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Abstract

Rivaroxaban, a direct factor Xa inhibitor, is a novel oral anticoagulant approved for stroke prevention in patients with nonvalvular atrial fibrillation and also approved in Europe (but not in the United States) to prevent recurrent ischemic events in patients with recent acute coronary syndromes. Advantages of rivaroxaban over oral anticoagulants such as warfarin are the lack of need for ongoing monitoring, a fixed-dose regimen, and fewer drug and food interactions. Drawbacks include a lack of an antidote and the absence of a widely available method to reliably monitor the anticoagulant effect. In patients at risk of stroke due to atrial fibrillation, rivaroxaban was noninferior compared to warfarin in preventing stroke/systemic embolism 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) trial and was associated with a similar risk of major bleeding; the incidence of intracranial hemorrhage was 33% lower with rivaroxaban. Concerns raised about the trial were the adequacy of warfarin management and the increase in event rate at the end of the trial. The drug acquisition cost of rivaroxaban is higher than that of warfarin although decision-analytic models suggest that it is cost effective in atrial fibrillation. In patients with recent acute coronary syndrome, low-dose rivaroxaban reduced mortality and the composite end point of death from cardiovascular causes, myocardial infarction and stroke, but this was accompanied by an increased risk of intracranial hemorrhage and major bleeding in the Rivaroxaban in Combination With Aspirin Alone or With Aspirin and a Thienopyridine in Patients With Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction (ATLAS ACS 2-TIMI) 51 trial. Thus, rivaroxaban appears to be a valuable addition to the therapeutic armamentarium in atrial fibrillation although caution should be exercised, given the limited experience in combination with novel oral antiplatelet agents. The role of rivaroxaban as part of a modern regimen in acute coronary syndrome continues to be evaluated.

Keywords

rivaroxaban anticoagulant atrial fibrillation acute coronary syndrome

Introduction

Rivaroxaban (Xarelto) is a novel oral anticoagulant (NOAC) that has been approved by the US Food and Drug Administration (FDA) for stroke and systemic embolism prevention in atrial fibrillation (AF). It has also been approved for venous thromboembolism (VTE) prevention in orthopedic surgery and for the acute treatment of VTE based on the Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism (RECORD) and EINSTEIN studies, respectively, and will not be discussed further as part of the review.^1

–7 Rivaroxaban has also been evaluated in acute coronary syndrome (ACS) and was recently approved for this indication in Europe.⁸ Rivaroxaban has several advantages over vitamin K antagonists (VKAs) such as warfarin, including a fixed dose, a lack of need for regular monitoring, and fewer food and drug interactions. However, there is no available direct antidote for rivaroxaban, no reliable and widely available test to monitor the anticoagulant activity of the drug, and it is more expensive than VKAs. The purpose of this article is to discuss the role of rivaroxaban in AF and ACSs by reviewing the clinical evidence from phase III trials and economic analyses.

Clinical Overview of Rivaroxaban

Rivaroxaban is an oral direct, reversible, and dose-dependent inhibitor of factor Xa, blocking free and bound factor Xa.⁹ It has a shallow dose–response curve for effectiveness but a steeper dose–response curve for safety; thus, small increases in dose have a limited effect on increasing the efficacy but may be accompanied by a rise in the risk of bleeding.

The liver is the main route of elimination for rivaroxaban and it is extensively metabolized by the cytochrome P450 (CYP) enzyme system.^10,11 Rivaroxaban is also excreted, in part, by permeability glycoprotein (P-gp) with potent P-gp inhibitors increasing rivaroxaban levels. Concomitant administration should be avoided with strong CYP3A4 and P-gp inhibitors (eg, azoles) and inducers (eg, rifampin), while caution should be exercised with weak CYP3A4 inhibitors and inducers. Rivaroxaban should be avoided in patients with Child-Pugh B or C hepatic impairment and in those with liver disease associated with coagulopathy as exposure is increased and has been associated with prolongation of prothrombin time (PT).

