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Abstract

The prevalence of venous thromboembolism is high in patients with COVID-19, despite prophylactic anticoagulation. The evidence that supports the preferred thromboprophylaxis regimen in non-critically ill patients with mild to moderate COVID-19 is still limited. Therefore, this systematic review and meta-analysis aimed to compare the clinical outcomes of hospitalized patients with mild to moderate COVID-19 who received standard thromboprophylaxis anticoagulation with intermediate to high prophylaxis regimens. We systematically searched MEDLINE and Embase databases for published studies until August 17th, 2022. We included studies on patients with mild to moderate COVID-19 who received thromboprophylaxis during their hospital stay. Patients who received standard prophylaxis dose “control group” were compared to patients who received intermediate to high prophylaxis “intervention group”. Random effect models were used when pooling crude numbers and adjusted effect estimates of study outcomes. A comprehensive analysis was conducted, encompassing seven studies involving a total of 1931 patients. The risk of all-cause thrombosis was not statistically different between the two groups (risk ratio [RR] 1.48, 95% confidence interval [CI] [0.11, 20.21]). The risk of minor bleeding was reported to be lower in patients who received intermediate to high prophylaxis (RR 0.64, 95% CI 0.21, 1.97), while had a higher risk of major bleeding compared with the standard prophylaxis (RR 1.40, 95% CI 0.43, 4.61); however, did not reach the statistical significance. The overall risk for all hospital mortality favored the utilization of intermediate to high doses over the standard thromboprophylaxis dosing (RR 0.47, 95%CI 0.29, 0.75). In medically ill patients with COVID-19, there is no difference between standard and intermediate to high prophylaxis dosing regarding thrombosis and bleeding. However, it appears that intermediate to high prophylaxis regimens are linked to additional survival benefits.

Keywords

anticoagulants COVID-19 thromboprophylaxis non-critically ill thrombosis VTE standard dose intermediate to high dose bleeding

Introduction

Several patients with Coronavirus disease 2019 (COVID-19) develop signs and symptoms related to venous thromboembolism (VTE).¹ The prevalence of VTE is high in critically ill patients with COVID-19 despite the use of prophylactic anticoagulation.² The reported prevalence of pulmonary embolism (PE) and deep vein thrombosis (DVT) in patients with COVID-19 was 7.8% and 11.2%, respectively.³ The development of pulmonary microvascular thrombosis may be attributed to the pathogenesis of COVID-19 in the lungs.²

Parenteral anticoagulation is recommended for thromboprophylaxis in acutely ill hospitalized patients with a high risk of thrombosis.^4,5 In patients with COVID-19, high D-dimer levels have been reported as one of the strongest predictors of mortality.² Therefore, higher parental thromboprophylaxis doses have been used in patients with COVID-19.⁶ A meta-analysis including randomized controlled trials (RCTs) comparing thromboprophylaxis standards dose to escalated dose in critically and non-critically ill patients with COVID-19, showed that escalated dose of anticoagulation was not associated with mortality benefit, but was associated with a significant increase in any bleeding in non-critically ill, but not in critically ill patients (P = 0.03).⁶ However, the benefit of escalated thromboprophylaxis regimen was demonstrated in patients with COVID-19 patients who were critically ill.^6,7

Despite the lack of solid evidence supporting standard thromboprophylaxis regimens in non-critically ill patients, clinical guidelines recommend using a standard prophylactic dose of anticoagulation for acutely ill patients with COVID-19 based on expert opinion.^4,8,9 The evidence that supports the preferred thromboprophylaxis regimen in non-critically ill patients with mild to moderate COVID-19 is still limited. Thus, this study aims to compare the clinical outcomes of non-critically ill hospitalized patients with mild to moderate COVID-19 who received standard thromboprophylaxis anticoagulation doses to intermediate to high regimens.

Methods

This systematic review and meta-analysis wasregistered in the international prospective register of systematic reviews (PROSPERO) with a reference number CRD42022350918. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline was followed during the design of this study.

