In reply:

Abstract

We thank Dr. Borek et al1Borek H.A. Rizer J. Ngo A. Fab antivenom controversy continues.Ann Emerg Med. 2017; 70: 925Google Scholar for their interest in our study. As with any clinical study, the active drug and placebo groups were not identically balanced in all respects. The slight imbalances in race and ethnicity were small and not statistically significant; and no biologically plausible mechanism or previous research suggests that race and ethnicity affect copperhead envenomation outcomes. As shown in Figure 2E, the placebo group has neither a clinically (0.6) nor a statistically (P=.19) significant difference in its pretreatment numeric pain scores.2Gerardo C.J. Quackenbush E. Lewis B. et al.The efficacy of Crotalidae polyvalent immune Fab (ovine) antivenom versus placebo plus optional rescue therapy on recovery from copperhead snake envenomation: a randomized, double-blind, placebo-controlled, clinical trial.Ann Emerg Med. 2017; 70: 233-244Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar We stratified randomization according to envenomation site (upper versus lower extremity), age (adult versus adolescent), and initial severity (mild versus moderate) to ensure proportional distribution of these variables in the treatment groups. We also included these variables in our least squared means multivariate model, thereby fully accounting for any residual imbalance. The concern of Borek et al about selection bias is unwarranted as this affects enrollment and not randomization. We did not measure the Patient-Specific Functional Scale score at enrollment. The specific wording of the scale instrument is the following: “Identify 3 activities that you were unable to do or are having difficulty doing as a result of your [snakebite].” To ask this information from a patient who had just been bitten and was still in the emergency department would have been invalid. Our approach to the Patient-Specific Functional Scale was consistent with administration guidelines for the instrument and with that of previous work.3Lavonas E.J. Gerardo C.J. Prospective study of recovery from copperhead snake envenomation: an observational study.BMC Emerg Med. 2015; 15: 1-21Crossref PubMed Scopus (17) Google Scholar An additional concern is that the effect size is of marginal benefit. The minimal clinically important difference for the Patient-Specific Functional Scale score in snake envenomation is unknown. It has been studied in various limb injury conditions, and the difference we observed in this study is similar to these values.4Hefford C. Abbott J.H. Arnold R. et al.The Patient-Specific Functional Scale: validity, reliability, and responsiveness in patients with upper extremity musculoskeletal problem.J Orthop Sports Phys Ther. 2012; 42: 56-65Crossref PubMed Scopus (125) Google Scholar As Dr. Borek's reference demonstrates, the minimal clinically important difference may be greater in other conditions, such as spinal disease. The lack of statistical significance in the difference in Patient-Specific Functional Scale score at 17 days is not evidence of minimal efficacy. This tertiary outcome was intended to augment or attenuate the findings of the primary outcome and should not be inappropriately used for hypothesis testing. We chose a primary outcome that was a clinically meaningful time point and would minimize the sample size required, which is consistent with the ethical principle of beneficence.5National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Ethical principles and guidelines for the protection of human subjects research (Office of the Secretary). April 1979. Department of Health, Education, and Welfare. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html. Accessed August 22, 2017.Google Scholar In contrast to the depiction by Borek et al of the “higher risks” of Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV), these risks are known to be quite low.6Schaeffer T.H. Khatri V. Reifler L.M. et al.Incidence of immediate hypersensitivity reactions and serum sickness following administration of Crotalidae polyvalent immune Fab antivenom: a meta-analysis.Acad Emerg Med. 2012; 19: 121-131Crossref PubMed Scopus (47) Google Scholar Cost is important and varies greatly between individual patients. We support shared decisionmaking, including discussions of risk, benefit, and cost with the patient. We also would like more evidence. However, 20 years of research has consistently shown FabAV to be effective and safe. The results of this study, in the context of the existing evidence, demonstrate that the balance of risk and benefit favors treatment, even in a group with low clinical severity. We believe that the decision to treat copperhead envenomation is no longer solely a physician decision but should be made with the patient in a manner consistent with his or her individual values. Fab Antivenom Controversy ContinuesAnnals of Emergency MedicineVol. 70Issue 6PreviewA recent Annals article1 reports effects of Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) therapy on recovery of limb function in patients with copperhead snake envenomation, concluding that treatment with FabAV reduces limb disability 14 days after envenomation. However, we are concerned with the validity and clinical significance of the study findings and conclusions. Full-Text PDF