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Introduction Patients with hereditary transthyretin amyloidosis associated with polyneuropathy (ATTRv-PN) experience deterioration in health-related quality of life (HRQOL) as the disease progresses. Findings from the randomized placebo-controlled phase III NEURO-TTR study showed treatment benefit of inotersen, an antisense oligonucleotide, for preserving or improving HRQOL after 65 weeks of treatment. The current analysis examines longitudinal trends in specific aspects of HRQOL, including polyneuropathy symptoms, daily activities, and physical, role, and social functioning in patients with ATTRv-PN receiving long-term treatment in a follow-up open-label extension (OLE) study. Methods One-hundred thirty-five patients with ATTRv-PN were enrolled in an ongoing 5-year OLE study following completion of NEURO-TTR. Eighty-five patients received continuous weekly treatment with inotersen in both studies (inotersen-inotersen group), while 50 patients switched from placebo to inotersen at OLE study baseline (placebo-inotersen group). Descriptive analyses of changes in domain scores and item responses through week 104 of the OLE study were conducted for measures of neuropathy-related and generic HRQOL: Norfolk QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2® Health Survey (SF-36v2), respectively. Results For both inotersen-inotersen and placebo-inotersen groups, all Norfolk QOL-DN and most SF-36v2 domain scores remained stable from OLE baseline through week 104. Differences in HRQOL between the two groups at OLE baseline were sustained through week 104. Analysis of item responses from NEURO-TTR baseline to OLE study week 104 (170 weeks) for the inotersen-inotersen group found no notable increases in the proportion of patients reporting substantial impairments across a wide variety of symptoms, daily activities, and functioning. Conclusion Long-term treatment with inotersen preserved HRQOL for patients with ATTRv-PN for periods of up to 3 years. The gap in HRQOL between those who had previously received inotersen or placebo in NEURO-TTR did not close by week 104 of the OLE phase, indicating the importance of early treatment for maintaining HRQOL in these patients. Trial Registration ClinicalTrials.gov Identifiers NCT01737398 for NEURO-TTR study; NCT02175004 for OLE study Infographic, Plain Language Summary Hereditary transthyretin amyloidosis with polyneuropathy is a rare disease that causes damage to nerves in the limbs, leading to pain, numbness, loss of sensitivity, and muscle weakness, with eventual loss of the ability to walk (i.e., patients require a wheelchair or are bedridden). As the disease progresses, patients’ quality of life, including their ability to engage in everyday activities, socialize with others, work, and live independently, continually worsens. In a recent clinical trial (the NEURO-TTR study), patients with this disease randomized to receive the drug inotersen for 66 weeks maintained their quality of life, while patients randomized to receive a placebo showed continued worsening. All patients completing the NEURO-TTR study could participate in an extension study during which all patients knowingly received inotersen for up to 5 years. We examined quality of life in patients through the first 2 years of this extension study. For all patients, regardless of previous treatment (inotersen or placebo), most aspects of quality of life did not change throughout the 2-year extension study, showing that inotersen can preserve quality of life of these patients for up to 2–3 years. However, while quality of life in patients who had received placebo in the NEURO-TTR study did not get worse during the extension study, it also did not improve to match that of patients who received inotersen during the NEURO-TTR study. This finding shows the importance of treating these patients with inotersen as early as possible to preserve their quality of life before it substantially deteriorates.

Supplemental Digital Content is available in the text., Goals: This US-based, retrospective claims study aimed to investigate disease burden and treatment patterns in patients with eosinophilic esophagitis (EoE), and to compare health care resource use (HCRU) in patients with EoE and matched controls without EoE. Materials and Methods: Patients with a diagnosis of EoE and ≥12 months of prediagnosis data were identified from the Truven Health MarketScan Research databases (January 2008 to September 2016) and followed up from the diagnosis date until termination of eligibility for a health plan. Patient clinical characteristics and HCRU were recorded in the 12 months before diagnosis; HCRU and treatment patterns were recorded during follow-up. HCRU in patients with EoE and matched controls was compared during the 12-month postdiagnosis period. Results: Among the 23,003 patients with EoE (mean age: 34.3 y; 64.8% male), gastroesophageal reflux disease was the most common prediagnosis condition (34.6%). After diagnosis, the most common off-label, first-line treatments were proton pump inhibitor monotherapy (52.8%) and topical corticosteroid monotherapy (21.5%). Overall, 3336 patients (14.5%) received at least 3 lines of off-label pharmacotherapy. Outpatient visits (recorded in 99.9% of patients on and postdiagnosis) were most frequently to gastroenterologists/pediatric gastroenterologists (49.5% prediagnosis, 72.6% on and postdiagnosis). Inpatient admissions and outpatient and emergency room visits were more likely in patients with EoE than in matched controls (P

Introduction Little is known about the burden of hereditary transthyretin (ATTRv) amyloidosis, a genetic, progressive, and fatal disease caused by extracellular deposition of transthyretin amyloid fibrils. The study’s aim was to estimate costs and disease burden associated with ATTRv amyloidosis in a real-world setting. Methods Using IBM® MarketScan® Commercial and Medicare Supplemental data, we identified patients at least 18 years of age with newly diagnosed ATTRv amyloidosis. Diagnosis required at least one medical claim with relevant diagnosis code (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] 277.30–.31, 277.39; ICD-10-CM E85.0–.4, E85.89, E85.9) between January 1, 2014 and December 31, 2016, and at least one additional criterion occurring during study period (2013–2017): at least 15 days diflunisal use without more than a 30-day gap; liver transplant; or claim with codes E85.1 or E85.2. First diagnosis date was study index. Continuous enrollment 1-year pre-index (baseline) and post-index (follow-up) was required. Patients with baseline amyloidosis diagnosis were excluded. Outcomes of interest were comorbidities and 1-year follow-up healthcare utilization and costs (also reported quarterly). Results Among 185 qualifying patients, mean age was 59.2 years (standard deviation 15.2), 54.1% were female, and baseline Charlson comorbidity index was 2.2 (2.5). Neuropathy (30.3%), diabetes (27.0%), and cardiovascular-related comorbidities, including dyspnea (25.9%) and congestive heart failure (21.6%), were common during follow-up. Nearly a quarter of patients (24.9%) were hospitalized during follow-up. Most hospitalizations and emergency department visits occurred in the first quarter post-diagnosis (18.9%, 17.8%, respectively) and dropped in subsequent quarters. The annual mean total cost was $64,066, with inpatient services contributing the majority of the expenses ($34,461), followed by outpatient ($23,853), and then pharmacy ($5752). As with utilization, costs were highest in the first quarter post-diagnosis and dropped in subsequent quarters. Conclusion Patients newly diagnosed with ATTRv amyloidosis have substantial healthcare utilization and costs in the first year, primarily the initial months, post-diagnosis. Further research should examine later costs associated with disease progression and end-of-life care.

