The
n e w e ng l a n d j o u r na l
of
m e dic i n e
c or r e sp ondence
Progesterone in Traumatic Brain Injury To the Editor: Limitations of all clinical trials that deal with acute head trauma include reliance on the Glasgow Coma Scale for initial neurometric quantitation of injury, reliance on the Glasgow Outcome Scale as the primary longitudinal measure of recovery, and the widely variegated heterogeneity of traumatic brain lesions.1,2 The Neurological Emergencies Treatment Trials investigators and the investigators in the Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (SYNAPSE) (Dec. 25 issue)3,4 made exemplary attempts to overcome multiple potential sources of bias, confounding, and subjectivity through the use of strong methods and statistical analyses. Given the paramount importance of finding the first evidence-based pharmacologic intervention for traumatic brain injury (TBI), it would be of immense value to determine whether the finding of no benefit of progesterone over placebo would be substantiated in a secondary post hoc data analysis, in which neurologic injury was disaggregated and stratified on the basis of pathoanatomical findings on neuroimaging studies. This largescale data set has the potential to exploit heterogeneity through testing the hypothesis that brain injuries with similar neuroimaging features (location, multifocality, size, and type of lesion) are likely to share common prognostic features and, therefore, common potential responses to pharmacotherapy.5 Michael S. Xydakis, M.D., Col. Geoffrey S.F. Ling, M.D., Ph.D. Uniformed Services University of the Health Sciences
Bethesda, MD [email protected]
James M. Ecklund, M.D. Inova Fairfax Medical Campus Falls Church, VA
No potential conflict of interest relevant to this letter was reported. 1. Xydakis MS, Ling GS, Mulligan LP, Olsen CH, Dorlac WC.
Epidemiologic aspects of traumatic brain injury in acute combat casualties at a major military medical center: a cohort study. Ann Neurol 2012;72:673-81. 2. Riechers RG II, Ramage A, Brown W, et al. Physician knowledge of the Glasgow Coma Scale. J Neurotrauma 2005;22:132734. 3. Wright DW, Yeatts SD, Silbergleit R, et al. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med 2014;371:2457-66. 4. Skolnick BE, Maas AI, Narayan RK, et al. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med 2014;371:2467-76. 5. Saatman KE, Duhaime AC, Bullock R, Maas AI, Valadka A, Manley GT. Classification of traumatic brain injury for targeted therapies. J Neurotrauma 2008;25:719-38. DOI: 10.1056/NEJMc1503138
To the Editor: The reports by Skolnick et al. and Wright et al. together highlight the need for studies of TBI to focus carefully on the molecular mechanisms of injury, rather than on gross clinical and radiologic observations thought to be correlated with prognosis. TBI encompasses heterothis week’s letters 1765 Progesterone in Traumatic Brain Injury 1767 Preexposure Prophylaxis for HIV Infection 1768 V122I Transthyretin Variant in Elderly Black Americans 1770 Surgical Treatment of Moderate Ischemic Mitral Regurgitation 1774 Treatment of Relapsed Multiple Myeloma 1775 Acute Hydrophilic-Polymer Nephropathy and Acute Renal Failure
n engl j med 372;18 nejm.org april 30, 2015
The New England Journal of Medicine Downloaded from nejm.org at Florida Atlantic University on August 12, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
1765
The
n e w e ng l a n d j o u r na l
geneous etiologic, anatomical, and molecular patterns of injury that exhibit different propensities to cause damaging cerebral edema and secondary hemorrhage.1,2 Without careful consideration of individual injuries, results of therapeutic trials remain difficult to interpret. In preclinical studies, progesterone reduced traumatic cerebral edema, at least in part by inhibiting inflammation.3 However, cerebral edema is a complex phenotypic end point that is initiated by diverse insults and that is not driven solely by inflammation. The pathologic influx of ions and water across endothelial cells is a sine qua non of all brain swelling.2 Moreover, secondary hemorrhage — that is, hemorrhagic progression of contusion4 — is the penultimate consequence of microvascular dysfunction in TBI. Targeting the node of the injury responsible for both may be a preferable alternative approach, given the recent identification of compelling new candidates.5 Arjun Khanna, B.S. Harvard Medical School
Boston, MA
J. Marc Simard, M.D., Ph.D. University of Maryland School of Medicine
Baltimore, MD
Kristopher T. Kahle, M.D., Ph.D. Harvard Medical School
Boston, MA [email protected] Dr. Simard reports holding a U.S. patent (7,757,285,574), “A novel non-selective cation channel in neural cells and methods for treating brain swelling,” and being a member of the scientific advisory board of, and holding shares in, Remedy Pharmaceuticals. No other potential conflict of interest relevant to this letter was reported. 1. Maas AIR, Stocchetti N, Bullock R. Moderate and severe
traumatic brain injury in adults. Lancet Neurol 2008;7:728-41.
