The value of time-to-onset in statistical signal detection of adverse drug reactions:a comparison with disproportionality analysis in spontaneous reports from the Netherlands

PURPOSE: In pharmacovigilance, the commonly used disproportionality analysis (DPA) in statistical signal detection is known to have its limitations. The aim of this study was to investigate the value of the time to onset (TTO) of ADRs in addition to DPA.METHODS: We performed a pilot study using individual case safety reports (ICSRs) for three drugs (Cervarix®, nitrofurantoin and simvastatin) from the Lareb spontaneous reporting database. TTO distributions for drug - ADR associations were compared to other ADRs for the same drug and to other drugs for the same ADR using two-sample Anderson-Darling testing. Statistically significant associations were considered true positive (TP) signals if the association was present in the official product information of the drug. Sensitivity and specificity for the TTO method were compared with the DPA method. As a measure of disproportionality, the reporting odds ratio (ROR) was used.RESULTS: In general, sensitivity was lower, and specificity was higher for the TTO method compared to DPA. The TTO method showed similar sensitivity for all three drugs, whereas specificity was lower for Cervarix®. Eight additional TP signals were found using the TTO method compared to DPA.CONCLUSIONS: Our study shows that statistical signal detection based on the TTO alone resulted in a limited number of additional signals compared to DPA. We therefore conclude that the TTO method is of limited value for full database statistical screening in our setting. Copyright © 2016 John Wiley &amp; Sons, Ltd.</p

Time to onset in statistical signal detection revisited:A follow-up study in long-term onset adverse drug reactions

PURPOSE: In a previous study, we developed a signal detection method using the time to onset (TTO) of adverse drug reactions (ADRs). The aim of the current study was to investigate this method in a subset of ADRs with a longer TTO and to compare its performance with disproportionality analysis. METHODS: Using The Netherlands's spontaneous reporting database, TTO distributions for drug-ADR associations with a median TTO of 7 days or more were compared with other drugs with the same ADR using the two-sample Anderson-Darling (AD) test. Presence in the Summary of Product Characteristics (SPC) was used as the gold standard for identification of a true ADR. Twelve combinations with different values for the number of reports and median TTO were tested. Performance in terms of sensitivity and positive predictive value (PPV) was compared with disproportionality analysis. A sensitivity analysis was performed to compare the results with those from the previous study. RESULTS: A total of 38 017 case reports, containing 32 478 unique drug-ADR associations. Sensitivity was lower for the TTO method (range 0.08-0.34) compared with disproportionality analysis (range 0.60-0.87), whereas PPV was similar for both methods (range 0.93-1.0). The results from the sensitivity analysis were similar to the original analysis. CONCLUSIONS: Because of its low sensitivity, the developed TTO method cannot replace disproportionality analysis as a signal detection tool. It may be useful in combination with other methods

Inclusion of Safety-Related Issues in Economic Evaluations for Seasonal Influenza Vaccines:A Systematic Review

(1) Background: Vaccines for seasonal influenza are a good preventive and cost-effective strategy. However, it is unknown if and how these economic evaluations include the adverse events following immunization (AEFI), and what the impact of such inclusion is on the health economic outcomes. (2) Methods: We searched the literature, up to January 2020, to identify economic evaluations of seasonal influenza vaccines that considered AEFIs. The review protocol was published in PROSPERO (CDR42017058523). (3) Results: A total of 52 economic evaluations considered AEFI-related parameters in their analyses, reflecting 16% of the economic evaluations on seasonal influenza vaccines in the initial study selection. Most studies used the societal perspective (64%) and evaluated vaccination of children (37%). Where considered, studies included direct medical costs of AEFIs (90%), indirect costs (27%), and disutilities/quality-adjusted life years loss due to AEFIs (37%). The majority of these studies accounted for the effects of the costs of AEFI on cost-effectiveness for Guillain–Barré syndrome. In those papers allowing cost share estimation, direct medical cost of AFEIs was less than 2% of total direct costs. (4) Conclusions: Although the overall impact of AEFIs on the cost-effectiveness outcomes was found to be low, we urge their inclusion in economic evaluations of seasonal influenza vaccines to reflect comprehensive reports for the decision makers and end-users of the vaccination strategies

Retroperitoneal fibrosis and β-blocking agents:Is there an association?

