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(Circulation. 1997;96:3396-3402.)
© 1997 American Heart Association, Inc.

Articles

Effect of Nadroparin, a Low-Molecular-Weight Heparin, on Clinical and Angiographic Restenosis After Coronary Balloon Angioplasty

The FACT Study

Jean-Marc Lablanche, MD; Eugène P. McFadden, MRCPI; Nicolas Meneveau, MD; Jean René Lusson, MD; Bernard Bertrand, MD; Jean-Philippe Metzger, MD; Victor Legrand, MD; Gilles Grollier, MD; Carlos Macaya, MD; Bernard de Bruyne, MD; Alec Vahanian, MD; Alain Grentzinger, MD; Christiane Masquet, MD; Jean-Eric Wolf, MD; Gerard Tobelem, MD; Sylvie Fontecave, MD; André Vacheron, MD; Pascal d'Azemar, MD; ; Michel E. Bertrand, MD

From the Centre Hospitalier Regional et Universitaire Lille, France (J.-M.L., E.P.M., M.E.B.); Centre Hospitalier Regional et Universitaire Besançon, France (N.M.); Centre Hospitalier Regional et Universitaire, Clermont-Ferrand, France (J.R.L.); Centre Hospitalier Regional et Universitaire, Grenoble, France (B.B.); Groupe Hospitalier Necker-Enfants Malades, Paris, France (J.-P.M., A.V.); Centre Hospitalier Universitaire de Liège, Belgium (V.L.); Centre Hospitalier Regional, Caen, France (G.G.); San Carlos University Hospital, Madrid, Spain (C.M.); O.L. Vrouwziekenhuis, Aalst, Belgium (B. de B.); Hôpital Tenon, Paris, France (A.V.); Centre Hospitalier Universitaire de Brabois, Vandoeuvre Les Nancy, France (A.G.); Hôpital Lariboisière, Paris, France (C.M., G.T.); Centre Hospitalier Universitaire, Dijon, France (J.-E.W.); Sanofi Research, Paris, France (S.F., P d'A.).

Correspondence to J.-M. Lablanche, MD, Service de cardiologie C, Hopital Cardiologique, 59037 Lille, France.

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Background Experimental studies suggest that the antiproliferative effect of heparin after arterial injury is maximized by pretreatment. No previous studies of restenosis have used a pretreatment strategy. We designed this study to determine whether treatment with nadroparin, a low-molecular-weight heparin, started 3 days before the procedure and continued for 3 months, affected angiographic restenosis or clinical outcome after coronary angioplasty.

Methods and Results In a prospective multicenter, double-blind, randomized trial, elective coronary angioplasty was performed on 354 patients who were treated with daily subcutaneous nadroparin (0.6 mL of 10 250 anti-Xa IU/mL) or placebo injections started 3 days before angioplasty and continued for 3 months. Angiography was performed just before and immediately after angioplasty and at follow-up. The primary study end point was angiographic restenosis, assessed by quantitative coronary angiography 3 months after balloon angioplasty. Clinical follow-up was continued up to 6 months. Clinical and procedural variables and the occurrence of periprocedural complications did not differ between groups. At angiographic follow-up, the mean minimal lumen diameter and the mean residual stenosis in the nadroparin group (1.37±0.66 mm, 51.9±21.0%) did not differ from the corresponding values in the control group (1.48±0.59 mm, 48.8±18.9%). Combined major cardiac-related clinical events (death, myocardial infarction, target lesion revascularization) did not differ between groups (30.3% versus 29.6%).

Conclusions Pretreatment with the low-molecular-weight heparin nadroparin continued for 3 months after balloon angioplasty had no beneficial effect on angiographic restenosis or on adverse clinical outcomes.

Key Words: angioplasty • anticoagulants • aspirin • heparin

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Restenosis after coronary balloon angioplasty detracts from its clinical value in the treatment of coronary artery disease. The pathophysiology of restenosis involves neointimal proliferation and vessel remodeling.^1,2 To date, despite the performance of many well-designed clinical trials, no pharmacological agent tested has been convincingly demonstrated to reduce restenosis.

