Silent myocardial ischemia monitoring predicts late as well as perioperative cardiac events in patients undergoing vascular surgery

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1 Silent myocardial ischemia monitoring predicts late as well as perioperative cardiac events in patients undergoing vascular surgery Peter F. Pasternack, MD, Eugene A. Grossi, MD, F. Gregory Baumann, PhD, Thomas S. Riles, MD, Patrick J. Lamparello, MD, Gary Giangola, MD, Aimee Y. Yu, BS, Konnie Mintzer, BS, and Anthony M. Imparato, MD, New Tork, N.Y. In a previous study we have shovm that perioperative monitoring for silent myocardial ischemia can noninvasively identi(y those patients undergoing peripheral vascular surgery who are at significantly increased risk for perioperative myocardial infarction. In the present study a group of 385 patients undergoing peripheral vascular surgery was studied long-term as well as short-term to determine whether perioperative monitoring for silent ischemia can identify those patients who are at significantly increased risk of late cardiac death or late cardiac complications as well as those patients at increased risk of perioperative myocardial infarction. All patients were monitored before, during, and after operation and were divided into two groups on the basis of results of monitoring: patients whose total duration of silent ischemia as a percentage of the total duration of perioperative monitoring was 1% or greater (group I, n = 120) and those for whom this value was less than 1% (group II, n = 265). Among patients in group % (16 of 120) suffered a perioperative myocardial infarction in contrast to only 1.1% (3 of 265) patients in group II (p < 0.001). Multivariate logistic regression analysis of preoperative and perioperative characteristics showed that the presence of a total perioperative percent time ischemic 1% or greater and age were the only significant predictors of perioperative myocardial infarction. Actuarial freedom at 24 months after operation for group I compared with group II was, respectively, 89.1% versus 98.4% for late myocardial infarction (p < 0.001), 89.5% versus 99.2% for late cardiac death (p < 0.00i), and 58.7% versus 69.4% for late cardiac death or late cardiac complication (angina, myocardial infarction, cardiac evaluation, or cardiac revascularization) (p < 0.02). Cox proportional hazards analysis showed that only the occurrence of a total perioperative percent time ischemic 1% or greater and age were significant independent predictors of early or late myocardial infarction and early or late cardiac death as combined end points. These results show that perioperative monitoring for silent myocardial ischemia can noninvasively identify those patients undergoing peripheral vascular surgery who are at increased risk for late cardiac death or complication as well as perioperative myocardial infarction. (J VASC SURG 1992;16: ) Coronary artery disease is the leading cause of early and late death after peripheral vasc~dar surgical procedures. 13 Although coronary angiography can From the Departments of Medicine and Surgery, New York University Medical Center, New York. Presented at the Thirty-ninth Scientific Meeting of the International Society for Cardiovascular Surgery, North American Chapter, Boston, Mass., June 3-4, Reprint requests: Peter F. Pasternack, MD, Suite 4C, Faculty Practice, New York University Medical Center, 530 First Ave., New York, NY /1/S6177 define the extent of coronary artery disease, this information does not noninvasively predict which patients are likely to suffer early or late cardiac death or complications in association with peripheral vascular surgery procedures. Silent myocardial ischemia, objective evidence of myocardial ischemia in the absence of angina, is recognized as an important aspect of coronary artery disease. Recent technologic developments permit relatively routine detection and quantitation of such manifestations of myocardial ischemia in the absence 171

2 172 Pasternack et al. Journal of VASCULAR SURGERY of angina pectoris through the use of highly sensitive digital monitors. A previous study has shown that among patients undergoing peripheral vascular surgery, a significantly greater amount of silent myocardial ischemia can be detected during the perioperative period in patients who suffer a perioperative myocardial infarction (MI) compared with those who do not. 4 The present long-term follow-up study in a large group of patients undergoing peripheral vascular surgery was undertaken to determine if perioperative silent myocardial ischemia was also predictive of late cardiac death:and complications. METHODS Patient population This study examined hospital and follow-up data on an expanded group of 385 patients who underwent one or more peripheral vascular surgery procedures at New York University Medical Center between September 1987 and May 1990 and were monitored for silent myocardial ischemia during the preoperative, intraoperative, and postoperative periods. Patients with a QRS duration greater than 120 msec or left ventricular hypertrophy with marked repolarization changes were excluded from the study. Otherwise patients were unselected. Preoperative baseline medications were not changed during preoperative monitoring. Thirty-one of these patients had a second vascular operation during