Objective
To assess the long‐term safety and 16‐week efficacy of subcutaneous tanezumab in patients with hip or knee osteoarthritis (OA).
Methods
This was a phase III randomized, double‐blind, active ...treatment–controlled (using nonsteroidal antiinflammatory drugs NSAIDs as the active treatment control) safety trial of tanezumab (56‐week treatment/24‐week posttreatment follow‐up) in adults who were receiving stable‐dose NSAID therapy at the time of screening and who had Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function scores of ≥5; patient global assessment (PtGA) of OA of fair, poor, or very poor; history of inadequate pain relief with standard analgesics; and no history or radiographic evidence of prespecified bone/joint conditions beyond OA. Patients received oral naproxen, celecoxib, or diclofenac twice daily (NSAID group; n = 996) or tanezumab 2.5 mg (n = 1,002) or 5 mg (n = 998) subcutaneously every 8 weeks. Coprimary efficacy end points at week 16 were changes in WOMAC pain and physical function scores and changes in PtGA. The primary joint safety end point over 80 weeks comprised adjudicated rapidly progressive OA type 1 or 2, primary osteonecrosis, subchondral insufficiency fracture, or pathologic fracture. Mean values, least squares mean values, and least squares mean differences between groups (with 95% confidence intervals 95% CIs) were calculated.
Results
Of 3,021 randomized patients, 2,996 received ≥1 treatment dose. Adverse events (AEs) were similar between patients treated with tanezumab 2.5 mg and those treated with NSAIDs, and were more prevalent in those treated with tanezumab 5 mg. Composite joint safety events were significantly more prevalent with tanezumab 2.5 mg and tanezumab 5 mg than with NSAIDs (observation time–adjusted rate/1,000 patient‐years 38.3 95% CI 28.0, 52.5 and 71.5 95% CI 56.7, 90.2, respectively, versus 14.8 95% CI 8.9, 24.6; P = 0.001 for tanezumab 2.5 mg versus NSAIDs; P < 0.001 for tanezumab 5 mg versus NSAIDs). Tanezumab 5 mg significantly improved pain and physical function but did not improve PtGA at week 16 when compared to NSAIDs; corresponding differences between the tanezumab 2.5 mg and NSAID groups were not statistically significant.
Conclusion
In patients previously receiving a stable dose of NSAIDs, tanezumab administered subcutaneously resulted in more joint safety events than continued NSAIDs, with differences being dose dependent. Pain and physical function improved with both doses of tanezumab compared to NSAIDs, reaching statistical significance with tanezumab 5 mg at 16 weeks.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Background
Currently available medications for chronic osteoarthritis pain are only moderately effective, and their use is limited in many patients because of serious adverse effects and ...contraindications. The primary surgical option for osteoarthritis is total joint replacement (TJR). The objectives of this study were to describe the treatment history of patients with osteoarthritis receiving prescription pain medications and/or intra-articular corticosteroid injections, and to estimate the incidence of TJR in these patients.
Methods
This retrospective, multicenter, cohort study utilized health plan administrative claims data (January 1, 2013, through December 31, 2019) of adult patients with osteoarthritis in the Innovation in Medical Evidence Development and Surveillance Distributed Database, a subset of the US FDA Sentinel Distributed Database. Patients were analyzed in two cohorts: those with prevalent use of “any pain medication” (prescription non-steroidal anti-inflammatory drugs NSAIDs, opioids, and/or intra-articular corticosteroid injections) using only the first qualifying dispensing (index date); and those with prevalent use of “each specific pain medication class” with all qualifying treatment episodes identified.
Results
Among 1 992 670 prevalent users of “any pain medication”, pain medications prescribed on the index date were NSAIDs (596 624 29.9% patients), opioids (1 161 806 58.3%), and intra-articular corticosteroids (323 459 16.2%). Further, 92 026 patients received multiple pain medications on the index date, including 71 632 (3.6%) receiving both NSAIDs and opioids. Altogether, 20.6% of patients used an NSAID at any time following an opioid index dispensing and 17.2% used an opioid following an NSAID index dispensing. The TJR incidence rates per 100 person-years (95% confidence interval CI) were 3.21 (95% CI: 3.20–3.23) in the “any pain medication” user cohort, and among those receiving “each specific pain medication class” were NSAIDs, 4.63 (95% CI: 4.58–4.67); opioids, 7.45 (95% CI: 7.40–7.49); and intra-articular corticosteroids, 8.05 (95% CI: 7.97–8.13).