Heparin has pharmacological actions that are potentially useful in reducing restenosis. In addition to its anticoagulant and antithrombotic effects, heparin has been shown to limit neointimal proliferation in vitro as well as in animal models of balloon injury.^3-5 The doses of unfractionated heparin that can safely be administered to humans are limited by the potential occurrence of bleeding complications. The pharmacological profiles of low-molecular-weight heparins differ from those of unfractionated heparin, with a longer half-life and greater bioavailability.^6,7 Low-molecular-weight heparins have shown as great or greater antiproliferative activity in vitro and in vivo than unfractionated heparin.^8,9

Studies in vitro have shown that the antiproliferative effect of low-molecular-weight heparin was 50 to 100 times greater in quiescent than in rapidly proliferating cells.¹⁰ Because evidence for smooth muscle cell proliferation can be demonstrated in the hours after balloon injury, it may be of critical importance to start treatment before arterial injury.¹¹ This suggestion is supported by experimental observations with heparin in an animal model.¹² Several studies examined the effects of unfractionated or low-molecular-weight-heparin on restenosis in humans, with negative results.^13-17 However, pretreatment was not used in any of these studies. We undertook the present study, the FACT study to determine whether nadroparin (Fraxiparine), a low-molecular-weight heparin, might influence angiographic restenosis after coronary balloon angioplasty.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Patient Selection and Inclusion and Exclusion Criteria
Patients were enrolled between May 1991 and December 1993 in 12 centers located in France, Belgium, and Spain. The coordinating center and angiographic core laboratory were located at the Hôpital Cardiologique, Lille, France. The 12 participating hospitals and the principal investigators are listed in "Appendix." The study protocol was approved by the ethical committees of the participating hospitals, and all patients gave written informed consent. Patients were eligible for inclusion if they were 18 to 75 years old, had angina and/or objective evidence of myocardial ischemia, and were scheduled for balloon angioplasty of a significant (>50%) stenosis that was documented on a recent coronary angiogram. Patients were excluded if they met any of the following criteria: women of childbearing potential, recent myocardial infarction (<3 weeks), insulin-dependent diabetes, severe uncontrolled hypertension, renal or hepatic impairment, history of bleeding, history of thrombocytopenia, history of allergy, contraindications to aspirin or to heparin, participation in another study, recent major surgery, treatment with oral anticoagulants, inability to give informed consent, or low likelihood of follow-up angiography because of a coexisting medical condition. Angiographic exclusion criteria were restenosis lesions, significant left main coronary artery disease, target lesions in a coronary bypass graft or in a vessel that was totally occluded, and perfusion grade of 0 or 1 as defined by the Thrombolysis in Myocardial Infarction Investigators.¹⁸

Treatment Protocol
After written informed consent was obtained, patients were randomized to receive once-daily subcutaneous injections of either nadroparin (0.6 mL of 10 250 anti-Xa IU/mL or placebo from 3 days before angioplasty until 3 months afterward. Before angioplasty, all patients were also treated with aspirin (250 mg/d). After angioplasty, the group randomized to nadroparin injections received placebo aspirin capsules, whereas the group randomized to placebo injections received aspirin (250 mg/d). The subcutaneous injections for the 3 days before angioplasty were given by nurses (either at the patient's home or in the hospital). Instruction in the technique of subcutaneous injection was given to all the patients during hospitalization; the injections were subsequently performed by the patients themselves. The investigators and patients were blinded to treatment allocation. The treatment kits, consisting of an appropriate number of prefilled syringes (containing nadroparin or placebo) and capsules (aspirin or placebo), were given to the patient on hospital discharge (with sufficient treatment for 1 month) and at the 1-month follow-up visit (with sufficient treatment for 2 months). Patient compliance with treatment was monitored by counting the used and unused syringes in the returned treatment kits.

Angioplasty Procedure and Angiographic Analysis
Angioplasty was performed at each center in accordance with local practice. A bolus dose of unfractionated heparin (10 000 IU) was administered at the start of the procedure, with an additional bolus (5000 IU) after each hour of the procedure. The patient remained in the study if the procedure was judged to be successful by the investigator (residual stenosis visually estimated as <50% with an absolute gain of >20%, without major complication). Coronary angiography was performed before, immediately after, 24 hours after, and 3 months after angioplasty. Follow-up angiography was performed earlier if there was a clinical indication. If a follow-up angiogram performed sooner than 2 months after angioplasty did not demonstrate restenosis, the patient was encouraged to return for another angiography at the end of the study.

