Predictors for improvement in patient-reported outcomes: post hoc analysis of a phase 3 randomized, open-label study of eculizumab and ravulizumab in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation leading to intravascular hemolysis (IVH), thrombosis, and impairments in quality of life (QoL). The aim of this study was to identify the clinical drivers of improvement in patient-reported outcomes (PROs) in patients with PNH receiving the complement component 5 (C5) inhibitors eculizumab and ravulizumab.This post hoc analysis assessed clinical outcomes and PROs from 246 complement inhibitor-naive patients with PNH enrolled in a phase 3 randomized non-inferiority study that compared the C5 inhibitors ravulizumab and eculizumab (study 301; NCT02946463). The variables of interest were lactate dehydrogenase (LDH) levels, a surrogate measure of IVH, and hemoglobin (Hb) levels. PROs were collected using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) to assess fatigue and QoL, respectively.Improvements in absolute mean LDH levels were significantly associated with improvements in mean FACIT-F score (p = 0.0024) and EORTC QLQ-C30 global health (GH) score (p < 0.0001) from baseline to day 183. Improvements in scores were achieved despite a non-significant increase in Hb levels. To understand the interaction between LDH and Hb, a regression analysis was performed: LDH response with Hb improvements was a significant predictor of improvement in fatigue. The independent effect of improved Hb did not significantly affect FACIT-F or EORTC QLQ-C30 GH scores.These findings suggest that LDH levels are an important determinant of fatigue and QoL outcomes in patients with PNH. CTR: NCT02946463, October 27, 2016.

Impact of Caring for Individuals With Heart Failure in the United States: A Systematic Literature Review.

BACKGROUND: Given the functional impairments and complex care routines associated with heart failure (HF), patients often rely on the support of informal caregivers. Although the importance of caregivers' roles is widely recognized, the intensity and time required for care duties may negatively impact caregiver health and well-being, potentially precipitating their own need for care. OBJECTIVE: The aim of this study was to synthesize estimates of economic, clinical, burden, and health-related quality-of-life impact among caregivers of those with HF in the United States. METHODS: A systematic review was conducted to identify studies reporting estimates of caregiver impact. Abstract and full-text review as well as data extraction were performed according to established guidelines. Patient and caregiver characteristics were summarized, as well as estimates of impact of caring for those with HF. RESULTS: From 3680 abstracts, 44 studies reporting caregiver burden estimates were included. Mean caregiver age ranged from 41.4 to 71.4 years; caregivers were primarily female (range, 49%-100%) and the patient's spouse/partner (21%-100%). Time spent caregiving (6 studies) ranged from 2 to 52 h/wk, and depression was identified in up to 40% of caregivers (9 studies). Numerous instruments were used to measure burden, which consistently documented the high impact of caregiving. CONCLUSIONS: This review demonstrates the multifaceted impact of caregiving for patients with HF. Despite limited data, notable findings included the considerable burden to caregivers, variability in time spent caregiving, and frequent experience of depression among caregivers, possibly leading to increased healthcare resource use. Future research is needed to better characterize the caregiving impact in HF, including evaluating the drivers of burden.

Application of text mining to the development and validation of a geographic search filter to facilitate evidence retrieval in Ovid MEDLINE: An example from the United States.

BACKGROUND: Given the increasing volume of published research in bibliographic databases, efficient retrieval of evidence is crucial and represents an opportunity to integrate novel techniques such as text mining. OBJECTIVES: To develop and validate a geographic search filter for identifying research from the United States (US) in Ovid MEDLINE. METHODS: US and non-US citations were collected from bibliographies of evidence-based reviews. Citations were partitioned by US/non-US status and randomly divided to a training and testing set. Using text mining, common one- and two-word terms in title/abstract fields were identified, and frequencies compared between US/non-US citations. RESULTS: Common US-related terms included (as ratio of frequency in US/non-US citations) US populations and geographic terms [e.g., 'Americans' (15.5), 'Baltimore' (20.0)]. Common non-US terms were non-US geographic terms [e.g., 'Japan' (0.04), 'French' (0.05)]. A search filter was developed with 98.3% sensitivity and 82.7% specificity. DISCUSSION: This search filter will streamline the identification of evidence from the US. Periodic updates may be necessary to reflect changes in MEDLINE's controlled vocabulary. CONCLUSION: Text mining was instrumental to the development of this search filter. A novel technique generated a gold standard set comprising >20,000 citations. This method may be adapted to develop subsequent geographic search filters.