Search Strategy and Study Selection

We searched the literature using MEDLINE and Embase databases. There were no restrictions on publication date or language. All studies published up until August 17, 2022, were included. Furthermore, we hand-searched the reference lists in review articles identified during this search and the final included studies to identify additional potentially eligible papers. We specified our search terms to those related to the population of interest, which is non-critically ill, hospital-admitted patients with COVID-19, and the intervention of interest, which is thromboprophylaxis. Full details of the search strategy, and the medical subject heading (MeSH) terms used is provided in the Supplemental Material 1.

Studies including adult patients aged 18 years or older, who were hospital admitted for non-critically ill COVID-19 and receiving intermediate to high prophylaxis anticoagulation doses during their hospital stay, were included. We compared two thromboprophylaxis regimens: the “control” for patients who received standard prophylaxis or “intervention” for those who received intermediate to high prophylaxis doses. We planned to include studies of any design (ie, observational, and interventional studies) and further perform the analysis separately by design. We excluded any study that included critically ill patients admitted to the intensive care units (ICUs) or treated in outpatient settings. Furthermore, studies investigating oral anticoagulation agents or VTE treatment doses of anticoagulation were excluded.

Titles and abstracts found in the literature search were first screened for eligibility by two independent reviewers (O.A. and K.A.) using Abstrackr, a web tool designed for screening the studies.¹⁰ Second, two independent reviewers (H.J. and A.H.) screened the full-text articles for eligibility. Any disagreements were resolved in discussion with a third reviewer (H.J. and K.A.).

Study Outcomes

The prespecified primary outcome was the risk of arterial and venous thrombotic events (All-cause thrombosis). Secondary outcomes were the risk of bleeding events (either major or minor), in-hospital mortality, ICU admission, and the need for organ support. Bleeding was defined by the International Society on Thrombosis and Haemostasis (ISTH).¹¹ Meta-analyses were conducted for this study's outcomes if they were reported by at least two or more of the eligible studies.

Data Extraction and Quality Assessment

Two independent reviewers extracted all the data regarding the sample size, characteristics of the study population, study subjects, outcome measurements, and results (S.A. and K.S.). A third reviewer (H.A. or K.A.) was consulted if there were any disagreements. We used a pre-defined data extraction form to extract all relevant data. The quality assessment was performed for eligible studies according to the Newcastle–Ottawa quality assessment scale (NOS), a validated scale for non-randomized studies.¹² This scale awards a maximum of nine points to each study: four for selecting participants and measuring exposure, two for comparing cohorts based on the design or analysis, and three for assessing outcomes and adequacy of follow-up. The results from the NOS were translated into the Agency for Healthcare Research and Quality standards of ‘good’, ‘fair’ and ‘poor’ quality.¹³ The Cochrane quality assessment tool was used to assess the quality of included randomized control trials.¹⁴ Two investigators assessed the quality of included studies independently, and a third investigator was consulted in case of any disagreements.

Data Synthesis

The meta-analysis was conducted by pooling the appropriate data using R statistical software version 4.1.2. Random effects models were used to combine data as some heterogeneity between studies was expected. The analysis was repeated using a fixed-effect model as a sensitivity analysis.

Studies that reported on at least one of the study outcomes were included in the meta-analysis. We performed meta-analyses of the study outcomes by either using crude numbers or adjusted analysis depending on the availability of these data, using DerSimonian and Laird random-effects models.¹⁵ The analyses were performed separately for studies that provided adjusted as opposed to crude numbers. For crude analysis, we pooled the data by using relative risk (RRs) when the number of events was available.

We used adjusted hazard ratios (HRs), odds ratios (ORs), and their 95% confidence internvals (CIs) of study outcomes if reported. However, we first converted the ORs to RRs before combining the calculated RRs and HRs using the method of Zhang and Yu.¹⁶ We included the most adjusted HRs or ORs reported; if only unadjusted ORs were reported, we included them as well. Furthermore, we ran the primary analysis, including all the eligible studies regardless of their design, then performed a sensitivity analysis by including only the observational studies.

