouse is an employee of Medtronic; and has given expert testimony for Thompson, Coe, Cousins and Irons, LLP.