Japanese rapid/living recommendations on drug management for COVID-19

Abstract

The coronavirus disease (COVID-19) has spread worldwide since early 2020, and there are still no signs of resolution. The Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (J-SSCG) 2020 Special Committee created the Japanese rapid/living recommendations on drug management for COVID-19 using the experience of creating the J-SSCGs. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to determine the certainty of the evidence and strength of the recommendations. The first edition of this guideline was released on 9 September, 2020, and this document is the revised edition (version 3.1) (released 30 March, 2021). Clinical questions (CQs) were set for the following seven drugs: favipiravir (CQ1), remdesivir (CQ2), hydroxychloroquine (CQ3), corticosteroids (CQ4), tocilizumab (CQ5), ciclesonide (CQ6), and anticoagulants (CQ7). Favipiravir is recommended for patients with mild COVID-19 not requiring supplemental oxygen (GRADE 2C); remdesivir for moderate COVID-19 patients requiring supplemental oxygen/hospitalization (GRADE 2B). Hydroxychloroquine is not recommended for all COVID-19 patients (GRADE 1B). Corticosteroids are recommended for moderate COVID-19 patients requiring supplemental oxygen/hospitalization (GRADE 1B) and severe COVID-19 patients requiring ventilator management/intensive care (GRADE 1A); however, their use is not recommended for mild COVID-19 patients not requiring supplemental oxygen (GRADE 1B). Tocilizumab is recommended for moderate COVID-19 patients requiring supplemental oxygen/hospitalization (GRADE 2B). Anticoagulant therapy is recommended for moderate COVID-19 patients requiring supplemental oxygen/hospitalization and severe COVID-19 patients requiring ventilator management/intensive care (GRADE 2C). We hope that these clinical practice guidelines will aid medical professionals involved in the care of COVID-19 patients.

Keywords: Coronavirus; GRADE approach; SIRS‐CoV‐2; evidence‐based medicine; practice guideline.

Fig. 1

Visual summary of recommendations on drug management for COVID‐19. For each medication, recommendations are provided depending on the severity of COVID‐19: mild, moderate, and severe.

Fig. 2

Recommendations of favipiravir for COVID‐19. We suggest favipiravir administration to mild COVID‐19 patients and have not made a clear recommendation on favipiravir administration to moderate and severe COVID‐19 patients. Net effect estimates of favipiravir in patients with mild COVID‐19 were calculated with the effects of each outcome, in which importance of mortality was considered as five times higher than those of other outcomes. Overall imprecision across outcomes was assessed as “likely net benefit”, based on the magnitude of point estimate and 95% confidence intervals of the calculated net effect estimates. CoE, certainty of evidence; GRADE, Grades of Recommendation, Assessment, Development, and Evaluation; SAE, severe adverse events.

Fig. 3

Recommendations of remdesivir for COVID‐19. We have not made a clear recommendation on remdesivir administration to mild COVID‐19 patients, suggest remdesivir administration to moderate COVID‐19 patients, and suggest against remdesivir administration to severe COVID‐19 patients. Net effect estimates of remdesivir in patients with moderate and severe COVID‐19 were calculated with the effects of each outcome, in which importance of mortality was considered as twice higher in moderate COVID‐19 and three times higher in severe COVID‐19, compared with those of other outcomes. Overall imprecisions across outcomes were assessed as “net benefit” in moderate COVID‐19 and “likely net benefit” in severe COVID‐19, based on the magnitude of point estimate and 95% confidence intervals of the calculated net effect estimates. CoE, certainty of evidence; GRADE, Grades of Recommendation, Assessment, Development, and Evaluation; SAE, severe adverse events.

Fig. 4

Recommendations of hydroxychloroquine for COVID‐19. We recommend against hydroxychloroquine administration to mild, moderate, and severe COVID‐19 patients. Net effect estimates of hydroxychloroquine in patients with mild, moderate, and severe COVID‐19 were calculated with the effects of each outcome, in which importance of mortality was considered as three times higher than those of other outcomes. Overall imprecision across outcomes was assessed as “likely net harm”, based on the magnitude of point estimate and 95% confidence intervals of the calculated net effect estimates. CoE, certainty of evidence; GRADE, Grades of Recommendation, Assessment, Development, and Evaluation; SAE, severe adverse events.

Fig. 5

Recommendations of corticosteroid for COVID‐19. We recommend against corticosteroid administration to mild COVID‐19 patients and recommend corticosteroid administration to moderate and severe COVID‐19 patients. Net effect estimates of corticosteroid in patients with severe COVID‐19 were calculated with the effects of each outcome, in which importance of mortality was considered as three times higher than those of other outcomes. Overall imprecisions across outcomes were assessed as “net benefit”, based on the magnitude of point estimate and 95% confidence intervals of the calculated net effect estimates. CoE, certainty of evidence; GRADE, Grades of Recommendation, Assessment, Development, and Evaluation; SAE, severe adverse events.

Fig. 6

Recommendations of tocilizumab for COVID‐19. We have not made a clear recommendation on tocilizumab administration to mild and severe COVID‐19 patients and suggest tocilizumab administration to moderate COVID‐19 patients. Net effect estimates of tocilizumab in patients with moderate and severe COVID‐19 were calculated with the effects of each outcome, in which importance of mortality was considered as twice higher than those of other outcomes. Overall imprecisions across outcomes were assessed as “net benefit” in moderate COVID‐19 and “possible net benefit” in severe COVID‐19, based on the magnitude of point estimate and 95% confidence intervals of the calculated net effect estimates. CoE, certainty of evidence; GRADE, Grades of Recommendation, Assessment, Development, and Evaluation; SAE, severe adverse events.

Fig. 7

Recommendations of anticoagulants for COVID‐19. We have not made a clear recommendation on anticoagulant administration to mild COVID‐19 patients and suggest anticoagulant administration to moderate and severe COVID‐19 patients. Net effect estimates of prophylactic and therapeutic anticoagulants in patients with moderate and severe COVID‐19 were calculated with the effects of each outcome, in which importance of mortality was considered as twice higher than those of other outcomes. Overall imprecisions across outcomes were assessed as “net benefit” for both prophylactic and therapeutic anticoagulants, based on the magnitude of point estimate and 95% confidence intervals of the calculated net effect estimates. CoE, certainty of evidence; GRADE, Grades of Recommendation, Assessment, Development, and Evaluation; VTE, venous thromboembolism.