Unstable Angina: Relationship of Clinical Presentation, Coronary Artery Pathology, and Clinical Outcome

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1 ~~~ ~ Clin. Cardiol. 16, (1993) Unstable Angina: Relationship of Clinical Presentation, Coronary Artery Pathology, and Clinical Outcome BARRY D. Bmm, M.D., JAY DINERMAN, M.D., RALP HARTKE, JR., M.D., C. Rlcw CONTI, M.D., F.A.C.C. Division of Cardiology, Department of Medicine, University of Florida College of Medicine, and the Veterans Administration Medical Center, Gainesville, Florida, USA Summary: Patients with unstable angina are heterogeneous with respect to presentation, coronary artery morphology, and clinical outcome. Subclassification of these patients based on clinical history has been proposed as a means of identifying individuals at increased cardiac risk. We applied such a classification system to 129 patients discharged from a coronary care unit with a diagnosis of acute myocardial ischemia. Patients were then assessed for cardiac events (recurrent angina requiring revascularization, myocardial infarction, death) 12 months following hospital discharge. Patients were classified as recent onset unstable angina preinfarction (n = 42), crescendo unstable angina preinfarction (n = 4), and unstable angina postinfarction (n = 39). Within each of these groups, the patients were further subclassified based on the occurrence of angina on effort, at rest, or both. No attempt was made to subset patients taking anti-ischemic drugs at the time of clinical presentation to the physician. Coronary angiographic pathology (morphology and number of vessels involved) was similar in the subgroups, but coronary artery thrombus was statistically more likely to be found in patients with crescendo rest angina preinfarction or with frequent anginal episodes at rest postinfarction. Mortality was significantly higher for patients with unstable angina postinfarction (7.7%) than preinfarction (1.1 %). No statistical differences were noted between the subgroups with respect to the occurrence of myocardial infarction or recurrent unstable angina requiring revascularization. These data suggest that subclassification of unstable angina patients based on clinical Reviews for this paper and the editorial decision to accept it were made by an editor other than Dr. Conti. Address for reprints: Barry D. Bertolet, M.D. Division of Cardiology Department of Medicine BOX J. Hillis Miller Health Center Gainesville, FL 32610, USA Received: October 15, 1992 Accepted with revision: December 16, 1992 characteristics at presentation is not useful to predict subsequent myocardial infarction or recurrent angina requiring revascularization. However, as one might expect, patients with recurrent angina postinfarction have a higher mortality rate than patients with unstable angina preinfarction, and patients with recurrent rest angina, either pre- or postinfarction, are more liely to have intracoronary thrombus than patients with new onset angina or crescendo effort angina; however, the presence of thrombus did not predict a poor clinical outcome. Key words: unstable angina, classification, coronary morphology, coronary artery disease, coronary thrombus Introduction Patients with unstable angina are a nonhomogeneous group of individuals. There are some data suggesting that subclassification based on clinical presentations has varied the risks for future cardiac events. Two such subgroup classification systems have been reported,'-* yet no one has related them to prognosis in a retrospective or prospective fashion. Any classification protocol is useful only if it provides prognostic information or identifies patients early on who require specific diagnostic studies or therapy in order to modify their condition. This report applies one subgroup classification system (Table I) in a retrospective fashion to all patients discharged from the coronary care unit (CCU) with the diagnosis of unstable angina who had angiopdphically proven coronary artery disease or documented myocardial ischemia.' Each patient was then observed over a 12-month period for any adverse cardiac events such as death, myocardial infarction, or recurrent unstable angina requiring revascularization. Materials and Methods Study Population The study population consisted of 129 consecutive patients discharged from the coronary care units at Shands Hospital at the University of Florida and the Gainesville VAMC from

