Hemoglobin and End-Organ Damage in Individuals with Sickle Cell Disease.

Background: Sickle cell disease (SCD) is an inherited, chronic, multifaceted blood disorder. Patients with SCD develop anemia, which has been associated with end-organ damage (EOD). Objectives: This retrospective, observational, repeated-measures study systematically characterizes the relationship between hemoglobin (Hb) level and EOD in adolescent and adult patients with SCD. Methods: The study population comprised patients with SCD aged ≥12 years with available Hb data from a US provider-centric health care database. For each patient, each Hb value over time was included as a separate observation. Study outcomes-the onset of any new EOD, including chronic kidney disease, pulmonary hypertension, stroke, and leg ulcer-were ascertained during the 1-year period after each Hb assessment. The association between Hb levels and risk of new EOD was estimated using multivariable generalized estimating equations. Results: A total of 16,043 unique patients with SCD contributed 44,913 observations. Adjusted odds of any EOD during the 1-year follow-up were significantly lower with higher Hb level. Risk reductions with higher Hb levels for chronic kidney disease, pulmonary hypertension, and leg ulcer were comparable. The risk of new EOD was significantly lower among adolescent and adult patients with higher Hb levels. Conclusions: In patients with SCD, higher Hb levels are associated with a reduced risk of developing EOD. Therapeutic strategies that result in higher Hb levels may offer clinical and economic value for patients with SCD. (Curr Ther Res Clin Exp. 2023; 84:XXX-XXX).

What drives transcranial Doppler velocity improvement in paediatric sickle cell anaemia: analysis from the Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort study.

Children with sickle cell anaemia (SCA) and conditional transcranial Doppler (TCD) flow velocities (conditional: 170-199 cm/s; normal: <170 cm/s) have an increased risk of stroke. The Sickle Cell Clinical Research and Intervention Program (SCCRIP), a lifetime observational study, assessed the influence of haematological markers on TCD velocities. In children (≤16 years) with SCA (HbSS/HbSß0 -thalassaemia) and conditional TCD velocities (n = 32), increases in haemoglobin and in fetal haemoglobin after hydroxyurea initiation were significantly associated with decreases in TCD velocities. The benefit of pharmacological intervention to increase haemoglobin and fetal haemoglobin and normalise TCD velocities was demonstrated in this real-world dataset.

Cognition and education benefits of increased hemoglobin and blood oxygenation in children with sickle cell disease.

BACKGROUND: Among individuals with sickle cell disease (SCD), decreased hemoglobin is associated with lower oxygen saturation (SpO2) and increased risk of stroke, both of which are associated with lower intelligence quotient (IQ) scores. Thus, increasing hemoglobin and SpO2 in individuals with SCD may increase IQ and educational attainment. METHODS: A cohort simulation model was built to determine academic performance and educational attainment based on cognitive function (measured by IQ) of a pediatric SCD cohort randomly assigned to treatment and control groups. The model contained two key stages: childhood (<10 years) and adolescence (≥10 years). In stage 1, increased hemoglobin and increased SpO2 (assigned to the treatment group) were determinants of higher IQ, prevention of IQ deterioration over time. Increased hemoglobin was also a determinant of decreased stroke risk. In stage 2, improvement in adolescent IQ as a result of treatment was a determinant of academic performance. RESULTS: In a simulated cohort of 2000 children and adolescents with SCD (52.5% female, 50% treated), stroke incidence was predicted to be 44.4% lower among the treated group than the untreated group (4.5% versus 8.1%, respectively). The average IQ among the treated group was estimated to be 91.1 compared with 82.9 in the untreated group (a 9.9% difference; P<0.001). Finally, high school (≥12 years of education) completion rates were estimated to be 64.7% higher among the treated group: 76.1% of the treated group was projected to complete high school compared with 46.2% of the untreated group. CONCLUSIONS: Our model predicts that an average improvement in hemoglobin of 1.1 g/dL (11 g/L) among individuals with SCD may be associated with improved neurocognition and educational outcomes. These improvements may also generate benefits not captured by our model, including improved quality of life, employment, and income.

Patient-Reported Experiences in Voxelotor-Treated Children and Adults with Sickle Cell Disease: A Semistructured Interview Study.

