Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor.

BACKGROUND: Ivacaftor is the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator demonstrating clinical benefit in patients with cystic fibrosis (CF). As ivacaftor is intended for chronic, lifelong use, understanding long-term effects is important for patients and healthcare providers. OBJECTIVE: This ongoing, observational, postapproval safety study evaluates clinical outcomes and disease progression in ivacaftor-treated patients using data from the US and the UK CF registries following commercial availability. METHODS: Annual analyses compare ivacaftor-treated and untreated matched comparator patients for: risks of death, transplantation, hospitalisation, pulmonary exacerbation; prevalence of CF-related complications and microorganisms and lung function changes in a subset of patients who initiated ivacaftor in the first year of commercial availability. Results from the 2014 analyses (2 and 3 years following commercial availability in the UK and USA, respectively) are presented here. RESULTS: Analyses included 1256 ivacaftor-treated and 6200 comparator patients from the USA and 411 ivacaftor-treated and 2069 comparator patients from the UK. No new safety concerns were identified based on the evaluation of clinical outcomes included in the analyses. As part of safety evaluations, ivacaftor-treated US patients were observed to have significantly lower risks of death (0.6% vs 1.6%, p=0.0110), transplantation (0.2% vs 1.1%, p=0.0017), hospitalisation (27.5% vs 43.1%, p<0.0001) and pulmonary exacerbation (27.8% vs 43.3%, p<0.0001) relative to comparators; trends were similar in the UK. In both registries, ivacaftor-treated patients had a lower prevalence of CF-related complications and select microorganisms and had better preserved lung function. CONCLUSIONS: While general limitations of observational research apply, analyses revealed favourable results for clinically important outcomes among ivacaftor-treated patients, adding to the growing body of literature supporting disease modification by CFTR modulation with ivacaftor. EU PAS REGISTRATION NUMBER: EUPAS4270.

The Cystic Fibrosis Foundation Patient Registry. Design and Methods of a National Observational Disease Registry.

RATIONALE: The Cystic Fibrosis Foundation Patient Registry (CFFPR) is an ongoing patient registry study that collects longitudinal demographic, clinical, and treatment information about persons with cystic fibrosis (CF) in the United States. CF is a life-shortening genetic disorder that occurs in approximately 1 in 3,500 births in the United States. High-quality observational data is important for clinical research, quality improvement, and clinical management. OBJECTIVES: To describe the data collection, patient population, and key limitations of the CFFPR. METHODS: Inclusion criteria for the CFFPR include diagnosis with CF or a CFTR-associated disorder, care at an accredited care center program, and provision of informed consent. Data from clinic visits and hospitalizations are collected through a secure website. Loss to follow-up and generalizability were examined using several methods. The accuracy of CFFPR data was evaluated with an audit of 2012 CFFPR data compared to the medical record. MEASUREMENTS AND MAIN RESULTS: Since 1986, the CFFPR contains the records of 48,463 individuals with CF. Participation among individuals seen at accredited care centers is high, and loss to follow-up is low. An audit of 2012 CFFPR data suggests that the CFFPR contains 95% of clinic visits and 90% of hospitalizations found in the medical record for these patients, and nearly all of the audited fields were highly accurate. CONCLUSIONS: Registries such as the CFFPR are important tools for research, clinical care, and tracking incidence, mortality and population trends.

Identification of risk for high hospital use: cost comparisons of four strategies and performance across subgroups.

OBJECTIVES: To determine the relative costs of four risk-identification strategies and compare their performance in predicting hospital use by different subgroups of older persons based on age, sex, and prior hospital use. DESIGN: Prospective validation study and cost-comparison analysis. SETTING: Community-based. PARTICIPANTS: Five thousand one hundred thirty-eight participants of the sixth wave of three sites of the Established Populations for Epidemiologic Studies of the Elderly. MEASUREMENTS: Four strategies (prior hospitalization data only, a 10-item self-report screen alone, self-report combined with two laboratory tests, and sequential self-report plus as-needed use of laboratory tests when the self-report screen is inconclusive) and 3-year Medicare Part A hospital cost data. RESULTS: Assuming that interventions based on screening would yield a total benefit of $1,000 per true-positive case and a cost of $400 for each false-positive case, the sequential strategy was slightly less expensive than the self-report only strategy; both were considerably less expensive than the combined or hospitalization-only strategies. Accuracy as measured by the area under the receiver operating characteristic curve for the sequential strategy was comparable for all subgroups (between 0.62 and 0.70) but was least accurate for those who had high prior use and for those aged 85 and older. CONCLUSION: A sequential screening strategy that administers laboratory tests selectively is slightly less expensive than one that uses only self-report items. This strategy is also accurate in both sexes, in those with various degrees of prior use, and in the oldest old.

Cognitive decline in high-functioning older persons is associated with an increased risk of hospitalization.

