Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Clinical Practice: Focus on Rivaroxaban in Stroke Prevention in Patients With Atrial Fibrillation

Abstract

Despite direct oral anticoagulants (DOACs) have overcome the most relevant limitations of vitamin K antagonists, many patients with atrial fibrillation are not receiving the appropriate anticoagulant therapy. In addition, when patients are anticoagulated with DOACs, some of them are not taking the dose recommended in the summary of product characteristics. This may be related, at least in part, to the concern about the applicability of findings from randomized clinical trials to real-life patients. In this context, performing studies in daily clinical practice to assess the efficacy and safety of DOACs in real-world setting is mandatory. The aim of this review is to update the current evidence regarding safety of rivaroxaban in clinical practice. The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) showed that rivaroxaban was at least as effective as warfarin for preventing stroke or systemic embolism, with similar rates of major bleeding but with lesser risk of intracranial and fatal bleedings. Data from noninterventional studies and registries have confirmed the good results of ROCKET-AF. Even more, rates of bleeding may be inferior in real-life patients, since they have a lower risk profile than those included in ROCKET-AF.

Keywords

clinical practice nonvalvular atrial fibrillation non-vitamin K antagonist oral anticoagulants real-life patients rivaroxaban ROCKET-AF

Introduction

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice.^1

–5 Atrial fibrillation markedly increases the risk of stroke. In addition, strokes in which the underline cause is AF are more severe, with higher mortality, disability, and recurrence rates.⁶ Therefore, reducing the risk of stroke in patients with AF with the appropriate antithrombotic therapy is mandatory.⁷ However, not all patients with AF have the same risk of thromboembolic outcomes. In addition, the risk of cardioembolic complications due to AF should be balanced with the risk of hemorrhage associated with anticoagulation.^7,8

During decades, vitamin K antagonists (VKAs) have been used for the prevention of stroke in patients with AF, since they effectively reduce the risk of thromboembolic complications, with a relative low risk of bleeding.^9,10 However, VKAs have many disadvantages that together with concerns about hemorrhagic complications have led to an underuse of oral anticoagulants in patients with AF in which anticoagulation is indicated.^2,11 On the other hand, although pivotal clinical trials and meta-analyses were performed with warfarin, it has been reported that efficacy, safety, and anticoagulation control are similar between warfarin and other VKAs.¹²

Direct oral anticoagulants (DOACs) have a wide therapeutic window, a predictable anticoagulant effect, low risk of interactions with other drugs, no monitoring of their anticoagulant effect is necessary, and fixed doses are taken.¹³ Data from clinical trials have shown that overall, in patients with AF, DOACs are at least as effective as warfarin for preventing stroke and systemic embolism, with a similar risk of major bleeding, but a lesser risk of intracranial hemorrhage, and mortality and an increased risk of gastrointestinal bleeding.^14

–17 However, although several meta-analyses have analyzed all phase 3 clinical trials with DOACs as whether they were similar, the fact is that the clinical characteristics of patients included in these studies were markedly different, being individuals included in Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) those at higher risk (Table 1).^18

–21 As a result, particular caution should be taken when performing direct comparisons between them.^18

–21

Table 1.

Clinical Characteristics of Patients Included in RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48 Trials.^a

Variable	RE-LY (n = 18 113)			ROCKET-AF (n = 14 264)		ARISTOTLE (n = 18 201)		ENGAGE AF-TIMI 48 (n = 14 071)^b
Variable	D 110 mg	D 150 mg	W	Rivaroxaban	W	Apixaban	W	Edoxaban 60 mg	W
Age (years)	71.4	71.5	71.6	73	73	70	70	72	72
Male (%)	64.3	63.2	63.3	60.3	60.3	64.5	65.0	62.1	62.5
Mean CHADS₂ score	2.1	2.2	2.1	3.48	3.46	2.1	2.1	2.8	2.8
Prior stroke/TIA (%)^c	19.9	20.3	19.8	54.9^c	54.6^c	19.2^c	19.7^c	28.1	28.3
Hypertension (%)	78.8	78.9	78.9	90.3	90.8	87.3	87.6	93.7	93.6
Diabetes (%)	23.4	23.1	23.4	40.4	39.5	25.0	24.9	36.4	35.8
Heart failure (%)	32.2	31.8	31.9	62.6	62.3	35.5	35.4	58.2	57.5

Abbreviations: D, dabigatran; ROCKET-AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; TIA, transient ischemic attack; W, warfarin.

^aData are taken from references.^18

–21

^bPatients randomized to edoxaban 60 mg or warfarin.

^cStroke, TIA, or systemic embolism.

A recent study performed in the United States has shown that after DOACs have been marketed, visits with anticoagulation use have significantly increased, of which 38.2% accounted for patients taking DOACs. In 2014, rivaroxaban was the most commonly prescribed DOAC for AF.²² However, it has been reported that low-dose DOACs usage according to the optimal dose is frequent in clinical practice, leading to an undertreatment of patients with nonvalvular atrial fibrillation (NVAF) taking DOACs.^23,24

Although evidence provided from clinical trials is well established, patients included in these studies may have lesser comorbidities and are strictly monitored. Consequently, the results of these studies regarding efficacy and safety may not be necessarily the same in real-life patients. In this context, studies performed in daily clinical practice to assess the efficacy and safety of DOACs in real-world setting are mandatory.²⁵ The aim of this review is to update the current evidence regarding the safety of rivaroxaban in clinical practice.

Pharmacokinetic Properties of Rivaroxaban

Rivaroxaban is an oral, direct factor Xa inhibitor, with a predictable and dose-dependent anticoagulant activity. After oral intake, rivaroxaban is quickly absorbed. In fact, the maximum concentration of rivaroxaban is achieved 2 to 4 hours after tablet intake. Despite no significant interactions between food and rivaroxaban have been described, rivaroxaban 15 and 20 mg should be taken together with food to increase oral bioavailability. Approximately two-thirds of rivaroxaban undergo metabolic degradation and are eliminated via renal and fecal routes by the same extent. The other one-third of rivaroxaban is directly excreted in the urine, largely by active renal secretion. The terminal half-life of rivaroxaban rises with age, from 5 to 9 hours in young individuals to 11 to 13 hours in elderly patients (Table 2).^26

–31

Table 2.

Pharmacokinetic Properties of Rivaroxaban.^a

Mechanism of Action	Factor Xa Inhibitor
C_max	2-4 hours.
Oral bioavailability	Rivaroxaban 2.5-10 mg: 80%-100%.
Oral bioavailability	Rivaroxaban 20 mg: 66% in fasting conditions (rivaroxaban should be taken together with food, since when taken together with food, the area under the curve increases by 39%).
Plasma protein binding	92%-95% (not dialyzable).
Metabolism	2/3: metabolic degradation (50% eliminated via renal and 50% via fecal).
Metabolism	1/3: directly excreted in the urine.
Terminal half-life	Young individuals: 5-9 hours.
Terminal half-life	Elderly patients: 11-13 hours.
Interactions with food	None.
Interactions with other drugs	Concomitant use of rivaroxaban with these drugs should be avoided: Strong inhibitors of both CYP3A4 and P-gp (ie, HIV protease inhibitors, or azole antimycotics). Potent CYP3A4 inducers (ie, rifampicin). Dronedarone.
	These drugs can be concomitantly used with rivaroxaban, but particularly caution should be taken when renal impairment is present: Drugs that strongly inhibit only 1 of the 2 elimination pathways (CYP3A4 and P-gp), such as clarithromycin. Drugs that moderately inhibit both pathways (CYP3A4 and P-gp), such as erythromycin.
Adjustment of dose according to different clinical conditions	Age: not required Extreme body weight: not required. Hepatic function: Cirrhosis Child-Pugh A: not required. Cirrhosis Child-Pugh B and C: contraindicated.
	Renal function: Creatinine clearance ≥50 mL/min: not required (20 mg once daily). Creatinine clearance 15 and 49 mL/min: rivaroxaban 15 mg once daily. Creatinine clearance <15 mL/min: not recommended.

Abbreviation: P-gp, P-glycoprotein.

