Impact of hospitalized vaso-occlusive crises in the previous calendar year on mortality and complications in adults with sickle cell disease: a French population-based study.

Background: Historically, sickle cell disease (SCD) patients experiencing frequent hospitalized vaso-occlusive crises (HVOC) have been associated with increased mortality, yet recent data reflecting the widespread use of hydroxyurea and advancements in disease management remain limited. Our study aims to assess the association between HVOC and mortality or severe complications in patients with SCD in this new treatment landscape. Methods: This was a retrospective observational cohort study using the French national health data system. Between 01-01-2012 and 12-31-2018, all SCD patients ≥16 years old (ICD-10 codes D57.0-2) were included and followed until 12-31-2018. HVOC was defined as a hospitalization of ≥1 night with primary diagnosis of SCD with crisis, following an emergency room visit. The association between HVOC and severe complications was assessed with a Cox proportional hazards model. Findings: In total, 8018 patients (56.6% females; 4538/8018) were included. The 2018 SCD standardized one-year period prevalence was 17.9 cases/100,000 person-years [17.4; 18.3]. The mean rate was 0.84 (1.88) HVOC/person-year. In 2018, 70% (5323/7605), 22% (1671/7605), and 8% (611/7605) of patients experienced 0, 1-2, or 3+ HVOCs, respectively. The median survival time between HVOCs was 415 days [386; 439]. Overall, 312 patients died (3.9%) with a mean age of 49.8 (19.4). Compared to patients without HVOC, the hazard ratios of death in patients with 1-2 or 3+ HVOCs the year prior to death were 1.67 [1.21; 2.30] and 3.70 [2.30; 5.93], respectively. Incidence of acute chest syndrome, pulmonary embolism, osteonecrosis, and sepsis increased with the HVOCs category, but not stroke. In 2018, 29.5% (180/611) of patients with 3+ HVOCs did not take hydroxyurea. Interpretation: Patients must be closely monitored during their hospitalizations to intensify treatment and check treatment compliance. Innovative therapies are also required. Funding: The study was funded by Novartis.

Therapeutic management and outcome of patients with advanced systemic mastocytosis treated with midostaurin: A comprehensive real-life study in the French national healthcare database.

Advanced Systemic Mastocytosis (Adv-SM) is rare and has a poor prognosis. Midostaurin (Rydapt® ) is one of the few treatments for Adv-SM in Europe. The study aims were to describe the characteristics of patients treated with midostaurin, their treatment modalities, outcomes, and serious events requiring hospitalization. This retrospective observational study was conducted using the French National Healthcare Database (SNDS) and included adult Adv-SM patients treated with midostaurin between 01-01-2012 and 09-30-2018. Kaplan-Meier method was used to assess survival and treatment duration. Eighty-one patients were included: 37 with Aggressive Systemic Mastocytosis (SM) (46%), 31 with SM with an Associated Hematological Neoplasm (38%), and 4 with Mast Cell Leukemia (5%). The SM subtype was undetermined in 9 patients (11%). The median age was 67 years; 64% of patients were male. Over the mean follow-up of 11.4 months, median midostaurin treatment duration was 8.4 months and 28 patients (35%) were still under treatment at the end of the study. One-year and 5-year overall survival rates estimated since the time of diagnosis were 83% and 56%, respectively. Twelve serious events (among those frequently reported during clinical trials and compassionate use) requiring hospitalization were identified; a causal association with Adv-SM treatment could neither be excluded nor established. In this first real-life study on patients treated with midostaurin for Adv-SM, the patients' characteristics, their management, treatment discontinuation, and survival were in line with previous results (compassionate use and clinical trials).

Pneumococcal and influenza vaccination coverage among at-risk adults: A 5-year French national observational study.

