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Unstable angina: Outcome according to clinical presentation
JACC Vol . 19. No. 7 Junc 1992:1 659-63
1659
Unstable Angina : Outcome According to Clinical Presentation AMADEO BETRIU, MD, MAGDA HERAS, MD, MARC COHEN, MD, FACC VALENTIN FUSTER, MD, FACCt Barcelona, Spain; Philadelphia, Pennsylvania ; Boston, Massachusetts
Unstable angina is a broad clinical diagnosis that includes patients atdiferent levels of risk for an unfavorable outcome . Although, as in other categories of coronary artery disease, the state of left ventricular function and the extent of coronary artery disease will determine long-term prognosis, recognition of clinical markers of an early unfavorable course may he of value in defining manage . ment strategies, This review focuses on the relevance of baseline clinical characteristics and noninvasive data in assessing the prognostic significance of unstable angina in light of its presenting features. Recurrence of chest pain within 48 h after admission carries a reduction In likelihood of survival of about 20% in patients with progressive or prolonged angina . Similarly, ECG changes on admission have a negative prognostic Implication, particularly in rest angina, as they predict recurrence of ischemia, myocardial
Unstable angina covers a wide range of clinical presentations with a common link ; an uncertain prognosis . In fact, uncertainty has been considered the hallmark of unstable angina . Given the variability in the natural history of patients with unstable angina, we rely on the identification of prognostic factors to dictate practical guidelines for therapeutic decisions . In this article, we review the prognostic significance of different forms of unstable angina to define management sbategirs, paying attention to the relevance of both baseline clinical characteristics and noninvasive data as indicators of outcome. Data from large representative series published over the past 2 decades are analyzed, with inclusion of results in medical or control arms in randomized trials, but old retrospective surveys relating prodromal events to subsequent myocardial infarction have been purposely avoided . When assessing the available information on unstable angina, one finds several limitations such as the definition of angina, including differences in the condition of patients entered in each study, the frequent inclusion of patients with
From the Department of Cardiology, Hospital Clinic, University of Barcelona, Barcelona, Spain; the 'Hahnemano University, Philadelphia, Pennsylvania; and the SCardiac Unit, Massachusetts General Hospital, Boston, Massachusetts, This work was supported in pan by Grant 9010596 from the Foodo de Investigaciooes Sanitaias (FiS), Madrid, Spain. Manuscript received July 22, 1991 ; revised tnanusedpl received December 3,1991, accepted January 7, 1992 . Add- for reorintc Amedeo Beaiu, MD, Department of Cardiology. Hospital Clinic, Villarroel 170, 09036 Barcelona, Spain. 01992 by the American College of Cadiology
infarction or need fee revascularteation in 90% of the puts, In variant angina, determinants of prognosis are level of disease activity, as judged by recurrence ofpain, ECG changes and use of calcium channel antagonists. Patients with angina after a myanr. dial infarction who have mare thanes episode of either angina or silent L'ehemia in 24 h have a 10% reduction la probabiE!y of survival during the lot year compared with that of asympeommic patients . An abrupt course, or the rapidity with which symptoms develop, is the maim determinant of progaesis in new onset angina. Thus, recurrent angina and ECG changes appear to be relevant prognostic markers in the patient subsets considered : if these are present, early coronary, aglogranhy, mud be performed and revasculartnation procedures should be coffered without delay . (J Am Call Cordial 1992;19:1659-63)
non-Q wave infarction, the lack of angtographic information in many series, the inclusion of patients with previous myocardial infarction (and therefore with different degrees of left ventricular dysfunction) and differences in the length of follow-up and the treatment received. It is now well known (1,2) that treatment with aspirin has significantly changed the outcome of patients with unstable angina, reducing the incidence of nonfatal myocardial infarction and cardiac death. Recent reports (3-5) have also demonstrated that heparin infusion and aspirin administration significantly decreased the incidence of refractory angina and acute myocardial infarction while definitive therapy was being determined . As a result, the current outcome of unstable angina might be expected to improve in relation to that of series completed before the routine use of aspirin or heparin . To circumvent some of these limitations in the study of unstable angina, Braunwald (6) recently proposed a clinical classification of this condition that separates exertional angina from rest angina and takes into account the presence of extracardiac precipitating causes, the presence of recent (<2 weeks) myocardial infarctien and the intensity of treatment received . Although this classification may elucidate the natural history and prognosis of the different groups of patients with unstable angina, its usefulness needs to be validated prospectively not only in research studies but in the clinical setting. Categoriesofunstableaugaa . A review ofpublished data allows us to define the "classic" categories of unstable 0735-1097192JSS.00
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IACC Vol . 19, No.7 Junc 1992 :1659-63
BETI5IU CT AL . PROGNOSIS IN UNSTABLE ANGINA
%-probability too96 5 92 90
1
92
7
90
survival
184 182 80 . N•1947
79
Survival without MI months
3
9
12
Figure 1. Kaplan-Meier actuarial curves showing the probability of survival and survival without myocardial infarction (Ml) for the Ist 12 months after progressive or prolonged angina . These 1,947 patients are pooled together from 10 different studies (i-3, 7-13).
angina : 1) progressive angina, worsening of symptoms with an increasing number of episodes of chest pain (crescendo pattern) ; 2) prolonged angina, the anginal episodes of longer duration only partially relieved by nitroglycerin ; 3) rest angina, anginal pain occurring at rest (possibly an "end stage" of the two preceding forms of angina) ; 4) variant angina, angina not related to physical activity and accompanied by transient ST segment elevation ; 5) posimyocardial infarction angina, angina occurring in the hospital after an acute myocardial infarction ; 6) new rnsel angina, angina that has developed within the preceding 30 to 60 days . In practice, it appears extremely difficult to find clear-cut categories . For example, so-called angina at rest is hardly ever found alone and generally occurs in association with the progressive and prolonged types and will be analyzed in this fashion.