^aData are taken from references.^{26

–37}

Pharmacokinetics (PKs) and pharmacodynamics (PDs) of rivaroxaban remain unchanged according to age, and no dose adjustment is required. Similarly, no dose adjustment is necessary in patients with extreme body weight. With regard to hepatic function, rivaroxaban is contraindicated in patients with hepatic disease associated with significant hemorrhagic risk, including patients with cirrhosis Child-Pugh B and C (Table 2).^26,32
–34

Determining renal function is important in patients taking rivaroxaban, since plasma concentrations increase as renal function declines. Thus, although no dose adjustment is required in individuals with a creatinine clearance ≥50 mL/min, rivaroxaban dose should be reduced from 20 to 15 mg once daily (OD) in patients with moderate or severe renal impairment (creatinine clearance 15 and 49 mL/min). Finally, in patients with creatinine clearance <15 mL/min, rivaroxaban is not recommended. Despite a recent study performed in hemodialysis patients without residual kidney function, a 10 mg dose of rivaroxaban resulted in drug exposure similar to that of 20 mg in healthy volunteers, rivaroxaban is not currently recommended for this population (Table 2).^{26

–31,35}

Rivaroxaban is metabolized via CYP3A4-, CYP2J2-, and CYP-independent mechanisms. Moreover, rivaroxaban is a substrate of the transporter proteins P-glycoprotein (P-gp) and breast cancer resistance protein. Concomitant use of rivaroxaban with strong inhibitors of both CYP3A4 and P-gp or potent CYP3A4 inducers should be avoided. However, those drugs that strongly inhibit only 1 of the 2 elimination pathways or that moderately inhibit both pathways can be concomitantly used with rivaroxaban, but particularly caution should be taken when renal impairment is present, with a more strict follow-up (Table 2).^{26,27

–31,36,37} Remarkably, in a post hoc analysis of ROCKET-AF, no evidence of differential outcomes in those patients treated with ≥1 combined CYP3A4 and P-gp inhibitors was observed.³⁸

Dabigatran and apixaban should be taken twice daily for the prevention of stroke or systemic embolism in patients with NVAF.^18

–21 By contrast, rivaroxaban and edoxaban should be taken only OD. The OD dose of rivaroxaban chosen for ROCKET-AF trial was largely based on the data of 2 phase 2 studies together with PK/PD studies. All these studies reported that the dose of 20 mg OD presented the best benefit–risk ratio compared with twice-daily doses of rivaroxaban or other OD doses.^26,39
–41

Rivaroxaban and ROCKET-AF

The ROCKET-AF trial was a phase 3 noninferiority study that analyzed the efficacy and safety of rivaroxaban compared with warfarin in patients with NVAF who were at moderate to high risk for stroke. In this study, 14 264 patients were randomized to receive rivaroxaban 20 mg OD (15 mg if creatinine clearance is 30-49 mL/min/1.73 m²) or dose-adjusted warfarin (international normalized ratio [INR] 2.0-3.0). The clinical characteristics of patients are shown in Table 1. Remarkably, patients included in ROCKET-AF were at high risk of both thromboembolic and bleeding complications (mean CHADS₂ score was 3.48, and 62.5% of patients had a HAS-BLED score ≥3).¹⁸

After a median follow-up period of 707 days (median duration of treatment exposure of 590 days), in the per-protocol population (all patients who received at least 1 dose of a study drug, did not have a major protocol violation, and were followed for events while receiving a study drug or within 2 days after discontinuation), rates of the primary efficacy end point (stroke or systemic embolism) were 1.7% per year in the rivaroxaban group and 2.2% per year in the warfarin group (hazard ratio [HR]: 0.79; 95% confidence interval [CI]: 0.66-0.96; P < .001 for noninferiority); in the as-treated safety population (patients who received at least 1 dose of a study drug and were followed for events, regardless of adherence to the protocol, while they were receiving the assigned study drug or within 2 days after discontinuation), these numbers were 1.7% per year and 2.2% per year, respectively (HR: 0.79; 95% CI: 0.65-0.95; P = .02 for superiority); and in the intention-to-treat analysis (all patients who underwent randomization and were followed for events during treatment or after premature discontinuation), 2.1% per year and 2.4% per year, respectively (HR: 0.88; 95% CI: 0.74-1.03; P < .001 for noninferiority; P = .12 for superiority).¹⁸

The principal safety end point (major and nonmajor clinically relevant bleeding) occurred similarly in rivaroxaban and warfarin groups (14.9% and 14.5% per year, respectively; HR: 1.03; 95% CI: 0.96-1.11; P = .44). Rates of major bleeding were also similar in both treatment groups (3.6% and 3.4% per year, respectively; HR: 1.04; 95% CI: 0.90-1.20; P = .58). However, the risk of intracranial hemorrhage (HR: 0.67; 95% CI: 0.47-0.93; P = .02), critical bleeding (HR: 0.69; 95% CI: 0.53-0.91; P = .007), and fatal bleeding (HR: 0.50; 95% CI: 0.31-0.79; P = .003) were less frequent with rivaroxaban. By contrast, major bleeding from a gastrointestinal site was more common with rivaroxaban compared with warfarin (3.15% vs 2.16%, respectively; P < .001).¹⁸

After the publication of ROCKET-AF, several substudies and post hoc analyses determining the efficacy and safety of rivaroxaban compared with warfarin in different subgroups of patients and clinical conditions have been published (Table 3).^{42

–59} Overall, the results of these substudies were consistent with the main results and emphasize the robustness of ROCKET-AF.

Table 3.

Efficacy and Safety of Rivaroxaban Compared With Warfarin According to Different Clinical Conditions.^a,b