2. Simard JM, Kent TA, Chen M, Tarasov KV, Gerzanich V.
Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol 2007;6:258-68. 3. Deutsch ER, Espinoza TR, Atif F, Woodall E, Kaylor J, Wright DW. Progesterone’s role in neuroprotection, a review of the evidence. Brain Res 2013;1530:82-105. 4. Kurland D, Hong C, Aarabi B, Gerzanich V, Simard JM. Hemorrhagic progression of a contusion after traumatic brain injury: a review. J Neurotrauma 2012;29:19-31. 5. Simard JM, Kilbourne M, Tsymbalyuk O, et al. Key role of sulfonylurea receptor 1 in progressive secondary hemorrhage after brain contusion. J Neurotrauma 2009;26:2257-67. DOI: 10.1056/NEJMc1503138
of
m e dic i n e
neuroprotective interventions for TBI have consistently failed to translate from bench to clinic.1 In the Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (PROTECT III) trial, we went to great lengths to control external sources of variability through rigorous clinical standardization, tight quality control on outcome assessment, and intense data monitoring. However, as indicated in the comments by both Xydakis et al. and Khanna et al., the injuries of our patients are a heterogeneous collection of anatomical, physiological, and molecular derangements that are themselves more variable and more complex than those modeled in the laboratory. Xydakis et al. hope that analysis of injury phenotype on neuroimaging studies may identify patients for whom progesterone may still show some signal of efficacy. We agree that this is a question of interest and collected extensive early and follow-up imaging in the PROTECT III trial to perform preplanned secondary analyses that incorporate a variety of conventional imaging findings. Khanna et al. argue for a more mechanistic analysis of injury phenotype. The potential importance of distinguishing patients by means of molecular biomarkers was also anticipated, and an ancillary study of serum biomarkers, independently funded by the National Institute of Neurological Disorders and Stroke, was performed in our study participants (ClinicalTrials.gov number, NCT01730443). Markers related to glial activation and inflammation, the integrity of the blood– brain barrier, neuronal integrity, and cell-death pathways, with serum collection at very early and very consistent intervals after injury, are being evaluated. It is not time to retreat. There is still much to learn from these trial data and from future investigations. Given the burden of disease, the amount of funding for TBI research is paltry in comparison with that for cancer research and other fields. However, it is time to improve the collaborative dialogue between basic scientists and clinical trialists to identify ways to overcome the challenges facing the translation of promising neuroprotective agents into effective treatments for acute neurologic injury.
