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, evidence‐based medicine, GRADE approach, practice guideline, SIRS‐CoV‐2
BACKGROUND
The coronavirus disease (COVID‐19), an infectious disease caused by the novel 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.
Stringent policies have been implemented to control infectious diseases worldwide, such as lockdowns. Medical care to save the lives of COVID‐19 patients is being offered day and night in the medical field. Based on the intensity and urgency of the social impact, clinical evidence of various qualities is being published daily in preprint and top journals regarding various drug therapies. In the presence of evidence of varying quality, clinicians have limited time to sift through the reliable evidence needed for decision making.
Therefore, the Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (J‐SSCG) 2020 Special Committee, jointly organized by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, made use of their experience to create the J‐SSCG based on the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system. We aimed to create a special edition specializing in the COVID‐19 drug management in order to provide the latest information on the websites of both societies and support evidence‐based medical care. The first edition of this clinical practice guideline was released on 9 September, 2020. This document is the revised 3.1 edition (released 30 March, 2021) (Table 1, Fig. 1).
Table 1.
Clinical questions (CQ) and recommendations
| CQ1 | Should favipiravir be administered to COVID‐19 patients? |
| Recommendation |
|
| CQ2 | Should remdesivir be administered to COVID‐19 patients? |
| Recommendation |
|
| CQ3 | Should hydroxychloroquine be administered to COVID‐19 patients? |
| Recommendation |
|
| CQ4‐1 | Should corticosteroid be administered to COVID‐19 patients? |
| Recommendation |
|
| CQ4‐2 | Should corticosteroid pulse therapy be administered to moderate/severe COVID‐19 patients? |
| Recommendation |
|
| CQ5 | Should tocilizumab be administered to COVID‐19 patients? |
| Recommendation |
|
| CQ6 | Should ciclesonide be administered by inhalation to COVID‐19 patients? |
| Recommendation |
|
| CQ7 | Should anticoagulants be administered to COVID‐19 patients? |
| Recommendation |
|
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.
OVERVIEW AND BASIC PRINCIPLES OF THIS CLINICAL PRACTICE GUIDELINE
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.
Target patient population for the recommendations
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.
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.
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 carried out.
Users of this clinical practice guideline
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.
Dissemination of this clinical practice guideline
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.
Funding
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 remuneration for the work.
Transparency in creating clinical practice guidelines
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.
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.
METHOD OF PREPARING THIS CLINICAL PRACTICE GUIDELINE
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.
Scope and clinical question planning
According to the current situation of COVID‐19 medical care in Japan, of the drug therapies available in clinical practice, those drugs with high clinical importance were selected as the focus of clinical questions (CQ). The selection was decided by the consensus of the Task Force members. The agreement criteria were two‐thirds or more of all participating members, and the degree of disagreement was evaluated using the Rand/UCLA method. 2
PICOT settings for recommendations
For a fully formulated comparative effectiveness systematic review topic as the base of recommendations, key questions in their final form concretely specify the patient populations, interventions, comparators, outcome measures of interest, timing (PICOT) to be addressed in the review.
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.
Table 2.
COVID‐19 severity classification in this guideline
| Severity | Oxygen saturation | Clinical condition | Place of medical treatment |
|---|---|---|---|
| Mild | SpO2 > 93% |
No respiratory symptoms Cough only, no shortness of breath |
Need medical treatment outside the medical institution (home and hotels) |
| Moderate | SpO2 ≤ 93% |
Shortness of breath, symptoms of pneumonia Oxygen administration required |
Need hospitalization at a medical institution |
| Severe | Need a mechanical ventilator | Need treatment in the intensive care unit |
SpO2, saturated oxygen in arterial blood.
Intervention treatment
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.
Comparison
Only direct (head‐to‐head) comparison was included in this practice guideline: intervention treatment versus standard treatment (or conventional care, placebo treatment) of interest.
Outcome
The importance of outcomes was graded using a 1–9 point scale (9 being most patient‐important). Ultimately, we set three significant patient outcomes (i.e., rated scale of 7–9) for making recommendations: all‐cause mortality, clinical improvement, and serious adverse events.
