- Email: [email protected]
Unstable angina pectoris: A randomized study of patients treated medically and surgically
REPORTS ON THERAPY
Unstable Angina Pectoris: A Randomized Study of Patients Treated Medically and Surgically
BILLY PUGH, MD MELVIN R. PLATT, MD, FACC LAWRENCE J. MILLS, MD, FACC DONALD CRUMBO, MD LAWRENCE R. POLINER, MD GEORGE C. CURRY, MD GUNNAR C. BLOMQVIST, MD, PhD, FACC ROBERT W. PARKEY, MD, FACC L. MAXIMILIAN JAMES
BUJA,
T. WILLERSON,
MD, MD,
FACC FACC’
Dallas, Texas
Fifty patients with the clinical syndrome of unstable angina pectoris were evaluated. Twenty-seven were randomized into medical or surgical treatment groups and subsequently followed up. the results of the study reveal that: (1) there is approximately a 16 percent incidence rate of signiffcant left main coronary artery disease in patients with this entity at our institution; (2) 10 percent of patients do not have angiographically significant coronary artery disease; (3) pain relief is better in the surgically treated patients, but the 1 l/2 year survival rate is not significantly different between the groups; (4) 50 percent of the medically treated patients again had the syndrome of unstable angina pectoris in the initial few months of the follow-up period; (5) the operative and late postoperative mortality rate in patients presenting with unstable angina pectoris and left main coronary artery disease in this small group of patients was 43 percent; and (6) four of six patients with this syndrome whose condition was deemed inoperable and who were not randomized died within the subsequent few months.
During the past few years, unstable angina pectoris has gained acceptance among cardiologists and cardiovascular surgeons as a distinct syndrome within the clinical spectrum of ischemic heart disease, bridging the gap between chronic stable angina and acute myocardial infarction. Efforts have been directed toward defining unstable angina precisely, determining the cardiac hemodynamic and angiographic factors responsible for the chest pain and assessing its initial and long-term significance.1-4 Proper treatment for unstable angina is not clear. It is generally believed that the prompt recognition, hospitalization and aggressive medical therapy of patients with unstable angina will reduce early mortality, but whether further reduction in the incidence of nonfatal myocardial infarction and mortality can be accomplished with coronary revascularization is controversial. To help resolve the issue, a study was begun at Parkland Memorial From the Departments of Internal Medicine (Cardiac Unit), Surgery, Radiology and Pathology at the University of Texas (Southwestern) Medical School, Dallas, Texas. This work was supported in part by Grant HL-17669 from the lschemic Heart Disease Specialized Center of Research, National Institutes of Health, Bethesda, Maryland: the Southwestern Medical Foundation and the Harry S. Moss Heart Fund. Manuscript received September 6, 1977; revised manuscript received December 12, 1977. Established Investigator of the American Heart Association, Dallas, Texas. Address for reprints: James T. Willerson, MD. lschemic Heart Center, L5 134, University of Texas Health Science Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235. l
Hospital in January 1974. Patients admitted to the coronary care unit who met our clinical criteria for unstable angina were studied with cardiac catheterization and, if found suitable, were randomized into medically or surgically treated groups. Follow-up studies have continued. In this paper we report our initial findings, through December 1976 (36 months).
Case Material
and Protocol
Criteria for unstable angina: Patients were included in the study if they were admitted with a chest pain pattern judged to represent unstable angina by the attending staff physician and, during the initial phase of hospitalization, did not demonstrate evidence of myocardial infarction by electrocardiographic and enzymatic criteria. Three patterns of pain were considered consistent with unstable angina: (1) chest pain with effort, of recent onset (within the previous 4 weeks) and progressive in nature, being provoked with less exertion, becoming more intense or persisting longer; (2) chest pain with effort, progressive in nature
June 1978
The American Journal ol CARDIOLOGY
Volume 41
1291
UNSTABLE ANGINA PECTORIS-PUGH ET AL.
and occurring in a patient with chronic stable angina or previous myocardial infarction; and (3) chest pain at rest, occurring without obvious provocation, lasting longer than 15 minutes and intense and recurrent. The study excluded patients whose pain was clearly related to a precipitating hemodynamic factor, such as a prolonged cardiac arrhythmia or severe hypertension, and whose pain promptly abated with correction of the initial factor.
TABLE I lnitlal Assessment of 50 Patients With Unstable Angina Pectoris Patients (no.) Pain pattern Type 1 Type II Type Ill Known prior myocardial infarct Yes No ggmT~-PYP mvocardial scintiarams Negative _ 2+ Coronary artery disease None Single vessel (RCA or LC,) LAD, 2 or 3 vessel LMCA Left ventricular ejection fraction Normal (X0%) Reduced (30X10%) Greatly reduced (<30%)
Acute myocardial infarction was excluded by standard criteria: (1) The electrocardiogram must not demonstrate new
Q wave formation or prominent R wave loss. Previous electrocardiograms were utilized for comparison when available. (2) Serum enzyme levels (creatine kinase, serum glutamic oxaloacetic transaminase and lactic dehydrogenase) must be normal on admission and not rise more than 50 percent of the initial value during subsequent hospitalization; the creatine kinase-B isoenzyme determined either with column separation and spectrophotometric measurements5 or with radioimmunoassays has also been utilized to exclude myocardial infarction at our institution for the past 1 l/2 years. (3) Myocardial scintigraphy using technetium-99m stannous pyrophosphate performed 24 to 48 hours after admission must not demonstrate a localized area of intense uptake (3 to 4+) characteristic of transmural infarction.7 Technetium-99m stannous pyrophosphate myocardial scintigrams graded 2+ or less did not preclude proceeding with cardiac catheterization, provided the electrocardiogram and cardiac enzymes did not demonstrate conclusive evidence5 of infarction, and that the positive scintigrams remained unchanged in intensity and localization at the time of repeat testing (generally over a 2 week period). We do regard such “2+” myocardial scintigrams as demonstrating severe cell injury, but without any change in intensity or regional myocardial localization over a 10 to 14 day period, it is more likely that the myocardial injury is chronic rather than acute.7-11 Protocol: All patients admitted to the coronary care unit during the 36 month period with one of the previously described patterns of chest pain were considered candidates for study. They were cared for in a standard manner; anticoagulant therapy was not given. When a myocardial infarct was excluded, medical therapy designed to prevent further episodes of myocardial ischemia was begun; typically this included oral administration of isosorbide dinitrate, 5 to 10 mg every 4 hours, and propranolol, 20 to 60 mg every 6 hours. Initial doses of these medications were increased as necessary to produce the desired clinical effect, avoiding hypotension and profound bradycardia. When the chest pain was relieved or markedly reduced, the nature of the study was explained to each patient and cardiac catheterization recommended. Verbal and written informed consent were subsequently obtained for cardiac catheterization and for surgery when the latter was performed. In the few patients whose severe chest pain persisted despite aggressive medical therapy, intraaortic balloon circulatory assistance was utilized to help control pain before cardiac catheterization. These patients did not enter the randomization process of the study but were instead treated surgically when their coronary anatomy and ventricular function permitted. Fifty patients consented to being included in this evaluation (Table I). There were 27 men and 23 women, ranging in age from 33 to 68 years (mean 52). All underwent left heart catheterization and selective coronary angiography with the Judkins or Sones technique, usually during the first 2 weeks of hospitalization. Ventricular function was assessed with angiographic dye injection and calculation of the left ventricular ejection fraction using standard geometric computations from the right anterior oblique projection. Significant
1292
June 1978
The American Journal of CARDIOLOGY
17 21 12
;: 31 19
; 32
a 40 2”
LAD = left anterior descending coronary artery; LC, = left circumflex coronary artery; LMCA = left main coronary artery; ggmT~ PYP = technetium-99m stannous pyrophosphate; RCA = right coronary artery.
disease of a coronary vessel was judged present if a 50 percent or greater segmental reduction in luminal diameter was found in the main left coronary artery or a 70 percent or greater luminai narrowing was found in the remaining coronary arteries. After catheterization, patients were returned to the coronary care unit, and medical therapy was resumed. Randomized groups: Patients were assigned randomly to medical or surgical treatment groups if they had significant disease of the left anterior descending coronary artery or significant two or three vessel disease, with left ventricular ejection fraction greater than 30 percent and left ventricular end-diastolic pressure before left ventricular angiography less than 18 mm Hg and if they were considered to have large enough distal vessels beyond regions of significant coronary obstructions to be suitable for revascularization. The randomization process was performed blindly by drawing a label from a partially covered box. Patients were excluded from the randomization process if they had insignificant coronary artery disease, isolated significant disease of the right or circumflex coronary artery or were judged unsuitable for revascularization because of greatly reduced ventricular function (left ventricular ejection fraction less than 30 percent) or severe distal coronary disease, or both. All such patients were treated medically. Patients with significant disease of the left main coronary artery were not randomized but were treated surgically.