Clinical Condition	Commentary
Elderly patients⁴²	44% of patients included in ROCKET-AF were ≥75 years old. Older individuals had more primary events (2.57% vs 2.05% per 100 patient-years; P = .0068) and major bleeding (4.63% vs 2.74% per 100 patient-years; P < .0001). However, when compared rivaroxaban with warfarin, the rates of stroke or systemic embolism were consistent among older (HR: 0.80; 95% CI: 0.63-1.02) and younger patients (HR: 0.95; 95% CI: 0.76-1.19; interaction P = 0.313). Rates of major bleeding rates were also consistent regardless of age (HR: 1.11; 95% CI: 0.92-1.34 and HR: 0.96; 95% CI: 0.78-1.19; interaction P = .336), as well as hemorrhagic stroke rates.
Patients with previous stroke or TIA⁴³	Overall, 52% of patients in ROCKET-AF had a previous stroke or TIA. Rates of stroke and systemic embolism in patients treated with rivaroxaban compared with warfarin were consistent among patients with previous stroke or TIA (HR: 0.94; 95% CI: 0.77-1.16) and those without (HR: 0.77; 95% CI: 0.58-1.01; interaction P = .23). Rates of major and nonmajor clinically relevant bleeding events in patients treated with rivaroxaban compared with warfarin were consistent among patients with previous stroke or TIA (HR: 0.96; 95% CI: 0.87-1.07) and those without (HR: 1.10; 95% CI: 0.99-1.21; interaction P = .08).
Patients with moderate renal impairment⁴⁴	In ROCKET-AF, patients were randomized to rivaroxaban 20 mg/d (15 mg/d if creatinine clearance is 30-49 mL/min) or dose-adjusted warfarin. Compared with patients with creatinine clearance >50 mL/min, those with moderate renal impairment were older and had higher event rates irrespective of study treatment. Among patients with moderate renal impairment, rates of stroke or systemic embolism similarly occurred in both treatment groups (HR: 0.84; 95% CI: 0.57-1.23 in the per-protocol population and HR: 0.86; 95% CI: 0.63-1.17 in the intention-to-treat analysis). Rates of major and nonmajor clinically relevant bleeding and intracranial bleeding were similar in both treatment groups. However, fatal bleeding was less frequent with rivaroxaban compared with warfarin (0.28% vs 0.74% per 100 patient-years; P = .047).
Patients with diabetes⁴⁵	Overall, 39.8% of patients had diabetes in ROCKET-AF. Compared with warfarin, the risk of stroke and systemic embolism with rivaroxaban in patients with diabetes was consistent with the overall trial results (HR: 0.74; 95% CI: 0.54-1.01; P = .055). Rates of major (HR: 0.98; 95% CI: 0.79-1.21; P = .84) and major or nonmajor clinically relevant bleeding (HR: 0.97; 95% CI: 0.86-1.08; P = .57) in patients with diabetes were similar in both groups, but with a trend to a lesser risk of intracranial hemorrhage with rivaroxaban (HR: 0.50; 95% CI: 0.23-1.06; P = .070).
Ischaemic cardiac outcomes⁴⁶	Overall, 17% of patients included in ROCKET-AF had prior myocardial infarction at baseline. Rates of cardiovascular death, myocardial infarction, or unstable angina were higher in those patients with prior myocardial infarction, with consistent results for rivaroxaban compared with warfarin according to the history of myocardial infarction. Rates of cardiovascular death, myocardial infarction, or unstable angina tended to be lower in patients assigned to rivaroxaban compared with warfarin (HR: 0.86; 95% CI: 0.73-1.00; P = .0509).
Patients with heart failure⁴⁷	Overall, 63.7% of patients had heart failure at baseline. The efficacy of rivaroxaban compared with warfarin was similar regardless of the history of heart failure (P interaction = .62). The risk of major or nonmajor clinically relevant bleeding with rivaroxaban was similar to warfarin regardless of the presence of heart failure (P interaction = .99). A reduction in hemorrhagic stroke was observed with rivaroxaban in patients with heart failure (HR: 0.38; 95% CI: 0.19-0.76; P interaction = .067). Among patients with heart failure, the efficacy of rivaroxaban was similar, regardless of ejection fraction; NYHA functional class; heart failure preserved or reduced ejection fraction; or CHADS₂ score.
Patients with peripheral artery disease⁴⁸	Overall, 5.9% of patients in ROCKET-AF had peripheral artery disease. Rates of stroke or systemic embolism were similar in patients with and without peripheral artery disease (HR: 1.04; 95% CI: 0.72-1.50; P = .84). Rates of major or nonmajor clinically relevant bleeding were also similar in patients with and without peripheral artery disease (HR: 1.11; 95% CI: 0.96-1.28; P = .17). The efficacy of rivaroxaban when compared with warfarin for the prevention of stroke or systemic embolism was similar regardless of the presence of peripheral artery disease (interaction P = .34). By contrast, there was a significant interaction for major or nonmajor clinically relevant bleeding according to the presence of peripheral artery disease (HR_{rivaroxaban-warfarin} in patients with peripheral artery disease: 1.40; 95% CI: 1.06-1.86 and HR_{rivaroxaban-warfarin} in patients without peripheral artery disease: 1.03; 95% CI: 0.95-1.11; interaction P = .037).
Patients with underlying native mitral and aortic valve disease⁴⁹	In ROCKET-AF, patients with mitral stenosis or artificial valve prostheses were excluded. Among 14 171 patients from ROCKET-AF, 14.1% had significant valvular disease. Rates of the primary efficacy outcome (stroke or systemic embolism) were consistent according to this condition (HR_{rivaroxaban vs warfarin} in patients with significant valvular disease: 0.83; 95% CI: 0.55-1.27 and HR_{rivaroxaban vs warfarin} in patients without significant valvular disease: 0.89; 95% CI: 0.75-1.07; interaction P = .76). However, the rates of the principal safety end point (major and nonmajor clinically relevant bleeding) were higher in patients with significant valvular disease (HR: 1.25; 95% CI: 1.05-1.49 and HR: 1.01; 95% CI: 0.94-1.10, respectively; interaction P = .034). By contrast, intracranial hemorrhage was less common with rivaroxaban in both groups.
Use of antiarrhythmic drugs⁵⁰	11.8% of patients included in ROCKET-AF were taking antiarrhythmic drugs (8% amiodarone and 3.8% other antiarrhythmic drugs). Time in therapeutic range was significantly lower in warfarin-treated patients receiving amiodarone than in those receiving no antiarrhythmic drugs (50% vs 58%; P < .0001). Compared with no antiarrhythmic drug, neither amiodarone nor other antiarrhythmic drugs were associated with increased mortality. In addition, similar rates of embolic and bleeding outcomes were reported according to the use of antiarrhythmic drugs. Compared with warfarin, rivaroxaban treatment effects in patients not on antiarrhythmic drug were consistent with the overall study. In those patients taking amiodarone, there was no significant interaction for the primary end point according to treatment assignment and renal dysfunction (P = .40).
Risk of intracranial hemorrhage⁵³	Predictors of intracranial hemorrhage were: race (Asian: HR: 2.02; 95% CI: 1.39-2.94; black: HR: 3.25; 95% CI: 1.43-7.41), age (HR: 1.35; 95% CI: 1.13-1.63 per 10-year increase), reduced serum albumin (HR: 1.39; 95% CI: 1.12-1.73 per 0.5 g/dL decrease), reduced platelet count <210 × 10⁹/L (HR: 1.08; 95% CI: 1.02-1.13 per 10 × 10⁹/L decrease), previous stroke or TIA (HR: 1.42; 95% CI: 1.02-1.96), and increased diastolic blood pressure (HR: 1.17; 95% CI: 1.01-1.36 per 10 mm Hg increase). Predictors of a reduced risk of intracranial hemorrhage were: randomization to rivaroxaban (HR: 0.60; 95% CI: 0.44-0.82) and history of congestive heart failure (HR: 0.65; 95% CI: 0.47-0.89).
Management of major bleeding⁵⁴	Among those patients who experienced major bleeding in ROCKET-AF, the use of fresh frozen plasma and prothrombin complex concentrates was less commonly used in those allocated to rivaroxaban compared with warfarin. By contrast, the use of packed red blood cells and outcomes after bleeding was similar in both treatment groups.
Clinical outcomes with rivaroxaban in patients transitioned from VKA therapy⁵⁷	Overall, 55.4% of patients in ROCKET-AF were VKA-experienced and 44.6% VKA-naive. The effect of rivaroxaban versus warfarin on stroke or systemic embolism was consistent between VKA-naive patients and VKA-experienced patients (interaction P = .36). During the first 7 days, rivaroxaban was associated with more bleeding than warfarin (HR in VKA-naive patients 5.83; 95% CI 3.25-10.44, and HR in VKA-experienced patients 6.66; 95% CI 3.83-11.58; interaction P = .53). After 30 days, rivaroxaban was associated with a lesser risk of bleeding compared with warfarin in VKA-naive patients (HR 0.84; 95% CI 0.74-0.95), but with a similar risk of bleeding in VKA-experienced patients (HR 1.06; 95% CI 0.96-1.17; interaction P = .003).
Outcomes after cardioversion and atrial fibrillation ablation⁵⁹	Over a median follow-up of 2.1 years, 143 patients underwent electrical cardioversion, 142 pharmacologic cardioversion, and 79 catheter ablation. The long-term incidence of stroke or systemic embolism, cardiovascular death, and death from all causes were not different before and after cardioversion or atrial fibrillation ablation. Hospitalization increased after cardioversion or atrial fibrillation ablation, but without evidence of a differential effect by randomized treatment (P interaction = .58). The incidence of stroke or systemic embolism and death was similar in both treatment groups.

Abbreviations: CI, confidence interval; HR, hazard ratio; NYHA, New York Heart Association; ROCKET-AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; TIA, transient ischemic attack; VKA, vitamin K antagonists.

^aData are taken from references.^{42

–59}

^bData from ROCKET-AF.

Japanese guidelines recommend lower levels of anticoagulation (ie, in this population, an INR target of 1.6-2.6 is recommended, rather than 2.0-3.0). In addition, it has been reported that considering PK–PD properties, the dosage of 15 mg OD is more adequate than 20 mg OD in Japanese population.^60,61 In J-ROCKET-AF, 1280 Japanese patients were randomized to rivaroxaban 15 mg OD (10 mg if creatinine clearance is 30-49 mL/min) or dose-adjusted warfarin according to the Japanese guidelines. The risk of major and nonmajor clinically relevant bleeding similarly occurred in both groups. Intracranial bleeding rates were 0.8% and 1.6%, respectively. Importantly, there was a strong trend for a reduction in the rate of stroke/systemic embolism with rivaroxaban compared with warfarin (HR: 0.49; P = .05).⁶²

It has been reported that the device used in ROCKET-AF for INR monitoring may provide an INR result that is lower than an automated, plasma-based laboratory INR in patients with some specific medical conditions (ie, patients with anemia, bleeding, or situations associated with high levels of fibrinogen). However, recent post hoc analyses of the ROCKET-AF data have shown that the results of the additional sensitivity analyses were consistent with those already reported for the primary efficacy and safety end points in patients with or without recall conditions. In addition, the European Medicines Agency has ruled out that the possible malfunction of the point-of-care device used for INR measurement in the ROCKET-AF trial had any significant clinical effect on the primary efficacy and safety outcomes in the trial.⁶³

Rivaroxaban in Real-Life Patients

Bleeding and Anticoagulant Therapy

Although in the last years the introduction of DOACs has increased the proportion of patients receiving anticoagulants, the fact is that a significant number of individuals with NVAF do not take anticoagulants despite a clear indication, or when used, many physicians prescribe low-dose DOACs instead of the optimal dose.^23,24,64,65 Moreover, there is concern about the applicability of findings from randomized clinical trials to real-life patients. Fortunately, in the last years, several studies performed in daily clinical practice have been published or are ongoing.