OBJECTIVES: To examine hospital use for patients with evidence of cognitive decline indicative of early cognitive impairment. DESIGN: Medicare Part A hospital utilization data were linked to data from the MacArthur Research Network on Successful Aging Community Study to examine the association between baseline cognition and decline in cognitive function over a 3-year period and any hospitalization over that same period. SETTING: New Haven, Connecticut, and East Boston, Massachusetts. PARTICIPANTS: Subjects (N=598) were from two sites of the MacArthur Research Network on Successful Aging Community Study, a 7-year cohort study of community-dwelling older persons with high physical and cognitive functioning. MEASUREMENTS: Multivariate logistic regression was used to determine the association between any hospitalization over 3 years (1988-91) as the outcome variable and baseline cognitive function and decline in cognition over 3 years as primary predictor variables. Decline was based upon repeated (1988 and 1991) measures of delayed verbal recall and the Short Portable Mental Status Questionnaire (SPMSQ). RESULTS: Of 598 subjects, 48 died between 1988 and 1991. No baseline (1988) delayed recall scores or change in recall scores (1988-91) were associated with hospitalization. Although 48.2% declined on verbal memory scores, decline was not associated with risk of hospitalization. Of 494 subjects with complete 3-year data, 31.2% declined at least one point on the SPMSQ, and 4.7% declined more than two points. Among individuals aged 75 and older at baseline, the adjusted odds ratio for hospitalization for those who declined more than 2 points compared with those who declined less was 7.8 (95% confidence interval=2.0-30.8). CONCLUSION: Although specific memory tests were not associated with hospitalization, high-functioning older persons who experienced decline in overall cognitive function were more likely to be hospitalized. Variation in baseline cognitive function in this high-functioning cohort did not affect hospitalization, but additional research is needed to evaluate associations with other healthcare costs.

Refining the categorization of physical functional status: the added value of combining self-reported and performance-based measures.

BACKGROUND: When considered individually, self-reported functional status and performance-based functional status predict functional status decline and mortality. However, what additional prognostic information is gained by combining these approaches remains unknown. METHODS: The authors used three waves of three sites (5138 participants) of the Established Populations for Epidemiologic Studies of the Elderly to determine the prognostic value of individual and combined approaches. Baseline self-reported (mobility and activities of daily living [ADL] items) and performance-based (Physical Performance Score) functional status information was classified into three and four hierarchical categories, respectively. RESULTS: Based on self-reported information alone, at 1 year, 73% participants had not changed, 15% declined, 6% improved, and 6% died. At 4 years, 53% had not changed, 24% declined, 2% improved, and 22% died. Based on performance-based assessment alone, at 4 years, 33% of the sample remained stable, 37% declined, 6% improved, and 24% died. In the top two self-reported categories, functioning on the performance-based assessment varied widely. Among those who were independent in all self-reported functioning, approximately 40% scored in each of the top two performance-based categories. Among persons in the top two self-reported categories, poorer performance was associated with progressively higher 1-year and 4-year mortality rates. Among persons with impaired mobility and at least 1 ADL dependency, the mortality rate was high and was not influenced by performance-based score. CONCLUSIONS: Combining self-reported and performance-based measurements can refine prognostic information, particularly among older persons with high self-reported functioning. However, if ADL dependency is present, performance-based measures do not add prognostic value regarding mortality.

The effect of self-reported and performance-based functional impairment on future hospital costs of community-dwelling older persons.

PURPOSE: We determined the prognostic value of self-reported and performance-based measurement of function, including functional transitions and combining different measurement approaches, on utilization. DESIGN AND METHODS: Our cohort study used the 6th, 7th, and 10th waves of three sites of the Established Populations for Epidemiologic Studies of the Elderly, linked to 1- and 4-year Medicare Part A hospital costs. We examined mean hospital expenditures based on (a) 1- and 4-year transitions in self-reported functional status; (b) 4-year transitions in performance-based functional status; (c) combined baseline self-reported and performance-based functional status; and (d) poorest self-reported and performance-based functional status during a 4-year period. RESULTS: Even modest declines in self-reported or performance-based functional status were associated with increased expenditures. When baseline self-reported and performance-based assessments were combined, mean 1- and 4-year adjusted costs were higher with progressively worse performance-based scores, even among those who were independent in self-reported function. When the poorest 4-year self-reported and performance-based functions were examined, self-reported functioning was the most important determinant of hospital costs, but within each self-reported functional level, poorer performance-based function was associated with progressively higher costs. IMPLICATIONS: The costs associated with even modest functional decline are high. Combining self-reported and performance-based measurements can provide more precise estimates of future hospital costs.

Respiratory microbiology of patients with cystic fibrosis in the United States, 1995 to 2005.

