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[Am Heart J 137(2):322-331, 1999. © 1999 Mosby-Year Book, Inc.]
Much of the published data about the natural history of unstable angina corresponds to selected patients included in randomized clinical trials. Therefore these patients may not represent the general population admitted to community hospitals.
Unstable angina is also quite heterogeneous, with a wide spectrum of clinical manifestations and prognostic categories.[10-14] in addition, most of the data on the evolution and prognosis of unstable angina were obtained before the development of new drugs and interventional procedures for management of this disease.
This multicenter study enrolled a large cohort of patients admitted with unstable angina to identify the clinical and electrocardiographic markers associated with in-hospital death and myocardial infarction, in the context of a nonselected population admitted consecutively to community hospitals and treated according to current therapeutic strategies.
This was a multicenter prospective study of consecutive patients admitted to coronary care units with unstable angina. To select a representative sample and safeguard against selection bias, all consecutive patients admitted to the coronary care unit with a suspicion of an acute ischemic syndrome were included in the database. If the admission diagnosis turned out to be Q-wave or non-Q-wave myocardial infarction, or if a nonischemic cause of chest pain became clearly evident, the process of data collection was interrupted and the patient censored from subsequent analysis. The diagnosis of Q-wave or non-Q-wave acute myocardial infarction present at admission was made on the basis of the finding of an elevated total creatine phosphokinase (CPK) plasma level (greater than 2-fold increase above normal value) at entry to the study or at any time up to 12 hours thereafter. for patients prescribed thrombolytic treatment or primary coronary angioplasty at entry, the enzymatic criteria were not required and the diagnosis was made on the basis of the finding of chest pain lasting more than 30 minutes plus >=1 mm ST elevation in at least 3 precordial or 2 standard electrocardiogram (ECG) leads.
Between March 1991 and May l992, 1172 consecutive patients with suspected acute ischemic syndrome were prospectively enrolled. This group represented 23% of the total population admitted to the coronary care units during that period of time. One hundred and thirty-four patients (11.4%) were excluded: 46 patients because of an evolving myocardial infarction unequivocally present at hospital admission and 88 patients because of noncardiac chest pain. The remaining 1038 patients with unstable angina formed the study population.
Data collected include demographics and baseline clinical variables. Electrocardiograms were routinely obtained at admission, during subsequent episodes of chest pain, and at hospital discharge. Serum total CPK levels were determined at admission, every 12 hours during the first 24 hours, and after a new chest pain episode during hospital stay. Changes in the ECG were considered positive if there was >=1 mm of ST-segment elevation or depression in at least 2 limb leads or 3 precordial leads or symmetric T-wave inversion in at least 3 limbs or precordial leads.
The treatment received, any coronary intervention, and all the in-hospital events (angina, acute myocardial infarction, and death) were also recorded. The investigator who was responsible for the patient was instructed to carry a daily prospective and systematic register of all new chest pain episodes in addition to all the information related to the associated electrocardiographic and enzymatic alterations. All the ECG tracings were examined by an ECG core lab reader who was blinded to the patient clinical condition to validate ST-segment changes >=1 mm, T-wave changes, left bundle branch block, and left ventricular hypertrophy. Serial electrocardiograms were compared to evaluate if the changes were transient or fixed. The medical treatment was entirely left to the discretion of the treating physician except for a strong recommendation to use aspirin in all patients.
End Points and Definition of Events
New episodes of ischemic chest pain after admission were classified as (1) recurrent angina, defined as angina occurring in the absence of full medical therapy or (2) refractory angina, angina occurring while the patient was receiving full medical therapy.
Full medical therapy was defined as the combination of aspirin and/or intravenous heparin, nitrates, and b-blockers or calcium antagonists at clinically effective doses. The adequacy for full medical therapy was left to the decision of the treating physician with suggested criteria of heart rate <60 beats/min and systolic blood pressure <120 mm Hg.
