Keywords
INTRODUCTION
Unstable anginais one of the most frequent reasons for hospital admission, and itscourse can also be complicated by a high incidence of inpatientcardiac events. Treatment of unstable angina is controversial,raising issues such as whether treatment combining heparin andaspirin is useful,1 the use of low molecular weightheparin,2,3 the use of IIb-IIIa receptorantagonists,4,5 the choice of a conservative strategy vsan interventionist strategy,6-9 and the new humoralprognostic markers.10
The diversity ofstudy design means studies regarding unstable angina must beperformed with caution, particularly with regard to the followingdata: a) heterogeneity of inclusion criteria, given thatsome studies do not require the presence of electrocardiographychanges during the occurrence of chest pain to classify the episodeas unstable angina,3,6,11-13 and others include patientswith unstable angina and non-Q-wave infarct;1-8,12,14,15b) heterogeneity of medical treatment, which in many casesis left to the discretion of the treating physician,16and c) heterogeneity in the indication for cardiaccatheterization, which in many cases is also left to the discretionof the treating physician.3,5,12,14,15,17 Given thedifferences encountered on these points in various studies, thefrequency rate of hospital episodes shows a certain variabilityfrom one series to the next.
Our studyincludes a homogenous series of patients with pure unstable angina,excluding patients non-Q-wave infarct and high risk patients, andwith the requirement that dynamic changes had to be evident onelectrocardiogram (ECG) during the pain episode for the patient tobe included in the study; by using these criteria we attempted toreduce the possibility of including patients with non-coronarychest pain. Anti-thrombotic treatment consisted of theadministration of aspirin and enozaparin, and a conservativestrategy was followed with regard to cardiac catheterization. Thestudy aim was to evaluate the frequency of inpatient cardiac eventsand the predictors of same.
MATERIAL AND METHODS
Study group
From January 17,1999 to December 18, 2001, 246 consecutive patients were admittedto our hospital with the diagnosis of unstable angina, according tothe following criteria: a) anginous chest pain at rest; b) dynamic electrocardiographic changes during the painepisode; c) normal CK-MB values (acute myocardial non-Q-waveinfarct was excluded), and d) the absence of a history ofacute myocardial infarct for 30 days previously (post-infarctangina excluded). For inclusion in the study, an ECG was requiredduring the pain episode that showed signs suggestive of ischemia,such as depression or elevation of the ST segment=0.1 mV, orinversion of the T-wave=0.1 mV. The CK-MB was determined upon thepatient´s arrival in the emergency room, and at 8, 12, 18 and24 hours after initiation of the pain, and in all cases the valuewas less than the upper limit of normal according to the protocolof our hospital (CK-MB activity <6% of total CK).
Treatment protocol
Upon admission,all patients received treatment with aspirin, enoxaparin (1mg/kg/12 hours), intravenous nitroglycerine, and beta-blockers orcalcium antagonists. In no case were IIb-IIIa receptor antagonistsadministered. For patients with an ST segment elevation, thisrapidly dropped (in less than 20 minutes) with the administrationof nitroglycerine, and therefore no patient required fibrinolitictreatment.
Analysis
Forty-eighthours after admission (range 24 to 72 hours) routine analysis,including fibrinogen analysis, was performed. In order to determinethe fibrinogen level, blood was collected with sodium citrate at aratio of 1:10. The sample was processed by the coagulant formationtechnique in an automatic coagulometer, and measurements were madeby the optical method. The variation coefficient for our laboratoryis less than 10%.
Indications for cardiac catheterization
The initialattitude was conservative. Thus, coronary angiography andrevascularization (if anatomically possible) were indicated withoutprevious stress test only in the case of recurrent angina despitemedical treatment. Before discharge, those patients stabilized withmedical treatment underwent a symptom-limited stress test accordingto the Bruce protocol, and patients with Bruce stage I-II ischemiawere selected to undergo coronary angiography.
Collection of clinical data
Coronary riskfactors and a history of ischemic heart disease and cardiac surgerywere noted in the clinical history. During hospital admission thefollowing episodes were made note of: a) recurrent angina,defined by recurrent chest pain with transitory changes on ECG butwithout CK-MB elevation; b) the need for cardiaccatheterization, and c) a major episode, defined by acutemyocardial infarct (recurrent chest pain with CK-MB elevation) ordeath.
