Practical guidance for using rivaroxaban in patients with atrial fibrillation: balancing benefit and risk

Figures & data

Table 1 Pharmacological properties of rivaroxaban, apixaban, and dabigatran etexilate

	Rivaroxaban	Apixaban	Dabigatran etexilate
Target enzyme	Factor Xa	Factor Xa	Thrombin
Prodrug	No	No	Yes
Oral bioavailability (%)	80–100	~50	6–7
Tmax, median (h)	2–4	3–4	0.5–2.0
T½ (h)	5–13	8–15	12–14
Route of elimination	Renal: 66% (36% as unchanged drug) Hepatobiliary: 28%^Citation25	Renal: ~27% Hepatobiliary: ~75%	Renal: 80% Hepatobiliary: 20%
Metabolism	CYP3A4, CYP2J2, and CYP-independent mechanisms; substrate for transporter P-gp	CYP3A4 mainly; substrate for transporter P-gp	Substrate for transporter P-gp

Note: Data from Bayer Pharma AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb/Pfizer EEIG.^1,53,54

Abbreviations: CYP, cytochrome P450; P-gp, P-glycoprotein; T_½, half-life.

Table 2 Summary of key findings from the Phase III ROCKET AF trial of rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation

	Event rate (number/100 patient-years)		Hazard ratio (95% CI)	P-value
	Rivaroxaban	Warfarin
Stroke or systemic embolism (per-protocol population)a	1.7	2.2	0.79 (0.66–0.96)	P<0.001 (noninferiority)
Stroke or systemic embolism (on-treatment, safety population)b	1.7	2.2	0.79 (0.65–0.95)	P=0.02 (superiority)
Ischemic stroke	1.34	1.42	0.94 (0.75–1.17)	P=0.581 (superiority)
Hemorrhagic stroke	0.26	0.44	0.59 (0.37–0.93)	P=0.024 (superiority)
Stroke or systemic embolism (ITT population)c	2.1	2.4	0.88 (0.74–1.03)	P<0.001 (noninferiority) P=0.12 (superiority)
During treatment	1.7	2.2	0.79 (0.66–0.96)	P=0.02 (superiority)
Principal safety end point: major and nonmajor clinically relevant bleeding eventsd	14.9	14.5	1.03 (0.96–1.11)	P=0.44
Major bleeding eventd	3.6	3.4	1.04 (0.90–1.20)	P=0.58
Critical bleeding	0.8	1.2	0.69 (0.53–0.91)	P=0.007
Fatal bleeding	0.2	0.5	0.50 (0.31–0.79)	P=0.003
Gastrointestinal bleeding	3.2	2.2	NR	P<0.001
Decrease in hemoglobin ≥2 g/dL	2.8	2.3	1.22 (1.03–1.44)	P=0.02
Intracranial hemorrhaged	0.5	0.7	0.67 (0.47–0.93)	P=0.02
Nonmajor clinically relevant bleeding eventd	11.8	11.4	1.04 (0.96–1.13)	P=0.35
Myocardial infarctionb	0.9	1.1	0.81 (0.63–1.06)	P=0.121
All-cause mortalityb	1.9	2.2	0.85 (0.70–1.02)	P=0.073

Notes:

a Included all patients who received at least one dose of a study drug, did not have a major protocol violation, and who were followed for events that occurred while receiving a study drug or within 2 days after discontinuation. Numbers of patients per treatment arm: rivaroxaban, n=6,958; warfarin, n=7,004

b included patients who received at least one dose of a study drug and who were followed for events, regardless of adherence to the protocol, while they were receiving the assigned study drug or within 2 days after discontinuation. Numbers of patients per treatment arm: rivaroxaban, n=7,061; warfarin, n=7,082

c included all patients who underwent randomization and who were followed for events during treatment or after premature discontinuation. Numbers of patients per treatment arm: rivaroxaban, n=7,081; warfarin, n=7,090

d numbers of patients per treatment arm for the safety analyses: rivaroxaban, n=7,111; warfarin, n=7,125. Data from Patel et al.⁸

Abbreviations: CI, confidence interval; ITT, intention-to-treat; NR, not reported.

Table 3 Rivaroxaban for stroke prevention in patients with nonvalvular AF – recommendations

Relevant patient group	Recommendations
Patients in whom rivaroxaban can be used	• Patients with nonvalvular AF with ≥1 risk factors for stroke, such as: congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke or TIA, and who do not have specific contraindications
	• Recommended rivaroxaban dose
	– In most patients, rivaroxaban 20 mg od is recommended, which includes patients in Asian countries outside of Japan who have normal renal function
	– In Japan, rivaroxaban 15 mg od is approved for patients with nonvalvular AF with normal renal function^Citation24
	– Patients with moderate renal impairment: (CrCl 30–49 mL/min): 15 mg od is generally recommended (10 mg od is recommended in Japan)a
	– Patients with severe renal impairment: (CrCl 15–29 mL/min), 15 mg od is recommended but should be used with caution owing to the risk of increased rivaroxaban exposurea
Patients who should not use rivaroxaban	Contraindications
	• Hypersensitivity to rivaroxaban or excipients
	• Clinically significant active bleeding, or lesion or condition at significant risk of major bleeding
	• Hepatic disease associated with coagulopathy, including cirrhotic patients with a Child–Pugh grade of B or C
	• Concomitant treatment with any other anticoagulant agent
	• Pregnancy or breast feeding
	Use not recommended
	• Renal insufficiency with CrCl <15 mL/min
	• Patients aged <18 years (no pediatric data are available)
	• Prosthetic heart valve(s)
	• Concomitant treatment with strong inhibitors of CYP3A4 and P-gp, such as HIV protease inhibitors (eg, ritonavir) or azole antimycotics (eg, ketoconazole)
	• Patients with an increased bleeding risk, such as
	– Congenital or acquired bleeding disorders
	– Uncontrolled severe arterial hypertension
	– Active ulcerative GI disease
	– Vascular retinopathy
	– Bronchiectasis or history of pulmonary bleeding
	• Rivaroxaban (15–20 mg od) is not recommended in patients who require dual antiplatelet therapy (eg, ASA plus a thienopyridine)
	– This includes patients with a recent ACS or who have recently received PCI