Progressive and Prolonged Angina : Angina at Rest Progressive and prolonged angina, analyzed together in most studies, account for the majority of patients with the diagnosis of unstable 0ngina. To assess the overall prognosis, we reviewed 10 representative series with a total of almost 2,000 patients (Fig . I) (1-3,7-13) . Fifty-three percent of these patients had electrocardiographic (ECO) changes as an inclusion criterion . Previous myocardial infarction had occurred in 39%; only 31% underwent coronary angiography . The in-hospital mortality rate ranged between 2% and 8%a with a mean survival rate of 96%a. At 1 year the mean survival rate was 90%. The event-free probability (probability of survival without infarction) was 89% at I month and 79% at I year . These patients were not treated uniformly because beta-adrenergic blocking agents were not routinely used in the earliest studies, and calcium channel antagonists became available only more recently . However, proof is still lacking that these therapies-regardless of their value in the
control of symptoms-might have changed the natural history of unstable angina . Patients presenting with angina at rest and ECG changes have been reported to have a poorer prognosis (14-16) . However, this patient group included a number of patient: with non-Q wave myocardial infarction or variant angina. Recurrence of chest pain. A recurrence of chest pain after admission may identify patients at higher risk . Gazes et al . (8), in a prospective study of 140 patients, found that the probability of survival at I year was significantly decreased (from 96% to 57%) in 54 patients who had persistent angina within 48 h after hospital admission. Similarly, Mulcahy et al . (9) studied 101 patients and demonstrated that the eventfree probability was reduced from 87% to 65% in 22 patients with repeated episodes of chest pain after admission to the coronary care unit . In their study, patients received only symptomatic treatment. Thus, patients with persistent angina had an unfavorable outcome compared with that of patients without recurrent chest pain . Several investigators (3-5) have reported that patients in the coronary care unit with angina at rest had significantly fewer episodes of chest pain when heparin and aspirin were added to routine triple antianginal drug therapy, which usually included intravenous nitrates. This result further indicates that a dynamic thrombotic process on a ruptured plaque is occurring in this subset of patients . However, the addition of aspirin, aspirin plus warfarin or warfarin alone for 3 months to routine antianginal medication did not successfully control symptoms, as demonstrated by Cohen et al . (15) . In their study 29 of 93 patients experienced recurrent ischemia and 46 underwent coronary revascularization within the 3-month period . Gerstenblith et al. (16) also found that medical treatment with nifedipine combined with nitrates and a beta-blocker, was superior to the addition of placebo to the same regimen but failed in 30 of 68 patients within a 4-month observation period . Role of electrocardiographic changes . The role of ECG changes in either symptomatic patients (angina) or asymptomatic patients (silent ischemia) has also been investigated. Severi et al . (17), who studied the prognostic significance of basal ECG and exercise tests in 374 patients, reported that the 54 patients with a normal basal ECG and an exercise test negative for ischemia had no deaths at I year and that Lhe 86 patients who had a normal basal ECG despite a positive exercise test had .s 97% probability of survival . The exercise test was performed after the patients' condition had stabilized ; however, there is no information on whether the need for more aggressive therapy or the physical impossibility of performing exercise might have introduced a bias in selecting the study population. Langer et al. (18) found ST segment shifts on the admission ECG in 60 of 135 patients who had rest or prolonged angina . In these patients the incidence of death, myocardial infarction or need for urgent revascularizalion during the hospital stay was 55% compared with 25% in patients without ST changes (p < 0 .005) . Similarly, 89 patients who
JACC Vol . 19, No . 7 June 1992 :1659-63
showed symptomatic or silent ST shifts on a 24-h Holier monitor had a poorer prognosis with a 48% rate of unfavorable events as compared with a rate of 20% in patients without ST shifts (p < 0.005). The admission ECG was less sensitive than was Holier ECG monitoring in identifying patients with an unfavorable prognosis (63% vs . 83%. respectively; p < 0.005); however, in the 33 patients whose admission ECG showed ST shifts, the results of Holier monitoring did not further increase the sensitivity . Only 4 (8%) of the 52 patients with an unfavorable hospital outcome had no ST segment shifts on either the admission ECG or Holler monitoring. By using a multiple regression model to define the best predictors of unfavorable outcome, of 14 variables analyzed, the duration of ST segment shift on Holier recording was second, the state of the coronary anatomy being the first . The prognostic significance of silent ischemia in patients with unstable angina who were receiving three-drug treatment was analyzed by Gottlieb et al . (19) in a series of 70 patients . Compared with the 33 patients without silent ischemia, the 37 patients with silent ischemia had a fivefold increase in the relative risk of sustaining an acute myocardial infarction or needing bypass surgery for recurrent angina at 30 days . Furthermore, the 17 patients who had ?60 min of silent ischemia/24 h had a significantly higher cumulative probability of an unfavorable outcome than did the 16 patients who had <60 min of ischemia. In addition, silent ischemia despite intensive medical treatment was the best predictor of these two outcomes among 15 demographic, ECG and angiographie variables selected for analysis. Nademanee et al . (20) reported similar findings in 49 patients with unstable angina followed up for 6 months with regard to cardiac death, myocardial infarction or need for revascularization. The 18 patients presenting with more than 60 min of silent ischemia in 24 h had a higher event rate (94%) than did the I I patients with <60 min of ischemia (27%) and the 20 patients with no silent ischemia (5%). The ECG changes in patients with angina at rest were assessed by Cohen et at . (21) in a study of 90 patients . They found ST segment changes during pain to be a reliable predictor of adverse clinical events (recurrent ischemia, infarction or need for revascularization) ; the positive predictive value for clinical events of ST deviation > 1 ran in at least two or more leads was 89% . Exercise testing . Recently, safety of exercise testing after early coronary care unit discharge for suspected unstable angina was demonstrated by Swahn et al . (22) in their study of 400 patients who did not have serious complications after the test. The same group reported that patients with suspected unstable coronary artery disease but wither :. ECG changes at rest and without signs of ischemia on exercise had a very low risk for coronary events within the next year (23) . However, the relative merits of early exercise testing and Halter ECG monitoring in predicting outcome in unstable angina is still lacking. Mulcahy et al. (24), who compared treadmill exercise testing and ambulatory ST segment mon-
