Open Health Systems Laboratory

BackgroundUncomplicated urinary tract infections (uUTIs) are common bacterial infections.AimTo evaluate the burden of uUTI in England for 1) potential determinants of disease progression; 2) extent and impact of antimicrobial prescribing non-concordant with treatment guidelines; and 3) healthcare burden and economic costs.Design & settingRetrospective cohort study utilising patient data (January 2017–February 2020) from the Clinical Practice Research Datalink (CPRD) linked to English Hospital Episode Statistics.MethodFemale patients aged ≥12 years with a new uUTI between 2018 and 2019, ≥14 months’ continuous CPRD enrolment (≥12 months baseline, ≥2 months follow-up), and ≥1 oral antibiotic prescription ±5 days of uUTI diagnosis were included. Baseline characteristics were described in patients with or without disease progression (hospitalisation for acute pyelonephritis, bacteraemia, or sepsis). Treatment non-concordance with current English guidelines was assessed. Burden (all-cause and urinary tract infection-related healthcare resource use [HCRU] and costs) was evaluated in a 1:1 age and comorbidity-matched uUTI-free cohort.ResultsOf 120 519 patients, 207 (0.2%) had disease progression requiring hospitalisation (during index uUTI episode); determinants included older age, index uUTI home consultation, prior hospitalisation, and medications prescribed for comorbid conditions in the prior 12 months (British National Formulary classes: cardiovascular system, eye, and other drugs and preparations). Non-concordant treatment was observed in 43.5% of patients. All-cause HCRU burden and costs were significantly higher in patients with uUTI versus age and comorbidity-matched controls (P<0.001) at 28 days (£160.06 versus £37.63) and in the 12-month follow-up (£1206.77 versus £460.97).ConclusionAll-cause HCRU burden and costs were significantly higher in patients with uUTI versus matched controls (P<0.001). Hospitalisation for acute pyelonephritis, bacteraemia, or sepsis following uUTI was uncommon.

This systematic literature review (SLR) assessed the humanistic and economic burden of focal epilepsy and primary generalized tonic–clonic seizures (PGTCS) in adults to evaluate these domains in both populations and identify evidence gaps to inform future research. A search was conducted on December 7, 2022, using MEDLINE and Embase to identify studies published from 2012 onwards reporting humanistic burden (patient‐reported or caregiver‐reported outcomes or utilities, qualitative evaluations), economic burden (productivity loss, caregiver and societal costs of epilepsy), and sleep‐related outcomes. Of the 2830 citations identified, 136 were included. Most studies were in the focal epilepsy population; very few studies reported outcomes in the PGTCS population. The presence of epilepsy‐specific instruments varied based on the domain evaluated. Epilepsy exerted considerable humanistic and economic burden. Indicators of poor disease control (e.g., high seizure frequency, resistance to anti‐seizure medications, polypharmacy) increased epilepsy burden. Seizure frequency and type, disease severity, and polypharmacy also affected work productivity. Adults with epilepsy, particularly focal epilepsy, reported higher indirect costs, more sick days accrued, and early entry into retirement. Caregivers similarly reported high productivity loss and absenteeism related to caregiving duties. The results of this SLR highlight the high humanistic and economic burden of focal epilepsy and PGTCS, although limited data were available for the PGTCS population. The results include patient‐reported outcome data specific to focal epilepsy and PGTCS, expanding the limited humanistic burden evidence identified in previous reviews, and show the effect of poor disease control on individuals' lives and as a driver of indirect costs.Plain Language SummaryOur systematic literature review identified studies that evaluated the impact of focal epilepsy and primary generalized tonic–clonic seizures on patients and their caregivers. We found that focal epilepsy negatively impacted patients' mental health and sleep and was associated with higher indirect costs and lower work productivity in people with more severe disease. The impact of primary generalized tonic–clonic seizures on patients was rarely reported, and future research is needed.

