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(Circulation. 2005;112:416-422.)
© 2005 American Heart Association, Inc.

Preventive Cardiology

Eight-Year Follow-Up of Patients With Permanent Vena Cava Filters in the Prevention of Pulmonary Embolism

The PREPIC (Prévention du Risque d’Embolie Pulmonaire par Interruption Cave) Randomized Study

The PREPIC Study Group^*

From the Thrombosis Research Group, Clinical Pharmacology Department, University Hospital, Saint-Etienne, France.

Correspondence to Hervé Decousus, MD, Groupe de Recherche sur la Thrombose (EA3065), CIC-EC (DHOS/INSERM), Centre Hospitalier et Universitaire de St-Etienne, Hôpital Bellevue, F-42055 Saint-Etienne, France. E-mail herve.decousus{at}chu-st-etienne.fr

Received October 6, 2004; revision received February 18, 2005; accepted March 3, 2005.

	Abstract

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Background— In a randomized trial in patients with proximal deep-vein thrombosis, permanent vena cava filters reduced the incidence of pulmonary embolism but increased that of deep-vein thrombosis at 2 years. An 8-year follow-up was performed to assess their very long-term effect.

Methods and Results— Four hundred patients with proximal deep-vein thrombosis with or without pulmonary embolism were randomized either to receive or not receive a filter in addition to standard anticoagulant treatment for at least 3 months. Data on vital status, venous thromboembolism, and postthrombotic syndrome were obtained once a year for up to 8 years. All documented events were reviewed blindly by an independent committee. Outcome data were available in 396 patients (99%). Symptomatic pulmonary embolism occurred in 9 patients in the filter group (cumulative rate 6.2%) and 24 patients (15.1%) in the no-filter group (P=0.008). Deep-vein thrombosis occurred in 57 patients (35.7%) in the filter group and 41 (27.5%) in the no-filter group (P=0.042). Postthrombotic syndrome was observed in 109 (70.3%) and 107 (69.7%) patients in the filter and no-filter groups, respectively. At 8 years, 201 (50.3%) patients had died (103 and 98 patients in the filter and no-filter groups, respectively).

Conclusions At 8 years, vena cava filters reduced the risk of pulmonary embolism but increased that of deep-vein thrombosis and had no effect on survival. Although their use may be beneficial in patients at high risk of pulmonary embolism, systematic use in the general population with venous thromboembolism is not recommended.

Key Words: vena cava filters • prevention • thrombosis • trials • pulmonary embolism

	Introduction

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Although anticoagulation remains the primary treatment for venous thromboembolism, vena cava filters are an important alternative or add-on therapeutic strategy,¹ used in up to 15% of patients with deep-vein thrombosis in a recent prospective registry.² However, very few reliable data on the long-term efficacy and safety of these devices are available.^3,4 Venous thromboembolism is a chronic disease with risk of recurrence that may persist for many years, and permanent vena cava filters may provide lifelong protection from potentially fatal pulmonary embolism. Conversely, use of vena cava filters may be complicated by adverse events, the frequency of which may increase over time. They have no prophylactic effect on the recurrence of deep-vein thrombosis, and their use may favor the development of the postthrombotic syndrome.³

See p 298

The PREPIC (Prévention du Risque d’Embolie Pulmonaire par Interruption Cave) study is the only long-term randomized study of filter placement in the prevention of pulmonary embolism.⁵ In 400 patients with proximal deep-vein thrombosis followed up for 2 years, the insertion of a vena cava filter in combination with standard anticoagulation was associated with a reduction in the occurrence of pulmonary embolism compared with anticoagulation alone. However, this beneficial effect was counterbalanced by a significant increase in deep-vein thrombosis; in addition, filters had no impact on mortality. We followed up the patients enrolled in the PREPIC study for up to 8 years to assess the very long-term effect of vena cava filters on venous thromboembolism recurrence, the development of postthrombotic syndrome, and mortality.

