key: cord-0900154-fqbiu331 authors: Yamakawa, Kazuma; Yamamoto, Ryo; Ishimaru, Go; Hashimoto, Hideki; Terayama, Takero; Hara, Yoshitaka; Hasegawa, Daisuke; Ishihara, Tadashi; Imura, Haruki; Okano, Hiromu; Narita, Chihiro; Mayumi, Takuya; Yasuda, Hideto; Yamada, Kohei; Yamada, Hiroyuki; Kawasaki, Tatsuya; Shime, Nobuaki; Doi, Kent; Egi, Moritoki; Ogura, Hiroshi; Aihara, Morio; Tanaka, Hiroshi; Nishida, Osamu title: Japanese Rapid/Living recommendations on drug management for COVID‐19 date: 2021-05-04 journal: Acute Med Surg DOI: 10.1002/ams2.664 sha: 6d95f980e706dd49c1e126187abf32fed55c8a3a doc_id: 900154 cord_uid: fqbiu331 The Coronavirus disease 2019 (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 September 9, 2020, and this document is the revised edition (ver. 3.1) (released on March 30, 2021). Clinical questions (CQs) were set for the following seven drugs: favipiravir (CQ1), remdesivir (CQ‐2), hydroxychloroquine (CQ‐3), corticosteroids (CQ‐4), tocilizumab (CQ‐5), ciclesonide (CQ‐6), and anticoagulants (CQ‐7). 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 administration 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); and anticoagulant therapy 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. This article is protected by copyright. All rights reserved The coronavirus disease 2019 (COVID- 19) , an infectious disease caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that developed at the end of 2019, has spread worldwide since the beginning of 2020, and there are still no signs of resolution. Most COVID-19 patients have an asymptomatic or mild course, but some of them develop a severe and fatal course, especially the elderly and those with underlying diseases. The main pathological condition is severe respiratory failure triggered by pneumonia, but it also presents with coagulopathy and multiple organ failure, and the mechanism has not been fully elucidated. Overview and basic principles of this clinical practice guideline 1) Purpose of the guideline COVID-19 is a serious disease that affects all age groups. It is of great social significance to create reliable clinical practice guidelines to support clinical practice. A variety of clinical evidence exists around preprint servers. However, clinicians have limited time to identify high-quality information. This clinical practice guideline aims to support appropriate decision-making in COVID-19 clinical practice. The target population was adult COVID-19 patients. It covered all patients, including mildly ill patients who were undergoing medical treatment outside the medical institution (home and hotels), This article is protected by copyright. All rights reserved moderately ill patients who required supplemental oxygen or hospitalization, and severely ill patients who required intensive care management. 3) Participation of representatives of relevant expert groups and external evaluation by experts A task force within the J-SSCG 2020 Special Committee was selected to work this clinical practice guideline. All Task Force members were physicians who were familiar with the treatment of sepsis and COVID-19. One core working member (MA) was commissioned as an expert on the GRADE approach adopted in this clinical practice guideline. 4) Devising ways to reflect the values and preferences of the target group (patients and the general public) The number of people with COVID-19 was limited, and no qualitative research on the values and preferences of patients was conducted. This includes all medical professionals such as physicians, nurses, pharmacists, physiotherapists, clinical engineers, pharmacists, and registered dietitians who are engaged in or involved in COVID-19 medical care. This clinical practice guideline will be published free of charge on the websites of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine. In addition, the latest version will be released on the Making GRADE the Irresistible Choice (MAGIC) app and will be provided in a form that is easy to use in clinical settings. This clinical practice guideline was prepared with funding from the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine. None of the members received any reward for the work. Audit committee members were appointed to conduct an internal peer review of various work processes in real time. The economic conflict of interest was applied and disclosed for 3 years from 2017, in accordance with the guidance on the criteria for participation in the formulation of clinical practice guidelines of the Japanese Association of Medical Sciences. This article is protected by copyright. All rights reserved 9) Revision schedules Updates will be made accordingly as evidence is modified or added. The period for continuing revision will last until the COVID-19 epidemic period is over. The decision to end the revision will be