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)

Discussion

This multi-center retrospective cohort study compared the effects of prophylactic anticoagulation with therapeutic anticoagulation on the clinical outcomes of hospitalized COVID-19 patients with varying degrees of disease severity. Our key observations include:^[1] The use of therapeutic dosage of anticoagulation did not improve survival among hospitalized COVID-19 patients; in fact, it may even have increased the risk of mortality, particularly among critical COVID-19 patients;^[2] Severe COVID-19 patients who received therapeutic dose of anticoagulation had longer hospital stay than those who received prophylactic dose;^[3] The incidence of thrombosis did not differ significantly between the therapeutic and prophylactic cohort groups, although in severe COVID-19 subgroup of patients therapeutic anticoagulation showed some protection against thrombosis (despite it being not statistically significant);^[4] Patients who received therapeutic anticoagulation had significantly higher risk of major bleeding than those who received prophylactic anticoagulation.

There are several possible explanations for the higher in-hospital mortality observed among critical COVID-19 patients who received therapeutic dose of anticoagulation in our study. Compared to the prophylactic cohort group, the therapeutic cohort patients had a higher baseline respiratory rate, a higher demand for oxygen supplementation and a longer hospital stay, all of which may be indicative of more severe disease and may explain why the therapeutic groups had a higher inpatient mortality. Furthermore, since the decision to put which patients on high-dose anticoagulation was largely based on the clinical judgment of treating physicians, patients with more severe disease may be more likely to be put on higher dose of anticoagulation. We attempted to control for all these differences using multivariable models that took into account various variables that could reflect disease severity; however, we cannot rule out the possibility of an unaccounted for variable which could explain the differences in outcome apart from anti-coagulation dosage. Another obvious contributing factor is the occurrence of major bleeding in those patients who were provided with a therapeutic dose of anticoagulation. Although the number of bleeding events was small in this study, there was in fact a significant difference in the incidence of major bleeding between the two cohort groups. However, this cannot entirely explain the observed difference in mortality. Because of the restricted diagnostic capacity in all of our study centers, some bleedings may have been missed, possibly rendering the observed bleeding events in our study an under-representative. More studies—preferably randomized control trials—with larger sample sizes so that increased numbers of bleeding events can be identified, are required to substantiate this.

The clinical outcomes which were impacted by anticoagulation dosage were notably dependent on the level of COVID-19 severity at baseline. Among our critical COVID-19 patients (patients who required at least face-mask with reservoir at admission), our study indicates that there was clearly a higher prevalence of in-hospital mortality in patients who were in the therapeutic group. There was also a higher incidence of major bleeding events among these groups. Moreover, there was no significant difference in the incidence of thrombosis between the two cohort groups. Although the explanation for the occurrence of higher mortality could be any of those mentioned above, these finding make us question the use of therapeutic dosage in critical COVID-19 patients. On the other hand, on our severe COVID-19 sub-group of patients, there was no significant difference in the prevalence of in-hospital mortality between our two cohort groups. However, this finding may be impacted by the overall lower mortality in severe groups and might require a higher sample size to detect a difference. In terms of thrombotic events, in the severe COVID-19 subgroup, there was a lower incidence of proven thrombosis among patients who received therapeutic anticoagulation (8/237 in prophylactic vs 1/235 in therapeutic; AOR 0.15, 95% CI, 0.02 – 1.20, p = 0.073), although this difference is not statistically significant. This finding, however, is severely limited by the paucity of diagnostic modalities to confirm suspected thrombosis, which considerably underrepresents the overall incidence of thrombotic events. In addition, the small number of events detected in this study might require a bigger study to further substantiate or refute this finding. Despite this however, among severe patients, therapeutic anticoagulation resulted in a significantly longer hospital stay and a slightly higher risk of bleeding as compared to prophylactic anticoagulation. This raises a concern whether the benefit of therapeutic doses of anticoagulation in severe COVID-19 patients subgroup outweighs the risk of longer hospital stay and higher bleeding events.

Our findings are consistent with a similar retrospective cohort study conducted on 311 COVID-19 patients admitted to Stony Brook University Hospital, which reported a possibility of higher inpatient mortality with the usage of high-dose anticoagulation. However, their study subjects included exclusively critical patients, and the majority of them were White population, which varied from ours.^[24] Additionally, a large randomized clinical trial which included 615 patients concluded that the use of therapeutic anticoagulation should be avoided without evidence of other indication. They found no difference in their primary outcome measures (hierarchical analysis of time to death, duration of hospitalization, and duration of supplemental oxygen to day 30) between the groups, but found a significantly higher risk of bleeding with therapeutic anticoagulation. This study is however different from ours in it is a randomized clinical trial, included mainly moderate COVID-19 patients, the anticoagulant used was primarily rivaroxaban and the setting is in Brazil.^[6] On the other hand, the analysis from the three RCTs (REMAP-CAP, ACTIV-4a, and ATTACC) found supporting evidence to the use of therapeutic anticoagulation particularly for non-critical COVID-19 patients and it was found to be non-beneficial for critical COVID-19 subgroup of patients.^[8,9] Our study found a similar result with these trials for the critical subgroup of patients where therapeutic anticoagulation had no survival benefit, but for the severe subgroup of patients (in their case "non-critical"), we found no statistically significant survival advantage unlike the report of the trials. This different result in the severe COVID-19 subgroup may be due to smaller sample size of our study, the difference in the study population (where our definition of severe COVID-19 included relatively more severe patients as compared to their "non-critical" patients), the difference in setting, and the difference in the study design. Although our study is merely an observational one, it is pertinent to our context because there is no available research on this controversial topic in Africa. The evidence we found from our data for critical COVID-19 patients in particular is in contrary to the recommendation of the current national COVID-19 treatment guideline. Although the practice has been changed in some centers following the result of recent RCTs, there is still inconsistency in practice from one treatment facility to another, highlighting the need for special attention and more investigation into this subject. Therefore, in addition to its practical clinical value, the study contributes to the advancement of scientific knowledge in our country.

This study has several limitations. To begin with, as the study is observational by its nature, we cannot make cause and effect conclusions, despite our attempts to control for residual confounding. Moreover, misclassification bias in distributing and selecting covariates leads to incomplete correction for confounding. To minimize these, we employed multivariable models with several covariates; however, to maximize the control for residual variables and for making a definitive conclusion, a randomized control trial will be needed. Second, a lack of diagnostic modalities such as spiral chest CT-scan, D-dimer, and doppler ultrasonography in some treatment facilities causes a large proportion of thrombotic complications to be left suspected and, in some cases, treated empirically. This has had an effect on our thrombosis incidence results. Third, due to the retrospective nature of the study and the unavailability of viral stain confirmation studies, we weren't able to account for the different viral strain types. Finally, the retrospective nature of the research design introduces unintentional patient selection bias, which is one of the reasons why randomized clinical trials are regarded so critically.

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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)