Prognosis in stable angina pectoris and silent myocardial ischemia

Prognosis in Stable Angina Pectoris and Silent Myocardial lschemia MICHAEL

E. ASSEY, MD

The results of current investigation suggest that a former clinical standby, namely, the presence or absence of angina, is no longer the principal prognostic factor for determining a patient’s risk of cardiac events, including myocardial infarction. In a retrospective analysis, patients with chronic stable angina were compared on the basis of presence or absence of angina during ischemia detected by thallium imaging. Patients were similar in terms of risk factors, clinical characteristics and catheterization data. At 30 months of follow-up, the myocardial

infarction rate was 22% in the silent group compared with 4% in the group with angina. ‘Transient asymptomatic ischemia has prognostic value independent of other variables such as exercise stress testing or cardiac catheterization data. Future prognostic studies should be careful to include! patient populations with similar characteristics; they also will need to provide protracted follow-up and utilize sensitive and reproducible diagnostic techniques. (Am J Cardiol

I

n this era of silent myocardial ischemia, chronic stable angina pectoris is increasingly difficult to define, For the purposes of this review, the syndrome includes patients who are out of the hospital, ambulatory, and stable enough to undergo exercise stress testing.

1988;61:19F-21F)

cording to the presence or absence of pain and the presence or absence of ST-segment depression. Patients with silent myocardial ischemia had a l-year survival rate of 76%, which was equivalent to that of patients with angina-whether or not they had STsegment depression. Seven-year survival rates of patients with silent myocardial ischemia were 86% for those with l-vessel disease, 73% for those with 2-vesse1 disease and 57% for those with 3-vessel involvement2 Thus, the extent of ischemia-in this case judged angiographically-determined prognosis, independent of angina. This, of course, had been suggested years before by Cohn et a1.3 In this study, the prognosis for patients with 3-vessel disease and silent ischemia was no better than that of patients with angina and similar coronary anatomy. Although the study of Amsterdam et al4 did not specifically look at mortality, it is well documented that in patients with chronic stable anginal, the extent of coronary artery disease and left ventricular ejection fraction are valid determinants of prognosis. These determinants were found to be the same in patients with ST-segment depression that occurred without angina or a minute before angina, and in those who had angina without ST-segment depression, or those who had simultaneous ST-segment depression and angina. It is likely that patients with chronic stable angina have a silent element even to their symptomatic ischemic episodes.

Current Data Rabaeusl evaluated 150 patients with effort angina who were asymptomatic during a positive exercise treadmill test. All had previous infarction or angiographically documented coronary artery disease. In 45 months of follow-up, 76 of these patients (51%) had a coronary event: 2.5% had unstable angina, 6% had myocardial infarction (MI], 7.5% died suddenly and 33% had to undergo coronary artery bypass grafting. During a &year follow-up, there were 11 sudden cardiac deaths plus a other cardiac deaths. Three of these “other” deaths occurred after infarction, 3 occurred after surgery and 2 resulted from late ischemic cardiomyopathy. Thus, the mortality rate totaled l3%, or 3.5%/year in this uncontrolled study.1 In the Coronary Artery Surgical Study (CASS), patients exercised and were classified into 4 groups acFrom the Division of Cardiology, Medical University of South Carolina College of Medicine, Charleston, South Carolina. Address for reprints: Michael E. Assey, MD, Division of Cardiology, 816 C5B, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425 19F

20F

A SYMPOSIUM:

TABLE

I

Exercise

SILENT

Stress

MYOCARDIAL

ISCHEMIA

AND

INFARCTION-PAST,

Test Variables* Group ISilent (n = 27)

Variable Exercise duration (set) Patients with 11 mm ST-segment depression over baseline Maximal heart rate (beats/min) Peak systolic blood pressure (mm Hg) Peak double product (heart rate X systolic BP)

450 11(41%)

TABLE

II

Medical

@ blockers Calcium channel blockers Nitrates Aspirin Digoxin Antiarrhythmic therapy

Cardiac

p Value

Variable

345 14 (50%)

<0.05 NS

Below normal ejection fraction (<50%) Elevated left ventricular end-diastolic pressure (>I2 mm Hg) Left main CAD 3-vessel CAD P-vessel CAD

129 166

121 152

NS NS

21,414

18,392

<0.05

Therapy*

Drug

III

AND

Group IlSymptomatic (n = 28)

* Exercise stress test variables in patients with silent vs symptomatic myocardial infarction. Only 41% of the asymptomatic patients and 50 % of the patients with angina had ST-segment depression on electrocardiography; therefore, stress testing that used ST-segment shifts only would have missed the diagnosis in as many as half the patients that were diagnosed as having ischemia based on thallium imaging. (Reprinted with permission by Am J Cardiol 1987;59:498.) BP = blood pressure; NS = not statistically significantly different.