Objective: Voxelotor is a first-in-class sickle hemoglobin-polymerization inhibitor that was approved in 2019 by the US Food and Drug Administration for treatment of patients with sickle cell disease (SCD) aged ≥12 years; in 2021, the approval was extended to children with SCD aged 4 to 11 years. Additionally, both the Ministry of Health and Prevention for the United Arab Emirates and the European Commission granted marketing authorization for voxelotor in September 2021 and February 2022, respectively, for treatment of SCD in adults and pediatric patients aged ≥12 years. Thus, additional information on the patient experience with voxelotor would be useful for patients, caregivers, and healthcare professionals alike. The purpose of this study was to conduct semistructured interviews in an effort to understand the experiences and perspectives of voxelotor-treated patients with SCD. Methods: One-time semistructured interviews with adults, adolescents, and children with SCD and their primary caregivers were conducted in the United States. Twenty-three adults and adolescents were recruited across 4 clinical sites, and 10 children-caregiver dyads were recruited from a single site. The interview was designed to elicit patient perspectives on symptomatic changes with voxelotor and the impact of treatment on patients' perceived health-related quality of life. Individual interview transcripts were analyzed using a thematic analytic approach, and concept saturation was assessed in both cohorts. Results: Most patients reported improvements in their SCD symptoms with voxelotor treatment, specifically regarding pain crises, jaundice, and fatigue. Almost all patients experienced improvements in self-reported health-related quality of life with voxelotor treatment. Conclusions: This study provides patient and caregiver perspectives on the symptomatic benefits of voxelotor treatment. These findings not only highlight the benefits of voxelotor treatment in improving symptoms and increasing health-related quality of life across the entire SCD population but also can inform further research on SCD-specific patient-reported outcomes.

Estimating the Lifetime Medical Cost Burden of an Allogeneic Hematopoietic Cell Transplantation Patient.

Allogeneic hematopoietic cell transplantation (allo-HCT) has the potential for curative outcomes for a variety of hematologic malignancies. Current allo-HCT studies often describe the outcomes and costs in the near term; however, research on the lifetime economic burden post-allo-HCT remains limited. This study was conducted to estimate the average total lifetime direct medical costs of an allo-HCT patient and the potential net monetary savings from an alternative treatment associated with improved graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS). A disease-state model was constructed using a short-term decision tree and a long-term semi-Markov partitioned survival model to estimate the average per-patient lifetime cost and expected quality-adjusted life years (QALYs) for an allo-HCT patient from a US healthcare system perspective. Key clinical inputs included overall survival, GRFS, incidence of both acute and chronic GVHD, relapse of the primary disease, and infections. Cost results were reported as ranges based on varying the percentage of chronic GVHD patients that remained on treatment after 2 years (15% or 39%). Over a lifetime, the average per-patient medical cost of allo-HCT was estimated to range from $942,373 to $1,247,917. The majority of the costs were for chronic GVHD treatment (37% to 53%), followed by the allo-HCT procedure (15% to 19%). The expected lifetime QALYs of an allo-HCT patient were estimated as 4.7. Lifetime per-patient treatment costs often exceed $1,000,000 for allo-HCT patients. Innovative research efforts focused on the reduction or elimination of late complications, particularly chronic GVHD, may provide the greatest value to improved patient outcomes.

Systematic review of the impact of erythropoiesis-stimulating agents on fatigue in dialysis patients.

BACKGROUND: One of the cardinal symptoms of anemia in chronic kidney disease (CKD) patients is fatigue. Recently, results from Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) raised questions about the role of erythropoiesis-stimulating agents (ESAs) in improving fatigue and the appropriate hemoglobin (Hb) target in anemic patients with CKD. These discussions should be considered with all available evidence to determine the level of benefits and risks associated with ESA therapy on fatigue among both early-stage CKD patients and end-stage renal disease patients on dialysis. METHODS: The study was a systematic review of the literature on fatigue in adults on maintenance dialysis therapy. The requirement for inclusion in the review was the measurement of fatigue before and after ESA treatment. Outcomes that were assessed were fatigue as measured by the Kidney Disease Questionnaire, the 36-item Short-Form general health survey, the Nottingham Health Profile, the Profile of Mood States or the Functional Assessment of Chronic Illness Therapy-Fatigue scale. Several different measures of fatigue were used in the studies. RESULTS: Fifteen articles met the criteria for inclusion, including 10 distinct studies and one extension study. There was one placebo-controlled randomized clinical trial (RCT) and one extension, five single-arm, three high versus low, one intravenous versus subcutaneous and one switch from epoetin alfa to darbepoetin alfa. The only placebo-controlled RCT found a 22-26% improvement in fatigue. Single-arm cohort studies demonstrated a reduction in fatigue after a substantial increase in Hb. Studies with a baseline Hb <10 g/dL and partial correction to a minimum Hb ≥ 10 g/dL showed an average improvement in fatigue of 34.6%. Studies with a baseline Hb ≥ 11 g/dL and full correction to a minimum Hb ≥ 12 g/dL showed an average improvement in fatigue of 5.5%, while studies with no change in Hb (either placebo or control group) showed a decline of 0.7% in fatigue outcomes. CONCLUSION: Partial correction of anemia with ESA results in improvement of fatigue among patients on dialysis, most strikingly in those patients with baseline Hb levels <10 g/dL.

