Modelling Long-Term Outcomes and Risk of Death for Patients with Post-Stroke Spasticity Receiving Abobotulinumtoxina Treatment and Rehabilitation Therapy.

OBJECTIVE: Stroke is associated with a high risk of death and cardiovascular events. Rehabilitation therapy is critical for functional recovery, to reduce hospital readmissions, all-cause and cardiovascular mortality, and stroke recurrence (long-term outcomes). Post-stroke spasticity may prevent effective recovery by restricting mobility. AbobotulinumtoxinA is an adjunctive therapy to physical therapy for post-stroke spasticity, but its long-term effects are unknown. The objective was to model the long-term clinical and economic outcomes of abobotulinumtoxinA for post-stroke spasticity. METHODS: Effects of abobotulinumtoxinA on treating post-stroke spasticity and evidence linking functional outcomes with long-term outcomes were collected in a focused literature review. A model was developed to estimate health benefits on long-term outcomes, direct medical costs, life- and qualityadjusted life-years for abobotulinumtoxinA injections plus rehabilitation therapy compared with rehabilitation therapy alone, from a UK perspective over a 10-year time-period. RESULTS: AbobotulinumtoxinA + rehabilitation therapy led to a risk reduction of 8.8% for all-cause mortality, and an increase of 13% in life-years and 59% in quality-adjusted life-years compared with rehabilitation therapy alone. AbobotulinumtoxinA + rehabilitation therapy was considered cost-effective compared with rehabilitation therapy alone (incremental cost-effectiveness ratio: £24,602). CONCLUSION: AbobotulinumtoxinA + rehabilitation therapy may improve long-term outcomes, including post-stroke survival, while being cost-effective for the treatment of post-stroke spasticity.

Prostaglandin F2α FP receptor antagonist improves outcomes after experimental traumatic brain injury.

BACKGROUND: Injuries to the brain promote upregulation of prostaglandins, notably the proinflammatory PGF2α, and overactivation of their cognate G-protein-coupled FP receptor, which could exacerbate neuronal damage. Our study is focused on investigation of the FP receptor as a target for novel neuroprotective drugs in a preclinical animal traumatic brain injury (TBI) model. METHODS: Accordingly, the effects of acute intraperitoneal post-treatment with selective FP antagonist AL-8810 were studied in wildtype (WT) and FP receptor knockout (FP-/-) mice after controlled cortical impact (CCI). Neurological impairments were evaluated using neurological deficit scores (NDS) and the grip strength test. Cortical lesions and overall brain pathology were assessed using immunohistochemistry. RESULTS: Morphological analyses of cerebral vasculature and anastomoses revealed no differences between WT and FP-/- mice. CCI produced cortical lesions characterized by cavitation, neuronal loss, and hematoma with a volume of 20.0 ± 1.0 mm(3) and significant hippocampal swelling (146.5 ± 7.4% of contralateral) compared with sham (P < 0.05). Post-treatment with AL-8810 (1 to 10 mg/kg) had no significant effect on cortical lesions, which suggests the irreversible effect of primary CCI injury, but significantly reduced hippocampal swelling to a size not significantly different from the sham group. Post-treatment with AL-8810 at a dose of 10 mg/kg significantly improved NDS at 24 and 48 hours after CCI (P < 0.001 and P < 0.01, respectively). In the AL-8810 group, CCI-induced decrease in grip strength was three-fold (2.93 ± 1.71) less and significantly different than in the saline-treated group. The FP-/- mice had significantly less hippocampal swelling, but not NDS, compared with WT mice. In addition, immunohistochemistry showed that pharmacologic blockade and genetic deletion of FP receptor led to attenuation of CCI-induced gliosis and microglial activation in selected brain regions. CONCLUSION: This study provides, for the first time, demonstration of the unique role of the FP receptor as a potential target for disease-modifying CNS drugs for treatment of acute traumatic injury.

Clinical burden and incremental cost of fractures in postmenopausal women in the United Kingdom.

