Disclaimer: The aim of these rapid reviews is to retrieve, appraise, summarize and update the available evidence on COVID-related health technology. The reviews have not been externally peer- reviewed; they should not replace individual clinical judgement and the sources cited should be checked. The views expressed represent the views of the authors and not necessarily those of their host institutions. The views are not a substitute for professional medical advice.

Copyright Claims: This review is an intellectual property of the authors and of the Institute of Clinical Epidemiology, National Institutes of Health-UP Manila and Asia-Pacific Center for Evidence Based Healthcare Inc.

BACKGROUND

The clinical phase of COVID-19 is divided into three: the viremia phase, the acute (pneumonia) phase, and the recovery phase. For the majority, the immune system is able to overcome the viremia phase, leading to clinical recovery. For some, progression to the acute (pneumonia) phase occurs usually in the 7th-14th day of illness. In this phase, T- and B-cells decrease, while inflammatory cytokines (e.g., IL-6) and D-dimer levels increase.1,2 This hypercoagulable state has been associated with poor prognosis.3 Sixty-four clinically relevant thrombotic events were confirmed in

aFrench cohort of 150 patients with COVID-19, despite anticoagulation. These were mainly pulmonary embolisms (16.7%). The risk of thrombosis in COVID-19 patients

with acute respiratory distress syndrome (ARDS) was 2.6 [95% CI: 1.1, 6.1), p = 0.035].4 A Dutch cohort of 184 patients with COVID-19 pneumonia in the intensive care unit was observed for occurrence of a composite outcome of symptomatic acute pulmonary embolism (PE), deep- vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients. Cumulative incidence of the composite outcome was 31% (95% CI: 20, 41), of which computed tomography pulmonary angiography (CTPA) and/or ultrasonography confirmed venous thromboembolism (VTE) in 27% (95% CI: 17, 37) and arterial thrombotic events in 3.7% (95% CI: 0, 8.2). PE was the most frequent thrombotic complication (n = 25, 81%).5 Many experts believe that giving LMWH during this phase may be beneficial.1,6-9 LMWH is believed to be beneficial due to its antithrombotic effect, anti- inflammatory function, and anti-viral properties.7

Scientists found a quantitative fusion assay dependent on SARS-CoV-2 S protein, ACE2, and TMPRSS2, and found that nafamostat, an anticoagulant used for disseminated intravascular coagulation, potently inhibited the fusion while camostat mesylate was about 10-fold less active. Furthermore, nafamostat mesylate blocked SARS- CoV-2 infection of Calu-3 cells with an EC50 around 10 nM, which is below its average blood concentration after intravenous infusion. These findings make nafamostat a likely candidate drug to treat COVID-19.10

There are four registered clinical trials investigating the efficacy and safety of anticoagulation for COVID-19 (Appendix 1).

This rapid review summarizes the available evidence on the efficacy and safety of anticoagulation in treating patients with COVID-19.

METHODS

We searched PubMed and MEDLINE on April 11, 2020 using the keywords “coronavirus infections”, “coronavirus”, “novel coronavirus”, “NCOV”, “COVID-19”, “2019-nCoV”, “Wuhan”, “severe acute respiratory distress syndrome coronavirus 2”, “SARS-CoV-2”; and “fibrinolytic agents”, “thrombolytic therapy”, “edoxaban”, “heparin”, “low-molecular weight heparin”, “new oral anticoagulant”, “antithrombotic”, “enoxaparin”, “tinzaparin”, “dalteparin”, “dabigatran”, “fondaparinux”, “unfractionated heparin”, “rivaroxaban”, “apixaban”, “anticoagulants”, “Factor Xa inhibitors”, “fibrin modulating agents”, and “blood coagulation”. Reference lists of included studies were examined for other relevant reviews. Search was done without language restrictions, yielding a total of 11 titles of articles. Grey literature database medRxiv.org was also searched using the terms “COVID-19”, “coagulation”, “heparin”, “low molecular weight heparin”, and “thrombosis”, resulting in 816 titles. Three review authors (EOS, JMA, and PPR) independently assessed the potential relevance of all titles

and abstracts identified through the searches. We selected articles based on the following inclusion criteria:

•Population: COVID-19 patients aged 18 years and above, excluding pregnant patients

•Exposure: Anticoagulation

•Outcomes: Reduction in disease progression or mortality, incidence of bleeding

•Study designs: Systematic reviews and meta-analyses, randomized controlled trials, or observational studies (case series, prospective or retrospective cohort studies)

Four articles were included in the first review after removal of duplicates and articles that did not meet our selection criteria. The validity of eligible articles was independently appraised by the authors. Disagreements were resolved through consensus.