Results Results of Initial Evaluation
Clinical features (Table I): Chest pain patterns: Of the 50 patients, 17 presented with new onset of progressive pain (type I), 21 with progressive pain in the setting of chronic stable angina or a prior myocardial infarct (type II) and 12 with recurrent pain at rest (type III). Sixteen of the 33 patients in the latter two groups had a known previous myocardial infarct.
Volume 41
UNSTABLE ANGINA PECTORIS-PUGH ET AL.
TABLE II
TABLE Ill
Comparisons of 14 Medically and 13 Surgically Treated Patients With Unstable Angina Pectoris
Results of Randomization in 27 Patients
Sex Mean age (yr) Pain pattern Type 1 Type II Type Ill Known prior myocardial Yes
Medically Treated Group
Surgically Treated Group
10M. 4P 49
6M, 7f= 52
: 3
5 3
:
t
10 4
9 4
: 4
s 7
12 2
11 2
Medically Treated Group
infarct
sg”fk-PYP myocardial scintigrams Negative 2+ Distribution of significant coronary disease LAD 2 vessel 3 vessel Left ventricular ejection fraction Normal (X0%) Reduced (30-50%)
LAD = left anterior descending coronary technetium-99m stannous pyrophosphate.
artery;
Patients (no.) Mean follow-up (mo) Nonfatal new Ml
14 18.9 0
Death (no. of patients) Clinical status (no. of patients) Pain-free Chronic angina Severe angina (operation)
1
1
Surgically Treated Group 13 17.8 t (preop) : (postop)
7 5
: (1 death)
Ml = myocardial infarction.
gsmT~-PYP =
tent of cardiac disease for these patients are outlined in Table II. The two groups are statistically similar with respect to sex and age, history of previous myocardial infarction, results of technetium-99m stannous pyrophosphate myocardial scintigrams, extent of coronary disease and left ventricular ejection fractions using Chi square analysis (P >0.2). Current Results of Randomization
Myocardial scintigraphy:
Nineteen patients, slightly more than one third of the total, demonstrated a technetium-99m stannous pyrophosphate scintigram graded 2+ (without definite electrocardiographic or enzymatic evidence of recent acute myocardial infarction). The remaining 31 patients had a negative scintigram. Cardiac catheterization data: The distribution of coronary disease was as follows in these patients: (1) no significant coronary artery disease (7 patients); (2) significant disease limited to the right or left circumflex coronary artery (3 patients); (3) significant disease of the left anterior descending coronary artery or two or three vessel disease without disease of the left main coronary artery, or both (32 patients); (4) significant two or three vessel coronary artery disease and significant disease of the left main coronary artery (8 patients). None of the patients with left main disease in this study had that as the sole significant coronary arterial lesion. Four patients were deemed unsuitable for operation because of severe disease of distal branches of two or three coronary arteries. Left ventricular ejection fraction (Table I) was normal (more than 50 percent) in 40 patients, reduced (30 to 50 percent) in 8 patients and greatly reduced (less than 30 percent) in 2 patients. The latter two patients had significant coronary artery disease but were considered unsuitable for operation because of a greatly reduced left ventricular ejection fraction. Therefore, in the 50 patients initially evaluated, 27 could be randomly placed into medical and surgical treatment groups. Randomization: Fourteen patients were randomized to medical therapy and 13 to surgical therapy. Biographical details, results of clinical evaluation and ex-
Medically treated group: After randomization to medical therapy, all 14 patients were discharged on antianginal medication considered sufficient to control their chest pain. All patients were treated with oral isosorbide dinitrate (mean dosage 40 mg/day), and 12 of the 14 were also treated with propranolol (mean dosage 140 mg/day). Two patients did not require propranolol in addition to isordil for symptomatic relief of angina. There were no in-hospital myocardial infarcts or deaths in the group (Table III). The mean follow-up time has been 18.9 months, and six patients have been followed up for more than 24 months. Mortality and morbidity: Eighteen months after initial randomization, one patient had an acute myocardial infarction and died on the 2nd hospital day with cardiogenic shock. No further patients have had acute myocardial infarcts among the 12 surviving patients. Clinical status: One patient is now pain-free on medication and has resumed full-time employment. Seven patients have chronic stable angina, and medical therapy has been continued. However, five patients had recurrence of severe angina pectoris 1 week to 6 months (mean 2 months) after randomization while on a program of medical therapy considered optimal. All were rehospitalized, were found to have had no new myocardial infarct and subsequently received surgical coronary revascularization. One of the five died in the immediate postoperative period. The remaining four survived the operation and are currently free of angina. Two of the four are men who have returned to full-time work. Exercise testing: Four of the eight patients remaining in the medically treated group were able to undergo exercise testing during the follow-up period. The remaining four patients were limited by leg pain with
June 1978
The American Journal of CARDIOLOGY
Volume 41
1293
UNSTABLE ANGINA PECTORIS-PUGH ET AL.
TABLE
IV
Exercise Testina After Medical or Suraical Treatment
lschemic S-T Segment Change
Patients (no.)
Test Limitation
2
Angina
Yes
2
Fatigue
No
1
Angina
Yes
6
Fatigue
No
Medical treatment
Peak VO2(% predicted normal maxi&& VOZ) 43 57 6”:
Surgical treatment
53
;: zl 30 58 Medical failures With later surgery
4
Fatigue
Yes (3) No (1)
!: 67 69
VOa = oxygen consumption.
exercise due to degenerative arthritis. The results of exercise testing are shown in Table IV. Oxygen uptake was estimated from work load and duration of work according to the method of Sanne.12 Work capacity was expressed as peak oxygen uptake in percent of normal age- and sex-specific maximal value, corrected for body size.‘3 Two patients (both with symptomatic stable angina) were limited by chest pain and ischemic S-T segment change at a low work load (43 and 57 percent, respectively) despite a low double product (systolic blood pressure X heart rate) at onset of ischemia related to propranolol therapy. The other two patients (including the one who is clinically without angina) were limited by fatigue without ischemic electrocardiographic changes. The four patients who had a recurrence of chest pain, were treated surgically and survived the operation recently underwent exercise testing. None had chest pain during the test, but three had significant S-T segment changes. All reached a work load corresponding to 50 to 75 percent of expected normal values (Table IV). Surgically treated group: Twelve of the 13 patients randomized to surgical therapy had coronary revascularization performed within 2 weeks of randomization. The single exception was a patient who had an acute subendocardial myocardial infarct while awaiting operation. He recovered without complication, and revascularization performed 6 weeks later was uneventful. Subsequent revascularization was performed because pain recurred after infarction although he was on a good medical regimen. These patients have been followed up for a mean of 17.8 months, four of them for more than 24 months. Mortality and morbidity (Table III): One patient died in the early postoperative period because of disseminated intravascular coagulation and uncontrollable
1294
June 1978
The American Journal of CARDIOLOGY
bleeding. Of the 12 patients surviving the operation, 8 had pre- and postoperative technetium-99m stannous pyrophosphate myocardial scintigrams. Six of these patients did not manifest increased pyrophosphate uptake 48 to 72 hours postoperatively on the repeat scintigram. Two patients had increased pyrophosphate uptake postoperatively and were believed to have had a perioperative infarct. These two patients also had electrocardiographic S-T and T wave changes consistent with this diagnosis. The rate of perioperative infarction in this small group of patients by these criteria was 25 percent. No subsequent deaths or nonfatal myocardial infarcts have occurred during the followup period. Clinical status: The 12 patients surviving operation have been followed up. Seven (58 percent) remain pain-free and require no antianginal medication. Five (42 percent) had a recurrence of angina 2 months to 1 year (mean 6 months) after operation. Medical therapy was initiated in all; three agreed to recatheterization. In these three patients, one had all grafts patent and no progression of disease in the native circulation; one had occlusion of one of three saphenous vein grafts; and one had occlusion of two of three grafts. The latter two patients are now being treated medically. In none of these three patients was the left ventricular ejection fraction lower than the preoperative value. Two patients refused restudy and are also being treated medically; both have chronic stable angina. Exercise testing: Seven surgically treated patients underwent postoperative exercise testing (Table IV). In one the test was limited by chest pain and ischemic S-T segment changes. The remaining six had neither angina nor electrocardiographic changes. However, two of the six have a low work capacity, that is, 30 and 40 percent of predicted maximal oxygen consumption was reached. Effort was good on both tests, suggesting that the limitation was due to diminished cardiac reserve. Course of Patients Not Randomized
As previously noted, 23 of the 50 patients with a clinical diagnosis of unstable angina were excluded from randomization on the basis of their catheterization findings (Table V). Inoperable: Six patients were considered unsuitable for revascularization: four because of severe distal coronary disease beyond the area or areas of significant proximal obstruction (one had disease of the left main coronary artery) and two because of greatly reduced left ventricular ejection fraction (20 and 26 percent, respectively). All six were treated medically. Four died during the follow-up period 2 weeks to 17 months (mean 6 months) after catheterization. All four died suddenly at home. Two are now being followed up; both are significantly limited by exertional angina (follow-up period 32 and 33 months, respectively). Left main coronary artery disease: Eight patients had significant disease of the left main coronary artery in addition to other lesions. Left ventricular ejection fraction was normal (ejection fraction greater than 50 percent) in three and reduced (ejection fraction 30 to 50 percent) in four.