nETRtU ET AL. PROGNOSIS IN UNSTABLE ANGINA
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iloring in 277 patients with stable angina . found the frequency of ambulatory ischemic episodes to be strongly related to a positive exercise test (p < 0.0001) . This relation was similar for both silent and painf.d ischemia, and the authors concluded that ambulatory ST monitoring added little to the results of the exercise test in aetecting ischemia . Variant Angina Prognosis in variant angina was studied in two large series of patients by Canadian and Japanese investigators (25,26) . Both studies were comparable with regard to the length of follow-up, prevalence of significant coronary disease (55% and 60%, respectively) and of multivessel disease (18% and 16% . respectively) . The two studies were also coincident in identifying independent predictors of outcome (death and myocardial infarction) : the use of calcium channel antagonists, the level of disease activity (assessed by either the number of spontaneous attacks or the extent of ST segment elevation) and the extent and severity of coronary artery disease . These findings are in agreement with previous studies with a shower follow-up in which patients with variant angina and normal coronary arteries (8% of the total population in one study [271 and 20% in another [28]) were found to have an excellent outcome . In both series, most of the untoward events occurred within the Ist 3 months of hospital admission . Postmyocardial Infarction Angina The prevalence of angina after acute myocardial infarction varies according to the criteria used for diagnosis . Bosch et al. (29) studied early ischemia (defined as angina with ECG changes ?24 h after an acute myocardial infarction) in 449 patients treated in the coronary care unit until hospital discharge . According to their criteria, the prevalence of post myocardial infarction angina was 18% . Early ischemia after infarction was predictable and was more frequent in patients with non-Q wave myocardial infarction, multivessel disease or previous angina . During a mean follow-up interval of 14 months, patients with early angina had a significantly lower survival rate (92% vs . 83% ; p = 0 .01) than did patients without angina . Eenhorin et ai . (30) analyzed the occurrence of angina after acute myocardial infarction in 867 patients enrolled in the Multicenter Post-AM! Program who were followed up for I to 4 years after infarction . Angina after acute myocardial infarction was diagnosed on clinical grounds. When only those episodes that occurred between discharge from the coronary care unit and final hospital discharge were computed, it was diagnosed in 286 patients with a prevalence of 33%. Survival rates were similar for patients with and without postinfarction angina, except for those who had high-frequency angina (more than I episode in 24 h) . In this study, high-frequency angina was an independent risk factor for cardiac death . Gottlieb et al . (31) found that silent ischemia on Hotter
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JACC Vol. 19, No . 7 June 1992:1659-61
BETRIU ET AL . PROGNOSIS IN UNSTABLE ANGINA
monitoring in high risk patients with a recent myocardial infarction (ejection fraction <40% or arrhythmias more severe than Lown class III) was the best predictor of death at I year, particularly among patients who could not perform the exercise test.
New Onset Angina Prognosis. There is controversy concerning the importance of new onset angina as an indicator of high iisk. Although many patients with acute myocardial infarction have prodromal chest pain, all patients with chronic stable angina and relatively good prognosis had recent onset angina at one time . This apparent paradox was addressed by Short and Stowers (32), who stressed the role of timing in recent onset angina after reviewing the history of 317 patients from the precise time of onset of chest pain to time of death or occurrence of myocardial infarction. The probability of an untoward event for those patients with abrupt onset of angina was 18% during the Ist week, decreasing to 5% in the next 3 weeks. Thus, prognosis seems to depend not only on the number of coronary vessels involved but on the rapidity with which symptoms develop . Extent of coronary artery disease . Using a different definition of angina of recent onset . Roberts et al . (10) found the probability of being event-free at 1 month identical to that observed by Short and Stowers . In their study of patients with documented coronary artery disease from the Data Bank of Duke University, long-term follow-up was mainly related to the extent of coronary artery disease . An important aspect of new onset angina is the accuracy of its diagnosis, as it depends on the clinical characteristics of the chest pain, particularly in patients with a normal ECG . We (33) prospectively assessed the natural history and the coronary anatomy of 104 consecutive patients with recent onset angina . Normal coronary arteries or lesions <50% were found in 36% of patients and single-vessel disease (stenosis >50%) in 30% . The probability of survival at I month for all patients was 99% and the probability of event-free survival was 90% . Predictors of coronary artery disease were chest pain on exertion, recurrent episodes of angina before entry into the study and an abnormal baseline ECG. These variables also predicted the probability of remaining event free, as all events were confined to the 54 patients with two or three of these risk factors.
