Rivaroxaban for Stroke Prevention in Atrial Fibrillation

A Critical Review of the ROCKET AF Trial

Jeremy S Paikin; Joshua J Manolakos; John W Eikelboom

Expert Rev Cardiovasc Ther. 2012;10(8):965-972.

ROCKET AF Trial Design

The ROCKET AF study was a blinded, double-dummy, randomized-controlled trial in which 14,262 patients with nonvalvular AF at increased risk for stroke were assigned to rivaroxaban 20 mg daily (or 15 mg daily in those with creatinine clearance [CrCl] 30–49 ml/min) or dose-adjusted warfarin (target INR: 2–3).

Objective

The main objective of the ROCKET AF trial was to demonstrate noninferiority of rivaroxaban compared with warfarin for the prevention of stroke or systemic embolism in patients with AF.

Patients

The ROCKET AF trial recruited patients from 1178 centers in 45 countries. Patients were eligible for inclusion if they had electrocardiographic evidence of AF within 30 days prior to randomization and either a history of stroke/transient ischemic attack (TIA) or systemic embolism or at least two of the following additional risk factors for stroke: heart failure or a left ventricular ejection fraction of 35% or less, hypertension, age ≥75 years or the presence of diabetes mellitus. By excluding AF patients without a previous stroke/TIA or systemic embolism who did not have at least two other risk factors for stroke, and by limiting inclusion of patients with two other stroke risk factors to 10% of the cohort at each site (other patients without a history of stroke/TIA or systemic embolism had to have at least three risk factors), the ROCKET AF trial included a patient population at higher risk of stroke than those included in other new oral anticoagulant trials in AF.^[6,7] A higher risk population increases study power but is less representative of the broader AF population that is expected to benefit from anticoagulant treatment.

The types of patients excluded from participation in the ROCKET AF trial were those at increased risk of bleeding (e.g., disabling stroke within 3 months or any stroke within 14 days of randomization, active bleeding, CrCl <30 ml/min, taking aspirin at doses exceeding 100 mg/day or dual antiplatelet therapy), those with another indication for anticoagulant therapy (e.g., prosthetic heart valve) and patients receiving treatment or potentially eligible for treatment with drugs that may interact with rivaroxaban (e.g., patients with HIV infection).

Interventions

The rivaroxaban dosing regimen evaluated in the ROCKET AF trial was selected on the basis of results of Phase II dose-finding studies in VTE treatment, which showed that long-term treatment with q.d. and b.i.d. rivaroxaban doses in the range of 20–60 mg/day, were associated with similar efficacy and a dose-dependent effect on bleeding. Thus the lowest effective dose of rivaroxaban (20 mg daily) was chosen for evaluation in the ROCKET AF trial.^[16] Unlike the RE-LY trial that used an open design,^[6] the ROCKET AF study employed a blinded design to reduce the potential for differential use of cointerventions based on the knowledge of treatment allocation and for biased ascertainment and reporting of outcomes. To preserve the integrity of the blinding, investigators used a point-of-care device to generate encrypted INR values, either real or sham depending on the treatment to which the patients were assigned.

Outcomes

The primary efficacy outcome was the composite of stroke and systemic embolism. Stroke was defined as an acute, focal neurologic deficit of presumed cerebrovascular etiology that persisted beyond 24 h. If the deficit lasted for less than 24 h, it was defined as a TIA. Brain imaging was encouraged for all suspected strokes and was performed in 82.1% of patients reported to have had a stroke. Systemic embolism was defined as acute vascular insufficiency associated with clinical or radiographic evidence of arterial occlusion (not associated with another likely cause). The primary safety outcome was the composite of major and clinically relevant nonmajor bleeding. Major bleeding was defined as clinically overt bleeding associated with any of the following: fatal outcome, involvement of a critical anatomic site (intracranial, spinal, ocular, pericardial, articular, retroperitoneal or intramuscular with compartment syndrome), fall in hemoglobin concentration ≥2 g/dl, transfusion of ≥2 units of whole blood or packed red cells, or permanent disability. Critically relevant nonmajor bleeding was defined as bleeding that did not meet the criteria for major bleeding, but necessitated medical treatment, unplanned medical attention or temporary interruption of the study drug. The protocol specified the need for follow-up visits at 1, 2 and 4 weeks then monthly thereafter for INR measurement and surveillance of primary safety and efficacy outcomes.