Volume 41
UNSTABLE ANGINA PECTORIS-PUGH
There were two deaths (28 percent) in the early postoperative period; a third patient died suddenly at home 9 months after apparently successful revascularization. All three deaths occurred in patients with a reduced left ventricular ejection fraction at preoperative catheterization (39,41 and 47 percent, respectively). Of the four survivors, three are currently pain-free and one has angina on heavy exertion only (mean follow-up period 13 months). Single vessel disease: Three patients had significant disease limited to the right or the left circumflex coronary artery; each was treated medically and none died. One is now pain-free and two have stable exertional angina. All three have had exercise tests while on medication, and none now have ischemic changes (mean follow-up time 28 months). Normal coronary anatomy: Despite clinical findings suggesting unstable angina, seven patients had no identified significant coronary lesions and no other documented cardiac or gastrointestinal abnormalities to explain their chest pain. Myocardial ischemia had been suggested not only by their complaint of chest pain, but also by electrocardiographic changes ranging from persistent minor ST-T wave changes to significant S-T depression occurring with chest pain and spontaneously resolving. Five of these seven patients also had at least one 2+ positive technetium-99m stannous pyrophosphate scintigram. None of these patients demonstrated coronary spasm during catheterization, and the cause of their pain remains uncertain. There have been no deaths or myocardial infarcts in this group during a mean follow-up time of 18 months. Six have had no recurrence of chest pain; one has chronic pain, now atypical for angina. Five recently underwent exercise testing and four had normal tests, whereas one had S-T segment changes suggestive of myocardial ischemia. Discussion Previous studies of patients with unstable angina: Initial studies on the outcome of patients who present with a pattern of chest pain more severe than stable angina pectoris but without evidence of myocardial infarction, now commonly referred to as unstable angina pectoris, demonstrated the serious nature of this syndrome. Early subsequent myocardial infarction (within 3 months) occurred in 22 to 49 percent and death in 1 to 32 percent of cases.lm4 However, with the increasing awareness of the entity of unstable angina and the trend toward hospitalization of such patients and aggressive medical treatment with long-acting nitrates and beta adrenergic blockade, early morbidity and mortality have significantly diminished. Rates of early myocardial infarction and death of 7 to 21 percent and 1 to 10 percent, respectively, are currently observed.14m16Indeed, Fischl et al.l7 reported that among 20 patients with unstable angina treated aggressively with oral propranolol, no deaths or transmural infarctions occurred during initial hospitalization. Despite the improvement in early prognosis, follow-up studies have shown that these patients continue to be at high risk for subsequent
ET AL.
TABLE V Unstable Angina Pectoris Surgical Treatment (no. of patients)
Medical Treatment (no. of patients) A. Randomized Patients (no. = 27) Total patients No limiting angina during follow-up
14 1 plus 4 after subsequent surgery
Stable angina Recurrence or progression of unstable angina pectoris Death
B. Nonrandomized Total patients Nod~;;~;~ry artery Single vessel (RCA, LCA) disease
Severe distal coronary artery disease or LV dysfunction Left main disease
13 7
:
5
1 plus 1 after subsequent surgery
1
Patients (no. = 23)
16 7 (no limiting angina during follow-up 3 (2 with no limiting angina during follow-up, 1 with stable angina) 6” (2 with stable severe angina, 4 who died) 7 (3 with no angina postoperatively, 1 with stable angina, 3 who died)
7
... ...
.
One of these patients also had left main coronary artery disease. LCA = left coronary artery; LV = left ventricular; RCA = right coronary artery. l
coronary events over the ensuing years. Krauss et al.16 reported a 20 percent incidence rate of myocardial infarction and a 15 percent death rate at 1 year, although in their study medical therapy was not standardized and exact coronary anatomy was not documented with coronary arteriography in every patient studied. In an effort to improve these figures, prompt cardiac catheterization and coronary revascularization have been performed in a significant number of patients in recent years.1a23 Initial reports have been encouraging, and claims of reduced mortality and frequency of subsequent infarction have been made. Although operative mortality appears to be slightly greater than among patients operated on during chronic stable angina, those surviving the operation have demonstrated marked improvement in symptoms and a small incidence of subsequent death.ls2e However, these studies are largely limited by lack of randomization and by short periods of follow-up. Three recent controlled studies are noteworthy. In patients with similar clinical symptoms and cardiac disease, Bertolasi et al.“’ reported a reduction in early mortality (from 15 to 7 percent) and in overall mortality rate (from 20 to 7 percent) among patients treated surgically compared with those treated
June 1878
The American Journal of CARDIOLOGY
Volume 41
1295
UNSTABLE ANGINA PECTORIS-PUGH
ET AL.
A SURGICALLY (N=13) q
c: 2o. 0
2
4
6
8
10 TIME
12
TREATED
MEDICALLY TREATED (N = 141
14
16
18
June 1978
22
(MONTHS)
medically. In contrast, Selden et a1.24found no significant differences in either early or late mortality (mean follow-up time 21 months) between the two groups. However, symptomatic relief of chest pain and functional work capacity during exercise testing were distinctly more favorable among the patients treated surgically. Preliminary results25 from a large multicenter randomized trial in patients with unstable angina pectoris have also suggested that short-term life expectancy does not differ between patients randomized to medical and surgically treated groups, but pain relief is better in the surgically treated patients. Clinical characteristics of patients with unstable angina: With respect to our initial assessment of the 50 patients, several important points emerge. Previous angiographic studies of the coronary anatomy in patients with unstable angina found a nearly equal distribution of single, double and triple vessel disease. Normal coronary anatomy was noted in approximately 10 percent of patients and disease of the left main coronary artery reported to occur rarely.26 Similar data have been reported for patients with chronic stable angina.2e However, two recent studies suggest that involvement of the left main coronary artery in unstable angina may be more prevalent than previously thought, approximating 15 percent. 2op24In our study, eight patients (16 percent) had significant disease of the left main coronary artery in conjunction with other significant coronary arterial lesions. Ten of 50 patients in our study had a reduced left ventricular ejection fraction (that is, values below 50 percent); 7 of these 10 had a known previous myocardial infarct. Among the 40 patients with a relatively normal left ventricular ejection fraction, 9 had a known prior myocardial infarct. This finding is in accord with the data of Bertolasi et a1.,21who previously suggested that reduced left ventricular function correlates with previous myocardial infarction in patients with unstable angina. Our data were also analyzed to determine if certain clinical features such as specific pattern of chest pain, history of prior myocardial infarct or results of tech-
1296
20
The American Journal of CARDIOLOGY
24
FIGURE 1. Survival curves during the first 18 months of follow-up in 27 patients with unstable angina pectoris randomized to medical and surgical therapy. There is no significant difference in survival between the two groups. N = number of patients.