Clinical Implications Unstable angina is a broad diagnosis that includes patients at different levels of risk for an unfavorable outcome . Determinants of prognosis . Although in unstable angina, as in other categories of coronary artery disease, the state of left ventricular function and the extent of coronary artery disease will determine long-term prognosis, recognition of clinical markers of an early unfavorable outcome is of paramount importance. Recurrence of chest pain 48 h after
admission reduces the likelihood of survival by about 20% . The ECG changes on admission have a negative prognostic implication, particularly in patients with rest angina, as they may predict recurrence of ischemia, myocardial infarction or need for revascularization in 80% of the patients . In variant angina, determinants of prognosis are the level of disease activity (recurrence of pain and ECG changes), the use of calcium channel antagonists and the extent of coronary artery disease . Patients who have more than one episode of angina in 24 h after a myocardial infarction have a 10% reduction in likelihood of survival during the 1st year compared with that of asymptomatic patients . Therapeutic implications . The persistence of chest pain and ECG changes appear to be particularly useful in predicting the outcome of patients with angina . When these prognostic markers are present, early coronary angiography must be performed and a revascularization procedure should be considered without delay . In their absence, a more conservative approach that may rely on the results of exercise testing is recommended . Heparin and aspirin have an important role in preventing acute myocardial infarction in patients with unstable angina . Although silent ischemia seems to add prognostic information in some patients, more studies are needed to identify those patients who require routine Hotter ECG monitoring, which is an expensive and not widely available test .
References 1 . Lewis HD, Davis JW, Archibald DG, et ai . Protective effects of aspirin against acute myasadial infarction and death in men with unstable angina: results of a Veterans Administration Cooperative Study . N Engl J Med 1983 :309:396-403. 2. Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyramne, or both in unstable angina. N Boat J Med 1985 ;313:1369-75 . 3 . Thsroux P, Ouimet H, McCans J, et al. Aspirin, heparin or both to treat acute unstable angina . N Evil I Med 1988 ;319:1105-11. 4 . The Risk Group. Risk of myocardial inflaction and death during Resonant with law dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 19soS36:827-30. 5 . Ned Sewed GO, Gensini GF, Poggessi L, et al . Effect of heparin, aspirin or alteplase in reduction of myocardial iscbaemia in refractory unstable angina. Lancet 1990;335:615-g. 6. Bmunweld E . Unstable angina: a classification. Circulation 1999;80: 410-4. 7. Fulton M, Lutz W, Donald KW, et al. Natural history of unstable angina . Lancet 1972;1 :860-5. 0 . Gazes PC, Mombley EM, Fads HM, Duncan RC, Humphries GB . Proinfarctional (unstable) angina : a prospective study: ten year follow-up. Circulation 1973 :48:331-7. 9 . Mubaby R, Daly L, Graham I, et al . Unstable angina : natural history and determinants of prognosis. Am J Cordial 1991 ;48:525-8. to, Roberts KB, Califf JIM, Harrel FE, Lee KL, Fryer DB, Rosati RA . The prognosis for patients with new-onset angina who have undergone cardiac cathelerization. Circulation 1983;68:970-8 . I1 . Luchi RI, Scott SM . Penpree RH, et al . Comparison of medical and surgical treatment for unstable angina pectoris : results of a Veterans Administration Cootxm6ve Study . N Engl I Med 1987 ;316:977-04. 12. Alison HW, Russell RO, Mantle JA, Koucboukos NT, Moreski RE, Rackley CE. Coronary anatomy and aderiography in patients with unstable angina pectoris . Am I Cordial 1978;41 :204-9 . 13. Unstable Angina Pectoris Study Group : Unstable angina pectoris : notional coopemlive study group to compare surgical and medical therapy .
