Rongwei Fu, PhD; Shelley Selph, MD; Marian McDonagh, PharmD; Kimberly Peterson, MS; Arpita Tiwari, MHS; Roger Chou, MD; Mark Helfand, MD, MS
Note: Annals peer review materials (original and revised manuscripts and communications, including peer reviewer, editorial, statistical, and author comments) are available at www.annals.org (see the Supplement).
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the YODA Project or Medtronic.
Acknowledgment: The authors thank Robin Paynter, MLIS, for conducting literature searches and Howard Balshem, MS; Susan Carson, MPH; Elaine Graham, MLS; Allison Lowe, BA; Edwin Reid, MS, MAT; Katie Reitel, MPH, MSW; Sujata Thakurta, MA; Ngoc Wasson, MPH; and Leah Williams, BS, for their contributions to this article.
Financial Support: By a research subcontract to Oregon Health & Science University under a sponsored research agreement between Yale University and Medtronic.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-2731.
Reproducible Research Statement: Study protocol: Available at www.crd.york.ac.uk/Prospero. Statistical code: SAS codes for meta-analysis are in the Appendix and are also available from Dr. Fu (e-mail, firstname.lastname@example.org). Data set: Accessible through the Yale University Open Access Data (YODA) Project at http://medicine.yale.edu/core/projects/yodap/index.aspx.
Requests for Single Reprints: Rongwei Fu, PhD, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code CSB669, Portland, OR 97239.
Current Author Addresses: Dr. Fu: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code CSB669, Portland, OR 97239.
Drs. Selph, McDonagh, Chou, and Helfand and Ms. Peterson: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239.
Ms. Tiwari: Oregon State University, College of Public Health and Human Sciences, 401 Waldo Hall, Corvallis, OR 97331.
Author Contributions: Conception and design: R. Fu, S. Selph, M. McDonagh, A. Tiwari, R. Chou, M. Helfand.
Analysis and interpretation of the data: R. Fu, S. Selph, M. McDonagh, K. Peterson, A. Tiwari, R. Chou, M. Helfand.
Drafting of the article: R. Fu, S. Selph, R. Chou, M. Helfand.
Critical revision of the article for important intellectual content: R. Fu, S. Selph, M. McDonagh, A. Tiwari, R. Chou, M. Helfand.
Final approval of the article: R. Fu, S. Selph, M. McDonagh, K. Peterson, R. Chou, M. Helfand.
Statistical expertise: R. Fu, A. Tiwari, R. Chou.
Obtaining of funding: R. Fu, M. Helfand.
Administrative, technical, or logistic support: R. Chou, M. Helfand.
Collection and assembly of data: R. Fu, S. Selph, K. Peterson, A. Tiwari, M. Helfand.
Recombinant human bone morphogenetic protein-2 (rhBMP-2) is used as a bone graft substitute in spinal fusion, which unites (fuses) bones in the spine. The accuracy and completeness of journal publications of industry-sponsored trials on the effectiveness and harms of rhBMP-2 has been called into question.
To independently assess the effectiveness and harms of rhBMP-2 in spinal fusion and reporting bias in industry-sponsored journal publications.
Individual-patient data (IPD) from 17 industry-sponsored studies; related internal documents; and searches of MEDLINE (1996 to August 2012), other databases, and reference lists.
Randomized, controlled trials (RCTs) and cohort studies of rhBMP-2 versus any control and uncontrolled studies of harms.
Effectiveness outcomes in IPD were recalculated using consistent definitions. Study characteristics and results were abstracted by 1 investigator and confirmed by another. Two investigators independently assessed quality using predefined criteria.
Thirteen RCTs and 31 cohort studies were included. For lumbar spine fusion, rhBMP-2 and iliac crest bone graft were similar in overall success, fusion, and other effectiveness measures and in risk for any adverse event, although rates were high across interventions (77% to 93% at 24 months from surgery). For anterior lumbar interbody fusion, rhBMP-2 was associated with nonsignificantly increased risk for retrograde ejaculation and urogenital problems. For anterior cervical spine fusion, rhBMP-2 was associated with increased risk for wound complications and dysphagia. At 24 months, the cancer risk was increased with rhBMP-2 (risk ratio, 3.45 [95% CI, 1.98 to 6.00]), but event rates were low and cancer was heterogeneous. Early journal publications misrepresented the effectiveness and harms through selective reporting, duplicate publication, and underreporting.
Outcome assessment was not blinded, and ascertainment of harms in trials was poor. No trials were truly independent of industry sponsorship.
In spinal fusion, rhBMP-2 has no proven clinical advantage over bone graft and may be associated with important harms, making it difficult to identify clear indications for rhBMP-2. Earlier disclosure of all relevant data would have better informed clinicians and the public than the initial published trial reports did.
Yale University and Medtronic.
Appendix Table 1. Search Strategies
Appendix Table 2. Outcome Variable Definitions/Criteria From Medtronic Protocols Compared With Those in Published Studies and IPD Analysis for Comparative Effectiveness and Harms
Appendix Table 3. Included Medtronic Studies of rhBMP-2
Summary of evidence search and selection.
ALIF = anterior lumbar interbody fusion; PLF = posterolateral lumbar fusion; PLIF = posterior lumbar interbody fusion; RCT = randomized, controlled trial.
* One trial is active (Actifuse ABX Versus INFUSE in Posterolateral Instrumented Lumbar Fusion [PLIF] With Interbody Fusion [ClinicalTrials.gov: NCT01013389]); the other is completed, but results have not been found (Spine Fusion Instrumented With BMP-2 vs Uninstrumented With Infuse BMP-2 Alone [ClinicalTrials.gov: NCT00405600]).
† Includes 1 Medtronic RCT with 3 patients.
‡ Documents provided by Medtronic for unpublished studies.
Table 1. Effectiveness End Points for ALIF and PLF With rhBMP-2 Versus ICBG
Table 2. Adverse Events in Trials of ALIF and PLF With rhBMP-2 Versus ICBG
Cumulative proportion of patients with ≥1 AE for ALIF (top) and PLF (bottom).
AE = adverse event; ALIF = anterior lumbar interbody fusion; ICBG = iliac crest bone graft; PLF = posterolateral lumbar fusion; rhBMP-2 = recombinant human bone morphogenetic protein-2; SAE = serious adverse event.
* We found no significant difference between the rhBMP-2 and ICBG groups at any time point for either outcome or surgery approach.
Appendix Table 4. Cancer Occurrence at 24 and 48 mo in Trials
Comparison of cancer risk between rhBMP-2 and control.
The forest plot shows the comparison of cancer risk in 5 studies at 24 mo and 4 studies at 48 mo. BCP = biphasic calcium phosphate; rhBMP-2 = recombinant human bone morphogenetic protein-2.
* We obtained the combined risk ratio by using a generalized linear fixed-effects model with binomial distribution and log link without correction for zero events. For zero events, we estimated the risk ratio from each study by adding a continuity correction of 0.5 for illustrative purposes.
Table 3. Comparison of IPD Analysis With Published Data in Medtronic-Sponsored Studies of rhBMP-2
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Fu R, Selph S, McDonagh M, et al. Effectiveness and Harms of Recombinant Human Bone Morphogenetic Protein-2 in Spine Fusion: A Systematic Review and Meta-analysis. Ann Intern Med. 2013;158:890–902. doi: https://doi.org/10.7326/0003-4819-158-12-201306180-00006
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Published: Ann Intern Med. 2013;158(12):890-902.
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