Use of XARELTO in Patients With COVID-19

SUMMARY

• PREVENT-HD was a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven trial evaluating the efficacy and safety of prophylactic XARELTO in symptomatic coronavirus disease 2019 (COVID-19) patients at risk for thrombotic events, hospitalization, and death. XARELTO was not found to reduce a composite endpoint of symptomatic venous and arterial thrombotic events, hospitalization, and death.^1-3
• A randomized, open-label, parallel-group, comparative trial was conducted that evaluated prophylactic enoxaparin compared to XARELTO in patients with moderate cases of COVID-19. No statistically significant differences in thrombotic or bleeding events between enoxaparin and XARELTO were found.⁴
• ACTION trial was an open-label, multicenter, randomized controlled trial that compared therapeutic and prophylactic anticoagulation in hospitalized patients with COVID-19 with elevated D-dimer concentrations. Most patients received XARELTO (90%) in the therapeutic arm and enoxaparin (84%) in the prophylactic arm. Therapeutic anticoagulation had consistent efficacy outcomes (composite of time to death, duration of hospitalization, or supplemental oxygen duration through 30 days) and increased bleeding compared with prophylactic anticoagulation.⁵
• MICHELLE TRIAL was an open-label, randomized controlled trial that compared prophylactic XARELTO vs no treatment in discharged COVID-19 patients who were at increased risk of venous thromboembolism (VTE). The primary efficacy outcome (a composite of thrombosis-related events) occurred in significantly fewer patients assigned to the XARELTO group vs those receiving no anticoagulation. No major bleeding occurred in either study group.⁶
• ROXANE trial was a single-center, randomized, open-label, prospective trial comparing XARELTO vs enoxaparin for the prophylactic management of VTE in patients diagnosed with mild to moderate COVID-19. Significantly fewer events occurred within the primary efficacy (composite of disease progression requiring treatment escalation, intensive care unit [ICU] transfer, thrombosis-related events, and death) and safety (bleeding) outcomes for the XARELTO vs enoxaparin arm.⁷
• ACT (Anti-coronavirus Therapies) inpatient trial was an open-label, multicenter, 2×2 factorial, randomized, controlled trial that evaluated antithrombotic therapy with XARELTO + aspirin for the prevention of disease progression in patients hospitalized with COVID-19. Compared to usual care, XARELTO + aspirin did not reduce the composite efficacy endpoint of major thrombosis, need for high-flow oxygen/mechanical ventilation, or death, but did increase bleeding events.⁸
• CARE (COVID Antithrombotic Rivaroxaban Evaluation) was an open-label, multicenter, randomized controlled trial that evaluated the prophylactic use of XARELTO compared to usual care in patients with mild or moderate COVID-19. There was no significant difference between XARELTO and usual care in the composite primary efficacy endpoint of VTE, need for mechanical ventilation, major adverse cardiovascular event, and death. There was no major bleeding in the usual care group and 1 event in the XARELTO group.⁹
• Thu et al (2025) conducted a quasi-experimental, open-label study at 3 hospitals in Ho Chi Minh City, Vietnam, to compare the rate of progression to severe disease, incidence of adverse events, changes in clinical symptoms, and laboratory parameters in 108 adult patients with mild COVID-19 receiving either XARELTO 10 mg once daily (OD) for 7 days (regimen 1) or methylprednisolone 16 mg OD + XARELTO 10 mg OD for 7 days (regimen 2). There was no statistically significant difference in the occurrence of adverse events between regimens 1 and 2 (P=0.270, as derived from Fisher’s exact test). No significant differences were observed between the treatment groups in body temperature, respiratory rate, oxygen saturation (SpO₂), heart rate, or blood pressure after adjustment for confounding factors, including age, sex, vaccination status, and baseline symptoms. Laboratory parameters showed improvements in both groups, with significant differences observed with regimen 2.¹⁰
• STIMULATE-ICP Consortium (2026) conducted an open-label, adaptive-platform, phase 3 randomized controlled trial nested within a pragmatic, multicenter, cluster-randomized integrated care pathway (ICP) trial for long coronavirus disease (COVID). The study evaluated the efficacy and safety of 3 classes of repurposed drugs vs no drugs for fatigue in adults aged ≥18 years with long COVID who had not previously been hospitalized for COVID-19. In the XARELTO group, the mean Fatigue Assessment Scale (FAS) score decreased from 36.9 (standard deviation [SD], 6.81) at baseline to 32.5 (SD, 8.9) at 12 weeks, representing a 4.4-point reduction, which met the definition for a minimally clinically important difference (MCID). At 24 weeks, the mean FAS score in the XARELTO group further reduced to 33.4 (SD, 8.73), representing a 3.5-point reduction from baseline, which also met the MCID definition. Overall, 199 (26%) of 778 patients reported an adverse event, including 70 (36%) of 197 patients in the XARELTO group.¹¹
• Some of the studies were terminated early due to lower than expected new COVID-19 cases and did not achieve goal enrollment. Two meta-analyses of randomized controlled trials that evaluated the safety and efficacy of XARELTO in patients with COVID-19 are summarized below: META-ANALYSES.^12,13
• Additional citations identified during a literature search have been included in the REFERENCES section for your review.^14-19

