Efficacy, safety, and tolerability of nivasorexant in adults with binge-eating disorder: A randomized, Phase II proof of concept trial.

OBJECTIVE: This Phase II, placebo-controlled, double-blind study investigated the efficacy, safety, and tolerability of nivasorexant in the treatment of adults with moderate to severe binge-eating disorder (BED). METHODS: Adults meeting the DSM-5 BED criteria were randomized 1:1 to placebo or nivasorexant (100 mg b.i.d.). The primary endpoint was the change from baseline to Week 12 in the number of binge eating (BE) days per week. Exploratory efficacy endpoints included cessation of BE in the last 4 weeks of treatment; and change from baseline to Week 12 in the number of BE episodes/week, the clinician global impression (CGI) of change, the Yale-Brown Obsessive-Compulsive Scale modified for BE, and the Hamilton rating scale for depression (HAMD-17). Key safety outcomes included treatment-emergent adverse events (TEAEs) and adverse events of special interest (i.e., somnolence and fatigue). RESULTS: Sixty-eight participants were randomized to each treatment arm. The change from baseline to Week 12 in the number of BE days/week was the same for placebo (least squares mean [LSM]: -2.93) and nivasorexant (LSM: -2.93), with no difference between the treatment groups (LSM difference = .000 [95% confidence interval (CI): -.69, .69], p = .9992). Furthermore, no differences between treatment groups were observed in the exploratory efficacy endpoints. Nivasorexant was well tolerated; the overall incidence of TEAEs was balanced between treatment groups, and the frequency of somnolence and fatigue in the nivasorexant group were similar to placebo. DISCUSSION: In this proof-of-concept study, 100 mg b.i.d. nivasorexant did not improve BE in adults with moderate to severe BED. PUBLIC SIGNIFICANCE: The results of this Phase II study indicate that nivasorexant was well tolerated in adults with BED, but did not improve binge eating behavior over placebo. Further research is needed to improve our understanding of the role of the orexin-1 receptor in BED.

Dementia incidence trend over 1992-2014 in the Netherlands: Analysis of primary care data.

BACKGROUND: Recent reports have suggested declining age-specific incidence rates of dementia in high-income countries over time. Improved education and cardiovascular health in early age have been suggested to be bringing about this effect. The aim of this study was to estimate the age-specific dementia incidence trend in primary care records from a large population in the Netherlands. METHODS AND FINDINGS: A dynamic cohort representative of the Dutch population was composed using primary care records from general practice registration networks (GPRNs) across the country. Data regarding dementia incidence were obtained using general-practitioner-recorded diagnosis of dementia within the electronic health records. Age-specific dementia incidence rates were calculated for all persons aged 60 y and over; negative binomial regression analysis was used to estimate the time trend. Nine out of eleven GPRNs provided data on more than 800,000 older people for the years 1992 to 2014, corresponding to over 4 million person-years and 23,186 incident dementia cases. The annual growth in dementia incidence rate was estimated to be 2.1% (95% CI 0.5% to 3.8%), and incidence rates were 1.08 (95% CI 1.04 to 1.13) times higher for women compared to men. Despite their relatively low numbers of person-years, the highest age groups contributed most to the increasing trend. There was no significant overall change in incidence rates since the start of a national dementia program in 2003 (-0.025; 95% CI -0.062 to 0.011). Increased awareness of dementia by patients and doctors in more recent years may have influenced dementia diagnosis by general practitioners in electronic health records, and needs to be taken into account when interpreting the data. CONCLUSIONS: Within the clinical records of a large, representative sample of the Dutch population, we found no evidence for a declining incidence trend of dementia in the Netherlands. This could indicate true stability in incidence rates, or a balance between increased detection and a true reduction. Irrespective of the exact rates and mechanisms underlying these findings, they illustrate that the burden of work for physicians and nurses in general practice associated with newly diagnosed dementia has not been subject to substantial change in the past two decades. Hence, with the ageing of Western societies, we still need to anticipate a dramatic absolute increase in dementia occurrence over the years to come.

