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Review 1: "Non-invasive Vagus Nerve Stimulation for Respiratory Symptoms of COVID-19: Results From a Randomized Controlled Trial (SAVIOR I)"

This preprint claims that nVNS therapy has the potential to reduce pro-inflammatory cytokines in patients with COVID-19. Both reviewers agree on the importance of the issues it raised. They suggested the inclusion of cost-effectiveness analysis in the ongoing SAVIOR II trial.

Published onOct 28, 2021
Review 1: "Non-invasive Vagus Nerve Stimulation for Respiratory Symptoms of COVID-19: Results From a Randomized Controlled Trial (SAVIOR I)"
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key-enterThis Pub is a Review of
Non-invasive Vagus Nerve Stimulation for Respiratory Symptoms of COVID-19: Results From a Randomized Controlled Trial (SAVIOR I)

ABSTRACTBackgroundSevere coronavirus disease 2019 (COVID-19) is characterized, in part, by an excessive inflammatory response. Evidence from animal and human studies suggests that vagus nerve stimulation can lead to reduced levels of various pro-inflammatory cytokines. We conducted a prospective randomized controlled study (SAVIOR-I) to assess the feasibility, efficacy, and safety of non-invasive vagus nerve stimulation (nVNS) for the treatment of respiratory symptoms and inflammatory markers among patients who were hospitalized for COVID-19 ( identifier: NCT04368156).MethodsParticipants were randomly assigned in a 1:1 allocation to receive either the standard of care (SoC) alone or nVNS therapy plus the SoC. The nVNS group received 2 consecutive 2-minute doses of nVNS 3 times daily as prophylaxis. Efficacy and safety were evaluated via the incidence of specific clinical events, inflammatory biomarker levels, and the occurrence of adverse events.ResultsOf the 110 participants who were enrolled and randomly assigned, 97 (nVNS, n=47; SoC, n=50) had sufficient available data and comprised the evaluable population. C-reactive protein (CRP) levels decreased from baseline to a significantly greater degree in the nVNS group than in the SoC group at day 5 and overall (ie, all postbaseline data points collected through day 5, combined). Procalcitonin level also showed significantly greater decreases from baseline to day 5 in the nVNS group than in the SoC group. D-dimer levels were decreased from baseline for the nVNS group and increased from baseline for the SoC group at day 5 and overall, although the difference between the treatment groups did not reach statistical significance. No significant treatment differences were seen for clinical respiratory outcomes or any of the other biochemical markers evaluated. No serious nVNS-related adverse events occurred during the study.ConclusionsnVNS therapy led to significant reductions in levels of inflammatory markers, specifically CRP and procalcitonin. Because nVNS has multiple mechanisms of action that may be relevant to COVID-19, additional research into its potential to be used earlier in the course of COVID-19 and possibly mitigate some of the symptoms associated with post-acute COVID-19 syndrome is warranted.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



The manuscript, "Non-invasive Vagus Nerve Stimulation for Respiratory Symptoms of COVID-19: Results From a Randomized Controlled Trial (SAVIOR I)," reports the results from a randomized controlled clinical trial to investigate the safety, efficacy, and feasibility of using non-invasive vagus nerve stimulation (nVNS) during the treatment of hospitalized patients with COVID-19. The study assessed 97 from 110 enrolled participants. Positive results were seen in some inflammatory biomarkers. To my knowledge, this is one of the more extensive studies in the field. It was adequately registered at, but its primary objective (reinforced by the title) was to assess the clinical effects of nVNS. However, the results highlight surrogate (inflammatory) and not clinical results. Since there are potential conflicts of interest regarding the study results, using a clinically oriented title and presenting a positive surrogate result may be an essential bias. Also, the authors must state what type of hypothesis they had regarding the results of the study. Were they testing equivalence, non-inferiority, or superiority?

Non-invasive vagus nerve stimulation may be applied with a diversity of devices. For example, adding measures of the Number Needed to Treat or to Harm and cost-effectiveness measures would be desired in this study since the actual study used a costly intervention (nVNS with gammaCore Sapphire™).

Other aspects of the study that should be reviewed:
* Statistical differences between study groups at baseline should be presented in table 3;
* CRP is a numerical endpoint with absolute values. Why was this variable analyzed as percentages of subjects with normal values? This procedure reduces the possibilities of robust statistical analysis done with numerical values (nominal scale);
* Regarding safety, how was it assessed systematically? Please, provide data regarding instruments used to evaluate the safety, and the participants' responses.

Alexa Beynon:

Thank you for this thoughtful review raising several important points about the SAVIOR I trial. You highlight well the need to interpret the biomarker improvements cautiously given the lack of clear clinical endpoint data. And citing potential conflicts of interest with the device manufacturer is prudent context as well.I agree including health economics data around the costs/affordability of the nVNS units would also help decision-makers weigh any surrogate marker benefits versus financial resources needed.Additionally, your note about clearly stating the hypothesis type (equivalence vs superiority) is well taken to frame expectations. As well as ensuring the baseline characteristics are sufficiently randomized as shown in Table 3.Finally, systematic tracking of safety via specific metrics would also give helpful assurance this intervention is well-tolerated.In summary, while the immunologic signals are intriguing early data, your review nicely captures the current limitations according to RCT best practices - highlighting the need to anchor any provisional findings free template with further evidence tying outcomes to patient benefit rather than just biomarkers alone. Thank you again for these insights guiding appropriate appraisal!

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