Remdesivir

All of our recommendations, unless specified, relate to acute COVID-19 in adults.

Some of our recommendations vary according to the severity of COVID-19 illness. Definitions of the categories are based on World Health Organization (WHO) criteria and can be viewed by clicking the plus (+) signs below.

RECOMMENDATION: We strongly recommend against use of Remdesivir in all patients with mild and critical COVID-19. We recommend against routine use of Remdesivir in moderate and severe COVID-19. However, clinicians may choose to use Remdesivir in selected patients with moderate to severe illness, such as those receiving low-flow oxygen therapy.

DATE OF RECOMMENDATION: 1st June 2021

Non-severe illness - Mild - STRONG RECOMMENDATION AGAINST USE

Definition of mild:

  • Symptomatic (any acute COVID-19 related symptoms)
  • AND respiratory rate <24/min
  • WITHOUT pneumonia or hypoxia
Non-severe illness - Moderate - CONDITIONAL RECOMMENDATION AGAINST USE - see Justification below

A conditional recommendation is one for which the panel is less confident about the balance between desirable and undesirable effects of the intervention, or other aspects, such as cost and feasibility.

Definition of non-severe:

NO features of severe or critical illness (see below).

Definition of moderate illness:

  • Pneumonia (clinical or radiological) OR hypoxia (SpO2 <94% in adults with no underlying lung disease)
  • AND respiratory rate ≤30/min
  • AND SpO2 ≥90% on room air
Severe illness - CONDITIONAL RECOMMENDATION AGAINST USE - see Justification below

A conditional recommendation is one for which the panel is less confident about the balance between desirable and undesirable effects of the intervention, or other aspects, such as cost and feasibility.

Definition of severe:

Pneumonia with ANY ONE of the following:

  • respiratory rate >30/min
  • severe respiratory distress
  • SpO2 <90% on room air
  • NO invasive or non-invasive respiratory support needed
Critical illness - STRONG RECOMMENDATION AGAINST USE

Definition of critical:

  • Requirement for high-level respiratory support: noninvasive ventilation, high-flow oxygen (≥20 litres per minute) or invasive mechanical ventilation
  • OR acute respiratory distress syndrome (PaO2/FiO2 ratio of <300)
  • OR sepsis
  • OR shock

Justification

COVID-19 contributes to a hypercoagulable state and thrombotic events are fairly common. Due to the frequency of arterial and venous thrombosis as well as micro-vascular thrombosis demonstrated on lung histology, many clinicians all over the world have opted to use therapeutic anticoagulation in patients with severe or critical illness. In addition, there are numerous reports suggesting that the delta variant (B.1.617.2), now the predominant strain circulating widely in India, results in many more thrombotic events and has also contributed to intrauterine deaths. Hence prophylactic anticoagulation is standard practice for all hospitalized patients with COVID-19. Standard prophylactic doses or Intermediate weight-adjusted doses of anticoagulation for thromboprophylaxis in hospital and ICU settings have been found to have similar safety and efficacy in preventing death or thrombosis, with a slightly higher risk of bleeding with Intermediate weight-based dosing anticoagulation. Hence with the present evidence available, we recommend only prophylactic dose anticoagulation in patients with mild, moderate (without hypoxia) or critical illness, though this may need to be individualized in obesity, pregnancy and renal insufficiency.

Overall among those with moderate (with hypoxia), severe and critical COVID-19 studied in the trials considered, therapeutic dose anticoagulation probably prevents clinically defined thrombotic events by 39% (risk ratio (RR) 0.61 (95% confidence interval (CI) 0.45 to 0.82); moderate certainty in the evidence). It may not reduce mortality, and we are very uncertain of its effect on organ support free days. It does, however, probably improve chance of survival without organ support at 28 days by 6% (95% CI 1% to 10%; moderate certainty in the evidence).

When the moderate (with hypoxia) to severe group of patients were considered separately, the initiation of therapeutic anticoagulation also led to a probable decrease in thrombotic events by 37% (95% CI 7% to 57%), probable increase in organ support free days (OSFD) by 5% (95% CI 1% to 10%), along with a probable increased risk of bleeding.

When the critical severity group was evaluated separately, therapeutic anticoagulation probably reduced thrombotic events by 43% (95% CI 11% to 63%) with probably no decrease in all-cause mortality or OSFD. In addition, there was probably no increase in bleeding (RR 1.39; 95% CI 0.71 to 2.71). Due to the increasing reports of thrombosis in all categories of patients in India, clinician discretion is advised for this critical category of patients. The group debated at length the advantages and disadvantages of therapeutic dose anticoagulation in this group. The group felt in the critical setting they are unable to pick up a thrombotic event easily which may impact eventual mortality and morbidity, and it is most often based on a clinical suspicion which are they are often unable to confirm as these patients are not amenable to easy shifting for a confirmatory radiology test. However, the group felt it is easy to pick up major bleeding. In addition, fatal bleeding events, reported only by the mpRCT (non-critical) trial, were only 3 in the therapeutic dose group as compared to 1 in the non-therapeutic dose group, though the actual numbers were not reported in the critical category.  Despite the uncertainty reflected in the various guidelines from NIH or NICE (1,2) where due to the lack of trial data they are unable to categorically recommend therapeutic over prophylactic dose, clinicians in India are increasingly recommending an intermediate or therapeutic dose of anticoagulation in severe and critical categories. However, more trials are required to support a conclusion that therapeutic dose anticoagulation is beneficial in the critical category.

Overall therapeutic dose anticoagulation is a low-cost intervention and needs to be weighed against hospitalization and ICU care costs that may result due to a thrombotic event. In addition, clinicians need to make a judgement call regarding the balance between risk of thrombosis and the risk of bleeding in an individual patient.

Evidence summary

Date of latest search: 9th June 2021

Date of completion of Summary of findings table and presentation to Expert Working Group: 24th May and 9th June 2021

Date of planned review: 27th December 2021

Evidence synthesis team:  Sushil S (SS), Jisha Sara John (JSJ), Richard Kirubakaran, Bhagteshwar Singh & Priscilla Rupali.

We acknowledge gratefully the assistance received from the authors of the multi-platform RCT [mpRCT] (ATTACC, ACTIV-4a, and REMAP-CAP platforms), specifically Ewan Goligher, who provided valuable assistance in evidence clarification and sharing of additional protocol documents.

Summary of findings tables

1. Outcomes in all categories of patients

Ref: All Cause Mortality (13-16), Thrombosis (13-16), Survival without organ support 28 days (15), OSFD (14,15), Major Bleeding (13-16)

Explanations:

a.  Not downgraded since risk of bias (RoB) assessment with RoB 2.0 tool scored 'some concerns' in only 1 domain of each of the studies, for this outcome. In the mpRCT studies [14;15], Domain 2 was marked down for 'some concerns' in view of significant deviations in intended interventions in trial, which probably did not affect outcomes. In HESACOVID trial [13], Domain 5 was marked down for 'some concerns' in view of not enough information being provided to completely rule out risk of bias in selection of the reported result.

b.  Downgraded by 1 level for serious indirectness: the differences in mechanisms of action and drug delivery caused concerns in comparability between the 2 interventions (Rivaroxaban & Heparins) for these outcomes. Aspects like the anti-inflammatory effects of heparins and dosages used in the Rivaroxaban regimen were also discussed in this regard. These putative differences in pharmacological characteristics between Rivaroxaban and Heparin, beyond their direct antithrombotic effects, informed the decision to downgrade for Indirectness in the outcomes not related to thrombosis or bleeding.

c.  Downgraded by 1 level for serious imprecision; 95% CI is wide ranging, from appreciable benefit to harm.

d.  Downgraded by 1 level for serious risk of bias; RoB assessment with RoB 2.0 tool scored 'some concerns' in 2 domains of the mpRCT studies [14;15]. In addition to Domain 2 as across all outcomes (see explanation a.), Domain 4 of RoB 2.0 tool was assessed to have some concerns because of the open-labelled nature of the trials which may have impacted aspects of assessment. This would not have a bearing on 'harder' outcomes like mortality, OSFD or major bleeding.

e.  Data provided in mpRCT [15] for this outcome was an Adjusted Proportional Odds Ratio (using a bayesian approach) of 1.30 (1.06 - 1.62). We decided to compute the RR from the numbers provided in the supplementary data for this outcome, assuming a baseline risk of 75.4%.

f.  Downgraded by 1 level for serious imprecision; 95% CI ranges from a clinically unimportant benefit to appreciable benefit.

g.  Downgraded by 1 level for serious inconsistency: the I-squared is 84%, and there is minimal overlap of the CIs of individual ORs.

h.  Downgraded by 1 level for serious indirectness: there was a very different baseline odds of higher organ-support free days: in one trial (mpRCT, Zarychanski et al. [14]) all participants were receiving organ support at baseline; in the other (mpRCT, Lawler et al. [15]) very few received organ support at baseline.

i.  Downgraded by 1 level for serious imprecision; 95% CI is wide ranging, from a clinically unimportant harm to appreciable harm.

