Transcatheter Versus Surgical Aortic Valve Replacement: Propensity-Matched Comparison.

BACKGROUND: Randomized trials support the use of transcatheter aortic valve replacement (TAVR) for the treatment of aortic stenosis in high- and intermediate-risk patients, but the generalizability of those results in clinical practice has been challenged. OBJECTIVES: The aim of this study was to determine the safety and effectiveness of TAVR versus surgical aortic valve replacement (SAVR), particularly in intermediate- and high-risk patients, in a nationally representative real-world cohort. METHODS: Using data from the Transcatheter Valve Therapy Registry and Society of Thoracic Surgeons National Database linked to Medicare administrative claims for follow-up, 9,464 propensity-matched intermediate- and high-risk (Society of Thoracic Surgeons Predicted Risk of Mortality score ≥3%) U.S. patients who underwent commercial TAVR or SAVR were examined. Death, stroke, and days alive and out of the hospital to 1 year were compared, as well as discharge home, with subgroup analyses by surgical risk, demographics, and comorbidities. RESULTS: In a propensity-matched cohort (median age 82 years, 48% women, median Society of Thoracic Surgeons Predicted Risk of Mortality score 5.6%), TAVR and SAVR patients experienced no difference in 1-year rates of death (17.3% vs. 17.9%; hazard ratio: 0.93; 95% confidence interval [CI]: 0.83 to 1.04) and stroke (4.2% vs. 3.3%; hazard ratio: 1.18; 95% CI: 0.95 to 1.47), and no difference was observed in the proportion of days alive and out of the hospital to 1 year (rate ratio: 1.00; 95% CI: 0.98 to 1.02). However, TAVR patients were more likely to be discharged home after treatment (69.9% vs. 41.2%; odds ratio: 3.19; 95% CI: 2.84 to 3.58). Results were consistent across most subgroups, including among intermediate- and high-risk patients. CONCLUSIONS: Among unselected intermediate- and high-risk patients, TAVR and SAVR resulted in similar rates of death, stroke, and DAOH to 1 year, but TAVR patients were more likely to be discharged home.

Tools for Economic Analysis of Patient Management Interventions in Heart Failure Cost-Effectiveness Model: A Web-based program designed to evaluate the cost-effectiveness of disease management programs in heart failure.

BACKGROUND: Heart failure disease management programs can influence medical resource use and quality-adjusted survival. Because projecting long-term costs and survival is challenging, a consistent and valid approach to extrapolating short-term outcomes would be valuable. METHODS: We developed the Tools for Economic Analysis of Patient Management Interventions in Heart Failure Cost-Effectiveness Model, a Web-based simulation tool designed to integrate data on demographic, clinical, and laboratory characteristics; use of evidence-based medications; and costs to generate predicted outcomes. Survival projections are based on a modified Seattle Heart Failure Model. Projections of resource use and quality of life are modeled using relationships with time-varying Seattle Heart Failure Model scores. The model can be used to evaluate parallel-group and single-cohort study designs and hypothetical programs. Simulations consist of 10,000 pairs of virtual cohorts used to generate estimates of resource use, costs, survival, and incremental cost-effectiveness ratios from user inputs. RESULTS: The model demonstrated acceptable internal and external validity in replicating resource use, costs, and survival estimates from 3 clinical trials. Simulations to evaluate the cost-effectiveness of heart failure disease management programs across 3 scenarios demonstrate how the model can be used to design a program in which short-term improvements in functioning and use of evidence-based treatments are sufficient to demonstrate good long-term value to the health care system. CONCLUSION: The Tools for Economic Analysis of Patient Management Interventions in Heart Failure Cost-Effectiveness Model provides researchers and providers with a tool for conducting long-term cost-effectiveness analyses of disease management programs in heart failure.

Reliability and construct validity of PROMIS® measures for patients with heart failure who undergo heart transplant.

