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(Circulation. 1998;98:294-299.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Early Increase of von Willebrand Factor Predicts Adverse Outcome in Unstable Coronary Artery Disease

Beneficial Effects of Enoxaparin

Gilles Montalescot, MD, PhD; François Philippe, MD; Annick Ankri, MD; Eric Vicaut, MD, PhD; Etienne Bearez, MD; Jean Ernest Poulard, MD; Didier Carrie, MD; Daniel Flammang, MD; Albert Dutoit, MD; Alain Carayon, MD; Claude Jardel, PhD; Monique Chevrot, MD; Jean Philippe Bastard, PhD; Fredérique Bigonzi, MD; Daniel Thomas, MD; ; for the French Investigators of the ESSENCE Trial

From the Department of Cardiology (G.M., F.P., D.T.), the Laboratory of Biochemistry (C.J., M.C., J.P.B.), and the Laboratory of Hemostasis (A.A.), Pitié-Salpétrière Hospital, Paris; the Laboratory of Biophysics (E.V.), Fernand Widal Hospital, Paris; the Department of Cardiology (E.B.), Arras Hospital, Arras; the Department of Cardiology (J.E.P.), Abbeville Hospital, Abbeville; the Department of Cardiology (D.C.), Purpan Hospital, Toulouse; the Department of Cardiology (D.F.), Angoulème Hospital, Angoulème; the Department of Cardiology (A.D.), Saint-Philibert Hospital, Lomme; the Laboratory of Biochemistry (A.C.), C.H.U. Pitié-Salpétrière, Paris; and Rhone-Poulenc-Rorer (F.B.), Croix de Berny, France.

Correspondence to Gilles Montalescot, MD, PhD, Department of Cardiology, Centre Hospitalier Universitaire Pitié-Salpétrière, 47 boulevard de l'Hôpital, 75013, Paris, France. E-mail gilles.montalescot{at}psl.ap-hop-paris.fr

	Abstract

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Background—The pathogenesis of unstable angina and non–Q-wave myocardial infarction is still poorly understood, and early evaluation of prognosis remains difficult. We therefore studied the predictive value of 5 biological indicators of inflammation, thrombogenesis, vasoconstriction, and myocardial necrosis, and we examined the effects of enoxaparin and unfractionated heparin on these markers after 48 hours of treatment.

Methods and Results—Sixty-eight patients with unstable angina or non–Q-wave myocardial infarction randomized in the international ESSENCE trial participated in this French substudy. C-reactive protein, fibrinogen, von Willebrand factor antigen, endothelin-1 and troponin I were measured on admission and 48 hours later. The composite end point of death, myocardial infarction, recurrent angina, or revascularization was significantly lower at 14 and 30 days of follow-up in patients allocated to enoxaparin compared with unfractionated heparin. All acute-phase reactant proteins were elevated on admission and increased further at 48 hours. Multivariate analysis demonstrated that the rise of von Willebrand factor over 48 hours was a significant and independent predictor of the composite end point at both 14 days and 30 days. Moreover the early increase of von Willebrand factor was more frequent and more severe with unfractionated heparin than with enoxaparin (mean change was +8.7±8.8% with enoxaparin versus +93.9±11.7% with unfractionated heparin, P<0.0001). The other clinical and biological variables did not predict outcome.

Conclusions—In patients with unstable angina or non–Q-wave myocardial infarction, the acute-phase proteins increase over the first 2 days despite medical treatment. The early rise of von Willebrand factor is an independent predictor of adverse clinical outcome at 14 days and at 30 days. Enoxaparin provides protection as evidenced by the reduced release of von Willebrand factor, which represents a favorable prognostic finding.