netium-99m stannous pyrophosphate myocardial scintigram correlated with (1) early morbidity or mortality, or (2) distribution of coronary disease found at cardiac catheterization. No reliable correlations among these findings were obtained in our study. Results of medical versus surgical treatment of unstable angina: Twenty-seven patients with comparable clinical findings and coronary anatomy were randomized into medically and surgically treated groups (Table VA). In the 14 patients treated medically, no early myocardial infarcts or deaths occurred. Of the 13 patients treated surgically, 1 had a nonfatal myocardial infarct before operation, and 1 died at operation (7 percent incidence rate). By electrocardiogram and technetium-99m stannous pyrophosphate scintigraphic criteria, two of eight patients (only eight had pre- and postoperative scintigrams) had a perioperative infarct (incidence rate 25 percent). The remaining four patients did not have electrocardiographic evidence of perioperative infarction, but we believe that technetium-99m stannous pyrophosphate scintigrams pre- and postoperatively add sensitivity to the recognition of perioperative damage, and without that test we are unable to determine reliably the true incidence of perioperative myocardial infarction.27*28 In the follow-up period, one late death occurred in nine patients who continued medical therapy (11 percent); no deaths occurred in the surgical group during the same period of follow-up. No late, nonfatal myocardial infarct was documented in either group. There was one operative death in the subset of five patients initially randomized to medical treatment but subsequently operated on for relentless symptoms. Excluding that subset, the overall mortality rate at a mean follow-up time of 1 l/2 years for the two groups was 11 percent in the medical and 7 percent in the surgical group (Fig. 1). These differences in mortality are not significant. The two groups are divergent with respect to current symptoms. In the medically treated group, only one patient is pain-free and able to resume full-time employment; seven are limited by chest pain during exertion, and five had severe pain requiring rehospitalization
Volume 41
UNSTABLE ANGINA PECTORIS-PUGH ET AL.
and subsequent coronary revascularization. In the surgically treated group, seven currently have no limiting angina; five have had recurrence of angina. The incidence rate of complete symptomatic relief in the medical group is only 8 percent, compared with 58 percent in the surgical group. These differences are statistically significant (P
related to the presence of left ventricular dysfunction and severity of coronary artery disease.“0s31 Seven patients were found to have no significant lesions of the coronary arteries, despite clinical features suggesting the presence of significant coronary artery disease. Five of these patients had 2+ technetium-99m stannous pyrophosphate myocardial scintigrams. Whether these represent “false positive” scintigrams or in fact served to identify small areas of muscle necrosis in the absence of typical occlusive coronary disease is uncertain. The occurrence of transient coronary spasm or a small coronary embolus resulting in limited necrosis theoretically might explain the chest pain in these patients without significant coronary angiographic lesions. However, in the follow-up period the seven patients have done well; six have had no recurrence of pain, and there have been no deaths. In summary, our study demonstrates that at a mean follow-up period of 1 l/2 years, no significant differences in mortality exist between patients with unstable angina pectoris randomized into medically and surgically treated groups. However, improvement in symptoms is distinctly more favorable among those treated surgically. The prognosis in patients with unstable angina pectoris but deemed unsuitable for operation and treated medically is very poor, and in those with disease of the left main coronary artery and reduced left ventricular ejection fraction treated surgically is less than ideal. Acknowledgment We express our appreciation to the medical and surgical house officers at Parkland Memorial Hospital for their help in the performance of these studies, to Mr. Norman Vance and Mr. Chuck Graham for technical assistance with the myocardial scintigraphic studies and to Mrs. Belinda Lambert and Mrs. Mary Rich for secretarial assistance.
References 1. Levy H: The natural history of changing patterns of angina pectoris. Ann Intern Med 44:1123-l 135, I956 2. Wood P: Acute and subacute coronary insufficiency. Br Med J 1: 1779-1782, 1961 3. Vakll RJ: Intermediate coronary syndrome. Circulation 24557-571, 1961 4. Vakll RJ: Preinfarction syndrome-management and follow-up. Am J Cardiol 1455-63, 1964 5. Wagner GS, Roe CR, Llmblrd LE, et al: The importance of identification of the myocardial specific isoenzyme of creatine phosphokinase (MB form) in the diagnosis of acute myocardial infarction. Circulation 47:263-269, 1973 6. WIlIerson JT, Stone YJ, Tlng R, et al: Radioimmunoassay of creatine kinase8 isoenzyme in human sera: results in patients with acute myocardial infarction. Proc Natl Acad Sci USA 74: 171 l1715,1977 7. Wlllerson JT, Parkey RW, Bonte FJ, et al: Technetium stannous pyrophosphate myocardial scintigrams in patients with chest pain of varying etiology. Circulation 51:1046-1052, 1975 8. Parkey RW, Bonte FJ, Meyer SL, et al: A new method for radionuclide imaging of acute myocardial infarction in humans. Circulation 50:540-546, 1974
9. Buja LM, Pollner L, Parkey RW, et al: Clinicopathologic findings in patients with persistently positive technetium-99m stannous pyrophosphate myocardial scintigrams after acute myocardial infarction. Circulation 56:1016-1023, 1977 10. Buja LM, Parkey RW, Stokely EM, et al: Pathophysiology of technetium-99m stannous pyrophosphate and thallium-201 scintigraphy of acute anterior myocardial infarcts in dogs. J Clin Invest 57:1508-1522, 1976 11. Buja LM, Tofe AF, Kulkarnl PV, et al: Sites and mechanisms of localization of technetium99m phosphorus radiopharmaceuticals in acute myocardial infarcts and other tissues. J Clin Invest 60: 724-740, 1977 12. Sanne H: Exercise tolerance and physical training of non-selected patients after myocardial infarction. Acta Med Stand (Suppl) 551:1-44,1973 13. Kattus A: Exercise testing and training of apparently healthy individuals. A Handbook for Physicians. Dallas, Texas, Am Heart Association, 1972. p 15 14. Gazes PC, Mobley EM Jr, Farls HM Jr, et al: Preinfarctional (unstable) angina-a prospective study-ten year follow-up. Circulation 481331-336, 1973 15. Watkins PC, Rueeell RO Jr, Rackley CE: Follow-up study of un-
June 1978
The American Journal of CARDIOLOGY
Volume 41
1297
UNSTABLE
16. 17.
18.
19. 20.
21.
22.
23.
ANGINA PECTORIS-PUGH
ET AL.
stable angina in a myocardial infarction research unit (abstr). Circulation 46:Suppl IMI-23, 1972 Krauss KR, Hutter AM Jr, DeSanctis RW: Acute coronary insufficiency. Circulation 45:Suppl 1:1-66-l-71, 1972 Fischl SJ, Herman MV, Gorlin R: The intermediate coronary syndrome. Clinical, angiographic and therapeutic aspects. N Engl J Med 268:1193-1198, 1973 Favaloro RG, Effler DB, Cheanvechai C, et al: Acute coronary insufficiency (impending myocardial infarction and myocardial infarction). Surgical treatment by the saphenous vein graft technique. Am J Cardiol 28598-607, 1971 Cheanvechai C, Eff ler DB, Hoop FD, et al: Emergency myocardial revascularization. Am J Cardiol 32:901-908, 1973 ContiCR, Brawley RK, Griffith LSC, et al: Unstable angina pectoris: morbidity and mortality in 57 consecutive patients evaluated angiographically. Am J Cardiol 32:745-750, 1973 Bertolasl CA, TrongC JE, Carreiio CA, et al: Unstable anginaprospective and randomized study of its evolution with and without surgery. Am J Cardiol 33:201-208, 1974 Miller DC, Cannom DS, Fogarty TJ, et al: Saphenous vein coronary artery bypass in patients with “preinfarction angina.” Circulation 47:234-241,1973 Scanlon PJ, Nemickas R, Moran JF, et al: Accelerated angina pectoris, clinical, hemodynamics, arteriographic, and therapeutic
1298
June 1978
The American Journal of CARDIOLOGY
experience in 85 patients. Circulation 47:19-26. 1973 24. Selden R, Neil1 WA, Ritzmann LW, et al: Medical versus surgical therapy for acute coronary insufficiency. A randomized study. N Engl J Med 293:1329-1333, 1975 25. Scheidt SS: Unstable angina: medical management or surgery. Cardiovasc Med 2:541-543, 1977 26. Cairns JA, Fantus IG, Klassen GA: Unstable angina pectoris. Am Heart J 92:373-386, 1976 27. Plan MR. Mills LJ, Parkey RW, et al: Perioperative myocardial infarction diagnosed by technetium-99m stannous pyrophosphate myocardial scintigrams. Circulation 54:Suppl lll:lll-24-111-27, 1976 28. Platt MR, Parkey RW, Willerson JT, et al: Technetium stannous pyrophosphate myocardial scintigrams in the recognition of myocardial infarction in patients undergoing coronary artery revascularization. Ann Thorac Surg 21:311-317, 1976 29. Cohen MV, Cohn PF, Herman MV, et al: Diagnosis and prognosis of main left coronary artery obstruction. Circulation 45:Suppl I:I57-l-65, 1972 30. Hultgren HN: Medical versus surgical treatment for unstable angina. Am J Cardiol38:479-486, 1976 3 1. Cannom DA, Harrison DC, Schroeder JS: Hemodynamic observations in patients with unstable angina pectoris. Am J Cardiol 33:17-22, 1974
Volume 41
Unstable Angina Pectoris: A Randomized Study of Patients Treated Medically and Surgically
BILLY PUGH, MD MELVIN R. PLATT, MD, FACC LAWRENCE J. MILLS, MD, FACC DONALD CRUMBO, MD LAWRENCE R. POLINER, MD GEORGE C. CURRY, MD GUNNAR C. BLOMQVIST, MD, PhD, FACC ROBERT W. PARKEY, MD, FACC L. MAXIMILIAN JAMES
BUJA,
T. WILLERSON,
MD, MD,
FACC FACC’
Dallas, Texas
Fifty patients with the clinical syndrome of unstable angina pectoris were evaluated. Twenty-seven were randomized into medical or surgical treatment groups and subsequently followed up. the results of the study reveal that: (1) there is approximately a 16 percent incidence rate of signiffcant left main coronary artery disease in patients with this entity at our institution; (2) 10 percent of patients do not have angiographically significant coronary artery disease; (3) pain relief is better in the surgically treated patients, but the 1 l/2 year survival rate is not significantly different between the groups; (4) 50 percent of the medically treated patients again had the syndrome of unstable angina pectoris in the initial few months of the follow-up period; (5) the operative and late postoperative mortality rate in patients presenting with unstable angina pectoris and left main coronary artery disease in this small group of patients was 43 percent; and (6) four of six patients with this syndrome whose condition was deemed inoperable and who were not randomized died within the subsequent few months.
