Initial Medical and Surgical Management of Unstable Angina Pectoris

Clin. Cardiol. 2. 311-316 (I979) G. Witzstrock Publishing House. Inc. Editorial Initial Medical and Surgical Management of Unstable Angina Pectoris Introduction The purpose of this report is to review the clinical definition. pathophysiology. and medical therapy of unstable angina and to compare the available results of four prospective random trials assessing medical and surgical therapy of these patients. The specific goal of this paper is to answer the important question. "What is the best way to treat patients with unstable angina at the time of initial presentation?" Definition of Unstable Angina Pectoris The definition of unstable angina is not precise. In the past. several terms have been used to define this subset of patients. Terms such as "pre-infarction angina" continue to be used without precise definition and probably contribute to the sense of urgency about surgical therapy. The term "unstable angina" itself may not be adequate but at least it indicates that the patient has chest pain and his condition is changing. The patient population under discussion is composed of individuals with chest pain considered to be suspicious for impending or extending myocardial infarction. Most agree that patients with recurrent rest pain or angina severe enough to require hospitalization fit the clinical definition. Patients with unstable angina can be divided into three broad subgroups: firstly. those with new onset of rest angina or new onset of minimal effort angina; secondly. patients with progression from stable angina (crescendo or accelerated). i.e. increased duration. intensity. and/or frequency of pain episodes or decreased responsiveness to nitrates; thirdly. those with recurrent angina immediately following a myocardial infarction. The clinical presentations of the first two subgroups frequently overlap. For example. many patients with crescendo effort angina progress to rest angina. In clinical practice. most patients admitted to the hospital with chest pain severe enough to be considered a myocardial infarction have rest angina. When an electrocardiogram is obtained in such patients during pain. ST segment depression or elevation is observed frequently. Pathophysiology of Unstable Angina Pectoris The pathophysiology of unstable angina pectoris is incompletely understood. However. since unstable angina occurs commonly at rest. it is likely that myocardial ischemia is the result of conditions in which coronary blood flow and oxygen supply are unable to meet the myocardial demand for oxygen under resting conditions. In some cases. aggravating factors such as tachyarrhythmias. systemic hypertension. anemia. thyrotoxicosis. etc., may be responsible for this imbalance of supply and demand. These conditions should be treated promptly with the appropriate therapy. In addition to considering rapid progression of atherosclerotic obstruction of the coronary arteries, one must also consider the possibility of such factors as recurrent platelet (3) or fibrin emboli and/or coronary spasm as being responsible for the chest pain. Maser; et al. (4) have shown that many anginal attacks at rest, with ST segment elevation or depression, are not preceded by a detectable increase in hemodynamic determinants of myocardial oxygen consumption. They have also shown that ischemic episodes characterized by ST segment elevation or depression, or an increase in voltage of T -waves. or normalization of T-waves with or without anginal pain

312 Editorial may occur in the same patient within a few minutes and show similar hemodynamic patterns. They further showed that by continuous monitoring of coronary sinus oxygen saturation with a fiberoptic catheter, a marked decrease in blood oxygen saturation precedes impairment of ventricular contraction, ST segment elevation or depression and chest pain. These findings point to a reduction in regional coronary flow as a pathophysiologic mechanism for the development of rest angina. Although these studies document the sequence of events in the individual attacks of angina pectoris, they do not offer any insight into the trigger mechanism for the event. The Clinical Problem The initial goals of therapy in patients with unstable angina must be to 1) prevent myocardial infarction, 2) preserve viable myocardium, 3) prevent death, and 4) relieve pain. To justify emergency coronary surgery a reduction in early myocardial infarction and death must be demonstrated. Therefore, these endpoints must be examined in surgically treated patients and compared to the same endpoints in comparable medically treated patients. Thus, to be fair to both forms of