PURPOSE: To evaluate the reliability and construct validity of measures from the Patient-Reported Outcomes Measurement Information System(®) (PROMIS(®)) for patients with heart failure before and after heart transplantation. METHODS: We assessed reliability of the PROMIS short forms using Cronbach's alpha and the average marginal reliability. To assess the construct validity of PROMIS computerized adaptive tests and short-form measures, we calculated Pearson product moment correlations between PROMIS measures of physical function, fatigue, depression, and social function and existing PRO measures of similar domains (i.e., convergent validity) as well as different domains (i.e., discriminate validity) in patients with heart failure awaiting heart transplant. We evaluated the responsiveness of these measures to change after heart transplant using effect sizes. RESULTS: Forty-eight patients were included in the analyses. Across the many domains examined, correlations between conceptually similar domains were larger than correlations between different domains of health, demonstrating construct validity. Health status improved substantially after heart transplant (standardized effect sizes, 0.63-1.24), demonstrating the responsiveness of the PROMIS measures. Scores from the computerized adaptive tests and the short forms were similar. CONCLUSIONS: This study provides evidence for the reliability and construct validity (including responsiveness to change) of four PROMIS domains in patients with heart failure before and after heart transplant. PROMIS measures are a reasonable choice in this context and will facilitate comparisons across studies and health conditions.

Introduction of the Tools for Economic Analysis of Patient Management Interventions in Heart Failure Costing Tool: a user-friendly spreadsheet program to estimate costs of providing patient-centered interventions.

BACKGROUND: Patient-centered health care interventions, such as heart failure disease management programs, are under increasing pressure to demonstrate good value. Variability in costing methods and assumptions in economic evaluations of such interventions limit the comparability of cost estimates across studies. Valid cost estimation is critical to conducting economic evaluations and for program budgeting and reimbursement negotiations. METHODS AND RESULTS: Using sound economic principles, we developed the Tools for Economic Analysis of Patient Management Interventions in Heart Failure (TEAM-HF) Costing Tool, a spreadsheet program that can be used by researchers and health care managers to systematically generate cost estimates for economic evaluations and to inform budgetary decisions. The tool guides users on data collection and cost assignment for associated personnel, facilities, equipment, supplies, patient incentives, miscellaneous items, and start-up activities. The tool generates estimates of total program costs, cost per patient, and cost per week and presents results using both standardized and customized unit costs for side-by-side comparisons. Results from pilot testing indicated that the tool was well-formatted, easy to use, and followed a logical order. Cost estimates of a 12-week exercise training program in patients with heart failure were generated with the costing tool and were found to be consistent with estimates published in a recent study. CONCLUSIONS: The TEAM-HF Costing Tool could prove to be a valuable resource for researchers and health care managers to generate comprehensive cost estimates of patient-centered interventions in heart failure or other conditions for conducting high-quality economic evaluations and making well-informed health care management decisions.

Economic evaluation of home blood pressure monitoring with or without telephonic behavioral self-management in patients with hypertension.

BACKGROUND: The Take Control of Your Blood Pressure trial evaluated the effect of a multicomponent telephonic behavioral lifestyle intervention, patient self-monitoring, and both interventions combined compared with usual care on reducing systolic blood pressure during 24 months. The combined intervention led to a significant reduction in systolic blood pressure compared with usual care alone. We examined direct and patient time costs associated with each intervention. METHODS: We conducted a prospective economic evaluation alongside a randomized controlled trial of 636 patients with hypertension participating in the study interventions. Medical costs were estimated using electronic data representing medical services delivered within the health system. Intervention-related costs were derived using information collected during the trial, administrative records, and published unit costs. RESULTS: During 24 months, patients incurred a mean of $6,965 (s.d., $22,054) in inpatient costs and $8,676 (s.d., $9,368) in outpatient costs, with no significant differences among the intervention groups. With base-case assumptions, intervention costs were estimated at $90 (s.d., $2) for home blood pressure monitoring, $345 (s.d., $64) for the behavioral intervention ($31 per telephone encounter), and $416 (s.d., $93) for the combined intervention. Patient time costs were estimated at $585 (s.d., $487) for home monitoring, $55 (s.d., $16) for the behavioral intervention, and $741 (s.d., $529) for the combined intervention. CONCLUSIONS: Our analysis demonstrated that the interventions are cost-additive to the health-care system in the short term and that patients' time costs are nontrivial.

Outcomes of inpatients with and without sickle cell disease after high-volume surgical procedures.

