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Background— The safety and effectiveness of non–vitamin K antagonist (VKA) oral anticoagulants, dabigatran or rivaroxaban, were compared with VKA in anticoagulant-naive patients with nonvalvular atrial fibrillation during the early phase of anticoagulant therapy. Methods and Results— With the use of the French medico-administrative databases (SNIIRAM and PMSI), this nationwide cohort study included patients with nonvalvular atrial fibrillation who initiated dabigatran or rivaroxaban between July and November 2012 or VKA between July and November 2011. Patients presenting a contraindication to oral anticoagulants were excluded. Dabigatran and rivaroxaban new users were matched to VKA new users by the use of 1:2 matching on the propensity score. Patients were followed for up to 90 days until outcome, death, loss to follow-up, or December 31 of the inclusion year. Hazard ratios of hospitalizations for bleeding and arterial thromboembolic events were estimated in an intent-to-treat analysis using Cox regression models. The population was composed of 19 713 VKA, 8443 dabigatran, and 4651 rivaroxaban new users. All dabigatran- and rivaroxaban-treated patients were matched to 16 014 and 9301 VKA-treated patients, respectively. Among dabigatran-, rivaroxaban-, and their VKA-matched–treated patients, 55 and 122 and 31 and 68 bleeding events and 33 and 58 and 12 and 28 arterial thromboembolic events were observed during follow-up, respectively. After matching, no statistically significant difference in bleeding (hazard ratio, 0.88; 95% confidence interval, 0.64–1.21) or thromboembolic (hazard ratio, 1.10; 95% confidence interval, 0.72–1.69) risk was observed between dabigatran and VKA new users. Bleeding (hazard ratio, 0.98; 95% confidence interval, 0.64–1.51) and ischemic (hazard ratio, 0.93; 95% confidence interval, 0.47–1.85) risks were comparable between rivaroxaban and VKA new users. Conclusions— In this propensity-matched cohort study, our findings suggest that physicians should exercise caution when initiating either non-VKA oral anticoagulants or VKA in patients with nonvalvular atrial fibrillation.

Purpose Using the French claims database (Systeme National d’Information Inter-Regimes de l’Assurance Maladie) linked to the hospital discharge database (Programme de Medicalisation des Systemes d’Information), this observational study compared the effectiveness of rosuvastatin and simvastatin prescribed at doses with close LDL-cholesterol-lowering potency on all-cause mortality and cardiovascular and cerebrovascular diseases (CCDs) in primary prevention. Methods This historical cohort included patients with no prior CCD, aged 40–79years, who initiated statin therapy with rosuvastatin 5mg or simvastatin 20mg in 2008–2009 in general practice. Follow-up started after a 1-year period used to select patients who regularly received the initial treatment. In an intention-to-treat analysis, patients were followed up to December 2011. In a per-protocol analysis, they were censored prematurely when they discontinued their initial treatment. Adjustment for baseline covariates (age, deprivation index, comedications, comorbidities, prior hospital admissions) was carried out by a Cox proportional hazards model. In the per-protocol analysis, estimation was done by “inverse probability of censoring weighting” using additional time-dependent covariates. Analyses were gender-specific. Results A total of 106941 patients initiated statin therapy with rosuvastatin 5mg and 56860 with simvastatin 20mg. Mean follow-up was 35.8months. For both genders and both types of analyses, the difference in incidence rates of mortality and/or CCD between rosuvastatin 5mg and simvastatin 20mg users was not statistically significant after adjustment (e.g., for CCD and/or mortality in men, in intention-to-treat analysis HR=0.94 [95% CI=0.85–1.04], in per-protocol analysis HR=0.98 [0.87–1.10]). Conclusions The results of this real-life study based on medico-administrative databases do not support preferential prescription of rosuvastatin compared to simvastatin for primary prevention of CCD. © 2013 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd. key words—rosuvastatin; simvastatin; comparative effectiveness; primary prevention; inverse probability of censoring weighting; SNIIRAM (Systeme National d’Information Inter-Regimes de l’Assurance Maladie); pharmacoepidemiology; pharmacoepidemiology