Time frame
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.
GRADE‐ADOLOPMENT for development of practical and trustworthy guideline
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 that we used is the COVID‐living NMA (https://covid‐nma.com/) and PubMed Central. We also included non‐peer‐reviewed preprint server articles. Conference abstracts and press releases were not adopted. This version 3.1 is created based on the evidence obtained as of 28 February, 2021.
Evaluation of the certainty of body of evidence using GRADE
Definition and evaluation method for the certainty of evidence
We assessed the certainty of evidence using the GRADE approach, and rated the certainty for each outcome as high (A), moderate (B), low (C), or very low (D) based on the following: eight factors of GRADE, that is, five factors might lead to the rating down of the certainty of evidence (risk of bias [RoB], inconsistency, indirectness, imprecision, and publication bias), and three factors might lead to the rating up (large effect, plausible confounding, and dose–response gradient). For individual studies and the overall evidence of RoB, Cochrane RoB 2.0 4 was used for randomized controlled trials (RCTs) and the risk of bias in non‐randomized studies of interventions (ROBINS‐I) tool 5 for non‐randomized studies.
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.
Formulation of recommendations and consensus building
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
Prompt disclosure of recommendations
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
RECOMMENDATIONS AND THEIR RATIONALES
CQ1: Should favipiravir be administered to COVID‐19 patients?
Recommendation
-
✓
We suggest favipiravir administration to mild COVID‐19 patients who do not require oxygen (weak recommendation/low certainty of evidence: GRADE 2C).
-
✓
We have not made a clear recommendation on favipiravir administration to moderate COVID‐19 patients requiring oxygen/inpatient care and severe COVID‐19 patients requiring ventilator management/intensive care (no recommendation).
Background
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 carried out. 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).
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.
Balance of benefits and harm
In five RCTs 9 , 10 , 11 , 12 , 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 1,000). 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.
Certainty of evidence
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.
CQ2: Should remdesivir be administered to COVID‐19 patients?
Recommendation
-
✓
We have not made a clear recommendation on remdesivir administration to mild COVID‐19 patients who do not require oxygen (no recommendation).
-
✓
We suggest remdesivir administration to moderate COVID‐19 patients requiring oxygen/hospitalization (weak recommendation/moderate certainty of evidence: GRADE 2B).
-
✓
We suggest against remdesivir administration to severe COVID‐19 patients requiring mechanical ventilation/intensive care (weak recommendation/moderate certainty of evidence: GRADE 2B).
Background
Remdesivir, developed as a therapeutic drug for Ebola hemorrhagic fever and Marburg virus infection, has been shown to have antiviral activity against single‐stranded RNA viruses such as Middle East respiratory syndrome (MERS) virus, severe acute respiratory syndrome (SARS) virus, 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 7 May, 2020, under the “special approval system.” It was officially approved in the United States on 22 October, 2020. Therefore, it is considered to be of great clinical significance in planning CQs (Fig. 3).
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.
Balance of benefits and harm
There were four RCTs 14 , 15 , 16 , 17 with the adopted evidence. The effect on all‐cause mortality in patients with mild COVID‐19 is unclear (a decrease of 3 per 1,000). Small effects were expected for all‐cause mortality (decrease of 22 per 1,000) and clinical improvement (increase of 68 per 1,000) in patients with moderate COVID‐19. No effect was expected for all‐cause mortality (increase of 62 per 1,000) or clinical improvement (decrease of 20 per 1,000) in patients with severe COVID‐19. There was no increase in the incidence of serious adverse events in patients with moderate and severe COVID‐19 (a decrease of 61 per 1,000).
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.
Certainty of evidence
The certainty of evidence for each outcome ranged from “low” to “moderate.” Analysis was undertaken 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 20 November, 2020, the World Health Organization made a conditional recommendation, but no severity classification was made. Although the recommended directions differ between moderate and severe, it is difficult to make a strict distinction between these two severities. However, recommendations may change due to the accumulation of evidence.