During the past few years, unstable angina pectoris has gained acceptance among cardiologists and cardiovascular surgeons as a distinct syndrome within the clinical spectrum of ischemic heart disease, bridging the gap between chronic stable angina and acute myocardial infarction. Efforts have been directed toward defining unstable angina precisely, determining the cardiac hemodynamic and angiographic factors responsible for the chest pain and assessing its initial and long-term significance.1-4 Proper treatment for unstable angina is not clear. It is generally believed that the prompt recognition, hospitalization and aggressive medical therapy of patients with unstable angina will reduce early mortality, but whether further reduction in the incidence of nonfatal myocardial infarction and mortality can be accomplished with coronary revascularization is controversial. To help resolve the issue, a study was begun at Parkland Memorial From the Departments of Internal Medicine (Cardiac Unit), Surgery, Radiology and Pathology at the University of Texas (Southwestern) Medical School, Dallas, Texas. This work was supported in part by Grant HL-17669 from the lschemic Heart Disease Specialized Center of Research, National Institutes of Health, Bethesda, Maryland: the Southwestern Medical Foundation and the Harry S. Moss Heart Fund. Manuscript received September 6, 1977; revised manuscript received December 12, 1977. Established Investigator of the American Heart Association, Dallas, Texas. Address for reprints: James T. Willerson, MD. lschemic Heart Center, L5 134, University of Texas Health Science Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235. l
Hospital in January 1974. Patients admitted to the coronary care unit who met our clinical criteria for unstable angina were studied with cardiac catheterization and, if found suitable, were randomized into medically or surgically treated groups. Follow-up studies have continued. In this paper we report our initial findings, through December 1976 (36 months).
Case Material
and Protocol
Criteria for unstable angina: Patients were included in the study if they were admitted with a chest pain pattern judged to represent unstable angina by the attending staff physician and, during the initial phase of hospitalization, did not demonstrate evidence of myocardial infarction by electrocardiographic and enzymatic criteria. Three patterns of pain were considered consistent with unstable angina: (1) chest pain with effort, of recent onset (within the previous 4 weeks) and progressive in nature, being provoked with less exertion, becoming more intense or persisting longer; (2) chest pain with effort, progressive in nature
June 1978
The American Journal ol CARDIOLOGY
Volume 41
1291
UNSTABLE ANGINA PECTORIS-PUGH ET AL.
and occurring in a patient with chronic stable angina or previous myocardial infarction; and (3) chest pain at rest, occurring without obvious provocation, lasting longer than 15 minutes and intense and recurrent. The study excluded patients whose pain was clearly related to a precipitating hemodynamic factor, such as a prolonged cardiac arrhythmia or severe hypertension, and whose pain promptly abated with correction of the initial factor.
TABLE I lnitlal Assessment of 50 Patients With Unstable Angina Pectoris Patients (no.) Pain pattern Type 1 Type II Type Ill Known prior myocardial infarct Yes No ggmT~-PYP mvocardial scintiarams Negative _ 2+ Coronary artery disease None Single vessel (RCA or LC,) LAD, 2 or 3 vessel LMCA Left ventricular ejection fraction Normal (X0%) Reduced (30X10%) Greatly reduced (<30%)
Acute myocardial infarction was excluded by standard criteria: (1) The electrocardiogram must not demonstrate new
Q wave formation or prominent R wave loss. Previous electrocardiograms were utilized for comparison when available. (2) Serum enzyme levels (creatine kinase, serum glutamic oxaloacetic transaminase and lactic dehydrogenase) must be normal on admission and not rise more than 50 percent of the initial value during subsequent hospitalization; the creatine kinase-B isoenzyme determined either with column separation and spectrophotometric measurements5 or with radioimmunoassays has also been utilized to exclude myocardial infarction at our institution for the past 1 l/2 years. (3) Myocardial scintigraphy using technetium-99m stannous pyrophosphate performed 24 to 48 hours after admission must not demonstrate a localized area of intense uptake (3 to 4+) characteristic of transmural infarction.7 Technetium-99m stannous pyrophosphate myocardial scintigrams graded 2+ or less did not preclude proceeding with cardiac catheterization, provided the electrocardiogram and cardiac enzymes did not demonstrate conclusive evidence5 of infarction, and that the positive scintigrams remained unchanged in intensity and localization at the time of repeat testing (generally over a 2 week period). We do regard such “2+” myocardial scintigrams as demonstrating severe cell injury, but without any change in intensity or regional myocardial localization over a 10 to 14 day period, it is more likely that the myocardial injury is chronic rather than acute.7-11 Protocol: All patients admitted to the coronary care unit during the 36 month period with one of the previously described patterns of chest pain were considered candidates for study. They were cared for in a standard manner; anticoagulant therapy was not given. When a myocardial infarct was excluded, medical therapy designed to prevent further episodes of myocardial ischemia was begun; typically this included oral administration of isosorbide dinitrate, 5 to 10 mg every 4 hours, and propranolol, 20 to 60 mg every 6 hours. Initial doses of these medications were increased as necessary to produce the desired clinical effect, avoiding hypotension and profound bradycardia. When the chest pain was relieved or markedly reduced, the nature of the study was explained to each patient and cardiac catheterization recommended. Verbal and written informed consent were subsequently obtained for cardiac catheterization and for surgery when the latter was performed. In the few patients whose severe chest pain persisted despite aggressive medical therapy, intraaortic balloon circulatory assistance was utilized to help control pain before cardiac catheterization. These patients did not enter the randomization process of the study but were instead treated surgically when their coronary anatomy and ventricular function permitted. Fifty patients consented to being included in this evaluation (Table I). There were 27 men and 23 women, ranging in age from 33 to 68 years (mean 52). All underwent left heart catheterization and selective coronary angiography with the Judkins or Sones technique, usually during the first 2 weeks of hospitalization. Ventricular function was assessed with angiographic dye injection and calculation of the left ventricular ejection fraction using standard geometric computations from the right anterior oblique projection. Significant
1292
June 1978
The American Journal of CARDIOLOGY
17 21 12
;: 31 19
; 32
a 40 2”
LAD = left anterior descending coronary artery; LC, = left circumflex coronary artery; LMCA = left main coronary artery; ggmT~ PYP = technetium-99m stannous pyrophosphate; RCA = right coronary artery.
disease of a coronary vessel was judged present if a 50 percent or greater segmental reduction in luminal diameter was found in the main left coronary artery or a 70 percent or greater luminai narrowing was found in the remaining coronary arteries. After catheterization, patients were returned to the coronary care unit, and medical therapy was resumed. Randomized groups: Patients were assigned randomly to medical or surgical treatment groups if they had significant disease of the left anterior descending coronary artery or significant two or three vessel disease, with left ventricular ejection fraction greater than 30 percent and left ventricular end-diastolic pressure before left ventricular angiography less than 18 mm Hg and if they were considered to have large enough distal vessels beyond regions of significant coronary obstructions to be suitable for revascularization. The randomization process was performed blindly by drawing a label from a partially covered box. Patients were excluded from the randomization process if they had insignificant coronary artery disease, isolated significant disease of the right or circumflex coronary artery or were judged unsuitable for revascularization because of greatly reduced ventricular function (left ventricular ejection fraction less than 30 percent) or severe distal coronary disease, or both. All such patients were treated medically. Patients with significant disease of the left main coronary artery were not randomized but were treated surgically.