Forest plots were inspected visually for the direction, magnitude of effects, and degree of overlap between the CIs. In addition, the P-value from the χ² test and the I² statistic (percentage of total variation across studies due to heterogeneity) were calculated to assess heterogeneity. Due to the limited number of studies included in this review, subgroup analyses were not feasible.

Results

Search Results and Study Characteristics

We had initially retrieved 370 potentially relevant studies. After screening titles and abstracts for eligibility, 49 studies were eligible for full-text review (Figure 1). Seven studies were included in the analysis, totaling 1931 patients from all the analyzed studies.^21–27 The detailed characteristics of included studies are presented in Table 1. Of the included studies, one was an RCT, one was a prospective observational trial, and five were retrospective cohorts. Outcomes reported in each study are presented with their definitions in Table 2.

Figure 1.

PRISMA Flow diagram of study selection process.

Table 1.

Characteristics of the Included Studies.

Author	Study Status	Year	Study site	Design	Location	Intervention	Primary Outcome	Secondary Outcome
Di Micco P, et al	Published	2021	Italy	Prospective	Italy	Intermediate to high-dose Enoxaparin 6000 IU in those PPS scoring 5, and 8000 IU in those PPS scoring at least 6	The composite of all events classified as DVT and/or PE occurring in the whole population during hospitalization. The combination of major bleeding and clinically relevant non-major bleeding occurring in the whole population during hospitalization.	All-cause death
Jiménez-Soto R, et al	Published	2021	Mexico	Retrospective	Mexico	Enoxaparin intermediate dose 0.5 mg/kg of weight bid or 40 mg bid	Major bleeding	Pulmonary embolism, ICU admission, mortality
Meizlish ML, et al	Published	2021	United States	Retrospective, cohort study	Umited States	Intermediate anticoagulation dose a maximum enoxaparin dose of ≥0.4 and <0.7 mg/kg every 12 h or subcutaneous UFH 7500 U at any frequency with a BMI <40 kg/m²	Hospital mortality	None
Mennuni MG, et al	Published	2021	Italy	Retrospective	Italy	Enoxaparin dose: higher dosage (>4000 IU daily)	All-cause death	Cardiovascular death, venous thromboembolism, new-onset severe ARDS, need of mechanical ventilation, major bleeding, clinically relevant non-major bleeding, in-hospital length of stay

Muñoz-Rivas N, et al	Published	2022	Spain	Randomized controlled trial	Spain	Tinzaparin intermediate (100 IU/kg) once daily	Composite endpoint of death, need for invasive mechanical ventilation, non-invasive ventilation, including high flow oxygen with a nasal cannula, and venous or arterial thrombosis within 30 days after randomization. Safety outcomes were major bleeding and clinically relevant non-major bleeding	Reduction of suspected systemic thrombotic events (myocardial infarcion, ischemic stroke, DVT, PE). Progression on the WHO progression scale. Progression to ARDS. Overall survival day 14, 30, and 90. Length of hospital stay.
Paolisso P, et al	Published	2020	Bolongo, Italy	Retrospective, cohort study	Bolongo, Italy	LMWH intermediate prophylaxis dose 40-60 mg twice daily for 7 days	All-cause death	ICU admission, orotracheal intubation, acute myocardial infarction, renal failure requiring continuous venovenous hemofiltration; extracorporeal membrane oxygenation; acute kidney injury, stroke, Heart failure, atrial fibrillation
Poulakou G, et al	Published	2021	Greece	Retrospective	Greece	Intermediate anticoagulation dose (ETHRA protocol)	Intubations or VTE or deaths during a follow-up of at least 14 hospitalization days. VTE included PE and DVT	Inflammatory biomarkers in patients treated with intermediate dosage versus those treated with other (or no) anticoagulation regimens; and (ii) safety of anticoagulation treatment measured as incidence of bleeding events, heparin-induced thrombocytopenia

ARDS, acute respiratory distress syndrome; BMI, body mass index; DVT, deep vein thrombosis; ETHRA, Enhanced dose THRomboprophylaxis in Admissions; ICU, intensive care unit; IU, international unit; LMWH, low molecular weight heparin; PE, pulmonary embolism; PPS, Padua Prediction Score; U, unit; UFH, unfractionated heparin; VTE, venous thromboembolism; WHO, world health organization

Table 2.