OBJECTIVE To explore in France the relationship between insulin glargine use and overall and specific cancer risks in type 2 diabetic patients compared with other basal insulins. RESEARCH DESIGN AND METHODS Data were extracted from French health insurance information system (Système National d'Information Inter-Régimes de l'Assurance Maladie) linked with data from the French Hospital Discharge database (Programme de Médicalisation des Systèmes d'Information). Included were 70,027 patients aged 40–79 years who started a basal insulin in 2007–2009. Cox proportional hazards models with age as time-scale were used to calculate multivariate-adjusted hazard ratios for associations between type of basal insulin and risk of overall cancer, breast cancer, and seven other cancer sites. RESULTS The median follow-up was 2.67 years in patients exposed to insulin glargine. Absolute event rates for all cancer in patients exposed to glargine versus other basal insulin users were 1,622 and 1,643 per 100,000 person-years, respectively. No significant association was observed between glargine exposure and overall cancer incidence after adjustment for sex, with a hazard ratio of 0.97 (95% CI 0.87–1.07), or after additional adjustment for any other hypoglycemic agent use and duration of diabetes. No increased risk of breast cancer was observed for glargine users compared with other basal insulins users, with a fully adjusted hazard ratio of 1.08 (0.72–1.62). CONCLUSIONS In a large cohort of patients newly treated by basal insulin, no increased risk of any cancer was observed in insulin glargine users compared with other basal insulin users. Because follow-up did not exceed 4 years, longer-term studies are needed.

Objective To assess the risk of pulmonary embolism, ischaemic stroke, and myocardial infarction associated with combined oral contraceptives according to dose of oestrogen (ethinylestradiol) and progestogen. Design Observational cohort study. Setting Data from the French national health insurance database linked with data from the French national hospital discharge database. Participants 4 945 088 women aged 15-49 years, living in France, with at least one reimbursement for oral contraceptives and no previous hospital admission for cancer, pulmonary embolism, ischaemic stroke, or myocardial infarction, between July 2010 and September 2012. Main outcome measures Relative and absolute risks of first pulmonary embolism, ischaemic stroke, and myocardial infarction. Results The cohort generated 5 443 916 women years of oral contraceptive use, and 3253 events were observed: 1800 pulmonary embolisms (33 per 100 000 women years), 1046 ischaemic strokes (19 per 100 000 women years), and 407 myocardial infarctions (7 per 100 000 women years). After adjustment for progestogen and risk factors, the relative risks for women using low dose oestrogen (20 µg v 30-40 µg) were 0.75 (95% confidence interval 0.67 to 0.85) for pulmonary embolism, 0.82 (0.70 to 0.96) for ischaemic stroke, and 0.56 (0.39 to 0.79) for myocardial infarction. After adjustment for oestrogen dose and risk factors, desogestrel and gestodene were associated with statistically significantly higher relative risks for pulmonary embolism (2.16, 1.93 to 2.41 and 1.63, 1.34 to 1.97, respectively) compared with levonorgestrel. Levonorgestrel combined with 20 µg oestrogen was associated with a statistically significantly lower risk than levonorgestrel with 30-40 µg oestrogen for each of the three serious adverse events. Conclusions For the same dose of oestrogen, desogestrel and gestodene were associated with statistically significantly higher risks of pulmonary embolism but not arterial thromboembolism compared with levonorgestrel. For the same type of progestogen, an oestrogen dose of 20 µg versus 30-40 µg was associated with lower risks of pulmonary embolism, ischaemic stroke, and myocardial infarction.

Aims/hypothesis Previous studies have suggested an increased risk of bladder cancer with pioglitazone exposure. We aimed to investigate the association between pioglitazone exposure and bladder cancer in France. Methods This cohort study involved use of data from the French national health insurance information system (Système National d'Information Inter-régimes de l'Assurance Maladie; SNIIRAM) linked with the French hospital discharge database (Programme de Médicalisation des Systèmes d'Information; PMSI). The cohort included patients aged 40 to 79 years who filled a prescription for a glucose-lowering drug in 2006. The cohort was followed for up to 42 months. Pioglitazone exposure was modelled as a time-dependent variable and defined by having filled at least two prescriptions over a 6-month period. Incident cases of bladder cancer were identified by a discharge diagnosis of bladder cancer combined with specific aggressive treatment. Statistical analyses involved a multivariate Cox model adjusted for age, sex and exposure to other glucose-lowering drugs. Results The cohort included 1,491,060 diabetic patients, 155,535 of whom were exposed to pioglitazone. We found 175 cases of bladder cancer among exposed patients and 1,841 among non-exposed patients. Incidence rates were 49.4 and 42.8 per 100,000 person-years, respectively. Pioglitazone exposure was significantly associated with bladder cancer incidence (adjusted HR 1.22 [95% CI 1.05, 1.43]). We observed a dose–effect relationship, with a significantly increased risk for high cumulative doses (≥28,000 mg, adjusted HR 1.75 [95% CI 1.22, 2.50]) and long duration of exposure (≥24 months, adjusted HR 1.36 [1.04, 1.79]). Conclusions/interpretation In this cohort of diabetic patients from France, pioglitazone exposure was significantly associated with increased risk of bladder cancer.

