The Effect of Anti-coagulation Dosage on the Outcome of Hospitalized COVID-19 Patients in Ethiopia

A Multi-Center Retrospective Cohort Study

Abel Girma Tessema; Zekarias Masresha Mengiste; Tsegaye Gebreyes Hundie; Hailemichael Getachew Yosef; Dawit Kebede Huluka; Abebaw Bekele Seyoum; Hannibal Kassahun Abate; Rawleigh Craig Howe

Disclosures

BMC Pulm Med. 2023;23(85)

Conclusion

Overall, our findings are consistent with the possibility, in critical COVID-19 patients, therapeutic anticoagulation may provide no survival benefit, pose a higher risk of in-hospital mortality, have no additional protection against thrombotic complications, and pose a greater bleeding risk when compared to prophylactic anticoagulation. In severe COVID-19 subgroup, patients who received therapeutic anticoagulation were observed to have a longer hospital stay and did not seem to have improved survival, although there was a slight protection against thrombosis observed as compared to prophylactic group. As a result of these findings, we conclude that the benefit of therapeutic anticoagulation for hospitalized COVID-19 patients in Ethiopia should be addressed in future studies, and we emphasize the critical need for a randomized control trial in our setup to substantiate our findings.

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Abbreviations
AHR = Adjusted Hazard Ratio; AOR = Adjusted Odds Ratio; ARDS = Acute Respiratory Distress Syndrome; BFH = Bulbula COVID-19 Field Hospital under Saint Peter's Specialized Hospital; BID = Twice a day; BMI = Body Mass Index; CI = Confidence Interval; COVID-19 = Coronavirus Disease of 2019; DVT = Deep Venous Thrombosis; EKGH = Eka Kotebe General Hospital; HIV/AIDS = Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome; HR = Hazard Ratio; IQR = Interquartile Range; ISTH = International Society on Thrombosis and Hemostasis; LMICs = Low- and Middle-Income Countries; LMWH = Low Molecular Weight Heparin; MCCC = Millennium COVID-19 Care Center; MI = Myocardial Infarction; MOD = Multi-organ Dysfunction; MOF = Multi-organ Failure; PCR = Polymerase Chain Reaction; PTE = Pulmonary Thromboembolism; RCT = Randomized Controlled Trial; RR = Relative Risk; RT-PCR = Real time Polymerase Chain Reaction; SC = Subcutaneous; SIC = Sepsis Induced Coagulopathy; SPSS = Statistical Package for Social Sciences; TID = Three times per day; UFH = Unfractionated Heparin; VTE = Venous Thromboembolism

Acknowledgements
The authors are very grateful for all the support received from Eka-Kotebe General Hospital, Saint Paul Hospital Millennium Medical College, and St. Peter's Specialized Hospital. The authors appreciate the dedication and commitment of Dr. Aregawi Ezighaye, Dr. Hawi Merga, Dr. Alazar Gizate, Dr. Rediet Tefera, Dr. Biruk Birhanu, Dr. Fasil Agegnehu and Dr. Eyoel Bassa in collecting clean data despite their demanding schedules. The authors further acknowledge the scientific support and generous assistance received from Dr. Amru Reshad, Dr. Edlawit Mesfin, Dr. Misikir Tesfaye, Dr. Liya Sisay, Dr. Bethelhem Solomon and Ebrahim Nursefa.

Funding
Armauer Hansen Research Institute funded the study.

Availability of data and materials
The datasets used and/or analyzed during the current study will be available from the corresponding author on reasonable request.

Declarations
Ethical approval and consent to participate
The study was approved by the Armauer Hansen Research Institute (AHRI)/All Africa Leprosy and Tuberculosis Rehabilitation and Training Center (ALERT) Ethics Review Committee, Ethiopia, with a protocol number PO-42–21. The need for informed consent for the use of deidentified medical records was waived by the aforementioned ethics committee. Documentation to support the approval and waiver for informed consent can be provided upon reasonable request. The data used in this study were anonymized before use. The study was conducted in accordance with the Declaration of Helsinki.