This cohort study of postmenopausal women in the United Kingdom aged ≥50years determined the incremental cost of health care and clinical outcomes in the 12months following incident, selected fractures (non-vertebral non-hip [NVNHF], vertebral [VF] and multiple [MF]). Incremental costs and outcomes of the fracture cohorts were compared with those of cohorts comprised of women without fractures who were individually matched on age and comorbidity. Cohorts were identified from The Health Improvement Network database, a primary health care database, from 2001 to 2005. We estimated 1-year incremental costs (hospitalizations; general practice, accident/emergency, and referral visits; and prescription medications) associated with each fracture type. Descriptive analyses examined occurrence of subsequent fractures and death. No long-term health care costs or outcomes were assessed. Overall, 14,030 women had NVNHF, 1471 had VF, and 193 had MF. The risk of death was greater for women with fractures than for women in the non-fracture cohorts. Mean incremental cost for fractures compared with no fractures was £1152 for VF; £690 for NVNHF, and £2581 for MF. Of the total incremental cost, hospitalizations represented 54%-90% and medications represented 7%-29%. In all fracture cohorts, most of the total annual costs were concentrated in the 6months after the date of fracture. Fractures among postmenopausal women represent an important burden to the health system due to the increase in health resource utilization and related costs. In this study, hospitalizations were the main driver of the overall incremental cost during the 12months following the fracture. Mortality in women in the selected fracture cohorts was higher than in women in the non-fracture cohorts.

Translating basic science research to clinical application: models and strategies for intracerebral hemorrhage.

Preclinical stroke models provide insights into mechanisms of cellular injury and potential therapeutic targets. Renewed efforts to standardize preclinical practices and adopt more rigorous approaches reflect the assumption that a better class of compounds will translate into clinical efficacy. While the need for novel therapeutics is clear, it is also critical that diagnostics be improved to allow for more rapid treatment upon hospital admission. Advances in imaging techniques have aided in the diagnosis of stroke, yet current limitations and expenses demonstrate the need for new and complementary approaches. Intracerebral hemorrhage (ICH) exhibits the highest mortality rate, displays unique pathology and requires specialized treatment strategies relative to other forms of stroke. The aggressive nature and severe consequences of ICH underscore the need for novel therapeutic approaches as well as accurate and expeditious diagnostic tools. The use of experimental models will continue to aid in addressing these important issues as the field attempts to translate basic science findings into the clinical setting. Several preclinical models of ICH have been developed and are widely used to recapitulate human pathology. Because each model has limitations, the burden lies with the investigator to clearly define the question being asked and select the model system that is most relevant to that question. It may also be necessary to optimize and refine pre-existing paradigms, or generate new paradigms, as the future success of translational research is dependent upon the ability to mimic human sequelae and assess clinically relevant outcome measures as means to evaluate therapeutic efficacy.

Gastrointestinal tolerability and patterns of switching in patients treated for primary osteoporosis: the Swedish Adherence Register Analysis (SARA).

The objective of this study was to describe and analyze the gastrointestinal tolerability and medication switching in patients receiving treatment for primary osteoporosis in Sweden. The study was based on all patients starting therapy with alendronate, risedronate, strontium ranelate, and raloxifene in Sweden between 2005 and 2009. The primary outcome measure was start of treatment with a gastroprotective agent, and the secondary outcome was hospitalization for a gastrointestinal adverse event (GIAE). Switching was analyzed while patients were on treatment. The crude incidence of gastroprotective treatment during the first 6 months after initiation of osteoporosis therapy was 5.14%, 5.93%, 4.25%, and 2.86% for patients prescribed alendronate, risedronate, strontium ranelate, and raloxifene, respectively. Patients prescribed raloxifene had a significantly lower risk of filling a prescription for a gastroprotective agent compared with alendronate. There was no significant difference in the risk of hospitalization for GIAEs. Less than 3% switched therapy while on treatment. Patients prescribed risedronate, strontium ranelate, and raloxifene had a significantly higher risk of switching compared with patients taking alendronate. In conclusion, no significant difference in the incidence of GIAEs was found between patients prescribed alendronate, risedronate, and strontium ranelate. Individuals prescribed raloxifene had a significantly lower risk of GIAEs compared with patients prescribed alendronate. No significant difference was found in the frequency of hospitalization for GIAEs. Switching between osteoporosis medications and drug classes was uncommon. Prescribers should consider the real-world gastrointestinal safety of osteoporosis drugs when choosing between treatment options to potentially improve medication adherence and consequently effectiveness.