INTRODUCTION: The risk of developing pneumococcal infections increases with certain chronic conditions and in immunocompromised patients. We aimed to monitor pneumococcal vaccination coverage in at-risk patients and to examine factors associated with pneumococcal vaccination in France. MATERIAL AND METHODS: In this annual cross-sectional study, at-risk patients were extracted between 2014 and 2018 from the National Health Insurance's (NHI) General scheme's claims database with their vaccine reimbursements. Descriptive analyses and a logistic model were performed to assess the influence of healthcare use and medical and demographic factors on pneumococcal vaccination. RESULTS AND DISCUSSION: In 2018, 4.5% of 4,045,021 at-risk adults were up to date with their pneumococcal vaccination. During the study period, the number of patients with chronic medical conditions (86% of 4,045,021) increased by 10.1%, but vaccination coverage decreased from 12.9% to 2.9%. The population with immunocompromised status (14% of 4,045,021) increased by 16.2% and vaccination coverage from 10.3% to 18.8%. Influenza vaccination coverage was much higher and stable (around 45.0%). Factors associated with pneumococcal vaccination were: immunocompromised status vs. having a chronic medical condition (odds ratio [OR] 4.72), influenza vaccination (OR 2.36-3.42), hepatitis B vaccination (OR 2.82), DTPolio vaccination (OR 1.52), ≥5 specialist physicians' visits (OR 1.17), and age above 74 (OR 1.12). Pneumococcal vaccine dispensing was extremely low (median of 9per GP,1per specialist over 9 years) despite frequent healthcare visits. CONCLUSION: Pneumococcal and influenza vaccination coverage of adults at risk of pneumococcal disease fell well below public health expectations. Invitations for pneumococcal vaccination should be sent by the NHI to high-risk patients. Patient management protocols should include pneumococcal vaccination. Patients with multiple comorbidities are a high-priority population given the large potential health gains offered by pneumococcal vaccination. Commitment of both scientific societies and health authorities is urgently needed to increase vaccination coverage in at-risk populations.

Hospital costs of Balloon Pulmonary Angioplasty (BPA) procedure and management for CTEPH patients: An observational study based on the French national hospital discharge database (PMSI).

INTRODUCTION: Since 2014, Balloon Pulmonary Angioplasty (BPA) has become an emerging and complementary strategy for chronic thromboembolic hypertension (CTEPH) patients who are not suitable for pulmonary endarterectomy (PEA) or who have recurrent symptoms after the PEA procedure. OBJECTIVE: To assess the hospital cost of BPA sessions and management in CTEPH patients. METHODS: An observational retrospective cohort study of CTEPH-adults hospitalized for a BPA between January 1st, 2014 and June 30th, 2016 was conducted in the 2 centres performing BPA in France (Paris Sud and Grenoble) using the French national hospital discharge database (PMSI-MCO). Patients were followed until 6 months or death, whichever occurred first. Follow-up stays were classified as stays with BPA sessions, for BPA management or for CTEPH management based on a pre-defined algorithm and a medical review using type of diagnosis (ICD-10), delay from last BPA procedure stay and length of stay. Hospital costs (including medical transports) were estimated from National Health Insurance perspective using published official French tariffs from 2014 to 2016 and expressed in 2017 Euros. RESULTS: A total of 191 patients were analysed; mainly male (53%), with a mean age of 64,3 years. The first BPA session was performed 1.1 years in median (IQR 0.3-2.92) after the first PH hospitalisation. A mean of 3 stays with BPA sessions per patient were reported with a mean length of stay of 8 days for the first stay and 6 days for successive stays. The total hospital cost attributable to BPA was € 4,057,825 corresponding to €8,764±3,435 per stay and €21,245±12,843 per patient. Results were sensitive to age classes, density of commune of residence and some comorbidities. CONCLUSIONS: The study generated robust real-world data to assess the hospital cost of BPA sessions and management in CTEPH patients within its first years of implementation in France.

Economic burden of highly active relapsing-remitting multiple sclerosis patients in the French national health insurance database.

BACKGROUND: As healthcare management of highly active-relapsing-remitting multiple sclerosis (HA-RRMS) patients is more complex than for the whole multiple sclerosis (MS) population, this study assessed the related economic burden from a National Health Insurance's (NHI's) perspective. RESEARCH DESIGN AND METHODS: Study based on French NHI databases, using individual data on billing and reimbursement of outpatient and hospital healthcare consumption, paid sick leave and disability pension, over 2010-2017. RESULTS: Of the 9,596 HA-RRMS adult patients, data from 7,960 patients were analyzed with at least 2 years of follow-up. Mean annual cost/patient was €29,813. Drugs represented 40% of the cost, hospital care 33%, disability pensions 9%, and all healthcare professionals' visits combined 8%. Among 3,024 patients under 60 years-old with disability pension, disability pension cost €7,168/patient/year. Among 3,807 patients with paid sick leave, sick leave cost €1,956/patient/year. Mean costs were €2,246/patient higher the first year and increased by €1,444 between 2010 and 2015, with a €5,188 increase in drug-related expenditures and a €634 increase in healthcare professionals' visits expenditures but a €4,529 decrease in hospital care expenditures. CONCLUSIONS: The cost of health care sick leaves, and disability pensions of HA-RRMS patients was about twice as high as previously reported cost of MS patients.

Risks of 23 specific malformations associated with prenatal exposure to 10 antiepileptic drugs.

