Comparative efficacy of two interventions to discontinue long-term benzodiazepine use: cluster randomised controlled trial in primary care.

BACKGROUND: Benzodiazepines are extensively used in primary care, but their long-term use is associated with adverse health outcomes and dependence. AIMS: To analyse the efficacy of two structured interventions in primary care to enable patients to discontinue long-term benzodiazepine use. METHOD: A multicentre three-arm cluster randomised controlled trial was conducted, with randomisation at general practitioner level (trial registration ISRCTN13024375). A total of 532 patients taking benzodiazepines for at least 6 months participated. After all patients were included, general practitioners were randomly allocated (1:1:1) to usual care, a structured intervention with follow-up visits (SIF) or a structured intervention with written instructions (SIW). The primary end-point was the last month self-declared benzodiazepine discontinuation confirmed by prescription claims at 12 months. RESULTS: At 12 months, 76 of 168 (45%) patients in the SIW group and 86 of 191 (45%) in the SIF group had discontinued benzodiazepine use compared with 26 of 173 (15%) in the control group. After adjusting by cluster, the relative risks for benzodiazepine discontinuation were 3.01 (95% CI 2.03-4.46, P<0.0001) in the SIW and 3.00 (95% CI 2.04-4.40, P<0.0001) in the SIF group. The most frequently reported withdrawal symptoms were insomnia, anxiety and irritability. CONCLUSIONS: Both interventions led to significant reductions in long-term benzodiazepine use in patients without severe comorbidity. A structured intervention with a written individualised stepped-dose reduction is less time-consuming and as effective in primary care as a more complex intervention involving follow-up visits.

Delaying progression to type 2 diabetes among high-risk Spanish individuals is feasible in real-life primary healthcare settings using intensive lifestyle intervention.

AIMS/HYPOTHESIS: To assess the feasibility and effectiveness of an active real-life primary care lifestyle intervention in preventing type 2 diabetes within a high-risk Mediterranean population. METHODS: A prospective cohort study was performed in the setting of Spanish primary care. White-European individuals without diabetes aged 45-75 years (n = 2,054) were screened using the Finnish Diabetes Risk Score (FINDRISC) and a subsequent 2 h OGTT. Where feasible, high-risk individuals who were identified were allocated sequentially to standard care, a group-based or an individual level intervention (intensive reinforced DE-PLAN [Diabetes in Europe-Prevention using Lifestyle, Physical Activity and Nutritional] intervention). The primary outcome was the development of diabetes according to WHO criteria. Analyses after 4-year follow-up were performed based on the intention-to-treat principle with comparison of standard care and the combined intervention groups. RESULTS: The standard care (n = 219) and intensive intervention (n = 333) groups were comparable in age (62.0/62.2 years), sex (64.4/68.2% women), BMI (31.3/31.2 kg/m(2)), FINDRISC score (16.2/15.8 points), fasting (5.3/5.2 mmol/l), 2 h plasma glucose (7.1/6.9 mmol/l) and self-reported interest to make lifestyle changes at baseline. Diabetes was diagnosed in 124 individuals: 63 (28.8%) in the standard care group and 61 (18.3%) in the intensive intervention group. During a 4.2-year median follow-up, the incidences of diabetes were 7.2 and 4.6 cases per 100 person-years, respectively (36.5% relative risk reduction, p < 0.005). The number of participants needed to be treated by intensive intervention for 4 years to reduce one case of diabetes was 9.5. CONCLUSIONS/INTERPRETATION: Intensive lifestyle intervention is feasible in a primary care setting and substantially reduces diabetes incidence among high-risk individuals. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov NCT01519505. FUNDING: Commission of the European Communities, Institute of Health Carlos III, Spanish Ministry of Health and Department of Health, Generalitat de Catalunya.

Shifting from glucose diagnostic criteria to the new HbA(1c) criteria would have a profound impact on prevalence of diabetes among a high-risk Spanish population.

