In-Hospital Clinical Ooutcomes of COVID-19 Patients Treated with Oral Anticoagulants

The coronavirus disease 2019 (COVID-19) virus, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an RNA virus. Infection with this virus can lead to a wide range of symptoms, from mild symptoms to lung infection with severe respiratory failure [1]. COVID-19 has beenclassified as a pandemicbythe World Health Organization [2]. Patients with COVID-19 may be asymptomatic; however, the disease may also present with symptomssuch as fever, chills, cough, shortness of breath, myalgia and headache. The case fatality rate is 2%–3%. The laboratory tests for COVID-19 are non specific and include creatine kinase, lactate dehydrogenase, D-dimer (a specific fibrin degradation product), haemogram, white blood cell count, serum C-Reactive Protein (CRP), sedimentation rate and procalcitonin. Lowlymphocytes and platelets can be seen in COVID-19 patients. Pathological changes in these parameters are also used as prognostic factors [3]. 

Since the COVID-19 pandemic is very new, copious studies about the characteristics and treatment of the virus and the disease are being added to the literature. However, despite the fact that there are many new scientific studies in the literature from day to day, there is neither sufficient nor definitive information about COVID-19 and its treatment. 

Although it is emphasised that impaired coagulation parameters are associated with a poor prognosis in COVID-19 [4], there are limited data in the literature on warfarin, New-Generation Oral Anticoagulants (NOAC) and low-molecular weight heparin treatments for the disease [5]. In this study, we aimed to investigate the effects of warfarin and NOAC use on the prognosis of patients diagnosed with COVID-19.

Sixty-two patients who were diagnosed with COVID-19, treated in intensive care and followed up in our hospital were included in the study. The patients data were collected retrospectively through the patient tracking system following ethics committee approval. Clinical findings, laboratory parameters, computed tomography and SARS-CoV-2 Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) were used to diagnose the patients with COVID-19. The patients were divided into two groups depending on theuse of either warfarin or NOACs. The NOACs used were apixaban, rivaroxaban, dabigatran and edoxaban. The types of chronic diseases, drugs used, haematological and biochemical parameters and prognoses in each group were statistically analysed. 

Samplecollection, nucleic acid isolation and RT-PCR reactions 

Combined nasopharynx and oropharynx swab samples were taken with a Dacrons wab, placed in a viral transport medium and immediately transported to the laboratory at 2ºC-8ºC. The samples were sent to the laboratory in accordance with the cold chain rules using the triple transport system and following infection prevention and control procedures. After the samples had been accepted in the microbiology laboratory, they were taken to a third-level biosecurity negative pressure room. The Bio-Speedy® Viral Nucleic Acid Isolation Kit for the isolation of total nucleic acid from samples (Bioeks, Istanbul, Turkey) was used. The isolation procedure was carried out in line with the manufacturer's recommendations. The Bio-Speedy® Covidien work for RT-PCR Detection Kit-19 RT-qPCR (Bioeks, Istanbul, Turkey) was used. PCR amplification and the evaluation of the results were carried out in accordance with the manufacturer’s recommendations. 

Statistical analysis 

Descriptive analyses were performed to provide information on the general characteristics of the study population. Visual (i.e.probabilityplots, histograms) and analytical (Kolmogorov-Smirnov test, Shapiro-Wilk test) methods were used to determine whether the data were normally distributed. The descriptive analyses were presented using medians and interquartile range for the non-normally distributed variables. The Mann-Whitney U test was used for the non parametric tests to compare these parameters. Pearson’s chi-square test was used to compare the categorical variables between the two groups. The categorical variables were presented as the frequency (% percentage). A p-value

Ethicalapproval 

Approval for this study was obtained from the ethics committee of Sakarya University, Faculty of Medicine (71522473/050.01.04/463).

When the demographic characteristics of the patients were compared, no significant differences were found between the two groups otherthan the use of insulin and alpha blocker therapy (Table 1). While all the patients using NOAC were taking the drug due to atrial fibrillation (AF), 19 of the patients using warfarin were using the drug because of AF, and four of them had a prosthetic heart valve..

Table 1: Comparison of baselinecharacteristicsandthedrugstheyuseof thewarfarinand NOAC groups.

CAD = Coronary Artery Disease, CVD = Cerebrovascular Disease, PAD = Peripheral Artery Disease, COPD = Chronic Obstructive Pulmonary Disease, CKD = Chronic Kidney Disease, CHF = Congestive Heart Failure, ACE = Angiotensin-converting Enzyme, ARB = Angiotensin Receptor Blocker, CCB = Calcium Channel Blocker, OAD = Oral Antidiabetic, MRA = Mineralocorticoid Receptor Antagonist. 

When the laboratory values of the patients in the two groups were compared, no differences were found except that the prothrombin time and international normalised ratio (PT-INR) values were higher in the warfarin group (Table 2). 

Table 2: Comparison of laboratory test results of the two groups.

