Evidence Report/Technology Assessment Number 189 Exercise-Induced Bronchoconstriction and Asthma Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov Contract No. HHSA 290-2007-10021-I Prepared by: University of Alberta Evidence-based Practice Center, Edmonton, AB, Canada Investigators Donna M. Dryden, Ph.D. Carol H. Spooner, B.Sc.N., M.Sc. Michael K. Stickland, Ph.D. Ben Vandermeer, M.Sc. Lisa Tjosvold, B.A., M.L.I.S. Liza Bialy, B.Sc. Kai Wong, B.Sc. Brian H. Rowe, M.D., M.Sc., C.C.F.P. (E.M.) AHRQ Publication No. 10-E001 January 2010 (Web site posting) Revised March 2010 This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders. Suggested Citation: Dryden DM, Spooner CH, Stickland MK, Vandermeer B, Tjosvold L, Bialy L, Wong K, Rowe BH. Exercise-Induced Bronchoconstriction and Asthma. Evidence Report/Technology Assessment No. 189 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No. 290-2007-10021-I) AHRQ Publication No. 10-E001. Rockville, MD: Agency for Healthcare Research and Quality. January 2010 (Web site posting); revised March 2010. No investigators have any affiliations or financial involvement (e.g., employment, consultancies, honoraria, stock options, expert testimony, grants or patents received or pending, or royalties) that conflict with material presented in this report. Preface The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments. To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release. AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality. We welcome comments on this evidence report. They may be sent by mail to the Task Order Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850, or by e-mail to [email protected]. Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H. Director Director, Center for Outcomes and Evidence Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality Beth A. Collins Sharp, R.N., Ph.D. Capt. Karen Lohmann Siegel, P.T., M.A. Director, EPC Program EPC Program Task Order Officer Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality iii Acknowledgments We are grateful to members of the technical expert panel, Dr. Louis-Philippe Boulet (Université Laval, Sainte-Foy, QC), Dr. Robert Cowie (University of Calgary, AB), Dr. Andrew Gregory (Vanderbilt University Medical Center, Nashville, TN), Dr. Cynthia LaBella (Children’s Memorial Hospital, Chicago, IL), Dr. Darcy Marciniuk (University of Saskatoon, SK), Dr. Kenneth Rundell (Marywood University, Scranton, PA), Dr. John Weiler (American Academy of Asthma Allergy and Immunology) and Karen Siegel (Agency for Healthcare Research and Quality), who provided direction for the scope and content of the review. We thank the Cochrane Airways Group for their assistance and providing access to their database of articles. We also thank all the individuals at AHRQ, the Scientific Resource Center, and the peer reviewers for their comments and suggestions. We thank Jennifer Seida for her work in developing the protocol, Mohammad Karkhaneh and Kate O’Gorman for assistance with data extraction and preparation of the appendices, Ken Bond for copyediting, and Simon Bow and Annabritt Chisholm for their assistance with literature retrieval. iv Structured Abstract Objectives: The objectives are: (1) to assess diagnostic test characteristics of six alternative index tests compared with the selected reference standard–a standardized exercise challenge test (ECT) in patients with suspected exercise-induced bronchoconstriction or asthma (EIB/EIA); (2) to determine the efficacy of a single prophylactic dose of four pharmacologic and one nonpharmacologic interventions versus placebo to attenuate EIB/EIA in patients with diagnosed EIB/EIA; and (3) to determine if regular daily treatment with short-acting or long-acting beta- agonists (SABA or LABA) causes patients with EIA to develop tachyphylaxis when additional prophylactic doses are used pre-exercise. Data Sources: A systematic and comprehensive literature search was conducted in 14 electronic databases (Diagnosis) and the Cochrane Airways Register (Therapy). Review Methods: Study selection, quality assessment, and data extraction were conducted independently by two reviewers. The primary outcome was the maximum percent fall in the post-exercise forced expiratory volume in 1 second (percent