Decision making in drug safety-a literature review of criteria used to prioritize newly detected safety issues.

PURPOSE: In drug safety, there is a lack of guidance on how prioritization of safety issues should be performed. The aim of this literature review is to provide an overview of criteria used for signal prioritization and of the associated decision support frameworks. METHODS: A search strategy was constructed to identify relevant articles in Medline/Embase databases from the period from 1 January 1995 to 31 August 2015. The prioritization criteria were extracted and classified in relevant categories. RESULTS: From an initial set of 63 articles, 11 were retained for full review. The articles mentioned 48 criteria used in the prioritization process, with a median of six criteria per study [range: 1-16]. More than half of the criteria (63%), referred to strength of evidence while 19% related to public health impact, 14% to general public and media attention and 4% to novelty of the drug event association. Fifteen criteria were tested for predictive value with 11 showing positive results, most of them from the strength of evidence category. Six decision-making frameworks are presented, which incorporate criteria from various categories. Five of these frameworks were tested against expert decisions or by other means, but only in one database each and for a limited set of products. CONCLUSIONS: There is a wide range of prioritization criteria described in the literature; however, few of them demonstrated predictive value. Many criteria with predictive value were related to strength of evidence category and to novelty. There were few attempts at integrating different criteria in decision support frameworks. Five of the frameworks were tested for validity and showed usefulness, while at least three are already in use for prioritization. Copyright © 2016 John Wiley & Sons, Ltd.

Risk of upper gastrointestinal bleeding from different drug combinations.

BACKGROUND & AIMS: Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin increases the risk of upper gastrointestinal bleeding (UGIB). Guidelines suggest avoiding certain drug combinations, yet little is known about the magnitude of their interactions. We estimated the risk of UGIB during concomitant use of nonselective (ns)NSAIDs, cyclooxygenase -2 selective inhibitors (COX-2 inhibitors), and low-dose aspirin with other drugs. METHODS: We performed a case series analysis of data from 114,835 patients with UGIB (930,888 person-years of follow-up) identified from 7 population-based health care databases (approximately 20 million subjects). Each patient served as his or her own control. Drug exposure was determined based on prescriptions of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin, alone and in combination with other drugs that affect the risk of UGIB. We measured relative risk (incidence rate ratio [IRR] during drug exposure vs nonexposure) and excess risk due to concomitant drug exposure (relative excess risk due to interaction [RERI]). RESULTS: Monotherapy with nsNSAIDs increased the risk of diagnosis of UGIB (IRR, 4.3) to a greater extent than monotherapy with COX-2 inhibitors (IRR, 2.9) or low-dose aspirin (IRR, 3.1). Combination therapy generally increased the risk of UGIB; concomitant nsNSAID and corticosteroid therapies increased the IRR to the greatest extent (12.8) and also produced the greatest excess risk (RERI, 5.5). Concomitant use of nsNSAIDs and aldosterone antagonists produced an IRR for UGIB of 11.0 (RERI, 4.5). Excess risk from concomitant use of nsNSAIDs with selective serotonin reuptake inhibitors (SSRIs) was 1.6, whereas that from use of COX-2 inhibitors with SSRIs was 1.9 and that for use of low-dose aspirin with SSRIs was 0.5. Excess risk of concomitant use of nsNSAIDs with anticoagulants was 2.4, of COX-2 inhibitors with anticoagulants was 0.1, and of low-dose aspirin with anticoagulants was 1.9. CONCLUSIONS: Based on a case series analysis, concomitant use of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin with SSRIs significantly increases the risk of UGIB. Concomitant use of nsNSAIDs or low-dose aspirin, but not COX-2 inhibitors, with corticosteroids, aldosterone antagonists, or anticoagulants produces significant excess risk of UGIB.

Increased risk of microscopic colitis with use of proton pump inhibitors and non-steroidal anti-inflammatory drugs.

