Anticoagulant Treatment of COVID-19 as Early as Possible—Sulodexide and Perspectives

Sulodexide in the Treatment of Patients with Early Stages of COVID-19: A Randomized Controlled Trial

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), infects endothelium, lung, heart, vascular system, gastrointestinal tube, kidney, and other organs via interaction of virus' spike S protein with angiotensin-converting enzyme 2 receptor on cell surfaces.[1] The infection mechanism includes proinflammatory changes in the arterial and venous walls resulting in endotheliitis followed by acute venous and arterial thrombosis contributing to up to 20% of COVID-19-related mortality.[2] However, patients may remain asymptomatic following infection or develop symptoms suspicious for COVID-19 approximately 5 days after infection with SARS-CoV-2.[3] Upon deterioration of symptoms, patients are hospitalized and anticoagulation with low-molecular weight heparin (LMWH) is now regarded as cornerstone therapy for admitted patients with COVID-19.[4] [5]

For asymptomatic patients with laboratory-confirmed COVID-19, it is uncertain whether hydroxychloroquine reduces hospitalization.[6] The National Institutes of Health treatment guidelines express uncertainty regarding the use of anti-SARS-CoV-2 monoclonal antibodies, bamlanivimab and casirivimab, in this population.[7] Fluvoxamine, otherwise used for compulsive obsessive disorder, exerts σ-1 receptor agonism with reduction of sepsis-related inflammatory response and was in a small randomized controlled trial (RCT) in nonhospitalized patients with COVID-19 associated with reduced clinical deterioration.[8] Convalescent plasma with high titers of SARS-CoV-2 antibodies reduced deterioration of respiratory symptoms in older outpatients with mild COVID-19 symptoms in a small RCT,[9] although a meta-analysis of four RCTs failed to demonstrate any benefit.[10]

Heparins and other glycosaminoglycans act on the thromboinflammatory process by their anticoagulant and nonanticoagulant effects.[11] Taking these potential new mechanisms of anticoagulants in consideration, the benefit of any glycosaminoglycan or anticoagulant of other origin may offer an attractive therapy for persons with mild or moderate symptoms of SARS-CoV-2 to prevent hospitalization.

Several studies are in progress to investigate the benefit of an anticoagulant given as early as possible for patients suffering from mild to moderate severity of COVID-19 using LMWH, sulodexide, the direct oral anticoagulants (DOACs) apixaban and edoxaban, and the antiplatelet drug acetylsalicylic acid (ASA) at various doses. Some studies add colchicine to ensure an anti-inflammatory action of DOACs or ASA ([Table 1]).[12] [13] [14] [15] [16] [17] [18] [19] The unmet clinical need is speeding up planning of studies and therefore, some of the planned or ongoing trials may be missing in this listing.

Table 1 Clinical studies on treatment of COVID-19 at home. Search results in https://clinicaltrials.gov with keywords: COVID-19, anticoagulation, as of 18 March 2021:

