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Circulation. 1995;91:2325-2334

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(Circulation. 1995;91:2325-2334.)
© 1995 American Heart Association, Inc.

Articles

Comparison of Surgical and Medical Group Survival in Patients With Left Main Coronary Artery Disease

Long-term CASS Experience

Presented in part at the American College of Cardiology 42nd Annual Scientific Session, March 16, 1993, Anaheim, Calif, and published as an abstract (J Am Coll Cardiol. 1993;21:455A).

Eugene A. Caracciolo, MD; Kathryn B. Davis, PhD; George Sopko, MD; George C. Kaiser, MD; Scott D. Corley, MS; Hartzell Schaff, MD; Herman A. Taylor, MD; Bernard R. Chaitman, MD; for the CASS Investigators

From the St Louis (Mo) University Health Sciences Center (E.A.C., G.C.K., B.R.C.); the University of Washington (K.B.D., S.D.C.), Seattle; the National Heart, Lung, and Blood Institute (G.S.), Bethesda, Md; the Mayo Clinic and Mayo Foundation (H.S.), Rochester, Minn; and the University of Alabama Medical Center (H.A.T.), Birmingham.


*    Abstract
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 *Abstract
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Background Observational and randomized studies designed to compare surgical and medical therapies in patients with left main coronary artery disease (LMCD) have shown that coronary artery bypass graft (CABG) surgery prolongs life in most patients with LMCD. The present report of 1484 patients with LMCD in the Coronary Artery Surgery Study (CASS) Registry extends the originally published 5-year surgical and medical group survival analysis to more than 16 years of follow-up and permits analysis of LMCD patient subgroups.

Methods and Results The CASS Registry contains 1484 patients with >=50% left main coronary artery stenosis initially treated with either surgical or nonsurgical therapy. The 15-year cumulative survival estimates were 37% for the 1153 patients in the surgical group compared with 27% for the 331 patients in the medical group. Median survival in the surgical group was 13.3 years (12.8 to 13.8 years, 95% confidence limits) compared with only 6.6 years (5.4 to 7.9 years) in the medical group (difference, 6.7 years; P<.0001). Median survival was also significantly longer in the surgical group stratified by age, sex, anginal class, left ventricular (LV) function, coronary anatomy, and the extent of LMCD. However, CABG surgery did not significantly prolong median survival in patient subgroups with (1) left main coronary stenosis of 50% to 59%; (2) normal LV systolic function; (3) normal or mildly abnormal LV systolic function and a right coronary artery stenosis >=70%; and (4) a nonstenotic (<=70%) right coronary artery. The 15-year cumulative survival for patients with normal LV systolic function in the surgical and medical groups was 42% and 51%, respectively. Median survival was 14.7 years in the surgical group and >15 years in the medical group (P=NS). In patients with normal LV systolic function and a right coronary artery stenosis >=70%, the 15-year cumulative survival rates were also similar in the surgical and medical groups (40% and 48%, respectively). Median survival was 14.3 years in the surgical group and 14.2 years in the medical group (P=NS). The 15-year cumulative survival estimates for all subgroups were affected by convergence of the surgical and medical survival group curves owing to a disproportionate increase in the late surgical group mortality. Overall, 25% of patients in the medical group ultimately underwent CABG surgery. If all medical group patients had survived long enough, about 47% would be estimated to have had surgery by 15 years.

Conclusions This report, which extends follow-up of more than 16 years in CASS Registry patients with LMCD, shows that CABG surgery prolongs life in most clinical and angiographic subgroups. However, median survival was not prolonged by CABG surgery in patients with normal LV systolic function, even if a significant right coronary artery stenosis (>=70%) also was present. These results extend our understanding of the natural history of LMCD and permit a more accurate estimate of long-term surgical and medical group survival.