Conclusions
In patients treated with prescription medications for osteoarthritis pain, opioids were more commonly prescribed at index than NSAIDs and intra-articular corticosteroid injections. Of the pain medication classes examined, the incidence of TJR was highest in patients receiving intra-articular corticosteroids and lowest in patients receiving NSAIDs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction
Based on post-marketing surveillance, concern has been raised that sodium–glucose cotransporter 2 inhibitors (SGLT2i) may increase the risk of necrotizing fasciitis of the perineum ...(Fournier’s gangrene, FG). As a result of the low incidence of FG, data from clinical trials may be insufficient to robustly assess this issue because of the relatively limited numbers of participants. Real-world evidence may help clarify the association between SGLT2i and FG in the type 2 diabetes (T2D) population.
Methods
A nested case–control study was performed using Truven Health MarketScan™ databases. Each patient with T2D hospitalized for FG between 1 April 2013 (when the first SGLT2i was available) and 31 March 2018 (latest available data) was matched (on the basis of sex, age, and cohort entry date) with six controls from the same cohort. The adjusted odds ratio (OR) of hospitalization for FG was estimated for patients receiving SGLT2i compared with those receiving two or more non-SGLT2i antihyperglycemic agents (AHAs) or insulin alone using conditional logistic regression.
Results
The cohort included 1,897,935 patients, with 216 hospitalized for FG (incidence rate, 5.2 events per 100,000 person-years). Patients with FG ranged from 23 to 79 years of age; 201 (93.1%) were men. Among the 216 FG cases, 9 (4.2%) were current SGLT2i users; among the 1296 matched controls, 100 (7.7%) were current SGLT2i users. Approximately 93% of SGLT2i were used in combination. The adjusted OR of FG in patients treated with SGLT2i compared with patients treated with two or more non-SGLT2i AHAs or insulin alone was 0.55 95% CI 0.25–1.18.
Conclusion
The study did not find that treatment with SGLT2i, as compared with treatment with two or more non-SGLT2i AHAs or insulin alone, was statistically significantly associated with an increased risk of hospitalization for FG. Additional studies are needed to corroborate the findings.
Few studies characterize older adult physical activity and sitting patterns using accurate accelerometer and concurrent posture measures. In this descriptive paper, we report accelerometer data ...collection protocols, consent rates, and physical behavior measures from a population-based cohort study (Adult Changes in Thought, ACT).
The ACT study holds enrollment steady at approximately 2000 members of Kaiser Permanente Washington aged 65+ without dementia undergoing detailed biennial assessments. In 2016 the ACT-Activity Monitor (ACT-AM) sub-study was initiated to obtain data from wearing activPAL and ActiGraph devices for 7 days following regular biennial visits. We describe the methods protocol of ACT-AM and present characteristics of people who did and did not consent to wear devices. We compute inverse probability of response weights and incorporate these weights in linear regression models to estimate means and 95% confidence intervals (CI) of device-based pattern metrics, adjusted for wear time and demographic factors, and weighted to account for potential selection bias due to device-wear consent.
Among 1885 eligible ACT participants, 56% agreed to wear both devices (mean age 77 years, 56% female, 89% non-Hispanic white, 91% with post-secondary education). On average, those who agreed to wear devices were younger and healthier. Estimated mean (95% CI) activPAL-derived sitting, standing, and stepping times were 10.2 h/day (603-618 min/day), 3.9 h/day (226-239 min/day), and 1.4 h/day (79-84 min/day), respectively. Estimated mean ActiGraph derived sedentary (Vector Magnitude VM < =18 counts/15 s), light intensity (VM 19-518 counts/15 s), and moderate-to-vigorous intensity (VM > 518 counts/15 s) physical activity durations were 9.5 h/day (565-577 min/day), 4.5 h/day (267-276 min/day), and 1.0 h/day (59-64 min/day). Participants who were older, had chronic conditions, and were unable to walk a half-mile had higher sedentary time and less physical activity.
Our recruitment rate demonstrates the feasibility of cohort participants to wear two devices that measure sedentary time and physical activity. Data indicate high levels of sitting time in older adults but also high levels of physical activity using cut-points developed for older adults. These data will help researchers test hypotheses related to physical behavior and health in older adults in the future.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may increase the risk of coronavirus disease 2019 (COVID-19) infection or affect disease ...severity. Prior studies have not examined risks by medication dose.
Methods
This retrospective cohort study included people aged ≥18 years enrolled in a US integrated healthcare system for at least 4 months as of 2/29/2020. Current ACEI and ARB use was identified from pharmacy data, and the estimated daily dose was calculated and standardized across medications. COVID-19 infections and hospitalizations were identified through 6/14/2020 from laboratory and hospitalization data. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for race/ethnicity, obesity, and other covariates.