OBJECTIVES: Microscopic colitis (MC) is characterized by chronic watery diarrhea. Recently, several drugs were reported to increase the risk of MC. However, studies lacked a clear exposure definition, did not address duration relationships, and did not take important biases into account. We estimated the risk of MC during drug use. METHODS: This is a population-based nested case-control study using a Dutch primary care database (1999-2013). Incident MC cases (aged ≥18 years) were matched to community-based and colonoscopy-negative controls on age, sex, and primary care practice. Drug use was assessed within 1 and 2 years before the index date. Adjusted odds ratios (OR) were calculated by conditional logistic regression. RESULTS: From the source population of 1,458,410 subjects, 218 cases were matched to 15,045 community controls and 475 colonoscopy-negative controls. Current use (≤3 months) of proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors, low-dose aspirin, angiotensin-converting enzyme (ACE) inhibitors and beta-blockers significantly increased the risk of MC compared with never use in community controls. Adjusted ORs ranged from 2.5 (95% confidence interval (CI): 1.5-4.2) for ACE inhibitors to 7.3 (95% CI: 4.5-12.1) for PPIs in the year prior to the index date. After accounting for diagnostic delay, only use of NSAIDs, PPIs, low-dose aspirin, and ACE inhibitors increased the risk of MC. Compared with colonoscopy controls, only use of PPIs (OR-adjusted 10.6; 1.8-64.2) and NSAIDs (OR-adjusted 5.6; 1.2-27.0) increased the risk of MC. CONCLUSIONS: NSAIDs and PPIs are associated with an increased risk of MC. The association of MC with use of the other drugs is probably explained by worsening of diarrhea/symptoms rather than increasing the risk of MC itself.

The role of electronic healthcare record databases in paediatric drug safety surveillance: a retrospective cohort study.

AIM: Electronic healthcare record (EHR)-based surveillance systems are increasingly being developed to support early detection of safety signals. It is unknown what the power of such a system is for surveillance among children and adolescents. In this paper we provide estimates of the number and classes of drugs, and incidence rates (IRs) of events, that can be monitored in children and adolescents (0-18 years). METHODS: Data were obtained from seven population-based EHR databases in Denmark, Italy, and the Netherlands during the period 1996-2010. We estimated the number of drugs for which specific adverse events can be monitored as a function of actual drug use, minimally detectable relative risk (RR) and IRs for 10 events. RESULTS: The population comprised 4 838 146 individuals (25 575 132 person years (PYs)), who were prescribed 2170 drugs (1 610 631 PYs drug-exposure). Half of the total drug-exposure in PYs was covered by only 18 drugs (0.8%). For a relatively frequent event like upper gastrointestinal bleeding there were 39 drugs for which an association with a RR ≥4, if present, could be investigated. The corresponding number of drugs was eight for a rare event like anaphylactic shock. CONCLUSION: Drug use in children is rare and shows little variation. The number of drugs with enough exposure to detect rare adverse events in children and adolescents within an EHR-based surveillance system such as EU-ADR is limited. Use of additional sources of paediatric drug exposure information and global collaboration are imperative in order to optimize EHR data for paediatric safety surveillance.

Use of experimental medicine approaches for the development of novel psychiatric treatments based on orexin receptor modulation.

Despite progress in understanding the pathological mechanisms underlying psychiatric disorders, translation from animal models into clinical use remains a significant bottleneck. Preclinical studies have implicated the orexin neuropeptide system as a potential target for psychiatric disorders through its role in regulating emotional, cognitive, and behavioral processes. Clinical studies are investigating orexin modulation in addiction and mood disorders. Here we review performance-outcome measures (POMs) arising from experimental medicine research methods which may show promise as markers of efficacy of orexin receptor modulators in humans. POMs provide objective measures of brain function, complementing patient-reported or clinician-observed symptom evaluation, and aid the translation from preclinical to clinical research. Significant challenges include the development, validation, and operationalization of these measures. We suggest that collaborative networks comprising clinical practitioners, academics, individuals working in the pharmaceutical industry, drug regulators, patients, patient advocacy groups, and other relevant stakeholders may provide infrastructure to facilitate validation of experimental medicine approaches in translational research and in the implementation of these approaches in real-world clinical practice.

Using electronic health care records for drug safety signal detection: a comparative evaluation of statistical methods.