Real-world effectiveness of voxelotor for treating sickle cell disease in the US: a large claims data analysis.

BACKGROUND: Sickle cell disease (SCD) is a genetic disease that impacts patients' quality of life, healthcare costs, and life expectancy. Elevated sickle hemoglobin (HbS), which readily polymerizes, causes red blood cell sickling, leading to chronic hemolytic anemia and complications often requiring hospitalization and transfusions. In 2019, voxelotor, which inhibits HbS polymerization, was approved for SCD treatment. OBJECTIVES: This study uses real-world evidence to assess voxelotor's effectiveness in SCD patients in typical clinical practice from 2019 to 2021 using a national medical claims database (N = 3128). RESULTS: After initiating voxelotor, 60.8% of patients with available hemoglobin (Hb) laboratory data (n = 74) showed a Hb increase >1 g/dL. Mean transfusion rate per patient-year dropped 52% in patients with ≥1 transfusion before treatment (n = 190). In patients with ≥1 of the corresponding events (n = 1065), decreases were observed in mean vaso-occlusive crisis (VOC) frequency (-23%); mean VOC-related hospitalizations and length of stay (LOS) time (-34% and -30%, respectively); mean all-cause hospitalization and LOS time (-37% and -23%, respectively); outpatient visits (-10%); iron chelation use (-46%); and prescribed opioids (-13%). CONCLUSION: These data align with randomized controlled trial results showing voxelotor improvements and support that voxelotor may lower transfusion and VOC rates in clinical practice.

Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: For decades, patients with sickle cell disease have had only a limited number of therapies available. In 2019, voxelotor (1500 mg), an oral once-daily sickle haemoglobin polymerisation inhibitor, was approved in the USA for the treatment of sickle cell disease in patients aged 12 years and older on the basis of HOPE trial data. To further describe the applicability of voxelotor as a treatment for this chronic illness, we report the long-term efficacy and safety of this drug at 72 weeks of treatment; the conclusion of the placebo-controlled HOPE trial. METHODS: HOPE is an international, randomised, double-blind, placebo-controlled, phase 3 trial done at 60 clinical sites in Canada, Egypt, France, Italy, Jamaica, Kenya, Lebanon, Netherlands, Oman, Turkey, the USA, and the UK. Patients (aged 12-65 years) with confirmed sickle cell disease, a haemoglobin concentration of 5·5-10·5 g/dL at enrolment, and who had between one and ten vaso-occlusive crisis events in the previous 12 months were enrolled. Patients receiving regularly scheduled transfusion therapy, who had received a transfusion in the previous 60 days, or who had been admitted to hospital for a vaso-occlusive crisis in the previous 14 days were excluded. Patients were randomly assigned (1:1:1) to receive either once-daily oral voxelotor 1500 mg, voxelotor 900 mg, or placebo for 72 weeks. Randomisation was done centrally by use of an interactive web response system, stratified by baseline hydroxyurea use (yes vs no), age group (adolescents [12 to <18 years] vs adults [18 to 65 years]), and geographic region (North America vs Europe vs other). The primary endpoint (already reported) was the proportion of patients who achieved a haemoglobin response at week 24. In this final analysis, we report prespecified long-term efficacy assessments by intention to treat, including changes in haemoglobin concentrations from baseline to week 72, changes in the concentration of haemolysis markers (absolute and percentage reticulocytes, indirect bilirubin concentrations, and lactate dehydrogenase concentrations) from baseline to week 72, the annualised incidence of vaso-occlusive crises, and patient functioning, as assessed with the Clinical Global Impression of Change (CGI-C) scale. Safety was assessed in patients who received at least one dose of treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT03036813. FINDINGS: Between Dec 5, 2016, and May 3, 2018, 449 patients were screened, of whom 274 were randomly assigned to the voxelotor 1500 mg group (n=90), the voxelotor 900 mg group (n=92), or the placebo group (n=92). At week 72, the adjusted mean change in haemoglobin concentration from baseline was 1·0 g/dL (95% CI 0·7 to -1·3) in the voxelotor 1500 mg group, 0·5 g/dL (0·3 to -0·8) in the voxelotor 900 mg group, and 0·0 g/dL (-0·3 to 0·3) in the placebo group, with a significant difference observed between the voxelotor 1500 mg group and the placebo group (p<0·0001), and between the voxelotor 900 mg group and the placebo group (p=0·014). Significant improvements in markers of haemolysis, as assessed by the difference in adjusted mean percentage change from baseline at week 72 versus placebo, were observed in the voxelotor 1500 mg group in indirect bilirubin concentrations (-26·6% [95% CI -40·2 to -12·9]) and percentage of reticulocytes (-18·6% [-33·9 to -3·3]). The proportion of patients in the voxelotor 1500 mg group who were rated as "moderately improved" or "very much improved" at week 72 with the CGI-C was significantly greater than in the placebo group (39 [74%] of 53 vs 24 [47%] of 51; p=0·0057). Serious adverse events unrelated to sickle cell disease were reported in 25 (28%) of 88 patients in the voxelotor 1500 mg group, 20 (22%) of 92 patients in the voxelotor 900 mg group, and 23 (25%) of 91 patients in the placebo group. Grade 3 or 4 adverse events were infrequent (ie, occurred in <10% of patients); anaemia occurred in five or more patients (two [2%] patients in the voxelotor 1500 mg group, seven [8%] patients in the voxelotor 900 mg group, and three [3%] patients in the placebo group). Of all 274 patients, six (2%) deaths occurred during the study (two deaths in each treatment group), all of which were judged as unrelated to treatment. INTERPRETATION: Voxelotor 1500 mg resulted in rapid and durable improvements in haemoglobin concentrations maintained over 72 weeks and has potential to address the substantial morbidity associated with haemolytic anaemia in sickle cell disease. FUNDING: Global Blood Therapeutics.

