Comparison of F(ab')2 versus Fab antivenom for pit viper envenomation: A prospective, blinded, multicenter, randomized clinical trial

Sean P. Bush, Anne Michelle Ruha, Steven A. Seifert, David L. Morgan, Brandon J. Lewis, Thomas C. Arnold, Richard F. Clark, William J. Meggs, Eric A. Toschlog, Stephen W. Borron, Gary R. Figge, Dawn R. Sollee, Farshad Shirazi, Robert Wolk, Ives De Chazal, Dan Quan, Walter García-Ubbelohde, Alejandro Alagón, Richard D. Gerkin, Leslie V Boyer

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Background. Crotalidae Polyvalent Immune Fab (Ovine) has been the only antivenom commercially available in the US since 2007 for treatment of Crotalinae envenomation. Late coagulopathy can occur or recur after clearance of Fab antivenom, often after hospital discharge, lasting in some cases more than 2 weeks. There have been serious, even fatal, bleeding complications associated with recurrence phenomena. Frequent follow-up is required, and additional intervention or hospitalization is often necessary. F(ab')2 immunoglobulin derivatives have longer plasma half life than do Fab. We hypothesized that F(ab')2 antivenom would be superior to Fab in the prevention of late coagulopathy following treatment of patients with Crotalinae envenomation. Methods. We conducted a prospective, double-blind, randomized clinical trial, comparing late coagulopathy in snakebitten patients treated with F(ab')2 with maintenance doses [F(ab')2/F(ab')2], or F(ab')2 with placebo maintenance doses [F(ab')2/placebo], versus Fab with maintenance doses [Fab/Fab]. The primary efficacy endpoint was coagulopathy (platelet count < 150 K/mm3, fibrinogen level < 150 mg/dL) between end of maintenance dosing and day 8. Results. 121 patients were randomized at 18 clinical sites and received at least one dose of study drug. 114 completed the study. Of these, 11/37 (29.7%) in the Fab/Fab cohort experienced late coagulopathy versus 4/39 (10.3%, p < 0.05) in the F(ab')2/F(ab')2 cohort and 2/38 (5.3%, p < 0.05) in the F(ab')2/placebo cohort. The lowest heterologous protein exposure was with F(ab')2/placebo. No serious adverse events were related to study drug. In each study arm, one patient experienced an acute serum reaction and one experienced serum sickness. Conclusions. In this study, management of coagulopathic Crotalinae envenomation with longer-half-life F(ab')2 antivenom, with or without maintenance dosing, reduced the risk of subacute coagulopathy and bleeding following treatment of envenomation.

Original languageEnglish (US)
Pages (from-to)37-45
Number of pages9
JournalClinical Toxicology
Volume53
Issue number1
DOIs
StatePublished - Jan 1 2015

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Antivenins
Randomized Controlled Trials
Placebos
Half-Life
Maintenance
Serum Sickness
Hemorrhage
Platelets
Platelet Count
Pharmaceutical Preparations
Fibrinogen
Immunoglobulins
Sheep
Hospitalization
Therapeutics
Derivatives
Plasmas
Recurrence
Serum
Proteins

Keywords

  • Antivenins
  • Snakes
  • Toxinology

ASJC Scopus subject areas

  • Toxicology
  • Medicine(all)

Cite this

Comparison of F(ab')2 versus Fab antivenom for pit viper envenomation : A prospective, blinded, multicenter, randomized clinical trial. / Bush, Sean P.; Ruha, Anne Michelle; Seifert, Steven A.; Morgan, David L.; Lewis, Brandon J.; Arnold, Thomas C.; Clark, Richard F.; Meggs, William J.; Toschlog, Eric A.; Borron, Stephen W.; Figge, Gary R.; Sollee, Dawn R.; Shirazi, Farshad; Wolk, Robert; De Chazal, Ives; Quan, Dan; García-Ubbelohde, Walter; Alagón, Alejandro; Gerkin, Richard D.; Boyer, Leslie V.

In: Clinical Toxicology, Vol. 53, No. 1, 01.01.2015, p. 37-45.

