XARELTO®: Safety profile in stroke risk reduction in nonvalvular atrial fibrillation (NVAF)

DEMONSTRATED SAFETY PROFILE WITH XARELTO®1,2

BLEEDING EVENTS (ON TREATMENT PLUS 2 DAYS) IN ROCKET AF*

  • Lower rates of most concerning bleeds: Fatal and ICH1
  • Higher rate of GI bleeds with XARELTO® versus warfarin1
    • No difference in fatal GI bleeds versus warfarin2

CONSISTENT# CLINICAL AND REAL-WORLD SAFETY OUTCOMES—TIME AND TIME AGAIN1,3-5

#Results are not intended for direct comparison with clinical trials because the real-world studies were observational trials with no comparator arm. Differences in study designs, patient populations, definitions of safety or efficacy outcomes, as well as data collection methods, make it difficult to make direct comparisons either with clinical trials or with each other.

MAJOR BLEEDING PROFILE IN CLINICAL TRIALS AND REAL-WORLD STUDIES1,3-5

GI BLEEDING PROFILE IN CLINICAL TRIALS AND REAL-WORLD STUDIES1,3-5

LESS THAN 1% OF PATIENTS EXPERIENCED ICH IN CLINICAL TRIALS AND REAL-WORLD STUDIES1,3-6

LESS THAN 1% OF PATIENTS EXPERIENCED FATAL BLEEDING IN CLINICAL TRIALS AND REAL-WORLD STUDIES1,3-5

ROCKET AF1

ROCKET AF trial design: A randomized, phase 3, multicenter, active-controlled, double-blind, double-dummy, event-driven study. Patients received XARELTO® 20 mg once daily (15 mg once daily in patients with CrCl 30 mL/min to 49 mL/min [n=7131]) or dose-adjusted warfarin (n=7133) titrated to an INR range of 2.0 to 3.0.

ROCKET AF: Primary efficacy endpoint was stroke (ischemic or hemorrhagic) and SE. The principal safety endpoint was a combination of major bleeding and nonmajor clinically relevant bleeding events.

PMSS3

PMSS study design: FDA-required, retrospective, observational study, with results based on 2.5 years of data from an ongoing, 5-year PMSS study to evaluate major bleeding with XARELTO® (n=44,793) in a real-world clinical setting through electronic medical records from the DoD database between 1/1/13 and 6/30/15.

PMSS Primary endpoint: Major bleeding as defined by the Cunningham algorithm.

Limitations: This was a retrospective study, and there was no comparator arm in the trial. This study used a claims-based definition of major bleeding.

XANTUS5

XANTUS study design: International, noninterventional, observational study investigated safety and efficacy in a real-world clinical setting through 311 clinical centers in Europe, Israel, and Canada. Consecutive consenting patients with NVAF newly started on XARELTO® (n=6784) were eligible and were followed up at 3-month intervals for 1 year or for at least 30 days after permanent discontinuation.

XANTUS: Primary outcomes included major bleeding events (defined using ISTH criteria), all-cause death, and any other AEs and SAEs. Secondary outcomes included symptomatic thromboembolic events (stroke, non-CNS SE, TIA, and MI) and nonmajor bleeding events.

Limitations: This was a single-arm, open-label study, and there was no comparator arm in the trial. Selection biases may have occurred because of patient self-selection participation or investigator selection around intact cognitive function. Outcomes per rivaroxaban dose were not adjusted for baseline risk factors.

REVISIT-US6

REVISIT-US study design: Retrospective study using US Truven MarketScan claims from January 2012 to October 2014 of newly initiated patients taking rivaroxaban (n=11,411), apixaban (n=4083), or warfarin (n=15,494) and 180 days of continuous medical and prescription benefits. Patients with a prior stroke, SE, or ICH were excluded.

REVISIT-US: Primary endpoint was the combination of ischemic stroke or ICH. Each component of this endpoint was also evaluated separately.

Limitations: The analysis excluded patients with prior stroke, SE, or ICH, which may have contributed to the low number of events. Propensity-score matching generated cohorts that were comparable in key characteristics; only those variables measured in US Truven MarketScan could be matched upon, and residual confounding cannot be excluded. Also, it was not possible to determine the duration of time warfarin users spent in the therapeutic INR range of 2.0 to 3.0. The US Truven MarketScan database does not allow reporting of lab (serum creatinine) and clinical data (body weight), which are required to determine whether rivaroxaban was consistent with labeling.

*Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment (on-treatment period).

Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.

Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid, and/or epidural hematoma.

§Hemorrhagic stroke in this table specifically refers to nontraumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days.

ǁGl bleeding events included upper GI, lower GI, and rectal bleeding.

Fatal bleeding is adjudicated death with the primary cause of death from bleeding.

**Major bleeding in ROCKET AF was defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome (ISTH criteria).

††The primary endpoint was major bleeding. A validated computer database algorithm developed by Cunningham et al, which identifies bleeding-related hospitalizations from a primary discharge diagnosis, was used to identify major bleeding events in this study. The definition of major bleeding is not an exact match with the ROCKET AF trial.

‡‡The primary outcomes included major bleeding events (defined using ISTH criteria), all-cause death, and any other AEs and SAEs. Secondary outcomes included symptomatic thromboembolic events (stroke, non-CNS SE, TIA, and MI) and nonmajor bleeding events. Major bleeding was defined using the ISTH criteria, which are the same criteria as in the ROCKET AF trial.

AE = adverse event; AF = atrial fibrillation; CrCl = creatinine clearance; DoD = Department of Defense; GI = gastrointestinal; HR = hazard ratio; ICH = intracranial hemorrhage; INR = international normalized ratio; ISTH = International Society of Thrombosis and Haemostasis; MI = myocardial infarction; N/A = not available; NOAC = non-vitamin K antagonist oral anticoagulant; non-CNS SE = non-central nervous system systemic embolism; PMSS = post-marketing safety surveillance; SAE = serious adverse event; SE = systemic embolism; TIA = transient ischemic attack.