Mark C. Simmonds, PhD, MA; Jennifer V.E. Brown, MSc, BA; Morag K. Heirs, MSc, MA; Julian P.T. Higgins, PhD, BA; Richard J. Mannion, PhD; Mark A. Rodgers, MSc, BSc; Lesley A. Stewart, PhD, MSc, BSc
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 Supplement 2).
Disclaimer: This study used data obtained from the YODA Project that included 17 clinical trials of rhBMP-2 funded by Medtronic. The analysis, interpretation, and reporting of these data were completed independently on an unrestricted basis, are solely the responsibility of the authors, and do not necessarily represent the official views of the YODA Project.
Acknowledgment: The authors thank Leah Carreon for providing the IPD from the trial by Glassman and colleagues (18), Kath Wright for performing the literature search, and Charlotte Seneschall for assistance in extracting data for the safety evaluation.
Grant Support: By a competitive grant from the YODA Project.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-2603.
Reproducible Research Statement: Study protocol: Available in Supplement 1. Statistical code: Not available because of large voulme. Data set: Available from the YODA Project (http://medicine.yale.edu/core/projects/yodap/index.aspx).
Requests for Single Reprints: Lesley A. Stewart, PhD, MSc, BSc, Centre for Reviews and Dissemination, University of York, York YO10 5DD, United Kingdom.
Current Author Addresses: Drs. Simmonds, Higgins, and Stewart; Ms. Brown; Ms. Heirs; and Mr. Rodgers: Centre for Reviews and Dissemination, University of York, York YO10 5DD, United Kingdom.
Dr. Mannion: Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, United Kingdom.
Author Contributions: Conception and design: M.C. Simmonds, J.P.T. Higgins, R.J. Mannion, M.A. Rodgers, L.A. Stewart.
Analysis and interpretation of the data: M.C. Simmonds, M.K. Heirs, J.P.T. Higgins, R.J. Mannion, M.A. Rodgers, L.A. Stewart.
Drafting of the article: M.C. Simmonds, J.V.E. Brown, M.K. Heirs, R.J. Mannion, M.A. Rodgers, L.A. Stewart.
Critical revision of the article for important intellectual content: M.C. Simmonds, M.K. Heirs, J.P.T. Higgins, R.J. Mannion, M.A. Rodgers, L.A. Stewart.
Final approval of the article: M.C. Simmonds, J.V.E. Brown, J.P.T. Higgins, R.J. Mannion, M.A. Rodgers, L.A. Stewart.
Statistical expertise: M.C. Simmonds, J.P.T. Higgins, L.A. Stewart.
Obtaining of funding: J.P.T. Higgins, R.J. Mannion, L.A. Stewart.
Administrative, technical, or logistic support: R.J. Mannion, M.A. Rodgers.
Collection and assembly of data: M.C. Simmonds, J.V.E. Brown, M.K. Heirs, M.A. Rodgers.
Recombinant human bone morphogenetic protein-2 (rhBMP-2) is widely used to promote fusion in spinal surgery, but its safety has been questioned.
To evaluate the effectiveness and safety of rhBMP-2.
Individual-participant data obtained from the sponsor or investigators and data extracted from study publications identified by systematic bibliographic searches through June 2012.
Randomized, controlled trials of rhBMP-2 versus iliac crest bone graft (ICBG) in spinal fusion surgery for degenerative disc disease and related conditions and observational studies in similar populations for investigation of adverse events.
Individual-participant data from 11 eligible of 17 provided trials sponsored by Medtronic (Minneapolis, Minnesota) (n = 1302) and 1 of 2 other eligible trials (n = 106) were included. Additional aggregate adverse event data were extracted from 35 published observational studies.
Primary outcomes were pain (assessed with the Oswestry Disability Index [ODI] or Short Form-36), fusion, and adverse events. At 24 months, ODI scores were 3.5% lower (better) with rhBMP-2 than with ICBG (95% CI, 0.5% to 6.5%) and radiographic fusion was 12% higher (CI, 2% to 23%). At or shortly after surgery, pain was more common with rhBMP-2 (odds ratio, 1.78 [CI, 1.06 to 2.95]). Cancer was more common after rhBMP-2 (relative risk, 1.98 [CI, 0.86 to 4.54]), but the small number of events precluded definite conclusions.