Isosorbide dinitrate (2 mg) was injected into the coronary artery before each angiogram and in both groups in an attempt to standardize vasomotor tone. The angiograms were recorded on standard 35-mm film. Three views of the stenosis were obtained at the time of angioplasty and were recorded on a worksheet to allow them to be duplicated exactly at the time of follow-up angiography. An attempt was made to obtain two orthogonal views for each lesion.

The core angiographic laboratory was located at the University of Lille. The quantitative analysis was performed on sequential angiograms filmed in the same projection. The frames were selected by the cardiologist who performed the quantitative analysis from the projection in which the stenosis appeared most severe just before angioplasty. Quantitative analysis was performed with the CAESAR system, a computerized automatic-analysis system that has been fully described elsewhere.¹⁹ We had previously determined the accuracy (defined as the signed difference between the measured and the true value) and the precision (defined as the standard deviation of these differences) of the CAESAR system in a study analyzing cine films of Plexiglas blocks containing precision drilled models of coronary arteries filled with contrast medium. The accuracy was 0.07 mm and the precision was 0.14 mm. To assess the intraobserver and interobserver variabilities of the system, 90 arterial segments from patients undergoing coronary angioplasty were analyzed by two independent observers and reanalyzed at a remote time. The mean intraobserver variation, expressed as the standard deviation of the differences, was 0.10 mm, and the interobserver variation was 0.11 mm.¹⁸

Clinical and Angiographic End Points
The primary end point was angiographic restenosis defined as a residual stenosis of <50% after angioplasty that became 50% at follow-up. Clinical end points were the occurrence of death, nonfatal target lesion myocardial infarction, coronary artery bypass graft surgery, or repeat target-vessel angioplasty within the 6 months after the procedure. Hemorrhage was considered to be major if it required premature treatment cessation. Target lesion myocardial infarction was defined clinically at the participating site.

Biological Surveillance
All patients had blood samples taken to determine complete blood cell count (including differential white cell count); activated partial thromboplastin and prothrombin times; liver function tests; and uric acid, creatinine, glucose, and cholesterol levels before treatment and at 3 months. Due to the potential hazard of heparin-associated thrombocytopenia, platelet counts were performed before treatment, just before angioplasty, every 4 days during the month after angioplasty, and at 3 months.

Definitions
Acute gain was defined as the difference between the MLD at the dilated site just before and immediately after the procedure. Late loss was defined as the MLD at the dilated site immediately after the procedure minus the MLD at the dilated site at the follow-up angiography. Net gain was defined as the MLD at the dilated site at the follow-up angiography minus the MLD at the dilated site just before angioplasty. The loss index was defined as the slope of the regression between late loss and acute gain. The balloon-to-artery ratio was defined as the nominal size of the balloon used divided by the reference diameter of the dilated vessel. Immediate recoil was defined as the largest nominal balloon size minus the MLD after angioplasty divided by the largest nominal balloon size. A significant fall in platelets was considered to be present if there was (1) a platelet count <50 giga/L with or without clinical signs or (2) a platelet count between 50 and 100 giga/L with clinical signs, or (3) a fall in platelet count of >40% accompanied by clinical signs.

Statistical Analysis
The primary end point was angiographic restenosis defined as a residual stenosis of <50% that became 50% at the follow-up angiography. For this end point, given an estimated restenosis rate of 40% in the control population, a sample size of 133 patients per group was required to demonstrate a reduction in restenosis to 25% in the active treatment group (allowing for a one-tailed error of .05 and a ß error of 0.20). To allow for procedures considered successful by the investigators but uncomplicated failure by the angiographic core laboratory and for dropouts, a total of 350 inclusions was planned. The statistical analysis was performed with SAS software (Version 6.08, SAS Institute). All tests were two-tailed, and values of P<.05 were considered significant. The baseline characteristics were compared in the two groups by use of t or ² tests as appropriate. The categorical restenosis rates were compared between the two groups with use of the ² test. The quantitative angiographic variables were compared between groups with use of the Wilcoxon test. The statistical unit was the patient; when more than one coronary segment was dilated, a mean value was calculated per patient. Clinical events related to the procedure and occurring during the predetermined 6-month follow-up were compared with use of the ² test. When more than one clinical event occurred per patient, the most severe event was used for the analysis with the following decreasing order of severity: death, nonfatal myocardial infarction, coronary artery bypass graft surgery, and target-vessel repeat angioplasty. To determine whether there were any differences between the groups in the timing of clinical events, the data were also analyzed using the Kaplan-Meier model. Quantitative data are presented in the text as mean±SD.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Baseline Characteristics
Between May 1991 and December 1993, 359 patients were randomized in the study. Three patients were excluded before treatment was started: 2 patients randomized to nadroparin withdrew consent, and 1 patient randomized to aspirin became clinically unstable and underwent uncomplicated angioplasty. Thus, 356 patients actually received treatment; 2 of these patients did not undergo angioplasty. One patient, randomized to nadroparin, developed an acute myocardial infarction after 1 day of treatment and was treated with thrombolytic therapy; 1 patient, in the control group, was referred for elective coronary artery bypass graft surgery due to the discovery of a previously unrecognized left main stem stenosis on the angiogram just before angioplasty. The baseline characteristics of the patients are given in detailed in Table 1. The groups were well matched for all variables apart from smoking, which was more frequent in the control group (P=.035).

