Dedicated mobile application for drug adverse reaction reporting by patients with relapsing remitting multiple sclerosis (Vigip-SEP study): study protocol for a randomized controlled trial

BackgroundThe reporting of adverse drug reactions (ADR) by patients represents an interesting challenge in the field of pharmacovigilance, but the reporting system is not adequately implemented in France. In 2015, only 20 MS patients in France reported ADR due to first-line disease-modifying drugs (DMD), while more than 3000 patients were initiated on DMD.The aim of this study is to validate a proof-of-concept as to whether the use of a mobile application (App) increases ADR reporting among patients with relapsing-remitting multiple sclerosis (RR-MS) receiving DMD.Methods/designWe designed a multi-centric, open cluster-randomized controlled trial, called the Vigip-SEP study (NCT03029897), using the App My eReport France® to report ADR to the appropriate authorities in E2B language, in accordance with European regulations. RR-MS patients who were initiated on, or switched, first-line DMD will be included. In the experimental arm, a neurologist will introduce the patient to the App to report ADR to the appropriate French authorities. In the control arm, the patient will be informed of the existence of the App but will not be introduced to its use and will then report ADR according to the usual reporting procedures. Primary assessment criteria are defined as the average number of ADR per patient and per center. We assume that the App will increase patient reporting by 10-fold. Therefore, we will require 24 centers (12 per arm: 6 MS academic expert centers, 3 general hospitals, 3 private practice neurologists), allowing for an expected enrollment of 180 patients (alpha risk 5%, power 90% and standard deviation 4%).DiscussionIncreasing patient reporting of ADR in a real-life setting is extremely important for therapeutic management of RR-MS, particularly for monitoring newly approved DMD to gain better knowledge of their safety profiles. To increase patient involvement, teaching patients to use tools, such as mobile applications, should be encouraged, and these tools should be tested rigorously

Elevated Stress-Hemoconcentration in Major Depression Is Normalized by Antidepressant Treatment: Secondary Analysis from a Randomized, Double-Blind Clinical Trial and Relevance to Cardiovascular Disease Risk

Major depressive disorder (MDD) is an independent risk factor for cardiovascular disease (CVD); the presence of MDD symptoms in patients with CVD is associated with a higher incidence of cardiac complications following acute myocardial infarction (MI). Stress-hemoconcentration, a result of psychological stress that might be a risk factor for the pathogenesis of CVD, has been studied in stress-challenge paradigms but has not been systematically studied in MDD.Secondary analysis of stress hemoconcentration was performed on data from controls and subjects with mild to moderate MDD participating in an ongoing pharmacogenetic study of antidepressant treatment response to desipramine or fluoxetine. Hematologic and hemorheologic measures of stress-hemoconcentration included blood cell counts, hematocrit, hemoglobin, total serum protein, and albumin, and whole blood viscosity.Subjects with mild to moderate MDD had significantly increased hemorheologic measures of stress-hemoconcentration and blood viscosity when compared to controls; these measures were correlated with depression severity. Measures of stress-hemoconcentration improved significantly after 8 weeks of antidepressant treatment. Improvements in white blood cell count, red blood cell measures and plasma volume were correlated with decreased severity of depression.Our secondary data analyses support that stress-hemoconcentration, possibly caused by decrements in plasma volume during psychological stress, is present in Mexican-American subjects with mild to moderate MDD at non-challenged baseline conditions. We also found that after antidepressant treatment hemorheologic measures of stress-hemoconcentration are improved and are correlated with improvement of depressive symptoms. These findings suggest that antidepressant treatment may have a positive impact in CVD by ameliorating increased blood viscosity. Physicians should be aware of the potential impact of measures of hemoconcentration and consider the implications for cardiovascular risk in depressed patients

Impact of EU regulatory label changes for diclofenac in people with cardiovascular disease in four countries:interrupted time series regression analysis

Objective: Due to cardiovascular safety concerns, the European Medicines Agency (EMA) recommended new contraindications and changes to product information for diclofenac across Europe in 2013. This study aims to measure their impact among targeted populations. Method: Quarterly interrupted time series regression (ITS) analyses of diclofenac initiation among cohorts with contraindications (congestive cardiac failure [CHF], ischaemic heart disease [IHD], peripheral arterial disease [PAD], cerebrovascular disease [CVD]) and cautions (hypertension, hyperlipidaemia, diabetes) from Denmark, the Netherlands, England and Scotland. Results: The regulatory action was associated with significant immediate absolute reductions in diclofenac initiation in all countries for IHD (Denmark −0.08%, 95%CI −0.13, −0.03; England −0.09%, 95%CI −0.13 to −0.06%; the Netherlands −1.84%, 95%CI −2.51 to −1.17%; Scotland −0.34%, 95%CI −0.38 to −0.30%), PAD and hyperlipidaemia, the Netherlands, England and Scotland for hypertension and diabetes, and England and Scotland for CHF and CVD. Post-intervention there was a significant negative trend in diclofenac initiation in the Netherlands for IHD (−0.12%, 95%CI −0.19 to −0.04), PAD (−0.13%, 95%CI −0.22 to −0.05), hypertension, hyperlipidaemia and diabetes, and in Scotland for CHF (−0.01%, 95%CI −0.02 to −0.007%), IHD (−0.017, 95%CI −0.02, −0.01%), PAD and hypertension. In England, diclofenac initiation rates fell less steeply. In Denmark changes were more strongly associated with the earlier EMA 2012 regulatory action. Conclusion: Although significant reductions in diclofenac initiation occurred, patients with contraindications continued to be prescribed diclofenac, the extent of which varied by country and target condition. Understanding reasons for such variation may help to guide the design or dissemination of future safety warnings