Patterns of Clinical Progression Among Patients With Autosomal Recessive Limb-Girdle Muscular Dystrophy: A Systematic Review.

OBJECTIVES: As the clinical course of autosomal recessive limb-girdle muscular dystrophy (LGMDR) is highly variable, this study characterized the frequency of loss of ambulation (LOA) among patients by subtype (LGMDR1, LGMDR2, LGMDR3-6, LGMDR9, LGMDR12) and progression to cardiac and respiratory involvement among those with and without LOA. METHODS: Systematic literature review. RESULTS: From 2929 abstracts screened, 418 patients were identified with ambulatory status data (LOA: 265 [63.4%]). Cardiac and/or respiratory function was reported for 142 patients (34.0%; all with LOA). Among these, respiratory involvement was most frequent in LGMDR3-6 (74.1%; mean [SD] age 23.9 [11.0] years) and cardiac in LGMDR9 (73.3%; mean [SD] age 23.7 [17.7] years). Involvement was less common in patients without LOA except in LGMDR9 (71.4% respiratory and 52.4% cardiac). CONCLUSIONS: This study described the co-occurrence of LOA, cardiac, and respiratory involvement in LGMDR and provides greater understanding of the clinical progression of LGMDR.

Progression to Loss of Ambulation Among Patients with Autosomal Recessive Limb-girdle Muscular Dystrophy: A Systematic Review.

BackgroundThe impact of age at autosomal recessive limb girdle muscular dystrophy (LGMDR) onset on progression to loss of ambulation (LOA) has not been well established, particularly by subtype. OBJECTIVES: To describe the characteristics of patients with adult-, late childhood-, and early childhood-onset LGMDR by subtype and characterize the frequency and timing of LOA. METHODS: A systematic review was conducted in MEDLINE, Embase and the Cochrane library. Frequency and timing of LOA in patients with LGMDR1, LGMDR2/Miyoshi myopathy (MM), LGMDR3-6, LGMDR9, and LGMDR12 were synthesized from published data. RESULTS: In 195 studies, 695 (43.4%) patients had adult-, 532 (33.2%) had late childhood-, and 376 (23.5%) had early childhood-onset of disease across subtypes among those with a reported age at onset (n = 1,603); distribution of age at onset varied between subtypes. Among patients with LOA (n = 228), adult-onset disease was uncommon in LGMDR3-6 (14%) and frequent in LGMDR2/MM (42%); LGMDR3-6 cases with LOA primarily had early childhood-onset (74%). Mean (standard deviation [SD]) time to LOA varied between subtypes and was shortest for patients with early childhood-onset LGMDR9 (12.0 [4.9] years, n = 19) and LGMDR3-6 (12.3 [10.7], n = 56) and longest for those with late childhood-onset LGMDR2/MM (21.4 [11.5], n = 36). CONCLUSIONS: This review illustrated that patients with early childhood-onset disease tend to have faster progression to LOA than those with late childhood- or adult-onset disease, particularly in LGMDR9. These findings provide a greater understanding of progression to LOA by LGMDR subtype, which may help inform clinical trial design and provide a basis for natural history studies.

Cost burden of breakthrough hemolysis in patients with paroxysmal nocturnal hemoglobinuria receiving ravulizumab versus eculizumab.