made by the board of directors of both the academic societies. To prepare the Japanese Rapid/Living recommendations on drug management for COVID-19, the task was carried out in accordance with the GIN-McMaster guideline development checklist (extension of the Guideline Development Checklist for rapid guidelines) 1 , and the GRADE approach was adopted to determine the strength and certainty of the evidence and recommendations. According to the current situation of COVID-19 medical care in Japan, the drug with a high clinical importance was selected as a CQ among the drug therapies available in clinical practice. The selection was decided by the consensus of the Task Force members. The agreement criteria were 2/3 or more of all participating members, and the degree of disagreement was evaluated using the Rand/UCLA method 2 . (2)-1: Target patient population The target population was adult COVID-19 patients. It covered all patients, including mildly ill patients who were undergoing medical treatment outside the medical institution (home and hotels), moderately ill patients who required supplemental oxygen or hospitalization, and severely ill patients who required intensive care management. The COVID-19 severity classification is defined as shown in Table 2 with reference to the Ministry of Health, Labor, and Welfare "Clinical Management of Patients with COVID-19" 3 . As a general rule, recommendations were made according to severity and, if necessary, recommendations were presented for each target subgroup depending on the CQ. (2)-2: Intervention treatment This article is protected by copyright. All rights reserved The target drugs were selected as appropriate, taking into consideration the state of evidence collection and social conditions at that time, through the discussion and voting of the governing committee and task force. Only direct (head-to-head) comparison was included in this practice guideline: intervention treatment vs. standard treatment (or conventional care, placebo treatment) of interest. The importance of outcomes was graded using a 1-9 point scale (9 being most patient-important). Ultimately, we set three significant patient outcomes (ie, rated scale of 7-9) for making recommendations: all-cause mortality, clinical improvement, and serious adverse events. As a general rule, the outcome was measured 28 days after the intervention, but depending on the evidence obtained, if there were no (or few) outcomes after 28 days, we also adopted those after 7 or 14 days. The "GRADE-ADOLOPMENT" approach to guideline production combines adoption, adaptation, and, as needed, de novo development of recommendations. The information sources of existing evidence synthesis which we used is the COVID-living NMA (https://covidnma.com/living_data/index.php) and PubMed Central. We also included non-peer-reviewed preprint server articles. Conference abstracts and press releases were not adopted. This ver. 3.1 is created based on the evidence obtained as of February 28, 2021. We assessed the certainty of evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach, and rated the certainty for each outcome as high This article is protected by copyright. All rights reserved (RCTs) and the risk of bias in non-randomized studies of interventions (ROBINS-I) tool 5 for nonrandomized studies. (4)-2: Calculation of net effect estimates for overall outcomes (net effect estimate) The GRADE Working Group introduced the concept of certainty of net benefit to clarify and simplify methodology to report and assess the balance of benefits and harms in the context of fully contextualizing certainty of evidence across outcomes 6 . Specifically, it can be predicted that the three critical outcomes set in this guideline are not equally patient-important. Therefore, to evaluate the balance between benefit and harm, the effects of these outcomes were integrated by taking into account the difference in importance (utility value), and the importance-adjusted net effect estimate was then calculated. The overall imprecision across outcomes was assessed based on the magnitude and confidence intervals of the calculated net effect estimates. The Panel Committee determined direction and strength of recommendation using the GRADE/DECIDE Evidence-to-Decision frameworks 7 , which includes four key criteria (certainty of evidence, balance of benefits and harms, patient values and preferences, cost/resource use), as well as acceptability and feasibility. According to GRADE/Evidence-to-Decision, the Panel graded the strength of recommendations as strong or conditional (for or against intervention of interest). If the overall certainty of evidence across the critical outcome was very low, however, it was decided to be no recommendation. The Panel Committee voted to reach consensus using the Rand/UCLA appropriateness method 