Wilson disease (WD) is a rare and potentially fatal genetic disorder caused by accumulation of toxic levels of copper. Current treatments include chelating agents and/or zinc. We characterized real-world US treatment patterns in patients with WD. This retrospective, observational medical chart review utilized deidentified clinical data, including treatment patterns, abstracted from patient medical charts between 01/2012 and 06/2017. Line of therapy was assessed based on disease presentation and aggregated. Index treatment was defined as the first line of therapy, followed by second line of therapy and third line of therapy. Results were summarized using descriptive statistics. A total of 225 patients were included (mean [SD] age at diagnosis: 24.7 [9.8] years). Initial disease presentation was both neurologic/psychiatric and hepatic in 52.9%, followed by neurologic/psychiatric (20.0%), hepatic (16.9%), and asymptomatic (10.2%). Median (first and third quartiles) duration of follow-up from diagnosis was 39.5 (33.8-60.4) months. The most common first line of therapy was penicillamine monotherapy in 45.5%, followed by trientine monotherapy (26.1%) and chelator/zinc combination therapy (21.2%). A total of 167/222 (75.2%) patients remained on first line of therapy during the follow-up period. Of the 13.5% who switched to second line of therapy, most changed to trientine monotherapy (53.3%). All those who switched to third line of therapy transitioned to zinc monotherapy (100.0%). Unexpectedly, 11.3% discontinued first line of therapy without transitioning to a subsequent therapy. The primary rationale for index monotherapy selection was improved efficacy (61.6%). Most discontinuations were due to side effects/tolerability (40.8%). Treatment patterns varied by initial disease presentation, practice setting, physician specialty, and geographic location. These results demonstrate a lack of consensus in the US regarding first-line treatment for patients with WD. Evidence-based treatment pathways informed by high-quality clinical trials for improved health outcomes are needed.

Transthyretin amyloidosis (ATTR) is a progressive, heterogeneous rare disease manifesting as ATTR polyneuropathy (ATTR-PN), ATTR cardiomyopathy (ATTR-CM), or a mixed phenotype. Tafamidis meglumine (20mg po qd) is approved in some markets to delay neurologic progression in ATTR-PN, while high-dose tafamidis (80/61mg po qd) is approved worldwide to reduce cardiovascular mortality and cardiovascular-related hospitalization in ATTR-CM. The objective of this study was to assess the real-world benefit of high-dose tafamidis for delaying neurologic progression in patients with mixed-phenotype variant ATTR-CM (ATTRv-CM). This exploratory, retrospective, observational cohort study evaluated anonymized electronic medical records and included adult patients with mixed-phenotype ATTRv-CM treated with high-dose tafamidis for at least 6months. Neurologic assessments included the Medical Research Council (MRC) Scale for Muscle Strength, Neuropathy Impairment Score (NIS) muscle weakness subscale, and Polyneuropathy Disability (PND) instrument. Modified body mass index (mBMI) was also assessed. Patients (N = 10) started tafamidis treatment an average of 3.8months after diagnosis, with an average treatment duration of 20.8months. Seven of 10 patients demonstrated normal muscle strength on the MRC scale throughout the study, and 9 of 10 patients had no decline in muscle strength during the post-treatment period. The NIS muscle weakness subscale score was ≤ 60 for all patients in the study at all time points, suggesting normal function to mild impairment. Six of 10 patients had no change in walking capacity as measured by the PND instrument at pre- and post-assessments, while one-third of patients had a decrease in PND stage (signaling improvement) from pre- to post-assessment. mBMI remained relatively stable throughout the study. This is the first real-world study to demonstrate the potential value of high-dose tafamidis for delaying neurologic disease progression in patients with mixed-phenotype ATTRv-CM. The findings underscore the importance of multidisciplinary assessment for patients with ATTR amyloidosis. ClinicalTrials.gov: NCT05139680.

