Chronic total coronary occlusions (CTO) are present

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1 Is Chronic Total Coronary Occlusion a Risk Factor for Long-Term Outcome After Minimally Invasive Bypass Grafting of the Left Anterior Descending Artery? David M. Holzhey, MD, Stephan Jacobs, MD, Thomas Walther, MD, PhD, Friedrich W. Mohr, MD, PhD, and Volkmar Falk, MD, PhD Department of Cardiac Surgery, Heart Center Leipzig, University of Leipzig, Leipzig, Germany, and Department of Cardiovascular Surgery, University Hospital Zurich, Zurich, Switzerland Background. Chronic total occlusion (CTO) of coronary vessels is still a challenge for percutaneous coronary intervention and recent data show unfavorable long-term results compared with medical therapy. It is unclear whether CTO is also a negative predictor for long-term outcome in minimally invasive bypass grafting. Methods. From 1996 to 2007 minimally invasive surgical revascularization of the left internal mammary artery to the left anterior descending artery (LAD) was performed in 1,800 patients. Demographic data, risk factors, perioperative outcome, and annual follow-up were obtained from all patients. Estimated survival and freedom from major adverse cardiac and cerebrovascular events or recurrence of angina with log-rank tests and Cox regression analysis for identification of independent risk factors were calculated for patients with (420 patients) and without (1,380 patients) CTO of the LAD. Results. Revascularization of the LAD could be completed in all but one patient (99.8% success rate with CTO). At 5 years estimated overall survival was 90.5% (95% confidence interval [CI] 85.8 to 95.5) with CTO and 90.4% (95% CI 85.8 to 95.1) without CTO (p 0.91). Freedom from major adverse cardiac and cerebrovascular events and angina with or without CTO at 5 years was 83.2% (95% CI 77.6 to 88.8) and 85.5% (95% CI 82.6 to 88.1), respectively (p 0.64). Chronic occlusion of the target vessel and other preoperative factors were not identified as risk factors for major adverse cardiac and cerebrovascular events during follow-up. Conclusions. As opposed to percutaneous coronary intervention, minimally invasive bypass grafting of a totally occluded LAD is almost always possible and chronic occlusion is not a negative predictor for short and long-term outcome. Minimally invasive bypass grafting of the LAD should be considered the treatment of choice for chronically occluded left anterior descending arteries. (Ann Thorac Surg 2010;89: ) 2010 by The Society of Thoracic Surgeons Chronic total coronary occlusions (CTO) are present in up to one-third of patients undergoing coronary angiography [1]. The rationale for revascularization of coronary vessels with chronic total occlusion is to maintain or improve ventricular function, relieve angina, and improve long-term survival. These effects have been shown in multiple studies [1 4]. Substantial efforts are made and variant techniques have been developed to reopen CTOs by percutaneous coronary intervention (PCI) [5, 6]. Initial success rates between 75% and 86% have been reported. Despite these advancements, PCI of CTO remains a challenge and delivers worse results than PCI of stenotic vessels [7]. Percutaneous coronary intervention of CTOs in high-risk patients after myocardial infarction was not superior to medical therapy alone [8]. Chronically occluded coronary Accepted for publication Jan 25, Address correspondence to Dr Holzhey, Heart Center Leipzig, Raemistrasse 100, Leipzig, Germany; dholzhey@web.de. vessels remain a risk factor for PCI both for the initial procedural success as well as for long-term outcome. The subject of the following study was to approach the question whether this is also true for coronary artery bypass patients undergoing isolated minimally invasive revascularization of the left anterior descending coronary artery through a small anterior thoracotomy. The literature in recent years has focused on treatment of CTO with PCI. Limited data on surgical revascularization of CTO