Dr. Wright and colleagues reply: An effective David W. Wright, M.D. treatment for patients with acute TBI remains elu- Emory University sive. Despite the discovery of many of the molecu- Atlanta, GA lar cascades that lead to secondary neuronal death, [email protected]
1766
n engl j med 372;18 nejm.org april 30, 2015
The New England Journal of Medicine Downloaded from nejm.org at Florida Atlantic University on August 12, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
correspondence
Sharon D. Yeatts, Ph.D. Medical University of South Carolina
Charleston, SC
Robert Silbergleit, M.D. University of Michigan
Ann Arbor, MI Since publication of their article, the authors report no further potential conflict of interest. 1. Xiong Y, Mahmood A, Chopp M. Animal models of trau-
matic brain injury. Nat Rev Neurosci 2013;14:128-42. DOI: 10.1056/NEJMc1503138
imaging, whereas Khanna et al. emphasize the need to focus on molecular mechanisms of injury, rather than on gross clinical and radiologic observations. TBI has appropriately been termed “the most complicated disease of the most complex organ of the body.”2 Better characterization of the disease processes in individual patients may permit more appropriate targeting of therapy. Determination of benefit will require mechanistic end points, but proof of clinical effectiveness should be based on multidimensional assessments of outcome. Large international efforts are currently ongoing in these directions.3 The International Initiative for Traumatic Brain Injury Research, instituted in 2011 as a collaboration among major funding agencies, has provided a substantial stimulus to these efforts.4 Brett E. Skolnick, Ph.D.
Dr. Skolnick and colleagues reply: We appreciate the acknowledgment by Xydakis et al. of our efforts to avoid potential sources of bias while conducting a very large, complex, multinational clinical trial of TBI. We relied on the Glasgow Coma Scale score as the primary entry criterion and the Glasgow Outcome Scale score as the primary end point, because these instruments have been Hofstra North Shore–LIJ School of Medicine shown to be robust over several decades. We agree Hempstead, NY that they have their limitations, and we support [email protected] the concept of multidimensional approaches to Andrew I.R. Maas, M.D., Ph.D. classification of initial severity and of outcome.1 University Hospital Antwerp However, how exactly these new pieces of infor- Edegem, Belgium mation may best be used to improve TBI trial Raj K. Narayan, M.D. design and sensitivity remains to be determined. Hofstra North Shore–LIJ School of Medicine Xydakis et al. raise an important point regard- Hempstead, NY ing the need to evaluate patient subgroups on the for the SYNAPSE Steering Committee basis of relevant criteria, whether biomarkers or Since publication of their article, the authors report no furimaging components. Indeed, we performed ex- ther potential conflict of interest. tensive prespecified subgroup analyses (see Table 1. Manley GT, Maas AI. Traumatic brain injury: an interna2 of our article) and post hoc subgroup analyses. tional knowledge-based approach. JAMA 2013;310:473-4. We found no hint of a trend toward efficacy in 2. Marklund N, Hillered L. Animal modelling of traumatic injury in preclinical drug development: where do we go any of these analyses, in patients with diffuse brain from here? Br J Pharmacol 2011;164:1207-29. injury, mass lesions, or traumatic subarachnoid 3. Maas AI, Menon DK, Steyerberg EW, et al. Collaborative Euhemorrhage or in those undergoing surgery. It ropean NeuroTrauma Effectiveness Research in Traumatic Brain (CENTER-TBI): a prospective longitudinal observational would therefore seem unlikely that progesterone Injury study. Neurosurgery 2015;76:67-80. had any benefit in these subpopulations. 4. Tosetti P, Hicks RR, Theriault E, Phillips A, Koroshetz W, It is of interest that Xydakis et al. suggest a Draghia-Akli R. Toward an international initiative for traumatic potential role for characterizing patients on the brain injury research. J Neurotrauma 2013;30:1211-22. basis of pathoanatomical findings from neuro- DOI: 10.1056/NEJMc1503138
Preexposure Prophylaxis for HIV Infection To the Editor: The study by Marrazzo et al. (Feb. 5 issue)1 highlights the need for cautious monitoring during the rollout of preexposure prophylaxis against human immunodeficiency virus
(HIV) infection. In keeping with the maxim “first, do no harm,” the burden of proof against potential harm needs to be high, because people who qualify for preexposure prophylaxis are generally
n engl j med 372;18 nejm.org april 30, 2015
The New England Journal of Medicine Downloaded from nejm.org at Florida Atlantic University on August 12, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
1767
n e w e ng l a n d j o u r na l
of
m e dic i n e
c or r e sp ondence