A search for new articles on ClinicalTrials.gov and the Chinese Clinical Trial Registry was done on April 24, 2020 using the terms “COVID-19” and “coagulation”, with the new search yielding a total of four titles of articles, from which three ongoing clinical trials were selected and included in this current update. MEDLINE and medRxiv.org were programmed to give daily alerts for new publications satisfying the research criteria. As of the latest update of this review, no alerts for new articles were received.

RESULTS

Characteristics of Included Studies

As of April 23, 2020, there is no randomized controlled trial that answers the question posted. However, we identified two retrospective cohorts that studied the association between disease progression and/or mortality in COVID-19 and the use of anticoagulants in addition to other interventions. A retrospective cohort and a network meta-analysis addressing the safety of anticoagulation were found (Appendix 2).

Critical Appraisal

Guide questions from the book Painless Evidence- Based Medicine were used to appraise the included studies.11 In the absence of any randomized controlled trial, the ideal study design to answer a question on efficacy and safety, we analyzed three retrospective cohort studies and one network meta-analysis.6,9,12,13

The efficacy outcomes should be interpreted with caution because of the high risk of bias. The studies by Shi et al (n =

42)and Tang et al (n = 449), which included patients with severe COVID-19, reported the association of mortality and improvement in laboratory parameters for coagulation and inflammation with the use of anticoagulation.6,9 Both studies had selection bias and lack of adjustment for the effects of various confounders.

For the safety outcome (incidence of bleeding), we did not find an article to directly answer this issue. The retrospective cohort by Yamakawa et al and the network

meta-analysis by Yatabe et al included patients with bacterial sepsis, not COVID-19 patients.12,13 In the network meta- analysis, the number of patients in the study was too limited to accurately evaluate the incidence of bleeding complications. The study by Yamakawa et al, which was a retrospective subgroup analysis, also had various methodologic limitations

–differences in baseline illness severity (which they tried to adjust through propensity score matching); ascertainment bias; lack of control of confounders; possibility of high false- positive results; and non-uniform treatment protocols used (Appendix 3).

Effectiveness Outcomes

Shi et al found that the use of LMWH was associated with the following changes in levels of surrogate markers in severe COVID-19: (1) significantly decreased D-dimer levels, signifying improved hypercoagulable state; (2) significantly decreased IL-6 levels; (3) greater increases in percentage of lymphocytes and platelet counts, suggesting reduced inflammation; and (4) no significant effect on C-reactive protein (CRP).6

LMWH was also found to reduce the risk of 28-day mortality in the study by Tang et al among patients with severe COVID-19 who met a sepsis-induced coagulopathy (SIC) score of at least four [OR 0.37 (95% CI: 0.15, 0.90), p = 0.029] and D-dimer levels more than six times elevated from the upper limit of normal [OR 0.44 (95% CI: 0.22, 0.87), p = 0.017]. 9

Overall, the dose, duration, and timing of anticoagulation for COVID-19 are not yet well established.

Safety Outcomes

The incidence of bleeding with anticoagulation comes from indirect evidence using studies on patients with DIC of sepsis. Yatabe et al found that bleeding complications did not differ significantly between anticoagulants and placebo, and that in terms of bleeding incidence, antithrombins might be the best to use, whereas heparin may be the worst.13 Similarly, Yamakawa et al found no significant difference in bleeding complications between anticoagulants and placebo; however, there was a consistent tendency towards an increase in bleeding-related transfusions in all Sequential Organ Failure Assessment (SOFA) score subsets considered.12

Recommendations from Other Guidelines

The International Society of Thrombosis and Hemostasis recommends that LMWH be considered in all patients (including non-critically ill) who require hospital admission for COVID-19 infection, in the absence of any contra- indications (active bleeding and platelet count less than 25 x 109/L.) Monitoring is advised in severe renal impairment.8

