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 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 rivaroxaban (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 rivaroxaban group compared to 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, ICU transfer, thrombosis-related events, and death) and safety (bleeding) outcomes for the XARELTO arm compared to enoxaparin.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 rivaroxaban 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 rivaroxaban group.⁹
• 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.^10,11
• Additional citations identified during a literature search have been included in the REFERENCES section for your review.^12-17

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 once daily (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, noncentral 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 4,000 patients to reach 90% power at a two-sided significance level of 5%, for a 30% reduction (hazard ratio [HR], 0.70) with an anticipated placebo event rate of 10%. 1,284 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=1,197, [XARELTO, n=599] and [placebo, n=598]), the primary efficacy endpoint occurred 12/599 (2.0%) 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 intensive care unit (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 rivaroxaban (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 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 (3.14%) vs the group that did not receive anticoagulation treatment (9.43%) (P=0.0293, relative risk (RR)=0.33 (0.13-0.90), 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 25-75 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 compared to 16 patients (14.2%) in the enoxaparin group (HR, 0.207; 95% CI, 0.069 to 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 to 0.910; P=0.032). Major bleeding including systemic bleeding, non-fatal bleeding leading to fall in hemoglobin (>2 grams per 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

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 plus aspirin for the prevention of disease progression in patients hospitalized with COVID-19 from October 2020 to February 2022. Data specific to XARELTO plus aspirin versus usual care is 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, stoke, 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 plus 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 plus 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 plus aspirin in the prespecified subgroups, except for patients with or without diabetes (P=0.027).

In the safety analysis, bleeding events occurred in 17 (1.6%) patients in the XARELTO plus 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 plus 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 plus 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.

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)¹⁰ 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. Relative risk (RR) of 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=0.60; 95% CI, 0.30-1.22, P=0.16, I²=0%) nor therapeutic doses (10.49% vs 6.88%, RR=1.52; 95% CI, 0.93-2.48, P=0.10, I²=0%) significantly reduced short-term all-cause mortality compared to 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 and the control group (6.80% 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)¹¹ conducted a prespecified meta-analysis of 2 randomized placebo-controlled trials (Gates MRI and PREVENT-HD) that evaluated XARELTO 10mg 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 10mg 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, 0.0175, P=0.69) or the secondary endpoint of all-cause hospitalization (RD: -0.0036; 95% CI, -0.0271, 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, -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, 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 04 October 2024.