Major in-hospital events were new myocardial infarction and death from any cause. Hospital mortality was defined as death occurring in the hospital at any moment from arrival through discharge. The criteria for new in-hospital acute myocardial infarction included all of the following: (1) new prolonged episode of chest pain after admission; (2) elevation of total CPK level greater than twice the limit of normal, and (3) the development of new Q-wave or ST-T changes on the ECG.
Events that occurred during or within 24 hours after an invasive procedure (coronary angiography, coronary angioplasty, or coronary bypass surgery) were considered procedure related. The remaining events were prospectively classified as spontaneous.
An ad-hoc committee blinded to the clinical variables and the administered treatment examined and validated all major events (acute myocardial infarction or death during hospitalization) with a systematic review of serial electrocardiograms, enzymatic curves, and clinical charts of all patients who had major events reported or adjudicated by investigators.
Statistical Analysis
The initially targeted sample of 1000 patients was based on a projected 24% rate of events (16% refractory angina, 6% acute myocardial infarction, and 2% death). An a level of significance <.05 was considered for all purposes. Unadjusted odds ratios and 95% confidence intervals were obtained for selected clinical factors judged to be associated with the outcome of interest. Univariate and forward stepwise multiple logistic regression models were used to evaluate the independent association of variables present at admission to in-hospital acute myocardial infarction or death. From 28 clinical and electrocardiographic variables, those identified of potential significance from the univariate analysis were chosen for forward stepwise selection into the model. The variables included in the model were age (with a cutoff point of 65 years), prior myocardial infarction, prior angina (angina preceding the 48-hour interval before admission), smoking (prior or current), the number of angina episodes during the last 48 hours before admission (with a cutoff rate of 3 hours), the presence of precipitating factors of angina (anemia, tachyarrythmias, fever, hypertension), and the finding of ST-segment depression on the admission ECG. Progressive angina was not included because of its significant association with prior angina (Pearson's r = 0.70).
The model was validated with the split-sample technique. A simple random sample of approximately 70% of the 1038 cases (the training set, n = 728) was used to derive the predictive model; the remaining 30% sample (the test set, n = 310) was used to test it. The rule obtained from the training set was applied to each member of the test set. The efficiency of the model was assessed by comparison of the area under the receiver operating characteristic (ROC) curves of the training and test samples.
The model was also tested on all 1038 cases to determine its overall predictive ability (by use of the area under the ROC curve), sensitivity, and specificity in predicting in-hospital death or myocardial infarction. The goodness of fit of the model was assessed by the Hosmer-Lemeshow test.
Kaplan-Meier survival curves were generated to calculate the cumulative probability of having a major event develop during hospitalization in the overall population and in the subgroups with and without refractory angina. Statistical analysis was performed with the SPSS system 7.5 package (Statistical Package for the Social Sciences, 1997) and the ROC Analyzer Program version 6.0.
The patients in this study were mostly elderly (age 60.18 ± 16 years), 65% were male, 78% reported prior angina (angina preceding the 48 hours interval before admission), and 32% had experienced a prior myocardial infarction (Table I). The study population was clearly unstable as manifested by the high frequency of resting chest pain (78%), prolonged (>30 minutes) chest pain (29%) and the last episode of pain within the 48 hours preceding admission (96.7%). Angina within 4 weeks and 2 weeks after infarction (postinfarction angina) was observed in 9.7% and 3.3% of cases, respectively. Precipitating factors of unstable angina were not identified in 76% of the population. There were relatively few smokers (21.3%), and the most prevalent risk factors were hypertension (60.3%) and hyperlipidemia (43.3%). The presence of heart failure at admission was infrequently reported (1.5%).
Left ventricular hypertrophy or complete left bundle branch block precluded the analysis of ST-T changes in 12.7% of patients. ST segment elevation was frequently observed (16%) and, in contrast, ST-segment depression was relatively infrequent (21%). Only 16% of the patients had a normal ECG at entry.