WBC = White Blood Cell, APTT = Activated Partial Tromboplastin Time, INR = International Normalized Ratio, Hs-cTnI = High sensitive Cardiac Troponin I, CK-MB = Creatine Kinase Myocardial Band 

The treatment of the patients with either warfarin or NOAC continued during their time in the ICU, and there was no difference between the two groups in terms of in-hospital mortality (Table 3). 

Table 3: In-hospital clinical outcomes of the study groups. 

When the subgroup mortality analysis was performed, 14 of the 23 (37.0%) patients with diabetes (p = 0.020), 7 of the 9 (14.5%) patients with chronic renal failure (p = 0.018), and 3 of the 11 (17.7%) patients with heart failure (p = 0.003) died, and these chronic diseases were statistically significant in terms of death among the COVID-19 patients. In the patients with exitus, the haemoglobin (10.2 ± 2.7 vs 12 ± 2.3, respectively; p = 0.012) and haematocrit (34.3 ± 7.5 vs 38 ± 7.7, respectively; p = 0.045) levels were lower compared to the patients who survived. Furthermore, these patients' CRP levels (103 ± 110 vs 44 ± 54, respectively; p = 0.047), procalcitonin levels (16 ± 35 vs 1 ± 2.5, respectively; p = 0.005) and sedimentation rates (62 ± 34 vs 42 ± 23, respectively; p = 0.005) were significantly different from those who were discharged in good health.

While COVID-19 can be asymptomatic, it can lead to flu-like symptoms, severe respiratory failure, multi-organ dysfunction and death [3,6]. Some laboratory parameters may also increase and decrease in the presence of COVID-19 infection depending on the pathogenesis of the disease. Lowly mphocytes, album in and platelets and high CRP, procalcitonin, lactate dehydrogenase, creatinine and D-dimer have been highlighted as poor prognostic factors [1,3,7,8].

Thrombotic complications cause very serious problems in patients who are positive for COVID-19 [9]. As with viral infections, COVID-19 infection also activates coagulation and can cause the excessive activation of platelets. In addition, by causing an inflammatory response systemically, it can affect the procoagulant and anticoagulant mechanisms in haemostasis and disrupt the balance between the two [10-12]. In autopsies of patients who died due to COVID-19, thrombus in the capillaries and small vessels and many microthrombi in the liver venous portal system were found to be present [13].

In cases where COVID-19 is severe, high D-dimer levels are encountered, revealing that they are associated with mortality. Again, these patients often have a coagulation disorder [14].

In our study, the effects of warfarin and new-generation oral anticoagulants used to treat patients with COVID-19 were examined, and it was determined that there was no difference in the effects of these two groups of drugs on mortality. As expected, the PT-INR levels were significantly higher in the group using warfarin, but no significant difference was found in the other laboratory parameters.

Based on the results of our study, neither warfarin nor NOACs were found to be superior in the treatment of patients with COVID-19 in terms of in-hospital clinical outcomes. The relatively low number of cases in this study was considered a limitation. Multicentre studies with larger case numbers should be conducted to verify these results.

All authors declare that there is no conflict of interest in this study.

1. Tian S, Hu N, Lou J, Chen K, Kang X, et al. (2020) Characteristics of COVID-19 infection in Beijing. J Infect 80: 401-406.
2. WHO (2020) Coronavirus disease (COVID-2019) press briefings. WHO, Geneva, Switzerland.
3. Madabhavi I, Sarkar M, Kadakol N (2020) COVID-19: A review. Monaldi Arch Chest Dis. 14: 90.
4. Tang N, Li D, Wang X (2020) Abnormal Coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 18: 844-847.
5. Kow CS, Sunter W, Bain A, Zaidi STR, Hasan SS, et al. (2020) Management of Outpatient Warfarin Therapy amid COVID-19 Pandemic: A Practical Guide. Am J Cardiovasc Drugs 26: 1-9.
6. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. (2020) Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet 395: 1054-1062.
7. Wang Y, Wang Y, Chen Y, Qin Q (2020) Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures. J Med Virol 92: 568-576.
8. Frater JL, Zini G, d'Onofrio G, Rogers HJ (2020) COVID-19 and the clinical hematology laboratory.Int J Lab Hematol 42: 11-18.
9. Levi M, Tachil J, Lba T, Levy JH (2020) Coagulationabnormalitiesandthrombosis in patientswith COVID-19. Lancet Haematol 7: 438-440.
10. Subramaniam S, Scharrer I (2018) Procoagulant activity during viral infections. Front Biosci (LandmarkEd) 23: 1060-1081.
11. Price LC, McCabe C, Garfield B, Wort SJ (2020) Thrombosis and COVID-19 pneumonia: theclotthickens! Eur Respir J 56: 2001608.
12. Connors JM, Jerrold HL (2020) COVID-19 and its implications for thrombosis and anticoagulation. Blood 135: 2033-2040.
13. Fox SE, Akmatbekov A, Harbert JL, Li G, Brown JQ, et al. (2020) Pulmonaryandcardiacpathology in Covid-19: Thefirstautopsyseriesfrom New Orleans. MedRxiv.
14. Tang N, Li D, Wang X, Sun Z (2020) Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 18: 844-847.