the study period, and one patient had a third vascular operation, but in these patients all results are analyzed with respect to the first operation only. Seventy-four percent of the patients were men and 26% were women. The mean age at operation was years (mean + SD). The patients had the following clinical evidence of coronary artery disease: history of exertional angina in 30.9%, history of rest angina in 6.2%, history of prior MI in 23.9%, and electrocardiograp~c (ECG) evidence of prior MI in 13.2%. The patients underwent one of three types of peripheral vascular surgical procedures. One hundred fifty-seven patients (40.8%) underwent abdominal aortic aneurysm repair, 126 (32.7%) underwent carotid artery endarterectomy, and 102 (26.5%) underwent infrainguinal lower extremity revascularization. The preoperative, intraoperative, and postoperative monitoring intervals used were not identical for all patients in the study. Furthermore, subsequent regression analysis showed a significant linear relationship (p < 0.05) between the duration of monitoring and both the duration and frequency of silent ischemia in the preoperative, intraoperative, postoperative, and total perioperative periods. To negate any possible problems associated with the fact that monitoring intervals were not identical for all patients, silent ischemia was not compared among patient groups in terms of the absolute duration or frequency of ischemia. Instead silent ischemia was expressed primarily in relative terms as the total duration of perioperative silent ischemia in minutes as a percentage of the total duration of perioperative monitoring in minutes, the perioperative percent time ischemic. The patients were divided into two groups based on their perioperative percent time ischemic. Group I (n = 120) comprised all patients whose perioperative percent time ischemic was 1% or greater. Group II (n ) contained all patients for whom this value was less than 1%. Pertinent preoperative clinical history characteristics of all patients are shown in Table I, and silent ischemia monitoring characteristics are summarized in Table 11. Digital electrocardiographic monitoring Patients were monitored for silent myocardial ischemia by means of a real-time ambulatory device, the QMED Monitor One Star (QMED Inc., Clark, N.J.), which continuously records and analyzes the ECG, as has been previously described in detail. 4,s During the preoperative period, QMED electrodes were attached in a lead CMs configuration, with the negative reference over the sternum and positive electrode in the V~ position. The earth electrode was attached over the right lower anterior ribs. The QMED electrodes were then connected to the recorder, and monitoring was started before operation (mean _+ SD preoperative monitoring interval: hours; group I, hours; group 11, hours; p > 0.05), and continued throughout the intraoperative (4.58 _ hours; group I, hours; group II, hours; p > 0.05) and postoperative periods (31.2 _ hours; group I, 31.8 _ hours; group I1, hours; p > 0.05). An ischemic ST segment change was defined before the study began as I mm or more of planar or downsloping ST segment depression in lead CMs. s The output of the monitor included indications of the presence or absence of ischemic changes and the duration and magnitude of ST segment depression. The monitor's algorithm excluded ectopic beats and noise and identified isoelectric, J, and J + 60 msec points in the beats classified as normal. Downsloping or horizontal ST depression of at least 1 mm lasting more than 40 seconds represents the threshold for detection of an ischemic event, but timing of event duration does not commence until the end of the

3 Volume 16 Number 2 August 1992 Silent myocardial ischemia monitoring 173 Table I. Preoperative clinical characteristics of all patients, group I, and group!i All patients Group I Group II (n = 385) (n = 120) (n = 265) p Mean age (yr) Percent male History of myocardial infarction History of exertional angina History of rest angina ECG evidence of prior M1 History of congestive heart failure History of hypertension History of diabetes History of coronary artery bypass surgery 69.0 _ ± , (73.8%) 83 (69.2%) 201 (75.8%) NS 92 (23.9%) 28 (23.3%) 64 (24.2%) NS 119 (30.9%) 47 (39.2%) 72 (27.2%) (6.2%) 12 (10.0%) 12 (4.5%) (I3.2%) 15 (12.5%) 36 (13.6%) N$ 21 (5.4%) 12 (10.0%) 9 (3.4%) (54.0%) 71 (59.2%) 137 (51.7%) NS 96 (24.9%) 44 (36.7%) 52 (19.6%) (13.0%) 18 (15.0%) 32 (12.1%) NS Group I, total perioperative percent time ischemic _> 1%; group II; total perioperative percent time ischemic < 1%. Mean ± SD; p is for group I versus group II. NS, p > Table IL Characteristics of silent myocardial ischemia among patients in groups I and II All patients Group I Group 27 (n = 385) (n = 120) (n = 265) p Total duration of perioperative monitoring (hr) Total duration of perioperative silent ischemia (hr) Total no. of perioperative ischemic episodes Total duration of perioperative silent ischemia as percent of total perioperative monitoring interval NS < ± ± 2.32 < % ± 2.3% 30.2% ± 32.4% 0.08% ± 0.2% < Mean -+ SD; p is for group I versus group II. NS, p > second validation period. The event is considered to be over when the ST amplitude has been above this threshold for longer than 40 seconds. Up to 91 short strips of ECG representative of control and