Research output: Contribution to journalArticle

Bush, SP, Ruha, AM, Seifert, SA, Morgan, DL, Lewis, BJ, Arnold, TC, Clark, RF, Meggs, WJ, Toschlog, EA, Borron, SW, Figge, GR, Sollee, DR, Shirazi, F, Wolk, R, De Chazal, I, Quan, D, García-Ubbelohde, W, Alagón, A, Gerkin, RD & Boyer, LV 2015, 'Comparison of F(ab')2 versus Fab antivenom for pit viper envenomation: A prospective, blinded, multicenter, randomized clinical trial', Clinical Toxicology, vol. 53, no. 1, pp. 37-45. https://doi.org/10.3109/15563650.2014.974263
Bush, Sean P. ; Ruha, Anne Michelle ; Seifert, Steven A. ; Morgan, David L. ; Lewis, Brandon J. ; Arnold, Thomas C. ; Clark, Richard F. ; Meggs, William J. ; Toschlog, Eric A. ; Borron, Stephen W. ; Figge, Gary R. ; Sollee, Dawn R. ; Shirazi, Farshad ; Wolk, Robert ; De Chazal, Ives ; Quan, Dan ; García-Ubbelohde, Walter ; Alagón, Alejandro ; Gerkin, Richard D. ; Boyer, Leslie V. / Comparison of F(ab')2 versus Fab antivenom for pit viper envenomation : A prospective, blinded, multicenter, randomized clinical trial. In: Clinical Toxicology. 2015 ; Vol. 53, No. 1. pp. 37-45.
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abstract = "Background. Crotalidae Polyvalent Immune Fab (Ovine) has been the only antivenom commercially available in the US since 2007 for treatment of Crotalinae envenomation. Late coagulopathy can occur or recur after clearance of Fab antivenom, often after hospital discharge, lasting in some cases more than 2 weeks. There have been serious, even fatal, bleeding complications associated with recurrence phenomena. Frequent follow-up is required, and additional intervention or hospitalization is often necessary. F(ab')2 immunoglobulin derivatives have longer plasma half life than do Fab. We hypothesized that F(ab')2 antivenom would be superior to Fab in the prevention of late coagulopathy following treatment of patients with Crotalinae envenomation. Methods. We conducted a prospective, double-blind, randomized clinical trial, comparing late coagulopathy in snakebitten patients treated with F(ab')2 with maintenance doses [F(ab')2/F(ab')2], or F(ab')2 with placebo maintenance doses [F(ab')2/placebo], versus Fab with maintenance doses [Fab/Fab]. The primary efficacy endpoint was coagulopathy (platelet count < 150 K/mm3, fibrinogen level < 150 mg/dL) between end of maintenance dosing and day 8. Results. 121 patients were randomized at 18 clinical sites and received at least one dose of study drug. 114 completed the study. Of these, 11/37 (29.7{\%}) in the Fab/Fab cohort experienced late coagulopathy versus 4/39 (10.3{\%}, p < 0.05) in the F(ab')2/F(ab')2 cohort and 2/38 (5.3{\%}, p < 0.05) in the F(ab')2/placebo cohort. The lowest heterologous protein exposure was with F(ab')2/placebo. No serious adverse events were related to study drug. In each study arm, one patient experienced an acute serum reaction and one experienced serum sickness. Conclusions. In this study, management of coagulopathic Crotalinae envenomation with longer-half-life F(ab')2 antivenom, with or without maintenance dosing, reduced the risk of subacute coagulopathy and bleeding following treatment of envenomation.",
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TY - JOUR

T1 - Comparison of F(ab')2 versus Fab antivenom for pit viper envenomation

T2 - A prospective, blinded, multicenter, randomized clinical trial

AU - Bush, Sean P.

AU - Ruha, Anne Michelle

AU - Seifert, Steven A.

AU - Morgan, David L.

AU - Lewis, Brandon J.

AU - Arnold, Thomas C.

AU - Clark, Richard F.

AU - Meggs, William J.

AU - Toschlog, Eric A.

AU - Borron, Stephen W.

AU - Figge, Gary R.

AU - Sollee, Dawn R.

