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(Circulation. 1996;93:1634-1639.)
© 1996 American Heart Association, Inc.

Articles

Thrombin Activity and Early Outcome in Unstable Angina Pectoris

Diego Ardissino, MD; Piera Angelica Merlini, MD; Gabriella Gamba, MD; Paolo Barberis, MD; Gloria Demicheli, MD; Sophie Testa, MD; Elisabetta Colombi, MD; Arnaldo Poli, MD; Raffaela Fetiveau, MD; Carlo Montemartini, MD

From the Division of Cardiology (D.A., P.B., G.D., E.C., A.P., R.F., C.M.) and the Department of Internal Medicine (G.G., S.T.), IRCCS, Policlinico S Matteo, University of Pavia, and the Second Division of Cardiology, Ca' Granda Niguarda Hospital (P.A.M.), Milan, Italy.

Correspondence to Diego Ardissino, MD, Divisione di Cardiologia, IRCCS, Policlinico S Matteo, 27100 Pavia, Italy.

	Abstract

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Background The blood coagulation system is frequently activated in the acute phase of unstable angina, but it is unknown whether the augmented function of the hemostatic mechanism may serve as a marker of increased risk for an early unfavorable outcome.

Methods and Results Plasma concentrations and 24-hour urinary excretion of fibrinopeptide A were prospectively determined in 150 patients with unstable angina. All patients underwent 24-hour Holter monitoring, during which time urine was collected; at the end of this period, a blood sample was taken and coronary arteriography was performed. The patients were followed up for the occurrence of cardiac events (death and myocardial infarction) until they underwent coronary revascularization or until they were discharged from the hospital. Fibrinopeptide A plasma levels and 24-hour urinary excretion were found to be abnormally elevated in 50% and 45% of the study population, respectively. During hospitalization, 11 patients developed myocardial infarction and 2 patients died. Kaplan-Meier analysis demonstrated a significantly higher probability of developing cardiac events in patients with abnormal rather than normal plasma levels of fibrinopeptide A (P<.01), whereas no difference in outcome was observed between patients with normal and those with abnormal 24-hour urinary excretion. Cox regression analysis showed that the only variables independently related to an early unfavorable outcome were the presence of persistent ischemia during 24-hour Holter monitoring (P<.0001), the presence of intracoronary thrombosis at angiography (P=.016), and abnormal fibrinopeptide A plasma levels (P=.038).

Conclusions Patients with unstable angina pectoris and abnormal fibrinopeptide A plasma levels are at increased risk for an early unfavorable outcome.

Key Words: angina • thrombosis • prognosis

	Introduction

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Intracoronary thrombosis is frequently observed in patients with unstable angina, and its presence has been associated with an increased risk of adverse outcome.^{1 2 3} The levels of biochemical markers of the activation of the coagulation system are higher in patients with ongoing thrombosis^{4 5 6} and may therefore be helpful in identifying those patients with unstable angina and intracoronary thrombosis who are at the greatest risk of progressing to myocardial infarction and death. Fibrinopeptide A is a reliable biochemical marker of thrombin activity that can be measured in plasma⁷ and in urine.^{8 9} Given its short half-life, the plasma levels of fibrinopeptide A provide insights into the activation of the coagulation system that relate only to the short time period of blood sampling. The amount of urinary fibrinopeptide A excreted over 24 hours has been reported to be an index of the cumulative action of thrombin on fibrinogen. This prospective study was designed to test whether either single plasma or 24-hour urinary excretion measurements of fibrinopeptide A can predict a high-risk subgroup of patients with unstable angina.

	Methods

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Eligible Patients
Two hundred forty-seven patients with unstable angina who were about to undergo elective coronary arteriography were considered eligible to enter the study. Unstable angina was defined as (1) chest pain of recent onset or (2) a sudden worsening of preexisting stable angina or postinfarction angina developing after an asymptomatic period of >12 weeks. The prerequisite for inclusion in the study was the occurrence of chest pain at rest associated with transient ischemic repolarization changes, ie, the ECG demonstration of 1-mm ST-segment depression or elevation 80 ms after the J-point, or the pseudonormalization of previously negative T waves. All of the patients fulfilled the criteria for class IIB or IIIB of Braunwald's classification of unstable angina.¹⁰

Exclusion Criteria
All the patients taking drugs that affect hemostatic function were deemed ineligible for the study. Ninety-seven patients were excluded because they had one of the following: (1) peripheral vascular disorders or valvular heart disease (10 patients); (2) previous coronary artery bypass surgery or coronary angioplasty (27 patients); (3) Q-wave myocardial infarction within the previous 3 months or large ventricular aneurysm (16 patients); (4) disorders of hemostasis (2 patients); (5) proteinuria, hematuria, or chronic renal failure (18 patients); (6) chronic inflammatory disease or malignancy (2 patients); or (7) enrollment in the GUSTO II Trial (22 patients).