exist. This may be due to the fact that occluded vessels usually present as an indication for surgery. Yet concerns about recovery of left ventricular function, microvascular function, potential low flow rates, and consecutive bypass graft failure as well as potentially impaired long-term outcome should be addressed for surgical revascularization as well. The following study focuses on short-term and longterm outcome after minimally invasive surgical revascularization of CTO of the left anterior descending artery (LAD) with the left internal mammary artery (LIMA) in the context of the published results for PCI by The Society of Thoracic Surgeons /10/$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg HOLZHEY ET AL 2010;89: MIDCAB FOR CHRONIC TOTAL OCCLUSIONS 1497 Material and Methods Between 1996 and 2007, 1,800 patients underwent minimally invasive revascularization of the left anterior descending artery and were included in the study. The procedure was performed by either minimally invasive direct coronary artery bypass grafting (1,586 patients plus 102 patients with telemanipulator-assisted LIMA harvest) or totally endoscopic coronary artery bypass grafting (85 patients without plus 27 patients with coronary pulmonary bypass). The details of the procedures have been described elsewhere [9]. Written informed consent for anonymous data collection and analysis of all patients was obtained before the operation. The local institutional review board approved the study and waived the need for additional patient consent. Demographic, intraoperative and postoperative data were collected in a prospective hospital database. A yearly follow-up of all patients, including all major cardiac and cerebral events (MACCE), death, myocardial infarction, target vessel revascularization, and stroke was obtained by postal contact or by telephone. Also, angiographic data were collected where available. The patients were divided into two groups. The first group included all patients with chronic total occlusion of the LAD (defined as an occluded LAD 3 months). The second group consisted of patients with one or more stenotic lesions of the LAD. Patients with an acute coronary syndrome or an occlusion of the LAD less than 3 months were excluded from the study. Furthermore each group was divided into two subgroups of patients who had suffered an anterior myocardial infarction prior to the revascularization or not, because revascularization after myocardial infarction has been seen as critical in a recent publication [8]. Statistical Analysis Kaplan-Meier analysis of survival and MACCE-free survival was calculated and groups were compared using the log-rank test. In addition, univariate and multivariate Cox regression analysis using a stepwise logistic regression model was applied to identify the impact of the following potential risk factors for death and MACCE during follow-up: age; body mass index; female gender; smoking; arterial hypertension; diabetes mellitus (oral or insulin treatment); hyperlipoproteinemia; chronic obstructive lung disease; peripheral vascular disease; impaired renal function (creatinine value 200 mol/l) previous cardiac operation; impaired left ventricular ejection fraction ( 0.30); previous anterior myocardial infarction; and chronically occluded LAD. Categoric variables are expressed as proportions and continuous variables as mean standard deviations throughout this study. The baseline characteristics and outcomes were compared using the 2 analysis (Pearson) for categoric data, and the Student s t test or the Mann- Whitney U test (after testing for normal distribution with the Kolmogorov-Smirnov-test) for continuous variables. Survival and freedom from reoperation were analyzed with Kaplan-Meier actuarial methods and compared using the log-rank test. Furthermore, risk factors for longterm outcome were evaluated using a Cox regression model and applying it for univariate and multivariate (forward logistic regression) analysis. For all risk factors, odds ratio, 95% confidence interval, and