Survival Comparison of Patients With Cystic Fibrosis in Canada and the United States

A comprehensive, multidisciplinary approach to medical care; early treatment of pulmonary disease; and aggressive management of malnutrition have translated into longer lives for persons with cystic fibrosis (13). Life expectancy depends on a patient's characteristics as well as his or her access to medical care and medications, which may vary both within and among countries (4, 5). Comparisons of national cystic fibrosis registry data have led to important discoveries in cystic fibrosis disease progression and increased our understanding of epidemiologic trends in cystic fibrosis mortality and clinical care (612). Recently, Goss and colleagues (7) showed that among persons aged 6 to 25 years with cystic fibrosis, pulmonary function was greater among patients in the United States than those in the United Kingdom, which was associated with differential prescribing of inhaled mucolytic therapies between the 2 countries. In 2011, the median age of survival for patients with cystic fibrosis in the U.S. Cystic Fibrosis Foundation Patient Registry (CFFPR) annual data report was 36.8 years, whereas it was 48.5 years in the Canadian Cystic Fibrosis Registry (CCFR) report (13, 14). Directly comparing estimates of median age of survival between national registry reports is problematic because of the inherent differences in methodologies used, data processing techniques, and ascertainment bias (15, 16). We recently showed that survival estimates may be over- or underestimated depending on how data are captured and processed, as well as the proportion of missing data (15). Using a standardized approach to data processing and survival calculations would provide greater confidence in international comparisons and in the identification of factors that may contribute to the observed differences. The objectives of this study were to determine whether using a standardized approach to data processing and survival calculations would confirm the observed difference between Canada and the United States and, if a survival gap persisted, to explore potential contributing factors. We hypothesized that differences in survival between the countries might be explained by variations in clinical characteristics of the patient populations, differential rates of transplantation, and variations between the health care systems. Methods This population-based cohort study used prospectively collected data from 42 Canadian and 110 U.S. cystic fibrosis care centers from 1990 through 2013. Each center that submits data to the registry obtains patient consent for the data to be collected. This study was approved by the Research Ethics Board of St. Michael's Hospital, Toronto, Ontario, and the Institutional Review Board of Seattle Children's Hospital, Seattle, Washington. A detailed description of both registries, as well as information on how patients are accrued and monitored within each registry, is outlined in the Supplement. The CCFR and CFFPR contain detailed demographic and clinical information on patients with a confirmed diagnosis of cystic fibrosis (17) receiving clinical care at accredited cystic fibrosis centers across Canada and the United States. The registries collect data on age, sex, age at diagnosis, race, symptoms at presentation, whether the patient was diagnosed through newborn screening, date of transplantation, and date and cause of death, as well as anthropometric measurements, lung function, bacteriology, cystic fibrosisrelated complications, and pancreatic status. Supplement. Data Supplement The research team evaluated each variable in the Canadian and U.S. registries and made comparisons regarding data definitions and how data are collected to establish a unified approach to each variable. Because the CCFR records the first stable clinical measurement per person per year, we selected the first stable measurement of the year for each patient in the CFFPR to mirror data collection methods. A stable measurement was defined as one that was taken from a routine outpatient clinic visit when the patient was not being treated for a pulmonary exacerbation. Missing date of diagnosis was imputed by using date of birth plus 30 days, whereas age at diagnosis was categorized as less than 2 or 2 or more years of age (18). Genotype was classified as homozygous delta F508, heterozygous delta F508, other, or missing. Race was categorized as white, other, or missing. The FEV1 was expressed as a percentage of the predicted values for healthy age- and sex-matched controls by using Global Lung Function Initiative reference equations (19). Body mass index (BMI) percentile was calculated for children between 2 and 19 years of age by using the Centers for Disease Control and Prevention growth charts (20). Children were then classified as underweight (BMI percentile, 12%), adequate weight (BMI percentile, 13% to 84%), or overweight (BMI percentile, 85%) (21). For persons aged 19 years and older, BMI was