2. Outcomes in the WHO moderate (on oxygen) and severe category of patients

Ref: All Cause Mortality (15,16), Thrombosis (15,16), Survival without organ support 28 days (15), OSFD (15), Major Bleeding (15,16)

Explanations

a.  Not downgraded since RoB assessment with RoB 2.0 tool scored 'some concerns' in only 1 domain of each of the studies [15;16], for this outcome. Domain 2 was marked down for 'some concerns' in view of significant deviations in intended interventions in trial; these probably did not affect outcomes.

b.  Downgraded by 1 level for serious inconsistency; the I-squared is 67%.

c.  Downgraded by 1 level for serious indirectness: the differences in mechanisms of action and drug delivery caused concerns in comparability between the 2 interventions (Rivaroxaban & Heparins) for these outcomes. Aspects like the anti-inflammatory effects of heparins and dosages used in the Rivaroxaban regimen were also discussed in this regard. These putative differences in pharmacological characteristics between Rivaroxaban and Heparin, beyond their direct antithrombotic effects, informed the decision to downgrade for Indirectness in the outcomes not related to thrombosis or bleeding.

d.  Downgraded by 1 level for serious imprecision; 95% CI is wide ranging, from appreciable benefit to harm.

e.  Downgraded by 1 level for serious risk of bias; RoB assessment with RoB 2.0 tool scored 'some concerns' in 2 domains for mpRCT (Lawler et al. [15]), and in one domain for the other trial [16], for measurement of this outcome. In the mpRCT (Lawler et al. [15]), In addition to Domain 2 (see explanation a.), Domain 4 of RoB 2.0 tool was assessed to have 'some concerns' because of the open-labelled nature of the trials which may have impacted aspects of assessment of this outcome [15;16]. This would not have a bearing on 'harder' outcomes like mortality, OSFD or major bleeding.

f.  Not downgraded for indirectness in these outcomes (Thrombosis/Bleeding), as the direct anti-thrombotic effect of therapeutic anticoagulation form both Rivaroxaban and Heparins could be considered comparable.

g.  Not downgraded for imprecision as, even at the upper 95% CI, the benefit was considered clinically significant by the expert working group.

h.  Data provided in mpRCT (Lawler et al [15]), was as Adjusted Proportional Odds Ratios (using a Bayesian approach). We decided to compute the RR, assuming a baseline risk of 75.4%, which we have mentioned in effects column.

i.  Downgraded by 1 level for serious imprecision; 95% CI ranges from a clinically unimportant benefit to appreciable benefit.

j.  Downgraded by 1 level for serious imprecision; 95% CI is wide ranging, from clinically low harmful effect to appreciable harm.

3.  Outcomes in critical category of patients

Ref: All Cause Mortality (13,14), Thrombosis (13,14), OSFD (14), Major Bleeding (13,14)

Explanations

a.  Not downgraded since RoB assessment with RoB 2.0 tool scored 'some concerns' in only 1 domain of each of the studies, for this outcome. In the mpRCT (Zarychanski et al. [14]), Domain 2 was marked down for 'some concerns' in view of significant deviations in the intended interventions in trial, which probably did not affect In HESACOVID trial [13], Domain 5 was marked down for 'some concerns' in view of not enough information being provided to completely rule out risk of bias in selection of the reported result.

b.  Downgraded by 1 level for serious imprecision; 95% CI ranges from appreciable benefit to harm.

c.  Downgraded by 1 level for serious risk of bias; RoB assessment with RoB 2.0 tool scored 'some concerns' in 2 domains for mpRCT (Zarychanski et al. [14]), and in one domain for other trials, for measurement of this outcome. In the mpRCT (Zarychanski et al. [14]), Domain 2 was marked down for 'some concerns' - see explanation a. Domain 4 was assessed to have 'some concerns' because of the open-labelled nature of the trials which may have impacted aspects of assessment of this outcome. This would not have a bearing on 'harder' outcomes like mortality, OSFD or major bleeding.

d.  Not downgraded for imprecision as, even at the upper 95% CI, the benefit was considered clinically significant by the expert working group.

e.  No data contributed towards this outcome from available trials in WHO Critical COVID-19 patients.

f.  Downgraded by 1 level for serious imprecision; 95% CI is wide ranging, from appreciable benefit to appreciable harm.

Background

Since December 2019, the worldwide pandemic of COVID-19, caused by the SARS-CoV-2 virus has adversely impacted humanity in diverse ways. Clinical studies of hospitalized patients with COVID-19 initially showed flu-like symptoms, most commonly cough, sore throat, fever, myalgia, and fatigue at onset of COVID-19 illness, which can then proceed to develop into a viral pneumonia with varying severity [3].

Abnormal coagulation profiles and thrombotic complications, both venous and arterial, are common among the hospitalized severe and critically ill patients [4], with pulmonary embolism the most common site [5].

In addition, multiple autopsy reports show unprecedented pulmonary microvascular thrombosis and endothelial damage [6] which could be related to the direct viral cytopathic effect on the endothelial cells due to shared receptors with the alveolar cells [7]. Other etiopathogenetic mechanisms include immune/cytokine mediated dysregulation of pro-coagulant & anti-fibrinolytic pathways.

Though hypercoagulability in COVID-19 is now well-recognized, uncertainty still exists as to how best to manage clotting risk in these patients. In addition, an increased risk of hypercoagulability leading to increased thrombotic events has been reported and recognized extensively in the media and among peers. There is a prevailing assumption that the delta variant in India may be contributing to an increased number of thrombotic events, however this needs to be systematically studied and documented.

Over the past year, several guidance documents have recommended the use of anticoagulation in hospitalized patients with COVID-19 [8]. Most of these guidelines recommend the use of unfractionated heparin (UFH) or low molecular weight heparin (LMWH), though the evidence is scarce with regard to which dose of anticoagulation i.e., prophylactic, intermediate, or therapeutic (“full”) dose should be employed in each severity group of COVID-19.

At present there is now fairly broad-based consensus from national and international guidelines that the standard of care is prophylactic dose anticoagulation to all in-patients with COVID-19 pneumonia. However, it remains unclear if specific severity sub-groups of patients will benefit from intermediate or therapeutic dose anticoagulation in the absence of a confirmed thrombotic event.

Methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Pubmed), Epistemonikos (COVID Living Overview of Evidence [L*OVE] platform), and the COVID‐19‐specific resource www.covid‐nma.com, for studies of any publication status and in any language published from March 2020 up to 15th April 2021. We also reviewed reference lists of systematic reviews and included studies.

We searched the Pubmed database and found 47 systematic reviews, and from COVID Living Overview of Evidence(L*OVE) platform found 46 potentially eligible records. After removing duplicates, and excluding reviews that did not include exclusively randomized control trial (RCT) data or did not include intended interventions, we found only one systematic review looking specifically at the outcome of mortality [9]. When analysed with the AMSTAR 2 tool [10] it was found to be of low quality, and also did not include most outcomes of interest as defined by the working group’s PICO.

So, we decided to proceed with a rapid review of available RCTs that compare outcomes between anticoagulation doses in COVID-19 patients.

Two reviewers (SS & JSJ) independently assessed eligibility of search results. One reviewer extracted data from each included study, and both assessed risk of bias using the Cochrane Risk of bias (RoB) v2.0 tool [11].

We extracted data for the following outcomes, pre-defined by the Expert Working Group:

  • Critical (primary for this review):
    • Mortality (all-cause) – at 21-30 days, or in-hospital
    • Thrombotic events
  • Important (secondary):
    • Time to clinical improvement
    • Organ support free days (OSFD): - ventilator, inotropic requirements.
    • Survival without organ support at day 28
    • Duration of hospitalization
    • Bleeding events

On searching Pubmed & COVID L*OVE platform and when restricting to RCTs, we found 19 records. After excluding extraneous records and trials that did not report any outcomes that could provide usable data for the review, we assessed 6 RCTs which compared differing doses of anticoagulation in COVID-19 patients.

We used RevMan v5.4 (12) to perform meta‐analysis using fixed-effect & random‐effects models for outcomes where pooling of effect estimates was appropriate. We used risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CIs).  Since the guidelines were going to be specific to each severity category we grouped studies as per their inclusion criteria into their severity categories and combined them as such to provide pooled estimates. We used the I2 statistic to measure residual heterogeneity. We used GRADE methodology to assess the certainty in the evidence, and documented this in a ‘Summary of findings’ table using GradeProGDT.

There are myriad dosing strategies for anticoagulation based on indication, organ dysfunction, BMI and adverse drug reactions, based on available literature and package insert recommendations. For purposes of our guidelines in the expert working group meeting it was decided to broadly group prophylactic & intermediate doses as non-therapeutic anticoagulation (up to and including 1mg/kg of enoxaparin or equivalent subcutaneously once daily) AND higher doses would be therapeutic dose anticoagulation (usually 1mg/kg enoxaparin or equivalent subcutaneously twice daily).

Though we are using the term anticoagulation, the intent of use of anticoagulation in all these trials was prophylaxis of thrombotic events, but two different doses are being compared in each of these trials: therapeutic vs. non-therapeutic, the latter of which may be prophylactic or intermediate dose.

Results

Of the 6 RCTs found, four attempted to compare therapeutic dose anticoagulation with non-therapeutic doses:

  • HESACOVID [13]: compared prophylactic vs. therapeutic dose of anticoagulation (20 participants).
  • mpRCT (Critically ill; Zarychanski et al.) pre-print [14]: a collaboration of 3 RCT platforms, ACTIV-4a, REMAP-CAP and ATTACC, looking specifically at critically ill patients (total of 1074 participants) – comparing therapeutic vs non-therapeutic dose of anticoagulation.
  • mpRCT (Non-critically ill; Lawler et al.) pre-print [15]: is a collaboration of above mentioned 3 RCT platforms, looking specifically at non-critically ill patients (total of 2291 participants) – comparing therapeutic vs non-therapeutic dose of anticoagulation.
  • COALITION-ACTION [16]: Looked specifically at the WHO moderate to severe categories of participants.

