Monitoring Pregnancies Exposed to Galcanezumab for Migraine in a United States Administrative Claims Database.

PURPOSE: Galcanezumab is a calcitonin gene-related peptide monoclonal antibody indicated for migraine prevention in adults. Due to the long half-life of galcanezumab and the prevalence of migraine in women of childbearing age, galcanezumab exposure may occur during pregnancy. However, real-world use and safety of galcanezumab during pregnancy has not been fully described. To help fill this gap, galcanezumab has two ongoing pregnancy safety studies, one of which is an insurance claims database study. METHODS: This database study is actively identifying and following pregnancies exposed to galcanezumab using commercial claims from the Healthcare Integrated Research Database (HIRD). Patient accrual is planned from September 2018 to June 2026, with a final study report planned for December 2027. This study requires 430 galcanezumab-exposed pregnancies with linked infants to reach power for comparative analysis of major congenital malformations. RESULTS: Recent monitoring of patient accrual, including data from 28 September 2018 to 31 January 2023, identified 207 galcanezumab-exposed pregnancies in women with migraine in the HIRD, of which 110 were live births and 73 of which were linked to an infant. This represents an annual accrual rate of approximately 17 pregnancies linked to infants, which is substantially lower than the 55 required annually to reach target size within current regulatory-committed study timelines. CONCLUSIONS: The accrual of a sufficient number of galcanezumab-exposed pregnancies represents a substantial, but not uncommon, barrier to conducting comparative analyses in pregnancy studies. Potential solutions that would allow for timely dissemination of important safety information to patients and providers may be available.

Potential Channeling Bias in the Evaluation of Cardiovascular Risk: The Importance of Comparator Selection in Observational Research.

BACKGROUND: Comparator selection is an important consideration in the design of observational research studies that evaluate potential associations between drug therapies and adverse event risks. It can affect the validity of observational study results, and potentially impact data interpretation, regulatory decision making, and patient medication access. OBJECTIVE: The aim of this study was to assess the impact of comparator selection bias using two real-world case studies evaluating an increased rate of acute myocardial infarction (AMI). METHODS: Data from the Truven Health Analytics MarketScan® electronic medical claims database were used to conduct two retrospective observational cohort studies, utilizing a cohort new-user design, comparing AMI risk between testosterone replacement therapy (TRT) and phosphodiesterase-5 inhibitors (PDE5is) in men treated for hypogonadism, and triptans versus other prescribed acute treatments for migraine in adults. All patients were enrolled continuously in a health plan (no enrollment gap > 31 consecutive days) for ≥ 1 year before index. Baseline period was defined as 365 days prior to index. Exposure was defined by prescription and outcome of interest was defined as occurrence of AMI. Using Cox proportional hazard models, primary analysis for the TRT cohort compared AMI risk between propensity score (PS)-matched TRT-treated and untreated patients; secondary analysis evaluated risk between PS-matched TRT-treated and PDE5i-treated patients. For the triptan cohort, primary analysis compared AMI/ischemic stroke risk between PS-matched triptan-treated and opiate-treated patients; secondary analysis evaluated risk between PS-matched triptan-treated and nonsteroidal anti-inflammatory drug (NSAID)-treated patients and PS-matched non-prescription-treated migraine patients and general patients. RESULTS: No significant association between TRT and AMI was observed among TRT-treated (N = 198,528, mean age 52.4 ± 11.4 years) versus PDE5i-treated men (N = 198,528, mean age 52.3 ± 11.5 years) overall (adjusted hazard ratio [aHR] 1.01; 95% CI 0.95-1.07; p = 0.80). Among patients with prior cardiovascular disease (CVD), risk of AMI was significantly increased for TRT-treated versus PDE5i-treated patients (aHR 1.13; 95% CI 1.03-1.25). The triptan study included three comparisons (triptans [N = 436,642] vs prescription NSAIDs [N = 334,152], opiates [N = 55,234], and untreated migraine [N = 1,168,212]), and a positive control (untreated vs general non-migraine patients [N = 11,735,009]). Analyses of MI risk in migraine patients prescribed triptans versus NSAIDs/opiates had mixed results: the point estimate ranged from 0.33 to 0.84 depending on chosen study window. CONCLUSIONS: Cardiovascular outcomes were not worse in hypogonadism patients with TRT versus PDE5i; however, a potential association with AMI was found in patients with prior CVD receiving TRT versus PDE5i. Findings pointed to a pseudo-protective effect of triptans versus untreated migraine patients or those potentially older and less healthy patients exposed to prescription NSAIDs or opiates. Triptan users should not be compared with those using other anti-migraine prescriptions when evaluating cardiovascular outcomes in migraine patients. Presence of high cardiovascular risks may contribute to channeling bias-healthier subjects being selected to receive treatment-highlighting the importance of choosing comparators wisely in observational studies.