In this study, we examined differences in inpatient costs, length of stay, and in-hospital mortality between hospitalizations for patients with and without sickle cell disease (SCD) undergoing high-volume surgical procedures. We used Clinical Classification Software (CCS) codes to identify discharges in the 2002-2005 Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project for patients who had undergone either cholecystectomy or hip replacement. We limited the non-SCD cohort to hospitals where patients with SCD had undergone the same procedure. We compared inpatient outcomes using summary statistics and generalized linear regression analysis to adjust for patient, hospital, and procedural characteristics. Overall, the median age of surgical patients with SCD was more than three decades less than the median age of patients without SCD undergoing the same procedure. In recognition of the age disparity, we limited the analyses to patients aged 18 to 64 years. Nonetheless, patients with SCD undergoing cholecystectomy or hip replacement were 12.1 and 14.4 years younger, had inpatient stays that were 73% and 82% longer, and incurred costs that were 46% and 40% higher per discharge than patients without SCD, respectively. Inpatient mortality for these procedures was low, approximately 0.6% for cholecystectomy and 0.2% for hip replacement and did not differ significantly between patients with and without SCD. Multivariable regression analyses revealed that higher inpatient costs among patients with SCD were primarily attributable to longer hospital stays. Patients with SCD who underwent cholecystectomy or hip replacement required more health care resources than patients without SCD. Am. J. Hematol. 2009. (c) 2009 Wiley-Liss, Inc.

Pulmonary hypertension associated with sickle cell disease: clinical and laboratory endpoints and disease outcomes.

Screening for pulmonary hypertension (pHTN) has not yet become routine in sickle cell disease (SCD), despite clinical evidence of its high prevalence and associated mortality. Our objectives are to identify clinical conditions and laboratory findings predictive of/or associated with pHTN. One hundred twenty-five adult outpatients with Hb SS, SC, SOArab, Sbeta(0), or Sbeta(+) thalassemia, who underwent echocardiography and/or right heart catheterization due to cardiorespiratory symptoms, were studied. pHTN was identified in 36% (28/77) of SS/Sbeta(0) and in 25% (12/48) of SC/SOArab/Sbeta(+) patients studied. In SS/Sbeta(0) patients, pHTN was associated with low hemoglobin, low GFR, increasing age, no history of treatment with hydroxyurea and a history of leg ulcers, with trends for associations with higher total bilirubin, LDH levels, systolic systemic blood pressure, history of avascular necrosis, seizures, and cerebrovascular events. Twelve (40%) of the SS/Sbeta(0) patients with pHTN had >or= 1+ proteinuria. (P<0.039). The presence of proteinuria correlated with lower GFR and had a high positive predictive value (0.60) for pHTN in subjects with SS/Sbeta(0). The data also provided evidence that pHTN in this population is associated with right heart failure, with echocardiographic evidence of right ventricle enlargement and pericardial effusion. This study confirmed that even relatively mild elevations in pulmonary pressure are associated with high prospective mortality (hazard ratio: 15.9). We concluded that pHTN has a high prevalence in all Hb S related syndromes and is associated with increased mortality in SS/Sbeta(0). Kidney dysfunction, as indicated by proteinuria or decreased GFR, also represents sufficient reason to screen for pHTN.

Distribution of optineurin sequence variations in an ethnically diverse population of low-tension glaucoma patients from the United States.

PURPOSE: Previous studies have suggested that Optineurin (OPTN) sequence variants contribute to low-tension glaucoma (LTG) in ethnically homogeneous populations. The purpose of this study is to evaluate the prevalence of OPTN sequence variants in an ethnically diverse population of LTG patients from the United States, and to describe the phenotype of patients with OPTN sequence variants preferentially found in LTG patients. METHODS: Genomic DNA purified from 67 LTG patients was screened for DNA sequence variants located in the exons and flanking introns of the OPTN gene using high-performance liquid chromatography analysis and direct genomic DNA sequencing. Eighty-six primary open-angle glaucoma probands and 100 control patients were also analyzed. RESULTS: Nine OPTN DNA sequence variants were identified in this patient population including the 2 previously identified heterozygous nonsynonymous single-nucleotide polymorphisms in exons 4 and 5. Four LTG patients with severe disease and positive family history of glaucoma, were found to have DNA sequence changes not found in primary open-angle glaucoma probands or control individuals including the previously reported E50K variation. CONCLUSIONS: The results of this study support the rare association of OPTN sequence variants with familial forms of LTG. The E50K mutation seems to be associated with a severe form of LTG, and although rare, the identification of this sequence variant in patients at risk may help direct appropriate therapy.