Pulmonary arterial hypertension (PAH) is a rare, progressive disease associated with significant morbidity and mortality. The phase 3 STELLAR trial tested sotatercept plus background therapy (BGT) versus placebo plus BGT. BGT was comprised of mono-, double-, or triple-PAH targeted therapy. Building on STELLAR findings, we employed a population health model to assess the potential long-term clinical impact of sotatercept. Based on the well-established ESC/ERS 4-strata risk assessment approach, we developed a six-state Markov-type model (low risk, intermediate-low risk, intermediate-high risk, high risk, lung/heart-lung transplant, and death) to compare the clinical outcomes of sotatercept plus BGT versus BGT alone over a lifetime horizon. State-transition probabilities were obtained from STELLAR. Risk stratum-adjusted mortality and lung/heart-lung transplant probabilities were based on COMPERA PAH registry data, and the post-transplant mortality probability was obtained from existing literature. Model outcomes were discounted at 3% annually. Sensitivity analyses were conducted to examine model robustness. In the base case, sotatercept plus BGT was associated with longer life expectancy from model baseline (16.5 vs 5.1years) versus BGT alone, leading to 11.5years gained per patient. Compared with BGT alone, sotatercept plus BGT was further associated with a gain in infused prostacyclin-free life years per patient, along with 683 PAH hospitalizations and 4 lung/heart-lung transplant avoided per 1000 patients. According to this model, adding sotatercept to BGT increased life expectancy by roughly threefold among patients with PAH while reducing utilization of infused prostacyclin, PAH hospitalizations, and lung/heart-lung transplants. Real-world data are needed to confirm these findings. ClinicalTrials.gov identifier, NCT04576988 (STELLAR).

Abstract Disclosure: Z. Li: Employee; Self; Employee of Kyowa Kirin, Inc., Princeton, NJ, USA. O. Zaidi: Other; Self; Employee of OPEN Health and received funding to complete this research. C. Chukwu: Other; Self; Employee of OPEN Health and received funding to complete this research. H. Heerssen: Other; Self; Employee of Kyowa Kirin, Inc., Princeton, NJ, USA. Y. Zhao: Other; Self; Employee of Kyowa Kirin, Inc., Princeton, NJ, USA. A. Dale: Other; Self; Employee of Kyowa Kirin, Inc., Princeton, NJ, USA. M. Bernauer: Other; Self; Employee of OPEN Health and received funding to complete this research. Introduction: X-linked hypophosphatemia (XLH) is a rare genetic musculoskeletal disease and the most common form of heritable hypophosphatemic rickets. The objective of this review was to summarize the disease burden and treatment patterns of XLH in the United States (US) and Canada. Methods: Publications from January 1, 2015, to June 3, 2022, were searched using the Medline, Embase, and EconLit databases. Observational studies reporting epidemiology, humanistic burden, economic burden, and treatment patterns in the US and Canada were included. Evidence on epidemiology, humanistic burden, and treatment patterns was expanded to other countries as limited US and Canada studies were identified. Results: A total of 1,218 publications were screened; 42 publications were included (6 from US or Canada; 36 did not report location or were from other countries). Epidemiology data (i.e., incidence, prevalence, mortality) were limited for patients with XLH in the US and Canada. The estimated number of people in the US with XLH was &amp;lt;50,000 in 2021. Globally, the incidence of XLH was estimated at 3.9 per 100,000 live births, and the prevalence ranged from 1.4 per 100,000 to 4.8 per 100,000. One United Kingdom-based study estimated an XLH mortality rate of 12.1 per 1,000 person-years. Sixteen publications reported clinical manifestations of XLH, which showed a high level of heterogeneity. Among children with XLH, frequent clinical manifestations (&amp;gt;80% in 1 or more publications) included active rickets, diminished height, gait disturbance, bone or joint pain, and leg bowing. Among adults with XLH, frequent clinical manifestations (&amp;gt;80% in 1 or more publications) included short stature, leg deformity, musculoskeletal pain, fatigue, osteoarthritis, enthesophytes, gait disturbance, dental abscesses, and joint stiffness or restricted range of motion. Humanistic burden data from the US was limited to 2 non-trial publications, which used, respectively, the 36-Item Short Form Survey (SF-36) and the Knee Injury and Osteoarthritis Outcome Score-Physical Function Shortform (KOOS-PS) instruments. These 2 publications reported lower health-related quality of life for patients with XLH compared with the general population. No publication was identified on economic burden, treatment patterns, or XLH guidelines in the US or Canada. A consensus statement from a US panel of experts recommends individualization of monitoring and disease management due to clinical heterogeneity. Conclusions: There are limited published data on disease burden or treatment patterns for XLH in the US or Canada. Further research should consider the epidemiological, humanistic, and economic burden of XLH among pediatric and adult populations in these countries. Presentation: Thursday, June 15, 2023