Survival following coronary artery bypass grafting in patients with severe angina pectoris (CASS)

J

THoRAc CARDIOVASC SURG

89:513-524, 1985

Survival following coronary artery bypass grafting in patients with severe angina pectoris (CASS) An observational study This observational study evaluates the effects of the severity of angina pectorisand the treatment method upon the survival of 4,209 patients in the Coronary Artery Surgery Study registry. In this nonrandomized study, these patientsmet the criteria used in the Coronary Artery SurgeryStudy randomized trial, except for the degree of angina pectoris and the methodof selection of treatment. The 5 year survival rate was 2:93% in patients with Class I and II angina pectoris and normal left ventricular function, regardlessof the number of involved vessels or treatment received. Late survival of surgically treated patients with Class and IV angina pectoris and normal left ventricular function was similar, regardless of the number of vessels involved (2:92 % at 5 years). Nonoperatively treated patientswith Class m and IV angina pectoris and normalleft ventricular function bad poorer 5 year survival rates, lowest (74%) in patients with three vessel disease (p < O.OOOI~ This difference was also observed in patients with abnormal left ventricular function, three vessel disease, andClass m and IV angina pectoris; the 5 year survival rates were82 % for the operative groupand 52 % for the nonoperative group (p < 0.0001). These data confrrm the importance of clinical as well as anatomicfactors in determining the prognosis of patients withischemic heart disease and indicate that coronary artery bypass grafting can improve late survival in patients with triple vessel disease and severe angina pectoris.

m

George C. Kaiser, M.D., St. Louis, Mo., Kathryn B. Davis, Ph.D., Lloyd D. Fisher, Ph.D., Seattle, Wash., William O. Myers, M.D., Marshfield, Wis., Eric D. Foster, M.D., Albany, N. Y, Eugene R. Passamani, M.D., Bethesda, Md., and Mary Jo Gillespie, M.S., Seattle, Wash.

h e initial reports of the Coronary Artery Surgery Study (CASS) randomized trial indicated that coronary artery bypass grafting (CABG) did not significantly alter late (5 year) survival or the incidence of myocardial infarction.!'? Two other cooperative randomized trials have been reported.v' The European Coronary Surgery Study Group reported improved survival in surgically treated patients with triple vessel disease and normal left ventricular function.' The Veterans Administration Cooperative Study of Stable Angina revealed a trend in favor of improved survival in surgically treated

Read at the Tenth Annual Meeting of The Western Thoracic Surgical Association, Maui, Hawaii, June 20-23, 1984. This collaborative Coronary Artery Surgery Study (CASS) was funded by the National Heart, Lung, and Blood Institute, Bethesda, Md. Address for reprints: George C. Kaiser, M.D., Department of Surgery, St. Louis University School of Medicine, 1325 S. Grand Blvd., St. Louis, Mo. 63104.

patients with triple vessel disease. This trend became statistically significant after exclusion of three hospitals.' Both of these cooperative studies included patients with more severe angina pectoris than the CASS randomized trial. In this report, we have reviewed two groups of patients from the CASS registry. The first included the CASS nonrandomized patients who qualified for inclusion in the trial but declined random assignment of treatment, henceforth referred to as "randomizable." All had mild angina pectoris or were asymptomatic survivors of myocardial infarction. The second included patients similar to the randomizable group save for the severity of angina pectoris, which in this group was Canadian Cardiovascular Society (CCS) Class III or IV.

Methods CASS consisted of a patient registry and a randomized trial. The details of the study design, protocol, and

513

5 1 4 Kaiser et al.

Table I. Variables considered in Cox survival analysis Age Gender Canadian Cardiovascular Society angina class Number of vessels diseased N umber of operable vessels Number of proximal vessels diseased Myocardial jeopardy index Left ventricular wall motion score Digitalis use Diuretic use Number of associated noncardiac illnesses History of congestive heart failure Beta blocker use Antiarrhythmic drug use Antiplatelet drug use Resting electrocardiogram: Normal Abnormal Q wave Arrhythmia ST-depression Recreational activity level Smoking history Family history of ischemic heart disease Previous history of myocardial infarction Angina-probable or definite Tranquilizer use Pacemaker use S3 sound Basilar rales Peripheral edema Left ventricular end-diastolic pressure

patient clinical characteristics at entry have been reported previously.' During the entry period, July, 1974, to June, 1979, 24,959 patients were enrolled who underwent coronary angiographic examination for suspected coronary artery disease at the 15 participating CASS registry sites. A subgroup of 780 patients with no or mild chronic stable angina pectoris were randomly assigned to medicalor surgical therapy and constituted the randomized trial. The initial results of this randomized trial from the 11 sites that participated in this aspect of the study have been published. I, 2, 6 From the remaining CASS registry at the 11 randomizing sites,' the records of 4,209 patients with all degrees of chronic stable angina pectoris were evaluated. There were 1,315 randomizable patients and 2,894 patients with Class III or IV angina pectoris. The randomizable patients met the CASS trial entry criteria but declined randomization. Those with Class III or IV angina pectoris met the CASS trial entrance criteria except for the severity of angina pectoris. Angina pectoris was classified according to the CCS classification as follows: Class I-angina pectoris arising