Statistical analysis
Quantitativevariables were expressed as mean ±standard deviation (SD)and were compared by the ANOVA test. Qualitative variables wereexpressed as percentages and were compared by the χ² test. Relativerisk (RR) was determined with confidence intervals (CI) of 95%. Thebest cut-off points for the quantitative fibrinogen value thatpredicted the risk of episodes was determined by using receiveroperator characteristic (ROC) curves. Multivariate analyses wereperformed by binary logistical regression analysis, and we includedthose variables that on univariate analysis showed a value of P<.1; the odds ratio (OR) and 95% CI werecalculated.
In all cases P<.05 was considered significant. For statistical analysis,the SPSS 9.0 (Chicago, Illinois) statistical package wasused.
RESULTS
Population characteristics
Table 1 showsthe population characteristics of patients included in the study.Mean age was 67±10 years.
The initialchanges on ECG that justified inclusion in the study were anisolated T-wave inversion in 50 patients (20%) and deviation in theST segment in 196 (80%), 146 with an ST segment decline (60%) and50 with an ST segment increase (20%).
Episodes during hospital admission
Eighty-eightpatients (36%) presented with recurrent angina, and 14 patients(5.8%) with major cardiac events, 8 with non-fatal acute myocardialinfarct, and 6 patients died. Cardiac catheterization was performedon 142 patients (58%), coronary angioplasty was indicated in 60patients (24%), and cardiac surgery was indicated in 32 patients(13%). One infarct and 1 death occurred following angioplasty, and2 deaths occurred following surgery; the remaining 10 majorepisodes occurred before cardiac catheterization. One deathoccurred in the first 24 hours following admission, before a bloodsample could be obtained to determine the fibrinogenlevel.
Predictors of episodes
Table 2 showsthe predictors of current angina by means of univariate analysis.Recurrent angina occurred more frequently in patients with ahistory of ischemic heart disease (41% vs 31%; P=.1; RR=1.5;95% CI, 0.9 to 2.6), a history of cardiac surgery (83% vs 33%; P=.001; RR=10.0; 95% CI, 2.1 to 46.7), ST segment deviation(41% vs 14%; P=.0001; RR=4.3; 95% CI, 1.9 to 10.1), and ahigher fibrinogen level (5.2 g/L±1.8 g/L vs 4.4g/L±1.4 g/L; P=0.001, RR=1.4, 95% CI, 1.1-1.7). Bymultivariate analysis (including the variables of history ofischemic heart disease, history of heart surgery, deviation of STsegment, and fibrinogen level), history of heart surgery(P=0.004, OR=22; 95% CI, 3 to 182), ST segment change(P=.01; OR=4.7; 95% CI, 1.4 to 15.9), and fibrinogen level(P=.009; OR=2.4; 95% CI, 1.3 to 4.6) were independentpredictors. The area below the ROC curve for the fibrinogen levelthat predicted recurrent angina was 0.63±0.04(P=0.004), and the best cut-off point for a fibrinogen levelpredictor was ≥4.5 g/L (43% vs 26%; P=.02; RR=2.1; 95%CI, 1.2 to 3.9).
Table 3 presentsthe variables related to the need for cardiac catheterization onunivariate analysis. A history of heart surgery (92% vs 56%; P=.02; RR=8.6; 95% CI, 1.1 to 68.3) and a higher fibrinogenlevel (4.9 g/L±1.5 g/L vs 4.3 g/L±1.5 g/L; P=.009; RR=1.3; 95% CI, 1.1 to 1.6) significantly increased theprobability of the need for cardiac catheterization. Onmultivariate analysis (including the variables of a history ofheart surgery and increased fibrinogen), a higher fibrinogen level(P=.01; OR=2.1; 95% CI 95%, 1.2 to 3.9) was the onlyindependent predictor variable. The fibrinogen level in the areabelow the ROC curve that predicted the need for cardiaccatheterization was 0.61±0.04 (P=.007), and the bestcut-off point for a predictor fibrinogen value was ≥4.5 g/L (66%vs 50%; P=.03; RR=2.0; 95% CI, 1.1 to 3.6).
Major events(Table 4) were only related to a higher fibrinogen value (6.7g/L±1.8 g/L vs 4.6±1.5 g/l; P=.001; RR=2.0;95% CI, 1.4-3.1), although there was a non-significant tendencytoward more major events in those patients with an ST segmentdeviation (6.6% vs 2.0%; P=.2). The area below the ROC curvefor fibrinogen as a predictor of a major episode was0.83±0.07 (P=.001), and the best cut-off point was afibrinogen value ≥5 g/L (10.8% vs 1.6%; P=.007; RR=7.7;95% CI, 5-38.7).