Definition(s) of Outcome.

Author	All Thrombosis	All-cause death	Major Bleeding	Minor Bleeding	Organ Support
Di Micco P, et al	NA	NA	Fatal bleeding or symptomatic bleeding in a critical area or organ, or bleeding causing a fall in hemoglobin level of ≥2 g/dL or more or leading to transfusion of two or more units of whole blood or red cells.	Clinical relevant non-major bleeding was defined as an overt bleeding not meeting the criteria for major bleeding but requiring medical intervention.	NA
Jiménez-Soto R, et al	Pulmonary embolism is defined as patients who had a positive CT pulmonary angiography determined by an experienced radiologist.	NA	Major bleeding was defined as symptomatic bleeding in a critical area or organ, fatal bleeding, bleeding requiring the transfusion of two or more units of whole blood or bleeding that causes a fall in hemoglobin level of 2 g/dl or more, as consistent with the ISTH definition.	Clinically relevant bleeding was defined as any sign or symptom of bleeding that is not classified as major but that meets one of the following criteria: requiring hospitalization or an increase in care level, requires a prompt face to face evaluation or that requires intervention by a healthcare professional.	NA
Meizlish ML, et al	NA	In hospital mortality competing to cumulative incidence of hospital discharge	NA	NA	NA
Mennuni MG, et al	Venous thromboembolism: including pulmonary embolism or deep venous thrombosis	All-cause death: during in-hospital stay in the two groups.	According to the ISTH definition	According to the ISTH definition	NA

Muñoz-Rivas N, et al	Venous or arterial thrombosis within 30 days after randomization	NA	According to the ISTH definition	According to the ISTH definition	Invasive mechanical ventilation, non-invasive ventilation, including high flow oxygen with nasal cannula
Paolisso P, et al	NA	NA	Gastro-intestinal bleedings /retroperitoneal hematomas	NA	Orotracheal intubation, renal failure requiring continuous veno-venous hemofiltration.

Poulakou G, et al	VTE included PE and DVT confirmed with imaging. Leg doppler ultrasound was performed upon clinical suspicion. A low threshold of suspicion for pulmonary embolism was maintained; imaging with computed tomography pulmonary angiogram was performed.	Deaths during a follow-up of at least 14 hospitalization days.	NA	Epistaxis and hemoptysis	Intubation

DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism;NA, not applicable; ISTH, International Society of Thrombosis and Haemostasis

Table 3.

Newcastle–Ottawa Quality Assessment Scale for Included Observational Studies.

	Selection				Comparability	Outcome			Total	AHRQ Standard
Author	Representativeness of the Exposed Cohort	Selection of the Non-Exposed Cohort	Ascertainment of Exposure	Demonstration that Outcome of Interest was not Present at Start of Study	Comparability of Cohorts on the Basis of the Design or Analysis	Assessment of Outcome	Was Follow-Up Long Enough for Outcomes to Occur	Adequacy of Follow-Up of Cohorts	9/9
Di Micco P, et al	*	*	0	*	0	0	*	0	4	Poor
Jiménez-Soto R, et al	*	*	*	*	*	*	*	0	7	Good
Meizlish ML, et al	*	*	*	0	*	*	*	0	6	Good
Mennuni MG, et al	*	*	*	*	**	*	*	0	8	Good
Paolisso P, et al	*	*	*	*	*	*	0	0	6	Poor
Poulakou G, et al	*	*	*	*	*	*	*	*	8	Good

Thresholds for converting the Newcastle–Ottawa scales to Agency for Health Research and Quality (AHRQ) standards (good, fair, and poor):

Good quality: 3 or 4 stars in the selection domain AND 1 or 2 stars in the comparability domain, AND 2 or 3 stars in the outcome/exposure domain.