The Journal of Thoracic and Cardiovascular Surgery

from strenuous or prolonged exertion; Class II-angina pectoris occurring with walking rapidly or climbing stairs; Class III-angina pectoris produced by walking one to two blocks on the level or climbing one flight of stairs at a normal pace; Class IV-angina pectoris occurring with any physical activity. Angina may be present at rest.' Coronary arteriography and left ventriculography were performed and analyzed according to a standard protocol. Both ejection fraction and left ventricular segmental wall motion were determined from the left ventriculogram performed in the right anterior oblique projection.' The severity and location of all significant coronary arterial lesions were also recorded. Inclusion into this study required that there be at least one operable, significantly stenosed vessel. Significant stenosis was defined as 70% or greater reduction in internal diameter of the right coronary, left anterior descending, and/or circumflex coronary arteries. In the case of the left main coronary artery, a 50% stenosis made the patient eligible for inclusion. A left main coronary stenosis of 70% or greater was cause for exclusion, as were an observed ejection fraction of less than 35%, planned valve replacement, or anticipated left ventricular aneurysmectomy. The results of management of those registry patients with less than CCS Class III angina pectoris and no other exclusionsfrom randomization have been reported elsewhere, and this group has been referred to as the randomizable subgroup of the registry.' These patients were identified from the registry during the randomization process and were the remaining portion of the pool from which the randomized patients were drawn. The entry characteristics of this group of randomizable patients were similar to those in the randomized study, with the exception that in the randomizable patients there was more extensive coronary vascular disease in the surgically treated patients and less extensivedisease in the medically treated patients when compared to the randomized groups." The major difference between the randomized and randomizable patients, however, was that treatment received in the randomizable group was not randomly assigned. Rather, in this group selectionof the treatment method was made by the physician, the patient, or both. Patients with Class III and IV angina pectoris were identified from the registry by the same selectioncriteria as for the randomized patients, except that the degree of angina pectoris was more severe and the treatment given was determined by the physician, surgeon, patient, or a combination of these. As in the randomized study, patients with unstable angina pectoris, prior CABG,

Volume 89 Number 4 April, 1985

congestive heart failure, coexisting illness likely to preclude 5 year survival, inoperable coronary anatomy, or age greater than 65 years were excluded. 1 CABG was performed by routine techniques of anesthesia, myocardial preservation, and graft anastomosis as performed at each participating institution. Hemodilution cardiopulmonary bypass was used at all institutions. The distal anastomoses usually were accomplished with intermittent or a single period of aortic cross-clamping in those patients in whom hypothermia or cardioplegia were used." Optimal medical management was recommended for all patients, whether they were treated operatively or nonoperatively. The details of both medical and surgical management have been published previously.I' They were representative of practice for the period 1974 to 1979. Operative risk factors for the registry have been detailed.P:" The occurrence of perioperative myocardial infarction has been evaluated also.v" Annual follow-up was obtained on all patients to assess vital status, quality of life, occurrence of cardiac events, medications being taken, and CABG or other operations having been performed. Follow-up electrocardiograms, death certificates, and discharge summaries of interval hospitalizations were obtained where appropriate.' Vital status was known in 99.8% of the patients at the termination of registry follow-up on Nov. 30, 1982. Routine postoperative cardiac catheterization for determination of progression of disease and graft patency were not required of patients in the CASS registry and were only performed when clinically indicated. For this reason, no statement can be made regarding graft patency in this group. However, the graft patency rate has been published for the randomized trial and the study as a whole.':" Differences between medical and surgical survival rates were tested by the log-rank statistic." Medically treated patients were defined as those who were treated nonoperatively or who had CABG late in their course. The number of days after enrollment within which 95% of the bypass procedures occurred or 90 days, whichever was longer, was determined for each hospital (average time, 4 months). Patients having CABG within this period for their hospital were excluded from the medical group. Patients with CABG after this period or with no CABG were considered to be medically treated. Exposure time for the medical group was counted from the average days to operation for the hospital where the patient was enrolled. Patients who died before this date were excluded from the analysis. This type of analysis removes the unfair bias of early deaths attributed to

CABG in patients with severe angina pectoris

5 15

Table II. Significant variables selected by the Cox analysis Covariate Left ventricular wall motion score (5-30) No. of associated noncardiac illnesses (0-8) No. of vessels diseased (0-3) Arrhythmia on electrocardiogram (0-1) Age Congestive heart failure history (0-1) Resting ST-segment depression (0-1) Smoking history (0-2) Female sex (0-1) Surgical therapy (0-1) Constant

