Coronary Artery Bypass Grafting Versus Coronary Implantation of Sirolimus-Eluting Stents in Patients with Diabetic Retinopathy

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1 Coronary Artery Bypass Grafting Versus Coronary Implantation of Sirolimus-Eluting Stents in Patients with Diabetic Retinopathy Takayuki Ohno, MD, Shinichi Takamoto, MD, Noboru Motomura, MD, Minoru Ono, MD, Jiro Ando, MD, Toshihiro Morita, MD, Hideo Fujita, MD, Yasunobu Hirata, MD, Ryozo Nagai, MD, Takashi Shigeeda, MD, and Akira Hirose, MD Departments of Cardiothoracic Surgery, Cardiology, and Ophthalmology, The University of Tokyo, Tokyo, Japan Background. We compared the 1-year outcome of coronary revascularization with sirolimus-eluting stents (SESs) or coronary artery bypass grafting (CABG) for coronary artery disease involving the left anterior descending artery (LAD) in diabetic patients according to their retinal status: no diabetic retinopathy (NDR) and diabetic retinopathy (DR). Methods. Between April 2004 and October 2005, 220 consecutive patients with coronary artery disease involving the LAD underwent implantation of SESs; of these, 25 patients had NDR and 54 had DR. For each group, we included a comparison group of diabetic patients who had undergone CABG and had the same retinal status. Results. During 1 year after revascularization, five cardiac events (cardiac death, myocardial infarction, and repeat revascularization) were noted in NDR-SES patients, four in NDR-CABG, 24 in DR-SES, and eight in DR-CABG patients. Most cardiac events were repeat revascularizations. Kaplan-Meier estimates of the incidence of cardiac events at 1 year were 21.1%, 11.4%, 44.0%, and 14.0%, respectively. Kaplan-Meier curves for cardiac events in SES patients were different from those of CABG patients for the DR group (p 0.003), but not NDR groups. After adjustments for the potential confounders, the hazard ratio of cardiac events in DR-SES patients was 2.8 (95% confidence interval, 1.1 to 6.9; p 0.02). Conclusions. Compared with SES implantation, CABG is more suitable for revascularization in patients with coronary artery disease involving the LAD and DR. (Ann Thorac Surg 2007;84:1474 8) 2007 by The Society of Thoracic Surgeons Diabetic retinopathy is a frequent and early sign of microvascular complication of diabetes mellitus and can be easily evaluated by direct ophthalmoscopy. The signs of diabetic retinopathy are reported to be present in nearly all patients with a 20-year history of type 1 diabetes and in nearly 80% of those with type 2 disease of similar duration [1, 2]. Recent research has shown that diabetic retinopathy and coronary artery disease are inflammatory diseases [3, 4]. In the diabetic eye, inflammatory mechanisms interact with metabolic risk factors to initiate, propagate, and activate lesions in the retina. Epidemiologic evidences indicate that diabetic retinopathy is associated with an increased risk of death from coronary artery disease and myocardial infarction [5 7]. We reported previously that diabetic retinopathy is an independent predictor of mortality and repeat revascularization after coronary artery bypass grafting (CABG) in diabetic patients [8]. Recently, we have shown that CABG conferred a survival advantage in patients with diabetic retinopathy compared with percutaneous coronary intervention [9]. A recent meta-analysis of the trials Accepted for publication June 7, Address correspondence to Dr Ohno, Department of Cardiothoracic Surgery, The University of Tokyo, 7-3-1, Hongo, Bunkyo-Ku, Tokyo, , Japan; takohno-tky@umin.net. of drug-eluting stents (DESs) confirmed that sirolimuseluting stents (SESs) reduced the rate of restenosis [10]. As a result, SESs are widely used in Japan, expanding beyond the simple lesions evaluated in clinical studies to more complex and longer lesions. Revascularization strategies often depend on the presence and degree of left anterior descending artery (LAD) disease. The purpose of this retrospective study was to compare the 1-year outcome after SES implantation or CABG in diabetic patients, according to their retinal status. Patients and Methods Selection of Patients Between April 2004 and October 2005, 220 consecutive patients underwent implantation of SESs for LAD