Two randomized trials studied the effect of intermediate vs. prophylactic dose anticoagulation:

  • INSPIRATION [17]: compared prophylactic vs. intermediate dose of anticoagulation (562 participants).
  • Usha Perepu et al, preprint [18]: compared prophylactic vs. intermediate dose of anticoagulation (176 participants).

Since we were providing category specific recommendations, HESACOVID [13] and mpRCT critical [14] were analysed together to enable evidence synthesis and a recommendation in the critical category of patients. In addition, mpRCT non-critically ill [15] and COALITION ACTION [16] were analysed together to provide a moderate-severe category specific recommendation as well. The results of INSPIRATION and Usha Perepu et al were kept separate from these other trials, in view of different comparator arms which were prophylactic and intermediate dose of anticoagulation. They are not presented in the results of this review.

The critical outcomes that were available and extracted for analysis from these studies included:

  • All-cause mortality (21-30 days),
  • Thrombosis,
  • Organ support free days (i.e., number of days without need for ICU-level organ support, including invasive and non-invasive mechanical ventilation)
  • Survival without organ support at 28 days
  • Major bleeding events.

We included 4 trials with 3,927 patients of which 1 trial did not contribute much data (13). The two trials which did not include a therapeutic dose of anticoagulation as a comparator arm were excluded from this analysis (17,18). The patients were compared across different pre-specified COVID19 severity groups, for the different outcomes as mentioned above (See summary of characteristics tables below). The duration of administration of anticoagulation varied from a minimum of 96 hours to 14 days or till the patient got better.

We tailored the severity strata in the study according to WHO COVID-19 Clinical management: living guidance severity classification (Interim document originally published under the title "Clinical management of COVID-19: interim guidance, 27 May 2020"(19).

Study Group
WHO severity criteria correlate
mpRCT (Critically ill) - Zarychanski et al.WHO Critical
mpRCT (non-Critically ill) - Lawler et al.WHO Severe & Moderate

The group of patients studied in the mpRCT(Critically ill) study (14), correlated directly with WHO critical severity criteria. The group of patients studied in the mpRCT(non-Critically ill) study(15), correlated with WHO severe category also overlapping with a few in the WHO moderate category.

Another aspect to be factored into the analysis was that, in COALITION-ACTION trial (16), the overwhelming majority of patients in the therapeutic dose arm(90.3%) received Rivaroxaban. This may have led to indirectness. Aspects like the anti-inflammatory effects of heparins, absorption of oral drugs and dosages used in the Rivaroxaban regimen were also discussed in this regard. These putative differences in pharmacological characteristics between Rivaroxaban and Heparin, beyond their direct antithrombotic effects, informed the decision to downgrade for indirectness in the outcomes not related to thrombosis or bleeding. (See further detailed explanations in SoF tables)

Overall analysis: Using GRADE methodology certainty of evidence is shown in Summary of Findings tables.

  • All-cause Mortality- Low certainty of evidence in 4 trials with 3927 patients, revealed that therapeutic dose anticoagulation may result in little to no difference in all-cause mortality, compared with non-therapeutic dose anticoagulation (RR 1.02, 95 % CI=0.82 to 1.27).
  • Thrombosis- Moderate certainty of evidence in 4 trials with 3807 patients, revealed that therapeutic dose anticoagulation probably reduces thrombosis, when compared with non-therapeutic dose anticoagulation (RR= 61, 95 % CI = 0.45 to 0.82).
  • Major bleeding- Moderate certainty of evidence in 3 trials with 3321 patients, revealed that therapeutic dose anticoagulation probably results in an increase in major bleeding, compared with non-therapeutic dose anticoagulation (RR 1.80, 95% CI = 1.13 to 2.86). There were 3 cases of fatal bleeds in mpRCT (non-critically ill) when given therapeutic dose anticoagulation vs 1 in the prophylactic dose anticoagulation.
  • OSFD- Very low certainty of evidence in 2 trials with 3301 patients, revealed a very uncertain effect of therapeutic dose anticoagulation on organ support-free days in hospitalized patients, compared with non-therapeutic dose anticoagulation when patients from WHO moderate, severe & critical COVID19 strata were combined from available trials (RR=1.06,95%CI 0.72-1.56).

Since guidelines are to provide recommendations for each severity strata, disaggregated data was also assessed to provide analysis to help formulate recommendations specific to each severity strata.

Analysis according to severity strata

WHO Critical group: Very low certainty evidence from 2 trials (13,14) showed that using therapeutic dose anticoagulation did not significantly reduce mortality in critical COVID19 illness (RR-1.01, 95 % CI = 0.86 to 1.19). However, moderate certainty evidence did show decreased thrombosis in patients (RR-0.57, 95 % CI = 0.37 to 0.89) but with no increase in bleeding (RR-1.39, 95 % CI = 0.71 to 2.71). In addition, moderate certainty evidence from 1 trial (28), showed that therapeutic anticoagulation did not improve days free of organ support compared to prophylactic dose anticoagulation [Odds Ratio (OR) 0.87, 95% CI 0.70 to 1.08]. However, the median OSFD in the therapeutic dose anticoagulation group was 3 days vs 5 days in the prophylactic dose anticoagulation group. It was also noted that 41% received low dose prophylactic dose anticoagulation and 51% received an intermediate dose prophylactic dose anticoagulation.

Bayesian analysis from Zarychanski et al (14). showed a posterior probability of futility of 99.8% and posterior probability of inferiority of 89.4% for impact of therapeutic anticoagulation on OSFD. DSMB stopped recruitment since pre-specified futility boundary for therapeutic anticoagulation was achieved. However, this was for OSFD not for mortality or thrombotic events.

WHO Moderate/Severe group: Very low certainty evidence from 2 trials (15,16) suggested that therapeutic anticoagulation provided no mortality benefit RR 1.02 (95% CI 0.79 to 1.30). However there was moderate certainty evidence that therapeutic dose anticoagulation did appear to prevent thrombosis by 37% (RR 0.63, 95 % CI 0.43 to 0.93) with a clinically appreciable risk of major bleeding of greater than  19%; RR 2.25, 95 % CI 1.19 to 4.27).In addition there was moderate certainty evidence from 1 trial (29) showing that therapeutic dose anticoagulation increased the probability of OSFD with OR 1.05, 95 % CI 1.01 to 1.10 and similarly survival without organ support RR 1.06 (95% CI 1.01 to 1.10). However fatal bleeds in mpRCT non- critically ill [15] revealed 3 bleeds in therapeutic dose anticoagulation vs 1 in the prophylactic dose anticoagulation group.

Bayesian analysis from mpRCT (non-critical) (15) showed a posterior probability of superiority of 99% for therapeutic anticoagulation improving OSFD. In this trial, deep venous thrombosis (DVT) was included as significant thrombosis which seems to have been excluded from mpRCT critical group (14).

Analysis of studies using non-therapeutic doses

In a brief analysis of RCTs INSPIRATION & Perepu et al.[17,18] which compared prophylactic vs intermediate dose anticoagulation (see table above), no statistically significant differences were noted in the outcomes of all-cause mortality [RR1.01,95% CI 0.84-1.21];thrombotic events [RR 1.17;95% CI 0.65-2.12];bleeding [RR 1.5;95%CI 0.82-2.71]; major bleeding [RR1.53;95%CI 0.55-4.26] assessed. (See relevant forest plot)

Summary of characteristics of included trials

Table 1: The four trials analysed for various outcomes

*  ICU: intensive care unit; RCT: randomized controlled trial

Table 2. Summary of D-dimer values and co interventions administered in these 4 trials

R: ritonavir; ULN: upper limit of normal

Forest plots

THERAPEUTIC VS NON-THERAPEUTIC DOSE OF ANTI-COAGULATION ACROSS ALL SUBGROUPS OF SEVERITY

  1. All-cause mortality (21-30 days)

2.  Thrombosis

3.  Major Bleeding

4.  Organ support free days (OSFD)

THERAPEUTIC VS NON-THERAPEUTIC DOSE OF ANTI-COAGULATION ACROSS CRITICAL SEVERITY SUBGROUP

  1. All-cause mortality (21-30 days)

  1. Thrombosis

  1. Major Bleeding

4.  Organ support free days

THERAPEUTIC VS NON-THERAPEUTIC DOSE OF ANTI-COAGULATION ACROSS MODERATE TO SEVERE SUBGROUP

  1. All cause mortality

2.  Thrombosis

3.  Bleeding

4.  Organ support free days

PROPHYLACTIC VS INTERMEDIATE DOSE OF ANTICOAGULATION

Evidence to decision

The Anticoagulation Expert Working Group met on 24th May 2021 to consider the use of therapeutic vs prophylactic dose anticoagulation in the management of COVID-19. A summary and then more detailed explanations of their judgements follow.