treatment, i.e., medical or surgical, the patients must be surgically suitable (proximal coronary artery stenosis, good distal vessels, reasonably good ventricular function and no other illnesses which would preclude surgery). It is now quite clear that a prospective random trial, comparing the results of optimal medical therapy and surgical therapy, is the best way to evaluate properly the goals of medical and surgical treatment. Medical Management In our view, all patients with unstable angina, regardless of ultimate therapy, should be treated during the initial stages of the illness with vigorous medical therapy. The demonstration that coronary vasospasm may be a frequent cause of angina at rest with ST segment elevation, with "normalization" of negative T-waves, or ST segment depression suggest that therapy should be individualized to each patient. The physician should try to establish whether angina at rest is due to increased myocardial oxygen demand over a limited fixed coronary reserve or is due to a sudden reduction in coronary blood flow not related to increased oxygen demands. Once these observations are made, a rational therapeutic approach to patients with unstable angina at rest can be determined. At the present time initial therapy should consist of I) admission to a hospital to rule out a myocardial infarction, to permit continuous monitoring, to provide prompt treatment of arrhythmias, and to relieve recurrent chest pain, 2) rest-this includes emotional as well as physical rest. Reassurance by a physician may be just as important as drugs to interrupt the cycle of angina, anxiety, more angina, etc., 3) removal or treatment of aggravating and/or precipitating factors such as thyrotoxicosis, anemia, hypertension, paroxysmal tachycardias and sympathomimetic drugs, 4) pharmacologic therapy appropriate to the individual patient. In many instances, long-acting sublingual or oral nitrates and/or topical nitroglycerin will effectively prevent recurrent episodes of rest angina. Individual attacks can be treated with sublingual nitroglycerin. Long-acting nitrates such as isosorbide dinitrate and erythrityl tetranitrate are usually given four times a day but can be used as often as every two hours. Topical nitroglycerin is slowly absorbed through the skin and may have an effect up to four hours. In the experience of most clinicians, beta blockers seem to control the symptoms of unstable angina. It is unclear why this should be the case since most episodes of rest angina occur without any obvious evidence of a preceding increase in myocardial oxygen demand. However, it should be pointed out that beta blockers may have other effects that favorably influence perfusion of ischemic myocardium: For example Mehta et al. (5) have shown that propranolol may reduce platelet aggregation across the myocardium at rest and during pacing-induced tachycardia. It is possible that factors initiating coronary vasospasm may be blocked by beta receptor blockade. The use of beta blockade in the treatment of unstable angina is empirical. If the patient responds favorably, then the drug should be continued. In most instances propranolol, 160-200 mg per day has been adequate to control symptoms although higher doses have been used effectively in some cases. Other pharmacologic agents (still under investigation in the United States) have been shown to be useful in treatment of rest angina. These include perhexiline maleate, nifedipine, verapamil, and diltiazem (2, 6,8). In animals these drugs share in common a mild epicardial vasodilator effect and an antidysrhythmic action probably related to inhibition of "slow channel" calcium transport across membranes. It has been suggested that blockade of slow calcium currents responsible for the action potential and contraction of smooth muscle in coronary arteries results in coronary dilatation. Why this mechanism should be more Clin. Cardiol. Vol. 2, October 1979

Editorial 313 effective than other directly acting vasodilators or the usually potent ischemia-associated metabolically-induced vasodilation has not been explained. If therapy with pharmacologic agents fails to control symptoms, it has been our practice to use intraaortic balloon counterpulsation. We have found that this is an effective method to control chest pain and other manifestations of ischemia in patients with unstable angina unresponsive to conventional medical therapy (nitrates and beta blockers in the United States). Weintraub et al. (I I) report that chest pain and electrocardiographic changes were abolished or significantly decreased in 15 of 16 patients treated in this manner. Theoretically, counterpulsation should decrease left