	Methods

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Study Population
The study protocol and population have been described previously.⁵ Briefly, the multicenter trial enrolled consecutive patients over 18 years of age with acute proximal deep-vein thrombosis confirmed by bilateral venography, with or without concomitant symptomatic pulmonary embolism, and considered to be at high risk for pulmonary embolism.⁵ Using a factorial design, the trial compared the use of a permanent vena cava filter with no filter and the administration of a low-molecular-weight heparin (enoxaparin, Aventis Pharma) with unfractionated heparin, both anticoagulant treatments being given for 8 to 12 days. All patients received vitamin K antagonists for at least 3 months, with a target international normalized ratio of 2.0 to 3.0. Thus, from September 1991 to February 1995, 400 patients with acute proximal deep-vein thrombosis were randomly assigned to receive a filter (200 patients) or not (200 patients). The main baseline demographic and clinical characteristics of patients were similar (Table 1).

View this table: [in this window] [in a new window]   TABLE 1. Summary of Baseline Characteristics

Vena Cava Filter
Four types of permanent vena cava filter were used: Vena Tech LGM (B. Braun), titanium Greenfield (Boston Scientific), Cardial (Bard), and Bird’s Nest (Cook Group).⁵ All filters were inserted percutaneously under fluoroscopic control through a femoral or jugular vein. For patients in the filter group, cavography was performed immediately to ensure that the upper extremity of the filter was located in the inferior vena cava, immediately below the renal veins.

Follow-Up
Follow-up visits were scheduled at 3 months and 1 year. At 2 years and then once per year, all patients received a telephone call from the coordinating center, the members of which were unaware of the treatment assignment. Each patient was asked to report any new symptoms of pulmonary embolism, recurrent deep-vein thrombosis, or postthrombotic syndrome. To improve reporting of new events to the coordinating center, all patients had an individualized card to be given to all practitioners who monitored them. Practitioners who had managed the events reported by the patient were contacted, and all clinical, biological, and radiological data were recorded centrally by the coordinating center. The vital status was recorded each year using the centralized administrative survival inquiry procedure with the death registry of city halls.

Clinical Outcomes
The primary efficacy outcome was symptomatic pulmonary embolism up to 8 years. Symptomatic pulmonary embolism was considered to have occurred if it was documented objectively (positive angiography, high-probability lung scan, spiral computed tomography (CT), or chest radiograph,)^5–10 or, in the event of death, at autopsy or if there was strong evidence that pulmonary embolism was the cause of death. The angiographic diagnosis of pulmonary embolism required the visualization of a new intraluminal defect or a sudden new arterial cutoff in comparison with the most recent angiographic examination. On ventilation/perfusion lung scanning, diagnosis was based on the visualization of at least 2 new segmental mismatched perfusion defects with no improvement in other areas in cases of initial extensive perfusion defects on the more recent lung scan. On spiral CT, pulmonary embolism was diagnosed if a central filling defect outlined by contrast material or complete occlusion was seen in a segmental or more proximal pulmonary artery. Diagnosis of recurrent pulmonary embolism could be based on abnormal chest radiograph suggestive of pulmonary embolism if there was strong clinical evidence of pulmonary embolism and associated acute proximal deep-vein thrombosis. Other outcomes were symptomatic recurrent deep-vein thrombosis, total clinical venous thromboembolism, postthrombotic syndrome, mechanical filter complications, major bleedings, and death due to any cause. Recurrence of deep-vein thrombosis, including deep-vein thrombosis of the lower limbs and filter thrombosis, was diagnosed if there was a new intraluminal filling defect on venography, a lack of compressibility at a new site or an extension to a new venous segment of the thrombus on ultrasonography, or a partial or complete occlusion of an abdominal vein (iliac or caval) on contrast-enhanced CT scan.^11,12 Diagnosis of postthrombotic syndrome was considered if, compared with the initial assessment at inclusion, at least 1 of the following objective features appeared or worsened: edema, varicose veins, trophic disorders, or ulcers. All documented outcome events were reviewed by an independent adjudication committee unaware of the treatment assignments.

Statistical Analysis
Only analysis of the comparison filter versus no filter was performed, the comparison between the 2 types of heparin being irrelevant 8 years after a 10-day treatment. All analyses were performed on an intention-to-treat basis. Cumulative rates of events were calculated by the Kaplan-Meier method. Data on patients who died or were lost to follow-up were censored. Comparison between groups was assessed with a 2-sided Mantel-Haenszel (log-rank) test.¹³ Evaluation of baseline demographic and clinical characteristics of patients as predictors of long-term events was performed with Cox proportional hazards models. The hazard ratio and associated 95% CI for these various potential predictors of long-term events were calculated. Stepwise modeling was performed to screen potential variables for inclusion in the final model, with a probability value of 0.15 or less required for a variable to enter and/or to leave each model (univariate analysis). A probability value of 0.05 or less was used for the final model.

