Embolism Associated with Atrial Fibrillation
Rivaroxaban is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Current evidence suggests that rivaroxaban is no less effective than warfarin for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and does not increase the risk of major bleeding relative to warfarin. However, there are limited data on the relative efficacy of rivaroxaban and warfarin for the reduction of stroke and systemic embolism when warfarin anticoagulation is well controlled. Efficacy of rivaroxaban for the prevention of postcardioversion stroke and systemic embolism in patients with atrial fibrillation has not been established. Efficacy and safety of the drug in patients with prosthetic heart valves also have not been established.
(See Patients with Prosthetic Heart Valves under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
The American College of Chest Physicians (ACCP), the American College of Cardiology (ACC), the American Heart Association (AHA), the American Stroke Association (ASA), and other experts currently recommend that antithrombotic therapy be administered to all patients with nonvalvular atrial fibrillation (i.e., atrial fibrillation in the absence of rheumatic mitral stenosis, a prosthetic heart valve, or mitral valve repair) who are considered to be at increased risk of stroke, unless such therapy is contraindicated. Recommendations regarding choice of antithrombotic therapy are based on the patient's risk for stroke and bleeding. In general, oral anticoagulant therapy (traditionally warfarin) is recommended in patients with atrial fibrillation who have a moderate to high risk for stroke and acceptably low risk of bleeding, while aspirin or no antithrombotic therapy may be considered in patients at low risk of stroke. Although many risk stratification methods have been used, patients considered to be at increased risk of stroke generally include those with prior ischemic stroke or transient ischemic attack (TIA), advanced age (e.g., 75 years or older), history of hypertension, diabetes mellitus, or congestive heart failure. In addition, population-based studies suggest that female sex is an important risk factor for stroke in patients with atrial fibrillation, particularly in patients 75 years of age or older, and AHA and ASA recommend the use of risk stratification tools that account for age- and sex-specific differences in stroke risk. One such tool is the CHA2DS2-VASc score, an extension of the CHADS2 system (which considers the risk factors congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and prior stroke/TIA) that adds extra points for female sex (1 point); previous myocardial infarction, peripheral arterial disease, or aortic plaque (1 point); and age 65-74 years (1 point) or 75 years or older (2 points).
The risk of thromboembolism in patients with atrial flutter is not as well established as it is in those with atrial fibrillation. In addition, many patients with atrial flutter have alternating periods of atrial fibrillation. Experts state that antithrombotic therapy in patients with atrial flutter generally should be managed in the same manner as in patients with atrial fibrillation.
Although warfarin traditionally has been used for oral anticoagulation in patients with atrial fibrillation at increased risk of stroke, some experts suggest that non-vitamin K antagonist oral anticoagulants such as rivaroxaban may provide certain advantages over warfarin (e.g., rapid onset of action, predictable anticoagulant effect, no requirement for coagulation monitoring, less potential for drug-drug and drug-food interactions) and may be considered as alternative therapy in selected patients. Rivaroxaban may be particularly useful in patients at moderate to high risk of stroke who are unable to comply with warfarin monitoring requirements or in whom a consistent therapeutic response to warfarin cannot be achieved (e.g., because of drug or food interactions), while warfarin may continue to be preferred in patients who have well-controlled international normalized ratios (INRs) (e.g., INR in the therapeutic range more than 70% of the time) and are compliant with regular laboratory monitoring. However, because of the lack of direct, comparative studies, the relative efficacy and safety of rivaroxaban and other non-vitamin K antagonist oral anticoagulants (e.g., apixaban, dabigatran, edoxaban) used for the prevention of stroke in patients with nonvalvular atrial fibrillation remain to be fully elucidated. Some evidence from indirect comparisons suggests that there may be important differences (e.g., bleeding risk) between these agents; however, results of such analyses should be interpreted with caution because of possible confounding factors (e.g., differences in study design and methods, patient populations, and anticoagulation control). AHA and ASA state that while clinical trials of non-vitamin K antagonist oral anticoagulants were not designed to determine differences in efficacy compared with warfarin in men versus women, apixaban, dabigatran, or rivaroxaban may be a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in women with paroxysmal or permanent atrial fibrillation and prespecified risk factors (according to CHA2DS2-VASc) who do not have a prosthetic heart valve or hemodynamically important valve disease, severe renal failure (creatinine clearance less than 15 mL/minute), lower body weight (less than 50 kg), or advanced liver disease (impaired baseline clotting function). When selecting an appropriate anticoagulant in patients with atrial fibrillation, the relative risks versus benefits should be considered for individual patients based on factors such as the absolute and relative risks of stroke and bleeding; patient compliance, preference, tolerance, and comorbidities; cost; availability of agents to reverse anticoagulant effects in case of bleeding complications; and other clinical factors such as renal function, availability of facilities to monitor INR; and degree of current INR control in patients already receiving warfarin.
Efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation were evaluated in a randomized, double-blind, noninferiority study (ROCKET AF) in approximately 14,000 adults with nonvalvular atrial fibrillation who were considered to be at moderate to high risk of stroke (defined as having a history of stroke, TIA, non-CNS systemic embolism, or at least 2 of the following additional risk factors: age 75 years or older, hypertension, heart failure or left ventricular ejection fraction of 35% or less, or diabetes mellitus). The study population consisted principally of Caucasian men with a mean age of 71 years and a mean Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke (doubled) (i.e., CHADS2) score of 3.5; approximately 55% of patients had a history of stroke, TIA, or non-CNS systemic embolism. Patients received either rivaroxaban (20 mg once daily for those with a creatinine clearance of at least 50 mL/minute or 15 mg once daily for those with a creatinine clearance of 30-49 mL/minute) or adjusted-dose warfarin (titrated to an international normalized ratio [INR] of 2-3) for a median duration of 590 days; median follow-up was 707 days.
The primary composite end point of the study was the incidence of stroke (hemorrhagic or ischemic) and non-CNS systemic embolism. The primary efficacy analysis was performed in the per-protocol (as-treated) population, which included all patients who received at least one 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 discontinuance of the drug. Outcome analyses also were performed in the intent-to-treat (per-randomization) population, which included all patients who underwent randomization and were followed for events during treatment or following premature discontinuance, and the safety population, which included all patients who received at least one dose of a study drug and were followed for events while they were receiving study drug or within 2 days after discontinuation, regardless of protocol adherence. Testing for superiority was performed if noninferiority was achieved.
Rivaroxaban was noninferior to warfarin for the primary composite outcome of time to first occurrence of stroke or non-CNS systemic embolism; noninferiority was demonstrated in both the per-protocol and intent-to-treat populations. Efficacy of rivaroxaban was consistent across a variety of patient subgroups, including in those with renal insufficiency, different CHADS2 scores, prior warfarin use, and history of stroke. Superiority of rivaroxaban over warfarin was not demonstrated in the intent-to-treat population in this study; the rate of stroke or non-CNS systemic embolism with rivaroxaban therapy was no different than that observed with warfarin therapy (annualized event rate of 2.1 and 2.4% of patients, respectively). However, superiority of rivaroxaban over warfarin was shown in the as-treated safety population. This difference in the results of superiority testing may be explained by the inclusion of embolic events in patients who discontinued drug treatment prematurely as well as those occurring during study drug treatment in the intent-to-treat population, while analysis of the per-protocol population only included events that occurred during drug treatment and for 2 days after drug discontinuance. In addition, a requirement for anticoagulation following study drug discontinuance was not specified in the ROCKET AF protocol; however, patients in the warfarin group generally continued to receive warfarin after the treatment portion of the study, while those who had received rivaroxaban during the treatment portion were switched to warfarin without a period of overlap and therefore were not adequately anticoagulated until a therapeutic INR with warfarin was obtained. During the 28 days following the end of the study, a higher incidence of stroke was observed in patients who had received rivaroxaban compared with those who had received warfarin.
(See Risk of Thrombosis Following Premature Discontinuance of Anticoagulation under Warnings/Precautions: Warnings, in Cautions.)There was no statistically significant difference in the risk of major and nonmajor clinically important bleeding between the treatment groups, although intracranial and fatal bleeding occurred less frequently in patients receiving rivaroxaban.
Patients who received warfarin in the ROCKET AF study had INRs within the therapeutic range of 2-3 only 55% of the time on average, which is lower than that reported with warfarin anticoagulation in other trials of non-vitamin K antagonist oral anticoagulants (e.g., dabigatran, apixaban) in patients with atrial fibrillation (e.g., 62-64%). It has been suggested that this difference may be explained in part by the inclusion of a higher-risk patient population in the ROCKET AF trial or to geographic variations among the study sites with respect to warfarin anticoagulation management skills. Therefore, data currently are insufficient to establish the relative efficacy of rivaroxaban and warfarin for the reduction of stroke and systemic embolism when warfarin therapy is well controlled.
Deep-Vein Thrombosis and Pulmonary Embolism
Major Orthopedic Surgery
Rivaroxaban is used for the prevention of postoperative deep-vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients undergoing total hip- or knee-replacement surgery.