Study Design
The patients were admitted to the coronary care unit and received standardized medical therapy consisting of a combination of metoprolol (100 to 200 mg/d), nifedipine (40 to 80 mg/d), transdermal or oral nitrates (40 to 80 mg/d) or intravenous nitroglycerin (0.5 to 1 µg·kg^-1·min^-1), and aspirin (100 to 325 mg/d). If the use of metoprolol was contraindicated, diltiazem (180 to 360 mg/d) was administered in association with nitrates. After enrollment, the patients underwent 24-hour Holter monitoring, during which time urine was collected. At the end of this period, a blood sample was taken and coronary arteriography was performed. No heparin was given before blood sampling. The patients were followed up for the occurrence of outcome events until they were discharged from the hospital. Twelve-lead ECGs were recorded whenever chest pain occurred. Creatine kinase levels were measured every morning and every 4 hours after any episode of prolonged chest pain. The study protocol was approved by the Institutional Committees, and the enrolled patients gave their explicit informed consent.

Outcome Events
The primary outcome event was the occurrence of in-hospital cardiac death or Q-wave or non–Q-wave myocardial infarction. Q-wave myocardial infarction had to be documented by prolonged chest pain, specific cardiac enzyme levels of more than twice the upper limit of normal, and the development of Q waves on the standard 12-lead ECG. The diagnosis of non–Q-wave myocardial infarction required only the first two characteristics.

The secondary outcome event was the combination of in-hospital cardiac death, Q-wave or non–Q-wave myocardial infarction, and the need for emergency coronary revascularization, whichever happened first. In the absence of left main coronary artery disease, the decision to perform emergency coronary revascularization was made on the basis of the patients' symptomatic response to the medical regimen and required at least one episode of angina at rest with accompanying ischemic ECG changes.

Periprocedural complications were considered to be death and myocardial infarction. Periprocedural death was defined as a death that occurred in relation to the revascularization procedure. Periprocedural myocardial infarction had to be documented by specific cardiac enzyme levels of more than twice the upper limit of normal and the development of new pathological Q waves on the standard 12-lead ECG.

Sample Collection and Processing
Blood. All the blood samples were collected immediately before coronary arteriography. Venipunctures were performed atraumatically by two specially trained investigators using 19-gauge needles and the two-syringe technique. After the first 3 mL was discarded, the samples were collected in plastic tubes containing fibrinopeptide A anticoagulant purchased from Mallinckrodt Diagnostica. The ratio of anticoagulant to blood was 1:9 vol/vol. The samples were immediately stored on ice and centrifuged at 2000g for 20 minutes to obtain platelet-poor plasma, which was then frozen at -70°C. Fibrinopeptide A was measured in paired samples run in duplicate with commercial radioimmunoassay kits according to the instructions of the manufacturer (RIA-mat FPA, Mallinckrodt Diagnostica). The evaluation of data precision revealed a coefficient of variation of 7.8%. The results are expressed as the average of the paired samples.

Urine. Urine was collected over the 24-hour period of continuous ECG monitoring on the day before coronary arteriography. To ensure the correct measurement of 24-hour urine volume, the patients were instructed to discharge their bladders completely just before the period of urine collection began and to empty their bladders again at the end of the collection period. Urine volume and pH were recorded, and all samples were tested for the presence of blood or protein before being immediately stored at -70°C. Before fibrinopeptide A determination, pH was corrected to 8.0 by addition of hydrochloric acid 1 mol/L or sodium hydroxide 1 mol/L. Urine was assayed in paired samples for fibrinopeptide A with commercial radioimmunoassay kits (RIA-mat FPA, Mallinckrodt Diagnostica) according to the manufacturer's instructions. The evaluation of data precision revealed a coefficient of variation of 5.3%. The results are expressed as the amount of 24-hour fibrinopeptide A urinary excretion, obtained by multiplying the average of paired samples by the urine volume.