Trial ID (ref.)	Anticoagulant control	Dose duration	Primary outcome	Participants (N)	Design	Estimated study end-date
NCT04400799[12]	Enoxaparin control	40 mg od No study drugs 14 days	Hospitalization all-cause mortality day 14	1,000	Prospective, open label randomized multicentric	April 2021
NCT04508439[13]	Enoxaparin enoxaparin	40 mg od and 1 mg/kg bw bid sc 15 days crossover 30 days total	Hospital care admission days in hospital care, days supplemental oxygen day 30	130	Prospective, randomized open label, crossover assignment, monocentric	December 2020
NCT04483830[15]	Sulodexide placebo	500 LRU bid placebo pills 21 days	Hospital care admission, days in hospital care, days supplemental oxygen, day 21 D-dimer and CRP, days 0 vs. 14	243	Prospective randomized placebo-controlled, multicentric	September 2020
NCT04746339[16]	Apixaban placebo	2.5 mg bid Placebo pills	Days alive and out of hospital day 30	1,000	Prospective, randomized, quadruple blind, multicentric	December 2021
NCT04498273[17]	Apixaban aspirin placebo	2.5 mg bid 5 mg bid 81 mg od No treatment 30 days	Composite endpoint: hospitalization for cardiovascular/pulmonary events, symptomatic VTE, arterial thromboembolism, myocardial infarction, ischemic stroke, all-cause mortality day 45	7,000	Prospective randomized quadrupleblind, multicentric	September 2021
NCT04516941[18]	Edoxaban colchicine control	60 mg od 30 mg od if CrCl ≤ 50 mL/min or BW ≤ 60 kg 25 ± 3 days 0.5 mg bid, 3 days 0.5 mg od day 4 to 14 ± 3 or 25 ± 3 No active treatment	Edoxaban vs. control: asymptomatic proximal DVT, symptomatic PE and DVT, myocardial infarction, ischemic stroke, non-CNS systemic embolism, mortality, day 25 ± 3 Colchicine vs. control: SARS-CoV-2 clearance rates determined by PCR or freedom from death or hospitalization, day 14 ± 3	420	Prospective randomized open label 22 factorial design bicentric	December 2021
NCT04324463[19]	Colchicine aspirin control rivaroxaban interferon-beta	0.6 mg bid 3 days 0.6 mg od day 4 to 25 75–100 mg od Usual care 25 days 2.5 mg bid, inpatients only Inpatients only	Colchicine–aspirin: composite of hospitalization or death day 45	4,000	Prospective open-label parallel group 22 factorial design randomized multicentric	June 2021
NCT04518735[24]	Chronic therapy warfarin, acenocumarol dabigatran, apixaban, edoxaban rivaroxaban aspirin, clopidogrel, prasugrel, ticagrelor, cangrelor, dipyridamole no anticoagulant therapy	According approved treatment regimens, any indication	VKA and antiplatelet therapy and control: comparison of clinical outcomes depending on previous antithrombotic therapy per group, mortality, transfer to the intensive care unit, day 28	1,707	Retrospective case–control monocentric	June 2020

Abbreviations: bid, twice a day; BW, body weight; CNS, central nervous system; DVT, deep vein thrombosis; od, once daily; PCR, polymerase chain reaction; PE, pulmonary embolism; sc, subcutaneous; VKA, vitamin K antagonist; VTE, venous thromboembolism.

The first trial is now published by Gonzalez Ochoa et al evaluating sulodexide for individuals with early stages of COVID-19 to reduce the proportion of hospitalized patients and their length of hospital stays, the proportion of patients requiring oxygen support, and the number of days on such support.[15] [20] They took advantage of the lack of an approved anticoagulant therapy to design a trial with the orally available glycosaminoglycan sulodexide versus placebo with blinding of study personal and participants. The low risk of bleeding during treatment with sulodexide may have increased the confidence in this treatment. A recent meta-analysis has shown that sulodexide was associated with reduced odds of all-cause mortality, cardiovascular mortality, myocardial infarction, and deep vein thrombosis, without a significant increase in bleeding compared with placebo or no treatment.[21]

Gonzalez Ochoa et al followed the standard procedures with permuted block randomization at a 1:1 ratio of capsules containing 500 lipid releasing units sulodexide or placebo given twice daily for 21 days. They included patients aged >40 years with suspicion of COVID-19 and with at least 3 days with two of the symptoms: cough, fever, or headache, plus one of runny nose, diarrhea, dyspnea, loss of taste or smell, conjunctivitis, and body or muscle ache. A polymerase chain reaction (PCR) test for SARS-CoV-2 had to be presented by participants within 3 days of randomization and if negative, medication was stopped and patients were observed until end of study for intention-to-treat (ITT) analysis. Follow-up of participants was done virtually or in person for 21 days and further until an outcome had occurred or until the end of the trial. The primary endpoint of hospitalization occurred statistically significantly less frequently in participants on sulodexide (17.4%) versus placebo (29.4%) (p = 0.031). Secondary endpoints showed significantly less frequent and shorter requirement of oxygen support at home plus in-hospital for participants on sulodexide compared with placebo. Length of hospital stay, mortality, and hemorrhage were not different between the groups. All results were confirmed by the ITT analysis.

The concentrations of D-dimer and C-reactive protein (CRP) were normal and not different between participants treated with sulodexide and placebo at baseline. At day 14, D-dimer and CRP were higher in both groups compared with baseline, but were significantly higher during administration of placebo compared with sulodexide. This finding is of particular interest for the pathophysiology of COVID-19 and the anticoagulant and anti-inflammatory properties of sulodexide and potential usefulness for identification of patients who may suffer from a progression of COVID-19 when treated at home.