AU - Shirazi, Farshad

AU - Wolk, Robert

AU - De Chazal, Ives

AU - Quan, Dan

AU - García-Ubbelohde, Walter

AU - Alagón, Alejandro

AU - Gerkin, Richard D.

AU - Boyer, Leslie V

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Background. Crotalidae Polyvalent Immune Fab (Ovine) has been the only antivenom commercially available in the US since 2007 for treatment of Crotalinae envenomation. Late coagulopathy can occur or recur after clearance of Fab antivenom, often after hospital discharge, lasting in some cases more than 2 weeks. There have been serious, even fatal, bleeding complications associated with recurrence phenomena. Frequent follow-up is required, and additional intervention or hospitalization is often necessary. F(ab')2 immunoglobulin derivatives have longer plasma half life than do Fab. We hypothesized that F(ab')2 antivenom would be superior to Fab in the prevention of late coagulopathy following treatment of patients with Crotalinae envenomation. Methods. We conducted a prospective, double-blind, randomized clinical trial, comparing late coagulopathy in snakebitten patients treated with F(ab')2 with maintenance doses [F(ab')2/F(ab')2], or F(ab')2 with placebo maintenance doses [F(ab')2/placebo], versus Fab with maintenance doses [Fab/Fab]. The primary efficacy endpoint was coagulopathy (platelet count < 150 K/mm3, fibrinogen level < 150 mg/dL) between end of maintenance dosing and day 8. Results. 121 patients were randomized at 18 clinical sites and received at least one dose of study drug. 114 completed the study. Of these, 11/37 (29.7%) in the Fab/Fab cohort experienced late coagulopathy versus 4/39 (10.3%, p < 0.05) in the F(ab')2/F(ab')2 cohort and 2/38 (5.3%, p < 0.05) in the F(ab')2/placebo cohort. The lowest heterologous protein exposure was with F(ab')2/placebo. No serious adverse events were related to study drug. In each study arm, one patient experienced an acute serum reaction and one experienced serum sickness. Conclusions. In this study, management of coagulopathic Crotalinae envenomation with longer-half-life F(ab')2 antivenom, with or without maintenance dosing, reduced the risk of subacute coagulopathy and bleeding following treatment of envenomation.

AB - Background. Crotalidae Polyvalent Immune Fab (Ovine) has been the only antivenom commercially available in the US since 2007 for treatment of Crotalinae envenomation. Late coagulopathy can occur or recur after clearance of Fab antivenom, often after hospital discharge, lasting in some cases more than 2 weeks. There have been serious, even fatal, bleeding complications associated with recurrence phenomena. Frequent follow-up is required, and additional intervention or hospitalization is often necessary. F(ab')2 immunoglobulin derivatives have longer plasma half life than do Fab. We hypothesized that F(ab')2 antivenom would be superior to Fab in the prevention of late coagulopathy following treatment of patients with Crotalinae envenomation. Methods. We conducted a prospective, double-blind, randomized clinical trial, comparing late coagulopathy in snakebitten patients treated with F(ab')2 with maintenance doses [F(ab')2/F(ab')2], or F(ab')2 with placebo maintenance doses [F(ab')2/placebo], versus Fab with maintenance doses [Fab/Fab]. The primary efficacy endpoint was coagulopathy (platelet count < 150 K/mm3, fibrinogen level < 150 mg/dL) between end of maintenance dosing and day 8. Results. 121 patients were randomized at 18 clinical sites and received at least one dose of study drug. 114 completed the study. Of these, 11/37 (29.7%) in the Fab/Fab cohort experienced late coagulopathy versus 4/39 (10.3%, p < 0.05) in the F(ab')2/F(ab')2 cohort and 2/38 (5.3%, p < 0.05) in the F(ab')2/placebo cohort. The lowest heterologous protein exposure was with F(ab')2/placebo. No serious adverse events were related to study drug. In each study arm, one patient experienced an acute serum reaction and one experienced serum sickness. Conclusions. In this study, management of coagulopathic Crotalinae envenomation with longer-half-life F(ab')2 antivenom, with or without maintenance dosing, reduced the risk of subacute coagulopathy and bleeding following treatment of envenomation.

KW - Antivenins

KW - Snakes

KW - Toxinology

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