ventricular systolic and diastolic pressure, thus, diminishing myocardial oxygen demands and increase diastolic aortic pressure, increasing blood flow. Despite these beneficial effects, intraaortic balloon counterpulsation does not stand alone as a therapy for patients with unstable angina. Instead, it should be viewed as a therapy which will diminish myocardial ischemia in patients with unstable angina and allow the safe performance of coronary angiography in preparation for surgical revascularization in patients with fixed coronary obstruction and persistent symptoms despite optimal medical therapy.. Patients responding to medical therapy during the initial hospitalization need to continue on an intensive medical program after discharge from the hospital. In addition to the usual pharmacologic therapy, patients should be encouraged to lose weight and stop smoking. Physicians should attempt to control blood pressure and/or cholesterol in patients where these factors are elevated. It has been our practice to perform an exercise stress test in these patients prior to discharge from the hospital. If the patients have a "positive" stress test at a low cardiac workload, i.e., heart rate below 120 beats/min, we recommend coronary angiography with the goal of detecting patients with physiologically significant left main coronary artery stenosis. Because of the poor prognosis, we recommend coronary surgery in this subgroup of patients (unstable angina plus left main coronary artery stenosis) whether or not symptoms are controlled by medical therapy. Results of Clinical Trials Comparing Medical and Surgical Therapy of Unstable Angina Pectoris Four prospective random trials comparing medical and surgical therapy in patients with unstable angina have been undertaken. These include the NHLBI trial (7) and those reported by Selden (10), Pugh (9), and Bertolas; (J). Patients in the NHLBI, Selden, and Pugh studies were randomized after coronary angiography whereas patients in the Bertolasi study were randomized prior to coronary angiography. Patients with left main coronary artery stenosis in the NHLBI study were excluded from randomization al1d offered surgical therapy. No patient in the NHLBI study was randomized to either form of therapy after failing a medical regimen prior to entrance into the study. Medical myocardial infarction rates during initial hospitalization varied from 0-8.3% (average 6%) (Table I). In contrast, myocardial infarction rate in the surgical patients varied from 11.7-17% (average 16%). Bertolasi divided his patients into two groups, intermediate and progressive. The group with the so-called "intermediate syndrome" had an 8.3% medical myocardial infarction rate during the hospitalization compared to a 13.5% surgical infarction rate. These latter figures are comparable to results in the NHLBI trial. Table I Myocardial infarction during initial hospitalization number of patients medical surgical NHLBI (7) 288 12/147 (8%) 24/ 141 (I 7"1,) Pugh (9) 27 0/14 (0%) 2/12 (17%) Selden (10) 40 0/19 (0%) 3/23 (13%) Bertolasi ( I ) intermediate 52 2/24 (8%) 4/28 ( 14%) progressive 61 0/27 (0%) 4/34 (12%) Total 468 14/231 (6%) 37/23 ( 160/..) Clin. Cardio!. Vol. 2, October 1979

314 Editorial The average mortality during the initial hospitalization was 4.3% for the entire medical group (range 0-20.8%) and 6.3% for the surgical group (range 5-10.7%) (Table 11). The group of patients with the intermediate syndrome, reported by Bertolasi, had the highest medical mortality (20.8%) and were inconsistent with the other studies. This mortality rate is slightly higher than that associated with myocardial infarction as reported by most coronary care units. Why this was the case is not clear. Table 1\ Mortality during initial hospitalization number of patients medical surgical NHLBI (7) Pugh (9) Selden (10) Bertolasi (I) in termed ia te progressive Total 288 27 40 52 61 468 4/147 (3%) 7/141(5%) 0/14 (0%) 1/13 (8%) 0/19 (0%) 1/21 (5%) 5/24 (21%) 3/28 (llro) 1/27 (4%) 3/34 (9%) 10/231 (4%) 15/237 (6%) The NHLBI study noted no significant change in the initial mortality before 1974 compared to after 1974. The myocardial infarction rate in the medically treated patients before and after 1974 was essentially the same (8 and 9%). However, there was a marked difference in the myocardial infarction rate in the surgically treated patients before 1974 (22%) compared to after 1974 (12%). This decrease in surgical myocardial infarction rate probably reflects an improvement in surgical techniques.. The above data, relating to initial management, are clear-cut and easy to interpret, i.e., infarction rate was higher with surgical therapy and the mortality