BACKGROUND: Drug safety monitoring relies primarily on spontaneous reporting, but electronic health care record databases offer a possible alternative for the detection of adverse drug reactions (ADRs). OBJECTIVES: To evaluate the relative performance of different statistical methods for detecting drug-adverse event associations in electronic health care record data representing potential ADRs. RESEARCH DESIGN: Data from 7 databases across 3 countries in Europe comprising over 20 million subjects were used to compute the relative risk estimates for drug-event pairs using 10 different methods, including those developed for spontaneous reporting systems, cohort methods such as the longitudinal gamma poisson shrinker, and case-based methods such as case-control. The newly developed method "longitudinal evaluation of observational profiles of adverse events related to drugs" (LEOPARD) was used to remove associations likely caused by protopathic bias. Data from the different databases were combined by pooling of data, and by meta-analysis for random effects. A reference standard of known ADRs and negative controls was created to evaluate the performance of the method. MEASURES: The area under the curve of the receiver operator characteristic curve was calculated for each method, both with and without LEOPARD filtering. RESULTS: The highest area under the curve (0.83) was achieved by the combination of either longitudinal gamma poisson shrinker or case-control with LEOPARD filtering, but the performance between methods differed little. LEOPARD increased the overall performance, but flagged several known ADRs as caused by protopathic bias. CONCLUSIONS: Combinations of methods demonstrate good performance in distinguishing known ADRs from negative controls, and we assume that these could also be used to detect new drug safety signals.

Electronic healthcare databases for active drug safety surveillance: is there enough leverage?

PURPOSE: To provide estimates of the number and types of drugs that can be monitored for safety surveillance using electronic healthcare databases. METHODS: Using data from eight European databases (administrative claims, medical records) and in the context of a cohort study, we determined the amount of drug exposure required for signal detection across varying magnitudes of relative risk (RR). We provide estimates of the number and types of drugs that can be monitored as a function of actual use, minimal detectable RR, and empirically derived incidence rates for the following adverse events: (i) acute myocardial infarction; (ii) acute renal failure; (iii) anaphylactic shock; (iv) bullous eruptions; (v) rhabdomyolysis; and (vi) upper gastrointestinal bleeding. We performed data simulation to see how expansion of database size would influence the capabilities of such system. RESULTS: Data from 1,947,452 individuals (59,594,132 person-years follow-up) who used 2,289 drugs in the EU-ADR network show that for a frequent event such as acute myocardial infarction, there are 531 drugs (23% of total) for which an association with RR = 2, if present, can be investigated. For a rare event such as rhabdomyolysis, there are 19 drugs (1%) for which an association of same magnitude can be investigated. CONCLUSION: Active surveillance using healthcare data-based networks for signal detection is feasible, although the leverage to do so may be low for infrequently used drugs and for rare outcomes. Extending database network size to include data from heterogeneous populations and increasing follow-up time are warranted to maximize leverage of these surveillance systems.

Connecting Cohorts to Diminish Alzheimer's Disease (CONCORD-AD): A Report of an International Research Collaboration Network.

Longitudinal observational cohort studies are being conducted worldwide to understand cognition, biomarkers, and the health of the aging population better. Cross-cohort comparisons and networks of registries in Alzheimer's disease (AD) foster scientific exchange, generate insights, and contribute to the evolving clinical science in AD. A scientific working group was convened with invited investigators from established cohort studies in AD, in order to form a research collaboration network as a resource to address important research questions. The Connecting Cohorts to Diminish Alzheimer's Disease (CONCORD-AD) collaboration network was created to bring together global resources and expertise, to generate insights and improve understanding of the natural history of AD, to inform design of clinical trials in all disease stages, and to plan for optimal patient access to disease-modifying therapies once they become available. The network brings together expertise and data insights from 7 cohorts across Australia, Europe, and North America. Notably, the network includes populations recruited through memory clinics as well as population-based cohorts, representing observations from individuals across the AD spectrum. This report aims to introduce the CONCORD-AD network, providing an overview of the cohorts involved, reporting the common assessments used, and describing the key characteristics of the cohort populations. Cohort study designs and baseline population characteristics are compared, and available cognitive, functional, and neuropsychiatric symptom data, as well as the frequency of biomarker assessments, are summarized. Finally, the challenges and opportunities of cross-cohort studies in AD are discussed.

