Severe left ventricular (LV) dysfunction caused by

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1 Revascularization in Severe Ventricular Dysfunction (15% < LVEF < 30%): A Comparison of Bypass Grafting and Percutaneous Intervention Koichi Toda, MD, PhD, Karen Mackenzie, MD, Mandeep R. Mehra, MD, Charles J. DiCorte, MD, James E. Davis, MD, P. Michael McFadden, MD, John L. Ochsner, MD, Christopher White, MD, and Clifford H. Van Meter, Jr, MD Departments of Surgery and Cardiology, Ochsner Clinic Foundation, New Orleans, Louisiana Background. We sought to determine the optimal approach to revascularization of patients with severe left ventricular (LV) dysfunction. Methods. We conducted a single-center observational study of 117 consecutive patients who had severe LV dysfunction (15% < LV ejection fraction < 30%) and underwent either coronary artery bypass grafting (CABG, n 69) or percutaneous revascularization (n 48) between 1992 and Results. The CABG group was younger (62 versus 67 years, p 0.026), and fewer previous bypasses (7% versus 40%, p < ) and fewer prior percutaneous revascularizations (16% versus 42%, p ) were noted. More vessels were revascularized (3 0.8 versus , p < ), and revascularization was more complete by CABG (84% versus 48%, p < ). Morbidity and mortality at 30 days were similar, and there was no significant difference in 3-year survival (73% versus 67%), although 3-year cardiac event-free survival (52% versus 25%, p ) and 3-year target vessel revascularization free survival (71% versus 41%, p < ) were significantly better in the CABG group, and LV ejection fraction was significantly improved after CABG. In the subgroup of patients 65 years of age or older and those without proximal left anterior descending coronary artery lesions, significant benefit of CABG in cardiac eventfree and target vessel revascularization free survival disappeared. Conclusions. We found that in clinically selected patients with severe ventricular dysfunction, CABG compared with percutaneous revascularization achieves more complete revascularization, improved LV function, fewer cardiac events, and fewer target vessel revascularizations, but does not affect mid-term survival. A prospective controlled trial with defined criteria for treatment assignment is warranted to confirm our results regarding the two revascularization strategies in patients with severe LV dysfunction. (Ann Thorac Surg 2002;74:2082 7) 2002 by The Society of Thoracic Surgeons Severe left ventricular (LV) dysfunction caused by severe coronary artery disease (CAD) carries a poor prognosis with medical treatment, including 2-year survival of 31% [1]. Coronary artery bypass grafting (CABG) in this population remains a surgical challenge because of increased operative mortality [2]. However, surgical studies have revealed that coronary revascularization can reverse systolic LV dysfunction secondary to hibernating myocardium [3]. Surgical revascularization also demonstrated the greatest benefit in the patients with the worst LV function [4], and randomized clinical trials have shown surgical revascularization can significantly improve survival in patients with low LV ejection fraction (EF) compared with medical treatment [5]. Presented at the Thirty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28 30, Address reprint requests to Dr Van Meter, Division of Thoracic Cardiovascular Surgery, Department of Surgery, Ochsner Clinic, 1514 Jefferson Highway, New Orleans, LA 07121; cvanmeter@ochsner.org. On the other hand, patients with LV dysfunction once were considered poor candidates for percutaneous revascularization (PCI), because acute closure of lesions after balloon dilatation might result in death if the treated coronary artery supplied the only remaining viable myocardium. Recent advances in interventional cardiology have allowed angioplasty and intracoronary stent placement in patients with multivessel disease. Intracoronary stents have reduced the need for both emergency CABG and subsequent revascularization procedures [6]. Rotational coronary atherectomy has expanded interventional options, and calcified or long lesions can be treated [7]. The advances in technology have improved the efficacy and safety of PCI in patients with depressed LVEF [8]. Because most randomized clinical trials comparing CABG and PCI exclude patients with low LVEF [9], little information exists clarifying the optimum revascularization strategy in patients with severe LV dysfunction.to examine the comparative benefits and risk of CABG and PCI in patients with severe LV dysfunction, this retrospective study was conducted by The Society of Thoracic Surgeons /02/$22.00 Published by Elsevier Science Inc PII S (02)

