Evidence Report/Technology Assessment Number 165 Hydroxyurea for the Treatment of Sickle Cell Disease 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 290-02-0018 Prepared by: The Johns Hopkins University Evidence-based Practice Center, Baltimore, MD Investigators Jodi B Segal, M.D., M.P.H John J Strouse, M.D Mary Catherine Beach, M.D., M.P.H Carlton Haywood, M.A Catherine Witkop, M.D., M.P.H Haeseong Park, M.D., M.P.H Renee F Wilson, M.Sc Eric B Bass, M.D., M.P.H Sophie Lanzkron, M.D AHRQ Publication No 08-E007 February 2008 This report is based on research conducted by the Johns Hopkins University Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No 290-02-0018) The findings and conclusions in this document are those of the author(s), who are responsible for its content, and not necessarily represent the views of AHRQ No statement in this report should be construed as an official position of AHRQ or of the U.S Department of Health and Human Services The information in this report is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services This report is intended as a reference and not as a substitute for clinical judgment This report may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies AHRQ or U.S Department of Health and Human Services endorsement of such derivative products may not be stated or implied 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: Segal JB, Strouse JJ, Beach MC, Haywood C, Witkop C, Park HS, Wilson RF, Bass EB, Lanzkron S Hydroxyurea for the Treatment of Sickle Cell Disease Evidence Report/Technology Assessment No 165 (Prepared by Johns Hopkins University Evidencebased Practice Center under contract No 290-02-0018) AHRQ Publication No 08-E007 Rockville, MD Agency for Healthcare Research and Quality February 2008 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 ii 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 This report was requested and funded by the National Institutes of Health (NIH), Office of Medical Applications of Research (OMAR) 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 epc@ahrq.gov Carolyn M Clancy, M.D Director Agency for Healthcare Research and Quality Jean Slutsky, P.A., M.S.P.H Director, Center for Outcomes and Evidence Agency for Healthcare Research and Quality Barry Kramer, M.D Director, Office of Medical Applications of Research, NIH Beth A Collins Sharp, R.N., Ph.D Director, EPC Program Agency for Healthcare Research and Quality Ernestine W Murray, B.S.N., R.N., M.A.S Task Order Officer Agency for Healthcare Research and Quality iii Acknowledgments The EPC thanks Allison Jonas for their assistance with literature searching, database management, and project organization, and Brenda Zacharko for her assistance with budget matters and final preparations of the report iv Structured Abstract Objective To synthesize the published literature on the efficacy, effectiveness, and toxicity of hydroxyurea (HU) when used for treatment of sickle cell disease (SCD); and to review the evidence regarding barriers to its use Data Sources Articles cited in MEDLlNE®, EMBASE, TOXLine, and CINAHL through June 30, 2007 Review Methods Paired reviewers reviewed each title, abstract, and article to assess eligibility They abstracted data sequentially and then independently graded the evidence Results In one small, randomized trial of HU in children with SCD; the yearly hospitalization rate was lower with HU than placebo (1.1 versus 2.8, p=0.002) The absolute increase in fetal hemoglobin (Hb F%) was 10.7 percent Twenty observational studies of HU in children reported similar increases in Hb F%, while hemoglobin concentration increased by roughly g/dl One large randomized trial tested the efficacy of HU in adults with SCD and found that after years of treatment, Hb F% increased by 3.2 percent and hemoglobin increased by 0.6 g/dl, The median number of painful crises was 44 percent (p based on consistent evidence from or more studies with no plausible confounders (+1); “very strong” if significant relative risk or odds ratio > based on direct evidence with no major threats to validity (+2)) Did the studies have evidence of a dose-response gradient? (+1) Did the studies have unmeasured plausible confounders that affected the magnitude of the observed association? (+1) Overall grade of evidence (high, moderate, low, very low) (insufficient if no studies or evidence is too sparse or inconsistent to draw conclusions) * enter if the studies evidence does not warrant a (-) or (+) score E-1 Reduction in hospitalization Reduction in neurological events Reduction in transfusion Score Sheet –Efficacy in Adults with SCD Outcomes Hb F% change Reduction in crises (pain/ACS) Protection against risk of bias Did the studies have important inconsistency? (-1) Was there some (-1) or major (-2) uncertainty about the directness or extent to which the people, interventions and outcomes are similar to those of interest? Were the studies sparse or imprecise? (-1) Did the studies show strong evidence of association between intervention and outcome? (“strong” if significant relative risk or odds ratio > based on consistent evidence from or more studies with no plausible confounders (+1); “very strong” if significant relative risk or odds ratio > based on direct evidence with no major threats to validity (+2)) Did the studies have evidence of a dose-response gradient? (+1) Did the studies have unmeasured plausible confounders that affected the magnitude of the observed association? (+1) Overall grade of evidence (high, moderate, low, very low) (insufficient if no studies or evidence is too sparse or inconsistent to draw conclusions) E-2 Reduction in hospitalization Reduction in neurological events Reduction in transfusion Mortality Score Sheet –Toxicity in Children with SCD Outcomes Leukemia (MDS/AML/Cyto genetic abnromalities Protection against risk of bias (relates to study design, study quality, reporting bias) Did the studies have important inconsistency? (-1) Was there some (-1) or major (-2) uncertainty about the directness or extent to which the people, interventions and outcomes are similar to those of interest? Were the studies sparse or imprecise? (-1) Did the studies show strong evidence of association between intervention and outcome? (“strong” if significant relative risk or odds ratio > based on consistent evidence from or more studies with no plausible confounders (+1); “very strong” if significant relative risk or odds ratio > based on direct evidence with no major threats to validity (+2)) Did the studies have evidence of a dose-response gradient? (+1) Did the studies have unmeasured plausible confounders that affected the magnitude of the observed association? (+1) Overall grade of evidence (high,moderate, low, very low) (insufficient if no studies or evidence is too sparse or inconsistent to draw conclusions) E-3 Developmenta l toxicities (in utero) Leg ulcers Growth delays Developmental toxicities in next generation Score Sheet –Toxicity in Adults with SCD Outcomes Leukemia (MDS/AML/Cytogenetic abnormalities Protection against risk of bias (relates to study design, study quality, reporting bias) Did the studies have important inconsistency? (-1) Was there some (-1) or major (-2) uncertainty about the directness or extent to which the people, interventions and outcomes are similar to those of interest? Was the data sparse or imprecise (-1) Did the studies show strong evidence of association between intervention and outcome? (“strong” if significant relative risk or odds ratio > based on consistent evidence from or more studies with no plausible confounders (+1); “very strong” if significant relative risk or odds ratio > based on direct evidence with no major threats to validity (+2)) Did the studies have evidence of a dose-response gradient? (+1) Did the studies have unmeasured plausible confounders that affected the magnitude of the observed association? (+1) Overall grade of evidence (high, moderate, low, very low) (insufficient if no studies or evidence is too sparse or inconsistent to draw conclusions) E-4 Leg ulcers Skin neoplasms Secondary malignancies Adverse preg Outcomes Spermatogenesis defects Score Sheet –Toxicity in Adults with Other Diseases Outcomes Leukemia (MDS/AML/Cytogen etic abnormalities Protection against risk of bias (relates to study design, study quality, reporting bias) Did the studies have important inconsistency? (-1) Was there some (-1) or major (-2) uncertainty about the directness or extent to which the people, interventions and outcomes are similar to those of interest? Was the data sparse or imprecise (-1) Did the studies show strong evidence of association between intervention and outcome? (“strong” if significant relative risk or odds ratio > based on consistent evidence from or more studies with no plausible confounders (+1); “very strong” if significant relative risk or odds ratio > based on direct evidence with no major threats to validity (+2)) Did the studies have evidence of a dose-response gradient? (+1) Did the studies have unmeasured plausible confounders that affected the magnitude of the observed association? (+1) Overall grade of evidence (high, moderate, low, very low) (insufficient if no studies or evidence is too sparse or inconsistent to draw conclusions) E-5 Leg ulcers Skin neoplasms Secondary malignancies Adverse preg Outcomes Spermatogenesis defects Grading the Evidence for Key Question – Barriers to Therapies Grading the Evidence for the Cross-sectional and Descriptive Studies about the Presence of Barriers After all of the articles were reviewed, the body of the evidence supporting the existence of particular barriers for each question was graded on the basis of the number of times the barrier was identified (quantity), protection against the bias in the studies (quality), and consistency First, the quantity of the evidence was initially judged as being Strong, Moderate, or Low on the basis of the following criteria: there had to be more than ten studies identifying a particular factor (i.e potential barrier or facilitator) to meet criteria for a “High” grade, six to ten studies to meet criteria for a “Moderate” grade, three to five studies to meet the criteria for a “Poor” grade, and two or fewer studies to meet the criteria for an “Insufficient” grade The initial grade for the evidence was then lowered by one level (i.e., changing from High to Moderate or from Moderate to Low) if 75% or less of the studies reviewed for each question attempted to