Coefficient

p Value

0.1203

<0.0001

0.1943

<0.0001

0.4519 0.4959

<0.0001 0.001

0.0269 0.3322

0.003 0.006

0.3072

0.02

0.1842 0.2587 0.8401 -1.8659

0.02 0.09 <0.0001

medical therapy in patients who may have been assigned to surgical treatment." Patients in the medically treated group who underwent late CABG were not excluded from analysis with that group. Surgically treated patients were defined as those patients who had operation during the period when 95% of patients had CABG in that enrolling hospital. Exposure time was counted from the day of operation. A Cox regression analysis of survival was done to adjust the comparison of medical and surgical therapy for a linear combination of factors known to affect survival." First a linear model was constructed from thirty covariates excluding the therapy variable (Table I). The variable most related to survival was chosen first for the model. At subsequent steps, all remaining variables were considered for possible inclusion in the model. The variable selection process ended when no more variables could contribute statistically significant (p < 0.05) information to the model. The significance of surgical therapy was assessed by adding the therapy variable to the model and testing if its coefficient was significantly different from zero. The subsequent addition of the therapy variable modified the coefficients and probability values of the other variables. The selected variables with their estimated coefficients and probability values are given in Table II. Of the patients with Class III and IV angina pectoris, 1,971 (68%) had operation recorded as the therapy recommended by the enrolling hospital.' Of these, 212 declined operation. To control for the effect of unrecorded variables that would have made patients ineligible for operation, all survival analyses were repeated,

The Journal of Thoracic and Cardiovascular Surgery

5 1 6 Kaiser et al.

Table ill. Entry historical findings Angina Class I and II Medicine No. of patients Age (yrs) Mean SD Gender (%) Male Female Work status (%) Full time Part time Retired or quit Other Cigarette use (%) Present smoker Former smoker Never smoked History of (%): Prior myocardial infarction Hypertension Congestive failure Diabetes mellitus Stroke Peripheral vascular disease Heart disease in family Medications at entry (%) Nitroglycerin Long-acting nitrates Beta blocker Antiarrhythmics Digitalis Antihypertensive or diuretic agents Documented myocardial infarction (%)

745

I

Angina Class III and IV Operation 570

Medicine 936

I

Operation 1,958

50.7 8.0

51.3 8.0

53.2 7.5

53.4 7.4

90.5 9.5

90.9 9.1

80.2 19.8

85.1 * 14.9

67.5 5.2 20.4 6.9

67.9 5.1 20.9 6.1

48.5 8.6 33.9 9.0

55.8t 5.7 30.4 8.1

34.8 48.3 16.9

30.5 51.1 18.4

43.8 38.1 18.1

37.1 * 45.9 17.0

58.6 27.4 3.3 7.1 1.1 7.5 44.5

55.4 27.2 3.6 5.4 1.1 9.0 51.1:j:

57.8 38.9 2.5 12.6 3.4 14.4 46.3

53.6:j: 36.7 1.7 11.2 2.1:j: 11.8 45.6

49.7 43.4 51.7 8.3 6.7 11.4 52.7

59.3* 49.8:j: 58.4:j: 6.5 8.4 19.1* 50.3

82.5 62.7 62.7 6.7 12.3 29.3 48.5

81.8 66.7:j: 7l.8t 7.4 10.9 23.6* 47.3*

*p < 0.001. tp < 0.0001. :j:p < 0.05.

and the 1,759 patients who had the recommended CABG were compared to the 212 who did not. Results

The angiographic and clinical descriptors of each group are listed in Tables III to V. A greater number of surgically treated patients with Class III and IV angina pectoris were male and were employed on a full-time basis. At entry, these patients also used long-acting nitrates, beta blockers, and antihypertensive drugs more frequently than those in the medical group. The nonoperatively treated patients with Class III and IV angina pectoris had a greater frequency of smoking and history of prior myocardial infarction or stroke. In those surgical patients with less severe angina pectoris, there was a greater occurrence of familial ischemic heart disease.

This group used nitroglycerin, long-acting nitrates, beta blockers, and antihypertensive medications more frequently than those treated nonoperatively. There were no other historical statistical differences between these groups (Table III). Systolic and diastolic hypertension and Q-wave evidence of myocardial infarction were observed more frequently in patients with Class III and IV angina pectoris treated nonoperatively. The remaining laboratory and physical findings otherwise were similar in this group and in those patients with mild angina pectoris (Table IV). The number of involved vessels and the severityof the stenoses were greater in patients treated by CABG, regardless of the degree of angina pectoris. In those patients with more severe angina pectoris treated surgi-

Volume 89

CABG in patients with severe angina pectoris

Number 4 April, 1985

5 17

Table IV. Entry physical and laboratory findings Angina Class I and /I Medicine Systolic pressure (mm Hg) Mean SD ~160 mm Hg (%) Diastolic pressure (mm Hg) Mean SD ~IOO mm Hg (%) Resting ECG Q wave MI (%) ST depression (%) Normal (%) Serum cholesterol (mgjdl) Mean SD Cardiothoracic ratio (%) ~50%

<50%

I

129.9 18.6 9.3

Angina Class 11/ and IV Operation

Medicine

130.0 18.7 8.1

131.7 20.2 11.9

129.8* 19.8 9.3*

I

Operation

80.2 I 1.1 6.3

80.9 12.0 9.3*

81.0 12.7 9.5

80.0* 11.9 7.8

24.2 6.5 30.9

22.8 8.3 27.5

27.9 15.0 22.6

23.5* 16.6 22.8

237.9 45.1

235.8 47.6

238.0 60.6

234.6 49.5

19.4 80.6

21.3 78.7

29.8 70.2

29.3 70.4

Legend: SD. Standard deviation. ECG, Electrocardiogram. MI. Myocardial infarction. 'p < 0.05.