2 Ann Thorac Surg TODA ET AL 2002;74: REVASCULARIZATION IN SEVERE VENTRICULAR DYSFUNCTION 2083 Patients and Methods Patients This study was conducted as a retrospective analysis of 117 consecutive patients who had severe LV dysfunction (LVEF between 30% and 15% at the time of the preoperative left ventriculogram or radionuclide study) and underwent isolated CABG (CABG with no other major open heart procedure) or PCI in Ochsner Clinic Foundation Hospital between October 1992 and September Patients were selected for CABG or PCI on the basis of a clinical decision by surgeons and cardiologists. The first procedure performed in the study period defined the treatment group regardless of how many or what kind of subsequent revascularizations ensued. Patients were excluded from the CABG group if they underwent emergency CABG within 6 hours after failed PCI. Patients were also excluded from both study groups if they underwent emergency CABG or PCI because of cardiogenic shock after acute myocardial infarction. Procedures Patients who were selected for operation underwent CABG with full sternotomy and standard cardiopulmonary bypass. Patients were cooled down to 32 C, and antegrade or antegrade and retrograde cold-blood cardioplegia were given for cardioplegic arrest. Percutaneous revascularization was performed using standard techniques. In these patients preoperative and postoperative variables were investigated by reviewing the clinical chart, and follow-up was conducted between November 1999 and February 2000 by telephone interviews and review of outpatient records. Definitions Unstable angina was defined as anginal pain accelerating in frequency and severity that necessitated heparin or nitroglycerin infusion. The number of diseased vessels was defined as the number of the three major coronary perfusion territories (anterior, lateral, and inferoposterior). Thirty-day mortality included noncardiac death, but long-term mortality excluded noncardiac death. Postoperative dialysis was defined as dialysis that was initiated for acute renal failure after the procedure. Patients who needed intubation for respiratory support for more than 3 days defined respiratory failure. A cerebrovascular accident was defined as a focal or global neurologic deficit confirmed by a neurologist. A cardiac event was defined as recurrent angina, myocardial infarction, or congestive heart failure that required hospitalization. Statistical Analysis Data were analyzed with computer software (StatView, version 5, Abacus Concepts, Berkeley, CA). Values are expressed as mean standard deviation. Fisher s exact test was used for categorical variables, and the Mann- Whitney U test was used to compare continuous variables. The Wilcoxon signed rank test was used to compare EF before and after procedures. Survival curves were generated using Kaplan-Meier methods, and the Table 1. Preoperative Clinical and Angiographic Characteristics of Patients Characteristic CABG (n 69) PCI (n 48) p Value Age (y) Female 23% 29% Unstable angina 48% 63% NYHA class III, IV 55% 35% Prior MI within 7 days 23% 23% Prior CABG 7% 40% Prior PCI 16% 42% COPD 32% 23% Dialysis 3% 2% DM 44% 40% PVD 32% 29% Smoking 49% 35% VT/VF 7% 10% No. of CAD Left main lesion 30% 19% Proximal LAD lesion 88% 60% EF (%) CABG coronary artery bypass grafting; COPD chronic obstructive pulmonary disease; DM diabetes mellitus; EF ejection fraction; LAD left anterior descending artery; MI myocardial infarction; No. of CAD the number of diseased coronary arteries; NYHA III, IV New York Heart Association class III, IV heart failure; PCI percutaneous revascularization; PVD peripheral vascular disease; VT/VF ventricular tachycardia/fibrillation. comparison between survival distributions was made by log rank test. The Cox proportional hazard model is used to calculated an adjusted hazard ratio of PCI patient risk to CABG patient risk. The Cox model was adjusted by patient severity of illness, including number of diseased coronary vessels, presence of New York Heart Association class III or IV heart failure and history of previous revascularization. A p value less than 0.05 was considered significant. Results Sixty-nine CABG and 48 PCI procedures were performed initially in the patients with severe LV dysfunction during the study period. Clinical and angiographic details before the procedure are listed in Table 1. There was no significant difference in EF and medical comorbidity before the procedure. However, the CABG group was younger, but had more severe (New York Heart Association class III/IV) heart failure, more diseased coronary arteries, and a greater prevalence of significant proximal left anterior descending coronary artery (LAD) lesions. Fourteen patients of 69 CABG patients (20%) and 32 patients of 48 PCI patients (67%) had previous revascularization. Fewer previous bypasses and fewer prior PCIs were noted in the CABG group. In the CABG group internal thoracic arteries and radial arteries were used in 55 (80%) and 3 patients (4.3%), respectively. Cross-clamp time was minutes, and cardiopulmonary bypass time was minutes. Combined antegrade and retrograde cardioplegia was