CLINICAL STUDIES

PREVENT-HD Trial

PREVENT-HD^1,2 was a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven trial that evaluated the efficacy and safety of XARELTO 10 mg OD in symptomatic outpatients with laboratory-confirmed COVID-19 who were at risk for thrombotic events, hospitalization, and death.

Study Design/Methods

• Patients were randomized 1:1 (stratified by the time from COVID-19 confirmation) to receive either XARELTO 10 mg or placebo OD for 35 days.³
• The primary efficacy endpoint was time to first occurrence of a composite of symptomatic VTE, myocardial infarction (MI), ischemic stroke, acute limb ischemia, non-central nervous system (CNS) systemic embolization, all-cause hospitalization, and all-cause mortality up to day 35.³
• The first major secondary outcome was a composite of symptomatic VTE, arterial thrombotic events, and all-cause mortality.³
• The principal safety endpoint was time to first occurrence of the International Society on Thrombosis and Haemostasis (ISTH) critical site and fatal bleeding on treatment.³

Results

• The trial expected to recruit approximately 4000 patients to reach 90% power at a 2-sided significance level of 5%, with a 30% reduction (hazard ratio [HR], 0.7) and an anticipated placebo event rate of 10%. A total of 1284 patients were randomized in the intention-to-treat (ITT) analysis. The trial was terminated early because of a lower than expected blinded pooled event incidence (3.2%) compared to what was planned (8.5%) (41 out of planned 333).¹
• A total of 1284 patients were randomized (1:1) to receive either XARELTO 10 mg (n=641) or placebo (n=643).²
• For efficacy outcomes, see Table: Efficacy Outcomes (ITT Population).

• In the modified ITT (mITT) population (N=1197 [XARELTO, n=599; placebo, n=598]), the primary efficacy endpoint occurred in 12/599 (2%) patients in the XARELTO group vs 16/598 (2.7%) patients in the placebo group (HR, 0.75; 95% confidence interval [CI], 0.35-1.58; P=0.439).¹
• The first major secondary outcome (composite of symptomatic VTE, arterial thrombotic events, and all-cause mortality) for the ITT population occurred in 2/641 patients (0.3%) in the XARELTO group and 7/643 patients (1.1%) in the placebo group (HR, 0.29; 95% CI, 0.06-1.37; P=0.095).¹
• For safety outcomes, see Table: Safety Outcomes (Safety Population).

Thromboprophylaxis and Clinical Outcomes in Moderate COVID-19 Patients: A Comparative Trial