Fair quality: 2 stars in the selection domain AND 1 or 2 stars in the comparability domain AND 2 or 3 stars in the outcome/exposure domain.

Poor quality: 0 or 1 star in the selection domain OR 0 stars in the comparability domain OR 0 or 1 star in the outcome/exposure domain.

Enoxaparin was assessed as intermediate to high dosing regimens in six of the included studies, including the following doses >4000 IU daily, 0.5 mg/kg twice daily, 40-60 mg twice daily, ≥0.4 and <0.7 mg/kg twice daily, or 6000-8000 IU daily in the intervention arm compared to standard prophylaxis regimen. While one study assessed tinzaparin (100 IU/kg) once daily, and one evaluated subcutaneous unfractionated heparin (UFH) 7500 U at any frequency as the studied intervention. The quality assessment of the included observational stuides is presented in Table 3. Five studies were rated as good quality, and one as poor quality. In the one included randomized control trial by Muñoz-Rivas et al, the risk of bias was high in blinding participants, personnel, and outcome assessment domains, while the risk of bias was low in the rest of the domains.

Study Outcomes

Thrombosis and Bleeding

The risk of all-cause thrombosis was reported in four of the included studies, with a RR of 1.48, 95% CI = 0.11, 20.21. No difference was found between the two groups, with an I²= 77% (Figure 2). Minor and major bleeding events were reported in four different study groups, with a RR of 0.64, 95% CI = 0.21, 1.97 and 1.40, 95% CI = 0.43, 4.61, respectively. The I² was 0% in both minor and major bleeding outcomes ((Figures 3 and 4). We repeated the minor bleeding analysis, excluding the one randomized trial in this review, and the results remained consistent (RR = 0.55, 95% CI = 0.06, 4.71, I² = 0%). When running the analyses using fixed-effect models the results remained similar with more narrower CIs.

Figure 2.

Forest plot showing the all-cause thrombosis risk ratio using random-effects models in patients receiving intermediate-high-dose prophylaxis (intervention) versus standard-dose prophylaxis (control). Central vertical line, “no difference” point between the two groups; horizontal line, 95% confidence interval; squares: risk ratio; diamonds: pooled risk ratio. CI, confidence interval; RR, risk ratio.

Figure 3.

Forest plot showing the minor bleeding risk ratio using random-effects models in patients receiving intermediate-high-dose prophylaxis (intervention) versus standard-dose prophylaxis (control). Central vertical line, “no difference” point between the two groups; horizontal line, 95% confidence interval; squares: risk ratio; diamonds: pooled risk ratio. CI, confidence interval; RR, risk ratio.

Figure 4.

Forest plot showing the major bleeding risk ratio using random-effects models in patients receiving intermediate-high-dose prophylaxis (intervention) versus standard-dose prophylaxis (control). Central vertical line, “no difference” point between the two groups; horizontal line, 95% confidence interval; squares: risk ratio; diamonds: pooled risk ratio. CI, confidence interval; RR, risk ratio.

Figure 5.

Forest plot showing the hospital mortality (most adjusted) relative risk using random-effects models in patients receiving intermediate-high-dose prophylaxis (intervention) versus standard-dose prophylaxis (control). Central vertical line, “no difference” point between the two groups; horizontal line, 95% confidence interval; squares: risk ratio; diamonds: pooled risk ratio. CI, confidence interval; RE, random-effect; RR, risk ratio.

Hospital Mortality

All included studies assessed hospital mortality as one of their outcomes. Using the most adjusted models reported in the studies, the overall RR was 0.47, 95% CI = 0.29, 0.75, I²= 33%, favoring the intermediate to high-dose prophylaxis compared to the standard dose (Figure 5). Consistent results were observed when unadjusted studies were excluded from the analysis with a RR of 0.41, 95% CI = 0.23, 0.72. Furthermore, when we excluded the RCT in this review and included only observational studies, the results remind consistent (RR = 0.46, 95% CI = 0.27, 0.77), with moderate heterogeneity (I² = 45%). When the analysis was performed on studies that reported crude hospital mortality rates, there was no difference between intervention and control groups (RR = 0.72, 95% CI = 0.35, 1.51, I² = 51%). The summary estimates did not change singifcantly when repeating the analysis using fixed-effects models.

