Channelling of COX-2 inhibitors to patients at higher gastrointestinal risk but not at lower cardiovascular risk: the Cox2 inhibitors and tNSAIDs description of users (CADEUS) study.

PURPOSE: To describe the characteristics of users of cyclo-oxygenase (COX)-2 inhibitors and traditional nonselective non-steroidal anti-inflammatory drugs (tNSAIDs) in France. METHODS: Between 1 August 2003 and 31 July 2004, patients who received at least one dispensing of celecoxib, rofecoxib or tNSAIDs were randomly sampled with a 1:1:2 target ratio within the French National Healthcare Insurance database. Patients and prescribers were asked to fill a questionnaire on socio-demographic characteristics, NSAID indication and use and previous medical history. For each respondent, healthcare resources used in the 6 months before inclusion were extracted from the database. Multivariate logistic regression was used to study the determinants of a first COX-2 inhibitor dispensing. RESULTS: Of the 45 217 patients included, 13 065 COX-2 inhibitors and 13 553 tNSAID users had prescriber data. Ninety seven per cent of COX-2 inhibitor prescriptions were for 'rheumatological' indications, whereas 37% of tNSAIDs use was for benign diseases (n = 2643) or analgesia (n = 2318). Among patients with rheumatological indications (n = 4730) and a first COX-2 inhibitor (n = 2427) or tNSAID (n = 2303) dispensing, multivariate analysis of factors associated with COX-2 inhibitors dispensing showed that, compared to new tNSAID users, new COX-2 inhibitor users were older, more often female, on sick leave or unemployed. COX-2 use was also associated with previous gastrointestinal history and previous gastroprotective agent dispensing, but not with previous cardiovascular (CV) history. CONCLUSION: The choice of NSAID depended largely on indication and on previous gastrointestinal history, in line with the recommendations of the French health authorities. Possible knowledge of CV risk associated with COX-2 inhibitors did not influence prescribing.

The CADEUS study: methods and logistics.

PURPOSE: At the request of the French Health authorities, a study called CADEUS (COX-2 inhibitors and NSAIDs: description of users) aimed to describe the users of cyclo-oxygenase (COX)-2 inhibitors and traditional non-selective non-steroidal anti-inflammatory drugs (tNSAIDs). We report here the methodology, logistics and study design performances. METHODS: CADEUS is a cohort study designed to include 40,000 patients randomly sampled monthly in the French National Healthcare Insurance database, who received at least one dispensation of celecoxib, rofecoxib or tNSAIDs (1:1:2), from September 2003 to August 2004. Patients and prescribers were asked to fill a questionnaire on indication, medical history, risk factors and hospitalizations since drug acquisition. There was no reminder. For each respondent, healthcare resources used for the 6 months before and after inclusion were extracted from the database. Response rate, response delay, responders and non-responders characteristics were assessed. RESULTS: Of the 222,879 patients and their prescribers contacted, 20.8% patients and 32.6% prescribers responded. Median response delay was 16 days for patients and 17 days for physicians. Factors associated with patient response were age, cohort, type of prescriber and period of inclusion. CONCLUSION: This is the first study of this design in France, combining data from a claims database and direct patient and prescriber questionnaires.

Diagnosis of liver fibrosis by transient elastography (FibroScan) and non-invasive methods in Crohn's disease patients treated with methotrexate.

BACKGROUND: Methotrexate is an effective treatment in Crohn's disease, which may induce liver fibrosis with high cumulative doses. Transient elastography (FibroScan, Echosens, Paris, France) is a new non-invasive rapid, allowing assessment of liver fibrosis by measurement of liver stiffness. AIM: A prospective study to evaluate liver fibrosis with FibroScan and non-invasive biochemical methods in Crohn's disease patients treated with methotrexate. METHODS: Consecutive Crohn's disease patients had evaluation of liver fibrosis with non-invasive methods. Two subgroups of patients were compared: cumulative dose of methotrexate of more than 1500 mg (group 1) and naive for methotrexate (group 2). Liver biopsy was performed in patients with persistent liver enzyme abnormalities or FibroScan value >8.7 kPa. RESULTS: Fifty-four consecutive Crohn's disease patients were fully investigated (45 females, mean age 41 +/- 14 years). Median FibroScan values were similar in group 1 (n = 21) and in group 2 (n = 33), 5.5 and 4.5 kPa, respectively. FibroScan values were not correlated with the cumulative dose of methotrexate. CONCLUSION: In Crohn's disease patients treated with a high dose of methotrexate, significant liver fibrosis is rare and not accurately detected with liver enzymes abnormalities. FibroScan could be recommended and liver biopsy could be performed only with patients with high values and/or with chronic liver enzymes abnormalities.

