Comparison of idrabiotaparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: the Borealis-Atrial Fibrillation Study.

BACKGROUND: Idrabiotaparinux, a long-acting inhibitor of factor Xa, was shown to be effective in the treatment of patients with venous thromboembolism. OBJECTIVE: To assess non-inferiority for the efficacy of idrabiotaparinux versus warfarin in patients with atrial fibrillation (AF) at risk of stroke and systemic embolism. Bleeding was also assessed. METHODS: This randomized, double-blind trial enrolled patients with electrocardiogram-documented AF. Idrabiotaparinux was administered weekly via subcutaneous injection, and warfarin was administered daily with dose adjustment to maintain the international normalized ratio between 2.0 and 3.0. Each idrabiotaparinux injection was 3 mg for the first 7 weeks, followed by 2 mg thereafter, except in patients with a creatinine clearance of 30-50 mL min(-1) or aged ≥ 75 years. The patients received 1.5 mg after the first 7 weeks. The efficacy outcome was the composite of all fatal or non-fatal strokes and systemic embolism. The safety outcome was clinically relevant bleeding (major and clinically relevant non-major bleeding). RESULTS: The study was terminated prematurely by the sponsor for strategic/commercial, not scientific, reasons, with 39% of the planned number of patients included and an average duration of treatment of 240 days. Of the 1886 idrabiotaparinux recipients, 20 developed stroke or systemic embolism (1.5% per year), whereas this occurred in 22 of the 1887 warfarin patients (1.6% per year, hazard ratio 0.98, 95% confidence interval 0.49-1.66). The annual incidence of bleeding was 6.1% in the idrabiotaparinux and 10.0% in the warfarin group (hazard ratio 0.61, 95% confidence interval 0.46-0.81). CONCLUSION: If anything, despite its early termination, the idrabiotaparinux regimen studied suggested a comparable efficacy to dose-adjusted warfarin, with a lower bleeding risk.

Efficacy of Daflon 500 mg in venous leg ulcer healing: a double-blind, randomized, controlled versus placebo trial in 107 patients.

The objective of this study was to evaluate the efficacy of Daflon 500 mg (Dios)* in venous ulcers. A multicenter, double-blind, randomized, controlled versus placebo (Plac) trial was conducted, with stratification according to the size of ulcer (< or = 10 cm and > 10 cm). The protocol called for a two-month treatment with Dios (one tablet = 450 mg micronized purified Diosmin) or a placebo, two tablets/day, in addition to compression therapy. Evaluations were performed every fifteen days, from D0 to D60. The primary endpoint, in accordance with Alexander House group requirements were: percentage of patients with complete ulcer healing, ie, comparison between Dios and Plac group at D60, and comparison of survival curves in each group between D0 and D60 (log rank test). Secondary endpoints included ulcer surface area assessed by computerized planimetric measurements, qualitative evaluation of ulcers, and symptoms. The patients were 105 men and women ranging in age from eighteen to eighty-five years, with standard compression stocking, who were undergoing standardized local care of ulcer and had no significant arterial disease (ankle/arm systolic pressure index > 0.8). Fifty-three patients received Dios, and 52 received Plac. The 2 groups were well matched for age (m +/- 1 SD = seventy-one +/- eleven years), gender, ulcer size, and associated disorders. Among patients with ulcer size < or = 10 cm (Dios = 44, Plac = 47) a significantly larger number of patients had a complete ulcer healing at two months in the Dios group (n = 14) in comparison with the Plac group (n = 6) (32% vs 13%, P = 0.028) with a significantly shorter time duration of healing (P = 0.037). No difference was shown for the secondary criteria, except for sensation of heavy legs (P = 0.039) and a less atonic aspect of ulcer (P = 0.030) in favor of Dios. Among the 14 patients with ulcer size > 10 cm (Dios = 9, Plac = 5), subjected to a descriptive analysis only, no ulcer healed. This study showed that a two-month course of Daflon 500 mg at a daily dose of two tablets, in addition to conventional treatment, is of benefit in patients with venous ulcer < or = 10 cm by accelerating complete healing.

Efficacy of Daflon 500 mg in the treatment of lymphedema (secondary to conventional therapy of breast cancer).

