Therapeutic dose Vs Nontherapeutic dose of thromboprophylaxis – Updated Recommendation

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

The panel recommends a dose of LMWH 40 mg OD to LMWH 1 mg/Kg/OD SC, or Unfractionated Heparin 5000 U Q12H SC.

Definition of mild:

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

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

The panel recommends a dose of LMWH 1 mg/Kg/BD SC.

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

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.

The panel recommends a dose of LMWH 1 mg/Kg/BD SC.

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

Therapeutic anticoagulation probably reduces thrombosis and thrombosis-related death without increasing risk of fatal bleeding in patients admitted to hospital with moderate to severe COVID-19.  While it does not have a mortality benefit in critical COVID-19 patients RR (1.02 95% Ci: 0.85 -1.22), it does reduce thrombosis without fatal bleeding in critical COVID-19 illness.

COVID-19 infection is associated with a hypercoagulable state. Thrombotic events, both venous and arterial thromboembolism have been noted. Therapeutic 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. Clinicians need to balance between the risk of thrombosis and the risk of bleeding in an individual patient.

With new Randomised Control trials (RCTs) available the group decided to update the recommendations based on a meta-analysis of 7 RCTs ^1–7.

In the light of the present variant being Omicron, it was noted that most of the patients with mild illness require only ambulatory or domiciliary care. Data was insufficient to make a recommendation for therapeutic anticoagulation in this category as there has been only one Open label RCT looking at non-severe Covid. However, though these patients were in hospital they had only non-severe COVID. The group noted very low to low certainty and hence were uncertain about the effect of therapeutic anticoagulation on all-cause mortality and thrombotic events in non-severe COVID-19 illness. Hence the working group suggested prophylactic anticoagulation be based on clinical judgement of the treating physician.

Meta analysis noted that therapeutic anticoagulation in moderate to severe cases of COVID-19 probably decreased thrombosis and thrombosis related death as compared to non-therapeutic anticoagulation [moderate certainty of evidence, [RR 0.46 (95% CI 0.27 - 0.80)] and [RR 0.62 (95% CI 0.39-1)] respectively. There was a slight increase in survival in patients without organ support. [moderate certainty of evidence, [RR 1.05 (95% CI 1.01-1.10)]. It was noted that there is increased risk of major bleeding in the therapeutic anticoagulation group [RR 1.78, 95% CI (1.00-3.15)], however only 5 cases of fatal bleeds were noted from 7 trials with 4747 patients, of which 4 are in the therapeutic anticoagulation group and 1 is in the prophylactic anticoagulation group. Based on this the working group made a strong recommendation for the use of therapeutic anticoagulation in moderate to severe Covid 19.

In Critical COVID-19 patients, therapeutic anticoagulation caused little or no difference in all-cause mortality or thrombosis related deaths compared to non-therapeutic anticoagulation group. There was no appreciable difference in organ support free days compared to non-therapeutic group [OR 0.86, 95%CI (0.7-1.06)]. Therapeutic dose anticoagulation probably does reduce thrombosis in critical covid-19 patients {moderate certainty of evidence, [RR 0.65 (95% CI 0.46-0.92)]}. The group discussed in detail about the pros and cons of therapeutic anticoagulation in this category of severity and made a conditional recommendation for therapeutic anticoagulation.

Date of latest search: 14 October 2021

Date of completion of Summary of findings table and presentation to Expert Working Group: 02 April 2022

Evidence synthesis team:  Sushil S(SS), Jisha Sara John (JS), 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 for sharing additional protocol documents, and Alexander Spyropoulous of the Hep-Covid trial who provided valuable assistance in evidence clarification.

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 COVID19 and is believed to be multifactorial. SARS-CoV-2 virus both directly and indirectly causes endothelial injury, microvascular inflammation, endothelial exocytosis, eventually contributing to an 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 COVID19 infection will benefit with therapeutic (full dose) anticoagulation in the absence of a confirmed thrombotic event.

Desirable effects

WHO Critical: Evidence shows that using therapeutic anticoagulation did not significantly reduce mortality in critical COVID-19 but does appear to prevent thrombotic events by 35% (8-54%) with no statistically significant increase in bleeding with a moderate certainty of evidence. Therapeutic anticoagulation also did not improve days free of organ support compared to prophylactic anticoagulation. In MPRCT trial, DSMB stopped recruitment in this category as it felt that therapeutic anticoagulation did not offer any advantage towards organ support free days 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.

WHO Moderate/Severe: The group noted that using therapeutic anticoagulation reduced thrombosis and increased the probability of OSFD but did not significantly reduce mortality or cause increased bleeding in moderate/severe category of COVID-19. The group felt that 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 felt 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.

WHO mild: The evidence for therapeutic anticoagulation in mild covid-19 infection is very uncertain and the group concluded that PDA should be considered based only if the patient’s risk factor profile, necessitates it.