Results Results of Initial Evaluation
Clinical features (Table I): Chest pain patterns: Of the 50 patients, 17 presented with new onset of progressive pain (type I), 21 with progressive pain in the setting of chronic stable angina or a prior myocardial infarct (type II) and 12 with recurrent pain at rest (type III). Sixteen of the 33 patients in the latter two groups had a known previous myocardial infarct.
Volume 41
UNSTABLE ANGINA PECTORIS-PUGH ET AL.
TABLE II
TABLE Ill
Comparisons of 14 Medically and 13 Surgically Treated Patients With Unstable Angina Pectoris
Results of Randomization in 27 Patients
Sex Mean age (yr) Pain pattern Type 1 Type II Type Ill Known prior myocardial Yes
Medically Treated Group
Surgically Treated Group
10M. 4P 49
6M, 7f= 52
: 3
5 3
:
t
10 4
9 4
: 4
s 7
12 2
11 2
Medically Treated Group
infarct
sg”fk-PYP myocardial scintigrams Negative 2+ Distribution of significant coronary disease LAD 2 vessel 3 vessel Left ventricular ejection fraction Normal (X0%) Reduced (30-50%)
LAD = left anterior descending coronary technetium-99m stannous pyrophosphate.
artery;
Patients (no.) Mean follow-up (mo) Nonfatal new Ml
14 18.9 0
Death (no. of patients) Clinical status (no. of patients) Pain-free Chronic angina Severe angina (operation)
1
1
Surgically Treated Group 13 17.8 t (preop) : (postop)
7 5
: (1 death)
Ml = myocardial infarction.
gsmT~-PYP =
tent of cardiac disease for these patients are outlined in Table II. The two groups are statistically similar with respect to sex and age, history of previous myocardial infarction, results of technetium-99m stannous pyrophosphate myocardial scintigrams, extent of coronary disease and left ventricular ejection fractions using Chi square analysis (P >0.2). Current Results of Randomization
Myocardial scintigraphy:
Nineteen patients, slightly more than one third of the total, demonstrated a technetium-99m stannous pyrophosphate scintigram graded 2+ (without definite electrocardiographic or enzymatic evidence of recent acute myocardial infarction). The remaining 31 patients had a negative scintigram. Cardiac catheterization data: The distribution of coronary disease was as follows in these patients: (1) no significant coronary artery disease (7 patients); (2) significant disease limited to the right or left circumflex coronary artery (3 patients); (3) significant disease of the left anterior descending coronary artery or two or three vessel disease without disease of the left main coronary artery, or both (32 patients); (4) significant two or three vessel coronary artery disease and significant disease of the left main coronary artery (8 patients). None of the patients with left main disease in this study had that as the sole significant coronary arterial lesion. Four patients were deemed unsuitable for operation because of severe disease of distal branches of two or three coronary arteries. Left ventricular ejection fraction (Table I) was normal (more than 50 percent) in 40 patients, reduced (30 to 50 percent) in 8 patients and greatly reduced (less than 30 percent) in 2 patients. The latter two patients had significant coronary artery disease but were considered unsuitable for operation because of a greatly reduced left ventricular ejection fraction. Therefore, in the 50 patients initially evaluated, 27 could be randomly placed into medical and surgical treatment groups. Randomization: Fourteen patients were randomized to medical therapy and 13 to surgical therapy. Biographical details, results of clinical evaluation and ex-
Medically treated group: After randomization to medical therapy, all 14 patients were discharged on antianginal medication considered sufficient to control their chest pain. All patients were treated with oral isosorbide dinitrate (mean dosage 40 mg/day), and 12 of the 14 were also treated with propranolol (mean dosage 140 mg/day). Two patients did not require propranolol in addition to isordil for symptomatic relief of angina. There were no in-hospital myocardial infarcts or deaths in the group (Table III). The mean follow-up time has been 18.9 months, and six patients have been followed up for more than 24 months. Mortality and morbidity: Eighteen months after initial randomization, one patient had an acute myocardial infarction and died on the 2nd hospital day with cardiogenic shock. No further patients have had acute myocardial infarcts among the 12 surviving patients. Clinical status: One patient is now pain-free on medication and has resumed full-time employment. Seven patients have chronic stable angina, and medical therapy has been continued. However, five patients had recurrence of severe angina pectoris 1 week to 6 months (mean 2 months) after randomization while on a program of medical therapy considered optimal. All were rehospitalized, were found to have had no new myocardial infarct and subsequently received surgical coronary revascularization. One of the five died in the immediate postoperative period. The remaining four survived the operation and are currently free of angina. Two of the four are men who have returned to full-time work. Exercise testing: Four of the eight patients remaining in the medically treated group were able to undergo exercise testing during the follow-up period. The remaining four patients were limited by leg pain with
June 1978
The American Journal of CARDIOLOGY
Volume 41
1293
UNSTABLE ANGINA PECTORIS-PUGH ET AL.
TABLE
IV
Exercise Testina After Medical or Suraical Treatment
lschemic S-T Segment Change
Patients (no.)
Test Limitation
2
Angina
Yes
2
Fatigue
No
1
Angina
Yes
6
Fatigue
No
Medical treatment
Peak VO2(% predicted normal maxi&& VOZ) 43 57 6”:
Surgical treatment
53
;: zl 30 58 Medical failures With later surgery
4
Fatigue
Yes (3) No (1)
!: 67 69
VOa = oxygen consumption.
exercise due to degenerative arthritis. The results of exercise testing are shown in Table IV. Oxygen uptake was estimated from work load and duration of work according to the method of Sanne.12 Work capacity was expressed as peak oxygen uptake in percent of normal age- and sex-specific maximal value, corrected for body size.‘3 Two patients (both with symptomatic stable angina) were limited by chest pain and ischemic S-T segment change at a low work load (43 and 57 percent, respectively) despite a low double product (systolic blood pressure X heart rate) at onset of ischemia related to propranolol therapy. The other two patients (including the one who is clinically without angina) were limited by fatigue without ischemic electrocardiographic changes. The four patients who had a recurrence of chest pain, were treated surgically and survived the operation recently underwent exercise testing. None had chest pain during the test, but three had significant S-T segment changes. All reached a work load corresponding to 50 to 75 percent of expected normal values (Table IV). Surgically treated group: Twelve of the 13 patients randomized to surgical therapy had coronary revascularization performed within 2 weeks of randomization. The single exception was a patient who had an acute subendocardial myocardial infarct while awaiting operation. He recovered without complication, and revascularization performed 6 weeks later was uneventful. Subsequent revascularization was performed because pain recurred after infarction although he was on a good medical regimen. These patients have been followed up for a mean of 17.8 months, four of them for more than 24 months. Mortality and morbidity (Table III): One patient died in the early postoperative period because of disseminated intravascular coagulation and uncontrollable
1294
June 1978
The American Journal of CARDIOLOGY
bleeding. Of the 12 patients surviving the operation, 8 had pre- and postoperative technetium-99m stannous pyrophosphate myocardial scintigrams. Six of these patients did not manifest increased pyrophosphate uptake 48 to 72 hours postoperatively on the repeat scintigram. Two patients had increased pyrophosphate uptake postoperatively and were believed to have had a perioperative infarct. These two patients also had electrocardiographic S-T and T wave changes consistent with this diagnosis. The rate of perioperative infarction in this small group of patients by these criteria was 25 percent. No subsequent deaths or nonfatal myocardial infarcts have occurred during the followup period. Clinical status: The 12 patients surviving operation have been followed up. Seven (58 percent) remain pain-free and require no antianginal medication. Five (42 percent) had a recurrence of angina 2 months to 1 year (mean 6 months) after operation. Medical therapy was initiated in all; three agreed to recatheterization. In these three patients, one had all grafts patent and no progression of disease in the native circulation; one had occlusion of one of three saphenous vein grafts; and one had occlusion of two of three grafts. The latter two patients are now being treated medically. In none of these three patients was the left ventricular ejection fraction lower than the preoperative value. Two patients refused restudy and are also being treated medically; both have chronic stable angina. Exercise testing: Seven surgically treated patients underwent postoperative exercise testing (Table IV). In one the test was limited by chest pain and ischemic S-T segment changes. The remaining six had neither angina nor electrocardiographic changes. However, two of the six have a low work capacity, that is, 30 and 40 percent of predicted maximal oxygen consumption was reached. Effort was good on both tests, suggesting that the limitation was due to diminished cardiac reserve. Course of Patients Not Randomized
As previously noted, 23 of the 50 patients with a clinical diagnosis of unstable angina were excluded from randomization on the basis of their catheterization findings (Table V). Inoperable: Six patients were considered unsuitable for revascularization: four because of severe distal coronary disease beyond the area or areas of significant proximal obstruction (one had disease of the left main coronary artery) and two because of greatly reduced left ventricular ejection fraction (20 and 26 percent, respectively). All six were treated medically. Four died during the follow-up period 2 weeks to 17 months (mean 6 months) after catheterization. All four died suddenly at home. Two are now being followed up; both are significantly limited by exertional angina (follow-up period 32 and 33 months, respectively). Left main coronary artery disease: Eight patients had significant disease of the left main coronary artery in addition to other lesions. Left ventricular ejection fraction was normal (ejection fraction greater than 50 percent) in three and reduced (ejection fraction 30 to 50 percent) in four.
