Fundam Clin Pharmacol

BACKGROUND: The combination dextropropoxyphene/paracetamol (DXP/P) was the most prescribed opioid analgesic until its withdrawal in 2011. OBJECTIVES: This study investigated dispensations of analgesics in chronic users of DXP/P during the 18 months following its withdrawal. METHODS: A cross-sectional study repeated yearly was conducted by using the French reimbursement database from 2006 to 2015. Chronic DXP/P users were defined as patients who received at least 40 boxes of DXP/P in the year prior to withdrawal. Data on analgesic dispensing were analyzed at DXP/P withdrawal (T0) and then every 6 months for 18 months. RESULTS: A total of 63 671 subjects had a DXP/P reimbursement in the year prior to its discontinuation, of whom 7.1% were identified as chronic users (mean age: 71.5 years, women: 68.7%). Among the patients taking DXP/P alone at T0 (74.6%), one fourth switched to a peripheral analgesic, one fourth to a combination of peripheral analgesic/opioid, one fourth to another opioid, and the others mainly discontinued their treatment (14.1%) or died. During the following 12 months, most of the subjects taking only peripheral analgesics continued this treatment, while half of the subjects with a combination of opioid/peripheral analgesic or taking only an analgesic remained on this type of treatment. CONCLUSION: Eighteen months after DXP/P withdrawal, more than 10% of patients stopped taking an analgesic. Vigilance is required regarding any change in analgesics by regularly reassessing patients' pain and, in the case of opioid treatments, by monitoring the risk of use disorders

Effectiveness of Recommended Drug Classes in Secondary Prevention of Acute Coronary Syndrome in France

Background: Guidelines for cardiovascular secondary prevention are based on evidence from relatively old clinical trials and need to be evaluated in daily clinical practice. Objectives: To evaluate effectiveness of the recommended drug classes after an acute coronary syndrome (ACS) for secondary prevention of cardiovascular diseases and all-cause mortality. Methods: This cohort study used data from a representative sample of the French national healthcare insurance system database (EGB). Patients hospitalised for an incident ACS between 2006 and 2011, and aged ≥ 20 years at time of ACS were included in the study. Patients non-exposed to any of the four recommended drug classes (beta-blockers, antiplatelet agents, statins, and angiotensin-converting-enzyme inhibitors, ACEI, or angiotensin II receptor blockers, ARB) in the first 3 months following ACS or who died during this period were not included in the cohort. Exposure status was determined daily during follow-up. Effectiveness of the four therapeutic classes in preventing the composite outcome ACS, transient ischemic attack, ischemic stroke, or all-cause-death was estimated using a time-dependent Cox proportional hazards model, which was adjusted for time-fixed confounders measured at baseline (general characteristics and characteristics of the initial ACS) and time-dependent confounders during follow-up (co-morbidities and co-medications). Results: Of the 2874 patients included in the study, 33.9% were women and the median age was 67 years (interquartile range, IQR: 56-77). The median time of follow-up was 3.6 years (IQR: 2.2-5.3). The risk of the composite outcome decreased with use of antiplatelet agents (adjusted hazard ratio (aHR) 0.76, 95% confidence interval (CI) 0.63; 0.91), use of statins (aHR 0.71, 95%CI 0.57; 0.87), and use of ACEI/ARB (aHR 0.67, 95%CI 0.57; 0.80). Use of beta-blockers was not associated with a lower risk of the composite outcome (aHR, 0.90, 95%CI 0.74; 1.09]). Conclusions: Use of antiplatelet agents, statins, and ACEI/ARB after an ACS, but not beta-blockers, was associated with a lower risk of cardiovascular morbidity and all-cause mortality

