To the Editor:
Dr. Fernandez et al. are right in saying that this study did not show a significant incidence of active bleeding. Since we could not ethically allow patients to become coagulopathic to the point of bleeding, we studied laboratory differences between groups, in a range of severity that signaled active venom effect but did not depend on actual bleeding.
Nonetheless, medically significant late bleeding did occur in one patient. The patient, who ultimately received 60 vials of Fab after envenomation by a timber rattlesnake (Crotalus horridus), had a platelet count nadir at 86,000 per mm; fibrinogen remained < 60 mg/dL despite repeated dosing with Fab and multiple transfusions. This patient bled twice, once with axillary and chest wall hemorrhage corresponding to a greater than 8-gram drop in hemoglobin on day 2.5, and once from an intrajugular catheter site on day 6.
The death in our study was attributed to “blunt force head and neck injuries” due to a high-speed traffic collision at which time the unrestrained patient had a blood alcohol level of 0.23 g/dL. The patient was pronounced dead within minutes of the accident. Autopsy revealed severe head and neck injuries but no bleeding other than what would be expected after the mechanism of injury. Study laboratory results prior to traffic collision had been normal (platelets: 330,000 per mm and fibrinogen: 459 mg/dL).
In addition to the death (n = 1), serious adverse events (SAEs) in the F(ab’)2 groups included swelling/soft tissue injury (n = 4), rhabdomyolysis (n = 1), and dementia (n = 1). Swelling/soft tissue injury and rhabdomyolysis were attributed to the envenomation process rather than to study drug, and dementia was unrelated. In the Fab group, the SAEs were soft tissue injury (n = 1) and coagulopathy (n = 1, above).
Serious bleeding complications, including fatalities, have been reported following pit viper bites treated with Fab, associated not only with thrombocytopenia but also with isolated defibrogenation. Some of these are listed in our paper's “Background”Citation1; others have been described more recently.Citation2 Many reports of bleeding arise in the southwest, where rattlesnake species are known for effects on both platelets and fibrinogen. Design of this study required estimation of risk in the more heterogeneous nationwide population, following a compelling but homogeneous sample in Phase 2.Citation3 The larger N in Phase 3 anticipated that differences between groups would be smaller when a wider variety of snakes were involved; this indeed proved to be the case.
Current guidelines recommend follow-up laboratory studies between second and seventh day after treatment with Fab antivenom for snakebite capable of causing coagulopathy.Citation4 This leads to retreatment with antivenom, not only preventing bleeding but also limiting the reliability of retrospective studies of bleeding. Our study implied that less-vigilant blood testing after treatment would be necessary with F(ab’)2 antivenom.
In much of the world, case variability is managed by the availability of more than one antivenom. In the US, a combination of high costs and patent enforcementCitation5 has restricted the market to a single polyvalent product, rendering physician's choice of the best management strategy essentially moot.
Declaration of interest
Rare Disease Therapeutics, Inc. (RDT) sponsored this study through contracts with the authors’ affiliated institutions, and Instituto Bioclon, SA de CV provided the F(ab’)2 antivenom for this study. The authors report remuneration for educational presentations from BTG international Inc (BTG) (SPB, AMR) and from RDT (AMR); participation in an expert panel sponsored by BTG that developed a treatment algorithm for pit viper envenomation (SPB, AMR, SAS); being investigators in phase 2 and/or phase 3 clinical trials of a black widow spider antivenom manufactured by Instituto Bioclon, under contract with Rocky Mountain Poison & Drug Center (SPB, AMR, SAS); being investigators in phase 2 and/or phase 3 clinical trials of a scorpion antivenom manufactured by Instituto Bioclon (AMR, LVB); and receiving a contract from Instituto Bioclon for development of North African antivenom (LVB).
References
- Bush SP, Ruha A-M, Seifert SA, Morgan DL, Lewis BJ, Arnold TC, et al. Comparison of F(ab’)2 versus Fab antivenom for pit viper envenomation: A prospective, blinded, multicenter, randomized clinical trial. Clin Toxicol (Phila) 2015; 53:37–45.
- Levine M, Ruha AM, Padilla-Jones A, Gerkin R, Thomas SH. Bleeding following rattlesnake envenomation in patients with pre envenomation use of antiplatelet or anticoagulant medications. Acad Emerg Med 2014; 21:301–307.
- Boyer LV, Chase PB, Degan JA, Figge G, Buelna-Romero A, Luchetti C, Alagón A. Subacute coagulopathy in a randomized, comparative trial of Fab and F(ab’)2 antivenoms. Toxicon 2013; 74:101–108.
- Lavonas EJ, Ruha AM, Banner W, Bebarta V, Bernstein JN, Bush SP, et al.; Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority. Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop. BMC Emerg Med 2011; 11:2.
- Wade, L. For Mexican antivenom maker, US market is a snake pit. Science 2014; 343:16–17.