Bleeding represents the most important complication of anticoagulation. However, the risk of hemorrhage differs according to the clinical characteristics of patients. In this context, it is not only important to stratify the risk of stroke (ie, CHA₂DS₂-Vasc score) but also the risk of bleeding (ie, HAS-BLED score).⁷ Thus, in a registry that included 7243 patients with AF from 7 European countries, 70.6% of patients with bleedings had a HAS-BLED score ≥3.⁶⁶ While in ARISTOTLE trial 36% of patients had a HAS-BLED score of 2 and 23% a HAS-BLED score ≥3, these numbers were 30% and 62.5%, respectively, in ROCKET-AF. This higher risk profile was in parallel with higher rates of major bleeding observed in ROCKET-AF. Thus, the annual rates of major bleeding in the warfarin arm were 3.09% in ARISTOTLE and 3.4% in ROCKET-AF.^18,20 Unfortunately, many physicians underestimate the risk of both, stroke and bleeding.⁶⁷ This underestimation of risk may explain, at least in part, the discrepancies between current recommendations and clinical practice.

On the other hand, not all bleedings are equally relevant. Thus, when prescribing anticoagulant therapy, it is more important to consider major hemorrhages, particularly intracranial and fatal bleeding, rather than any hemorrhage.^14,68 In the meta-analysis of Agarwal et al that included 8 clinical trials, the annual rates of major bleeding with warfarin varied from 1.40% to 3.40% and the annual rates of intracranial bleeding from 0.33% to 0.8%.⁶⁹ In a meta-analysis of 11 studies (5 on AF and 6 on venous thromboembolism), the risk of fatal bleeding was significantly and markedly reduced by DOACs compared with VKA.⁷⁰ In ROCKET-AF, compared with warfarin, rivaroxaban significantly reduced the risk of intracranial and fatal bleeding by 33% and 50%, respectively.¹⁸

In addition, it is not only important to analyze the frequency of bleeding but also the intensity. Thus, a recent study that compared patients with intracerebral hemorrhage while taking rivaroxaban or warfarin showed that rivaroxaban-associated intracerebral hemorrhage occurred in patients at high risk for major bleeding. In addition, compared with the group of patients taking warfarin, those patients in the rivaroxaban group had a relatively small hematoma, no expansion of hematoma, and favorable functional and vital outcomes.⁷¹

Safety of Rivaroxaban in Real-Life Patients

Several studies have analyzed the safety of rivaroxaban in clinical practice. In a study that retrospectively analyzed data from the US Department of Defense, 27 467 patients with NVAF taking rivaroxaban between January 1, 2013, and March 31, 2014, were investigated. In this study, the incidence of major bleeding was 2.86 per 100 person-years. Compared with those patients without major bleeding, those patients with major bleeding were older (78.4 vs 75.7 years) and had more comorbidities, including hypertension (95.6% vs 75.8%), ischemic heart disease (64.2% vs 36.7%), heart failure (48.5% vs 23.7%), and chronic kidney disease (38.7% vs 16.7%). CHADS₂ score was also significantly higher in those patients with major bleeding (3.0 vs 2.2). Major bleeding was most commonly gastrointestinal (88.5%) or intracranial (7.5%). The incidence of fatal bleeding was 0.08 per 100 person-years (Table 4, Figure 1).⁷² Updated data of this study recently presented at 2015 American College of Cardiology congress showed that in the first 18 months of the study, with 31 833 patients taking rivaroxaban, the incidence of major bleeding and fatal bleeding remained 2.85 and 0.09 per 100 person-years, respectively.⁷⁵

Table 4.

Safety of Rivaroxaban in Real-Life Patients With AF.

Study	Beyer-Westendorf (Dresden NOAC Registry)	Tamayo (US Department of Defense Military Health System-MHS)	Camm (XANTUS)
Number of patients	1776 rivaroxaban (1200 AF)	27 467 rivaroxaban	6784 rivaroxaban
Type of study	Prospective	Retrospective	Prospective
Follow-up (treatment duration)	388 days (274 days)	455 days (≈222 days)	329 days (329 days)
Mean CHADS₂ score	2.4	2.2	2.0
Major bleeding (annual rates)	3.1%	2.86%	2.1%
Fatal bleeding (annual rates)	≈0.15%^a	0.08%	0.2%
Conclusions	Rates of major bleeding could be lower than that of warfarin	Rates of major bleeding were consistent with that of ROCKET-AF. Fatal bleeds were rare	Patients had a lower risk than in ROCKET- AF. Event rates were low

Abbreviations: AF, atrial fibrillation; NOAC, non-interventional oral anticoagulation; ROCKET-AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; XANTUS, Xarelto on Prevention of Stroke and Non-central Nervous System Systemic Embolism in Patients With Non-valvular Atrial Fibrillation.

^aEstimated, Data taken from references.^72,73,74

Figure 1.

Risk of major bleeding, intracranial bleeding, and fatal bleeding in Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF; rivaroxaban arm) and real-life cohorts of patients taking rivaroxaban. *Estimated, data are taken from references.^18,72,73,74

A recent study performed in primary care setting in Switzerland included 537 consecutive patients with NVAF who started treatment with rivaroxaban. Mean age of patients was 73 years, 57% were men, mean CHADS₂ score was 2.2, and mean HAS-BLED score was 2.4. About 56% of patients were switched from VKA to rivaroxaban, and the remaining 44% were VKA naive. After 3 months of treatment, 2 (0.37%) major nonfatal bleeding and 11 (2.05%) minor bleeding events occurred. In those patients who changed from VKA to rivaroxaban, both patient’s satisfaction and overall physician satisfaction significantly increased. About 5.6% of patients withdrew from rivaroxaban treatment, mainly due to their side effects.⁷⁶

The Dresden Non-Interventional Oral Anticoagulation registry is an ongoing large and prospective noninterventional registry in which more than 230 physicians from Dresden (Saxony), Germany, include patients treated with a DOAC. The main inclusion criteria were age ≥18 years, planned DOAC anticoagulation for at least 3 months, and therapeutic DOAC indication including AF, deep vein thrombosis, pulmonary embolism, and other indications. In this study, efficacy and safety of rivaroxaban were analyzed. Between October 1, 2011, and December 31, 2013, 1776 patients treated with rivaroxaban were included (age 74 years; 51.4% male; 17.5% prior coronary artery disease; 11.4% previous stroke or systemic embolism; 10.8% impaired renal function). During this time, rates of major bleeding were 3.1 per 100 patient-years in patients with AF, and 4.1 per 100 patient-years in patients with venous thromboembolism. Case fatality rates of bleeding leading to hospitalizations were 5.1% at day 30 and 6.3% at day 90 after bleeding (Table 4, Figure 1).⁷³

Data from Xarelto on Prevention of Stroke and Non-central Nervous System Systemic Embolism in Patients With Non-valvular Atrial Fibrillation (XANTUS) study have been recently reported in the 2015 European Society of Cardiology congress. The XANTUS was an observational, prospective, postauthorization, noninterventional, and single-arm study aimed to collect data in real-life patients with NVAF, with a special focus on safety outcomes. In fact, XANTUS was the first international, prospective, and observational study aimed to describe the use of rivaroxaban in patients with NVAF. In XANTUS, 6784 consecutive patients from 311 centers in Europe, Israel, and Canada with NVAF newly started on rivaroxaban were included. The mean observation period was 329 days. With regard to the clinical characteristics of the patients, mean age was 71.5 years, 41% were women, 19% had prior stroke/transient ischemic attack (TIA)/systemic embolism, and 9.4% had documented severe or moderate renal insufficiency. Mean CHADS₂ score was 2.0 and mean CHA₂DS₂-VASc score was 3.4. A total of 78.7% of patients were taking rivaroxaban 20 mg OD, 20.8% 15 mg OD, and 0.5% another dose (Tables 4 and 5). Rates of major bleeding and fatal bleeding were 2.1 and 0.2 events per 100 patient-years, respectively (Tables 4 and 6, Figure 1).⁷⁴ Compared with patients included in ROCKET-AF (rivaroxaban arm), XANTUS study patients had lesser comorbidities and a lower mean CHADS₂ score. This translated into a lesser risk of bleeding (Tables 5 and 6).^18,74

Table 5.