Key Words: coronary disease • bypass • surgery


*    Introduction
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 up arrowAbstract
 *Introduction
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down arrowResults
down arrowDiscussion
down arrowReferences
 
Since the first clinical description of left main coro-nary artery disease (LMCD) by Herrick in 1912,1 numerous studies have shown that stenosis of the left main coronary artery is of critical prognostic importance.2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Observational studies of medically4 5 6 7 and surgically8 9 10 11 12 13 14 15 16 treated patients with LMCD support the widely accepted belief that in general, coronary artery bypass graft (CABG) surgery lessens symptoms and significantly prolongs survival. More importantly, observational18 19 20 21 22 and randomized23 24 25 26 27 28 29 studies designed to directly compare surgical and medical therapy in patients with left main stenosis have confirmed the benefits of surgical revascularization, although in all but two of the randomized studies23 24 follow-up was less than 4 years.

Analyses of patient subgroups with LMCD show that the prognosis of medically treated patients is not always poor and can vary, depending on specific clinical and angiographic criteria.3 10 18 27 28 29 More than a decade ago, Chaitman et al18 reported on the 4-year cumulative survival of almost 1500 patients in the Coronary Artery Surgery Study (CASS) Registry with >=50% LMCD initially treated with surgical and medical therapy. Overall, CABG surgery significantly prolonged the 4-year cumulative survival compared with medical therapy (88% versus 63%, respectively). However, CABG surgery did not prolong survival in women and in angiographic subsets of patients with a left-dominant circulation, a nonstenotic dominant right coronary artery (RCA), and a stenotic dominant RCA with normal left ventricular (LV) systolic function. A lesser but still significant survival benefit from surgical revascularization was seen in the entire subgroup of patients with normal LV systolic function. The present study extends these initial observations to more than 16 years of follow-up.

This is the longest follow-up of the largest cohort of patients with LMCD initially treated with CABG surgery and nonsurgical therapy and is clinically relevant for two reasons. First, a longer duration of follow-up allows an increased number of events, which then provides greater power to differentiate between treatment groups. Second, the duration of the specific treatment strategy over time can be evaluated and compared with the duration of the therapeutic benefit.


*    Methods
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 *Methods
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Patient Population
The CASS Registry, an NHLBI-funded study, contains data from 24 958 patients who underwent coronary angiography at 14 participating centers in the United States and 1 in Canada between 1974 and 1979 for suspected or proven coronary artery disease. The registry contains 1484 patients with LMCD, defined as a >=50% reduction in luminal diameter, who did not have CABG surgery before enrollment and who had no congenital cardiac abnormalities or concomitant cardiovascular procedures at the time of CABG surgery (ie, aneurysm resection or valve surgery). All registry patients, including those 14 who participated in the randomized trial and those who were randomizable, are included in the present study report.

The 1484 patients (331 medical, 1153 surgical) are fewer than the 1492 patients (309 medical, 1183 surgical) in the previous report,18 primarily because of different exposure time criteria.

Clinical and Angiographic Variables
The definitions of clinical variables used in the CASS were described previously.30 Angina pain was classified according to the Canadian Cardiovascular Society grading system as follows: class I, chest pain only with prolonged or strenuous exertion; class II, chest pain with rapid or moderate walking (>2 blocks) or stair climbing (>1 flight) in the cold or wind or under emotional stress; class III, chest pain with minimal walking or stair climbing; and class IV, chest pain with any level of physical activity or even at rest.31 Patients whose angina was unrelated to exertion were grouped with classes III and IV. Unstable angina was defined as angina of recent onset or crescendo angina within 2 months of angiography or acute coronary insufficiency. A history of myocardial infarction required that the patient had been informed by a physician of a definite event. The congestive heart failure (CHF) score included the number of positive responses (zero to four) to a history of heart failure, use of diuretic drugs, use of digitalis, and the presence of pulmonary rales on the admission physical examination.

Coronary angiography was performed by either the brachial or the femoral technique. Several views of each coronary artery were analyzed. The severity of arterial stenoses, defined as the maximal percent reduction in the luminal diameter, was recorded for each of 27 coronary segments. In this study, >=50% reduction in the left main luminal diameter was considered significant, while a stenosis of >=70% was required for all other coronary segments.

Left ventriculography was performed in the 30° right anterior oblique view. The ventriculogram was divided into five segments (anterobasal, anterolateral, apical, diaphragmatic, and posterobasal), and the systolic contraction pattern of each segment was evaluated visually and scored numerically as follows: 1, normal; 2, moderate hypokinesis; 3, severe hypokinesis; 4, akinesis; 5, dyskinesis; and 6, aneurysmal. The LV score was derived from the sum of these scored segments and was 5 in patients with normal LV systolic function. The ejection fraction was calculated by the area-length method32 in 1119 patients with technically adequate LV angiograms. Table 1Down summarizes the baseline clinical and angiographic characteristics of the 1153 surgical group patients and the 331 medical group patients.