The observational studies were diverse and at risk of bias.
At 24 months, rhBMP-2 increases fusion rates, reduces pain by a clinically insignificant amount, and increases early postsurgical pain compared with ICBG. Evidence of increased cancer incidence is inconclusive.
Yale University Open Data Access Project.
Summary of evidence search and selection.
ICBG = iliac crest bone graft; IPD = individual-patient data; RCT = randomized, controlled trial.
* One additional RCT (19) was eligible, but IPD were not provided.
Table 1. Summary of Trials That Provided Individual-Participant Data Used in the Analyses
Appendix Table 1. Details of Publications of Medtronic Trials
Appendix Table 2. Missing Outcome Data in Medtronic Trials
Meta-analyses of pain outcomes at 6 wk and 3, 6, 12, and 24 mo after surgery.
Points on the plot represent mean differences in changes in scores (from preoperative values) at each time point, and vertical lines show the 95% CIs. For the first 3 outcomes, points below the dotted line indicate a benefit of rhBMP-2; for the SF-36 PCS score, points above the line indicate a benefit of rhBMP-2. ICBG = iliac crest bone graft; PCS = Physical Component Summary; rhBMP-2 = recombinant human bone morphogenetic protein-2; SF-36 = Short Form-36.
Reduction in pain scores from preoperative results, by treatment received.
ICBG = iliac crest bone graft; PCS = Physical Component Summary; rhBMP-2 = recombinant human bone morphogenetic protein-2; SF-36 = Short Form-36.
Results of 1-stage meta-analyses of pain and function outcomes at 6 wk and 3, 6, 12, and 24 mo after surgery.
Forest plot of RR for successful fusion 24 mo after surgery.
ALIF = anterior lumbar interbody fusion; BCP = biphasic calcium phosphate; ICBG = iliac crest bone graft; PLIF = posterior lumbar interbody fusion; rhBMP-2 = recombinant human bone morphogenetic protein-2; RR = relative risk.
Subgroup analyses for Oswestry Disability Index (top) and successful fusion (bottom), by surgical approach.
ALIF = anterior lumbar interbody fusion; BCP = biphasic calcium phosphate; ICBG = iliac crest bone graft; MD = mean difference; PLIF = posterior lumbar interbody fusion; rhBMP-2 = recombinant human bone morphogenetic protein-2; RR = relative risk.
MD in operating time (minutes) between rhBMP-2 and ICBG in the Medtronic trials.
Details on the Medtronic trials are available in Appendix Table 1. ALIF = anterior lumbar interbody fusion; BCP = biphasic calcium phosphate; ICBG = iliac crest bone graft; MD = mean difference; PLIF = posterior lumbar interbody fusion; rhBMP-2 = recombinant human bone morphogenetic protein-2.
Meta-analysis of use of 4 types of pain medication in Medtronic trials.
ICBG = iliac crest bone graft; rhBMP-2 = recombinant human bone morphogenetic protein-2.
Relationship between relative risk for fusion and mean difference in pain outcomes across trials 24 mo after surgery.
PCS = Physical Component Summary; SF-36 = Short Form-36.
Meta-analysis of adverse events at or shortly after surgery in 11 Medtronic trials.
Details on the Medtronic trials are available in Appendix Table 1. ICBG = iliac crest bone graft; OR = odds ratio; rhBMP-2 = recombinant human bone morphogenetic protein-2.
Meta-analysis of all adverse events in 11 Medtronic trials.
Meta-analyses of adverse events.
Table 2. Incidence of Cancer in the Medtronic Trials
Forest plot of cancer incidence in the Medtronic trials.
The number of cancer cases is the total number occurring during the 2-y follow-up. Details on the Medtronic trials are available in Appendix Table 1. BCP = biphasic calcium phosphate; ICBG = iliac crest bone graft; rhBMP-2 = recombinant human bone morphogenetic protein-2; RR = relative risk.