Analysis of spontaneous reports of thromboembolic adverse drug reactions associated with cyproterone/ethinylestradiol

Introduction: After media attention on thromboembolic adverse drug reactions (ADRs) and the use of cyproterone/ethinylestradiol [1], the Netherlands Pharmacovigilance Centre Lareb received a high number of reports about this association, which called for a more detailed analyses. Aim: To provide an overview of the characteristics of all reports of thromboembolic ADRs associated with the use of cyproterone/ethinylestradiol submitted to Lareb until April 3rd 2013 focusing on character, circumstances, off-label use and degree of recognition of the ADRs. Methods: Reports were selected from the Lareb database based on ATCcode G03HB01 using an MS Access- query. Lareb analysed the reporter type, seriousness of the reaction according to the CIOMS criteria, patient's age at the occurrence of the ADR, patient's BMI (kg/m2), indication, ADRs classified as arterial thrombosis (including MedDRA- Preferred Terms like myocardial infarction, transient ischemic attack), venous thrombosis, pulmonary embolism or unspecified thrombosis, latency period, outcome of the reaction, treatment of the ADR, delay between the first symptoms and diagnosis of the ADR, presence of risk factors including smoking and Factor-V-Leiden deficiency. Results: On April 3, 2013 Lareb had received a total of 621 reports about cyproterone/ethinylestradiol, including 309 reports of thromboembolic ADRs which were further analysed. Reported ADRs consisted of arterial thrombosis (N = 52), venous thrombosis (N = 40), pulmonary embolism (N = 155) and thrombosis with an unspecified location (N = 128). A total of 299 reports of thromboembolic ADRs were classified as serious, including 18 cases with a fatal outcome. Patient's mean age was 30.5 years and mean BMI was 24.3 kg/m2. The primary indications for use were acne (N = 147), oral contraceptive (N = 122), hirsutism (N = 10), other (N = 15) or the indication was unknown (N = 15). Of the 309 patients with a thromboembolic ADR, 261 were known to have been treated with anticoagulant drugs. In 31 cases the thromboembolic ADR was initially not recognized as such by either the patient or their healthcare professional. The median time to onset was 2-3 years, however many patients reported a longer latency period. There was no distinction between the time of onset in respect to the reported ADR. No differences in risk factors seem to exist between labeled and off-label indications. In 291 out of 309 reports, the reporter was a consumer. Conclusions: The reported thromboembolic ADRs are a known risk related to the use of cyproterone/ethinylestradiol, but may be misdiagnosed initially. From the reports that Lareb received it is evident that t offlabel use is frequent

The role of co-morbidities in the development of an AEFI after COVID-19 vaccination in a large prospective cohort with patient-reported outcomes in the Netherlands

Background: The effect of a preexisting comorbidity on the occurrence of adverse events after immunization (AEFIs) has been studied poorly. In this longitudinal cohort study, we assess the association between co-morbidities and the occurrence of AEFIs after COVID-19 vaccination. Also, we described the occurrence of flare-ups and their manifestation after COVID-19 vaccination in people with rheumatic diseases. Research design and methods: We performed multivariable logistic regression to investigate the association between the occurrence of AEFIs and 10 common comorbidities using patient-reported data from people vaccinated with the AstraZeneca, Johnson&amp;Johnson, Moderna, or Pfizer vaccine. Results: Occurrence of any AEFI, injection site reactions, headache, fatigue, and/or malaise was significantly associated with presence of comorbidities, including psychological disorders, musculoskeletal disorders, and endocrine disorders after the first and second doses (OR ranges 1.23–1.77). One participant with rheumatoid arthritis experienced a flare-up after receiving the first dose of the AstraZeneca vaccine. Discussion/conclusion: The results showed that the odds of reporting an AEFI after COVID-19 vaccination is significantly higher in the presence of some comorbidities whilst flare-ups are uncommon after receiving COVID-19 vaccination in people with rheumatic disease. In-depth research is needed to validate our results and unravel the observed associations from a mechanistic perspective.</p