	Results

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Among 400 patients initially recruited in the study, outcome data were available in 396 (99%). No information on nonfatal clinical events between 3 months and 8 years was available for 3 patients, and the 8-year vital status was not known for 1 patient. At 8 years, 198 patients (49.5%) were alive, and 201 (50.3%) patients had died.

Concomitant Treatments
Vitamin K antagonists were prescribed for only 3 months after the index thromboembolic event in 38% of patients in the filter group and 36% of patients in the no-filter group. Thirty-five percent of patients in both groups received vitamin K antagonists over the entire 8-year study period or until their death. At 8 years, vitamin K antagonists were being prescribed to 50% of living patients in both groups (Figure 1). Nineteen percent of patients in both groups wore elastic stockings for only 3 months after the index thromboembolic event; they were worn during the entire study period by 45% and 47% of patients in the filter and no-filter group, respectively. At 8 years, 61% and 63%, respectively, of living patients were still using elastic stockings.

View larger version (16K): [in this window] [in a new window]   Figure 1. Percentage of patients receiving vitamin K antagonists according to year after index deep-vein thrombosis and treatment groups.

Recurrent Venous Thromboembolism
One or more documented episodes of pulmonary embolism occurred in 9 patients (a cumulative rate of 6.2%) in the filter group compared with 24 patients (15.1%) in the no-filter group (hazard ratio 0.37, 95% CI 0.17 to 0.79; P=0.008; Table 2; Figure 2A). Fifteen of these 33 events were diagnosed by ventilation-perfusion lung scanning, 8 by pulmonary angiography, 2 by spiral CT, and 1 by chest radiograph with acute deep-vein thrombosis; 7 events were fatal, and the diagnosis of pulmonary embolism was based on strong evidence that it was the cause of death in 6 patients or at autopsy in 1 patient. There were no differences in the diagnosis methods in the 2 study groups. Pulmonary embolism was fatal in 2 patients in the filter group and 5 in the no-filter group. After adjustment in multivariate analysis, filter insertion remained significantly (P=0.014) associated with reduction of pulmonary embolism (Table 3). Pulmonary embolism at inclusion was significantly (P=0.032) associated with an increased risk of pulmonary embolism at 8 years.

View this table: [in this window] [in a new window]   TABLE 2. Cumulative Rate of Clinical Outcomes at 8 Years*

View larger version (16K): [in this window] [in a new window]   Figure 2. Kaplan-Meier analysis of time to pulmonary embolism (A; filter versus no filter: hazard ratio 0.37, 95% CI 0.17 to 0.79, P=0.008), deep-vein thrombosis (B; filter versus no filter: hazard ratio 1.52, 95% CI 1.02 to 2.27, P=0.042), and death (C; filter versus no filter: hazard ratio 0.97, 95% CI 0.74 to 1.28, P=0.83) over a period of 8 years after index thromboembolic event according to treatment groups.

View this table: [in this window] [in a new window]   TABLE 3. Predictive Factors of Venous Thromboembolism at 8 Years According to Baseline Characteristics (Multivariate Analysis)

One or more documented episodes of deep-vein thrombosis occurred in 57 patients (35.7%) in the filter group and 41 (27.5%) in the no-filter group (hazard ratio 1.52, 95% CI 1.02 to 2.27; P=0.042; Figure 2B). Of these 98 events, 76 were diagnosed on ultrasonography, 20 on venography, and 2 on contrast-enhanced CT scan. These last 2 cases concerned 2 cancer patients for whom a scan was performed to diagnose thrombosis and exclude an extrinsic compression of the iliac and caval veins. There were no differences in diagnosis methods in the 2 study groups. Two of the 26 filter thromboses observed in patients in the filter group were associated with pulmonary embolism. On multivariate analysis, known cancer at inclusion was associated with a significantly (P=0.007) increased incidence of deep-vein thrombosis recurrence at 8 years (Table 3). Overall, venous thromboembolism occurred in 58 patients (36.4%) in the filter group and 55 (35.4%) in the no-filter group (P=0.54; Table 2). Among these patients, 35 (60%) and 29 (54%), respectively, did not receive a vitamin K antagonist at the time of venous thromboembolism recurrence.