Key Words: coronary disease • von Willebrand factor • C-reactive protein • fibrinogen • heparin

	Introduction

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Unstable angina and non–Q-wave myocardial infarction (unstable coronary artery disease) share the same pathophysiology, clinical presentation, and difficulty of risk assessment for future cardiac events. Recurrence of chest pain despite medical therapy and ECG changes indicate a poorer prognosis. Conventional serum markers such as creatine kinase and its isoenzyme MB lack sensitivity and specificity for the initial risk evaluation.^{1 2 3 4} Recently, troponin T and troponin I, which are early specific markers of myocardial necrosis, have been shown to be reliable indicators of prognosis in large populations of patients with acute coronary syndromes.^{2 3 4} Inflammation is present in unstable coronary artery disease and may precipitate the thrombogenic process by enhancing the local hemostatic and vasoconstrictor responses. Increased plasma concentrations of acute-phase reactant proteins such as C-reactive protein and fibrinogen have been reported in unstable coronary artery disease.^{5 6 7 8} These markers provide some prognostic information and they require de novo synthesis by the liver. von Willebrand factor, another protein of the acute phase reaction, is stored in the Weibel-Palade bodies of endothelial cells and in the platelet -granules and can be released rapidly at the local site of the injured artery without de novo protein synthesis. von Willebrand factor mediates platelet adhesion to exposed subendothelium, and raised plasma levels of von Willebrand factor have been reported in patients with acute myocardial infarction and after coronary angioplasty, but little attention has been focused on unstable coronary artery disease.^{9 10 11 12 13 14 15} Recently, an elevated level of von Willebrand factor has been reported to be a risk factor for coronary heart disease with other hemostatic factors (fibrinogen and factor VIII).¹⁶

We undertook a prospective study in unstable coronary artery disease patients to further evaluate the prognostic value of these factors of inflammation and hemostasis (C-reactive protein, fibrinogen, von Willebrand factor), of the early marker of myocardial damage troponin I, and of the endothelial vasoconstrictor peptide endothelin-1, which has been reported to increase after coronary angioplasty and in the early hours of myocardial infarction or unstable coronary artery disease.^{17 18 19 20}

	Methods

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This study was conducted in 6 of the French centers involved in the international ESSENCE trial, which demonstrated the clinical superiority of enoxaparin (100 anti-Xa units/kg every 12 hours) compared with adjusted-dose intravenous unfractionated heparin in patients hospitalized for unstable coronary artery disease.²¹ The benefit observed with enoxaparin was similar in patients with unstable angina as in patients with non–Q-wave myocardial infarction. Patients were sampled twice, on admission and 48 hours later, to determine the predictive value of the changes in the biochemical parameters. The relation of each biochemical variable to the outcome at 14 and 30 days of follow-up was assessed directly by univariate analysis and multivariately after adjustment for other associated clinical and biological variables. In addition, we examined the treatment effects of enoxaparin versus unfractionated heparin on biological variables and clinical outcome.

Study Patients
Sixty-eight patients were enrolled in 6 of the French centers participating in this substudy of the international ESSENCE trial, which involved 3171 patients overall. To be randomized, patients had to have experienced rest angina lasting >10 minutes suggestive of myocardial ischemia, with the last episode of chest pain within the last 24 hours, and demonstrated evidence of coronary artery disease as shown by 1 of the following: (1) ECG changes; (2) previous myocardial infarction, PTCA, or CABG; (3) previous positive exercise treadmill test in men or previous positive thallium exercise test in women; and (4) previous coronary angiography showing >50% narrowing of any coronary artery.²¹

Exclusion criteria included the presence of left bundle-branch block or pacemaker, persistent ST-segment elevation, secondary angina with an identified precipitating factor (eg, severe anemia, thyrotoxicosis, heart failure, tachydysrhythmia, or severe hypertension), contraindications to anticoagulation, current need for oral anticoagulant (eg, heart valve prosthesis), and renal failure. Written informed consent was obtained from all patients. The ESSENCE study and this substudy were both approved by the Pitié-Salpétrière Ethics Committee.