Continuous ECG Monitoring
Continuous two-channel ECG monitoring was performed by selection of the two leads that had demonstrated the most pronounced reversible ischemic changes on the initial qualifying 12-lead ECG recorded during the episode of chest pain. The recorders were amplitude-modulated reel-to-reel two-channel Holter monitoring units (model 445, Delmar Avionics), calibrated before placement. The frequency response of these recorders is 0.05 to 100 Hz. The ECG monitoring tapes were scanned by a cardiologist at 60 times real time for the presence, frequency, and duration of ischemic episodes, defined as transient 1-mm ST-segment elevations or depressions 80 ms after the J-point lasting 1 minute. A printout of any potential ischemic episode was obtained. Persistent ischemia was considered to have occurred in the event of at least one symptomatic or asymptomatic ischemic attack during the 24-hour monitoring period.

Coronary Arteriography
Selective coronary arteriography was performed by either the standard Sones or Judkins technique. A narrowing 70% was considered significant coronary stenosis (50% in the case of the left main coronary artery). The patients were classified as having 1-, 2-, or 3-vessel disease according to the number of vessels with significant stenosis. The coronary artery supplying the ischemic zone was identified by reference to the ECG location of reversible ST-segment changes during chest pain. By the method of Ambrose et al,¹¹ a qualitative morphological analysis of the lesion was performed by two experienced cardiologists who were blinded with respect to the biochemical results and outcome. Intracoronary thrombi were defined as spherical, ovoid, or irregular intraluminal defects surrounded on at least three sides by contrast medium just distal to or within a coronary stenosis.

Statistical Analysis
The deviations from the normal distribution of plasma concentrations and urinary excretion of fibrinopeptide A were tested by calculating the coefficients of skewness and kurtosis. Given that the values were found to be nonnormally distributed, the upper normal limits of fibrinopeptide A plasma concentrations and urinary excretion were calculated by determination of the 95th percentile of the distribution in a control group of 20 healthy blood donors matched for age, sex, and smoking habits. Plasma concentrations above the upper normal limit of 9.4 ng/mL were considered abnormal, as was a urinary excretion of more than the upper normal limit of 11.1 µg/24 hours. Time to an end point for patients with normal or abnormal fibrinopeptide A plasma levels or urinary excretion was analyzed by the Kaplan-Meier method and compared by means of the log-rank test with a two-tailed significance level. The patients who underwent emergency coronary revascularization were considered to be exposed to the risk of a primary outcome event only up to the day on which they underwent the procedure. Multivariate analysis was used to determine whether abnormal fibrinopeptide A plasma levels were independently related to the risk of an unfavorable primary and secondary outcome. The analysis was carried out with the Cox proportional hazards model and included the variables found to be significant at univariate analysis as well as those reported to be related to in-hospital outcome in previous studies. Univariate analysis was performed by means of the ² test with Yates' correction for categorical data, the unpaired t test for normally distributed continuous variables, or the Mann-Whitney U test for nonnormally distributed continuous variables. The clinical characteristics considered were age, sex, history of hypertension, smoking, prior myocardial infarction, diabetes, and the duration of unstable angina. The selected ECG variables were the direction of the ST-segment shifts on the qualifying ECG and the presence of persistent ischemia during 24-hour Holter monitoring. The biochemical data analyzed were the presence of abnormal fibrinopeptide A plasma levels and 24-hour urinary excretion. The angiographic variables were the number of vessels with significant stenosis, the presence of left main artery disease, the morphology of the ischemia-related lesion (concentric, eccentric type I, eccentric type II, multiple irregularities, total occlusion), the presence of intracoronary thrombosis, and the left ventricular ejection fraction determined by left ventriculography. A two-tailed value of P<.05 was considered to indicate statistical significance. Statistical testing was carried out by means of BMDP statistical software.

	Results

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The study population consisted of 150 patients, 61% of the eligible patients. The blood samples from 6 patients were prospectively excluded because of technical problems associated with sampling. Of the 144 patients in whom plasma fibrinopeptide A was analyzed, 72 (50%) had abnormally elevated values and 72 (50%) had values within the normal range. Twenty-four-hour urinary excretion of fibrinopeptide A was assessed in 146 patients and was found to be abnormally high in 66 (45%).