AIM: Retroperitoneal fibrosis (RPF) is a rare chronic fibro-inflammatory disorder which may be secondary to certain drugs, including beta-blocking agents (BBAs). However, their causative role is unclear. We aimed to investigate this association. METHODS: Disproportionality analysis was carried out on cases from 1985 to October 4, 2020 in VigiBase®, the WHO pharmacovigilance database. The Bayesian-based IC025 metric and reporting odds ratio were used in order to assess the adverse event signal. We also analysed all published case reports from the literature regarding BBA-associated RPF to assess the value of suggested supportive clinical evidence. RESULTS: 1.599 individual case safety reports (ICSRs) of RPF were reported to VigiBase®, of which 132 (32%) concerned 16 different single BBA. For 12 of these agents (75%), reporting of RPF was disproportionate, indicating a potential safety signal. Line listing analysis of ICSRs showed no consistent time interval from start of BBA to RPF diagnosis (range 0,7-264 mo). Dechallenge was negative or unknown in the majority of cases (74%). In 18 published cases from the literature, time from start of BBA to RPF diagnosis varied widely (range 3-156 mo). BBA were discontinued 6 mo before (n=1) or at the time of RPF diagnosis (n=17). Most patients (84%) also received RPF specific treatment. Follow-up (FU) duration was short (median 5 mo [range 1-24 mo]) and in most cases (83%) relevant FU data were lacking. CONCLUSION: Although disproportionality analysis indicated a potential safety signal for RPF associated with BBAs, clinical evidence did not support a cause and effect relationship

Economic evaluations of chronic obstructive pulmonary disease pharmacotherapy:how well are the real-world issues of medication adherence, comorbidities and adverse drug-reactions addressed?

INTRODUCTION: When estimating the cost-effectiveness or budget impact of chronic obstructive pulmonary disease (COPD) medication, it is common practice to use trial data for clinical inputs. However, such inputs do not always reflect the real-world situation. Previous reviews recognized the need for taking real-world data (medication adherence, comorbidity and adverse drug reactions [ADRs]) into account. Whether recent cost-effectiveness analyses of COPD medication implemented those recommendations is unknown. AREAS COVERED: The authors reviewed recent economic evaluations of COPD-maintenance treatments focusing on medication adherence, comorbidity and ADRs. EXPERT OPINION: In most registration trials of COPD treatment, strict inclusion and exclusion criteria are applied. During trials, patient monitoring is well controlled. As such, medication adherence is often higher than seen in less controlled, real-world environments with more heterogeneous characteristics. Additionally, safety data collected in trials may not be widely generalizable due to more comorbidity and polypharmacy in the real-world. Consequently, when merely relying on trial data, the impact of adherence, comorbidity and ADRs on the cost-effectiveness can be underestimated. To overcome these real-world data gaps, use of pragmatic trials and observational studies in addition to strictly controlled trial data is recommended. To catalyze implementation of these real-world issues, reporting checklists should be updated

Safe use of radiopharmaceuticals in patients with chronic kidney disease:A systematic review

BACKGROUND: Patients with chronic kidney disease (CKD) may need to have their radiopharmaceutical dosage adjusted to prevent adverse effects and poor outcomes, but there are few recommendations on radiopharmaceutical dosing for this group of patients. The aim of this study is to provide an overview of the available information on radiopharmaceutical dose recommendations for patients with CKD. METHODS: We performed a systematic literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We conducted a literature search in the MEDLINE (PubMed) and Embase databases and screened potentially relevant studies using inclusion and exclusion criteria. We independently assessed the included observational studies’ methodologies and extracted relevant data. RESULTS: Of the 5795 studies first identified, 34 were included in this systematic review. These studies described three radiopharmaceuticals: [(131)I]sodium iodine, [(18)F]fludeoxyglucose, and [(131)I]iobenguane. Twenty-nine studies (85.3%) reported data on patients with CKD stage 5, while only three studies mentioned CKD patients in other stages (8.8%). CONCLUSION: We found no consistent recommendations for radiopharmaceutical dosing in patients with CKD. Although some studies do mention dosing difficulties in patients with CKD, information is available for only a few radiopharmaceuticals, and recommendations are sometimes contradictory. Further research on radiopharmaceutical dosing in patients with CKD is needed to determine whether these patients require specific dosing, especially for therapeutic radiopharmaceuticals where a non-optimised dose may lead to an increased risk of toxicity for non-targeted organs. Including patients with CKD in studies and providing specific information about dosing in these patients should be a priority for the radiopharmaceutical community

Electronic Health Record-Triggered Research Infrastructure Combining Real-world Electronic Health Record Data and Patient-Reported Outcomes to Detect Benefits, Risks, and Impact of Medication:Development Study