p values were calculated. Statistical significance was considered at the p less than 0.05 level. Data analysis was performed using Microsoft EXCEL (Microsoft Corp, Redmond, WA) and SPSS 17.0 (SPSS, Inc, Chicago, IL). Results Four hundred twenty patients with CTO of the LAD plus 1,380 patients with a stenotic lesion of the LAD were analyzed. The demographic and preoperative data of all patients are summarized in Table 1. Bypass grafting of the LAD could be performed in all patients with stenotic lesions and in all but one patient, where a totally occluded LAD turned out to be too small to bypass (99.8% procedural success). Periprocedural mortality was 1.1% for the CTO group and 0.7 for the stenotic group (p 0.358). Follow-up amounts to 1,065 patient years in the CTO and 3,269 patient years in the stenotic group, respectively. Overall survival during follow-up for the CTO Table 1. Baseline Patient Characteristics Characteristics CTO Stenotic Lesion p Value Number 420 1,380 Age, mean SD (years) Male 76.0% 72.9% BMI, mean SD (kg/m 2 ) Arterial hypertension 77.4% 79.6% Hyperlipidemia 70.0% 66.2% Renal insufficiency 1.7% 2.5% (creatinine 200) Occlusive arterial 11.4% 14.6% disease DM 16.2% 18.3% IDDM 7.4% 9.5% COLD 7.4% 7.5% Current or ex-smoker 32.1% 30.9% Previous PCI-stent LAD 20.7% 16.4% Prior anterior MI 5.3% 4.0% Poor ejection fraction Additive EuroSCORE Logistic EuroSCORE (%) 3.30% 5.0% 3.34% 4.9% BMI body mass index; COLD chronic obstructive lung disease; CTO chronic total occlusion; DM diabetes mellitus; EuroSCORE European System for Cardiac Operative Risk Evaluation; IDDM insulin dependent diabetes mellitus; LAD left anterior descending artery; MI myocardial infarction; PCI percutaneous coronary intervention; SD standard deviation.

3 1498 HOLZHEY ET AL Ann Thorac Surg MIDCAB FOR CHRONIC TOTAL OCCLUSIONS 2010;89: Table 2. Complications-Mortality During Follow-Up Variables Total Number CTO Per Patient Year Stenotic Lesions Total Number Per Patient Year Deaths cardial % % Deaths noncardial % % Deaths, unknown % % reason Stroke % % Reintervention target % % vessel Myocardial infarction % % Redo cardiac surgery, % % other than LAD bypass Recurrence of angina % % Thoracic wall hernia % % Thoracic wound infections % % CTO chronic total occlusion; LAD left anterior descending artery. versus the stenotic group was 98.0% (95% confidence interval [CI] 96.5 to 99.5) versus 98.0% (95% CI 96.4 to 99.5) after 1 year (p ) and 90.5% (95% CI 85.8 to 95.5) versus 90.4% (95% CI 85.8 to 95.1) after 5 years (p ), respectively. An angiographic follow-up that was obtained 6 to 12 months postoperatively of a part of the patients in the context of previous studies which showed a patency rate of the LIMA-to-LAD-bypass of 98% (94 of 96 patients) in the CTO group and 96% (290 of 301 patients) in the stenotic group (p ). Relevant complications and reasons for mortality during follow-up are listed in Table 2. Kaplan-Meier analysis of survival and combined MACCE showed no significant differences between the two groups (Fig 1). Further stratification of the patients into subgroups of patients with or without history of anterior myocardial infarction shows an inferior outcome for patients who had suffered an anterior infarction before the operation. Again, there was no significant difference between the stenotic and CTO group to be found (Fig 2). The results of univariate Cox regression analysis are shown in Figure 3. Multivariate Cox regression analysis revealed the following independent risk factors for death during follow-up: age at operation (odds ratio [OR] 1.081/year, 95% CI to 1.111/year, p ), female gender (OR 0.474, 95% CI to 0.855, p 0.013), diabetes mellitus with insulin therapy (OR 3.075, 95% CI to 5.386, p ), preoperative renal insufficiency (creatinine 200 mol/l) (OR 4.183, 95% CI to 8.930, p ), previous cardiac surgery (OR 1.912, 95% CI to 3.821, p 0.067), preoperative left ventricular ejection fraction less than 0.30 (OR 4.673, 95% CI to 8.506, p ), previous anterior myocardial infarction (OR 1.629, 