2 Minute Medicine Rewind December 2, 2019

Association of Anticoagulant Therapy With Risk of Fracture Among Patients With Atrial Fibrillation

1. Direct oral anticoagulants, specifically apixaban, were associated with lower risk of fracture in patients with atrial fibrillation compared to warfarin.

Evidence Rating Level: 2 (Good)

Warfarin is commonly used to prevent cardioembolic events in individuals with atrial fibrillation (AF). The impact of warfarin treatment on bone health is clinically important, particularly in those susceptible to bone fractures due to falls and other events. With the advent and approval of direct oral anticoagulants (DOACs), the safety and efficacy of these medications can be investigated to clarify this controversy in individuals with nonvalvular AF, specifically in terms of future fractures and fracture-related hospitalizations. The objective of this prospective cohort study was to examine the effect of DOACs versus warfarin in terms of risk of incident fractures in individuals with non-valvular AF. Using MarketScan administrative claims data from 167,275 individuals with AF between January 2010 and September 30, 2015, new DOAC users were matched to up to three warfarin-only new users. Participants were matched by propensity score using Cox proportional hazards regression models to compare warfarin and DOAC groups. Outcomes of interest were hip fractures, fractures requiring hospitalization and all clinical fractures. Overall, new users of DOACs were found to be at decreased risk of fracture-related hospitalizations (HR 0.87, 95% CI 0.79 to 0.96) and overall fractures (HR 0.93, 95% CI 0.88 to 0.98) compared to new users of warfarin. The difference in incidences of hip fractures across groups was not significant. Of all DOACs, apixaban resulted in the most significant differences compared to warfarin, with reduced hip fractures (HR 0.67, 95% CI 0.45 to 0.98), fracture-related hospitalizations (HR 0.60, 95% CI 0.47 to 0.78), and overall fractures (HR 0.86, 95% CI 0.75 to 0.98). Subgroup analyses found that DOAC-related hip fractures in individuals with AF were lower in those with suspected osteoporosis (HR 0.74, 95% CI 0.58 to 0.96) compared to those without (HR 1.06, 95% CI 1.06, 0.86 to 1.30), with similar findings when analyzing fracture-related hospitalizations. Therefore, DOAC use, particularly apixaban, was found to be associated with reduced incidences of fractures and fracture-related hospitalizations compared to warfarin, with potential additive benefits for those with comorbid osteoporosis.

Treatment Effect of Omalizumab on Severe Pediatric Atopic Dermatitis: The ADAPT Randomized Clinical Trial

1. In treatment-resistant childhood atopic dermatitis, omalizumab significantly reduced the severity of dermatitis and improved quality of life compared to placebo.

Evidence Rating Level: 1 (Excellent)

Anti-IgE medications such as omalizumab are well-tolerated in patients with severe asthma and atopy; however, no large randomized trials have examined its efficacy in children experiencing treatment-resistant atopic dermatitis. The objective of this double-blind, placebo-controlled study was to examine the effectiveness of omalizumab in treating severe atopic dermatitis in children, with the objective Scoring Atopic Dermatitis (SCORAD) index 24 weeks post-treatment initiation as the primary outcome of interest. Sixty-two participants aged 4 to 19 years (mean [SD] age = 10.3 [4.2] years) were recruited following initial screenings, which required a SCORAD index of 40 or greater and resistance to standard treatment. Participants were randomly assigned to placebo (n = 32) or omalizumab (n = 30) for 24 weeks, with dosage being based on participants’ initial body weight and total IgE (30-1,500 IU/mL). Assessments were conducted at 24 weeks as well as 48-week follow-ups, including the SCORAD, Children’s Dermatology Life Quality Index/Dermatology Life Quality Index (CDLQI/DLQI), and the Pediatric Allergic Disease Quality of Life Questionnaire (PADQLQ). Following 24 weeks, adjusted SCORAD indices demonstrated an average reduction of 6.9 points between groups, with the omalizumab group showing significantly greater improvement (95% CI -12.2 to -1.5, p=0.1). Mean changes in CDLQI/DLQI scores (-3.5; 95% CI -6.4 to -0.5) and PADQLQ scores (-0.5; 95% CI -0.9 to 0.0) both favored the omalizumab group. These differences were significant despite lower potent topical corticosteroid use in the treatment group. Overall, study findings suggested that omalizumab significantly reduced atopic dermatitis severity, improved quality of life and potential topical corticosteroid-sparing in children with atopy, severe eczema and high total IgE levels with treatment-resistant disease.