!ACC Val. 39. Na. 7 lane 1992 : 1 659-63 II. I.-ho" lal experience and initial fall-up resole in pat :enle wile one . [9m and nine . vessel disease, Am I Cannot 19!8 :42:639-96 . 14 . FMhi JI, Cohen M . Fasler V . The broad tenor am or . .!able angina
pcdnos and its impli®t 00s Inn FA- .>ntmllcd tads. Am I Cordial 39S6d8:sa7-50, IS, Cabers M, Adams PC, Haokias L, tab Y1, Faster V. Usefuh . : o: antithrombmic therapy in resting angina persons or nor Q roast myocar dial iaraictian in Wesenting death and myocardial lafarnlon la pilot study from the Anlhhrn .ohatic lhcropy in Acnm Carnnry Synch- 91049 Group!. Am J Cardiol 1999;96.i287-92. 16. Gerstenbhth G, Oayua1 P, Achnf SC, n al. Niredipine in oraable angina: a double-tuna, mndommed trial . N Enpf I Med 1982iIR6965 .9 . 17- Severn S, Dntos E, Mannonn, P, Michelassi C, L'A6haie A TFr basal elec00wrmaipnm and the e68ratw stress cast in assessing pragansis in patients wrlh unstable angina, Ear HeaA J 1998 .9:491-GI6 . !anger A, Freeman MR, Armstrong PW . ST sagu nt slsfl in mamhIr .00:00 : palbophysilogy and association with mmn .y anatomy and
honpial nt0come . I Am Call Cordial 1969:17 :1495-502 . 19. CwtdiebSO,WeisfeldtML .OuyangP .MellOnED .GerslenbiuhG.5den1 ischemia as a marker for early unfavorable oulcomet in patient, with amtshle angina. N E.91 I Mad 1986014 :1214-9 . 20. Nademanee K, ] .=chat V, losephson MA, Rieders D, VaghAwalla Mody F. Single BN, Irragnoslic eigni0cance ofs8em myocardial i •.chem :a in pmients with unstable angina . J Am Coil Cardiac 1597,12 :1-9. 21 . Cohen M, Hawkins L.Greenberg S. Fuster V . Usefulness oFSf-segmem changes in >2 leads on the emergency room elenrneardio0mm in either 011stable angina pedant or .on-Q wava myocardial in6rotiania pnethcling outcome . Am J Cardiol 1991 ;67:1358-73 . 22 . Swahn E, Aseskog W . Wailentin L . Early exercise lesliig after coronary care for saspectedan'tsblecaronary artery disease : safely and diagnostic value . Eus Head J 1986;7'594-601 . 23. Swahn E, Areskog M, BergLnd 1J, Walfridssan H . Wdlenlia L Preds-
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lave impodance of dimcal findings and a prwischnrge exercise test in paaierxs wish suspecud unstable .,an- angry disease . Am 1 Cordial 1997-9 . N 900 0,09 D . Keegrurl. 5part0w f-Yanb A . Wright C . Kox K. lschemia in the a,nbularory se W.&-she cool isdxndc burden: relasbn to exercise testing m1d investigative 2nd tberapeutie impiiwiions . J t .;, Call Clediel 1989:14 :1166-72 25. WA[ag .4 . Waless DD, Miller DD, Roy D, PrIldis GB, Thfroon P. Long-term prognosis ofhnlieents 0th vmiaol angina . Circulation 1967 :76: 997-: Yasue H. Takua,oa A . Na., M . et al . Long-term prognosis for patients with racism amino and ioB_1ential fa
660 6. 29 . Botch X, Therona P . Waters DD, Pelletier GB, Roy D . Early paslinfaneisrhensa: dsueal, sengiogaphic, and prognostic significance . Circa!=; --r ee7:75:900-95 . .0. Benhmin J, Nedra- ML, C arleen ED, Moss Al and the Multicente : Possinf lion Rewards Group . Gccorreace, characteristics and pmgoostic significance of early pmmeole myocardial infarction angina pectoris . Am I Cordial IM;62 :679-05 . 31 . Goulml, SO, Golllieh SH . Achuff SC. et al. Silent ischemia on Holier monitoring predcts Mortality in Mgla .risk postiref=tian patients. JAMA 1901:2591030-5. 32. Slxan D, 5lawers M . Pragtosis of new and worsening angina F=nuris lleiterl. Bill 1976;L1260. 33 . C-attafxr A. Roig E. Set .^_ A, et a] . Risk otmt:6oatian and p:o0nn .is of pawnsith ne am onset angina . Ear Heart 11990 ;11 :868-75.
1659
Unstable Angina : Outcome According to Clinical Presentation AMADEO BETRIU, MD, MAGDA HERAS, MD, MARC COHEN, MD, FACC VALENTIN FUSTER, MD, FACCt Barcelona, Spain; Philadelphia, Pennsylvania ; Boston, Massachusetts
Unstable angina is a broad clinical diagnosis that includes patients atdiferent levels of risk for an unfavorable outcome . Although, as in other categories of coronary artery disease, the state of left ventricular function and the extent of coronary artery disease will determine long-term prognosis, recognition of clinical markers of an early unfavorable course may he of value in defining manage . ment strategies, This review focuses on the relevance of baseline clinical characteristics and noninvasive data in assessing the prognostic significance of unstable angina in light of its presenting features. Recurrence of chest pain within 48 h after admission carries a reduction In likelihood of survival of about 20% in patients with progressive or prolonged angina . Similarly, ECG changes on admission have a negative prognostic Implication, particularly in rest angina, as they predict recurrence of ischemia, myocardial
