A randomized clinical trial to evaluate the effect of post-intensive care multidisciplinary consultations on mortality and the quality of life at 1 year.

PURPOSE: Critical illness is associated with long-term increased mortality and impaired quality of life (QoL). We assessed whether multidisciplinary consultations would improve outcome at 12 months (M12) after intensive care unit (ICU) discharge. METHODS: We performed an open, multicenter, parallel-group, randomized clinical trial. Eligible are patients discharged alive from ICU in 11 French hospitals between 2012 and 2018. The intervention group had a multidisciplinary face-to-face consultation involving an intensivist, a psychologist, and a social worker at ICU discharge and then at M3 and M6 (optional). The control group had standard post-ICU follow-up. A consultation was scheduled at M12 for all patients. The QoL was assessed using the EuroQol-5 Dimensions-5 Level (Euro-QoL-5D-5L) which includes five dimensions (mobility, self-care, usual activities, pain, and anxiety/depression), each ranging from 1 to 5 (1: no, 2: slight, 3: moderate, 4: severe, and 5: extreme problems). The primary endpoint was poor clinical outcome defined as death or severe-to-extreme impairment of at least one EuroQoL-5D-5L dimension at M12. The information was collected by a blinded investigator by phone. Secondary outcomes were functional, psychological, and cognitive status at M12 consultation. RESULTS: 540 patients were included (standard, n = 272; multidisciplinary, n = 268). The risk for a poor outcome was significantly greater in the multidisciplinary group than in the standard group [adjusted odds ratio 1.49 (95% confidence interval, (1.04-2.13)]. Seventy-two (13.3%) patients died at M12 (standard, n = 32; multidisciplinary, n = 40). The functional, psychological, and cognitive scores at M12 did not statistically differ between groups. CONCLUSIONS: A hospital-based, face-to-face, intensivist-led multidisciplinary consultation at ICU discharge then at 3 and 6 months was associated with poor outcome 1 year after ICU.

Neurogenic heterotopic ossification of the hip: Magnetic resonance imaging versus computed tomography for pre-surgical assessment.

PURPOSE: Neurogenic heterotopic ossification (NHO) of the hip is a frequent complication of spinal cord injuries, often requiring surgical management. Pre-surgical imaging assessment is essential, usually with computed tomography (CT)-scan. We aimed to compare magnetic resonance imaging (MRI) and CT for pre-surgical imaging assessment of the NHO, particularly for their relationships with vessels and nerves. METHOD: This prospective study included consecutive patients who underwent surgery for NHO from July 2019 to April 2022. All patients had CT angiography and MRI including Zero Echo Time and TRICKS sequences. Radiologists used standardized reports for CT and MRI to evaluate NHO and their features, bone mineralization, and relation to the arteries, veins and nerves. Agreement between pre-surgical CT and MRI was evaluated. RESULTS: Twenty-four patients (mean age: 53.5 ± 12.2 years) were included, among which 7 had bilateral NHO (31 hips). NHO were anterior in 15/31 hips (48 %), multifragmented in 25/31 hips (81 %). Mild and significant demineralization was most frequent. Gutter and tunnel were reported in 11.1 % of the arteries. Nerves were more often identified in MRI than in CT-scan. Agreement coefficients between CT and MRI were excellent for NHO location (0.95) and implantation (0.92), good for fragmentation (0.70), contact with joint capsule (0.66), bone mineralization (0.74), and relation to arteries (0.85), veins (0.76), sciatic nerve (0.7) and moderate for femoral nerve (0.47). CONCLUSION: MRI exhibited a good agreement with CT for pre-surgical assessment of NHO of the hip, especially to evaluate their relationships with the arteries, veins and sciatic nerve. Femoral nerves were more often identified in MRI than in CT-scan.

Association between vaccination and the risk of central demyelination: results from a case-referent study.