PTSD, Psychotropic Medication Use, and the Risk of Dementia Among US Veterans: A Retrospective Cohort Study.

OBJECTIVE: To determine the associations between PTSD, psychotropic medication use, and the risk for dementia. DESIGN: Retrospective cohort. PARTICIPANTS: Nationwide sample of US veterans (N = 417,172) aged ≥56 years during fiscal year (FY) 2003 without a diagnosis of dementia or mild cognitive impairment at baseline (FY02-03) and ≥1 clinical encounter every 2 years during follow-up (FY04-12). MEASURES: Demographic characteristics; diagnosis of PTSD, dementia, and medical and psychiatric comorbidity (defined by ICD-9 codes); and psychotropic medication use including selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), novel antidepressants (NA), benzodiazepines (BZA), and atypical antipsychotics (AA). Cox proportional hazard models examined for associations between PTSD diagnosis, psychotropic medication use, and risk for a dementia diagnosis. RESULTS: PTSD diagnosis significantly increased the risk for dementia diagnosis (HR = 1.35; [95% CI = 1.27-1.43]). However, there were significant interactions between PTSD diagnosis and use of SSRIs (P < .001), NAs (P = .014), and AAs (P < .001) on the risk for dementia diagnosis. HR for dementia diagnosis among veterans diagnosed with PTSD and not using psychotropic medications was 1.55 [1.45-1.67]. Among veterans diagnosed with PTSD prescribed SSRI, SNRI, or AA, HR for dementia diagnosis varied by drug class use ranging from 1.99 for SSRI to 4.21 for AA, relative to veterans without a PTSD diagnosis and no psychotropic medication receipt. BZAs or SNRIs use at baseline was associated with a significantly increased risk for dementia diagnosis independent of a PTSD diagnosis. CONCLUSION: PTSD diagnosis is associated with an increased risk for dementia diagnosis that varied with receipt of psychotropic medications. Further research would help to delineate if these findings are due to differences in PTSD severity, psychiatric comorbidity, or independent effects of psychotropic medications on cognitive decline.

Systemic and localized extra-central nervous system bacterial infections and the risk of dementia among US veterans: A retrospective cohort study.

INTRODUCTION: Emerging evidence indicates associations between extra-central nervous system (CNS) bacterial infections and an increased risk for dementia; however, epidemiological evidence is still very limited. METHODS: This study involved a retrospective cohort of a national sample of US veterans (N = 417,172) aged ≥56 years. Extended Cox proportional hazard models adjusted for demographic characteristics and medical and psychiatric comorbidities determined the associations between systemic and localized extra-CNS bacterial infections occurring >2 years before the initial dementia diagnosis and the risk for dementia. RESULTS: Exposure to any extra-CNS bacterial infection was associated with a significantly increased risk for dementia (hazard ratio [HR] = 1.20 [95% confidence interval = 1.16-1.24]). Independently, septicemia (HR = 1.39 [1.16-1.66]), bacteremia (HR = 1.22 [1.00-1.49]), osteomyelitis (HR = 1.20 [1.06-1.37]), pneumonia (HR = 1.10 [1.02-1.19]), urinary tract infections (HR = 1.13 [1.08-1.18]), and cellulitis (HR = 1.14 [1.09-1.20]) were associated with a significantly increased risk for dementia. DISCUSSION: Both systemic and localized extra-CNS bacterial infections are associated with an increased risk for developing dementia.

Can infections cause Alzheimer's disease?

Late-onset Alzheimer's disease (AD) is the most prevalent cause of dementia among older adults, yet more than a century of research has not determined why this disease develops. One prevailing hypothesis is that late-onset AD is caused by infectious pathogens, an idea widely studied in both humans and experimental animal models. This review examines the infectious AD etiology hypothesis and summarizes existing evidence associating infectious agents with AD in humans. The various mechanisms through which different clinical and subclinical infections could cause or promote the progression of AD are considered, as is the concordance between putative infectious agents and the epidemiology of AD. We searched the PubMed, Web of Science, and EBSCO databases for research articles pertaining to infections and AD and systematically reviewed the evidence linking specific infectious pathogens to AD. The evidence compiled from the literature linking AD to an infectious cause is inconclusive, but the amount of evidence suggestive of an association is too substantial to ignore. Epidemiologic, clinical, and basic science studies that could improve on current understanding of the associations between AD and infections and possibly uncover ways to control this highly prevalent and debilitating disease are suggested.