Low hemoglobin increases risk for cerebrovascular disease, kidney disease, pulmonary vasculopathy, and mortality in sickle cell disease: A systematic literature review and meta-analysis.

Sickle cell disease (SCD) is characterized by deoxygenation-induced polymerization of hemoglobin in red blood cells, leading to hemolytic anemia, vaso-occlusion, and the development of multiple clinical complications. To characterize the clinical burden associated with differences in hemoglobin concentration and hemolysis measures, a systematic literature review of MEDLINE, EMBASE, and related meta-analyses was undertaken. For quantitative analyses related to hemoglobin concentration, pooled results were analyzed using random effects models to control for within-and between-study variability. To derive risk ratios associated with hemoglobin concentration change, we combined ratios of means from select studies, which reported hazard and odds ratios in meta-analyses for hemoglobin concentration-related outcomes and changes between groups. Forty-one studies were identified for inclusion based on relating hemoglobin concentration to clinical outcomes. Meta-analyses demonstrated that mean hemoglobin concentration was significantly lower in patients with cerebrovascular disease (0.4 g/dL), increased transcranial Doppler velocity in cerebral arteries (0.6 g/dL), albuminuria (0.6 g/dL), elevated estimated pulmonary artery systolic pressure (0.9 g/dL), and in patients that subsequently died (0.6 g/dL). In a risk reduction meta-analysis, modeled increased hemoglobin concentrations of 1 g/dL or greater resulted in decreased risk of negative clinical outcomes of 41% to 64%. In conclusion, chronic anemia is associated with worse clinical outcomes in individuals with SCD and even modest increases in hemoglobin concentration may be beneficial in this patient population. This systematic review has been registered on Prospero (Registration number CRD42018096860; https://www.crd.york.ac.uk/prospero/).

The Economic Burden of End-Organ Damage Among Medicaid Patients with Sickle Cell Disease in the United States: A Population-Based Longitudinal Claims Study.

BACKGROUND: The management of sickle cell disease (SCD), an inherited, chronic, and multifaceted condition, is associated with considerable health care resource utilization (HRU) and costs, especially for Medicaid. Anemia affects most patients with SCD and correlates with end-organ damage (EOD), such as stroke, chronic kidney disease (CKD), end-stage renal disease (ESRD), and pulmonary hypertension (PH). Limited research has been conducted to quantify the economic burden of EOD among patients with SCD. OBJECTIVE: To estimate the effect of EOD on HRU and direct costs and productivity loss incurred by patients with SCD on Medicaid. METHODS: Patients with ≥ 3 nondiagnostic SCD ICD-9-CM/ICD-10-CM codes in ≤ 5 years (January 1, 2013-December 31, 2017) were identified in the MarketScan Medicaid claims database. The earliest SCD diagnosis date was the index date. Continuous enrollment at least 3 months before and 1 month after the index date were required. Patients' post-index periods were divided into 3-month intervals (referred to as "intervals"). History of stroke, CKD, ESRD, and PH were identified in patients' claims histories from January 1, 2008. Intervals within 1 year and more than 1 year after an acute stroke event were also defined. All-cause HRU, direct costs, and productivity losses were summed across intervals and stratified by EOD type. Multivariate regression models were used to estimate the effect of stroke, CKD, ESRD, and PH on annual total cost, inpatient days, and number of emergency department visits by controlling for patients' demographic characteristics and other SCD complications. RESULTS: In total, 10,784 Medicaid patients with SCD (average age: 18.5 years; female: 54.5%) contributed to 152,455 intervals. Approximately 12% of the intervals had EOD. Patients with EOD had higher all-cause health care costs and more inpatient days, emergency department visits, outpatient visits, laboratory tests, and outpatient pharmacy claims than patients without EOD. After controlling for patient characteristics, among Medicaid patients with SCD annual costs within 1 year after stroke were 4.68-fold versus patients with no EOD (more than 1 year after stroke: 2.08-fold; CKD: 2.19-fold; ESRD: 3.40-fold; PH: 2.32-fold). Adjusted mean annual costs for adult patients with SCD on Medicaid were $285,816 and $127,393 within 1 year and more than 1 year after stroke and $135,493, $209,172, and $148,174 for CKD, ESRD, and PH, respectively. Patients with multiple SCD complications had even higher costs. The mean annual time patients with SCD spent receiving health care services ranged from 56 to 62 days for those with EOD versus 21 to 25 days among those without EOD, which created additional economic burden. CONCLUSIONS: When Medicaid patients with SCD experience EOD, the economic burden is significantly increased through direct costs to the health care system and indirect costs from productivity loss to society. SCD management strategies that potentially reduce the risk of EOD offer clinical and economic value to patients and society. DISCLOSURES: Funding for this study was provided by Global Blood Therapeutics (GBT). Campbell is a consultant for GBT, Bluebird Bio, and Cyclerion and receives research funding from Novartis, GBT, and Cyclerion. Cong and Agodoa are employees of and have equity ownership in GBT. Song, Martinez, Black, Lew, Varker, and Chan are employees of IBM Watson Health, which received research funding from GBT for this study. Lanzkron receives research funding from GBT, Pfizer, Ironwood, HRSA, and NIH. A poster based on this study was presented at the 61st ASH Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

Estimated Life Expectancy and Income of Patients With Sickle Cell Disease Compared With Those Without Sickle Cell Disease.

Importance: Individuals with sickle cell disease (SCD) have reduced life expectancy; however, there are limited data available on lifetime income in patients with SCD. Objective: To estimate life expectancy, quality-adjusted life expectancy, and income differences between a US cohort of patients with SCD and an age-, sex-, and race/ethnicity-matched cohort without SCD. Design, Setting, and Participants: Cohort simulation modeling was used to (1) build a prevalent SCD cohort and a matched non-SCD cohort, (2) identify utility weights for quality-adjusted life expectancy, (3) calculate average expected annual personal income, and (4) model life expectancy, quality-adjusted life expectancy, and lifetime incomes for SCD and matched non-SCD cohorts. Data sources included the Centers for Disease Control and Prevention, National Newborn Screening Information System, and published literature. The target population was individuals with SCD, the time horizon was lifetime, and the perspective was societal. Model data were collected from November 29, 2017, to March 21, 2018, and the analysis was performed from April 28 to December 3, 2018. Main Outcomes and Measures: Life expectancy, quality-adjusted life expectancy, and projected lifetime income. Results: The estimated prevalent population for the SCD cohort was 87 328 (95% uncertainty interval, 79 344-101 398); 998 were male and 952 were female. Projected life expectancy for the SCD cohort was 54 years vs 76 years for the matched non-SCD cohort; quality-adjusted life expectancy was 33 years vs 67 years, respectively. Projected lifetime income was $1 227 000 for an individual with SCD and $1 922 000 for a matched individual without SCD, reflecting a lost income of $695 000 owing to the 22-year difference in life expectancy. One study limitation is that the higher estimates of life expectancy yielded conservative estimates of lost life-years and income. The analysis only considered the value of lost personal income owing to premature mortality and did not consider direct medical costs or other societal costs associated with excess morbidity (eg, lost workdays for disability, time spent in the hospital). The model was most sensitive to changes in income levels and mortality rates. Conclusions and Relevance: In this simulated cohort modeling study, SCD had societal consequences beyond medical costs in terms of reduced life expectancy, quality-adjusted life expectancy, and lifetime earnings. These results underscore the need for disease-modifying therapies to improve the underlying morbidity and mortality associated with SCD.

Impact of voxelotor (GBT440) on unconjugated bilirubin and jaundice in sickle cell disease.

For many patients with sickle cell disease (SCD), jaundice is a significant clinical disease manifestation that impacts on patient well-being. We report a case of a patient with SCD and chronic jaundice treated with voxelotor (GBT440), a novel small molecule hemoglobin oxygen affinity modulator and potential disease-modifying therapy for SCD. The case patient is a 27-year-old Black male with a long history of SCD with clinical jaundice and scleral icterus. After starting voxelotor, the patient reported that his jaundice cleared within one week, and that he felt much better with more energy, and was relieved after his eyes cleared. Voxelotor reduced bilirubin and unconjugated bilirubin (by up to 76%), and hemoglobin improved from 9.9 g/dL at baseline to 11.1 g/dL at 90 days. Jaundice impacts many adults with SCD, significantly impacting self-image. Voxelotor treatment reduced bilirubin levels and improved jaundice, resulting in an improved sense of well-being in our case patient.

Patient-Reported Outcomes in Chronic Heart Failure: Applicability for Regulatory Approval.

OBJECTIVES: The study sought to review the characteristics of existing patient-reported outcome (PRO) instruments used with chronic heart failure (HF) patients and evaluate their potential to support an approved U.S. Food and Drug Administration (FDA) product label claim. BACKGROUND: PROs, including symptoms and their associated functional limitations, contribute substantially to HF patient morbidity. PRO measurements capture the patient perspective and can be systematically assessed with structured questionnaires, however rigorous recommendations have been set by the FDA regarding the acceptability of PRO measures as a basis for product label claims. METHODS: Extensive searches of databases and specialty guidelines identified PRO instruments used in patients with chronic HF. Information on critical properties recommended by the FDA guidance were systematically extracted and used to evaluate the selected PRO instruments. RESULTS: Nineteen PRO instruments used with chronic HF patients were identified. The Kansas City Cardiomyopathy Questionnaire and Minnesota Living with Heart Failure Questionnaire were the most extensively evaluated and validated in studies of this population. However, judged by criteria listed in the FDA PRO guidance, no existing PRO measure met all of the criteria to support a product label claim in the United States. CONCLUSIONS: Currently available chronic HF PRO measures do not fulfill all the recommendations provided in the FDA PRO guidance and therefore may not support an FDA-approved product label claim. Future investigations are merited to develop a PRO measure for use in patients with chronic HF in accordance with the FDA guidance.

Denosumab for Elderly Men with Osteoporosis: A Cost-Effectiveness Analysis from the US Payer Perspective.

Purpose. To evaluate the cost-effectiveness of denosumab versus other osteoporotic treatments in older men with osteoporosis from a US payer perspective. Methods. A lifetime cohort Markov model previously developed for postmenopausal osteoporosis (PMO) was used. Men in the model were 78 years old, with a BMD T-score of -2.12 and a vertebral fracture prevalence of 23%. During each 6-month Markov cycle, patients could have experienced a hip, vertebral or nonhip, nonvertebral (NHNV) osteoporotic fracture, remained in a nonfracture state, remained in a postfracture state, or died. Background fracture risks, mortality rates, persistence rates, health utilities, and medical and drug costs were derived from published sources. Previous PMO studies were used for drug efficacy in reducing fracture risk. Lifetime expected costs and quality-adjusted life-years (QALYs) were estimated for denosumab, generic alendronate, risedronate, ibandronate, teriparatide, and zoledronate. Results. Denosumab had an incremental cost-effectiveness ratio (ICER) of $16,888 compared to generic alendronate and dominated all other treatments. Results were most sensitive to changes in costs of denosumab and the relative risk of hip fracture. Conclusion. Despite a higher annual treatment cost compared to other medications, denosumab is cost-effective compared to other osteoporotic treatments in older osteoporotic US men.

Treatment satisfaction in postmenopausal women suboptimally adherent to bisphosphonates who transitioned to denosumab compared with risedronate or ibandronate.

CONTEXT: For many patients, adhering to postmenopausal osteoporosis treatment is a challenge. Higher treatment satisfaction is associated with greater persistence with these therapies, which is associated with better outcomes. OBJECTIVE: This study aimed to evaluate the change in treatment satisfaction in postmenopausal women who were suboptimally adherent to daily or weekly oral bisphosphonates and who transitioned to denosumab vs a monthly oral bisphosphonate. DESIGN AND SETTING: Pooled data of outpatients from two international, multicenter, randomized, open-label studies were analyzed. PATIENTS: Postmenopausal women (n = 1703) age 55 years or greater with low bone mineral density who were suboptimally adherent with prior oral bisphosphonate therapy, as assessed by the Osteoporosis-Specific Morisky Medication Adherence Scale, were included in the study. INTERVENTIONS: Patients received denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-kappa B ligand, 60 mg s.c. every 6 months vs the oral bisphosphonates ibandronate or risedronate, 150 mg once monthly for 12 months. MAIN OUTCOME MEASURES: Change in treatment satisfaction scores from baseline to months 6 and 12 were measured using the Treatment Satisfaction Questionnaire for Medication (TSQM). The TSQM is a validated tool that measures perception of four domains of treatment satisfaction: effectiveness, side effects, convenience, and global satisfaction. RESULTS: Patients in both treatment groups showed improvement from baseline for all four TSQM domains at 6 and 12 months. However, the denosumab group had significantly (all P < .001) greater improvements among all four TSQM domains at 6 and 12 months compared with the oral bisphosphonate group. CONCLUSIONS: Women with low adherence to oral bisphosphonates reported greater treatment satisfaction when transitioned to denosumab vs switching to a monthly oral bisphosphonate.

Burden of illness for osteoporotic fractures compared with other serious diseases among postmenopausal women in the United States.

OBJECTIVES: To provide a national estimate of the incidence of hospitalizations due to osteoporotic fractures (OFs) in women; compare this with the incidence of myocardial infarction (MI), stroke, and breast cancer; and assess temporal trends in the incidence and length of hospitalizations. PATIENTS AND METHODS: The study included all women 55 years and older at the time of admission, admitted to a hospital participating in the US Nationwide Inpatient Sample for an outcome of interest. We performed a retrospective analysis of hospitalizations for OFs (hip, forearm, spine, pelvis, distal femur, wrist, and humerus), MI, stroke, or breast cancer, using the US Nationwide Inpatient Sample, 2000-2011. RESULTS: From 2000 to 2011, there were 4.9 million hospitalizations for OF, 2.9 million for MI, 3.0 million for stroke, and 0.7 million for breast cancer. Osteoporotic fractures accounted for more than 40% of the hospitalizations in these 4 outcomes, with an age-adjusted rate of 1124 admissions per 100,000 person-years. In comparison, MI, stroke, and breast cancer had age-adjusted incidence rates of 668, 687, and 151 admissions per 100,000 person-years, respectively. The annual total population facility-related hospital cost was highest for hospitalizations due to OFs ($5.1 billion), followed by MI ($4.3 billion), stroke ($3.0 billion), and breast cancer ($0.5 billion). CONCLUSION: These data provide evidence that in US women 55 years and older, the hospitalization burden of OFs and population facility-related hospital cost is greater than that of MI, stroke, or breast cancer. Prioritization of bone health and supporting programs such as fracture liaison services is needed to reduce this substantial burden.

A systematic review of osteoporosis medication adherence and osteoporosis-related fracture costs in men.

BACKGROUND AND OBJECTIVE: Male osteoporosis is an increasingly important public health concern. Although several medications are approved for the treatment of osteoporosis, medication non-adherence and the associated consequences are not well documented in male populations. Our objective was to identify and summarize the current knowledge related to osteoporotic medication adherence, the potential implications of non-adherence to the medication, and the cost of osteoporosis-related fractures and health-resource utilization in men. METHODS: Two separate systematic searches were conducted concurrently: one to identify literature reporting male-specific adherence to anti-osteoporotic medication and the clinical consequence of non-adherence in men, and the other to identify literature reporting the cost and resource burden of osteoporosis-related fractures in men. The PubMed, MEDLINE, EMBASE, and Cochrane databases were searched using a date range of 1 January 1998 to 30 June 2012, and citations were screened based on pre-defined criteria. RESULTS: The percentage of males adherent to bisphosphonates [medication possession ratio (MPR) >0.8] over a 1-year period ranged from 32% to 64%. The data imply worse clinical outcomes with treatment non-adherence. Costs and resource use associated with osteoporosis-related fractures in men are high, with hip fractures generating the most cost. CONCLUSIONS: One-third to two-thirds of men are not adherent to bisphosphonates. Non-adherence is associated with increased fracture risk. Estimates of direct and indirect osteoporosis-related fracture costs are also substantial in men, and may even be more costly than in women. More robust data would better inform disease management initiatives that could improve adherence to medication and outcomes in men with osteoporosis.

The inpatient experience and predictors of length of stay for patients hospitalized with systolic heart failure: comparison by commercial, Medicaid, and Medicare payer type.

OBJECTIVE: Descriptions of the inpatient experience for patients hospitalized with systolic heart failure (HF) are limited and lack a cross-sectional representation of the US population. While length of stay (LOS) is a primary determinant of resource use and post-discharge events, few models exist for estimating LOS. RESEARCH DESIGN AND METHODS: MarketScan(®) administrative claims data from 1/1/2005-6/30/2008 were used to select hospitalized patients aged ≥18 years with discharge diagnoses for both HF (primary diagnosis) and systolic HF (any diagnostic position) without prior HF hospitalization or undergoing transplantation. RESULTS: Among 17,597 patients with systolic HF; 4109 had commercial; 2118 had Medicaid; and 11,370 had Medicare payer type. Medicaid patients had longer mean LOS (7.1 days) than commercial (6.3 days) or Medicare (6.7 days). In-hospital mortality was highest for patients with Medicaid (2.4%), followed by Medicare (1.3%) and commercial (0.6%). Commercial patients were more likely to receive inpatient procedures. Renal failure, pressure ulcer, malnutrition, a non-circulatory index admission DRG, receipt of a coronary artery bypass procedure or cardiac catheterization, or need for mechanical ventilation during the index admission were associated with increased LOS; receipt of a pacemaker device at index was associated with shorter LOS. LIMITATIONS: Selection of patients with systolic HF is limited by completeness and accuracy of medical coding, and results may not be generalizable to patients with diastolic HF or to international populations. CONCLUSION: Inpatient care, LOS, and in-hospital survival differ by payer among patients hospitalized with systolic HF, although co-morbidity and inpatient procedures consistently influence LOS across payer types. These findings may refine risk stratification, allowing for targeted intensive inpatient management and/or aggressive transitional care to improve outcomes and increase the efficiency of care.

Rates and predictors of 30-day readmission among commercially insured and Medicaid-enrolled patients hospitalized with systolic heart failure.

BACKGROUND: Heart failure (HF) readmission rates are primarily derived from Medicare enrollees. Given increasing public scrutiny of HF readmissions, understanding the rate and predictors in populations covered by other payers is also important, particularly among patients with systolic dysfunction, for whom most HF-specific therapies are targeted. METHODS AND RESULTS: MarketScan Commercial and Medicaid Administrative Claims Databases were used to identify all first hospitalizations with an International Classification of Diseases-9 discharge diagnosis code for HF (primary position) and systolic HF (any position) between January 1, 2005, and June 30, 2008. Among 4584 unique systolic HF index admissions (mean age 55 years), 30-day crude readmission rates were higher for Medicaid than commercially insured patients: all-cause 17.4% versus 11.8%; HF-related 6.7% versus 4.0%, respectively. In unadjusted analysis, higher comorbidity and prior healthcare utilization predicted readmission; age, sex, and plan type did not. After adjustment for case mix, the odds of all-cause and HF-related readmission were 32% and 68% higher, respectively, among Medicaid than commercially insured patients (P<0.02 for both). No significant differences in readmission rates were seen for managed care versus fee-for-service or capitated versus noncapitated plan types. CONCLUSIONS: Compared with commonly cited Medicare HF readmission rates of 20% to 25%, Medicaid patients with systolic HF had lower 30-day readmission rates, and commercially insured patients had even lower rates. Even after adjustment for case mix, Medicaid patients were more likely to be readmitted than commercially insured patients, suggesting that more attention should be focused on readmissions among socioeconomically disadvantaged populations.