Appendix Table 3. Details of Published Studies Reporting on the Safety of rhBMP-2 Surgery
Heterotopic bone formation, radiculitis, and dysphagia in nonrandomized studies of rhBMP-2.
ACDF = anterior cervical discectomy and fusion; ICBG = iliac crest bone graft; CSA = cervical spinal arthrodesis; LIF = lumbar interbody fusion; PCF = posterior cervical fusion; PLF = posterolateral lumbar fusion; PLIF = posterior lumbar interbody fusion; rhBMP-2 = recombinant human bone morphogenetic protein-2; RR = relative risk; SCP = silicated calcium phosphate; TLIF = transforaminal lumbar interbody fusion.
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Anthony H. Woodward, MD
July 24, 2013
TO THE EDITOR: The meta-analysis and the systematic review about rhBMP-2 (1-2) both published in the June18 issue are very interesting and contain an immense amount of information. They were greeted with exuberant commentary in the Annals and elsewhere. They were reported in national and regional newspapers.
But what new information do they offer? Simmonds et al independently reanalyzed the individual-participant data (IPD) provided by Medtronic, or said they did. For adverse events, Simmonds et al state (page 878), a "full clinical assessment of these narratives (i.e., "the clinical study reports") was beyond the scope of this project". One trial was checked, but it seems for the rest, "Medtronic classifications" were accepted. For their meta-analysis of 11 Medtronic trials, however, Simmonds et al did use "the supplied IPD rather than data reported in" the previously published reports of these trials. They also used "the Medtronic definitions of fusion" despite concerns about their possibly excessive stringency (page 885). Yu et al had "patient-level data" from Medtronic via the YODA Project but not (personal communication) the actual patient charts. The data still came from Medtronic.
Even after this laborious reanalysis, Fu et al found that for its only approved spinal use - anterior lumbar interbody fusion - rhBMP-2 provided slightly better fusion rates and greater overall success than using iliac crest bone graft, although the differences did not reach statistical significance. Simmonds et al found "clear evidence that rhBMP-2 improves rates of fusion" although the eventual improvement in back pain and quality of life was below "previously described, clinically meaningfully thresholds". Hardly an outright condemnation of rhBMP-2.
Both groups found increased adverse effects from rhPMP-2. But Simmonds et al reported that the results of their analysis of the RCTs "were generally inconclusive" (page 883). From their literature review, Simmonds et al concluded that rhBMP-2 recipients were more likely to have heterotopic bone, leg pain and radiculitis, osteolysis, and retrograde ejaculation. The only report of significant increase in heterotopic bone was a 2 page report (3) in a Supplement of minimally invasive transforaminal fusion which doesn't sound like the approved use. The increased incidence risk of radiculitis does not reach statistical significance according to Figure 6 in the report by Simmonds et al. A higher rate of retrograde ejaculation in fusion procedures using rhBMP-2 and an open anterior approach had already been reported (4).
Fu et al also found many adverse effects but their meta-analysis for anterior lumbar interbody fusion "showed no significant difference s between groups for any specific adverse event, including lumbar radiculitis" or retrograde ejaculation.
The risk of cancer was evaluated in both reviews. Fu et al found that the use of rhBMP-2 was associated with an increased risk for cancer through 24 months but "the strength of evidence was low due to sparse data". Simmonds et al also found cancer was more common among rhBMP-2 recipients. Only one study of the approved use of rhBMP-2 was found with a report of cancer and the RR was not significant. The highest risk of cancer was reported in the trial of AMPLIFY: this preparation of rhBMP-2 on a different carrier from INFUSE for posterior lumbar fusion did not gain FDA approval. Again, the association of cancer with rhBMP-2 had been reported previously (6).
As far as clinical information then, nothing new but greater detail, accuracy and reliability. But what caught media attention was the omission in the previously published studies of reports of adverse events and of cancer in the recipients of rhBMP-2.
It is all too true that several papers claimed there were no adverse events from the use of rhBMP-2, whereas the FDA reviews found many adverse events. Particularly disturbing is the absence of reports of cancer in the published studies of AMPLIFY when the FDA Panels identified an increased incidence of cancer in recipients of rhBMP-2. Again, these discrepancies had already been publicized. Fu et al confirm the marked underreporting of the adverse events which occurred in patients treated with either rhBMP-2 or iliac crest bone graft. But when all the information including that from the FDA and from Medtronic is analyzed, the incidence of adverse events is not much greater in the recipients of rhBMP-2.
