Therapeutic dose Vs Nontherapeutic dose of thromboprophylaxis – Previous Recommendation

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

Definition of Severe illness

Pneumonia with ANY ONE of the following:

• severe respiratory distress or respiratory rate >30/min
• SpO2 <90% on room air
• NO invasive or non-invasive respiratory support needed

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

Definitions:

Mild illness:

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

• Symptomatic (any acute COVID-19 related symptoms)
• AND respiratory rate <24/min • WITHOUT pneumonia or hypoxia Moderate illness without hypoxia:

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

• Pneumonia (clinical or radiological)
• AND respiratory rate ≤30/min
• AND SpO2 ≥94% on room air

Definitions

Moderate illness with hypoxia

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

• Hypoxia (SpO2 <94% on room air)
• AND respiratory rate ≤30/min
• AND SpO2 ≥90% on room air

Severe illness:

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

A conditional recommendation is one for which the desirable effects probably outweigh the undesirable effects (weak recommendation FOR an intervention) or undesirable effects probably outweigh the desirable effects (weak recommendation AGAINST an intervention) but appreciable uncertainty exists. This implies that not all will be best served by this recommendation and decisions can be made by the patient and caregiver based on patient values, resources and setting with a clear understanding of the ensuing harms and benefits.

Definitions:

Critical illness:

• 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

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.

Date of latest search: 9^th June 2021

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

The Anticoagulation Expert Working Group met on 24^th 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/Severe: therapeutic 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.

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.

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.

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.

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.

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