The return of myocardial ischemia after coronary artery

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1 Occurrence and Risk Factors for Reintervention After Coronary Artery Bypass Grafting Joseph F. Sabik III, MD; Eugene H. Blackstone, MD; A. Marc Gillinov, MD; Nicholas G. Smedira, MD; Bruce W. Lytle, MD Background Reintervention after coronary artery bypass grafting (CABG) is common. We sought to determine its occurrence and identify patient characteristics and operative techniques that influence the need or bias for reintervention. Methods and Results From 1971 to 1998, patients underwent primary isolated CABG, and 1000 patients per year were actively followed-up every 5 years (n ). A multivariable time-related analysis was performed to model freedom from first coronary reintervention (either reoperation or percutaneous coronary intervention) and identify patient and operative characteristics associated with first reintervention. A total of 3997 patients underwent coronary reintervention, percutaneous in 1638 and reoperation in Freedom from reintervention was 99%, 96%, 88%, 73%, 60%, and 46% at 1, 5, 10, 15, 20, and 25 years, respectively. Risk of reintervention (hazard function) demonstrated a short, rapidly declining early phase followed by a longer, slow-rising late phase. Patient variables increasing the likelihood of coronary reintervention included younger age (P ), higher triglycerides (P 0.002), lower high-density lipoprotein (P 0.006), diabetes mellitus (P ), and more extensive coronary artery disease (P ). Increasing extent of arterial grafting performed at primary operation decreased the likelihood of coronary reintervention (P ). Conclusions Reintervention after primary CABG is common. Risk factors for arteriosclerosis and type of bypass conduit influence the need or bias for repeat coronary therapy. Aggressive post-cabg risk factor reduction and extensive arterial grafting at primary operation should decrease coronary reinterventions. (Circulation. 2006;114[suppl I]:I-454 I-460.) Key Words: angioplasty coronary disease revascularization risk factors surgery The return of myocardial ischemia after coronary artery bypass grafting (CABG) is common. 1 It has been estimated that by 15 years postoperatively, 62% of patients will have recurrent ischemia, 36% will experience a myocardial infarction, and 28% will undergo coronary reoperation or percutaneous coronary intervention (PCI). 2,3 The reason is progression of arteriosclerosis in native coronary arteries and failure of bypass grafts. To better understand the need for repeat coronary intervention after myocardial revascularization, we determined occurrence of coronary reintervention (both reoperation and PCI) to 25 years after primary CABG, and patient characteristics and operative techniques driving the need or bias for coronary reintervention. Patients and Methods Patients From 1971 to 1998, patients underwent primary isolated CABG at Cleveland Clinic. The first 1000 patients of each year were actively followed-up every 5 years (n ) and comprise the study population. Patient, operative, and follow-up variables were obtained from the Cardiovascular Information Registry; use of these data for clinical research has been approved by the Institutional Review Board. Mean follow-up was years, with patients followed-up 5 years, years, years, years, and years. Six hundred seventy-one patients (2.5%) were lost to follow-up. Total follow-up was patient-years. Study End Point End point of the study was first coronary reintervention, either PCI or isolated reoperative CABG, for recurrent myocardial ischemia. Patients who underwent reoperative CABG with concomitant cardiac procedures, such as valve replacement or repair, aortic replacement, or left ventricular aneurysmectomy, were excluded. Statistical Methods Analysis Time from primary CABG to first coronary reintervention was estimated both nonparametrically, using the Kaplan-Meier method, 4 and parametrically, using a multiphase hazard method. 5 The latter involved determining the number of hazard phases, appropriate form of equation for each phase, and parameters characterizing distribution of times to coronary reintervention (for additional details, see From the Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, Ohio. Presented at the American Heart Association Scientific Sessions, Dallas, Tex, November 13 16, Correspondence to Joseph F. Sabik III, Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, 9500 Euclid Avenue/Desk F24, Cleveland, OH sabikj@ccf.org 2006 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA I-454