Meanwhile, the Philippine Society on Vascular Medicine suggests initiation of anticoagulation using prophylactic dose heparin on hospitalized patients with COVID-19 (on admission or at any time during the hospital course) if any

of the following are present: (1) International Society of

Thrombosis and Hemostasis (ISTH) criteria: D-dimer >2ug/ ml, ± prolonged protime, ± platelet < 100 x 109/L; (2) Padua Prediction Score (for risk of VTE) of 4; (3) (SIC) score of 4; or (4) critical illness (admission to the intensive care unit requiring mechanical ventilation or FiO2 of 60% or higher).14

CONCLUSION

Based on low-quality evidence, there seems to be benefit, seen as reduction in 28-day mortality and improvement in inflammatory and coagulation markers, with the use of anticoagulants in severe COVID-19.

There is no observed increase in the incidence of bleeding related to the use of anticoagulants for COVID-19. Moreover, studies on patients with sepsis-related DIC show no significant difference in bleeding incidence between the anticoagulant and the placebo group. However, there was a tendency towards increased bleeding-related transfusions in the anticoagulation group.

The efficacy and safety of anticoagulants in the treatment of COVID-19 need to be confirmed through randomized controlled trials.

Declaration of Conflict of Interest

No conflict of interest.

REFERENCES

1.Lin L, Lu L, Cao W, Li T. Hypothesis for potential pathogenesis of SARS-CoV-2 infection--a review of immune changes in patients with viral pneumonia. Emerg Microbes Infect. 2020; 9(1):727-32.

2.Li T, Lu H, Zhang W. Clinical observation and management of COVID-19 patients. Emerg Microbes Infect. 2020; 9(1):687–90.

3.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. 2020; 18(4):844-7.

4.Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020; 46(6):1089-98.

5.Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020; 191:145-7.

6.Shi C, Wang C, Wang H, Yang C, Cai F, Zeng F, et al. Clinical observations of low molecular weight heparin in relieving inflammation in COVID-19 patients : A retrospective cohort study. medRxiv preprint. 2020.

7.Thachil J. The versatile heparin in COVID-19. J Thromb Haemost. 2020;18(5):1020-22.

8.Thachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020; 18(5):1023-6.

9.Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-9.

10.Yamamoto M, Kiso M, Sakai-Tagawa Y, Iwatsuki-Horimoto K, Imai M, Takeda M, et al. The anticoagulant nafamostat potently inhibits SARS-CoV-2 infection in vitro: an existing drug with multiple possible therapeutic effects. bioRxiv preprint. 2020. doi: https://doi. org/10.1101/2020.04.22.054981.

11.Dans AL, Dans LF, Silvestre MAA (editors). Painless Evidence-based Medicine. Wiley. 2017;

12.Yamakawa K, Umemura Y, Hayakawa M, Kudo D, Sanui M,Takahashi H, et al. Benefit profile of anticoagulant therapy in sepsis: A nationwide multicentre registry in Japan. Crit Care. 2016; 20(1):229.

13.Yatabe T, Inoue S, Sakamoto S, Sumi Y, Nishida O, Hayashida K, et al. The anticoagulant treatment for sepsis induced disseminated intravascular coagulation; network meta-analysis. Thromb Res. 2018;171:136–42.

14.Philippine Society of Vascular Medicine. PSVM Interim Guidelines on Vascular Procedures and Treatment Interventions During the COVID-19 Pandemic. 2020.

1 Trial Evaluating Efficacy and Safety of	Not yet	20 April to 31 July 2020	RCT	France
Anticoagulation in Patients with COVID-19	recruiting		Open-label (Phase 2)
Infection, Nested in the Corimmuno-19 Cohort
(CORIMMUNO-COAG) (NCT04344756)