Combining electronic healthcare databases in Europe to allow for large-scale drug safety monitoring: the EU-ADR Project.

PURPOSE: In this proof-of-concept paper we describe the framework, process, and preliminary results of combining data from European electronic healthcare record (EHR) databases for large-scale monitoring of drug safety. METHODS: Aggregated demographic, clinical, and prescription data from eight databases in four countries (Denmark, Italy, Netherlands, the UK) were pooled using a distributed network approach by generation of common input data followed by local aggregation through custom-built software, Jerboa(©). Comparison of incidence rates of upper gastrointestinal bleeding (UGIB) and nonsteroidal anti-inflammatory drug (NSAID) utilization patterns were used to evaluate data harmonization and quality across databases. The known association of NSAIDs and UGIB was employed to demonstrate sensitivity of the system by comparing incidence rate ratios (IRRs) of UGIB during NSAID use to UGIB during all other person-time. RESULTS: The study population for this analysis comprised 19,647,445 individuals corresponding to 59,929,690 person-years of follow-up. 39,967 incident cases of UGIB were identified during the study period. Crude incidence rates varied between 38.8 and 109.5/100,000 person-years, depending on country and type of database, while age-standardized rates ranged from 25.1 to 65.4/100,000 person-years. NSAID use patterns were similar for databases within the same country but heterogeneous among different countries. A statistically significant age- and gender-adjusted association between use of any NSAID and increased risk for UGIB was confirmed in all databases, IRR from 2.0 (95%CI:1.7-2.2) to 4.3 (95%CI: 4.1-4.5). CONCLUSIONS: Combining data from EHR databases of different countries to identify drug-adverse event associations is feasible and can set the stage for changing and enlarging the scale for drug safety monitoring.

EU-ADR healthcare database network vs. spontaneous reporting system database: preliminary comparison of signal detection.

The EU-ADR project aims to exploit different European electronic healthcare records (EHR) databases for drug safety signal detection. In this paper we report the preliminary results concerning the comparison of signal detection between EU-ADR network and two spontaneous reporting databases, the Food and Drug Administration and World Health Organization databases. EU-ADR data sources consist of eight databases in four countries (Denmark, Italy, Netherlands, and United Kingdom) that are virtually linked through distributed data network. A custom-built software (Jerboa©) elaborates harmonized input data that are produced locally and generates aggregated data which are then stored in a central repository. Those data are subsequently analyzed through different statistics (i.e. Longitudinal Gamma Poisson Shrinker). As potential signals, all the drugs that are associated to six events of interest (bullous eruptions - BE, acute renal failure - ARF, acute myocardial infarction - AMI, anaphylactic shock - AS, rhabdomyolysis - RHABD, and upper gastrointestinal bleeding - UGIB) have been detected via different data mining techniques in the two systems. Subsequently a comparison concerning the number of drugs that could be investigated and the potential signals detected for each event in the spontaneous reporting systems (SRSs) and EU-ADR network was made. SRSs could explore, as potential signals, a larger number of drugs for the six events, in comparison to EU-ADR (range: 630-3,393 vs. 87-856), particularly for those events commonly thought to be potentially drug-induced (i.e. BE: 3,393 vs. 228). The highest proportion of signals detected in SRSs was found for BE, ARF and AS, while for ARF, and UGIB in EU-ADR. In conclusion, it seems that EU-ADR longitudinal database network may complement traditional spontaneous reporting system for signal detection, especially for those adverse events that are frequent in general population and are not commonly thought to be drug-induced. The methodology for signal detection in EU-ADR is still under development and testing phase.

Huntington's Disease in Israel: A Population-Based Study Using 20 Years of Routinely-Collected Healthcare Data.