Objectives: Although complement inhibition is highly effective, patients with paroxysmal nocturnal hemoglobinuria (PNH) may experience intravascular breakthrough hemolysis (BTH). Underlying causes may include elevated free C5, pregnancy, or non-pregnancy complement-activating conditions (e.g. infections). This study compared BTH-related resource utilization and costs in PNH patients treated with eculizumab versus ravulizumab. Methods: A cost model was developed using data from a targeted literature review and a survey of experienced clinicians. Costs associated with BTH episodes were calculated by cause and weighted by the proportion attributed to each cause and the cost of treating each episode. The model captured direct medical costs in 2018 US dollars. Annual BTH-related healthcare resource utilization was also calculated. Results: BTH episodes in the literature were commonly associated with elevated lactate dehydrogenase and aspartate aminotransferase, hemoglobinuria, transfusion needs, and/or recurrence of PNH symptoms. The majority of BTH management costs in eculizumab-treated patients related to changing from the approved dosing regimen following an episode of BTH, rather than acute management. No ongoing dosing changes were expected for ravulizumab-treated patients following episodes of BTH, substantially reducing its ongoing management costs. Resource utilization was greater for eculizumab-treated patients than ravulizumab-treated patients due to higher incidence of BTH, and risk of elevated free C5-related BTH. Total incremental cost was substantially lower for ravulizumab- vs eculizumab-treated patients ($407 vs $9379); results were consistent when pregnant women were not included ($386 vs $3472). Conclusion: Overall resource use and costs for BTH are estimated to be lower for PNH patients receiving ravulizumab compared with eculizumab.

A US cost-minimization model comparing ravulizumab versus eculizumab for the treatment of atypical hemolytic uremic syndrome.

AIMS: Ravulizumab, engineered from eculizumab, provides sustained C5 inhibition in atypical hemolytic uremic syndrome (aHUS) while reducing dosing frequency (every 8 vs 2 weeks, respectively). Treatment choice often carries significant financial implications. This study compared the economic consequences of ravulizumab and eculizumab for treating aHUS. MATERIALS AND METHODS: A cost-minimization model compared direct medical costs for ravulizumab and eculizumab in treating aHUS, assuming equivalent efficacy and safety, and took a US payer perspective, a lifetime horizon, and a 3.0% cost discount rate. The base case modeled adult and pediatric treatment-naïve populations, with characteristics based on clinical trials, and treatment patterns (duration, discontinuation, re-initiation) derived from eculizumab studies with long-term follow-up. Treatment costs (2019 US$) were based on wholesale drug acquisition costs, Centers for Medicare & Medicaid fee schedules, and published disease management studies. Sensitivity analyses were conducted by adjusting relevant variables. RESULTS: Ravulizumab provided lifetime per-patient cost reductions (discounted) of 32.4% and 35.5% vs eculizumab in adult and pediatric base cases, respectively. Total costs for ravulizumab vs eculizumab were $12,148,748 and $17,979,007, respectively, for adults, and $11,587,832 and $17,959,814, respectively, for children. Pre-discontinuation treatment contributed the largest proportion of total costs for ravulizumab (94.8% and 88.0%) and eculizumab (94.8% and 87.8%) in adults and children, respectively. Across sensitivity analyses, ravulizumab provided cost reductions vs eculizumab. LIMITATIONS: The model included several typical assumptions. Base case patients with more severe stages of chronic kidney disease were assumed not to discontinue treatment, nor to experience an excess mortality risk in either treatment arm, which may not reflect real-world clinical observations. Additionally, rebates and discounts on medication acquisition or administration were not considered. CONCLUSIONS: In US patients with aHUS, ravulizumab provided cost reductions of 32.4-35.5% vs eculizumab, with a reduced dosing frequency for ravulizumab. The magnitude of reductions was consistent across sensitivity analyses.

A review of published anticholinergic scales and measures and their applicability in database analyses.

BACKGROUND/OBJECTIVES: Available metrics for characterizing cumulative anticholinergic exposure over time may not be well suited for use across all US data sources. In this review, the properties of existing anticholinergic scales and measures were evaluated to determine their suitability for implementation in observational studies relying on administrative data. METHODS: A targeted literature review was conducted to identify available anticholinergic scales and measures. Suitability of the identified scales and measures for quantification of anticholinergic exposure was evaluated based on pre-defined criteria. Agreement between selected scales was characterized by the percentage overlap of included drugs and inter-scale Spearman's correlation of scores. RESULTS: Sixteen scales were identified; six were relevant and suitable for the quantification of anticholinergic exposure. When implemented on administrative data the Anticholinergic Drug Scale and Anticholinergic Cognitive Burden scale demonstrated the most agreement, with an inter-scale correlation coefficient of 0.82. Scale performance varied by outcome of interest, and underlying disease profile of the population of interest. Variability across the two measures ("average daily dose" and "cumulative dose") was observed, with neither considering both dose and anticholinergic potency in score calculations. CONCLUSIONS: Accurate quantification of anticholinergic burden is important in assessing relative risks versus benefits of prescribing anticholinergic medications. In this review, the Anticholinergic Drug Scale and the Anticholinergic Cognitive Burden scale and the average daily dose and cumulative dose measures, were determined to be well suited for the quantification of anticholinergic exposure, particularly in the context of administrative data analyses; however, methods to characterize anticholinergic burden through consideration of both anticholinergic dose and potency are needed.