Objective Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare disease characterized by rapid neuropathic progression. In pivotal studies of gene-silencing treatments, the modified Neuropathy Impairment Score + 7 tests (mNIS + 7) and Norfolk-Quality of Life (QOL)-Diabetic Neuropathy (DN) questionnaire assessed treatment impact on neuropathic progression. Establishing responder definition (RD) thresholds for these measures would enable evaluation of clinically meaningful treatment benefit. Methods mNIS + 7 and Norfolk-QOL-DN were administered at baseline and week 65 to 165 adults with ATTRv-PN receiving inotersen (n = 106) or placebo (n = 59) in the NEURO-TTR study. Anchor-based approaches for estimating RD thresholds were used for Norfolk QOL-DN, while distribution-based approaches were used for both measures. Responders were patients with a score change Results The mean RD estimates were 12.2 points and 8.8 points for mNIS + 7 and Norfolk QOL-DN, respectively. The proportions of patients whose change in score indicated improvement or stabilization were statistically significantly larger for inotersen than placebo for all estimated RD thresholds for mNIS + 7 (64–86% responders for inotersen vs. 27–46% for placebo, ORs = 3.8–7.2, ps ps Discussion Establishing RD thresholds for these instruments enables evaluation of clinically relevant and individual-level treatment benefit on neuropathic progression. Across RDs estimated using multiple methods, a higher proportion of patients receiving inotersen than placebo showed improved or stabilized neuropathic progression at week 65. Trial registration ClinicalTrials.gov Identifier: NCT01737398; Date of registration: November 29, 2012.

Background We aimed to compare neuropathic progression rate between hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and other peripheral neuropathies, including diabetic peripheral neuropathy (DPN) and Charcot-Marie-Tooth disease (CMT). Methods Literature searches identified studies reporting neuropathic progression, measured by Neuropathy Impairment Score (NIS) or NIS-Lower Limbs (NIS-LL). Our study also included unpublished data from a clinical registry of patients who were diagnosed with different peripheral neuropathies and seen at the Oregon Health & Science University (OHSU) during 2016–2020. Meta-analysis and meta-regression models examined and compared annual progression rates, calculated from extracted data, between studies of ATTRv-PN and other peripheral neuropathies. Results Data were synthesized from 15 studies in which NIS and/or NIS-LL total scores were assessed at least twice, with ≥12 weeks between assessments, among untreated patients with ATTRv-PN or other peripheral neuropathies. Meta-analysis models yielded that the annual progression rate in NIS total scores was significantly different from zero for studies in ATTRv-PN and CMT (11.77 and 1.41; both P P = 0.147). Meta-regression models showed significantly faster annual progression in studies in ATTRv-PN, which statistically exceeded that in other peripheral neuropathies by 12.45 points/year for NIS, and 6.96 for NIS-LL (both P Conclusions Peripheral nervous function deteriorates more rapidly in patients with ATTRv-PN than for other peripheral neuropathies. These findings may improve understanding of the natural history of neuropathy in ATTRv-PN, facilitate early diagnosis, and guide the development of assessment tools and therapies specifically targeting neuropathic progression in this debilitating disease.

Background Despite emerging treatments for hereditary transthyretin (ATTRv) amyloidosis, the disease is often misdiagnosed, with reported diagnostic delays of up to several years. Knowledge of the patient journey leading up to diagnosis may help to promote earlier intervention. The study’s objective was to examine patient clinical characteristics and healthcare utilization prior to ATTRv amyloidosis diagnosis. Methods Patients ≥ 18 years and newly diagnosed with ATTRv amyloidosis identified in IBM® MarketScan® Commercial and Medicare Supplemental data using a claims-based algorithm as follows: diagnosis required ≥ 1 medical claim with relevant amyloidosis diagnosis code (ICD-10-CM: E85.0-.4, E85.89, E85.9; excludes light chain and wild type) during identification (ID) period (1/1/2016–12/31/2017), and ≥ 1 occurrence of qualifying criteria during 2011–2017: ≥ 15 days diflunisal use without > 30-day gap, liver transplant, or claim with specific codes E85.1 or E85.2. The index date was defined as the date of first claim with amyloidosis diagnosis code in ID period. Patients had continuous enrollment ≥ 5 years pre-index date (look-back period). Occurrence of selected comorbid conditions and symptoms and healthcare utilization (testing, emergency department visits and hospitalization) measured during the look-back period; demographics, physician specialty, and Charlson comorbidity index (CCI) measured 1 year pre-index. Patients with an ICD-9/10 amyloidosis code during the look-back period were excluded. An ATTRv-free reference cohort was created from a random sample of enrollees who lacked any diagnosis of amyloidosis and matched 3:1 to ATTRv patients on age, gender, and region to provide reference values; same index and enrollment requirement as match. Results For the 141 qualifying patients with ATTRv and 423 matched controls, mean (standard deviation) age was 62.5 (14.2) years and 53.9% were female. Mean CCI for ATTRv cohort was 2.7 (3.0) versus 1.1 (1.9) among controls. Selected comorbidities, testing, visits, and hospitalization were common among patients with ATTRv during the look-back period with higher rates versus controls. Conclusions Patients with ATTRv amyloidosis experience multiple neurological, cardiovascular, and other clinical manifestations, testing, and hospitalization prior to diagnosis. Occurrence of potential markers of illness is most common in the year before diagnosis.

Background Improved lung function and fewer pulmonary exacerbations (PEx) were observed with lumacaftor/ivacaftor (LUM/IVA) in patients with cystic fibrosis homozygous for F508del. It is unknown whether PEx reduction extends to patients without early lung function improvement. Methods Post hoc analyses of pooled phase 3 data (NCT01807923, NCT01807949) categorized LUM/IVA-treated patients by percent predicted forced expiratory volume in 1 s (ppFEV1) change from baseline to day 15 into threshold categories (absolute change ≤0 vs >0; relative change Results LUM (400 mg q12h)/IVA (250 mg q12h)–treated patients (n = 369) experienced significantly fewer PEx vs placebo, regardless of threshold category. With LUM/IVA, PEx rate per patient per year was 0.60 for those with absolute change in ppFEV1 > 0 and 0.85 for those with absolute change ≤0 (respective rate ratios vs placebo [95% CI]: 0.53 [0.40–0.69; P Conclusions LUM/IVA significantly reduced PEx, even in patients without early lung function improvement.