Postthrombotic Syndrome
Postthrombotic syndrome was observed in 109 patients (70.3%) in the filter group and 107 (69.7%) in the no-filter group (Table 2). Approximately half of these patients experienced the first sign of postthrombotic syndrome within 3 years after the index thromboembolic event (data not shown). The most common signs of postthrombotic syndrome were edema and varicose veins.

Mortality
Ninety-eight patients (48.1%) in the filter group and 103 (51.0%) in the no-filter group had died at 8 years (Figure 2C). The main causes of death were cancer (49 patients), unexplained death presumed to be of cardiovascular origin (32 patients), cardiac disease (22 patients), and bleeding (17 patients). Pulmonary embolism was directly involved in the death of 7 patients (1.8%). Known cancer (hazard ratio 2.08, 95% CI 1.47 to 2.95; P<0.001), cardiac or respiratory insufficiency (hazard ratio 1.79, 95% CI 1.32 to 2.45; P<0.001), and age (hazard ratio 1.60 per 10 years, 95% CI 1.37 to 1.88; P<0.001) were the only significant predictors of death at 8 years.

	Discussion

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PREPIC shows that 8 years after the insertion of a permanent vena cava filter in patients with proximal deep-vein thrombosis with or without pulmonary embolism, pulmonary embolism occurrence was reduced significantly, although not eliminated, compared with no-filter patients. However, these beneficial findings were offset by an increased occurrence of deep-vein thrombosis in the lower limbs. Interestingly, vena cava filters did not increase the risk of postthrombotic syndrome. Vena cava filters had no impact on total mortality.

Patients enrolled in the present study may be considered to represent a high-risk population. Their mean age was 5 to 25 years higher than that of patients enrolled in other published long-term studies on venous thromboembolism.^14–25 All patients had proximal deep-vein thrombosis, which unlike distal deep-vein thrombosis is a risk factor for venous thromboembolism recurrence.^23,26 More than a third had symptomatic pulmonary embolism associated with deep-vein thrombosis. Taken together, these points may explain why, although consistent with the results of previous comparable studies, the rates of clinical events over time observed in the present study are at the higher end of the range observed in these studies.^{15–17,19–21,23,24} The 8-year rate of mortality was 50.5% compared with rates between 29.8% and 52.5% in previous studies.^17,19 Likewise, the cumulative incidence of recurrent venous thromboembolism at 5 years in the present study was 26%, whereas in other studies, it varied between 13.0% and 27.9%.^15,17,20,23 Consequently, this high-risk population was monitored closely, and at 8 years, 60% of living patients were using elastic stockings and 50% were still receiving vitamin K antagonists. Interestingly, overall, 57% of patients with venous thromboembolism recurrence did not receive vitamin K antagonists at the time of the thrombotic event. Similar data were found in a recent large, long-term prospective study of patients with pulmonary embolism, in which 62.5% of venous thromboembolism recurrences occurred after cessation of oral anticoagulant treatment.²⁷

With respect to the cumulative rate of occurrence of postthrombotic syndrome at 8 years, the 70.1% rate is substantially higher than the 29.1% rate reported in the study by Prandoni et al.¹⁷ However, in the latter study, the mean age of patients was 10 years younger than in the present study, and high age is a risk factor for postthrombotic syndrome.²⁸ Also, only patients with a first episode of symptomatic deep-vein thrombosis (including distal events) were enrolled in the study by Prandoni et al.¹⁷ In PREPIC, 24% of patients had postthrombotic syndrome at inclusion. Moreover, patients with proximal deep-vein thrombosis are more likely to develop venous stasis syndrome than patients with distal deep-vein thrombosis,²⁹ and rates comparable to ours were found in patients with proximal deep-vein thrombosis.¹⁸