Before hospitalization, treatment consisted of aspirin in half of the patients (50.6%), b-blockers in 31%, nitrates in 44%, and calcium antagonists in 42%. Combined treatment with aspirin, nitrates, and b-blockers or calcium antagonists was administered to 27% of the study population.
Table II depicted the baseline characteristics of patients with and without major complications during hospitalization. Patients with complications were older and had greater frequency of prior angina, ST-segment depression on admission electrocardiogram, and repetitive angina (> 3 episodes) during the last 48 hours preceding admission.
Conversely, the history of previous infarction was less frequent among patients without complications during hospitalization.
In-Hospital Management
Antithrombotic treatment was administered in the hospital to 94% of patients, with heparin in 57% (intravenous in 34%, subcutaneous heparin in 23%), aspirin in 88%, and ticlopidine in 5% of the patients. Heparin was used in 34.7% and 63.9% of patients with or without precipitating factors, respectively. Anti-ischemic therapy consisted of the administration of nitrates in 81%, b-blockers in 71%, and calcium antagonists in 56%.
A coronary angiography was performed in 50.2% of the population. The most relevant angiographic findings were normal or nonsignificant stenosis in 5.4%, 1-vessel disease in 32%, multivessel disease in 61%, and left main involvement in 10%.
A quarter of the population was submitted to revascularization procedures (coronary artery bypass grafting was performed in 14% and coronary angioplasty in 10.8%). There was a positive relation between the presence and severity of angina after admission and the need for invasive procedures, either diagnostic or therapeutic: 29.5% and 44.2% in patients with recurrent and refractory angina, respectively, and 11.1% in the subgroup without angina after admission (P < .001). The indications for revascularization procedures were angina after admission in 71%, inducible ischemia in 6%, angiographic findings in 21%, and preference of the patient or his/her physician in the remainder.
Clinical Events
During hospital stay, 40.8% of the patients had at least 1 new episode of cardiac pain (Table III). Recurrent angina was diagnosed in 200 patients (19.3%) and refractory angina in 223 (21.5%) patients.
New acute myocardial infarction was diagnosed in 54 patients (5.2%), and there were 42 in-hospital deaths (4.1%). The combined end point of death and myocardial infarction occurred in 83 patients (8.1%).
The incidence of new acute myocardial infarction was higher during the first day and declined thereafter. On the other hand, cases of death were evenly distributed during hospitalization. The Kaplan-Meier event-free survival curve for in-hospital infarction or death is shown in Fig 1. Fig 2 shows the in-hospital survival curve of patients free of infarction, death, or refractory angina.
The rate of "spontaneous" (non-procedure-related) acute myocardial infarction and death was 3.1% and 1.4%, respectively. Acute myocardial infarction and death related to an interventional procedure rates were 1.0% and 3.8%.
Relation Between Clinical Characteristics and Outcome
Univariate analysis. The clinical variables present at admission and associated with an adverse outcome through the hospitalization period are summarized in Table IV. New acute myocardial infarction or death was associated with ST-segment depression (odds ratio [OR] 2.00, 95% confidence interval [CI] 1.20 to 3.40; P = .008), the number of chest pain episodes within the last 48 hours (OR 1.84, 95% CI 1.12 to 3.07; P = .01), prior angina (OR 2.70, 95% CI 1.34 to 5.57; P = .001), and age >65 years (OR 1.64, 95% CI 1.00 to 2.70; P = .01). A negative trend was noted for smoking history (OR 0.51, 95% CI 0.31 to 0.83; P = .005), and prior acute myocardial infarction (OR 0.58, 95% CI 0.32 to 1.03; P = .039). Age (OR 2.26, 95% CI 1.06 to 4.69; P = .01), and prior angina (OR 4.9, 95% CI 1.16 to 12.5, P = .009), were the only univariate predictors of in-hospital mortality.