Unstable angina covers a wide range of clinical presentations with a common link ; an uncertain prognosis . In fact, uncertainty has been considered the hallmark of unstable angina . Given the variability in the natural history of patients with unstable angina, we rely on the identification of prognostic factors to dictate practical guidelines for therapeutic decisions . In this article, we review the prognostic significance of different forms of unstable angina to define management sbategirs, paying attention to the relevance of both baseline clinical characteristics and noninvasive data as indicators of outcome. Data from large representative series published over the past 2 decades are analyzed, with inclusion of results in medical or control arms in randomized trials, but old retrospective surveys relating prodromal events to subsequent myocardial infarction have been purposely avoided . When assessing the available information on unstable angina, one finds several limitations such as the definition of angina, including differences in the condition of patients entered in each study, the frequent inclusion of patients with
From the Department of Cardiology, Hospital Clinic, University of Barcelona, Barcelona, Spain; the 'Hahnemano University, Philadelphia, Pennsylvania; and the SCardiac Unit, Massachusetts General Hospital, Boston, Massachusetts, This work was supported in pan by Grant 9010596 from the Foodo de Investigaciooes Sanitaias (FiS), Madrid, Spain. Manuscript received July 22, 1991 ; revised tnanusedpl received December 3,1991, accepted January 7, 1992 . Add- for reorintc Amedeo Beaiu, MD, Department of Cardiology. Hospital Clinic, Villarroel 170, 09036 Barcelona, Spain. 01992 by the American College of Cadiology
infarction or need fee revascularteation in 90% of the puts, In variant angina, determinants of prognosis are level of disease activity, as judged by recurrence ofpain, ECG changes and use of calcium channel antagonists. Patients with angina after a myanr. dial infarction who have mare thanes episode of either angina or silent L'ehemia in 24 h have a 10% reduction la probabiE!y of survival during the lot year compared with that of asympeommic patients . An abrupt course, or the rapidity with which symptoms develop, is the maim determinant of progaesis in new onset angina. Thus, recurrent angina and ECG changes appear to be relevant prognostic markers in the patient subsets considered : if these are present, early coronary, aglogranhy, mud be performed and revasculartnation procedures should be coffered without delay . (J Am Call Cordial 1992;19:1659-63)
non-Q wave infarction, the lack of angtographic information in many series, the inclusion of patients with previous myocardial infarction (and therefore with different degrees of left ventricular dysfunction) and differences in the length of follow-up and the treatment received. It is now well known (1,2) that treatment with aspirin has significantly changed the outcome of patients with unstable angina, reducing the incidence of nonfatal myocardial infarction and cardiac death. Recent reports (3-5) have also demonstrated that heparin infusion and aspirin administration significantly decreased the incidence of refractory angina and acute myocardial infarction while definitive therapy was being determined . As a result, the current outcome of unstable angina might be expected to improve in relation to that of series completed before the routine use of aspirin or heparin . To circumvent some of these limitations in the study of unstable angina, Braunwald (6) recently proposed a clinical classification of this condition that separates exertional angina from rest angina and takes into account the presence of extracardiac precipitating causes, the presence of recent (<2 weeks) myocardial infarctien and the intensity of treatment received . Although this classification may elucidate the natural history and prognosis of the different groups of patients with unstable angina, its usefulness needs to be validated prospectively not only in research studies but in the clinical setting. Categoriesofunstableaugaa . A review ofpublished data allows us to define the "classic" categories of unstable 0735-1097192JSS.00
1660
IACC Vol . 19, No.7 Junc 1992 :1659-63
BETI5IU CT AL . PROGNOSIS IN UNSTABLE ANGINA
%-probability too96 5 92 90
1
92
7
90
survival
184 182 80 . N•1947
79
Survival without MI months
3
9
12
Figure 1. Kaplan-Meier actuarial curves showing the probability of survival and survival without myocardial infarction (Ml) for the Ist 12 months after progressive or prolonged angina . These 1,947 patients are pooled together from 10 different studies (i-3, 7-13).
angina : 1) progressive angina, worsening of symptoms with an increasing number of episodes of chest pain (crescendo pattern) ; 2) prolonged angina, the anginal episodes of longer duration only partially relieved by nitroglycerin ; 3) rest angina, anginal pain occurring at rest (possibly an "end stage" of the two preceding forms of angina) ; 4) variant angina, angina not related to physical activity and accompanied by transient ST segment elevation ; 5) posimyocardial infarction angina, angina occurring in the hospital after an acute myocardial infarction ; 6) new rnsel angina, angina that has developed within the preceding 30 to 60 days . In practice, it appears extremely difficult to find clear-cut categories . For example, so-called angina at rest is hardly ever found alone and generally occurs in association with the progressive and prolonged types and will be analyzed in this fashion.