Study Design: ESSENCE Study
The international ESSENCE study¹⁹ was a randomized, double-blind, parallel group trial. Patients received either weight-adjusted enoxaparin (100 anti-Xa units/kg) subcutaneously at 12-hour intervals and intravenous bolus and infusion of unfractionated heparin placebo or subcutaneous enoxaparin placebo and intravenous bolus unfractionated heparin followed by continuous infusion adjusted according to the activated partial-thromboplastin time (aPTT). All patients received aspirin therapy (100 to 325 mg daily). The study treatment was administered for a minimum of 48 hours and up to a maximum of 8 days. End points were evaluated at 14 days and 30 days: new myocardial infarction, recurrent angina, revascularization procedure, or death. The primary outcome was the composite end point of death, myocardial infarction, or recurrent angina with ECG changes or prompting intervention. All clinical events were adjudicated independently by an end point committee unaware of treatment assignments and biological results. Myocardial infarction as an end point was clearly defined in the protocol, especially for patients admitted with a non–Q-wave myocardial infarction. Although creatine kinase (CK) enzymes were required to be elevated for reinfarction within 16 hours and CK data were examined as supportive information, they were not part of the formal definition for reinfarction within 16 hours of admission. Patients were required to exhibit a new episode of severe ischemic discomfort at rest accompanied by new or recurrent ST-segment elevation of >0.1 mV in at least two contiguous leads and the ischemic discomfort and/or ST-segment elevation had to persist for at least 30 minutes. After 16 hours, reinfarction was defined by cardiac enzymes or ECG evidence of myocardial infarction (enzyme: reelevation of CK-MB to above normal if prior CK-MB was in the normal range, or >50% above prior level if the prior level was above the normal range).

Study Design: Present Study
Blood was sampled twice in each patient at baseline and at 48 hours. All measurements were performed in a central laboratory (Pitié-Salpétrière Hospital) at the end of the study. For the purpose of this substudy, we used the ESSENCE database with demographic data, baseline characteristics, validated clinical events, and revascularization procedures of the 68 patients. Clinical follow-up was performed at both 14 days and 30 days. The primary objective of this study was the composite end point of death, myocardial infarction, recurrent angina, or any revascularization procedure at 14 days of follow-up. The same composite end point was also assessed at 30 days of follow-up (secondary objective).

Biological Measurements
Venous blood (9 volumes) was collected into a Vacutainer tube containing 0.129 mol/L trisodium citrate (1 volume) for fibrinogen and von Willebrand factor antigen measurements. Platelet-poor plasma was obtained by centrifugation at 3000g for 20 minutes at 10°C. Plasma was separated into aliquots and stored at -80°C. Fibrinogen was measured by the Clauss thrombin time method (Thrombin Reagent, Baxter, Dade Division) with an STA analyzer.²² The normal range was 1.7 to 3.7 g/L. The plasma concentrations of von Willebrand factor antigen were measured with an ELISA technique (Asserachrom von Willebrand factor, Diagnostica Stago). The normal range was 60% to 110%. The interassay and intra-assay coefficient of variation was <5% for both fibrinogen and von Willebrand factor measurements.

To determine C-reactive protein, blood was collected into a Vacutainer tube with no additive. After centrifugation, serum was divided into aliquots and stored at -80°C until further analysis. C-reactive protein was measured by immunonephelometry on a Behring Nephelometer BNII (Behring). The sensitivity of the assay was 0.8 mg/L, normal values being <5 mg/L.

Troponin I was measured by enzyme immunoassay on an Opus analyzer (Behring). The sensitivity of the assay was 0.5 µg/L, normal values being <2 µg/L.

For endothelin measurements, blood was collected into Vacutainer tubes containing ethylene diamino tetra-acetic acid, immediately centrifuged, and frozen at -80°C. Endothelins were extracted with the ethyl silica minicolumns (Amprep C2, 500 mg Amersham) from up to 2 mL of plasma, eluted by methanol 80%/TFA in the Tris HCl pH 7.4 radioimmunoassay buffer. Endothelin concentrations were determined by radioimmunoassay as previously described.²³ The antibody specificity (ie, cross-reactivity of different peptides at 50% binding concentration) was endothelin (ET)-1 100%, ET-2 475%, ET-3 78%, and big ET 0.46%. The sensitivity of the assay was 0.25 pg/tube and the interassay and intra-assay reproducibility was 6.1% and 15%, respectively.

