XARELTO®: Clinical trial and real-world evidence in stroke risk reduction in nonvalvular atrial fibrillation (NVAF)
HOW MUCH EFFICACY AND SAFETY EVIDENCE SUPPORTS YOUR FIRST-CHOICE NOAC?
XARELTO®—EXTENSIVELY STUDIED IN CLINICAL TRIAL AND THE REAL WORLD IN PATIENTS AT RISK‡1, 3-6
PUBLISHED OUTCOMES WITH XARELTO® IN MORE THAN 176,000 REAL-WORLD PATIENTS WITH NVAF§3-5, 7-18
ONLY XARELTO® was proven in patients with a mean CHADS2 score of 3.5—ROCKET AF
- CHADS2 was used in the pivotal trial to determine stroke risk and is calculated based on the risk factors of CHF, hypertension, aged ≥75 years, diabetes mellitus, prior stroke, or TIA. ACC/AHA guidelines now recommend use of CHA2DS2-VASc19
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.
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-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) with a CHA2DS2-VASc score of ≥2 and ≥180 days of continuous medical and prescription benefits. Patients with a prior stroke, SE, or ICH were excluded. Rivaroxaban and apixaban users were 1:1 propensity score matched individually to warfarin users.
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. Since MarketScan data were only available through October 2014, apixaban analyses may have been underpowered. Additional analyses should be performed once sample sizes in claims databases grow larger.
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.
*Taken with evening meal.
†Patients were considered at an increased risk for stroke if they had a higher CHADS2 score (range 1-6). Patients in ROCKET AF had a mean CHADS2 score of 3.5.
‡Not an all-inclusive list of real-world studies.
§Based on the following registries, claims databases, and studies: Optum Labs (1) = 5434; IMS Health LifeLink = 1649; Truven Health = 5563; Danish nationwide administrative registries = 1303; Symphony = 3654; Japanese registry = 1035; Dresden NOAC = 1200; DoD database = 44,793; XANTUS = 6784; RELIEF = 1039; REVISIT-US = 11,411; Optum Labs (2) = 16,175; Danish national prescription registry = 5693; Medicare database = 66,651; Nielsen Reduced Dose = 3476.
AE = adverse event; AF = atrial fibrillation; CrCl = creatinine clearance; DoD = Department of Defense; ICH = intracranial hemorrhage; INR = international normalized ratio; ISTH = International Society on Thrombosis and Haemostasis; MI = myocardial infaraction; 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.