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  • Fernando Tortosa

Early high-titer plasma therapy for COVID-19: A call for caution

Actualizado: feb 5

  • Ragusa Martin, MD.

  • Tortosa Fernando, MD. MSc

  • Hugo Norberto Catalano, MD, PhD.

  • Ariel Izcovich, MD, PhD, GDCE.



We read with great interest the study by Libster et al. and congratulate the authors for such an effort in such exceptional circumstances.[1] However we think that the study has several limitations whose consideration is essential for its proper interpretation.


In the first place as stated by Kaptz,[2] the proposed approach of identifying and treating high risk patients with early non-severe symptoms might not be feasible as it would probably stress out the healthcare system by diverging resources to a subgroup of patients that would not develop severe disease even if not treated. Other potential barriers include patients' preferences for not abandoning their homes (in the study 34% initially eligible were not included because they refused to receive the intervention for this reason or became ineligible) and insufficient plasma provision to massively treat all patients with risk factors and early symptoms.


In second place, the following methodological limitations should be accounted for when assessing the certainty in the reported estimates of effect:


  1. Primary efficacy outcome is a surrogate: “severe disease” (defined as tachypnea or hypoxemia) is a substitute outcome of uncertain significance. Its association with death is necessary but not sufficient to consider it a valid surrogate.[3,4] Furthermore, of the 38 patients that developed the primary outcome (“severe disease”) only 10 (26%) were treated with oxygen flow of 100%. It is not clear how the reported reduction in this “severe” but not so “severe” condition would translate to critical outcomes like invasive mechanical ventilation requirements or death. In addition the fact that the outcome was defined by measurements like respiratory rate or SaO2 which have significant variability over short periods of time makes it particularly vulnerable to outcome-measurement bias. We acknowledge that the authors approached this issue by blinding patients, healthcare providers and outcome assessors. However, local transfusion medicine teams, in charge of administering the intervention and monitoring patients in the first 12 hours after the infusion, were aware of the study arm which may have compromised the blinding of the outcome assessors.

  2. The primary outcome estimate of effect is fragile: Overall, the number of participants that developed the primary outcome was 38 (13 in the intervention and 25 in control). Calculated fragility index is 1 (https://clincalc.com/Stats/FragilityIndex.aspx) which means that if one patient in the experimental group was "converted" from not having the primary endpoint to having the primary endpoint, the estimate of effect would lose statistical significance (p> 0.05).[5] This issue becomes even more relevant by considering that the authors stopped the study early in the context of a large benefit which might have resulted in an overestimation of the treatment effects.[6]


In conclusion, we consider that the results reported by Libster et al. place convalescent plasma in the list of potentially useful interventions for treating patients with COVID-19. However, above mentioned limitations make it imperative to exert caution until adequately powered studies measuring critical outcomes confirm or discard these findings.



References

  1. Libster R, Pérez Marc G, Wappner D, Coviello S, Bianchi A, Braem V, et al. Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. N Engl J Med. 2021 Jan 6;NEJMoa2033700

  2. Katz LM. (A Little) Clarity on Convalescent Plasma for Covid-19. N Engl J Med [Internet]. 2021 Jan 13 [cited 2021 Jan 22]; Available from: https://doi.org/10.1056/NEJMe2035678

  3. Izcovich A, Ragusa MA, Tortosa F, Lavena Marzio MA, Agnoletti C, Bengolea A, et al. Prognostic factors for severity and mortality in patients infected with COVID-19: A systematic review. Lazzeri C, editor. PLoS ONE. 2020 Nov 17;15(11):e0241955

  4. Walter SD, Sun X, Heels-Ansdell D, Guyatt G. Treatment effects on patient-important outcomes can be small, even with large effects on surrogate markers. Journal of Clinical Epidemiology. 2012 Sep;65(9):940–5.

  5. Walsh M, Srinathan SK, McAuley DF, Mrkobrada M, Levine O, Ribic C, et al. The statistical significance of randomized controlled trial results is frequently fragile: a case for a Fragility Index. J Clin Epidemiol. 2014 Jun;67(6):622–8.

  6. Bassler D, Briel M, Montori VM, Lane M, Glasziou P, Zhou Q, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA. 2010 Mar 24;303(12):1180–7.





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