Progesterone in Traumatic Brain Injury To the Editor: Limitations of all clinical trials that deal with acute head trauma include reliance on the Glasgow Coma Scale for initial neurometric quantitation of injury, reliance on the Glasgow Outcome Scale as the primary longitudinal measure of recovery, and the widely variegated heterogeneity of traumatic brain lesions.1,2 The Neurological Emergencies Treatment Trials investigators and the investigators in the Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (SYNAPSE) (Dec. 25 issue)3,4 made exemplary attempts to overcome multiple potential sources of bias, confounding, and subjectivity through the use of strong methods and statistical analyses. Given the paramount importance of finding the first evidence-based pharmacologic intervention for traumatic brain injury (TBI), it would be of immense value to determine whether the finding of no benefit of progesterone over placebo would be substantiated in a secondary post hoc data analysis, in which neurologic injury was disaggregated and stratified on the basis of pathoanatomical findings on neuroimaging studies. This largescale data set has the potential to exploit heterogeneity through testing the hypothesis that brain injuries with similar neuroimaging features (location, multifocality, size, and type of lesion) are likely to share common prognostic features and, therefore, common potential responses to pharmacotherapy.5 Michael S. Xydakis, M.D., Col. Geoffrey S.F. Ling, M.D., Ph.D. Uniformed Services University of the Health Sciences
Bethesda, MD [email protected]
James M. Ecklund, M.D. Inova Fairfax Medical Campus Falls Church, VA
No potential conflict of interest relevant to this letter was reported. 1. Xydakis MS, Ling GS, Mulligan LP, Olsen CH, Dorlac WC.
Epidemiologic aspects of traumatic brain injury in acute combat casualties at a major military medical center: a cohort study. Ann Neurol 2012;72:673-81. 2. Riechers RG II, Ramage A, Brown W, et al. Physician knowledge of the Glasgow Coma Scale. J Neurotrauma 2005;22:132734. 3. Wright DW, Yeatts SD, Silbergleit R, et al. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med 2014;371:2457-66. 4. Skolnick BE, Maas AI, Narayan RK, et al. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med 2014;371:2467-76. 5. Saatman KE, Duhaime AC, Bullock R, Maas AI, Valadka A, Manley GT. Classification of traumatic brain injury for targeted therapies. J Neurotrauma 2008;25:719-38. DOI: 10.1056/NEJMc1503138
To the Editor: The reports by Skolnick et al. and Wright et al. together highlight the need for studies of TBI to focus carefully on the molecular mechanisms of injury, rather than on gross clinical and radiologic observations thought to be correlated with prognosis. TBI encompasses heterothis week’s letters 1765 Progesterone in Traumatic Brain Injury 1767 Preexposure Prophylaxis for HIV Infection 1768 V122I Transthyretin Variant in Elderly Black Americans 1770 Surgical Treatment of Moderate Ischemic Mitral Regurgitation 1774 Treatment of Relapsed Multiple Myeloma 1775 Acute Hydrophilic-Polymer Nephropathy and Acute Renal Failure
n engl j med 372;18 nejm.org april 30, 2015
The New England Journal of Medicine Downloaded from nejm.org at Florida Atlantic University on August 12, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
1765
The
n e w e ng l a n d j o u r na l
geneous etiologic, anatomical, and molecular patterns of injury that exhibit different propensities to cause damaging cerebral edema and secondary hemorrhage.1,2 Without careful consideration of individual injuries, results of therapeutic trials remain difficult to interpret. In preclinical studies, progesterone reduced traumatic cerebral edema, at least in part by inhibiting inflammation.3 However, cerebral edema is a complex phenotypic end point that is initiated by diverse insults and that is not driven solely by inflammation. The pathologic influx of ions and water across endothelial cells is a sine qua non of all brain swelling.2 Moreover, secondary hemorrhage — that is, hemorrhagic progression of contusion4 — is the penultimate consequence of microvascular dysfunction in TBI. Targeting the node of the injury responsible for both may be a preferable alternative approach, given the recent identification of compelling new candidates.5 Arjun Khanna, B.S. Harvard Medical School
Boston, MA
J. Marc Simard, M.D., Ph.D. University of Maryland School of Medicine
Baltimore, MD
Kristopher T. Kahle, M.D., Ph.D. Harvard Medical School
Boston, MA [email protected] Dr. Simard reports holding a U.S. patent (7,757,285,574), “A novel non-selective cation channel in neural cells and methods for treating brain swelling,” and being a member of the scientific advisory board of, and holding shares in, Remedy Pharmaceuticals. No other potential conflict of interest relevant to this letter was reported. 1. Maas AIR, Stocchetti N, Bullock R. Moderate and severe
traumatic brain injury in adults. Lancet Neurol 2008;7:728-41.