categorized according to World Health Organization guidelines (22) as underweight (<18.5 kg/m2), adequate weight (18.5 to 24.9 kg/m2), or overweight (25.0 kg/m2). On the basis of the literature, respiratory bacteria may have a differential effect on survival. We categorized patients whose respiratory tract specimens grew several organisms in a given year according to the organism that carried the worst prognosis in terms of survival. This categorization allowed us to create mutually exclusive groups to avoid combining less virulent organisms with ones associated with a worse prognosis. On the basis of this hierarchical classification, patients with several types of bacteria cultured in a given year were categorized as follows: Burkholderia cepacia complex took precedence over any other type of infection, methicillin-resistant Staphylococcus aureus took precedence over Pseudomonas aeruginosa, and P aeruginosa took precedence over all remaining organisms. Cystic fibrosisrelated diabetes (CFRD) was defined by the clinic according to published consensus guidelines (23). Pancreatic status was determined by patients' use of pancreatic enzyme replacement therapy; it was used as a surrogate for disease severity in the multivariable analysis, because CFTR (cystic fibrosis transmembrane conductance regulator) genotype and pancreatic status are highly correlated (24), and few patients had missing data for pancreatic enzyme replacement therapy. Previous literature suggests that most patients reported as lost to follow-up at some point during follow-up will return to the cystic fibrosis center within 2 years of nonattendance (5). Thus, patients were considered lost to follow-up if they had no death date recorded and their last reporting year was more than 2 years from the end of the study. The single-payer universal health insurance program in Canada provides comprehensive medical care to all Canadian citizens, whereas the United States uses a multipayer approach to health care. Patients in the United States were grouped into mutually exclusive categories according to their health insurance coverage as follows: continuous Medicaid or Medicare (receiving Medicare and/or Medicaid in all 5 years), intermittent Medicaid or Medicare (receiving Medicaid and/or Medicare in at least 1 but not all 5 years), other (any other insurance besides Medicaid or Medicarepredominantly employer-provided private insurance), and none or unknown (no or unknown insurance in all 5 years). Statistical Analyses Demographic and clinical variables were summarized by country, with categorical variables expressed as frequency and proportion and continuous variables summarized as median and range. Differences between countries were compared by using the MannWhitney U test for continuous variables and the chi-square test for categorical variables. P values are heavily influenced by sample size; thus, the large sample sizes herein will render very small differences statistically significant. As such, the standardized difference (SD) was used to determine statistical significance. An SD greater than 10 was used to determine statistically significant differences between the countries (25). We used period survival analysis to calculate median age of survival estimates over time. Median age of survival for each year was calculated for each 5-year window beginning with the period 1986 to 1990 and ending with 2009 to 2013. Differences in median age of survival between the 2 countries over time were evaluated from 1990 to 2013 by using segmented regression analysis to determine whether significant change points emerged when the differences in median age of survival diverged (26). We further explored differences in survival by adjusting for patient and clinical characteristics with a multivariable Cox proportional hazards model that used data from the most recent 5 years (2009 to 2013), which reflected a contemporary cohort of patients with cystic fibrosis. The multivariable Cox proportional hazards analysis was first conducted on data from all patients, including those who received transplants, and adjusted for time-independent characteristics (sex, race, age at diagnosis, and pancreatic status) and transplant status. Subsequently, we conducted additional multivariable analyses that included time-varying clinical characteristics known to be prognostic for patient survival, such as FEV1, BMI, CFRD, and microbiology. We excluded patients younger than 6 years because lung function measurements are not reliably measured until the age of 6 years. Because clinical outcomes after transplantation, particularly FEV1, do not represent cystic fibrosis lung disease, this analysis censored patients at the time of transplantation. Country, sex, age at diagnosis, race, genotype, pancreatic status, and insurance status were modeled as time-independent covariates. Missing lung function and BMI measurements were imputed by using multiple imputation (27) (see the Supplement for additional details on survival calculations