Volume 41
UNSTABLE ANGINA PECTORIS-PUGH
There were two deaths (28 percent) in the early postoperative period; a third patient died suddenly at home 9 months after apparently successful revascularization. All three deaths occurred in patients with a reduced left ventricular ejection fraction at preoperative catheterization (39,41 and 47 percent, respectively). Of the four survivors, three are currently pain-free and one has angina on heavy exertion only (mean follow-up period 13 months). Single vessel disease: Three patients had significant disease limited to the right or the left circumflex coronary artery; each was treated medically and none died. One is now pain-free and two have stable exertional angina. All three have had exercise tests while on medication, and none now have ischemic changes (mean follow-up time 28 months). Normal coronary anatomy: Despite clinical findings suggesting unstable angina, seven patients had no identified significant coronary lesions and no other documented cardiac or gastrointestinal abnormalities to explain their chest pain. Myocardial ischemia had been suggested not only by their complaint of chest pain, but also by electrocardiographic changes ranging from persistent minor ST-T wave changes to significant S-T depression occurring with chest pain and spontaneously resolving. Five of these seven patients also had at least one 2+ positive technetium-99m stannous pyrophosphate scintigram. None of these patients demonstrated coronary spasm during catheterization, and the cause of their pain remains uncertain. There have been no deaths or myocardial infarcts in this group during a mean follow-up time of 18 months. Six have had no recurrence of chest pain; one has chronic pain, now atypical for angina. Five recently underwent exercise testing and four had normal tests, whereas one had S-T segment changes suggestive of myocardial ischemia. Discussion Previous studies of patients with unstable angina: Initial studies on the outcome of patients who present with a pattern of chest pain more severe than stable angina pectoris but without evidence of myocardial infarction, now commonly referred to as unstable angina pectoris, demonstrated the serious nature of this syndrome. Early subsequent myocardial infarction (within 3 months) occurred in 22 to 49 percent and death in 1 to 32 percent of cases.lm4 However, with the increasing awareness of the entity of unstable angina and the trend toward hospitalization of such patients and aggressive medical treatment with long-acting nitrates and beta adrenergic blockade, early morbidity and mortality have significantly diminished. Rates of early myocardial infarction and death of 7 to 21 percent and 1 to 10 percent, respectively, are currently observed.14m16Indeed, Fischl et al.l7 reported that among 20 patients with unstable angina treated aggressively with oral propranolol, no deaths or transmural infarctions occurred during initial hospitalization. Despite the improvement in early prognosis, follow-up studies have shown that these patients continue to be at high risk for subsequent
ET AL.
TABLE V Unstable Angina Pectoris Surgical Treatment (no. of patients)
Medical Treatment (no. of patients) A. Randomized Patients (no. = 27) Total patients No limiting angina during follow-up
14 1 plus 4 after subsequent surgery
Stable angina Recurrence or progression of unstable angina pectoris Death
B. Nonrandomized Total patients Nod~;;~;~ry artery Single vessel (RCA, LCA) disease
Severe distal coronary artery disease or LV dysfunction Left main disease
13 7
:
5
1 plus 1 after subsequent surgery
1
Patients (no. = 23)
16 7 (no limiting angina during follow-up 3 (2 with no limiting angina during follow-up, 1 with stable angina) 6” (2 with stable severe angina, 4 who died) 7 (3 with no angina postoperatively, 1 with stable angina, 3 who died)
7
... ...
.
One of these patients also had left main coronary artery disease. LCA = left coronary artery; LV = left ventricular; RCA = right coronary artery. l
coronary events over the ensuing years. Krauss et al.16 reported a 20 percent incidence rate of myocardial infarction and a 15 percent death rate at 1 year, although in their study medical therapy was not standardized and exact coronary anatomy was not documented with coronary arteriography in every patient studied. In an effort to improve these figures, prompt cardiac catheterization and coronary revascularization have been performed in a significant number of patients in recent years.1a23 Initial reports have been encouraging, and claims of reduced mortality and frequency of subsequent infarction have been made. Although operative mortality appears to be slightly greater than among patients operated on during chronic stable angina, those surviving the operation have demonstrated marked improvement in symptoms and a small incidence of subsequent death.ls2e However, these studies are largely limited by lack of randomization and by short periods of follow-up. Three recent controlled studies are noteworthy. In patients with similar clinical symptoms and cardiac disease, Bertolasi et al.“’ reported a reduction in early mortality (from 15 to 7 percent) and in overall mortality rate (from 20 to 7 percent) among patients treated surgically compared with those treated
June 1878
The American Journal of CARDIOLOGY
Volume 41
1295
UNSTABLE ANGINA PECTORIS-PUGH
ET AL.
A SURGICALLY (N=13) q
c: 2o. 0
2
4
6
8
10 TIME
12
TREATED
MEDICALLY TREATED (N = 141
14
16
18
June 1978
22
(MONTHS)
medically. In contrast, Selden et a1.24found no significant differences in either early or late mortality (mean follow-up time 21 months) between the two groups. However, symptomatic relief of chest pain and functional work capacity during exercise testing were distinctly more favorable among the patients treated surgically. Preliminary results25 from a large multicenter randomized trial in patients with unstable angina pectoris have also suggested that short-term life expectancy does not differ between patients randomized to medical and surgically treated groups, but pain relief is better in the surgically treated patients. Clinical characteristics of patients with unstable angina: With respect to our initial assessment of the 50 patients, several important points emerge. Previous angiographic studies of the coronary anatomy in patients with unstable angina found a nearly equal distribution of single, double and triple vessel disease. Normal coronary anatomy was noted in approximately 10 percent of patients and disease of the left main coronary artery reported to occur rarely.26 Similar data have been reported for patients with chronic stable angina.2e However, two recent studies suggest that involvement of the left main coronary artery in unstable angina may be more prevalent than previously thought, approximating 15 percent. 2op24In our study, eight patients (16 percent) had significant disease of the left main coronary artery in conjunction with other significant coronary arterial lesions. Ten of 50 patients in our study had a reduced left ventricular ejection fraction (that is, values below 50 percent); 7 of these 10 had a known previous myocardial infarct. Among the 40 patients with a relatively normal left ventricular ejection fraction, 9 had a known prior myocardial infarct. This finding is in accord with the data of Bertolasi et a1.,21who previously suggested that reduced left ventricular function correlates with previous myocardial infarction in patients with unstable angina. Our data were also analyzed to determine if certain clinical features such as specific pattern of chest pain, history of prior myocardial infarct or results of tech-
1296
20
The American Journal of CARDIOLOGY
24
FIGURE 1. Survival curves during the first 18 months of follow-up in 27 patients with unstable angina pectoris randomized to medical and surgical therapy. There is no significant difference in survival between the two groups. N = number of patients.