BACKGROUND: Huntington's disease (HD) is a rare, genetic, neurodegenerative disease. Obtaining population-level data on epidemiology and disease management is challenging. OBJECTIVE: To investigate the epidemiology, clinical manifestations, treatment, and healthcare utilization of patients with HD in Israel. METHODS: Retrospective population-based cohort study, including 20 years of routinely collected data from Maccabi Healthcare Services, an insurer and healthcare provider for one-quarter of the Israeli population. RESULTS: The study cohort included 109 adult patients (aged ≥18 years) diagnosed with HD, with mean age of 49.9 years and 56%females. The most common HD-related conditions were anxiety (40%), behavioral problems (34%), sleep disorders (21%), and falls (13%). Annual incidence rates for HD ranged from 0.17 to 1.34 per 100,000 from 2000 to 2018; the 2018 crude prevalence in adults was 4.36 per 100,000. Median survival from diagnosis was approximately 12 years (95%CI: 10.4-15.3). The most frequent symptomatic treatments were antidepressants (69%), antipsychotics (63%), and tetrabenazine (63%), the only drug approved for the treatment of HD chorea in Israel during the examined period. Patterns of healthcare utilization changed as disease duration increased, reflected by increased frequency of emergency department visits and home visits. CONCLUSION: This retrospective population-based study provides insights into the prevalence, incidence, clinical profile, survival, and resource utilization of patients with HD in ethnically diverse Israel. The findings in this study are generally consistent with the international literature and demonstrate the value of routinely collected healthcare data as a complementary resource in HD research.

Data mining on electronic health record databases for signal detection in pharmacovigilance: which events to monitor?

PURPOSE: Data mining on electronic health records (EHRs) has emerged as a promising complementary method for post-marketing drug safety surveillance. The EU-ADR project, funded by the European Commission, is developing techniques that allow mining of EHRs for adverse drug events across different countries in Europe. Since mining on all possible events was considered to unduly increase the number of spurious signals, we wanted to create a ranked list of high-priority events. METHODS: Scientific literature, medical textbooks, and websites of regulatory agencies were reviewed to create a preliminary list of events that are deemed important in pharmacovigilance. Two teams of pharmacovigilance experts independently rated each event on five criteria: 'trigger for drug withdrawal', 'trigger for black box warning', 'leading to emergency department visit or hospital admission', 'probability of event to be drug-related', and 'likelihood of death'. In case of disagreement, a consensus score was obtained. Ordinal scales between 0 and 3 were used for rating the criteria, and an overall score was computed to rank the events. RESULTS: An initial list comprising 23 adverse events was identified. After rating all the events and calculation of overall scores, a ranked list was established. The top-ranking events were: cutaneous bullous eruptions, acute renal failure, anaphylactic shock, acute myocardial infarction, and rhabdomyolysis. CONCLUSIONS: A ranked list of 23 adverse drug events judged as important in pharmacovigilance was created to permit focused data mining. The list will need to be updated periodically as knowledge on drug safety evolves and new issues in drug safety arise.

The Association of Multimorbidity With Preclinical AD Stages and SNAP in Cognitively Unimpaired Persons.

BACKGROUND: Multimorbidity (defined as ≥2 chronic conditions) has been associated with increased risk of mild cognitive impairment and cross-sectionally with imaging biomarkers of neurodegeneration in cognitively unimpaired persons aged ≥70 years. Its association with preclinical Alzheimer's disease stages has not been studied in detail yet. The objective of the study was to assess the cross-sectional association of multimorbidity with preclinical Alzheimer's disease stages and suspected non-amyloid pathophysiology in cognitively unimpaired participants of the Mayo Clinic Study of Aging (≥50 years of age). METHODS: The study included 1,535 cognitively unimpaired participants with multimorbidity, 11C-PiB positron emission topography and magnetic resonance imaging data available. Abnormal (elevated) 11C-PiB-positron emission topography retention ratio (A+; standardized uptake value ratio >1.42) and abnormal (reduced) Alzheimer's disease signature cortical thickness (N+; <2.67 mm) were used to define biomarker combinations (A-N-, A+N-, A-N+, A+N+). Chronic medical conditions were ascertained by using the Rochester Epidemiology Project medical records linkage system and International Classification of Diseases criteria. Cross-sectional associations were examined using multinomial logistic regression models adjusting for age, sex, education, and apolipoprotein E ɛ4 allele status. RESULTS: Frequency of A+, N+, A+N+, and A-N+ biomarker groups increased significantly with increasing number of chronic conditions. Multimorbidity was significantly associated with A+N+ (vs A-N-; odds ratio, 1.76, 95% confidence interval 1.02, 2.90) and A-N+ (vs A-N-; odds ratio, 2.16, 95% confidence interval 1.47, 3.18). There was a dose-response relationship between increasing number of chronic conditions (eg, 0-1, 2-3, and 4+) and the odds of A+N+ and A-N+ (vs A-N-). CONCLUSIONS: Multimorbidity was associated with biomarker combinations that included neurodegeneration with or without elevated amyloid deposition (ie, A-N+, A+N+). The associations should be validated in longitudinal studies.