BACKGROUND: Few studies documented the potential association between vaccination and the risk of central demyelination (CD). Specifically, anti-hepatitis B and anti-human papillomavirus (HPV) vaccines have been the subject of distrust with regard to their implication to trigger CD. METHODS: From a systematic national registry, patients with first signs of CD (cases) were identified and documented for their exposure to vaccination up to 24 months before the first signs occurred. This exposure was compared to that of a representative sample of general practice patients without a history of CD, randomly selected from a national registry (referents). CD cases were 2:1 matched on age, sex, index date (ID), and region of residence. Vaccines against influenza, HPV, hepatitis B and diphtheria-tetanus-pertussis-poliomyelitis-haemophilus (DTPPHae) were considered. Associations between vaccination and CD were assessed using multivariate conditional logistic regressions, controlled for confounding factors. FINDINGS: 564 CD cases were matched to 1,128 randomly selected referents (age range: 2-79 years old). Overall, 123 (22%) CD cases and 320 (28%) referents had received at least one vaccine within 24 months before ID. Adjusted odds ratios (ORs) for any vaccination were 0.69, 95% confidence interval (CI) [0.54-0.88] with respect to any CD first signs, 0.68 [0.51-0.90] for myelitis and 0.70 [0.42-1.17] for optic neuritis. Adjusted ORs for any CD first signs were 1.02 [0.71-1.47] for influenza vaccine (administered in 9.6% of cases and 10.4% of referents) and 0.72 [0.53-0.99] for DTPPHae vaccine (administered in 10.8% of cases and 14.5% of referents). Vaccines against hepatitis B and HPV were only administered in 1.1% and 1.2% of cases and in 2.9% and 3.2% of referents respectively, which statistically explained the point estimates < 1 (ORs of 0.39 [0.16-0.94] and of 0.32 [0.13-0.80]). INTERPRETATION: No increased risk of CD incidence was observed amongst vaccinated patients. Lower rates of vaccination against hepatitis B and HPV observed in patients with CD compared to referents may be due to the reluctance of physicians to vaccinate patients considered at risk of CD.

International cohort study on the effectiveness of dronedarone and other antiarrhythmic drugs for atrial fibrillation in real-world practice (EFFECT-AF).

AIMS: To evaluate the effectiveness and safety of dronedarone compared with other commonly used antiarrhythmic drugs (AADs) for preventing atrial fibrillation (AF) recurrences. METHODS AND RESULTS: An international observational cohort study in Germany, Spain, Italy, and the USA enrolling patients with AF receiving AAD therapy. Patients with New York Heart Association (NYHA) Class IV heart failure were excluded. Participants were followed for up to 18 months, regardless of discontinuation or subsequent AAD switches. Atrial fibrillation recurrence was captured by hospitalization, emergency room visit, or electrocardiogram-based documentation of AF. Confounding bias was controlled for in the analysis of AF recurrence using multivariate models of 19 variables for adjustment. A total of 1009 participants [mean age 67.2 (10.8) years, male to female ratio 1.3] were recruited from 170 centres, 693 (69%) of which were from across Europe and the remaining 316 (31%) from the USA. At the time of enrolment, participants were taking dronedarone (51%) or other AADs (49%) [flecainide or propafenone (42%), sotalol (11%), and amiodarone (47%)]. No significant differences in the risk of first confirmed AF recurrence with dronedarone vs. other AADs [crude hazard ratio (HR) 1.10 (95% confidence interval 0.85-1.42); adjusted HR 1.16 (0.87-1.55)] were found, irrespective of whether univariate or multivariate models were used. Reported safety events were in accordance with the known safety profile of dronedarone. CONCLUSION: In this population of patients from either Europe or the USA receiving dronedarone or another AAD, the effectiveness of dronedarone was comparable to that observed for other AADs in preventing first AF recurrence.

Stroke Prevention by Anticoagulants in Daily Practice Depending on Atrial Fibrillation Pattern and Clinical Risk Factors.