Summary of judgements –

EtD summary table –

Problem

Hypercoagulability is a recognized phenomenon in COVID-19 and is believed to be multifactorial. SARS-CoV-2 virus both directly and indirectly causes endothelial injury, microvascular inflammation, endothelial exocytosis, endotheliitis contributing to acute respiratory distress syndrome. In post-mortem studies microvascular occlusion with platelet-fibrin thrombi have been reported. In addition, changes in circulating prothrombotic factors and stasis due to immobility encountered in the critically ill has led to a recognized prothrombotic state in COVID-19 infection, translating to increased arterial and venous thrombosis. This has led to the practice of prophylactic anticoagulation for all hospitalized COVID-19 patients. However there exists an area of equipoise whether patients with severe or critical COVID-19 infection will benefit with therapeutic (full) dose anticoagulation in the absence of a confirmed thrombotic event. This has especially become even more important as the country goes through a massive second wave probably caused by the delta variant B.1.617.2 starting in early February, which anecdotally seems to cause more thrombosis as per various reports in the media, however we need to await cohort studies for this to be accurately assessed.

Desirable effects

WHO Critical: At present, evidence shows that using therapeutic dose anticoagulation probably does not significantly reduce mortality in critical COVID-19 but does appear to prevent thrombotic events by 42% (95% CI 11-63%) with a moderate certainty of evidence. Therapeutic dose anticoagulation also did not improve days free of organ support compared to prophylactic dose anticoagulation. The DSMB stopped recruitment in this category as it felt that therapeutic dose anticoagulation did not offer any advantage in OSFD (as a pre-specified Bayesian post probability of futility was achieved). The group discussed this at length and felt that preventing thrombosis was important even in the absence of mortality benefit. Panel also noted that most of the evidence was contributed to by the mPRCT critical trial [14] with very few patients in HESACOVID [13].

WHO Moderate (with hypoxia)/Severe: The group noted that using therapeutic dose anticoagulation probably reduced thrombosis and increased the probability of OSFD but did not significantly reduce mortality (very-low certainty evidence), though it probably increased bleeding in moderate/severe category of COVID-19. The group felt that right now thrombosis was an important event to prevent as it was difficult to recognize or confirm and probably would contribute to significant morbidity. However, the group felt that bleeding was easy to pick up and was rarely fatal. Hence the group that in an intensive care setting prevention of thrombosis was an important intervention. The various thrombotic events were reviewed and pulmonary embolism seemed to contribute to most of the events with other events recorded being myocardial infarction and strokes.

Undesirable effects

WHO Critical: The mPRCT (Critical)[14] had >500 participants in each arm and the incidence of bleeding in each group was similar. The absolute difference in bleeding between the two groups was 1%, suggesting no clinically important increase in the risk of bleeding. The DSMB of ACTIV-4 component of the mPRCT trial had recommended an early interim analysis to assess for effectiveness or harm, however the study was terminated as the futility threshold was reached suggesting that there was no benefit of therapeutic dose anticoagulation over non-therapeutic dose anticoagulation on the primary outcome of OSFD.

WHO Moderate (with hypoxia)/Severe: The mPRCT (Non-critical) [15] had >1000 patients in each arm and the incidence of bleeding in the therapeutic dose group was higher in this group. Despite the pooled risk ratio of 2.26, when considering absolute effects, this would translate to only 12 per 1000 (1.2 per 100) more bleeding events per patients treated, with a lower confidence interval bound of only 1 per 1000 difference between groups.

The panel also discussed the absence of data regarding anticoagulation in the mild and moderate groups without hypoxia and felt that decisions about anticoagulation in those groups could be based on evidence from non-randomized studies and clinical experience.

Certainty of evidence

Overall the quality of evidence in the WHO moderate (with hypoxia), severe and critical categories was felt to be moderate, though a minority of outcomes achieved only very low or very low certainty in the evidence.

Values 

Outcomes noted were considered to be important in overall patient management especially in the setting of the pandemic. The group felt that the outcomes of mortality, thrombotic events, bleeding and organ support free days were certainly important to all stakeholders. They felt that there was no uncertainty or variability. However, they did note some unusual points in the way outcomes were assessed (for example, the Bayesian analyses were difficult to quantify and interpret). Other points noted include:

Critical group: The group discussed the uncertainty as to whether thrombotic events could have contributed to mortality. There is no clear breakup of mortality in the pre-print or supplement. Clinically significant pulmonary embolism seems to have contributed to most of the thrombotic events, but it was not specified as to whether they were all major arterial or just segmental embolism. It also seemed unlikely that a patient who is severely or critically ill would have been shifted out for a CT pulmonary angiogram (CTPA). Deep vein thrombosis was excluded in this group as a major thrombotic event.

Moderate: In the mpRCT non-critical [15] group, deep vein thrombosis was included as significant thrombosis which was excluded from mpRCT critical[14] group.

Balance of effects

Given that the country has recently faced a shortage of beds, oxygen and intensive care, if an intervention could reduce organ support and thrombosis it would be of benefit.

WHO Critical: There are very few trials overall to inform evidence and there seemed to be no mortality benefit or decrease in OSFD between therapeutic dose anticoagulation and non-therapeutic dose anticoagulation. There was a decrease in thrombotic events with no increase in bleeding noted. The DSMB stopped the larger trial [14] as futility end-point for OSFD was reached in interim assessment.

WHO Moderate/Severetherapeutic dose anticoagulation appeared to increase OSFD, and prevent thrombotic events with a slightly increased risk for major bleeding. There was no mortality benefit between the 2 arms. OSFD should be given importance in the moderate category as it saves resources and prevents morbidity.

Resource requirements

There are likely to be negligible savings or costs pertaining to implementation of therapeutic dose anticoagulation. Drugs used for this are relatively cheap, widely available and unlikely to incur a significant cost nor are they likely to result in significant savings. Health care workers in the country are fairly experienced with the use of the same and are aware of the various monitoring implications. Cost of implementation is low and needs to be weighed against hospitalization and intensive care costs. Though monitoring of anticoagulation efficacy with Anti-Xa testing will be possible only in an advanced hemostasis laboratory, if widely employed to ensure therapeutic efficacy it may also protect against unnecessary bleeding. However, this will increase costs and probably unnecessary in most instances. There is also possible ineffectiveness of therapy in view of high rates of heparin resistance documented in published data but overall costs of implementing therapeutic dose anticoagulation are likely low if we are able to save on costs of hospitalisation and intensive care beds.

Certainty of evidence of required resources

Resources required for implementation of therapeutic dose anticoagulation are minimal and the certainty of evidence for this is high.

Cost effectiveness

At the moment there are no data relating to the cost effectiveness of this intervention and studies need to be done to be sure of the same. The group recognized the minimal costs and resources required to deliver as it is a subcutaneous injection which can be delivered by most health care workers easily. It is also likely that even if patients in the moderate category are given therapeutic dose anticoagulation, hospitalization will be dictated by disease severity rather than administration of anticoagulation, given that most health care settings and health professionals are comfortable with delivery of this intervention in the outpatient settings. There are also many novel oral anticoagulants available which have been proven to have similar efficacy as heparin and could potentially be employed as substitutes, however data with these are scarce in the COVID-19 setting.

Equity

As the cost and resource requirements of anticoagulation delivery are reasonable, implementation can be equitable.

Acceptability

This intervention would be considered acceptable to patients and health care workers as it is in common use for a variety of indications other than COVID-19.

Feasibility

Therapeutic dose anticoagulation is a feasible intervention which can be easily implemented in all health care settings by any health care professional.

Implementation considerations

There is anecdotal evidence that thrombotic risk is increased with the newer delta variant [20], so thrombosis is increasingly being noticed in the second wave of COVID-19 in India. Whether this is more apparent due to the increased numbers of patients in a short space of time, or whether there is a true correlation of the delta variant with an increased risk of thrombosis remains to be determined. In mild or moderate non-hospitalized patients, there seems to be no routine role for anticoagulation.

Moderate (hypoxic) and severe: The group felt that for these severity groups the evidence suggests a positive benefit vs. risk balance in favour of therapeutic anticoagulation. Other considerations, such as feasibility and low cost, were also favourable. Important clinical outcomes like prevention of thrombotic events and reduced need for ICU-level organ support, including invasive and non-invasive mechanical ventilation (OSFD) were noted with minimal harm or bleeding risk.  Overall the group given the evidence felt therapeutic dose anticoagulation should definitely be considered in this group of patients.

Critical: However, the group was less certain in the critical category of illness. Evidence revealed there was prevention of thrombotic events but no improvement with regard to mortality or organ support. In addition, no harm was demonstrated. Anecdotally most clinical members of the expert working group reported that they use either intermediate or therapeutic doses routinely in their intensive care areas and felt that this decision should be individualized according to the clinical picture of the patient or with monitoring of anti-Xa levels.

Overall, anticoagulation is feasible to implement widely and easily. There is evidence for Injectable low molecular weight heparin and Unfractionated Heparin through the data presented. However, Direct Oral Anti Coagulants (DOACs) like Rivaroxaban/Apixaban are being used in COVID-19 patients widely in clinical practice. However, in our analysis they were studied only in one of the smaller trials and hence data regarding its efficacy in COVID-19 is scarce. Given the increased risk in bleeding noted and difficulty in immediate reversal of anticoagulant effect of DOACs, decision to prescribe these should weigh these benefits and harms especially when administering at therapeutic doses.