Analysis of ALDH1A2, CYP26A1, CYP26B1, CRABP1, and CRABP2 in human neural tube defects suggests a possible association with alleles in ALDH1A2.

BACKGROUND: Vitamin A (retinol), in the form of retinoic acid (RA), is essential for normal development of the human embryo. Studies in the mouse and zebrafish have shown that retinol is metabolized in the developing spinal cord and must be maintained in a precise balance along the anteroposterior axis. Both excess and deficiency of RA can affect morphogenesis, including failures of neural tube closure. METHODS: We chose to investigate 5 genes involved in the metabolism or synthesis of RA, ALDH1A2, CYP26A1, CYP26B1, CRABP1, and CRABP2, for their role in the development of human neural tube defects, such as spina bifida. RESULTS: An association analysis using both allelic and genotypic single-locus tests revealed a significant association between the risk for spina bifida and 3 polymorphisms in the gene ALDH1A2; however, we found no evidence of a significant multilocus association. CONCLUSIONS: These results may suggest that polymorphisms in ALDH1A2 may influence the risk for lumbosacral myelomeningocele in humans.

SNPs in the neural cell adhesion molecule 1 gene (NCAM1) may be associated with human neural tube defects.

Neural tube defects (NTDs) are common birth defects, occurring in approximately 1/1,000 births; both genetic and environmental factors are implicated. To date, no major genetic risk factors have been identified. Throughout development, cell adhesion molecules are strongly implicated in cell-cell interactions, and may play a role in the formation and closure of the neural tube. To evaluate the role of neural cell adhesion molecule 1 (NCAM1) in risk of human NTDs, we screened for novel single-nucleotide polymorphisms (SNPs) within the gene. Eleven SNPs across NCAM1 were genotyped using TaqMan. We utilized a family-based approach to evaluate evidence for association and/or linkage disequilibrium. We evaluated American Caucasian simplex lumbosacral myelomeningocele families (n=132 families) using the family based association test (FBAT) and the pedigree disequilibrium test (PDT). Association analysis revealed a significant association between risk for NTDs and intronic SNP rs2298526 using both the FBAT test (P=0.0018) and the PDT (P=0.0025). Using the HBAT version of the FBAT to look for haplotype association, all pairwise comparisons with SNP rs2298526 were also significant. A replication study set, consisting of 72 additional families showed no significant association; however, the overall trend for overtransmission of the less common allele of SNP rs2298526 remained significant in the combined sample set. In addition, we analyzed the expression pattern of the NCAM1 protein in human embryos, and while NCAM1 is not expressed within the neural tube at the time of closure, it is expressed in the surrounding and later in differentiated neurons of the CNS. These results suggest variations in NCAM1 may influence risk for human NTDs.

Early adult-onset POAG linked to 15q11-13 using ordered subset analysis.

PURPOSE: Primary open-angle glaucoma (POAG) is a complex inherited disorder. It has been demonstrated in other complex disorders that phenotypic heterogeneity may be the result of genetic heterogeneity and that stratification analysis can be used to increase the power of detection. Ordered subset analysis (OSA) is a recently described method that utilizes the variability of phenotypic traits to determine underlying genetic heterogeneity. METHODS: Eighty-six multiplex families with POAG were clinically ascertained for genetic analysis. Age at diagnosis (AAD) was used as a surrogate for age of onset in affected family members. Nine genetic markers within the 15q11-13 interval on chromosome 15 were used for OSA analysis. RESULTS: An 11-cM linkage interval with a peak LOD score of 3.24 centered at the GABRB3 locus (P = 0.013 by permutation test) was identified in a subset of 15 families, which represents 17% of the total dataset (15/86 families). The mean AAD for the affected OSA families was 44.1 +/- 9.1 years (SD). The mean AAD for the complementary group was 61.3 +/- 10.4 years. African-American and white families were well represented in the OSA subset. CONCLUSIONS: Linkage was identified for POAG to an 11-cM region on chromosome 15, designated GLC1I. This result provides further evidence that AAD and other phenotypic traits can be used as stratification variables to identify genes in complex disorders such as POAG and suggests that the 15q11-13 locus is one of the largest genetic contributors to POAG identified to date.

