Anne L. Stephenson, MD, PhD; Jenna Sykes, MMath; Sanja Stanojevic, PhD; Bradley S. Quon, MD, MSc; Bruce C. Marshall, MD; Kristofer Petren, BA, BSc; Josh Ostrenga, MSc; Aliza K. Fink, DSc; Alexander Elbert, PhD; Christopher H. Goss, MD, MSc
Note: Dr. Stephenson had full access to all of the data in the study and takes responsibility for the integrity of the data, the accuracy of the data analysis, and the decision to submit the manuscript for publication.
Acknowledgment: The authors acknowledge the support of the U.S. Cystic Fibrosis Foundation and Cystic Fibrosis Canada, which made this study possible. They also acknowledge and thank all of the patients and families in the United States and Canada who consent to be part of their respective national cystic fibrosis patient registries, as well as the cystic fibrosis clinic staff who spend many hours inputting the data.
Grant Support: This study was funded by a Cystic Fibrosis Foundation grant (STEPHE14A0). Dr. Goss receives funding from the Cystic Fibrosis Foundation, the National Institutes of Health (grants R01HL103965, R01HL113382, R01AI101307, U M1HL119073, and P30DK089507), and the U.S. Food and Drug Administration (grant R01FD003704).
Disclosures: Dr. Stephenson reports grants from the Cystic Fibrosis Foundation during the conduct of the study and personal fees from Cystic Fibrosis Canada outside the submitted work. Ms. Sykes reports grants from the Cystic Fibrosis Foundation during the conduct of the study. Dr. Quon is supported by a Cystic Fibrosis Canada Clinician–Scientist Award, but Cystic Fibrosis Canada played no role in the study design or preparation of the manuscript. Dr. Goss reports board membership at KaloBios Pharmaceuticals and Boehringer Ingelheim; consultancy for Vertex Pharmaceuticals and Novartis; grants from Vertex Pharmaceuticals, the Cystic Fibrosis Foundation, the National Institutes of Health, and the U.S. Food and Drug Administration; speaking fees from Hoffmann–La Roche, Johns Hopkins University, the European Cystic Fibrosis Society, and Medscape; and an honorarium from Gilead Sciences. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-0858.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: Not available. Statistical code: Available from Dr. Stephenson (e-mail, firstname.lastname@example.org). Data set: Available upon request from the Cystic Fibrosis Foundation and Cystic Fibrosis Canada.
Requests for Single Reprints: Anne L. Stephenson, MD, PhD, St. Michael's Hospital, 30 Bond Street, 6th Floor, Bond Wing, Toronto, Ontario M5B 1W8, Canada; e-mail: email@example.com.
Current Author Addresses: Dr. Stephenson and Ms. Sykes: St. Michael's Hospital, 30 Bond Street, 6th Floor, Bond Wing, Toronto, Ontario M5B 1W8, Canada.
Dr. Stanojevic: Institute of Health Policy, Management and Evaluation, University of Toronto, 155 College Street, Toronto, Ontario M5T 3M6, Canada.
Dr. Quon: Centre for Heart Lung Innovation, Department of Medicine, University of British Columbia, #166–1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.
Drs. Marshall, Fink, and Elbert; Mr. Petren; and Mr. Ostrenga: Cystic Fibrosis Foundation, 6931 Arlington Road, Bethesda, MD 20814.
Dr. Goss: Division of Pulmonary and Critical Care Medicine, Department of Medicine and Pediatrics, University of Washington Medical Center, 1959 Northeast Pacific Street, Seattle, WA 98195.
Author Contributions: Conception and design: A.L. Stephenson, S. Stanojevic, B.S. Quon, B.C. Marshall, A. Fink, C.H. Goss.
Analysis and interpretation of the data: A.L. Stephenson, J. Sykes, S. Stanojevic, B.S. Quon, K. Petren, A. Fink, A. Elbert, C.H. Goss.
Drafting of the article: A.L. Stephenson, S. Stanojevic, B.S. Quon, C.H. Goss.
Critical revision for important intellectual content: A.L. Stephenson, J. Sykes, S. Stanojevic, B.S. Quon, C.H. Goss.
Final approval of the article: A.L. Stephenson, J. Sykes, S. Stanojevic, B.S. Quon, B.C. Marshall, K. Petren, J. Ostrenga, A. Fink, A. Elbert, C.H. Goss.
Statistical expertise: J. Sykes, S. Stanojevic, J. Ostrenga, C.H. Goss.
Obtaining of funding: A.L. Stephenson, S. Stanojevic, B.S. Quon, C.H. Goss.
Administrative, technical, or logistic support: A.L. Stephenson, K. Petren, A. Elbert.
Collection and assembly of data: A.L. Stephenson, J. Sykes, K. Petren, J. Ostrenga, A. Elbert.
In 2011, the median age of survival of patients with cystic fibrosis reported in the United States was 36.8 years, compared with 48.5 years in Canada. Direct comparison of survival estimates between national registries is challenging because of inherent differences in methodologies used, data processing techniques, and ascertainment bias.