AIM: To investigate changes in the prevalence of diabetes and pre-diabetes by shifting from 2-h plasma glucose and/or fasting plasma glucose diagnostic criteria to the proposed new HbA(1c) -based criteria when applied to a Mediterranean population detected to have a high risk of Type 2 diabetes. METHODS: Individuals without diabetes aged 45-75 years (n = 2287) were screened using the Finnish Diabetes Risk Score questionnaire, a 2-h oral glucose tolerance test plus HbA(1c) test. Prevalence and degree of diagnostic overlap between three sets of criteria (2-h plasma glucose, fasting plasma glucose and HbA(1c) ) and three diagnostic categories (normal, pre-diabetes and diabetes) were calculated. RESULTS: Defining diabetes by a single HbA(1c) measurement resulted in a dramatic decrease in prevalence (1.3%), particularly in comparison with diabetes defined by 2-h plasma glucose (8.6%), but was also significant with regard to fasting plasma glucose (2.8%). A total of 201 screened subjects (8.8%) were classified as having diabetes and 1023 (44.7%) as having pre-diabetes based on at least one of these criteria; among these, the presence of all three criteria simultaneously classified only 21 and 110 individuals respectively, about ten percent of each group. The single overlap index between subjects diagnosed as having diabetes by 2-h plasma glucose/fasting plasma glucose vs. HbA(1c) was 13.9/28%. Similarly, the single overlap index regarding pre-diabetes was 19.2/27.1%. CONCLUSIONS: A shift from the glucose-based diagnosis to the HbA(1c) -based diagnosis for diabetes will reduce diabetes prevalence with a low overall or single degree of overlap between diagnostic categories in this high-risk Spanish population.

[The Framingham function overestimates stroke risk for diabetes and metabolic syndrome among Spanish population]. / La escala de Framingham sobrevalora el riesgo cerebrovascular de la diabetes y el síndrome metabólico en la población española.

OBJECTIVE: To estimate stroke risk for diabetes, isolated or associated to metabolic syndrome (MS) according WHO and National Cholesterol Education Program (NCEP) criteria. DESIGN: Multicentre and prospective cohort study. SETTING: Primary health care. PARTICIPANTS: Subjects between 55-85 years-old without any evidence of stroke, included from 1998 in a random population sample for MS follow-up during routine practice in Reus (Tarragona, Spain). MAIN MEASUREMENTS: Stroke risk was achieved using Framingham function by means of a computerized algorithm using a diagnostic factorial design (diabetes and/or MS). Theoretical stroke risk and cumulated incidence of stroke events (1998-2003) were compared. RESULTS: Among 728 subjects (412 women, mean age =66 years old, body mass index =29 kg/m2), 457 (62.8%) did not have diabetes, nor MS, 93 (12.8%) had MS without diabetes, 72 (9.9%) diabetes without MS, and 106 (14.5%) presented both conditions (WHO rules). According NCEP criteria were 60.7%, 14.8%, 7.8%, and 16.7%, respectively. Ten-year estimated stroke risk accounted for (WHO/NCEP) 8.4/9.1%, 10.8/10.5%, 18/17.3%, and 18.8/19.1%. Cumulated incidence for stroke events were: 2.8%, 1.4%, 5.4%, and 3.8% (WHO), and 2.5%, 2.8%, 3.5%, and 5.8%, respectively (NCEP). CONCLUSIONS: Stroke risk scores were extremely increased among diabetic subjects irrespective to MS diagnose. The Framingham function probably overestimates stroke risk among Spanish individuals.

[Undiagnosed diabetes and impaired glucose metabolism on high risk Spanish population. The IGT study]. / Diabetes ignorada y otras alteraciones del metabolismo glucídico en la población española de alto riesgo. El Estudio ITG. Grupo de Investigación ITG.

BACKGROUND: To estimate the prevalence of undiagnosed diabetes and impaired glucose metabolism on high risk Spanish population, contrasting phenotypic features according to both sets of criteria, World Health Organization (WHO) and American Diabetes Association (ADA). SUBJECTS AND METHODS: Cross-sectional, multicentre (10 health-care centres, 230,000 inhabitants), selective risk-factor study. WHO diagnoses (normal, impaired glucose tolerance [IGT] and diabetes) were based on the 2 h plasma glucose (2hPG) following a 75 g oral glucose tolerance test (OGTT) and ADA diagnoses according the fasting plasma glucose (FPG) (normal, impaired FPG and diabetes). Prevalence, diagnostic overlap index and 22 clinical and biological parameters were compared. RESULTS: The study included 580 subjects (330 women), mean age 58.1 years and body mass index 31.2 kg/m2, 292 (50.3%) with only one risk factor and 288 (49.7%) with two or more risk factors. WHO diagnoses were: 291 (50.2%) normal glucose tolerance (95% CI: 46.2-54.2%), 157 (27.1%) IGT (23.5-30.7%) and 132 (22.7%) diabetes (19.3-26.1%). ADA diagnoses were: 355 (61.2%) normal FPG (57.2-65.2%), 146 (25.2%) IFG (21.7-28.7%) and 79 (13.6%) diabetes (10.9-16.3%). The prevalence of diabetes decreased 9.1% (from -11.4 to -6.8%). The diagnostic overlap was 33.5% for diabetes and 19.3% for impaired glucose homeostasis (IGT-FPG). Omitting the OGTT half the diabetic subjects with 2hPG > or = 200 mg/dl (11.1 mM) but FPG < 126 mg/dl (7 mM) would remain undiagnosed. By changing screening criteria (FPG instead of 2hPG) the risk related to traditional factors such as age or a first-degree relative with diabetes would reduce. CONCLUSIONS: Applying ADA criteria, the high prevalence of undiagnosed glucose abnormalities would decrease. These results suggest that it is strongly advisable the continued use of the 2hPG for diabetes screening on high risk Spanish population.