cally, left ventricular function was better when assessed by left ventricular wall motion score or ejection fraction. This difference in left ventricular function was not observed in those patients with mild angina pectoris (Table V). The overall operative mortality for the patients in the surgical group was 2.3%. The operative mortality for those patients with Class I and II angina pectoris was 1.2%; for those with Class III and IV angina pectoris it was 2.6% (p = 0.05). The operative mortality for patients with a normal ejection fraction (::::0.5) was 1.9%; whereas in those with an abnormal ejection fraction «0.5) it was 3.7% (p = 0.03). In patients with triple vessel disease the operative mortality was 1.9% for those with Class I and II angina pectoris and 2.9% for those with Class III and IV angina pectoris (p = 0.36). Analysis of operative mortality by further division into subgroups, including site, yielded numbers too small and confidence limits too large to be meaningful. The 5 year survival rate was excellent (::::93%), regardless of the number of involvedvesselsor treatment received in those patients with Class I and II angina pectoris and normal left ventricular function (ejection fraction ::::0.5) (Fig. 1). In those patients with severe angina pectoris and normal left ventricular function who were treated surgically, the survival rate was excellent, remaining at 92% or greater at 5 years, regardless of the number of stenotic vessels. In contrast, in the patients

treated nonoperatively, the 5"year survival rate progressively decreased as the number of involved vessels increased (one vessel disease 95%, two vessel disease 83%, three vessel disease 74%). This difference between treatment methods was statistically significant in those patients with severe angina pectoris and triple vessel disease (Fig. 1). The 5 year survival rate of patients with impaired left ventricular function (ejection fraction <0.5) was poorer than that of patients with normal ejection fraction, regardless of the method of treatment or the number of stenotic vessels (Figs 1 and 2). The 5 year survival rate was greater in those patients with mild angina pectoris, who were treated surgically, being 86%, 92%, and 89% for one, two, and three vessel disease, respectively. The comparable 5 year survival rates were 76%, 88%, and 82% for one, two, and three vessel disease treated nonoperatively. These differences were not statistically significant (Fig. 2). The 5 year survival rate of patients with severe angina pectoris and impaired left ventricular function who underwent CABG was consistently greater than that of patients treated nonoperatively, being 94%, 87%, and 82% for one, two, and three vessel disease, respectively. Comparable figures for patients treated nonoperatively were 85%, 80%, and 52%. This trend increased as the number of stenotic vessels increased, and it was statistically significant in those patients with triple vessel

The Journal of Thoracic and Cardiovascular Surgery

5 1 8 Kaiser et al.

Table V. Entry angiographic findings Angina Class I and II Medicine Diseased vessels (2:70% stenosis) (%) One vessel Two vessels Three vessels LMCA stenosis (500/0-69%) (%) Proximal LAD stenosis (2:70%) (%) LV score (%) 5 (normal) 6-10 (mild impairment) 11-15 (moderate impairment) 2: 16 (severe impairment) Ejection fraction 2:0.50 0.35-0.49 s;0.34 L VEDP (mm Hg) Mean SD

Angina Class 11/ and IV Operation

Medicine

40.3 36.8 23.0 2.3 27.4

20.7' 33.2 46.1 9.1' 46.1 '

35.7 33.3 31.0 4.1 30.8

18.5' 32.6 48.9 5.8t 45.1'

41.6 42.7 13.5 2.2

41.5 40.4 15.9 2.2

33.2 39.0 20.2 7.6

37.6' 39.8 18.7 3.9

81.0 14.9 4.1

80.9 16.4 2.7

72.1 22.1 5.8

79.5+ 17.1 3.5

12.46 6.3

11.9 5.5

12.8 6.8

13.0 6.7

I

I

Operation

Legend: LMCA, Left main coronary artery. LAD, Left anterior descending. LV, Left ventricular.

"p < 0.0001. tp < 0.05. :j:p <0.001.

disease (Fig. 2). The 5 year survival rates of both the medically and surgically' treated patients were consistently lower in those with severe angina pectoris and impaired left ventricular function than in comparable groups of patients with severe angina pectoris and normal left ventricular function (Figs. 1 and 2). The effect of operation on survival was adjusted for the effects of the variables shown in Table II by the Cox method of survival analysis. In the presence of the effects of these variables, the operation variable was still highly significant (p < 0.(001). The effect of CABG was also significant when the analysis was restricted to patients for whom operation was recommended by the enrolling hospital (p < 0.(001). Discussion This observational study demonstrates that clinical factors, especially the degree of angina pectoris, influence the survival of patients with ischemic heart disease. Furthermore, in certain subsets of patients with severe angina pectoris, namely those with triple vessel disease, CABG favorably influences late survival. This effect of surgical treatment was not observed in patients with single or double vessel disease or in patients with mild angina pectoris.