rate was essentially the same in both groups. Interpretation of data relating to long-term survival, myocardial infarction rate, and symptoms in these patients is complicated by the fact that all patients randomized to medicine were not held in that category for their entire follow-up. For example, patients with persistent angina pectoris on medical therapy who were dissatisfied with their life style often received later surgery to relieve symptoms. In addition, some ofthe patients randomized to surgery had to undergo reoperation because of persistent symptoms and several patients were not improved by surgery and required intensive medical therapy. As a result of this crossover, long-term results are likely to be reported in patients according to the original assignment to medical or surgical therapy. When data are analyzed in this fashion, there is no significant difference in mortality or myocardial infarction rate in patients followed for variable periods of time. However, the NHLBI study attempted to deal with this problem of medical patients who later received surgery by analyzing survival curves by several different techniques. Survival curves were replotted comparing randomized medical patients up to the time of later surgery versus randomized surgical patients-there was no statistically significant difference in the survival rate. Similarly, the plot of the survival curve of the randomized medical patients who did not receive later surgery compared to randomized surgical patients revealed no statistically significant difference in their survival. Finally, when the survival curve of patients randomized to medicine who later received surgery were plotted against the patients initially randomized to surgery, it appears that the patients receiving later surgery had a better survival. However, the numbers in this group are small and do not reach statistical significance. The conclusions of these observations indicate that delaying surgery in these patients did not jeopardize their survival. None of the other studies analyzed their data in this fashion. However, Bertolasi showed a difference in survival in patients with "intermediate syndrome" (Table III). The medically treated group had a 32-month survival rate of 60%, whereas the surgically treated group had a 32-month survival rate of 900/0. Except for the clinical presentation, it is not clear how the patients with the "intermediate syndrome" differed from the patients with the "progressive" angina. In all studies reported, survivors of surgical therapy had significantly less symptoms than survivors of medical therapy (Table IV). Once again, one must recognize that the data are reported in these patients according to the original assignment to medical or surgical therapy. Thus, several patients who received later surgery, and were improved, are considered in the medically randomized group. Despite this problem, the difference in symptomatic status of the patients reported is striking. In the NHLBI study during the Clin. Cardiol. Vol. 2, October' I 979

Editorial 315 first year of follow-up, patients with two- or three-vessel disease randomized to medical therapy had a statistically higher incidence of Class III or IV angina compared to patients randomized to surgery (40% medical versus 14% surgical). This difference was consistent in all four random trials but the difference in symptomatic status of patients reported by Bertolasi was not so striking. Table III Total mortality and myocardial infarction rate average duration number of death m~ocardial infarction of follow-up patients medical surgical medical surgical NHLBI (30 months) (7) 288 13/147 (9%) 14/141 (\0%) 32/147 (22%) 43/141 (30%) Pugh (18 months) (9) 27 1/14 (7%) 1/13 (8%) 1/14 (0%) 3/13 (23%) Selden (4 months) (10) 40 0/19 (0%) 1/21 (5%) 2/19 (i 1%) 3/21 (14%) Bertolasi (32 months) (I) intermediate 52 11/24 (46%) 3/28 (11%) 9/24 (38%) 4/28 (14%) progressive 61 2/27 (7%) 3/34 (9%) 2/27 (7%) 4/34 (12%) Totals 468 24/231 (12%) 22/237 (9%) 45/231 (19%) 57/237 (24%) Includes myocardial infarction and deaths during initial hospitalization and following discharge based on original assignment to medical or surgical therapy Table IV Follow-up functional class III-IV average duration of follow-up medical surgical N H LBI (30 months) (7) 45% 15% Pugh (18 months) (9) 38% 0% Selden (4 months) (10) 63% 4.7% Bertolasi (32 months) (I) intermediate 16.6% 3.5% progressive 18.5% 0% Summary The definition of unstable angina is not precise but most agree that patients with recurrent rest pain or angina severe enough to require hospitalization for control of symptoms fit the clinical definition. The pathophysiology of unstable angina