This 8-year follow-up study extends the findings obtained previously at 2 years.⁵ At that time, the occurrence of pulmonary embolism was decreased by 50% in patients in the filter group compared with patients in the no-filter group (P=0.16); the risk was decreased by 63% at 8 years (P=0.008). It must be pointed out that 12 of the 24 pulmonary embolisms that occurred in patients in the no-filter group occurred between 2 and 8 years, which shows that pulmonary embolism may occur many years after the index thromboembolic event. We also confirm that among patients with symptomatic deep-vein thrombosis with or without pulmonary embolism who are treated with anticoagulants for at least 3 months, fatal pulmonary embolism is a relatively rare event,³⁰ and cancer is the leading cause of mortality.^15,17,19 The finding of an increased incidence of deep-vein thrombosis in patients with vena cava filters may be related to the thrombotic occlusion of those filters leading to venous stasis upstream in the legs: among 57 patients in the filter group with deep-vein thrombosis, 26 experienced filter thrombosis. Overall, the rate of recurrent symptomatic venous thromboembolism in the filter and no-filter groups was comparable. This result is consistent with the finding by White et al,²² who, in a population-based retrospective analysis of linked hospital discharge abstracts, showed that there was no difference in the 1-year relative hazard of rehospitalization for venous thromboembolism between filter- and no-filter–treated patients. Contrary to what might have been expected,³ vena cava filters did not increase the occurrence of postthrombotic syndrome. It is possible that the use of a clinical scale proven to reproducibly assess postthrombotic syndrome may have yielded different results.^17,31 However, 2 factors may have masked a potential deleterious effect of vena cava filters on the development of postthrombotic syndrome: a substantial number of patients had postthrombotic syndrome at inclusion, and the use of elastic stockings¹⁸ during the 8 years of follow-up was high in the 2 study groups.

Our findings are likely to be valid. The follow-up rate was close to 100%. All recurrent events were diagnosed objectively by recommended methods and validated by a committee unaware of the treatment. Patients were treated according to standard practice with at least 3 months of anticoagulants. Although the duration of treatment with vitamin K antagonists was not randomized, the administration of anticoagulants was comparable in the 2 study groups; however, it is possible that the diagnosis of pulmonary embolism may have been underestimated in patients in the filter group, because local clinicians tend to suspect pulmonary embolism less frequently in patients with a filter than in patients without a filter.

Risk stratification is essential when choosing the most appropriate treatment of pulmonary embolism. Due to the good benefit-to-risk ratio of long-term anticoagulation,^32–34 this therapeutic strategy is generally offered to patients with a high risk of venous thromboembolism recurring as pulmonary embolism.³⁵ The high-risk group includes, as confirmed in the present study, patients whose initial thromboembolic event is a pulmonary embolism,^25,30 particularly if this event is idiopathic or if patients also have cancer (Table 3). Likewise, patients who develop venous thromboembolism in nonsurgical situations have a higher risk of pulmonary embolism than those who had venous thromboembolism after surgery.³⁶ Moreover, patients presenting with pulmonary embolism are more likely to die of recurrent pulmonary embolism than are patients presenting with deep-vein thrombosis.^30,37,38 However, anticoagulation alone may not be sufficient in such high-risk patients. In PREPIC, among 24 nonfilter patients who developed pulmonary embolism, 46% were receiving vitamin K antagonists at the time of the thrombotic event. Accordingly, trials are warranted to assess the additional benefit provided by vena cave filters in patients at high risk of pulmonary embolism who are receiving long-term anticoagulation.

In conclusion, the present study shows that vena cava filters in patients with deep-vein thrombosis with or without pulmonary embolism protect against the long-term development of pulmonary embolism without favoring the development of postthrombotic syndrome. However, because their insertion is associated with a significant increase in the occurrence of deep-vein thrombosis, the systematic use of permanent vena cava filters in the general population with venous thromboembolism is not recommended. Vena cava filters may be beneficial in selected patients at higher risk of fatal pulmonary embolism, especially those whose initial thromboembolic event is a pulmonary embolism, idiopathic or cancer-associated. Further studies are needed to better define patients in whom the use of vena cava filters may be favorable.

	Appendix

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Writing Commitee: Herve Decousus (Chairman), Fabrice-Guy Barral, Andrea Buchmuller-Cordier, Bernard Charbonnier, Phillippe Girard, Christian Lamer, Silvy Laporte, Alain Leizorovicz, Patrick Mismetti, Florence Parent, Sara Quenet, Karine Rivron-Guillot, Bernard Tardy.

