XARELTO®: Efficacy profile in stroke risk reduction in patients with nonvalvular atrial fibrillation (NVAF)

PROVEN ONCE-DAILY,*
24-HOUR STROKE RISK REDUCTION1,2

PROVEN ONCE-DAILY,*
24-HOUR STROKE RISK REDUCTION1,2

*Taken with evening meal.

Effectively reduced risk of stroke/SE in ROCKET AF versus warfarin1

ITT population

ITT population

(n=14,171)

NVAF Efficacy 1

  • Stroke or SE event rates per 100 patient-years were 2.4 in patients taking warfarin and 2.1 in patients taking XARELTO®1
  • 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 SE when warfarin therapy is well controlled1

†Superiority was achieved in the safety, as-treated population in a secondary analysis of patients taking at least 1 dose of XARELTO®. The ITT population demonstrated noninferiority.

‡A 12% RRR in stroke or SE was observed in patients receiving XARELTO® (n=269) versus warfarin (n=306), HR = 0.88 (95% CI: 0.74-1.03), P<0.001. RRR was calculated using 1 minus the HR.

§Not statistically significant.

ITT population

(n=14,171)

NVAF Efficacy 1

  • Stroke or SE event rates per 100 patient-years were 2.4 in patients taking warfarin and 2.1 in patients taking XARELTO®1
  • 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 SE when warfarin therapy is well controlled1

†Superiority was achieved in the safety, as-treated population in a secondary analysis of patients taking at least 1 dose of XARELTO®. The ITT population demonstrated noninferiority.

‡A 12% RRR in stroke or SE was observed in patients receiving XARELTO® (n=269) versus warfarin (n=306), HR = 0.88 (95% CI: 0.74-1.03), P<0.001. RRR was calculated using 1 minus the HR.

§Not statistically significant.

Safety, as-treated population (patients taking ≥1 dose)

Safety, as-treated population (patients taking ≥1 dose)

(n=14,143)

NVAF Efficacy 2

  • Stroke or SE event rates per 100 patient-years were 2.2 in patients taking warfarin and 1.7 in patients taking XARELTO®1
  • 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 discontinuation1
  • 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 SE when warfarin therapy is well controlled1
  • 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

†Superiority was achieved in the safety, as-treated population in a secondary analysis of patients taking at least 1 dose of XARELTO®. The ITT population demonstrated noninferiority.

||A 21% RRR in stroke or SE was observed in patients receiving XARELTO® (n=189) versus warfarin (n=243), HR = 0.79 (95% CI: 0.65-0.95), P=0.02. RRR was calculated using 1 minus the HR.

Safety, as-treated population (patients taking ≥1 dose)

(n=14,143)

NVAF Efficacy 2

  • Stroke or SE event rates per 100 patient-years were 2.2 in patients taking warfarin and 1.7 in patients taking XARELTO®1
  • 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 discontinuation1
  • 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 SE when warfarin therapy is well controlled1
  • 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

†Superiority was achieved in the safety, as-treated population in a secondary analysis of patients taking at least 1 dose of XARELTO®. The ITT population demonstrated noninferiority.

||A 21% RRR in stroke or SE was observed in patients receiving XARELTO® (n=189) versus warfarin (n=243), HR = 0.79 (95% CI: 0.65-0.95), P=0.02. RRR was calculated using 1 minus the HR.

Lower rates of stroke/SE in patients with NVAF who have obesity versus patients with normal weight4

A ROCKET AF subgroup analysis of patients with obesity versus patients with normal weight (n=8495)

NVAF Efficacy 3
  • Stroke and SE event rates per 100 patient-years were 2.93 in the normal weight group (166 events in 3,289 patients), and 1.88 in the obese group (179 events in 5,206 patients)4

37% of patients in the ROCKET AF trial had obesity and 13% had a BMI >35 kg/m2. These patients had a mean CHADS2 score of 3.5 and a median age of 70 years4,5

REAL-WORLD EVIDENCE STUDY IN NVAF PATIENTS WITH MORBID OBESITY (N=7126)**6

XARELTO® graphic highlighting comparable risk reduction in cases of NVAF and morbid obesity in the largest RWE evidence study
  • The composite risk of ischemic stroke/SE was 1.7 (59/3563) in patients taking warfarin and 1.5 (52/3563) in patients taking XARELTO®

ROCKET AF1

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 moderate renal impairment defined as 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.

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

ROCKET AF Post Hoc Obesity Analysis4

Study design: Post hoc analysis of the ROCKET AF trial where patients were grouped according to
BMI: 18.50 kg/m2 to 24.99 kg/m2 (n=3289); 25.00 kg/m2 to 29.99 kg/m2 (n=5535); ≥30 kg/m2 (n=5206).

Study endpoints: The primary efficacy endpoint was the composite of stroke and SE. Secondary efficacy endpoints were stroke and ischemic stroke. The principal safety endpoint was the composite of major and nonmajor clinically relevant bleeding events.

NVAF and Morbid Obesity Real-World Study6

Study design: Retrospective cohort study using data from the Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental databases from December 1, 2010, through December 31, 2016. Patients were identified who were initiated on XARELTO® or warfarin (first pharmacy claim date was the index date), who had ≥1 medical claim with an AF diagnosis during the past 12 months prior to or on the index date, and ≥1 medical claim for morbid obesity. Patients were required to have continuous enrollment 12 months before index date and at least 3 months after treatment initiation. Patients receiving XARELTO® or warfarin were 1:1 propensity score matched.

Study endpoints: The primary outcome was the composite risk of ischemic stroke and SE. Secondary outcomes included major bleeding risk.

Obesity was defined as BMI ≥30 kg/m2.

#RRR calculated using 1 minus the HR.

**Patients were identified using ICD diagnosis codes for morbid obesity and BMI ≥40 kg/m2.

AF = atrial fibrillation; ARR = absolute risk reduction; BMI = body mass index; CrCl = creatinine clearance; DOAC = direct oral anticoagulant; ICD = International Classification of Disease; INR = international normalized ratio; ITT = intent-to-treat; OR = odds ratio; RRR = relative risk reduction; SE = systemic embolism.

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References: 1. Patel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. 2. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78(4):412-421. 3. Lesaffre E. Superiority, equivalence, and non-inferiority trials. Bull NYU Hosp Jt Dis. 2008;66(2):150-154. 4. Balla SR, Cyr DD, Lokhnygina Y, et al. Relation of risk of stroke in patients with atrial fibrillation to body mass index (from patients treated with rivaroxaban and warfarin in the rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation trial). Am J Cardiol. 2017;119(12):1989-1996. 5. Data on file. Janssen Pharmaceuticals, Inc. Based on the ROCKET AF Clinical Study Reports. 6. Peterson ED, Ashton V, Chen Y-W, Wu B, Spyropoulos AC. Comparative effectiveness, safety, and costs of rivaroxaban and warfarin among morbidly obese patients with atrial fibrillation. Am Heart J. 2019;212:113-119.