Enoxaparin achieves anticoagulant effect by activating antithrombin. Routine laboratory monitoring for efficacy is not usually necessary. However, in special situations such as obesity, renal insufficiency, and pregnancy, laboratory monitoring may be required. The peak anti-factor Xa (anti-Xa) level is the recommended test for monitoring enoxaparin efficacy. Blood samples should be withdrawn about 3–5 hours after dose administration. In patients on therapeutic anticoagulation with unfractionated heparin, APTT monitoring can be done and maintained 1.5 to 2 times the control. In other anticoagulation regimens using low molecular weight heparin or Fondaparinux, regular anti-Xa monitoring is not recommended other than in obese, pregnancy or in renal insufficiency patients. In addition, in obese patients that intermediate dose of anticoagulation may need to be considered over prophylactic dose anticoagulation to achieve the required prophylactic levels. Renal insufficiency may prompt also prompt dose modification. In pregnancy data is still evolving and decisions regarding the required dose may need to take into consideration indications other than COVID-19. In the setting that heparin resistance is suspected, even in the setting of unfractionated heparin, anti-Xa levels should be monitored. Target peak anti-Xa for the treatment doses of twice-daily enoxaparin is 0.6–1.0 IU/mL. The target peak anti-Xa level for prophylactic doses of enoxaparin is 0.2–0.5 IU/mL [22].

The following points are to be considered prior to initiating anticoagulation in patients:

  1. Contra-indications to anticoagulation:
    - Absolute: Platelets <20,000/mm3,
    - Relative: platelets <50,000/mm3; Brain metastases; Recent major trauma; Major abdominal surgery within the past 2 days; Gastrointestinal or genitourinary bleeding within the past 14 days; Endocarditis; Severe hypertension (systolic BP >200 or diastolic BP >120 mmHg).
  2. Specific contraindications and dosing considerations:
  • Enoxaparin (taken from literature for Lovenox®): Known hypersensitivity to enoxaparin, heparin or other LMWHs; History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies; Active major bleeding and conditions with a high risk of uncontrolled haemorrhage including recent haemorrhagic stroke. (Refer to product literature for further details, including dosing for renal failure.)

For alternative drugs, consult product literature.

Subgroup Considerations

The subgroups of children <18 years of age, pregnant women, asymptomatic, mild and out-patients were excluded from most studies. Some studies also excluded those on dialysis for chronic kidney disease, chronic liver and lung diseases as well as those on antiplatelet therapy.

The utility of D-dimer was also evaluated as part of a subgroup analysis. In the mpRCT (non-critical [15]) study it was noted that a high D-dimer is associated with a high risk of mortality and organ support and thus the adjusted absolute treatment benefits were more apparent, as the groups were stratified according to a high D-dimer, low D-dimer and unknown D-dimer values. However, in this trial, it seemed that the benefit of therapeutic dose anticoagulation was irrespective of the D-dimer values. The COALITION ACTION trial [16] included only patients with an elevated D-dimer with the values ranging from 1-3 times the upper limit of normal in 75% of participants to >3 times the upper limit of normal in 25% of participants in each arm. In the mpRCT (critical[14]) and HESACOVID [13] trials, no stratification was done according to the D-dimer values. The mean D-dimer values were 827 ng/ml in 48% of therapeutic dose anticoagulation vs 890 ng/mL in 46% of non-therapeutic dose anticoagulation (both values nearly twice the upper limit of normal) in mpRCT (critical [12]). In HESACOVID [13] the mean value of D-dimer was >4 times normal in the intervention and control groups.

There is no defined role for monitoring of D-dimer in non-hospitalised COVID-19 patients. A high D-dimer is known to be associated with an increased risk of venous thromboembolism in patients without COVID-19, and in COVID-19 it has been correlated with a poorer prognosis and increased mortality (21). However, whether a high D-dimer value can be extrapolated to an increased risk of arterial or venous thrombosis in COVID-19, as in the non-COVID-19 literature and thus higher mortality due to this is yet to be determined. Hence in hospitalized patients with COVID-19 with no clinical or radiological evidence of thrombosis, there is insufficient data to recommend regular monitoring of D-dimer or to base management strategies on the same.

Monitoring and Evaluation

At this point, it seems that the balance of effects considering the incidence of thrombosis vs risk of bleeding favours therapeutic dose anticoagulation over prophylactic dose anticoagulation in the moderate with hypoxia to severe categories of patients. This conditional recommendation regarding use of anticoagulation may be revisited as evidence emerges. In addition to evidence of benefit, with its widespread use in India, there may be additional cohort evidence emerging regarding incidence of thrombosis and bleeding with therapeutic dose anticoagulation which the group will monitor. In addition, the COVID Guidelines India anticoagulation expert working group is embarking on a survey to assess if the risk of thrombosis has increased in the second wave as compared to the first which may provide supporting evidence towards institution of therapeutic anticoagulation. However, we need to be cautious towards interpretation of any data relating to outcomes with different dosing strategies, as this would be non-randomized data.

Research Priorities

It has been shown that therapeutic dose anticoagulation probably improves clinical outcomes in patients with moderate (with hypoxia) and severe COVID-19, but this remains uncertain in critically ill COVID-19 patients. This seems counterintuitive, though it could be explained by the premise that critically ill patients are too far into the thrombo-inflammatory phase of illness where it may be futile. However, more studies are required to explore this critical group further; to identify which subpopulations might benefit most, based on risk factors and comorbidities; and to determine the utility of biomarkers like D-dimer. Studies also need to be done in mild and moderate COVID-19 illness without hypoxia, including in outpatients, to ascertain whether any form of anticoagulation can prevent progression of illness and/or hospital admission. Dose and duration of post-discharge anticoagulation in the absence of a suspected or confirmed thrombotic event is another area where considerable equipoise exists. All of these are urgent research priorities considering the country’s recent manpower, oxygen, and intensive care unit bed shortages.

References
  1. NIH(National Institute for Health) COVID-19 treatment guidelines. Anti-thrombotic therapy in patients with COVID-19. https://www.covid19treatmentguidelines.nih.gov/therapies/antithrombotic-therapy/ last updated February 11,2021 accessed last 23 June 21
  2. NICE(National institute for Health Care Excellence). COVID-19 rapid guideline: Reducing   the risk of venous thromboembolism in over 16s with COVID-19 NICE guideline [NG191]; Published: 23 March 2021; Last updated: 03 June 2021; accessed on 23st June 21 via URL https://www.nice.org.uk/guidance/NG191 or https://app.magicapp.org/#/guideline/L4Qb5n/rec/LwomXL
  3. Wang, D. et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA 323, 1061–1069 (2020).
  4. Tang, N., Li, D., Wang, X. & Sun, Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J. Thromb. Haemost. 18, 844–847 (2020).
  5. Klok, F. A. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb. Res. (2020) doi:10.1016/j.thromres.2020.04.013.
  6. Ackermann, M. et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N. Engl. J. Med. 0, null (2020).
  7. Hoffmann, M. et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 181, 271-280.e8 (2020).
  8. Cuker, A. et al. American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. Blood Adv. 5, 872–888 (2021).
  9. Ongoing Living Update of Potential COVID-19 Therapeutics Options Summary of Evidence. Rapid Review. Pan American Health Organization. Available online :- https://iris.paho.org/handle/10665.2/52294 Accessed on 6th May 2021 .
  10. Shea, B. J. et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 358, j4008 (2017).
  11. Cochrane Handbook for Systematic Reviews of Interventions. ‘Assessing risk of bias in a randomized trial’.  accessed at URL https://training.cochrane.org/handbook/current on 25 May 2021.
  12. Review Manager (RevMan) [Computer program]. Version 5.4, The Cochrane Collaboration, 2020 Available at revman.cochrane.org
  13. Lemos, A. C. B. et al. Therapeutic versus prophylactic anticoagulation for severe COVID-19: A randomized phase II clinical trial (HESACOVID). Thromb. Res. 196, 359–366 (2020).
  14. Remap-Cap, T., ACTIV-4a, Investigators, A. & Zarychanski, R. Therapeutic Anticoagulation in Critically Ill Patients with Covid-19 – Preliminary Report. medRxiv 2021.03.10.21252749 (2021) doi:10.1101/2021.03.10.21252749.
  15. The ATTACC, A.-4a et al. Therapeutic Anticoagulation in Non-Critically Ill Patients with Covid-19. medRxiv 2021.05.13.21256846 (2021) doi:10.1101/2021.05.13.21256846.
  16. Lopes DR, de Barrose Silva PGM, Furtado RH et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID19 and elevated D-Dimer concentration (ACTION): an open label,multicentre, randomised controlled trial. https://doi.org/10.1016/ S0140-6736(21)01203-4.
  17. INSPIRATION Investigators et al. Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial. JAMA 325, 1620–1630 (2021).
  18. Perepu, U. et al. Standard Prophylactic Versus Intermediate Dose Enoxaparin in Adults with Severe COVID-19: A Multi-Center, Open-Label, Randomised Controlled Trial. https://papers.ssrn.com/abstract=3840099 (2021) doi:10.2139/ssrn.3840099.
  19. WHO Clinical management of COVID-19: interim guidance, 25 January 2021 https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-1.
  20. Doctors spot new trend in Covid 2nd wave: Strokes in recovering or discharged patients [Internet]. [cited 2021 Jun 22]. Available from: https://theprint.in/health/doctors-spot-new-trend-in-covid-2nd-wave-strokes-in-recovering-or-discharged-patients/655613/
  21. Zhang L, Yan X, Fan Q et al. D‐dimer levels on admission to predict in‐hospital mortality in patients with Covid‐19. J Thromb Haemost.2020 Apr 19 : 10.1111/jth.14859. doi: 10.1111/jth.14859 [Epub ahead of print]
  22. Tahaineh L, Edaily SM, Gharaibeh SF. Anti-factor Xa levels in obese patients receiving enoxaparin for treatment and prophylaxis indications. Clin Pharmacol. 2018;10:63-70
    https://doi.org/10.2147/CPAA.S161599