To assess the activity of a purified, micronized, flavonoidic fraction (Dios; Daflon 500 mg*) on upper limb lymphedema occurring after breast cancer therapy, a monocenter, randomized, double-blind, parallel group vs placebo (Plac) trial was carried out. One hundred and four women with lymphedema were included; 94 completed the study (46 Dios, 48 Plac). A subset of 24 patients with more severe lymphedema (10 Dios, 14 Plac) was subjected to a separate analysis. Treatment consisting of Dios or Plac was given two tablets daily over a six-month period. A radionuclide lymphoscintigraphy using technetium-99m was performed at inclusion and at the end of the treatment. The upper limb volume was measured every two months. In the overall population the evolution of parameters was not different between Dios and Plac. In the 24 patients with a more severe lymphedema, the lymphoscintigraphic parameters (m +/- sd) were as follows: lymphatic migration speed was significantly improved by Dios in comparison with Plac (delta Speed cm/minute: 0.84 +/- 0.6 vs 0.14 +/- 0.26, P = 0.005). The half-life of the colloidal compound was significantly improved over time in the Dios group (delta half-life = 10.3 +/- 13.07 minute, P = 0.034) but not in the Plac group (delta half-life = 0.53 +/- 15.51 minute, P = 0.086). The change over time of colloidal clearance was close to significance in the Dios group (delta clearance microL/minute: 2.18 +/- 3.10, P = 0.054) but not in the Plac group (0.11 +/- 2.26, P = 0.86). No significant difference was found for evolution of lymphedema volume, despite a tendency in favor of Dios. This can be related to wide distribution of volume values and small numbers of patients. In conclusion, these results suggest a beneficial therapeutic activity of Dios at the usual dose of two tablets/day in patients affected with more severe lymphedema. The clear improvement of the lymphatic speed illustrates its known lymphokinetic activity. Further studies with a higher dosage could confirm the beneficial activity of this drug in secondary lymphedema.

Benefit of a 2-month treatment with a micronized, purified flavonoidic fraction on venous ulcer healing. A randomized, double-blind, controlled versus placebo trial.

OBJECTIVE: To assess the efficacy of a micronized purified flavonoid fraction (Daflon 500 mg = Dios) in venous leg ulcer healing, in addition to compression therapy and standardized local care. DESIGN: Double-blind, multicentre, randomized, parallel groups, controlled versus placebo trial; stratification according to ulcer size. SUBJECTS: 107 patients, with venous ulcer of the leg for at least 3 months, and accepting bandaging therapy. RESULTS: 105 patients (Dios = 53, placebo = 52) were available for an intention to treat (ITT) analysis. Age (mean +/- SD, 71+/-11 years), gender (M = 33, F = 74) and ulcer size were evenly distributed among both groups. 99 patients completed the protocol (Dios = 51, placebo = 48). Among the 91 patients with ulcer size < or = 100 cm (Dios = 44, placebo = 47), a significantly higher number of patients had complete ulcer healing at 2 months in the Dios group (n = 14) in comparison to the placebo group (n = 6) after ITT analysis (32 vs. 13%, p = 0.028) and after per protocol analysis (32 vs. 14%, p = 0.048), and a shorter time duration of healing (p = 0.037). Among the 14 patients with ulcer size > 10 cm (Dios = 9, placebo = 5), no ulcer healed. CONCLUSION: This study showed that a 2-month course of purified micronized flavonoid fraction (2 tablets/day), in addition to conventional treatment, is of benefit in patients by accelerating complete healing of venous leg ulcers which are < or = 10 cm in diameter.

The human saphenous vein in pharmacology: effect of a new micronized flavonoidic fraction (Daflon 500 mg) on norepinephrine induced contraction.

Local acidosis (pH 6.4) depresses reactivity of vascular smooth muscle and especially the response of human isolated saphenous veins to exogenous norepinephrine. Experiments were performed to study, under acidosis conditions, the interaction between Daflon 500 mg, a micronized fraction of 90% diosmin and 10% hesperidin, and norepinephrine on human rings of veins. Varicose veins were obtained by conservative varicose veins surgery and normal veins from patients undergoing coronary artery bypass graft surgery. Isometric tension was recorded from venous rings in organ chambers filled with Krebs-Henseleit solution (pH 7.4; 37 degrees C). Metabolic acidosis (from pH 7.4 to 6.4) was obtained by lowering the HCO3- concentration of the Krebs-Henseleit solution. Cumulative concentration-response curves for norepinephrine (10(-7) to 10(-5)M) were obtained at pH 6.4 in the presence or in the absence of Daflon 500 mg (10(-5)M) added 20 min previously to the organ bath. Under acidotic conditions, Daflon 500 mg induced a shift to the left of the concentration-response curves for norepinephrine. This potentiation was significant in both normal and varicose veins and was increased in proportion with the pathological status of the venous rings. These results support the therapeutic benefits of Daflon 500 mg in chronic venous insufficiency.