The angiographic pattern of coronary arterial lesions has become a strong influence in the choice of the method of treatment of ischemic heart disease. Because the medical community and the lay public have assumed that extensive disease portends a poorer prognosis, the more extensive the disease the more likely is CABG to be advised and accepted. This effect of a conscious choice is borne out in the present study, as the surgically treated patients at baseline had a significantly greater degree of vessel involvement than those in the medical group regardless of the angina pectoris class. That this method of treatment selection is no better than random assignment in the management of patients with mild angina pectoris was illustrated in the comparison of the randomized and randomizable groups reported previously." However, the addition of the clinical factor of more severe angina pectoris to the angiographic pattern, as emphasized in this report, provides additional information and should aid in selection of appropriate therapy. This effect of clinical features has been noted in the Veterans Administration Cooperative Study for Coronary Arterial Occlusive Disease, in which four risk factors were shown to divide patients into terciles of varying risk.v" These four clinical factors in order of

Volume 89

CABG in patients with severe angina pectoris

Number 4 April, 1985

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Fig. 1. Five-year survival curves for patients with normal left ventricular function (EF 2: 0.5) in subgroups according to severity of angina pectoris and number of diseased vessels. Patients with Class I-II angina pectoris: A, One vesseldisease. B, Two vessel disease. C, Three vesseldisease. Patients with Class III-IV angina pectoris: D. One vessel disease. E. Two vessel disease. F, Three vessel disease.

decreasing importance were (1) ST-segment depression on the resting electrocardiogram, (2) history of myocardial infarction, (3) history of hypertension, and (4) New York Heart Association (NYHA) Functional Classification III or IV. The patients with only one risk factor

present were clinically at low risk, whereas those with two or more risk factors, especially the more significant factor of electrocardiographic ST-segment depression, had a greater risk for death." The number of vessels involved was evaluated by taking into consideration the

The Journal of Thoracic and Cardiovascular Surgery

5 2 0 Kaiser et al.

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82 52

25.019

Fig. 2. Five-year survival curves for patients with abnormal left ventricular function (EF < 0.5) in subgroups according to severity of angina pectoris and number of diseased vessels. Patients with Class I-II angina pectoris: A, One vessel disease. B, Two vessel disease. C, Three vessel disease. Patients with Class III-IV angina pectoris: D, One vessel disease. E, Two vessel disease. F, Three vessel disease.

variable risk terciles. By this technique, the number of involved vessels was found to be an independent risk factor." Combining left ventricular function with the number of diseased vessels reduced but did not eliminate the amount of independent information obtained."

The present study evaluates one of these risk factors, the degree of angina pectoris. In the Veterans Administration cooperative study, 57% of the patients had NYHA Class III or IV angina pectoris." The Veterans Administration study revealed a statistically significant

Volume 89 Number 4 April, 1985

improvement in late survival in patients with three vessel disease in the high-risk tercile treated surgically.' The European Coronary Surgery Study revealed improved survival in patients with three vessel disease treated with CABG. Class III angina pectoris was present in 42% of their patients, according to a conversation with E. Varnauskas on April 26, 1984. The remaining patients in that study (58%) had Class I and II angina pectoris. Patients with NYHA Class IV angina pectoris were excluded by design from randomization in this cooperative study. The CASS randomized trial did not show improved survival following CABG in patients with mild angina pectoris.' By definition, these patients were all in CCS Class 0, I, or II.' Identical findings were reported in the similar but larger CASS randomizable group previously reported and included in this study for comparison." There were suggestive trends of improved survival in patients with three vessel disease, abnormal left ventricular function, and mild angina pectoris treated surgically, in the randomized trial, but these differences were not statistically significant. Both the randomized and randomizable patients, by definition, had less than Class III angina pectoris. This difference in the degree of angina pectoris encountered in the patients of the three randomized studies may explain some of the differences noted in late survival of patients with ischemic heart disease treated operatively or nonoperatively. The excellent late survival of patients treated nonoperatively in the CASS randomized trial may have been substantially affected by clinical factors. J By the methods of analysis used in this study, patients undergoing CABG within the specified time at each site were placed in the surgical group. Patients receiving nonoperative therapy, but undergoing CABG later than this entry period, were maintained in the nonoperatively treated group. This method of analysis may have improved the survival rate of these nonoperatively treated patients. However, with the maintenance of these operatively treated patients in the nonoperative group, CABG, applied early in the patient's course, still exerted a profound influence upon the late survival in those patients with triple vessel disease and severe angina pectoris. In this report, patients with Class III and IV angina pectoris were selected in a manner similar to the selection method for those considered potential candidates for randomization with the exception of more severe angina pectoris. For this reason, patients in this study were included only from the 11 randomizing sites. Various factors have been assessed to delineate any possible known differences between these patients with Class III and IV angina pectoris and those with mild