Justification

Low and very low certainty evidence from five randomized controlled trials (RCTs), indicates that Remdesivir may have little to no effect on all-cause mortality, progression to oxygen therapy, adverse events, thrombotic events and secondary infections in people hospitalized with COVID-19. Remdesivir’s effect on time to clinical recovery, progression to invasive mechanical ventilation and serious adverse events are very uncertain. It may reduce time to clinical improvement and progression to non invasive ventilation/high flow oxygen therapy, however trials which reported this benefit were conducted when steroids were not the standard of care. Hence it is uncertain as to whether Remdesivir provides a benefit over and above that clearly demonstrated by steroids. Only one study reported a possible mortality benefit when given to patients receiving low-flow oxygen, which may be biologically plausible as antivirals often have a greater effect when given earlier in a viral illness.

Overall, the benefit of Remdesivir in the treatment of COVID-19 is uncertain as there was significant heterogeneity among the trials, lower usage of steroids as compared to what would be standard of care today and wide confidence intervals in effect estimates of critical outcomes. Hence at this point there is insufficient evidence to recommend this drug routinely given the cost and availability of this drug in resource-limited settings.

Evidence summary

Date of latest search: 15th April 2021.

Date of completion & presentation to Expert Working Group: 14th May 2021.

Date of planned review: 15th July 2021.

Evidence synthesis team:  Anupa Thampy, Hanna Alexander, Naveena Princy, Richard Kirubakaran, Bhagteshwar Singh and Priscilla Rupali.

Summary of findings table

Click here for an Interactive Summary of Findings table 1 - Efficacy outcomes (opens in a new window).

Summary of Findings Table 1 - Efficacy Outcomes:

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Explanations:

a. Wang 2020, ACTT Beigel 2020, Spinner 2020, Solidarity 2021, Mahajan 2021
b. Downgraded by one for level serious indirectness; The usage of steroids varied across the studies
c. Downgraded by one level for serious imprecision; the 95% CI is wide
d. ACTT Beigel 2020, Spinner 2020. Pooled estimate is from 2 trials at 10 days
e. Downgraded by one level for serious risk of bias; Spinner 2020 was at high risk of bias and contributed to 36.1% of the weight in the metanalysis
f. Downgraded by one level for serious indirectness; Spinner 2020 had moderate severity patients only and ACTT Beigel 2020 had a mixture of patients of different severity.
g. Downgraded by two levels for very serious imprecision; It is difficult to determine the clinical significance of the difference in the time to clinical improvement with hazard ratios, but the 95% CI was wide and included no difference.
h. Wang 2020, ACTT Beigel 2020 , Spinner 2020. Pooled estimate from 3 trials at 10 days
i. Downgraded by one level for serious risk of bias ; Spinner 2020 was at high risk of bias and contributed 25.9% of the weight to the pooled effect estimate.
j. Downgraded by one level for serious indirectness; The three studies included patients with different grades of disease severity and Spinner 2020 included only patients with moderate severity.
k. ACTT Beigel 2020
l. Downgraded by two levels for imprecision; 95% CI is very wide
m. Downgraded by one level serious indirectness; as very few people in ACTT Beigel 2020 were given steriods
n. Downgraded by one level for serious imprecision.The data were from only one trial and the number of events were too few to satisfy the requirements for the optimal information size (OIS) [The OIS for a RRR of 2 percent needs at least 700 events for the intervention to be significant (Remdesivir arm: 52/307, placebo arm: 64/266)]. The 95% CI of the effect estimate included clinically important and potentially clinically non-appreciable benefits with Remdesivir.
o. ACTT Beigel 2020, Solidarity 2021
p. Downgraded by two levels for very serious inconsistency; the I2 is 91%.

Click here for an Interactive Summary of Findings table 2 - Complications & Safety Outcomes (opens in a new window).

Summary of Findings Table 2 - Complications & Safety Outcomes:

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Explanations:

a. ACTT Beigel 2020, Wang 2020
b. Not downgraded for indirectness: Wang 2020 and ACCT Beigel 2020 included similar proportions of patients with severe disease and the incidence of adverse events was unlikely to have been confounded by severity.
c. Downgraded by two levels for very serious imprecision; the number of events were few and the 95% CI of the effect estimate included clinically important reductions and increases in thrombotic events with Remdesivir.
d. Downgraded by one level for serious inconsistency; the I2 is 65%
e. Downgraded by one level for serious imprecision: The number of events were few and the 95% CI of the effect estimate included a substantial reduction as well as a modest increase in the incidence of infections with Remdesivir compared to placebo/SOC.
f. Wang 2020, Spinner 2020
g. Downgraded by one level for serious risk of bias; Spinner 2020 was judged to be at high risk of bias and contributed 56.5 % of weight in the metanalysis
h. ACTT Beigel 2020 , Wang 2020, Spinner 2020
i. Downgraded by one level serious inconsistency; as I2 is 76%
j. Downgraded by two levels very serious imprecision; the 95% CI is very wide

Background

Remdesivir is a monophosphoramidate adenosine analogue prodrug which is metabolized to an active triphosphate form that inhibits viral RNA synthesis via RNA dependent RNA polymerase [1]. It was developed as a therapeutic agent for treating RNA-based viruses such as Ebola virus, MERS, SARS-CoV-1 and other zoonotic coronaviruses [2]. It has demonstrated in vitro and in vivo antiviral activity against SARS-CoV-2 [3].

Remdesivir is widely used across the world and a number of guidelines have recommended its use in severe COVID-19 patients [4;5]. The recent WHO living guideline provides a conditional recommendation against the usage of Remdesivir in COVID-19 irrespective of the severity of the disease [6].

Since Remdesivir is currently the only antiviral drug recommended for severe COVID-19 by the Ministry of Health & Family Welfare guidelines, and appears to have a relatively good safety profile, it has been in high demand. Its current limited availability in India has led to a crisis involving desperate crowds flouting Covid-19 restrictions to avail the drug.

This review aims to provide a summary of the available evidence from randomized clinical trials of Remdesivir for treatment of acute COVID-19, for any duration, which could guide clinicians and researchers regarding the appropriate use of this drug in the future.

Methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Epistemonikos, and the COVID‐19‐specific resource www.covid‐nma.com, for studies of any publication status and in any language. We also reviewed reference lists of systematic reviews and included studies. We performed all searches up to 15 April 2021.

We included randomized controlled trials (RCTs) testing Remdesivir in people with COVID‐19, and extracted data for the following pre-defined outcomes:

  • Critical (primary for this review):
    • Mortality (all-cause): at 28-30 days, or in-hospital
    • Progression to:
      - Oxygen therapy
      - Ventilation: non-invasive or invasive
      - Critical/Intensive care (any reason)
    • Time to clinical improvement
    • Time to clinical recovery
    • Adverse events: all and serious
  • Important (secondary):
    • Time to negative PCR for SARS-CoV-2
    • Duration of hospitalization
    • Complications of COVID-19:
      • Thrombotic events
      • Pulmonary function/fibrosis
      • Long COVID/post-acute sequelae COVID
      • Secondary infections

Two reviewers independently assessed eligibility of search results. One reviewer extracted data from each included study, and assessed risk of bias using the Cochrane Risk of bias (RoB) v2.0 tool. Data and RoB assessments were checked by the second reviewer. The entire RoB assessment was scrutinized by the whole team for this review, to reach consensus.

We used RevMan 5.4 to perform meta‐analysis using a random‐effects model for outcomes where pooling of effect estimates was appropriate. We used risk ratios (RR) for dichotomous outcomes and hazard ratios for continuous outcomes, with 95% confidence intervals (CIs). We performed a subgroup analysis to explore the effect on mortality stratified by different oxygen and ventilation requirements at baseline.

We used the I2 statistic to measure residual heterogeneity. We used GRADE methodology to assess the certainty in the evidence, and documented this in a ‘Summary of findings’ table using GradeProGDT.

Results

We included five trials involving 7452 participants, all of whom were adults, and 3886 of whom received Remdesivir [7-11]. Two trials reported each from a single country: China [7] and India [10]; two from multiple countries in North America, Europe and Asia [8;11]; one recruited worldwide [9]. All trials were done in hospitalized patients. Disease severity, prevalence of comorbidities, and use of co‐interventions varied substantially between trials. Out of the five trials three [7;9;11] were found to have low risk of bias across all domains for all outcomes and two [8;10] had high risk of bias across multiple domains. Risk of bias for each domain per trial is displayed alongside the forest plots below.