Background and Purpose: The objective of the study was to assess the effectiveness of individual direct oral anticoagulants versus vitamin K antagonists for primary prevention of stroke (ischemic and hemorrhagic) in routine clinical practice in patients with various clinical risk factors depending on their atrial fibrillation (AF) patterns. Methods: A nested case-referent study was conducted using data from 2 national registries of patients with stroke and AF. Stroke cases with previous history of AF were matched to up to 2 randomly selected referent patients with AF and no stroke. The association of individual anticoagulant use with ischemic or hemorrhagic stroke was studied in patients with or without permanent AF using multivariable conditional logistic models, controlled for clinically significant risk factors and multiple other cardiovascular risk factors. Results: In total, 2586 stroke cases with previous AF and 4810 nonstroke referent patients with AF were retained for the study. Direct oral anticoagulant users had lower odds of stroke of any type than vitamin K antagonist users: the adjusted-matched OR for ischemic stroke were 0.70 (95% CI, 0.50­0.98) for dabigatran, 0.68 (95% CI, 0.53­0.86) for rivaroxaban, and 0.73 (95% CI, 0.52­1.02) for apixaban while for hemorrhagic stroke they were 0.31 (95% CI, 0.14­0.68), 0.64 (95% CI, 0.39­1.06), and 0.70 (95% CI, 0.33­1.49), respectively. The effects of individual direct oral anticoagulants relative to vitamin K antagonists were similar in permanent AF and nonpermanent AF patients. Conclusions: Similar results were observed for each direct oral anticoagulant in real life as those observed in the pivotal clinical trials. The pattern of AF did not affect the outcome.

Valproic Acid as an Adjuvant Treatment for Generalized Convulsive Status Epilepticus in Adults Admitted to Intensive Care Units: Protocol for a Double-Blind, Multicenter Randomized Controlled Trial.

BACKGROUND: Generalized convulsive status epilepticus (GCSE) is a frequent medical emergency. GCSE treatment focuses on the administration of benzodiazepines followed by a second-line antiepileptic drug (AED). Despite this stepwise strategy, GCSE is not controlled in one-quarter of patients and is associated with protracted hospitalization, high mortality, and long-term disability. Valproic acid (VPA) is an AED with good tolerability and neuroprotective properties. OBJECTIVE: This study aims to demonstrate that administration of VPA as an adjuvant for first- and second-line treatment in GCSE can improve outcomes. METHODS: A multicenter, double-blind, randomized controlled trial was conducted, comparing VPA with a placebo in adults admitted to intensive care units (ICUs) for GCSE in France. GCSE was diagnosed by specifically trained ICU physicians according to standard criteria. All patients received standard of care, including a benzodiazepine and a second-line AED (not VPA), at the discretion of the treating medical team. In the intervention arm, VPA was administered intravenously at a loading dose of 30 mg/kg over 15 minutes, followed by a continuous infusion of 1 mg/kg/hour over the next 12 hours. In the placebo group, an identical intravenous administration of 0.9% saline was used. The primary outcome was the proportion of patients discharged alive from the hospital by day 15. Secondary outcomes were frequency of refractory and super refractory GCSE, ICU-related morbidity, adverse events related to VPA, and cognitive dysfunction at 3 months. Statistical analyses will be performed according to the intent-to-treat principle. RESULTS: The first patient was randomized on February 18, 2013, and the last patient was randomized on July 7, 2018. Of 248 planned patients, 98.7% (245/248) were enrolled across 20 ICUs. At present, data management is still ongoing, and all parties involved in the trial remain blinded. CONCLUSIONS: The Valproic Acid as an Adjuvant Treatment for Generalized Convulsive Status Epilepticus (VALSE) trial will evaluate whether the use of VPA as an adjuvant for first- and second-line treatment in GCSE improves outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01791868; https://clinicaltrials.gov/ct2/show/NCT01791868. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/22511.

Impact of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Hypertensive Patients with COVID-19 (COVIDECA Study).

Effect of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) among hypertensive patients with coronavirus disease 2019 (COVID-19) is debated. The aim of the COVIDECA study was to assess the outcome of ACEI and ARB among hypertensive patients presenting with COVID-19. We reviewed from the Assistance Publique-Hôpitaux de Paris healthcare record database all patients presenting with confirmed COVID-19 by RT-PCR. We compared hypertensive patients with ACEI or ARB and hypertensive patients without ACEI and ARB. Among 13,521 patients presenting with confirmed COVID-19 by RT-PCR, 2,981 hypertensive patients (mean age: 78.4 ± 13.6 years, 1,464 men) were included. Outcome of hypertensive patients was similar whatever the use or non-use of ACEI or ARB: admission in ICU (13.4% in patients with ACEI or ARB versus 14.8% in patients without ACEI/ARB, p = 0.35), need of mechanical ventilation (5.5% in patients with ACEI or ARB vs 6.3% in patients without ACEI/ARB, p = 0.45), in-hospital mortality (27.5% in patients with ACEI or ARB vs 26.7% in patients without ACEI/ARB, p = 0.70). In conclusion, the use of ACEI and ARB remains safe and can be maintained in hypertensive patients presenting with COVID-19.