Renal impairment results in modest increases in drug exposure, with a more pronounced effect on factor Xa inhibition.¹² Rivaroxaban should be avoided in patients with a creatinine clearance (CrCl) of less than 15 mL/min. In patients with AF having a CrCl of 15 to 50 mL/min, a reduced dose is recommended (15 mg vs 20 mg).¹³ As patients with a CrCl of 15 to 30 mL/min were excluded from clinical trials, recommendations for these patients are based on pharmacokinetic data.^1,2,6,8 Periodic renal function monitoring is recommended in patients with rivaroxaban as clinically indicated.¹⁴

Rivaroxaban has a half-life of 5 to 11 hours in healthy younger individuals and 11 to 13 hours in elderly individuals. It is dosed once daily in patients with AF.¹⁵ Findings from the phase II dose-ranging ACS study showed that efficacy and bleeding were generally similar between the once-daily and twice-daily dosing groups; however, pharmacokinetic studies showed more consistent levels (lower peaks and more shallow troughs) with twice-daily dosing compared to once daily dosing.¹⁶ Thus, twice-daily dosing was studied in the phase III ACS trial.⁸

In pregnancy, rivaroxaban is labeled as category C, while during lactation, rivaroxaban should be discontinued or nursing should be halted.¹⁷ The safety and effectiveness have not been established in pediatrics although there is an ongoing pharmacodynamic and pharmacokinetic study (NCT01684423) and a clinical study in venous thrombosis in children (NCT01145859).¹⁸

Although routine monitoring is not required, it may be considered in cases of severe bleeding, renal failure, need for urgent surgery, or in patients at extremes of body weight. The PT is influenced by rivaroxaban in a dose-dependent manner but only with some and not all reagents.¹⁹ In addition, activated partial thromboplastin time and antifactor Xa activity are also affected by rivaroxaban but a standard for calibration for this agent is currently lacking.

Rivaroxaban should be discontinued at least 24 hours (longer in patients with renal impairment) before a planned procedure although the risk of bleeding should be weighed against the urgency of the intervention and should be restarted as soon as hemostasis is established. Stopping rivaroxaban in patients with AF, without substituting another anticoagulant, increases the risk of thrombotic events. Caution should be exercised when administering rivaroxaban to patients receiving neuraxial anesthesia or undergoing spinal puncture.

Rivaroxaban lacks a specific antidote.²⁰ A recent study showed that 4-factor prothrombin complex concentrates reversed the anticoagulant effect of rivaroxaban.²¹ In vitro data suggest that recombinant factor VIIa (rFVIIa) and factor VIII inhibitor bypassing activity (FEIBA) may partially reverse the effect of rivaroxaban.²² However, clinical data are lacking and the thromboembolic potential and high cost of these agents are of concern. Plasma-derived and recombinant factor Xa antidotes show promise but additional data are needed. Of note, Phase II trial results of a recombinant protein antidote in healthy volunteers are expected soon.²³

Rivaroxaban in AF

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) study was a double-blind, double-dummy trial in which patients with nonvalvular AF and a history of stroke or at least 2 risk factors for stroke (ie, heart failure or left ventricular ejection fraction less than or equal to 35%, hypertension, age 75 or more, or diabetes) were eligible for entry.²⁴ Patients were randomized to receive rivaroxaban 20 mg once a day (15 mg daily if CrCl 30-49 mL/min) or international normalized ratio (INR)-adjusted warfarin daily (goal INR 2-3). Key exclusion criteria were prosthetic heart valves, hemodynamically significant mitral stenosis, planned cardioversion, CrCl less than 30 mL/min, significant liver disease or aspartate transaminase more than 3 times the upper limit, and active bleeding/significant risk of bleeding. Patients were also excluded if they were receiving strong inhibitors or strong inducers of CYP3A4. Patients on aspirin plus thienopyridines within 5 days of randomization were ineligible for study entry.

