Abstract
Dear Editor,
In the recently published article by Evaniew and associates, 1 the authors report a retrospective “Propensity Score-Matched Cohort” analysis of the neurological outcomes related to the use of the “NASCIS II” 24 h high dose methylprednisolone (MP) regimen in acute spinal cord injury (SCI) patients between 2004 and 2014 at 18 of the 31 participating Canadian sites involved in the Rick Hansen Spinal Cord Injury Registry (RHSCIR). The outcomes of 44 patients treated with the NASCIS II MP protocol initiated within 8 h were compared with those of a group of 44 who did not receive MP treatment. The non-MP patients were selected from a total group of 1555 SCI persons who did not receive the NASCIS II MP protocol.
The results obtained from this paired analysis showed no significant differences between the Total Motor Score, Upper Extremity Motor Score, or Lower Extremity Motor Score in patients who received high dose MP versus those who did not. The high dose MP group, however, did show a significant increase in the incidence of total complications, but not in regard to any of the individual complications. The authors stated the following conclusion regarding the acute treatment of SCI with high dose MP: “These findings support guideline recommendations against its routine administration, and validate trends toward decreasing utilization.”
Five comments:
1. It cannot be ignored that this article and the analysis it reports concerning the use of the 24 h NASCIS II high dose MP dosing regimen during the first 8 h after SCI has several serious problems. The first problem involves an intrinsic irony. The authors claim in the first paragraph of their Methods section that “This article's primary objective (establishing whether the NASCIS II MP regimen begun within the first 8 h post-injury is efficacious in improving recovery after acute SCI) was specified a priori during the development of RHSCIR, along with several other research objectives.”
Specifically, the irony is that in contrast to this stated objective dating back to the beginning of RHSCIR in 2004, repeated efforts have been vigorously lead by one of the co-authors of the present study, Dr. R.J. Hurlbert (refs. 16, 17, 21, 23, 49, 50, 53, and 54 in Evaniew et al), over the last 15 years to remove the NASCIS II methylprednisolone protocol as a treatment option from SCI treatment guidelines. This effort has clearly undermined the achievement of one of the original key objectives of the RHSCIR—to determine whether high dose MP has any therapeutic value in acute SCI. Indeed, evidence of the effectiveness of Dr. Hurlbert's anti-MP efforts is apparent in the fact that of the total of 1601 RHSCIR registry patients used in the current analysis, only 46 (2.9%) were found to have received the NASCIS II MP treatment protocol, begun within the first 8 h after SCI.
The tiny percentage of patients with SCI treated at the participating Canadian centers involved in the RHSCIR clearly indicates that the use of the NASCIS II protocol in Canadian centers fell into widespread disfavor years ago, even though during the 10 year duration of RHSCIR patients accrual, the use of MP was stated in SCI treatment guidelines as an acute SCI treatment option. Indeed, as stated in the Introduction, during the 10 year existence of the RHSCIR, the use of NASCIS II MP has decreased from only 20 patients between 2004 and 2006, 25 patients from 2007 to 2010, to only 1 patient from 2011 through March 2014.
Moreover, the authors reveal that 25 of the 46 patients received the 24 h NASCIS II MP treatment at non-RHSCIR community hospitals before their transfer to an RHSCIR acute RHSCIR site. As shown in Table 1 of Evaniew et al, this resulted in those patients having a significantly longer time from injury to their first ISNCSCI examination (72 h vs. 56 h for the non-MP patients, p < 0.01). These facts seriously undermine the assertion that determining the efficacy and safety of high dose MP was a serious objective of the RHSCIR.
2. A second problem in the current analysis is the statement in the Introduction that only 7 of the 18 acute care RHSCIR sites ever enrolled at least 1 patient with SCI who was treated with the NASCIS II high dose MP protocol. Because this means that 11 centers never used MP in any of their patients with SCI, then where were the “propensity score-matched” non-MP treated patients drawn from? Certainly, it would have been appropriate to match non-MP treated subjects from the seven centers that had used MP with an equal number of matched patients from each of those same centers.
In designing a prospective multicenter randomized treatment trial, clearly it would be expected that the investigators would enroll approximately the same number of untreated and treated subjects only from those centers that treated some SCI patients with MP compared to an equal number who were not treated with MP. Even though this was a retrospective analysis rather than a randomized prospective trial, balancing the untreated and MP-treated from only the seven centers that used MP at least in one of their patients would have controlled for subtle, but possibly significant acute SCI management differences between centers.