95% CI to 2.554, p 0.033). Independent risk factors for MACCE during follow-up were age at operation (OR 1.043/year, 95% CI to 1.061/year, p ), diabetes mellitus with insulin therapy (OR 1.721, 95% CI to 2.715, p 0.02), preoperative renal insufficiency (creatinine 200 mol/l) (OR 2.863, 95% CI to 5.763, p 0.003), preoperative left ventricular ejection fraction less than 0.30 (OR 2.529, 95% CI to 4.306, p 0.001), previous cardiac surgery (OR 1.749, 95% CI to 3.133, p 0.060), and previous anterior myocardial infarction (OR 2.020, 95% CI to 2.770, p ). A chronically occluded LAD was no risk factor for occurrence of MACCE during follow-up in any of the analyses. Comment Minimally invasive revascularization of the LAD has become a routine procedure and has been shown to be safe and effective [9]. Comparisons with off-pump revascularization through a sternotomy have yielded similar results [10 12]. Surgical revascularization of the LAD is almost always possible with low complication rates and good long-term results. Several recent publications and meta-analyses deal with the comparison of minimally invasive direct coronary artery bypass grafting and PCI-stenting of the LAD [11, 13 20]. Because patients with CTO of the LAD were excluded from these trials, no conclusions can be drawn with regard to this subset of patients. Fig. 1. Kaplan-Meier plots of survival (A) chronic total occlusion (CTO) and major cardiac and cerebral events-free survival (B) comparing patients with CTO versus stenotic lesions of the left anterior descending artery.

4 Ann Thorac Surg HOLZHEY ET AL 2010;89: MIDCAB FOR CHRONIC TOTAL OCCLUSIONS 1499 Fig 2. Kaplan-Meier plots of survival (A) and major cardiac and cerebral events-free survival (B) with additional distinction between patients who had suffered an anterior myocardial infarction (ami)or not. Fig 3. Results of the univariate Cox regression analysis for major cardiac and cerebral events during follow-up. (BMI body mass index; COLD chronic obstructive lung disease; Crea creatinine; CTO chronic total occlusion; DM diabetes mellitus; EF ejection fraction; LAD left anterior descending artery; poad peripheral occlusive arterial disease; pt patient.) Except for a very small series of patients and papers on coronary endarterectomy we have found no publication dealing with the specific aspects of surgical revascularization in the setting of totally occluded coronary vessels [21]. This may be explained by the fact that the primary concern is the target vessel downstream and not the lesion itself. There is generally no difference in the revascularization technique whether the vessel is highly stenotic or completely occluded. In the cardiologic literature chronically totally occluded coronary vessels, the different revascularization techniques, procedural success rates, short-term and long-term outcome, and the impact of successful reopening of the vessel on ventricular function and microcirculation are extensively discussed [1 8, 22 32]. In a large series of patients Hochman and colleagues [8] showed no benefit of PCI of CTOs after myocardial infarction in the long run. Safley and colleagues [32] differentiated between the different coronary vessels and demonstrated that successful PCI of an occluded LAD is associated with better 5-year-survival compared with failed PCI, whereas no significant survival benefits could be found after successful PCI of the circumflex or right coronary artery. Further studies show improvement of left ventricular perfusion and function [4, 33]. Despite technical advancements, PCI of CTOs remains challenging and primary success rates are reported in the range from 70 to 86% [4, 8, 22, 23, 27, 31, 32]. Elezi and colleagues [7] reported a higher incidence of target vessel restenosis and re-revascularization after PCI of CTOs compared with PCI of stenotic lesions. This is consistent with more recent studies that show short-term restenosis rates for CTOs from 30 to 50% at angiographic follow-up [4, 22]. The results of some important studies are summarized