Statistical Analysis
Results are expressed as mean±SEM. Simple linear regression was used to test the association between continuous variables. Potential associations between clinical or biological parameters and the composite end point at 14 days and 30 days were first tested by univariate procedures with Student's t or ² tests. To estimate the potential predictive values of biological parameters independent of clinical parameters, all biological variables with a P value <0.20 in the univariate procedure were analyzed multivariately with stepwise logistic regression in a model including all clinical variables (Biomedical Data Processing Package, UCLA).²⁴ To avoid an overestimation of the number of predictive variables, we used conservative criteria to select predictive variables: (1) limits to enter or remove variables in the regression equation must have 5% probability value, (2) the ratio between the corresponding regression and its standard error must be >2,²⁵ and (3) results were verified with two different numerical procedures, asymptotic covariance estimate and maximum likelihood method. To give an estimation of the increase in risk caused by high von Willebrand factor, we used a logistic procedure to calculate the odds ratio (OR) corresponding to the group of patients with values of von Willebrand factor higher than the median value of von Willebrand factor versus those with values lower than the median value. Unadjusted OR and OR adjusted for all clinical baseline variables tested in the multivariate procedure were calculated. The conclusions are based on the results of the multivariate analysis and data of the univariate screening procedure are presented only for information.

	Results

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Clinical Characteristics
Sixty-eight patients were included in this substudy in 6 centers. Thirty-four patients were assigned to unfractionated heparin and 34 to enoxaparin. The admission diagnosis was unstable angina in 50 patients and non–Q-wave myocardial infarction in 18 patients. At least 1 clinical end point occurred in 26 patients at 14 days and in 27 patients at 30 days. Age, sex, weight, and medical history did not differ between the patients with or without an end point during the 14-day follow-up (see Table 1). Blood pressure tended to be higher and ECG changes were significantly more frequent in patients with an adverse outcome, but these parameters were not significant predictors of the outcome at 14 days and 30 days after multivariate analysis. Mean study drug duration was 3.6±0.4 days in the group of patients with an end point at 14 days and 3.9±0.2 days in the patients without an end point.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Patients With or Without an End Point at 14 Days of Follow-up

Biological Variables and Outcome
The mean plasma level of von Willebrand factor in the whole population increased from 179.9±9.2% at baseline to 227.7±9.9% at 48 hours (P<0.0001), and the rise was 2-fold higher in patients with an end point at 14 days than in those without an end point (P=0.02; see Table 2). von Willebrand factor increased over the first 2 days in 86% of patients who experienced a clinical end point at day 14. Plasma levels of von Willebrand factor at the entry and their changes over 48 hours ( von Willebrand=von Willebrand H₄₈-von Willebrand H₀) did not correlate with the troponin I levels on admission or to the changes of troponin I levels over the first 48 hours. The median value of von Willebrand was 36%. Multivariate analysis confirmed that von Willebrand over the first 48 hours was a significant predictor of adverse outcome at both 14 days (² test for improvement of likelihood ratio=5.6) and 30 days (² test for improvement of likelihood ratio=4.1) in patients admitted for unstable coronary artery disease. This factor was predictive independent of all the other biological and clinical variables. The increase in risk associated to high von Willebrand was also assessed by estimation of OR for patients with von Willebrand higher than the median value of von Willebrand versus those with values lower than the median value. Unadjusted or adjusted OR (95% CI) were 6.1 (1.5 to 23.9) and 6.5 (1.3 to 34.2) for the composite end point at 14 days (primary objective of the study).

View this table: [in this window] [in a new window]   Table 2. Univariate and Multivariate Analyses for Biological Variables

There was a dramatic increase over the first 48 hours of the plasma levels of fibrinogen (from 3.16±0.10 to 3.77±0.15 g/L, P<0.0001) and C-reactive protein (from 8.3±2.3 to 24.1±5.0 mg/L, P<0.001), but there were no significant differences for both parameters between the patients with or without an end point at 14 days (see Table 2). The changes of C-reactive protein plasma levels over the first 48 hours correlated significantly to the changes of fibrinogen plasma levels over the same period (r=0.84, P<0.0001). The correlations between the changes in von Willebrand factor and fibrinogen (r=0.51, P<0.0001) or C-reactive protein (r=0.48, P=0.0005) were significant but not as strong.