TABLE

PRESENT

Group ISilent (n = 27)

Group IISymptomatic (n = 28)

p Value

18 (67%) 11(41%) 11(41%) 7 (26%) 9 (33%) 2(7%)

18 (64%) 17 (61%) 22 (82%) 11(39%) 10 (36%) 1(4%)

NS NS 0.01 NS NS NS

* Medical treatment in the 2 groups ranged from p blockade to antiarrhythmic therapy. The only significant difference was in the use of nitrates, which was almost twice as frequent in the symptomatic than in the silent group. NS = not statistically significantly different.

Falcone et al5 reported equal survival in 269 symptomatic and 204 asymptomatic patients with similar coronary anatomy and left ventricular ejection fractions. However, patients with silent ischemia were characterized by the following: a longer exercise duration, higher peak double product, more ST-segment depression at peak exercise and exercise-induced ventricular ectopy-a fertile substratum for sudden death in this otherwise chronic stable angina group.

Radionuclide Imaging in Patients with Stable Angina and Silent Myocardial lschemia Radionuclide imaging studies have given additional insight into characteristics of patients with silent myocardial ischemia and can enhance detection of those at increased risk for cardiac events. Reisman et al6 performed thallium imaging studies in over 1,000 patients who had no previous history of MI or coronary bypass surgery. About 10% of them (160 patients) had hypoperfusion during stress that reached normal levels at rest. Of this group, 83 were asymptomatic and 77 had angina. The cardiac event rate at 1 year was low. However, patients with chronic

FUTURE

Catheterization Group ISilent (n = 27)

Data” Group IlSymptomatic (n = 28)

p Value

3(11%)

4 (14%)

NS

12 (44%)

13 (46%)

NS

1(4%) IO (37%) 8 (30%)

2 (7%) 12 (43%) 11 (39%)

NS NS NS

l Cardiac catheterization data were not significantly different groups. An approximately equal distribution was seen in occurrence and 3-vessel disease in the asymptomatic and symptomatic groups. with permission by Am J Cardiol 1987:59:498.) CAD = coronary artery disease; NS = not statistically significantly

in the 2 of I-, 2(Reprinted different.

stable angina may have to be followed longer than 1 year to define the true endpoint, unlike unstable patients who may have a definable endpoint as early as 30 to 60 days. A cardiac event (death, MI, bypass] occurred in 7 (8%) of the asymptomatic and in 14 (18%) of the symptomatic patients. When the events were evaluated in terms of whether these patients had achieved 85% of predicted heart rate, something very important appeared: When unable to reach maximal predicted heart rate, the asymptomatic patients had an event rate similar to that of the symptomatic patients, and the amount of perfusion defect, as judged by number and size of thallium defects, was similar. Therefore, thallium testing identified a high-risk group in an otherwise asymptomatic cohort of patients, Radionuclear angiography can also be useful when risk-stratifying patients with chronic stable angina. In 131 patients at the National Institutes of Health who underwent cardiac catheterization and exercise testing, there was a very high prevalence of silent ischemia. Patients in this study most likely to have angina were those with left main and 3-vessel disease or a low ejection fraction. All of the deaths occurred in patients who had both an exercise-induced decrease in ejection fraction and ST-segment depression. Dividing these patients into subsets of those with angina and silent myocardial ischemia, the risk of dying with left main disease or with left main and 3-vessel disease was independent of the presence or absence of angina during the test.