CQ3: Should hydroxychloroquine be administered to COVID‐19 patients?
Recommendation
-
✓
We recommend against hydroxychloroquine administration to all COVID‐19 patients (strong recommendation/moderate certainty of evidence: GRADE 1B).
Background
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).
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.
Balance of benefits and harm
There were 17 RCTs 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 with the adopted evidence. In 16 RCTs with 9,767 cases, the absolute effect on all‐cause mortality at 28 days was expected to increase by 12 per 1,000 according to point estimation. In addition, in seven RCTs with 6,428 cases, the clinical improvement on day 28 was expected to increase by 6 per 1,000. On the contrary, in 14 RCTs with 7,314 cases, serious adverse events were expected to increase by 2 per 1,000. 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 1,000. 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.
Certainty of evidence
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.”
CQ4‐1: Should corticosteroid be administered to COVID‐19 patients?
Recommendation
-
✓
We recommend against corticosteroid administration to mild COVID‐19 patients who do not require oxygen (strong recommendation/moderate certainty of evidence: GRADE 1B).
-
✓
We recommend corticosteroid administration to moderate COVID‐19 patients requiring oxygen/hospitalization (strong recommendation/moderate certainty of evidence: GRADE 1B).
-
✓
We recommend corticosteroid administration to severe COVID‐19 patients requiring ventilator management/intensive care (strong recommendation/high certainty of evidence: GRADE 1A).
Background
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).
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.
Balance of benefits and harm
There were seven RCTs 26 , 35 , 36 , 37 , 38 , 39 , 40 with the adopted evidence. In the mild COVID‐19 group, one RCT with 1,535 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 4,314 cases were adopted, and a moderate effect was expected in all‐cause mortality and clinical improvement (decrease of 156 per 1,000). No data were available for serious adverse events. In the severe COVID‐19 group, five RCTs with 1,967 were adopted, and it was expected to have a great effect on all‐cause mortality and clinical improvement (decrease of 284 per 1,000). 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.
CQ4‐2: Should corticosteroid pulse therapy be administered to moderate/severe COVID‐19 patients?
Recommendation
-
✓
We have not made clear recommendations on corticosteroid pulse therapy for moderate COVID‐19 patients requiring oxygen administration/hospitalization and severe COVID‐19 patients requiring ventilator management/intensive care (no recommendation).
Background
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. 41 This RCT determined that the target patients were admitted to the intensive care unit but were not ventilated. As such, it was classified as “moderate” in the classification of this guideline. However, approximately 75% received high‐flow or high‐concentration 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 1,000). No data were available for clinical improvement, and serious adverse events were expected to have a slight effect (13 per 1,000 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.”
CQ5: Should tocilizumab be administered to COVID‐19 patients?
Recommendation
-
✓
We have not made a clear recommendation on tocilizumab administration to mild COVID‐19 patients who do not require oxygen (no recommendation).
-
✓
We suggest tocilizumab administration to moderate COVID‐19 patients requiring oxygen/hospitalization (weak recommendation/moderate certainty of evidence: GRADE 2B).
-
✓
We have not made a clear recommendation on tocilizumab administration to severe COVID‐19 patients requiring mechanical ventilation/intensive care (no recommendation).
Background
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 carried out; 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).
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.
Balance of benefits and harm
In nine RCTs 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 with 6,376 cases of severe/moderate COVID‐19 inpatients, tocilizumab for moderate COVID‐19 was expected to decrease all‐cause mortality by 29 per 1,000 and increase clinical improvement by 45 per 1,000 on day 28. The incidence of serious adverse events did not increase (a decrease of 25 per 1,000). For severe COVID‐19, a decrease of 20 per 1,000 was expected for all‐cause mortality at 28 days, and an increase of 24 per 1,000 for improvement of clinical symptoms. The incidence of serious adverse events did not increase (7 per 1,000 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.
Certainty of evidence
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.
CQ6: Should ciclesonide be administered by inhalation to COVID‐19 patients?