ischemic episodes for each patient were available for visual confirmation in the printed output. The monitor was programmed not to record episodes of ST segment change associated with a wide QRS ( 120 msec). The diagnosis of acute perioperative MI was made on the basis of abnormal elevation of the serum creatine phosphokinase (CPK) MB isoenzyme level as determined daily for the first 5 postoperative days. Data collection and statistical analysis The study provided for the collection of 110 data points on each patient related to general clinical information, such as preoperative medical history and results of diagnostic tests, overall monitoring information, and follow-up data. This information was obtained by reviewing the patient's hospital record or by direct questioning of the patient and by examining the record from the special ECG monitor. Follow-up information was obtained directly from the patient at the time of a follow-up office visit or, in most cases, by telephone interview with the patient, the patient's physician, or both, and was 96.6% complete. The mean follow-up was months (median, 23.7 months; range, 1 to 42 months; total, patient-years). All data were entered into a computer and analyzed by means of the statistical software packages SPSS (SPSS Inc., Chicago, Ill.) or SAS (SAS Institute Inc, Cary, N.C.). All results are expressed as the mean _+ 1 SD except as otherwise indicated. Analysis of the significance of differences in preoperative and postoperative characteristics was performed by chi-square analysis or the unpaired Student's t test as appropriate. The significance of differences in continuous variables between patients who suffered perioperative MI and patients who avoided MI was determined by a nonparametric method, the Mann-Whitney U test (Wilcoxon rank sum W test). Actuarial curves for late cardiac death or complications were obtained by the life-table method, and the overall significance of difference between groups was determined by the approach of Lee and Desu. 6 The results of actuarial analysis are reported as _+ 1 SE. Logistic regression analysis was used for multivariate analysis of categoric variables to determine the best set of variables independently predictive of perioperative /Vii. The Cox proportional hazards model was used to analyze data related to avoidance of early and late adverse cardiac events, including MI

4 174 Pasternack et al. lournal of VASCULAR SURGERY Table III. Indexes of silent ischemia among 385 patients undergoing peripheral vascular surgery with or without perioperative myocardial infarction Myocardial No myocardial infarction infarction p value No. of patients 19 Time monitored before operation (hr) 15.8 _ 12.9 Time monitored during operation (hr) 4.64 _ 2.06 Time monitored after operation (hr) Total time monitored in the perioperative period (hr) Duration of preoperative SI (hr) 2.83 _ 4.36 Duration of intraoperative SI (hr) _ 2.42 Duration of postoperative SI (hr) Total duration of perioperative SI (hr) No. of preoperative SI episodes 8.53 _ No. of intraoperative SI episodes No. of postoperative SI episodes 19.5 _ Total no. of perioperative SI episodes Duration of SI as percent of preoperative monitoring interval 22.8% _+ 36.8% Duration of SI as percent of intraoperative monitoring interval 25.4% % Duration of SI as percent of postoperative monitoring interval 25.7% % Total duration of SI as percent of total perioperative monitoring 23.4% % interval _ 12.9 NS 4.58 _ NS NS 51.0 _ 18.6 NS _ _ _ ~.0064: % % % % % % % % Sir, Silent ischemia. and cardiac death, to define the effect of explanatory variables on freedom from such cardiac events. RESULTS Of the 385 patients who entered the study, the occurrence of one or more episodes of silent myocardial ischemia was detected in the preoperative, intraoperative, or postoperative period in 57.4% (221 of 385) of patients. During a period of preoperative monitoring of _ 12.9 hours (range, 0.11 to 88.0 hours), 33.5% of patients (129 of 385) showed evidence of silent ischemia. Among these patients the number of preoperative ischemic episodes was 11.7 _+ 13.4, the total duration of preoperative ischemia was 4.8 _ 8.6 hours, and the total duration of preoperative silent ischemia as a percentage of the total duration of preoperative monitoring time (percent time ischemic) was 27.8% +_ 35.2%. Of the 129 patients who demonstrated preoperative silent ischemia, 115 (89.2%) also had intraoperative or postoperative ischemia. During a period of intraoperative monitoring of hours (range, 0.25 to 13.5 hours), 36.1% of patients (139 of 385) showed evidence of silent ischemia. In these patients the number of intraoperative ischemic episodes was 3.6 _+ 3.2, the total duration of intraoperative ischemia was 1.0 +_ 1.6 hours, and the percent time ischemic was 23.9% %. During a period of postoperative monitoring of hours (range, 2.4 to hours), 46.0% of patients (177 of 385) showed evidence of silent ischemia. Among these patients the number of postoperative ischemic episodes was 13.9 _+ 15.9, the total duration of postoperative ischemia was 7.0 _ hours, and the percent time ischemic was 21.4% _+ 31.9%. Nineteen patients (4.9%) suffered a perioperative MI, and five patients (1.3%) died before discharge from the hospital. Just as in a previous study of a smaller number of these patients, there