Jeanne Lenzer wrote in “Why we can’t trust clinical guidelines” [1] that “one expert estimated that more patients had been killed by the treatment in the past decade than died in the 9/11 World Trade Center attacks.” The treatment was methylprednisolone (MP) and the expert was neurosurgeon Fred Geisler who assumed that 10,000 people with spinal cord injury (SCI) received high-dose MP each year for 22 years, that half of them had multiple injuries that predisposed them to MP-induced complications, and that these people had a 3.4% increased risk of death extrapolated from the MRC CRASH trial [2] of 48-hour MP treatment of traumatic brain injury (TBI). Geisler estimated that 3740 spinal-injured people died from MP usage, which he points out is more than the 2996 people who died in the 9/11/01 terrorist attacks of New York and Washington DC. I write to question the claim of higher mortality due to MP treatment of SCI and the suggestion that MP has killed more people with SCI than the number of people who died in the 9/11/01 attack on New York for the following reasons.
• First, Geisler applied the overall 3.4% mortality increase from the CRASH study to acute SCI. As pointed out by Michael Bracken, mild TBI from the MRC CRASH study [2] is the category that is comparable with acute SCI. Severe TBI is associated with much higher mortality rates than SCI. In CRASH, the overall mortality rate in the control group was 22.3% (1075/4819) compared to 25.7% (1248/4854) in MP-treated group. The 6-month mortality rates of subjects with mild head injury in CRASH were 6.3% (89/1420) vs. 5.8% (86/1483) respectively for 48-hour MP-treated and control subjects, close to 5-7% mortality rates for placebo and MP-treated SCI observed in the NASCIS trials [3, 4]. If Geisler had used data from mild TBI from CRASH, the increased mortality risk would be a more reasonable 0.5% (i.e. 6.3%-5.8%) rather than 3.4% (i.e. 22.3%-25.7%).
• Second, Geisler assumed that 100% of 10,000 acute SCI patients per year for 22 years (1991-2013) received the MP treatment used in the CRASH trial. This is not possible. The CRASH trial used a 48-hour high-dose MP that NASCIS 3 recommended in 1997 only for patients treated between 3-8 hours after injury. The 24-hour course of MP is supposed to be given only if the therapy could be started within 3 hours. High-dose MP was not recommended for people with gunshot wounds or multiple traumas, both conditions excluded by NASCIS 2 and 3. High-dose MP was used in less than 60% of acute SCI patients. After 2007, use of high-dose MP fell to less than 40% of acute SCI in the U.S. Thus, probably less than 20% of people with acute SCI received the 48-hour course of MP between 1997 and 2013.
• Third, Lenzer stated that Geisler’s estimate is for the “the past decade” but Geisler said that his calculations were for 22 years. If only the past decade were considered, even using the erroneous assumptions that 10,000 people/year with SCI received the 48-hour course of MP and that 50% of these people were subject to the 3.4% mortality risk observed in CRASH, the number of people affected would be 1,700. Using more realistic assumptions that 20% of 10,000 people with new SCI received the 48-hour MP therapy each year between 1997 and 2013 and MP treatment killed 0.5% of them, this adds up to 160 people, a far cry from 3740 that Geisler estimated.
• Finally, there is no credible evidence that a 24-hour or 48-hour course of high-dose MP increases mortality in SCI [5]. NASCIS 2 [4] showed no significant difference amongst placebo-treated (12/171 or 7.0%), 24-hour MP-treated (7/166 or 4.2%), and naloxone-treated subjects (10/154 or 6.5%). NASCIS 3 likewise revealed no significant differences amongst 24-hour MP-treated patients (9/166, 5.4%), 48-hour tirilazad mesylate-treated patients (12/167, 7.2%), and 48-hour MP-treated patients (10/166, 6.0%). Several other studies [6-8] also found no significant differences of mortality rates between untreated and MP-treated patients in acute SCI. Chikuda, et al. [9] recently reviewed 3508 patients who had cervical SCI in Japan, 824 of whom received high-dose MP (>5000 mg). MP-treated patients had higher risks of gastrointestinal bleeding (8.6%) than unmatched controls (3.1%, p<0.001) or propensity matched controls (3.8%, p<0.001). However, in-hospital mortality rates of MP-treated patients (2.8%) did not differ significantly from mortality rates of unmatched controls (3.4%, p=0.485) or a propensity-matched control group (3.1%, p=0.884).
So, let us stop indulging in speculative estimates and focus on evidence instead. Given the controversy regarding the efficacy of MP and the dearth of alternative therapies for acute SCI, a randomized placebo-controlled clinical trial of MP for acute spinal cord injury would meet clinical equipoise and should help settle this issue.