Study of the incremental cost and clinical burden of hip fractures in postmenopausal women in the United Kingdom.

OBJECTIVE: To determine the incremental cost of healthcare and clinical outcomes in the 12 months following incident hip fractures among postmenopausal women in the UK. METHODS: Retrospective cohort study of women aged 50 years or older hospitalized for an incident hip fracture within 1 week of the fracture date who were age- and comorbidity-matched to women without fracture. Cohorts were identified in the Health Improvement Network database, and followed up for 1 year. RESULTS: Among 2,427 women who had a hip fracture and a recorded hospitalization, the mean [SD] age was 81 [9.3] years. About 18% of women without fractures were hospitalized during follow-up and 18% of women with hip fractures and 4% of women without fractures had at least one emergency admission (RR, 4.7; 95% CI, 3.8-5.8). There were no major differences in use of general practitioner visit, referral visits, or in prescription of medications. Mortality was 18% in the hip fracture cohort and 7% in the non-fracture cohort (RR, 2.5; 95% CI, 2.1-3.0). The overall 1-year mean incremental cost of hip fractures was £4,222 (95% CI, £4,105-4,339); most of this cost (97%) was for hospitalizations, with an increment of £4,095. About 98% of the incremental cost occurred in the first 6 months following hip fracture. CONCLUSIONS: The results of this study indicate that the cost and clinical burden associated with hip fractures in postmenopausal women in the UK are considerable. The incremental cost is mostly related to the cost of hospitalization and treatment of the hip fracture. Key limitations were the inclusion of only those women with a recorded hospitalization, and that costs associated with rehabilitation services, social services, and long-term care were not recorded in this study, although these are important contributors to the total cost of fractures.

Less frequent dosing of erythropoiesis stimulating agents in patients undergoing dialysis: a European multicentre cost study.

OBJECTIVE: To calculate the variable costs involved with the process of delivering erythropoiesis stimulating agents (ESA) in European dialysis practices. METHODS: A conceptual model was developed to classify the processes and sub-processes followed in the pharmacy (ordering from supplier, receiving/storing/delivering ESA to the dialysis unit), dialysis unit (dose determination, ordering, receipt, registration, storage, administration, registration) and waste disposal unit. Time and material costs were recorded. Labour costs were derived from actual local wages while material costs came from the facilities' accounting records. Activities associated with ESA administration were listed and each activity evaluated to determine if dosing frequency affected the amount of resources required. RESULTS: A total of 21 centres in 8 European countries supplied data for 142 patients (mean) per hospital (range 42-648). Patients received various ESA regimens (thrice-weekly, twice-weekly, once-weekly, once every 2 weeks and once-monthly). Administering ESA every 2 weeks, the mean costs per patient per year for each process and the estimates of the percentage reduction in costs obtainable, respectively, were: pharmacy labour (10.1 euro, 39%); dialysis unit labour (66.0 euro, 65%); dialysis unit materials (4.11 euro, 61%) and waste unit materials (0.43 euro, 49%). LIMITATION: Impact on financial costs was not measured. CONCLUSION: ESA administration has quantifiable labour and material costs which are affected by dosing frequency.

Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of fracture and need for parathyroidectomy in CKD.