is not completely understood, but in addition to coronary atherosclerosis, one must consider the possible contribution made by coronary artery spasm. Initial therapy should include emotional and physical rest, elimination of aggravating and/or precipitating factors, and vigorous prophylactic therapy with nitrates. Beta blockers should be tried, and, if the patient responds favorably, the drug should be continued. Other agents (calcium antagonists) have been shown to be effective but are still under investigation in the United States. Random trials comparing medical and surgical therapy indicate that, during the initial hospitalization, myocardial infarction rate was higher with surgical therapy and the mortality rate was essentially the same in both groups. Thus, it is difficult to justify emergency surgery in these patients. Long-term mortality rates and symptomatic status of patients are difficult to analyze because patients randomized to medicine often received subsequent surgery. However, the NHLBI trial was unable to detect a difference in survival even if the surgery was delayed several months after discharge from the hospital. It is also apparent that survivors of surgical therapy have significantly less symptoms than survivors of medical therapy. The following can be used as guidelines for the evaluation and therapy of patients with unstable angina. I) Admission to a hospital for intensive medical therapy. 2) Exercise testing prior to discharge in medical responders. Patients with a positive test at "low" cardiac workload should undergo coronary angiography Clin. Cardial. Vol. 2, October 1979

316 Editorial and be considered for cardiac surgery. Patients with a positive exercise test at "high" cardiac workload may be tried on continued intensive medical therapy and retested at a later date. Patients with a negative exercise stress test should be continued on an intensive medical therapy. 3) Patients who respond poorly to initial medical therapy should undergo angiography and subsequent coronary artery surgery. In clinical practice, patients are selected for surgery based on the following criteria: I) data available from published studies; 2) obvious failure of medical therapy to control symptoms; 3) patient's desire for operation (generally related to symptoms); 4) surgeon's competence and track record; 5) physician's desire for operation (generally related to 1-4); and 6) financial resources (some countries simply cannot afford the operation). References I. Bertolasi CA, Tronge JE, Riccitelli MA et al.: Natural history of unstable angina with medical or surgical therapy. Chest 70, 596 (1976) 2. Curry RC, Pepine CJ, Conti CR: Refractory variant angina treated with perhexiline maleate: Results in 14 patients (abstr). Circulation 58 (11),179 (1978) 3. Folts JD, Crowell ED, Rowe GG: Platelet aggregation in partially obstructed vessels and its elimination with aspirin. Circulation 54, 365 (1976) 4. Maseri A, Severi S, De Nes M et al.: "Variant" angina: one aspect of a continuous spectrum of vasospastic myocardial ischemia. Pathogenetic mechanisms, estimated incidence in clinical and coronary arteriographic findings in 138 patients. Am J Cardiol 42, 10 19 (1978) 5. Mehta J, Mehta P, Pepine CJ: Platelet aggregation in aortic and coronary venous blood in patients with and without coronary disease. "I. Role of tachycardia stress and propranolol. Circulation 58, 881 (1978) 6. Muller JE, Gunther SJ: Nifedipine therapy for prinzmental's angina. Circulation 57,137 (1978) 7. National Cooperative Study Group. Unstable angina pectoris-national Cooperative Study Group to compare surgical and medical therapy. II. In-hospital experience and initial follow-up results in patients with one, two and three vessel disease. Am J Cardiol 43, 839 (1978) 8. Parodi 0, Simonetti I, Maseri A: Management of crescendo angina by verapamil. A double blind cross-over study in CCU, Circulation 56 (suppl IH), 224 (1977) 9. Pugh D, Platt M R, Mills LJ et al.: Unstable angina pectoris: A randomized study of patients treated medically and surgically. Am J Cardiol41, 1291 (1978) 10. Selden R, Neill W A, Ritzman L W et al.: Medical versus surgical therapy for acute coronary insufficiency. A randomized study. New Engl J Med 293, 1329 (1975) II. Weintraub RM, Voukydis PC, Aroesty JM et al.: Treatment of pre-infarction angina with intra-aortic balloon counter pulsation and surgery. Am J Cardiol 34,809 (1974) e. R. CONTI, M.D. R. e. CURRY, JR., M.D. L. G. CHRISTIE, JR., M. D. J. MEHTA, M.D. e. J. PEPINE, M.D. Department of Medicine Division of Cardiology University of Florida Box J-277 JHM Health Center Gainesville, Florida 32610 Clin. Cardiol. Vol. 2, October 1979