2 B. D. Bertolet et al.: Clinical presentation, coronary artery pathology, and clinical outcome in unstable angina 7 TABLE I Clinical classification of unstable angina patients pteinfarctiona (no recent MI) Recent onset chest discomfod Effort and rest Crescendo chest discomfoltc Effort and rest Postinfarctiond (recent MI) Occasional chest discomfort' Frequent chest discomfortf a Patients admitted to CCU because of acute myocardial ischemia, not infarction. b Symptoms present for less than 1 month. Symptoms occuning more frequently, longer in duration, or with less exertion than in previous month. Patients admitted to CCU with acute myocardial infarction who have angina prior to discharge. One to two episodedday. /Three or more episodedday. January 1, 19, through December 31, 19. All 90 preinfarction patients were admitted to the CCU with chest pain suspicious for acute myocardial ischemia. After 24 hours none had enzyme or ECG evidence of myocardial infarction. The 39 postinfarction patients developed recurrent angina despite an initial stabilization of symptoms with medical therapy. There was no standard diagnostic or therapeutic protocol, but rather, a therapeutic strategy developed for the individual patient was utilized. At discharge from the CCU, the diagnosis of unstable angina was made based on the clinical history and documented evidence of ischemic heart disease. All patients had coronary artery disease proven at coronary angiography, or by ECG evidence of a previous myocardial infarction, ST-segment depression during pain or during exercise testing, or by radionuclide studies in a few instances. Coronary angiography was performed within 10 days of admission to hospital. Data Collection In addition to clinical presentation, cardiac risk factors and prescribed antiangina medications were recorded. Hypeension was defined as a diastolic blood pressure 2 90 mmhg, or a history of hypertension with concomitant use of antihypertensive medications. Hypercholesterolemia was defined as a total cholesterol mg/dl, or history of elevated cholesterol treated with diet or drugs. Diabetes was considered present when the fasting blood glucose was mg/dl, or if the patient was using hypoglycemic agents. Initial standard 12-lead ECGs were also evaluated for ST-T changes suggestive of myocardial ischemia, as well as left ventricular hypertrophy (LVH). ECG changes considered compatible with ischemia were transient ST-segment elevation or depression 2 1 mm 0 ms after the J point, or transient T-wave flattening or inversion. ECG changes compatible with LVH were defined as the S-wave voltage (mm) from leads VI or V2 plus R-wave voltage (mm) from leads V5 Or v mm. Coronary angiograms were assessed for coronary artery stenosis and morphology by two cardiologists. A 50% stenosis of the left main coronary artery or a 70% stenosis of any other coronary arteries was consided sigmticant. Coronary artery morphology classification is shown in Table II. Drug therapy for preinfarction and postinfarction unstable angina in the coronary care unit consisted of thrombolytic agents, 0 (0%); beta-blockers, 49 (3%); heparin, 79 (61%); calcium antagonists, 91 (71%); aspirin, 1 (6%); nitrates, 127 (9%). The frequency of use of any of the above drug pups was similar between the unstable angina patients preinfarction and postinfarction. Recorded Cardiac Events The status of patients was assessed for cardiac events for 1 year following discharge utilizing the medical record andor telephone contact. Follow-up data were obtained in 126 of the 129 patients by one or both methods. Recorded cardiac events were recurrent unstable angina pectoris requiring revascularization, myocardial infarction, and death. TABLE II Classification of coronary artery morphology (3) Morphology type A B B2 C Lesion characteristics Discrete Less than 1 cm in length Noncalcified Bend < 45 ' Presence of one of the following descriptions: 1-2 cm in length Calcified Eccentric Ulcerated or irregular Bend 2 45" and <60" Recent occlusion Presence of two or more of the descriptions in B Greater than 2 cm in length Extremely calcified Extremely irregular Bend 2 60" Chronic occlusion

3 Clin. Cardiol. Vol. 16, February 1993 Data Analysis For comparison between the subgroups, statistical analysis is based on analysis of variance (ANOVA) followed by paired t-tests. All values are expressed as mean f standard error. Differences between group means are considered significant at p< ReSUltS Patient Demographics and CliNad Presentation Patient demographics and clinical presentation are summarized in Table III. The clinical presentation of the 90 unstable angina patients preinfarction and 39 postinfarction was varied, as one might expect, and the data are summarized in Table IV. Of the preinfarction patients with recent onset unstable angina, 14 of 42 (33%) were receiving antiangina drugs at admission. These drugs, that is, beta blockers or calcium antagonists, were prescribed for nonischemic conditions such as hypertension. Of the preinfarction patients with crescendo unstable angina, 42 of 4 (7.5%) were receiving antiangina medications at the time of admission. Of the postinfarction patients, 36 of 39 (92.3%) were receiving antiangina medication at the time of develop ment of their recurrent angina. Thus, antiangina drugs were used more commonly (as one might expect) in patients with crescendo and postinfarction angina than in patients with recent onset angina. Electrocardiography during Chest Pain ECG abnormalities suggestive of myocardial ischemia were noted in 53% of the initial ECGs obtained. The distribution of abnormal ECGs for each subgroup is shown