protect against the risk of bias through controlling for potential confounders in the cross-sectional studies OR if the reported barriers were not cited by the population that would be most knowledgeable about the barrier in the descriptive studies (e.g healthcare providers themselves saying they had limited knowledge was considered greater protection against bias than if patients had reported the same finding) The initial quantity score was left unchanged if our criteria for protection against the risk of bias were met The resulting score was then revised further based on the consistency of the evidence, which was an assessment of the extent to which any particular factor (i.e potential barrier or facilitator) was found across studies to be a barrier to, a facilitator of, or to have no association with the appropriate therapy of interest The score was lowered by one level if less than 75%, and lowered by two levels if less than 50%, of the studies found an independent variable to be a barrier, facilitator, or have no association with the therapy of interest The score was raised by one level (i.e., from Poor to Moderate or from Moderate to High) if 100% of the studies examining any particular independent variable found it to be a barrier, facilitator, or have no association with the therapy of interest Grading the Evidence for the Intervention Studies Criteria to grade the body of the evidence for the intervention studies were similar to the criteria used earlier in the report, and therefore were different criteria than that presented above for KQ4a-e For each therapy of interest, the evidence that an intervention could overcome barriers to that therapy of interest was given an initial grade of High if the evidence contained at least one randomized controlled trial, Moderate if there was at least one controlled trial (not randomized), and Low if the evidence contained no controlled trials Grades of High or Moderate were then lowered by one level if there were serious concerns about the presence of bias in the findings Grades were lowered by one additional level in the presence of important inconsistencies in the findings across studies, any uncertainty about the directness or extent to which the people, interventions, and outcomes were similar to the sickle cell populations of interest, or if the findings were too imprecise or sparse to estimate an effect Grades were then raised by one additional level in the presence of strong evidence of association between the intervention and the outcome, evidence of a doseresponse gradient, or if all plausible unmeasured confounders would have reduced the observed effect Grades were raised by two levels in the presence of very strong evidence of association between the intervention and the outcome The overall grade of the body of this evidence was given as the final grade that resulted from the above assessments A grade of Insufficient was given if there were no studies examining potential interventions to overcome barriers to an appropriate therapy of interest, or of the existing body of evidence was deemed to be too sparse or inconsistent to draw conclusions E-6 Appendix F Appendix F: Technical Experts and Peer Reviewers Erica Liebelt, MD, PhD National Toxicology Program Associate Professor of Pediatrics and Emergency Medicine Director, Medical Toxicology Services UAB School of Medicine Birmingham, AL Kofi Anie, PhD Clinical Health Psychologist Central Middlesex Hospital Honorary Senior Lecturer Imperial College London London, England Wylie Burke, MD, PhD Professor and Chair Department of Medical History and Ethics University of Washington Seattle, WA Heidi Malm, PhD Associate Professor Loyola University Chicago Chicago, IL Martin H Steinberg, MD Professor of Medicine, Pediatrics, Pathology and Laboratory Medicine, Boston University School of Medicine Director, Center of Excellence in Sickle Cell Disease Boston Medical Center Boston, MA Christine Corbin Program Coordinator Sickle Cell Disease Association of America, Inc Baltimore, MD Peter Fagan, PhD Johns Hopkins HealthCare LLC Glen Burnie, MD Jeffery Keefer, MD, PhD Division of Pediatric Hematology Johns Hopkins University School of Medicine Baltimore, MD F-1 Internal Technical Experts Samuel Charache, MD, PhD Emeritus Professor of Medicine and Pathology John Hopkins School of Medicine Baltimore, MD James F Casella, MD Rainey Professor of Pediatric Hematology Department of Pediatrics Johns Hopkins University School of Medicine Baltimore, MD Cynthia S Rand, PhD Professor of Medicine Division of Pulmonary and Critical Care Medicine Johns Hopkins University School of Medicine Baltimore, MD F-2 ... on the efficacy and/or effectiveness of hydroxyurea treatment of hematologic diseases, the toxicity of hydroxyurea in the treatment of any disease, and the barriers to the treatment of sickle cell. .. have sickle cell disease? What are the short- and long-term harms of hydroxyurea treatment? What are the barriers to the use of hydroxyurea treatment (and other therapies) for patients who have sickle. .. practice) of hydroxyurea treatment for patients who have sickle cell disease? What are the short- and long-term harms of hydroxyurea treatment? What are the barriers to the use of hydroxyurea treatment