ICU Admission and Need for Organ Support

Only three studies reported ICU admission: Jiménez-Soto et al, Paolisso et al, and Muñoz-Rivas et al. These studies had no difference between the intervention and control groups. The reported overall RR is 1.12, 95% CI = 0.59, 2.11, and I²= 0% (Figure 6). We repeated the analysis, excluding the RCT, and the results remained consistent (RR = 1.14, 95% CI = 0.06, 19.01, and I²= 11%).

Figure 7.

Forest plot showing the need for organ support risk ratio using random-effects models in patients receiving intermediate-high-dose prophylaxis (intervention) versus standard-dose prophylaxis (control). Central vertical line, “no difference” point between the two groups; horizontal line, 95% confidence interval; squares: risk ratio; diamonds: pooled risk ratio. CI, confidence interval; RR, risk ratio.

Three studies assessed organ support requirements: Mennuni et al, Jiménez-Soto et al, and Muñoz-Rivas et al. There was no difference in organ support requirement between the two groups, the overall RR for all included studies was 2.14, 95% CI = 0.32, 14.20, and I²= 82% (Figure 7). The analysis was re-performed by excluding the randomized trial in the review, and the results remained consistent.

Figure 6.

Forest plot showing ICU Admission risk ratio using random-effects models in patients receiving intermediate-high-dose prophylaxis (intervention) versus standard-dose prophylaxis (control). Central vertical line, “no difference” point between the two groups; horizontal line, 95% confidence interval; squares: risk ratio; diamonds: pooled risk ratio. CI, confidence interval; RR, risk ratio.

Discussion

This meta-analysis summarized the available evidence on the efficacy and safety of intermediate versus standard doses of thromboprophylaxis in medically ill hospitalized patients with COVID-19. The main finding of this study is that the intermediate dose of thromboprophylaxis seems to be associated with survival benefits when compared with the standard prophylactic dose. However, there is no difference between intermediate to high versus standard prophylactic thromboprophylaxis dose in terms of all-cause thrombosis, minor and major bleeding events, ICU admission, and the need for organ support. Noteworthy that the evidence is mainly derived from observational studies where low molecular weight heparin (LMWH) was the main anticoagulant agent used for thromboprophylaxis.

Interestingly, there was no observed difference in the risk for VTE in higher versus standard prophylactic doses of thromboprophylaxis. However, it has been noted that the analyses of details on the screening or the diagnostic algorithm strategies for VTE were absent. Thus, minor VTE might be uncaptured in most of the studies. Furthermore, besides its anticoagulant action, LMWH has anti-inflammatory effects, which might justify its beneficial role in terms of mortality, above and beyond simply reducing VTE, especially in the early stages of the disease state.¹⁷

The ISTH guidance document and the NIH guideline recommend against intermediate to high prophylactic doses over the standard thromboprophylaxis in medically ill hospitalized patients to reduce the risk of thromboembolism and other adverse outcomes.^18,19 The available evidence is mainly derived from the X-COVID-19 RCT study, in which 183 patients were randomized to receive either an intermediate or standard prophylactic dose.²⁰ The study concluded no difference in the need for mechanical ventilation or all-cause mortality.²⁰ Zero thrombotic events in the intervention group and six PEs in the control group.²⁰ However, it is noteworthy that the study was prematurely discontinued due to slow recruitment and the lack of DVT characteristics and imaging.²⁰ The current meta-analysis included only randomized or observational studies that provided similar outcomes.