Introduction Hereditary transthyretin amyloidosis (ATTRv) is often associated with progressive infiltrative cardiac involvement, with cardiac symptoms occurring sometimes years prior to diagnosis. Hypothesis ATTRv patients demonstrate significant cardiovascular symptom manifestations and healthcare utilization prior to diagnosis. Methods Newly diagnosed ATTRv patients in IBM® MarketScan® Commercial and Medicare Supplemental data (US) were identified using a claims-based algorithm. Diagnosis required ≥1 claim with relevant amyloidosis diagnosis code (ICD-10-CM: E85.0-.4, E85.89, E85.9) during identification (ID) period (1/2016-12/2017), and the occurrence of ≥1 qualifying criteria during 2011-2017: ≥15 days diflunisal use, liver transplant, or claim with code E85.1 (neuropathic heredofamilial amyloidosis) or E85.2 (heredofamilial amyloidosis unspecified). Index date was defined as date of first claim with amyloidosis code in ID period, and the pre-index period as the 5 years prior to index date. Patients with an ICD-9/10 amyloidosis code during this period were excluded to focus on the newly diagnosed. Control subjects without ATTRv were identified and matched (age, gender, region) to ATTRv patients (ratio 3:1); meeting the same index and enrollment requirements. Frequency of selected cardiovascular (CV) conditions and healthcare use were measured in the pre-index period; demographics and Charlson comorbidity index (CCI) were measured 1 year pre-index. Results Among 141 patients with ATTRv and 423 matched controls, mean (SD) age was 62.5 (14.2) years and 53.9% were female. Mean CCI for ATTRv patients was 2.7 (3.0) vs 1.1 (1.9) for controls. In the pre-index period, CV conditions were more common among ATTRv patients relative to controls: chest pain (51.8 vs. 28.1%), dyspnea (49.6 vs 25.8%), bleeding (41.8 vs 21.3%), edema (27.0 vs 12.8%), heart failure (23.4 vs 5.9%), ventricular hypertrophy (19.9 vs 5.7%), hypotension (18.4 vs 6.1%), atrial fibrillation/flutter (18.0 vs 8.9%), stroke (12.8 vs 6.1%), and aortic stenosis (10.6 vs 4.5%); conditions were relatively higher in each pre-index year. Hospitalization (47.5 vs. 24.3%), emergency department visits (60.3 vs. 47.0%) and cardiac testing (81.6 vs. 65.7%) were also more frequent among ATTRv patients. Median time (months) to ATTRv diagnosis from initial symptom manifestation were largest for chest pain (43.0), dyspnea (41.1), aortic stenosis (39.2), and atrial fibrillation/flutter (34.3). Conclusions ATTRv patients have considerable CV disease burden in the 5 years preceding diagnosis. Increased awareness of characteristic CV manifestations may increase clinical suspicion, leading to early diagnosis and prompt intervention.

Background Hereditary transthyretin amyloidosis (hATTR or ATTRv [variant]) is a progressive and fatal disease often associated with infiltrative cardiac involvement, with cardiac symptoms sometimes occurring years before diagnosis. Because there are available treatments for hATTR, prompt recognition and early diagnosis is imperative. Nurses who work closely with patients with heart failure are positioned to recognize the symptoms and early signs that should raise clinical suspicion and uncover an underlying diagnosis of hATTR. Objective To determine whether patients with hATTR demonstrate significant cardiovascular symptom manifestations and health care utilization before diagnosis. Methods Patients with newly diagnosed hATTR were identified in IBM® MarketScan® Commercial and Medicare Supplemental data (United States) using a claims-based algorithm. Diagnosis required ≥1 claim with relevant amyloidosis diagnosis code (ICD-10-CM: E85.0-.4, E85.89, E85.9) during the identification (ID) period (January 2016-December 2017), and the occurrence of ≥1 qualifying criterion during 2011-2017: ≥15 days diflunisal use, liver transplant, or claim with code E85.1 (neuropathic heredofamilial amyloidosis) or E85.2 (heredofamilial amyloidosis unspecified). Index date was defined as date of first claim with amyloidosis code in the ID period, and preindex period was defined as the 5 years before index date. Patients with a preexisting ICD-9/10 amyloidosis code during this period were excluded to focus on patients who were newly diagnosed. Control subjects without hATTR were identified and matched (age, sex, region) to patients with hATTR (ratio 3:1); these subjects were assigned same index and met same continuous enrollment requirement during preindex period. Frequency of selected cardiovascular conditions and health care use were measured in the preindex period; demographics and Charlson comorbidity index (CCI) were measured 1 year preindex. Results Among 141 patients with hATTR and 423 matched controls, mean (SD) age was 62.5 (14.2) years and 53.9% were female. Mean CCI for patients with hATTR was 2.7 (3.0) versus 1.1 (1.9) for controls. In the preindex period, cardiovascular conditions/symptoms were more common among patients with hATTR relative to controls: chest pain (51.8 vs 28.1%; P Conclusions Patients with hATTR have considerable cardiovascular disease burden in the 5 years preceding diagnosis. Increased awareness of characteristic cardiovascular manifestations among nurses may increase clinical suspicion, leading to early diagnosis and prompt intervention.

Background & Aims Quantification of eosinophilic esophagitis (EoE) symptoms is crucial for assessing treatment outcomes. We aimed to explore the effect of budesonide oral suspension (BOS) on dysphagia and pain with swallowing. Methods We performed a secondary analysis of data from a phase 2 multicenter, double-blind, trial (conducted from July 2012 through October 2014) of patients with EoE, 11–40 y old, who were randomly assigned to groups given placebo or BOS (2.0 mg twice daily) for 12 weeks. Symptoms were quantified using the Dysphagia Symptom Questionnaire (DSQ) from baseline to week 12 of therapy. Results Overall, 93 patients were randomly assigned to groups; the prespecified modified intention-to-treat analysis set comprised 87 patients (38 from the placebo group and 49 from the BOS group). Improvements from baseline in least-squares mean (standard error) DSQ (Q2+Q3) scores were observed. The difference between groups was statistically significant only at week 12 (placebo vs BOS: week 4, −4.9 [1.7] vs −7.4 [1.5]; P = .265; week 8, −7.4 [2.1] vs −10.3 [1.8]; P = .288; week 12, −7.5 [1.9] vs −14.3 [1.7]; P = .01). Similar findings were observed for pain (Q4) scores (placebo vs BOS: week 4, −2.5 [0.8] vs −3.3 [0.7]; P = .484; week 8, −3.0 [0.8] vs −4.9 [0.7]; P = .066; week 12, −3.1 [0.8] vs −4.9 [0.7]; P = .109). More severe DSQ and DSQ+pain scores were associated with presence of other symptoms (such as regurgitation) and physician-rated severity. Improvements in DSQ and DSQ+pain scores were greater in patients with either a histologic or endoscopic response than in patients without a response. Conclusions In a secondary analysis of data from a phase 2 trial of patients with EoE, we found evidence for improvements in dysphagia and pain scores in patients who received BOS (2.0 mg twice daily) vs placebo. Pain with swallowing should be considered in the clinical assessment of patients with EoE. ClinicalTrials.gov no: NCT01642212 .