Clin Pharmacol Ther

Dabigatran and rivaroxaban at standard (SD) or reduced doses (RD) have been compared to warfarin in non-valvular atrial fibrillation (NVAF), but not to each other. This was a new user study of SD and RD dabigatran or rivaroxaban for NVAF in the French healthcare database, matched on gender, age, date of first dispensing, and high-dimensional propensity score, followed 2 years. Hazard ratios [95% Confidence Intervals] of stroke or systemic embolism (SSE), major bleeding (MB) or death, were computed. In matched SD patients (8,290 per arm), mean age 67, HR for dabigatran vs. rivaroxaban were SSE 0.92 [0.67-1.26], MB 0.59 [0.39-0.90], death 0.84 [0.65-1.11]. In RD patients (7639 per arm), mean age 80, HR for dabigatran vs. rivaroxaban were SSE 0.73 [0.59-0.94], MB 0.74 [0.57-0.96], death 0.95 [0.83-1.09]. In conclusion, at either dose dabigatran had similar or better effectiveness than rivaroxaban, but lower bleeding risk. Death rates were not different. This article is protected by copyright. All rights reserved

Br J Clin Pharmacol

BACKGROUND: We compared the 1-year safety and effectiveness of dabigatran 110 mg (D110) or 150 mg (D150) to vitamin K antagonists (VKA) in patients with non-valvular atrial fibrillation (NVAF), METHODS: New user cohort study of patients dispensed D110 or D150 vs. VKA in 2013 for NVAF, followed 1 year in the French Systeme National des Donnees de Sante (SNDS, 66 million persons). D110 and D150 users were matched 1:1 with VKA users on sex, age, date of first drug dispensing, and high-dimensional propensity score (hdPS). Hazard ratios (HR [95% confidence intervals]) for stroke and systemic embolism (SSE), major bleeding (MB), and death were computed using Cox proportional hazards or Fine and Gray models during exposure. RESULTS: In 14,442 matched D110 and VKA patients, mean age 79, 49% male, 91% with CHA2 DS2 -VASc >/=2 and 8% with HAS-BLED >3, incidence rates of SSE were 1.9% and 2.6% person-years (HR 0.69 [0.56-0.84]), MB 1.8% and 2.9% (0.62 [0.51-0.76]), death 7.2% and 8.6% (0.84 [0.76-0.94]). In 8,389 matched D150 and VKA patients, mean age 67, 67% male, 65% with CHA2 DS2 -VASC >/= 2; 3, incidence rates were for SSE 1.4% and 1.9% (0.76 [0.56-1.04]), MB 0.6 % and 1.9% (0.30 [0.20-0.46]), death 1.6% and 3.6% (0.46 [0.35-0.59]). Numbers needed to treat to observe one fewer death were 78 for D110, 88 for D150 CONCLUSION: In real life D110 and D150 were at least as effective and safer than VKA

Correction to: Comparative Real-Life Effectiveness and Safety of Dabigatran or Rivaroxaban vs. Vitamin K Antagonists: A High-Dimensional Propensity Score Matched New Users Cohort Study in the French National Healthcare Data System SNDS

Correction to: American Journal of Cardiovascular Drugs (2020) 20:81–103 https://doi.org/10.1007/s40256-019-00359-