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angina pectoris to whom they were compared. When patients with Class III angina pectoris were compared to those with Class IV angina pectoris, there was no difference in survival; hence, these groups were combined for analysis in this report. The difference in survival between groups also occurred when the data were examined in only patients for whom CABG was the recommended therapy. After adjustments for all these known factors, the difference between operative and nonoperative treatment in patients with severe angina pectoris and three vessel disease remained. Since this is a nonrandomized study, it is still possible that undetected factors might be responsible for these observed differences between treatment groups. The current observations strongly confirm the importance of clinical factors in assessing the effect of management of patients with ischemic heart disease. Additionally, this study emphasizes that angiographic factors, while important in determining the course of patients with ischemic heart disease, are not the only modifying elements of their systemic disease. Lastly, this observational study does not refute the findings of the CASS randomized trial of mildly symptomatic patients. Rather, it strongly supports the findings of that cooperative study and emphasizes the importance of understanding the entire spectrum of ischemic heart disease. In managing patients with ischemic heart disease, one must consider where the individual patient fits in this clinical spectrum and recommend treatment accordingly. REFERENCES CASS Principal Investigators and their Associates: Coronary Artery Surgery Study (CASS): A randomized trial of coronary artery bypass surgery. Survival Data. Circulation 68:939-950, 1983 2 CASS Principal Investigators and their Associates: Myocardial infarction and mortality in the Coronary Artery Surgery Study (CASS) randomized trial. N Engl J Med 310:750-758,1984 3 European Coronary Surgery Study Group: Long-term results of prospective randomized study of coronary artery bypass surgery in stable angina pectoris. Lancet 2:11731180, 1982 4 Takaro T, Hultgren HN, Detre KM, Peduzzi P: The Veterans Administration Cooperative Study of Stable Angina. Current status. Circulation 65:Suppl 2:60-67, 1982 5 Principal Investigators of CASS and their Associates (Killip T, editor, FisherLD, MockMB, associate editors): National Heart, Lung and Blood Institute Coronary Artery Surgery Study (CASS). Circulation 63:Suppl 1:1-81, 1981 6 CASS Principal Investigators and their Associates: Coronary Artery Surgery Study (CASS): A randomized trial of coronary artery bypass surgery. Quality of life in

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patients randomly assigned to treatment groups. Circulation 68:951-960, 1983 Campeau L: Grading of angina pectoris. Circulation 54:522-523, 1976 CASS Principal Investigators and their Associates: Comparability of entry characteristics and survival in randomized patients and nonrandomized patients meeting randomization criteria. J Am Coll Cardiol 3:114-128, 1984 Berger RL, Davis KB, Kaiser GC, Foster ED, Hammond GL, Tong TGL, Kennedy JW, Sheffield T, Ringqvist I, Wiens RD, Chaitman BR, Mock M: Preservation of the myocardium during coronary artery bypass grafting. Circulation 64:Suppl 2:61-66, 1981 Kennedy, JW, Kaiser GC, Fisher LD, Maynard C, Fritz JK, Myers W, Mudd JG, Ryan TJ, Coggin J: Multivariate discriminant analysis of the clinical and angiographic predictors of operative mortality from the Collaborative Study in Coronary Artery Surgery (CASS). J THoRAc CARDIOVASC SURG 80:876-887, 1980 Kennedy JW, Kaiser GC, Fisher LD, Fritz JK, Myers W, Mudd JG, Ryan TJ: Clinical and angiographic predictors of operative mortality from the Collaborative Study in Coronary Artery Surgery (CASS). Circulation 63:793802, 1981 Fisher LD, Kennedy JW, Davis KB, Maynard C, Fritz JK, Kaiser GC, Myers WO, and the Participating CASS Clinics: Association of sex, physical size, and operative mortality after coronary artery bypassin Coronary Artery Surgery Study (CASS). J THoRAc CARDIOVASC SURG 84:334·341,1982 Chaitman BR, Alderman -EL, Sheffield LT, Tong T, Fisher L, Mock MB, Weins RD, Kaiser GC, Roitman D, Berger R, Gersh B, Schaff H, Bourassa MG, KillipT, and the Participating CASS Medical Centers: Use of survival analysis to determine the clinical significance of new Q waves after coronary bypass surgery. Circulation 67:302309, 1983 Kalbfleish JD, Prentice RL: The Statistical Analysis of Failure Time Data, New York, 1980,John Wiley & Sons, Inc. Chaitman BR, Davis K, Fisher LD, Bourassa M, Mock MB, Lesperance J, Rogers WJ, Tyras DH, Judkins MP, Ringqvist I, Killip T: A life table and Cox regression analysis of patients with combined proximal left anterior descending and proximal left circumflex coronary artery disease. Non-left main equivalent lesions (CASS). Circulation 68:1163-1170, 1983 Detre K, Peduzzi P, Murphy M, Hultgren H, Thomsen J, Oberman A, Takaro T, and the Veterans Administration CooperativeStudy Group for Surgery for Coronary Arterial Occlusive Disease: Effect of bypasssurgery on survival in patients in low- and high-risk subgroups delineated by use of simple clinicalvariables. Circulation 63:1329-1338, 1981 Detre K, Hultgren H, Takaro T: Veterans Administration CooperativeStudy for Coronary Artery Occlusive Disease. III. Methods and baseline characteristics, including expe-

