To the Editor:
We appreciate the letter 1 contributed by Drs. Boyer and Ruha in reply to our practice guidelines 2 and welcome their comments. They focus on the serious complication of late coagulopathy, which has assumed greater clinical attention with the advent of Fab antivenom (AV) as the sole AV currently commercially available in the United States.
Our paper is intended as a broad guide for management of patients envenomed by pitvipers in the United States and Canada, and thus it includes necessarily succinct coverage of numerous important topics with evidence-based recommendations for patient management. We agree that late coagulopathy is a common complication of rattlesnake envenomations that can even be fatal, and although mentioned in the guidelines, we welcome this opportunity to further discuss this concern, and increase the emphasis on the importance of diagnosing and treating late coagulopathy.
Our guidelines suggest repeat coagulation studies at 2 to 3 days and again 5 to 7 days after the final AV dose. The rationale for these recommendations was that detecting recurrence earlier would be more advantageous to the patient. These recommendations are similar to other consensus guidelines. 3 Although it is difficult to directly compare studies, published data indicate a broad range of severely envenomed patients exhibiting late coagulopathy at 18% to 53% 4 –8 after treatment with Fab AV, with some evidence suggesting that mild envenomations have a lower incidence at 5%. 5 Late coagulopathy can lead to the clinical sequelae of late bleeding, and although it is less common (0.9%; 95% CI, 0.4%–2.2% in a study of 1017 patients), 9 the consequences can be fatal. Thus the clinician must be diligent in ensuring proper follow-up to envenomed patients and evaluating late coagulopathy.
It must be noted that our recommendations err on the conservative side as we suggest repeat laboratory evaluation for late coagulopathies beginning after the last dose of AV, rather than after the time of envenomation. In more severe envenomations that require repeat dosing of AV, this would extend the time period to pick up late coagulopathies. We concur that more extended follow-up and laboratory testing (eg, at 10 and 14 days after envenomation) would be reasonable, especially after severe envenomations. This recommendation was not included in our paper because we did not find sufficiently strong evidence for making such delineation, and thus recommended avoidance of activities that might predispose to or cause bleeding for 14 days.
We excluded discussion of F(ab′)2 AV pharmacotherapy in our recommendations, but will take the opportunity now to expand on the topic. Crotalidae Immune F(ab′)2 is an equine-derived AV (immunized with venom of Bothrops asper and Crotalus durissus) indicated for the management of adult and pediatric patients with North American rattlesnake envenomation. Venom-specific F(ab′)2 fragments of immunoglobulin G bind and neutralize venom toxins, which allows redistribution away from target tissues and elimination from the body. Each vial contains 120 mg of protein that will neutralize 780 to 790 times the mouse median lethal dose of B asper and C durissus venom, respectively. Package insert dosing instructions of F(ab′)2 begin with a 10-vial initial dose, 10-vial additional dose(s) as needed to achieve initial control, and 4-vial observation and late dosing, 10 and thus differ from Fab AV recommended 4 to 6 vials.
Our objective was to provide actionable guidelines for current practice. Although F(ab′)2 AV received US Food and Drug Administration (FDA) approval in May 2015 and current evidence supports its use for the treatment of rattlesnake envenomation, it is not expected to be available for general use until 2018 owing to legal action and subsequent settlement. We echo the sentiments of Drs. Boyer and Ruha 1 and lament the fact that F(ab′)2 AV was not made commercially available immediately after FDA approval, as patients may have benefited from its use, as well as the potential price reductions that could result from having an AV competitor in the market. However, we refrained from suggesting the use of F(ab′)2 AV in the current practice guidelines for the Wilderness Medical Society until it is generally available. Making such recommendations could cause confusion and unintentionally contribute to inconsistent management of patients through the recommendation of a preferred therapy that is not yet generally available. When F(ab′)2 AV becomes commercially available, we look forward to updating our recommendations to reflect its availability.
It is important to emphasize that the incidence of late coagulopathy requires further careful study, specifically regarding F(ab′)2 AV pharmacotherapy. Although a single comparative study of Fab and F(ab′)2 AVs 11 provided good quality evidence that F(ab′)2 has a more favorable pharmacokinetic profile resulting in improved clinical outcomes (ie, lowered risk of late coagulopathy), 12 analysis of clinical experience is still quite limited. Additional investigations of the risks and benefits of F(ab′)2 AV pharmacotherapy and the aggregation of clinical use data would be beneficial.
We appreciate the comments and opinions of Boyer and Ruha, 1 and are pleased to reinforce the importance of careful follow-up of all patients who have been envenomed by pitvipers and further discuss F(ab′)2 AV.