Primary Outcome Events
During hospitalization, 2 patients died, and 4 patients developed Q-wave and 7 non–Q-wave myocardial infarction. One hundred thirty-seven patients did not experience a primary outcome event. The distribution of the primary outcome event according to normal or abnormal levels of plasma or urinary fibrinopeptide A is shown in the upper part of Table 1. Kaplan-Meier analysis demonstrated a significantly higher probability of developing a primary outcome event in patients with abnormal fibrinopeptide A plasma levels than in those with normal levels (P<.01) (Fig 1), whereas no difference in outcome was observed between patients with normal and abnormal 24-hour fibrinopeptide A urinary excretion. The clinical, ECG, biochemical, and angiographic characteristics of the patients with and without primary outcome events during hospitalization are reported in Table 2. At univariate analysis, the characteristics found to be significantly associated with primary outcome events were the presence of persistent ischemia during 24-hour Holter monitoring (P<.0001), abnormal fibrinopeptide A plasma levels (P=.0089), and the presence of eccentric lesions of type II morphology (P=.013). Cox regression analysis showed that the presence of persistent ischemia during 24-hour Holter monitoring (P<.0001), the presence of intracoronary thrombosis at angiography (P=.016), and an abnormal fibrinopeptide A plasma level (P=.038) were independent predictors of primary outcome events. No other predictors were significant after these variables were taken into account.

View this table: [in this window] [in a new window]   Table 1. Distribution of Primary and Secondary Outcome Events and Periprocedural Complications in Patients With Normal or Abnormal Plasma and 24-Hour Urinary Excretion Levels of FPA

View larger version (13K): [in this window] [in a new window]   Figure 1. Kaplan-Meier curves comparing the probability of developing death or Q-wave or non–Q-wave myocardial infarction during hospitalization in patients with normal and abnormal fibrinopeptide A (FPA) plasma levels.

View this table: [in this window] [in a new window]   Table 2. Clinical, ECG, Biochemical, and Angiographic Characteristics of Patients With and Without Primary and Secondary Events During Hospitalization

Secondary Outcome Events
During hospitalization, 45 patients experienced a secondary outcome event (2 deaths, 4 Q-wave and 7 non–Q-wave myocardial infarctions, and 32 emergency coronary revascularizations). The distributions of the secondary outcome events according to normal or abnormal levels of plasma or urinary fibrinopeptide A are shown in Table 1. The probability of developing a secondary outcome event was higher in patients with abnormal rather than normal plasma levels of fibrinopeptide A (P<.001) (Fig 2), whereas no differences in the secondary outcome were observed between patients with normal or abnormal 24-hour urinary excretion. The clinical, ECG, biochemical, and angiographic characteristics of the patients with and without secondary outcome events during hospitalization are reported in Table 2. At univariate analysis, the characteristics found to be significantly associated with secondary outcome events were the presence of persistent ischemia during 24-hour Holter monitoring (P<.0001), abnormal fibrinopeptide A plasma levels (P<.0001), the presence of left main coronary artery disease (P=.012), and the presence of ST-segment depression on the qualifying ECG (P=.034). Cox regression analysis showed that the presence of an abnormal fibrinopeptide A plasma level (P<.0001), the presence of left main coronary artery disease (P=.009), the persistence of ischemia during 24-hour Holter monitoring (P=.03), and the presence of intracoronary thrombosis at angiography (P=.04) were independent predictors of secondary outcome events.

View larger version (13K): [in this window] [in a new window]   Figure 2. Kaplan-Meier curves comparing the probability of developing death, Q-wave or non–Q-wave myocardial infarction, or the need for emergency coronary revascularization during hospitalization in patients with normal and abnormal fibrinopeptide A (FPA) plasma levels.

	Discussion

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The syndrome of unstable angina encompasses a broad spectrum of clinical conditions, all of which are characterized by severe transient myocardial ischemia involving different pathogenetic mechanisms. Maseri et al¹² emphasized the role of coronary artery vasoconstriction in precipitating episodes of unstable angina, whereas Moise et al¹³ observed that unstable angina is associated with a progression in the extent and severity of coronary atherosclerosis. More recently, coronary artery thrombosis secondary to plaque rupture and fissuring has emerged as an important pathogenetic mechanism of unstable angina.^{14 15} The complications of unstable angina (namely, cardiac death and myocardial infarction) have also been related to coronary thrombosis.^{1 2 3} Because patients with unstable angina and intracoronary thrombosis are at risk and may benefit from more aggressive antithrombotic therapy, the early identification of thrombus is important. At present, no reliable routine technique for the identification of intracoronary thrombosis is available. Coronary arteriography, commonly used to visualize intracoronary thrombi, has been reported to underestimate their real prevalence, whereas the use of the more sensitive angioscopy is difficult and, in any case, not readily available.¹⁶ The levels of biochemical markers of the activation of the hemostatic mechanism are elevated in patients with ongoing thrombosis,¹⁷ and they have been proposed as a means of noninvasively detecting patients with unstable angina in whom intracoronary thrombosis is likely to be the prevailing pathogenetic mechanism. However, it is still not known whether abnormally elevated levels of coagulation activation markers are associated with an increased risk for an early unfavorable outcome.