BACKGROUND: Numerous improvements in diagnostic and therapeutic strategies for patients with cystic fibrosis (CF) have occurred during the past 2 decades. We hypothesized that these changes could impact trends in respiratory microbiology. METHODS: Data from the Cystic Fibrosis Foundation Patient Registry were used to examine trends in the incidence and prevalence of bacterial pathogens isolated from patients with CF in the United States from 1995 to 2005. RESULTS: The number of patients with CF in the patient registry increased from 19,735 in 1995 to 23,347 in 2005. During the study period, the reported annual prevalence of Pseudomonas aeruginosa significantly declined from 60.4% in 1995 to 56.1% in 2005 (p < 0.001). The decline was most marked in children 6 to 10 years old (48.2 to 36.1%) and adolescents 11 to 17 years old (68.9 to 55.5%). Both the incidence (21.7% in 1995 and 33.2% in 2005) and prevalence (37.0% in 1995 and 52.4% in 2005) of methicillin-susceptible Staphylococcus aureus significantly increased and the age-specific prevalence was highest in patients 6 to 17 years old. The prevalence of methicillin-resistant S aureus increased from 0.1% in 1995 to 17.2% in 2005 and from 2002 to 2005 was highest in adolescents 11 to 17 years old. Both the prevalence and incidence of Burkholderia cepacia complex declined, while the prevalence of Haemophilus influenzae, Stenotrophomonas maltophilia, and Alcaligenes xylosoxidans increased. CONCLUSIONS: Data from the patient registry suggest that the epidemiology of bacterial pathogens in patients with CF changed during the study period. Future studies should continue to monitor changing trends and define the association between these trends and care practices in CF.

Do muscle mass, muscle density, strength, and physical function similarly influence risk of hospitalization in older adults?

OBJECTIVES: To examine the association between strength, function, lean mass, muscle density, and risk of hospitalization. DESIGN: Prospective cohort study. SETTING: Two U.S. clinical centers. PARTICIPANTS: Adults aged 70 to 80 (N=3,011) from the Health, Aging and Body Composition Study. MEASUREMENTS: Measurements were of grip strength, knee extension strength, lean mass, walking speed, and chair stand pace. Thigh computed tomography scans assessed muscle area and density (a proxy for muscle fat infiltration). Hospitalizations were confirmed by local review of medical records. Negative binomial regression models estimated incident rate ratios (IRRs) of hospitalization for race- and sex-specific quartiles of each muscle and function parameter separately. Multivariate models adjusted for age, body mass index, health status, and coexisting medical conditions. RESULTS: During an average 4.7 years of follow-up, 1,678 (55.7%) participants experienced one or more hospitalizations. Participants in the lowest quartile of muscle density were more likely to be subsequently hospitalized (multivariate IRR=1.47, 95% confidence interval (CI)=1.24-1.73) than those in the highest quartile. Similarly, participants with the weakest grip strength were at greater risk of hospitalization (multivariate IRR=1.52, 95% CI=1.30-1.78, Q1 vs. Q4). Comparable results were seen for knee strength, walking pace, and chair stands pace. Lean mass and muscle area were not associated with risk of hospitalization. CONCLUSION: Weak strength, poor function, and low muscle density, but not muscle size or lean mass, were associated with greater risk of hospitalization. Interventions to reduce the disease burden associated with sarcopenia should focus on increasing muscle strength and improving physical function rather than simply increasing lean mass.

Development of a method to identify seniors at high risk for high hospital utilization.

BACKGROUND: A small percentage of older persons account for most Medicare costs. If persons at high risk for high health care utilization can be identified, resources can be directed to improve their health care and reduce utilization. OBJECTIVE: To develop an efficient and economical approach to identifying older persons at risk for high future health care utilization. DESIGN: Validation cohort. SETTING: Three communities. SUBJECTS: Five thousand one hundred thirty-eight community-dwelling persons aged 71 years or older. MAIN OUTCOME MEASURES: High utilization (defined as >or=11 hospital days during 3 years) and overall Part A Medicare hospital costs during 3 years. RESULTS: Predictive multivariable models were created that relied on prior hospitalization only, self-report only, and combined self-report and physical examination/lab data. Ten self-report items (hospitalizations in prior year and year before that, male gender, fair/poor health, not working, infrequent religious participation, needing help bathing, unable to walk 1/2 mile, diabetes, and taking loop diuretics) and two lab tests (low serum albumin and iron) remained as independent predictors of high utilization. Based upon these variables, approximately 1/4 of the population was identified as being at high risk (>or=0.28 probability) for high health care utilization and those identified accounted for approximately half of all Medicare Part A costs for the entire population. Finally, a two-phase strategy was developed in which tests are only administered to individuals whose risk cannot be adequately determined by self-report variables (approximately 1/4 of subjects). CONCLUSIONS: Simple questions and laboratory tests can accurately and efficiently identify seniors at high risk for high health care utilization.