The following comparisons were investigated in the trials (we compared outcomes for arms randomized to Remdesivir vs. outcomes for arms randomized to standard of care or placebo):

  • Two trials [7;11] compared Remdesivir with placebo (1299 participants)
  • Three trials [8-10] compared Remdesivir with standard of care (6153 participants). Of these, one trial [8] had two arms with different durations of Remdesivir (5 days arm and 10 days arm) compared with a standard of care arm (596 participants).

Our expert working group classified progression to oxygen, non-invasive ventilation (NIV) and invasive mechanical ventilation (IMV) as critical outcomes and mortality, time to clinical improvement and thrombotic or secondary infections as important outcomes. However, as the situation in the country evolved, the guidelines group upgraded mortality, time to clinical recovery and time to clinical improvement as critical outcomes, as an effect on those could reduce pressure on the overwhelmed health system.

Critical (primary) Outcomes

As presented in the ‘Summary of findings’ table, the evidence is of low or very low certainty about the effect of Remdesivir on mortality, progression to non-invasive ventilation or high flow oxygen, progression to invasive mechanical ventilation, time to clinical recovery (not requiring oxygen or hospitalised care) and adverse events leading to drug discontinuation.

(a) All-cause mortality: Low certainty of evidence in 7400 patients in five RCTs [7-11] found little or no difference between Remdesivir and placebo or standard of care (RR 0.94; 95% CI 0.82 to 1.07).There were no significant differences observed even when trials were stratified by severity, risk of bias or steroid usage.

(b) Time to clinical recovery (time to achieve WHO score 1,2,3 or not requiring hospitalization for oxygen or medical care): In 1459 patients from two RCTs [8;11], the hazard ratio (HR) for reduction of time to clinical recovery in participants receiving Remdesivir compared with those receiving placebo or standard of care was 1.22 (95% CI 1.06 to 1.41). The evidence was of very low certainty. The median time reported in two studies ranged from 6-10 days in the Remdesivir group vs 7-15 days in the control groups (See Results Table 1 for results from each trial). A mean difference to quantify the magnitude of potential benefit was not available.

(c) Time to clinical improvement (>2 point reduction in the WHO ordinal score): Low certainty evidence from 1688 participants in three RCTs [7;8;11] suggested that Remdesivir may decrease time to clinical improvement (HR 1.25; 95% CI 1.12 to 1.40). The median and IQR ranged from 6-21 days in the Remdesivir group vs. 6-23 days in the control group. (See Results Table 1 for results from each trial). A mean difference to quantify the magnitude of potential benefit was not available.

(d) Progression to oxygen therapy: Low certainty evidence in 138 patients from one RCT [11], found that Remdesivir may make little or no difference in progression to oxygen therapy vs. standard of care (SOC)/placebo (RR 0.81; 95% CI 0.54 to 1.22).

(e) Progression to non-invasive ventilation (NIV) or high flow oxygen (HFO): Evidence from 573 patients in one RCT [11] found that Remdesivir may reduce progression to NIV or HFO (RR 0.70; 95% CI 0.51 to 0.98) and varied as widely as 2% to 49% with small sample size and few events.

(f) Progression to invasive mechanical ventilation: The evidence from 5730 patients in two RCTs [9;11] found that the effect of Remdesivir on progression to invasive mechanical ventilation was very uncertain (RR 0.78; 95% CI 0.44 to 1.39).

(g) Adverse events: Low certainty evidence from 817 patients in two RCTs [7;8] revealed Remdesivir may contribute to few or no additional adverse events as compared to placebo (RR 1.11; 95% CI 0.97 to 1.28). In addition, very low certainty evidence from 1877 patients in three RCTs [7;8;11] were found regarding the effects of Remdesivir on adverse effects leading to drug discontinuation (RR1.68; 95% CI 0.46 to 6.09).

(h) Duration of hospitalization: This was reported in two studies as a median and hence a meta-analysis could not be performed. Wang 2020 [7] reported a median (IQR) of 21 (12 to 31) days in the Remdesivir group vs. 21 (13.5 to 28.5) days in the SOC or placebo groups. ACTT Beigel 2020 [11] reported median (IQR) as 12 (6-28) days vs. 17 (8-28) days in the SOC/placebo groups.

Important (secondary) outcomes:

(1) Thrombotic events: Low certainty evidence from two RCTs [7;11] in 1281 participants suggests that Remdesivir may make little or no difference to occurrence of thrombotic events when compared to placebo or SOC (RR 0.74; 95% CI 0.40 to 1.37).

(2) Secondary infections: Low certainty evidence from two RCTs [7;11] in 1281 participants suggests that Remdesivir make little or no difference to occurrence of secondary infections when compared to placebo or SOC (RR 0.44; 95% CI 0.16 to 1.18).

No comparative data could be extracted for time to negative PCR; or post-acute COVID-19 pulmonary function/fibrosis or other sequelae.

Subgroup analysis

A subgroup analysis was attempted as pre-specified by the Expert Working Group.

  • In two RCTs [7;9] with 1,463 participants, in the subgroup with pneumonia but no hypoxia Remdesivir did not show a mortality benefit (RR 0.85; 95% CI 0.42 to 1.72).
  • In one RCT [7] Remdesivir showed no mortality benefit when participants were stratified by shorter duration of symptoms (<10 days; RR 0.76; 95% CI 0.29 to 1.95) or ≥10 days of symptoms (RR 1.48; 95% CI 0.45 to 4.88).

Disaggregated data could not be obtained for co-morbidities, inflammatory markers or different age groups. Subgroups of pregnancy, lactation, renal failure, liver failure were excluded from most trials. No data were available separately for immunocompromised individuals in any of the trials.

Results Table 1: Time to clinical improvement and recovery

*Time to clinical improvement was defined as the time to a two-point reduction in patients’ admission status on a six-point ordinal scale

#Time to clinical recovery was defined as the time to being non-hospitalized, or hospitalized with no oxygen or medical care requirement

Summary of characteristics of included trials

Study


Intervention
and comparator arms


Design


Location;
care setting


Age,
average in years


No
of participants randomized


Participant
characteristics


ACTT
Beigel 2020


Remdesivir (200 mg loading dose on
day 1, followed by 100 mg daily for up to 9 additional days) vs. Placebo for
up to 10 days


Double
blind RCT


USA,
Europe and Asia; Inpatients


Remdesivir: 58.6


Placebo:
59.2


Remdesivir: 541


Placebo:
521


Patients
with confirmed COVID-19 (mild-critical)


 


≥18 years
inpatients with confirmed COVID-19 with evidence of
LRTI (clinically or radiologically)


Mahajan
2021


Remdesivir 5 days (200 mg on day 1,
followed by


100
mg of once daily for the subsequent


four
days) vs. SOC


Open
label RCT


India;
Inpatients


Remdesivir: 58.08


SOC:
57.41


 


Remdesivir: 10


SOC:
10


Patients
with confirmed COVID-19 (moderate-severe)


 


All
participating patients


in the study had radiographic evidence of
pneumonia, RR>24/min and oxygen saturation of 94% or less. Mechanical
ventilation excluded


Solidarity
Pan 2021


Remdesivir (200 mg on day 0 and 100
mg on days 1 through 9) vs. SOC


Open
label RCT


Worldwide; Inpatients


Not
Reported


Remdesivir: 2750


SOC:
2725


 


Patients
with COVID-19 (mild-critical)


 


18 years old inpatients with Covid-19
were not known to have received any trial drug, were not expected to be
transferred elsewhere within 72 hours, and, in the physician’s view, had no
contraindication to any trial drug.


Spinner
2020


Remdesivir 5-day and 10-day course (200
mg on day 1, followed by 100 mg once daily for the subsequent days) vs. SOC


 


Open
label RCT


US, Europe and Asia; Inpatients


 


Remdesivir 10-day arm: 56


Remdesivir 5-day arm: 58


SOC:
57


 


Remdesivir 10-day arm: 197


Remdesivir 5-day arm: 199


SOC:
200


 


Patients
with COVID-19 (mild-severe)


 


Hospitalized patients>12 years with
SARS-CoV-2 infection and moderate COVID-19 pneumonia (defined as any
radiographic evidence of pulmonary infiltrates and oxygen saturation >94%
on room air) were enrolled


Wang
2020


Remdesivir (200 mg on day 1
followed by 100 mg on days 2–10) vs. Placebo for 10 days


Double
blind RCT


China;
Inpatients


Remdesivir: 66·0


Placebo:
64·0


 


Remdesivir: 158


Placebo:
79


 


Patients
with confirmed COVID-19 (severe)


 


≥18
years inpatients with SARS-CoV-2 infection, with an
interval from symptom onset to enrolment of 12 days or less, SPO2 of 94% or
less on room air or PaO2/FiO2 <=300 mm Hg and radiologically confirmed
pneumonia.


Forest plots

1. Mortality, all-cause:

2. Time to clinical recovery:

3. Time to clinical improvement:

4. Progression to oxygen therapy / 5. Progression to non-invasive ventilation/high-flow oxygen / 6. Progression to invasive mechnical ventilation:

7. Complications: thrombotic events / 8. Complications: secondary infections:

9. Any adverse events:

10. Adverse drug reactions leading to drug discontinuation:

Evidence to decision

The Antiviral Expert Working Group met on 14th May 2021 to consider remdesivir as a treatment for COVID-19. Conflict of interest declarations were reviewed by the Steering Committee; none were found to be relevant to remdesivir.