in Table V. There was no difference among the various subgroups. Coronary Artery Pathology (Morphology) Coronary angiography was performed in 101 of 129 (7%) of the study population. Table VI summarizes these results. Left main coronary artery stenosis was identified in 13 of 101 (1 3%) patients studied by angiography. Multivessel disease was present in 50 of 101 (50%). and single-vessel disease was observed in 3 of 101 (3%). The frequency and distribution of CAD was similar among the groups, yet there was a trend (p = 0.15) toward more multivessel disease in the mscendo unstable angina and unstable angina postinfarction groups than in the recent onset unstable angina group. The morphology of the diseased coronary arteries was classified as in Table II. Table W summarizes the coronary morphology arranged according to the unstable angina groups. The angiographic appearance of coronary thrombus was noted in 1 of 101 (1%) patients, but was identified only in patients with crescendo unstable angina pre- or postinfarction occurring at rest. TABLE In Demographics of unstable angina patients and clinical presentation Preinfarction Postinfarction Clinical Recent onset Crescendo Recurrent feature angina (n = 42) angina (n = 4) angina (n = 39) Age (mean) 37- (5.4) 3-1 (60.) 46-7 (61.6) Male 30 (73%) 32 (67%) 35 (90%) Female 12 (29%) 16 (33%) 4(10%) Hypertension 22 (52%) 25 (52%) 15 (39%) Elevated cholesterol 10 (24%) 16 (33%) 7(1%) Diabetes (19%) I3 (27%) 12(31%) Smoking 32 (76%) 25 (52%) 21 (54%) Fn CAD 19 (45%) 23 (4%) 19 (49%) LVH (ECG) 3 (7%) 6(13%) 2 (5%) Abbreviations: FH CAD = family history of coronary artery disease, LVH = left ventricular hypertrophy. TABLE IV Clinical presentation of unstable angina Preinfarction (90 patients) Recent onset (42 patients) Effo~t angina Effort and rest angina Rest angina Crescendo (4 patients) % Effort angina Effort and rest angina Rest angina Postinfarction (39 patients) Effort angina: frequent (3 or more) episodedday Rest angina: occasional (1-2) episodedday Rest angina: frequent (3 or more) episodedday Cardiac Events % I Over a 12-month period after initial discharge from the CCU, 44 cardiac events occurred in 35 of the 129 patients. The majority of these events occurred within the first 6 months (W44, 77%). These results are summarized in Table VIII. Mortalily: Four of the 129 patients died (3.1 %). Of these patients, three had ischemic changes on the admission ECG; all had rest pain. No deaths occurred within the 1 -month period after admission, but three occurred within the first 6 months. Three underwent coronary angiography-one had left main disease and two had 2-vessel CAD. The coronary artery morphology was type B (Table n) with associated thrombus in each case. The difference in mortality between unstable angina patients preinfarction, ( 1/90, l. l %), compared with unstable angina patients postinfarction (3/39,7.7%) was statistically significant (p < 0.05). Myocardial infarction: Of the 129 patients, 16 (12.4%) evolved a myocardial infarction; of these (69%) had is-

4 B. D. Bertolet et al.: Clinical presentation, coronary artery pathology, and clinical outcome in unstable angina 9 TABLE V Initial ECG among unstable angina subgroups Clinical presentation Patients - ST-T Changes + ST-T Changes Preinfarction Recent onset angina Effort Effodrest 4 7 Rest Subtotal Crescendo angina Effo~t Effodrest Rest Subtotal POs!irifmtion angina Occasional rest Frequent effort Frequent rest Subtotal Total ~~ ST-T change, ST-segment elevation or depression and/or 10" T-wave axis shift from baseline suggestive of myocardial ischemia. chemic changes on the initial ECG. Four of the MIS occurred within the first 4 weeks after discharge, with 12 of 16 taking place within 6 months after discharge. Coronary angiography revealed an equal distribution of stenotic coronary vessels; three patients had angiographic evidence of coronary thrombosis. Coronary morphology demonstrated two type A, three type B, nine type B2, and one type C lesions. No difference was noted between the two unstable angina preinfmtion groups, recent onset (7/42, 17%), and crescendo (6/4, 12.5%), nor between those with effort-induced unstable angina (3/24,12.5%) and unstable angina at rest (1 3/105,12.4%), nor between those with unstable angina preinfarction (13/90,14.4%) and postinfarction (3/39,7.7%). Recurrent unstable angina requiring revascularization: Of the 129 patients, 24 (1.6%) developed recurrent unstable angina requiring revascularization and of these (40%) had ischemic changes on the initial admission ECG. Recurrent angina within the first month following dischge occurred in three pa- TABLE VI Coronary artery pathology among unstable angina subgroups clinical Number with presentation Patients angiogram Lh4 CAD 3-v CAD 2-v CAD I-VCAD Preinfatrtion Recent onset angina Effort Effodrest Rest Subtotal Crescendo angina Effort Effodrest Rest Subtotal Postinfarction Angina Occasional rest Frequent effort Frequent rest Subtotal Total Abbreviations: LM = left main, CAD = coronary artery disease.