Idarucizumab for Reversion of Anticoagulant Effect in Daily Practice

International audienceBackground and Purpose— We compared the 1-year safety and effectiveness of rivaroxaban 15 mg (R15) or rivaroxaban 20 mg (R20) to vitamin K antagonists (VKAs) in patients with nonvalvular atrial fibrillation. Methods— New user cohort study of patients dispensed R15 or R20 versus VKA in 2013 or 2014 for nonvalvular atrial fibrillation, followed 1 year in the French Système National des Données de Santé (66 million people). R15 and R20 users were matched 1:1 with VKA users on sex, age, date of first drug dispensing, and high-dimensional propensity score. Hazard ratios (95% CIs) for stroke and systemic embolism, major bleeding, and death were computed using Cox proportional hazards or models by Fine and Gray during exposure. Results— In 31 171 matched R20 and VKA, mean age, 71; 62% men; 76% with CHA 2 DS 2 -VASc ≥2; 5% HAS-BLED >3 (hypertension, abnormal renal and liver function, stroke, bleeding, labile INR, elderly, drugs or alcohol); incidence rates for stroke and systemic embolism were 1.5% and 1.9% (hazard ratio, 0.79 [0.69–0.90]); major bleeding, 1.5% and 2.2% (0.67 [0.59–0.77]); death, 3.9% and 5.8% (0.67 [0.61–0.73]). In 23 314 matched R15 and VKA patients, mean age, 80; 47% men; 93% with CHA 2 DS 2 -VASc ≥2 and 9% with HAS-BLED >3; incidence rates of stroke and systemic embolism were 2.3% and 2.1% (1.05 [0.92–1.21]); major bleeding, 2.4% and 2.9% (0.84 [0.74–0.96]); death, 9.1% and 10.8% (0.85 [0.79–0.90]). Numbers needed to treat to observe one fewer death (NNT) were 46 for R15 and 61 for R20. Conclusions— In real life in France over 2013 to 2015, R15 and R20 were at least as effective and safer than VKA. Clinical Trial Registration— URL: http://www.encepp.eu . Unique identifier: EUPAS14567

Nurses' internal contamination by antineoplastic drugs in hospital centers: a cross-sectional descriptive study

OBJECTIVE: The aim of this study was to assess internal antineoplastic drugs (ADs) contamination in the nursing staff in French hospital centers, using highly sensitive analytical methods. METHODS: This cross-sectional study included nurses practicing in care departments where at least one of the five ADs studied was handled (5-fluorouracil, cyclophosphamide, doxorubicin, ifosfamide, methotrexate). The nurses study participation lasted 24 h including collection of three urine samples and one self-questionnaire. All urine samples were assayed by ultra-high-performance liquid chromatography-tandem mass spectrometry methods with very low value of the lower limit of quantification (LLOQ). RESULTS: 74 nurses were included, 222 urine samples and 74 self-questionnaires were collected; 1092 urine assays were performed. The percentage of nurses with internal AD contamination was 60.8% and low levels of urinary concentrations were measured. Regarding nurses with internal contamination (n = 45), 42.2% presented internal contamination by methotrexate, 37.8% by cyclophosphamide, 33.3% by ifosfamide, 17.8% by 5-fluorouracil metabolite and 6.7% by doxorubicine. Among the positive assays, 17.9% (n = 26/145) were not explained by exposure data from the self-questionnaire but this could be due to the skin contact of nurses with contaminated work surfaces. CONCLUSIONS: This study reported high percentage of nurses with internal ADs contamination. The low LLOQ values of the used analytical methods, allowed the detection of ADs that would not have been detected with the current published methods: the percentage of contamination would have been 17.6% instead of the 60.8% reported here. Pending toxicological reference values, urine ADs concentrations should be reduced as low as reasonably achievable (ALARA principle)

Pharmacol Res

BACKGROUND: Venous thromboembolism (VTE) after total knee or hip replacement (TKR, THR) is usually prevented with low-molecular weight heparin (LMWH), and increasingly by direct oral anticoagulants (DOAC). The aim of the present study was to compare the benefit-risk and medical costs of DOAC vs. LMWH in a real-life setting. METHODS: All patients with THR or TKR in France between Jan-1st 2013 and Sep-30th 2014, discharged to home, were identified and followed-up for 3 months in the French nationwide claims database, SNDS. DOAC users were 1:1 matched with LWMH users on gender, age and propensity score. Relative risks (RR) of hospitalized VTE, hospitalized bleeding and death were estimated using quasi-Poisson models. Medical costs were calculated according to the societal perspective, including total cost for outpatient claims and national DRG costs for hospitalisations. RESULTS: Most DOAC users (>/= 98.8%) were matched to a LMWH patient. For the 63,238 matched THR patients, the 3-month absolute risk of VTE was 0.9 per thousand with DOAC and 2.5 per thousand with LMWH (RR = 0.35 [0.23 to 0.54]), of bleeding 1.8 per thousand and 2.1 per thousand (0.88 [0.62-1.25]), death 0.7 per thousand and 1.1 per thousand (0.68 [0.40-1.15]). For the 31,440 matched TKR patients, risks were 1.6 per thousand and 2.3 per thousand (0.69 [0.42-1.16]) for VTE, 2.4 per thousand and 3.8 per thousand (0.64 [0.43 to 0.97]) for bleeding, and 0.6 per thousand and 0.8 per thousand (0.69 [0.30-1.62]) for all-cause death. Mean medical costs were 28% and 21% lower with DOAC than LMWH for THR and TKR, respectively. This nationwide study found a very low risk of VTE, hospitalized bleeding and death after THR or TKR discharge in patients with VTE prevention in real-life setting, with better benefit-risk profiles of DOAC compared to LMWH, and associated cost savings