To use a standardized approach to calculate cystic fibrosis survival estimates and to explore differences between Canada and the United States.
42 Canadian cystic fibrosis clinics and 110 U.S. cystic fibrosis care centers.
Patients followed in the Canadian Cystic Fibrosis Registry (CCFR) and U.S. Cystic Fibrosis Foundation Patient Registry (CFFPR) between 1990 and 2013.
Cox proportional hazards models were used to compare survival between patients followed in the CCFR (n = 5941) and those in the CFFPR (n = 45 448). Multivariable models were used to adjust for factors known to be associated with survival.
Median age of survival in patients with cystic fibrosis increased in both countries between 1990 and 2013; however, in 1995 and 2005, survival in Canada increased at a faster rate than in the United States (P < 0.001). On the basis of contemporary data from 2009 to 2013, the median age of survival in Canada was 10 years greater than in the United States (50.9 vs. 40.6 years, respectively). The adjusted risk for death was 34% lower in Canada than the United States (hazard ratio, 0.66 [95% CI, 0.54 to 0.81]). A greater proportion of patients in Canada received transplants (10.3% vs. 6.5%, respectively [standardized difference, 13.7]). Differences in survival between U.S. and Canadian patients varied according to U.S. patients' insurance status.
Ascertainment bias due to missing data or nonrandom loss to follow-up might affect the results.
Differences in cystic fibrosis survival between Canada and the United States persisted after adjustment for risk factors associated with survival, except for private-insurance status among U.S. patients. Differential access to transplantation, increased posttransplant survival, and differences in health care systems may, in part, explain the Canadian survival advantage.
U.S. Cystic Fibrosis Foundation.
Median age of survival over time.
Top. Median survival age obtained by using a 5-year rolling window, Canada versus the United States, 1990–2013. Bottom. Difference in median age of survival between Canada and the United States, 1990–2013. Circles represent the point estimates for the difference.
Table 1. Characteristics of Contemporary Patients With Cystic Fibrosis in Canada and the United States, 2009–2013*
Unadjusted univariate subgroup analysis comparing the risk for death in Canada versus the United States overall and in several subgroups (2009–2013).
The hazard ratio and 95% CI for each variable are displayed. The dashed line is the null line, indicating no difference between countries.
Creation of the study cohort for multivariable analysis (2009–2013).
The percentage of excluded deaths for each country was calculated by dividing the total number of excluded deaths by the total number of initial deaths in each country.
Table 2. Risk for Death: Multivariable Model Adjusted for Patient Characteristics, 2009–2013 (n = 37 080)
Table 3. Risk for Death: Multivariable Analysis Adjusted for Patient and Clinical Characteristics, 2009–2013 (n = 29 209)*
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Zhe Hui Hoo, Rachael E Curley, Martin J Wildman
March 24, 2017
Stephenson et al (1) highlights important CF outcome differences between Canada and the US. One method to systematically explore these differences is the ‘pyramid model of investigation’ (2). The first step is review of data. According to the supplementary material, 81-84% of people with CF in the US were captured in the US registry (USCFFPR) whereas the Canadian registry (CCFR) captured nearly everyone with CF in Canada. USCFFPR also has significantly more people lost to follow-up. Comparisons of USCFFPR and national mortality data from 1992-2005 showed USCFFPR missing ~20% of CF deaths (3) and higher median age at death was derived from national mortality data compared to USCFFPR data (4). This might contribute to some of the survival differences. The second step is consideration of case-mix. Survival differences persisted despite appropriate adjustments of all the important case-mix factors captured by both registries. The third step is to explore whether structure and resources might be important in influencing outcomes. Survival differences disappeared when comparisons included only US people with private insurance, suggesting that differences in structures and resources might be important. However, teasing out the confounding effect of deprivation is difficult. This leads to the fourth step of the pyramid: process of care. Processes of care focusing on lung health can be broadly divided into rescue treatment with IV antibiotics and preventative inhaled therapies. Understanding the possible contribution of care processes is important since they may be amenable to improvement. CCFR only started collecting maintenance treatment data from 2011 and maintenance treatment data in registries are difficult to interpret since only ~50% of prescribed treatments are actually collected and the proportion of collected medications used correctly is uncertain. Technology now makes routine monitoring of adherence data feasible and linking such data with registries would greatly enhance the power of registry comparisons. Previous studies have shown that more intensive intravenous antibiotics use is associated with better FEV1 (5). Intravenous data is robustly captured by