Childhood illness can impose significant costs and health strains on family members, but these are not routinely captured by pediatric economic evaluations. This review investigated how family “spillover effects” related to costs and health outcomes are considered in pediatric cost-utility analyses (CUAs). We reviewed pediatric CUAs published between 2000 and 2015 using the Tufts Medical Center Cost-effectiveness Analysis (CEA) Registry and the Pediatric Economic Database Evaluation (PEDE) Registry. We selected studies conducted from the societal perspective and included in both registries. We investigated how frequently family spillover was incorporated into analyses, and how the inclusion of spillover health effects and costs changed CUA results. We found 142 pediatric CUAs meeting inclusion criteria. Of those, 105 (72%) considered either family spillover costs (n = 98 time costs, n = 33 out-of-pocket costs, n = 2 caregiver healthcare costs) or health outcomes (n = 15). Twenty-four studies included 43 pairs of incremental cost-effectiveness ratios (ICERs) with and without spillover. In 19 pairs of ICERs, adding spillover changed the ICER enough to cross a common cost-effectiveness threshold (i.e., $50,000/QALY, $100,000/QALY, $150,000/QALY; values are in 2016 US$). Incorporating spillover generally made interventions more cost-effective (n = 18; 42%), or did not change CUA results enough to cross a threshold (n = 24; 56%). Including family spillover reduced ICERs by 31% ($40,000/QALY) on average. Most pediatric CUAs conducted from a societal perspective include family costs but fewer include family health effects. Inclusion of family spillover effects tends to make CUA results more favorable. Future pediatric CUAs should aim to more fully incorporate the family burden of illness.

Summary Background Chronic hepatitis C virus (HCV) infection and its treatment impact patients' health-related quality of life (HRQL). Aim To report on treatment impact and predictors of HRQL among treatment-naive patients with genotype 1 chronic HCV infection who received 12-week telaprevir (T) with 24 (T12PR24) or 48 weeks (T12PR48) peginterferon alpha-2a/ribavirin (PR), or 48 weeks of PR in the ADVANCE study. Methods The EQ-5D-3L (EQ-5D) questionnaire (index range: 0–1) was completed at baseline and weeks 4, 12, 24, 36, 48 and 72. Patients indicated their health state on five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Descriptive statistics for the EQ-5D index and descriptive system and area under the curve from baseline to week 12 were calculated. Predictors of EQ-5D index were identified using multivariate analyses. Results Data from 722 patients were included. The mean EQ-5D index decreased during the first 12 weeks and returned to baseline by week 72 (T12PR24 by week 36) across treatments. In multivariate analysis, sustained virological response (SVR) at week 72 was associated (P

Background The analysis aimed to examine the impact of pulmonary exacerbations (PEs) and lung function on generic measures of HRQL in patients with cystic fibrosis (CF) using trial-based data. Methods In a 48-week randomized, placebo-controlled study of ivacaftor in patients ≥12 years with CF and a G551D-CFTR mutation the relationship between PEs, PE-related hospitalizations and percent predicted forced expiratory volume in one second (ppFEV1) with EQ-5D measures (index and visual analog scale [VAS]) was examined in post-hoc analyses. Multivariate mixed-effects models were employed to describe the association of PEs, PE-related hospitalizations, and ppFEV1 on EQ-5D measures. Results One hundred sixty one patients (age: mean 25.5 [SD 9.5] years; baseline ppFEV1: 63.6 [16.4]) contributed 1,214 observations (ppFEV1: no lung dysfunction [n = 157], mild [n = 419], moderate [n = 572], severe [n = 66]). Problems were most frequently reported on pain/discomfort, anxiety/depression, and usual activities EQ-5D items. The mean (SE) EQ-5D index nominally decreased (worsened) with worsening severity of lung dysfunction (P = 0.070): 0.931 (0.023); mild: 0.923 (0.021); moderate: 0.904 (0.018); severe: 0.870 (0.020). 146 PEs were experienced by 72 patients, including 52 PEs (35.6 %) that required hospitalization. Mean EQ-5D index and VAS scores were lowest (worst) within 1 week (before or after PE start) for PEs requiring hospitalization. Pulmonary exacerbations, PE-related hospitalizations, and ppFEV1 were significant predictors of EQ-5D index and VAS. Conclusions In a clinical study of patients with CF (≥12 years of age and a G551D-CFTR mutation), PEs, primarily those requiring hospitalization, were associated with low EQ-5D index and VAS scores. The impact of ppFEV1 was relatively smaller. Reducing PEs, in particular those requiring hospitalization, would likely improve HRQL among these patients. Trial registration ClinicalTrials.gov, NCT00909532; URL: clinicaltrials.gov, May 26, 2009 Electronic supplementary material The online version of this article (doi:10.1186/s12955-016-0465-z) contains supplementary material, which is available to authorized users.

Objective.Patients with rheumatoid arthritis (RA) are at increased risk of death. Modern RA therapy has been shown to improve health status, but the relationship of such improvements to mortality risk is unknown. We assessed the relationship between health status and all-cause mortality in patients with RA, using the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Study Short Form-36 questionnaire (SF-36) physical and mental component summary scores (PCS, MCS).Methods.Subjects (n = 10,319) were selected from the National Data Bank for Rheumatic Diseases, a prospective longitudinal observational US study with semiannual assessments of HAQ, PCS, and MCS. Risk of death up to 7 years through 2006 was obtained from the US National Death Index. Relationship of HAQ, PCS, and MCS to mortality was assessed using Cox regression models; prediction accuracy was compared using Harrell’s concordance coefficient (C).Results.Over 64,888 patient-years of followup, there were 1317 deaths. Poorer baseline health status was associated with greater mortality risk. Adjusting for age, sex, and baseline PCS and MCS, declines in PCS and HAQ were associated with higher risk of death. HAQ improvement was associated with reduced mortality risk from 6 months through 3 years; a similar relationship was not observed for PCS or MCS improvement. Controlling for baseline values, change in PCS or HAQ did not improve prediction accuracy.Conclusion.The HAQ and the SF-36 PCS are similarly and strongly associated with mortality risk in patients with RA. Change in these measures over time does not appear to add to predictive accuracy over baseline levels.