2 . For the rapid publication of recommendations, the MAGIC Authoring and Publication Platform (MAGICapp) was utilized, designed by MAGIC that supports efficient guideline writing, dissemination, dynamic updating, and consultation decision-making in the medical field 8 . This article is protected by copyright. All rights reserved requiring ventilator management/intensive care (no recommendation) Favipiravir is an antiviral drug approved in March 2014 for new or re-emerging influenza virus infections. The effect on RNA virus is expected due to the selective inhibition of RNA polymerase by the triphosphorylated product converted in vivo. Since the early days of the pandemic, drugs have been provided for compassionate use, and multiple RCTs have been conducted. Although the drug is expected to be effective against COVID-19, its efficacy has not been determined, and it is likely to have great clinical significance in planning CQs (Fig.2 ). • Balance of benefits and harm. In five RCTs 9-13 with 579 cases, point estimates were expected to have a moderate effect on clinical improvement in 7-11 days (an increase of 129 per 1000). Serious adverse events were unlikely to occur, but the previously mentioned teratogenicity should be noted. The assessment of mortality outcomes was inadequate because the patients targeted for RCTs had predominantly mild symptoms. Based on the above statements, on the balance between benefit and harm, it was determined that favipiravir administration was more beneficial for patients with mild COVID-19. However, for patients with moderate and severe COVID-19, the balance between the benefits and harms of favipiravir could not be determined. The certainty of evidence was judged to be " moderate " or "low" in terms of clinical improvement, all-cause mortality, and serious adverse events. Taking this direction into consideration, the overall certainty of evidence was judged to be "low" for mild COVID-19 patients and "no adopted studies" for patients with moderate or severe COVID-19. and SARS-CoV-2. It is a drug whose therapeutic target is RNA-dependent RNA polymerase, which is essential for the self-renewal of RNA viruses. In Japan, it was approved as a therapeutic drug for the novel coronavirus infection on May 7, 2020, under the "special approval system." It was officially approved in the United States on October 22, 2020. Therefore, it is considered to be of great clinical significance in planning CQs (Fig.3 ). There were four RCTs 14-17 with the adopted evidence. The effect on all-cause mortality in patients For mild COVID-19, the range of estimated effects was wide and undeterminable, and for moderate COVID-19, the benefit of remdesivir administration was determined to be greater. However, it was determined that the harm caused by the administration of remdesivir would be greater in severe COVID-19 patients. The certainty of evidence for each outcome ranged from "low" to " moderate." Analysis was performed according to the severity, and it was judged to be "low" for mild COVID-19, "moderate" for moderate COVID-19, and " moderate" for severe COVID-19. • Others (tolerability and feasibility). On November 20, 2020, the World Health Organization made a conditional recommendation, but no severity classification was made. Although the recommended directions differ between moderate and This article is protected by copyright. All rights reserved severe, it is difficult to make a strict distinction between these two severities. However, recommendations may change due to the accumulation of evidence. Recommendation  We recommend against hydroxychloroquine administration to all COVID-19 patients (strong recommendation/moderate certainty of evidence: GRADE 1B). Hydroxychloroquine is a therapeutic agent for malaria and has been used for the treatment of autoimmune diseases because of its immunomodulatory effects. In Japan, its manufacturing and marketing were approved in July 2015 for systemic lupus erythematosus. In recent years, it has become known for its antiviral effect against coronaviruses that cause SARS and MERS. Once it was found to have in vitro activity against SARS-CoV-2, it has been used mainly in the United States as a drug expected to be effective against COVID-19. However, its effectiveness has not been determined, and it was judged that the clinical significance was significant in CQ planning (Fig.4 ). There were 17 RCTs 18-34 with the adopted evidence. In 16 RCTs with 9767 cases, the absolute effect on all-cause mortality at 28 days was expected to increase by 12 per 1000 according to point estimation. In addition, in seven RCTs with 6428 cases, the clinical improvement on day 28 was expected to increase by 6 per 1000. On the contrary, in 14 RCTs with 7314 cases, serious adverse events were expected to increase by 2 per 1000. When the relative