Background— The type of medical coverage in patients with acute myocardial infarction (AMI) may affect their treatment and outcome. Methods and Results— We used the reimbursement database from the French National Health Insurance to determine the impact of full medical coverage (Couverture Médicale Universelle Complémentaire, CMUC), a free supplemental insurance for low-income earners P =0.45). In-hospital mortality was also comparable (3.1% versus 2.8%, P =0.69). There was no difference in early use of secondary prevention medications after multivariate adjustment. At 30 months, survival and acute coronary syndrome–free survival were lower in CMUC patients (trend, not significant after adjustment). Long-term adherence to statin therapy was lower in CMUC patients (64% versus 77%; adjusted relative risk, 0.82; 95% confidence interval, 0.73–0.92). Conclusions— Free full coverage for socially deprived people levels inequalities in the acute and midterm treatment of AMI patients. However, full reimbursement per se is not sufficient to ensure optimal patient adherence to secondary prevention medications and may not be enough to prevent an excess of long-term events.

Summary Background An ageing population and the extension of indications will in all probability result in an increasing number of cardiac device implantations. Methods Patients implanted in 2008 and 2009 were identified by means of the French National Hospital Discharge database to establish the implantation rate and the National Health Insurance (NHI) Information System database for patient profiles (76% of the population). Results Of the 64,306 pacemaker implantations (1003.7 per million inhabitants [pmi]) in 2009, 21.4% were single chamber, 75.4% double chamber and 3.2% triple chamber (CRT-P). Of the 9028 cardioverter-defibrillator implantations (140.8 pmi) in 2009, 30.1% were single chamber, 27.5% double chamber and 42.5% triple chamber (CRT-D), accounting for 65% of cardiac resynchronization therapy (CRT) implants. Among NHI beneficiaries, 58.6% of cardioverter-defibrillators were implanted for primary prevention. Between 2008 and 2009, CRT-P implantations increased by 8.8% and CRT-D implantations by 29.3%. Regional variations in implantation rates were observed regarding single-chamber pacemakers (15–33%) and CRT-D among CRT (46.2–73.8%). Pacemaker implantations cost €158.4 million overall, 4.5% of which was for CRT-P; cardioverter-defibrillator implantations cost €96 million, 49% of which was for CRT-D. For NHI beneficiaries, 11.9% of CRT-P patients and 6.5% of CRT-D patients already had a device of the same type implanted in the 3 preceding years. Conclusion The results confirm the increase in cardioverter-defibrillator implantations in France. The implantation rate remains lower than that in the USA but falls within the European average. Reasons behind significant regional variations in implantation rates need further study.

Purpose To evaluate and quantify in diabetic patients treated with benfluorex in France, a fenfluramine-derivated product, a possible increase in risk of valvular heart disease, previously suggested by several published case reports. Methods This was a French comparative cohort study using data from two large national linked databases, health insurance system (SNIIRAM) and hospitalization (PMSI). Patients aged 40–69 years with reimbursement for oral antidiabetic and/or insulin in 2006 were eligible. Exposed patients were defined as patients with at least one benfluorex reimbursement in 2006. Selected admission diagnoses of interest in 2007 and 2008 PMSI databases were valvular insufficiency for any cause, mitral insufficiency, aortic insufficiency, and valvular replacement surgery with cardiopulmonary bypass. Relative risks (RR) were adjusted on gender, age, and history of chronic cardiovascular disease. Results A total of 1 048 173 diabetic patients were included, with 43 044 (4.1%) exposed to benfluorex. The risk of hospitalization in 2007 and 2008 for any cardiac valvular insufficiency was higher in the benfluorex group: crude RR ¼ 2.9 [95% confidence interval 2.2–3.7] and adjusted RR ¼ 3.1 [2.4–4.0], with a lower risk for patients with lower cumulative dose of benfluorex. Adjusted RR for mitral insufficiency and aortic insufficiency admissions were 2.5 [1.9–3.7] and 4.4 [3.0–6.6], respectively. Adjusted RR for valvular replacement surgery was 3.9 [2.6– 6.1]. Conclusions Benfluorex in diabetic patients was significantly associated with hospitalization for valvular heart disease in the 2 years following benfluorex exposure. Linkage between SNIIRAM and PMSI databases is in France a valuable tool to quantify the risk of serious adverse drug reactions. Copyright # 2010 John Wiley & Sons, Ltd.