Undesirable effects

WHO Critical: The mPRCT (Critical) had around >500 patients in each arm and the incidence of bleeding in each group was similar. The actual difference in bleeding between the two groups was 1% suggesting that present evidence showed that the risk of bleeding was not increased. The DSMB of ACTIV-4 component of the mPRCT trial had recommended an early interim analysis to watch for the same, however the study was terminated as the futility threshold was reached suggesting that there was no benefit of TDA over PDA in the primary outcome of OSFD.

WHO Moderate/Severe: The mPRCT (Noncritical) had around >1000 patients in each arm and the incidence of bleeding in the therapeutic dose group was slightly increased suggesting that in WHO moderate and severe COVID infection there seemed to be a mildly increased risk of bleeding.

The panel also discussed regarding the absence of data regarding anticoagulation in the mild and moderate groups without hypoxia and felt that decision re 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, severe and critical categories was felt to be High.

Values 

The primary premise was to compare therapeutic dose anticoagulation vs nontherapeutic dose of anticoagulation in the management of hospitalized COVID-19 infection and hence clinically relevant outcomes were carefully chosen which could help a clinician on the ground level to decide which dose would of utility. The group felt that the outcomes of mortality, thrombotic events, bleeding, and Organ support free days were certainly important. They felt that there was no uncertainty or variability. The group felt that the composite outcomes of thrombosis or death and ICU admission or death in 28 days were fair outcomes that could clearly demonstrate the utility of the intervention (therapeutic dose of anticoagulation) in preventing progression of COVID-19 illness.

Balance of effects

WHO Critical: There are only 7 trials to inform evidence and there seemed to be no mortality benefit or decrease in Organ support free days [OSFD] between therapeutic anticoagulation and prophylactic anticoagulation. There was however a decrease in thrombotic events but with a possible chance of increased bleeding noted.

WHO Moderate/Severe: Therapeutic anticoagulation appeared to increase OSFD, prevent thrombotic events and a composite outcome thrombosis or death, with a slightly increased risk for major bleeding. There was no overall mortality benefit. The group felt that 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 the therapeutic 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 experienced with the use of the same and are aware of the various monitoring implications. Cost of implementation is low and needs to weigh against hospitalization and ICU care costs. Though monitoring of anticoagulation efficacy with Anti Xa testing will be possible only in an advanced haemostasis laboratory, if widely employed to ensure therapeutic efficacy it will likely also protect against unnecessary bleeding. However, this will increase costs and is 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 anticoagulation are likely low if we can save on costs of hospitalisation and intensive care beds.

Certainty of evidence of required resources

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

Cost effectiveness

Now there is no data regard 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 HCWs easily. It is also likely that even if patients in the moderate category are given therapeutic 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 requirements of anticoagulation delivery are reasonable, implementation can be equitable.

Feasibility

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

As the Omicron variant has taken over as the variant of concern over the delta variant, the evidence for use of therapeutic anticoagulation in mild COVID-19 patients is uncertain and use of anticoagulation in out-patients is out of the scope of this review.

The working group felt that therapeutic anticoagulation in hospitalized patients with moderate disease (those who have progressively increasing O2 requirement) or severe disease might prevent thrombotic events, without any reduction in mortality.  This subset might have increased probability of surviving to hospital discharge with reduced need for ICU-level organ support, including invasive and non-invasive mechanical ventilation (OSFD), with slightly increased risk for major bleeding. The evidence in critical group shows some benefit but the group felt it should be a case-to-case decision based on clinical judgement since in critical patients, bleeding maybe catastrophic. The trials did not show much difference in organ support free days in both the therapeutic anticoagulation and prophylactic anticoagulation groups.

Though there was no data regard to the cost effectiveness of this intervention, resources required for implementation of therapeutic anticoagulation are minimal in this subgroup of patients. This intervention of therapeutic dose anticoagulation is feasible to implement widely and easily. The evidence is for injectable low molecular weight heparin, unfractionated heparin, and oral anticoagulants.

The subgroups of children <18 years of age, pregnant women, and asymptomatic 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.

Mild and non-severe COVID patients were evaluated in one RCT. The  BEMICOP ¹study included only non-severe COVID patients and compared prophylactic vs therapeutic doses of Bemiparin. This study favoured a prophylactic dose of Bemiparin. However, the study was limited by its small sample size (32 in the therapeutic arm and 33 in the prophylactic arm). Anticoagulation should be avoided for outpatient mild COVID cases even though this subgroup of patients has not been studied in RCT.

There is no defined role for monitoring of D-dimer in non-hospitalized COVID-19 patients. A high D-dimer is known to be associated with an increased risk of venous thromboembolism in patients without COVID-19. In COVID-19, D-dimer has been correlated with a poorer prognosis and increased mortality. However, whether a high D-dimer value can be extrapolated to an increased risk of arterial or venous thrombosis in COVID-19, however it has been associated independently with a higher risk of mortality ¹⁹. 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 base management strategies on the same.