The objective of the present study was to describe a new model of the cost-effectiveness of treatment of generalized anxiety disorder (GAD) and its application to a comparison of pregabalin versus venlafaxine extended-release (XR) from a Spanish healthcare perspective. Microsimulation techniques, including Hamilton Anxiety Scale (HAM-A) score, number of weeks with minimal or no anxiety (HAM-Aor= 9), and quality-adjusted life-years (QALYs), were used to predict treatment outcomes for patients with moderate-to-severe GAD who would be treated with pregabalin vs venlafaxine XR. Expected levels of healthcare utilization and unit cost of care are derived from Spanish published sources. We express cost-effectiveness alternatively in terms of incremental cost per additional week with minimal or no anxiety, and incremental cost per QALY gained [in 2007 Euros (euro)]. Considering costs of drug treatment only, the incremental cost [mean (95% confidence interval)] of pregabalin (vs venlafaxine XR) would be euro96 (euro86, euro107) per additional week with minimal or no anxiety, and euro32,832 (euro29,656, euro36,308) per QALY gained. When other medical care costs are considered, cost-effectiveness ratios decline to euro70 (euro61, euro80) per additional week with no or minimal anxiety, and euro23,909 (euro20,820, euro27,006) per QALY gained. We conclude that, using a new microsimulation model of the treatment of GAD, pregabalin appears to be cost-effective vs venlafaxine XR in a Spanish healthcare setting.

Objective To assess cost-effectiveness of abatacept in patients with moderately to severely active RA and inadequate response to MTX. Methods We developed a simulation model to depict progression of disability [in terms of the HAQ Disability Index (HAQ-DI)] in women aged 55-64 yrs with moderately to severely active RA and inadequate response to MTX. At model entry, patients were assumed to receive either only MTX or MTX plus abatacept. Patients were then tracked from model entry until death. Future health-state utilities and medical-care costs (except study therapy) were estimated based on predicted values of the HAQ-DI. The model was estimated using data from a Phase III clinical trial of abatacept plus various secondary sources. Cost-effectiveness was expressed in terms of incremental cost (2006 US$) per quality-adjusted life-year (QALY) gained over alternatively 10 yrs and a lifetime. Costs and health effects were both discounted at 3% annually. Results Over 10 yrs, abatacept would yield 1.2 additional QALYs (undiscounted) per patient (4.6 vs 3.4 for MTX) at an incremental (discounted) cost of $51,426 ($103,601 vs $52,175, respectively); over a lifetime, corresponding figures were 2.0 QALYS (6.8 vs 4.8) and $67,757 ($147,853 vs $80,096). Cost-effectiveness was [mean (95% CI)] $47,910 ($44,641, $52,136) per QALY gained over 10 yrs and $43,041 ($39,070, $46,725) per QALY gained over a lifetime. Findings were robust in sensitivity analyses. Conclusion Abatacept is cost-effective by current standards of medical practice in patients with moderately to severely active RA and inadequate response to MTX.

BACKGROUND The current study was conducted to characterize the risks and clinical consequences of oral mucositis (OM) in patients with head and neck carcinoma (HNC) who are receiving radiation therapy. METHODS Data regarding 450 HNC patients who had received radiation therapy were collected via chart review from 154 U.S. medical and radiation oncologists. Information obtained included patient characteristics, treatments received, highest recorded grade of OM during radiation therapy (none, mild, moderate, or severe), and outcomes potentially associated with mucosal injury. RESULTS The mean age (± standard deviation [SD]) of the study subjects was 61.3 years (12.3 yrs); the majority of patients (80%) were men. Primary tumor locations included the oropharynx (26.4%), larynx (26.4%), oral cavity including the lip (24.4%), hypopharynx (13.6%), and nasopharynx (9.1%). The majority of tumors were new and were classified as AJCC Stages III or IV. The majority of patients (83%) received standard radiation therapy; the mean (± SD) cumulative dose was 6285 centigrays (cGy) (± 1158 cGy). Approximately 33% of the patients received concomitant chemotherapy. The majority of patients (83%) developed OM; 29% developed severe OM. Patients with severe OM were more likely to have nasopharyngeal or oropharyngeal tumors (adjusted odds ratio [OR] of 10.1 [95% confidence interval (95% CI), 2.1–49.9] and 6.9 [95% CI, 2.4–19.7], respectively), and to have received cumulative radiation doses > 5000 cGy (OR of 10.4; 95% CI, 2.9–37.1) and concomitant chemotherapy (OR of 3.3; 95% CI, 1.4–8.0). Patients with OM had more unplanned breaks in radiation therapy (OR of 3.8; 95% CI, 1.7–8.5) and hospital admissions (OR of 3.5; 95% CI, 1.3–9.5). CONCLUSIONS HNC patients with nasopharyngeal or oropharyngeal tumors, and those who receive cumulative radiation doses > 5000 cGy or concomitant chemotherapy, are more likely to develop OM. Patients with OM are at a higher risk of unplanned breaks in radiation therapy and hospitalization. Cancer 2006. © 2005 American Cancer Society.

Objective To compare expected outcomes and costs of care in patients with chronic schizophrenia or schizoaffective disorders who are treated with risperidone versus olanzapine. Methods A Markov model was developed to examine outcomes and costs of care in patients with chronic schizophrenia or schizoaffective disorders receiving risperidone or olanzapine. The time frame of interest was 1 year. The model focused particular attention on the likelihood of therapy switching and discontinuation as a result of treatment-emergent side effects, as the efficacy of these two agents is similar. Measures of interest included the incidence of relapse and selected side effects including extrapyramidal symptoms (EPS), prolactin-related disorders and diabetes, expected change in body weight, and the percentage of patients remaining on initial therapy at the end of 1 year. Costs of antipsychotic therapy and psychiatric and nonpsychiatric services also were examined. Results At 1 year, the rate of EPS was estimated to be slightly higher for risperidone, as was the incidence of symptomatic prolactin-related disorders. The expected incidence of diabetes mellitus, while low, was slightly higher for olanzapine. Approximately 25% and 4% of olanzapine and risperidone patients, respectively, were projected to experience an increase in body weight ≥ 7%. The estimated percentage of patients remaining on initial therapy at the end of 1 year was higher for risperidone than olanzapine (76.9% vs. 45.6%, respectively). Expected mean total costs of care per month of therapy were $2163 for risperidone and $2316 for olanzapine. Results from sensitivity analyses suggest that the probability of therapy discontinuation following weight gain > 5 kg would have to be lower than 0.1 for the number of patients remaining on therapy at the end of 1 year to be the same for risperidone and olanzapine. Conclusions Compared with risperidone, treatment with olanzapine may result in greater increases in body weight, higher rates of therapy discontinuation, and higher costs of medical-care services.