Consent for publication
Not applicable.

Table 1. Demography, baseline characteristics and clinical variables of hospitalized COVID-19 patients in Ethiopia
		Prophylactic anticoagulation (n = 237)	Therapeutic anticoagulation (n = 235)	p-value
Hospital	Eka-Kotebe General Hospital	83 (35.0%)	91 (38.7%)	0.648
	Millennium COVID-19 Care Center	99 (41.8%)	96 (40.9%)
	COVID-19 St. Peter's Field Hospital	55 (23.2%)	48 (20.4%)
Age in years, median (IQR)		59.00 (45.5 – 67.0)	60.00 (48.0 – 67.0)	0.711
Gender	Male, n (%)	154 (65.0%)	135 (57.4%)	0.108
Gender	Female, n (%)	83 (35.0%)	100 (42.6%)	0.108
Comorbidity, n (%)
Hypertension		85 (35.9%)	83 (35.3%)	0.924
Diabetes Mellitus		76 (32.1%)	74 (31.5%)	0.921
HIV/AIDS		11 (4.6%)	12 (5.1%)	0.834
Asthma		10 (4.2%)	13 (5.5%)	0.508
Stroke		7 (3.0%)	5 (2.1%)	0.772
Malignancy		2 (0.84%)	5 (2.1%)	0.284
Ischemic Heart Disease		3 (1.3%)	4 (1.7%)	0.724
Prior history of Tuberculosis		2 (0.8%)	5 (2.1%)	0.284
Chronic Kidney Disease		4 (1.69%)	1 (0.43%)	0.372
Chronic Liver Disease		2 (0.8%)	1 (0.43%)	1.000
Schizophrenia		0 (0.0%)	3 (1.3%)	0.123
Smoking, n (%)		3 (1.3%)	6 (2.6%)	0.337
COVID-19 Severity at admission, n (%)
Severe		147 (62.0%)	133 (56.6%)	0.261
Critical		90 (38.0%)	102 (43.4%)	0.261
Type of Oxygen therapy used at admission, n (%)				0.021
Nasal cannula		107 (45.1%)	80 (34.0%)
Simple Face mask		40 (16.9%)	53 (22.6%)
Face mask with reservoir		28 (11.8%)	41 (17.4%)
Non-invasive ventilation		53 (22.4%)	44 (18.7%)
Invasive ventilation		9 (3.8%)	17 (7.2%)
Vital Sign, median (IQR)
Heart rate, bpm		94.00 (86.0 – 106.0)	94.00 (83.0 – 105.0)	0.221
Respiratory rate, rate/min		28.00 (24.0 – 32.0)	31.00 (26.0 – 36.0)	< 0.001
Diastolic blood pressure, mm Hg		75.00 (67.0 – 83.5)	72.00 (65.0 – 80.0)	0.095
Systolic blood pressure, mm Hg		126.00 (111.5 – 145.0)	129.00 (112.0 – 142.0)	0.958
Laboratory values, median (IQR)
Hemoglobin, g/dL		14.10 (13.0 – 15.5)	14.05 (13.0 – 15.3)	0881
Hematocrit, %		41.60 (38.4 – 45.2)	42.00 (38.5 – 45.0)	0.553
Total WBC count, × 10 ³/mL		9.60 (6.4 – 11.9)	8.94 (6.4 – 13.1)	0.831
Neutrophil, %		87.50 (81.0 – 92.0)	89.85 (81.5 – 92.4)	0.144
Lymphocyte, %		6.35 (3.7 – 10.4)	6.30 (3.9 – 10.6)	0.745
Platelet count, 10 ⁹/L		244.50 (175.8 – 315.0)	234.00 (167.5 – 310.8)	0.622
Alanine aminotransferase, U/L		40.60 (25.6 – 65.1)	31.95 (22.8 – 62.5)	0.479
Aspartate aminotransferase, U/L		40.95 (29.1 – 62.2)	38.00 (27.1 – 60.1)	0.887
Creatinine, mg/dL		0.72 (0.62 – 0.90)	0.80 (0.60 – 1.0)	0.112
Urea, mg/dL		32.50 (21.3 – 46.5)	24.30 (16.1 – 37.1)	0.001
Sodium, mmol/L		138.00 (134.0 – 140.0)	137.00 (133.0 – 140.0)	0.456
Potassium, mmol/L		4.26 (3.90 – 4.70)	4.10 (3.70 – 4.60)	0.055

