XARELTO®: Efficacy profile in stroke risk reduction in nonvalvular atrial fibrillation (NVAF)
ONCE DAILY* 24-HOUR STROKE RISK REDUCTION1,2
*Taken with evening meal.
EFFECTIVELY REDUCED RISK OF STROKE OR SYSTEMIC EMBOLISM IN ROCKET AF
- XARELTO® demonstrated noninferiority versus warfarin, but superiority was not established. There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled
‡Primary efficacy endpoint data are shown for all randomized patients followed to site notification that the study would end (ITT population).
§A 12% RRR in stroke or systemic embolism was observed in patients receiving XARELTO® (n=269) versus warfarin (n=306) (HR [95% CI]: 0.88 [0.74-1.03]), P=0.12. RRR was calculated using 1 minus the HR.
- A superiority analysis was conducted in the safety population during treatment (safety, as-treated population), which included patients who received at least 1 dose of study drug and were followed for events, while they were receiving treatment or within 2 days after discontinuation
- XARELTO® demonstrated noninferiority versus warfarin, but superiority was seen in the safety, as-treated population. There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled
- The conventional method for establishing superiority is in the ITT population using data from all patients who were randomized to treatment, and this analysis did not support the superiority of XARELTO® to warfarin3
llA 21% RRR in stroke or systemic embolism was observed in patients receiving XARELTO® (n=189) versus warfarin (n=243) (HR [95% CI]: 0.79 [0.65-0.95]), P=0.02. RRR was calculated using 1 minus the HR.
Secondary efficacy endpoints in ROCKET AF4
- Consistent results across a composite of stroke, SE, vascular death, with or without MI
EFFICACY SEEN IN PATIENTS AT HIGH RISK: MEAN CHADS2 SCORE = 3.51
CONSISTENT¶ CLINICAL AND REAL-WORLD EFFICACY OUTCOMES—TIME AND TIME AGAIN1,5,6
¶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.
EFFICACY PROFILE IN CLINICAL TRIAL AND REAL-WORLD STUDIES
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 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.
†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.
AE = adverse event; AF = atrial fibrillation; CrCl = creatinine clearance; HR = hazard ratio; ICH = intracranial hemorrhage; INR = international normalized ratio; ISTH = International Society of Thrombosis and Haemostasis; ITT = intent-to-treat; MI = myocardial infarction; NOAC = non-vitamin K antagonist oral anticoagulant; non-CNS SE = non-central nervous system systemic embolism; RRR = relative risk reduction; SAE = serious adverse event; SE = systemic embolism; TIA = transient ischemic attack.