The mean basal levels of endothelin-1 and troponin-I were both elevated on admission and they did not change significantly over the first 2 days. The levels did not differ either between the groups of patients with or without an end point at 14 days.

Treatment Effects
Patients allocated to enoxaparin experienced fewer clinical events than the patients treated with unfractionated heparin at both 14 days (9 versus 17 patients, P=0.04) and 30 days (9 versus 18 patients, P=0.02) of follow-up. When examining all the events of the first 14 days of follow-up, the superiority of enoxaparin over unfractionated heparin was present for each individual element of the composite end point (Table 3). Furthermore, the rise of von Willebrand factor over the first 48 hours of treatment after admission was more frequent and more pronounced in the unfractionated heparin group than in the enoxaparin group (mean change of von Willebrand factor was +8.7±8.8% in the enoxaparin group versus +93.9±11.7% in the unfractionated heparin group, P<0.0001, see Figure). The rise of von Willebrand factor according to the treatment group and the presence or not of an event of the composite end point is shown in Table 4. The early rise of von Willebrand factor is associated with all individual events of the composite end point. The patients free of events in the enoxaparin group did not increase their von Willebrand factor plasma levels over 48 hours. Treatment with enoxaparin did not alter the plasma levels of the other biological variables measured in this study.

View this table: [in this window] [in a new window]   Table 3. Number of Events at 14-Day Follow-up in Each Treatment Group

View larger version (14K): [in this window] [in a new window]   Figure 1. Absolute changes of von Willebrand factor (vWF) levels (%) over 48 hours (von Willebrand factor level at 48 hours [%]-von Willebrand factor level at entry [%]) in patients randomized to receive unfractionated heparin or enoxaparin. The rise of von Willebrand factor was more pronounced in patients receiving unfractionated heparin than in those receiving enoxaparin (P<0.0001 between mean values shown in the figure).

View this table: [in this window] [in a new window]   Table 4. von Willebrand Factor (%) in Each Treatment Group According to Presence of an Event

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Our study confirms that the first hours of evolving unstable coronary artery disease are associated with a significant acute-phase response. The baseline levels of C-reactive protein, fibrinogen, and von Willebrand factor are elevated in our patients on admission and these levels further increase over the first 48 hours, showing the presence of an ongoing inflammatory process despite antithrombotic and anti-ischemic therapies. We demonstrate further that an early increase of von Willebrand factor is a strong independent predictor of adverse clinical outcome at both 14 and 30 days of follow-up. Another important finding of this study is the major treatment effect of enoxaparin observed on von Willebrand factor levels. The von Willebrand factor plasma levels increase dramatically over 48 hours in patients treated by unfractionated heparin, whereas this response is blunted in patients receiving enoxaparin. This might explain the clinical benefit observed with enoxaparin in the present substudy and in the main ESSENCE trial.

Several prior studies have reported elevated values of acute-phase proteins in patients with unstable coronary artery disease,^{5 6 7 8} and few of them investigated their prognostic importance. von Willebrand factor has not drawn much attention in unstable coronary artery disease despite its major role in the platelet–vessel wall interaction and its predictive value of acute coronary syndromes in coronary patients.²⁶ This adhesive protein participates in the inflammatory process of unstable coronary artery disease and increases more markedly and more often in our patients who experience a major clinical event within the 14 days and 30 days follow-up. The absence of a relation with troponin I levels suggests that the rise of von Willebrand factor is not secondary to myocardial cell damage. In contrast to other proteins involved in the inflammatory process, von Willebrand factor can be released rapidly and act locally as a potent thrombogenic factor, which may explain its better predictive value compared with C-reactive protein and fibrinogen, which were not predictors of outcome in our group of patients.