Mohamed et al (2022)⁴ conducted a randomized, open-label, parallel-group, single-center clinical trial designed to evaluate the safety, efficacy, and clinical outcomes of prophylactic enoxaparin and XARELTO in adult patients with moderate cases of COVID-19 admitted to the intermediate care unit (IMCU). Participants at the Minia University Hospital in Egypt were randomized to receive XARELTO 10 mg (n=58) OD or enoxaparin 0.5 mg/kg (n=66) every 12 hours. The outcomes were IMCU duration, number of patients transferred from the IMCU to the ICU, ICU duration, total length of hospital stay, in-hospital mortality rate, and rate of bleeding or thrombotic complications. There were no significant differences between XARELTO vs enoxaparin when looking at mean IMCU duration (5.2 vs 4.9 days; P=0.39), number of patients transferred from the IMCU to the ICU (13 [22.4%] vs 14 [21.2%]; P=0.87) or mean total length of hospital stay (6.1 vs 5.9 days; P=0.73). There was no significant difference in mean ICU duration for patients in the XARELTO (8 days) group compared to the enoxaparin (9.2 days) group (P=0.32). There were 6 in-hospital deaths (10.3%) in the XARELTO group and 8 in-hospital deaths (12.1%) in the enoxaparin group (P=0.76) while there were 7 patients (12.1%) compared to 6 patients (9.1%) who experienced thrombotic events in the XARELTO and enoxaparin groups, respectively (P=0.59). There were no instances of moderate or severe bleeding, and there was 1 (1.7%) reported mild bleeding event in the XARELTO group compared to 2 (3%) mild bleeding events in the enoxaparin group (P=0.64).

ACTION Trial

ACTION⁵ was an open-label, multicenter, randomized controlled trial designed to compare the efficacy and safety of therapeutic vs prophylactic anticoagulation in hospitalized patients (n=615) with COVID-19 and elevated D-dimer concentrations. Patients in the therapeutic anticoagulation arm (n=311) received either XARELTO (20 mg or 15 mg OD) for stable patients, or enoxaparin (1 mg/kg twice daily), or unfractionated heparin (to achieve a 0.3-0.7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by XARELTO to day 30. Patients in the prophylactic anticoagulation arm (n=304) received standard enoxaparin or unfractionated heparin. Most patients received XARELTO (90%) in the therapeutic arm and enoxaparin (84%) in the prophylactic arm. The primary efficacy outcome was a composite of time to death, duration of hospitalization, or duration of supplemental oxygen use through 30 days analyzed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group). The primary safety outcome was major or clinically relevant non-major bleeding defined according to the ISTH criteria. The primary efficacy outcome was not statistically significant between the therapeutic or prophylactic anticoagulation treatment arms. The number of wins was 28899 (34.8%) in the therapeutic group and 34288 (41.3%) in the prophylactic group (win ratio, 0.86 [95% CI, 0.59-1.22], P=0.40). The total number of ties was 19837 (23.9%). Twenty-six (8%) patients who received therapeutic anticoagulation and 7 (2%) patients who received prophylactic anticoagulation experienced major or clinically relevant bleeding (relative risk [RR], 3.6; 95% CI, 1.61-8.27; P=0.0010).

MICHELLE TRIAL

MICHELLETrial⁶ was an open-label, randomized controlled trial designed to evaluate the safety and efficacy of XARELTO in discharged COVID-19 patients. Inclusion criteria were: hospitalization for ≥3 days with standard dose thromboprophylaxis prior to randomization, and total modified IMPROVE VTE Risk Score ≥4 or total modified IMPROVE VTE Risk Score 2 or 3 and D dimer >500 ng/mL during index hospitalization. Patients received either XARELTO 10 mg OD (n=160) or no anticoagulant treatment (n=160) for 35+/-4 days. The primary efficacy outcome was a composite efficacy endpoint of symptomatic VTE, VTE-related death, and VTE detected at bilateral lower limbs venous duplex scan and computed tomography pulmonary angiogram and symptomatic arterial thromboembolism, MI, non-hemorrhagic stroke, major adverse limb event (MALE), and cardiovascular (CV) death at day 35 post-hospital discharge. Key safety outcome included incidence of major bleeding according to the ISTH criteria. The primary efficacy outcome was statistically significant between the XARELTO group vs the group that did not receive anticoagulation treatment (3.14% vs 9.43%; RR, 0.33; 95% CI, 0.13-0.90; P=0.0293; number needed to treat [NNT]=16; relative risk reduction [RRR]=67%). Incidence of major bleeding was 0% in both the XARELTO and the control group.