View this table: [in this window] [in a new window]   Table 1. Baseline Clinical Characteristics (Intention-to-Treat Population)

Procedural Outcome
Angioplasty was performed in 175 patients in the nadroparin group and 179 patients in the control group (Fig. 1). In 7 patients (4.0%) randomized to nadroparin and 7 patients (3.9%) in the control group, the procedure was judged an uncomplicated failure by the investigator, and study treatment was discontinued. A small number of patients who had successful procedures with adjunctive nonballoon techniques (stent or atherectomy) forbidden by protocol were also withdrawn (Fig. 1), as were patients with periprocedural complications (Fig. 1, Table 2), which did not differ between groups.

View larger version (25K): [in this window] [in a new window]   Figure 1. Flow chart outlining the progress of the study. PTCA indicates percutaneous transluminal coronary angioplasty; QCA, quantitative coronary angiography.

View this table: [in this window] [in a new window]   Table 2. Procedural Complications and Clinical Follow-up (Intention-to-Treat Population)

Angiographic Restenosis
The main angiographic and procedural characteristics of the population are given in Table 3. The duration of treatment before angioplasty, time to follow-up angiography, and extent of compliance with treatment were similar in both groups. There were no differences between the groups in the location of the dilated lesions or angiographic characteristics of the lesions before angioplasty. Major procedural variables such as the total duration of balloon inflations, number of inflations, and mean balloon-to-artery ratio were also similar in the two groups.

View this table: [in this window] [in a new window]   Table 3. Angiographic and Procedural Characteristics (Per-Protocol Population)

The major results of the quantitative coronary angiographic analysis are presented in Table 4 and Fig. 2. The mean MLD did not differ significantly between groups before angioplasty, immediately after angioplasty, or at follow-up. The late loss and loss index did not differ significantly between groups. With the categorical approach, the restenosis rate in the nadroparin group was 41.0% compared with 38.8% in the control group (P=.75).

View this table: [in this window] [in a new window]   Table 4. Quantitative Angiographic Data (Per-Protocol Population)

View larger version (17K): [in this window] [in a new window]   Figure 2. Cumulative frequency distribution curves of the MLD (in mm) at the dilated site, before angioplasty (Pre-PTCA), immediately after angioplasty (Post-PTCA), and at follow-up (F-up). The nadroparin group is indicated by a continuous line, and the control group by a dotted line.

Clinical Outcome
Clinical follow-up was available for all patients at 3 months. Six-month follow-up was available for all except 2 patients (1.1%) in the nadroparin group and 3 patients (1.7%) in the control group. The combined rate of major events was similar in the groups: 30.3% in the nadroparin group versus 29.6% in the control group (Table 2), as was the time course of such events (Fig. 3).

View larger version (10K): [in this window] [in a new window]   Figure 3. Kaplan-Meier plots of survival without a major cardiac-related clinical event. The nadroparin group is indicated by a continuous line, and the control group by a dotted line.

Bleeding and Other Complications
The occurrence of side effects or of adverse events was evaluated in the entire population of patients (356) who had received at least one injection (nadroparin or placebo). The rate of major hemorrhagic complications was significantly (P=.012) higher in the nadroparin group (Table 5): five were hematomas at the femoral access site, of which four occurred during the 24-hour period after angioplasty when the patients were receiving additional unfractionated heparin at a therapeutic dose; one was an upper gastrointestinal tract hemorrhage.