TERC is not a major gene in human neural tube defects.

BACKGROUND: Neural tube defects (NTDs) are the second most common birth defects, after congenital heart defects. Telomerase, the reverse transcriptase that maintains telomere DNA, has been shown to be important for neural tube development and bilateral symmetry in the brain. In knockout mice null for the telomerase RNA component (TERC), telomere loss results in the failure of neural tube closure, primarily at the forebrain and midbrain. METHODS: We investigated TERC for variants that may predispose to human NTDs in 477 NTD cases with a variety of phenotypic presentations. RESULTS: Two novel single nucleotide polymorphisms were identified in the human TERC sequence but showed no association with the NTD phenotype. CONCLUSIONS: Variants in TERC are unlikely to be a major risk factor for the most common form of human NTDs, lumbosacral myelomeningocele.

Lack of association of mutations in optineurin with disease in patients with adult-onset primary open-angle glaucoma.

OBJECTIVE: To determine whether mutations in the optineurin gene contribute to susceptibility to adult-onset primary open-angle glaucoma. METHODS: The optineurin gene was screened in 86 probands with adult-onset primary open-angle glaucoma and in 80 age-matched control subjects. Exons 4 and 5, containing the recurrent mutations identified in patients with normal-tension glaucoma, were sequenced in all individuals studied, while the remaining exons were screened for DNA sequence variants with denaturing high-performance liquid chromatography. RESULTS: The recurrent mutation, Met98Lys, previously found to be associated with an increased risk of disease was found in 8 (9%) of 86 probands. We also found the Met98Lys mutation in 10% of individuals from a control population of similar age, sex, and ethnicity. Consistent segregation of the mutation with the disease was not demonstrated in any of the 8 families. No other DNA changes altering the amino acid structure of the protein were found. CONCLUSION: The mutations in the optineurin gene associated with normal-tension glaucoma are not associated with adult-onset primary open-angle glaucoma in this patient population. Clinical Relevance Genetic abnormalities that render the optic nerve susceptible to degeneration are excellent candidates for genetic factors that could contribute to adult-onset primary open-angle glaucoma. Mutations in optineurin have been associated with normal-tension glaucoma, but are not associated with disease in patients with adult-onset primary open-angle glaucoma. This result may indicate that normal-tension glaucoma is not necessarily part of the phenotypic spectrum of adult open-angle glaucoma.

Reduction in the minimum candidate interval in the dominant-intermediate form of Charcot-Marie-Tooth neuropathy to D19S586 to D19S432.

As part of an on-going genomic screen of unlinked Charcot-Marie-Tooth disease type 2 (CMT2) families, we identified 11 regions in the genome with lod scores > or = 1.0. One of these regions was near the recently identified CMTDI1 locus on 19q. We show evidence of linkage of DUK 1118 to this region and our data reduce the minimum candidate interval for CMTDI1 to the 9-cM interval spanned by D19S586 and D19S432. We also demonstrate that five additional CMT2 families are unlinked to 19q markers, providing further evidence of CMT2 heterogeneity.

A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10).

We have identified a missense mutation in the motor domain of the neuronal kinesin heavy chain gene KIF5A, in a family with hereditary spastic paraplegia. The mutation occurs in the family in which the SPG10 locus was originally identified, at an invariant asparagine residue that, when mutated in orthologous kinesin heavy chain motor proteins, prevents stimulation of the motor ATPase by microtubule-binding. Mutation of kinesin orthologues in various species leads to phenotypes resembling hereditary spastic paraplegia. The conventional kinesin motor powers intracellular movement of membranous organelles and other macromolecular cargo from the neuronal cell body to the distal tip of the axon. This finding suggests that the underlying pathology of SPG10 and possibly of other forms of hereditary spastic paraplegia may involve perturbation of neuronal anterograde (or retrograde) axoplasmic flow, leading to axonal degeneration, especially in the longest axons of the central nervous system.