Real-World Eculizumab Dosing Patterns Among Patients with Paroxysmal Nocturnal Hemoglobinuria in a US Population.

Purpose: Current pharmacologic management of paroxysmal nocturnal hemoglobinuria (PNH) consists of C5 inhibitors, eculizumab and ravulizumab; however, because patients experience incomplete symptom control, off-label doses may be utilized. We conducted a retrospective, longitudinal cohort study of provider-based claims data to assess the real-world eculizumab dosing patterns in PNH patients. Patients and Methods: Patients were ≥12 years, received ≥2 eculizumab infusions between January 1, 2015 and September 30, 2019, and had ≥3 months of continuous clinical activity prior to index. The index date was the first claim for eculizumab. Patients with ≥1 diagnosis of another indication for eculizumab were excluded. Treatment patterns including the proportion with high, label-recommended, and low dosages during induction (first 28 days) and maintenance (beginning day 29) phases were described. The proportion and time-to-first dose escalation, defined as an increase in dose or frequency of infusion, were assessed among a subset of patients (ie, escalation analysis cohort). Results: A total of 707 patients were examined. Mean (standard deviation [SD]) starting dose was 862mg (412mg) and was higher than label-recommended 600mg for 64% of the patients. Mean (SD) dose per infusion was 859mg (391mg) during the induction phase; average dose was higher than label-recommended 600mg for 68%. Mean (SD) dose per infusion during the maintenance phase was 1005mg (335mg); average dose was higher than label-recommended 900mg for 43%. Dose escalation occurred in 40/121 escalation analysis cohort patients. Median time-to-first dose escalation was ~12 months. Conclusion: Results suggest that deviations from label-recommended dosing patterns were common. Future budget impact assessments of eculizumab should account for real-world dosing patterns to comprehensively assess costs and benefits.

Comparative effectiveness of pegcetacoplan versus ravulizumab in patients with paroxysmal nocturnal hemoglobinuria previously treated with eculizumab: a matching-adjusted indirect comparison.

OBJECTIVE: In the absence of a head-to-head study, we assessed the comparative effectiveness of pegcetacoplan, a targeted C3 complement inhibitor, vs. ravulizumab, a C5 complement inhibitor, among patients with paroxysmal nocturnal hemoglobinuria (PNH) previously treated with eculizumab using matching-adjusted indirect comparison methodology. METHODS: Individual patient data from the PEGASUS study (NCT03500549) comparing pegcetacoplan and eculizumab enabled adjustment for baseline differences compared with published results from the ALXN1210-PNH-302 study (NCT03056040), comparing ravulizumab and eculizumab. Adjusted differences and 95% confidence intervals (CIs) were computed via weighted Wald tests for comparisons of pegcetacoplan vs. ravulizumab, anchored to the common comparator eculizumab. RESULTS: Sixty-eight patients from PEGASUS (36 pegcetacoplan; 32 eculizumab) and 195 from ALXN1210-PNH-302 (97 ravulizumab; 98 eculizumab) were included. Compared with ravulizumab, treatment with pegcetacoplan was associated with more transfusion avoidance (adjusted difference [95% CI] = +71.4% [53.5%, 89.3%]), hemoglobin level stabilization (+75.5% [56.4%, 94.6%]), lactate dehydrogenase (LDH) level normalization (+64.0% [41.8%, 86.1%]), and fewer blood transfusions (-5.7 units [-7.2, -4.2]). Additionally, patients who received pegcetacoplan experienced clinically meaningful improvements in fatigue (+8.2 points [3.8, 12.6]), global health status (+9.6 points [0.1, 19.0]), physical functioning (+11.5 points [3.6, 19.5]), and fatigue symptoms (-13.3 points [-23.7, -3.0]), compared with ravulizumab. Mean change from baseline in LDH level was not significantly different for pegcetacoplan vs. ravulizumab. CONCLUSIONS: Results suggest that among patients previously treated with eculizumab, clinical, hematological, and quality of life endpoints were better for patients who received the C3 complement inhibitor pegcetacoplan vs. patients who received ravulizumab, a C5 complement inhibitor.