References Cited
1. Lenzer, J., Why we can't trust clinical guidelines. BMJ, 2013. 346: p. f3830.
2. Edwards, P., et al., Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet, 2005. 365(9475): p. 1957-9.
3. Bracken, M.B., et al., Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. Jama, 1997. 277(20): p. 1597-604.
4. Bracken, M.B., et al., A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med, 1990. 322(20): p. 1405-11.
5. Bracken, M.B., Steroids for acute spinal cord injury. Cochrane database of systematic reviews, 2012. 1: p. CD001046.
6. Tsutsumi, S., et al., Effects of the Second National Acute Spinal Cord Injury Study of high-dose methylprednisolone therapy on acute cervical spinal cord injury-results in spinal injuries center. Spine, 2006. 31(26): p. 2992-6; discussion 2997.
7. Suberviola, B., et al., Early complications of high-dose methylprednisolone in acute spinal cord injury patients. Injury, 2008. 39(7): p. 748-52.
8. Ito, Y., et al., Does high dose methylprednisolone sodium succinate really improve neurological status in patient with acute cervical cord injury?: a prospective study about neurological recovery and early complications. Spine (Phila Pa 1976), 2009. 34(20): p. 2121-4.
9. Chikuda, H., et al., Mortality and morbidity after high-dose methylprednisolone treatment in patients with acute cervical spinal cord injury: a propensity-matched analysis using a nationwide administrative database. Emerg Med J, 2013. [10.1136/emermed-2012-202058]
Competing interests:
Dr. Young was an investigator in both NASCIS 2 and 3 trials and an author of publications from these two trials. He has received travel support and honoraria from Upjohn, Pharmacia, and Pfizer to speak at conferences. He runs ChinaSCINet, a clinical trial network that tests therapies for SCI. He serves as a voluntary (unpaid) global medical director for Stemcyte, helping organize their research and clinical trials. Stemcyte donates umbilical cord blood to ChinaSCINet. Dr. Young helped found Acorda Therapeutics in 1995 and served on its Board of Directors from 1995-2012. He founded the Journal of Neurotrauma and served as its Editor in Chief from 1984 to 1991.
24 August 2013
Wise Young
Richard H. Shindell Chair in Neuroscience
Rutgers University
W. M. Keck Center for Collaborative Neuroscience, 604 Allison Road, Piscataway, NJ 08854-8082 USA
Rapid Response:
Re: Why we can’t trust clinical guidelines
Jeanne Lenzer wrote in “Why we can’t trust clinical guidelines” [1] that “one expert estimated that more patients had been killed by the treatment in the past decade than died in the 9/11 World Trade Center attacks.” The treatment was methylprednisolone (MP) and the expert was neurosurgeon Fred Geisler who assumed that 10,000 people with spinal cord injury (SCI) received high-dose MP each year for 22 years, that half of them had multiple injuries that predisposed them to MP-induced complications, and that these people had a 3.4% increased risk of death extrapolated from the MRC CRASH trial [2] of 48-hour MP treatment of traumatic brain injury (TBI). Geisler estimated that 3740 spinal-injured people died from MP usage, which he points out is more than the 2996 people who died in the 9/11/01 terrorist attacks of New York and Washington DC. I write to question the claim of higher mortality due to MP treatment of SCI and the suggestion that MP has killed more people with SCI than the number of people who died in the 9/11/01 attack on New York for the following reasons.
• First, Geisler applied the overall 3.4% mortality increase from the CRASH study to acute SCI. As pointed out by Michael Bracken, mild TBI from the MRC CRASH study [2] is the category that is comparable with acute SCI. Severe TBI is associated with much higher mortality rates than SCI. In CRASH, the overall mortality rate in the control group was 22.3% (1075/4819) compared to 25.7% (1248/4854) in MP-treated group. The 6-month mortality rates of subjects with mild head injury in CRASH were 6.3% (89/1420) vs. 5.8% (86/1483) respectively for 48-hour MP-treated and control subjects, close to 5-7% mortality rates for placebo and MP-treated SCI observed in the NASCIS trials [3, 4]. If Geisler had used data from mild TBI from CRASH, the increased mortality risk would be a more reasonable 0.5% (i.e. 6.3%-5.8%) rather than 3.4% (i.e. 22.3%-25.7%).