Results
Among 322,044 individuals, 826 developed COVID-19 infection. Among people using ACEI/ARBs, 204/56,105 developed COVID-19 (3.6 per 1,000 individuals) compared with 622/265,939 without ACEI/ARB use (2.3 per 1,000), yielding an adjusted OR of 0.91 (95% CI 0.74–1.12). For use of <1 defined daily dose (DDD) vs. nonuse, the adjusted OR for infection was 0.92 (95% CI 0.66–1.28); for 1 to <2 DDDs, 0.89 (95% CI 0.66–1.19); and for ≥2 DDDs, 0.92 (95% CI 0.72–1.18). The OR was similar for ACEIs and ARBs and in subgroups by age and sex. 26% of people with COVID-19 infection were hospitalized; the adjusted OR for hospitalization in relation to ACEI/ARB use was 0.98 (95% CI 0.63–1.54), and there was no association with dose.
Conclusions
These findings support current recommendations that individuals on these medications continue their use.
Graphical Abstract
Sedentary behavior (SB) is a recognized risk factor for many chronic diseases. ActiGraph and activPAL are two commonly used wearable accelerometers in SB research. The former measures body movement ...and the latter measures body posture. The goal of the current study is to quantify the pattern and variation of movement (by ActiGraph activity counts) during activPAL-identified sitting events, and examine associations between patterns and health-related outcomes, such as systolic and diastolic blood pressure (SBP and DBP).
The current study included 314 overweight postmenopausal women, who were instructed to wear an activPAL (at thigh) and ActiGraph (at waist) simultaneously for 24 hours a day for a week under free-living conditions. ActiGraph and activPAL data were processed to obtain minute-level time-series outputs. Multilevel functional principal component analysis (MFPCA) was applied to minute-level ActiGraph activity counts within activPAL-identified sitting bouts to investigate variation in movement while sitting across subjects and days. The multilevel approach accounted for the nesting of days within subjects.
At least 90% of the overall variation of activity counts was explained by two subject-level principal components (PC) and six day-level PCs, hence dramatically reducing the dimensions from the original minute-level scale. The first subject-level PC captured patterns of fluctuation in movement during sitting, whereas the second subject-level PC delineated variation in movement during different lengths of sitting bouts: shorter (< 30 minutes), medium (30 -39 minutes) or longer (> 39 minute). The first subject-level PC scores showed positive association with DBP (standardized
: 2.041, standard error: 0.607, adjusted p = 0.007), which implied that lower activity counts (during sitting) were associated with higher DBP.
In this work we implemented MFPCA to identify variation in movement patterns during sitting bouts, and showed that these patterns were associated with cardiovascular health. Unlike existing methods, MFPCA does not require pre-specified cut-points to define activity intensity, and thus offers a novel powerful statistical tool to elucidate variation in SB patterns and health.
ClinicalTrials.gov NCT03473145; Registered 22 March 2018; https://clinicaltrials.gov/ct2/show/NCT03473145 ; International Registered Report Identifier (IRRID): DERR1-10.2196/28684.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Hip-worn accelerometer cut-points have poor validity for assessing children's sedentary time, which may partly explain the equivocal health associations shown in prior research. Improved ...processing/classification methods for these monitors would enrich the evidence base and inform the development of more effective public health guidelines. The present study aimed to develop and evaluate a novel computational method (CHAP-child) for classifying sedentary time from hip-worn accelerometer data. Across participant-seasons, CHAP-child correctly classified each epoch as sitting or non-sitting relative to activPAL, with mean balanced accuracy of 87.6% (SD = 5.3%). Sit-to-stand transitions were correctly classified with mean sensitivity of 76.3% (SD = 8.3). For most participant-season level variables, CHAP-child estimates were within + or - 11% (mean absolute percent error MAPE) of activPAL, and correlations between CHAP-child and activPAL were generally very large (> 0.80). For the current practice 100 cpm method, most MAPEs were greater than + or - 30% and most correlations were small or moderate (less than or equai to 0.60) relative to activPAL. There was strong support for the concurrent validity of the CHAP-child classification method, which allows researchers to derive activPAL-equivalent measures of sedentary time, sit-to-stand transitions, and sedentary bout patterns from hip-worn triaxial ActiGraph data. Applying CHAP-child to existing datasets may provide greater insights into the potential impacts and influences of sedentary time in children.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
BACKGROUND:The need for antimicrobial therapies effective against multidrug resistant organisms for children remains unmet. Tigecycline shows antibacterial activity across a broad spectrum of ...bacteria and is approved for treating complicated skin and skin-structure infections, complicated intra-abdominal infections and, in the United States, community-acquired bacterial pneumonia for adult patients. No blinded, randomized phase 3 tigecycline clinical trials on neonates or children have been completed or planned. This review aimed to provide a comprehensive synthesis of all the existing data sources, both on-label and off-label, for tigecycline use in children.
