Concomitant Use of XARELTO with Cilostazol

SUMMARY

• Concomitant use of drugs affecting hemostasis increases the risk of bleeding during XARELTO therapy. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.¹
• A disproportionality analysis² and case reports^3,4 describing the concomitant use of XARELTO and cilostazol are summarized below.
• An additional reference identified during a literature search is included in the reference section for your review.⁵

CLINICAL DATA

Sridharan et al (2025)² conducted a disproportionality analysis using frequentist and Bayesian approaches to assess the risk of hemorrhage associated with combinations of antiplatelet and anticoagulant agents, including novel oral anticoagulants, using data from the United States Food and Drug Administration (USFDA) Adverse Event Reporting System (AERS). Data were collected from March 2004 to June 2024, covering 82 quarters.

• Of 29,153,222 reports in the USFDA AERS database, 160,715 were included in the analysis.
• For the combination of XARELTO and cilostazol, the proportion of spontaneously reported hemorrhage cases compared with the reported total adverse events was 0.54.
• The reporting odds ratio for hemorrhage associated with XARELTO and cilostazol was 19.32 (95% confidence interval [CI], 14.22-26.24).
• Signal detection metrics for the XARELTO-cilostazol combination were as follows: relative reporting ratio, 9.4; proportional reporting ratio, 9.4 (95% CI, 8.2-10.9); signal by frequentist approach, 89; Information component (IC025), 2.4; and Empirical Bayes geometric mean (EBGM05), 6.9.
• Reported outcomes for the XARELTO-cilostazol combination included 21 deaths, 6 life-threatening events, and 70 hospitalizations. The χ² test value was 67.2 (df=10; P=0.0001).

Case ReportS

A 74-year-old female with a history of type 2 diabetes mellitus and dyslipidemia experienced recurrent episodes of slurred speech and right-sided facial droop lasting 1 to 2 minutes. She subsequently developed left parietal convexity subarachnoid hemorrhage; 1 month later, she presented with recurrent slurred speech and transient focal neurologic episodes. She was initiated on aspirin 100 mg once daily and XARELTO 10 mg once daily for an unrecalled indication. In the interim, she developed increasing forgetfulness and difficulty managing finances and business activities and was started on a rivastigmine 4.6 mg patch once daily, with noted improvement in cognitive impairment. In May 2025, she presented with left-sided weakness, slurred speech, and left-sided facial droop. Magnetic resonance imaging demonstrated a right frontotemporoparietal hemorrhage with subfalcine herniation and intraventricular extension. She underwent right frontal craniotomy with hematoma evacuation, and tissue biopsy confirmed cerebral amyloid angiopathy. During the same admission, an acute infarct in the left parieto-occipital lobe was identified. Cilostazol 50 mg twice daily was initiated on day 2 post-ictus and increased to 100 mg twice daily at discharge. A repeat computed tomography scan performed 28 days after cilostazol initiation showed no new hemorrhages or hemorrhagic conversion of the previously identified acute infarct in the left parieto-occipital lobe. Seven days after discharge, she experienced an episode of rightward gaze preference with versive head turning to the right and was started on levetiracetam 500 mg twice daily, which was increased to 1 g twice daily. At the 3-month follow-up after the intracerebral hemorrhage event, no new neurologic symptoms or seizures were reported, and the patient was initiated on physical therapy twice weekly.³

An 86-year-old, frail, male patient, with multiple comorbidities, was admitted to the hospital for critical lower limb ischemia. Medical history includes nonvalvular atrial fibrillation, dyslipidemia, chronic obstructive pulmonary disease, megaloblastic anemia, and mild to moderate chronic kidney disease. Examination revealed multiple steno-obstructive lesions, ankle-brachial index of about 0.3-0.35 in both legs, and fibrocalcific atherosclerotic plaques in lower limb arteries. Patient began intravenous heparin and both aspirin 100 mg/day and clopidogrel 75 mg/day. The patient was discharged after 10 days and continued clopidogrel 75 mg/day along with warfarin. After 3 months of therapy, the patient was switched to XARELTO 15 mg/day (creatinine clearance, 15-49 mL/min) and cilostazol at a starting dose of 150 mg/day, which was increased up to 200 mg/day. Limb perfusion was good and there was no major or minor hemorrhagic or thrombotic events after approximately 32 months from start of therapy. The limb was saved and blood count, coagulation, serum creatinine, and liver function were stable. Patient died of acute respiratory insufficiency due to severe pulmonary infection after his last follow-up.⁴

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 19 August 2026.