3 2084 TODA ET AL Ann Thorac Surg REVASCULARIZATION IN SEVERE VENTRICULAR DYSFUNCTION 2002;74: Table 2. Morbidity and Mortality Within 30 Days After Procedure Variable CABG (n 69) PCI (n 48) p Value CVA 4% 4% Dialysis for ARF 1.4% 4.2% Respiratory failure 9% 10% VT/VF 10% 6% LOS (d) day mortality 7% 8% ARF acute renal failure; CABG coronary artery bypass grafting; CVA cerebrovascular accident; PCI percutaneous revascularization; respiratory failure patients who needed intubation for more than 3 days; VT/VF ventricular tachycardia/fibrillation. used in 32 patients (46%). In the PCI group intracoronary stents were placed in 32 patients (67%), and coronary atherectomy was performed in 7 patients (15%). Percutaneous revascularization was applied for left main coronary artery disease in 2 patients, LAD disease in 19 patients, and saphenous vein graft disease in 13 patients. Coronary artery bypass grafting revascularized more vessels than PCI (3 0.8 versus , p ), and complete revascularization was achieved in more patients by CABG (84% versus 48%, p ). Cardiopulmonary bypass was used in 1 patient for complicated PCI, and 2 patients (4%) needed emergency CABG after PCI. The CABG group hospital stay was slightly longer than that of the PCI group, but there was no significant difference in morbidity and mortality within 30 days after procedure (Table 2). Five operative deaths occurred in the CABG group. One patient was unable to be weaned from cardiopulmonary bypass, 2 patients died of low output syndrome, 1 patient died of ventricular tachycardia, and 1 patient died of sepsis secondary to pneumonia. Four patients died after PCI. Three patients died of ventricular tachycardia, and 1 patient died of low output syndrome. Thirty-two patients (46%) in the CABG group and 18 patients (38%) in the PCI group were followed by echocardiography at 1 year after the procedures. Echocardiography did not show significant difference in the EF between the two groups before the procedures. Coronary artery bypass grafting significantly improved EF from 25% 4% to 37% 15% at 1 year (p ) after operation. However, no significant improvement in EF was appreciated after PCI (26% 4% before PCI, 30% 13% at 1 year after PCI). Ninety-one percent of CABG patients and 90% of PCI patients were followed completely. The PCI group was followed for months, which is statistically shorter than the CABG group (51 19 months), because we have fewer PCI patients between 1992 and 1994 (25 CABG patients versus 13 PCI patients) and more patients with low EF were assigned to PCI between 1995 and 1997 (44 CABG patients versus 35 PCI patients). Cardiac event free survival curves are shown in Figure 1A. In the CABG group 26 patients needed rehospitalization because of angina (3 patients), myocardial infarction (4 patients), Fig 1. Kaplan-Meier cardiac event free survival curves: coronary artery bypass grafting (CABG) versus percutaneous revascularization (PCI) (A), Kaplan-Meier target vessel revascularization (TAVER) free survival curves: CABG versus PCI (B), Kaplan-Meier survival curves: CABG versus PCI (C). and congestive heart failure (19 patients). In the PCI group 28 patients needed rehospitalization because of angina (17 patients), myocardial infarction (2 patients), and congestive heart failure (9 patients). Cardiac event free survival rate at 3 years was 52% in the CABG group and 25% in the PCI group, and there was a significant difference in cardiac event free survival curves (p ). Target vessel revascularization (TAVER) free survival curves are shown in Figure 1B. In the CABG group 1 patient underwent redo CABG, 3 patients underwent PCI, and 1 patient underwent heart transplantation. In the PCI group 14 patients underwent repeat PCI, 4 patients needed CABG including two emergency CABGs, and 1 patient underwent heart transplantation. The TAVER-free survival rate at 3 years was 71% in the CABG group and 41% in the PCI group, and there was a significant difference in the TAVER-free survival curves (p ). Survival curves are shown in Figure 1C.