For practical purposes, especially as far as decision regarding the role of therapeutic anticoagulation is concerned, we suggest continuing the previous WHO classification of the disease spectrum into mild, moderate, severe and critical categories²⁰.

Data pertaining to the role of anticoagulation in mild category of disease is sparse and needs to be covered separately since it was not a part of this PICO Question, and these patients now are often managed as out-patients. There is a need for monitoring this arm though and we propose an independent evaluation of this subset of patients during the coming waves, if any.

For patients with moderate disease with hypoxia and for those with severe disease, the balance of effects comparing the risk of thrombosis vs risk of bleeding continues to favor therapeutic dose anticoagulation over prophylactic dose anticoagulation. These seemed to be a significant difference in the number of patients falling into these two groups in the third wave as compared to the second wave i.e., with more patients with mild as compared to severe or critical disease all over the country.

For patient with critical disease, though the data is not clear in this category, since the worsening from severe to critical disease often proceeds as a continuum, it would be practically difficult to switch from therapeutic to prophylactic modality in a given patient unless clear criteria for stopping anticoagulants are met. Bleed scores may be used in this regard. More research is therefore needed in this area.

A preponderance of observational, non-randomized data suggests increased risk of thrombosis in all severities of COVID-19, correlation of D-Dimer with disease severity and benefit of post-discharge anticoagulation. These findings are not borne out in randomized trials and hence will not be considered in the framing of these guidelines. Therefore, we need to be cautious towards interpretation of any data relating to outcomes with different dosing strategies, as this would be non-randomized data.

1.Research needs to focus on duration of anticoagulation in COVID-19 in critical and severe cases.

2. Role of D dimer in tailoring anticoagulation

3. Role of Anticoagulation in COVID-19 as prophylaxis in high-risk groups with mild COVID 19.

4. Anticoagulation with varying clinical picture as seen with different variants of COVID-19

5. Role of anticoagulants in Vaccine Induced Thrombotic Thrombocytopenia.

6. Duration of anticoagulants in Vaccine Induced Thrombotic Thrombocytopenia

1. Marcos-Jubilar, M. et al. Therapeutic versus Prophylactic Bemiparin in Hospitalized Patients with Nonsevere COVID-19 Pneumonia (BEMICOP Study): An Open-Label, Multicenter, Randomized, Controlled Trial. Thromb. Haemost. 122, 295–299 (2022).
2. Lopes, R. D. et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. The Lancet 397, 2253–2263 (2021).
3. 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).
4. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N. Engl. J. Med. 385, 777–789 (2021).
5. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. N. Engl. J. Med. 385, 790–802 (2021).
6. Sholzberg, M. et al. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ 375, n2400 (2021).
7. Spyropoulos, A. C. et al. Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial. JAMA Intern. Med. 181, 1612–1620 (2021).
8. Wang, D. et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA 323, 1061–1069 (2020).
9. 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. JTH 18, 844–847 (2020).
10. Klok, F. A. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb. Res. 191, 145–147 (2020).
11. Ackermann, M. et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N. Engl. J. Med. 383, 120–128 (2020).
12. 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).
13. Cuker, A. et al. American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: January 2022 update on the use of therapeutic-intensity anticoagulation in acutely ill patients. Blood Adv. bloodadvances.2022007561 (2022) doi:10.1182/bloodadvances.2022007561.
14. Moores, L. K. et al. Thromboprophylaxis in Patients With COVID-19: A Brief Update to the CHEST Guideline and Expert Panel Report. CHEST 0, (2022).
15. Morici, N. et al. Enoxaparin for thromboprophylaxis in hospitalized COVID-19 patients: comparison of 40 mg o.d. vs 40 mg b.i.d. The X-COVID19 Randomized Clinical Trial. http://medrxiv.org/lookup/doi/10.1101/2021.11.17.21266488 (2021) doi:10.1101/2021.11.17.21266488.
16. 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).
17. 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).
18. Connors, J. M. et al. Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial. JAMA 326, 1703–1712 (2021).
19. Li, Y. et al. Clinical Significance of Plasma D-Dimer in COVID-19 Mortality. Front. Med. 8, 638097 (2021).
20. Therapeutics and COVID-19: living guideline. https://www.who.int/publications/i/item/WHO-2019-nCoV-therapeutics-2022.1.

Covid Management Guidelines India Group - Anticoagulation Working Group. Prophylactic Vs Therapeutic dose anticoagulation. Covid Guidelines India; Published online on August 08th, 2022; URL: https://indiacovidguidelines.org/therapeutic-dose-vs-nontherapeutic-dose-of-thromboprophylaxis/(accessed )