Table 2. Binary logistic regression analysis with odds ratio for in-hospital mortality
		Inpatient mortality, n (%)	Total	Crude OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value
Age	< 60 yrs	66 (24.1%)	274
Age	> 60 yrs	88 (44.4%)	198	2.52 (1.70–3.74)	< 0.001	2.74 (1.60–4.69)	< 0.001
Vaccine status	Not received	149 (33.7%)	442
Vaccine status	Received at least 1 dose	5 (16.7%)	30	0.39 (0.15–1.05)	0.062	0.23 (0.07–0.84)	0.025
Hypertension	No	89 (27.4%)	304
Hypertension	Yes	65 (38.0%)	168	1.52 (1.03–2.27)	0.037	1.52 (0.87–2.65)	0.139
History of Stroke	No	148 (32.2%)	460
History of Stroke	Yes	6 (50.0%)	12	2.11 (0.67–6.65)	0.203	2.44 (0.47–12.52)	0.286
Malignancy	No	148 (31.8%)	465
Malignancy	Yes	6 (85.7%)	7	12.85 (1.53–107.71)	0.019	19.70 (1.52–255.44)	0.023
COVID-19 Severity	Severe	25 (8.9%)	280
COVID-19 Severity	Critical	129 (67.2%)	192	20.56 (12.55–34.76)	< 0.001	23.37 (13.45–40.62)	< 0.001
Anticoagulation dosage	Prophylactic	66 (27.8%)	237
Anticoagulation dosage	Therapeutic	88 (37.4%)	235	1.55 (1.05–2.29)	0.027	1.70 (1.02–2.84)	0.042

Table 3. Cox proportional hazard model for in-hospital mortality
	Crude HR (95% CI)^a	p-value	Adjusted HR (95% CI)^a	>p-value
Age^b	1.03 (1.02—1.04)	< 0.001	1.03 (1.02—1.04)	< 0.001
Vaccination Status	0.52 (0.21—1.26)	0.145	0.43 (0.17—1.06)	0.067
Hypertension	1.48 (1.07 – 2.04)	0.017	1.25 (0.90—1.75)	0.188
COVID-19 Severity	6.63 (4.31 – 10.10)	< 0.001	9.03 (4.30 – 18.99)	< 0.001
Anticoagulation dosage	1.23 (0.89 – 1.69)	0.215	1.41 (1.01 – 1.96)	0.042

^aHazard ratios of in-hospital mortality before and after adjusting for potential confounders given (only variables with p < 0.25 in univariate analysis are included)
^bAll independent variables are categorical except age which is continuous

Table 4. Cox regression analysis for length of hospital stay
Covariates	Severe		Covariates	Critical
Covariates	Adjusted HR (95% CI)	p-value	Covariates	HR (95% CI)	p-value
Anticoagulation dosage	0.76 (0.59 – 0.98)	0.033	Anticoagulation dosage	0.61 (0.36 – 1.04)	0.069
Age	0.99 (0.98 – 1.00)	0.047
Gender (male sex)	1.21 (0.93 – 1.58)	0.151
Stroke	0.32 (0.12 – 0.88)	0.027

Left: subgroup analysis for severe patients, Right: subgroup analysis for critical patients. (Variables with p < 0.25 in univariate analysis are included)