Progressive and Prolonged Angina : Angina at Rest Progressive and prolonged angina, analyzed together in most studies, account for the majority of patients with the diagnosis of unstable 0ngina. To assess the overall prognosis, we reviewed 10 representative series with a total of almost 2,000 patients (Fig . I) (1-3,7-13) . Fifty-three percent of these patients had electrocardiographic (ECO) changes as an inclusion criterion . Previous myocardial infarction had occurred in 39%; only 31% underwent coronary angiography . The in-hospital mortality rate ranged between 2% and 8%a with a mean survival rate of 96%a. At 1 year the mean survival rate was 90%. The event-free probability (probability of survival without infarction) was 89% at I month and 79% at I year . These patients were not treated uniformly because beta-adrenergic blocking agents were not routinely used in the earliest studies, and calcium channel antagonists became available only more recently . However, proof is still lacking that these therapies-regardless of their value in the
control of symptoms-might have changed the natural history of unstable angina . Patients presenting with angina at rest and ECG changes have been reported to have a poorer prognosis (14-16) . However, this patient group included a number of patient: with non-Q wave myocardial infarction or variant angina. Recurrence of chest pain. A recurrence of chest pain after admission may identify patients at higher risk . Gazes et al . (8), in a prospective study of 140 patients, found that the probability of survival at I year was significantly decreased (from 96% to 57%) in 54 patients who had persistent angina within 48 h after hospital admission. Similarly, Mulcahy et al . (9) studied 101 patients and demonstrated that the eventfree probability was reduced from 87% to 65% in 22 patients with repeated episodes of chest pain after admission to the coronary care unit . In their study, patients received only symptomatic treatment. Thus, patients with persistent angina had an unfavorable outcome compared with that of patients without recurrent chest pain . Several investigators (3-5) have reported that patients in the coronary care unit with angina at rest had significantly fewer episodes of chest pain when heparin and aspirin were added to routine triple antianginal drug therapy, which usually included intravenous nitrates. This result further indicates that a dynamic thrombotic process on a ruptured plaque is occurring in this subset of patients . However, the addition of aspirin, aspirin plus warfarin or warfarin alone for 3 months to routine antianginal medication did not successfully control symptoms, as demonstrated by Cohen et al . (15) . In their study 29 of 93 patients experienced recurrent ischemia and 46 underwent coronary revascularization within the 3-month period . Gerstenblith et al. (16) also found that medical treatment with nifedipine combined with nitrates and a beta-blocker, was superior to the addition of placebo to the same regimen but failed in 30 of 68 patients within a 4-month observation period . Role of electrocardiographic changes . The role of ECG changes in either symptomatic patients (angina) or asymptomatic patients (silent ischemia) has also been investigated. Severi et al . (17), who studied the prognostic significance of basal ECG and exercise tests in 374 patients, reported that the 54 patients with a normal basal ECG and an exercise test negative for ischemia had no deaths at I year and that Lhe 86 patients who had a normal basal ECG despite a positive exercise test had .s 97% probability of survival . The exercise test was performed after the patients' condition had stabilized ; however, there is no information on whether the need for more aggressive therapy or the physical impossibility of performing exercise might have introduced a bias in selecting the study population. Langer et al. (18) found ST segment shifts on the admission ECG in 60 of 135 patients who had rest or prolonged angina . In these patients the incidence of death, myocardial infarction or need for urgent revascularizalion during the hospital stay was 55% compared with 25% in patients without ST changes (p < 0 .005) . Similarly, 89 patients who
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showed symptomatic or silent ST shifts on a 24-h Holier monitor had a poorer prognosis with a 48% rate of unfavorable events as compared with a rate of 20% in patients without ST shifts (p < 0.005). The admission ECG was less sensitive than was Holier ECG monitoring in identifying patients with an unfavorable prognosis (63% vs . 83%. respectively; p < 0.005); however, in the 33 patients whose admission ECG showed ST shifts, the results of Holier monitoring did not further increase the sensitivity . Only 4 (8%) of the 52 patients with an unfavorable hospital outcome had no ST segment shifts on either the admission ECG or Holler monitoring. By using a multiple regression model to define the best predictors of unfavorable outcome, of 14 variables analyzed, the duration of ST segment shift on Holier recording was second, the state of the coronary anatomy being the first . The prognostic significance of silent ischemia in patients with unstable angina who were receiving three-drug treatment was analyzed by Gottlieb et al . (19) in a series of 70 patients . Compared with the 33 patients without silent ischemia, the 37 patients with silent ischemia had a fivefold increase in the relative risk of sustaining an acute myocardial infarction or needing bypass surgery for recurrent angina at 30 days . Furthermore, the 17 patients who had ?60 min of silent ischemia/24 h had a significantly higher cumulative probability of an unfavorable outcome than did the 16 patients who had <60 min of ischemia. In addition, silent ischemia despite intensive medical treatment was the best predictor of these two outcomes among 15 demographic, ECG and angiographie variables selected for analysis. Nademanee et al . (20) reported similar findings in 49 patients with unstable angina followed up for 6 months with regard to cardiac death, myocardial infarction or need for revascularization. The 18 patients presenting with more than 60 min of silent ischemia in 24 h had a higher event rate (94%) than did the I I patients with <60 min of ischemia (27%) and the 20 patients with no silent ischemia (5%). The ECG changes in patients with angina at rest were assessed by Cohen et at . (21) in a study of 90 patients . They found ST segment changes during pain to be a reliable predictor of adverse clinical events (recurrent ischemia, infarction or need for revascularization) ; the positive predictive value for clinical events of ST deviation > 1 ran in at least two or more leads was 89% . Exercise testing . Recently, safety of exercise testing after early coronary care unit discharge for suspected unstable angina was demonstrated by Swahn et al . (22) in their study of 400 patients who did not have serious complications after the test. The same group reported that patients with suspected unstable coronary artery disease but wither :. ECG changes at rest and without signs of ischemia on exercise had a very low risk for coronary events within the next year (23) . However, the relative merits of early exercise testing and Halter ECG monitoring in predicting outcome in unstable angina is still lacking. Mulcahy et al. (24), who compared treadmill exercise testing and ambulatory ST segment mon-