Complementary Universal Health insurance (CMUC) providing free access to health care has been available in France, since 2000 for people with an annual income50% of the poverty threshold.Data were derived from the French national health insurance reimbursements and short-stay admissions database for 2007 (80% of subjects under the age of 60 years in France, including 4.8 million CMUC beneficiaries). Rate ratios were calculated by dividing the rate of CMUC beneficiaries by that of other beneficiaries standardized for the sex and age distribution of CMUC beneficiaries.The hospitalization rate of CMUC beneficiaries was 17.2% and the standardized rate for non-CMUC beneficiaries was 13.2% (ratio: 1.3). It was equally raised regardless of gender and age of CMUC beneficiaries. The hospital mortality rate was 0.61% for CMUC beneficiaries and the adjusted rate for non-CMUC beneficiaries was 0.35% (1.8). The hospitalization ratio for CMUC beneficiaries was1 for all of the 22 major diagnostic categories, including psychiatry, toxicology and alcohol (3.7), HIV (3.3), infectious diseases other than HIV (1.9), burns (2.6), trauma (1.7) and female genital tract tumours (1.6) but not breast tumours (0.8). Hospitalizations for investigations such as endoscopies were also more frequent, as well as stays of48 h for radiotherapy (1.6), chemotherapy (1.5) and dialysis (2.2).In this low-income population with free access to health care, hospitalization and hospital mortality rates were higher for many diseases that are known targets for prevention and screening actions.

Summary Background International guidelines recommend long-term use of evidence-based treatment (EBT) combining beta-blockers, aspirin/clopidogrel, statins and either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs/ARBs) after a myocardial infarction (MI), to reduce cardiac morbidity and mortality. Aims To evaluate medication adherence after hospital admission for MI and the relationship with mortality and readmission for acute coronary syndrome. Methods Observational, 30-month follow-up of patients admitted for acute MI in France in the first half of 2006 and still alive 6 months later. Data from the national hospital discharge database and the outpatient medications reimbursement database were linked for all patients covered by the general health insurance scheme (70% of the French population). A patient was considered as adherent when the proportion of days covered by a filled prescription was greater than 80%. Results The proportion of nonadherent patients was 32.0% for beta-blockers, 24.0% for statins, 22.7% for ACEIs/ARBs, 18.3% for aspirin/clopidogrel and 50.0% for combined EBT. Adherence to EBT was decreased significantly by age greater than 74 years, comorbidities and full healthcare coverage for low earners. Prior EBT use and stent implantation, before or during index hospitalization, increased adherence. After adjustment for patient characteristics and management, prior use of each class decreased mortality. Nonadherence to EBT after MI increased mortality and readmission (hazard ratio = 1.43, P Conclusion After MI, nonadherence to EBT is associated with a marked increase in all-cause mortality and readmission for acute coronary syndrome. Cost-effective strategies for adherence improvement should be developed among patient groups with poor adherence.

Summary Background Both French and international guidelines recommend long-term use of betablockers, antiplatelet drugs, statins, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (ACE-I/ARB) after a myocardial infarction (MI), but data on their combined use are scarce in France. Aims To evaluate the use of combined medication 6 months after hospital admission for MI and the factors that can significantly influence their use. Methods All hospital admissions for MI in France from January to June 2006 were selected from the national hospital discharge database. Data on medications used 6 months before and after hospitalization for patients covered by the general health insurance scheme (70% of French population) were collected from the reimbursement information system. A medication was considered to be used when there were more than three reimbursement applications over the 6 months following the index episode. Comorbidities were ascertained from the use of disease-specific medication reimbursements and registration in the national database of full coverage for 30 long-term disorders. Results Of the 11 671 patients included, 82% were reimbursed for betablockers, 92% for antiplatelets, 85% for statins, 80% for ACE-I/ARBs and 62% for all four classes. After adjustment, significant underuse was found for women, the elderly and those with several comorbidities. Treatment at a university hospital or high-volume centre, follow-up by a cardiologist and use of revascularization procedures were associated with improved rates of combination therapy use. Conclusion Overall, use of recommended medications after MI in France is satisfactory, though not optimal. Specific recommendations focusing on subgroups such as older patients or those with comorbidities, as well as information directed towards non-specialized healthcare professionals, should help to improve appropriate use of these medications.