3. Most unfortunate is the fact that the authors did not indicate the specific times of treatment initiation. They only state that: “Administration of the NASCIS II bolus and infusion of methylprednisolone was confirmed to begin within eight hours of patient's injuries, as per this protocol.” Interestingly, the authors do make note of the fact that the NASCIS III trial showed that initiation of the 24 h MP regimen in the first 3 h after injury resulted in better recovery than if the dosing regimen was not started until between 3 and 8 h post-SCI. 2,3
Considering the increasingly negative climate regarding MP use in Canadian SCI treatment centers during the time frame of the RHSCIR, it is logical to be concerned that if those centers who still used the 24 hour NASCIS II MP protocol in at least some of their patients with acute SCI, they would have viewed it as a last resort, possibly initiating MP administration near the expiration of the 8 h window. If that is true, then the MP protocol was not given an optimum chance to exert a neuroprotective effect in the 44 patients who received it. Remarkably, Evaniew and colleagues does not provide any data on the average treatment initiation time to dispute this possibility.
4. In their Relation to Previous Literature section, the authors fail to mention that in those patients treated within the first 8 h after SCI in the NASCIS II trial, 4 there was a significant increase at 6 months in both the sensory and motor scores in MP treated patients. Because the current RHSCIR analysis emphasizes treatment within the first 8 h after SCI, it would have been more appropriate to reference the 8 h analysis in the NASCIS II publication rather than what the present authors refer to as the primary analysis in which patients treated in the NASCIS II trial before and after 8 hr, lumped together, failed to show an improvement in the 6 month motor score.
In other words, an oft-repeated criticism of the NASCIS II trial is that it failed to meet the primary end-point of improved neurological recovery in all of the MP treated patients who received MP treatment initiation within 14 h after SCI. Accordingly, Hurlbert has long maintained that splitting the NASCIS II outcome data into patients treated within the first 8 h versus those treated after 8 h was purely a post hoc analysis. 5,6
The NASCIS principal investigator, Dr. Michael Bracken, has stated, however, that the decision to split the NASCIS II MP outcome data into an early treatment (
5. Also in their Relation to Previous Literature section, the authors predictably use the results of this analysis to bolster the repetitive efforts by Hurlbert and colleagues 5,6 to support their contention that the NASCIS II results are inaccurate. Specifically, they contend that high dose MP, because of the potential for glucocorticoid receptor-mediated immunosuppressive side effects, is too dangerous to be used in patients with SCI. Ironically, their Table 5 showed that these specific expected side effects of 24 h high dose MP (e.g., urinary tract infections, pneumonia, surgical site infection, or sepsis) were not significantly more common in MP treated RHSCIR patients. Statistically, they were not even close (p values ranged from 0.27 to 0.61).
Accordingly, their data actually confirms the NASCIS II data showing that confining the MP protocol to 24 h is not associated with an increase in glucocorticoid side effects. 4 Only when the present authors totaled up the cumulative number of complications were the authors able to achieve statistical significance favoring nonuse of high dose MP. This result greatly undermines the assertion that the steroid side effect risk to neurological benefit ratio is too high to warrant the routine use of MP in acute SCI treatment.
In closing, there are multiple problems that are clearly seen in the current analysis of the outcomes of RHSCIR database SCI patients treated with the NASCIS II 24 h high dose MP. Moreover, it continues to be remarkable to this writer that many SCI treating clinicians will probably put more faith in this type of unbalanced retrospective analysis instead of the results of the NASCIS II and III multicenter randomized, placebo-controlled trials that first demonstrated the efficacy and surprising safety profile of 24 h high dose MP, considering that glucocorticoid's potential immunosuppression-related side effects. SCI, which is typically devastating to patients and their families, remains a major unmet medical need for which no acute pharmacological neuroprotective treatment other than high dose MP is available.
This writer freely admits to some potential bias regarding the use of MP in acute SCI because he was one of the main pre-clinical investigators involved the discovery of the efficacy of high dose MP in animal models of acute SCI that lead to the NASCIS II and III trials. 9 In addition, however, he was among the first to detail the limitations of high dose MP that caused him to leave academia for a 20 year career in the pharmaceutical industry during which he was involved in the discovery of the nonglucocorticoid steroid tirilazad, 10 which was included in the NASCIS III trials and shown to produce statistically the same degree of functional improvement as either 24 or 48 h high dose MP, but without glucocorticoid side effects that occurred with MP when its administration was extended to 48 h. 2,3 Unfortunately, additional trials with tirilazad in acute SCI were never conducted.
Thus, there remains an urgent need to discover more effective and safer neuroprotective drugs for acute SCI. Until that occurs, however, 24 h high dose MP remains the only available treatment for patients with acute SCI that possesses phase III clinical trial evidence to support its efficacy and overall safety when initiated during the first 8 h after SCI, 4 and preferably within the first 3 h, 2 remains the only available hope for modifying the early pathophysiology of acute SCI and potentially improving outcomes of patients with SCI. In that regard, readers are urged to review the 2014 publication by Dr. Michael Fehlings (U. Toronto), arguably the leading contemporary authority on SCI clinical trials as well as a co-author of Evaniew and coworkers because he contributed patients to the RHSCIR, and who provides a more accurate analysis of the efficacy and safety of high dose MP in acute SCI. 11