netium-99m stannous pyrophosphate myocardial scintigram correlated with (1) early morbidity or mortality, or (2) distribution of coronary disease found at cardiac catheterization. No reliable correlations among these findings were obtained in our study. Results of medical versus surgical treatment of unstable angina: Twenty-seven patients with comparable clinical findings and coronary anatomy were randomized into medically and surgically treated groups (Table VA). In the 14 patients treated medically, no early myocardial infarcts or deaths occurred. Of the 13 patients treated surgically, 1 had a nonfatal myocardial infarct before operation, and 1 died at operation (7 percent incidence rate). By electrocardiogram and technetium-99m stannous pyrophosphate scintigraphic criteria, two of eight patients (only eight had pre- and postoperative scintigrams) had a perioperative infarct (incidence rate 25 percent). The remaining four patients did not have electrocardiographic evidence of perioperative infarction, but we believe that technetium-99m stannous pyrophosphate scintigrams pre- and postoperatively add sensitivity to the recognition of perioperative damage, and without that test we are unable to determine reliably the true incidence of perioperative myocardial infarction.27*28 In the follow-up period, one late death occurred in nine patients who continued medical therapy (11 percent); no deaths occurred in the surgical group during the same period of follow-up. No late, nonfatal myocardial infarct was documented in either group. There was one operative death in the subset of five patients initially randomized to medical treatment but subsequently operated on for relentless symptoms. Excluding that subset, the overall mortality rate at a mean follow-up time of 1 l/2 years for the two groups was 11 percent in the medical and 7 percent in the surgical group (Fig. 1). These differences in mortality are not significant. The two groups are divergent with respect to current symptoms. In the medically treated group, only one patient is pain-free and able to resume full-time employment; seven are limited by chest pain during exertion, and five had severe pain requiring rehospitalization
Volume 41
UNSTABLE ANGINA PECTORIS-PUGH ET AL.
and subsequent coronary revascularization. In the surgically treated group, seven currently have no limiting angina; five have had recurrence of angina. The incidence rate of complete symptomatic relief in the medical group is only 8 percent, compared with 58 percent in the surgical group. These differences are statistically significant (P
related to the presence of left ventricular dysfunction and severity of coronary artery disease.“0s31 Seven patients were found to have no significant lesions of the coronary arteries, despite clinical features suggesting the presence of significant coronary artery disease. Five of these patients had 2+ technetium-99m stannous pyrophosphate myocardial scintigrams. Whether these represent “false positive” scintigrams or in fact served to identify small areas of muscle necrosis in the absence of typical occlusive coronary disease is uncertain. The occurrence of transient coronary spasm or a small coronary embolus resulting in limited necrosis theoretically might explain the chest pain in these patients without significant coronary angiographic lesions. However, in the follow-up period the seven patients have done well; six have had no recurrence of pain, and there have been no deaths. In summary, our study demonstrates that at a mean follow-up period of 1 l/2 years, no significant differences in mortality exist between patients with unstable angina pectoris randomized into medically and surgically treated groups. However, improvement in symptoms is distinctly more favorable among those treated surgically. The prognosis in patients with unstable angina pectoris but deemed unsuitable for operation and treated medically is very poor, and in those with disease of the left main coronary artery and reduced left ventricular ejection fraction treated surgically is less than ideal. Acknowledgment We express our appreciation to the medical and surgical house officers at Parkland Memorial Hospital for their help in the performance of these studies, to Mr. Norman Vance and Mr. Chuck Graham for technical assistance with the myocardial scintigraphic studies and to Mrs. Belinda Lambert and Mrs. Mary Rich for secretarial assistance.
References 1. Levy H: The natural history of changing patterns of angina pectoris. Ann Intern Med 44:1123-l 135, I956 2. Wood P: Acute and subacute coronary insufficiency. Br Med J 1: 1779-1782, 1961 3. Vakll RJ: Intermediate coronary syndrome. Circulation 24557-571, 1961 4. Vakll RJ: Preinfarction syndrome-management and follow-up. Am J Cardiol 1455-63, 1964 5. Wagner GS, Roe CR, Llmblrd LE, et al: The importance of identification of the myocardial specific isoenzyme of creatine phosphokinase (MB form) in the diagnosis of acute myocardial infarction. Circulation 47:263-269, 1973 6. WIlIerson JT, Stone YJ, Tlng R, et al: Radioimmunoassay of creatine kinase8 isoenzyme in human sera: results in patients with acute myocardial infarction. Proc Natl Acad Sci USA 74: 171 l1715,1977 7. Wlllerson JT, Parkey RW, Bonte FJ, et al: Technetium stannous pyrophosphate myocardial scintigrams in patients with chest pain of varying etiology. Circulation 51:1046-1052, 1975 8. Parkey RW, Bonte FJ, Meyer SL, et al: A new method for radionuclide imaging of acute myocardial infarction in humans. Circulation 50:540-546, 1974
9. Buja LM, Pollner L, Parkey RW, et al: Clinicopathologic findings in patients with persistently positive technetium-99m stannous pyrophosphate myocardial scintigrams after acute myocardial infarction. Circulation 56:1016-1023, 1977 10. Buja LM, Parkey RW, Stokely EM, et al: Pathophysiology of technetium-99m stannous pyrophosphate and thallium-201 scintigraphy of acute anterior myocardial infarcts in dogs. J Clin Invest 57:1508-1522, 1976 11. Buja LM, Tofe AF, Kulkarnl PV, et al: Sites and mechanisms of localization of technetium99m phosphorus radiopharmaceuticals in acute myocardial infarcts and other tissues. J Clin Invest 60: 724-740, 1977 12. Sanne H: Exercise tolerance and physical training of non-selected patients after myocardial infarction. Acta Med Stand (Suppl) 551:1-44,1973 13. Kattus A: Exercise testing and training of apparently healthy individuals. A Handbook for Physicians. Dallas, Texas, Am Heart Association, 1972. p 15 14. Gazes PC, Mobley EM Jr, Farls HM Jr, et al: Preinfarctional (unstable) angina-a prospective study-ten year follow-up. Circulation 481331-336, 1973 15. Watkins PC, Rueeell RO Jr, Rackley CE: Follow-up study of un-
June 1978
The American Journal of CARDIOLOGY
Volume 41
1297
UNSTABLE
16. 17.
18.
19. 20.
21.
22.
23.
ANGINA PECTORIS-PUGH
ET AL.
stable angina in a myocardial infarction research unit (abstr). Circulation 46:Suppl IMI-23, 1972 Krauss KR, Hutter AM Jr, DeSanctis RW: Acute coronary insufficiency. Circulation 45:Suppl 1:1-66-l-71, 1972 Fischl SJ, Herman MV, Gorlin R: The intermediate coronary syndrome. Clinical, angiographic and therapeutic aspects. N Engl J Med 268:1193-1198, 1973 Favaloro RG, Effler DB, Cheanvechai C, et al: Acute coronary insufficiency (impending myocardial infarction and myocardial infarction). Surgical treatment by the saphenous vein graft technique. Am J Cardiol 28598-607, 1971 Cheanvechai C, Eff ler DB, Hoop FD, et al: Emergency myocardial revascularization. Am J Cardiol 32:901-908, 1973 ContiCR, Brawley RK, Griffith LSC, et al: Unstable angina pectoris: morbidity and mortality in 57 consecutive patients evaluated angiographically. Am J Cardiol 32:745-750, 1973 Bertolasl CA, TrongC JE, Carreiio CA, et al: Unstable anginaprospective and randomized study of its evolution with and without surgery. Am J Cardiol 33:201-208, 1974 Miller DC, Cannom DS, Fogarty TJ, et al: Saphenous vein coronary artery bypass in patients with “preinfarction angina.” Circulation 47:234-241,1973 Scanlon PJ, Nemickas R, Moran JF, et al: Accelerated angina pectoris, clinical, hemodynamics, arteriographic, and therapeutic
1298
June 1978
The American Journal of CARDIOLOGY
experience in 85 patients. Circulation 47:19-26. 1973 24. Selden R, Neil1 WA, Ritzmann LW, et al: Medical versus surgical therapy for acute coronary insufficiency. A randomized study. N Engl J Med 293:1329-1333, 1975 25. Scheidt SS: Unstable angina: medical management or surgery. Cardiovasc Med 2:541-543, 1977 26. Cairns JA, Fantus IG, Klassen GA: Unstable angina pectoris. Am Heart J 92:373-386, 1976 27. Plan MR. Mills LJ, Parkey RW, et al: Perioperative myocardial infarction diagnosed by technetium-99m stannous pyrophosphate myocardial scintigrams. Circulation 54:Suppl lll:lll-24-111-27, 1976 28. Platt MR, Parkey RW, Willerson JT, et al: Technetium stannous pyrophosphate myocardial scintigrams in the recognition of myocardial infarction in patients undergoing coronary artery revascularization. Ann Thorac Surg 21:311-317, 1976 29. Cohen MV, Cohn PF, Herman MV, et al: Diagnosis and prognosis of main left coronary artery obstruction. Circulation 45:Suppl I:I57-l-65, 1972 30. Hultgren HN: Medical versus surgical treatment for unstable angina. Am J Cardiol38:479-486, 1976 3 1. Cannom DA, Harrison DC, Schroeder JS: Hemodynamic observations in patients with unstable angina pectoris. Am J Cardiol 33:17-22, 1974
Volume 41