importance of mortality outcomes fluctuated between 1-5 times the other outcomes, the net effect estimate for adverse effects increased from 8 to 56 per 1000. In either case, the point estimates indicate the harm of hydroxychloroquine. Therefore, it was determined that the harm caused by hydroxychloroquine administration was greater than the benefit. The certainty of evidence for all-cause mortality, clinical improvement, and serious adverse events was judged to be "high," "high," and "low," respectively. Considering the imprecision of the net effect estimate across all outcomes, the overall certainty of evidence was set to be "moderate." This article is protected by copyright. All rights reserved Various types of corticosteroids have been used for the treatment of various diseases for a long time. It is speculated that the mechanism by which COVID-19 becomes severe is that organ damage occurs due to an excessive immune response to the host, such as viral pneumonia (H5N1 influenza, SARS, and H1N1 influenza) that were prevalent in the past. Corticosteroids are expected to attenuate immune responses. Therefore, CQ planning is considered to have a significant clinical significance (Fig.5 ). • Balance of benefits and harm. There were seven RCTs [35] [36] [37] [38] [39] [40] [41] with the adopted evidence. In the mild COVID-19 group, one RCT with 1535 cases was adopted, and no effect was expected on all-cause mortality. No data were available for clinical improvement or any serious adverse events. In the moderate COVID-19 group, four RCTs with 4314 cases were adopted, and a moderate effect was expected in all-cause mortality and clinical improvement (decrease of 156 per 1000). No data were available for serious adverse events. In the severe COVID-19 group, five 5RCTs with 1967 were adopted, and it was expected to have a great effect on all-cause mortality and clinical improvement (decrease of 284 per 1000). There were a few serious adverse events. Therefore, regarding the balance of benefit and harm, it was judged that the benefit was superior in moderate/severe COVID-19 patients, and the harm was greater in mild COVID-19 patients. • Certainty of evidence Only one outcome was adopted for mild COVID-19, and the overall certainty of evidence was "moderate." It was rated as "moderate" in the moderate and "high" in the severe groups. This article is protected by copyright. All rights reserved Corticosteroid pulse therapy is a treatment method that has been investigated for its effectiveness in patients with viral pneumonia, such as SARS, and in patients with extremely severe respiratory failure, such as acute respiratory distress syndrome, to whom high-dose corticosteroids are administered. It is a treatment method that sets it apart from other corticosteroid therapies, and a new CQ was developed for patients with severe illness. • Balance of benefits and harm. We adopted one RCT for hospitalized patients 42 . This RCT determined that the target patients were admitted to the intensive care unit but was not ventilated. As such, it was classified as "moderate" in the classification of this guideline. However, approximately 75% received high-flow or highconcentration oxygen therapy and targeted the more severe group among patients with moderate COVID-19. Sixty-two cases were adopted, and a large effect was expected in all-cause mortality at the time of discharge (decrease of 369 per 1000). No data were available for clinical improvement, and serious adverse events were expected to have a slight effect (13 per 1000 reductions). However, the quality of the RCT was low, the dose of corticosteroids was different from the general dose in Japan, and the overall certainty of evidence was very low. As such, the balance of the effects was unclear. • Certainty of evidence The overall certainty of evidence was set to "very low." This article is protected by copyright. All rights reserved Increased production of inflammatory cytokines, including interleukin 6 (IL-6), has been reported to be associated with disease progression in COVID-19 patients. Tocilizumab, an IL-6 receptor antagonist, is expected to suppress the action of inflammatory cytokines in COVID-19 patients and improve prognosis. As such, many clinical studies have been conducted; however, its effectiveness has not been clarified. This CQ was formulated because it is likely to have great clinical significance as a candidate for COVID-19 therapeutic drugs (Fig.6 ). • Balance of benefits and harm. In nine RCTs 43-51 with 6376 cases of severe/moderate COVID-19 inpatients, tocilizumab for moderate COVID-19 was expected to decrease all-cause mortality by 29 per 1000 and increase clinical improvement by 45 per 1000 on day 28. The incidence of serious adverse events did not increase (a decrease of 25 per 1000). For severe COVID-19, a decrease of 