disease at the University of Tokyo Hospital, Tokyo, Japan. Three experienced operators performed percutaneous coronary intervention according to standard technique and their experience. The SESs (Cypher, Cordis, Johnson & Johnson, Miami Lakes, FL) were available in diameters of 2.50 to 3.50 mm and in lengths of 13 to 33 mm. Before the procedure, patients received 100 mg of aspirin once a day and 100 mg of ticlopidine twice a day for 2 days, and after the procedure, they received 100 mg of aspirin once daily for an indefinite 2007 by The Society of Thoracic Surgeons /07/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg OHNO ET AL 2007;84: CABG VERSUS DES 1475 period and 100 mg of ticlopidine twice a day for at least 3 months. Patients were eligible for inclusion in this study if they (1) underwent the SES procedure for LAD disease, (2) had diabetes mellitus, and (3) had serial follow-up for at least 12 months after the procedure at our institute. The diagnosis of diabetes mellitus was considered confirmed in all patients treated with oral hypoglycemic agents or insulin, or those with a glycosylated hemoglobin value exceeding 6.5%. Ninety-nine patients met the criteria and their ophthalmologic records in our hospital, including ophthalmologic charts, fundus photography, and fluorescein retinal angiography, were reviewed to evaluate the stage of diabetic retinopathy. We used the most recent ophthalmologic records up until the time of SES implantation to determine the retinal status at the time of the procedure, and 79 diabetic patients were classified into two groups: 25 without diabetic retinopathy (NDR) and 54 with diabetic retinopathy (DR). Although an eye examination for diabetic patients is standardized in our hospital, the remaining 20 patients had not undergone ophthalmologic examination and were excluded from this study. The main reason for not having eye examination was a short history of diabetes. For each group, a comparison group with the same retinal status was selected by reviewing the data of 397 consecutive patients who underwent isolated CABG at our hospital. Inclusion criteria were similar to those applied to SES patients: (1) bypass surgery for LAD, (2) CARDIOVASCULAR Table 1. Comparison of Patient Characteristics in Each Study Group Characteristic a NDR-SES (n 25) NDR-CABG (n 35) p Value DR-SES (n 54) DR-CABG (n 57) p Value Mean age-year Female sex 6 (24.0) 7 (20.0) (20.3) 16 (28.0) 0.47 Treatment of diabetes Oral hypoglycemic agents 16 (64.0) 22 (62.9) (50.0) 24 (42.1) 0.52 Insulin 4 (16.0) 2 (5.7) (35.1) 20 (35.1) 0.99 Glycosylated hemoglobin Left-ventricular ejection fraction Current smoker 9 (36.0) 13 (37.1) (16.7) 7 (12.3) 0.70 Arterial hypertension 20 (80.0) 22 (62.9) (74.0) 39 (8.4) 0.65 Hyperlipidemia 15 (60.0) 20 (57.1) (75.9) 41 (71.9) 0.79 Previous myocardial infarction 5 (20.0) 7 (20.0) (13.0) 8 (14.0) 0.99 Previous revascularization 7 (28.0) 7 (20.0) (20.4) 11 (19.3) 0.99 Peripheral arterial disease 4 (16.0) 6 (17.1) (13.0) 9 (15.8) 0.68 Stroke 2 (8.0) 1 (2.9) (3.7) 4 (7.0) 0.68 Serum creatine (mg/dl) b b 0.27 Requiring dialysis 2 (8.0) 0 NA 8 (14.8) 6 (10.5) 0.69 Indication for revascularization Stable angina pectoris 9 (36.0) 14 (40.0) (37.0) 23 (40.4) 0.87 Acute coronary syndrome 6 (24.0) 6 (17.1) (22.2) 7 (12.3) 0.25 Silent myocardial ischemia 6 (24.0) 8 (22.9) (24.1) 17 (29.8) 0.63 Congestive heart failure 4 (16.0) 6 (17.1) (22.2) 9 (17.5) 0.53 Multivessel disease 17 (68.0) 35 (100) (88.9) 55 (96.5) 0.15 No. of coronary vessel disease Coronary artery treated (grafts or stents) Left main 1 (4.0) 10 (18.5) Left anterior descending 25 (100) 35 (100) (100) 54 (100) 1.00 Left circumflex 12 (48.0) 21 (60.0) (46.3) 39 (68.4) 0.03 Right 12 (48.0) 24 (68.6) (51.9) 43 (75.4) No. of stents LITA-LAD graft 35 (100) 57 (100) No. of grafts No. of arterial grafts Follow-up angiography 22 (88.0) 32 (91.4) (87.0) 51 (89.5) 0.92 Duration of ticlopldine therapy (months) a Categoric data are expressed as number (%); continuous data as means SD. b P 0.05 for the comparison with NDR-SES patients. CABG coronary artery bypass grafting; DR diabetic retinopathy; LAD left anterior descending artery; LITA left internal thoracic artery; NDR no diabetic retinopathy; SES sirolimus-eluting stent.