The primary end point was stroke (including both ischemic and hemorrhagic stroke) and systemic embolism, while the main safety end points were major bleeding (clinically overt bleeding associated with death, involving a critical site, fall in hemoglobin by at least 2 g/dL, or transfusion of at least 2 units of packed red blood cells or whole blood) and clinically relevant nonmajor bleeding (overt bleeding not meeting criteria for major bleeding but associated with medical intervention, unscheduled contact with physician, temporary cessation of drug, pain, or impairment of daily activities).

Patients (n = 14 171) were, on average, 73 years old and 60% were male. More than 50% of the population was from Europe, with some 20% from North America. Based on the distribution of CHADS₂ scores, the population was at high risk of stroke. The percentage of patients having a CHADS₂ score of 3, 4, and 5 or 6 were 44%, 29%, and 15%, respectively. About half the population had a prior stroke/transient ischemic attack (TIA)/embolism, while about 60% had previously received VKAs. The median follow-up period was 707 days.

Rivaroxaban was noninferior to warfarin for the primary end point of stroke and systemic embolism in the per protocol, as treated population (Table 1). The incidence of hemorrhagic stroke, but not ischemic stroke, was lower with rivaroxaban. There were no statistically significant differences in the rates of death or of myocardial infarction (MI) between the 2 treatment groups although favorable reductions (hazards ratio [HR] for death 0.85, P = .07; HR for MI 0.81, P = .12) were observed with rivaroxaban. In addition, there were significantly fewer intracranial hemorrhages (ICHs) among rivaroxaban patients than warfarin patients (0.5 vs 0.7 events per 100 patient years; HR 0.67, 95% confidence interval [CI] 0.47-0.93). The incidence of major and clinically relevant nonmajor bleeding was not significantly different between warfarin and rivaroxaban (RR 1.03, 95% CI: 0.96-1.11). Although major bleeding occurred with similar frequency between the groups, the subcomponents of critical bleeding and fatal bleeding were more prevalent in the warfarin group. Meanwhile, declines in hemoglobin and transfusion were more common in the rivaroxaban group.

Table 1.

ROCKET-AF: Key Results in Safety Population, on Treatment Population (Except Where Indicated).

End point (Per 100 Patient Years)	Rivaroxaban, N = 7111	Warfarin, N = 7125	HR (95% CI)
Efficacy
Stroke, systemic embolism, per protocol, as treated	1.7	2.2	0.79 (0.66-0.96)
Stroke, systemic embolism, intent-to-treat	2.1	2.4	0.88 (0.75-1.03)
Hemorrhagic stroke	0.26	0.44	0.59 (0.37-0.93)
Ischemic stroke	1.34	1.42	0.94 (0.75-1.17)
Myocardial infarction	0.9	1.1	0.81 (0.63-1.06)
Mortality	1.9	2.2	0.85 (0.70-1.02)
Safety
Major + clinically relevant nonmajor bleeding	14.9	14.5	1.03 (0.96-1.11)
Major bleeding	3.6	3.4	1.04 (0.90-1.20)
Hemoglobin drop of at least 2 g/dL	2.8	2.3	1.22 (1.03-1.44)
Transfusion ≥2 units of packed red cells or whole blood	1.6	1.3	1.25 (1.01-1.55)
Critical site of bleeding^a	0.8	1.2	0.69 (0.53-0.91)
Fatal bleeding	0.2	0.5	0.50 (0.31-0.79)
Clinically relevant nonmajor bleeding	11.8	11.4	1.04 (0.96-1.13)
Intracranial hemorrhage	0.5	0.7	0.67 (0.47-0.93)

Abbreviations: CI, confidence interval; HR, hazards ratio; 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.

^a Intracranial, spinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal.