2 Sabik et al Coronary Artery Bypass Grafting I-455 To identify which patient characteristics and operative techniques (Appendix) were associated with coronary reintervention, multivariable analyses were performed in the hazard-function domain. Bootstrap aggregation (bagging) using the median rule was used for variable selection, including selecting appropriate transformations of continuous and ordinal variables. 6,7 Interactions among selected variables were also sought by bagging. The P value criterion for retention of variables in the final model was Presentation Categorical variables are presented as frequencies and percentages. Continuous variables are summarized by mean and standard deviation. Asymmetric confidence limits are equivalent to 1 standard error (68%). Variables and Definitions Values of patient characteristics and operative techniques used in the multivariable analyses were obtained at primary CABG. Left ventricular function was graded as normal (ejection fraction [EF] 60%), mild dysfunction (EF 40% to 59%), moderate dysfunction (EF 25% to 39%), and severe dysfunction (EF 25%). A coronary artery system was considered importantly stenotic if it contained 50% diameter obstruction. Incomplete revascularization was defined as failure to graft any system containing 50% stenosis, or both left anterior descending coronary artery (LAD) and circumflex systems for 50% left main trunk stenosis. The authors had full access to the data and take full responsibility for their integrity. All authors have read and agree to the manuscript as written. Results Nonrisk-Adjusted Freedom from Reintervention A total of 3997 patients underwent coronary reintervention, percutaneous in 1638 and reoperation in Nonriskadjusted freedom from reintervention was 99%, 96%, 88%, 73%, 60%, and 46% at 1, 5, 10, 15, 20, and 25 years, respectively (Figure 1A). A 2-phase hazard model was identified, consisting of a short, rapidly declining early phase followed by a long, slow-rising late phase that began 1.5 years after primary CABG (Figure 1B). Two hundred five patients underwent coronary reintervention during the early phase and 3792 during the late phase. Risk Profiles of Reintervention Versus No-Reintervention Patients Preoperative characteristics of patients who underwent reintervention were different from those who did not (Table 1). Patients who underwent reintervention were younger, more likely to be male, more symptomatic, and had higher serum triglycerides and total cholesterol, better left ventricular function, more incomplete revascularization, and less internal thoracic artery (ITA) grafting. Multivariable analysis identified four general categories of factors associated with likelihood of undergoing reintervention: patient demography, noncardiac comorbidity, cardiac comorbidity, and operative technique at primary CABG (Table 2). Because the early hazard phase was small and late phase large, factors influencing the late phase had a greater impact on likelihood of reintervention. Patient Demography Older patients were less likely than younger ones to undergo repeat coronary intervention (P ; Figure 2). However, with greater surgical experience, likelihood of an older Figure 1. Freedom from reintervention after primary isolated CABG for all patients (n ). A, Parametric and actuarial estimates. Solid line represents parametric estimates enclosed within dashed 68% confidence limits ( 1 standard error). Symbols represent actuarial estimates at yearly intervals, and error bars represent 68% confidence limits. Numbers in parentheses are number of patients at risk. B, Hazard function (instantaneous risk). Dashed lines are 68% confidence limits. patient undergoing coronary reintervention increased (P 0.003). Diabetes mellitus was associated with having a coronary reoperation or PCI (Figure 3). Patients treated with insulin or oral medications had a similar and elevated risk of undergoing reintervention (P ). Patients with diet-controlled diabetes also had an increased risk of reintervention, but not as great as those treated pharmacologically (P 0.005). Risk associated with pharmacologically treated diabetes decreased with greater surgical experience (P 0.005). Increased serum lipid levels were also associated with repeat coronary intervention (Figure 4). Higher total cholesterol (P 0.007) and triglycerides (P ) increased the likelihood of reintervention, whereas higher high-density lipoprotein lowered risk (P ). History of smoking was associated with lower likelihood of coronary reintervention (P ). Coronary artery disease of the LAD (P 0.002), circumflex (P 0.003), or right coronary artery (P 0.008) increased the

3 I-456 Circulation July 4, 2006 TABLE 1. Baseline Patient Characteristics (n ) Reintervention No Yes (n ) (n 3997) Characteristic N (%) N (%) P Demography Age (years, mean SD) Male (82) 3445 (86) Diabetes mellitus (medically treated) 3553 (17) 291 (9) History of smoking (54) 1730 (50) Laboratory Values (mean SD) Total cholesterol LDL HDL Triglycerides Blood urea nitrogen NYHA class I 4005 (18) 487 (12) II 7778 (34) 1420 (36) III 2380 (10) 393 (10) IV 8791 (38) 1695 (43) Left ventricular dysfunction None (46) 2306 (58) Mild 6649 (30) 1102 (28) Moderate 3536 (16) 421 (11) Severe 1818 (8) 139 (3) Previous myocardial infarction (56) 1881 (47) Coronary artery disease ( 50% stenosis) LMT 3384 (15) 419 (11) LAD (92) 3562 (89) LCx (76) 2766 (69) RCA (82) 3045 (76) N of diseased systems ( 50% stenosis) (1) 15 (1) (10) 608 (15) (29) 1357 (34) (60) 2007 (51) Operative Procedure Intra-aortic balloon pump 340 (2) 24 (1) Incomplete revascularization 4735 (21) 879 (22) 0.05 Single ITA grafting (56) 1949 (49) Bilateral ITA grafting 2000 (9) 174 (4) ITA graft to LAD (59) 1898 (48) LCx 2169 (9) 189 (5) RCA 636 (3) 70 (2) HDL indicates high-density lipoprotein; ITA, internal thoracic artery; LAD, left anterior descending coronary artery; LCx, left circumflex coronary artery; LDL, low-density lipoprotein; LMT, left main trunk; NYHA, New York Heart Association; RCA, right coronary artery; SD, standard deviation. TABLE 2. Risk Factors for Reintervention After Primary Isolated CABG: Direction of Influence on Early and Late Hazard Phase by Multivariable Analysis Is Indicated Hazard Phase Factor Early Late Demography Older age and later date of operation Male Higher NYHA class Diabetes mellitus and later date of operation History of smoking Laboratory Values Higher HDL Higher total cholesterol Higher triglycerides Better left ventricular function History of myocardial infarction Coronary Artery Stenosis Any LAD stenosis and later date of operation Any circumflex stenosis Any RCA stenosis Greater degree of RCA stenosis Previous operative procedure ITA graft to LAD ITA graft to LCx ITA graft to RCA Postoperative Support IABP postoperatively Experience Later date of operation IABP indicates intra-aortic balloon pump. likelihood of coronary reintervention. Risk associated with LAD disease also increased with greater surgical experience (P 0.02). Better left ventricular function (P ) increased the likelihood of reintervention, whereas history of a myocardial infarction decreased it (P ). The more symptomatic a patient at primary operation, the greater was the risk of reintervention (P ). Operative Procedure More extensive ITA grafting reduced the risk of reintervention (Figure 5). ITA grafts to the LAD (P ), circumflex (P 0.002), and right coronary artery (P 0.02) lowered the likelihood of repeat coronary intervention. Intra-aortic balloon pump insertion at primary operation increased the risk of early reintervention (P ). Patients who underwent operation later in the series were less likely to undergo reintervention (P ).

4 Sabik et al Coronary Artery Bypass Grafting I-457 Figure 2. Predicted freedom from coronary reintervention after primary isolated CABG stratified by age. Format is as in Figure 1. Discussion Background Coronary artery bypass grafting is effective in prolonging survival and relieving angina However, its effectiveness in eliminating myocardial ischemia is transient, with only 22% of patients free of ischemic events 15 years postoperatively. 2 Return of myocardial ischemia is caused by progression of arteriosclerosis in native coronary arteries and failure of the primary operation. Coronary reintervention, by either percutaneous methods or reoperation, is often performed to relieve patients recurrent symptoms. To better understand coronary reintervention after CABG, we determined its occurrence and identified patient characteristics and operative techniques that influence need or bias for reintervention. Principal Findings Coronary reintervention after CABG is common, with less than half of patients free of reintervention 25 years after surgery. Patient characteristics as well as operative techniques influenced need or bias for reintervention. Some patient characteristics increased the likelihood of reintervention (eg, arteriosclerosis risk factors), whereas others decreased it. Operative factors influencing the likelihood of reintervention were conduit choice and success of primary CABG. These findings are similar to those we recently reported for likelihood of undergoing coronary reoperation after primary CABG. 16 Risk Factors for Arteriosclerosis Diabetes mellitus, elevated triglycerides, and total cholesterol were associated with increased risk of coronary reintervention. These are known risk factors for arteriosclerosis that likely increase the need for reintervention by accelerating arteriosclerosis in coronary arteries and saphenous vein bypass grafts. In contrast, elevated high-density lipoprotein decreased risk of reintervention, probably by slowing development and progression of arteriosclerosis. Comorbidity Smoking, older age, and worse left ventricular function were all associated with decreased occurrence of reintervention. A possible explanation is that these factors increase the risk associated with reintervention and therefore may bias treatment in favor of medical therapy. Patients who were more symptomatic at primary operation were more likely to require reintervention. This may be Figure 3. Predicted freedom from coronary reintervention after primary isolated CABG stratified by diabetes mellitus and its treatment by either diet or medicine. Format is as in Figure 1.

5 I-458 Circulation July 4, 2006 Figure 4. Predicted freedom from coronary reintervention after primary isolated CABG stratified by elevated and normal serum lipid levels. Elevated lipids triglycerides of 300 and total cholesterol of 350. Normal lipids triglycerides of 100 and total cholesterol of 150. Format is as in Figure 1. because they had a lower symptom threshold to myocardial ischemia and thus were more likely to present with recurrent symptoms and undergo coronary reintervention to relieve them. ITA Grafts More extensive ITA grafting at primary operation reduced the need for coronary reintervention. Because of their resistance to arteriosclerosis, ITA grafts are more likely to remain patent than saphenous vein grafts. 17 Therefore, they should have a longer-lasting effect on prevention of myocardial ischemia than saphenous vein grafts. Sergeant et al similarly found that likelihood of coronary reoperation or PCI was reduced by more extensive ITA grafting at primary operation. 3 The incremental benefit of 1 and then 2 ITA grafts on both survival and freedom from reoperation has been previously reported Another reason ITA grafting may reduce coronary reintervention is that physicians and surgeons may be reluctant to intervene in patients with patent ITA grafts. Supporting this hypothesis is Sergeant et al s finding that ITA grafting did not decrease risk of return of angina after CABG. 2,3 It is therefore surprising that, despite a similar likelihood of experiencing recurrent angina, patients with previous ITA grafting are less likely to undergo coronary reintervention than patients with saphenous vein grafts alone. This bias against reintervening when ITA grafts are present may be appropriate. Patients with recurrent ischemia and patent ITA grafts are less likely to derive a survival benefit from reintervention than patients without patent ITA grafts. Success of Primary Operation Placing an intra-aortic balloon pump at primary CABG was associated with increased likelihood of early ( 18 months after primary CABG) reintervention. Need to insert an intraaortic balloon at primary operation suggests ineffective revascularization, possibly because of incomplete revascularization or early graft failure. An ineffective operation will not relieve myocardial ischemia, and therefore early coronary reintervention for symptom relief may be required. Surprisingly, incomplete revascularization was not found by multivariable analysis to increase the likelihood of coronary reintervention. This may be because of incomplete revascularization being highly correlated with another factor (such as intra-aortic balloon pump insertion) found by multivariable analysis to be associated with reintervention; if that is the case, incomplete revascularization would not appear to be a risk factor per se for reintervention. Figure 5. Predicted freedom from reintervention after primary isolated CABG stratified by single, double, or no ITA grafting at primary operation. Format is as in Figure 1.

6 Sabik et al Coronary Artery Bypass Grafting I-459 Limitations This study analyzes the clinical practice of coronary reintervention after primary CABG; it does not analyze the actual need for coronary reintervention. Because many factors go into the decision to proceed with coronary reintervention, including patient comorbidities, amount of ischemic myocardium, risk of reintervention, and benefits of the procedure, our findings on the occurrence and risk factors for coronary reintervention may be biased. Another limitation is that 3 decades of coronary surgery were included in this study, during which both surgical and medical therapy for coronary artery disease changed. However, a long observation period has advantages as well, including many years of follow-up data available for analysis and ability to evaluate the effect of surgical strategies that were common early in the series but not today, such as saphenous vein revascularization of the LAD. The association of preoperative risk factors and operative techniques on the likelihood of having a coronary reintervention were evaluated in this study. However, we did not determine how postoperative medical therapy and risk factor modification influenced the occurrence of coronary reintervention. This information was not available. Implications These findings suggest that reducing arteriosclerosis risk factors and ITA grafting at primary CABG will lower the need for repeat coronary intervention. Although we could not determine influence of postoperative risk factor modification on occurrence of coronary reintervention, it is logical to suggest that such modification would be beneficial. Support for this comes from the finding that aggressive lipid reduction after CABG decreased both saphenous vein graft arteriosclerosis and need for coronary reintervention. 21 Summary Coronary reintervention after primary CABG is common. Risk factors for arteriosclerosis progression and ITA grafting influence the need or bias for reintervention. Arteriosclerosis risk-factor reduction and extensive ITA grafting should decrease occurrence of coronary reintervention after primary surgical revascularization. Appendix Variables Considered in Analyses Demography Sex, age (years), height (cm), weight (kg), body surface area (m 2 ), body mass index (kg m 2 ) New York Heart Association functional class (I, II, III, IV) Left Ventricular Function Left ventricular function (normal; mild, moderate, and severe dysfunction), previous myocardial infarction, left ventricular segmental wall motion abnormalities (septal, anterior, inferior, lateral, apical, basilar, none) Family history of coronary artery disease, atrial fibrillation, complete heart block History of cigarette smoking, peripheral vascular disease, carotid stenosis, hypertension, diabetes mellitus (diet-controlled, oraltreated, and insulin-treated), renal insufficiency Preoperative Laboratory Values Total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, creatinine, blood urea nitrogen, hematocrit Coronary Artery Anatomy and Stenosis Dominance (left, right, codominant), number of coronary artery systems with stenosis 50% (1, 2, 3), left main trunk stenosis (any, 50% stenosis, 70% stenosis), left anterior descending stenosis (any, 50% stenosis, 70% stenosis), circumflex stenosis (any, 50% stenosis, 70% stenosis), right coronary artery stenosis (any, 50% stenosis, 70% stenosis) Procedure Complete revascularization; incomplete revascularization of left anterior descending, circumflex, or right coronary artery system; any internal thoracic artery grafting; internal thoracic artery graft to left anterior descending, circumflex, or right coronary artery; any saphenous vein grafting; saphenous vein graft to left anterior descending, circumflex, or right coronary artery Experience Date of operation Postoperative Management Intra-aortic balloon pump None. 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