Prescription of Benzodiazepines, Z-Drugs, and Gabapentinoids and Mortality Risk in People Receiving Opioid Agonist Treatment

1. Co-prescription of benzodiazepines and z-drugs with opioid agonists was associated with a significantly increased risk of drug-related poisoning in opioid-dependent individuals.

Evidence Rating Level: 2 (Good)

Opioid agonist treatment (OAT) is common and effective for individuals with opioid dependence. Concurrent medications, particularly sedatives, prescribed alongside OAT may increase risk of adverse events and mortality despite their benefits. The objective of this cohort study was to examine the association between prescription of concurrent sedatives and treatment retention, and whether concurrent sedative prescription was associated with overall benefit or harm in opioid-dependent individuals on OAT (buprenorphine or methadone). Using data from a United Kingdom database of 12,118 adult primary care patients prescribed OAT between 1998 and 2014, the use of benzodiazepines, z-drugs (zaleplon, zolpidem, and zopiclone), and gabapentinoids concurrently with opioid agonists buprenorphine or methadone and associations with all-cause mortality, drug-related poisoning (DRP), and non-DRP were examined. Over 36,126 person-years of follow-up, 657 deaths and 29,540 OAT episodes were reported, of which 42% were co-prescribed benzodiazepines, 20% co-prescribed z-drugs, and 8% co-prescribed gabapentinoids. Concurrent benzodiazepine use was associated with increased methadone treatment duration (466 [95% CI 450 to 483] vs. 286 [275 to 297] days). There was also a dose-dependent response in benzodiazepine normal dose (adjusted HR 2.51, 95% CI 1.57 to 4.01, p<0.001) and high dose (4.57, 95% CI 2.46 to 8.47, p<0.001). Co-prescription was associated with increased risk of DRP (adjusted HR 2.96 (95% CI 1.97 to 4.43)), though not with non-DRP. Z-drug co-prescription was also associated with increased risk of DRP, while gabapentinoid drugs showed a significant association with non-DRP. The findings of this study highlight the importance of clinical judgment in the treatment of opioid-dependent individuals, such that concurrent use of benzodiazepines, z-drugs, and gabapentinoids increase risk of mortality irrespective of treatment stage.

Growth Faltering is Associated With Altered Brain Functional Connectivity and Cognitive Outcomes In Urban Bangladeshi Children Exposed to Early Adversity

1. Height-for-age z-score was negatively associated with brain functional connectivity (FC), with FC serving as a mediating factor between child growth and future intellectual functioning in a sample of impoverished children.

Evidence Rating Level: 2 (Good)

Poverty and early childhood adversity are known risk factors for neurodevelopmental delays and chronic disorders. However, little research has been done on this population using neuroimaging techniques and behavioral assays. The objective of this cohort study was to examine associations between physical growth, brain functional connectivity and cognitive development among children using high-density EEG. The study recruited infants (n = 92) and toddlers (n = 118) living in an urban area of Bangladesh who were born at 34 weeks’ gestation or later, with no history of brain injury or neurological impairments or delays. Socioeconomic status (SES) was assessed via observation and questionnaires, and caregiving was assessed via interviews during EEG assessment. Investigators evaluated height-for-age z-score (HAZ) at three, four, five, and six months (for infant group) and 24, 30, and 36 months (for toddler group). HAZ were averaged across time points due to high correlationsEEG data was collected at six months for infants and 36 months for toddlers. Prevalence of stunting in infants and toddlers, defined as at least two SDs below the population mean, were 16.30% and 33.06%, respectively. Infants were placed into three categories: stunted (n = 39), middle HAZ (n = 39), and high HAZ (n = 40). Cognitive assessment was conducted with the Mullen Scales of Early Learning (MSEL) and the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III), though these tests are not normed for the Bangladeshi setting and warrant caution in interpretation. For six-month-old infants, average whole-brain FC varied across frequency bands with peaks in theta (mean = 5.68 [1.23]), while the peak for 36-month-old toddlers was found in the alpha band (mean = 7.67 [1.48]). Peak frequency of global FC at 36 months was lower for stunted children than non-stunted toddlers, though no significant associations were discovered. No associations were found with SES, HAZ, or other covariates with whole-brain FC in the infant cohort. For the toddler group, however, 24-36-month HAZ was negatively correlated with theta (β  = -0.267, p = 0.14) and beta FC (β  = -0.298, p = 0.005). Whole-brain FC in these bands were also found to be stronger in stunted than non-stunted children. WPPSI-III scores at 36 months were negatively associated with brain FC in theta (β = -0.179, p = 0.042) and alpha (β = -0.202, p = 0.020) bands, but no associations were found between MSEL scores and FC. The model of theta band was acceptable (χ2(1) = 0.277, p = 0.599; CFI = 1.0; SRMR = 0.009; RMSEA < 0.001) while the model of beta was a poor fit. Longitudinal path analysis determined that HAZ was negatively associated with 36-month FC in beta and theta bands, both of which were also negatively associated with 48-month intellectual functioning. Indirect effects of HAZ on cognitive performance through brain FC in beta (95% CI of standardized estimate 0.03 to 0.13) and theta (95% CI of standardized estimate 0.001 to 0.105). This study is the first to suggest that brain FC may play a critical, mediating role in cognitive impairments resulting from early adversity

Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials

1. While well-tolerated in early and mild Alzheimer’s disease, the BACE1 inhibitor lanabecestat was generally ineffective in slowing cognitive and functional decline.

Evidence Rating Level: 1 (Excellent)

Amyloid plaques and neurofibrillary tangles are defining pathological characteristics of Alzheimer’s disease (AD). Inhibitors of the beta-site APP-cleaving enzyme 1 (BACE1) may reduce the formation of Aβ peptides. Therefore, the objective of the AMARNATH and DAYBREAK-ALZ randomized, global multicenter, double-blind, placebo-controlled trials was to assess the effectiveness and safety of the BACE1 inhibitor lanabecestat in slowing cognitive deterioration and disease progression compared to placebo in early and mild AD. AMARANTH occurred over the course of 104 weeks, andincluded individuals across the spectrum from AD-related mild cognitive impairment (MCI) to mild AD dementia. DAYBREAK-ALZ  similarly included mild AD dementia patients, with a 78-week placebo-controlled period, and a subsequent 78-week period during which all participants transitioned to lanabecestat. Participants were stratified by cognitive status at baseline and equally randomized to once-daily doses of 20mg lanabecestat, 50mg lanabecestat, or placebo. Evaluative tools to determine impairment were the 13-item Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-Cog13), Alzheimer’s Disease Cooperative Study-Instrumental Activities of Daily Living Inventory (ADCS-iADL), Functional Activities Questionnaire (FAQ), Integrated Alzheimer’s Disease Rating Scale (iADRS), Clinical Dementia Rating-sum of boxes (CDR-SB), Neuropsychiatric Inventory (NPI), and Mini-Mental Status Examination (MMSE). Reported adverse events, weight and vital signs, laboratory tests, physical examination (e.g., neurological/imaging, dermatological), and suicidality were also assessed throughout the studies. Lastly, biomarkers related to amyloid markers (CSF Aβ-42 and Aβ-40), hippocampal volume (MRI), and amyloid burden (florbetapir PET) were evaluated. The primary outcome was change from baseline in the ADAS-Cog13. A total of 2,218 participants were eligible for AMARANTH (mean [SD] age = 71.3 [7.1] years) and 1,722 were eligible for DAYBREAK-ALZ (mean [SD] age = 72.3 [7.0] years). Baseline cognitive and functional scores were similar across studies in spite of their disease status differences, though all scored at least one SD below the population mean for MCI and three SDs below for mild AD. Both studies were discontinued early for futility, which likely impacted results. Incidence of deaths were similar across treatment groups in both of these studies; study discontinuation due to adverse events was highest in the 50mg lanabecestat group (difference 2.5%). Specifically,the 50mg lanabecestat group experienced increased hair hypopigmentation, and both lanabecestat groups resulted in a higher number of emergent psychiatric events. Regarding cognitive and functional capacities during the studies’ durations, lanabecestat did not slow decline compared to placebo. The 20- and 50mg treatment arms in AMARANTH showed significantly greater hippocampal volume loss (-0.52% and -0.48%, respectively) compared to placebo, but these findings were not observed in DAYBREAK-ALZ. However, no significant differences were found in cognitive measures and, in certain cases, worsening of function was noted in lanabecestat groups without distinguishable differences between the two studies. Despite early termination, these large studies suggest that the BACE1 inhibitor lanabecestat does not appear to serve as a disease-modifying agent under current conditions.

Image: PD

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