Philippe Ricordeau

Benfluorex and valvular heart disease: a cohort study of a million people with diabetes mellitus

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.

Evidence-based pharmacotherapy after myocardial infarction in France: Adherence-associated factors and relationship with 30-month mortality and rehospitalization

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<0.0001). 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.

Comparison of the short-term risk of bleeding and arterial thromboembolic events in nonvalvular atrial fibrillation patients newly treated with dabigatran or rivaroxaban versus vitamin K antagonists: a French nationwide propensity-matched cohort study.

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.

HPV vaccination in France: Uptake, costs and issues for the National Health Insurance

INTRODUCTION Two vaccines for primary prevention of cervical cancer are available in France, Gardasil® and Cervarix®, since 2007 and 2008 respectively. Currently, the French guidelines indicate vaccination of girls aged 14 with a catch-up program for females from 15 to 23 years old. In France, the reimbursement rate for these vaccines is 65% of the vaccine price, resulting in Gardasil® being the fifth highest drug expenditure of the main scheme of the French National Health Insurance in 2008. The purpose of this study is to provide data on vaccination coverage and costs in France until 31 December 2009. In addition, the current vaccination coverage rate is compared with the coverage rates assumed in cost-effectiveness studies. METHODS Data were extracted from the National Health Insurance Information System (SNIIRAM). The SNIIRAM records all reimbursements of medical costs to patients--including drugs--by the French public Health Insurance Schemes since 2004. The analysis was performed for the period of July 2007 until December 2009 using the data of the general scheme of National Health Insurance covering about 88% of the French population, i.e., 56.5 million people. Vaccination rates for one or three doses were determined for the target and catch-up population using the 2009 reference population from the general health insurance scheme as the denominator. RESULTS The cumulative number of doses reached 2,900,000 at the end of 2009. About 1,200,000 girls and young women have been reimbursed for at least one vaccine dose, of these 96.5% females aged 14-23 years. Among the target group, reimbursement for at least one dose remained low, from 50.8% for girls aged 14 years in 2007 to 41.7% and 20.5% for girls aged 14 years in 2008 and 2009 respectively. In terms of complete vaccination, only 33.3% of girls of the age of 14 years in 2007 and 23.7% in 2008 were reimbursed for 3 doses of HPV vaccine. The maximum uptake in the catch-up group for both 1 and 3 doses was observed for women born in 1992 (15 years in 2007) with 52.5% and 35.6% respectively. CONCLUSION Low rates of coverage have been observed both in the target and catch-up groups in France. Considering this, the cost-effectiveness of vaccination in combination with opportunistic screening or organized screening needs to be re-evaluated.

Changes by age in breast cancer incidence, mammography screening and hormone therapy use in France from 2000 to 2006

BACKGROUND In 2003, US breast cancer incidence rates fell. Recent French data reveal also a decline in 2005-2006. This study aims to present the trends in breast cancer incidence by age and to identify the respective impact of mammography screening and use of hormone replacement therapy (HRT) in the French context. METHODS Breast cancer incidence rates were calculated from the new cases of breast cancer among affiliates of the general scheme of the French National Health Fund between 2000 and 2006. Data concerning HRT and mammograms were extracted from the reimbursement databanks of the National Health Fund and from the National Screening Programme. RESULTS Breast cancer incidence decreased between 2003 and 2006 only for women aged 50 or above. The strongest declines were observed among the 55-59 and 60-64-year-old groups (12.9 and 7.7%, respectively). We observed a slight decline in the age groups of 50-54 and 65-69 (0.7 and 2.1%, respectively). Volumes of mammograms increased continuously between 2000 and 2006 from 1,600,000 to 3,470,000 for women aged 50-74 years old. In 2004, the National Screening Programme achieved complete geographic coverage. At the same time, the number of HRT users has dropped by 62% between 2001 and 2006. We observed the highest prevalence of HRT and the highest decrease in breast cancer incidence rates in the age group of 55-59. CONCLUSIONS The recent reduction in breast cancer incidence in France for women aged 50 years or above, in 2005-2006, was accompanied by a substantial reduction in HRT prescriptions after 2002 for all age groups. The drop in HRT parallels the drop in breast cancer incidence for the women between the ages of 55-59 and 60-64. The high-level of development of screening in France during the same period could not account for the reduction in breast cancer incidence.

Low dose oestrogen combined oral contraception and risk of pulmonary embolism, stroke, and myocardial infarction in five million French women: cohort study.

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.

Combined secondary prevention after hospitalization for myocardial infarction in France: Analysis from a large administrative database

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.