Medical conditions in patients with pancreatic and biliary diseases: validity and agreement between data from questionnaires and medical records. PANKRAS II Study Group.

The aims of the study were to assess the agreement between data from personal interviews and medical records on selected medical conditions, to evaluate the validity of each source of information, and to estimate the prevalence of these conditions in pancreatobiliary pathology. Between 1992 and 1995, 602 patients with pancreatobiliary diseases were included in the PANKRAS II Study. Information from interview and medical records was available in 88% of cases. The agreement between both data sources was poor only for cholecystitis and mental disorders. The validity of both sources of information was high or acceptable for all conditions except for cholecystitis. Prevalence of past medical conditions was similar to that reported previously and varied according to diagnosis, gender, age, educational level, and hospital of admission. Research aimed at assessing the prevalence of less common diseases should consider subject- and health-related factors in collecting information.

[The attitude of primary health care physicians in the metropolitan area of Barcelona about the diagnosis and treatment of Helicobacter pylori infection in gastroduodenal diseases]. / Actitud de los médicos de atención primaria del área metropolitana de Barcelona frente al diagnóstico y tratamiento de la infección por Helicobacter pylori en enfermedades gastroduodenales.

AIM: To evaluate the attitude of primary health care physicians versus the diagnosis and treatment of infection by Helicobacter pylori in patients with dyspepsia and gastroduodenal ulcer. DESIGN: An observational, transversal study was performed by a self administered questionnaire from June to October, 1997. PARTICIPANTS: Primary health care physicians from 38 reformed Medical Centers in the metropolitan area of Barcelona were included in the study. RESULTS: Of the 359 doctors to whom the questionnaire was sent, 283 responded (78.8%). In a patient with dyspepsia 95.4% would first request endoscopy. If they knew of the presence of infection by Helicobacter pylori 96.1% would administer eradication treatment in patients with gastric and duodenal ulcer and 15% would also do so if the endoscopy were normal. If the presence of infection by Helicobacter pylori were unknown in a patient with gastroduodenal ulcer, 65.3% would treat with anti-H2 or proton pump inhibitors associated with a diagnostic test of infection by Helicobacter pylori. If the physician decided to carry out eradication treatment of Helicobacter pylori infection, 98.6% would use one of the regimes recommended by different scientific societies. If confirmation of eradication of Helicobacter pylori infection were requested, 89% would do so one and three months after completion of treatment. In patients with gastric ulcer, 69.3% would request endoscopy on completion of treatment. The percentage of physicians specialized in Family and Community Medicine who would carry out eradication treatment in patients with duodenal ulcer and Helicobacter pylori infection and who would request endoscopies in patients with dyspepsia was found to be statistically significant in comparison with physicians without this specialty. CONCLUSIONS: The attitude of primary care physicians in the metropolitan area of Barcelona with regard to the diagnosis and treatment of infection by Helicobacter pylori in gastroduodenal diseases largely reflects the recommendations recently made by several scientific societies. In general there are no significant differences with respect to this attitude in regard to the age and sex of the physician, although their training was found to influence in some of the responses analyzed.

Ki-ras mutations in exocrine pancreatic cancer: association with clinico-pathological characteristics and with tobacco and alcohol consumption. PANK-ras I Project Investigators.