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iloring in 277 patients with stable angina . found the frequency of ambulatory ischemic episodes to be strongly related to a positive exercise test (p < 0.0001) . This relation was similar for both silent and painf.d ischemia, and the authors concluded that ambulatory ST monitoring added little to the results of the exercise test in aetecting ischemia . Variant Angina Prognosis in variant angina was studied in two large series of patients by Canadian and Japanese investigators (25,26) . Both studies were comparable with regard to the length of follow-up, prevalence of significant coronary disease (55% and 60%, respectively) and of multivessel disease (18% and 16% . respectively) . The two studies were also coincident in identifying independent predictors of outcome (death and myocardial infarction) : the use of calcium channel antagonists, the level of disease activity (assessed by either the number of spontaneous attacks or the extent of ST segment elevation) and the extent and severity of coronary artery disease . These findings are in agreement with previous studies with a shower follow-up in which patients with variant angina and normal coronary arteries (8% of the total population in one study [271 and 20% in another [28]) were found to have an excellent outcome . In both series, most of the untoward events occurred within the Ist 3 months of hospital admission . Postmyocardial Infarction Angina The prevalence of angina after acute myocardial infarction varies according to the criteria used for diagnosis . Bosch et al. (29) studied early ischemia (defined as angina with ECG changes ?24 h after an acute myocardial infarction) in 449 patients treated in the coronary care unit until hospital discharge . According to their criteria, the prevalence of post myocardial infarction angina was 18% . Early ischemia after infarction was predictable and was more frequent in patients with non-Q wave myocardial infarction, multivessel disease or previous angina . During a mean follow-up interval of 14 months, patients with early angina had a significantly lower survival rate (92% vs . 83% ; p = 0 .01) than did patients without angina . Eenhorin et ai . (30) analyzed the occurrence of angina after acute myocardial infarction in 867 patients enrolled in the Multicenter Post-AM! Program who were followed up for I to 4 years after infarction . Angina after acute myocardial infarction was diagnosed on clinical grounds. When only those episodes that occurred between discharge from the coronary care unit and final hospital discharge were computed, it was diagnosed in 286 patients with a prevalence of 33%. Survival rates were similar for patients with and without postinfarction angina, except for those who had high-frequency angina (more than I episode in 24 h) . In this study, high-frequency angina was an independent risk factor for cardiac death . Gottlieb et al . (31) found that silent ischemia on Hotter
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BETRIU ET AL . PROGNOSIS IN UNSTABLE ANGINA
monitoring in high risk patients with a recent myocardial infarction (ejection fraction <40% or arrhythmias more severe than Lown class III) was the best predictor of death at I year, particularly among patients who could not perform the exercise test.
New Onset Angina Prognosis. There is controversy concerning the importance of new onset angina as an indicator of high iisk. Although many patients with acute myocardial infarction have prodromal chest pain, all patients with chronic stable angina and relatively good prognosis had recent onset angina at one time . This apparent paradox was addressed by Short and Stowers (32), who stressed the role of timing in recent onset angina after reviewing the history of 317 patients from the precise time of onset of chest pain to time of death or occurrence of myocardial infarction. The probability of an untoward event for those patients with abrupt onset of angina was 18% during the Ist week, decreasing to 5% in the next 3 weeks. Thus, prognosis seems to depend not only on the number of coronary vessels involved but on the rapidity with which symptoms develop . Extent of coronary artery disease . Using a different definition of angina of recent onset . Roberts et al . (10) found the probability of being event-free at 1 month identical to that observed by Short and Stowers . In their study of patients with documented coronary artery disease from the Data Bank of Duke University, long-term follow-up was mainly related to the extent of coronary artery disease . An important aspect of new onset angina is the accuracy of its diagnosis, as it depends on the clinical characteristics of the chest pain, particularly in patients with a normal ECG . We (33) prospectively assessed the natural history and the coronary anatomy of 104 consecutive patients with recent onset angina . Normal coronary arteries or lesions <50% were found in 36% of patients and single-vessel disease (stenosis >50%) in 30% . The probability of survival at I month for all patients was 99% and the probability of event-free survival was 90% . Predictors of coronary artery disease were chest pain on exertion, recurrent episodes of angina before entry into the study and an abnormal baseline ECG. These variables also predicted the probability of remaining event free, as all events were confined to the 54 patients with two or three of these risk factors.
Clinical Implications Unstable angina is a broad diagnosis that includes patients at different levels of risk for an unfavorable outcome . Determinants of prognosis . Although in unstable angina, as in other categories of coronary artery disease, the state of left ventricular function and the extent of coronary artery disease will determine long-term prognosis, recognition of clinical markers of an early unfavorable outcome is of paramount importance. Recurrence of chest pain 48 h after
admission reduces the likelihood of survival by about 20% . The ECG changes on admission have a negative prognostic implication, particularly in patients with rest angina, as they may predict recurrence of ischemia, myocardial infarction or need for revascularization in 80% of the patients . In variant angina, determinants of prognosis are the level of disease activity (recurrence of pain and ECG changes), the use of calcium channel antagonists and the extent of coronary artery disease . Patients who have more than one episode of angina in 24 h after a myocardial infarction have a 10% reduction in likelihood of survival during the 1st year compared with that of asymptomatic patients . Therapeutic implications . The persistence of chest pain and ECG changes appear to be particularly useful in predicting the outcome of patients with angina . When these prognostic markers are present, early coronary angiography must be performed and a revascularization procedure should be considered without delay . In their absence, a more conservative approach that may rely on the results of exercise testing is recommended . Heparin and aspirin have an important role in preventing acute myocardial infarction in patients with unstable angina . Although silent ischemia seems to add prognostic information in some patients, more studies are needed to identify those patients who require routine Hotter ECG monitoring, which is an expensive and not widely available test .
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