Can Electronic Health Records Databases Complement Spontaneous Reporting System Databases? A Historical-Reconstruction of the Association of Rofecoxib and Acute Myocardial Infarction.

Background: Several initiatives have assessed if mining electronic health records (EHRs) may accelerate the process of drug safety signal detection. In Europe, Exploring and Understanding Adverse Drug Reactions (EU-ADR) Project Focused on utilizing clinical data from EHRs of over 30 million patients from several European countries. Rofecoxib is a prescription COX-2 selective Non-Steroidal Anti-Inflammatory Drugs (NSAID) approved in 1999. In September 2004, the manufacturer withdrew rofecoxib from the market because of safety concerns. In this study, we investigated if the signal concerning rofecoxib and acute myocardial infarction (AMI) could have been identified in EHR database (EU-ADR project) earlier than spontaneous reporting system (SRS), and in advance of rofecoxib withdrawal. Methods: Data from the EU-ADR project and WHO-VigiBase (for SRS) were used for the analysis. Signals were identified when respective statistics exceeded defined thresholds. The SRS analyses was conducted two ways- based on the date the AMI events with rofecoxib as a suspect medication were entered into the database and also the date that the AMI event occurred with exposure to rofecoxib. Results: Within the databases participating in EU-ADR it was possible to identify a strong signal concerning rofecoxib and AMI since Q3 2000 [RR LGPS = 4.5 (95% CI: 2.84-6.72)] and peaked to 4.8 in Q4 2000. In WHO-VigiBase, for AMI term grouping, the EB05 threshold of 2 was crossed in the Q4 2004 (EB05 = 2.94). Since then, the EB05 value increased consistently and peaked in Q3 2006 (EB05 = 48.3) and then again in Q2 2008 (EB05 = 48.5). About 93% (2260 out of 2422) of AMIs reported in WHO-VigiBase database actually occurred prior to the product withdrawal, however, they were reported after the risk minimization/risk communication efforts. Conclusion: In this study, EU-EHR databases were able to detect the AMI signal 4 years prior to the SRS database. We believe that for events that are consistently documented in EHR databases, such as serious events or events requiring in-patient medical intervention or hospitalization, the signal detection exercise in EHR would be beneficial for newly introduced medicinal products on the market, in addition to the SRS data.

Association Between Functional Performance and Alzheimer's Disease Biomarkers in Individuals Without Dementia.