Effects of Daflon 500 mg* on haemoconcentration and alterations of white blood cell count elicited by the upright position in anaesthetized dogs.

In the passive upright position, arterial and venous pressures in the human feet increase capillary pressure which leads to the filtration of fluid from the circulating plasma into the tissues of the feet. Loss of fluid concentrates both red cells and plasma so that the haematrocrit and plasma protein concentration of venous blood leaving the feet greatly exceed their mean values in the circulation. To study this phenomenon in animals, we used Beagle dogs in upright position. In blood of saphenous vein, red cells, haematocrit and plasma protein concentration have been studied. As in human (Moyses et al. Haemoconcentration and accumulation of white cells in the feet during venous stasis. Int J Microcirc Clin Exp 1987;5:311-20) red cells, haematocrit and plasma protein concentration increase in upright position. The increases in red cells, haematocrit and plasma protein concentration were higher and levels were greater after 2 hours when compared to the corresponding values after 1 hour. Daflon 500 mg, a micronized purified flavonoidic fraction, (200 mg/kg-1 per os) administered 20 minutes before upright position, significantly reduced these increases. This model might be a suitable model to test drugs interfering with venous stasis.

Long-term control of blood pressure by rilmenidine in high-risk populations.

Efficacy and acceptability of rilmenidine in populations with high cardiovascular risk has been established in short- or mid-term studies (1.5-6 months) enrolling relatively small numbers of patients. The present open study was undertaken to compare, on a larger scale, the efficacy and acceptability of a 12-month rilmenidine treatment in high-risk outpatients versus the results obtained in the general population and to check for unexpected adverse events. A total of 2,635 hypertensive patients (supine diastolic blood pressure [SDBP] > 90 mm Hg) were enrolled, including a high-risk population with 1,591 patients aged > 60 (60.3%), 1,007 patients with dyslipidemia (38.2%), 393 with diabetes (14.9%), 328 with chronic renal failure (12.4%), 301 with angina pectoris (11.4%), and 84 with chronic heart failure (3.2%). All patients were treated by rilmenidine 1 mg/day during the first 6 weeks; then (at 1.5 months), if SDBP was > 90 mm Hg, dosage of rilmenidine was 1 mg twice daily during the following 6 weeks. From month 3 to month 12, any other antihypertensive drugs could be added if SDBP remained > 90 mm Hg. In comparison with the general population, the percentage of high-risk patients whose monotherapy normalized blood pressure (SDBP < or = 90 mm Hg) was slightly lower at month 1.5 (58-66%, according to the risk group, vs 68% in the general population) and month 3 (73-82% vs 85%). At month 12, all treatments taken as a whole (monotherapy and combination therapy) led to the normalization of blood pressure in 94% of patients in the general population and in populations at risk.(ABSTRACT TRUNCATED AT 250 WORDS)

[Thrombosis of the renal veins in the newborn: treatment and long term prognosis]. / Thrombose des veines rénales du nouveau-né: traitement et pronostic à long terme.

Thirty-nine neonates with renal vein thrombosis diagnosed in our hospital department between 1973 and 1991 were studied retrospectively. Twenty-five patients were and 14 were not treated with urokinase (UK). Among the five deaths (13%), four occurred at the acute stage from non-renal complications and one occurred at the age of three months from end-stage renal failure. Eight patients (21%) have moderate renal failure after a mean follow-up of 7.4 years; a single patient (2%) developed end-stage renal failure after 7.9 years and 25 patients (64%) have a normal glomerular filtration rate after a mean follow-up of 4.5 years. Rates of death and chronic renal failure were 8% and 32%, respectively, in the group given UK and 21% and 7%, respectively, in the group not given UK. Among 54 involved kidneys, only 10 (19%) recovered normal function and morphological features. Functional impairment was seen in 11 of 37 (30%) kidneys treated by UK and 10 of 17 (59%) kidneys not treated by UK. Although these data suggest that UK may be effective in promoting recanalization of renal veins obstructed by thrombosis, confirmatory evidence could be obtained only by performing a prospective therapeutic trial.