4 Ann Thorac Surg TODA ET AL 2002;74: REVASCULARIZATION IN SEVERE VENTRICULAR DYSFUNCTION 2085 There was no significant difference in survival curves (p ), and survival rate at 3 years was 73% in the CABG group and 67% in the PCI group. As shown in Table 1, there were differences in the patient s severity of illness, including age, presence of significant proximal LAD lesion, number of diseased coronary vessels, presence of New York Heart Association class III or IV heart failure, and history of previous revascularization between the CABG group and the PCI group. These differences may have impacted cardiac event free survival, TAVER-free survival, and survival. For further analysis each group was divided into subgroups: patients 65 years of age or older, patients younger than 65 years of age, patients with significant proximal LAD lesion, and patients without significant proximal LAD lesion. For each subgroup the adjusted hazard ratio of PCI patient risk to CABG patient risk was calculated, while controlling differences in the patient severity of illness, including number of diseased coronary vessels, presence of New York Heart Association class III or IV heart failure, and history of previous revascularization. Figure 2 presents the logarithms of the 95% confidence interval (CI) for adjusted hazard ratio of PCI patient death and cardiac event to CABG patient death and cardiac event (A), PCI patient death and TAVER to CABG patient death and TAVER (B), and PCI patient death to CABG patient death (C). A logarithm of the 95% CI whose lower limit is above 0 (the 95% CI is above 1) indicates that the adjusted hazard ratio of PCI is significantly higher than CABG, namely CABG has significantly better freedom from the risk. On the other hand a logarithm of the 95% CI whose upper limit is below 0 (the 95% CI is below 1) denotes that the adjusted hazard ratio of PCI is significantly lower than CABG, namely PCI has significantly better freedom from the risk. Figure 2A shows that CABG has significantly better freedom from death and cardiac event in the whole patients cohort (All), patients with significant proximal LAD lesion (LAD[ ]), and patients younger than 65 years (Young), but CABG loses the significantly better freedom from death and cardiac event in the subgroup of patients without significant proximal LAD lesion (LAD[ ]), and patients older than 64 years (Elderly). Figure 2B shows that CABG has significantly better freedom from death and TAVER in patients younger than 65 years, but CABG loses the significantly better freedom from death and TAVER in the subgroup of patients without significant proximal LAD lesion (LAD[ ]) and patients older than 64 years (Elderly). Coronary artery bypass grafting does not have significantly better freedom from death in any of the subgroups (Fig 2C). Comment This retrospective study demonstrated no survival benefit by CABG compared with PCI in patients with severe LV dysfunction (15% LVEF 30%), although CABG achieved more complete revascularization, improved LVEF, and reduced cardiac events, and TAVERs. The completeness of revascularization has been found to be Fig 2. Logarithms (Ln) of the 95% confidence interval (CI) for adjusted hazard ratio of percutaneous revascularization (PCI) patient death and cardiac event to coronary artery bypass grafting (CABG) patient death and cardiac event (A), PCI patient death and target vessel revascularization (TAVER) to CABG patient death and TAVER (B), and PCI patient death to CABG patient death (C). A logarithm of the 95% CI whose lower limit is above 0 (the 95% CI is above 1) indicates that the adjusted hazard ratio of PCI is significantly higher than CABG, namely CABG has significantly better freedom from the risk. On the other hand a logarithm of the 95% CI whose upper limit is below 0 (the 95% CI is below 1) denotes that adjusted hazard ratio of PCI is significantly lower than CABG, namely PCI has significantly better freedom from the risk. (All the entire patient cohort; LAD[ ] patients with significant proximal left anterior descending artery lesion; LAD[ ] patients without significant proximal left anterior descending artery lesion; Young patients younger than 65 years; Elderly patients older than 64 years.) an important predictor of long-term survival and functional status after CABG [10]. However, a recent randomized study demonstrated that incomplete revascularization by PCI in patients with multivessel disease and preserved LVEF does not compromise hospital mortality and long-term survival, although freedom from angina and repeat revascularization at 5 years were significantly lower than the patients randomized to CABG [11]. Our results suggest that incomplete revascularization by PCI may salvage patients even with severe LV dysfunction and prolong intermediate survival to the extent that CABG can achieve with complete revascularization.