5 120 Clin. Cardiol. Vol. 16, February 1993 TABLE VU Coronary morphology type among unstable angina groups Clinical Angiography Morphology type (%) presentation Patients (n) A B 2 C Thrombus Preinfarction unstable angina Recent onset (23) 4() I (51) 5 (14) 0 Crescendo (15) (2) 1 (45) 5 (13) 7 Postinfarction Recurrent angina () 17 (65) 6 (23) l(4) II Total I6 (16) 32 (32) 42 (42) II () 1 TABLE VUI Cardiac events occurring during a 12-month period related to general clinical presentation ( 129 patients) Recent onset Crescendo preinfarction preinfmtion Postinfarction (n = 42) (n = 4) (n = 39) Event Time span Death MI RARR Death MI RARR Death MI RARR total <I months - I months months I 7-12 months I Total number 0 7 II (%I (0) (17) (26) (2) (13) (17) () () (13) Abbreviations: MI = myocardial infarction, RARR = recurrent angina requiring revascularization. tients, with 19 of 24 events occurring within the fmt 6 months of follow-up. The extent of coronary artery pathology was varied. However, no statistical differences were noted either between patients with unstable angina preinfarction ( 19/90,21 %) and those with unstable angina postinfatdon (5/39,13%), or between patientswithunstableanginaatrest(20/105,19%)andthosewith effort-induced unstable angina (4/24,17%), or between the two subclassifications of preinfmtion unstable angina. Ninety-four patients (73%) had no defined cardiac event in the 1 -year follow-up; however, 19 of these patients (20%) did have recurrent angina which was treated successfully by further aggressive medical therapy. Determination of Risk Cardiac events could not be predicted based on age, sex, cardiac risk factors, admission ECG, coronary anatomy, and coronary artery morphology (Tables IX and X). No difference could be found in the number of cardiac risk factors present in patients who ultimately had a cardiac event (2.2) and those who did not (2.0). Similarly, ischemic changes on the initial admission ECG did not identify those at risk for future events. Of the 35 patients who had a cardiac event, 19 (54%) had initial ECG changes suggestive of ischemia, compared with 49 of 94 (52%) patients with no event. Neither the extent of the coronary artery disease nor coronary artery morphology could project future cardiac events. The positive predictive value for each category evaluated was less than 50%. The diagnosis of coronary throm- bus at angiography was made in 1 of 60 (30%) patients with either crescendo unstable angina occurring at rest preinfmtion or frequent unstable angina occurring at rest postinfarction. No thrombus was noted at the time of coronary angiography in the other unstable angina groups. This difference attained statistical significance (p ~0.001). However, evidence of coronary thrombosis did not predict adverse cardiac risk. Discussion In this analysis, a detailed clinical classification protocol of unstable angina was used in 129 hospitalized patients over a TABLE IX Cardiac event rate occuning during a 12-month period related to age, sex, ECG changes, and risk factors Cardiac event No cardiac event Total n = 35 (27%) n = 94 (63%) n = 129 (%) Age (mean) 3-2 (59.2) 37- (60.7) 37- (60.3) Male (%) 2 (0) 69 (73) 97 (75) Ischemic changes on initial ECG 19 (56) 49 (52) 6 (53) Mean number cardiac risk factors

6 B. D. Bertolet et al.: Clinical presentation, coronary artery pathology, and clinical outcome in unstable angina 121 TABLE X PhologY Cardiac event rate occurring during a 12 month period related to coronary angiographic disease severity and coronary artery mor- Coronary artery pathology Anatomy Angiograms Left main 3-v CAD 2-v CAD 1-v CAD Morphology A B B2 C Angiographic coronary artery thrombus Cardiac events No cardiac events Total Patients Death MI RAW Patients patients Abbreviations: MI = myocardial infarction, RARR = recurrent unstable angina requiring revascularization, CAD = coronary artery disease Zmonth period following discharge from the hospital in an attempt to identify risk for future cardiac events. Cardiac risk factors were present in a majority of these patients; however, neither their presence nor number correlated with futw events. ECG changes suggestive of ischemia noted on admission were not predictive of cardiac events. However, a majority of patients who died (3/4) or evolved a myocardial infarction (1 