Predictive value of fibrinogen
The study groupwas divided into fibrinogen quartiles (<3.5, 3.5-4.3, 4.4-5.5,>5.6 g/L) (Figure 1). When the fibrinogen level increased, wenoted a progressive increase in the rate of recurrent angina (23%,27%, 30%, and 50%; P=.02; RR of the fourth vs the firstquartile =3.3; 95% CI, 1.3 to 8.1; P=.01), the need forcatheterization (35%, 58%, 61%, and 66%; P=.02; RR of thefourth quartile vs the first quartile =3.6; 95% CI, 1.5 to 8.5; P=.004), and major episodes (0%, 2%,1%, 4.5%, and 12%; P=.04; RR of the fourth quartile vs the first quartile =2.0;95% CI, 1.6 to 2.4; P=0.03).
Fig.1. Division of thestudy population into quartiles by fibrinogen values (<3.5,3.5-4.3, 4.4-5.5, >5.6 g/L). When the fibrinogen levelincreased, a progressive increase in the rate of recurrent anginawas observed (23%, 27%, 30%, and 50%; P=.02; RR of thefourth quartile vs the first quartile =3.3; 95% CI, 1.3 to 8.1; P=.01), the need for catheterization (35%, 58%, 61%, and 66%;P=.02; RR of the fourth quartile vs the first quartile =3.6;95% CI, 1.5 to 8.5; P=.004), and major episodes (0%, 2.1%,4.5%, and 12%; P=.04; RR of the fourth quartile vs the firstquartile =2.0; 95% CI, 1.6 to 2.4; P=.03).
DISCUSSION
The principalfindings of our study were as follows: a) the hospitalcourse of patients with unstable angina with dynamicelectrocardiographic changes who are initially treatedconservatively is complicated by a high rate of cardiac episodessuch as recurrent angina in 36% of cases, the need forcatheterization in 58%, and major episodes in 5.4%, and b)elevation of fibrinogen levels is associated with all unfavorableepisodes, while a history of cardiac surgery and a decline in theST segment during the pain episode is associated with recurrentangina.
Natural history of unstable angina
The history ofunstable angina varies from one study to another as a function ofthe inclusion criteria used. Our series analyzed patients withhigh-risk unstable angina by requiring the presence of dynamicelectrocardiographic changes during the pain episode for patientinclusion in the study. In other studies, documentation ofelectrocardiographic changes during the episode of chest pain wasnot a requirement for inclusion of patients;11-14eliminating this requirement may result in the inclusion oflower-risk patients or of patients with non-coronary chest pain. Onthe other hand, we excluded patients with non-Q-wave infarct. Otherseries group together unstable angina and non-Q-waveinfarct.1-8,15 Although theoretically both entitiesshare the same pathogenesis, which consists of serious coronarystenosis without occlusion and with no or a small amount ofmyocardial necrosis,18-20 could produce extensiveinfarcts, in spite of Q-waves not being observed on surface ECG, aprognostic implication that is clearly different from that of pureunstable angina without necrosis or with minimalnecrosis.
Our studyfinding of a rate of 36% for recurrent angina during admission isgreater than that reported in other series.1,3,21 Osleret al1 found a rate of 17% for recurrent angina onmeta-analysis that included studies of unstable angina ornon-Q-wave infarct treated with aspirin and intravenous heparin. Inthe ESSENCE study,3 the rate of inpatient recurrentangina was 13% in the subgroup treated with aspirin and enoxaparin(the same treatment regimen as in our study). The differences areexplained by the inclusion criteria used. Therefore, our patientpopulation would be very much exposed to recurrent ischemia, as thedynamic electrocardiographic changes without enzyme elevation wouldindicate serious ischemia and a myocardium at risk withoutnecrosis.
In spite of thehigh incidence of recurrent angina, the frequency of majorinpatient episodes is similar to3,15 or lowerthan1,4,5 that of other series that also includedsubgroups of patients treated with aspirin and subcutaneous orintravenous heparin. Probably the exclusion of patients withnon-Q-wave infarct and post-infarct angina, on one hand, and theavailability of a hemodynamic laboratory for urgent catheterizationin the case of recurrent angina on the other, would justify thisrelatively lower incidence of major episodes in comparison with thehigh rate of recurrent angina.