The burden cost of French patients suffering from irritable bowel syndrome.

BACKGROUND: The impact of irritable bowel syndrome (IBS) on health-care resource use in France is evaluated, and explanatory variables determined. METHODS: A questionnaire comprising socio-demographic characteristics, symptoms, consumption of resources, quality of life and impact of IBS on productivity was administered by telephone to a sample of 253 French adults with IBS recruited from the general population, and diagnosed with IBS using several well-known diagnostic criteria. The medical costs were estimated on a monthly basis and included medication(s), physicians' consultations, investigations and hospitalizations. RESULTS: Mean age was 48.3 years and 75% of subjects were women (192). Thirty-six percent of subjects had suffered from IBS for more than 10 years; 77% had consulted a general practitioner and 43% a gastroenterologist. Twenty-nine percent of subjects had undergone an investigation and 25% reported hospitalization; 61% of patients reported that they were taking medication. The average monthly medical costs was 71.8 euros (95% CI = [57.6-86.0]) with an asymmetric distribution (median = 28.1 euros) because of a high proportion of subjects (27%) who reported receiving no care at all. The two principal cost components were investigations (39%), and hospitalizations (22%). The highest medical costs were associated with subjects who were very elderly or suffered from severe symptoms (very severe pain), and were correlated with the lowest quality of life scores. CONCLUSION: IBS has a major impact on resource consumption and the productivity of patients. Determination of the variables to explain medical costs showed that advanced age, severe pain and deterioration in quality of life could be predictive of high medical costs.

Successful treatment with infliximab and methotrexate of pyostomatitis vegetans associated with Crohn's disease.

A 35-year-old woman with severe fistulizing Crohn's disease presented with pyostomatitis vegetans affecting both the mouth and the vulva. The coalescing pustules transformed within several days into vegetating lesions on areas of inflammation. Microbial assessments revealed no pathogenic agent. Histology showed neutrophilic microabscesses, but no granulomas. Three injections of infliximab and maintenance therapy with methotrexate resulted in rapid and complete regression of both the pyostomatitis vegetans and the Crohn's disease. Infliximab and methotrexate may be a promising treatment for the rare cases of pyostomatitis vegetans associated with Crohn's disease.

[Upper gastrointestinal bleeding in patients treated by low-dose aspirin]. / Hémorragies digestives hautes et aspirine à faible dose.

AIM OF THE STUDY: To estimate the number of people treated by low-dose aspirin (<330 mg daily) in France and to evaluate the risk of upper gastrointestinal bleeding associated with low-dose aspirin treatment. SUBJECTS AND METHODS: One thousand six hundred and two patients with upper gastrointestinal bleeding were included between January and June 1996 in 4 French areas. Data about patients characteristics, drugs recently used, and bleeding lesions were prospectively collected. Five hundred seventy five cases were matched for sex, age and area with control people without previous upper gastrointestinal bleeding. Low-dose aspirin intake in the population was estimated from the control group. Aspirin intake in the previous 7 days in cases and in controls was compared by logistic regression, adjusted for other gastrotoxic drugs intake. RESULTS: Low-dose aspirin is taken by about 1.2 millions adults in France. In 1 602 patients, gastrointestinal bleeding was related to a peptic ulcer in 34%. Aspirin was associated with higher risk of upper gastrointestinal bleeding: OR=1.68 (1.03-2.74) with low-dose, and OR 1.42 (0.91-2.21) with higher doses. CONCLUSION: About 2.8% of the population is exposed to low-dose aspirin in France. This treatment seems to be associated with a high risk of upper gastrointestinal bleeding.

Hepatic porphyrin concentration and uroporphyrinogen decarboxylase activity in hepatitis C virus infection.