The two reviews are accompanied by four editorials, including one cosigned by no less than 12 editors from the Annals, one from the Chief Medical Officer, Medtronic which can only be described as postmodern, and one from the director of the YODA Project who calls the publication of these reviews "a historic moment".
The North American Spine Society at www.spine.org produced two responses to these publications. The longer is attributed to Eugene Carragee, MD, Editor in Chief of The Spine Journal. Dr Carragee considers the report of the YODA Project to be "the latest and saddest shock to Medtronic’s" rhBMP-2 product, confirming "the findings of The Spine Journal’s editorial review of 2011", the lead author of which was Dr Carragee.
Dr Carragee rightly castigates the "Medtronic-associated" authors' misrepresentation of the efficacy of rhBMP-2 and underreporting of the complications of its use. He writes, As YODA project director Dr. Harlan Krumholz delicately puts it, “Evidence suggests that some data are not missing at random.” But that sentence is in a paragraph referring to clinical trials in general; Dr. Krumholz gives 2 references, neither refer to BMP. Dr Carragee adds, "The Annals editors are more blunt: “Early journal publications misrepresented the effectiveness and harms through selective reporting, duplicate publication, and underreporting.” Ouch." In the online copy of Annals I do not see that statement.
But neither review addresses the usual reason to use rhBMP-2 for lumbar fusion, which is to avoid the pain and possible complications of harvesting iliac crest bone graft. The reviewers' lists of adverse events do not seem to include specific adverse events from iliac crest harvesting. This omission is surprising; if the rates of clinical success and fusion after iliac crest bone graft or rhBMP-2 are similar, then it's advantage rhBMP-2 for its only approved use in anterior lumbar fusion if the adverse events from iliac crest bone graft harvesting are counted. Excluding that unexplained increase in cancers, of course.
He who pays the piper calls the tune: Medtronic paid - apparently directly and indirectly - the surgeons who praised rnBMP-2, YODA Project paid - indirectly - the reviewers who disparaged it. The irony is that it's all Medtronic's money. The pity is that Medtronic took the money from our healthcare insurance premiums and our contributions to Medicare.
Anthony H. Woodward, MD.
10737 SW Lancaster Rd, Portland, OR 97219
Potential Conflicts of Interest: None
1 Simmonds MC, Brown JV, Heirs MK, Higgins JP, Mannion RJ, Rodgers MA, et al. Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion. A meta-analysis of individual-participant data. Ann Intern Med. 2013; 158:877-89.
2 Fu R, Selph S, McDonagh M, Peterson K, Tiwari A, Chou R, 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.
3 Gray RJ, Rampersaud YR. Comparison of the incidence of radiculitis and radiographic adverse event following minimally invasive lumbar transforaminal interbody fusions (TLIF) with and without the use of bone morphogenetic protein (BMP). Spine J. 2010; 10:8S-9S.
4 Comer GC, Smith MW, Hurwitz EL, Mitsunaga KA, Kessler R, Carragee EJ. Retrograde ejaculation after anterior lumbar interbody fusion with and without bone morphogenetic protein-2 augmentation: a 10-year cohort controlled study. Spine J. 2012; 2:881-90.
5 Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. 2011; 11:471-91.
6 Devine JG, Dettori JR, France JC, Brodt E, McGuire RA. The use of rhBMP in spine surgery: is there a cancer risk? Evid Based Spine Care J. 2012; 3:35-41.
Simmonds MC, Brown JV, Heirs MK, Higgins JP, Mannion RJ, Rodgers MA, et al. Safety and Effectiveness of Recombinant Human Bone Morphogenetic Protein-2 for Spinal Fusion: A Meta-analysis of Individual-Participant Data. Ann Intern Med. 2013;158:877-889. doi: 10.7326/0003-4819-158-12-201306180-00005
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Published: Ann Intern Med. 2013;158(12):877-889.
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