both registries. We urge the authors to also compare differences in intravenous antibiotics use, which may help to identify potential opportunities for improvement.References:1. Stephenson AL, Sykes J, Stanojevic S, Quon BS, Marshall BC, Petren K, et al. Survival Comparison of Patients With Cystic Fibrosis in Canada and the United States: A Population-Based Cohort Study. Ann Intern Med. 2017 Mar 14. doi: 10.7326/M16-0858. [Epub ahead of print]2. Mohammed MA, Rathbone A, Myers P, Patel D, Onions H, Stevens A. An investigation into general practitioners associated with high patient mortality flagged up through the Shipman inquiry: retrospective analysis of routine data. BMJ. 2004;328:1474-7. [PMID: 15205291] doi:10.1136/bmj.328.7454.14743. Nick JA, Chacon CS, Brayshaw SJ, Jones MC, Barboa CM, St Clair CG, et al. Effects of gender and age at diagnosis on disease progression in long-term survivors of cystic fibrosis. Am J Respir Crit Care Med. 2010;182:614-26. [PMID: 20448091] doi:10.1164/rccm.201001-0092OC4. Chowdhury F, Wildman MJ, Gunn E, Bilton D. Cystic Fibrosis deaths in USA and UK: comparisons of registry and routine data. Thorax. 2001;66(Suppl 4):A163-4. doi:10.1136/thoraxjnl-2011-201054c.2365. Schechter MS, Regelmann WE, Sawicki GS, Rasouliyan L, VanDevanter DR, Rosenfeld M, et al. Antibiotic treatment of signs and symptoms of pulmonary exacerbations: a comparison by care site. Pediatr Pulmonol 2015;50:431-40. [PMID: 25530325] doi:10.1002/ppul.23147
Maggie McIlwaine MCSP, PhD
University of British Columbia
This is an important cohort study exploring the differences in survival of Cystic Fibrosis (CF) patients in Canada compared to the United States. The authors attribute these differences to, access to transplantation and differences in the health care systems. While the authors reported differences in treatment with regards to mucolytics and inhaled antibiotics, they failed to examine the effect of the differences in the use of airway clearance techniques (ACTs) between the two countries. A review of the data registries of both Canada and the US shows significant differences in ACTs used in each country. In Canada, the predominantly reported ACT used in the 2014 Canadian CF data registry1 was the Positive Expiratory Pressure technique (PEP), which together with Oscillating PEP (Osc PEP), accounted for 50% of ACTs used by CF patients. Modified postural drainage, which is primarily used by pre-schoolers accounted for another 30%, less than 5% used HFCWO. This is in sharp contrast to the 2014 US patient data registry2 which reported 74% of CF patients using High Frequency Chest Wall Oscillation (HFCWO) for their ACT and only 8.7% using PEP or Osc PEP.In 2013, we reported the results of a multicentre randomized controlled study across 12 Canadian CF centres comparing the two predominant ACTs used in each country, PEP and HFCWO3. The results of this one year study found the use of HFCWO was associated with a significant increase in the number of pulmonary exacerbations compared to PEP (2.0 v 1.14, P = 0.007). Pulmonary exacerbations are associated with reduced lung function4. A multi-centre study in the US on the use of HFCWO also reported HFCWO was associated with a greater decline in lung function compared to oscillating PEP in FEF25-75% % predicted per year ( -2.32, Osc PEP v -0.16. P=0.035)6.Both of these multicentre studies one in Canada and the other in the US have demonstrated that HFCWO has been associated with an increase in pulmonary exacerbations and a decline in lung function compared to PEP or Osc PEP. Interestingly, both these techniques were introduced to CF clinics in Canada and the US in the early 1990’s, just before there was a divergence in survival between the two countries. Unfortunately, the authors of this study did not include the choice of ACT in their analysis of long-term survival, yet as demonstrated, it is an important variant that warrants examination in the context of survival.References.1. Cystic Fibrosis Canada. Annual Registry Report. Toronto, ON, Canada: Cystic Fibrosis Canada; 2014.2. Cystic Fibrosis Foundation. Cystic Fibrosis Foundation National patient Registry Annual data report. Bethesda, MD, USA: Cystic Fibrosis Foundation; 2014.3. McIlwaine MP. Alarie N. Davidson GF. Lands LC. Ratjen F. Milner R. Owen B. Agnew JL Long-term multicentre randomised controlled study of high frequency chest wall oscillation versus positive expiratory pressure mask in cystic fibrosis. Thorax 2013;68(8):746-51.4. Waters V and Ratjen F. Pulmonary Exacerbations in Children with Cystic Fibrosis. Ann Am Thorac Soc. 2015;Vol 12 (suppl 2): S200-S206. 5. Sontag MK, Quittner AL, Modi AC, et al. Lessons learned from a randomized trial airway secretion clearance techniques in cystic fibrosis. Pediatr Pulmonol 2010;45:291–300.
Stephenson AL, Sykes J, Stanojevic S, Quon BS, Marshall BC, Petren K, et al. Survival Comparison of Patients With Cystic Fibrosis in Canada and the United States: A Population-Based Cohort Study. Ann Intern Med. 2017;166:537–546. doi: 10.7326/M16-0858
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Published: Ann Intern Med. 2017;166(8):537-546.
Published at www.annals.org on 14 March 2017
Gastroenterology/Hepatology, Pancreatic Disease, Pulmonary/Critical Care.
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