Systematic review and meta-analysis of the safety and efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2) for spinal fusion Jennifer V E Brown Morag K Heirs Julian P T Higgins Richard J Mannion Mark A Rodgers Charlotte C Seneschall Mark C Simmonds Lesley A Stewart Kath Wright Centre for Reviews and Dissemination (CRD) University of York YO10 5DD United Kingdom May 2013 Acknowledgements We thank the following people for their help and support in this research project: We are indebted to Vanda Castle for coordinating telephone conferences and team meetings and for typing the adverse events tables from clinical study reports and to Beth Hodshon of the YODA team for her professional and efficient handling of our queries to Medtronic. We thank S D Glassman and Leah Carreon for providing of IPD from their trial. We are also grateful to Pamela Hayden, Director, Research & Quality Improvement at the North American Spine Society for sharing our call for evidence with society members and to Mark Schoene, editor of The BackLetter for publishing it and to everyone who responded. We thank Dr Eugene Carragee for providing one of his manuscripts prior to publication for inclusion in our safety analyses. ii Authors' Contributions All authors were actively involved in this project. Jennifer Brown was involved in eligibility screening, data extraction, assessment of risk of bias and mapping of the adverse events publications. She contributed to the writing of the report. Morag Heirs contributed to the management and checking of data provided by Medtronic. She was involved in the eligibility screening, data extraction and risk of bias assessment processes. She contributed to the writing of the report. Julian Higgins contributed to development of the proposal and protocol, undertook some of the analyses for safety, provided methodological advice and contributed to writing the report. Richard Mannion contributed to development of the proposal and protocol, provided advice on clinical significance and context and contributed to writing the report. Mark Rodgers contributed to development of the protocol. He was involved in eligibility screening, data extraction, and assessment of risk of bias and conducted some statistical analyses. He contributed to writing the report. Charlotte Seneschall undertook the data extraction of the MedWatch forms. Mark Simmonds was responsible for the management and checking of data provided by Medtronic and Glassman. He conducted the individual participant data meta-analyses and most of the other statistical analyses. He contributed to the writing of the report. Lesley Stewart devised the project and developed the proposal with input from co-applicants. She was responsible for the overall direction and supervision of the project and contributed to the writing of the report. Kath Wright developed and ran the database search strategies, set up current awareness searches, maintained the Endnote library of references and wrote up the literature searching process. Corresponding author: Professor Lesley Stewart Centre for Reviews and Dissemination University of York Heslington York YO10 5DD UK [email protected] iii Contents Contents Acknowledgements .................................................................................................................................. ii Authors' Contributions ............................................................................................................................. iii Contents .................................................................................................................................................. iv List of Tables .......................................................................................................................................... vii List of Figures .......................................................................................................................................... ix Abbreviations and Glossary..................................................................................................................... xi Preface ................................................................................................................................................... xii Executive Summary ............................................................................................................................... xiv 1. Introduction .................................................................................................................................. 1 2. General Methods ......................................................................................................................... 3 2.1. Overview of our approach ....................................................................................................... 3 2.2. Establishing benefits and harms of rhBMP-2 in spinal fusion ................................................. 3 2.3. Overview of approach in establishing the reliability of the publicly available evidence........... 3 2.4. Objectives ................................................................................................................................ 3 2.5. Protocol .................................................................................................................................... 3 2.6. Inclusion criteria ....................................................................................................................... 4 2.7. Literature searches .................................................................................................................. 4 2.8. Review processes ................................................................................................................... 5 3. Methods: Efficacy ........................................................................................................................ 7 3.1. Data sources used ................................................................................................................... 7 3.2. Outcomes of interest ............................................................................................................... 7 3.3. Data management and checking of individual participant data ............................................... 9 3.4. Risk of bias .............................................................................................................................. 9 3.5. Statistical analysis ................................................................................................................... 9 4. Methods: Safety ......................................................................................................................... 13 4.1. Data sources.......................................................................................................................... 13 4.2. Outcomes of interest ............................................................................................................. 13 4.3. Individual participant data ...................................................................................................... 13 4.4. Cancer ................................................................................................................................... 15 4.5. MedWatch forms ................................................................................................................... 15 4.6. Data from the wider literature ................................................................................................ 15 5. Methods: Reliability of the Evidence ......................................................................................... 18 5.1. Identifying the evidence ......................................................................................................... 18 5.2. Data collection ....................................................................................................................... 18 5.3. Data synthesis ....................................................................................................................... 18 6. Results: Included Studies .......................................................................................................... 19 6.1. Search Results ...................................................................................................................... 19 6.2. Data supplied by Medtronic ................................................................................................... 25 6.3. IPD from other sources .......................................................................................................... 25 iv Contents 6.4. Timeline of Medtronic trials and events relating to the use of rhBMP-2 ................................ 25 7. Results: Efficacy ........................................................................................................................ 27 7.1. Data checking and quality summary ..................................................................................... 27 7.2. Pain and functionality scores ................................................................................................. 32 7.3. Spinal fusion .......................................................................................................................... 35 7.4. Impact of type of surgery on efficacy outcomes .................................................................... 37 7.5. Impact of patient-level factors on