von Willebrand factor mediates platelet adhesion to sites of vascular damage through the interaction with platelet glycoprotein Ib. This interaction not only promotes the initial attachment of platelets to subendothelium but acts also as a platelet agonist²⁷ and plays a role in thrombus formation through exposure of glycoprotein IIb/IIIa, to which von Willebrand factor and fibrinogen can bind.²⁸ The role of von Willebrand factor in these processes is most significant at high shear rates.²⁹ The von Willebrand factor binding site for platelet glycoprotein Ib overlaps with an important heparin binding domain.³⁰ Heparin bound to von Willebrand factor prevents the protein binding to glycoprotein Ib and impairs von Willebrand factor–dependent platelet hemostatic mechanisms in vitro and in vivo in human beings.^{31 32} Subspecies of heparin have been developed to enhance potency to inhibit von Willebrand factor/platelet interaction, but the precise von Willebrand factor–binding domains of heparin are not yet identified.³³ Unfractionated heparin and enoxaparin may not have the same affinity for von Willebrand factor, leading to a possible difference in platelet deposition on the injured artery. In contrast to unfractionated heparin, low-molecular-weight heparin exhibits considerably less binding to plasma proteins, has a higher bioavailability, a more pronounced anti-Xa effect including at the surface of platelets, and resists to platelet factor 4.^{34 35 36} The success of low-molecular-weight heparin to reduce thrombin generation and platelet activation is consistent with our finding of a better control of von Willebrand factor release during an acute coronary event. This von Willebrand factor effect may reflect the key intervention of enoxaparin in the platelet-endothelium interaction. In addition, von Willebrand factor circulates in plasma as a noncovalent complex with Factor VIII, protecting Factor VIII from inactivation and delivering it at the sites of vascular injury.³⁷ A better control of von Willebrand factor plasma levels provides less Factor VIIIa available for thrombin generation, which is a major agonist of both endothelial cells and platelets. Less thrombin generation may limit further the release of von Willebrand factor stored in Weibel-Palade bodies and -granules,³⁸ and previous reports have shown that therapeutic doses of enoxaparin reduce significantly thrombin generation.^{39 40}

Thus the effect of enoxaparin on the high levels of von Willebrand factor initially measured in our patients could reduce both platelet deposition through von Willebrand factor–glycoproteins interactions and thrombin generation through von Willebrand factor–Factor VIII interaction. These actions may prevent further von Willebrand factor release and control better the ongoing thrombotic process. This effect of enoxaparin on von Willebrand factor may be an important explanation for its superiority over unfractionated heparin in a platelet-mediated coronary event. One limitation of our study is the small sample size, which does not allow us to see ECG changes, troponin I, or fibrinogen as significantly predictive of outcome after multivariate analysis. Moreover, our data do not demonstrate a causal relation between the changes of von Willebrand plasma levels under treatment and the clinical efficacy of enoxaparin in unstable coronary artery disease patients but suggest a mechanism to explain the clinical benefit observed with enoxaparin in the ESSENCE trial.¹⁹ Further studies are needed to determine if it is a specific property of enoxaparin or a common characteristic to all low-molecular-weight heparins and to prove that this effect of enoxaparin is responsible for its efficacy in unstable coronary artery disease.

In conclusion, our data confirm the previous reports of an inflammatory process in unstable coronary artery disease and demonstrate that the early increase of von Willebrand factor, an acute-phase and thrombogenic protein, predicts severe coronary events complicating unstable coronary artery disease. The blunting of the early von Willebrand factor rise by enoxaparin may relate to the better clinical outcome observed in our study and more widely in the ESSENCE trial. In addition to the pathogenetic and clinical importance, the present results point to von Willebrand factor as a new pharmacologic target to prevent thrombosis at high shear rates.

	Acknowledgments

 
We would like to thank Marc Cohen, MD, Allegheny University Hospital, Philadelphia, Pa, for discussion of the data and expert revision of the manuscript. We thank M. Novakowski and M.H. Genevée for their technical assistance.

	Footnotes

 
Presented in part at the 19th Congress of the European Society of Cardiology, August 1997, Stockholm, Sweden.

Received December 12, 1997; revision received March 4, 1998; accepted March 17, 1998.

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