Clinical Characteristics of Patients Included in XANTUS Study and ROCKET-AF Trial (Rivaroxaban Arm).^a

Variable	XANTUS (n = 6784)	ROCKET-AF (n = 7131)	P
Age (years)	71.5	73	<.001
Sex, female (%)	40.8	39.7	NS
Mean CHADS₂ score	2.0	3.48	<.001
Hypertension (%)	74.7	90.3	<.001
Congestive heart failure (%)	18.6	62.6	<.001
Previous stroke/TIA/systemic embolism (%)	19.0	54.9	<.001
Diabetes (%)	19.6	40.4	<.001
Previous myocardial infarction (%)	10.1	16.6	<.001

Abbreviations: ROCKET-AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; TIA, transient ischemic attack; XANTUS, Xarelto on Prevention of Stroke and Non-central Nervous System Systemic Embolism in Patients With Non-valvular Atrial Fibrillation.

^aData are taken from references.^18,74

Table 6.

Event Rates of Patients Included in XANTUS Study and ROCKET-AF Trial (Rivaroxaban Arm).^a,b

	XANTUS (n = 6784)	ROCKET-AF (n = 7131)	P
Efficacy outcomes
Stroke/systemic embolism	0.8	1.7	<.001
Stroke	0.7	1.7	<.001
Myocardial infarction	0.4	0.9	<.001
Safety outcomes
Major bleeding	2.1	3.6	<.001
Fatal bleeding	0.2	0.2	NS
Intracranial hemorrhage	0.4	0.5	.03
Major gastrointestinal bleeding	0.9	2.0	<.001

Abbreviations: ROCKET-AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; XANTUS, Xarelto on Prevention of Stroke and Non-central Nervous System Systemic Embolism in Patients With Non-valvular Atrial Fibrillation.

^aData are taken from references.^18,74

^bAnnual rates, 100 patient-years.

In other study that included patients with AF newly initiated on rivaroxaban (n = 3654) or warfarin (n = 14 616), with a CHADS₂ score ≥1, bleeding events similarly occurred in both groups.⁷⁷ Another retrospective analysis of 2579 patients taking dabigatran or rivaroxaban reported similar rates of major bleeding than that of randomized clinical trials.⁷⁸

With regard to major bleeding from a gastrointestinal site, these were more common with rivaroxaban compared with warfarin in ROCKET-AF (3.15% vs 2.16%, respectively; P < .001). However, the most severe gastrointestinal bleeding, those who required transfusion of >4 U of whole blood or packed red blood cells, similarly occurred in both treatment groups (49 patients with rivaroxaban compared with 47 patients with warfarin). Only 1 patient in the rivaroxaban group and 5 patients in the warfarin group had a fatal gastrointestinal bleeding. Even more, in ROCKET-AF, there were 27 fatal bleedings, but only 1 had a gastrointestinal origin.¹⁸ On the other hand, it has been reported that this increased risk of anticoagulant-related gastrointestinal bleeding may facilitate the unmasking of preexisting malignancies from this origin, leading to the early detection of gastrointestinal cancer.⁷⁹ Rates and severity of gastrointestinal bleeding have been specifically analyzed in real-life patients. In a retrospective analysis of 170 consecutive patients with AF from a TIA clinic, who started either dabigatran (n = 88) or rivaroxaban therapy (n = 93), with a total of 86 patient-years of exposure, gastrointestinal bleeding occurred in 5% (n = 4) of the patients treated with dabigatran (mean age 84 years, all of them with at least 2 comorbidities) and in 1% of the patients treated with rivaroxaban (this patient was 96 years old and had many comorbidities).⁸⁰ In a study that included patients with AF with a CHADS₂ score ≥1, newly initiated on rivaroxaban or warfarin, the risk of gastrointestinal bleeding was similar in both groups (HR: 1.28; 95% CI: 0.99-1.63).⁷⁷ In a retrospective, propensity-matched cohort study, new users of dabigatran, rivaroxaban, and warfarin from November 1, 2010, to September 30, 2013, were analyzed. In patients with AF, the incidence of gastrointestinal bleeding associated with rivaroxaban was 2.84 events per 100 patient-years, compared with 3.06 per 100 patient-years in those treated with warfarin (Table 7).⁸¹ In summary, although in ROCKET-AF major bleeding from a gastrointestinal site was more frequent with rivaroxaban than with warfarin, severe gastrointestinal bleeding similarly occurred in both groups. In addition, studies performed in real-life patients have not confirmed this increased risk of gastrointestinal bleeding compared with warfarin.

Table 7.

Risk of Gastrointestinal Bleeding of Rivaroxaban Compared With Warfarin in Real-Life Patients With Atrial Fibrillation.^a

	Hazard Ratio	95% Confidence Interval
Total gastrointestinal bleeding events	0.93	0.69-1.25
Upper gastrointestinal bleeding events	1.05	0.72-1.54
Lower gastrointestinal bleeding events	0.77	0.48-1.24

^aData are taken from reference.⁸¹

Another relevant question to be answered is whether those patients at higher risk of bleeding can be identified in order to reduce their hemorrhagic risk. In ROCKET-AF, predictors of major bleeding were increasing age, baseline diastolic blood pressure ≥90 mm Hg, history of chronic obstructive pulmonary disease or gastrointestinal bleeding, prior acetylsalicylic acid use, and anemia. By contrast, female sex and diastolic blood pressure <90 mm Hg were associated with a decreased risk of major bleeding.⁸² In other study, prescriber errors, impaired renal function, concomitant treatment with antiplatelet drugs or P-gp inhibitors, old age, and low body weight were associated with increased risk of hemorrhage under DOACs.⁸³ As a result, a correct selection of patients, an adequate prescription of DOACs, the control of factors that increase the risk of bleeding, such as avoiding antiplatelet drugs or P-gp inhibitors and reducing blood pressure values to recommended targets, and a close follow-up of frail patients may reduce the risk of bleeding in patients with AF taking DOACs.

Efficacy of Rivaroxaban in Real-Life Patients

Different studies have analyzed the efficacy of rivaroxaban in clinical practice. REal-LIfe Evidence on stroke prevention in patients with atrial Fibrillation was a retrospective study aimed to compare the effectiveness of newly initiated rivaroxaban or VKA therapy among patients with NVAF in Germany. The primary end point was the time to composite of ischemic stroke, TIA, intracerebral hemorrhage, other nontraumatic intracranial hemorrhage including subdural hemorrhage, and myocardial infarction within 1 year of treatment initiation. Remarkably, the incidence of the primary end point was lower in rivaroxaban compared with VKA users (1.97 vs 3.68 events per 100 person-years; HR: 0.54; 95% CI: 0.31-0.92). In addition, rates of individual end points were numerically less frequent in the rivaroxaban cohort.⁸⁴ In the registry performed in Switzerland, after 3 months of treatment, only 1 (0.19%) ischemic stroke occurred.⁷⁶ In a study that included patients with AF newly initiated on rivaroxaban or warfarin, stroke or systemic embolism events similarly occurred in both groups. Importantly, rivaroxaban was associated with a lesser risk of venous thromboembolic events (HR: 0.36; 95% CI: 0.24-0.54; P < .0001) and treatment nonpersistence (HR: 0.66; 95% CI: 0.60-0.72; P < .0001).⁷⁷

In XANTUS, after 329 days of treatment, the rates of stroke were 0.7 events per 100 patient-years (Table 6).⁷⁴ Compared with patients included in ROCKET-AF (rivaroxaban arm), XANTUS study patients had a lesser risk of stroke and myocardial infarction (Table 6).^18,74

Discussion

Despite the introduction of DOACs that mitigate many of the limitations of VKA, a significant proportion of patients with NVAF remain without antithrombotic treatment, and when anticoagulated with DOACs, some of them are not taking the dose recommended in the summary of product characteristics.^2,23,24 For example, in XANTUS, despite only 9.1% of patients had a creatinine clearance 15 to <50 mL/min, 20.8% of patients were taking rivaroxaban 15 mg OD.⁷⁴ Similarly, data from the GLORIA-AF registry also showed that patients with NVAF at high risk of stroke were undertreated with oral anticoagulants, since initial therapy was often not prescribed in accordance with guideline recommendations.^85,86 Although it is uncertain whether this has an impact on a higher risk of thrombotic complications, overall, in “real-life” patients, the rates of stroke or systemic embolism seem lower than that reported in clinical trials (0.8 vs 1.7 events per 100 patient-years; Table 6).^18,74 On the other hand, since anticoagulants increase the risk of bleeding, this may be balanced with the risk of stroke that patients with NVAF have. In this context, it is mandatory to perform a correct risk stratification of this population.⁷ In addition, the identification and correction when possible of those factors that increase the risk of bleeding (ie, blood pressure control) may improve the risk–benefit ratio in favor of anticoagulation.