was a significantly (p ~ 0.05) greater total duration of periopera~ive ischemic time, total number of perioperative ischemic episodes, and total duration of perioperative ischemic time as a percent of total monitoring time in the 19 patients who suffered a perioperative MI compared with the 366 patients who did not (Table HI). Furthermore, 13.3% (16 of 120) of patients who had a total percent time ischemie >_ 1% (group I) had a perioperative MI in contrast to only 1.1% (3 of 265) patients who had a total percent time ischemic less than 1% (p < 0.001). The only other significant differences between patients who suffered a perioperative MI and those who did not were that the former were older and a higher percentage suffered befdre operation from exertional angina, angina at rest, and congestive heart failure (Table W). A logistic regression model was used to perform multivariate analysis of categoric perioperative factors to determine which of these migl~t be significant predictors of perioperative MI. The variables tested

5 Volume 16 Number 2 August 1992 Silent myocardial ischemia monitoring 175 included whether total perioperative percent time ischemic was 1% or greater or not (group I or group II), percent time ischemic before operation, percent time ischemic during operation, percent time ischemic after operation, total percent time ischemic, age, sex, and history of each of the following: exertional angina, ~ angina at rest, congestive heart failure, preoperative MI, hypertension, diabetes, and ECG evidence of a previous MI. The occurrence of a total perioperative percent time ischemic 1% or greater (beta, 1030; p < 0.00I) and age (beta, 0.08; p < 0.04) were found to be the only significant predictors of perioperative MI with odds ratios of 3.67 and 1.08, respectively. When the Cox proportional hazards model was applied, the confounding variables considered were age, sex, whether total perioperative percent time ischemic was 1% or greater, total perioperative percent time ischemic, percent time ischemic before operation, percent time ischemic during operation, percent time ischemic after operation, total number of perioperative ischemic episodes, total perioperative minutes of ischemia, and preoperative history of each of the following: exertional angina, angina at rest, congestive heart failure, preoperative MI, hypertension, diabetes, and ECG evidence of a previous MI. When all confounding variables were controlled for, only the occurrence of a total perioperative percent time ischemic 1% or greater and age were significant independent predictors of earty or late MI and cardiac death as combined end points (p < 0.05). Only the occurrence of a total perioperative percent time ischemic 1% or greater and exertional angina proved to be significant independent predictors of all postdischarge adverse cardiac events (cardiac death, MI, cardiac evaluation by stress test or catheterization, and cardiac revascularization by coronary artery bypass surgery or balloon angioplasty).. Of the 380 hospital survivors 323 patients (85.0%) were still alive at follow-up, with 15 patients (3.9%) suffering late cardiac death, 29 patients (7.6%) suffering late noncardiac death, and 13 patients (3.4%) lost to follow-up. Seventeen patients (4.5%) smffered an MI during the follow-up period; it was fatal in five patients (1.3%) (Table V). Sixty-five patients (17.1%) experienced angina during the follow-up period, with 13 patients (3.4%) experiencing a new onset of angina. Thirty-seven patients (9.7%) underwent cardiac catheterization during the follow-up period. Ten patients (2.6%) were subjected to coronary artery bypass grafting, and 12 patients (3.2%) underwent coronary angio- Table IV. Comparison of preoperative characteristics of patients with perioperative MI and patients without perioperative MI (mean _ SD) Perioperative No perioperative MI (n =19) _MI (n =366) p Mean age (yr) Percent male 73.7% 73.8% NS History of myo- 7 (3618%) 85 (23.2%) NS cardial infarction History of exer- 12 (63.2%) 107 (29.2%) tional angina Histo.ry O f rest 4 (21.1%) 20 (5.5%) angina ECG evidence of 5 (26.3%) 46 (12.6%) NS prior MI History of conges- 3 (15.8%) 18 (4.9%) five heart failure History of hyper- 11 (57.9%) 197 (53.8%) NS tension History of diabetes 5 (26.3%) 91 (24.9%) NS History of coro- 1 (5.3%) 49 (13.4%) NS nary artery bypass surgery plasty during the period of follow-up. No deaths were associated with either of these revascularization procedures. Actuarial freedom from late MI at 24 months after surgery was 95% for all patients and only 91% for patients in group I as compared with 98% for group II (p _< 0.001) (Fig. 1) (Table VI). Survival from late cardiac death at 24 months was 96% overall and 90% for patients in group I in contrast to 99% for patients in group II (p < 0.001) (Fig. 2). Late cardiac revascularization by either coronary artery bypass surgery or balloon angioplasty was avoided by 96% ofau patients, 95% in group I and 96% in group II (p > 0.05). Ninety percent of all patients escaped late MI, late cardiac death, and late revascularization, Nat only 81% of patients in group I avoided all these events in contrast to 94% of patients in group II (p < 0.001). The actuarial freedom from late cardiac death and late cardiac complications (MI, angina, cardiac evaluation by stress test or catheterization, and cardiac revascularization by coronary artery bypass surgery or balloon angioplasty) was 74% for all patients. Only 64% of patients in group I avoided these events in contrast to 78% of patients in group II (p < 0.02) (Fig. 3). DISCUSSION It has been shown in an earlier study that perioperative monitoring for silent myocardial ischemia noninvasively identifies those patients undergo-