METHODS:Data on tigecycline use in children were identified from published and unpublished sources including clinical trials, expanded access and compassionate use programs, databases of healthcare records and patient safety monitoring.
RESULTS:Pharmacokinetic simulations predicted that tigecycline 1.2 mg/kg (maximum dose 50 mg) every 12 hours (q12h) in children 8–11 years and 50 mg q12h in children 12 to <18 years would achieve exposure similar to adults receiving 50 mg q12h. Available phase 2 pediatric clinical trial data and data from other sources demonstrated similar clinical efficacy between adult and pediatric patients treated with tigecycline. These data showed no new or unexpected safety concerns with tigecycline in children.
CONCLUSIONS:Information presented here may help guide the appropriate use of tigecycline in children with multidrug resistant infections. Continued pharmacovigilance from real-world observational studies may also further refine appropriate use of tigecycline.
Introduction:
Older adults, who already have higher levels of social isolation, loneliness, and sedentary behavior, are particularly susceptible to negative impacts from social distancing mandates ...meant to control the spread of COVID-19. We sought to explore the physical, mental, and social health impacts of the pandemic on older adults and their coping techniques.
Materials and Methods:
We conducted 25 semi-structured interviews with a sub-sample of participants in an ongoing sedentary behavior reduction intervention. Interviews were recorded and transcribed, and iterative coding was used to extract key themes.
Results:
Most participants reported an increase in sedentary behavior due to limitations on leaving their home and increased free time to pursue seated hobbies (e.g., reading, knitting, tv). However, many participants also reported increased levels of intentional physical activity and exercise, particularly outdoors or online. Participants also reported high levels of stress and a large decrease in in-person social connection. Virtual connection with others through phone and video was commonly used to stay connected with friends and family, engage in community groups and activities, and cope with stress and social isolation. Maintenance of a positive attitude and perspective gained from past hardships was also an important coping strategy for many participants.
Discussion:
The COVID-19 pandemic and associated social distancing measures have impacted older adults' perceived levels of activity, stress, and social isolation, but many leveraged technology and prior life experiences to cope. These themes could inform future interventions for older adults dealing with chronic stress and isolation.
Abstract
Background
Early detection of dementia may improve patient care and quality of life, yet up to half of people with dementia are undiagnosed. Electronic health record (EHR) data could be used ...to help identify individuals at risk of having undiagnosed dementia for outreach and assessment, but acceptability to people with dementia and caregivers is unknown.
Methods
We conducted five focus groups at Kaiser Permanente Washington (KPWA), an integrated healthcare system in Washington State, to explore people’s feelings about timing of dementia diagnosis, use of EHR-based tools to predict risk of undiagnosed dementia, and communication about risk. We recruited people enrolled in KPWA who had dementia or mild cognitive impairment, people enrolled in KPWA who had neither diagnosis, and caregivers (i.e., loved ones of people with dementia who assist with various tasks of daily life). People who were non-white or Hispanic were oversampled. Two team members analyzed transcripts using thematic coding.
Results
Forty people (63% women; 59% non-white or Hispanic) participated in the focus groups. Themes that arose included: perceived pros and cons of early dementia diagnosis; questions and concerns about a potential tool to assess risk of undiagnosed dementia; and preferences related to patient-provider conversations disclosing that a person was at high risk to have undiagnosed dementia. Participants supported early diagnosis, describing benefits such as time to adjust to the disease, plan, involve caregivers, and identify resources. They also acknowledged the possible psychosocial toll of receiving the diagnosis. Participants supported use of an EHR-based tool, but some people worried about accuracy and privacy. Participants emphasized that information about risk of undiagnosed dementia should be communicated thoughtfully by a trusted provider and that the conversation should include advice about prognosis, treatment options and other resources when a new dementia diagnosis was made.
Conclusion
People with dementia or mild cognitive impairment, people with neither diagnosis, and caregivers of people with dementia supported using EHR-based tools to help identify individuals at risk of having undiagnosed dementia. Such tools must be implemented carefully to address concerns and ensure that people living with dementia and their caregivers are adequately supported.
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