BACKGROUND Venous thromboembolism (VTE) is a frequent and potentially costly complication of major orthopedic surgery. OBJECTIVE To estimate the economic consequences of VTE following major orthopedic surgery. METHODS Using a large healthcare claims database, we identified all patients who underwent total hip replacement, major knee surgery, or hip fracture repair from January 1993 to December 1998. Patients with clinical VTE (cases) were identified based on a diagnosis of deep vein thrombosis or pulmonary embolism within 90 days of surgery (index admission) and ≥1 prescription for warfarin or unfractionated heparin within 30 days of the date of initial VTE diagnosis. Each case was matched (using age and procedure type) to 2 randomly selected patients who did not have any claims for clinical VTE (matched controls). Utilization and billed charges were then examined over a 90-day period following admission. Cases were stratified based on whether VTE was first noted during the index admission or thereafter. RESULTS A total of 11 960 patients were identified who underwent total hip replacement, major knee surgery, or hip fracture repair (n = 3171, 3955, 4834, respectively). Over a 90-day period, 259 patients (2.2%) developed clinical VTE. Most cases (61.8%) occurred after hospital discharge. For patients with in-hospital VTE, mean length of stay for the index admission was 4.5 days longer than that of matched controls (11.1 vs 6.6); by day 90, there was a 5.4-day difference in total hospital days. Mean billed charges for the index admission were $17 552 higher ($52 037 vs $34 485); the difference rose to $18 834 by day 90 ($54 480 vs $35 646). For patients who developed clinical VTE following hospital discharge, there was a 3.4-day difference in total hospital days at day 90 (10.2 vs 6.8) as a result of readmissions for VTE; mean total billed charges at day 90 were $5765 higher ($41 411 vs $35 646) CONCLUSION Among patients who have undergone major orthopedic surgery, the economic consequences of VTE are substantial, regardless of the setting in which it occurs.

To evaluate risk factors for ventilator-associated pneumonia (VAP), as well as its influence on in-hospital mortality, resource utilization, and hospital charges.Retrospective matched cohort study using data from a large US inpatient database.Patients admitted to an ICU between January 1998 and June 1999 who received mechanical ventilation for24 h.Risk factors for VAP were examined using crude and adjusted odds ratios (AORs). Cases of VAP were matched on duration of mechanical ventilation, severity of illness on admission (predicted mortality), type of admission (medical, surgical, trauma), and age with up to three control subjects. Mortality, resource utilization, and billed hospital charges were then compared between cases and control subjects.Of the 9,080 patients meeting study entry criteria, VAP developed in 842 patients (9.3%). The mean interval between intubation, admission to the ICU, hospital admission, and the identification of VAP was 3.3 days, 4.5 days, and 5.4 days, respectively. Identified independent risk factors for the development of VAP were male gender, trauma admission, and intermediate deciles of underlying illness severity (on admission) [AOR, 1.58, 1.75, and 1.47 to 1.70, respectively]. Patients with VAP were matched with 2,243 control subjects without VAP. Hospital mortality did not differ significantly between cases and matched control subjects (30.5% vs 30.4%, p = 0.713). Nevertheless, patients with VAP had a significantly longer duration of mechanical ventilation (14.3 +/- 15.5 days vs 4.7 +/- 7.0 days, p0.001), ICU stay (11.7 +/- 11.0 days vs 5.6 +/- 6.1 days, p0.001), and hospital stay (25.5 +/- 22.8 days vs 14.0 +/- 14.6 days, p0.001). Development of VAP was also associated with an increase of$40,000 USD in mean hospital charges per patient ($104,983 USD +/- $91,080 USD vs $63,689 USD+/- $75,030 USD, p0.001).This retrospective matched cohort study, the largest of its kind, demonstrates that VAP is a common nosocomial infection that is associated with poor clinical and economic outcomes. While strategies to prevent the occurrence of VAP may not reduce mortality, they may yield other important benefits to patients, their families, and hospital systems.

The economic costs of clinical venous thromboembolism (VTE) in hospitalized patients after major orthopedic surgery were assessed. The discharge summaries and itemized bills from 220 U.S. acute care hospitals were examined. All patients who underwent total hip or knee replacement surgery or hip-fracture repair at these hospitals between January 1998 and June 1999 were identified and included in the study sample. Length of hospital stay, use of intensive care services, and costs of inpatient care were compared between patients with and without secondary diagnoses of deep vein thrombosis (DVT) without pulmonary embolism (PE) (DVT only) or PE with or without DVT. Mean length of hospital stay was more than twice as long for patients with VTE (11.5 and 12.4 days for DVT only and PE, respectively, versus 5.4 days for no VTE; p < 0.0001 for both comparisons). Mean time in the intensive care unit was roughly 10-fold greater (1.7 days for DVT only and 2.7 days for PE versus 0.2 day for no VTE; p < 0.0001). Mean total costs of inpatient care were almost twofold higher for patients with VTE ($17,114 for DVT only and $18,521 for PE versus $9,345 for no VTE; p < 0.0001 for both comparisons). Findings were unchanged in multivariate analyses controlling for differences in baseline characteristics between patients with and without VTE. Patients who develop in-hospital clinical VTE following major orthopedic surgery have significantly longer stays in the 'hospital and approximately twofold higher costs of inpatient care.

BACKGROUND Carvedilol reduces disease progression in heart failure, but to our knowledge, its effects on hospitalizations and costs have not been evaluated. OBJECTIVES We examined the effects on hospitalization frequency and costs in the U.S. Carvedilol Heart Failure Trials Program. This program consisted of four concurrent, multicenter, double-blind, placebo-controlled studies involving 1,094 patients with New York Heart Association class II to IV heart failure, which treated patients with placebo or carvedilol for up to 15 months (median, 6.5 months). METHODS Detailed resource utilization data were collected for all hospitalizations occurring between randomization and the end of follow-up. In-patient care costs were estimated based on observed levels of resource use. RESULTS Compared with placebo, carvedilol reduced the risk of hospitalization for any reason by 29% (p = 0.009), cardiovascular hospitalizations by 28% (p = 0.034) and heart failure hospitalizations by 38% (p = 0.041). Carvedilol also decreased the mean number of hospitalizations per patient (for cardiovascular reasons 30% [p = 0.02], for heart failure 53% [p = 0.03]). Among hospitalized patients, carvedilol reduced severity of illness during hospital admission, as reflected by shorter length of stay and less frequent use of intensive care. For heart failure hospital admissions, carvedilol decreased mean length of stay by 37% (p = 0.03) and mean number of intensive care unit/coronary care unit days by 83% (p = 0.001), with similar effects on cardiovascular admissions. As a result, estimated inpatient care costs with carvedilol were 57% lower for cardiovascular admissions (p = 0.016) and 81% lower for heart failure admissions (p = 0.022). CONCLUSIONS Carvedilol added to angiotensin-converting enzyme inhibition reduces hospitalization risk as well as severity of illness and resource utilization during admission in patients with chronic heart failure.