ROXANE TRIAL

ROXANE trial⁷ was a single-center, randomized, open-label, prospective trial comparing the efficacy and safety of XARELTO vs enoxaparin for the prophylactic management of VTE in patients diagnosed with mild to moderate COVID-19. A total of 230 patients between the ages of 25 to 75 years were randomized in a 1:1 ratio to receive XARELTO (10 mg [n=65] or 15 mg [n=50]) or enoxaparin (40 mg [n=62] or 60 mg [n=51]) at a COVID-19-dedicated hospital in Mumbai, India. The dose of each study medication was determined based on whether the patient had mild or moderate disease. The primary outcome was a composite of all major, clinically relevant hemorrhagic and thrombotic events. The primary efficacy endpoints were progression of disease requiring treatment escalation, transfer to ICU, the incidence of radiologically confirmed new or recurrent deep vein thrombosis or pulmonary embolism (PE), stroke and systemic embolism, MI, death from vascular causes and all-cause death. The primary safety endpoint was bleeding, including major and clinically relevant non-major bleeding. Both enoxaparin and XARELTO were administered for the duration of hospital stay (median treatment duration of 8 days for both).

The primary efficacy outcome occurred in 4 patients (3.5%) in the XARELTO group vs 16 patients (14.2%) in the enoxaparin group (HR, 0.207; 95% CI, 0.069-0.621; P=0.005). One patient (0.9%) in the XARELTO group and 3 patients (2.7%) in the enoxaparin group required transfer to the ICU due to suspected or confirmed PE or cardiorespiratory failure (P=0.304). The primary safety outcome occurred in 5 patients (4.3%) in the XARELTO group and 14 patients (12.4%) in the enoxaparin group (HR, 0.328; 95% CI, 0.118-0.91; P=0.032). Major bleeding, including systemic bleeding, nonfatal bleeding leading to fall in hemoglobin (>2 g/dL), requiring interruption or discontinuation of therapy was observed in 1 patient (0.9%) in the XARELTO group and 3 patients in the enoxaparin group (2.7%) (P=0.304).

As an independent treatment strategy, eligible patients in either treatment group were discharged on prophylaxis with XARELTO (10 mg OD, N=117). The mean duration of therapy was 39 days. During the course of therapy, seven patients experienced any adverse event. An acute coronary event was observed in one patient, and one patient died due to a non-vascular cause.

ACT INPATIENT TRIAL

The ACT inpatient trial⁸ was an open-label, multicenter, 2×2 factorial randomized controlled trial that evaluated usual care compared to either anti-inflammatory therapy with colchicine or antithrombotic therapy with XARELTO + aspirin for the prevention of disease progression in patients hospitalized with COVID-19 from October 2020 to February 2022. Data specific to XARELTO + aspirin vs usual care are summarized here. Patients symptomatic with laboratory-confirmed COVID-19 disease, age ≥18 years, and within 72 hours of hospital admission, or with clinical decline if already hospitalized, were included. Patients with advanced kidney or liver disease, or patients who were pregnant or lactating, on ventilation for ≥72 hours, or had a medical indication or contraindication to the intervention, were excluded. The primary outcome for antithrombotic comparison was the composite of major thrombotic events (PE, acute limb ischemia, stroke, and MI), need for high-flow oxygen, mechanical ventilation, or death. A total of 2119 patients were randomized 1:1 to receive either XARELTO 2.5 mg twice daily + aspirin 100 mg OD for 28 days (n=1063) or control (n=1056) defined as usual care by the local investigator. All outcomes were assessed at day 45.

There was no significant reduction in the primary outcome of major thrombosis, high-flow oxygen, ventilation, or death with the XARELTO + aspirin group vs the control group (281 [26.4%] events vs 300 [28.4%] events; HR, 0.92; 95% CI, 0.78-1.09; P=0.32). No evidence of benefit was observed with XARELTO + aspirin in the prespecified subgroups, except for in patients with or without diabetes (P=0.027).

In the safety analysis, bleeding events occurred in 17 (1.6%) patients in the XARELTO + aspirin group and 7 (0.66%) patients in the control group (P=0.042). Serious bleeding events occurred in 2 (0.19%) patients in the XARELTO + aspirin group and 6 (0.57%) patients in the control group (P=0.18). There were no serious adverse events leading to treatment discontinuation in the XARELTO + aspirin group.

