170. Utilizing big data to determine the safety profile of recombinant human BMP-2 in spinal fusion surgery: an analysis of 5 databases from 2003 to 2017

Abstract

<h3>BACKGROUND CONTEXT</h3> The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion remains controversial. While rhBMP-2 safety concerns revealed misrepresentations in industry-sponsored research, previous observational studies reached conflicting conclusions regarding rhBMP-2 safety and effectiveness. rhBMP-2 is FDA approved for lumbar fusion with specific fusion devices. <h3>PURPOSE</h3> The purpose of the study was to investigate the complications associated with the use of rhBMP-2 for spinal fusion at a population-based level to determine its risk. <h3>STUDY DESIGN/SETTING</h3> The study design was a retrospective observational comparative cohort design comparing a target group to a comparator group for the risk of an outcome. <h3>PATIENT SAMPLE</h3> The patient sample comprised of two groups. Our target group consisted of first-time recipients of any spinal fusion procedure, of at least 18 years of age at the time of procedure, who received rhBMP-2 at the time of the procedure. Our comparator group consisted of first-time recipients of any spinal fusion procedure, who did not receive rhBMP-2. We restricted the study dates from 1/1/2003, when rhBMP-2 was introduced to the market, to 12/31/2017. <h3>OUTCOME MEASURES</h3> The outcome measures investigated included any reoperations requiring refusion and postoperative complications, which comprised of infection, seroma/hematoma, radiculitis, heterotopic ossification and cancer. The analysis of cancer included 18 subtypes of benign and malignant neoplasms. The observation period for these outcomes started after the date of surgery and concluded at the end of the study period. <h3>METHODS</h3> We utilized research tools developed in the Observational Health Data Sciences and Informatics (OHDSI) community (Hripcsak et al, 2015) to develop a common research protocol and data vocabulary encompassing the four claims databases and one electronic records database. The four insurance claims databases were IBM MarketScan Commercial Claims and Encounters (US employer-based private payer; patient aged 65 years or older), Optum ClinFormatics (US private payer; primarily aged 65 years or younger), IBM MarketScan Medicare Supplemental Beneficiaries (US retirees; patients aged > 65 years), IBM MarketScan Multi-state Medicaid (US Medicaid enrollees; all ages). The electronic health record database is Optum Pan-Therapeutic (US health systems; all ages). We then implemented a suite of methods and analyses to address confounding and bias inherent to observation studies, including propensity scoring and estimation of hazard ratios using a stratified Cox proportional hazard model. We combined the estimates from the data sources into a summary HR using a random effects model meta-analysis. To control for unmeasured confounding, we employed negative and positive controls to quantify the systemic bias in the system and compute adjusted HR estimates and confidence intervals. <h3>RESULTS</h3> Across all five databases, 60,427 patients were identified in the target group and 349,771 patients were identified in the comparator group, totaling 161,213 and 923,822 years of patient observation, respectively. rhBMP-2 was associated with statistically significantly fewer postoperative infections, with a hazard ratio of 0.88 (95% CI: 0.78-0.99). No significant difference was seen with the other outcomes, including reoperations for refusion, seroma/hematoma, radiculitis, heterotopic ossification, and development of benign or malignant neoplasms. Substantial control of measured confounding was demonstrated by propensity score adjustment, and negative and positive controls revealed noticeable residual bias that was controlled for through confidence interval calibration. <h3>CONCLUSIONS</h3> In the largest longitudinal observational study to date, rhBMP-2 was determined to be safe and effective as compared to non-rhBMP-2 usage in spinal fusion, with lower rate of postoperative infections. Importantly, no increased rates of cancer were detected. Coding error and the retrospective design may be an important source of bias. Despite these limitations, the large population size and statistical design give considerable significance to the results and conclusions of this study. <h3>FDA DEVICE/DRUG STATUS</h3> Medtronic Infuse (Approved for this indication).