2. Simard JM, Kent TA, Chen M, Tarasov KV, Gerzanich V.
Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol 2007;6:258-68. 3. Deutsch ER, Espinoza TR, Atif F, Woodall E, Kaylor J, Wright DW. Progesterone’s role in neuroprotection, a review of the evidence. Brain Res 2013;1530:82-105. 4. Kurland D, Hong C, Aarabi B, Gerzanich V, Simard JM. Hemorrhagic progression of a contusion after traumatic brain injury: a review. J Neurotrauma 2012;29:19-31. 5. Simard JM, Kilbourne M, Tsymbalyuk O, et al. Key role of sulfonylurea receptor 1 in progressive secondary hemorrhage after brain contusion. J Neurotrauma 2009;26:2257-67. DOI: 10.1056/NEJMc1503138
of
m e dic i n e
neuroprotective interventions for TBI have consistently failed to translate from bench to clinic.1 In the Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (PROTECT III) trial, we went to great lengths to control external sources of variability through rigorous clinical standardization, tight quality control on outcome assessment, and intense data monitoring. However, as indicated in the comments by both Xydakis et al. and Khanna et al., the injuries of our patients are a heterogeneous collection of anatomical, physiological, and molecular derangements that are themselves more variable and more complex than those modeled in the laboratory. Xydakis et al. hope that analysis of injury phenotype on neuroimaging studies may identify patients for whom progesterone may still show some signal of efficacy. We agree that this is a question of interest and collected extensive early and follow-up imaging in the PROTECT III trial to perform preplanned secondary analyses that incorporate a variety of conventional imaging findings. Khanna et al. argue for a more mechanistic analysis of injury phenotype. The potential importance of distinguishing patients by means of molecular biomarkers was also anticipated, and an ancillary study of serum biomarkers, independently funded by the National Institute of Neurological Disorders and Stroke, was performed in our study participants (ClinicalTrials.gov number, NCT01730443). Markers related to glial activation and inflammation, the integrity of the blood– brain barrier, neuronal integrity, and cell-death pathways, with serum collection at very early and very consistent intervals after injury, are being evaluated. It is not time to retreat. There is still much to learn from these trial data and from future investigations. Given the burden of disease, the amount of funding for TBI research is paltry in comparison with that for cancer research and other fields. However, it is time to improve the collaborative dialogue between basic scientists and clinical trialists to identify ways to overcome the challenges facing the translation of promising neuroprotective agents into effective treatments for acute neurologic injury.