[Prognosis of prune belly syndrome]. / Pronostic du syndrome d'aplasie des muscles de la paroi abdominale.

The Prune Belly syndrome (PBS) is unfrequent. Fourteen cases have been followed in our unit during the last 20 years. Four infants (29%) died during the first months of life, because of neonatal sepsis (2 cases) or end-stage renal failure (2 cases). Among the other 10 cases, 6 (43%) had normal glomerular filtration rate at a mean age of 10 years 6 months (6 months to 15 years), 4 had chronic renal failure, including 3 cases who developed end-stage renal failure at 8, 8 years 8 months and 17 years respectively. Resection of an urethral obstruction was performed in 2 cases. This surgical indication remains widely accepted, while the current tendency is to limit ureteral surgery in PBS. Orchidopexy was performed in 4 children, 3 of them less than 6 years 6 months of age. Fertility of these early operated children remains to be established, as all adults reported in the literature remain sterile when orchidopexy was not performed or was performed after age 6.

Immunogenicity of hepatitis B vaccine (HEVAC B) in children with advanced renal failure.

The immune response after hepatitis B (HB) vaccine HEVAC B was studied in 33 children (mean age 10 +/- 4 years) with advanced renal failure. Responders and protected patients were defined by antibody titres to HB surface antigen (anti-HBs) of greater than 10 and 50 mIU/ml, respectively. All received the initial recommended three injections at monthly intervals, and 23 received a booster injection (IB) 11 +/- 1 months after the third injection (I3). Loss of protection after I3 led to additional injections in 8 patients (25%). Vaccine was well tolerated and no HB infection occurred during the follow-up period (19 +/- 10 months). The percentage of responders was 91% 2 +/- 1 months after I3, and 100% 1 month, 13 +/- 1 months and 26 +/- 2 months after IB. The percentages of protected patients at these dates were 91%, 95%, 100% and 100%. Anti-HBs titres 1-3 months after I3 were useful for indicating those patients likely to have a rapid decline in anti-HBs titres, thus requiring serial anti-HBs determinations and additional injections to prevent a loss of protection. We conclude that at the expense of a reinforced vaccination schedule in 25% of patients, HEV AC B vaccine can safely achieve a sustained protection in more than 90% of uraemic children.

Microsurgical creation and follow-up of arteriovenous fistulae for chronic haemodialysis in children.

Three hundred and eighty children underwent 434 angioaccesses. Of these angioaccesses, 113 were constructed in 74 children weighing under 10 kg. Most accesses (n = 340) were distal arteriovenous fistulae (AVF). After microsurgery there was a 96% immediate patency. Seventy percent of AVF, excluding distal ulnarbasilic AVF, were functional, sometimes after secondary superficialization of the vein. Eighty-five per cent of the distal radial-cephalic AVF are still patent after 2 years, 60% are still patent after 4 years. These radial-cephalic AVF required 65 repeat anastomoses, and 12 ligations of the proximal-radial artery in order to reduce to 50% the high blood flow (pre-reduction average index = 900 ml/min per m2. The patency rate of arteriovenous-bridge grafts was not encouraging. The severity of stenoses in the proximal-venous trunks, sometimes related to previous catheterization, is emphasized. Advantages of the radial-cephalic wrist AVF in children are highlighted.

[The intellectual development of children with severe early kidney insufficiency]. / Développement intellectuel des enfants atteints d'insuffisance rénale grave précoce.