6 176 Pasternack et al. journal of VASCULAR SURGERY Table V. Incidence of late cardiac death and complication among patients in groups I and II All patients Group I Group 17 (n = 38o) (n = HZ) (n = 263) No. late MIs (%) 17 (4.5%) 11 (9.4%) 6 (2.3%) No. late fatal MIs (%) 5 (1.3%) 4 (3.4%) 1 (0.4%) No. of patients 65 (17.1%) 30 (25.6%) 35 (13.3%) with angina (%) No. of patients 13 (3.4%) 6 (5.1%) 7 (2.7%) with new angina (%) No. of patients 37 (9.7%) 13 (11.1%) 24 (9.1%) undergoing cardiac catheterization (%) No. of patients 10 (2.6%) 4 (3.4%) 6 (2.3%) undergoing coronary artery bypass grafting (%) No. of patients 12 (3.2%) 6 (5.1%) 6 (2.3%) undergoing coronary angioplasty (%) No. of late cardiac 15 (4.0%) 12 (10.3%) 3 (1.1%) deaths (%) Group I, Total perioperative percent time ischemic -> 1%; group II, total perioperative percent time ischemic < 1%. hag peripheral vascular surgery who are at increased risk for perioperative MI. 4 In the previous study of 200 patients a significantly greater total duration of perioperative ischemic time, total number of perioperative ischemic episodes, and total duration of perioperative ischemic time as a percent of total monitoring time were demonstrated in those patients who suffered a perioperative lvli compared with those who did not. Multivariate logistic regression analysis of preoperative characteristics in 200 patients showed the occurrence of perioperative silent myocardial ischemia and angina at rest to be the only significant predictors of perioperative/vii. In a related study, Mangano et al.7,8 used Holter monitoring or the automated monitoring used in this study to detect ST segment depression 1 mm or greater in 100 patients with or at risk for coronary artery disease who were undergoing noncardiac surgery. The patients were monitored for up to 2 clays before operation, during operation, and during the first week after operation. No mention is made of any attempt to normalize results in terms of the length of the monitoring period. Forty-two percent of the patients underwent major vascular surgery. Results showed that episodes of perioperative silent ischemia were quite common in these patients, especially during the first 3 days of the postoperative period. In addition, the incidence of episodes was significantly higher in patients who had a perioperative adverse cardiac event. These authors suggested an association between postoperative silent ischemia and perioperative severely adverse cardiac events. Raby et al. 9,x placed Holter monitors on 176 patients for 24 to 48 hours before peripheral vascular surgery. Apparently no attempt was made to norrealize results in terms of the length of the monitoring period, and patients were divided into those who demonstrated one or more episodes of silent ischemia before operation and those who did not show any preoperative silent ischemia. Analysis of the results showed that the occurrence of preoperative ischemia was the only independent predictor of adverse cardiac events (mean follow-up, 20.5 months). Other investigators monitored 59 patients undergoing lower extremity or extraanatomic vascular bypass procedures for silent ischemia from the evening before surgery until-the third postoperative day. 11 No attempt to normalize results for the length of the monitoring period was described. Results showed that only patients who demonstrated some perioperative silent ischemia suffered perioperative MI or cardiac death. The present study examined a group of 385 patients who were undergoing peripheral vascular surgery in an attempt to determine if monitoring for perioperative silent ischemia could predict late cardiac death and complications as well as perioperative MI. The results have confirmed previous findings that patients who suffer perioperative MI also demonsttate significantly more perioperative silent ischemia (Table III). Among patients in group % (16 of 120) had a perioperative MI, but only 1.1% (3 of 265) of patients in group II suffered an MI (p < 0.001). Multivariate logistic regression analysis showed that only the occurrence of percent time ischemic of 1% or greater and age were independent predictors of perioperative MI (odds ratios 3.67 and 1.08, respectively). Since only 68.9% of patients had a cardiac ejection fraction available, it was not possible to attempt to confirm our previous findings that patients undergoing peripheral vascular surgery who have low cardiac ejection fractions as determined by preoperative resting gated blood pool studies have a significantly higher incidence of perioperative MI than patients with higher ejection fractions. 12'13 In addition, the usefulness of silent myocardial ischemia monitoring as a predictor of late cardiac events has been demonstrated in this study, By