View this table: [in this window] [in a new window]   Table 5. Platelet, Hemorrhagic, and Clotting Disorders and Hematological Parameters

There were no significant changes in red blood cell, white blood cell, or platelet count during the study period (Table 5). At baseline, the eosinophil count was similar in the nadroparin (0.17±0.13 giga/L) and control (0.18±0.15 giga/L) groups. At 3 months, the eosinophil count was significantly (P=.003) higher in the nadroparin group (0.29±0.28 giga/L) than in the control group (0.20±0.17 giga/L). None of the biochemical parameters measured differed at baseline. However, uric acid levels fell significantly (P=.007) from 351±89 µmol/L at baseline to 334±77 µmol/L at 3 months in the nadroparin group, whereas no change occurred in the control group.

Two patients in the control group developed significant thrombocytopenia. One had a fall in platelet level of >40% associated with a hematoma at the puncture site; the pretreatment platelet count (284 giga/L) fell to 161 giga/L after 5 days of treatment. Treatment was continued and the platelet count on day 9 had returned to normal (303 giga/L). The second developed thrombocytopenia with an absolute platelet count of 24 giga/L at 15 days after the start of treatment. Treatment was stopped and the platelet count returned to normal. No patient in the nadroparin group developed significant thrombocytopenia.

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The major finding of this study was that pretreatment for 3 days with the low-molecular-weight nadroparin, continued for 3 months after the procedure, did not affect clinical or angiographic outcomes after coronary balloon angioplasty.

Restenosis after coronary balloon angioplasty seems to result from several interrelated pathophysiological mechanisms. Evidence from studies in animals and from angiographic and intravascular ultrasound studies in humans suggests that neointimal proliferation and vessel remodeling are the two major mechanisms of late luminal narrowing after successful angioplasty.^1,2,12 The relative importance of these two processes remains unclear and may differ among subgroups of patients.

Unfractionated heparin is used during coronary angioplasty for its anticoagulant and antithrombotic properties. However, heparin has additional pharmacological actions that might be potentially useful in reducing restenosis. Heparin has been shown to limit neointimal proliferation in vitro as well as in animal models of balloon injury.^3-5 The doses of unfractionated heparin that can safely be administered in humans are limited by the potential occurrence of bleeding complications. The use of low-molecular-weight heparins reduces the potential for bleeding complications. The pharmacological profiles of low-molecular-weight heparins differ from those of unfractionated heparin, with a longer half-life and better bioavailability.^6,7 Low-molecular-weight heparins have shown as great or greater antiproliferative activity in vitro and in vivo than unfractionated heparin.^8,9

Nadroparin (Fraxiparine) is a low-molecular-weight heparin with a mean molecular mass of nadroparin of 4500 d; 90% of the molecular components range between 2000 and 8000 d. The bioavailability of nadroparin, administered subcutaneously, is almost 100% and greater than that of unfractionated heparin. It is absorbed rapidly from subcutaneous injection sites, distributed rapidly, and excreted mainly in the urine.

The present study represents the first report of pretreatment followed by sustained use of a low-molecular-weight heparin to prevent restenosis in humans. Ellis et al¹³ randomly assigned 416 patients to receive a continuous infusion of heparin or dextrose for 18 to 24 hours after angioplasty. The restenosis rate did not differ significantly between the groups. Brack et al¹⁴ randomized 339 patients who had undergone uncomplicated angioplasty to receive either high-dose subcutaneous heparin (12 500 IU BID) or no heparin for 4 months; there was no significant difference between groups in angiographic or clinical outcome. Faxon et al⁵ randomized 458 patients after successful angioplasty to receive low-molecular-weight heparin (40 mg/d enoxaparin SC) or placebo injections for 1 month. They found that treatment with enoxaparin did not reduce the incidence of angiographic restenosis or occurrence of clinical events over 6 months. The treatment was well tolerated, although in-hospital minor bleeding was more common in enoxaparin-treated patients than in control aubjects.⁵

Cairns et al,¹⁶ in the EMPAR study, used a 2x2 factorial design to examine the effects of enoxiparin, a low-molecular-weight heparin, and of fish oils (-3 fatty acids) on restenosis after coronary balloon angioplasty. Treatment with fish oil (or placebo) was begun a median of 6 days before angioplasty; enoxiparin was begun after sheath removal, and placebo injections were not used. There was no evidence for a clinically important reduction in restenosis with either agent.