Participating Centers (in order of the number of patients enrolled): Bellevue Hospital, Saint-Etienne: Y. Page, B. Tardy, P. Mismetti, I. Cusey, C. Comtet, and J.C. Bertrand; Antoine Béclère Hospital, Clamart: F. Parent, G. Simonneau, and D. Musset; Clinique St. Vincent, Besançon: R. Faivre and P.Y. Petiteau; Trousseau Hospital, Tours: G. Pacouret and B. Charbonnier; General Hospital, Firminy: P. Sagnol and P. Mathern; Laënnec Hospital, Paris: G. Meyer and H. Sors; Cavale Blanche Hospital, Brest: L. Bressolette and D. Mottier; General Hospital, Roanne: P. Mottet and G. Tempelhoff; Hôtel Dieu Hospital, Angers: A. Furber and P. Geslin; Lariboisière Hospital, Paris: G. Simoneau, P. Molho-Sabatier, and J.F. Bergmann; General Hospital Lucien Hussel, Vienne: C. Poulain and B. Veyre; Belle-Isle Hospital, Metz: J. Hermann and H. Joffreau; Nord Hospital, Marseille: C. Juhan and Y. Alimi; Clinique St. Hilaire, Agen: R. Constans and J.L. Leymarie; Fleyriat Hospital, Bourg en Bresse: G. Demingeon and L. Holzapfel; Côte de Nacre Hospital, Caen: O. Coffin; Clinique du Mail, La Rochelle: J.P. Marcadé and J.P. Chantereau; Pasteur Hospital, Nice: F. Lemoigne; St. Joseph Hospital, Paris: P. Priollet, I. Lazareth, and G. Farkas; Germon et Gauthier Hospital, Béthune: B. D’Hautefeuille, C. Mycinski, and A. Senoussi; Lyon Sud Hospital, Lyon: C. Guerin; Hôtel Dieu Hospital, Rennes: B. Schleich and A. Le Helloco; General Hospital, Albi: M. Ammor and D. Galley; General Hospital, Allauch: M. Escande and B. Diadema; General Hospital, Annecy: J.B. Driancourt and P. Achard; General Hospital, Bourgoin-Jailleux: A. Pinel; General Hospital Louis Pasteur, Dole: F. Apffel and D. Magnin; La Tronche Hospital, Grenoble: P. Carpentier; General Hospital, Le Mans: D. Fagart; Dupuytren Hospital, Limoges : P. Lacroix; Broussais Hospital, Paris: J. Emmerich and J.N. Fiessinger; R. Beauchant Hospital, Poitiers: J. Allal; Clinique de la Jomayère, Saint-Etienne: J.M. Gallot-Lavallée; Avicenne Hospital, Bobigny: L. Guillevin; Pellegrin Hospital, Bordeaux: G. Sassous; Intercommunal Hospital, Fréjus: R. Mossaz; Emile Roux Hospital, Le Puy: J.P. Saboye and M. Viallet; Croix Rousse Hospital, Lyon: J.C. Guerin; Salvator Hospital, Marseille: J.M. Sainty; La Beauchée Hospital, St. Brieuc: F. Zimbacca; General Hospital, St. Chamond: J.H. Payre; Purpan Hospital, Toulouse: A. Barret; Steering Committee: H. Decousus, Y. Page, X. Barral, L. Barritault, H. Boccalon, J.P. Boissel, P. Carpentier, B. Charbonnier, J.N. Fiessinger, Y. Huet, A. Leizorovicz, J. Marzelle, G. Meyer, E. Neuhart, H. Rousseau, and G. Simonneau; Independent Adjudication Committee: P. Girard, P. Hervé, and C. Lamer.

	Acknowledgments

 
This study was supported by grants from Ministère Français de la Santé (PHRC), Paris, France, and from Fondation de l’Avenir. The authors gratefully acknowledge the contributions of all members of the PREPIC Study Group listed in reference ⁵. They are also indebted to Jean-Yves Darmon and Yves Cadroy (MediBridge Clinical Research, Vélizy, France) for providing editorial assistance.

	Footnotes

 
*Investigators and Committees participating in the PREPIC study are listed in the Appendix.

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