BACKGROUND: Real-world data from electronic health records (EHRs) represent a wealth of information for studying the benefits and risks of medical treatment. However, they are limited in scope and should be complemented by information from the patient perspective. OBJECTIVE: The aim of this study is to develop an innovative research infrastructure that combines information from EHRs with patient experiences reported in questionnaires to monitor the risks and benefits of medical treatment. METHODS: We focused on the treatment of overactive bladder (OAB) in general practice as a use case. To develop the Benefit, Risk, and Impact of Medication Monitor (BRIMM) infrastructure, we first performed a requirement analysis. BRIMM’s starting point is routinely recorded general practice EHR data that are sent to the Dutch Nivel Primary Care Database weekly. Patients with OAB were flagged weekly on the basis of diagnoses and prescriptions. They were invited subsequently for participation by their general practitioner (GP), via a trusted third party. Patients received a series of questionnaires on disease status, pharmacological and nonpharmacological treatments, adverse drug reactions, drug adherence, and quality of life. The questionnaires and a dedicated feedback portal were developed in collaboration with a patient association for pelvic-related diseases, Bekkenbodem4All. Participating patients and GPs received feedback. An expert meeting was organized to assess the strengths, weaknesses, opportunities, and threats of the new research infrastructure. RESULTS: The BRIMM infrastructure was developed and implemented. In the Nivel Primary Care Database, 2933 patients with OAB from 27 general practices were flagged. GPs selected 1636 (55.78%) patients who were eligible for the study, of whom 295 (18.0% of eligible patients) completed the first questionnaire. A total of 288 (97.6%) patients consented to the linkage of their questionnaire data with their EHR data. According to experts, the strengths of the infrastructure were the linkage of patient-reported outcomes with EHR data, comparison of pharmacological and nonpharmacological treatments, flexibility of the infrastructure, and low registration burden for GPs. Methodological weaknesses, such as susceptibility to bias, patient selection, and low participation rates among GPs and patients, were seen as weaknesses and threats. Opportunities represent usefulness for policy makers and health professionals, conditional approval of medication, data linkage to other data sources, and feedback to patients. CONCLUSIONS: The BRIMM research infrastructure has the potential to assess the benefits and safety of (medical) treatment in real-life situations using a unique combination of EHRs and patient-reported outcomes. As patient involvement is an important aspect of the treatment process, generating knowledge from clinical and patient perspectives is valuable for health care providers, patients, and policy makers. The developed methodology can easily be applied to other treatments and health problems

Body weight gain in clozapine-treated patients:Is norclozapine the culprit?

The antipsychotic drug clozapine is associated with weight gain. The proposed mechanisms include blocking of serotonin (5-HT2a/2c ), dopamine (D2 ) and histamine (H1 ) receptors. Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2) to norclozapine, a metabolite with more 5-HT2c -receptor and less H1 blocking capacity. We hypothesized that norclozapine serum levels correlate with body mass index (BMI), waist circumference and other parameters of the metabolic syndrome. We performed a retrospective cross-sectional study in 39 patients (female n = 8 (20.5%), smokers n = 18 (46.2%), average age 45.8 ± 9.9 years) of a clozapine outpatient clinic in the Netherlands between 1 January 2017 and 1 July 2020. Norclozapine concentrations correlated with waist circumference (r = 0.354, P = .03) and hemoglobin A1c (HbA1c) (r = 0.34, P = .03). In smokers (smoking induces CYP1A2), norclozapine concentrations correlated with waist circumference (r = 0.723, P = .001), HbA1c (r = 0.49, P = .04) and BMI (r = 0.63, P = .004). Elucidating the relationship between norclozapine and adverse effects of clozapine use offers perspectives for interventions and treatment options

Anaphylactic Reaction to Tc-99m Macrosalb

A 49-year-old woman developed an anaphylactic reaction to Tc-99m macrosalb used for pulmonary scintigraphy. The patient received an intravenous injection of Tc-99m macrosalb 120 MBq, containing macroaggregates of human albumin 0.14 mg. Within 1 min she developed itching all over her body, an itching throat and dyspnoea. This was followed by urticaria and facial oedema. She was diagnosed with an anaphylactic shock. The patient received clemastine and prednisone, and fully recovered after release from the hospital. According to the Naranjo assessment algorithm, the relationship between the allergic reaction and the administration of Tc-99m macrosalb should be considered as 'probable'