Real-World Healthcare Resource Utilization (HRU) and Costs of Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Receiving Eculizumab in a US Population.

INTRODUCTION: To evaluate the economic burden and treatment patterns of patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with eculizumab, a C5 inhibitor, who were defined as blood transfusion-dependent (TD) versus blood transfusion-free (TF) in the US population. METHODS: Patients aged at least 12 years with at least two claims for eculizumab infusion (first claim was the index date) were identified from the IBM® MarketScan® Research Databases (April 1, 2014-September 30, 2019). The overall PNH eculizumab user cohort was stratified into the TD cohort (i.e., at least one claim for blood transfusion within 6 months following any eculizumab infusion, including on the infusion date) or the TF cohort (i.e., all non-TD patients). Treatment patterns, healthcare resource utilization (HRU), and costs were evaluated and compared during follow-up (i.e., index date to end of enrollment or data availability). RESULTS: Of 151 patients in the overall cohort (mean age 36.7 years; 55.6% female), 55 were TD (mean age 35.1 years; 67.3% female) and 96 were TF (mean age 37.6 years; 49.0% female). A total of 61% of patients (TD, 66%; TF, 58%) discontinued eculizumab, with TD patients having a shorter median time to discontinuation (TD, 0.5 years; TF, 0.9 years). TD patients had more all-cause hospitalizations than TF patients (p < 0.05). TD patients incurred higher all-cause direct medical costs (adjusted cost difference = $247,848) and medical-related absenteeism costs (adjusted cost difference = $4186) than TF patients (all p < 0.05), largely driven by hospitalizations. Similar trends were observed for PNH-related HRU and costs. CONCLUSIONS: The economic burden of patients with PNH treated with eculizumab is greater among those dependent on blood transfusions.

Treatment of transfusional iron overload in patients with myelodysplastic syndrome or severe anemia: data from multicenter clinical practices.

BACKGROUND: Patients with myelodysplastic syndrome (MDS) or severe anemia requiring repeated red blood cell (RBC) transfusions risk developing transfusional iron overload, which can reduce survival. Iron chelation therapy (ICT) has been shown to improve survival and quality of life in patients; however, ICT utilization in clinical practices is not well understood. STUDY DESIGN AND METHODS: Medical records of patients diagnosed with MDS or severe anemia at least 6 months before data extraction, aged at least 21 years at diagnosis, and who received at least one RBC transfusion were reviewed. ICT eligibility was defined as at least 20 units of RBCs transfused or at least two serum ferritin levels exceeding 1000 microg/L. Study endpoint was ICT treatment rate among ICT-eligible patients with lower-risk MDS (International Prognostic Scoring System [low or intermediate-1]; World Health Organization [refractory anemia {RA}, refractory anemia with ringed sideroblasts {RARS}, refractory cytopenia with multilineage dysplasia {RCMD}, refractory cytopenia with multilineage dysplasia and ringed sideroblasts, or 5q]; French-American-British [RA/RARS]). RESULTS: Among 78 ICT-eligible patients with lower-risk MDS, 32 (41%) received ICT. At ICT initiation, treated patients received on average 13.3 transfusions (27.6 units) and mean first post-ICT initiation serum ferritin was twice the MDS Foundation recommendation at 1949 microg/L. Median overall survival for all ICT-eligible patients was significantly longer for those ICT-treated patients than untreated patients (8.7 years vs. 4.7 years, log-rank p = 0.02; multivariate hazard ratio 0.372, p = 0.03). CONCLUSION: This study finds only 41% of ICT-eligible patients with lower-risk MDS received ICT in clinical practice, and treatment was initiated later than recommended. Receipt of ICT was associated with significantly longer survival.

The cost of health care for children and adults with sickle cell disease.