Notes: Rivaroxaban should only be prescribed if a positive benefit–risk balance is likely based on the patient’s overall clinical presentation. For cases in which caution is recommended, regular assessments (eg, CrCl, bleeding assessments) should be incorporated into the overall management plan.

a To help determine appropriate dosing, renal function should be assessed in all patients (irrespective of age) before rivaroxaban is initiated, although treatment should not be delayed if renal function cannot be assessed immediately. Data from Bayer Pharma AG.¹

Abbreviations: ACS, acute coronary syndrome; AF, atrial fibrillation; ASA, acetylsalicylic acid; CrCl, creatinine clearance; CYP, cytochrome P450; GI, gastrointestinal; HIV, human immunodeficiency virus; NSAID, nonsteroidal anti-inflammatory drug; od, once daily; P-gp, P-glycoprotein; PCI, percutaneous coronary intervention; TIA, transient ischemic attack.

Figure 1 Algorithm for use of a reduced dose of rivaroxaban (15 mg once daily instead of 20 mg once daily) in patients with nonvalvular atrial fibrillation, according to the patient characteristics.

Note: *HAS-BLED bleeding score. Data from Pisters et al.⁵⁵
Abbreviations: CrCl, creatinine clearance; Hb, hemoglobin.

Table 4 Potential interactions between rivaroxaban and the drugs affecting the CYP3A4 and P-gp pathways

	Strong inhibitors of both CYP3A4 and P-gp	Moderate to strong inhibitors of CYP3A4 or P-gp	Strong CYP3A4 inducers	Substrates of CYP3A4 or P-gp
Effect on rivaroxaban plasma concentrations	Increase rivaroxaban plasma concentrations	Increase rivaroxaban plasma concentrations but not clinically relevant	May decrease rivaroxaban concentrations	No clinically relevant effect
Drugs	HIV protease inhibitors (eg, ritonavir); azole antimycotics (eg, ketoconazole, itraconazole, voriconazole, posaconazole); conivaptan	Fluconazole; erythromycin; clarithromycin; telithromycin; amiodarone;a verapamil	Rifampicin;b phenytoin;b carbamazepine;b phenobarbital; St John’s wortb	Digoxin; atorvastatin; midazolam
Recommendation in patients receiving rivaroxaban	Do not coadminister with rivaroxaban	Permitted; use with caution in patients with renal impairment or at an increased bleeding risk	Permitted; use with caution	Permitted

Notes:

a Because of limited clinical data, coadministration of rivaroxaban with dronedarone should be avoided;¹

b US prescribing information stipulates that concomitant use of rivaroxaban with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampicin, St John’s wort) should be avoided.² Data from Bayer Pharma AG and Janssen Pharmaceuticals Inc.^1,2

Abbreviations: CYP, cytochrome P450; P-gp, P-glycoprotein.

Figure 2 (A) Switching from VKAs to rivaroxaban. (B) Switching from rivaroxaban to VKAs.

Note: *15 mg od in patients with a CrCI 15–49 mL/min.
Abbreviations: CrCl, creatinine clearance; INR, international normalized ratio; od, once daily; VKA, vitamin K antagonist.

Figure 3 Managing patients requiring an invasive procedure or surgery.

Abbreviation: PCC, prothrombin complex concentrate.

Figure 4 Management of patients with atrial fibrillation experiencing ischemic stroke.

Notes: *Confirmed with a chromogenic anti-factor Xa assay (or PT assay with a rivaroxaban-sensitive reagent, if anti-factor Xa assays are not available); **after confirmation, with neuroimaging, that the risk of hemorrhagic conversion has subsided; ^†in patients who have controlled blood pressure and a normal platelet count.
Abbreviation: PT, prothrombin time.

Figure 5 Assessment of bleeding risk in patients receiving rivaroxaban: anticoagulant-related and patient-related risk factors.

Abbreviations: bid, twice daily; NSAID, nonsteroidal anti-inflammatory drug; od, once daily.

Figure 6 Recommended strategies for managing bleeding events.

Notes: Rivaroxaban is not dialyzable because of its high plasma protein binding. In patients with mild/local bleeding, the balance between the need to manage a bleeding event and the increased risk of stroke in nonanticoagulated patients should be considered. *Activated charcoal may only be useful to reduce rivaroxaban absorption after overdose if administered shortly after tablet intake.
Abbreviations: FFP, fresh frozen plasma; PCC, prothrombin complex concentrate; rFVIIa, recombinant factor VIIa.

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