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  		Table 1. Clinical and Angiographic Variables in CASS Registry Patients With >=50% Left Main Stenosis

CABG Surgery
The surgical techniques and variables in the CASS and specifically in patients with >=50% left main stenosis were reported previously.33 34 35 All patients in the surgical group received saphenous vein grafts, internal thoracic artery grafts, or both. The average number of grafts was 3.1±0.9 (SD) per patient. A left internal thoracic artery graft was used in 9.5% of patients at the time of their initial surgery. In the surgical group, 7% of patients (80 patients) had only left main stenosis. The percent of patients with single-, double-, and triple-vessel coronary disease (in addition to left main stenosis >=50%) was 13%, 27%, and 52%, respectively. The percent of patients who received one, two, three, or four or more grafts (distal anastomoses) at the time of their initial CABG surgery was 2%, 21%, 48%, and 30%, respectively. Operative mortality, defined as death within 30 days of surgery, was 4.6%.

Data Acquisition
Follow-up data were obtained by a standardized questionnaire administered at yearly intervals after entry. Detailed description of the cause of death was obtained for deaths from 1974 to 1982. As of February 24, 1993, the vital status of 100% of patients was known. The minimum and maximum range of follow-up at this date was 8.9 and 16.7 years, respectively. In nonsurvivors, the circumstances of death were determined from hospital records or by telephone interview with the treating physician or family members.

Assignment to Treatment Groups for Analysis
Classification of registry patients into surgical and medical groups is not easily defined, a common problem in all published observational studies.36 Medical group patients were defined as those who did not undergo CABG surgery or who had very late surgery. In the first year after enrollment, the number of days in which 95% of the CABG operations were performed was determined for each hospital (average time, 4 months). Patients who underwent CABG surgery within this interval or within 90 days after enrollment were defined as surgically treated patients. Survival for medical group patients began on the day of surgery. Survival time for nonsurgically treated patients was dated from the average time to surgery for that particular hospital. This method eliminates the bias that occurs when all early deaths are included in the medical group.

Statistical Considerations
Survival in various subgroups was computed with Kaplan-Meier survival curves over 15 years and by calculation of median survival times. Median survival time was estimated as the time point at which the Kaplan-Meier survival curves crossed 50%. CIs for medians were calculated by a nonparametric asymptotic method,37 and statistical significance was determined by a median test for censored data.38 The log-rank statistic and the Cox proportional-hazards model were not used for surgical-medical group comparisons because the surgical and medical group survival rates decrease nonproportionally. The log-rank statistic, however, was used to compare survival within surgical and medical subgroups because the proportional-hazards assumption is justifiable within treatment groups.

The rates of CABG surgery over time after enrollment angiography were estimated by Kaplan-Meier time-to-event analyses. Randomized patients were excluded from the analyses of CABG surgery rates because their assignment to surgery was determined by a random process. Patients who died were removed from the group at risk (censored) at their time of death.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
down arrowDiscussion
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Comparison of Baseline Clinical and Angiographic Characteristics (Table 1Up)
Of the 1484 predominantly male patients with >=50% left main stenosis, 1153 (78%) initially underwent CABG surgery, and 331 (22%) were initially treated nonsurgically, a treatment based on physician and patient preferences. Patients in the surgical group had more severe angina (62% class III or IV) compared with the medical group (39%, P<.0001). Fewer patients had a history of CHF in the surgical group compared with the medical group (8% versus 19%, P<.0001). Similarly, the mean CHF score was lower in the surgical group compared with the medical group (0.53±0.86 versus 0.82±1.16, P<.0001). Only 4% in the surgical group had a CHF score of 3 or 4 compared with 14% in the medical group. The surgical group had better LV systolic function (LV score, 8.0; LV ejection fraction, 60%) compared with the medical group (LV score, 10.1; LV ejection fraction, 50.4%; P<.0001) and a more severe degree of left main stenosis (72.5% versus 62.9%, P<.0001).