OBJECTIVE: To assess the association between exposure to monotherapy with 10 different antiepileptic drugs (AEDs) during the first 2 months of pregnancy and the risk of 23 major congenital malformations (MCMs). METHODS: This nationwide cohort study, based on the French health care databases, included all pregnancies ≥20 weeks and ending between January 2011 and March 2015. Women were considered to be exposed when an AED had been dispensed between 1 month before and 2 months after the beginning of pregnancy. The reference group included pregnant women with no reimbursement for AEDs. MCMs were detected up to 12 months after birth (24 months for microcephaly, hypospadias, and epispadias). Odds ratios (ORs) were adjusted for potential confounders for MCMs with at least 5 cases. Otherwise, we calculated crude ORs with exact confidence intervals (CIs). RESULTS: The cohort included 1,886,825 pregnancies, 2,997 of which were exposed to lamotrigine, 1,671 to pregabalin, 980 to clonazepam, 913 to valproic acid, 579 to levetiracetam, 517 to topiramate, 512 to carbamazepine, 365 to gabapentin, 139 to oxcarbazepine, and 80 to phenobarbital. Exposure to valproic acid was associated with 8 specific types of MCMs (e.g., spina bifida, OR 19.4, 95% CI 8.6-43.5), and exposure to topiramate was associated with an increased risk of cleft lip (6.8, 95% CI 1.4-20.0). We identified 3 other signals. We found no significant association for lamotrigine, levetiracetam, carbamazepine, oxcarbazepine, and gabapentin. CONCLUSIONS: These results confirm the teratogenicity of valproic acid and topiramate. Because of the small numbers of cases and possible confounding, the other 3 signals should be interpreted with appropriate caution.

Development of an algorithm to identify pregnancy episodes and related outcomes in health care claims databases: An application to antiepileptic drug use in 4.9 million pregnant women in France.

PURPOSE: Access to claims databases provides an opportunity to study medication use and safety during pregnancy. We developed an algorithm to identify pregnancy episodes in the French health care databases and applied it to study antiepileptic drug (AED) use during pregnancy between 2007 and 2014. METHODS: The algorithm searched the French health care databases for discharge diagnoses and medical procedures indicative of completion of a pregnancy. To differentiate claims associated with separate pregnancies, an interval of at least 28 weeks was required between 2 consecutive pregnancies resulting in a birth and 6 weeks for terminations of pregnancy. Pregnancy outcomes were categorized into live births, stillbirths, elective abortions, therapeutic abortions, spontaneous abortions, and ectopic pregnancies. Outcome dates and gestational ages were used to calculate pregnancy start dates. RESULTS: According to our algorithm, live birth was the most common pregnancy outcome (73.9%), followed by elective abortion (17.2%), spontaneous abortion (4.2%), ectopic pregnancy (1.1%), therapeutic abortion (1.0%), and stillbirth (0.4%). These results were globally consistent with French official data. Among 7 559 701 pregnancies starting between 2007 and 2014, corresponding to 4 900 139 women, 6.7 per 1000 pregnancies were exposed to an AED. The number of pregnancies exposed to older AEDs, comprising the most teratogenic AEDs, decreased throughout the study period (-69.4%), while the use of newer AEDs increased (+73.4%). CONCLUSIONS: We have developed an algorithm that allows identification of a large number of pregnancies and all types of pregnancy outcomes. Pregnancy outcome and start dates were accurately identified, and maternal data could be linked to neonatal data.

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.

Association Between Oral Fluoroquinolone Use and Retinal Detachment.