Warfarin management, as assessed by the time in therapeutic range, indicated that only slightly more than half of the time (55%) did the patients on warfarin have an INR of 2.0 to 3.0. This is similar to what has been reported in a large US Veterans population²⁵ and lower than other contemporary trials^26,27 and far below “best practice centers” in Sweden.²⁸

There was a sharp rise in the event rate in the rivaroxaban arm (more than 3-fold excess) as patients transitioned to a VKA at the end of the trial. This has been attributed to a slow (>30 days) average time to achieve a therapeutic INR among patients who were transitioning from rivaroxaban to warfarin after study completion. However, an increase in thrombogenicity, either due to abrupt cessation of factor Xa inhibition or due to the depletion of protein C and S that first occurs as warfarin is being loaded, may also have played a role.

Food and Drug Administration Advisory Committee

Although the FDA reviewers cited several concerns (eg, inadequacy of warfarin management, higher risk population with greater comorbidities enrolled compared to pivotal warfarin trials, dose selection, and sharp increase in event rate at the end of the trial), the FDA advisory committee voted for approval, concluding that there was a continued need for new therapies in this area and that concerns could be addressed in postmarketing studies.

Updated Guidelines

Four guidelines from major professional societies have addressed the use of NOAC in AF.^14,29
–31 The European Society of Cardiology recommends the use of NOAC over INR-adjusted VKA in patients with a CHA₂DS₂-VASc score of 1 or higher (Class IIa, level of evidence A).¹⁴ In patients with a CrCl of 30 to 49 mL/min, a reduced dose of rivaroxaban is recommended (15 mg daily instead of 20 mg daily; Class IIa, level of evidence C). Similarly, guidelines from the Canadian Cardiovascular Society have a strong recommendation (high-quality evidence) that NOAC be used over INR-adjusted VKA in patients with a CHADS₂ score of 1 or higher.³⁰ The American Heart Association/American Stroke Association recommended rivaroxaban 20 mg daily as an alternative to warfarin in patients at moderate to high risk of stroke (prior TIA, stroke, systemic embolism, or 2 other risk factors; Class IIa, level of evidence B) with a reduced dose of 15 mg daily in patients with a CrCl of 15 to 50 mL/min (Class IIb, level of evidence C).²⁹ Guidelines from the American College of Chest Physicians do not provide recommendations for rivaroxaban although do recommend another NOAC, dabigatran, over INR-adjusted VKA in patients with a CHADS₂ score of at least 1 (Grade 2b).³¹

Rivaroxaban in Acute Coronary Syndromes

Although the underlying disease state and background antiplatelet therapies differ, the experiences with rivaroxaban in patients with venothromboembolism and AF have provided important insights into the dosing of rivaroxaban in patients with ACS. Rivaroxaban in Combination With Aspirin Alone or With Aspirin and a Thienopyridine in Patients With Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction (ATLAS ACS-TIMI) 46 was a phase 2, dose-finding trial designed to test a broad range of rivaroxaban doses (total daily doses of 5 mg-20 mg) in once-daily and twice-daily regimens among patients with a recent ACS treated with antiplatelet therapies (of whom 78% received dual antiplatelet therapy). Rivaroxaban reduced a secondary composite end point of death, MI, or stroke compared with placebo and was associated with a dose-dependent increased risk of bleeding.¹⁶ Lower doses of twice-daily rivaroxaban appeared to have had the more favorable balance of efficacy and safety.

Based on these observations, a phase 3 trial was designed to evaluate 2 low doses of rivaroxaban—2.5 mg twice daily and 5 mg twice daily—as adjunctive therapy in patients with post-ACS (ATLAS-ACS-2-TIMI 51).⁸ Patients younger than 55 years old were also required to have an additional risk feature such as diabetes mellitus or a prior MI (excluding the index event). Standard adjunctive ACS therapies including dual antiplatelet therapy were encouraged according to practice guidelines. Key exclusion criteria were a platelet count less than 90 000 per mm³, a hemoglobin level less than 10 g/dL, CrCl less than 30 mL/min at screening, clinically significant gastrointestinal bleeding within 12 months before randomization, previous ICH, and previous ischemic stroke or TIA while taking both aspirin and a thienopyridine.