Long-term Cumulative Survival
The 15-year cumulative survival rate of the 1153 patients who initially underwent CABG surgery was 37% versus 27% in the 331 patients who initially received nonsurgical therapy (Fig 1Down). The mortality rate in the surgical group was initially low but gradually increased relative to the rate in the medical group. Although the magnitude of cumulative survival difference between the surgical and medical groups was relatively small after 15 years, the median survival in the surgical group was 13.3 years (12.8 to 13.8 years, 95% confidence limits) compared with only 6.6 years (5.4 to 7.9 years) in the medical group (difference, 6.7 years; P<.0001).



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  		Figure 1. Graph showing 15-year cumulative survival estimates in 1484 Coronary Artery Surgery Study Registry patients with >=50% left main coronary artery stenosis who were initially treated with coronary artery bypass graft surgery (1153 patients) and nonsurgical therapy (331 patients). The number of patients at risk for each follow-up interval is depicted next to the cumulative survival.

Influence of Clinical Variables
CABG surgery significantly prolonged median survival in all patient subgroups stratified by age, sex, and angina class (Table 2Down). Advanced age and severe angina pectoris were associated with poor survival in the medical group. In patients >=65 years of age at the time of randomization, the median medical group survival was only 4.4 years; in patients with class III or IV angina, the median medical group survival was only 5.3 years.


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  		Table 2. Median and 15-Year Cumulative Survival in Surgical and Medical Group Patients With >=50% Left Main Stenosis Stratified by Clinical Variables

Influence of Angiographic Variables
LV Function
The 15-year cumulative survival in surgical and medical group patients was significantly affected by the LV systolic function (Fig 2Down). The 15-year cumulative survival rates in patients with normal LV systolic function (LV score, 5) in the surgical and medical groups were 42% and 51%, respectively. Median survival was not significantly different for patients with normal LV function. For these patients, median survival was 14.7 years in the surgical group and >15 years in the medical group (P=.94) (Table 3Down).



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  		Figure 2. Graphs showing 15-year cumulative survival estimates stratified by left ventricular (LV) score: LV score, 5 (A); LV score, 6 to 10 (B); LV score, 11 to 14 (C); and LV score >=15 (D). The 15-year cumulative survival estimates were similar in the surgical and medical groups in patients with normal LV systolic function (LV score, 5) and mildly impaired LV systolic function (LV score, 6 to 10). More severe degrees of LV dysfunction (LV score >10) adversely affected survival in both the surgical and medical groups.


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  		Table 3. Median Survival in Surgical and Medical Group Patients With >=50% Left Main Stenosis Stratified by Angiographic Variables

However, there were significant differences in survival for patients with impaired LV function (Fig 2Up). For patients with mild impairment (LV score, 6 to 10) of LV function, 15-year survival rates were similar (41% for the surgical group and 38% for the medical group), but median survival was significantly different (difference, 3.7 years; P=.01) (Table 3Up). The difference in median survival between the surgical and medical group patients increased with more severe LV dysfunction to 6.3 years for patients with an LV score of 11 to 14 and 7.5 years for patients with an LV score >=15 (both P<.0001) (Table 3Up). The patients with the worst LV function had the poorest prognosis in both treatment groups; only 17% of surgically treated patients and <3% of nonsurgically treated patients with severe hypokinesis (LV score >=15) were alive after 15 years of follow-up (Fig 2Up).

RCA Stenosis
A right-dominant or balanced circulation was present in 93% of the surgical group and 92% of the medical group patients. The 15-year cumulative survival rates were decreased in both surgically and nonsurgically treated patients with >=70% stenosis of the dominant or balanced RCA (36% and 22%, respectively) (Fig 3Down). For these patients, median survival was 12.7 years in the surgical group and only 5.6 years in the medical group (difference, 7.1 years; P<.0001) (Table 3Up). Median survival for LMCD patients with RCA stenosis <70% was 14.9 years in the surgical group and 10.2 years in the medical group (P=NS) (Table 3Up).