Clinical trials have shown that in patients with NVAF, DOACs are at least as effective as warfarin for preventing stroke and systemic embolism, with similar rates of major bleeding, but importantly, with a lesser risk of intracranial hemorrhage and mortality.^14

–17 Therefore, DOACs are safer than VKA. However, the doubt that emerged was whether these results could be applied to real-life patients. In the last years, a number of noninterventional studies and registries have confirmed the safety of DOACs in clinical practice. In addition, some registries performed with rivaroxaban suggest that the rates of bleeds are similar or even lower than that of ROCKET-AF.^72–74 This could be explained by the fact that patients included in ROCKET-AF were at very high risk of stroke and bleeding¹⁸ and that in clinical practice not all patients with AF have the same risk.

In ROCKET-AF, treatment with rivaroxaban was associated with an increased risk of gastrointestinal bleeding. However, very severe gastrointestinal bleeding occurred similarly in both groups.¹⁸ In addition, studies performed in real-life patients have not confirmed this increased risk of gastrointestinal bleeding compared with warfarin.^77,81 As a result, patients with a high risk of gastrointestinal bleeding can be treated with rivaroxaban, but a close follow-up is recommended.

The lack of a specific antidote has been suggested as another reason for not prescribing DOACs. However, first, there is a specific antidote currently marketed for one of the DOACs. In fact, idarucizumab, an antibody fragment, has been shown to completely reverse the anticoagulant effect of dabigatran within minutes.⁸⁷ Second, the current management of patients with severe bleeding is actually very similar in case of VKA or DOACs. Moreover, since DOACs have a short half-life, reversing their anticoagulant effect may not be necessary in a great number of individuals. Nevertheless, in some patients, the use of prohemostatic agents may be necessary. In case of rivaroxaban, activated prothrombin complex concentrate and prothrombin complex concentrate are particularly recommended, and when insufficient, recombinant factor VIIa may be also useful. Importantly, specific reversal agents are currently under investigation, such as andexanet alfa or PER977.^88
–90 It is very likely that in the next future, some of these reversal agents will be available for rivaroxaban.

Since in patients taking VKA the anticoagulant activity must be monitored, no important concerns about medication adherence had been suggested. Since this is not necessary with DOACs, doubts about treatment persistence have emerged. However, different studies have actually shown the opposite, medication persistence is significantly higher with DOACs than with VKA.^91,92 It has been reported that overall persistence with rivaroxaban is high, with a discontinuation rate of approximately 15% in the first year of therapy and few additional discontinuations thereafter. Unfortunately, data regarding whether the dosage of rivaroxaban had an impact on medication adherence were not reported.⁹² On the other hand, in patients with NVAF, OD dosing regimens are associated with a higher likelihood of adherence compared with patients on twice-daily regimens.⁹³ A recent study has reported that rivaroxaban users have a higher medication adherence when compared to dabigatran or apixaban users.⁹⁴ Therefore, rivaroxaban may assure a good adherence to treatment in this population.

Another controversial issue is the management of patients who fail rivaroxaban and present with an acute ischemic stroke.⁹⁵ First, the time in which anticoagulation should be restarted is challenging, since it depends on many factors. In many patients, if hemorrhagic transformation has not occurred, oral anticoagulation may generally be initiated 1 to 2 weeks after the stroke.⁹⁶ Second, adherence to rivaroxaban should be determined. In case of poor adherence, it is likely that the best option may be the use of VKA, since anticoagulation monitoring is mandatory for these drugs. Third, since oral bioavailability of rivaroxaban 15 and 20 mg decreases in fasting conditions, it is mandatory to assure that patients take rivaroxaban together with food.^95,26

Finally, one disadvantage of DOACs is that they are more expensive than VKA. As a result, cost-effectiveness studies are mandatory to assess which patients will benefit more from this therapy. Overall, rivaroxaban is a cost-effective therapeutic alternative in patients with NVAF, particularly in those patients at high risk of stroke or bleeding or when INR control is not optimal.^97,98

Conclusion

Data from noninterventional studies and registries confirm the good results of ROCKET-AF. Even more, the rates of bleeding are inferior in real-life patients, since they have a lower risk profile than those included in ROCKET-AF. Therefore, rivaroxaban is a good alternative for the prevention of stroke and systemic embolism in real-life patients with NVAF.

Highlights

Despite DOACs have overcome many of the limitations of VKA, a significant proportion of patients with NVAF remains without antithrombotic treatment, and when anticoagulated with DOACs, some of them are not taking the dose recommended in the summary of product characteristics.

The ROCKET-AF showed that rivaroxaban was at least as effective as warfarin for preventing stroke or systemic embolism, with similar rates of major bleeding but with lesser risk of intracranial and fatal bleedings.

A number of noninterventional studies and registries have confirmed the safety of rivaroxaban in real-life patients. Even, more, the rates of bleeding are inferior in real-life patients, since they have a lower risk profile than those patients included in ROCKET-AF.

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Domingo Marzal-Martín has collaborated as a speaker, scientific advisor, and training activities with Bayer.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Marcelo Sanmartín-Fernández has received grant support from Bayer; has received honoraria as advisor from Bayer, Boehringer, and BMS; and has received honoraria as speaker from Bayer, Boehringer, and Pfizer. Editorial assistance was provided by Content Ed Net, Madrid, Spain.

References

Rahman

Kwan

Benjamin

. Global epidemiology of atrial fibrillation. Nat Rev Cardiol. 2014;11(11):639–654.

Barrios

Calderon

Escobar

de la Figuera

; Primary Care Group in the Clinical Cardiology Section of the Spanish Society of Cardiology. Patients with atrial fibrillation in a primary care setting: Val-FAAP study [in English, Spanish]. Rev Esp Cardiol. 2012;65(1):47–53.

Chugh

Havmoeller

Narayanan

. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129(8):837–847.

Poli

Antonucci

. Epidemiology, diagnosis, and management of atrial fibrillation in women. Int J Womens Health. 2015;7:605–614.

Sheikh

Patel

Nalluri

. Trends in hospitalization for atrial fibrillation: epidemiology, cost, and implications for the future. Prog Cardiovasc Dis. 2015;58(2):105–116.

Masjuán

Álvarez-Sabín

Blanco

. Current management of antithrombotic treatment in patients with non valvular atrial fibrillation and prior history of stroke or transient ischemic attack [in Spanish]. Rev Neurol. 2014;59(1):25–36.

Camm

Lip

De Caterina

; ESC Committee for Practice Guidelines (CPG). 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012;33(21):2719–2747.

Barrios

Escobar

Prieto

. Anticoagulation control in patients with nonvalvular atrial fibrillation attended at primary care centers in Spain: the PAULA study. Rev Esp Cardiol (Engl Ed). 2015;68(9):769–776.

Hart

Pearce

Aguilar

. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12):857–867.

10.

Aguilar

Hart

Pearce

. Oral anticoagulants versus antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no history of stroke or transient ischemic attacks. Cochrane Database Syst Rev. 2007;(3):CD006186.

11.

Haeusler

Gerth

Limbourg

; AFNET registry investigators. Use of vitamin K antagonists for secondary stroke prevention depends on the treating healthcare provider in Germany—results from the German AFNET registry. BMC Neurol. 2015;15:129.

12.

Barrios

Escobar

Prieto

Lobos

Polo

Vargas

. Control of anticoagulation with warfarin or acenocoumarol in Spain. Do they differ? Rev Esp Cardiol (Engl Ed). 2015;68(12):1181–1182.