1/16) had ischemic ECG changes at admission. Coronary angiographic pathology was similar among the clinical subgroups. The distribution of CAD in this study was similar to that noted by Plotnick et al4 in 190 in their angiographic studies of unstable angina patients, that is, there was a trend toward more multivessel disease in the crescendo unstable angina p up compared with the recent onset angina group. There was, however, no relationship between coronary artery stenosis or the number of stenotic vessels and future cardiac events. The majority of patients had complex coronary artery morphology (type B or C); however, the positive predictive value of morphology on future cardiac events was poor. Bugiardini and associates? in unstable angina patients, found that the coronary morphology had a positive predictive value of only 55% in identtfying patients with unfavorable clinical outcomes. In a preliminary report, Hernandez et al6 using the Braunwald classification of unstable angina pectoris, tried to correlate clinical presentation with coronary artery pathology in 6 patients. There were 15 patients in Class I (new onset of severe angina or accelerated angina, no rest pain); 15 in Class II (angi- M at rest within the past month but not within the preceding 4 h); and 3 in Class IU (angina at rest within 4 h). There were no differences in the clinical variables among the groups. Ischemic ECG changes were recognized in 5%. There was a trend for more three-vessel CAD among Class I patients. Left main coronary artery disease was noted in five patients (7%), all Class III. Otherwise, the distribution of coronary pathology among the subclasses was without significant differences. These investigators concluded that Braunwald s classification does not allow prediction of coronary anatomy. The abstract contained no information concerning cardiac events. Conclusion This study yielded the following results: The classification scheme used identified subgroups of unstable angina patients likely to have coronary thrombus on angiography (rest angina); however, the presence of thrombus did not predict a poor clinical outcome. Mortality was signfxantly higher in unstable angina patients postinfarction (7.7%) compared with unstable angina patients preinfarction ( 1.1 %). Certain groups of patients, [i.e., those with no ischemic ECG changes at admission (47%) or those with recent onset unstable angina], considered by many to represent low risk, were just as likely to have cardiac events as other subgroups. Subclassification of unstable angina patients was not useful in predicting myocardial infarction or recurrent angina requiring revascularization. Overall, these patients, with medical intervention, have a low 1-year mortality (3%), but a high incidence of myocardial infarction (12%) and recurrent unstable angina requiring revascularization (19%). Seventy-seven percent of these events occurred in the 6-month period following discharge from the CCU. One may speculate that these cardiac events occurred in those patients with persistent unrecognized (silent) myocardial

7 122 Clin. Cardiol. Vol. 16, February 1993 ischemia. Perhaps identification and quantification of persistent myocardial ischemia might identify those patients who are at high risk for future cardiac events. References 1. Conti CR Editor's Note. Clin Cutriiol (199) 2. Braunwald E: Unstable angina: A classification. Circulutiori 0, (199) 3. Ryan TJ, Faxon DP, Gunnar RM, Kennedy JW, King ITI SB, Loop FD, Peterson KL, Reeves TJ, Williams DO, Winters WL, Fisch C, DeSanctis RW, Dodge HT, Weinberg SL: Guidelines for percutaneous transluminal coronary angioplasty. A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee on Percutaneous Transluminal Coronary Angioplasty). J Am C d Cudid 12, (I 9) Plotnick G, Fisher ML, Carliner NH, Becker LC: Cardiac catheterization in patients with unstable angina. J Am Med Assoc 244, ( 190) Bugiardini R, Pozzati A, Borghi A. Morgagni GL, Ottani F, Muzi A, Pudda P: Angiographic morphology in unstable angina and its relation to transient myocardial ischemia and hospital outcome. Am J Curdiol67.46CkW ( I99 1) Hernandez MV, Escobar E, Florenzano F, Marin P Unstable angi- M: Angiographic correlation of Bmunwalds classification. Abstracts of the XIV Interumericun Congress of Cudiology No. 33,9 (1992)