Although sickle cell disease (SCD) is marked by high utilization of medical resources, the full cost of care for patients with SCD, including care not directly related to SCD, is unknown. The purpose of this study was to estimate the total cost of medical care for a population of children and adults with SCD. We used data from individuals diagnosed with SCD enrolled in the Florida Medicaid program during 2001-2005 to estimate total, SCD-related, and non-SCD-related cost per patient-month based on patient age at the time of health care use. Across the 4,294 patient samples, total health care costs generally rose with age, from $892 to $2,562 per patient-month in the 0-9- and 50-64-year age groups, respectively. Average cost per patient-month was $1,389. Overall, 51.8% of care was directly related to SCD, the majority of which (80.5%) was associated with inpatient hospitalizations. Notably, non-SCD-related costs were substantially higher than those reported for the general US population. These results suggest a discounted (3% discount rate) lifetime cost of care averaging $460,151 per patient with SCD. Interventions designed to prevent SCD complications and avoid hospitalizations may reduce the significant economic burden of the disease.

Venous thromboembolism after orthopedic surgery: implications of the choice for prophylaxis.

INTRODUCTION: Venous thromboembolism (VTE) is an important cause of morbidity and mortality following major orthopedic surgeries. In clinical trials, fondaparinux and low molecular weight heparins have been shown to be more effective than unfractionated heparin (UFH) in preventing VTE. We retrospectively analyzed a large hospital discharge database to assess the occurrence of clinically detected VTE as a function of the injectable antithrombotic agent used for VTE prophylaxis in orthopedic surgery. METHODS: The Premier's Perspective database, representing over 500 hospitals across the US, was utilized to identify patients receiving dalteparin, enoxaparin, fondaparinux, or UFH following hip or knee replacement or hip fracture surgery between January 2003 and March 2005. The primary outcome was the proportion of patients in each cohort with a VTE, while secondary outcomes included VTE occurrence during index hospitalization, and proportion of patients with a VTE-associated hospital readmission. RESULTS: A total of 144,806 patients were included in the study. Significantly fewer fondaparinux patients experienced a VTE event (1.5%) compared to enoxaparin (2.3%), dalteparin (2.1%), and UFH (4.2%). After controlling for baseline covariates, the odds of experiencing a VTE was significantly higher for other treatments when compared to fondaparinux (odds ratios: dalteparin=1.22 [95% CI: 1.01 to 1.46] p=0.0370; enoxaparin=1.39 [1.19 to 1.62], p<0.0001; UFH=1.98 [1.67 to 2.34], p<0.0001). Significantly fewer fondaparinux-treated patients experienced an event during the index hospitalization or were readmitted for a VTE compared to other treatments. CONCLUSIONS: Similar to clinical trial findings, patients receiving fondaparinux in this study experienced fewer VTE events following orthopedic surgeries.

Use of diagnostic tests and procedures for disease-modifying therapy users and non-disease-modifying therapy users with multiple sclerosis.

We examined the use of 23 diagnostic procedures and monitoring tests for users of disease-modifying therapy (DMT) and non-DMT users with multiple sclerosis (MS). The Medstat MarketScan(®) Commercial Claims and Encounters database (2003-2007), which is composed of medical and pharmacy claims for approximately 8 million beneficiaries from 45 US commercial health plans, was used to identify DMT users with an index claim for an MS drug and a 6-month baseline period without MS drugs. Patients were followed for 12 months. Logistic regression models were used to estimate differences in rates and proportion of patients receiving procedures and tests between cohorts. Baseline rates for DMT users (n = 12,455) included MRIs (76.8%), spinal taps (15.7%), neuropsychological testing (4.7%), chemistry panels (61.4%), complete blood cell counts (76.7%) and liver function tests (60.5%). Relative to non-DMT users (n = 25,534), DMT users were more likely to receive an MRI, neuropsychological testing, chemistry panels, complete blood cell counts and liver function tests.

Incidence and clinical complications of myelodysplastic syndromes among United States Medicare beneficiaries.