BACKGROUND: Chronic kidney disease (CKD) is associated with such complications as fractures and the need for parathyroidectomy. Mineral metabolism control in patients with CKD has been poor. Studies have assessed fractures and parathyroidectomy risk with mineral disturbances, but with considerable diversity in methods. Thus, a systematic review was conducted to assess method or clinical heterogeneity by comparing the design, analytical techniques, and results of studies. STUDY DESIGN: Systematic review of the MEDLINE, EMBASE, and Cochrane databases between 1980 and December 2007. SETTING & POPULATION: Patients with CKD or dialysis patients. SELECTION CRITERIA FOR STUDIES: Observational and clinical trials investigating the risk of fractures or parathyroidectomy with mineral disturbances. PREDICTOR: Mineral metabolism variables (phosphorus, calcium, and parathyroid hormone [PTH] levels). OUTCOMES: Fractures, need for parathyroidectomy. RESULTS: 9 studies were identified that assessed fractures (n = 6) or need for parathyroidectomy (n = 3). Data for fractures or parathyroidectomy risk in predialysis patients are absent. Diversity across studies was observed in populations, methods of exposure assessment, adjusted covariates, and reference mineral levels used in risk estimation. A significant fracture risk was observed with increasing PTH levels. However, additional data are required to understand fracture risk with changes in phosphorus or calcium levels. Data supported greater parathyroidectomy risk with increasing PTH, phosphorus, or calcium levels. LIMITATIONS: Clinical and method heterogeneity across studies precluding the quantitative synthesis of data. CONCLUSIONS: Serious limitations were observed in the number, quality, and method rigor of studies. Despite heterogeneity across studies, data suggest a significant parathyroidectomy risk with mineral disturbances and a fracture risk with increasing PTH levels in dialysis patients. Additional high-quality data for risk of fractures or parathyroidectomy with changes in phosphorus, calcium, or PTH levels is required to highlight the importance of managing such common, but subclinical, conditions as mineral metabolism disturbances.

Diminished quality of life and physical function in community-dwelling elderly with anemia.

The occurrence of anemia in older adults has been associated with adverse outcomes including functional decline, disability, morbidity, and mortality. It is not clear to what extent these outcomes are the result of the anemia or concurrent illness. We performed a cross-sectional, observational study to determine whether lower hemoglobin concentrations in older adults are associated with reduced health-related quality of life, functional status, depression, disability, and physical strength, independent of chronic disease. Three sites participated in this research: an academic geriatric practice, a hospital-based geriatric outpatient unit, and a community-based multispecialty internal medicine group. Health-related quality of life and functional status were measured using the Short Form-36 Health Survey (SF-36) and the Functional Assessment of Chronic Illness Therapy-Anemia (FACIT-An). Disability and depression were assessed using the Instrumental Activities of Daily Living (IADL) and the Geriatric Depression Scale (GDS) questionnaires, respectively. Handgrip strength was used as a physical performance measure. Anemia was defined as hemoglobin <13 g/dL for men or <12 g/dL for women. The mean SF-36 physical health component summary scores were 38.9 (with anemia) and 44.1 (without anemia) (p<0.001). Anemia was associated with greater fatigue (p < 0.001), lower handgrip strength (p = 0.014), increased number of disabilities (p=0.005), and more depressive symptoms (p = 0.002). Multivariate regression analysis, adjusted for demographic and clinical characteristics, demonstrated strong associations for reduced hemoglobin, even within the "normal" range, and poorer health-related quality of life across multiple domains. Thus, anemia was independently associated with clinically significant impairments in multiple domains of health-related quality of life, especially in measures of functional limitation. Mildly low hemoglobin levels, even when above the World Health Organization (WHO) anemia threshold, were associated with significant declines in quality of life among the elderly.

Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of all-cause mortality, cardiovascular mortality and cardiovascular events in chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a powerful risk factor for all-cause mortality and its most common aetiology, cardiovascular (CV) mortality. Mineral metabolism disturbances occur very early during the course of CKD but their control has been poor. A number of studies have assessed the relationship between all-cause mortality, CV mortality and events with mineral disturbances in CKD patients, but with considerable discrepancy and heterogeneity in results. Thus, a systematic review was conducted to assess methodological and clinical heterogeneity by comparing designs, analytical approaches and results of studies. METHODS: Medline, EMBASE and Cochrane databases were systematically searched for articles published between January 1980 and December 2007. RESULTS: Thirty-five studies were included in the review. All-cause mortality was the most commonly assessed outcome (n = 29). Data on CV mortality risk (n = 11) and CV events (congestive heart failure, stroke, myocardial infarction) (n = 4) are limited. The studies varied in populations scrutinized, exposure assessments, covariates adjusted and reference mineral levels used in risk estimation. A significant risk of mortality (all-cause, CV) and of CV events was observed with mineral disturbances. The data supported a greater mortality risk with phosphorus, followed by calcium and parathyroid hormone (PTH). The threshold associated with a significant all-cause mortality risk varied from 3.5-3.9 mg/dL (reference: 2.5-2.9) to 6.6-7.8 mg/dL (reference: 4.4-5.5) for high phosphorus, <3 mg/dL (reference: 5-7) to <5 mg/dL (reference: 5-6) for low phosphorus, 9.7-10.2 mg/dL (reference: < or =8.7) to >10.5 mg/dL (reference: 9-9.5) for high calcium, < or =8.8 mg/dL (reference: >8.8) to <9 mg/dL (reference: 9-9.5) for low calcium and >300 pg/mL (reference: 200-300) to >480 pg/mL (reference: < or =37) for PTH. Thresholds at which the CV mortality risk significantly increased were >5.5 (reference: 3.5-5.5) and >6.5 mg/dL (reference: <6.5) for phosphorus and >476.1 pg/mL (reference: <476.1) for PTH. CONCLUSIONS: Serious limitations were observed in the quality and methodology across studies. In spite of enormous heterogeneity across studies, a significant mortality risk was observed with mineral disturbances in dialysis patients. Data on risk in pre-dialysis patients were less conclusive due to even more limited (numerically) evidence.

A meta-analysis of the relative doses of erythropoiesis-stimulating agents in patients undergoing dialysis.

Background. Erythropoiesis-stimulating agents (ESAs) such as epoetin alfa and beta, and darbepoetin alfa have improved the management of anaemia secondary to chronic kidney disease. Numerous studies have reported a dose reduction when patients receiving dialysis were converted from epoetin to darbepoetin alfa using the starting dose conversion of 200:1 as indicated on the prescribing label by the European Medicines Agency. The objective of this meta-analysis was to summarize the existing body of scientific evidence to evaluate the potential dose savings when comparing epoetin alfa or beta to darbepoetin alfa. Method. Medline and EmBase were searched to identify all published trials investigating ESA treatment in anaemic patients receiving dialysis and converted from epoetins to darbepoetin alfa. We selected prospective randomized controlled, non-randomized and observational studies involving patients on dialysis that compared epoetin and darbepoetin alfa dosing. Results. Of 573 articles identified, 9 studies met the eligibility criteria and were included in our analysis. The overall percentage dose savings attained when dialysis patients were converted from epoetin to darbepoetin alfa was 30% (range: 4%-44%). Greater dose savings were noted with intravenous administration (33%) compared with subcutaneous (27%) and between switch-over studies (31%) and RCTs (27%). In all studies, target haemoglobin levels were maintained before and after conversion. Conclusion. This meta-analysis demonstrates that when using an initial 200:1 conversion ratio, as indicated on the European label, from epoetin to darbepoetin, a subsequent reduction in dose was observed and an average 30% dose savings could be achieved.

Biomarkers and health-related quality of life in end-stage renal disease: a systematic review.

BACKGROUND AND OBJECTIVES: Health-related quality of life (HRQOL) predicts mortality in ESRD, yet adoption of HRQOL monitoring is not widespread, and regulatory authorities remain predominantly concerned with monitoring traditional biologic parameters. To assist with future efforts to adopt HRQOL monitoring while acknowledging the importance of biomarkers, this study sought to establish which domains of HRQOL are most affected by ESRD and to measure the strength of evidence linking common biomarkers to HRQOL in ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A systematic review was performed to identify studies that measured HRQOL in ESRD. Data were abstracted according to a conceptual model regarding the measurement of HRQOL differences, and HRQOL data were converted to weighted mean effect sizes and correlation coefficients. RESULTS: The impact of ESRD was largest in the Short Form 36 domains of physical functioning (e.g., role-physical, vitality) and smallest in mental functioning (e.g., mental health, role-emotional). Dialysis adequacy, as measured by Kt/V, was a poor correlate for Short Form 36 scores. Similarly, mineral metabolism (e.g., calcium x phosphorous, parathyroid hormone) and inflammatory (e.g., C-reactive protein, TNF) biomarkers had small effect sizes and correlations with HRQOL. In contrast, hematocrit demonstrated small to moderate relationships with mental and physical HRQOL, and nutritional biomarkers (e.g., albumin, creatinine, body mass index) demonstrated moderate to large relationships. CONCLUSIONS: HRQOL in ESRD is most affected in the physical domains, and nutritional biomarkers are most closely associated with these domains. In contrast, Kt/V, mineral metabolism indices, and inflammatory markers are poor HRQOL correlates.