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  		Figure 3. Graphs showing 15-year cumulative survival estimates in patients with a right dominant or balanced circulation with and without >=70% stenosis in the right coronary artery (RCA): RCA stenosis >=70% (A); RCA stenosis <70% (B). The 15-year cumulative survival was similar in both treatment groups when the RCA stenosis was <70%. RCA stenosis >=70% adversely affected survival in both the surgical and medical groups.

LV Function and RCA Stenosis
Patients with a right-dominant or balanced circulation and an RCA stenosis >=70% survived longer if they had normal LV function (Fig 4Down). For these patients, the median survival was 14.3 years in the surgical group and 14.2 years in the medical group (difference, 0.1 year; P=.83) (Table 3Up). In patients with an LV score of 6 to 10, median survival was 13.3 in the surgical group and 10.1 in the medical group (difference, 3.2 years; P=.14). For those with an LV score >10, there was a significant difference in median survival in the surgical compared with the medical group patients (difference, 7.4 years; P<.0001).



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  		Figure 4. Graph showing 15-year cumulative survival estimates in patients with a right coronary artery (RCA) stenosis >=70% and normal left ventricular (LV) systolic function (LV score, 5). Cumulative survival rates were similar in the two treatment groups and better than the 36% and 22% survival rates for the surgical and medical groups, respectively, in the overall group of patients with an RCA stenosis of >=70%.

Degree of LMCD
The severity of the LMCD significantly affected the cumulative survival in the medical group but not in the surgical group (Fig 5Down). The 10-year cumulative survival of the medical group ranged from 50% for patients with 50% to 59% left main stenosis to 21% for patients with a left main stenosis >=80%. Median survival in the medical group ranged from 9.8 years in patients with 50% to 59% left main stenosis to 2.9 years in patients with >=80% left main stenosis (Table 3Up). In the surgical group, median survival ranged from 13.0 to 13.8 years in the four strata of left main stenoses (Fig 5Down, Table 3Up).



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  		Figure 5. Graphs showing 15-year cumulative survival estimates of surgically and nonsurgically treated patients stratified by the percent stenosis of left main coronary artery (LMCA sten) disease (LMCD). A, Surgical group survival was similar for all degrees of LMCD. B, Medical group survival was adversely affected by more severe degrees of LMCD. The log-rank statistic was used to compare survival within the surgical and medical subgroups because the proportional-hazards assumption is justifiable within treatment groups.

The difference in median survival between the medical and surgical groups was larger for patients with higher degrees of left main stenosis. The difference was 3.2 years (P=.09) for left main stenosis of 50% to 59%, 9.4 years (P=.0001) for left main stenosis of 60% to 69%, 7.2 years (P<.0001) for left main stenosis of 70% to 79%, and 10.2 years (P<.0001) for left main stenosis >=80% (Table 3Up).

Incremental CABG Surgery
Of patients initially treated nonsurgically, 25% had at least one CABG operation at some point during follow-up; 12% of the surgical group and 2% of the medical group had more than one CABG operation (Table 4Down). After the first year, about 3% of the medical group patients had surgery each year. If all medical group patients had survived long enough, about 47% would be estimated to have had surgery by 15 years (Fig 6Down).


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  		Table 4. Number of Patients Who Underwent CABG Surgery Stratified by Initial Treatment Group



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  		Figure 6. Graph showing Kaplan-Meier estimates of the surgical and medical group patients who did not have surgery by 15 years of follow-up. By definition, all patients in the surgical group had early surgery. About 3% of the nonsurgically treated patients had surgery each year. If all medical group patients had survived long enough, about 47% would be estimated to have had surgery by 15 years. CABG indicates coronary artery bypass graft.

Mortality Analysis
Of the 760 patients who died in this study, 323 had completed mortality forms. In the surgical group, 172 deaths were recorded; in the medical group, 151 deaths were recorded. Death caused by myocardial infarction and sudden death occurred more frequently in the medical group, while noncardiovascular deaths were recorded more frequently in the surgical group.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
Since the first report by Cohen and Gorlin22 in 1972 on the surgical and medical treatment of patients with significant stenosis of the left main coronary artery, relatively few published studies directly compare surgical and medical therapies.