ACCP recommends routine thromboprophylaxis in all patients undergoing major orthopedic surgery, including total hip- or knee-replacement surgery, because of the high risk of postoperative venous thromboembolism. According to ACCP, thromboprophylaxis with an appropriate antithrombotic agent or an intermittent pneumatic compression device should be continued for at least 10-14 days and possibly for up to 35 days after surgery. ACCP and other clinicians consider rivaroxaban to be an acceptable option for pharmacologic thromboprophylaxis in patients undergoing total hip- or knee-replacement surgery, although ACCP suggests that a low molecular weight heparin generally is preferred because of its relative efficacy and safety and extensive clinical experience. Rivaroxaban may be a reasonable choice in situations in which a low molecular weight heparin is not available or cannot be used (e.g., in patients with heparin-induced thrombocytopenia or in those who refuse or are uncooperative with subcutaneous injections). ACCP states that when selecting an appropriate thromboprophylaxis regimen, factors such as relative efficacy and bleeding risk as well as logistics and compliance issues should be considered. For additional details on prevention of venous thromboembolism in patients undergoing major orthopedic surgery, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at http://www.chestnet.org.
Efficacy and safety of rivaroxaban for the prevention of postoperative venous thromboembolism after major orthopedic surgery are based principally on the results of 4 randomized, double-blind, double-dummy trials known as the RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep-vein Thrombosis and Pulmonary Embolism) trials. In these trials, rivaroxaban was more effective than subcutaneous enoxaparin in preventing venous thromboembolism in patients undergoing elective total hip-replacement (RECORD 1 and 2) or total knee-replacement (RECORD 3 and 4) surgery and was associated with similar rates of bleeding. The primary efficacy and safety end points in all 4 trials were identical; however, there were differences with respect to dosage and duration of enoxaparin therapy. Patients received oral rivaroxaban (10 mg once daily initiated at least 6-8 hours after surgery) or subcutaneous enoxaparin sodium (40 mg once daily initiated 12 hours before surgery and resumed 6-8 hours after wound closure in RECORD 1, 2, and 3, or 30 mg twice daily initiated 12 hours before surgery and resumed 12-24 hours after wound closure in RECORD 4). Treatment generally was continued for 31-39 days in the hip-replacement trials and for 10-14 days in the knee-replacement trials. However, in RECORD 2, the duration of active drug treatments was different; rivaroxaban was administered for 31-39 (mean 33.5) days (with placebo injection for 10-14 days) while enoxaparin was administered for 10-14 (mean 12.4) days (with placebo tablets for 31-39 days).
In all 4 RECORD trials, the incidence of the composite primary outcome of DVT (symptomatic or venographic), nonfatal PE, and all-cause mortality was substantially lower in patients receiving rivaroxaban than in those receiving enoxaparin. Treatment with rivaroxaban resulted in relative risk reductions for venous thromboembolism of 70 and 79%, respectively, in patients undergoing hip replacement in RECORD 1 and 2, and relative risk reductions of 49 and 31%, respectively, in patients undergoing knee replacement in RECORD 3 and 4. Rivaroxaban was generally well tolerated across all trials and rates of major bleeding or any bleeding event were generally similar between treatment groups.
Some clinicians have suggested that the observed differences in outcome between the rivaroxaban and enoxaparin groups in the RECORD trials were influenced by differences in dosage and/or duration of enoxaparin therapy. In RECORD 1-3, an enoxaparin sodium dosage of 40 mg once daily was used, while the preferred dosage for thromboprophylaxis after hip-replacement surgery and the only recommended dosage for knee-replacement surgery in the US is 30 mg every 12 hours (i.e., twice daily), which was used only in the RECORD 4 trial. In addition, enoxaparin was given for an average of approximately 2 weeks versus approximately 5 weeks for rivaroxaban in the RECORD 2 trial. It has been suggested that use of a potentially suboptimal enoxaparin sodium dosage of 40 mg daily in RECORD 1-3 and an unequal (shorter) duration of enoxaparin therapy in RECORD 2 may have contributed to the increased risk of the primary efficacy end point with enoxaparin in these trials. In addition, in RECORD 3, which employed the 40-mg once-daily dosage of enoxaparin sodium in patients undergoing total knee replacement, there was an absolute risk difference of 9.2% favoring rivaroxaban for the primary end point (any DVT, nonfatal PE, and all-cause mortality in the modified intent-to-treat population), while in RECORD 4, which employed the US FDA-labeled enoxaparin sodium dosage of 30 mg every 12 hours for the same indication, the absolute risk difference favoring rivaroxaban for the same primary end point was only 3.2%. In an attempt to account for differences in study design among the RECORD trials, an analysis of pooled data that used only the period of active treatment common to all 4 trials (the 12 +/- 2 days in which enoxaparin was administered) as the primary efficacy end point was performed; results of this analysis supported those of the individual trials with regard to the greater efficacy of rivaroxaban versus enoxaparin for reduction of total venous thromboembolism.