7 Volume 16 Number 2 August 1992 Silent myocardial ischemia monitoring C 90 P E R C E N T r -E~ GROUP II GROUP I p < [GGIIJ I i I t I _ I L I u I J MONTHS POST OP Fig. 1. Actuarial freedom from late MI for patients with total perioperative percent time ischemic 1% or greater (group I) versus patients with total perioperative percent time ischemic less than 1% (group II) (G I, group I; G II, group II). Table VI. Actuarial freedom at 24 months from late cardiac death and complications for group I compared with group II All patients Group I Group H (n = 3so) (n = HZ) (n = 263) p Late MI Late cardiac death Late revascularization (CABG or PTCA) Late cardiac death or revascularization Late MI, cardiac death, or revascularization Late cardiac death or any cardiac complication (late angina, MI, cardiac evaluation, revasoalarization) 95.9% % 90.7% % 98.4% % < % + 1.1% 89.5% + 3.2% 99.2% + 0.5% < % % 94.7% + 2.3% 96.1% + 1.4% NS 91.6% % 83.9% % 95.2% % < % % 80.7% % 94.2% % < % % 64.1% % 77.8% % <0.02 CABG, Coronary artery bypass grafting; PTCA, percutaneous transluminal coronary angioplasty. actuarial analysis after 2 years of follow-up significantly fewer patients in group I had avoided late MI and late cardiac death compared with group II (Table VI) (Figs. 1 and 2). Only 64% of patients in group I avoided late cardiac death and late cardiac complications (angina, MI, cardiac evaluation by stress test or catheterization, and cardiac revascularization by coronary artery bypass surgery or balloon angioplasty) in contrast to 78% of patients in group II (Fig. 3). Use of silent myocardial ischemia monitoring may be a more useful alternative to stress testing in predicting early and late cardiac deaths, especially in patients with peripheral vascular disease. Many such patients are unable to exercise to a maximum level because of the presence of lower extremity ischemia) 4 The effectiveness of perioperative silent ischemia monitoring in predicting early and late cardiac events compared with dipyridamole-thallium testing is currently under investigation.is The present study with ischemia for 1% or greater of total perioperative monitoring time as a criterion and any MI or late adverse cardiac event as end points (mean follow-up, 21.5 months) had a sensitivity of 43%, a specificity of 74%, a positive predictive value of 46%, and a negative predictive value of 72%. It should prove possible to modify the risk of an adverse cardiac event in patients undergoing peripheral vascular surgery who are identified as having a critical level of perioperative silent myocardial ischemia. Stimulation of cardiac beta~adrenergic receptors by endogenous catecholamines increases myocardial oxygen consumption and can aggravate myocardial ischemia) 6 Drugs that block the betaadrenergic receptors can moderate the effects of catecholamines and decrease myocardial oxygen re-

8 178 Pasternack et al Journal of VASCULAR SURGERY P E R C E N T 80 7O O [] GROUPII GROUPI p <.001 6O 50 0 II GI I I I I I I I I I I MONTHS POST OP Fig. 2. Actuarial survival from late cardiac death for patients with total perioperative percent time ischemic 1% or greater (group I) versus patients with total perioperative percent time ischemic less than 1% (group II) (G I, group I; G II, group II) P 80 E R -~- C 70 E "E]- GROUP ' ~ ~',.T N 5O Xv II G I f t f t r p t ~ t t I MONTHS POST OP Fig. 3. Actuarial survival from late cardiac death and freedom from late cardiac complications (angina, MI, cardiac evaluation by stress test or catheterization, and cardiac revasoalarization by coronary artery bypass surgery or balloon angioplasty) for patients with total perioperative percent time ischemic 1% or greater versus patients with total perioperative percent.time ischemic less than 1% (group II) (G I, group I; G II, group II). quirements by reducing systemic arterial pressure, heart rate, and cardiac contractility at rest and during exercise. 17 In addition, recent studies have shown that beta-adrenergic blockade with metoprolol can reduce the frequency and duration of silent myocardial ischemic episodes in ambulatory patients with coronary artery disease. 1s,19 The Goteborg metoprolol trial has demonstrated that institution of metoprolol therapy on admission for patients with suspected acute MI can produce a 36% reduction in death from MI regardless of the patient's age, previous infarction status, or history of beta-blocker therapy. 2 Metoprolol also has been fotmd to reduce the frequency and duration of intraoperative silent ischemia in patients undergoing peripheral vascular surgery. 21 Since patients with a total perioperative percent time ischemic of 1% or greater had a significantly worse actuarial survival from late cardiac death and