Decongestant use and the risk of myocardial infarction and stroke: a case-crossover study.

Pharmacovigilance reports of cerebral and cardiovascular events in those who use decongestants have triggered alerts related to their use. We aimed to assess the risk of stroke and myocardial infarction (MI) associated with the use of decongestants. We conducted a nested case-crossover study of patients with incident stroke and MI identified in France between 2013 and 2016 in two systematic disease registries. Decongestant use in the three weeks preceding the event was assessed using a structured telephone interview. Conditional logistic multivariable models were used to estimate the odds of incident MI and stroke, also accounting for transient risk factors and comparing week 1 (index at-risk time window, immediately preceding the event) to week 3 (reference). Time-invariant risk factors were controlled by design. In total, 1394 patients with MI and 1403 patients with stroke, mainly 70 years old or younger, were interviewed, including 3.2% who used decongestants during the three weeks prior to the event (1.0% definite exposure in the index at-risk time window, 1.1% in the referent time window; adjusted odds ratio (aOR), 0.78; 95%CI, 0.43-1.42). Secondary analysis yielded similar results for individual events (MI/stroke). We observed no increased risk of MI or stroke for patients 70 years of age and younger without previous MI or stroke who used decongestants.

Eculizumab as an emergency treatment for adult patients with severe COVID-19 in the intensive care unit: A proof-of-concept study.

BACKGROUND: Complement pathway inhibition may provide benefit for severe acute respiratory illnesses caused by viral infections such as COVID-19. We present results from a nonrandomized proof-of-concept study of complement C5 inhibitor eculizumab for treatment of severe COVID-19. METHODS: All patients (N = 80) with confirmed SARS-CoV-2 infection and severe COVID-19 admitted to our intensive care unit between March 10 and May 5, 2020 were included. Forty-five patients were treated with standard care and 35 with standard care plus eculizumab through expanded-access emergency treatment. The prespecified primary outcome was day-15 survival. Clinical laboratory values and biomarkers, complement levels, and treatment-emergent serious adverse events (TESAEs) were also assessed. FINDINGS: At day 15, estimated survival was 82.9% (95% CI: 70.4%‒95.3%) with eculizumab and 62.2% (48.1%‒76.4%) without eculizumab (log-rank test, P = 0.04). Patients treated with eculizumab experienced a significantly more rapid decrease in lactate, blood urea nitrogen, total and conjugated bilirubin levels and a significantly more rapid increase in platelet count, prothrombin time, and in the ratio of arterial oxygen tension over fraction of inspired oxygen versus patients treated without eculizumab. Eculizumab-associated changes in complement levels, laboratory values, and biomarkers were consistent with terminal complement inhibition, reduced hypoxia, and decreased inflammation. TESAEs of special interest occurring in >5% of patients treated with/without eculizumab were ventilator-associated pneumonia (51%/24%), bacteremia (11%/2%), gastroduodenal hemorrhage (14%/16%), and hemolysis (3%/18%). INTERPRETATION: Findings from this proof-of-concept study suggest eculizumab may improve survival and reduce hypoxia in patients with severe COVID-19. Randomized studies evaluating the efficacy and safety of this treatment approach are needed. FUNDING: Programme d'Investissements d'Avenir: ANR-18-RHUS60004.

The systematic case-referent method.