Strengths and limitations of the study were considered by the authors and some may be worth to be added.

Strengths of the study:

• Not to wait for the results of the PCR result for SARS-CoV-2 to start the study drug.

• To use the higher of the available doses of sulodexide for the participants.

• To determine D-dimer and CRP at start and after 14 days to generate information on the potential benefit of the anticoagulant and anti-inflammatory actions of sulodexide for home treatment.

Limitations may be added, such as:

• The relatively small sample size and that 12% could not be analyzed due to lack of data.

• The lack of dose adjustment or change to LMWH or a DOAC in participants with increase of D-dimer at day 14.

• The lack of analysis according to elevation of D-dimer and/or CRP at day 14 per group.

Publikationsverlauf

Eingereicht: 21. März 2021

Angenommen: 06. April 2021

Accepted Manuscript online:
08. April 2021

Artikel online veröffentlicht:
15. Juni 2021

• References

• 1 Varga Z, Flammer AJ, Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395 (10234): 1417-1418
• 2 Bikdeli B, Madhavan MV, Gupta A. et al; Global COVID-19 Thrombosis Collaborative Group. Pharmacological agents targeting thromboinflammation in COVID-19: review and research implications for future research. Thromb Haemost 2020; 120 (07) 1004-1024
• 3 Choi HM, Moon SY, Yang HI, Kim KS. Understanding viral infection mechanisms and patient symptoms for the development of COVID-19 therapeutics. Int J Mol Sci 2021; 22 (04) 1737
• 4 Gerotziafas GT, Catalano M, Colgan MP. et al; Scientific Reviewer Committee. Guidance for the management of patients with vascular disease or cardiovascular risk factors and COVID-19: position paper from VAS-European Independent Foundation in Angiology/Vascular Medicine. Thromb Haemost 2020; 120 (12) 1597-1628
• 5 Cuker A, Tseng EK, Nieuwlaat R. et al. American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. Blood Adv 2021; 5 (03) 872-888
• 6 Singh B, Ryan H, Kredo T, Chaplin M, Fletcher T. Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19. Cochrane Database Syst Rev 2021; 2: CD013587
• 7 NIH. COVID-19treatment guidelines: therapeutic management of adults with COVID-19. Accessed May 13, 2021 at: https://www.covid19treatmentguidelines.nih.gov/therapeutic-management/
• 8 Lenze EJ, Mattar C, Zorumski CF. et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial. JAMA 2020; 324 (22) 2292-2300
• 9 Libster R, Pérez Marc G, Wappner D. et al; Fundación INFANT–COVID-19 Group. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N Engl J Med 2021; 384 (07) 610-618
• 10 Janiaud P, Axfors C, Schmitt AM. et al. Association of convalescent plasma treatment with clinical outcomes in patients with COVID-19: A systematic review and meta-analysis. JAMA 2021; 325 (12) 1185-1195
• 11 Drouet L, Harenberg J, Torri G. The multiple faces of heparin: opportunities in COVID-19 infection and beyond. Thromb Haemost 2020; 120 (10) 1347-1350
• 12 ClinicalTrials.gov., NCT04400799:. Enoxaparin for primary thromboprophylaxis in ambulatory patients with COVID-19. , Accessed March 18, 2021 at: https://clinicaltrials.gov/ct2/show/NCT04400799
• 13 ClinicalTrials.gov. NCT04508439. Effect of the use of anticoagulant therapy during hospitalization and discharge in patients with COVID-19 infection. . Accessed March 18, 2021 at: https://clinicaltrials.gov/ct2/show/NCT04508439
• 14 Barco S, Bingisser R, Colucci G. et al. Enoxaparin for primary thromboprophylaxis in ambulatory patients with coronavirus disease-2019 (the OVID study): a structured summary of a study protocol for a randomized controlled trial. Trials 2020; 21 (01) 770
• 15 ClinicalTrials.gov. NCT04483830. Suloexide in the treatment of early stages of COVID-19 (SulES-COVID). . Accessed March 18, 2021 at: https://clinicaltrials.gov/ct2/show/NCT04483830