The primary efficacy end point was a composite of death from cardiovascular causes, MI, or stroke. A secondary efficacy end point was combined death from any cause, MI, or stroke. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding not related to coronary artery bypass grafting (CABG; defined as any intracranial or clinically overt bleeding event that is associated with a decrease in hemoglobin of ≥5 g/dL or an absolute drop in hematocrit of ≥15%). Bleeding requiring medical attention was defined as any bleeding event that required medical treatment, surgical treatment, or laboratory evaluation that did not meet the criteria for TIMI major bleeding or TIMI minor bleeding.

The average age of patients (n = 15 526) was 62 years; approximately 75% were male and 73% were white. The ST-segment elevation MI (STEMI) was the most common index diagnosis (50%) while similar proportions of patients had non-STEMI (26%) and unstable angina (24%). The patients were generally managed with an invasive approach (approximately 80% underwent angiography prior to randomization) with percutaneous coronary intervention or CABG performed in 60% of patients for the index event. Approximately 40% of patients were from Eastern Europe, 20% were from Asia, 14% were from Western Europe; North American patients accounted for <6% of study participants. Aspirin, thienopyridines, and statins were used almost universally at baseline (more than 98%, 92%, and 83%, respectively, with 93% receiving dual antiplatelet therapy), with 66% of patients using β-blockers and 40% on angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers.

Twice-daily rivaroxaban, regardless of dose, significantly reduced the risk of the primary efficacy end point compared to placebo (Table 2). In the lower dose group, the difference was driven by a reduction in death from cardiovascular causes, while in the higher dose group, the benefit was due to a reduction in MI. Death from any cause was significantly less common with rivaroxaban 2.5 mg twice a day versus placebo but not with rivaroxaban 5 mg.

Table 2.

ATLAS-ACS-2-TIMI 51 (ATLAS-2): Key Results in Modified Intention-to-Treat Population.

End point (Per 100 Patient Years), HR (95% CI; all vs placebo)	Rivaroxaban 2.5 mg twice daily, N = 5114	Rivaroxaban 5 mg twice a day, N = 5114	Placebo, N = 5113
Cardiovascular death, MI, stroke (primary end point)	9.1, 0.84 (0.72-0.97)	8.8, 0.85 (0.73-0.98)	10.7
Death from cardiovascular causes	2.7, 0.66 (0.51-0.86)	4%, 0.94 (0.75-1.20)	4.1
Myocardial infarction	6.1, 0.90 (0.75-1.09)	4.9, 0.79 (0.65-0.97)	6.6
Stroke	1.4, 1.13 (0.74-1.73)	1.7, 1.34 (0.90-2.02)	1.2
Death from any cause, MI, stroke	9.3, 0.83 (0.72-0.97)	9.1, 0.84 (0.73-0.98)	11%
Death from any cause	2.9, 0.68 (0.53-0.87)	4.4, 0.95 (0.76-1.19)	4.5
Stent thrombosis	2.2, 0.65 (0.45-0.94)	2.3, 0.73 (0.51-1.04)	2.9
TIMI major bleeding (non-CABG related)	1.8, 3.46 (2.08-5.77)	2.4, 4.47 (2.71-7.36)	0.6
TIMI bleeding requiring medical attention	12.9, 1.79 (1.55-2.07)	16.2, 2.39 (2.08-2.75)	7.5
Intracranial hemorrhage	0.4, 2.83 (1.02-7.86)	0.7, 3.74 (1.39-10.07)	0.2

Abbreviations: ATLAS-ACS-2-TIMI 51, Rivaroxaban in Combination With Aspirin Alone or With Aspirin and a Thienopyridine in Patients With Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction; CABG, coronary artery bypass grafting; CI, confidence interval; HR, hazard ratio; MI, myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction.