3 1476 OHNO ET AL Ann Thorac Surg CABG VERSUS DES 2007;84: diabetes mellitus, and (3) serial follow-up for at least 12 months after surgery. Our Institutional Review Board approved this study for conduction of clinical and outcomes research in these patients, Informed consent for study participation was not required because the study relied on information obtained as part of routine clinical care. End Points Information on all patients and controls was prospectively entered into a computer database at the time of their treatment and at each clinical follow-up visit. The primary end point was adverse cardiac events, defined as a composite of death from cardiac causes, myocardial infarction, stent thrombosis in the case of SES implantation, and repeat revascularization, during 1 year after the initial coronary revascularization. Myocardial infarction was defined as the presence of new Q waves in at least two contiguous leads and an elevated creatinine kinase MB fraction; or in the absence of pathologic Q waves, an increase in creatinine kinase level to more than twice the upper limit of the normal range plus a high level of creatinine kinase MB or troponin I. Stent thrombosis was defined as acute coronary syndromes with angiographic documentation of vessel occlusion or thrombus within the target vessel; or in the absence of angiographic confirmation, either acute myocardial infarction in the distribution of the treated vessels or cardiac death within 30 days. Patients undergoing SES implantation were asked to agree to a coronary angiographic follow-up study at 6 months or earlier if anginal symptoms occurred. Patients undergoing CABG were asked to agree to postoperative coronary angiographic study during the initial hospitalization. Repeat revascularization was considered to be driven by ischemia if stenosis of any target vessel in the case of SES implantation, or graft in the case of CABG, was at least 50% of the diameter of the vessel as determined by quantitative coronary angiography in the presence of ischemic signs or symptoms or if the stenosis was at least 70% of the diameter of the vessel even the absence of ischemic signs or symptoms. Statistical Analysis We analyzed the data using SPSS 11 software (SPSS Inc, Chicago, IL). Data are expressed as mean standard deviation. Differences between groups were examined by the Student t test for continuous variables and 2 test or Fisher exact test for categoric variables. The rate of adverse cardiac events was estimated according to Kaplan-Meier methods and was compared using the log-rank test. Multivariate Cox proportional hazards modeling was used to adjust for the potential confounders and demographic variables. A two-sided value of p 0.05 was considered indicative of a statistically significant difference. Results Patient Characteristics Table 1 lists the baseline and angiographic characteristics of the enrolled patients, stratified by retinal status and revascularization strategy. Although baseline characteristics were similar between SES patients and CABG patients for each group, fewer diseased vessels were noted in SES patients than the corresponding CABG patients. Follow-up angiography was performed in 22 NDR-SES patients (88.0%) and 47 DR-SES patients (87.0%). Postoperative angiography was performed in 32 NDR-CABG patients (91.4%) and 51 DR-CABG patients (89.4%). Table 2. One-Year Outcomes Outcomes a NDR-SES (n 25) (%) NDR-CABG (n 35) (%) p Value DR-SES (n 54) (%) DR-CABG (n 57) (%) p Value In-hospital events Death from cardiac causes (1.9) 0 Myocardial infarction 1 (4.0) Repeat revascularization 0 2 (8.0) 0 4 (7.0) Percutaneous 0 2 (8.0) 0 4 (7.0) Surgical Stent thrombosis 0 0 Out-of-hospital events Death from cardiac causes (5.6) 1 (1.8) 0.57 Myocardial infarction (5.6) 0 Repeat revascularization 4 (16.0) 2 (8.0) (38.9) 3 (5.3) Percutaneous 3 (12.0) 2 (8.0) (35.2) 3 (5.3) Surgical 1 (4.0) 0 2 (3.7) 0 Stent thrombosis 0 2 (3.7) Events during the 1-year follow-up Adverse cardiac events a 5 (20.0) 4 (16.0) (44.4) 8 (14.0) a Defined as a composite of death from cardiac causes, myocardial infarction, and repeat revascularization. CABG coronary artery bypass grafting; DR diabetic retinopathy; NDR denotes no diabetic retinopathy; SES sirolimus-eluting stent.