The aims of this study were (i) to assess the prevalence and spectrum of codon 12 Ki-ras mutations in patients diagnosed with exocrine pancreatic cancer (EPC) in 2 general hospitals between 1980 and 1990, (ii) to analyze the association of this genetic alteration with clinical and pathological characteristics, and (iii) to determine the association of Ki-ras mutations with tobacco and alcohol consumption. DNA was amplified from paraffin-embedded tissue samples and mutations in codon 12 of Ki-ras were detected using the artificial RFLP technique. Cox proportional-hazards regression and unconditional logistic regression were applied. Codon 12 Ki-ras mutations were detected in 30 of 51 cases for which molecular results were available. The amino-acid substitutions were Asp (8), Val (6), and Arg (3). A double mutation, including always a Val, was detected in 5 cases. None of the 4 nonductal pancreatic neoplasms were mutated. The mutation prevalence was 79% in metastases and 54% in primary tumors. The risk of a mutated tumor was 3 times higher in alcohol drinkers than in non-drinkers, and a linear trend was apparent. When age, gender, hospital, and tobacco and alcohol consumption were taken into account, a high risk for mutations was detected in patients who only smoked and in patients who only drank, but less so in patients who both smoked and drank. These results raise novel hypotheses regarding the role of tobacco and alcohol in EPC.

Sex as a prognostic factor in gastric cancer.

The aim of this study was to assess whether survival of gastric cancer patients differed between males and females. Although it is well known that the incidence of gastric cancer is higher for men than for women, the existence of a sex-specific prognosis has seldom been addressed. Studies based on population registries have not assessed the role of stage and histology. Cases of histologically confirmed gastric carcinoma were obtained from three Spanish hospitals in Soria (n = 405), Barcelona (n = 249) and Mataró (n = 197). Differences in possible confounders were tested between men and women and survival analyses were performed separately by hospital. Cox's proportional hazards models were used to account for age, tumour stage, histology and tumour sub-location. Only in Mataró was a significant difference in the stage distribution observed between women and men, with a lower proportion of local stage tumours among women (P = 0.047). No statistically significant differences of histological type between men and women were observed in any of the centres. After adjusting for tumour stage and age, women were observed to have significantly better survival in Barcelona (female to male hazard ratio (HR) = 0.578, P < 0.001); this effect was marginal in Soria (HR = 0.788, P = 0.092) and non-significant in Matar-o (HR = 0.895, P = 0.54). Age-adjusted hazard ratios were calculated within each tumour stage. For Barcelona, the effect of better prognosis among women was most marked at local stage (HR = 0.320, P = 0.013), and in Soria at the regional stage (HR = 0.426, P = 0.002). Although in Mataró all HRs were below unity, none were statistically significant. Little effect was observed at the disseminated stage. The other covariables exerted no influence. Women appear to have a better prognosis than men, and the difference could be tumour stage dependent. Confirmation of these findings would give a valuable insight into gastric cancer growth and ultimately be of use in planning treatment.

[Agreement between information supplied by the patient and a family member on medical history, consumption of tobacco, alcohol and coffee and diet in cancer of the exocrine pancreas and extrahepatic biliary tract]. / Concordancia entre la información facilitada por el paciente y un familiar sobre antecedentes patológicos, consumo de tabaco, de alcohol, de café, y dieta en el cáncer de páncreas exocrino y del sistema biliar extrahepático.

OBJECTIVE: No study on mutations in the K-ras oncogene and cancer of the exocrine pancreas or cancer of the biliary system has analyzed the reliability of clinical and epidemiological information. METHODS: Agreement between patient and surrogate on factors potentially related to both tumours was evaluated within a multicentre prospective study. Interviews were personally administered to both patient and surrogate (N = 110 pairs). Agreement was examined via the simple kappa index (k), the weighted kappa index (kw), the percentage of simple agreement, and the percentages of positive and negative agreement. RESULTS: Agreement for medical history was excellent (k between 0.89 and 0.76), as it was for tobacco consumption (k = 0.98). Agreement was moderate for coffee consumption (k = 0.68), frequencies of food groups (kw from 0.66 to 0.38), and consumption of alcoholic drinks (k from 0.66 to 0.32). Surrogates indicated a higher consumption of alcohol than patients. CONCLUSION: Surrogates can be an alternative source of information when patients cannot be interviewed, but information on alcohol consumption should be treated with caution.

Ki-ras mutations as a prognostic factor in extrahepatic bile system cancer. PANK-ras I Project Investigators.