Recommendation
-
✓
We have not made a clear recommendation on ciclesonide inhalation to all COVID‐19 patients (no recommendation).
Background
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.
Recommendation rationale
Regarding ciclesonide inhalation, no RCTs with officially published results as of 28 February, 2021, were found in the living systematic review. Similarly, non‐randomized studies were also unavailable there. Therefore, in this CQ, we undertook our own additional search on PubMed, CENTRAL, and others. As a result, one observational study 51 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).
CQ7: Should anticoagulants be administered to COVID‐19 patients?
Recommendation
-
✓
We have not made a clear recommendation on anticoagulant administration to mild COVID‐19 patients who do not require oxygen (no recommendation).
-
✓
We suggest anticoagulant administration to moderate COVID‐19 patients requiring oxygen administration/hospitalization and severe COVID‐19 patients requiring ventilator management/intensive care (weak recommendation/low certainty of evidence: GRADE 2C).
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).
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.
Balance of benefits and harm
There were 17 observational studies 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 with the adopted evidence. Anticoagulant therapy for moderate and severe COVID‐19 patients is expected to have a moderate effect on prophylactic/therapeutic doses for all‐cause mortality at discharge (prophylactic dose; decrease of 116 per 1,000, therapeutic dose: decrease of 107 per 1,000). Prophylactic doses are not expected to be effective for venous thromboembolism (VTE) (a decrease of 69 per 1,000). The effects of therapeutic doses on VTEs are unknown. The occurrence of severe bleeding does not increase with the prophylactic dose (decrease of 20 per 1,000) and therapeutic dose (increase of 7 per 1,000).
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.
Certainty of evidence
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”.
DISCLOSURE
Approval of the research protocol: N/A.
Informed consent: N/A.
Registry and the registration no. of the study/trial: N/A.
Animal studies: N/A.
Conflict of interest: The Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine submitted this conflict of interest (COI) disclosure jointly, based on the same policy issued by the Japanese Association of Medical Sciences. In accordance with these guidelines, organizations are only required to disclose COI that relate to associated companies or for‐profit organizations as financial COI. We asked all members to submit their financial and academic COI for the past three years (2017–2019), in accordance with the current policy, shown in Document S1.
Supporting information
Doc. S1. The financial and academic conflict of interest forms of all menbers for the past three years (2017–2019).
Acknowledgments
We would like to thank Editage for their English language editing, and Mr. Tsuda (Davinci Medical Illustration Office) for the medical illustration service.
Funding information
No funding information provided.
References
- 1. Morgan RL, Florez I, Falavigna M, et al. Development of rapid guidelines: 3. GIN‐McMaster Guideline Development Checklist extension for rapid recommendations. Health Res. Policy Syst. 2018; 16: 63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Fitch KBS, Aguilar MD, Burnand B, et al. The Rand/UCLA Appropriateness Method User's Manual. Santa Monica, CA: RAND Corporation, 2001. [Google Scholar]
- 3. Clinical Management of Patients with COVID‐19: A guide for front‐line healthcare workers.
- 4. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ (Clinical research ed) 2019; 366: l4898. [DOI] [PubMed] [Google Scholar]
- 5. Sterne JA, Hernán MA, Reeves BC, et al. ROBINS‐I: a tool for assessing risk of bias in non‐randomised studies of interventions. BMJ (Clinical research ed) 2016; 355: i4919. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Alper BS, Oettgen P, Kunnamo I, et al. Defining certainty of net benefit: a GRADE concept paper. BMJ Open 2019; 9: e027445. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Alonso‐Coello P, Oxman AD, Moberg J, et al. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ 2016; 353: i20. [DOI] [PubMed] [Google Scholar]
- 8. MAGIC (Making Grade the Irresistible Choice) website. Available from: https://magicevidence.org/.