• 16 ClinicalTrials.gov. NCT04746339. Apixaban for PrOphyLaxis of thromboemboLic Outcomes in COVID-19. . Accessed March 18, 2021 at: https://clinicaltrials.gov/ct2/show/NCT04746339
• 17 ClinicalTrials.gov. NCT04498273. COVID-19 Positive outpatient thrombosis prevention in adults aged 40–80. . Accessed March 18, 2021 at: https://clinicaltrials.gov/ct2/show/NCT04498273
• 18 ClinicalTrials.gov. NCT04516941. CorONa Virus edoxabaN ColchicinE (CONVINCE) COVID-19. . Accessed March 18, 2021 at: https://www.clinicaltrials.gov/ct2/show/NCT04516941
• 19 ClinicalTrials.gov. NCT04324463. Anti-coronavirus therapies to prevent progression of coronavirus disease 2019 (COVID-19) trial (ACTCOVID19). . Accessed March 18, 2021 at: https://clinicaltrials.gov/ct2/show/NCT04324463
• 20 Gonzalez Ochoa AJ, Raffetto J, Hernandez Ibarra AG. et al. Sulodexide in the treatment of patients with early stages of COVID-19: a randomized controlled trial. Thromb Haemost 2021;
• 21 Bikdeli B, Chatterjee S, Kirtane AJ. et al. Sulodexide versus control and the risk of thrombotic and hemorrhagic events: meta-analysis of randomized trials. Semin Thromb Hemost 2020; 46 (08) 908-918
• 22 Fuentes HE, McBane II RD, Wysokinski WE. et al. Direct oral factor Xa inhibitors for the treatment of acute Cancer-associated venous thromboembolism: a systematic review and network meta-analysis. Mayo Clin Proc 2019; 94 (12) 2444-2454
• 23 Harenberg J, Bauersachs R, Ageno W. Does chronic treatment with oral anticoagulants ameliorate the clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in coronavirus disease 2019 (COVID-19)?. Semin Thromb Hemost 2020;
• 24 ClinicalTrials.gov. NCT04518735. Evolution of COVID-19 in Anticoagulated or antiaggregated patients (CORONA Study). . Accessed March 18, 2021 at: https://www.clinicaltrials.gov/ct2/show/NCT04518735
• 25 Tremblay D, van Gerwen M, Alsen M. et al. Impact of anticoagulation prior to COVID-19 infection: a propensity score-matched cohort study. Blood 2020; 136 (01) 144-147
• 26 Flam B, Wintzell V, Ludvigsson JF, Mårtensson J, Pasternak B. Direct oral anticoagulant use and risk of severe COVID-19. J Intern Med 2021; 289 (03) 411-419
• 27 van Haren FMP, Richardson A, Yoon HJ. et al. INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP): Protocol and statistical analysis plan for an investigator-initiated international metatrial of randomised studies. Br J Clin Pharmacol 2020;
• 28 Ball L, Schultz MJ, Pelosi P. Nebulised heparin for patients on ventilation: implications for COVID-19 pneumonia. Lancet Respir Med 2021; 9 (04) 321-322
• 29 Harenberg J, Malsch R, Angelescu M. et al. Anticoagulant effects and tissue factor pathway inhibitor after intrapulmonary low-molecular-weight heparin. Blood Coagul Fibrinolysis 1996; 7 (04) 477-483
• 30 Li C, Luo F, Liu C. et al. Effect of a genetically engineered interferon-alpha versus traditional interferon-alpha in the treatment of moderate-to-severe COVID-19: a randomised clinical trial. Ann Med 2021; 53 (01) 391-401
• 31 Good SS, Westover J, Jung KH. et al. AT-527, a double prodrug of a guanosine nucleotide analog, is a potent inhibitor of SARS-CoV-2 in vitro and a promising oral antiviral for treatment of COVID-19. Antimicrob Agents Chemother 2021; 65 (04) x
• 32 Richardson A, Shah S, Harris C, McCulloch G, Antoun P. Anticoagulation for the pregnant patient with a mechanical heart valve, no perfect therapy: review of guidelines for anticoagulation in the pregnant patient. Case Rep Cardiol 2017; 2017: 3090273
• 33 Harenberg J, Beyer-Westendorf J, Crowther M. et al; Working Group Members. Accuracy of a rapid diagnostic test for the presence of direct oral factor Xa or thrombin inhibitors in urine—a multicenter trial. Thromb Haemost 2020; 120 (01) 132-140