in Table 3. The aim of our study was to show the long-term outcome after minimally invasive surgical revascularization of a chronically occluded LAD in a large series of patients and to compare them with patients with only stenotic lesions. It could be shown that minimally invasive left internal mammary artery bypass grafting of the LAD yields very good long-term results and that an occluded LAD is not an additional risk factor for surgery as it is for PCI. Successful revascularization of the anterior wall improves long-term outcome of patients. A chronically occluded LAD should therefore always be revascularized. The short-term and long-term results published so far are in favor of LIMA-to-LAD-bypass grafting over PCI of CTOs (Table 3). Therefore, surgical revascularization (minimally invasive or through sternotomy) should be considered as first-line therapy in these cases. If PCI of the LAD is attempted and fails or yields a doubtable result, surgical revascularization should consequently be considered as the next step. A controlled randomized intention-to-treat study comparing the different therapeutic strategies (medical-pci- surgical) would be desir-

5 1500 HOLZHEY ET AL Ann Thorac Surg MIDCAB FOR CHRONIC TOTAL OCCLUSIONS 2010;89: Table 3. Selection of Published Results of Percutaneous Coronary Intervention of Chronic Total Occlusion Author (Number of Patients) Target Vessel RCA/LCx/LAD Primary Success Follow-Up of Patients With Successful PCI Survival Angiography Werner et al 2005 [4] (n 168) 72/6/48 75% At months: - 17% reocclusion - 35% restenosis 50% - 49% reintervention Arslan et al 2006 [22] (n 172 with DM) Hochman et al 2006 [8] (n 1,082 after MI; plus EF 0.50 or proximal LAD occlusion) 33/49/35 68% KM at 4 years: 85% Angiography for ACS: % restenosis 529/173/ % KM at 4 years: 90.9% After 4 years: % re intervention Aziz et al 2007 [23] (n 543) 156/69/ % KM at 2 years: 97.5% Safley [32] (n 2,608) 990/682/936 75% KM at 5 years: 87.7%/ 86.1%/88.9% Valenti et al 2008 [31] (n 486) 160/63/97 71% KM at 3 years: 91.6% Present study (n 420).../.../ % KM at 1 year: 98.0% KM at 5 years: 90.5% Bypass patency at 6 to 12 months: 98% ACS acute coronary syndrome; DM diabetes mellitus; EF ejection fraction; KM Kaplan-Meier survival; LAD left anterior descending artery; LCx left circumflex coronary artery; MI myocardial infarction; RCA right coronary artery. able to find the best option for the patients with CTO of the LAD in the future. Although data collection was prospective the analysis was done retrospectively from a patient database. We report a single-center experience from a high-volume center which cannot be interpolated without further studies. Furthermore, in our study only revascularization of the LAD was discussed and conclusions about other coronary vessels cannot be drawn. References 1. Braden GA. Chronic total coronary occlusions. Cardiol Clin 2006;24: Baks T, van Geuns RJ, Duncker DJ, et al. Prediction of left ventricular function after drug-eluting stent implantation for chronic total coronary occlusions. J Am Coll Cardiol 2006;47: Jin J, Huang L, Wang H, et al. Value of myocardial regional perfusion on long-term function in collateral-dependent myocardium. South Med J 2008;101: Werner GS, Surber R, Kuethe F, et al. Collaterals and the recovery of left ventricular function after recanalization of a chronic total coronary occlusion. Am Heart J 2005;149: Christ G, Glogar D. 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6 Ann Thorac Surg HOLZHEY ET AL 2010;89: MIDCAB FOR CHRONIC TOTAL OCCLUSIONS 1501 pump coronary artery bypass in single-vessel disease. Heart Surg Forum 2009;12:E Thiele H, Neumann-Schniedewind P, Jacobs S, et al. Randomized comparison of minimally invasive direct coronary artery bypass surgery versus sirolimus-eluting stenting in isolated proximal left anterior descending coronary artery stenosis. J Am Coll Cardiol 2009;53: Hayashi Y, Hirata N, Satoh H, et al. Minimally invasive direct coronary artery bypass for completely obstructed left anterior descending