5 2086 TODA ET AL Ann Thorac Surg REVASCULARIZATION IN SEVERE VENTRICULAR DYSFUNCTION 2002;74: However, patients must be followed closely and receive subsequent treatment and intervention as necessary. It is interesting to see similar results in a randomized study that compared CABG and PCI in patients with preserved LV function. There were no significant differences in survival in any of the nine randomized trials that compared CABG and PCI, but these trials showed that the need for TAVER was significantly higher in PCI, and most trials found that CABG resulted in greater freedom from angina [9]. There is one nonrandomized study that compared CABG and PCI in patients with LVEF less than 40% [12]. They showed significantly improved cardiac event free survival and freedom from TAVER, but no significant difference in survival between CABG and PCI. Because our study as well is not randomized, the differences in age, extent of coronary artery disease and heart failure, and completeness of revascularization between groups bias the result. Because two nonrandomized studies demonstrated no difference in survival between these revascularization strategies, a prospective controlled trial with defined criteria for treatment assignment is necessary and warranted to confirm our results regarding two revascularization strategies in patients with severe LV dysfunction. Analysis of adjusted hazard ratios of patient death and cardiac event, and patient death and TAVER, showed significant benefits of CABG in patients younger than 65 years of age or patients with significant proximal LAD lesions. This result suggests that these two subgroups may be appropriate criteria for surgical revascularization in a future prospective controlled trial. A recent study has indicated that high-risk patients including LV dysfunction have a benefit from off-pump CABG [13]. Although not used in our study, application of new technology such as off-pump CABG and minimum invasive direct coronary artery bypass grafting in this patient group may reduce myocardial injury and systemic inflammatory response secondary to cardiopulmonary bypass and cardioplegic arrest. Although intracoronary stenting was used in 67% of our patients, new refinements in stent design and adjunctive pharmacologic therapy are reducing event of restenosis, which is the greatest weakness of PCI and will improve patient outcomes [14]. These evolving technologies will have a great impact on both revascularization strategies. Despite advances in the medical treatment for coronary artery disease and heart failure, coronary artery disease with severe LV dysfunction ultimately has a poor prognosis. We and other authors suggested that CABG can be an alternative in patients waiting for heart transplantation, because ventricular dysfunction may be reversible by restoration of coronary perfusion, if viable hibernating myocardium is present [15]. Our current data demonstrated 1-year survival of 84% after CABG and 73% after PCI which are comparable to the survival after transplantation (86%) and survival on the waiting list (80%) [16]. Considering the shortage of donor hearts and the long waiting list, CABG and PCI may be alternatives to heart transplantation in selected patients or a bridge to heart transplantation. In conclusion, this observational study suggests that in clinically selected patients with severe LV dysfunction, a strategy of CABG compared with PCI achieves more complete revascularization, improved LV function, fewer cardiac events, and fewer TAVERs, but does not affect mid-term survival. A prospective controlled trial with defined criteria for treatment assignment and long-term follow-up is warranted to confirm our results regarding two revascularization strategies in the patients with severe LV dysfunction. References 1. Franciosa JA, Wilen M, Ziesche S, et al. Survival in men with severe chronic left ventricular failure due to either coronary heart disease or idiopathic dilated cardiomyopathy. Am J Cardiol 1983;51: Kennedy JW, Kaiser GC, Fisher LD, Guinn GA, Ryan TJ. Clinical and angiographic predictors of operative mortality from the Collaborative Study in Coronary Artery Surgery (CASS). Circulation 1981;63: Kaul TK, Agnihotri AK, Fields BL, Riggins LS, Wyatt DA, Jones CR. Coronary artery bypass grafting in patients with an ejection fraction of twenty percent or less. J Thorac Cardiovasc