A summary and then more detailed explanations of the Expert Working Group's judgements follow.

Summary of judgements

Problem

The COVID-19 pandemic in India with more than 25 million cases and over 0.3 million deaths has significantly impacted and stressed the health structure of the country. With a shortage of intensive care unit beds, oxygen and trained personnel the country is facing a major health crisis. This has prompted many irrational treatment interventions which are neither beneficial nor cost effective. Remdesivir, though touted as an antiviral with possible benefit in the early viral replication phase of the disease, has not lived up to its promise. However, it continues to be prescribed widely and often at exorbitant costs due to lack of availability. The group judged the problem to be of utmost priority.

Desirable effects

The group agreed that Remdesivir may have no effect on mortality and progression to oxygen therapy or invasive mechanical ventilation. They noted that it may reduce progression to NIV/high flow oxygen. The group agreed that that the hazard ratio for the time to clinical improvement (2 point reduction in WHO ordinal scale) may favour Remdesivir over placebo/SOC, however the magnitude of this reduction in days was unclear. The effect of Remdesivir on time to clinical recovery (time to discharge or not requiring oxygen/medical care) was very uncertain.

The group also noted that the early trials did not use steroids as much as they are used now. In addition, the median duration of oxygen requirement was around 3 weeks in the ACTT-1 trial (11), which is quite prolonged compared to what we have seen more recently suggesting that treatment protocols have since evolved. They also noted that there were some potential differences in subgroups of oxygen/respiratory support within a single trial but this was not reflected in the pooled subgroup analyses. Overall the benefit provided by Remdesivir over and above steroids was unclear and indicates a possible niche for further trials. It may reduce time to clinical improvement which does have implications for a health system which is overwhelmed with a shortage of supplies and hospital beds. Taking these factors into consideration, overall the group members suggested a small benefit for Remdesivir.

Undesirable effects

Adverse events were not different between groups, nor were there adverse events leading to discontinuation, suggesting this drug may be safe. The group noted evidence was lacking in pregnancy, renal and liver disease and overall judged the undesirable effects as trivial.

Certainty of evidence

The group felt that there was low to very low certainty in the evidence for all outcomes, including those judged as critical.

Values

The group felt that there is possibly important uncertainty or variability regarding values. The time to clinical improvement and progression to NIV/high flow oxygen were the only outcomes that favored Remdesivir over placebo/SOC. Though the certainty of evidence was low regarding the effect estimate, the group agreed that stakeholders (for e.g., individual patient, health care providers, public or private health systems etc.) may value the beneficial effect of Remdesivir on these outcomes differently.

Balance of effects

The group discussed at length regarding the balance of effects and judged that at present with the evidence available the balance of effects was unknown. The benefit extended only to time to clinical improvement but even the effect size was small with an unclear magnitude of benefit with very low to low certainty of evidence. Panel members were clear they were not worried about adverse events. It is quite safe and has been extensively used in the country with no signal of harm. They felt the reduction of time to clinical improvement could have indirect benefits as it could free up the resources like hospital beds, oxygen supplies and also indirectly impact patients' risk of nosocomial infections and other complications. However all these benefits need to be weighed against the presence of very low evidence of clinical benefit.

Resources required

The group felt that the costs were moderate. The erratic supply chain has led to an increased demand for this drug with uncertain clinical benefit thus driving up costs. In addition being an intravenous drug and mostly advised for those with moderate to severe disease it has led to a situation where people need to be admitted to be given this drug thus adding hospitalization costs. The group includes clinicians in different types of Indian hospitals who have a good idea of drug and hospitalization costs.

Certainty of evidence of required resources

No studies reporting this were reviewed by the group.

Cost effectiveness

The group noted the lack of data from available cost effectiveness studies relevant to the Indian context. There are only benefits in time to clinical improvement and progression to NIV/high flow oxygen which may result in early discharge and save hospital beds, supplies and costs; however this was low certainty evidence. This highlights the uncertainty regarding cost effectiveness that requires evidence from new clinical studies specific to the Indian context.

Equity

At this point in time this intervention reduces equity due to cost and need for hospitalization. In addition, availability is currently an issue, which forces people to obtain this drug via illegal means and further reduces equity for a drug of questionable benefit. It is possible that in future cost or availability may not be an issue.

Acceptability

The group felt that this intervention is likely to have wide acceptance by all the relevant stakeholders (policy-makers, patients and clinicians), if further research proves its efficacy in the absence of increased adverse events.

Feasibility

This is a feasible intervention in the moderate to severe groups requiring oxygen as they are likely to need hospitalization by virtue of oxygen support. However, feasibility could be impacted significantly by availability.

Implementation considerations

Remdesivir should ONLY be considered in a narrow subset of patients requiring low-flow oxygen as it may reduce time to clinical improvement saving hospital resources for sicker patients. The signals of benefit in terms of reducing length of illness are modest, and these trials were carried out before corticosteroids became standard of care, therefore we do not know whether this small benefit of Remdesivir persists when patients requiring oxygen are also given steroids.

Clinicians may still choose to use Remdesivir given the evidence has not excluded the possibility of benefit but the possibility of harm remains. Given, low to very low certainty of evidence of benefit from Remdesivir, due consideration needs to be given to costs incurred and deviation of attention from the interventions and supportive care which have proven mortality benefit in the management of severe COVID-19 for an intervention of uncertain benefit. Additionally, patients require admission to hospital for administration of this intravenous drug.

The current recommendation is based on the evidence to date and will be updated as new evidence emerges.

Subgroup considerations

The group carefully considered a potential subgroup effect across patients with different levels of oxygen and ventilation requirement (i.e. measures of severity), early administration of Remdesivir and utility in non-severe patients.

(a) Oxygen requirement:  For this analysis, the participants were stratified as: no supplemental oxygen requirement, low flow oxygen, high flow oxygen and non-invasive ventilation and invasive mechanical ventilation. A single trial [11] in which fewer than 25% of participants were on steroids reported a mortality benefit in those on low-flow oxygen with Remdesivir. However, this apparent benefit from a subgroup analysis, could be the result of chance, as the meta-analysis showed no significant difference in mortality across all subgroups. Since the overall certainty of evidence (for any level of severity) was low, the effect of Remdesivir in this subgroup remains very uncertain.

(b) Early administration: Subgroup analysis to determine if Remdesivir benefits those patients who present early (<10 days) was considered, however only one study [7] addressed this and no mortality benefit was reported.

(c) Non severe patients: Two studies [9;11] had included patients with no oxygen requirements which could be extrapolated to a non-severe group; however, there was no mortality benefit noted.

The committee had a priori requested analyses of other important subgroups of patients including children, age > 50 years and those with co-morbidities, but unfortunately there were no data to address outcomes in these subgroups specifically.

Monitoring and evaluation

The conditional recommendation against the use of Remdesivir will be revisited as new evidence emerges. Along with efficacy data, evidence of undesirable effects should be monitored with widespread use, such as bradycardia, hypotension and liver dysfunction. The certainty of evidence for any adverse events was low and for adverse events leading to drug discontinuation was very low, thus potential drug-related harm has still not been ruled out.

Research priorities

There is considerable uncertainty surrounding the benefit of Remdesivir in moderate to severe COVID-19. Hence there is a need for conduct of well-structured, adequately powered randomized controlled trials to address the following:

  1. Does Remdesivir have a benefit over and above that conferred by steroids in those requiring oxygen or respiratory support?
  2. Does Remdesivir offer a benefit in those with moderate COVID-19 not on oxygen/respiratory support but who are at high risk of progression?
  3. What are the benefits or harms of using Remdesivir in pre-specified subgroups such as immunocompromised, renal failure patients on dialysis, pregnant women and children?
References
  1. Eastman RT, Roth JS, Brimacombe KR, Simeonov A, Shen M, Patnaik S, et al. Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19. ACS Cent Sci. 2020 May 27;6(5):672–83.
  2. Frediansyah A, Nainu F, Dhama K, Mudatsir M, Harapan H. Remdesivir and its antiviral activity against COVID-19: A systematic review. Clin Epidemiol Glob Health. 2021;9:123–7.
  3. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research. 2020 Mar;30(3):269–71.
  4. Rochwerg B, Agarwal A, Zeng L, Leo Y-S, Appiah JA, Agoritsas T, et al. Remdesivir for severe covid-19: a clinical practice guideline. BMJ. 2020 Jul 30;370:m2924.
  5. COVID-19 Treatment Guidelines Panel: Coronavirus disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health 2020.
  6. Organization WH. Therapeutics and COVID-19: living guideline, 31 March 2021. World Health Organization; 2021.
  7. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. 2020 May 16;395(10236):1569–78.
  8. Spinner CD, Gottlieb RL, Criner GJ, Arribas López JR, Cattelan AM, Soriano Viladomiu A, 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 Sep 15;324(11):1048.
  9. Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results. New England Journal of Medicine. 2021 Feb 11;384(6):497–511.
  10. Mahajan L, Singh AP, Gifty. Clinical outcomes of using remdesivir in patients with moderate to severe COVID-19: A prospective randomised study. Indian J Anaesth. 2021 Mar;65(Suppl 1):S41–6.
  11. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the Treatment of Covid-19 — Final Report. N Engl J Med [Internet]. 2020 Oct 8 [cited 2021 May 12]; Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262788/