PURPOSE: To assess the prevalence and prognostic significance of Ki-ras codon 12 mutations in extrahepatic biliary system cancer (EBSC). PATIENTS AND METHODS: Patients diagnosed with EBSC between 1980 and 1990 (N = 111) were selected from two hospitals. DNA was amplified from paraffin-embedded tissues and mutations in codon 12 of Ki-ras were detected using the artificial restriction fragment-length polymorphism (RFLP) technique. RESULTS: Tissue was available from 68.5% of patients. The prevalence of mutations was 41%. There was no association between mutations and clinical and pathologic characteristics; however, mutations in Ki-ras were associated with survival, with a median survival duration of 7.7 months for patients with wild-type Ki-ras and 1.7 months for patients with mutated tumors (hazards ratio [HR] = 1.67; P = .075). Among patients with stage I to II tumors, the chance of dying of patients with the mutation was 7.8 times higher than that of patients without the mutation (P = .087); the corresponding HR for patients with stage III to IV disease was 2.9 (P = .003). After adjusting for age, tumor site, histology, differentiation, and stage, the HR for Ki-ras mutations was 2.12 (P = .026). CONCLUSION: Ki-ras codon 12 mutations are an independent prognostic indicator in patients with EBSC. Mutation detection may be of help in the management of these patients.

Diagnostic certainty and potential for misclassification in exocrine pancreatic cancer. PANKRAS I Project Investigations.

Whereas over the last decade epidemiologic studies on exocrine pancreatic cancer (EPC) continued to show a remarkable heterogeneity in diagnostic criteria applied to define caseness, the actual magnitude and consequences of misclassification remain largely unexplored. The objectives were: (1) to estimate the degree of certainty with which cases of EPC are diagnosed in the two participating hospitals (to this end a diagnostic certainty classification (DCC) was developed; (2) to test whether characteristics of cases differed by degree of diagnostic certainty; and (3) to assess what influence different definitions of case might have on risk estimates for tobacco and alcohol. All cases with a discharge diagnosis of EPC who attended at the Hospital del Mar between 1980-90 and at the Hospital Son Dureta between 1983-90 were identified through their respective tumor registries, and their clinical records were reviewed. Only 52% of 140 cases were classified in the group with a higher probability of EPC (group H). Diagnostic certainty appeared somewhat greater among women (age-adjusted odds ratio [ORa] 1.60, p = 0.18). Group H showed a higher proportion of cases with an interval from first symptom to diagnosis < or = 1 month (ORa = 2.38, p < 0.05) and the proportion of adenocarcinomas was slightly higher than in less certain cases (group L) (p = 0.051). A radical treatment was exclusively attempted in group H (p < 0.001). DCC cut-off points had a significant effect on the proportion of smokers and of alcohol drinkers, as well as on the percent of cases with pathological (cytohistological) confirmation. The proportion of cases unlikely to be of pancreatic origin in spite of having pathological confirmation was high enough to cause significant misclassification bias. Because past exposure to certain risk factors may differ among cases with different diagnostic certainty, we suggest to initially include in the case group patients who in spite of lacking pathological confirmation have strong clinical evidence supporting the diagnosis of EPC; subsequently, risk estimates should be computed across strata of diagnostic certainty to assess whether heterogeneity exists. In exocrine pancreatic cancer the impact of misclassification of disease status upon etiologic and prognostic estimates deserves at least as much attention as misclassification of exposure.

Cancer survival and the duration of symptoms. An analysis of possible forms of the risk function. ISDS II Project Investigators.

The time interval between onset of symptoms and the diagnosis of cancer [symptom to diagnosis interval (SDI), or duration of symptoms] is a highly complex variable reflecting patient behaviour, the clinical course, the functioning of the health system and tumour biology. In order to assess possible forms of the risk function of SDI upon cancer survival whilst taking into account the effects of age, sex, tumour site and stage at diagnosis, 1887 symptomatic cases of lung, breast, stomach, colon, rectal, bladder cancer and lymphomas registered in the Tumour Registry of the Hospital del Mar (Barcelona) were analysed by means of survival curves and Cox proportional hazards regression. Subjects (mean age 64 years) were followed for a median length of 15 months after diagnosis (follow-up rate 93.5%). SDI showed a weak relationship with tumour stage at diagnosis and with survival: out of the seven sites studied, only in breast cancer was tumour extension at diagnosis significantly influenced by duration of symptoms, and only lung and rectal cancers showed a detectable form of the risk function of SDI upon survival; neither was linear, and for rectal cancer the relationship was complexly related with tumour stage. Hence, results show that forms of the risk function of duration of symptoms on cancer survival are specific to tumour sites, and that the interval should not be represented as a linear, continuous term. Studies analysing more complex sets of factors, processes and forms of the SDI function are needed.