IMPORTANCE: Several studies have focused on the current use of oral fluoroquinolones and the risk for retinal detachment (RD), but the existence of this association is under debate. Given the widespread fluoroquinolone use, investigation of this association is essential. OBJECTIVE: To assess the association between oral fluoroquinolone use and the risk for RD, including the rhegmatogenous and exudative types. DESIGN, SETTING, AND PARTICIPANTS: This case-crossover study included 27,540 adults with RD from French health care databases from July 1, 2010, through December 31, 2013. Patients with a history of RD or retinal break, endophthalmitis, intravitreal injection, choroidal retinal vitreal biopsy, and human immunodeficiency virus infection or those hospitalized within 6 months of RD were excluded. The risk period of primary interest was current use, defined as exposure to fluoroquinolones within 10 days immediately before RD surgery, according to previous findings. Oral fluoroquinolone use was assumed to start on the day the prescription was dispensed. MAIN OUTCOMES AND MEASURES: Exposure to fluoroquinolones during the risk period (1-10 days) compared with the control period (61-180 days). The association was also assessed regarding use in the recent (11-30 days) and past (31-60 days) intermediate risk period, type of fluoroquinolone, and type of RD. RESULTS: Of the 27,540 eligible patients (57% men; mean [SD] age, 61.5 [13.6] years), 663 patients with RD were exposed to fluoroquinolones during the observation period, corresponding to 80 cases exposed during the 10-day risk period (≤10 days before RD) and 583 cases exposed during the control period (61-180 days). We found a significant increased risk for RD during the 10-day period after the dispensing of oral fluoroquinolones, with an adjusted odds ratio of 1.46 (95% CI, 1.15-1.87). The risk was significantly increased for rhegmatogenous and exudative RD, with adjusted odds ratios of 1.41 (95% CI, 1.04-1.92) and 2.57 (95% CI, 1.46-4.53), respectively. Recent and past use of fluoroquinolones were not associated with a higher risk for RD, with adjusted odds ratios of 0.94 (95% CI, 0.78-1.14) and 1.06 (95% CI, 0.91-1.24), respectively. CONCLUSIONS AND RELEVANCE: Current oral fluoroquinolone use was associated with an increased risk for RD, including the rhegmatogenous and exudative types. These findings, along with the available literature, suggest an association between fluoroquinolone use and the risk for RD. The nature of this association should be further investigated in future studies.

Compliance with pregnancy prevention plan recommendations in 8672 French women of childbearing potential exposed to acitretin.

PURPOSE: Acitretin is an oral synthetic aromatic analogue of retinoic acid available in most European countries since 1988. It is mainly used to treat severe psoriasis. Like all systemic retinoids, acitretin is teratogenic. Strict pregnancy prevention is required in women of childbearing potential who use acitretin. This study assessed compliance with Pregnancy Prevention Plan (PPP) recommendations, specifically looking at compliance with pregnancy testing (PT) and pregnancy occurrence. METHODS: A cohort of 8672 women aged 15-49 years initiating acitretin treatment from 1 January 2007 through 31 December 2013 was identified using French SNIIRAM (administrative claims data) and PMSI (hospitalisations data) databases. Pregnancy tests (PTs) were identified from reimbursed serum ßHCG and urine laboratory PTs. To satisfy PT criteria, patients who started treatment had to undergo a PT within 3 days before acitretin was dispensed. Pregnancies were identified by a pregnancy-related hospital stay or an outpatient medical abortion. RESULTS: A PT was performed in only 12% of women starting treatment and was rarely performed during treatment or during the 24 months following discontinuation of treatment. Compliance with PPP recommendations although poor appeared to be better among private dermatologists, as a PT was performed for 16% of treatment initiations (vs. 4% for general practitioners, p < 0.001). Moreover, 470 pregnancies were reported corresponding to 27 pregnancies per 1000 person-years at risk of teratogenicity. CONCLUSIONS: This study highlights poor compliance with acitretin PPP recommendations in France. Physicians and pharmacists must more rigorously apply the acitretin PPP recommendations, and patients must be better informed about acitretin's risk of teratogenicity.

Estimate of venous thromboembolism and related-deaths attributable to the use of combined oral contraceptives in France.

PURPOSE: To estimate the number of venous thromboembolic events and related-premature mortality (including immediate in-hospital lethality) attributable to the use of combined oral contraceptives in women aged 15 to 49 years-old between 2000 and 2011 in France. METHODS: French data on sales of combined oral contraceptives and on contraception behaviours from two national surveys conducted in 2000 and 2010 were combined to estimate the number of exposed women according to contraceptives generation and age. Absolute risk of first time venous thromboembolism in non-users of hormonal contraception and increased risk of thromboembolism in users vs. non-users of hormonal contraception were estimated on the basis of literature data. Finally, immediate in-hospital lethality due to pulmonary embolism and premature mortality due to recurrent venous thromboembolism were estimated from the French national database of hospitalisation and literature data. RESULTS: In France, more than four million women are daily exposed to combined oral contraceptives. The mean annual number of venous thromboembolic events attributable to their use was 2,529 (778 associated to the use of first- and second-generation contraceptives and 1,751 to the use of third- and fourth-generation contraceptives), corresponding to 20 premature deaths (six with first- and second-generation contraceptives and fourteen with third- and fourth-generation contraceptives), of which there were eight to nine immediate in-hospital deaths. As compared to the use of first- and second-generation contraceptives, exposure to third- and fourth-generation contraceptives led to a mean annual excess of 1,167 venous thromboembolic events and nine premature deaths (including three immediate in-hospital deaths). CONCLUSIONS: Corrective actions should be considered to limit exposure to third- and fourth-generation contraceptives, and thus optimise the benefit-risk ratio of combined oral contraception.