Surg 1996;111: Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10- year results from randomized trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet 1994;344: Passamani E, Davis KB, Gillespie MJ, Killip T. A randomized trial of coronary artery bypass surgery. Survival of patients with a low ejection fraction. N Engl J Med 1985;312: Moussa I, Reimers B, Moses J, et al. Long-term angiographic and clinical outcome of patients undergoing multivessel coronary stenting. Circulation 1997;96: Bertrand ME, Lablanche JM, Leroy F, et al. Percutaneous transluminal coronary rotary ablation with Rotablator (European experience). Am J Cardiol 1992;69: Stevens T, Kahn JK, McCallister BD, et al. Safety and efficacy of percutaneous transluminal coronary angioplasty in patients with left ventricular dysfunction. Am J Cardiol 1991; 68: Eagle KA, Guyton RA, Gibbons RJ, et al. ACC/AHA guidelines for coronary artery bypass graft surgery. J Am Coll Cardiol 1999;34: Luciani GB, Montalbano G, Casali G, Mazzucco A. Predicting long-term functional results after myocardial revascularization in ischemic cardiomyopathy. J Thorac Cardiovasc Surg 2000;120: Bourassa MG, Kip KE, Jacobs AK, et al. Is a strategy of intended incomplete percutaneous transluminal coronary angioplasty revascularization acceptable in nondiabetic patients who are candidates for coronary artery bypass graft surgery? J Am Coll Cardiol 1999;33: Okeefe JH, Allan JJ, McCallister BD, et al. Angioplasty versus bypass surgery for multivessel coronary artery disease with left ventricular ejection fraction 40%. Am J Cardiol 1993; 71: Yokoyama T, Baumgartner FJ, Gheissari A, Capouya ER, Panagiotides GP, Declusin RJ. Off-pump versus on-pump coronary bypass in high-risk subgroups. Ann Thorac Surg 2000;70: Baim DS, Cutlip DE, Midei M, et al. Final results of a randomized trial comparing the MULTI-LINK stent with the

6 Ann Thorac Surg TODA ET AL 2002;74: REVASCULARIZATION IN SEVERE VENTRICULAR DYSFUNCTION 2087 Palmaz-Schatz stent for narrowings in native coronary arteries. Am J Cardiol 2001;87: Van Meter CH Jr, Smart FW, Ventura HO, et al. High-risk surgery as an alternative to transplantation. Tex Heart Inst J 1994;21: UNOS Scientific Registry Data as of September 7, DISCUSSION DR THEODORE C. KOUTLAS (Greenville, NC): I am curious about your inclusion of patients who have had prior coronary artery bypass grafting. It seems very disproportionate, more people had undergone prior coronary artery bypass grafting in the percutaneous group, and I think that puts some selection bias into your study. Some of these percutaneous revascularizations in these patients, were they to prior vein grafts or were the majority to the native coronary circulation, do you know? DR TODA: Yes. In this study I remember that in 13 cases they did percutaneous revascularization for vein graft disease. Otherwise they treated native vessels. DR LISHAN AKLOG (Boston, MA): The time of the study spans a period when the use of stents increased over time. Could you tell us what percentage of patients in the percutaneous revascularization group received a stent and what percentage had simple angioplasty? DR TODA: In this study 67% of the patients had a coronary stent. DR JONATHAN HAMMOND (Hartford, CT): I was disappointed to see that survival was essentially the same at 3 years. Did you assess New York Heart Association functional class at 3 years, was improvement noted and sustained, and was there a difference between the two groups? DR TODA: No, I did not assess the change of the New York Heart Association class in the follow-up; however, we know that the ejection fraction was improved after operation. DR BRIGITTE R. OSSWALD (Heidelberg, Germany): I think it is a very important thing to stress on those people who really have a severe left ventricular dysfunction; however, I was a bit disappointed about the number of factors you included in your analysis. These people do have a high comorbidity, and I missed something like dialysis dependency and neurologic disorders like stroke, transient ischemic attack, and some more timerelated, detailed factors concerning the comorbidity. Do you intend to include some more factors in your analysis? DR TODA: Yes. Preoperatively we assess the comorbidities, including cerebrovascular accident. As I have shown here, there is no difference in the co-morbidity including cerebrovascular accident.