Karsch et al,¹⁷ in the REDUCE study, studied the effects of reviparin, a low-molecular-weight heparin, begun at the time of arterial access for angioplasty and continued for 28 days on restenosis. They used a group of patients treated with unfractionated heparin for 24 hours followed by placebo subcutaneous injections for 28 days as control subjects. There was no difference in angiographic restenosis between the groups.

The present study extends these findings by demonstrating than even when treatment is started 3 days before angioplasty, low-molecular-weight heparin has no detectable effect on angiographic or clinical restenosis after balloon angioplasty. In the light of recent advances in our understanding of the pathophysiology of restenosis, in particular the demonstration that restenosis after balloon angioplasty is related to vascular remodeling that involves chronic recoil in a substantial proportion of cases, the results of the present study are not unexpected. However, the negative results of the present study and of the studies cited above do not rule out a role for low-molecular-weight heparins after interventional procedures. Intracoronary stent implantation provides a model in which restenosis, if it occurs, is almost exclusively related to smooth muscle cell proliferation. The present study shows that in patients undergoing angioplasty, pretreatment for 3 days continued for 3 months is both feasible and safe. Further studies, using similar treatment regimens, are needed to determine whether low-molecular-weight heparins derivatives have a therapeutic role in the prevention of in-stent restenosis.

Study Limitations
When this study was designed, it was thought that the major mechanism of restenosis was neointimal proliferation. Subsequent studies have shown that vascular remodeling also plays a major, perhaps even preeminent, role in the pathophysiology of restenosis.² Second, the power of this study was calculated on the basis of predefined angiographic end points. The power to detect a difference in clinical events was insufficient. Nevertheless, the absence of angiographic benefit suggests that it is unlikely that a clinical benefit would have been detected, even in a larger group of patients.

	Selected Abbreviations and Acronyms

 

CAESAR = Computer-Assisted Evaluation of Stenosis and Restenosis FACT = Fraxiparine Angioplastie Coronaire Transluminale MLD = minimal lumen diameter

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
In addition to the study authors, the following investigators participated in the FACT study: Study Coordinator, J.-M. Lablanche; Steering Committee, A. Vacheron, G. Tobelem, J.-C. Arcan, J.-M. Lablanche; Safety Committee, L. Drouet, W. Wijns; Angiography Core Laboratory, E. P. Mc Fadden, C. Bauters, J.-M. Lablanche, M. E. Bertrand; Centre Hospitalier Régional et Universitaire, Hôpital Cardiologique, Lille, France; Study Monitoring, S. Fontecave, V. Vajou, K. Attié; Sanofi Recherche, France; Statistical Analysis, S. Claudel, C. Le Louet; Sanofi Recherche, France. Participating centers were in France, Centre Hospitalier Regional et Universitaire, Besançon, N. Meneveau, J.-P. Bassand; Centre Hospitalier Regional et Universitaire, Clermont-Ferrand, J.-R. Lusson, J. Cassagnes; Centre Hospitalier Universitaire de Brabois, Vandoeuvre Les Nancy, A. Grentzinger, N. Danchin; Centre Hospitalier Regional et Universitaire, Grenoble, J. Machecourt, B. Bertrand; Groupe Hospitalier Necker-Enfants Malades, Paris, J.-P. Metzger, J.-L. Georges; Hôpital Tenon, Paris, A Vahanian, E. Dadez; Hôpital Lariboisière, Paris, C. Masquet, C. Eiferman; Centre Hospitalier Universitaire, Dijon, F. André, M. Fraison, J. E. Wolf; Centre Hospitalier Universitaire, Caen, G. Grollier, E. Lecluse; in Belgium, Centre Hospitalier Universitaire de Liège, V. Legrand, C. Martinez; O. L. Vrouwziekenhuis, Aalst, B. de Bruyne, W. Wijns, P. Nellens, G. R. Hendrickx; and in Spain: San Carlos University Hospital, Madrid, C. Macaya.

Received July 23, 1997; accepted August 1, 1997.

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