Statistics

The primary statistical analysis employed a Cox model using treatment as a covariate. The noninferiority margin of 1.46 for the primary outcome was derived from a meta-analysis by Hart et al. of studies comparing VKA with placebo/non-VKA control for stroke prevention in AF,^[2] and was selected with the intent of preserving at least 50% of the benefit of VKAs for stroke prevention. Based on expected event rates of 2.3% per 100 patient years in patients treated with warfarin and a warfarin drop-out rate of 14% per year, it was estimated that 14,000 patients would be needed to have 95% power to demonstrate noninferiority.

Analytic Approach

The protocol specified that the primary analysis for the noninferiority of rivaroxaban as compared with warfarin for the prevention of stroke or systemic embolism would be tested using a per-protocol analysis. The per-protocol population was defined as all patients who received at least one dose of a study drug, did not have a major protocol violation (e.g., permanent discontinuation of randomly assigned treatment prior to a primary outcome event) and were followed for events while receiving a study drug or within 2 days after discontinuation. If noninferiority was met, the protocol specified that the superiority would also be tested in the same per-protocol population, but also including patients who had a major protocol violation (this is described as the safety population). Bleeding outcomes and other efficacy outcomes were also analyzed using the safety population. Secondary analyses for noninferiority and superiority were performed in the intention-to-treat (ITT) population, which included all patients who underwent randomization and were followed for events to the end of the study irrespective of whether they continued on study treatment.

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Abstract and Introduction
Pharmacology of Rivaroxaban & Mechanism of Action
ROCKET AF Trial Design
Results
Expert Commentary
US FDA Approval
Five-year View
References
Sidebar

Table 1. Comparison of drug characteristics of rivaroxaban and vitamin antagonists.
Feature	Rivaroxaban	Vitamin K antagonists
Target	Factor Xa	Vitamin K epoxide reductase
Half-life (h)	5–13	72–96
Metabolism	CYP3A4, CYP2C8 and P-gp	CYP2C9
Route of elimination	66% renal^†, 33% biliary	Biliary
Drug interactions	Potent inhibitors of CYP3A4 and P-gp^‡	Antibiotics, antifungals, anticonvulsants, SSRIs and antiarrythmics
Routine coagulation monitoring	None	INR

†Half of renally-cleared rivaroxaban is cleared as unchanged drug and half as inactive metabolites.
‡Potent inhibitors of both CYP3A4 and P-gp include azole antifungals (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and protease inhibitors (e.g., atanazavir).
INR: International normalized ratio; P-gp: P-glycoprotein; SSRI: Selective serotonin inhibitor.
Adapted with permission from [9,21].

Table 2. Stroke or systemic embolism in the rivaroxaban group compared with the warfarin group.
Study population	Rivaroxaban			Warfarin			Hazard ratio	p-value
Study population	Patients (n)	Events (n)	Event rate (number per 100 patient years)	Patients (n)	Events (n)	Event rate (number per 100 patient years)	Rivaroxaban vs warfarin (95% CI)	Noninferiority	Superiority
Per-protocol population	6958	188	1.7	7004	241	2.2	0.79 (0.66–0.96)	<0.001
Intention-totreat population	7081	269	2.1	7090	306	2.4	0.88 (0.75–1.03)	<0.001	0.12

Adapted with permission from [8].