Compared with medically treated patients, CABG surgery has been demonstrated in both observational18 19 20 21 22 and randomized23 24 25 26 27 28 29 trials to prolong survival in patients with significant (>=50%) LMCD. However, these studies all reported small numbers of patients with follow-up data limited to 4 years, except the randomized Veterans Administration Cooperative Study of Coronary Artery Bypass Surgery24 and the European Coronary Surgical Study (ECSS),23 25 which reported on 11- and 10-year follow-up data, respectively.

In 1981, Chaitman et al18 reported on the 4-year cumulative survival of almost 1500 patients in the CASS Registry managed with an initial treatment strategy of surgical revascularization or medical therapy. Overall, CABG surgery significantly prolonged the 4-year cumulative survival compared with medical therapy (88% versus 63%, respectively). Notably, the 3-year cumulative survival of the CASS Registry surgical group with >=50% left main stenosis was similar to surgical survival in the ECSS25 26 and in the Veterans Administration Cooperative Study.29 The 3-year cumulative survival rate in the CASS medical group was similar to that of the ECSS medical group in patients with an LV ejection fraction >=50%.

Baseline Characteristics
A greater percent of patients in the surgical group had class III or IV angina. This is not surprising because when the CASS Registry was initiated in 1974, CABG surgery was an accepted method for providing relief of ischemic pain syndromes in a substantial majority of patients with significant coronary artery disease who had failed medical therapy.39

In two CASS Registry studies,40 41 improved 5- and 6-year cumulative survival was reported in surgically treated patients with severe angina pectoris (class III and IV) and three-vessel coronary artery disease. Kaiser et al41 reported prolonged survival in surgically treated patients with an LV ejection fraction >=50% who otherwise fulfilled all inclusion criteria for the CASS randomized trial except for class III or IV angina pectoris. Myers et al40 extended these findings, reporting on improved survival in surgically treated patients with normal LV systolic function who had more than one proximal stenosis, three-vessel disease, and severe angina pectoris.

Nonsurgically treated patients had a more frequent history of CHF and worse LV systolic function, reflecting the bias of not operating on these patients because of the higher operative mortality rate.33 34 35

Clinical Variables
CABG surgery prolonged long-term cumulative survival and median survival in all subgroups of patients stratified by age, sex, and angina class. In the initial CASS report, the surgical survival benefit in women at 3 years was not statistically significant. The high operative mortality rate in women (8%) may explain this finding because the survival curves in men and women are similar after 1 year (Fig 7Down). Previous CASS reports showed a higher operative mortality in women, presumably because of their proportionally smaller coronary arteries.33 34 35



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  		Figure 7. Graph showing 15-year cumulative survival estimates in the surgically treated group stratified by gender. The higher operative mortality in women accounts for the difference in long-term survival.

Angiographic Variables
LV Function
LV systolic function is an important predictor of long-term survival in patients with LMCD. CABG surgery did not improve median and long-term survival in patients with >=50% LMCD with normal LV systolic function even if RCA stenosis >=70% also was present.

LV function is an important predictor of survival in patients with chronic ischemic heart disease24 42 43 44 45 46 47 48 49 50 51 and in survivors of myocardial infarction.52 In the CASS Registry, at 12 years of follow-up of medically treated patients, only 10% with three-vessel disease and severe LV systolic dysfunction (LV ejection fraction <0.35) are still alive.42 Twelve-year survival, not stratified by the number of diseased vessels, was 21% in the group with severe LV systolic dysfunction. Conversely, medically treated patients with good LV systolic function (LV ejection fraction >=0.50) had a cumulative survival of 81%, 70%, and 58% for one-, two-, and three-vessel disease, respectively.42

Similarly, Myers et al43 reported that the 5-year survival of surgically treated patients in the CASS Registry was significantly affected by the preoperative LV function. Patients with normal or mildly abnormal LV function (score, 5 to 11), moderate LV dysfunction (score, 12 to 16), and severe LV dysfunction (score >=17) had 5-year survival rates of 92%, 80%, and 65%, respectively.

Previous reports of medically treated patients with significant LMCD show that LV function is an important predictor of survival. In a series of 163 consecutive patients treated medically with >=50% left main stenosis, Conley et al4 showed that the 1-year survival was 95% for patients with normal LV function and 61% for patients with abnormal LV function. Lim et al6 showed that in 141 medically treated patients with LMCD, the lowest 5-year cumulative survival was in patients with diminished LV function.