History of heart surgery
In spite of thefact that our study only included 12 patients with a history ofheart surgery, this variable was a potent predictor of recurrentangina and the need for cardiac catheterization. Eighty-threepercent of patients with a history of heart surgery presented withrefractory angina and 92% required catheterization. These datasuggest the usefulness of a strategy of routine catheterization incases of unstable angina with a previous history of anaortocoronary graft, although the possibility of successfulrevascularization are limited in these patients.22 Ahistory of heart surgery was not related to the occurrence of majorepisodes, probably due to the limited number of patients includedin our study.
Dynamic ECG changes
The dynamic ECGchanges recorded in our study were a decrease in ST segment in 60%of patients, an increase in ST segment in 20% of patients, andisolated T-wave inversion in the remaining 10% of patients. Datapublished in other studies shows a greater proportion of T-wavechanges. Thus, in the TRIM study,23 in the subgroup thatpresented with electrocardiographic changes, in 29% of patientsthere was an increase in the ST segment, 18% had a decrease in STsegment, and 53% had T-wave inversion. In the ESSENCEstudy,3 of the subgroup of patients withelectrocardiographic changes who were treated with enoxaparin, 10%showed an increase in the ST segment, 33% showed a decrease in theST segment, and 57% showed T-wave changes, although in this studythe subcategories of patients as a function of ECG were notmutually exclusive.
In our series,changes in the ST segment increased the probability of recurrentangina in comparison with T-wave changes. In series that included60%23 and 28%24 of patients withoutelectrocardiographic changes, the deviation of the ST segm ent wasassociated with recurrent ischemia, while T-wave inversion had nopredictive value. The ST segment changes have also been related tothe occurrence of major episodes,25-27 although we onlyfound a tendency that did not reach statistical significance. Twofactors could explain the lack of statistical significance: a) the exclusion of patients with non-Q-wave infarcts andpost-infarct angina, and b) the low rate of major episodesthat limited the statistical power of the analysis of itspredictors.
Fibrinogen
AN increasedfibrinogen level is a predictor of a poor prognosis for patientswith unstable angina and non-Q-wave myocardialinfarct.28-31 The relationship of various risk factorsto fibrinogen has been described, such as age, smoking, obesity, asedentary lifestyle, diabetes, and arterialhypertension.32 Nevertheless, after adjustment for theprincipal risk factors, fibrinogen remained an independent riskfactor for acute myocardial infarction and death in patients withischemic heart disease.33 In our study, elevation offibrinogen levels increased the probability of all unfavorableinpatient episodes, independently of coronary risk factors, and wasthe only variable associated with major cardiac events. Threemechanisms may explain the relationship between fibrinogen and apoor prognosis:29 a) a marker for a state ofhypercoagulability that favors coronary thrombosis; b) acutephase reactant due to a high inflammatory reaction in theatheromatous plaque of a coronary vessel, and c) an acutephase reactant due to myocardial damage. Given that we excludedpatients with non-Q-wave infarcts, this last mechanism does notappear to be the culprit in our study.
Clinical implications
Currently, thereis controversy regarding whether to follow a conservative orinterventionist strategy in the treatment of patients with unstableangina and non-Q-wave infarcts.6-9 In our series,cardiac catheterization was performed in 58% of patients, in spiteof an initially conservative treatment strategy. This data suggeststhat in high-risk unstable angina, defined by dynamicelectrocardiographic changes, routine catheterization uponadmission may be appropriate, at least for the subgroup of patientswith markers for a poor prognosis during their hospital course: ahistory of heart surgery, ST segment changes on the initial ECG,and an increase in fibrinogen value.
Limitations
When we beganour study, determination by means of troponin testing was notavailable in our hospital. Therefore, patients with non-Q-waveinfarcts were excluded via CK-MB values. If there a troponin testhad been available, some patients might possibly have been placedin the category of «micro infarct,» or infarct per thenew definition of acute myocardial infarct.34 Similarly,obtaining samples for the determination of fibrinogen values wasnot homogenous with respect to the time of hospital admission, andthere was a range of 24 to 72 hours from the time of admission tothe extraction of blood for the sample.
Correspondence: Dr. J. Sanchis Forés.
Servei de Cardiologia.
Hospital Clínic Universitàri.
Blasco Ibáñez, 17. 46010 València.España.
E-mail: sanchis_juafor@gva.es