coronary artery. J Cardiovasc Surg (Torino) 2002;43: Arslan U, Balcioglu AS, Timurkaynak T, Cengel A. The clinical outcomes of percutaneous coronary intervention in chronic total coronary occlusion. Int Heart J 2006;47: Aziz S, Stables RH, Grayson AD, Perry RA, Ramsdale DR. Percutaneous coronary intervention for chronic total occlusions: improved survival for patients with successful revascularization compared to a failed procedure. Catheter Cardiovasc Interv 2007;70: Fiocchi F, Sgura F, Di Girolamo A, et al. Chronic total coronary occlusion in patients with intermediate viability: value of low-dose dobutamine and contrast-enhanced 3-T MRI in predicting functional recovery in patients undergoing percutaneous revascularisation with drug-eluting stent. Radiol Med 2009;114: Ge J, Zhang F. Retrograde recanalization of chronic total coronary artery occlusion using a novel reverse wire trapping technique. Catheter Cardiovasc Interv 2009;74: Goyal BK. DES in CTO: cosmetic or clinical benefit. Catheter Cardiovasc Interv 2009;73: Grantham JA, Marso SP, Spertus J, House J, Holmes DR Jr, Rutherford BD. Chronic total occlusion angioplasty in the United States. JACC Cardiovasc Interv 2009;2: Kim MH, Yu LH, Mitsudo K. A new retrograde wiring technique for chronic total occlusion. Catheter Cardiovasc Interv 2010;75: Lee NH, Seo HS, Choi JH, Suh J, Cho YH. Recanalization strategy of retrograde angioplasty in patients with coronary chronic total occlusion analysis of 24 cases, focusing on technical aspects and complications. Int J Cardiol 2009 [epub ahead of print]. 30. Rathore S, Hakeem A, Pauriah M, Roberts E, Beaumont A, Morris JL. A comparison of the transradial and the transfemoral approach in chronic total occlusion percutaneous coronary intervention. Catheter Cardiovasc Interv 2009;73: Valenti R, Migliorini A, Signorini U, et al. Impact of complete revascularization with percutaneous coronary intervention on survival in patients with at least one chronic total occlusion. Eur Heart J 2008;29: Safley DM, House JA, Marso SP, Grantham JA, Rutherford BD. Improvement in survival following successful percutaneous coronary intervention of coronary chronic total occlusions: variability by target vessel. JACC Cardiovasc Interv 2008;1: Pavlovic SV, Sobic-Saranovic DP, Beleslin BD, et al. Oneyear follow-up of myocardial perfusion and function evaluated by gated SPECT MIBI in patients with earlier myocardial infarction and chronic total occlusion. Nucl Med Commun 2009;30: The Society of Thoracic Surgeons: Forty-Seventh Annual Meeting Mark your calendars for the Forty-Seventh Annual Meeting of The Society of Thoracic Surgeons (STS) to be held at the San Diego Convention Center, San Diego, California, from January 31 February 2, Come to San Diego to learn from the experts, network with colleagues from around the world, and prepare for whatever the future may hold. This pre-eminent educational event in cardiothoracic surgery is open to all physicians, residents, fellows, engineers, perfusionists, physician assistants, nurses, or other interested individuals. Meeting attendees will be provided with the latest scientific information for practicing cardiothoracic surgeons. Attendees will benefit from traditional Abstract Presentations, as well as Surgical Forums, Breakfast Sessions, Surgical Motion Pictures, and Wet Lab sessions. Parallel sessions on Monday and Tuesday will focus on specific subspecialty interests. An advance program with a registration form, hotel reservation information, and details regarding spouse/ guest activities will be mailed to STS members this fall. Nonmembers may contact the Society s secretary, David A. Fullerton, MD, to receive a copy of the advanced program; however, detailed meeting information will be available on the STS website at David A. Fullerton, MD Secretary The Society of Thoracic Surgeons 633 N Saint Clair St, Suite 2320 Chicago, IL Telephone: (312) Fax: (312) sts@sts.org website: by The Society of Thoracic Surgeons Ann Thorac Surg 2010;89: /10/$36.00 Published by Elsevier Inc