9 Vohune 16 Number 2 August 1992 Silent myocardial ischemia monitoring 179 late cardiac complications, these patients may benefit from coronary angiography and myocardial revascularization in an attempt to prevent late cardiac death. Of note is that there were no deaths related to coronary artery bypass or coronary angioplasty in this study. Despite the promising results presented here, it should be noted that until large scale random trials can demonstrate the cost-effectiveness of perioperative monitoring for silent ischemia, more clearly define the criteria for determining the degree of risk, and measure the efficacy of therapeutic measures undertaken in response to critical levels of perioperative silent ischemia, it is not possible to make accurate recommendations regarding the routine clinical implementation of this monitoring technique. REFERENCES i. Hertzer NR. Fatal myocardial infarction following abdominal aortic aneurysm resection: three hundred forty-three patients followed 6-11 years post-operatively. Ann Surg 1980;192: Hertzer NR. Fatal myocardial infarction following lower extremity revascularization: two hundred seventy-three patients fbllowed 6 to 11 post-operative years. Ann Surg 1981;193: Hertzer NR, Lees CD. Fatal myocardial infarction following carotid endarterectomy: three hundred thirty five patients followed 6-11 years after operation. Ann Surg 198I;194: Pasternack PF, Grossi EA, Baurnarm FG, et al. The value of silent myocardial ischemia monitoring in the prediction of perioperative myocardial infarction in patients undergoing peripheral vascular surgery. I VASC SURG 1989;10: Levin RI, Cohen D, Frisbie W, et al. Potential for real-time processing of the continuously monitored electrocardiogram in the detection, quantitation, and intervention of silent myocardial ischemia. Cardiology Cfinics 1986;4: Lee MB, Desu M. A computer program for comparing k samples with right censored data. Comput Programs Biomed 1972;2: Mangano DT, Hollenberg M, Fegert G, et al. Perioperative myocardial ischemia in patients undergoing noncardiac surgery- I: incidence and severity during the 4-day perioperative period. J Am Coil Cardiol 1991;17: Mangano DT, Wong MG, London MJ, Tuban IF, Rapp JA, Study of Perioperative Ischemia Research Group. Perioperatire myocardial ischemia in patients undergoing noncardiac surgery- II: incidence and severity during the 1st vceek after surgery. J Am Coil Cardiol 1991;17: Raby KE, Goldman L, Creager MA, et al. Correlation between preoperative ischemia and major cardiac events after peripheral vascular surgery. N Engl J Med 1989;321: Raby KE, Goldman L, Cook F, et al. Long-term prognosis of myocardial ischemia detected by Holier monitoring in peripheral vascular disease. Am J Cardiol 1990;66: I McCann RL~ Clements FM. Silent myocardial ischemia in patients undergoing peripheral vascular surgery: incidence and association with perioperative cardiac morbidity and mortality. J VASC SURG 1989;9: Pasternack PF, Imparato AM, Bear G, et al. The value of radionuchde angiography as a predictor of perioperative myocardial infarction in patients undergoing abdominal aortic aneurysm resection. J Vasc SURG 1984;1: Pasternack PF, Imparato AM, Riles TS, et al. The value of the radionuclide angiogram in the prediction of perioperative myocardial infarction in patients undergoing lower extremity revascularization procedures. Circulation 1985 ;72(suppl H): II Gage AA, Bhayana JN, Balu V, Hook N. Assessment of cardiac risk in surgical patients. Arch Surg 1977;112: Younis LT, Aguirre F, Byers S, et al. Perioperative and long-term prognostic value of intravenous dipyridamole thallium scintigraphy in patients with peripheral vascular disease. Am Heart J 1990;119: Frishman WH, Furberg CD, Friedewald WT. 13-adrenergic blockade for sur,avors of acute myocardial infarction. N Engl J Med 1984;310: Frishman WH. Multifactorial actions of J3-adrenergic blocking drugs in ischemic heart disease: current concepts. Circulation 1983;67(suppl I):Ill Imperi GA, Lambert CR, Coy K, Lopez L, Pepine Cj. Effects of titrated beta blockade (metoproloi) on silent myocardial ischemia in ambulatory patients with coronary artery disease. Am J Cardiol 1987;60: Pepine CJ, Hill JA, Imperi GA, Nolwell N. Beta-adrenergic blockers in silent myocardial ischemia. Am J Cardiol 1988; 61:I8-21B. 20. Hjalmarson A, Healitz J, Holmberg S, et al. The Goteborg metoprolol trial. Circulation 1983;67(suppl I):I Pasternack PF, Grossi EA, Baumann FG, et al. Beta blockade to decrease silent myocardial ischemia during peripheral vascular surgery. Am J Surg 1989;158: Submitted June 10, 1991; accepted Jan. 8, DISCUSSION Dr. Harry Bush (New York, N.Y.). When patients are admitted with peripheral vascular disease, approximately 60% of them have significant coronary plaque disease. It has been observed that late survival is predicated more by this coexisting cardiac disease than the manifestations of peripheral vascular disease. Although the statistical risk is clear, the need to identify specific individuals who have an increased operative risk of adverse cardiac events has led to the testing of multiple predictive strategies. These same tests are now being applied to late survival. This important article supports the hypothesis that if a patient demonstrates objective evidence of coronary insufficiency, the risk

10 180 Pasternack et al. Journal of VASCULAR SURGERY of a late cardiac death is significantly increased after a successful corrective surgery for peripheral vascular disease. Ambulatory continuous ECG monitoring is the latest in this group of predictive coronary risk tests and is attractive because of its ready availability, low costs, and noninvasive characteristics. Pasternack and his colleagues at New York University and other groups have previously reported the efficacy of this technique in defining perioperative risk. They have now reported a late follow-up of these initial studies of perioperative risks. This report observed that patients who were free of perioperative ischemia had increased freedom from late myocardial infarction and had increased survival. As all good studies do, it raises