13.

Barrios

Escobar

. Rivaroxaban: a once-daily anticoagulant for the prevention of thromboembolic complications. Expert Rev Cardiovasc Ther. 2013;11(2):129–141.

14.

Rong

Jia

Huang

Lynn

Zhang

. Safety of the direct-acting anticoagulants in patients with atrial fibrillation: a meta-analysis. Thromb Res. 2015;135(6):1117–1123.

15.

Nunes

Rodrigues

Gonçalves

. Comparative analysis and meta-analysis of major clinical trials with oral factor Xa inhibitors versus warfarin in atrial fibrillation. Open Heart. 2014;1(1):e000080.

16.

Jia

Lynn

Rong

Zhang

. Meta-analysis of efficacy and safety of the new anticoagulants versus warfarin in patients with atrial fibrillation. J Cardiovasc Pharmacol. 2014;64(4):368–374.

17.

Ruff

Giugliano

Braunwald

. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955–962.

18.

Patel

Mahaffey

Garg

; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–891.

19.

Connolly

Ezekowitz

Yusuf

; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–1151.

20.

Granger

Alexander

McMurray

; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–992.

21.

Giugliano

Ruff

Braunwald

; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–2104.

22.

Barnes

Lucas

Alexander

Goldberger

. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128(12):1300–1305.

23.

Belen

Canbolat

Bayyigit

Helvaci

Pusuroglu

Kilickesmez

. A new gap in the novel anticoagulants’ era: undertreatment. Blood Coagul Fibrinolysis. 2015;26(7):793–797.

24.

Kilickiran Avci

Vatan

Tok

. The trends in utilizing nonvitamin K antagonist oral anticoagulants in patients with nonvalvular atrial fibrillation: a real-life experience. Clin Appl Thromb Hemost. 2015. pii:1076029615581365.

25.

Barón-Esquivias

Fernández-Avilés

Atienza

Pastor Pueyo

Toro

Sanmartín Fernández

. Efficacy and safety of rivaroxaban in real-life patients with atrial fibrillation. Expert Rev Cardiovasc Ther. 2015;13(4):341–353.

26.

European Medicines Agency (EMA). Xarelto®, “Summary of Product Characteristics”. Web site. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000944/WC500057108.pdf. Updated July 17, 2015. Accessed August 31, 2016.

27.

Trujillo

Dobesh

. Clinical use of rivaroxaban: pharmacokinetic and pharmacodynamic rationale for dosing regimens in different indications. Drugs. 2014;74(14):1587–1603.

28.

Kubitza

Becka

Mück

Krätzschmar

. Pharmacodynamics and pharmacokinetics during the transition from warfarin to rivaroxaban: a randomized study in healthy subjects. Br J Clin Pharmacol. 2014;78(2):353–363.

29.

Kreutz

. Pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct factor Xa inhibitor. Curr Clin Pharmacol. 2014;9(1):75–83.

30.

Mueck

Stampfuss

Kubitza

Becka

. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet. 2014;53(1):1–16.

31.

Salem

Sabouret

Funck-Brentano

Hulot

. Pharmacology and mechanisms of action of new oral anticoagulants. Fundam Clin Pharmacol. 2015;29(1):10–20.

32.

Kubitza

Becka

Roth

Mueck

. The influence of age and gender on the pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct factor Xa inhibitor. J Clin Pharmacol. 2013;53(3):249–255.

33.

Safouris

Demulder

Triantafyllou

Tsivgoulis

. Rivaroxaban presents a better pharmacokinetic profile than dabigatran in an obese non-diabetic stroke patient. J Neurol Sci. 2014;346(1-2):366–367.

34.

Kubitza

Roth

Becka

. Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban, an oral, direct factor Xa inhibitor. Br J Clin Pharmacol. 2013;76(1):89–98.

35.

De Vriese

Caluwé

Bailleul

. Dose-finding study of rivaroxaban in hemodialysis patients. Am J Kidney Dis. 2015;66(1):91–98.

36.

Wannhoff

Weiss

Schemmer

Stremmel

Gotthardt

. Increased levels of rivaroxaban in patients after liver transplantation treated with cyclosporine A. Transplantation. 2014;98(2):e12–e13.

37.

Moore

Vaidyanathan

Natarajan

Ariyawansa

Haskell

Turner

. An open-label study to estimate the effect of steady-state erythromycin on the pharmacokinetics, pharmacodynamics, and safety of a single dose of rivaroxaban in subjects with renal impairment and normal renal function. J Clin Pharmacol. 2014;54(12):1407–1420.

38.

Piccini

Hellkamp

Washam

. Polypharmacy and the efficacy and safety of rivaroxaban versus warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Circulation. 2016;133(4):352–356.

39.

Agnelli

Gallus

Goldhaber

; ODIXa-DVT Study Investigators. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in patients with acute symptomatic Deep-Vein Thrombosis) study. Circulation. 2007;116(2):180–187.

40.

Buller

Lensing

Prins

; Einstein-DVT Dose-Ranging Study Investigators. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT Dose-Ranging Study. Blood. 2008;112(6):2242–2247.

41.

Girgis

Patel

Peters

. Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET AF. J Clin Pharmacol. 2014;54(8):917–927.

42.

Halperin

Hankey

Wojdyla

; ROCKET AF Steering Committee and Investigators. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation 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 (ROCKET AF). Circulation. 2014;130(2):138–146.

43.

Hankey

Patel

Stevens

; ROCKET AF Steering Committee Investigators. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol. 2012;11(4):315–322.

44.

Fox

Piccini

Wojdyla

. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011;32(19):2387–2394.

45.

Bansilal

Bloomgarden

Halperin

; ROCKET AF Steering Committee and Investigators. Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: the Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF Trial). Am Heart J. 2015;170(4):675–682.

46.

Mahaffey

Stevens

White

; ROCKET AF Investigators. Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial. Eur Heart J. 2014;35(4):233–241.

47.

van Diepen

Hellkamp

Patel

. Efficacy and safety of rivaroxaban in patients with heart failure and nonvalvular atrial fibrillation: insights from ROCKET AF. Circ Heart Fail. 2013;6(4):740–747.

48.

Jones

Hellkamp

Halperin

. Efficacy and safety of rivaroxaban compared with warfarin in patients with peripheral artery disease and non-valvular atrial fibrillation: insights from ROCKET AF. Eur Heart J. 2014;35(4):242–249.

49.

Breithardt

Baumgartner

Berkowitz

; ROCKET AF Steering Committee & Investigators. Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial. Eur Heart J. 2014;35(47):3377–3385.

50.

Steinberg

Hellkamp

Lokhnygina

; ROCKET AF Steering Committee and Investigators. Use and outcomes of antiarrhythmic therapy in patients with atrial fibrillation receiving oral anticoagulation: results from the ROCKET AF trial. Heart Rhythm. 2014;11(6):925–932.

51.

Wong

Oomman

; Executive Steering Committee and the ROCKET AF Study Investigators. Rivaroxaban for stroke prevention in East Asian patients from the ROCKET AF trial. Stroke. 2014;45(6):1739–1747.

52.

Piccini

Hellkamp

Lokhnygina

; ROCKET AF Investigators. Relationship between time in therapeutic range and comparative treatment effect of rivaroxaban and warfarin: results from the ROCKET AF trial. J Am Heart Assoc. 2014;3(2):e000521.

53.

Hankey

Stevens

Piccini

; ROCKET AF Steering Committee and Investigators. Intracranial hemorrhage among patients with atrial fibrillation anticoagulated with warfarin or rivaroxaban: the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation. Stroke. 2014;45(5):1304–1312.

54.

Piccini

Garg

Patel

; ROCKET AF Investigators. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J. 2014;35(28):1873–1880.

55.

Sherwood

Douketis

Patel

; ROCKET AF Investigators. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation. 2014;129(18):1850–1859.

56.

Patel

Hellkamp

Lokhnygina

. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: analysis from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). J Am Coll Cardiol. 2013;61(6):651–658.

57.

Mahaffey

Wojdyla

Hankey

. Clinical outcomes with rivaroxaban in patients transitioned from vitamin K antagonist therapy: a subgroup analysis of a randomized trial. Ann Intern Med. 2013;158(12):861–868.

58.

Mahaffey

Hellkamp

Patel

. End of study transition from study drug to open-label vitamin K antagonist therapy: the ROCKET AF experience. Circ Cardiovasc Qual Outcomes. 2013;6(4):470–478.