The systematic case-referent method is a special case-referent design originally developed for pharmacoepidemiologic research purposes. It consists in the systematic collection of series of incident cases of various disorders and the assembling of a general reference pool, from which "controls" are secondarily selected to be matched to specific cases. Both series are collected independently from each other and with no a priori hypothesis to be investigated. The reference pool can be either general or limited to a subpopulation, representative of the source population of the cases. Based on clinical recruitment of cases and referents, the design allows a very high specificity of diagnosis and documentation of clinical variables. All cases and referents are systematically documented on all treatments received before the incidence of the cases or before identification of referents. This documentation is done preferentially using objective sources assembled independently (linkage to claims data, medical records, pharmacy records, prescription records, hospital discharge letters). It can be completed with patients' interviews using standardised research tools, in particular for over-the-counter drug use and self-medication, and for the documentation of adherence to treatment and specific time-windows of exposure. Likewise, all cases and all referents are systematically documented on a series of risk factors, which are common to most epidemiological studies and are not hypothesis-dependent. Whenever the documentation of a confounding factor specific to the disease at hand is necessary, additional questionnaires can be applied to all or a sample of patients. The method has been successfully implemented for the pharmacoepidemiologic study of myocardial infarction, stroke, lupus, multiple sclerosis, rheumatoid arthritis, Guillain Barré syndrome, idiopathic thrombocytopenic purpura, type 1 diabetes mellitus, suicide attempts, breast cancer, and other disorders, for the analysis of the risk or preventing action of NSAIDs, statins, antiplatelet agents, anticoagulants, insulins, vaccines and other drugs.

Clinical and economic burden of severe asthma: A French cohort study.

OBJECTIVE: To describe the clinical and economic burden of severe asthma in France over 12 months. METHODS: Data were retrieved from the observational, prospective "Cohorte Obstruction Bronchique et Asthme" (COBRA) cohort, which has enrolled nearly 1000 asthma patients since 2007 from throughout France. Patients undergoing treatment with GINA step-4 or 5 medications uninterruptedly for 12 months (thus defining "severe asthma") were identified and their clinical data used to describe the clinical burden of asthma (exacerbations, symptoms outside exacerbations, and level of asthma control). Patients' utilization of healthcare resources was described and used to estimate the direct medical costs incurred to treat severe asthma. RESULTS: 155 patients were included in the present study. Over the 12-month period of interest, 128 (83%) patients experienced at least one asthma exacerbation, 22 (14%) patients were hospitalized for asthma, 133 (86%) patients experienced continuous symptoms outside exacerbations, and 77 (50%) patients experienced important limitations in daily life activities. The median number of asthma-related drugs used was 4. The mean estimated annual asthma-related cost was 8,222 euros (standard deviation, SD = 11,886), including 7,229 euros (SD = 11,703) for controller medications. CONCLUSION: Symptoms outside exacerbation periods are highly prevalent in severe asthma patients, for whom the main driver of medical costs is controller medication.

Dronedarone, amiodarone and other antiarrhythmic drugs, and acute liver injuries: a case-referent study.

BACKGROUND: Spontaneous reports of acute liver injuries (ALI) in patients taking dronedarone triggered an EMA alert in 2011. This study aimed to assess the risk of ALI for class III antiarrhythmic drugs controlling for the use of other potential ALI-inducing drugs. METHODS: Between 2010 and 2014, consecutive ALI cases (≥50 years-old) were identified across Germany. ALI was defined as a new increase in at least one of the transaminases ≥3 times the upper limit of normal (ULN) or ≥2 ULN if alkaline phosphatase, with ("definite" case) or without ("biochemical" case) suggestive signs/symptoms of ALI, excluding other liver diseases. Recruited community controls were matched to cases on gender, age and inclusion date. Exposure to antiarrhythmic drugs and co-medication up to 2 years before ALI onset was informed by patients and confirmed by physicians' prescriptions. Adjusted Odds Ratios (aOR) were obtained from conditional multivariable logistic regressions, adjusted for a multivariate disease risk score and co-medication. RESULTS: 252 cases and 1081 matched controls were included (59.1% females; mean age: 64 years). Exposure to class III antiarrhythmic drugs was 4.0% in cases and 1.5% in controls, aOR = 3.6 (95% CI: 1.6-8.4). Associations with exposure to dronedarone and amiodarone were respectively 3.1 (95% CI: 0.7-14. 8) and 5.90 (1.7-20.0). Restricting the analysis to definite or severe ALI cases did not change these results. CONCLUSIONS: Class III antiarrhythmic drugs were associated with ALI, amiodarone displaying the highest risk, and results were robust to case definitions. Continued vigilance is needed for patients taking these drugs.