20 per 1000 was expected for all-cause mortality at 28 days, and an increase of 24 per 1000 for improvement of clinical symptoms. The incidence of serious adverse events did not increase (7 per 1000 decrease). Based on the above statements, it was determined that the benefit of tocilizumab administration would outweigh harm in moderate COVID-19 patients. In critically ill patients, the certainty of evidence for the overall outcome was very low; therefore, we decided not to specify the recommendation. The balance between the benefits and harm of tocilizumab was undeterminable in patients with mild COVID-19. The certainty of evidence for each outcome was "moderate" in moderate COVID-19 patients and "low" in severe COVID-19 patients. Considering the net effect estimate, the overall certainty of evidence was judged to be "moderate" for moderate COVID-19 patients and "very low" for severe COVID-19 patients. This article is protected by copyright. All rights reserved patients (no recommendation). Ciclesonide is an inhaled corticosteroid used worldwide for the treatment of bronchial asthma. It is one of the drugs widely used for the treatment of COVID-19 in Japan because the effectiveness of the drug was reported at the beginning of the COVID-19 pandemic. However, the drug is not frequently used as a therapeutic drug in other countries, and its effectiveness is controversial. Therefore, it likely has a great clinical significance as to whether or not the drug should be used as a therapeutic drug for COVID-19, and this CQ was formulated. Regarding ciclesonide inhalation, no RCTs with officially published results as of February 28, 2021, were found in the living SR. Similarly, non-randomized studies were also unavailable there. Therefore, in this CQ, we performed our own additional search on PubMed, CENTRAL and others As a result, one observational study 52 that suggested the benefits of ciclesonide was extracted. However, the risk of bias was high, such as unadjusted confounding factors, and the sample size was very small (n = 23). From the viewpoint of quality, this study was not included in the analysis. Based on the above statements, it was determined that it is not possible to present a clear recommendation at this time. On the contrary, some of the results of the RACCO Study (jRCTs031190269), an RCT for asymptomatic and mild COVID-19 patients in Japan, were released. It should be noted that the result refuted the benefit of ciclesonide (in the ciclesonide group, exacerbation of pneumonia on chest computed tomography was significantly higher). This article is protected by copyright. All rights reserved 1. Background Coagulopathy due to angiopathy associated with viral infection is considered a pathological condition of COVID-19. Pulmonary embolism is one of the causes of death from COVID-19, and it is expected that prevention of thrombus formation will lead to improvement in patient prognosis. There are two administration methods for anticoagulant therapy: prophylactic and therapeutic. Given that the clinical significance of examining the effectiveness of anticoagulant therapy itself, including the dose, is likely great, this CQ was formulated (Fig.7) . Based on the above statements, it was determined that the benefits of anticoagulant therapy would outweigh the harm in patients with moderate and severe COVID-19. There was no evidence for anticoagulant therapy in patients with mild COVID-19 and, therefore, it was indeterminate. For all-cause mortality, VTE, and severe bleeding outcomes, the certainty of evidence was "low" for both prophylactic and therapeutic doses. Therefore, the overall certainty of evidence was judged to be "low". Development of rapid guidelines: 3. 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All rights reserved Thrombotic complications and anticoagulation in COVID-19 pneumonia: a New York City hospital experience The impact of protocol-based high-intensity pharmacological thromboprophylaxis on thrombotic events in critically ill COVID-19 patients COVID-19 associated coagulopathy: Thrombosis, hemorrhage and mortality rates with an escalated-dose thromboprophylaxis strategy COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection High rates of 30 day mortality in patients with cirrhosis and COVID-19 Anticoagulation and bleeding risk in patients with COVID-19 Incidence of thrombosis and hemorrhage in hospitalized cancer patientswith COVID-19 Incidence of symptomatic, imageconfirmed venous thromboembolism following hospitalization for COVID-19 with 90-day follow-up Association of Treatment Dose Anticoagulation With In-Hospital SurvivalAmong Hospitalized Patients With COVID-19 We would like to thank Editage (www.editage.jp) for their English language editing, and Mr. Tsuda (Davinci Medical Illustration Office) for their medical illustration service.