Compared to placebo, rivaroxaban, irrespective of dose, was associated with an increased risk of TIMI major bleeding not related to CABG. Likewise, there was a higher incidence of TIMI major bleeding that required medical attention and ICH (P < .05 for each rivaroxaban dose vs placebo). The rates of other adverse events in the rivaroxaban groups were not different from those in the placebo group. The rates of bleeding were significantly lower in the 2.5 mg group compared to the 5 mg group (TIMI minor bleeding [0.9% vs 1.6%, P = .046], TIMI bleeding requiring medical attention [12.9% vs 16.2%, P < .001], and fatal bleeding [0.1% vs 0.4%, P = .04]).

Food and Drug Administration and European Medicine Agency Reviews

The FDA Cardiovascular and Renal Drugs Advisory Committee voted 6 to 4 against recommending approval of rivaroxaban for ACS in May 2012.³² Concerns cited by the committee included increased bleeding (compared to placebo), amount of missing data, and use of a modified intent-to-treat analysis. In January 2014, this committee voted unanimously against approving rivaroxaban for use in the 90 days following ACS.³³

Of note, the European Medicines Agency recently recommended that rivaroxaban 2.5 mg twice a day be approved in adult patients after an ACS with elevated cardiac biomarkers when coadministered with aspirin alone or with aspirin plus clopidogrel or ticlopidine for the prevention of atherothrombotic events.³⁴

Postmarketing Requirements

The FDA has mandated 2 postmarketing studies for rivaroxaban: (1) a pharmacovigilance study of risk factors, clinical management, and outcome of cases of major bleeding, and (2) a clinical trial to evaluate the effect of renal impairment plus concurrent use of P-gp inhibitors and moderate CYP3A4 inhibitors.³⁵ The manufacturer is required to develop a 5 mg tablet or scored 10 mg tablet for patients at risk of increased exposure to drug. The European Medicines Agency has required an observational cohort study in 15 000 rivaroxaban patients as well as drug utilization database analyses to assess bleeding risk, renal impairment, overdose, drug interactions, use in pregnancy and lactation, and use in VTE prevention in orthopedic surgery.³⁶

Ongoing Studies With Rivaroxaban

Rivaroxaban studies that are currently in progress¹⁸ include those that are examining the transition of rivaroxaban to and from warfarin (NCT01507051); reversal of rivaroxaban in healthy volunteers using PCC, FEIBA, rFVIIa as well as a novel rivaroxaban decoy—Fxa-GLAless (NCT01210755); and use in patients scheduled for cardioversion (NCT01747746 and NCT01674647). The VENTURA AF study is evaluating the use of rivaroxaban compared to VKA in the setting of catheter ablation (NCT01729871). Also, studies in patients with AF are underway with rivaroxaban given on an “as-needed basis” (ie, when a device detects AF has occurred) that is hypothesized to reduce the risk of bleeding compared to continuous use (NCT01706146) as well as trials in patients with both AF and ACS (NCT01812200). One of the largest ongoing studies (N = 2110) with rivaroxaban is An OPen-label, Randomized, Controlled, Multicenter Study ExplorIng TwO TreatmeNt StratEgiEs of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention - PIONEER AF-PCI (NCT01830543); the purpose of this study is to evaluate the safety of 2 different treatment strategies with rivaroxaban and compared to a treatment strategy utilizing a VKA as the anticoagulant, with various combinations of background antiplatelet therapy over the course of 12 months.