PURPOSE: To determine the incidence and complications of myelodysplastic syndromes (MDS) among Medicare beneficiaries. METHODS: Retrospective review of 2003 Medicare Standard Analytic Files utilizing International Classification of Diseases for Oncology ninth edition CM code 238.7 to identify new MDS patients, with 3-year follow-up. RESULTS: Among 1,394,343 individuals in Medicare Standard Analytic Files age > or = 65 years, 162 per 100,000 were coded as newly diagnosed MDS during 2003 yielding a calculated 45,000 new cases in the United States Medicare > or = 65 years population. Patients with MDS were older (median age, 77 years), and over-represented by males. Among patients with MDS diagnosed during first quarter of 2003, 73.2% suffered cardiac-related events during 3-year follow-up, which exceeded the Medicare population (54.5%; P < .01) even when age adjusted (odds ratio, 2.10; P < .01). Significant increases in prevalence of diabetes (40.0% v 33.1%), dyspnea (49.4% v 28.5%), hepatic diseases (0.8% v 0.2%), and infections (sepsis: 22.5% v 6.1%) were noted in MDS (all P < .01) compared with the Medicare population. Patients with MDS requiring RBC transfusions had greater prevalence of these comorbidities. Acute myeloid leukemia developed within 3 years in 9.6%, with increased transformation among transfused (24.6%; P < .001). The 3-year Kaplan-Meier age-adjusted survival for MDS was 60.0%, which was significantly lower than the Medicare population (84.7%; hazard ratio, 3.08; P < .001), and mortality was further increased among transfused MDS (P < .01). In 2003, median payment for MDS was $16,181, compared to $1,575 for the Medicare population (P < .001). CONCLUSION: MDS is a common hematologic malignancy of the elderly, which places patients at risk for comorbid conditions. Transfusion dependency identifies patients with MDS at additional increased risk of organ impairment and shortened survival.

Use of antipsychotic drugs in patients with Alzheimer's disease treated with rivastigmine versus donepezil: a retrospective, parallel-cohort, hypothesis-generating study.

BACKGROUND AND OBJECTIVE: Rivastigmine and donepezil are two cholinesterase inhibitors (ChEIs) indicated for the treatment of mild-to-moderate Alzheimer's disease. Dementia-related behavioural issues are typically managed by environmental modification and the use of psychotropics including antipsychotic medications. However, ChEIs have also been associated with reductions in behavioural symptoms in Alzheimer's disease patients. This retrospective, parallel-cohort, hypothesis-generating study investigated whether treatment with rivastigmine is associated with reduced prescription of antipsychotic medications compared with treatment with donepezil. METHODS: A combined analysis of two claims databases was conducted. Patients were included if they had a diagnosis of Alzheimer's disease and were newly initiated on either rivastigmine or donepezil. Patients with prior use of memantine and/or antipsychotics were excluded. Kaplan-Meier and Cox analyses were conducted to compare the rate of antipsychotic drug use between the rivastigmine and donepezil groups. RESULTS: A total of 956 patients receiving rivastigmine and 12 778 patients receiving donepezil formed the study population. Analysis revealed that 64 (6.7%) rivastigmine and 989 (7.7%) donepezil recipients received antipsychotic medications (log-rank test from Kaplan-Meier analysis, p = 0.2289). The Cox regression analysis showed that rivastigmine was associated with a statistically significant reduction in the prescription of antipsychotic drugs relative to donepezil (hazard ratio 0.73; p = 0.044). Older age, longer time between Alzheimer's disease diagnosis and first ChEI dispensing, lower dose of ChEI at treatment initiation and the presence of baseline depression and neuropsychiatric symptoms were associated with a significantly increased likelihood of antipsychotic drug use. CONCLUSIONS: In this retrospective analysis, Alzheimer's disease patients with no prior use of antipsychotics initiated on rivastigmine had a significantly lower rate of prescription of antipsychotic drugs than those treated with donepezil.