Effectiveness of new antiplatelets in the prevention of recurrent myocardial infarction.

OBJECTIVE: To compare ticagrelor and prasugrel with clopidogrel for recurrent fatal and non-fatal myocardial infarction (reMI) in real-life conditions. METHODS: Case-referent study using the Pharmacoepidemiological General Research eXtension (PGRx)-acute coronary syndrome (ACS) registry. Cases were patients with reMI from a cohort with index ACS or external to the cohort (same sites). Referents from the cohort, without recurrent event, were matched on index ACS type and date, age and sex with reMI cases. Multivariate conditional logistic regression assessed the OR (95% CI) for reMI associated with ticagrelor and prasugrel vs clopidogrel, adjusted for aspirin use and cardiovascular risk factors. RESULTS: 1047 cases and 2234 matched referents were included. Compared with clopidogrel, ticagrelor and prasugrel were associated with respective ORs of 0.65 (95% CI 0.52 to 0.81) and 0.71 (95% CI 0.53 to 0.96) for reMI occurrence. ORs for ticagrelor and prasugrel vs clopidogrel were: 0.50 (95% CI 0.38 to 0.67) and 0.66 (95% CI 0.45 to 0.95), 0.39 (95% CI 0.24 to 0.62) and 0.44 (95% CI 0.26 to 0.75), 0.63 (95% CI 0.43 to 0.92) and 1.20 (95% CI 0.69 to 2.07), 1.11 (95% CI 0.72 to 1.72) and 0.82 (95% CI 0.44 to 1.54) when index ACS was a first MI, a first ST-elevated MI (STEMI), a first non-STEMI and a recurrent ACS, respectively, and 0.63 (95% CI 0.45 to 0.87) and 0.77 (95% CI 0.41 to 1.45) for patients aged ≥70 years. CONCLUSIONS: This real-world study showed a significant reduction of reMI with new antiplatelets compared with clopidogrel, ticagrelor being associated with a greater decrease of risk notably for first, either STEMI or non-STEMI. The larger magnitude of effect may be attributed to potential residual confounding or higher effectiveness compared with efficacy reported in trials (EMA Post Authorisation Study Registry Number EUPAS5905).

Correlates and predictors of antipsychotic drug polypharmacy in real-life settings: Results from a nationwide cohort study.

Reasons for using antipsychotic polypharmacy (APP) in routine clinical practice, despite a potentially unfavorable risk-benefit ratio, are poorly understood. This research aimed to determine (1) if severe courses of schizophrenia were associated with APP and (2) if a schizophrenia-related acute event would predict a switch to APP in the short term. Observational prospective data (at baseline and 6months) were drawn from a French nationwide cohort ("Cohorte Générale Schizophrénie"), which included 1859 inpatients and outpatients with schizophrenia. APP was defined as the prescription of ≥2 antipsychotic drugs (there being different active substances). Early-onset schizophrenia, legal guardianship, higher lifetime maximal severity of illness and comorbid antisocial personality were used as proxies for severe courses of schizophrenia. Schizophrenia-related acute events included hospitalization and recent suicide attempts. Logistic regression models were used to determine (1) whether the use of APP at baseline (vs. monotherapy) was associated with a severe course of schizophrenia or not, independent of acute events, and (2) if a switch to APP at 6months (vs. remaining on monotherapy) was associated with acute events, independent of severe courses of schizophrenia. Increased odds of APP use at baseline were independently associated with legal guardianship (OR=1.6; 95%CI=1.3, 2.0) and higher lifetime maximum severity of illness (OR=1.3; 95%CI=1.2, 1.5). A switch to APP at 6months was predicted by a hospitalization occurring since baseline (OR=6.1; 95%CI=3.9, 9.4). In routine clinical practice, APP is more likely prescribed to patients with severe courses of illness, possibly indicating the difficulty to manage these patients.

Effect of an Institutional Medication Adherence Program for Long-Acting Injectable Risperidone on Adherence and Psychiatric Hospitalizations: Evidence from a Prospective Cohort Study.