59.

Piccini

Stevens

Lokhnygina

; ROCKET AF Steering Committee & Investigators. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol. 2013;61(19):1998–2006.

60.

Kaneko

Tanigawa

Hashizume

Kajikawa

Tajiri

Mueck

. Confirmation of model-based dose selection for a Japanese phase III study of rivaroxaban in non-valvular atrial fibrillation patients. Drug Metab Pharmacokinet. 2013;28(4):321–331.

61.

Japanese Circulation Society Joint Working Group. Guidelines for pharmacotherapy of atrial fibrillation (JCS 2008): digest version. Circ J. 2010;74(11):2479–2500.

62.

Hori

Matsumoto

Tanahashi

; J-ROCKET AF Study Investigators. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation. Circ J. 2012;76(9):2104–2111.

63.

Patel

Hellkamp

Fox

; ROCKET AF Executive Committee and Investigators. Point-of-care warfarin monitoring in the ROCKET AF trial. N Engl J Med. 2016;374(8):785–758.

64.

Steinberg

Holmes

Ezekowitz

. Rate versus rhythm control for management of atrial fibrillation in clinical practice: results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. Am Heart J. 2013;165(4):622–629.

65.

Lip

Rushton-Smith

Goldhaber

; GARFIELD-AF Investigators. Does sex affect anticoagulant use for stroke prevention in nonvalvular atrial fibrillation? The prospective global anticoagulant registry in the FIELD-Atrial Fibrillation. Circ Cardiovasc Qual Outcomes. 2015;8(2 suppl 1):S12–S20.

66.

Le Heuzey

Ammentorp

Darius

. Differences among western European countries in anticoagulation management of atrial fibrillation. Data from the PREFER IN AF registry. Thromb Haemost. 2014;111(5):833–841.

67.

Steinberg

Kim

Thomas

; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Investigators and Patients. Lack of concordance between empirical scores and physician assessments of stroke and bleeding risk in atrial fibrillation: results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. Circulation. 2014;129(20):2005–2012.

68.

Verheugt

Granger

. Oral anticoagulants for stroke prevention in atrial fibrillation: current status, special situations, and unmet needs. Lancet. 2015;386(9990):303–310.

69.

Agarwal

Hachamovitch

Menon

. Current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation: a meta-analysis. Arch Intern Med. 2012;172(8):623–631.

70.

Caldeira

Rodrigues

Barra

. Non-vitamin K antagonist oral anticoagulants and major bleeding-related fatality in patients with atrial fibrillation and venous thromboembolism: a systematic review and meta-analysis. Heart. 2015;101(15):1204–1211.

71.

Hagii

Tomita

Metoki

. Characteristics of intracerebral hemorrhage during rivaroxaban treatment: comparison with those during warfarin. Stroke. 2014;45(9):2805–2807.

72.

Tamayo

Frank Peacock

Patel

, Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of 27467 patients taking rivaroxaban. Clin Cardiol. 2015;38(2):63–68.

73.

Beyer-Westendorf

Förster

Pannach

. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood. 2014;124(6):955–962.

74.

Camm

Amarenco

Haas

; XANTUS Investigators. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J. 2016;37(14):1145–1153.

75.

Tamayo

Patel

Yuan

. Post-marketing pharmacovigilance study for the active detection and evaluation of major bleeding in rivaroxaban users with non-valvular atrial fibrillation. J Am Coll Cardiol. 2015;65(suppl 10):A281.

76.

Engelberger

Noll

Schmidt

. Initiation of rivaroxaban in patients with nonvalvular atrial fibrillation at the primary care level: The Swiss Therapy in Atrial Fibrillation for the Regulation of Coagulation (STAR) Study. Eur J Intern Med. 2015;26(7):508–514.

77.

Laliberté

Cloutier

Nelson

. Real-world comparative effectiveness and safety of rivaroxaban and warfarin in nonvalvular atrial fibrillation patients. Curr Med Res Opin. 2014;30(7):1317–1325.

78.

Fontaine

Mathews

Woller

Stevens

Lloyd

Evans

. Major bleeding with dabigatran and rivaroxaban in patients with atrial fibrillation: a real-world setting. Clin Appl Thromb Hemost. 2014;20(7):665–672.

79.

Clemens

Strack

Noack

Konstantinides

Brueckmann

Lip

. Anticoagulant-related gastrointestinal bleeding—could this facilitate early detection of benign or malignant gastrointestinal lesions? Ann Med. 2014;46(8):672–678.

80.

Beg

Patel

Bhuva

. Mind over matter? Gastrointestinal bleeding due to the use of novel oral anticoagulants in stroke prevention. Presented at: British Society of Gastroenterology Annual General Meeting; June 16-19, 2014. Gut. 63:A58–A59.

81.

Abraham

Singh

Alexander

. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. BMJ. 2015;350:h1857.

82.

Goodman

Wojdyla

Piccini

; ROCKET AF Investigators. Factors associated with major bleeding events: insights from the ROCKET AF trial (Rivaroxaban Once-Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). J Am Coll Cardiol. 2014;63(9):891–900.

83.

Pfeilschifter

Luger

Brunkhorst

Lindhoff-Last

Foerch

. The gap between trial data and clinical practice—an analysis of case reports on bleeding complications occurring under dabigatran and rivaroxaban anticoagulation. Cerebrovasc Dis. 2013;36(2):115–119.

84.

Coleman

Antz

Ehlken

Evers

. REal-LIfe Evidence of stroke prevention in patients with atrial fibrillation—the RELIEF study. Int J Cardiol. 2016;203:882–884.

85.

Halperin

Huisman

Diener

. Patterns of newly detected atrial fibrillation and antithrombotic treatment in North America (GLORIA-AF Phase III). J Am Coll Cardiol. 2015;65(10S):A1520.

86.

Halperin

Huisman

Diener

. Antithrombotic treatment in relation to age in patients with newly diagnosed atrial fibrillation in North America (GLORIA-AF Phase III). J Am Coll Cardiol. 2015;65(10S):A1528.

87.

Pollack

Jr Reilly

Eikelboom

. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511–520.

88.

Crowther

. Antidotes for novel oral anticoagulants: current status and future potential. Arterioscler Thromb Vasc Biol. 2015;35(8):1736–1745.

89.

Proietti

Lip

. Antidotes to non-vitamin K oral anticoagulants: necessary or not? Expert Opin Pharmacother. 2015;16(11):1573–1576.

90.

Sarich

Seltzer

Berkowitz

. Novel oral anticoagulants and reversal agents: considerations for clinical development. Am Heart J. 2015;169(6):751–757.

91.

Martinez

Katholing

Wallenhorst

Freedman

. Therapy persistence in newly diagnosed non-valvular atrial fibrillation treated with warfarin or NOAC. A cohort study. Thromb Haemost. 2016;115(1):31–39.

92.

Beyer-Westendorf

Förster

Ebertz

. Drug persistence with rivaroxaban therapy in atrial fibrillation patients-results from the Dresden Non-Interventional Oral Anticoagulation Registry. Europace. 2015;17(4):530–538.

93.

Laliberté

Nelson

Lefebvre

Schein

Rondeau-Leclaire

Duh

. Impact of daily dosing frequency on adherence to chronic medications among nonvalvular atrial fibrillation patients. Adv Ther. 2012;29(8):675–690.

94.

McHorney

Crivera

Laliberté

. Adherence to non-vitamin-K-antagonist oral anticoagulant medications based on the Pharmacy Quality Alliance measure. Curr Med Res Opin. 2015;31(12):2167–2173.

95.

Cieri

Kusmierski

. Acute ischemic stroke in a patient with documented compliance to rivaroxaban. Austin J Pharmacol Ther. 2014;2(9):id1050.

96.

Heidbuchel

Verhamme

Alings

. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2015;17(10):1467–1507.

97.

Lee

Anglade

Pham

Pisacane

Kluger

Coleman

. Cost-effectiveness of rivaroxaban compared to warfarin for stroke prevention in atrial fibrillation. Am J Cardiol. 2012;110(6):845–851.

98.

Kleintjens

Simoens

. Cost-effectiveness of rivaroxaban versus warfarin for stroke prevention in atrial fibrillation in the Belgian healthcare setting. Pharmacoeconomics. 2013;31(10):909–918.