This prospective cohort study shows that, in patients with unstable angina, an abnormally elevated fibrinopeptide A plasma level is associated with an increased risk of an early unfavorable outcome. Persistent myocardial ischemia during 24-hour Holter monitoring, the presence of intracoronary thrombosis at angiography, and high plasma levels of fibrinopeptide A were the only variables independently related to the occurrence of in-hospital myocardial infarction and death. However, although the association between persistent myocardial ischemia and early unfavorable outcome was highly significant, the presence of an abnormal fibrinopeptide A plasma level was only weakly predictive of a primary adverse outcome event (for example, 85% of patients with abnormal fibrinopeptide A plasma levels had no event).

Fibrinopeptide A is a very sensitive and specific marker of the activation of the coagulation system. Plasma concentrations and urinary excretion of fibrinopeptide A have been found to be abnormally high in the majority of patients with unstable angina in its active phase,^{6 18 19} being greatest in patients showing ST-segment shifts during episodes of chest pain²⁰ and in those with angiographically detectable intracoronary thrombosis.²¹ Fibrinopeptide A is a short-lived 16-amino-acid peptide liberated from fibrinogen by the action of thrombin. Approximately 70% of the total fibrinopeptide A produced is proteolytically degraded by intravascular and extravascular peptidases; the remaining 30% is filtered by the kidney. Most of the filtered fibrinopeptide A is catabolized by renal tubular peptidases, but 0.2% to 0.5% is excreted in urine.⁸ Because of its short half-life, plasma measurements of fibrinopeptide A give information on fibrinogen proteolysis only at the time of blood sampling. This could be a limitation in the setting of unstable angina, in which the intermittence of thrombus generation has been clearly documented.²² Recently, the amount of fibrinopeptide A excreted in 24-hour urine has been proposed as an index of the cumulative thrombin action on fibrinogen in patients who are not in steady state.⁹ In the present study, abnormal 24-hour urinary excretion of fibrinopeptide A was not associated with an increased risk for an adverse outcome. The fact that an abnormal fibrinopeptide A plasma level is a predictor of adverse outcome, whereas fibrinopeptide A urinary excretion is not, may be explained by individual variability in catabolism. The differences in cumulative thrombin activity, as assessed by 24-hour urinary excretion, may not be detected as a result of variable rates of excretion. The absence of any correlation between the plasma levels and 24-hour urinary excretion of fibrinopeptide A in our population supports this hypothesis.¹⁹ Clinical, ECG, and angiographic variables have been studied extensively in relation to prognosis in patients with unstable angina. Although there is compelling evidence that thrombosis plays a major role in the pathogenesis of this syndrome, no prospective study concerning the influence of hemostatic function on outcome has yet been reported. This lack of information is probably a result of technical difficulties in assessing hemostatic function in large cohorts of patients with unstable angina. However, a few cross-sectional studies have indirectly suggested that there might be an association between the activation of the coagulation system and an unfavorable outcome. Fibrinopeptide A levels have been shown to be five times higher in patients who had died suddenly of cardiac death than in patients who had died suddenly of other causes, and this difference was almost entirely due to the high fibrinopeptide A levels in subjects with a previous history of ischemic heart disease.²³ Further indirect evidence of the association between thrombin activity and early outcome in patients with unstable angina derives from therapeutic trials; heparin, which is known to reduce fibrinopeptide A plasma levels,²⁴ has been shown to have a protective effect against early cardiac events.^{25 26 27}

Conclusions
This study shows that, in patients with unstable angina, the activation of the hemostatic mechanism is associated with an increased risk of an early unfavorable outcome. This finding emphasizes the central role of coronary thrombosis in the pathogenesis of the complications of unstable angina and supports the importance of antithrombotic therapy for the prevention of such complications in this syndrome. However, from our cohort study, no conclusion can be drawn on the clinical usefulness of measuring plasma fibrinopeptide A for the assessment of the risk in individual patients. Further studies are needed to investigate whether the recognition of hemostatic system activation in patients with unstable angina has implications that may help clinical decision making.

Received July 11, 1995; revision received November 7, 1995; accepted November 7, 1995.

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