Br J Clin Pharmacol

Aims : To assess the effectiveness of dimethyl fumarate (DMF) on annual rate of relapse subject to treatment (ARRt) and disability progression in multiple sclerosis (MS) compared to injectable immunomodulators (IMM), teriflunomide (TERI) and fingolimob (FTY), in real-life setting. Methods : A population-based cohort study was conducted using data of the French nationwide claims database, SNDS. All patients initiating IMM, TERI, FTY or DMF between 1 July 2015 and 12 December 2017, with 4.5 years of database history and 1–3.5 years of follow-up were included in this study. DMF patients were 1:1 matched to IMM, TERI or FTY using a high dimensional propensity score. Negative binomial regression and a logistic regression model were used to estimate the relative risk (RR ± [95% CI]) of ARRt and the odds ratio (OR ± [95% CI]) of disability progression, respectively. Results : Overall, 9304 subjects were identified: 29.0% initiated DMF, 33.2% TERI, 5.6% FTY and 32.2% an IMM. The matched cohorts consisted of 1779 DMF-IMM patients, 1679 DMF-TERI patients, and 376 DMF-FTY patients. DMF significantly reduced ARRt compared to IMM (RR 0.72 [0.61–0.86]) and TERI (0.81 [0.68–0.96]) and did not show any significant difference when compared with FTY. The risk of the progression of MS-specific disability was not significantly different for any matched cohorts. Conclusion : DMF is associated with lower risk of treated relapse for patients with RRMS than other first-line RRMS agents (TERI and IIM)

Atherosclerosis

BACKGROUND AND AIMS: We aimed to compare the effectiveness of ticagrelor vs. clopidogrel or prasugrel on recurrence of acute coronary syndromes (ACS) in real-life conditions, as requested by regulatory authorities at the time of marketing. METHODS: We performed a cohort study in SNDS, the French national healthcare database. All patients with a hospital admission for ACS in 2013 were followed one year. Patients on ticagrelor, clopidogrel or prasugrel were matched 1:1 using age, gender, index ACS type, and high-dimensional propensity scores (hdPS). Outcomes were ACS, stroke, all-cause death, and major bleeding, compared within matched groups using Cox proportional hazards models analysis during treatment. RESULTS: 54,048 ACS were hospitalized in 2013. At discharge, 19,796 were dispensed clopidogrel, 8242 prasugrel, and 13,916 ticagrelor. Per group, 9224 ticagrelor vs. clopidogrel, 6752 ticagrelor vs. prasugrel, and 4676 prasugrel vs. clopidogrel patients were matched. Compared to clopidogrel, ticagrelor was associated with a lower hazard ratio of death 0.73 [0.59-0.90] and composite criterion (0.88, 95% CI [0.79-0.99] but not ACS 0.92 [0.80-1.06], stroke (0.96 [017-5.53]) or major bleeding (1.02 [0.82-1.26]). Prasugrel was not different from ticagrelor or clopidogrel for any outcome, in matched patients. CONCLUSIONS: Ticagrelor in real-life conditions in matched populations was associated with a lower risk of all-cause death than clopidogrel, and a lower risk of composite outcome, as in the main pivotal clinical trial. Ticagrelor and prasugrel were not different, nor were prasugrel and clopidogrel