Dr. Wright and colleagues reply: An effective David W. Wright, M.D. treatment for patients with acute TBI remains elu- Emory University sive. Despite the discovery of many of the molecu- Atlanta, GA lar cascades that lead to secondary neuronal death, [email protected]
1766
n engl j med 372;18 nejm.org april 30, 2015
The New England Journal of Medicine Downloaded from nejm.org at Florida Atlantic University on August 12, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
correspondence
Sharon D. Yeatts, Ph.D. Medical University of South Carolina
Charleston, SC
Robert Silbergleit, M.D. University of Michigan
Ann Arbor, MI Since publication of their article, the authors report no further potential conflict of interest. 1. Xiong Y, Mahmood A, Chopp M. Animal models of trau-
matic brain injury. Nat Rev Neurosci 2013;14:128-42. DOI: 10.1056/NEJMc1503138
imaging, whereas Khanna et al. emphasize the need to focus on molecular mechanisms of injury, rather than on gross clinical and radiologic observations. TBI has appropriately been termed “the most complicated disease of the most complex organ of the body.”2 Better characterization of the disease processes in individual patients may permit more appropriate targeting of therapy. Determination of benefit will require mechanistic end points, but proof of clinical effectiveness should be based on multidimensional assessments of outcome. Large international efforts are currently ongoing in these directions.3 The International Initiative for Traumatic Brain Injury Research, instituted in 2011 as a collaboration among major funding agencies, has provided a substantial stimulus to these efforts.4 Brett E. Skolnick, Ph.D.
Dr. Skolnick and colleagues reply: We appreciate the acknowledgment by Xydakis et al. of our efforts to avoid potential sources of bias while conducting a very large, complex, multinational clinical trial of TBI. We relied on the Glasgow Coma Scale score as the primary entry criterion and the Glasgow Outcome Scale score as the primary end point, because these instruments have been Hofstra North Shore–LIJ School of Medicine shown to be robust over several decades. We agree Hempstead, NY that they have their limitations, and we support [email protected] the concept of multidimensional approaches to Andrew I.R. Maas, M.D., Ph.D. classification of initial severity and of outcome.1 University Hospital Antwerp However, how exactly these new pieces of infor- Edegem, Belgium mation may best be used to improve TBI trial Raj K. Narayan, M.D. design and sensitivity remains to be determined. Hofstra North Shore–LIJ School of Medicine Xydakis et al. raise an important point regard- Hempstead, NY ing the need to evaluate patient subgroups on the for the SYNAPSE Steering Committee basis of relevant criteria, whether biomarkers or Since publication of their article, the authors report no furimaging components. Indeed, we performed ex- ther potential conflict of interest. tensive prespecified subgroup analyses (see Table 1. Manley GT, Maas AI. Traumatic brain injury: an interna2 of our article) and post hoc subgroup analyses. tional knowledge-based approach. JAMA 2013;310:473-4. We found no hint of a trend toward efficacy in 2. Marklund N, Hillered L. Animal modelling of traumatic injury in preclinical drug development: where do we go any of these analyses, in patients with diffuse brain from here? Br J Pharmacol 2011;164:1207-29. injury, mass lesions, or traumatic subarachnoid 3. Maas AI, Menon DK, Steyerberg EW, et al. Collaborative Euhemorrhage or in those undergoing surgery. It ropean NeuroTrauma Effectiveness Research in Traumatic Brain (CENTER-TBI): a prospective longitudinal observational would therefore seem unlikely that progesterone Injury study. Neurosurgery 2015;76:67-80. had any benefit in these subpopulations. 4. Tosetti P, Hicks RR, Theriault E, Phillips A, Koroshetz W, It is of interest that Xydakis et al. suggest a Draghia-Akli R. Toward an international initiative for traumatic potential role for characterizing patients on the brain injury research. J Neurotrauma 2013;30:1211-22. basis of pathoanatomical findings from neuro- DOI: 10.1056/NEJMc1503138
Preexposure Prophylaxis for HIV Infection To the Editor: The study by Marrazzo et al. (Feb. 5 issue)1 highlights the need for cautious monitoring during the rollout of preexposure prophylaxis against human immunodeficiency virus
(HIV) infection. In keeping with the maxim “first, do no harm,” the burden of proof against potential harm needs to be high, because people who qualify for preexposure prophylaxis are generally
n engl j med 372;18 nejm.org april 30, 2015
The New England Journal of Medicine Downloaded from nejm.org at Florida Atlantic University on August 12, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
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