Multivariate analysis. The model was constructed with all the variables present at admission and found significant at the univariate analyses at a level of P < .10. As shown in Table V, the multivariate analysis retained the following independent admission predictors of myocardial infarction or death: ischemic ST-segment depression in the ECG upon admission (OR 2.13, 95% CI 1.23 to 3.68, P = .006), prior angina (OR 2.23, 95% CI 0.98 to 5.05, P = .05), the number of angina episodes within the last 48 hours before admission (OR 1.63, 95% CI 0.98 to 2.70, P = .05), and smoking history (OR 0.69, 95% CI 0.56 to 0.85, P = .004). Age >65 years (OR 1.49, 95% CI 1.09 to 2.03, P = .03) was significantly related to in-hospital death.
The overall predictive efficiency was similar in the training and test samples (ROC curves areas 0.57 ± 0.05 and 0.53 ± 0.04 respectively, P = .29).
On all 1038 patients, the area under the ROC curve for the model was 0.59 ± 0.03. The sensitivity and specificity of the model were computed. To ensure at least 80% sensitivity, a predicted probability cutpoint of 0.06 was required (ie, if the predicted probability was >=0.06, the patient was classified as positive). This cutpoint resulted in a sensitivity of 80% and a specificity of 33%. The Hosmer-Lemeshow goodness-of-fit statistic was 3.51 (degrees of frequency = 7, P = .83).
Postadmission Angina and Prognosis
The occurrence of angina after admission (recurrent or refractory) showed a strong univariate relation with the incidence of in-hospital acute myocardial infarction or death (14.4% vs 3.2%, or 5.04, 95% CI 2.86 to 8.87; P < .0001) and death alone (6.9% vs 1.1%, or 6.45, 95% CI 2.61 to 5.9; P < .0001) (Table III). Fig 3 shows the Kaplan-Meier infarction-free survival curves in patients with or without refractory angina. Absence of refractory angina from admission to discharge was associated to a better hospital outcome. This association persisted even when only non-procedure-related ("spontaneous") events were taken into consideration 10.3% vs 2.3% of acute myocardial infarction or death in patients with or without refractory angina, respectively (OR 4.40, 95% CI 2.35 to 8.22; Table IV).
Prognostic Assessment at Hospital Presentation
This study indicates that with current treatment the clinical variables continue to be useful short-term predictors at the time of hospital admission.
After performing multivariate logistic regression analysis, prior angina, ST-segment depression at the admission ECG, the number of pain episodes in the last 48 hours preceding admission, smoking history, and increased age were all independently associated to adverse in-hospital outcome. However, this model showed low specificity (33%).
In this study it was also confirmed that at the time of hospital presentation, the severity of preadmission symptoms is an important determinant of in-hospital prognosis.[11-14] Prior angina and the number of episodes of angina during the 48 hours preceding admission were independent predictors of an adverse outcome by multivariate logistic regression analysis. This finding is a contribution to the elucidation of the controversy regarding the importance of these clinical features as indicators of high risk. In the past, both a long history of ischemic disease and the lack of preceding symptoms have been suggested to identify high-risk subgroups.[13-15]
Our study confirms that prognosis is worse in patients with ST-segment depression on admission ECG.[16-20] As shown in previous studies,[18,19] T-wave changes, although common, have no such prognostic value. This analysis did not take into account the extension and severity of ST-segment or T-wave changes and therefore we cannot rule out the possibility of a worse prognostic significance associated with more severe ECG abnormalities.
In agreement with other reports,[21] patients who smoke cigarettes showed a better in-hospital course. In another study by Barbash et al,[22] more advanced coronary artery disease explained the worse prognosis of nonsmokers. One explanation might be that smokers have less-advanced atherosclerotic disease at the time of their first clinical episode of ischemic disease.