fall FEV1). The diagnostic threshold for a positive ECT was a percent fall FEV1 of 10 percent or more. Sensitivity (SN) and specificity (SP) were calculated. For therapy, mean differences (MD) in the percent fall FEV1 and 95 percent confidence intervals (CI) (random effects model) were calculated. A positive MD indicates the intervention works better than the control. Results: For the diagnostic reviews, 5,318 citations yielded 28 relevant studies; for the therapy reviews, 1,634 citations yielded 109 relevant RCTs Diagnostic test results versus ECT: self-reported history (2 studies) SN=36–89 percent, SP=85–86 percent; methacholine challenge (16 studies) SN=0–100 percent, SP=0–100 percent; sport specific challenges (5 studies) SN=0–100 percent, SP=0–100 percent; eucapnic voluntary hyperpnea (7 studies) SN=25–90 percent, SP=0–71 percent; free running asthma screening test (3 studies) SN=60–67 percent, SP=47–67 percent; mannitol (3 studies) SN=58–96 percent, SP=65-78 percent. All SN and SP calculations indicated substantial heterogeneity that could not be explained by sensitivity or subgroup analyses. Therapy results: SABA offered greater protection than mast cell stabilizers (MCS) (12 studies); MD=6.8 (95 percent CI: 4.5, 9.2) but combining them offered no additional benefit; SABA versus MCS plus SABA (5 studies) MD=1.3 (95 percent CI: -6.3, 8.9). Leukotriene receptor antagonists (LTRA), MCS, ipratropium bromide, and interval warmup routines provided statistically significant attenuation of EIA when compared with placebo; inhaled corticosteroids (ICS) and other warmup routines did not. Single-dose intervention versus placebo results are: LTRA (9 studies) MD=8.9 (95 percent CI: 6.9, 11.0); MCS (nedocromil sodium) (17 studies) MD=15.6 (95 percent CI: 13.2, 18.2); interval warmup versus no warmup (4 studies) MD=10.6 (95 percent CI: 6.5, 14.7); ICS (4 studies) MD=5.0 (95 percent CI: 0.0, 9.9); continuous low intensity warmup versus no warmup (3 studies) MD=12.6 (95 percent CI: -1.5, 26.7); continuous high intensity warmup versus no warmup (2 studies) MD=9.8 (95 percent CI: ­ 6.4, 26.0). After daily LABA (salmeterol) use for 3 to 4 weeks (4 studies), the percent fall FEV1 following an ECT at 2 and 4 weeks was greater than at day 1 in the LABA arm indicating that tachyphylaxis to prophylactic LABA use occurred. Daily SABA use for 1 week (1 study) also v indicated development of tachyphylaxis. However, both LABA and SABA continued to have an attenuating effect on EIA. Conclusions: Given the small number of studies comparing EIB/EIA diagnostic tests, the heterogeneity of the study populations, and the varied study methodologies, there is no clear evidence that any of the index tests are a suitable replacement for a standardized ECT to diagnose EIB/EIA in the general population. All bronchodilator agents and most anti-inflammatory agents when used as pre- treatment are somewhat effective in attenuating the percent fall FEV1 associated with EIA. There is evidence that the protective effect of LABA and SABA decreases with the daily use of these drugs. There is no evidence of an attenuating benefit following single- dose pre-treatment with ICS. There is a role for LTRA and MCS; however, the attenuation appears less than with bronchodilator agents. Finally, pre-exercise interval warmup appears to be effective in attenuating the FEV1 falls associated with EIA. UPDATE: The following section was added on 3/15/2010: On February 18, 2010 the Food and Drug Administration issued a drug safety communication requiring changes to use of Long-Acting Beta-Agonists (LABAs) in the treatment of asthma. These changes are based on FDA's analyses of studies showing an increased risk of severe exacerbation of asthma symptoms in some patients using LABAs for the treatment of asthma. The FDA cautioned that LABAs should only be used long- term in patients whose asthma cannot be adequately controlled on asthma controller medications and then, LABAs should be used only in combination with these other medications. The Exercise-Induced Bronchoconstriction and Asthma (EIB/EIA) Evidence Report was conducted prior to the FDA warning and focused on studies that examined whether individuals using LABAs develop a tolerance (tachyphylaxis) to long term regular use of the drugs.