CARE TRIAL

CARE⁹ was an open-label, multicenter, randomized controlled trial that evaluated the use of XARELTO in patients with mild or moderate COVID-19. Patients aged ≥18 years with suspected or confirmed mild or moderate COVID-19 presenting within 7 days from symptom onset were included. Patients were randomized 1:1 to receive either XARELTO 10 mg OD for 14 days or control (routine care).

The primary efficacy outcome was the composite of VTE, need for mechanical ventilation, major adverse cardiovascular events (acute MI, stroke, or acute limb ischemia), and death. Key safety outcomes included the ISTH criteria for major bleeding, which include fatal bleeding, and/or symptomatic bleeding in a critical area or organ.

Enrollment was prematurely stopped due to a sustained reduction in new COVID-19 cases.

A total of 657 patients were randomized to the XARELTO (n=327) or control (n=330) group. The primary efficacy outcome was not significantly different between the XARELTO (4% [n=14]) and control (6% [n=19]) groups (RR, 0.74; 95% CI, 0.38-1.46; P=0.476). Hospitalization rates in both the XARELTO and control groups were 11% (RR, 0.98; 95% CI, 0.64-1.51) when COVID-19-related hospitalization was included. The incidence of major bleeding was reported in 1 patient (<1%) in the XARELTO group and no patients in the control group.

Thu et al (2025)¹⁰ conducted a quasi-experimental, open-label study at the following 3 hospitals in Ho Chi Minh City, Vietnam: Hoan My Thu Duc Hospital, Hoan My Van Phuc 1 Hospital, and Hoan My Van Phuc 2 Hospital. The study compared the rate of progression to severe disease, incidence of adverse events, changes in clinical symptoms, and laboratory parameters in 108 adult patients with mild COVID-19 receiving either XARELTO 10 mg OD for 7 days (regimen 1) or methylprednisolone 16 mg OD + XARELTO 10 mg OD for 7 days (regimen 2).

There was no statistically significant difference in the occurrence of adverse events between regimens 1 and 2 (P=0.270, as derived from Fisher’s exact test). Only 1 patient receiving regimen 1 experienced a nonserious adverse event related to XARELTO, whereas no adverse events were reported with regimen 2. See Table: Adverse Effects When Using Medication According to the Study Protocol.

Changes in clinical symptoms were analyzed using a generalized estimating equations (GEE) model. No significant differences were observed between the treatment groups for body temperature, respiratory rate, SpO₂, heart rate, or blood pressure after adjustment for confounding factors, such as age, sex, vaccination status, and baseline symptoms. See Table: Comparison of Changes in Clinical Symptoms Between Regimens 1 and 2 (n=108).

On day 7, the mean ± SD white blood cell (WBC) count was 7.1±2.12 G/L with regimen 1 and 10.49±3.18 G/L with regimen 2. The mean ± SD platelet count was 257.12±66.8 G/L with regimen 1 and 279.17±64.2 G/L with regimen 2. For regimens 1 and 2, respectively, the mean ± SD aspartate aminotransferase (AST) level was 28.74±17.95 U/L and 30.31±20.41 U/L and the mean ± SD alanine aminotransferase (ALT) level was 24.9±17.59 U/L and 32.66±23.62 U/L. The mean ± SD CD4 count was 1016.07±334.08 with regimen 1 and 1270.36±470.33 with regimen 2. The mean ± SD activated partial thromboplastin time (APTT) was 41.36±9.73 seconds with regimen 1 and 35.37±6.87 seconds with regimen 2.

Laboratory parameters improved in both groups, with significant differences observed with regimen 2. Using the GEE multivariable model, for regimen 2 vs regimen 1, the WBC level differed by +0.29 G/L (95% CI, 0.148-0.432; P<0.001), platelet level by +0.102 G/L (95% CI, 0.008-0.195; P=0.032), AST level by +0.335 U/L (95% CI, 0.070-0.599; P=0.013), ALT level by +0.397 U/L (95% CI, 0.115-0.680; P=0.006), CD4 count by +0.458 (95% CI, 0.259-0.656; P<0.001), and APTT by -0.083 seconds (95% CI, -0.137 to -0.028; P=0.003).