An Evaluation of Longitudinal Measures of Anticholinergic Exposure for Application in Retrospective Administrative Data Analyses.

INTRODUCTION: As continuous exposure to anticholinergics has been associated with adverse outcomes, accurately measuring exposure is important. However, no gold standard measure is available, and the performance of existing measures has not been compared. Our objective was to compare the properties of the Cumulative Anticholinergic Burden (CAB) measure against two existing measures of anticholinergic exposure and to assess their compatibility for use in observational studies based on claims data. METHODS: The average daily dose, cumulative dose and CAB measures were evaluated on: the applicability for use with anticholinergic burden scales, the ability to consider duration and/or accumulation of exposure, and consideration of anticholinergic dose, potency, and residual effect. To calculate each measure empirically, Truven MarketScan claims data from 2012 to 2015 were analyzed. Cumulative anticholinergic exposure over 1-year post-enrollment was calculated for each measure using Anticholinergic Cognitive Burden scale scores. Median [interquartile range (IQR)] and ranges of measure scores, and Spearman's correlation coefficients between measures, were estimated. Due to the differing methods of calculation, the absolute values of each score cannot be compared. RESULTS: The properties of the different measures varied, with only the CAB considering both dose and theoretical potency. The cohort included 99,742 individuals (mean age = 73.1 years; 54.9% female). Among individuals prescribed anticholinergics (n = 55,969), 1-year median (IQR) scores based on average daily dose, cumulative dose and CAB measures were 0.9 (0.3-1.5), 16.9 (7.3-33.9) and 203 (68-500), respectively. Measures were highly inter-correlated (r2 = 0.74-0.83). CONCLUSIONS: Considering both potency and dose, the CAB may prove a more comprehensive measure of anticholinergic burden; however, additional research is necessary to demonstrate whether it has any association with relevant health-related outcomes. FUNDING: Astellas Pharma Global Development, Inc.

Serum Uric Acid and the Risk of Incident and Recurrent Gout: A Systematic Review.

OBJECTIVE: Lowering serum uric acid (SUA) levels can essentially cure gout; however, this is not widely practiced. To summarize epidemiologic evidence related to this causal link, we conducted a systematic review of the published literature reporting the association between SUA level and incident and recurrent gout (i.e., gout flares). METHODS: We systematically searched Medline, EMBASE, and the Cochrane Database of Systematic Reviews using separate search strategies for incident gout and recurrent gout. We screened 646 abstracts to identify 8 eligible articles reporting gout incidence and 913 abstracts to identify 18 articles reporting recurrent gout. RESULTS: For both gout incidence and recurrence, a graded trend was observed where the risk was increased with higher SUA levels. Gout incidence rates per 1000 person-years from population-based studies ranged from 0.8 (SUA ≤ 6 mg/dl) to 70.2 cases (SUA ≥ 10 mg/dl). Recurrent gout risk in clinical cohorts ranged from 12% (SUA ≤ 6 mg/dl) to 61% (SUA ≥ 9 mg/dl) among those receiving urate-lowering therapy (ULT), and 3.7% (SUA 6-7 mg/dl) to 61% (SUA > 9.3 mg/dl) after successful ULT. Retrospective database studies also showed a graded relationship, although the strength of the association was weaker. Studies reporting mean flares or time-to-flare according to SUA showed similar findings. CONCLUSION: This systematic review confirms that higher SUA levels are associated with increased risk of incident and recurrent gout in a graded manner. Although few prospective cohorts have evaluated incident and recurrent gout according to SUA, the existing evidence underscores the need to treat to SUA targets, as recommended by the American College of Rheumatology and the European League Against Rheumatism.