Previous studies have shown a high prevalence of hepatitis C virus (HCV) infection in patients with porphyria cutanea tarda (PCT). The aim of this study was to assess hepatic porphyrin concentrations (HPC) and hepatic uroporphyrinogen decarboxylase (UROD) activity in HCV-infected patients free of PCT. Thirty-two HCV-infected patients (20 M, 12 F, mean age 51 years) and seven control patients (4 M, 3 F, mean age 59 years) free of liver disease, were studied. Knodell's score was determined on liver biopsy by two independent anatomopathologists. Measurement of HPC and hepatic UROD activity levels were carried out on liver biopsy. Relative to controls, HCV-infected patients had high HPC levels (mean +/- SD: 47 +/- 20 vs. 17 +/- 6 pmol/mg protein, P < 0.001) and low hepatic UROD activity levels (514 +/- 95 vs. 619 +/- 125 pmol Copro/h/mg protein, P < 0.05). HPC was not correlated with hepatic UROD activity and the increase was due to coproporphyrin accumulation. No correlation was observed between HPC or hepatic UROD activity values and HCV-RNA concentrations, Knodell's score, hepatic fibrosis, periportal necrosis, periportal inflammation or hepatic iron content in HCV-infected patients. Hepatocellular necrosis was significantly correlated with HPC value (P < 0.005). Hence, in HCV-infected patients, HPC is significantly increased and hepatic UROD activity is very slightly decreased as compared to controls. HPC values and UROD activity are not correlated with HCV-RNA concentrations, hepatic iron content and hepatic fibrosis. The small increase in HPC values in hepatitis C infection is linked with hepatic injury and not with a direct effect on hepatic UROD enzyme.

[Acid-sensitive esophagus: natural history and effect on the quality of life. Comparison with gastroesophageal reflux]. / OEsophage acido-sensible: histoire naturelle et retentissement sur la qualité de vie. Comparaison avec le reflux gastro-oesophagien.

UNLABELLED: The acid hypersensitive esophagus (AHE) is characterized by a normal esophageal acid exposure but a significant association between symptoms and reflux episodes. The natural history of AHE remains poorly known. We therefore conducted a follow-up study to compare the initial presentation and natural history of AHE and classical GERD. Quality of life (QOL) was also assessed. PATIENTS AND METHODS: Two groups of patients referred to our laboratory for 24-hour pH-monitoring (between 1991 and 1996) were compared. Group 1 consisted of 127 consecutive patients with AHE. Group 2 consisted of 101 patients with GERD. All patients were invited by mail to fill-in two questionnaires, the first concerning clinical course and therapeutic needs and the second QOL (questionnaire Reflux-Qual). Finally 62% and 59% of group 1 and 2 respectively did respond to both questionnaires. The corresponding follow-up periods were 4.1 and 4.3 years, respectively. RESULTS: The two groups did not differ at initial presentation with regard to age, sex, symptoms prevalence and severity of esophagitis (80% of group 1 and 75% of group 2 were endoscopy-negative patients). At an average follow-up of 4 years symptoms persisted in 80% and 71% of patients respectively. Seventy five per cent of patients in both groups continued to take antireflux drugs. QOL scores were similarly reduced in both groups (71 +/- 26 vs 70 +/- 27). CONCLUSIONS: The initial presentation and clinical outcome of AHE and GERD are similar. QOL is notably impaired and the majority of patients continue to receive antireflux medications.

Epidemiology and course of acute upper gastro-intestinal haemorrhage in four French geographical areas.

OBJECTIVE: To compare incidence rates and epidemiological characteristics of acute upper gastrointestinal haemorrhage (AUGIH) in France with those of other European studies. DESIGN: Population-based multi-centre prospective survey. SETTING: 29 public hospitals and 96 private specialists in gastroenterology in four administrative areas in France during 1996. SUBJECTS: A total of 2133 AUGIH patients 18 years and over were included in the six-month study. OUTCOME MEASURES: Incidence and mortality. RESULTS: The overall incidence in France was 143 cases per 100000 persons per year, classified as out-patients (16%), emergency admissions (59%) and in-patients (25%). The incidence rates increased with age except for in-patients, and were higher in males. Peptic ulcer (36.6%), varices (13.7%) and erosive disease (12.3%) were the most frequent diagnoses. In 677 patients (31.7%), aspirin, antiinflammatory drugs or corticosteroids were taken on the 7 days before bleeding. The overall mortality (out-patients excluded) was 14.3% (10.7% for emergency patients and 23% for in-patients). Mortality was associated with comorbidities (especially malignancies, cirrhosis, asthma or respiratory deficiency), was lower in emergency patients using non-steroid anti-inflammatory drugs, and higher in in-patients using corticosteroids. CONCLUSIONS: In France, patients with AUGIH are frequently managed as out-patients. Gastrotoxic drug use is frequently associated with AUGIH and constitutes a strategic opportunity for preventive treatment. Discrepancies between countries are not clearly explained either by demographic factors or by drug use, but this may be related to the emphasis on AUGIH in in-patients.