• Second, Geisler assumed that 100% of 10,000 acute SCI patients per year for 22 years (1991-2013) received the MP treatment used in the CRASH trial. This is not possible. The CRASH trial used a 48-hour high-dose MP that NASCIS 3 recommended in 1997 only for patients treated between 3-8 hours after injury. The 24-hour course of MP is supposed to be given only if the therapy could be started within 3 hours. High-dose MP was not recommended for people with gunshot wounds or multiple traumas, both conditions excluded by NASCIS 2 and 3. High-dose MP was used in less than 60% of acute SCI patients. After 2007, use of high-dose MP fell to less than 40% of acute SCI in the U.S. Thus, probably less than 20% of people with acute SCI received the 48-hour course of MP between 1997 and 2013.
• Third, Lenzer stated that Geisler’s estimate is for the “the past decade” but Geisler said that his calculations were for 22 years. If only the past decade were considered, even using the erroneous assumptions that 10,000 people/year with SCI received the 48-hour course of MP and that 50% of these people were subject to the 3.4% mortality risk observed in CRASH, the number of people affected would be 1,700. Using more realistic assumptions that 20% of 10,000 people with new SCI received the 48-hour MP therapy each year between 1997 and 2013 and MP treatment killed 0.5% of them, this adds up to 160 people, a far cry from 3740 that Geisler estimated.
• Finally, there is no credible evidence that a 24-hour or 48-hour course of high-dose MP increases mortality in SCI [5]. NASCIS 2 [4] showed no significant difference amongst placebo-treated (12/171 or 7.0%), 24-hour MP-treated (7/166 or 4.2%), and naloxone-treated subjects (10/154 or 6.5%). NASCIS 3 likewise revealed no significant differences amongst 24-hour MP-treated patients (9/166, 5.4%), 48-hour tirilazad mesylate-treated patients (12/167, 7.2%), and 48-hour MP-treated patients (10/166, 6.0%). Several other studies [6-8] also found no significant differences of mortality rates between untreated and MP-treated patients in acute SCI. Chikuda, et al. [9] recently reviewed 3508 patients who had cervical SCI in Japan, 824 of whom received high-dose MP (>5000 mg). MP-treated patients had higher risks of gastrointestinal bleeding (8.6%) than unmatched controls (3.1%, p<0.001) or propensity matched controls (3.8%, p<0.001). However, in-hospital mortality rates of MP-treated patients (2.8%) did not differ significantly from mortality rates of unmatched controls (3.4%, p=0.485) or a propensity-matched control group (3.1%, p=0.884).
So, let us stop indulging in speculative estimates and focus on evidence instead. Given the controversy regarding the efficacy of MP and the dearth of alternative therapies for acute SCI, a randomized placebo-controlled clinical trial of MP for acute spinal cord injury would meet clinical equipoise and should help settle this issue.
References Cited
1. Lenzer, J., Why we can't trust clinical guidelines. BMJ, 2013. 346: p. f3830.
2. Edwards, P., et al., Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet, 2005. 365(9475): p. 1957-9.
3. Bracken, M.B., et al., Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. Jama, 1997. 277(20): p. 1597-604.
4. Bracken, M.B., et al., A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med, 1990. 322(20): p. 1405-11.
5. Bracken, M.B., Steroids for acute spinal cord injury. Cochrane database of systematic reviews, 2012. 1: p. CD001046.
6. Tsutsumi, S., et al., Effects of the Second National Acute Spinal Cord Injury Study of high-dose methylprednisolone therapy on acute cervical spinal cord injury-results in spinal injuries center. Spine, 2006. 31(26): p. 2992-6; discussion 2997.
7. Suberviola, B., et al., Early complications of high-dose methylprednisolone in acute spinal cord injury patients. Injury, 2008. 39(7): p. 748-52.
8. Ito, Y., et al., Does high dose methylprednisolone sodium succinate really improve neurological status in patient with acute cervical cord injury?: a prospective study about neurological recovery and early complications. Spine (Phila Pa 1976), 2009. 34(20): p. 2121-4.
9. Chikuda, H., et al., Mortality and morbidity after high-dose methylprednisolone treatment in patients with acute cervical spinal cord injury: a propensity-matched analysis using a nationwide administrative database. Emerg Med J, 2013. [10.1136/emermed-2012-202058]
Competing interests: Dr. Young was an investigator in both NASCIS 2 and 3 trials and an author of publications from these two trials. He has received travel support and honoraria from Upjohn, Pharmacia, and Pfizer to speak at conferences. He runs ChinaSCINet, a clinical trial network that tests therapies for SCI. He serves as a voluntary (unpaid) global medical director for Stemcyte, helping organize their research and clinical trials. Stemcyte donates umbilical cord blood to ChinaSCINet. Dr. Young helped found Acorda Therapeutics in 1995 and served on its Board of Directors from 1995-2012. He founded the Journal of Neurotrauma and served as its Editor in Chief from 1984 to 1991.