- 9. Lou Y, Liu L, Qiu Y. Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID‐19 patients: an exploratory randomized, controlled trial. medRxiv 2020.04.29.20085761. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Ivashchenko AA, Dmitriev KA, Vostokova NV, et al. AVIFAVIR for treatment of patients with moderate COVID‐19: interim results of a phase II/III multicenter randomized clinical trial. Clin. Infect. Dis. 2020; ciaa1176. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Balykova L, Грановская МВ, Заславская КЯ, et al. Hoвыe вoзмoжнocти нaпpaвлeннoй пpoтивoвиpycнoй тepaпии COVID‐19: peзyльтaты мнoгoцeнтpoвoгo клиничecкoгo иccлeдoвaния эффeктивнocти и бeзoпacнocти пpимeнeния пpeпapaтa Apeпливиp. Infektsionnye bolezn. 2020; 9: 16–29. [Google Scholar]
- 12. Ruzhentsova T, Chukhliaev P, Khavkina D, et al. Phase 3 trial of coronavir (favipiravir) in patients with mild to moderate COVID‐19. SSRN Electron. J. 2020. Available at: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3696907 [PMC free article] [PubMed] [Google Scholar]
- 13. Udwadia ZF, Singh P, Barkate H, et al. Efficacy and safety of favipiravir, an oral RNA‐dependent RNA polymerase inhibitor, in mild‐to‐moderate COVID‐19: A randomized, comparative, open‐label, multicenter, phase 3 clinical trial. Int. J. Infect. Dis. 2020; 103: 62–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of covid‐19 ‐ final report. N. Engl. J. Med. 2020; 383: 1813–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID‐19: a randomised, double‐blind, placebo‐controlled, multicentre trial. Lancet 2020; 395: 1569–78. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID‐19: A randomized clinical trial. JAMA 2020; 324: 1048–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. WHO Solidarity Trial Consortium , Pan H, Pet R, et al. Repurposed antiviral drugs for COVID‐19 Interium WHO SOLIDARITY trial results. N. Eng. J. Med. 2021; 384: 497–511. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Horby P, Mafham M, Linsell L, et al. Effect of hydroxychloroquine in hospitalized patients with COVID‐19. N. Engl. J. Med. 2020; 383: 2030–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID‐19: results of a randomized clinical trial. medRxiv. 2020.03.22.20040758. [Google Scholar]
- 20. Chen J, Liu D, Liu L, et al. A pilot study of hydroxychloroquine in treatment of patients with moderate COVID‐19. J. Zhejiang Univ. 2020; 49: 215–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ 2020; 369: m1849. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Chen L, Zhang Z, Fu J, et al. Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID‐19: a prospective open‐label randomized controlled study. medRxiv. 2020.06.19.20136093. [Google Scholar]
- 23. Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early COVID‐19: a randomized trial. Ann. Intern. Med. 2020; 173: 623–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Mitjà O, Corbacho‐Monné M, Ubals M, et al. Hydroxychloroquine for early treatment of adults with mild Covid‐19: a randomized‐controlled trial. Clin. Infect. Dis. 2020; ciaa1009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild‐to‐moderate Covid‐19. N. Engl. J. Med. 2020; 383: e119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Chen CP, Lin YC, Chen TC, et al. A multicenter, randomized, open‐label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate Coronavirus disease 2019 (COVID‐19). medRxiv 2020.07.08.20148841. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Dubee V, Pierre‐Marie R, Bruno V, et al. A placebo‐controlled double blind trial of hydroxychloroquine in mild‐to‐moderate COVID‐19. medRxiv 2020.10.19.20214940. [Google Scholar]
- 28. Pan H, Peto R, Henao‐Restrepo A‐M, et al. Repurposed antiviral drugs for Covid‐19 ‐ interim WHO Solidarity Trial results. N. Engl. J. Med. 2020; 384: 497–511. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Abd‐Elsalam S, Esmail E, Khalaf M, et al. Hydroxychloroquine in the treatment of COVID‐19: a multicenter randomized controlled study. Am. J. Trop. Med. Hyg. 2020; 103: 1635–9. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