Economics of Rivaroxaban

Several economic analyses of rivaroxaban in patients with AF have been conducted, primarily using Markov modeling of key clinical trials.^37

–42 In the 2 US models, the incremental cost-effectiveness ratio (ICER) with rivaroxaban varied from US$3190 to US$27 498 per quality-adjusted life years (QALY) gained compared to warfarin.^39,40 In the United States, a cost/QALY gained of less than US$50 000 to US$100 000 is generally accepted to be a cost-effective therapy based on Medicare’s coverage for dialysis.⁴³

In an analysis from the United Kingdom,⁴² the ICER of rivaroxaban over warfarin was £18 883 per QALY gained, where a cost/QALY of less than £30 000 is generally considered to be acceptable for National Health Service coverage of drugs. Similarly, a Canadian analysis found an ICER of $Can55 757 per QALY/gained.³⁷

Another economic analysis estimated the reduction in event costs compared to warfarin based on the ROCKET-AF study.³⁸ Of note, drug and monitoring costs were excluded. There was a reduction in costs associated with primary and secondary events such as stroke and MI (−US$142 and −US$57, respectively) coupled with an increase in costs associated with bleeding (US$111), leading to a reduction in total costs of US$89 (95% CI US$135 to −US$301).

From the patients’ perspective, the key cost will be copayments for rivaroxaban. A sample review of major health plans in the United States generally shows that warfarin is associated with lower out-of-pocket expenses (tier 1) compared to rivaroxaban (tier 2 or 3) which may also be subject to quantity limits or prior authorization.⁴⁴ In 2012, the average copayment for tier 1, tier 2, tier 3, and tier 4 drugs was US$10, US$29, US$51, and US$79, respectively.⁴⁵

Conclusion

The advent of NOAC represents a major advance in cardiology. In AF, rivaroxaban is at least as effective as warfarin in preventing stroke and systemic embolism with a similar risk of bleeding.⁶ Notably, rivaroxaban is associated with a lower risk of hemorrhagic stroke and ICH by 41% and 33%, respectively. In addition, available information suggests that rivaroxaban is cost effective compared to warfarin.^41,42 Several national guidelines are now suggesting these newer agents over warfarin in patients with AF requiring oral anticoagulation, placing a high value on comparisons that show similar efficacy and bleeding but fewer ICH.^14,30 However, in patients already on warfarin with stable INR and no bleeding, there may be less incentive to switch to the NOAC, especially given higher out-of-pocket costs to patients. Even in patients well controlled with warfarin, rivaroxaban, like other NOACs, offers several practical advantages over warfarin including ease of use, lack of need for routine monitoring, fewer drug–drug interactions, and no food–drug interactions. Issues such as how to reverse the anticoagulant effect prior to emergent procedures or during a serious hemorrhage, transition to VKAs, use during cardioversion, and monitor the anticoagulant effect remain under investigation and these data are eagerly awaited.

The role of rivaroxaban in patients with ACS (approved in Europe but not in the United States) continues to be explored. The current standard of care in patients with ACS is the use of dual antiplatelet agents—aspirin plus a P2Y12 inhibitor.^14,46 However, the novel P2Y12 inhibitors (eg, prasugrel and ticagrelor) have not been studied in combination with rivaroxaban.

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. Prabashni Reddy has no conflicts of interest to declare. Robert P. Giugliano is a member of the TIMI Study Group, which has received research grant support from AstraZeneca, Daiichi Sankyo, Johnson & Johnson, Merck, and Sanofi to conduct clinical trials with antithrombotic drugs. Dr. Giugliano has received honoraria for CME lectures and/or consulting from Bristol-Myers Squibb, Pfizer Daiichi Sankyo, Jansssen, Merck, and Sanofi.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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The Role of Rivaroxaban in Atrial Fibrillation and Acute Coronary Syndromes

Abstract

Keywords

Introduction

Clinical Overview of Rivaroxaban

Rivaroxaban in AF

Food and Drug Administration Advisory Committee

Updated Guidelines

Rivaroxaban in Acute Coronary Syndromes

Food and Drug Administration and European Medicine Agency Reviews

Postmarketing Requirements

Ongoing Studies With Rivaroxaban

Economics of Rivaroxaban

Conclusion

Footnotes

Declaration of Conflicting Interests

Funding

References