In the RECORD trials, use of a definition of major bleeding that did not include surgical site bleeding unless it necessitated reoperation or resulted in death may have resulted in a more conservative estimate of bleeding risk in these trials than in other comparative studies of other non-vitamin K antagonist oral anticoagulants and enoxaparin. Differences in the timing of initiation of rivaroxaban and enoxaparin therapy (preoperatively in RECORD 1-3; 6-8 hours postoperatively for rivaroxaban versus 12-24 hours postoperatively for enoxaparin in RECORD 4) potentially could have affected relative bleeding risk. The overall incidence of major bleeding in the RECORD trials was low (less than 1%), and these trials were not designed with enough statistical power to demonstrate differences in the end point of major bleeding. However, there was a trend toward increased bleeding events (numerically more frequent) with rivaroxaban in the RECORD trials. In a pooled analysis of data from all 4 trials, a small but statistically significant increase in the end point of major plus clinically relevant nonmajor bleeding was demonstrated for rivaroxaban versus enoxaparin in the total treatment duration pool; however, analysis of the active treatment pool at day 12+/-2 (i.e., the enoxaparin-controlled period common to all 4 RECORD studies) did not reveal a statistically significant difference in bleeding between the 2 groups.
The manufacturer states that rivaroxaban is not recommended as initial therapy (as an alternative to heparin) in patients with PE who have hemodynamic instability or who may receive thrombolytic therapy or undergo pulmonary embolectomy.
(See Patients with Pulmonary Embolism under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Treatment and Secondary Prevention
Rivaroxaban is used for the initial treatment of acute DVT and/or PE. The drug also is used beyond the initial 6 months of treatment to reduce the risk of recurrent venous thromboembolic events (secondary prevention) in patients with DVT and/or PE.
Rivaroxaban is recommended by ACCP and other experts as an acceptable option for initial and long-term anticoagulant therapy in patients with acute proximal DVT of the leg and/or PE. In such patients, ACCP recommends that anticoagulant therapy be continued beyond the acute treatment period for at least 3 months, and possibly longer depending on the individual clinical situation (e.g., location of thrombi, presence or absence of precipitating factors, presence of cancer, patient's risk of bleeding). Although rivaroxaban may offer some advantages over existing anticoagulant drugs for the treatment of venous thromboembolism (e.g., oral administration, no requirement for routine coagulation monitoring, minimal drug and food interactions), ACCP generally suggests the use of warfarin or a low molecular weight heparin rather than rivaroxaban for long-term anticoagulant therapy pending additional data and experience with rivaroxaban. The relative efficacy and safety of rivaroxaban versus other non-vitamin K antagonist oral anticoagulants (e.g., apixaban, dabigatran) for the treatment of venous thromboembolism remains to be established in controlled, comparative trials. For additional information on treatment of venous thromboembolism, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at http://www.chestnet.org.
In 2 randomized, open-label, noninferiority studies (EINSTEIN DVT and EINSTEIN PE) designed to evaluate efficacy and safety of rivaroxaban for the initial treatment and secondary prevention of venous thromboembolism, treatment with rivaroxaban was noninferior to therapy with enoxaparin and a vitamin K antagonist in preventing recurrent thromboembolic events. Patients in the studies were given either rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) or a standard anticoagulant regimen consisting of enoxaparin sodium (1 mg/kg subcutaneously twice daily for at least 5 days), followed by a vitamin K antagonist (warfarin or acenocoumarol adjusted to maintain an INR of 2-3). The average duration of therapy in both treatment groups was approximately 200 days. The primary efficacy outcome in these studies was a composite of symptomatic recurrent DVT or nonfatal or fatal PE. The primary efficacy outcome (based on the intent-to-treat population) occurred in 2.1 or 3% of patients receiving rivaroxaban or standard therapy, respectively, in the EINSTEIN DVT study, and in 2.1 or 1.8% of patients receiving rivaroxaban or standard therapy, respectively, in the EINSTEIN PE study. The incidence of major and clinically relevant nonmajor bleeding was similar between the treatment groups.
In a double-blind, placebo-controlled extension study (EINSTEIN EXT) in patients who had already completed a course of anticoagulant therapy with rivaroxaban or a vitamin K antagonist, continued treatment with rivaroxaban was substantially more effective than placebo in reducing the rate of recurrent DVT, nonfatal PE, or fatal PE. Patients in the extension study received rivaroxaban 20 mg daily or placebo for an additional 6 or 12 months (average duration of 190 days). Recurrent thromboembolism occurred in 1.3% of patients receiving rivaroxaban compared with 7.1% of those receiving placebo. Major bleeding occurred in 0.7% of patients in the rivaroxaban group and in none of the patients in the placebo group.
Additional studies and experience are needed to evaluate the efficacy and safety of rivaroxaban for the treatment of cancer-related venous thromboembolism; relatively few patients with cancer were included in the principal efficacy studies evaluating rivaroxaban for the treatment and secondary prevention of venous thromboembolism.