Some common clinical variables, such as diabetes and heart failure, did not appear as predictors in this analysis. Also, these variables did not turn out to be independent predictors in an analysis involving 3171 patients with non-ST-segment elevation ischemic syndrome in the ESSENCE trial.[23]
We surveyed very evident heart failure with overt respiratory distress only. Thus the low frequency of heart failure at the time of presentation may be a reflection of these diagnostic criteria. It was not possible to assess either the predictive value of exertional unstable angina or that of subacute angina at rest (patients without angina within the preceding 48 hours) because 96.7% of our patients belonged to Braunwald's type III classification.[24]
In-Hospital Prognostic Assessment
Recently reported comparisons of early conservative versus early invasive therapeutic strategy[25,26] indicates that there is no benefit associated with the routine use of any of these strategies. Therefore it is still necessary to adjust the therapeutic recommendation to the individual needs of each patient. Because of the lack of other adequate markers of instability, clinical risk stratification performed at admission and during hospitalization is still essential to identify patients at high risk in which an early interventional strategy may be recommended. The findings of this study are consistent with this appreciation: the appearance of refractory angina, the clinical hallmark of instability,[27,28] was followed by a rise in the rate of interventions and of major events of 44.2% and 22.7%, respectively, whereas persistent relief of symptoms after admission was associated with a favorable in-hospital outcome and a lower procedural rate (11.1%).
Although thrombotic complications related to procedures driven by symptoms can be considered to belong to the unstable state,[29] interventions can confound the predictive analyses because recurrence of angina prompts the physician to intervene. The existence of an intrinsic adverse significance associated with refractory angina is supported by our finding of a significant relation between refractory angina and major nonprocedural ("spontaneous") events.
Limitations
Because no valid universal definition of refractory angina exists, the criteria used in this study may be different from those used by others.[4,5] Because of the pragmatic character of the study, neither the presence of ECG evidence of ischemia nor the use of heparin during the episodes of chest pain were required for the diagnosis of refractory angina.
In this study the use of intravenous heparin was less than what might be anticipated (57%) because in recent years there has been a greater trend toward increased use. However, the use of heparin was higher in patients without precipitating factors (69.7%). This finding is not unexpected because in primary unstable angina (Braunwald class B) the presence of a thrombus can be presumed[24] and the use of heparin treatment is well substantiated. The studies by Theroux[30] and Wallentin[31] showed the effectiveness of intravenous heparin and low-molecular-weight heparin in preventing major complications during the acute phase of unstable angina. Consequently, in our study, a lower incidence of refractory angina and a better outcome could have been observed if heparin had been used more frequently or if a more stringent definition of refractory angina had been used. Nonetheless, mortality rate in this series was similar to that reported in recent trials. At 30 days the death rate was 3.6% and 3.9% in the heparin arms of the studies ESSENCE[32] and GUSTO II B,[33] respectively. In the PURSUIT trial,[34] 30-day mortality rate was 3.7% in the control arm. In the TIMI-IIIB study,[25] the death rate of the early conservative arm was 4.7% at 42 days. In the PRISM PLUS study,[35] the 30-day mortality rate was 4.0% in patients treated with heparin.
Clinical Implications
The relative benefits of early invasive and early conservative treatment strategies have been debated for many years.[36] Either of these approaches is considered clinically appropriate for many patients.[25,26] Accordingly, the identification of candidates for a more aggressive strategy has become of utmost importance. Because of its simplicity and wide availability, clinical and ECG markers are widely used for this purpose.[37,38] Unfortunately, the specificity of the clinical predictors is insufficient to fulfill the requirements of risk stratification under the current therapeutic modalities.
In recent years, serum markers such as troponin T and C-reactive protein have become the focus of interest for risk stratification of unstable angina, with promising results.[39-42] It is very likely that routine measurements of these markers will contribute to the identification of those patients at highest risk for cardiac events. A major question to be explored is how much information these new biochemical markers will add to what is already provided by the classic clinical predictors.
Acknowledgements
We thank Gianni Tognoni, MD, for his assistance in the design of the study; Dr Pierre Theroux for helpful comments on early drafts of this paper; and María Elena Aizpurua for secretarial assistance.
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