- 30. Lyngbakken MN, Jan‐Erik B, Eskesen A, et al. A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics. Nat. Commun. 2020; 11: 5284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Ulrich RJ, Troxel AB, Carmody E, et al. Treating COVID‐19 with hydroxychloroquine (TEACH): a multicenter, double‐blind randomized controlled trial in hospitalized patients. Infect. Dis. 2020; 7: ofaa446. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Self WH, Semler MW, Leither LM, et al. Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID‐19: a randomized clinical trial. JAMA 2020; 324: 2165–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Omrani AS, Pathan SA, Thomas SA, et al. Randomized doubleblinded placebo‐controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non‐severe Covid‐19. EClinicalMedicine. 2020; 29‐30: 100645. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Ader F, Peiffer N, Poissy J, et al. Antiviral drugs in hospitalized patients with COVID‐19 the DisCoVeRy trial. medRxiv. 2021.01.08.20248149. [Google Scholar]
- 35. Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with Covid‐19. N. Engl. J. Med. 2021; 384: 693–704. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator‐free in patients with moderate or severe acute respiratory distress syndrome and COVID‐19: The CoDEX randomized clinical trial. JAMA 2020; 324: 1307–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Angus DC, Derde L, Al‐Beidh F, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID‐19: the REMAP‐CAP COVID‐19 corticosteroid domain randomized clinical trial. JAMA 2020; 324: 1317–29. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Dequin PF, Heming N, Meziani F, et al. Effect of hydrocortisone on 21‐day mortality or respiratory support among critically ill patients with COVID‐19: a randomized clinical trial. JAMA 2020; 324: 1298–306. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Jeronimo CMP, Farias MEL, Val FFA, et al. Methylprednisolone as adjunctive therapy for patients hospitalized with COVID‐19 (Metcovid): a randomised, double‐blind, phase IIb, placebo‐controlled trial. Clin. Infect. Dis. 2021; 72: e373–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Tang X, Feng YM, Ni JX, et al. Early use of corticosteroid may prolong SARSCoV‐2 shedding in non‐intensive care unit patients with COVID‐19 pneumonia: a multicenter, single‐blind, randomized control trial. Respiration; Int. Rev. Thoracic Dis. 2021; 100: 116–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41. Edalatifard M, Akhtari M, Salehi M, et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID‐19 patients: results from a randomized controlled clinical trial. Eur. Respir. J. 2020; 56: 2002808. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. Rosas I, Bräu N, Waters M, et al. Tocilizumab in hospitalized patients with severe COVID‐19 pneumonia. N. Engl. J. Med. 2021; 384: 1503–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43. Wang D, Fu B, Peng Z, et al. Tocilizumab ameliorates the hypoxia in COVID‐19 moderate patients with bilateral pulmonary lesions: a randomized, controlled, openlabel, multicenter trial. Front. Med. 2021. Epub ahead of print. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44. Stone JH, Frigault MJ, Serling‐Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with Covid‐19. N. Engl. J. Med. 2020; 383: 2333–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45. Hermine O, Mariette X, Tharaux PL, et al. Effect of tocilizumab vs usual care in adults hospitalized with COVID‐19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern. Med. 2021; 181: 32–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46. Salvarani C, Dolci G, Massari M, et al. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID‐19 pneumonia: a randomized clinical trial. JAMA Intern. Med. 2021; 181: 24–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47. Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with covid‐19 pneumonia. N. Engl. J. Med. 2021; 384: 20–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48. Veiga VC, Prats JAGG, Farias DLC, et al. Coalition covid‐19 Brazil VI Investigators. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ 2019; 2021: n84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49. REMAP‐CAP Investigators , Gordon AC, Mouncey PR, et al. Interleukin‐6 receptor antagonists in critically ill patients with Covid‐19. N. Engl. J. Med. 2021; 384: 1491–502. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50. RECOVERY Collaborative Group , Horby PW, Pessoa‐Amorim G, Leon Peto, et al. Tocilizumab in patients admitted to hospital with COVID‐19 (RECOVERY): preliminary results of a randomised, controlled, open‐label, platform trial. medRxiv 2021.02.11.21249258. [Google Scholar]
