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)

Background

Several studies^[1–5] have established that COVID-19 patients are at increased risk of developing thrombotic complications; however, the optimal dose of pharmaco-prophylaxis to administer to hospitalized patients is still a topic of controversy due to the ongoing emergence of conflicting evidence.^[6–9]

One of the earliest pieces of evidence on the benefit of anticoagulation for COVID-19 patients was from a retrospective study conducted in Tongji Hospital in Wuhan, China which showed that the 28-day mortality was significantly lower in heparin-users as compared to non-users.^[10] This finding was further supported by other studies,^[11,12] and as a result standard dose thromboprophylaxis was adopted as part of routine clinical care for COVID-19 patients who require inpatient care.^[7,13] Despite the use of low-dose anticoagulation however, in some studies,^[14] a high proportion of patients were still developing life-threatening thrombotic complications suggesting a need for more aggressive anticoagulation in hospitalized COVID-19 patients, especially in critical patients.^[15]

This prompted several observational and randomized controlled trial (RCT) studies comparing high-dose (therapeutic) anticoagulation and low-dose (prophylactic) anticoagulation in the outcome of hospitalized COVID-19 patients. Some studies came out supporting therapeutic anticoagulation while others revealed contradictory findings, indicating the possibility that administering high-dose anticoagulation without documented evidence of thrombosis provided no additional benefit.^[16–18]

The ACTION trial reported, in patients hospitalized with COVID-19 with elevated D-dimer concentration, therapeutic anticoagulation did not improve clinical outcomes and increased bleeding.^[6] On the other end, the HEP-COVID RCT demonstrated significant reduction in thrombosis and mortality in patient who were provided with high-dose anticoagulation.^[8] The finding of this trial was partly supported by a recent meta-analysis done on three randomized trials (REMAP-CAP, ACTIV-4a, and ATTACC), reporting superior outcomes in therapeutic patient groups for non-critical COVID-19 patients^[19] and inferior outcomes for critical COVID-19 patients who received therapeutic anticoagulation as compared to those who received prophylactic anticoagulation.^[20,21]

All this evidence and recommendations however are from studies done in high-income nations and require patient stratification based on laboratory tests like D-dimer, which are typically unavailable in most low- and middle-income settings. A pragmatic recommendation for low- and middle-income countries (LMICs) indicated administration of prophylactic anticoagulation for all hospitalized COVID-19 patients if there are no contraindications.^[7] It recommended against empiric therapeutic anticoagulation in the absence of clinical suspicion for venous thromboembolism (VTE).

In the Ethiopian context, the current national COVID-19 treatment guideline, which was last updated in September 2020, recommends the use of therapeutic dose for critical and prophylactic dose for severe COVID-19 disease.^[13] With the emergence of more recent evidence from RCTs recommending the opposite, there has been inconsistency in the dosage of anticoagulant usage in the country.^[19–21] While some centers have changed the practice in accordance to the results of these RCTs, others are still adhering to the national guideline recommendation. As such, there is a need for a contextual study and update as there is no evidence on dosage and efficacy of anticoagulation, nor any studies on thrombotic complications of COVID-19 in Ethiopia. This study aims to provide insight into the effect of anticoagulation dose on clinical outcomes of hospitalized COVID-19 patients in Ethiopia.

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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)