rience with medical treatment. Am J CardioI40:212-225, 1977

Cooperating clinical sites

University of Alabama in Birmingham' William J. Rogers, M.D.,· Richard O. Russell, Jr., M.D., Albert Oberman, M.D., and Nicholas T. Kouchoukos, M.D. Albany Medical College: Eric D. Foster, M.D.,· Julio A. Sosa, M.D.,· Joseph T. Doyle, M.D., Martin F. McKneally, M.D., Joseph B. McIlduff, M.D., Harry Odabashian, M.D., and Thomas M. Older, M.D. Boston University: Thomas Ryan, M.D.,· David Faxon, M.D., Laura Wexler, M.D., Robert L. Berger, M.D., Donald Weiner, M.D., and Carolyn H. McCabe, B.S. Loma Linda University: Melvin P. Judkins, M.D.,· and Joan Coggin, M.D.· Marshfield Medical Foundation, Inc. and Marshfield Clinic: William Myers, M.D.,· Richard D. Sautter, M.D.,· John N. Browell, M.D., Dieter M. Voss, M.D., and Robert D. Carlson, M.D. Massachusetts General Hospital: J. Warren Harthorne, M.D.,· W. Gerald Austen, M.D.,· Robert Dinsmore, M.D., Frederick Levine, M.D., and John McDermott, M.D. Mayo Clinic and Mayo Foundation: Robert L. Frye, M.D.,· Bernard Gersh, M.D., David R. Holmes, M.D., Michael B. Mock, M.D., Hartzell Schaff, M.D., Ronald E. Vlietstra, M.D., and Lloyd Fisher, Ph.D. Miami Heart Institute: Arthur J. Gosselin, M.D.,· Parry B. Larsen, M.D., and Paul Swaye, M.D. Montreal Heart Institute: Martial G. Bourassa, M.D.,· Bernard R. Chaitman, M.D., Claude Goulet, M.D., and Jacques Lesperance, M.D. New York University: Ephraim Glassman, M.D.,· and Michael Schloss, M.D. St. Louis University: George C. Kaiser, M.D.,· J. Gerard Mudd, M.D.,· Robert D. Wiens, M.D., Hendrick B. Barner, M.D., John E. Codd, M.D., Denis H. Tyras, M.D., and Vallee L. Willman, M.D. St. Luke's Hospital Center: Harvey G. Kemp, Jr., M.D.,· and Airlie Cameron, M.D. Stanford University: Edwin Alderman, M.D.,· Francis H. Koch, M.D., Paul R. Cipriano, M.D., James F. Silverman, M.D., and Edward B. Stinson, M.D. Medical College of Wisconsin: Felix Tristani, M.D.,· Harold L. Brooks, M.D.,· and Robert J. Flemma, M.D. Yale University: Lawrence S. Cohen, M.D.,· Rene Langou, M.D., Alexander S. Geha, M.D., Graeme L. Hammond, M.D., and Richard K. Shaw, M.D. Central Electrocardiographic Laboratory. University of Alabama: L. Thomas Sheffield, M.D.,· David Roitman, M.D., and Carol Troxell, B.S. Coordinating Center. University of Washington: *Principal Investigator.

Volume 89 Number 4 April. 1985

Kathryn Davis, Ph.D., * Mary Jo Gillespie, M.S., J. Ward Kennedy, M.D., and Richard Kronmal, Ph.D. Chairman of the Steering Committee: Thomas Killip, M.D., Henry Ford Hospital. National Heart, Lung, and Blood Institute: Eugene R. Passamani, M.D., Thomas Robertson, M.D., and Charles Hollingsworth, Ph.D.

Discussion DR. RICHARD P. ANDERSON Seattle. Wash.

In 1973 a small group of cardiac surgeons, cardiologists, and biostatisticians met at the offices of the National Heart Lung, and Blood Institute in response to a Request for Proposal concerning coronary artery disease. From that meeting grew the Coronary Artery Surgery Study-CASS. Now, II years, 25,000 patients 24 million dollars, and over 60 publications later, it is useful to recall the temper of those times. Enthusiasm for coronary bypass grafting was sweeping the country. Many surgeons approached the top of their learning curves, and operative mortality rates had fallen to previously unheard of low levels. As usual, reports of nonoperatively (that is, medically) treated patients were scarce, and the efficacy of beta-blocker therapy was not fully appreciated. No reports of randomized medical versus surgical therapy then existed, but few surgeons, I think, doubted that myocardial revascularization would prolong life and prevent myocardial infarction, just as it demonstrably relieved angina. During the next 2 years, CASS evolved into a multicenter patient registry and a randomized controlled trial. A tremendous amount of ~seful information has come from the nonrandomized registry In recent years. These reports are distinguished by the large nu~ber of patients who have been enrolled, by the many vanables that have been recorded, and by the very high quality of the data analysis that has been provided. However, it is the randomized studies that have generated the widest interest. The results of the randomized study, ostensibly showing no difference between medical and surgical therapy, were first reported in November, 1983, in Circulation. The fact that 25% of the medical patients crossed over to surgical treatment created a serious problem for the investigators. They chose to address this problem by analyzing their data on the basis of treatment assigned rather than treatment :eceived. After making a lengthy justification for this strategy In the manuscript, they claimed that censoring of the data at the time of crossover did not change the results, although neither their method of censoring nor the raw data were recorded. However, they acknowledged that, "CASS cannot definitively test the true contrast in outcome between medical and surgical therapy." Adherence to a standard that made good statistical sense made nonsense of the original question, namely, which was better, medical or surgical therapy? This sort of ambiguity really did not do very much to excite the interest of the lay press, which gave the story very little play 'Principal Investigator.