- 51. Yamasaki Y, Ooka S, Tsuchida T, et al. The peripheral lymphocyte count as a predictor of severe COVID‐19 and the effect of treatment with ciclesonide. Virus Res. 2020; 290: 198089. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52. Albani F, Sepe L, Fusina F, et al. Thromboprophylaxis with enoxaparin is associated with a lower death ratein patients hospitalized with SARS‐CoV‐2 infection. A cohort study. EClinicalMedicine 2020; 27: 100562. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53. Ionescu F, Jaiyesimi I, Petrescu I, et al. Association of anticoagulation dose and survival in hospitalized COVID‐19 patients: A retrospective propensity score‐weighted analysis. Eur. J. Haematol. 2020; 106: 165–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54. Nadkarni GN, Lala A, Bagiella E, et al. Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with COVID‐19. J. Am. Coll. Cardiol. 2020; 76: 1815–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55. Hsu A, Liu Y, Zayac AS, et al. Intensity of anticoagulation and survival in patients hospitalized with COVID‐19 pneumonia. Thromb. Res. 2020; 196: 375–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56. Gonzalez‐Porras JR, Belhassen‐Garcia M, Lopez‐Bernus A, et al. Low molecular weight heparin in adults inpatient COVID‐19. SSRN Electron. J. 2020. Available at: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3586665. [Google Scholar]
- 57. Rentsch CT, Beckman JA, Tomlinson L, et al. Early initiation of prophylactic anticoagulation for prevention of COVID‐19 mortality: a nationwide cohort study of hospitalized patients in the United States. medRxiv. 2020.12.09.20246579. [Google Scholar]
- 58. Fauvel C, Weizman O, Trimaille A, et al. Pulmonary embolism in COVID‐19 patients: a French multicentre cohort study. Eur. Heart. J. 2020; 41: 3058–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59. Yu Y, Tu J, Lei B, et al. Incidence and risk factors of deep vein thrombosis in hospitalized COVID‐19 patients. Clin. Appl. Thromb. Hemost. 2020; 26: 1076029620953217. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60. Hanif A, Khan S, Mantri N, et al. Thrombotic complications and anticoagulation in COVID‐19 pneumonia: a New York City hospital experience. Ann. Hematol. 2020; 99: 2323–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61. Atallah B, Sadik ZG, Salem N, et al. The impact of protocol‐based high‐intensity pharmacological thromboprophylaxis on thrombotic events in critically ill COVID‐19 patients. Anaesthesia 2021; 76: 327–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62. Daughety MM, Morgan A, Frost E, et al. COVID‐19 associated coagulopathy: Thrombosis, hemorrhage and mortality rates with an escalated‐dose thromboprophylaxis strategy. Thromb. Res. 2020; 196: 483–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63. Al‐Samkari H, Karp Leaf RS, Dzik WH, et al. COVID‐19 and coagulation: bleeding and thrombotic manifestations of SARS‐CoV‐2 infection. Blood 2020; 136: 489–500. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64. Iavarone M, D'Ambrosio R, Soria A, et al. High rates of 30 day mortality in patients with cirrhosis and COVID‐19. J. Hepatol. 2020; 73: 1063–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65. Musoke N, Lo KB, Albano J, et al. Anticoagulation and bleeding risk in patients with COVID‐19. Thromb. Res. 2020; 196: 227–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66. Patell R, Bogue T, Bindal P, et al. Incidence of thrombosis and hemorrhage in hospitalized cancer patientswith COVID‐19. J. Thromb. Haemost. 2020; 18: 2349–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67. Salisbury R, Iotchkova V, Jaafar S, et al. Incidence of symptomatic, imageconfirmed venous thromboembolism following hospitalization for COVID‐19 with 90‐day follow‐up. Blood. Adv. 2020; 4: 6230–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68. Paranjpe I, Fuster V, Lala A, et al. Association of treatment dose anticoagulation with in‐hospital survival among hospitalized patients with COVID‐19. J. Am. Coll. Cardiol. 2020; 76: 122–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Doc. S1. The financial and academic conflict of interest forms of all menbers for the past three years (2017–2019).