Adult patients (≥18 years old) with	Tinzaparin	Standard of Care	Primary outcomes;
COVID-19 pneumonia hospitalized	(INNOHEP®) IU/	for COVID-19 and a	1. Survival without ventilation (VNI or
in conventional or intensive care	kg/24h for 14 days if	subcutaneous preventive	mechanical ventilation) [Time Frame: day
units divided into 2 groups:	creatinine clearance	anticoagulation for at least	14 ] (Group 1)
	(Cockcroft) ≥ 20mL/	14 days with enoxaparin	2. Ventilator free survival [Time Frame: day 28 ]
Group 1 - patients not requiring	min, otherwise	4000 IU/24h, tinzaparin	(Group 2)
ICU at admission with mild disease	unfractionated	3500 IU/24h or dalteparin
to severe pneumopathy according	heparin	5000 IU/24h if creatinine
to the WHO criteria of severity of	(Calciparine®,	clearance (Cockcroft) ≥
COVID pneumopathy, and with	Héparine	30mL/min or unfractionated
symptom onset before 14 days, with	Sodique Choay®)	heparin 5000 IU/12h
need for oxygen but no non-invasive	subcutaneously or	if creatinine clearance
ventilation (NIV) or high flow	intravenous with	< 30mL/min
	an anti-Xa target
Group 2 - Respiratory failure AND	between 0.5 and 0.7
	IU/mL for 14 days
requiring mechanical ventilation;
WHO progression scale ≥6; no
do-not-resuscitate (DNR) order

2 Preventing COVID-19 Complications With Low-	Not yet	14 April to	RCT	Switzerland	Adult patients with COVID-19
and High-dose Anticoagulation (COVID-HEP)	recruiting	30 November 2020	Single-blind (Phase 3)		infections admitted to an acute
(NCT04345848)					non-critical medical ward with
					admission D-dimer levels >1000
					ng/mL or an acute critical ward
					(ICU or intermediate care unit)

Therapeutic doses	Prophylactic doses of
of subcutaneous	subcutaneous enoxaparin or
enoxaparin or	intravenous unfractionated
intravenous	heparin from admission until
unfractionated	end of hospital stay or clinical
heparin from	recovery using 2 different
admission until end	doses of anticoagulation.
of hospital stay or	If hospitalized in the
clinical recovery using	ICU, an augmented
2 different doses of	thromboprophylaxis regimen
anticoagulation.	as standard of care.

Primary outcomes:

1.Composite outcome arterial or venous thrombosis, disseminated intravascular coagulation and all-cause mortality [Time Frame: 30 days]

2.Risk of arterial or venous thrombosis, disseminated intravascular coagulation and all-cause mortality

3 Austrian CoronaVirus Adaptive Clinical Trial	Recruiting 16 April to	RCT	Austria	Adult patients (≥18 years old) with
(ACOVACT) (NCT04351724)	01 December 2020	Open-label (Phase 2		confirmed COVID-19 who are
		and Phase 3)		hospitalized, with O2 saturation <94%
				on room air or >3% drop if with COPD.
				eGFR >20 mL/min required for
				patients in the rivaroxaban substudy

Rivaroxaban 2.5 mg 2-0-2 or 10 mg ½-0- 1/2, as applicable

Thromboprophylaxis	Time to clinical improvement (defined as
according to local standard,	time from randomization to a sustained
most likely to be low	improvement (>48 hours) of ≥1 category on
molecular weight heparin	2 consecutive days (compared to the status
	at randomization) measured on a proposed
	7-category WHO ordinal scale, as follows:
	1.	Not hospitalized, no limitations on activities
	2.	Not hospitalized, limitation on activities
	3.	Hospitalized, not requiring supplemental
		oxygen
	4.	Hospitalized, requiring supplemental oxygen
	5.	Hospitalized, on non-invasive ventilation or
		high flow oxygen devices
	6.	Hospitalized, on invasive ventilation or ECMO
	7.	Death

4 Effects of different VTE prevention methods	Recruiting 10 Feb to 10 April 2020	Nonrandomized	China
on the prognosis of hospitalized patients with		controlled trial
novel coronavirus pneumonia (COVID-19)
(ChiCTR2000030946)

Adult patients aged (18-80 years)	Low molecular weight	Mechanical preventive	Effects of low molecular weight heparin and
diagnosed with confirmed new	heparin therapy	antiocagulation	mechanical preventive anticoagulation on the
coronavirus pneumonia and in need of			prognosis of hospitalized patients with novel
hospitalization and with VTE score ≥4			coronavirus pneumonia (effects not specified)