Recent studies have suggested that patients with neonatal onset of severe renal failure may be at risk for mental retardation. We studied the intellectual development of 13 pediatric patients with neonatal onset of severe renal failure who immediately received active medical therapy. The verbal, performance, and overall intelligence quotient (IQ) was determined using the Weschler-PPSI and the WISC-R at a mean age of 7 years and 4 months (4 years 5 months to 15 years 8 months). Mean overall IQ was 89 (73 to 106), mean verbal IQ was 94.7 (79 to 124) and mean performance IQ was 85.6 (69 to 112). Overall IQ was greater than 100 (101 to 106) in three patients (23%), and under 100 in ten patients (77%), with values of 87 to 92 in six cases (46%) and 73 to 84 in four cases (31%). A significant negative correlation (p less than 0.05) was found between the IQ and the length of hospital or medical institution stays during the first year of life. We found no significant correlation either between IQ and severity of renal failure, quality of growth or nutritional status before the age of two, or between IQ and dose of aluminum ingested. Our results suggest that early severe renal failure does not induce severe mental retardation. However, in 77% of studied children the IQ was within the lower portion of the normal range or under this normal range. This proportion is greater than that seen in normal children from similar socioeconomic backgrounds. Reducing hospital stays and separations from home, as well as even more active nutritional management, may help to improve these children's mental abilities.

Hickman catheter for haemodialysis in paediatric patients.

Twelve Hickman catheters were inserted in nine children in order to establish access for haemodialysis or plasmapheresis. Catheters were implanted either through the external or internal jugular vein and the tip located in the right atrium or superior vena cava. Mean blood flow was 25-55 ml/min with single lumen catheters and 83-100 ml/min with double lumen catheters. Three catheters had to be removed because of obstruction, whilst seven remained in situ until an arteriovenous fistula had matured or renal function was restored. Infection in two cases was successfully treated with antibiotics and transient obstruction by urokinase instillation. Following catheter removal, angiographic studies showed that with one exception all catheterized vessels were obstructed, but this did not prevent from ipsilateral arteriovenous fistulas to mature satisfactorily.

[Acute kidney failure caused by hyperphosphoremia in tumor lysis]. / Insuffisance rénale aiguë par hyperphosphorémie au cours des lyses tumorales.

We report the cases of two children presenting with tumor lysis syndrome responsible for major hyperphosphatemia, hypocalcemia and acute renal failure and treated by hemodialysis. Twenty similar cases have been reported in the literature. Hyperphosphatemia responsible for hypocalcemia and renal failure occurs within 24 to 48 hours after the onset of chemotherapy, is maximal on the 2nd or 3rd day and is, on the average, of 7 days duration. Short-term functional renal prognosis is good but long-term studies are lacking. The usual preventive measures are not always sufficient to prevent these accidents. A dialysis is appropriate when phosphatemia rises rapidly and exceeds 5 mmol/l, when the creatinine plasma level exceeds 200 mumol/l and kaliemia 6 mmol/l and when hyperphosphatemia is associated with severe clinical signs.

[Clinical study and effect of nitroxoline on fecal flora in children]. / Activité clinique et effet de la nitroxoline sur la flore fecale chez l'enfant.

Twelve children (mean age: 4) are treated in practice office with nitroxoline (200 mg/kg/24 h) during 10 days for urinary tract infection. A study on the effect of nitroxoline against the fecal flora is undertaken in a group of 21 children who receive nitroxoline during 4 days or a long period. Bacteriological and clinical efficacy is checked when urinary concentrations of nitroxoline are greater than 16 mg/l. The results show 8 clinical and bacteriological success one true failure and 3 failure due to a non-compliance to the treatment. No qualitative and quantitative modification of the fecal flora is observed after treatment with nitroxoline.

[Chronic renal insufficiency in the child. Etiology, development and prognosis]. / Insuffisance rénale chronique chez l'enfant. Etiologie, évolution et pronostic.

Our study concerned 147 children with chronic renal failure (CRF) (creatinine clearance less than 50 ml/min/1.73 m2). Its goal was to analyse the distribution of primary renal diseases, natural history of renal failure (RF) according to etiology, and long term survival. Renal diseases responsible for RF were: malformations of the urinary tract (38%), glomerular pathology (26%), hereditary renal diseases (20%), isolated renal hypoplasias (11%), and miscellaneous (5%). Corticoresistant nephrosis accounted for 34% of glomerular diseases and nephronophtisis 63% of hereditary renal diseases. On the whole, RF was related with an uropathy or renal hypoplasia in half of cases and with congenital renal disease in almost 3/4 of cases. The natural history varied according to primary renal disease: slow deterioration after a period of relative stability for uropathy or renal hypoplasias, slow and regular deterioration for nephronophtisis, rapid deterioration for glomerular diseases.