BACKGROUND: Long-acting injectable (LAI) atypical antipsychotics are associated with improved adherence and reduced relapse rates in schizophrenia but reminder-based interventions may further improve outcomes. OBJECTIVES: To assess an institutional medication adherence program's (IMAP) effectiveness on adherence and psychiatric hospitalizations among schizophrenia patients taking risperidone LAI (RLAI). METHODS: Between 2009 and 2010, we recruited patients meeting DSM-IV criteria for schizophrenia treated with RLAI receiving outpatient care from psychiatric centres in France. The IMAP consisted of calling patients 48 hours prior to their scheduled RLAI injections and within 3 days of a missed appointment. Centres applying the IMAP to ≥50% of scheduled patient injections were deemed compliant. Patients were followed up to one year for adherence (≥80% of scheduled RLAI injections received within 5 days of the scheduled date) and psychiatric hospitalizations. RESULTS: Among 506 patients recruited from 36 centres, the hospitalization rate was 32.5 per 100 person-years. 15 centres treating 243 patients were IMAP compliant and 21 centres treating 263 patients were not. IMAP compliance was associated with lower psychiatric hospitalization rates (crude RR: 0.64 [95% CI: 0.44-0.93]; adjusted RR: 0.78 [95% CI: 0.47-1.27]). Nearly 75% of patients were adherent to RLAI. While patient adherence had little impact on hospitalization rates (adjusted RR: 0.92 [95% CI: 0.59-1.44]), IMAP compliance was more effective among non-adherent (adjusted RR: 0.45 [95% CI: 0.16-1.28]) than adherent (adjusted RR: 0.88 [95% CI: 0.51-1.53]) patients. CONCLUSIONS: IMAPs may improve patient adherence and reduce psychiatric hospitalizations, particularly among patients with difficulties adhering to LAI antipsychotics.

Risk of autoimmune diseases and human papilloma virus (HPV) vaccines: Six years of case-referent surveillance.

BACKGROUND: Safety of HPV vaccines is still in question due to reports of autoimmune diseases (ADs) following HPV immunization. OBJECTIVES: To assess the risk of ADs associated with HPV vaccination of female adolescents/young adults in France. METHODS: Systematic prospective case-referent study conducted to assess the risks associated with real-life use of HPV vaccines. Cases were female 11-25 years old with incident ADs [central demyelination/multiple sclerosis (CD/MS), connective tissue disease (CTD), Guillain-Barré syndrome (GBS), type-1 diabetes (T1D), autoimmune thyroiditis (AT), and idiopathic thrombocytopenic purpura (ITP)]. Cases were consecutively and prospectively identified at specialized centers across France (2008-2014) and individually matched by age and place of residence to referents recruited in general practice. Risk was computed using multivariate conditional logistic regression models adjusted for family history of ADs, living in France (north/south), co-medications and co-vaccinations. RESULTS: With a total of 478 definite cases matched to 1869 referents, all ADs combined were negatively associated to HPV vaccination with an adjusted odds ratio of 0.58 (95% confidence interval: 0.41-0.83). Similar results were obtained for CD/MS, AT, CT, and T1D, the last two not reaching statistical significance. No association was found for ITP and GBS. Sensitivity analyses combining definite and possible cases with secondary time window showed similar results. CONCLUSION: Exposure to HPV vaccines was not associated with an increased risk of ADs within the time period studied. Results were robust to case definitions and time windows of exposure. Continued active surveillance is needed to confirm this finding for individual ADs.

Antiepileptic drugs and risk of suicide attempts: a case-control study exploring the impact of underlying medical conditions.

PURPOSE: Randomized-controlled trials and claims databases suggest that antiepileptic drug (AED) use may increase the risk of suicide attempts (SA). The present case-control study explores the impact of underlying indications on this potential association. METHODS: Physicians collected the medical history; prior 12-month drug use was obtained from standardized telephone interviews with patients. The association between AED use and SA was explored using multivariate conditional logistic regression. The analyses were replicated after stratification on depression and neurological disorders (epilepsy, migraine, and chronic neuropathic pain). RESULTS: Between 2008 and 2012, 506 adults with an incident SA were recruited in suicide treatment centers from across France and socio-demographically matched to 2829 controls from primary care settings. The association between AED use and odds of SA was not significant overall (odds ratio [OR], 1.5; 95% confidence interval [CI], 0.9-2.4). No association was observed for patients with neurological disorders (OR, 1.1; 95%CI, 0.5-2.4) as opposed to patients with depression (OR, 1.6; 95%CI, 1.0-2.5), but unmeasured confounding was suspected. CONCLUSIONS: Our results suggest that the association observed between AED use and increased odds of non-fatal SA in patients with either a lifetime history of depression or no neurological disorder may be explained by the presence of an underlying psychiatric disorder. Accounting for underlying indications is crucial in drug safety studies, as these can cause a reported association (or lack thereof) to be misleading. This may require the prospective collection of medical data at a patient level. Copyright © 2017 John Wiley & Sons, Ltd.