In the Veterans Administration Cooperative Study of Stable Angina, Detre et al27 analyzed the 53 medically treated patients (out of 113 in the Veterans Administration Cooperative Study with >=50% left main stenosis) stratified by the presence or absence of LV dysfunction. Of the 53 medically treated patients, 20 patients had normal LV function, and 33 patients had abnormal LV function. At 18 months of follow-up in the medically treated group, 85% of those with normal LV function and 60% of those with abnormal LV function were alive. From the same study, Hultgren et al28 compared the medical and surgical groups of patients with >=50% left main stenosis and diminished LV function and found that at 18 months of follow-up, surgical group survival was 86% compared with 58% in the medical group.

Coronary Pathology
In the current study, the degree of LMCD was shown to affect long-term survival in the medical group but not in the surgical group, extending the results of the earlier report to 15 years. Although Lim et al6 found no significant relation between the degree of left main stenosis and survival, both Conley et al4 and Campeau et al10 reported a reduction in the survival of patients with more severe degrees of LMCD who were treated medically.

An RCA stenosis >=70% was present in 76% of both surgical and medical group LMCD patients (right-dominant or balanced circulation) on enrollment angiography and adversely affected survival in both the surgical and medical groups. Surprisingly, LMCD patients with a nonstenotic RCA had extended median survival in both treatment groups.

Long-term Follow-up
Of the 331 patients initially treated nonsurgically, 25% ultimately had CABG surgery. As estimated by Kaplan-Meier time-to-event analysis, about 47% of the medical group would have had surgery by 15 years of follow-up if they had survived long enough (Fig 6Up). This figure is higher than the 38%, 36%, and 38% rates of CABG surgery at 10 to 12 years of follow-up in randomized medical group patients in the CASS,45 ECSS,23 and Veterans Administration Cooperative Study.24

In the randomized ECSS trial, 31 patients in the medical group and 28 patients in the surgical group had >=50% stenosis of the left main coronary artery. At 10 years of follow-up, 64% of the surgical group and 61% of the medical group were alive. Because the ECSS randomized only patients with an LV ejection fraction >=50%, stratification by LV function is not possible.

In the Veterans Administration Cooperative Study, the 11-year cumulative survival of the 48 patients with >=50% left main stenosis randomized to surgical treatment was 59%. A comparison to the assigned medical group was not made because only 4 of the initial 43 medical patients were still being treated medically at 7 years; 44% (19 patients) died, and 47% (20 patients) had CABG surgery.

The 15-year cumulative survival in the 1484 CASS Registry patients with >=50% LMCD is affected by convergence of the surgical and medical group survival curves after approximately 8 years, which is a result of a disproportionate increase in the surgical group mortality. Convergence of the medical and surgical survival curves is also seen in the various subgroup analyses. Although not seen at 10 years of follow-up in the CASS randomized trial45 or among randomizable patients,53 in the randomized Veterans Administration Cooperative Study, the survival curves achieved a maximal difference between surgically and medically assigned patients at 7 years, diminishing to a nonsignificant survival difference by year 11.24 In the randomized ECSS trial, the maximal difference between surgically and medically assigned patients was seen at 5 years.25 During the subsequent 7 years, the percentage of patients who survived decreased more rapidly in the surgical group compared with the medical group.23

The late mortality increase in patients randomized to CABG surgery compared with medical treatment in both the Veterans Administration Cooperative Study and ECSS is postulated to result from disease progression in the native coronary arteries and graft occlusion from atherosclerosis.54 In the Montreal Heart Institute series,55 after 10 years of follow-up, only 60% to 65% of saphenous vein grafts remained patent. Virtually all conduits in the Veterans Administration Cooperative Study and ECSS were saphenous veins, whereas in the CASS randomized trial, 16% of conduits were internal thoracic artery grafts. Previous studies showed that intimal thoracic artery grafting of the left anterior descending artery substantially improves patient survival.56 57 In the current study, almost 10% of patients in the surgical group received an internal thoracic artery conduit.

The long-term follow-up of more than 16 years in this study provides unique data that may in part explain the late decrease in the surgical group survival. In the surgical group, a noncardiovascular cause of death was recorded in 20% of the patients compared with 6% in the medical group (in patients from 1974 to 1982, when a mortality form was recorded). At 4 years of follow-up, noncardiac death totaled 2% in the surgical group and 1% in the medical group.18 On enrollment in the registry, the mean age of these predominantly male (87%) patients was 57 years. As a higher proportion of surgical survivors enter their seventh decade, a higher percentage of noncardiovascular deaths can be expected.

Rationale for Surgical-Medical Group Comparisons by Use of Median Survival
To emphasize important differences in the surgical and medical group survival curves, which are often large despite similar survival estimates at 15 years, we evaluated the 15-year surgical and medical group survival rates by comparing the estimated median survival times.

In this study, the hazard rate for the surgical group is initially high for the perioperative period. Then it immediately falls to a low rate and gradually increases over the 15 years of follow-up. On the cumulative survival curve (Fig 1Up), this hazard rate is reflected by an initial decrease in the surgical group survival, which is then followed by a gradually increasing slope. For the medical group, there is an initial higher hazard after enrollment angiography (although less than the hazard associated with CABG surgery), which is then followed by a constant or slightly decreasing hazard over the 15 years of follow-up.

Because the hazard for CABG surgery patients is increasing but the hazard for medical group patients is constant or decreasing, these data do not satisfy the proportional-hazards assumption necessary for the log-rank statistic to be interpreted easily or for the Cox survival model to be applicable.

Surgical and Nonsurgical Therapies in the CASS Registry
Comparisons of CABG surgery and nonsurgical therapy in the CASS Registry patients with LMCD reflect the prevailing surgical techniques and medications available between 1974 and 1979 for the management of patients with chronic ischemic heart disease. Operative mortality was somewhat higher in the CASS Registry patients compared with current standards of practice, and the widespread use of the internal thoracic artery has improved long-term graft patency rates compared with use of saphenous vein graft conduits.56 57

Current medical therapy not available at the time of patient enrollment in the CASS Registry includes frequent use of calcium channel blocking agents for management of ischemia and of vasodilators and angiotensin-converting enzyme inhibitors for the management of congestive heart failure and LV dysfunction.58 59 60 61 62 63 The use of vasodilators and ACE inhibitors may have improved survival in the medical group because significantly more patients with severe LV systolic dysfunction were treated nonsurgically.

Both treatment groups would have benefited initially from the current ongoing public health initiatives, which include lipid-lowering regimens and cessation of smoking, although in the randomized CASS trial the number of patients smoking at the 10-year follow-up was not different between the surgical and medical groups.64 Although coronary angioplasty has become a mainstay in the treatment of ischemic heart disease in the last decade, it is not a relevant modality in patients with significant LMCD.

Clinical Implications
The data from more than 16 years of follow-up of CASS Registry patients with significant LMCD extend the reported 4-year survival data and are consistent with the published literature. Overall, CABG surgery prolonged survival in patients with >=50% stenosis of the left main coronary artery. However, median survival was not prolonged by CABG surgery in the following patient subgroups: (1) left main stenosis <60%; (2) normal LV systolic function, even if a significant RCA stenosis (>=70%) also was present; and (3) a nonstenotic (<70%) RCA. At 15 years of follow-up, a disproportionate increase in mortality in the surgical group was observed, which no doubt is multifunctional but probably is due in part to ongoing attrition of the saphenous vein graft conduits and to an excess of noncardiovascular deaths. It is anticipated that with the appropriate selection of patients and newer forms of therapy targeted to retard atherosclerosis in the graft conduits, CABG surgery will remain an important treatment strategy to prolong survival and improve the quality of life in patients with significant LMCD.


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  		Table 5. Causes of Death (for Which a Mortality Form Was Recorded) in the Surgical and Medical Groups


*    Acknowledgments
 
This work was supported by research contracts from the NHLBI, Bethesda, Md.


*    Footnotes
 
Reprint requests to Kathryn B. Davis, PhD, CASS Coordinating Center, University of Washington, 107 NE 45th St, Room 530, Seattle, WA 98105.

Received August 10, 1994; revision received November 7, 1994; accepted November 20, 1994.


*    References
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*References
 

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