STIMULATE-ICP Consortium (2026)¹¹ conducted an open-label, adaptive-platform, phase 3 randomized controlled trial nested within a pragmatic, multicenter, cluster-randomized ICP trial for long COVID. The study evaluated the efficacy and safety of 3 classes of repurposed drugs vs no drugs for fatigue in adults aged ≥18 years with long COVID who had not previously been hospitalized for COVID-19. A total of 778 patients were randomized to receive XARELTO 10 mg OD (n=197), colchicine 500 μg twice daily (n=192), famotidine 40 mg OD + loratadine 10 mg OD (n=193), or no drugs (n=196) for 12 weeks. The primary outcome was fatigue, assessed using FAS, at 12 weeks. Secondary outcomes included the FAS score at 24 weeks and the EQ-5D-5L visual analogue scale (EQ-VAS) scores at 12 and 24 weeks.

The median number of long COVID symptoms at baseline was 9 (interquartile range [IQR], 8-9). The mean baseline FAS score was 36.8 (SD, 7.49), and the median symptom duration was 775 days (IQR, 381-1163).

Across all treatment groups, the mean FAS score decreased by a clinically relevant 4.3 points from baseline to 12 weeks, decreasing from 36.8 (SD, 7.49) to 32.5 (SD, 9.13), respectively; though heterogeneity was observed in the response, most patients experienced a substantial reduction. In the XARELTO group, the mean FAS score decreased by 4.4 points, from 36.9 (SD, 6.81) at baseline to 32.5 (SD, 8.9) at 12 weeks, meeting the MCID definition. After adjustment for the baseline FAS score, sex, ICP allocation, and trial site, the FAS score at 12 weeks in the XARELTO group compared with the no-drug group was -1.06 points (95% CI, -2.47 to 0.35; P=0.139). At 24 weeks (12 weeks after drug cessation), the FAS score in the XARELTO group compared with the no-drug group was 0.04 points (95% CI, -1.45 to 1.53; P=0.96). Within the XARELTO group, the mean FAS score decreased from 36.9 (SD, 6.81) at baseline to 33.4 (SD, 8.73) at 24 weeks, with the 3.5-point decrease meeting the MCID definition. See Table: FAS Scores for XARELTO from Before Long COVID Diagnosis and at Baseline, 12 Weeks, and 24 Weeks.

In a post hoc analysis adjusting the FAS outcome model for symptom duration, the estimated change in the mean FAS score in the XARELTO group compared with the no-drug group at 12 weeks was -1.02 points (95% CI, -2.44 to 0.4; P=0.158). The model-coefficient estimated effect size for each additional year of long COVID was 0.46 (95% CI, -0.05 to 0.98; P=0.078).

In a sensitivity analysis restricted to patients who completed the full 84-day treatment allocation, findings for week 12 FAS scores were consistent in size and direction with those from the primary analysis but were no longer significant at the 5% level (-0.7 points [95% CI, -2.35 to 0.94; P=0.4] in the XARELTO group).

The mean baseline EQ-VAS score was 52.6 (SD, 21.9). At 12 weeks, the XARELTO group demonstrated an EQ-VAS score of 4.84 points (95% CI, 1.36-8.32; P=0.006) compared with the no-drug group. At 24 weeks, the EQ-VAS scores in the drug groups remained similar to those observed at 12 weeks, but the score in the no-drug group increased to a value comparable to those observed in the drug groups.

Overall, 199 (26%) of 778 patients reported an adverse event, including 70 (36%) of 197 patients in the XARELTO group. The median number of adverse events per patient was 0 (IQR, 0-1) for all patients. Most adverse events were mild or moderate in severity. Minor bleeding or menorrhagia was reported in 26 (13%) patients receiving XARELTO. Ten serious adverse events occurred in 8 (1%) of 778 patients, with 5 serious adverse events reported in 3 (2%) of 197 patients in the XARELTO group. All serious adverse events required hospitalization and were considered unrelated to the study treatment.

META-ANALYSES

Some of the studies evaluating XARELTO use in patients with COVID-19 were terminated early due to lower than expected new COVID-19 cases. Meta-analyses incorporated multiple randomized clinical trials in part to try to overcome the limited enrollment of individual studies.

Shen et al (2024)¹² conducted a meta-analysis of randomized controlled trials that evaluated safety and efficacy of XARELTO in COVID-19 patients. A total of 6 trials (1 single center and 5 multicenter) were included in this analysis (including PREVENT-HD, ACTION, MICHELLE, and CARE trials described above). In these studies, study group received XARELTO while the control group received placebo, enoxaparin, or unfractionated heparin as an anticoagulation regimen. RRs for the outcomes were evaluated. Statistical heterogeneity was calculated using the I² statistic. Significant heterogeneity was present if I² was ≥50%. A random-effects model was used with significant heterogeneity; otherwise, a fixed-effect model was used. Results were as follows:

• Short-term all-cause mortality: Short-term all-cause mortality rates were comparable for both groups. Neither prophylactic (0.92% vs 1.52%; RR, 0.6; 95% CI, 0.3-1.22; P=0.16; I²=0%) nor therapeutic (10.49% vs 6.88%; RR, 1.52; 95% CI, 0.93-2.48; P=0.10; I²=0%) doses significantly reduced short-term all-cause mortality vs control.
• Major bleeding rate (defined by ISTH criteria): Neither prophylactic (fixed-effects model, RR, 3.01; 95% CI, 0.31-28.89; P=0.34; I²=0%) nor therapeutic doses (fixed-effects model, RR, 2.53; 95% CI, 2.86-7.43; P=0.09; I²=0%) of XARELTO significantly increased the major bleeding rate.
• Overall bleeding rate: There was a significant increase in overall bleeding rate for both prophylactic (2.84% vs 0.84%; RR, 3.28; 95% CI, 1.7-6.33; P=0.0004; I²=0%) and therapeutic doses (11.3% vs 3.72%; RR, 3.06; 95% CI, 1.66-5.63; P=0.0003; I²=67%) of XARELTO anticoagulation compared to control.
• Thrombotic events: 4 trials showed that XARELTO significantly reduced thrombotic events at a prophylactic dosage compared to the placebo group (0.31% vs 1.37%; RR, 0.27; 95% CI, 0.08-0.95; P=0.04; I²=17%). No significant difference between patients treated with therapeutic doses vs the control group (6.8% vs 11.2%; RR, 0.38; 95% CI, 0.06-2.31; P=0.29; I²=69%) was found in 2 trials.
• Hospitalization: 3 studies investigated hospitalization rates. There was no significant difference found between the XARELTO group and the control groups, respectively (5.24% vs 4.84%; fixed-effects model, RR, 1.08; 95% CI, 0.76-1.54; P=0.66; I²=0%).

Hsia et al (2024)¹³ conducted a prespecified meta-analysis of 2 randomized placebo-controlled trials (Gates MRI and PREVENT-HD) that evaluated XARELTO 10 mg daily in prehospital patients with COVID-19. Both these trials stopped recruitment ahead of the plan. Totally, these trials randomly allocated 1728 patients with acute COVID-19 to XARELTO 10 mg daily or placebo. Pooled risk differences (RD) were reported for outcomes and between-study heterogeneity was assessed with the I² statistic.

• XARELTO did not reduce the primary endpoint of composite of symptomatic VTE, MI, ischemic stroke, acute limb ischemia, noncentral nervous system systemic embolism, all-cause hospitalization, and all-cause mortality (RD, 0.0044; 95% CI, -0.0263 to 0.0175; P=0.69) or the secondary endpoint of all-cause hospitalization (RD, -0.0036; 95% CI, -0.0271 to 0.0198; P=0.76) compared to placebo. No significant heterogeneity was observed.
• Thrombotic events were infrequent overall and were less frequent with XARELTO compared to placebo (pooled RD, -0.0068; 95% CI, -0.0132 to -0.0006; P=0.03, I²=0%).
• One major bleeding event was observed in a patient treated with XARELTO in PREVENT-HD and none in the Gates MRI study (pooled RD, 0.0013; 95% CI, -0.0028 to 0.0054; P=0.53 vs placebo, I²=0%).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 08 September 2026.