Background and Aim According to guidelines, diabetic patients with high cardiovascular risk should receive a statin. Despite this consensus, fibrate monotherapy is commonly used in this population. We assessed the frequency and clinical consequences of the use of fibrates for primary prevention in patients with diabetes and high cardiovascular risk. Design Retrospective cohort study based on nationwide data from the medical and administrative databases of French national health insurance systems (07/01/08-12/31/09) with a follow-up of up to 30 months. Methods Lipid-lowering drug-naive diabetic patients initiating fibrate or statin monotherapy were identified. Patients at high cardiovascular risk were then selected: patients with a diagnosis of diabetes and hypertension, and >50 (men) or 60 (women), but with no history of cardiovascular events. The composite endpoint comprised myocardial infarction, stroke, amputation, or death. Results Of the 31,652 patients enrolled, 4,058 (12.8%) received a fibrate. Age- and gender-adjusted annual event rates were 2.42% (fibrates) and 2.21% (statins). The proportionality assumption required for the Cox model was not met for the fibrate/statin variable. A multivariate model including all predictors was therefore calculated by dividing data into two time periods, allowing Hazard Ratios to be calculated before (HR540) of follow-up. Multivariate analyses showed that fibrates were associated with an increased risk for the endpoint after 540 days: HR540 = 1.73 (1.28–2.32). Conclusion Fibrate monotherapy is commonly prescribed in diabetic patients with high cardiovascular risk and is associated with poorer outcomes compared to statin therapy.

To explore in France the relationship between insulin glargine use and overall and specific cancer risks in type 2 diabetic patients compared with other basal insulins.Data were extracted from French health insurance information system (Système National d'Information Inter-Régimes de l'Assurance Maladie) linked with data from the French Hospital Discharge database (Programme de Médicalisation des Systèmes d'Information). Included were 70,027 patients aged 40-79 years who started a basal insulin in 2007-2009. Cox proportional hazards models with age as time-scale were used to calculate multivariate-adjusted hazard ratios for associations between type of basal insulin and risk of overall cancer, breast cancer, and seven other cancer sites.The median follow-up was 2.67 years in patients exposed to insulin glargine. Absolute event rates for all cancer in patients exposed to glargine versus other basal insulin users were 1,622 and 1,643 per 100,000 person-years, respectively. No significant association was observed between glargine exposure and overall cancer incidence after adjustment for sex, with a hazard ratio of 0.97 (95% CI 0.87-1.07), or after additional adjustment for any other hypoglycemic agent use and duration of diabetes. No increased risk of breast cancer was observed for glargine users compared with other basal insulins users, with a fully adjusted hazard ratio of 1.08 (0.72-1.62).In a large cohort of patients newly treated by basal insulin, no increased risk of any cancer was observed in insulin glargine users compared with other basal insulin users. Because follow-up did not exceed 4 years, longer-term studies are needed.

Background We aimed to determine the representation of elderly people in published reports of randomized controlled trials (RCTs). We focused on trials of 4 medications—pioglitazone, rosuvastatin, risedronate, and valsartan—frequently used by elderly patients with chronic medical conditions. Methods and Findings We selected all reports of RCTs indexed in PubMed from 1966 to April 2008 evaluating one of the 4 medications of interest. Estimates of the community-based “on-treatment” population were from a national health insurance database (SNIIR-AM) covering approximately 86% of the population in France. From this database, we evaluated data claims from January 2006 to December 2007 for 1,958,716 patients who received one of the medications of interest for more than 6 months. Of the 155 RCT reports selected, only 3 studies were exclusively of elderly patients (2 assessing valsartan; 1 risedronate). In only 4 of 37 reports (10.8%) for pioglitazone, 4 of 22 (18.2%) for risedronate, 3 of 29 (10.3%) for rosuvastatine and 9 of 67 (13.4%) for valsartan, the proportion of patients aged 65 or older was within or above that treated in clinical practice. In 62.2% of the reports for pioglitazone, 40.9% for risedronate, 37.9% for rosuvastatine, and 70.2% for valsartan, the proportion of patients aged 65 or older was lower than half that in the treated population. The representation of elderly people did not differ by publication date or sample size. Conclusions Elderly patients are poorly represented in RCTs of drugs they are likely to receive.