74. Methylprednisolone in acute traumatic spinal cord injury: case-matched outcomes from the NASCIS2 and SYGEN historical SCI studies with contemporary statistical analysis

BACKGROUND CONTEXT Methylprednisolone (MP) to treat acute traumatic spinal cord injury (SCI) remains controversial since the release of NASCIS2 in 1990. International guidelines and recommendations remain ambiguous; a more accurate analysis is required to address this critical knowledge gap. PURPOSE As NASCIS2 and SYGEN used identical MP dosage, it was possible to construct a new case-level pooled SCI dataset satisfying contemporary criteria and incorporating ASIA assessments (not performed in the original NASCIS2 study). This allows a more robust analysis of the effect of MP for SCI than compared to the original NASCIS2 alone. STUDY DESIGN/SETTING Contemporary analysis of case-level match data from two historical SCI studies; NASCIS II and SYGEN. PATIENT SAMPLE Patients enrolled in both studies with SCI injury levels caudal to T10 were excluded, together with lower extremity motor scores (LEMS) > 46, Glasgow Coma Scale (GCS) ≤ 11, and age 75 years, and then standardized to the American Spinal Injuries Association (ASIA) grading and scoring format including only patients with ASIA A/B/C injuries (D/E excluded). OUTCOME MEASURES The change in LEMS, total motor score and ASIA grade from baseline to 26 weeks were compared for patients who were administered MP compared to patients who were administered placebo/Naloxone. METHODS Original source data from both studies was assimilated at a case-level to create a universal database of 1,074 patients. Change in LEMs, total motor score and ASIA grade were compared in patients administered placebo in the NASCIS2 study (n=113) with those receiving MP (n=431) from the NASCIS2 and SYGEN studies. RESULTS The combined dataset from both studies increased the MP group from 106 to 431 patients. Recovery of LEMS from baseline to 26 weeks were separated statistically into five different injury severity cohorts (p< 0.0001). These cohorts contained groups with severe floor (62.9%) and ceiling (10.7%) effects which could not be attributed to any drug effect. The NASCIS2 dataset duplicated the positive effect for MP vs placebo in the < 8 hour subgroup when recovery of motor function on only the right-side of body was measured (the methodology reported in the original NASCIS2 study). However, when total motor score is calculated administration of MP did not enhance ASIA motor score improvement in the lower extremities at 26 weeks regardless of initial ASIA grade severity. Analysis of descending ASIA motor and sensory neurologic levels in cervical ATSCI patients at 26 weeks also found no MP drug effect. CONCLUSIONS In the most comprehensive analysis of the original NASCIS2 data ever performed (with the addition of case-matched patients from the SYGEN study), no evidence exists of an improvement in neurological recovery at 26 weeks when MP is administered compared to placebo. The results inform clinical decision making related to MP use in traumatic SCI and to serve as a potential framework for future clinical trial design in SCI. FDA Device/Drug Status This abstract does not discuss or include any applicable devices or drugs. Methylprednisolone (MP) to treat acute traumatic spinal cord injury (SCI) remains controversial since the release of NASCIS2 in 1990. International guidelines and recommendations remain ambiguous; a more accurate analysis is required to address this critical knowledge gap. As NASCIS2 and SYGEN used identical MP dosage, it was possible to construct a new case-level pooled SCI dataset satisfying contemporary criteria and incorporating ASIA assessments (not performed in the original NASCIS2 study). This allows a more robust analysis of the effect of MP for SCI than compared to the original NASCIS2 alone. Contemporary analysis of case-level match data from two historical SCI studies; NASCIS II and SYGEN. Patients enrolled in both studies with SCI injury levels caudal to T10 were excluded, together with lower extremity motor scores (LEMS) > 46, Glasgow Coma Scale (GCS) ≤ 11, and age 75 years, and then standardized to the American Spinal Injuries Association (ASIA) grading and scoring format including only patients with ASIA A/B/C injuries (D/E excluded). The change in LEMS, total motor score and ASIA grade from baseline to 26 weeks were compared for patients who were administered MP compared to patients who were administered placebo/Naloxone. Original source data from both studies was assimilated at a case-level to create a universal database of 1,074 patients. Change in LEMs, total motor score and ASIA grade were compared in patients administered placebo in the NASCIS2 study (n=113) with those receiving MP (n=431) from the NASCIS2 and SYGEN studies. The combined dataset from both studies increased the MP group from 106 to 431 patients. Recovery of LEMS from baseline to 26 weeks were separated statistically into five different injury severity cohorts (p< 0.0001). These cohorts contained groups with severe floor (62.9%) and ceiling (10.7%) effects which could not be attributed to any drug effect. The NASCIS2 dataset duplicated the positive effect for MP vs placebo in the < 8 hour subgroup when recovery of motor function on only the right-side of body was measured (the methodology reported in the original NASCIS2 study). However, when total motor score is calculated administration of MP did not enhance ASIA motor score improvement in the lower extremities at 26 weeks regardless of initial ASIA grade severity. Analysis of descending ASIA motor and sensory neurologic levels in cervical ATSCI patients at 26 weeks also found no MP drug effect. In the most comprehensive analysis of the original NASCIS2 data ever performed (with the addition of case-matched patients from the SYGEN study), no evidence exists of an improvement in neurological recovery at 26 weeks when MP is administered compared to placebo. The results inform clinical decision making related to MP use in traumatic SCI and to serve as a potential framework for future clinical trial design in SCI.