[Management of upper digestive hemorrhage occurring in the community: patterns of patient care in 4 French administrative areas]. / Prise en charge des hémorragies digestives hautes communautaires. Trajectoires des malades dans 4 départements français.

AIMS: To describe patterns of health care management in patients with upper gastrointestinal hemorrhage and to identify factors linked to the different patterns. PATIENTS AND METHODS: We conducted a prospective study of patients over 18 with upper gastrointestinal hemorrhage (inpatients excluded) among all public hospitals and private practice gastroenterologists in 4 French administrative areas (3 in Northern France and one in the South West). RESULTS: One thousand six hundred and two patients were included over a six-month period (1996). An endoscopic procedure was performed in 1532 patients in public (70%) or private (20.5%) hospitals, or at private office (9.5%). Hospitalization was necessary in 78.8% of the patients in university, non university public or private hospitals (38.9, 45.5 and 15.6%, respectively) with a median duration of 6.5 days. Admission was associated to old age, short delay between hemorrhage and endoscopic procedure, previous gastrointestinal bleeding, cirrhosis or cancer, bleeding from peptic ulcer or esogastric varices. Endoscopic hemostasis was performed in 21.4% of the patients, more often in university and no university public hospitals. Surgery was necessary in 4% of the patients. Death rate was 10.7%. Important geographical variations were observed concerning referral patterns. Patients' characteristics did not differ between the 4 areas. On the other hand, health care supply provided in the management of upper gastrointestinal hemorrhage was different in the four French geographical areas. CONCLUSION: a) An initial endoscopic procedure is nearly always performed in patients with an upper gastrointestinal hemorrhage in France; in 1 patient out of 10, endoscopy was performed in a private gastroenterologist office; b) hospital admission was strongly related to epidemiological and clinical criteria of severity; c) the geographical variations observed in referral patterns depend in part on health care supply; d) upper gastrointestinal haemorrhage status could be used as an indicator of the quality of health care organizations.

[Assessment of quality of life of patients with gastroesophageal reflux. Elaboration and validation of a specific questionnaire]. / Mesure de la qualité de vie chez les malades ayant un reflux gastro-oesophagien. Elaboration et validation d'un questionnaire spécifique.

UNLABELLED: Quality of life is frequently impaired in patients with gastro-esophageal reflux. The aim of this study was the validation of a new specific quality of life questionnaire in patients with gastro-esophageal reflux. METHODS: A questionnaire was generated as follows: a) item generation with patients, b) item reduction, c) psychometric validation and comparison to a reference questionnaire (SF36) in patients with symptomatic gastro-esophageal reflux, d) assessment of reproducibility, and e) responsiveness over time. RESULTS: The primary questionnaire was made of 104 items. Two hundred twenty three patients were enrolled, 38 items were selected in 7 dimensions. One item was deleted following a new analysis conducted in 349 patients. Cronbach coefficient ranged from 0.84 to 0.91 for the specific questionnaire and from 0.78 to 0.90 for the SF36 questionnaire. Dimensions of specific questionnaire and SF36 were correlated. Quality of life was more impaired in patients with more frequent symptoms. Severity of endoscopic lesions was partly correlated with impaired quality-of-life. Reproducibility and responsiveness over time were correct. The final valid questionnaire was made of 37 items in 7 dimensions. CONCLUSION: This work is the first validation of a specific questionnaire in French which has the ability to measure quality of life in patients with gastro-esophageal reflux. The use of this questionnaire during therapeutic trials might allow to be more accurate in assessment of treatment efficacy.

Diagnosis of choledocholithiasis: EUS or magnetic resonance cholangiography? A prospective controlled study.