OBJECTIVES: To examine the cross-sectional association between functional performance and Alzheimer's disease (AD) neuroimaging biomarkers in individuals without dementia (cognitively unimpaired (CU), and those with mild cognitive impairment (MCI)). DESIGN: Cross-sectional. SETTING: Olmsted County, Minnesota. PARTICIPANTS: Population-based Mayo Clinic Study of Aging (MCSA) participants (aged ≥ 50, mean age 71.3 ± 10.2; 53.4% male; 28.3% apolipoprotein (APO)E ε4 allele carriers, 1,578 CU, 204 MCI) who underwent 11 C-Pittsburgh compound B (11 C-PiB) positron emission tomography (PET) (N=1,782). MEASUREMENTS: We defined an abnormal (high) 11 C-PiB-PET retention ratio as a standardized uptake value ratio greater than 1.42 (high amyloid; A+), abnormal (reduced) AD signature cortical thickness (neurodegeneration; N+) as less than 2.67 mm (MRI measurement), and biomarker groups according to the combination of abnormality (or not) for amyloid accumulation (A+/A-) and neurodegeneration (N+/N-). Functional performance was assessed using the Clinical Dementia Rating (CDR) Sum of Boxes (SOB) for functional domains and the Functional Activities Questionnaire (FAQ). RESULTS: Participants with a CDR-SOB (functional) score greater than 0 were almost 4 times as likely to have N + (odds ratio (OR)=3.92, 95% confidence interval (CI)=1.77-8.67, adjusting for age, sex, education, global cognitive z-score, and APOE ε4 allele status; p<.001) and those with a FAQ score greater than 0 were 1.5 times as likely to have A + (OR=1.48, 95% CI=1.04-2.11, p=.03). Higher FAQ scores were associated with greater odds of A+N + and A-N + in CU participants. CONCLUSION: The findings of this cross-sectional study supplement limited available information that supports an association between functional performance and AD neuroimaging biomarkers very early in the dementia pathophysiology. The associations should be validated in longitudinal studies. J Am Geriatr Soc 66:2274-2281, 2018.

Evaluating the Safety Profile of Non-Active Implantable Medical Devices Compared with Medicines.

Recent safety issues involving non-active implantable medical devices (NAIMDs) have highlighted the need for better pre-market and post-market evaluation. Some stakeholders have argued that certain features of medicine safety evaluation should also be applied to medical devices. Our objectives were to compare the current processes and methodologies for the assessment of NAIMD safety profiles with those for medicines, identify potential gaps, and make recommendations for the adoption of new methodologies for the ongoing benefit-risk monitoring of these devices throughout their entire life cycle. A literature review served to examine the current tools for the safety evaluation of NAIMDs and those for medicines. We searched MEDLINE using these two categories. We supplemented this search with Google searches using the same key terms used in the MEDLINE search. Using a comparative approach, we summarized the new product design, development cycle (preclinical and clinical phases), and post-market phases for NAIMDs and drugs. We also evaluated and compared the respective processes to integrate and assess safety data during the life cycle of the products, including signal detection, signal management, and subsequent potential regulatory actions. The search identified a gap in NAIMD safety signal generation: no global program exists that collects and analyzes adverse events and product quality issues. Data sources in real-world settings, such as electronic health records, need to be effectively identified and explored as additional sources of safety information, particularly in some areas such as the EU and USA where there are plans to implement the unique device identifier (UDI). The UDI and other initiatives will enable more robust follow-up and assessment of long-term patient outcomes. The safety evaluation system for NAIMDs differs in many ways from those for drugs, but both systems face analogous challenges with respect to monitoring real-world usage. Certain features of the drug safety evaluation process could, if adopted and adapted for NAIMDs, lead to better and more systematic evaluations of the latter.

The frequency and influence of dementia risk factors in prodromal Alzheimer's disease.

We investigated whether dementia risk factors were associated with prodromal Alzheimer's disease (AD) according to the International Working Group-2 and National Institute of Aging-Alzheimer's Association criteria, and with cognitive decline. A total of 1394 subjects with mild cognitive impairment from 14 different studies were classified according to these research criteria, based on cognitive performance and biomarkers. We compared the frequency of 10 risk factors between the subgroups, and used Cox-regression to examine the effect of risk factors on cognitive decline. Depression, obesity, and hypercholesterolemia occurred more often in individuals with low-AD-likelihood, compared with those with a high-AD-likelihood. Only alcohol use increased the risk of cognitive decline, regardless of AD pathology. These results suggest that traditional risk factors for AD are not associated with prodromal AD or with progression to dementia, among subjects with mild cognitive impairment. Future studies should validate these findings and determine whether risk factors might be of influence at an earlier stage (i.e., preclinical) of AD.