Anemia as a predictor of cardiovascular events in patients with elevated serum creatinine.

Patients with anemia and patients with chronic kidney disease have elevated risks for cardiovascular disease. Available studies have been too small to provide details about the relationship or to provide for extensive covariate control. In a large insurance database with linked laboratory values, records of women with serum creatinine >1.2 mg/dl and men with serum creatinine >1.4 mg/dl, identified from July 2000 through June 2003, were sought, and the insurance claims searches for hospitalizations that were associated with myocardial infarction, coronary revascularization, unstable angina, stroke, or congestive heart failure. New onset of dialysis also was sought. Multivariate Poisson regression was used to estimate rate ratios for these events at various hemoglobin (Hb) levels, with adjustment for patient characteristics and previous event history. Among 88,657 patients with high serum creatinine, the risk for hospitalization with myocardial infarction was two to five times higher in anemic (Hb <12 g/dl) patients than in people with Hb from 12.0 to 12.9 g/dl. A similar but less dramatic pattern of higher incidence of coronary revascularization was observed with lower Hb levels. Risks for hospitalization with congestive heart failure declined regularly with increasing Hb levels from a doubling of risk at Hb <10 g/dl to a 61% decrease at 15 g/dl, both relative to 12.0 to 12.9 g/dl. The risk for progression to dialysis was only slightly elevated (7 to 34%) in anemic patients. Anemia raises the risk for cardiovascular disease in patients with elevated serum creatinine.

Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study.

BACKGROUND: Previous studies have associated reduced hemoglobin levels with increased adverse events in heart failure. It is unclear, however, whether this relation is explained by underlying kidney disease, treatment differences, or associated comorbidity. METHODS AND RESULTS: We examined the associations between hemoglobin level, kidney function, and risks of death and hospitalization in persons with chronic heart failure between 1996 and 2002 within a large, integrated, healthcare delivery system in northern California. Longitudinal outpatient hemoglobin and creatinine levels and clinical and treatment characteristics were obtained from health plan records. Glomerular filtration rate (GFR; mL.min(-1).1.73 m(-2)) was estimated from the Modification of Diet in Renal Disease equation. Mortality data were obtained from state death files; heart failure admissions were identified by primary discharge diagnoses. Among 59,772 adults with heart failure, the mean age was 72 years and 46% were women. Compared with that for hemoglobin levels of 13.0 to 13.9 g/dL, the multivariable-adjusted risk of death increased with lower hemoglobin levels: an adjusted hazard ratio (HR) of 1.16 and 95% confidence interval (CI) of 1.11 to 1.21 for hemoglobin levels of 12.0 to 12.9 g/dL; HR, 1.50 and 95% CI, 1.44 to 1.57 for 11.0 to 11.9 g/dL; HR, 1.89 and 95% CI, 1.80 to 1.98 for 10.0 to 10.9; HR, 2.31 and 95% CI, 2.18 to 2.45 for 9.0 to 9.9; and HR, 3.48 and 95% CI, 3.25 to 3.73 for <9.0 g/dL. Hemoglobin levels > or = 17.0 g/dL were associated with an increased risk of death (adjusted HR, 1.42; 95% CI, 1.24 to 1.63). Compared with those with a GFR > or = 60 mL . min(-1).1.73 m(-2), persons with a GFR <45 mL.min(-1).1.73 m(-2) had an increased mortality risk: adjusted HR, 1.39 and 95% CI, 1.34 to 1.44 for 30 to 44; HR, 2.28 and 95% CI, 2.19 to 2.39 for 15 to 29; HR, 3.26 and 95% CI, 3.05 to 3.49 for <15; and HR, 2.44 and 95% CI, 2.28 to 2.61 for those on dialysis. Relations were similar for the risk of hospitalization. The findings did not differ among patients with preserved or reduced systolic function, and hemoglobin level was an independent predictor of outcomes at all levels of kidney function. CONCLUSIONS: Very high (> or = 17 g/dL) or reduced (<13 g/dL) hemoglobin levels and chronic kidney disease independently predict substantially increased risks of death and hospitalization in heart failure, regardless of the level of systolic function. Randomized trials are needed to evaluate whether raising hemoglobin levels can improve outcomes in chronic heart failure.