In this study, we examine the cost effectiveness of carvedilol for the treatment of chronic heart failure (CHF). We use a Markov model to project life expectancy and lifetime medical care costs for a hypothetical cohort of patients with CHF who were assumed alternatively to receive carvedilol plus conventional therapy (digoxin, diuretics, and angiotensin-converting enzyme inhibitors) or conventional therapy alone. Patients on carvedilol were assumed to experience a reduced risk of death and hospitalization for CHF, which is consistent with findings from the US Carvedilol Heart Failure Trials Program. The benefits of carvedilol were projected under 2 alternative scenarios. In the first ("limited benefits"), benefits were conservatively assumed to persist for 6 months, the average duration of follow-up in these clinical trials, and then end abruptly. In the other ("extended benefits"), they were arbitrarily assumed to persist for 6 months and then decline gradually over time, vanishing by the end of 3 years. We estimated our model using data from the US Carvedilol Heart Failure Trials Program and other sources. For patients receiving conventional therapy alone, estimated life expectancy was 6.67 years; corresponding figures for those also receiving carvedilol were 6.98 and 7.62 years under the limited and extended benefits scenarios, respectively. Expected lifetime costs of CHF-related care were estimated to be $28,756 for conventional therapy, and $36,420 and $38,867 for carvedilol (limited and extended benefits, respectively). Cost per life-year saved for carvedilol was $29,477 and $12,799 under limited and extended benefits assumptions, respectively. The cost effectiveness of carvedilol for CHF compares favorably to that of other generally accepted medical interventions, even under conservative assumptions regarding the duration of therapeutic benefit.

Work productivity is impacted in hepatitis C virus (HCV)-infected patients and has been linked to treatment. In two Phase 3 trials, ADVANCE and ILLUMINATE, treatment-naive genotype 1 chronic HCV-infected patients received 12-week telaprevir (T) with 24 (T12PR24)- or 48 (T12PR48)-week peginterferon alfa-2a/ribavirin. The objective of this analysis was to examine the impact of chronic HCV infection and its treatment with combination therapy on work productivity. The 5-item, self-reported work productivity questionnaire (WPQ) was administered in Phase 3 trials to assess unemployment status, days unable to work due to HCV/treatment, reduced hours worked and impact on productivity in prior 4 weeks. Descriptive statistics and multivariate regression analyses were employed in analyses of pooled trial data. About 1147 patients were included; 22% (n = 255) were unemployed at baseline, with 8% being unemployed due to health reasons. At week 12, there were no differences by treatment regimen in the number of days unable to work. At week 48, improvements were observed earlier among patients receiving the shorter duration of T combination treatment. Mean (95% CI) change from baseline in days unable to work was -0.48 (-0.85, -0.11) days for T12PR24, 1.43 (0.63, 2.24) days for T12PR48 and 1.24 (0.18, 2.30) days for PR48 with placebo. Predictors of days unable to work were identified and include demographic characteristics, pretreatment and on-treatment levels of fatigue, as well regional variation. In post hoc analyses of the ADVANCE and ILLUMINATE trials, work productivity decreased during the initial 12 weeks regardless of treatment group.

Background— Many hospitalized medically ill patients are at risk of venous thromboembolism (VTE). Risk factors include prior VTE, older age, immobility, obesity, cardiac or respiratory failure, and cancer (at-risk patients). Although guidelines recommend use of VTE prophylaxis for at-risk patients, many may not receive it. Methods and Results— Using a database linking admission records from >150 US hospitals to health insurance claims, we identified people ≥40 years of age, hospitalized from 2003 to 2008. We excluded patients who: (1) were treated for VTE or hospitalized in the previous 30 days; (2) were admitted for traumatic injury or surgery; (3) had hypercoagulability at admission; or (4) received therapeutic dosages of low-molecular weight heparin, unfractionated heparin, or fondaparinux at admission. We examined the use of VTE prophylaxis (both pharmacological and nonpharmacological) on day 1 or 2 in hospital among at-risk patients; predictors of receipt of prophylaxis were examined using multivariate logistic regression. The study population consisted of 49 948 patients, of whom 34 374 (69%) were at risk. Only 18% of at-risk patients received VTE prophylaxis on day 1 or 2 in hospital, typically with low-molecular weight heparin (56% of patients receiving prophylaxis), intermittent pneumatic compression (25%), warfarin (16%), or graduated compression stockings (11%). Use of prophylaxis exceeded 25% only in patients admitted from nursing homes and those with prior VTE. Although there were several significant predictors of receipt of VTE prophylaxis, model discrimination was relatively poor (C-statistic=0.61). Conclusion— The majority of at-risk hospitalized medically ill patients do not receive VTE prophylaxis.

BACKGROUND. I-lie risk, severity, and patient-reported outcomes of radiation-induced mucositis among head and neck cancer patients were prospectively estimated.METHODS. A validated, patient-reported questionnaire (OMDQ), the FACT quality of life (QOL), and the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scales Were used to measure mucositis (reported as mouth and throat Soreness), daily functioning, and Use of analgesics. Patients were studied before radiotherapy (RT), daily during RT, and for 4 weeks after RT.RESULTS. contrary to previous reports, the risk of mucositis was virtually identical in the 126 patients with oral cavity or oropharynx tumors (99% overall; 85% grade 3-4) compared with 65 patients with tumors of the larynx or hypopharynx (98% overall; 77% grade 3-4). The mean QOL score decreased significantly during RT, from 85.1 at baseline to 69.0 at Week 6, corresponding with the peak of mucositis severity The mean functional status score decreased by 33% from 18.3 at baseline to 12.3 at week 6. The impact of mucositis on QOL was proportional to its severity, although even a score of I or 2 (mild or moderate) was associated with a significant reduction in QOL (from 93.6 at baseline to 74.7 at Week 6). Despite increases in analgesic use from 34% at baseline to 80% at Week 6, mean mucositis scores exceeded 2.5 at Week 6.CONCLUSIONS. Mucositis occurs among virtually all patients who are Undergoing radiation treatment of head and neck cancers. The detrimental effects on QOL and functional status are significant, and opioid analgesia provides inadequate relief. Preventive rather than symptom palliation measures are needed. Cancer 2008;113:2704-13. (C) 2008 American Cancer Society.