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and simply awaited a better day. That came on March 22 1984, when the combined results of myocardial infarction and mortality were published in The New England Journal of Medicine. These results purported to show no difference in treatment results between medicine and operation. No longer bound by the rigorous editorial supervision of Circulation, the authors dismissed the whole question of analysis by "intentto-treat" in four sentences, and they concluded, "As compared with medical therapy, coronary bypass appears neither to prolong life nor to prevent myocardial infarction in patients who have mild angina, or who are asymptomatic after myocardial infarction in the 5-year period after coronary arteriography. " That is quite a departure from, "CASS cannot definitively test the true contrast in outcome," and one that certainly was not lost on the lay press. The headlines I saw that week said "Bypass Surgery Fails to Prolong Survival," or somethin~ quite similar. A number of my patients were confused, and some were badly misled by newspaper accounts of the study. I hope that this can be avoided in the future. I believe it can if the CASS principal investigators will give as much attention to the dissemination of their information to the general public as they do to the medical community. Since these investigators have elected to analyze their data by intent-to-treat strategy in order to preserve the integrity of the randomization process, they should especially forebear unqualified conclusions either in professional or in lay publications. ' Dr. Kaiser's report is welcome news to those who believe that coronary bypass grafting prolongs survival. He has shown this clearly for patients with three vessel disease. He has concluded that clinical factors, for example, the severity of angina, modify the clinical course of the disease, just as do angiographic factors, such as extent of disease or ventricular function. His manuscript, however, concludes with the statement that these findings support the findings of the randomized study by emphasizing the different aspects of the spectrum of ischemic heart disease. I would like to suggest a different conclusion. Suppose that ~he severity ~f symptoms is related to anatomic and physiological progression of disease, a time-related variable that right now cannot be measured with accuracy. In the randomized study, when symptoms progressed, patients crossed over to surgical therapy. Operation provided an improved prognosis, but this was credited to medical therapy because of the intent-to-treat strategy. Thus, the medical group was protected from the adverse consequences of progression of disease by bypass grafting, but the outcome was credited to medical therapy. Therefore, I question whether this study fully supports the conclusions of the randomized trial, and I would ask Dr. Kaiser whether or not he finds this argument sufficiently compelling to call for a reexamination of the data of the randomized trial, and especially the issue of crossovers. I have two final questions. First, I wonder if the CASS results have any influence in your institution, or in the other participating institutions, on the introduction of percutaneous transluminal coronary angioplasty (PTCA)? In other words, have patients with mild angina been denied PTCA because

5 2 4 Kaiser et al.

everybody believes those results? Also, is the National Heart, Lung, and Blood Institute interested in instituting a trial of PTCA? Certainly, I would call for such a trial. I think it is long overdue. However, if it is done, I think we are going to have this problem of crossover to surgical therapy once again. Despite my criticisms, I would like to commend Dr. Kaiser and his co-authors for this report. This observational study is certainly one of the finest we are likely to see on this particular subject. The results are of great importance. DR. KAISER (Closing) Dr. Anderson and I have discussed the problem of crossovers many times. This is a criticism of almost every randomized trial. How one handles crossovers may convert a randomized study into an observational study, thereby losing the power of randomization, which has as its greatest strength the ability to equalize unknown and unmeasurable factors in each group. From the statistical standpoint, if one wants to benefit from the power of randomization, one needs to adhere to the study design. Whether it is clinically appropriate or not is philosophical. The Veterans Administration cooperative study did not show any difference between treatment groups of patients with three vessel disease initially. It did show a difference between groups, however, when the data from three hospitals with the highest operative mortality were eliminated from analysis. It also showed a difference when the patients were graded according to risk terciles. With either of these techniques, their study is no longer a randomized study, but an observational one. That fact does not mean-that those data are invalid but rather, no longer being randomized, the study loses the strength of randomization. I think this is the only issue. It is not whether CABG is good or bad; it is whether one wants to maintain the power of randomization.

The Journal of Thoracic and Cardiovascular Surgery

At the time of the press conference announcing the initial results of the CASS randomized trial, unfortunately, a terrorist had just driven a truckload of explosives into the barracks of our marines in Lebanon. That event dominated the headlines and rightfully so. Subsequently, with publication of the myocardial infarction data of the randomized trial, more newspaper coverage occurred. We believe that this report does support the CASS randomized trial in that it covers a group of patients not included in the CASS randomized trial. The data that were included in the CASS randomized trial are of mildly symptomatic patients. This is a small subgroup of patients in the entire spectrum of patients with ischemic heart disease. One cannot take the information from that small subgroup of patients and use it to prognosticate about the entire spectrum of patients with ischemic heart disease. That point is supported by this presentation. The fact that randomization was not responsiblefor the lack of observed survival differences in the randomized trial is supported by the results of the mildly symptomatic patients included in this study and previouslypublished as the randomizable patients. In these patients, treatment method was selected rather than randomly assigned. Physician or patient selection of the type of treatment still results in no differences in late survival between treatment groups in these mildly symptomatic patients, however. Many of us were concerned about possiblemisinterpretation of the data from the CASS randomized trial. Therefore, we believed it was important to develop these data and present them before a national society, so that they would receive appropriate airing, not only by their presentation but also in their subsequent publication. I, too, am concerned about PTCA. I know of no plans for a national cooperative randomized PTCA trial.