Retrospective Findings in Patients with Chronic Stable Angina and Silent Myocardial lschemia My colleagues and I performed a retrospective study of 55 patients with angiographically documented coronary artery disease. Group I comprised 27 patients who had transient ischemia without angina during thallium testing; group II comprised 28 patients who had ischemia with angina during the procedure. All of the patients had undergone cardiac catheterization within 6 months of the study; 90% had undergone catheterization within 6 weeks. Patients were followed

April

21, 1968

for at least 2.5 years to determine the significance of a reversible thallium defect detected during exercise testing that was unrecognized by the patient. Study endpoints were hospitalization for unstable angina, MI and sudden cardiac death. In the silent group, 41% of patients had ST-segment depression compared with 507’0 of the symptomatic patients. Thus, if we had just looked at electrocardiographic changes, ischemia would have been detected in only half of qur patjents. The absence of angina in group’1 was not due to a submaximal exercise load; all patients were pushed to exhaustion, and the double product was higher in the silent group than in the symptomatic group (Table I]. The clinical characteristics of the 2 groups were similar in terms of known risk factors for coronary atherosclerosis. Qrug therapy could not be controlled in this study. However, there was only 1 difference in treatment betweeri the groups: Patients who were symptomatic on the treadmill were taking nitrates more frequently, usually in the form of supplemental sublingual nitroglycerin (Table II]. Cardiac catheterization data were also similar in both groups (Table III]. Considering their hemodynamics, these patients should have had a very low complication rate. But at 30 months of follow-up, acute MI had occurred in 6 asymptomatic patients (22%) and in 1 symptomatic patient (4%). There were no unusual findings in the 6 patients who had the infarcts. One of the patients had l-vessel, 2 had &vessel and 3 had %vessel disease. In 3 of the asymptomatic patients, infarction terminated in death, for a mortality rate of 11%. None of the patients with angina died. The incidence of hospitalizatipn for unstable angina was 48% in the silent group vs 57% in the group with angina.8 We coqcluded that transient ischemia, identified in this manner, has prognostic value independent of other variables such as standard exercise testing and cardiac catheterization data. The demonstration of exercise-induced silent ischemia may predispose the patient to a higher infarct rate. Certainly, the absence

THE AMERICAN

JOURNAL

of angina did not impart patients.

OF CARDIOLOGY

Volume

61

21F

a better prognosis to these

Considerations for Future Prognostic Studies In planning future prospective studies on the prognosis of stable angina patients with silent myocardial ischemia, investigators should be carefu! to select subj ects who are free of prognosis-altering medications or interventions, particularly bypass surgery. Our study contained an element of bias because participants were receiving medical treatment. Althoug‘h we tried to minimize the impact of this by demonstrating equal therapy between groups, a given therapy may not have the same effect in one patient as in another. The study populations should be well defined and homlogeneous, with no recent history of MI, and follow-up will have to be prolonged if we are to determine true prognosis. Finally, techniques for detecting silent myocardial ischemia will need to be sensitive and highly reproducible.

References 1. Rabaeus M, Righetti A, Moret P. Long-term follow-up of patients with positive exercise test without hngina in a referred populat@. In: Rutishauer W, Roskamm H, eds. Silent Myacardial Ischemia. Berlin: Springer-Verlag, 1984;165-169. 2. Weiner D, Ryan TJ, McCabe CH, Luk S, Chaitman BR, Sheffield T, Tristan! F, Fisher LD. Significance of silent myocordial ischemia during exercise testing in patients with coronary artery disease. ,jm J Cardiol1987;59:725-729. 3. Cohn PF, Harris P, Barry WH, Rosali RA, Rosenbaum D, Waternaux C. Prognostic importance of angina1 symptoms in angiographically defined COTonary artery disease. Am J Cardiol 1981;47:233-237. 4. Amsterdam EA, Martschinske R, Laslett LJ, Rutledge JC, Zakauddin Y. Symptomatic and silent myocardiql ischemia during exercjse testing in coranary artery disease. Am J Cardiol 1986;58;43B-46B. 5. Falcone C, de Servi S, Poma E, Campana C, Scire A, Montemartini C, Specchia G. Clinical significande of exercise-induced silent myocardipl ischemia in patients with coronary artery disease. JACC 1987;9:295-299. 6. Reisman S, Ladenheim M, Staniloff H, Rozanski A, Berman DS. Asymptomatic patients with exercise TL-201 hypoperfusion: identification of a highrisk subset. Circulation 1985;72:fII:III-445. ‘7. Bonow R, Bacharach SL, Green MV, La Freniere RL, Epstein SE. Prognostic implications of symptoniatic versus asymptomatic [silent) myocardial ischemia induced by exercise in qildly symptomatic and in asymptomatic patients with angiographically documented’ coronary artery diseqsd. Am J Cardiol 1987;60:778-783. 8. Assey ME, Walters GL, Hendrix GH, Carabello BA, Usher BW, Spann JF. Incidence of acute inyocardial infarction in patients with exercise-induced silent myocardial ischemiq. Am J Cardiol 1987;59:497-500.