BACKGROUND: Endoscopic ultrasonography (EUS) appears to be the best imaging method for the diagnosis of choledocholithiasis. The aim of this preliminary, prospective, controlled study was to assess the accuracy of EUS and magnetic resonance cholangiopancreatography (MRCP) in the diagnosis of common bile duct stones. METHODS: From December 1995 through April 1997, all patients referred because of suspicion of the presence of common bile duct stones were included in the study. EUS and MRCP were performed. Each examination was performed by a different operator unaware of the result of the other procedure. The definitive diagnosis was established by means of endoscopic retrograde cholangiography with sphincterotomy or a surgical procedure. RESULTS: Forty-three patients (18 men, 25 women) with a mean age of 60.9 +/- 14.5 years (range 25 to 81 years) were included in the study. Eleven patients were excluded because of unavailability of magnetic resonance imaging(n = 5) or EUS (n = 6). Ten patients (31.2%) had choledocholithiasis. For this diagnosis, the sensitivity of EUS was 100%, the specificity was 95.4%, the positive predictive value was 90.9%, and the negative predictive value was 100%. The corresponding values for MRCP were 100%, 72.7%, 62.5%, and 100%, not significantly different from EUS results. The accuracy of EUS was 96.9%, and that of MRCP was 82.2%. CONCLUSION: This preliminary study confirmed EUS as an accurate and noninvasive procedure for the diagnosis of common bile duct stones. MRCP, which had a high sensitivity and high negative predictive value, might be an accurate technique for patients with a contraindication to EUS.

[Hemorrhaging eso-gastro-duodenal ulcers: epidemiology and management. A multicenter prospective study]. / Les ulcères oeso-gastro-duodénaux hémorragiques: épidémiologie et prise en charge. Etude prospective multicentrique.

UNLABELLED: The aim of this study was to estimate the incidence, and to describe the characteristics and medical care in patients with bleeding upper gastrointestinal ulcers in the general population. PATIENTS AND METHODS: A study was performed over six months in 1996 in 4 French geographical areas: Finistère, Gironde, Seine-Maritime, and the Somme (3 million people minimum 18 years). All public or private hospitals, and specialist gastroenterologists in private practice participated in the study, based on a standardized questionnaire. RESULTS: Over 6 months 793 patients with bleeding ulcers were identified, corresponding to 27 per 100,000 inh./year or 24,000 cases in France. Most patients were men (60%) and 40.1% were 75 years and older. The ulcer was oesophageal (6%), gastric (47%), or duodenal (69%). In 406 patients (51.2%) a chronic disease was present (cancer, cirrhosis, circulatory, respiratory or cardiac disease). In 237 cases (29.9%) the ulcer occurred in patients, 453 patients (57.1%) were admitted and 103 patients (13%) were managed as outpatients. Gastrotoxic drugs were taken by 349 patients (44%): non steroidal anti-inflammatory drugs (18.7%), aspirin (21.2%, including 2/3 with doses under 330 mg/day), corticosteroids (7.8%) and 24.3% had anticoagulant therapy. Patients were managed in university hospitals (39.3%), other public or non profit hospitals (44.2%) or private hospital (16.5%) with geographical differences between the 4 areas. Therapeutic endoscopy was performed in 16.9% and a surgical procedure was performed in 5.9%. The mortality rate (outpatients excluded) was 13.5% (n = 93), but only 2% (n = 16) of death were associated with a bleeding ulcer: mortality was higher in inpatients (24.1%) than in out patients (8.1%). A chronic disease was also associated with higher mortality (17.9% versus 8.1%). CONCLUSION: Bleeding ulcers are frequent and severe, especially in inpatients or associated with chronic conditions. A gastrotoxic drug used is found in about fifty percent of the cases.

Pharmacokinetics of milnacipran in liver impairment.

The pharmacokinetics of single 50 mg oral and intravenous doses of milnacipran, a new non tricyclic antidepressant drug, were compared in 11 chronic liver impaired (LI) subjects and in 6 control subjects. Hepatic impairments, classified according to the PUGH scale were moderate (1 grade A), intermediate (6 grade B) and severe (4 grade C). Concentrations of unchanged drug and its conjugated form (its main metabolite) were measured in plasma and urines. In control subjects, milnacipran present high absolute bioavailability (mean value of 90%). Around 50% of the dose are excreted in urines as unchanged, while around 14% are excreted as glucuroconjugate. The remaining is composed of free and conjugated phase I inactive metabolites. Administration of milnacipran in LI subjects results in non significant changes in its pharmacokinetics, although its variability is increased. Unchanged drug exposure is not modified in LI subjects, while plasma levels of the conjugate are slightly decreased compared to the control group. This could either be due to a slight reduction in the conjugation process, or to a change in the distribution of the drug as urine excretion of both unchanged and conjugated forms are not modified compared to the control group. A few LI subjects present supra-bioavailability resulting in higher drug exposure after oral administration than after intravenous infusion. These modifications are not clinically relevant as drug exposure of the parent drug is not modified. As the unchanged drug is the only compound responsible for the activity of milnacipran, no dosage adjustment is needed in patients presenting liver impairment.