Summary Purpose: To estimate the cost-effectiveness of pregabalin as add-on therapy in patients with refractory partial epilepsy. Methods: We developed a model to estimate clinical and economic outcomes over 1 year in a hypothetical cohort of patients with refractory partial epilepsy assumed alternatively to receive add-on therapy with pregabalin (300 mg/day) or no add-on therapy. For each patient in the model, we estimated the occurrence of seizure and side effects, using techniques of stochastic simulation. We assigned health-state utilities to each day of follow-up based on whether or not seizure or side effects were predicted to occur. Patients could discontinue therapy due to lack of efficacy or side effects. Outcomes included expected numbers of days without seizure (“seizure-free [SF] days”), quality-adjusted life-years (QALYs), and costs of therapy. Cost-effectiveness was assessed alternatively in terms of incremental cost per SF day gained and incremental cost per QALY gained. Results: Add-on therapy with pregabalin was estimated to result in an average gain of 23.8 SF days over one year; the estimated additional cost of therapy was $678. Incremental cost (mean, 95% CI) per SF day gained was $28.45 ($27.25, $29.44); corresponding estimates of incremental cost per QALY gained were $52,893 ($49,249, $56,983). Conclusions: In patients with refractory partial epilepsy, the cost-effectiveness of pregabalin 300 mg/day compares favorably with published estimates of cost-effectiveness for other add-on antiepileptic drugs.

This study was undertaken to explore the perceived impact of having a seizure (SZ) compared with having an adverse effect (AE). Patients (N=201) with partial-onset epilepsy taking two or more antiepileptic drugs (AEDs) rated their health state from 0 to100 based on their health today, hypothetical health if experiencing a SZ today, and hypothetical health if experiencing an AE today. Overall health status ratings (HLTH) declined as SZ frequency increased (P=0.01). Perceived decrements in HLTH with SZs were greatest for patients with the least frequent SZs (P=0.001) and the most recent SZs (P=0.004). Perceived decrements in HLTH with SZs compared with AEs (SZ-AE) differed across SZ recency groups (P0.05 except for muscle incoordination and weakness). Patients with the more remote SZs were most concerned with SZ control; patients with more recent SZs were more sensitive to AED side effects. These data provide insight into the risk-benefit concerns of patients at equipoise when addressing the efficacy and AEs of AEDs.

To assess the relationship between oral mucositis (OM) and adverse clinical and economic outcomes in patients with hematologic malignancies receiving allogeneic hematopoietic stem-cell transplantation (HSCT).A retrospective chart review study of 281 allogeneic HSCT recipients with hematologic malignancies was undertaken at a single academic center. OM extent and severity were assessed across eight oropharyngeal sites using a validated scale, which was scored as follows: no erythema/ulceration=0; erythema only=I; ulceration, one site=II; ulceration, two sites=III; ulceration, three sites=IV and ulceration, four or more sites=V. OM assessments began on the day of conditioning and continued twice weekly within 28 days or hospital discharge. Analyses examined the relationship between the worst OM grade and selected adverse outcomes, including days with fever, days of total parenteral nutrition (TPN), days of parenteral narcotic therapy, incidence of significant (common terminology criteria (CTC) grade 3 or 4) infection, mortality and inpatient days and charges.The mean age of the study subjects was 41 years. Of the patients, 96% (n = 269) received total body irradiation and 76% (n = 214) experienced an OM grade ofor =II (i.e., ulceration). The worst OM grade was significantly (p0.05) associated with the number of days of TPN and parenteral narcotic therapy, number of days with fever, incidence of significant infection, time in hospital and total inpatient charges.OM is associated with worse clinical and economic outcomes in patients with hematologic malignancies undergoing allogeneic HSCT.

Background Major orthopedic surgery patients who receive antithrombotics as prophylaxis against VTE may be at higher risk of bleeding. The clinical and economic consequences of this complication may be relevant to therapeutic decision-making. Objective To assess the impact of major bleeding following major orthopedic surgery on length of stay (LOS) and inpatient charges. Methods Using a database with information on ∼750,000 admissions annually to 100+ US acute-care hospitals, we identified all patients who underwent major orthopedic surgery between January 1, 1998 and December 13, 2000. Patients were stratified according to whether or not they experienced major postoperative bleeding prior to hospital discharge, defined as (a) fatal bleeding; (b) nonfatal bleeding at critical site; (c) re-operation due to bleeding; and (d) overt bleeding with bleeding index (BI) ≥ 2, where BI = number of blood units transfused plus pre-bleeding minus post-bleeding hemoglobin (g/dL) values. LOS and total inpatient charges were compared between patients with and without major bleeding. Results The incidence of major bleeding among 23,518 patients who underwent major orthopedic surgery was 2.6%. In multivariate analyses controlling for differences in baseline characteristics between patients with and without major bleeds, adjusted mean LOS was 1.8 days longer among those with major bleeding (95% CI: 1.5, 2.0) (6.1 days vs. 4.3 days for those without bleeds); adjusted mean total inpatient charges were $7593 higher (95% CI: $6622, $8646) ($25,669 vs. $18,076). Conclusion Bleeding following major orthopedic surgery may increase length of stay and total hospital charges and should be an important consideration in choice of VTE prophylaxis.

OBJECTIVE: To evaluate the cost-effectiveness of carvedilol, a β-blocker that is approved for use in the US for the treatment of heart failure, based on data from Phase III clinical trials. METHODS: We conducted an economic evaluation alongside the US Carvedilol Heart Failure Trials Program, which consisted of four concurrent, randomized, double-blind, placebo-controlled clinical trials; the mean duration of follow-up across these four trials was 6.5 months (the program was terminated prematurely based on a finding of a 65% mortality benefit). Using data from these trials, we examined the cost-effectiveness of carvedilol in terms of the estimated cost per death averted among patients randomized to such therapy versus those receiving placebo. Attention was focused on the cost of carvedilol therapy plus the cost of cardiovascular-related inpatient care. Costs of care were estimated by combining information on healthcare utilization from the clinical trials with secondary sources of cost data. RESULTS: Patients randomized to receive carvedilol had lower mean ± SD estimated costs of cardiovascular-related inpatient care over 6.5 months compared with those receiving placebo ($1912 ± $7595 vs. $4463 ± $20 565, respectively). As mortality also was lower among carvedilol patients, the estimated cost per death averted was negative. The probability that carvedilol would both increase survival and decrease costs of cardiovascular-related care over a 6.5-month period was estimated to be 0.98. CONCLUSIONS: Data from the US Carvedilol Heart Failure Trials Program indicate that carvedilol reduces mortality in patients with heart failure; our study suggests that it also may be cost-saving over a period of approximately six months.