Depression, anemia and health-related quality of life in chronic hepatitis C.

BACKGROUND/AIMS: Hepatitis C (HCV) infected patients have significant health-related quality of life (HRQL) impairment which worsens during anti-viral therapy. Our aim was to examine the association of HRQL with treatment-induced depression and anemia. METHODS: Two hundred and seventy-one HCV patients who received pegylated interferon alfa 2b and ribavirin were included. Data on HRQL, depressive symptoms, laboratory values and socio-demographic characteristics were collected. RESULTS: Mean age was 47.1+/-6.5, 69% were male, and 73% were White. HCV patients' HRQL declined during anti-viral therapy but returned to or exceeded baseline levels within 24 weeks of completion. Anemia and depression were both associated with HRQL impairment. The effects of depression on HRQL were strong; once depression scores were included other factors were no longer significant. Patients' depressive symptoms tended to increase during the initial half of treatment regimen. Those with higher body mass index (BMI), cirrhosis, and women reported more HRQL impairments. HRQL scales were generally not associated with alcohol abuse, age, race, ALT and HCV RNA levels. CONCLUSIONS: Anti-viral therapy for HCV is associated with diminished HRQL. Although anemia and depression were associated with this impairment, depression was the most consistent predictor. Future studies are needed to see whether proactive management of these side effects can improve patients' HRQL and the efficacy of antiviral therapy for hepatitis C.

Erythropoietic growth factors for treatment-induced anemia in hepatitis C: a cost-effectiveness analysis.

BACKGROUND & AIMS: Treatment-induced anemia undermines the efficacy of antiviral therapy in hepatitis C by mandating ribavirin dose reduction and diminishing adherence to therapy. Erythropoietic growth factors (EGFs) may correct treatment-induced anemia, facilitate maintenance of full-dose therapy, and improve rates of sustained virologic response (SVR). We sought to determine the cost effectiveness of adjunctive treatment with an EGF vs standard care in the treatment of hepatitis C. METHODS: We used a decision analysis to calculate the cost effectiveness of 2 treatment strategies for a patient cohort with chronic hepatitis C, increased transaminase levels, and no cirrhosis who were receiving pegylated-interferon and ribavirin (RBV): (1) RBV dose-reduction for anemia, followed by discontinuation of therapy if anemia persisted (standard care strategy), (2) adjunctive treatment with EGF therapy for anemia, with RBV dose reduction reserved for persistent anemia despite EGF therapy (EGF strategy). We conducted cost-effectiveness and cost-utility analyses to compare short- and long-term outcomes between the strategies. RESULTS: The percentage achieving SVR was 52.3% in the standard care strategy and 59.5% in the EGF strategy. Compared with standard care, the EGF strategy cost an incremental $36,568 per unadjusted life-year gained and $16,443 per quality-adjusted life-year gained. In a sensitivity analysis, if a third-party payer was willing to pay $50,000 per quality-adjusted life-year gained for the use of an EGF, then 86.1% of patients would be within the budget. CONCLUSIONS: Compared with standard care, adjunctive therapy with an EGF for the management of treatment-induced anemia may increase the probability of achieving SVR, increase unadjusted lifespan, and increase quality-adjusted lifespan at an acceptable cost.

Impact of hepatitis C on health related quality of life: a systematic review and quantitative assessment.

Hepatitis C virus (HCV) diminishes health related quality of life (HRQOL), and it is now common to measure HRQOL in clinical trials. We sought to summarize the HRQOL data in HCV, and to establish the minimally clinically important difference (MCID) in HRQOL scores in HCV. We performed a systematic review to identify relevant studies, and converted HRQOL data from each study into clinically interpretable statistics. An expert panel used a modified Delphi technique to estimate the MCID in HCV. We found that patients with HCV scored lower than controls across all scales of the SF-36. Patients achieving sustained virological response (SVR) scored higher across all scales versus patients without SVR, especially in the physical health domains. HRQOL differences did not correspond with differences in liver histology or ALT levels. Based upon the published data, the expert panel concluded that the SF-36 vitality scale was most relevant in patients with HCV, and generated a mean MCID of 4.2 points on this scale. In conclusion, patients with HCV have a clinically significant decrement in HRQOL versus controls, and physical HRQOL improves in patients achieving SVR but not in those without SVR. The data further suggest that traditional outcomes fail to capture the full spectrum of illness related to chronic HCV. A difference of 4.2 points on the SF-36 vitality scale can be used as an estimate of the MCID in HCV, and this value may be used as the basis for power calculations in clinical trials evaluating HRQOL. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html).

Effects of anakinra monotherapy on joint damage in patients with rheumatoid arthritis. Extension of a 24-week randomized, placebo-controlled trial.

OBJECTIVE: To determine the effects of treatment on the radiologic manifestations of joint damage in patients with rheumatoid arthritis (RA) who participated in a 24-week extension study of a randomized, placebo-controlled clinical trial of anakinra, a recombinant human interleukin 1 receptor antagonist. METHODS: The patients had entered a 24-week, randomized, double-blind, placebo-controlled study. Anakinra was self-administered by subcutaneous injection of 30, 75, or 150 mg/day. Upon completion of the placebo-controlled phase, the patients entering the extension study who had received placebo were randomized to one of the 3 treatment dosages for a further 24 weeks, and the patients who had been initially randomized to one of the 3 anakinra dosages continued to receive the same dosage. Radiographs of the hands were obtained at baseline and at 24 and 48 weeks. The radiographs were evaluated using a modified Sharp method. RESULTS: A total of 472 patients were recruited. The mean change in the total modified Sharp score of 178 patients who completed 48 weeks treatment, including all dosages, was significantly less than the change observed in 58 patients who received placebo for 24 weeks and anakinra for 24 weeks (p = 0.015). A significant reduction in the change of the total modified Sharp score was observed in the patients who received anakinra 75 and 150 mg/day. The total modified Sharp score was reduced significantly more during the second 24-week treatment period, compared to the first (p < 0.001). Significant reductions in the second 24-week period were observed following anakinra 75 mg/day (p = 0.006) and 150 mg/day (p = 0.008). CONCLUSION: Patients with RA who received anakinra for 48 weeks demonstrated significant slowing of radiographic joint damage. The treatment effect observed after the first 24-week period appeared to increase when anakinra was continued for 48 weeks.

Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate.

OBJECTIVE: To determine the potential for additive or synergistic effects of combination therapy with the selective anti-tumor necrosis factor alpha agent etanercept and the anti-interleukin-1 agent anakinra. METHODS: Two hundred forty-four patients in whom rheumatoid arthritis (RA) was active despite methotrexate therapy were treated with subcutaneous etanercept only (25 mg twice weekly), full-dosage etanercept (25 mg twice weekly) plus anakinra (100 mg/day), or half-dosage etanercept (25 mg once weekly) plus anakinra (100 mg/day) for 6 months in a double-blind study at 41 centers in the US. Patients had never previously received anticytokine therapy. Patient response was measured with the American College of Rheumatology (ACR) core set criteria, a health-related quality-of-life questionnaire, and the Disease Activity Score. Safety was assessed by the number of adverse events and clinical laboratory values. Plasma concentrations of both agents and antibody formation against both agents were also assessed. RESULTS: Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone, regardless of the regimen, but was associated with an increased safety risk. Thirty-one percent of the patients treated with full-dosage etanercept plus anakinra achieved an ACR 50% response, compared with 41% of the patients treated with etanercept only. This result was not statistically significant (P = 0.914). The incidence of serious infections (0% for etanercept alone, 3.7-7.4% for combination therapy), injection-site reactions, and neutropenia was increased with combination therapy. Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent. CONCLUSION: Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA.