Summary

• In the safety population of ROCKET AF, the incidence of thrombocytopenia was 0.48% in the warfarin group and 0.30% in the XARELTO group.¹
• In the safety population of EINSTEIN-DVT, the incidence of thrombocytopenia was 0.2% with XARELTO and 0.2% with enoxaparin/vitamin K antagonist (VKA).²
• In the safety population of EINSTEIN-PE, the incidence of thrombocytopenia was 0.1% in the XARELTO group and 0.3% in the enoxaparin/VKA group.³
• Across all four RECORD Studies, the incidence rates of thrombocytopenia were similar in both the XARELTO and enoxaparin treatment groups.^4-7
• In the observational study XAMOS (XArelto^® in the prophylaxis of post-surgical venous thromboembolism after elective Major ORthopaedic Surgery of hip or knee), the incidence of thrombocytopenia was significantly lower in the XARELTO group (0.08%) compared with the standard of care (SOC; 0.23%).⁸
• Several case reports regarding the incidence of thrombocytopenia following the use of XARELTO have been identified.^9-13

PRODUCT LABELING

Adverse Reactions

Post-Marketing Experience¹⁴

The following adverse reactions have been identified during post-approval use of XARELTO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia

CLINICAL STUDIES

A summary of the incidence rates of thrombocytopenia from the ROCKET-AF, EINSTEIN-DVT and EINSTEIN-PE studies are presented in Table: Incidence of Treatment-Emergent Thrombocytopenia (Safety Population) - Summary of ROCKET-AF, EINSTEIN-DVT, and EINSTEIN-PE. No specific information on thrombocytopenia was noted in the EINSTEIN-Extension study publication.¹⁵ The definition of thrombocytopenia was not noted in these publications.

Across all four RECORD studies, thrombocytopenia was defined as a platelet count less than 100 giga/L or less than half of the patients baseline platelet count. The safety population included all patients who had taken at least one dose of study medication, regardless of surgery. The incidence rates of thrombocytopenia were similar in both the XARELTO and enoxaparin treatment groups across all four RECORD studies. A summary of the incidence rates of thrombocytopenia from the RECORD 1-4 studies are presented in Table: Incidence of Thrombocytopenia (Safety Population) in RECORD 1-4.

Study Characteristics

Stroke Prevention in Nonvalvular Atrial Fibrillation

The ROCKET AF trial was a Phase III, randomized, double-blind, double-dummy, active-controlled, parallel-group, multi-center, event-driven, non-inferiority study to evaluate the efficacy and safety of XARELTO 20 mg once daily with the evening meal (15 mg once daily with the evening meal in patients with creatinine clearance [CrCl] 30 to <50 mL/min) to warfarin (titrated to  international normalised ratio [INR] 2.0 to 3.0) for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) at moderate-to-high risk for stroke. The median duration of treatment exposure was 590 days; the median follow-up period was 707 days.¹⁶

Treatment of Deep Vein Thrombosis, Pulmonary Embolism, and Reduction in the Risk of Recurrence

The EINSTEIN program consists of three randomized trials of XARELTO:

1. EINSTEIN-DVT - The Acute DVT Study was a Phase III, randomized, open-label, event-driven, noninferiority trial that compared oral XARELTO alone (15 mg twice daily [BID] for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin (1.0 mg/kg BID) followed by dose-adjusted oral VKA (warfarin or acenocoumarol) in patients with confirmed symptomatic deep vein thrombosis (DVT) without symptomatic pulmonary embolism (PE).¹⁵
2. EINSTEIN-PE - The Acute PE Study was a Phase III, randomized, open-label, event-driven, noninferiority study evaluating the efficacy and safety of oral XARELTO (15 mg BID for 3 weeks followed by 20 mg once daily) versus subcutaneous enoxaparin (1.0 mg/kg BID) followed by dose-adjusted oral VKA in patients with acute symptomatic PE with or without DVT.¹⁷
3. EINSTEIN-Extension - For the continued treatment in patients who have received treatment for either acute DVT or PE. The Continued Treatment Study was a Phase III, randomized, double-blind, event-driven superiority study comparing XARELTO 20 mg once daily to placebo in patients with confirmed symptomatic PE or DVT who have been treated for 6 to 12 months with XARELTO or VKA.¹⁵ No specific information on thrombocytopenia was noted in this publication.

Prophylaxis of DVT Following Hip or Knee Replacement Surgery

As part of the Phase III RECORD clinical trial program, four randomized, double-blind, double-dummy, multi-national studies (RECORD1, RECORD2, RECORD3, and RECORD4)^18-21 compared efficacy and safety between oral XARELTO 10 mg once daily and subcutaneous enoxaparin 40 mg once daily (RECORD1-3) or 30 mg BID (RECORD4) for prevention of venous thromboembolism (VTE) in patients undergoing elective total hip replacement (THR, RECORD1-2) or total knee replacement (TKR, RECORD3-4).

• In both RECORD1 and 2, patients undergoing THR were given XARELTO for 35 ± 4 days. In RECORD3 and 4, patients undergoing TKR were given XARELTO for 12 ± 2 days. Enoxaparin was given for 13 ± 2 days in RECORD3 or 12 ± 2 days in RECORD4. All patients were followed up for 30–35 days after the last dose of study medication.

<The RECORD clinical development program, a comprehensive program of 4 phase III studies with over 12,000 patients, studied XARELTO^® (XARELTO tablets) for the prophylaxis of venous thromboembolism (VTE) in patients undergoing knee (RECORD 3 and 4) or hip (RECORD 1 and 2) replacement surgery. The data from the RECORD program were submitted to the FDA. XARELTO^® was approved on July 1, 2011 by the FDA for the indication studied in the RECORD program.

In the RECORD 4 study, patients received either oral XARELTO 10 mg once daily, beginning at least 6–8 h after surgery, or subcutaneous enoxaparin 30 mg every 12 hours, starting 12–24 hours after surgery. Data from RECORD 4 are not included in the approved product labeling for XARELTO^®.

Since publication of RECORD 4 findings, the sponsor company conducted a verification of the data for all patients in this clinical trial. With respect to study findings, additional adverse events/serious adverse events were identified; however, the distribution of those was balanced between study groups. In the company’s view, verification findings did not appreciably change the conclusions of the study. Thus, the RECORD 4 findings reported in the publication remain consistent with the overall results from the total RECORD program.>

Acute Coronary Syndrome

ATLAS-ACS TIMI-51²² was a randomized, multi-center, double-blind, event-driven trial to determine whether XARELTO (2.5 mg BID or 5 mg BID), when added to SOC, was safe and reduced the risk of the composite of cardiovascular death, MI, or stroke in patients with acute coronary syndrome (ACS) compared with placebo. Standard medical therapy included low dose aspirin. Patients were stratified by the investigator’s intention to administer thienopyridine (clopidogrel or ticlopidine) or not at the time of enrollment. The mean duration of treatment with the study medication was 13.1 months.

• No specific information on thrombocytopenia was noted in this publication.

Prevention of VTE in Medically Ill Patients Requiring Hospitalization

MAGELLAN²³ trial was a phase 3 international, randomized, double-blind, active-comparator-controlled study to evaluate the efficacy and safety of once-daily oral XARELTO, compared to standard-duration once-daily subcutaneous enoxaparin, and to evaluate the role of extended-duration XARELTO (up to 39 days) for the prevention of VTE in acutely ill medical patients who required hospitalization.

• No specific information on thrombocytopenia was noted in this publication.

The MARINER^24,25 study was a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven study that evaluated the efficacy and safety of XARELTO 10 mg once daily (7.5 mg once daily if CrCl ≥30 to <50 mL/min) compared with placebo in the prevention of symptomatic VTE and VTE-related death after hospital discharge in high-risk, medically ill patients for a period of 45 days posthospital discharge.

• No specific information on thrombocytopenia was noted in this publication.

OBSERVATIONAL STUDIES

The XAMOS trial was an international, observational, open-label study that assessed the efficacy and safety of XARELTO in daily clinical practice for prophylaxis of VTE in patients after elective THR or TKR.⁸

• 17,701 patients were randomized to receive XARELTO (N=8844) or SOC (N=8745). The SOC included low molecular weight heparins (LMWHs), unfractionated heparins, fondaparinux, dabigatran etexilate, acetylsalicylic acid, and VKA. Most patients received LMWHs (81.7%).
• Bleeding and other adverse events were considered treatment-emergent if the event started on or after the day of the first dose and up to 2 days after the last dose of a VTE prophylactic drug. Serious adverse events were followed until a final outcome was obtained.
• The incidence of thrombocytopenia was significantly lower in the XARELTO group (0.08%; n=7) compared with the SOC or LMWH group (0.23%; n=20); (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.15-0.81).⁸

CASE REPORTS

Mima et al (2015)⁹ reported a case involving a 75-year-old male patient who developed acute thrombocytopenia after treatment with XARELTO for paroxysmal AF.

• Due to complications with warfarin, the patient was transitioned to XARELTO 10 mg daily via nasogastric tube.
• The platelet count rapidly decreased from 16.8x10⁴/mcL at baseline to 7.3x10⁴/mcL 2 days after initiation of XARELTO therapy. Lansoprazole and XARELTO were the only recently added agents and both were discontinued.
• The platelet count increased to 16.4x10⁴/mcL after 11 days. Lansoprazole was believed to be the offensive agent and therefore XARELTO was restarted.
• Five days later the platelet count decreased to 5.2x10⁴/mcL. XARELTO therapy was discontinued, and the platelet count rapidly improved.
• Patient was restarted on warfarin on day 198 with dose adjustments and transferred for rehabilitation. No further complications were reported.

Pop et al (2018)¹⁰ reported a case of a 66-year-old male patient who developed acute onset of thrombotic lesions and idiopathic thrombocytopenia purpura after starting treatment with XARELTO and flecainide 4 months prior for AF.

• The patient presented to the emergency department with a skin rash and light-headedness after losing consciousness at a cardiovascular visit earlier in the day.
• The patient’s significant laboratory values included a platelet count of 1x10³/mcL, red blood count of 4.05x10⁶/mcL, hemoglobin of 12.1 g/dL, and a hematocrit of 35.6%.
• XARELTO and flecainide were discontinued, and aggressive hydration was initiated in addition to transfusing 1 unit of platelets.
• Immune globulin was started 24 hours after admission for 3 consecutive days at 75 g with steroids.
• After 6 days the patient was discharged with a platelet count of 119X10³/mcL.

Iliev et al (2020)¹¹ reported a case of an 81-year-old female who developed an intraparenchymal hemorrhage in the left hemisphere of her brain following oral anticoagulant transition to XARELTO (20 mg/day) therapy 20 months prior for AF.

Tığlıoğlu et al (2020)¹² reported a case of a 76-year-old female who developed suspected drug-induced thrombocytopenia following a transition to XARELTO (20 mg/day) from warfarin 12 days prior due to irregular INR and gastrointestinal bleeding. Thrombocytopenia was expected to be drug-induced after other possible etiologies for coagulation abnormalities and thrombocytopenia were excluded.

He et al (2020)¹³ reported a case of a 70-year-old male who developed suspected drug-induced thrombocytopenia after being switched from warfarin to XARELTO 10 mg/day.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 23 October 2024.