4 Ann Thorac Surg OHNO ET AL 2007;84: CABG VERSUS DES Fig 1. Kaplan-Meier cumulative event-free curves for adverse cardiac events, defined as a composite of deaths from cardiac causes, myocardial infarction, and repeat revascularization, of diabetic patients who received a sirolimus-eluting stent (SES, dark line) or coronary artery bypass surgery (CABG, light line) in patients (A) without retinopathy (NDR) and (B) with retinopathy (DR). One-Year Outcome Table 2 presents adverse cardiac events after revascularization. There were five cardiac events in NDR-SES patients, four in NDR-CABG patients, 24 in DR-SES patients, and eight in DR-CABG patients. Most cardiac events were repeat revascularizations. Kaplan-Meier estimates of the rate of cardiac events at 1 year were 21.1%, 11.4%, 44.0%, and 14.0%, respectively. Kaplan-Meier cumulative event-free curves for cardiac events were not significantly different between SES patients and CABG patients in the NDR group (p 0.32; Fig 1A) but were significantly different in the DR group (p 0.003; Fig 1B). After adjustments for age, sex, glycosylated hemoglobin level, serum creatinine level, insulin treatment, and leftventricular ejection fraction, the hazard ratio of cardiac events in DR-SES patients was 2.8 (95% confidence interval, 1.1 to 6.9; p 0.02). Comment 1477 In the present study, we compared the 1-year outcome by the revascularization strategies of SESs or CABG for diabetic patients, according to the presence or absence of DR. We found that DR patients who undergo SES implantation are at increased risk of adverse cardiac events compared with DR patients who undergo CABG. These finding strongly indicate that CABG is more suitable for revascularization in patients with LAD disease and DR compared with SES implantation. The incidence of cardiac events in our SES patients seems higher compared with that reported in previous studies of SESs [11 13]. The high incidence can be attributed to the inclusion in the present study of patients with a high frequency of challenging morphology such as multivessel disease and small coronary vessels beyond the simple lesions included in the previous studies. In addition, clopidogrel and glycoprotein IIb/IIIa inhibitors were not used in our study because these drugs are not approved in Japan; therefore, differences in antithrombotic therapy may partially account for the high incidence of target vessel failure. After adjustment for age, sex, glycosylated hemoglobin level, serum creatinine level, insulin treatment, and left ventricular ejection fraction, the 1-year clinical outcome of DR patients was better after CABG than after SES implantation. In this regard, epidemiologic evidence indicates that the risks of death from coronary artery disease and myocardial infarction among DR patients are higher than those among NDR patients [5 7]. SES implantation is targeted at existing culprit lesions but not future lesions and, therefore, does not reduce the risk of myocardial infarction after revascularization. In contrast, CABG bypasses most of the epicardial vessels including those at risk for future events that are responsible for most of the myocardial infarctions and may render these events less fatal; therefore, CABG could confer the most benefit among DR patients. Although congestive heart failure was not included in the adverse cardiac events because of the retrospective nature of this study, we showed previously that patients with advanced DR are at high risk for congestive heart failure after CABG, suggesting that patients with advanced DR have irreversible diabetic cardiomyopathy [14]. Patients with an early stage of DR usually have less severe renal and cardiac functional impairment compared with patients with an advanced stage of DR. Taken together, the indication for CABG would be particularly strong for patients with an early stage of DR before proceeding to the advanced stage of DR. The present study has some caveats: First, we used a strict criterion for the diagnosis of diabetes mellitus; therefore, patients with mild diabetes mellitus may have been excluded. Second, according to the protocol of eye screening for DR, most DR patients in this study underwent an eye examination every 6 to 12 months, and we used the most recent ophthalmologic records up until the time of revas- CARDIOVASCULAR

5 1478 OHNO ET AL Ann Thorac Surg CABG VERSUS DES 2007;84: cularization to approximate the stage of DR at the time of the procedure. Therefore, the retinal status at the time of the procedure may have been underestimated in some NDR patients. Third, our patient sample was small. A larger and longer follow-up would be required to assess influences of the stage of DR on cardiac outcome. Finally, the clinical outcomes were retrospectively evaluated. Because our clinical practice incorporates close follow-up of our patients at our hospital, however, the retrospective nature of the analysis should not pose a problem. References 1. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 1984;102: Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 1984;102: Antonetti DA, Barber AJ, Bronson SK, at al. Diabetic retinopathy: seeing beyond glucose-induced microvascular disease. Diabetes 2006;55: Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352: Klein R, Klein BE, Moss SE, Cruickshanks KJ. Association of ocular disease and mortality in a diabetic population. Arch Ophthalmol 1999;117: Henricsson M, Nilsson A, Heiji A, Janzon L, Groop L. Mortality in diabetic patients participating in an ophthalmological control and screening programme. Diabet Med 1997; 14: Mittinen H, Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Retinopathy predicts coronary heart disease events in NIDDM patients. Diabetes Care 1996;19: Ono T, Kobayashi J, Sasako Y, et al. The impact of diabetic retinopathy on long-term outcome following coronary artery bypass graft surgery. J Am Coll Cardiol 2002;40: Ohno T, Ando J, Ono M, et al. The beneficial effect of coronary-artery-bypass surgery on survival in patients with diabetic retinopathy. Eur J Cardiothorac Surg 2006;30: Babapulle MN, Joseph L, Belisle P, et al. A hierarchical Bayesian meta-analysis of randomized clinical trials of drugeluting stents. Lancet 2004;364: Moses JW, Leon MB, Popma JJ, et al; SIRIUS Investigators. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349: Windecker S, Remondino A, Eberli FR, et al. Sirolimuseluting and paclitaxel-eluting stents for coronary revascularization. N Engl J Med 2005;353: Kastrati A, Dibra A, Mehilli J, et al. Predictive factors of restenosis after coronary implantation of sirolimus- or paclitaxel-eluting stents. Circulation 2006;113: Ono T, Ohashi T, Asakura T, et al. The impact of diabetic retinopathy on cardiac outcome after coronary artery bypass graft surgery: a prospective observational study. Ann Thorac Surg 2006;81: