Recurrence of Angina After Coronary Artery Bypass Surgery: Predictors and Prognosis (CASS Registry)

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JACC Vol. 26, No. 4 895 Recurrence of Angina After Coronary Artery Byass Surgery: Predictors and Prognosis (CASS Registry) AIRLIE A. C. CAMERON, MD, FACC, KATHRYN B. DAVIS, PHD, FACC,* WILLIAM J.

1 JACC Vol. 26, No Recurrence of Angina After Coronary Artery Byass Surgery: Predictors and Prognosis (CASS Registry) AIRLIE A. C. CAMERON, MD, FACC, KATHRYN B. DAVIS, PHD, FACC,* WILLIAM J. ROGERS, MD, FACCq New York, New York; Seattle, Washington: and Birmingham, Alabama Objectives. This study sought to define the redictors and rognosis of ostoerative angina in atients undergoing coconary artery byass surgery. Background. Angina recurs in the first ostoerative year in 20% to 30% of atients after coronary artery byass surgery. The Coronary Artery Surgery Study Registry rovides an oortunity to study the redictors and rognosis of ostoerative angina in a large samle. Methods. All atients with isolated coronary artery byass surgery in the registry were identified, and anginal status was determined on a yearly basis. The influence of angina on mortality, recurrent myocardial infarction and need for reoeration was determined. Results. Angina recurred in the first year in 24% of atients and by the sixth year in 40%. The significant redictors in a multivariate analysis were minimal coronary artery disease, reoerative angina, use of vein grafts only, revious myocardial infarction, incomlete revascularization, female gender, smoking and younger age. In subsequent years imortant redictors were angina in the first ostoerative year, female gender, younger age and incomlete revascularization. The resence of angina in the first ostoerative year was associated with more frequent myocardial infarction ( = 0.04) and greater need for reoeration ( = 0.003) but did not affect survival during the 6-year follow-u eriod. Conclusions. These findings show that the redictors of ostoerative angina are features that are or could be redicted before byass surgery. Thus, atients with these features before byass surgery, could be advised that they would be more likely to exerience ostoerative angina than those without these features. Postoerative angina is associated with an increased risk of late myocardial infarction and reoeration. (JAm CoU Cardiol 1995;26:895-9) Angina ectoris occurring after aortocoronary artery byass surgery is articularly discouraging because this symtom is the most frequent indication for coronary artery byass surgery. Recurrence of angina in the first year alone has been reorted in 20% to 30% (1,2) of atients undergoing byass surgery. It is unclear whether angina after byass surgery has the same rognostic imlications for survival or has the same redictive value for future myocardial infarctions or need for coronary artery byass surgery as occurs in unoerated atients with angina. The Coronary Artery Surgery Study (CASS) Registry rovides an oortunity to evaluate the revalence, redictive factors and rognosis of angina occurring after byass surgery From the Division of Cardiology, St. Luke's-Roosevelt Hosital Center and College of Physicians and Surgeons, Columbia University, New York, New York; *Deartment of Biostatisties, University of Washington, Seattle, Washington; and ~Deartment of Medicine, University of Alabama, Birmingham, Alabama. This study was resented in art at the 63rd Annual Scientific Sessions of the American Heart Association, Dallas, Texas, November The Coronary, Artery Surgery Study (CASS) was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Manuscrit received Setember 19, 1994; revised manuscrit received May 16, 1995, acceted May 24, Address for corresoondence: Dr. Airlie A. C. Cameron, Division of Cardiology, St. Luke's-Roosevelt Hosital Center, l lll Amsterdam Avenue, New York, New York at 15 articiating centers during a 4- to 8-year follow-u eriod. Methods Patients. From the CASS Registry of 24,958 atients, the 9,557 atients who underwent coronary artery byass surgery without other associated cardiac surgery within 3 years were identified. In the resent study, only atients with indeendent grafts to a single anastomotic site were included. Excluded were atients undergoing reoeration (n ), atients with congenital anomalies of the coronary arteries (n -- 47) and atients with double (n = 22) or sequential (n = 21) internal thoracic artery grafts and Y (n = 439) or sequential (n = 2,236) sahenous vein grafts. Two study grous were defined: one for analysis of the redictors of angina and the second for analysis of rognosis of angina after coronary artery byass surgery. Follow-u. Follow-u for CASS Registry atients was done at annual intervals after enrollment angiograhy, so that the first follow-u after byass surgery could have occurred any time within the first ostoerative year. For the analysis of redictors of angina after coronary artery byass surgery, the study grou included 5,289 atients who were alive and had follow-u l year after byass surgery, lus or minus 90 days. ~,1!)95 by thc American ('t~llcgc ol (ardioh~g? /95/$9.51t (95)002S0-H

2 896 CAMERON ET AL. JACC Vol. 26, No. 4 ANGINA AFTER BYPASS SURGERY The 90-day window was also used in analyzing angina at 2 and 3 years ostoeratively. The analysis of the relation of angina to survival and to the incidence of reoeration and myocardial infarction included 6,158 atients who had a follow-u visit at any time within 1 year after byass surgery lus 90 days. Time to event data were dated from the day of byass surgery. Annual follow-u was accomlished by mail and telehone interviews according to CASS rotocol (3) for u to 8 years (mean 5.5 years). Angina. At baseline and at each annual follow-u visit, the resence of chest ain was determined according to standardized rotocol (3) and defined as definite, robable, robably not, and definitely not angina. For the resent study, atients classified as having definite or robable angina were considered to have angina. When the analysis was reeated including only atients classified as having definite angina, the same results were obtained. Cigarette smoking status was determined at baseline. Cigarette smokers were those smoking more than one-half ack er week. Current smokers included those smoking within the revious 3 months. History of diabetes included all diabetic atients, insulin deendent and non-insulin deendent. Incomlete revascularization was resent when a major coronary artery with a visually estimated stenosis ->70% reduction in diameter did not receive a byass graft. Minimal coronary disease meant there were no lesions ->70% in a major coronary artery segment and no lesion ->50% in the left main coronary artery. Surgical riority was designated as elective, urgent or emergent. Reoeration included only reeat oerations with coronary artery byass rocedures. The atients were analyzed according to the resence or absence of ostoerative angina, with the 1,253 atients having angina at the first ostoerative year comared with the remaining 4,036 atients. Statistical analysis. Baseline characteristics of atients who develoed or did not develo ostoerative angina were comared using the standard t test or chi-square tests for continuous and categoric variables, resectively. A stewise logistic regression was used to develo a multivariate model in which all variables listed in the univariate table (Table 1) were allowed to enter the model. For recurrent angina in the second and third years, angina status in the revious years was also used as a redictor variable. Survival robability following the first-year of follow-u was estimated using the Kalan-Meier method, and the survival difference between atients with angina and those without angina was tested using the log-rank statistic. The Cox regression model was used to estimate the association between recurrent angina and survival adjusted for other factors known to be associated with survival. The rates of reoeration and myocardial infarction at 6 years were estimated by the Kalan- Meier method and comared by the log-rank test. Table 1. Univariate Analysis of Characteristics of 1,253 Patients With and 4,036 Patients Without Angina at First Annual Postoerative Follow-U Visit P No Angina Angina Age (yr) < 0,001 Women Current smoker < Hyertension Diabetes Preoerative angina < Prior infarction Elective byass surgery Comlete revascularization Vein grafts only Minimal coronary disease Data resented are mean value _+ SD or ercent of atients. 5,289) of atients had angina at the first annual follow-u visit, which increased to >40% by the sixth ostoerative year (Fig. 1). Univariate analysis (Table 1) showed that atients who had angina in the first ostoerative year were younger and more likely to be smokers or to have had reoerative angina or a myocardial infarction. Cessation of cigarette smoking was associated with a reduction in ostoerative angina. Postoerative angina was resent in the first ostoerative year in 27% of current smokers, 23% of former smokers and 21% of those who never smoked ( < 0.001). Early aearance of angina was more common with the use of vein grafts only and with incomlete revascularization. This beneficial effect of internal thoracic artery grafts was seen only in the first ostoerative year and only in those who had had reoerative angina (93% of atients reorted reoerative angina). Predictors. Angina in the first ostoerative year was not related to the number of vessels diseased, rovided that there was at least one significant lesion in a major coronary vessel. The ercent of atients reorting angina was 25% (285 of Figure 1. Prevalence of angina after coronary artery byass surgery for the first 6 ostoerative years % with Angina Results Patients. Annual follow-u was obtained in 99.5% of atients. After coronary artery byass surgery, 24% (1,253 of Follow-u year 5 6

JACC Vol. 26, No. 4 CAMERON ET AL. 897 ANGINA AFTER BYPASS SURGERY Table 2. Multivariate Analysis of Predictors of Angina During First Postoerative Year Risk Minimal coronab' disease 2.40 0.

3 JACC Vol. 26, No. 4 CAMERON ET AL. 897 ANGINA AFTER BYPASS SURGERY Table 2. Multivariate Analysis of Predictors of Angina During First Postoerative Year Risk Minimal coronab' disease Preoerative angina 2.16 < Vein grafts only 1.37 { Prior infarction 1.27 < {i.0(ll Incomlete revascularization b Female gender 1.22 {I.112 Current smoker yr younger age 1.01 < Predictors are listed in order of relative risk estimate. 1,152) for those with single-, 24% (422 of 1,739) for doubleand 22% (514 of 2,315) for trile-vessel disease. However, 43~ (23 of 53) of atients having no major coronary vessel with ->70% stenosis (i.e., minimal coronary disease) exerienced angina in the first ostoerative year ( = 0.04). Angina in the first ostoerative year was not influenced by gender, resence of hyertension or diabetes, surgical riority or ventricular function. Multivariate analysis (Table 2) showed that the significant redictors of angina in the first ostoerative year were minimal coronary disease, reoerative angina, use of vein grafts only, revious myocardial infarction, incomlete revascularization, female gender, smoking and younger age. Predictors of angina in the second ostoerative year (Table 3) included, most imortantly, angina in the first ostoerative year and also female gender, diabetes, hyertension and younger age. Analysis of activity level did not suggest that older atients had less angina than younger atients because of less activity. By the third and subsequent ostoerative years (Table 3), the resence of angina can nearly all be exlained by Table 3. Multivariate Analysis of Predictors of Angina During Second and Third Postoerative Years Ri~k 2nd yr Angina in Ist yr 5.8S < 0.(101 Female gender 1.56 < 0.(~11 Preoerative angina 1.41~ 0.02 Diabetes Hyertension 1.1 ~ 0.02 Prior infarction I. 1/~ yr younger age I.{ rd yr Angina in 2nd yr I1.26 < (I,001 Angina in 1st yr 2.71~ < 0.0(I1 Preoerative angina I.,";2 < Incomlete revascularization 1.42 < Female gender 1.3 t) < II.001 Less than two-vessel disease Predictors are listed in order of relative risk estimates. ]'able 4. Multivariate Analysis of Predictors of Mortality in Patients After Coronary Artery Byass Surgery Risk Current smoker 1.62 < Not elective byass surgery 1.50 < 0.00l Diabetes l Vein grafts only l 1 Hyertension 1.42 < Incomlete revascularization More vessels diseased Higher left ventricular score 1.14 < vr older age < Angina at baseline (t Angina at Ist follow-u (t Predictors are listed in order of relative risk estimate. the status of angina in revious years. Female gender and incomlete revascularization remain significant redictors. Survival. The resence of angina in the first ostoerative year did not affect survival (Fig. 2), with cumulative survival rates at the sixth ostoerative year of 88% both for atients with and without angina during their first ostoerative year. Multivariate analysis (Table 4) with a Cox regression model using as covariates those variables already shown to be associated with survival for this study grou (4) demonstrated that angina in the first ostoerative year was not a redictor of mortality. There was no survival benefit for those with angina in the first ostoerative year but with relief of angina in the second year comared with those with continuing angina. Angina with onset in the second ostoerative year similarly did not affect survival. In atients stratified by the resence or absence of baseline angina, there was no adverse influence on survival from the develoment of angina in the first ostoerative year. Myocardial infarction (Table 5) during the follow-u eriod was infrequent, but the robability of infarction occurring was higher in atients with than without angina in the first ostoerative year ( = 0.04). In addition, the rate of reoeration was higher in atients with than without angina in their first ostoerative year ( = 0.003). Discussion Angina. The incidence of angina after byass surgery varies considerably among reorted studies (2-6), undoubtedly as a result of varying definitions of this clinical entity. In the resent study, angina was reorted as resent even if just one eisode occurred er year. Thus, the incidence might be higher than in other studies because of different definitions. Alternatively, the actual incidence may be underestimated because atients who died before their scheduled follow-u visit had unknown ostoerative anginal status and could not be included. Aearance of angina in the first ostoerative year could be attributed to incomlete revascularization or technical factors leading to erioerative or early graft failure. Progression of disease or vein graft

898 CAMERON ET AL. JACC Vol. 26, No. 4 ANGINA AFTER BYPASS SURGERY loo i00 94 94 > 88 ~ 82 o m 76 --- NO ANGINA P : 0.72 ANGINA 88 82 76 Figure 2.

4 898 CAMERON ET AL. JACC Vol. 26, No. 4 ANGINA AFTER BYPASS SURGERY loo i > 88 ~ 82 o m NO ANGINA P : 0.72 ANGINA Figure 2. Cumulative survival rates of atients with and without angina in their first ostoerative year. Numbers below abscissa are number of atients followed u in each grou and their survival rates. 70 YEAR N 0 Survival i i00 i I I I I failure from accelerated atherosclerosis would not generally be exected to lay a role so early ostoeratively. Smoking. The resent study demonstrates the value of stoing smoking, even for atients with advanced coronary atherosclerosis requiring coronary artery byass surgery. In a study (7) of 551 atients with unstable angina or myocardial infarction with a follow-u eriod of u to 18 years, cessation of smoking was associated with lower overall mortality, although there was no change in the rate of sudden death. Analysis of data from the Multifactor Primary Prevention Trial (8), a study of men with uncomlicated angina ectoris, showed that continued smoking was associated with a less favorable rognosis than that seen in former smokers with angina. These three studies have demonstrated the adverse influence of continued smoking in three different oulations. Promt cessation of cigarette smoking should be a rimary goal for all these atients. Gender. Women were more at to have angina in the second and subsequent ostoerative years. Female gender has been identified as an indeendent redictor of mortality (9) after coronary artery byass surgery as well as associated with higher oerative mortality rates (10). The ostulated reasons for this imaired rognosis include the small body size (11) and thus smaller vessels as well as the more frequent risk factors (12,13), such as diabetes, hyertension and older age, in the women at the time of resentation for coronary artery byass surgery. In addition, it has been shown that women have lower vein graft atency rates (1). Presumably any of these features could be resonsible for the more frequent recurrence of angina in women than in men noted in the resent study. Internal thoracic artery. The internal thoracic artery byass graft had a beneficial influence on the aearance of early ostoerative angina, but this influence did not extend ast the Table 5. Myocardial Infarction and Reoeration for Coronary Artery Disease Over a 6-Year Period in Patients With and Without Angina During First Postoerative Year Angina No Angina (n - 1,704) (n - 4,454) Myocardial infarction (%) Reoeration (%) first ostoerative year, erhas because of rogression of disease or failure of associated vein grafts. Others have noted both an early (9) and a sustained (14) benefit, with reduction in angina, with the use of the internal thoracic artery for byass surgery. In addition, these reorts noted an imroved survival (9) and less need for reoeration (15) in atients with angina and an internal thoracic artery byass comared with atients with angina and use of vein grafts alone. Survival. In the resent study, angina in the first or second ostoerative year did not have a demonstrable adverse effect on survival during the 7-year follow-u eriod. Early deaths were not included because atients had to be alive at their next follow-u visit to ascertain anginal status and thus to enter the study. As a result, the atients with the worst rognosis, that is, those who died before their first follow-u visit, were excluded, and this exclusion ossibly biased the results. It is not known whether this bias equally underestimated mortality in both the angina and no-angina grous. The low overall mortality rate, -2%/year, and the short follow-u eriod of 7 years means that there is very little margin to ermit the absence of angina to exress itself as an imroved survival. In studies of atients who do not undergo byass surgery (8), angina does exert an adverse effect. One study (16) with 54 ostoerative atients concluded that over a 1-year follow-u eriod, atients with unstable angina and revious coronary artery byass surgery had more fatal and nonfatal cardiac events than those with unstable angina and no byass surgery. In the current study, which rincially included atients with stable angina, recurrent angina was a marker for late myocardial infarction and need for reoeration. However, these events did not adversely affect survival. It is unclear what influence, if any, current ractices of angiolasty and other coronary interventions would have on survival. However, there is no reason that the redictors of ostoerative angina would be any different under today's standard of care than during the time of CASS enrollment. Conclusions. The results of the resent study show that redictors of ostoerative angina are either features that are known before byass surgery (i.e., reoerative angina, revious myocardial infarction, younger age, female gender, hyertension and diabetes) or are features that might be anticiated

5 JACC Vot. 26, No. 4 CAMERON ET AL. 899 ANGINA AFTER BYPASS SURGERY before byass surgery (e.g., incomlete revascularization or use of vein grafts only). Thus, atients with these secific features could be advised before byass surgery that they would be more likely to exerience ostoerative angina than those without these features. Cessation of smoking should be emhasized because its benefit is aarent even in the ostoerative atient. Finally, the adverse clinical imlications of ostoerative angina, namely, increased risk of myocardial infarction and need for reoeration, mandate further clinical evaluation of atients with ostoerative angina. References 1. Cameron A, Kem HG Jr, Shimomura S, et al. Aortocoronary byass surgery, a 7-year followu. Circulation 1975;60:Snl I:I Laird-Meeter K, Ten Katen HJ, Brower RW, et al. Angina ectoris, one to 10 years after aorto-coronab' byass surgery. Eur Heart J 1983;4: The Princial Investigators of CASS and Their Associates (The National Heart, Lung and Blood Institute). Coronary Artery Surgery Study. Circulation 1981;63:Sul I:I Cameron A, Davis KB, Green GE, Myers WO, Pettinger M. Clinical imlications of internal mammary artery byass grafts: the Coronary Artery Surgery Study exerience. Circulation 1988;77: Loo FD, Lytle BW, Gill CC, Golding LAR, Cosgrove DM, Taylor PC. Trends in selection and results of coronary artery, reoerations. Ann Thorac Surg 1983;36: Kirklin JW, Nastel DC, Blackstone EH, Pohost GM. Summary of a consensus concerning death and ischemic events after coronary artery byass grafting. Circulation 1989;79:Sul I:I Daly LE, Hickey N, Graham IM, Mulcahy R. Predictors of sudden death u to 18 years after a first attack of unstable angina or myocardial infarction. Br Heart J 1987;58: Hagman M, Wilhemsen L, Pennert K, Wedel H. Factors of imortance for rognosis in men with angina ectoris derived from a random oulation samle. The Multifactor Primary Prevention Trial, Gothenburg Sweden. Am J Cardiol 1988;61: Cameron A, Kem HG Jr, Green GE. Byass surgery with the internal mammary artery graft: 15 year follow-u. Circulation 1986;74:Sul III:II Eaker ED, Kronmal R, Kennedy JW, Davis K. Comarison of the long-term, ostsurgical survival of women and men in the Coronary Artery Surgery Study (CASS). Am Heart J 1989;117: Fisher LD, Kennedy JW, Davis KB, et al, and the Particiating CASS Clinics. Association of sex, hysical size and oerative mortality after coronary artery byass in the Coronary Artery Surgery Study (CASS). J Thorae Cardiovasc Surg 1982;84: Douglas JS, King SB, Jones EL, Craver JM, Bradford JM, Hatcher CR. Reduced efficacy of coronary byass surgery in women. Circulation 1981;64: Sul II:II Loo FD, Golding LR, MacMillan JP, Cosgrove DM, Lytle BW, Sheldon WC. Coronary artery surgery in women comared with men: analyses of risk and long-term results. J Am Coil Cardiol 1983;1: Loo FD, Lytle BW, Cosgrove DM, et al. Influence of the internal-mammary artery graft on 10-year survival and other cardiac events. N Engl J Med 1986;314: Cameron A, Green GE, Kem HG Jr. Role of internal mammary artery in reoerations for coronary artery disease. Adv Cardiol 1988;36: Waters DD, Walling A, Roy D, Theroux P. Previous coronary artery byass grafting as an adverse rognostic factor in unstable angina ectoris. Am J Cardiol 1986;58:465-9.

Journal of the American College of Cardiology Vol. 38, No. 1, by the American College of Cardiology ISSN /01/$20.

Journal of the American College of Cardiology Vol. 38, No. 1, 2001 2001 by the American College of Cardiology ISSN 0735-1097/01/$20.00 Published by Elsevier Science Inc. PII S0735-1097(01)01308-0 Acute