Risk of bleeding and arterial thromboembolism in patients with non-valvular atrial fibrillation either maintained on a vitamin K antagonist or switched to a non-vitamin K-antagonist oral anticoagulant: a retrospective, matched-cohort study

BACKGROUND Patients with non-valvular atrial fibrillation who are receiving or have been previously exposed to a vitamin K antagonist could be switched to a non-vitamin K-antagonist oral anticoagulant (NOAC) but little information is available about the risk of bleeding and arterial thromboembolism after such a switch. We aimed to compare the risk of bleeding between individuals who switched and those who remained on a vitamin K antagonist (non-switchers) in real-world conditions. METHODS We did a matched-cohort study with information from French health-care databases. We extracted data for adults (aged ≥18 years) with non-valvular atrial fibrillation who received their first prescription for a vitamin K antagonist (fluindione, warfarin, or acenocoumarol) between Jan 1, 2011, and Nov 30, 2012, and who were either switched to a NOAC (dabigatran or rivaroxaban) or maintained on the vitamin K antagonist. Each switcher was matched with up to two non-switchers on the basis of eight variables, including sex, age, and international normalised ratio number. The primary endpoint was incidence of bleeding (intracranial haemorrhage, gastrointestinal haemorrhage, or other) in switchers versus non-switchers, and switchers stratified by type of NOAC versus non-switchers, noted from databases of hospital admissions. Each patient was followed up to 1 year; the study closed on Oct 1, 2013. FINDINGS Of 17,410 participants, 6705 switched to a NOAC (switchers) and 10,705 remained on vitamin K-antagonist therapy (non-switchers). Median age of participants was 75 years (IQR 67-82), 8339 (48%) were women, and the median duration of vitamin K-antagonist exposure before a switch was 8.1 months (IQR 3.9-14.0). After a median follow-up of 10.0 months (IQR 9.8-10.0), we noted no difference between groups for bleeding events (99 [1%] in switchers vs 193 [2%] in non-switchers, p=0.54). In adjusted multivariate analyses, the risk of bleeding in switchers was not different from that in non-switchers (hazard ratio [HR] 0.87; 95% CI 0.67-1.13, p=0.30). Additionally, no differences were noted when the risk of bleeding was compared between switchers from a vitamin K antagonist to dabigatran (HR 0.78, 95% CI 0.54-1.09, p=0.15), switchers from a vitamin K antagonist to rivaroxaban (HR 1.04, 95% CI 0.68-1.58, p=0.86), and non-switchers. INTERPRETATION In this matched-cohort study, our findings suggest that patients with non-valvular atrial fibrillation who switch their oral anticoagulant treatment from a vitamin K antagonist to a non-vitamin K antagonist are not at increased risk of bleeding. Future studies with longer follow-up might be needed. FUNDING None.

Coût de la prise en charge de l’IRCT en France en 2007 et impact potentiel d’une augmentation du recours à la dialyse péritonéale et à la greffe

INTRODUCTION This study estimates the costs for the national health insurance in 2007 of the patients with end-stage renal disease (ESRD) according to therapies modalities. METHOD Data for all patients covered by the general health insurance scheme (77% of the French population) from hospital discharge and outpatients reimbursement databases were linked. ESRD therapies were identified using an algorithm mainly based on discharge diagnosis and immunosuppressive drugs refunds. RESULTS Extrapolated to all French population at the end of 2007, 60,900 patients had an ESRD therapy: 30,900 were treated on haemodialysis (HD) (51%), 2600 on peritonea dialysis (DP) (4%) and 27,300 had a kidney transplant (45%). Patients with dialysis therapies had more often complementary universal coverage for low earners. According to the French regions, patient treated with DP were between 0 to 26% and 19 to 57% for those with a transplant. The total refund cost for National Health Insurance was four billion euro of which 77% for HD. Annual mean costs per patient were 64 keuro for DP, 89 keuro for HD, 86 keuro for the year of transplantation and 20 keuro for the following years. A 25% increase of DP would allow a decrease of the annual cost of 155 millions euro and 900 transplantations more each year during 10 years a decrease of 2.5 billions euro. CONCLUSION The increase of ESRD prevalence and its total cost require patients and professionals information and formation about the less expensive and more autonomous therapies and others alternatives facing the lack of kidney transplants from deceased donors.

The Best Use of the Charlson Comorbidity Index With Electronic Health Care Database to Predict Mortality.

Background:The most used score to measure comorbidity is the Charlson index. Its application to a health care administrative database including International Classification of Diseases, 10th edition (ICD-10) codes, medical procedures, and medication required studying its properties on survival. Our objectives were to adapt the Charlson comorbidity index to the French National Health Insurance database to predict 1-year mortality of discharged patients and to compare discrimination and calibration of different versions of the Charlson index. Methods:Our cohort included all adults discharged from a hospital stay in France in 2010 registered in the French National Health Insurance general scheme. The pathologies of the Charlson index were identified through ICD-10 codes of discharge diagnoses and long-term disease, specific medical procedures, and reimbursement of specific medications in the past 12 months before inclusion. Results:We included 6,602,641 subjects at the date of their first discharge from medical, surgical, or obstetrical department in 2010. One-year survival was 94.88%, decreasing from 98.41% for Charlson index of 0–71.64% for Charlson index of ≥5. With a discrimination of 0.91 and an appropriate calibration curve, we retained the crude Cox model including the age-adjusted Charlson index as a 4-level score. Conclusions:Our study is the first to adapt the Charlson index to a large health care database including >6 million of inpatients. When mortality is the outcome, we recommended using the age-adjusted Charlson index as 4-level score to take into account comorbidities.