Childhood immune thrombocytopenia: A nationwide cohort study on condition management and outcomes.

OBJECTIVES: Nationwide prospective cohort study exploring (i) the factors associated with treatment initiation (vs. watchful waiting) in children with primary immune thrombocytopenia (ITP) followed in routine clinical practice and (ii) the predictors of chronicity at 12 months. PROCEDURE: Between 2008 and 2013, 23 centers throughout France consecutively included 257 children aged 6 months-18 years and diagnosed with primary ITP over a 5-year period. Data on ITP clinical features along with medical management were collected at baseline and 12 months. Multivariate logistic regressions were used to determine (i) and (ii) as defined above, providing odds ratio (OR) with 95% confidence interval (95% CI). RESULTS: One hundred thirty-seven (53%) children were males, median age was 4.6 years, median platelet count was 7 × 109/l, and 214 (81%) patients initiated medication. Factors independently associated with treatment initiation included platelet counts <10 × 109/l (P < 0.0001) and mucocutaneous bleeding symptoms at baseline (P < 0.001). At 12 months, data were available for 211 (82%) children, of whom 160 (74%) had recovered. Predictors of chronicity included female gender (OR = 2.2; 95% CI = 1.0-4.8), age ≥10 years (OR = 2.6; 95% CI = 1.1-6.0), and platelet counts ≥10 × 109 /l (OR = 3.2; 95% CI = 1.5-6.9). CONCLUSIONS: In routine clinical practice, the decision to apply a watchful waiting strategy seems to be driven by platelet counts even in the absence of bleeding symptoms, resulting in treatment being initiated in more than 80% of the children surveyed. Overall, younger children with ITP showed good prognosis, with lower platelet counts and, to a lesser extent, male gender predicting more favorable outcomes.

Model-observational bridging study on the effectiveness of ezetimibe on cardiovascular morbidity and mortality in France: A population-based study.

BACKGROUND: To evaluate the real-life impact of ezetimibe on cardiovascular (CV) morbidity and mortality in France. OBJECTIVE: To estimate the number of non-fatal and fatal CV events that could be prevented and corresponding number of patients needed to treat (NNT) with ezetimibe to prevent one CV event over 5 years. METHODS: Non-interventional 48-month follow-up cohort conducted in hypercholesterolemic patients starting on ezetimibe <3 months at study entry, either as monotherapy or combined with statins. Prediction modeling using discrete event simulation with calibrated Framingham CV risk equations was applied to data from pivotal clinical trials on ezetimibe and real-life data derived from the cohort. RESULTS: A total of 3215 patients in the cohort accumulated 9314 person-years of follow-up for an average of 2.9 years. Mean age was 61.5 (standard deviation [SD] = 10.7), 54.6% were males, and 27.0% had a history of CV disease. Baseline LDL-cholesterol averaged 4.1 mmol/L (159 mg/dL; SD = 1.0) and HDL-C 1.6 mmol/L (62 mg/dL; SD = 0.5). LDL-C decreased in the first 12 months in ezetimibe-LLT (lipid-lowering therapy) initiators, switchers (monotherapy), and combination therapy with a statin by respectively 21.3%, 6.4%, and 29.1%. The corresponding predicted rate reductions of CV events (non-fatal and fatal) compared to no treatment or to a statin (combination therapy) were respectively 8, 2, and 12 per 1000 patients treated over 5 years, with a global NNT of 143 patients over 5 years. CONCLUSION: These results, accounting for observed CV event rates, risk factors evolution over time and adherence to treatment in real life, were consistent with those from clinical trials.