questions. First, the patients were monitored for a mean of 31 hours after operation. Others have reported that an increased incidence of ischemic events occurs both clinically and with ECG monitoring later than 72 hours after operation. Do you have any later follow-up monitoring? Have you found this at all useful? Second, the report does not define the criteria to diagnose the late cardiac events other than to describe the mechanism of a telephone interview. Were there any hard data for review for the late cardiac events? Third, both you and others observed the highest incidence of ischemic events during the postoperative period. In the group that only had postoperative ischemia, did you observe any difference in late cardiac events? Although you show that there is a clear statistical association with later cardiac events, you did not demonstrate the sensitivity or specificity and particularly the positive and negative predictive values of ambulatory ECG monitoring. Do you feel that you can arrive at your conclusions without this information? Last, the clinical significance of ambulatory ECG monitoring is still unclear. From your data, the information confirms that a negative study shows a very low risk of adverse cardiac events. Your data also show that even patients with a negative preoperative study had a 31% risk of adverse cardiac events within 2 years of this study. Do you have any suggestions as to how this positive predictive value of the screening technique could be augmented by other testing modalities, and what strategy do you currently recommend? Dr. Peter Pasternack. Dr. Bush, in response to your first question, we have found no benefit to date in monitoring these patients for more than 30 hours after operation, which is the average time that we have followed them. Actually, for this test really to be most useful clinically, the results of preoperative monitoring would have to be significant. In this regard, multivariate logistic regression analysis of our earlier data has shown that the presence of preoperative silent ischemia and the presence of rest angina are the only two factors tested that enable us to predict which patients are significandy more likely to suffer acute MIs. The patient with preoperative ischemia has a 4.8 times greater risk of suffering a perioperative MI. The patient with rest angina has a 5.2 times greater chance of suffering a perioperative MI. The sensitivity of silent ischemia monitoring as discussed here is 43% and the specificity is 74%. These findings are comparable to those in a study by Raby et al., which was published last year in the American Journal of Cardiology. I think there are other factors that have to be taken into account, and monitoring for silent ischemia is only one variable in evaluating these patients. One could argue that indications of the presence of clinical coronary disease are also helpful. In fact, as far as late follow-up is concerned, we found that not only is silent ischemia monitoring helpful in predicting the occurrence of late death, but the presence of either exertional or rest angina is also helpful. But one reason that we suggest that it is beneficial to monitor patients for silent ischemia is that such data are surely objective. Someone questioning a patient regarding the presence or absence of angina is really dealing with subjective criteria. Another thing that we tend to look at in evaluating these patients, because there are certain patients who were missed by silent ischemia monitoring who suffered early and late MIs, is the presence of a low ejection fraction, less than 35%. We have fotmd this characteristic to be helpful in identifying those patients with significant coronary disease, along with, as I mentioned before, the presence of exertional or rest angina. So, I think that coupling silent ischemia monitoring with the information obtained from an ejection fraction and with the clinical history enables us to pick up most patients who are going to have perioperative or late cardiac problems. Dr. Jerry Goldstone (San Francisco, Calif.). Dr. Pasternack, you indicated that the difference or the breakout between the groups I and groups II was a 1% total ischemia time. Could you tell us how you derived that figure? Dr. Pasternack. This break point was derived from probit scale analysis. Initially we were going to analyze the data in terms of the absolute incidence of ischemia, for instance 10 episodes of ischemia during the monitoring period, or the presence of ischemia for more than 1 hour, irrespective of the length of the monitoring period. But, then we reexamined our data and realized that the various monitoring intervals differed from patient to patient. Furthermore, regression analysis showed that a significant correlation existed between the length of the monitoring period and both the incidence of ischemic episodes and the total duration of ischemia. So, to standardize for the amount of time that these patients were monitored, we thought it more appropriate to express our data in percent time ischemic which negates the variations in monitoring time between patients. This is an important point that has been ignored in some other studies that simply looked at the presence or absence of silent ischemia irrespective of the duration of the monitoring time. That is how we arrived at that number.