Incidence of acute care adverse events and long-term health-related quality of life in patients with TSCI.

BACKGROUND CONTEXT: Adverse events (AEs) with significant resultant morbidity are common during the acute hospital care of patients with traumatic spinal cord injury (TSCI). The Rick Hansen SCI Registry (RHSCIR) collects Canada-wide data on patients with TSCI, such as sociodemographic, injury, diagnosis, intervention, and health outcome details. These data contribute to an evidence base for informing best practice and improving SCI care. As the RHSCIR captures data on patients from prehospital to community phases of care, it is an invaluable resource for providing information on health outcomes resulting from TSCI, including outcomes related to AEs. PURPOSE: To determine the incidence and types of AEs occurring in patients with TSCI during acute care and the impact on length of stay (LOS) and health-related quality of life (HRQOL). STUDY DESIGN/SETTING: Prospective cohort study at an academic quaternary referral center. PATIENT SAMPLE: Patients with TSCI discharged from our institution between 2008 and 2010 were identified using the RHSCIR. The RHSCIR includes patients admitted to one of the participating centers across Canada, who have been clinically diagnosed with an acute TSCI or classified as AIS A, B, C, D, or cauda equina. OUTCOME MEASURES: Acute-phase LOS and HRQOL were assessed for impact resulting from the number and type of AEs experienced. Health-related quality of life was determined using the short-form 36 (SF-36) physical and mental component summary scores and functional independence measure. METHODS: Data related to patients' injury, diagnoses, hospital admission, and SF-36 scores were obtained from the local RHSCIR. Data on intra-, pre-, and postoperative AEs were collected prospectively using the Spine Adverse Events Severity System data collection system, documenting all AEs experienced by each patient. Multivariate analyses were performed to determine whether patient and injury characteristics were associated with the number and type of AEs experienced and whether these were associated with LOS and HRQOL determined on follow-up. RESULTS: One hundred seventy-one patients with TSCI were included, 81.3% were men and mean age at injury was 47.2±20.3 years. Adverse events occurred in 77.2% of patients, 14.6% experienced an intraoperative and 73.7% experienced a pre/postoperative event. The most frequent pre/postoperative AEs were urinary tract infections (UTIs) (32.2%), pneumonias (32.8%), neuropathic pain (15.2%), decubitus ulcers (14.6%), and delirium (18.7%). Length of stay was significantly affected by decubitus ulcers, delirium, pneumonias, and UTIs (p<.01), increasing 1.7 (UTIs) to 2.2 (decubitus ulcers) times compared with patients without the specific AEs. Health-related quality of life was not affected by acute care AEs but rather those identified at 1-year follow-up. CONCLUSIONS: This prospective study found that more than 77% of patients with TSCI sustain an AE during acute hospital care, significantly higher than previously reported. We demonstrate the utility of a dedicated AE collection system and the effect of these events on health status.

Onset, risk factors, and impact of delirium in patients with traumatic spinal cord injury.

Delirium is a commonly reported acute care adverse event in patients with traumatic spinal cord injury (TSCI), but studies specifically investigating it in this population are lacking. The purpose of this study was to characterize the onset, risk factors, and impact of delirium in patients with TSCI. Patients discharged between 2008 and 2010 were identified from a prospective registry in an acute SCI center. Controls were matched to delirium cases based on date of discharge from acute care. Patient characteristics, risk factors, and the hospital unit (intensive care, spine step-down, spine ward) in which delirium occurred were collected retrospectively. Length of stay (LOS) was calculated and compared between cases and controls. A predictive model was built for patient characteristics and risk factors associated with delirium using logistical regression. There were 192 patients identified from the study group; 34 (17.7%) were delirium cases and 34 were selected as controls. Most delirious episodes were reported during high acuity care (76.5%). The median time interval between injury and delirium identification was 8.5 days (interquartile range=5-31). Age at injury (p<0.01) and initial motor score (p<0.05) were significantly associated with delirium. Patients with delirium had significantly greater LOS than controls (median LOS=46.9 vs. 15.3 days respectively, p<0.0001). Elderly patients who sustain a TSCI and have a low motor score on admission are at increased risk of delirium. These results could contribute to the development of a screening program to address the problem of delirium in the TSCI population.