The present analysis included mainly observational studies. Most studies used LMWH for thromboprophylaxis. Intermediate-high compared with standard prophylactic dose appeared to be associated with a 53% decrease in in-hospital mortality. However, there was no difference between intermediate to high thromboprophylaxis and standard prophylactic dosing for those studies that reported crude hospital mortality rates. Hence, concluding the survival benefit of the intervention thromboprophylaxis group remains questionable. The finding might highlight the selection bias of the included observational studies: higher doses were selectively administered in patients with higher risk for severe disease due to their baseline risk factors or high levels of indices of COVID-19 severity. Thus, their adverse prognosis might mitigate the benefit of this strategy or even mislead to the link between high dose and mortality. Adjustment for appropriate confounders seems necessary; however, randomized trials are the most relevant studies for providing the highest level of evidence. The X-COVID-19 open-label RCT trial, although limited by its small sample size, showed no statistical difference in all causes of death at 30 days. Interestingly though, numerically higher death rates were reported with patients who received the intermediate prophylactic dose.

Safety is also of paramount importance; this analysis found no difference between major and minor bleeding events with intermediate versus standard thromboprophylaxis doses. An interesting finding that can be analyzed further in medically ill patients considered to be of high risk, such as those with elevated D-Dimer 2 > times the normal upper limit, requiring oxygen supplementation, or having low oxygen saturation rates. These patients are ideal candidates for treatment doses of anticoagulation, deemed that they have low bleeding risk. Therefore, this approach might be optional for those deemed high risk but with moderate to high bleeding risk.

Although this meta-analysis is one of the few studies that focused on the effect of anticoagulation therapy in subjects hospitalized with non-critical COVID-19, some limitations exist. First, this review mainly included observational studies conducted at different times during the pandemic. Nonetheless, we have performed a rigorous process in choosing studies that are similar enough in terms of inclusion criteria and exposure definitions to minimize methodological heterogeneity. In addition, whenever possible, we performed the analysis once using crude numbers and adjusted analysis, and the results remained consistent. Second, the studies had multiple variations, including variability between co-interventions. Third, although this review included studies on non-critically ill subjects hospitalized with COVID-19, the severity level differed across studies and might impact the current study results.

Conclusion

In patients who are medically ill with mild-moderate COVID-19, there is no difference between standard and intermediate-high prophylaxis dosing regarding thrombosis, bleeding, ICU admission, and organ support. However, using intermediate-high prophylaxis dosing seems to be associated with survival benefits. Moreover, further RCTs focusing on the timing of anticoagulation and those carrying risk factors for disease severity are highly warranted.

Supplemental Material

sj-docx-1-cat-10.1177_10760296231191123 - Supplemental material for Thromboprophylaxis in Hospitalized Non-Critically Ill Patients With Mild-to-Moderate COVID-19 Infection: A Systematic Review and Meta-Analysis

Supplemental material, sj-docx-1-cat-10.1177_10760296231191123 for Thromboprophylaxis in Hospitalized Non-Critically Ill Patients With Mild-to-Moderate COVID-19 Infection: A Systematic Review and Meta-Analysis by Awatif Hafiz, Hadeel Alkofide, Khalid Al Sulaiman, Hala Joharji, Sarah Aljohani, Khadijah A. Sarkhi, Reem Alharbi, Ghazwa B. Korayem, Mashael AlFaifi, Samiah Alsohimi and Ohoud Aljuhani in Clinical and Applied Thrombosis/Hemostasis

Footnotes

Acknowledgments

We would like to thank all the investigators who participated in this project from the Saudi critical care pharmacy research (SCAPE) platform.

Author Contributions

All authors made a significant contribution to the work reported. Conceptualization was done by A.H. and H.A. Methodology was done by K.A. Software was done by K.A. Validation was done by S.A. and K.S. Formal analysis was done by K.A. Investigation was done by O.A., K.A., H.J., H.A., and A.H. Data curation was done by H.J. Writing–original draft preparation was done by H.J., S.A., K.S., and R.A. Writing–review and editing was done by A.H., H.A., G.K., M.A., and S.S. Visualization was done by G.K. and M.A. Supervision was done by O.A. Project administration was done by O.A. All authors gave the final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Khalid Al Sulaiman

Supplemental Material

Supplemental material for this article is available online.

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