Table 3. ROCKET AF: bleeding outcomes in rivaroxaban group compared with the warfarin group.
Events	Rivaroxaban (number per 100 patient years)	Warfarin (number per 100 patient years)	Rivaroxaban versus warfarin hazard ratio (95% CI)
Primary safety outcome: major and nonmajor clinically relevant bleeding	14.9	14.5	1.03 (0.96–1.11); p = 0.44
Major bleeding	3.6	3.4	1.04 (0.90–1.20); p = 0.58
Decrease in hemoglobin ≥2 g/dl	2.8	2.3	1.22 (1.03–1.44); p = 0.02
Major GI bleeding	3.2	2.2	p < 0.001^†
Transfusion	1.6	1.3	1.25 (1.01–1.55); p = 0.04
Critical bleeding^‡	0.8	1.2	0.69 (0.53–0.91); p = 0.007
Intracranial bleeding	0.5	0.7	0.67 (0.47–0.93); p = 0.02
Fatal bleeding	0.2	0.5	0.50 (0.31–0.79); p = 0.003

All analyses of rates of bleeding were based on the time to first event in the safety population.
†Hazard ratio not reported.
‡Bleeding events were considered critical if they occurred in intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular (with compartment syndrome) or retroperitoneal sites.
GI: Gastrointestinal.
Adapted with permission from [8].

Table 4. ROCKET AF trial: stroke or systemic embolism rates according to quartiles of center time-in-therapeutic range for warfarin.
TTR (%)	Rivaroxaban event rate (number per 100 patient years)	Warfarin event rate (number per 100 patient years)	Rivaroxaban versus warfarin hazard ratio (95% CI)
≤50.71	1.77	2.53	0.70 (0.48–1.03)
50.89–58.44	1.94	2.18	0.89 (0.62–1.29)
58.46–65.66	1.90	2.14	0.89 (0.62–1.28)
≥65.71	1.33	1.80	0.74 (0.49–1.12)
p-value^†			0.736

Analyses are based on time to first event for the safety population; n = 7061 for the rivaroxaban group and n = 7082 for the warfarin group.
†p-values are for interaction between center-based TTR and treatment.
TTR: Time in therapeutic range (international normalized ratio 2.0–3.0 inclusive).
Adapted with permission from [17].

Table 5. ROCKET AF trial: bleeding rates according to quartiles of center time-in-therapeutic range for warfarin.
TTR (%)	Rivaroxaban vs warfarin
TTR (%)	Major or clinically relevant nonmajor bleeding, hazard ratio (95% CI)	Major bleeding, hazard ratio (95% CI)	Intracranial hemorrhage, hazard ratio (95% CI)
≤50.71	0.81 (0.69–0.96)	0.75 (0.54–1.04)	0.79 (0.38–1.63)
50.89–58.44	0.96 (0.81–1.12)	1.01 (0.74–1.37)	0.63 (0.32–1.24)
58.46–65.66	1.02 (0.88–1.18)	1.03 (0.78–1.34)	0.79 (0.42–1.48)
≥65.71	1.23 (1.08–1.40)	1.30 (1.01–1.66)	0.50 (0.25–1.03)
p-value^†	<0.001	0.073	0.778

Analyses are based on time to first event for the safety population; n = 7111 for the rivaroxaban group and n = 7125 for the warfarin group.
†p-values are for interaction between center-based TTR and treatment.
TTR: Time in therapeutic range (international normalized ratio 2.0–3.0).
Adapted with permission from [17].

Table 6. ROCKET AF: efficacy and safety outcomes according to renal function.
Outcome	CrCl 30–49 ml/min			CrCl ≥50 ml/min			p-value for interaction
Outcome	Rivaroxaban 15 mg (n = 1474), number per 100 patient years	Warfarin (n = 1476), number per 100 patient years	Rivaroxaban vs warfarin hazard ratio (95% CI)	Rivaroxaban 20 mg (n = 5637), number per 100 patient years	Warfarin (n = 5640), number per 100 patient years	Rivaroxaban vs warfarin hazard ratio (95% CI)	p-value for interaction
Stroke or systemic embolism	2.32	2.77	0.84 (0.57–1.23)	1.57	2.00	0.78 (0.63–0.98)	0.76
Major or clinically relevant nonmajor bleeding	17.82	18.28	0.98 (0.84–1.14)	14.24	13.67	1.04 (0.96–1.13)	0.45