Summary: A score that can accurately determine the risk of major bleeding during anticoagulant therapy may help to make decisions on anticoagulant use. RIETE is an ongoing registry of consecutive patients with acute venous thromboembolism (VTE). We composed a score to predict the risk for major bleeding within three months of anticoagulant therapy. Of 19,274 patients enrolled, 13,057 (67%) were randomly assigned to the derivation sample, 6,572 to the validation sample. In the derivation sample 314 (2.4%) patients bled (fatal bleeding, 105). On multivariate analysis, age >75 years, recent bleeding, cancer, creatinine levels >1.2 mg/dl, anemia, or pulmonary embolism at baseline were independently associated with an increased risk for major bleeding. A score was composed assigning 2 points to recent bleeding, 1.5 to abnormal creatinine levels or anemia, 1 point to the remaining variables. In the derivation sample 2,654 (20%) patients scored 0 points (low risk); 9,645 (74%) 1–4 points (intermediate); 758 (5.8%) >4 points (high risk). The incidences of major bleeding were: 0.3% (95% confidence interval [CI]: 0.1–0.6), 2.6% (95% CI: 2.3–2.9), and 7.3% (95% CI: 5.6–9.3), respectively. The likelihood ratio test was:0.14 (95% CI:0.07–0.27) for patients at low risk;2.96 (95% CI:2.18–4.02) for those at high risk. In the validation sample the incidence of major bleeding was:0.1%,2.8%,and 6.2%,respectively. In conclusion, a risk score based on six variables documented at entry can identify VTE patients at low, intermediate, or high risk for major bleeding during the first three months of therapy.

Background: Results from observational studies may be inconsistent because of variations in methodological and clinical factors that may be intrinsically related to the database (DB) where the study is performed.Objectives: The objectives of this paper were to evaluate the impact of applying a common study protocol to study benzodiazepines (BZDs) (anxiolytics, hypnotics, and related drugs) and the risk of hip/femur fracture (HFF) across three European primary care DBs and to investigate any resulting discrepancies.Methods: To measure the risk of HFF among adult users of BZDs during 2001–2009, three cohort and nested case control (NCC) studies were performed in Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) (Spain), Clinical Practice Research Datalink (CPRD) (UK), and Mondriaan (The Netherlands). Four different models (A–D) with increasing levels of adjustment were analyzed. The risk according to duration and type of BZD was also explored. Adjusted hazard ratios (cohort), odds ratios (NCC), and their 95% confidence intervals were estimated.Results: Adjusted hazard ratios (Model C) were 1.34 (1.23–1.47) in BIFAP, 1.66 (1.54–1.78) in CPRD, and 2.22 (1.55–3.29) in Mondriaan in cohort studies. Adjusted odds ratios (Model C) were 1.28 (1.16–1.42) in BIFAP, 1.60 (1.49–1.72) in CPRD, and 1.48 (0.89–2.48) in Mondriaan in NCC studies. A short‐term effect was suggested in Mondriaan, but not in CPRD or BIFAP. All DBs showed an increased risk with the concomitant use of anxiolytic and hypnotic drugs.Conclusions: Applying similar study methods to different populations and DBs showed an increased risk of HFF in BZDs users but differed in the magnitude of the risk, which may be because of inherent differences between DBs.

The oral administration of vitamin B12 offers a potentially simpler and cheaper alternative to parenteral administration, but its effectiveness has not been definitively demonstrated. The following protocol was designed to compare the effectiveness of orally and intramuscularly administered vitamin B12 in the treatment of patients ≥65 years of age with vitamin B12 deficiency. The proposed study involves a controlled, randomised, multicentre, parallel, non-inferiority clinical trial lasting one year, involving 23 primary healthcare centres in the Madrid region (Spain), and patients ≥65 years of age. The minimum number of patients required for the study was calculated as 320 (160 in each arm). Bearing in mind an estimated 8-10% prevalence of vitamin B12 deficiency among the population of this age group, an initial sample of 3556 patients will need to be recruited. Eligible patients will be randomly assigned to one of the two treatment arms. In the intramuscular treatment arm, vitamin B12 will be administered as follows: 1 mg on alternate days in weeks 1 and 2, 1 mg/week in weeks 3–8,and 1 mg/month in weeks 9–52. In the oral arm, the vitamin will be administered as: 1 mg/day in weeks 1–8 and 1 mg/week in weeks 9–52. The main outcome variable to be monitored in both treatment arms is the normalisation of the serum vitamin B12 concentration at weeks 8, 26 and 52; the secondary outcome variables include the serum concentration of vitamin B12 (in pg/ml), adherence to treatment, quality of life (EuroQoL-5D questionnaire), patient 3satisfaction and patient preferences. All statistical tests will be performed with intention to treat and per protocol. Logistic regression with random effects will be used to adjust for prognostic factors. Confounding factors or factors that might alter the effect recorded will be taken into account in analyses. The results of this study should help establish, taking quality of life into account, whether the oral administration of vitamin B12 is an effective alternative to its intramuscular administration. If this administration route is effective, it should provide a cheaper means of treating vitamin B12 deficiency while inducing fewer adverse effects. Having such an alternative would also allow patient preferences to be taken into consideration at the time of prescribing treatment. This trial has been registered with ClinicalTrials.gov, number NCT 01476007, and under EUDRACT number 2010-024129-20.

Viral tropism plays a major role in HIV pathogenesis and may influence the activity of entry inhibitors. The impact of antiretroviral therapy use on the dynamics of viral tropism over time is still poorly understood. HIV co-receptor usage was determined longitudinally for over 5 years in 237 plasma specimens collected from 73 distinct HIV-1-infected drug-naive individuals, 42 of whom initiated antiretroviral therapy thereafter and 31 who remained untreated. Viral tropism was estimated genotypically using the phenotype predictor software webPSSM, considering as X4 virus populations those with pure X4 and dual/mixed X4/R5 variants. At baseline, the prevalence of X4 viruses was 3.2% and 14.6% in patients who remained untreated and in those who initiated antiretroviral therapy, respectively (P = 0.112). Mean plasma HIV-RNA was lower in the former compared with the latter (3.8 ± 0.9 versus 4.5 ± 0.9 log; P < 0.004), while conversely the mean CD4 count was greater in untreated than in those who had begun therapy (536 ± 191 versus 278 ± 192 cells/mm³; P < 0.001). During follow-up, switch in co-receptor use occurred overall in 26% of the study population, with no significant differences between the groups. Emergence of X4 viruses was significantly associated with lower CD4 counts regardless of antiretroviral treatment exposure. The use of antiretroviral therapy does not seem to influence the selection of X4 viruses, which mainly occur in patients with low CD4 counts.