Clinical Use of Rivaroxaban: Pharmacokinetic and Pharmacodynamic Rationale for Dosing Regimens in Different Indications
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- Trujillo, T. & Dobesh, P.P. Drugs (2014) 74: 1587. doi:10.1007/s40265-014-0278-5
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Target-specific oral anticoagulants have become increasingly available as alternatives to traditional agents for the management of a number of thromboembolic disorders. To date, the direct Factor Xa inhibitor rivaroxaban is the most widely approved of the new agents. The dosing of rivaroxaban varies and adheres to specific schedules in each of the clinical settings in which it has been investigated. These regimens were devised based on the results of phase II dose-finding studies and/or pharmacokinetic modeling, and were demonstrated to be successful in randomized, phase III studies. In most cases, the pharmacodynamic profile of rivaroxaban permits once-daily dosing. A once-daily dose is indicated for the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee replacement surgery, the long-term prevention of stroke in patients with non-valvular atrial fibrillation, and the long-term secondary prevention of recurrent VTE. Twice-daily dosing is required in the acute phase of treatment in patients with VTE and in the combination of rivaroxaban with standard single or dual antiplatelet therapy for secondary prevention after acute coronary syndrome events. This article reviews the empirical and clinical rationale supporting the dose regimens of rivaroxaban in each clinical setting.
Rivaroxaban dose regimen
Prevention of stroke and systemic embolism in patients with atrial fibrillation at moderate to high stroke riska
20 mg od
15 mg od in patients with CrCl 15–49 mL/min
Ongoing provided the risk of stroke outweighs the risk of bleedingb
Prevention of venous thromboembolism in patients who have undergone major hip or knee replacement surgery
10 mg od
12–14 days after knee replacement 35 days after hip replacement
Treatment of deep vein thrombosis and pulmonary embolism and prevention of recurrent venous thromboembolism
15 mg bid for 3 weeks (acute treatment)
20 mg od thereafter (secondary prevention)
Generally at least 3 months but to continue as long as the risk of recurrent VTE outweighs the risk of bleedingd
Prevention of atherothrombotic events in patients with recent acute coronary syndrome and elevated cardiac biomarkers (Europe only)e
2.5 mg bid in combination with single or dual antiplatelet therapyf
Based on the individual patient’s risk of ischemic events against bleeding risks
Rivaroxaban and the other TSOACs, apixaban, edoxaban, and dabigatran, overcome many of the perceived limitations of traditional anticoagulants. Unlike heparins, they are taken orally, but have a comparably rapid onset of action. Compared with warfarin and other VKAs, the TSOACs have predictable pharmacokinetics and pharmacodynamics that allow for fixed dosing (in the patient populations studied to date), do not require routine coagulation monitoring, and have fewer drug and food interactions . Despite these advantages, the long-term use of TSOACs presents different challenges, including drug accumulation in patients with renal dysfunction (varies by drug), lack of an antidote or standardized reversal strategy when life-threatening bleeding is encountered, and difficulties in quantifying the degree of anticoagulation with commonly available assays in emergency situations such as urgent surgery (specific anti-Factor Xa assays, although preferred, may not be routinely available or practical in acute situations) . As mentioned previously, predictable dose–concentration response with TSOACs allows for standard fixed dosing for various populations. Dosing for TSOACs is based on phase II and III clinical trial data. This represents a paradigm shift from the dosing of traditional anticoagulants that are typically titrated to specific goals via coagulation assay monitoring.
Dosing in the various clinical settings for the TSOACs takes into account many factors, including the specific pharmacokinetics of each agent, the pharmacodynamic effects observed (which may have a different timeline than the clearance or half-life of the specific agent), decisions on the acceptable peak-to-trough ratios observed with once-daily or twice-daily dosing schemes, as well as the clinical outcomes of different regimens tested in phase II and III clinical trials. Specific dosing regimens for rivaroxaban are approved for each clinical setting in which it is used. The dosing regimens have been developed based on preclinical data and clinical studies to take into account the balance of antithrombotic efficacy and bleeding risk. In many clinical scenarios, pharmacokinetic and pharmacodynamic data support the use of once-daily rivaroxaban doses because its antithrombotic effect persists for at least 24 hours for doses above 5 mg . In this review, the empirical and clinical rationale supporting the dose regimens of rivaroxaban in each clinical setting will be discussed, with consideration of both the general populations and relevant special patient groups.
2 Pharmacokinetic and Pharmacodynamic Characteristics of Rivaroxaban in Healthy Subjects and Specific Populations
2.1 Healthy Subjects
Severe renal impairment vs healthy subjectsa
Moderate hepatic impairment vs healthy subjectsa
Absence vs presence of foodb,c
Co-administration with strong CYP3A4 and P-gp inhibitor vs withouta
Absolute bioavailability (%)
66 vs ≥80 %
Area under the concentration–time curve (ng/mL/h)
64 % higher
127 % higher
39 % higher
Approximately 150 % higher
Maximum concentration (ng/mL)
35 % higher
27 % higher
76 % higher
53–72 % higher
Time to maximum concentration (h)
Similar to control
Similar to control
Similar to control
Apparent half-life (h)
5–9 (young), 11–13 (elderly)
Similar to control
Similar to control
Similar to control
2.2 Renal and Hepatic Impairment
Exposure to rivaroxaban (area under the concentration–time curve [AUC]) was increased by 44, 52, and 64 % in patients with mild (creatinine clearance [CrCl] 50–79 mL/min), moderate (CrCl 30–49 mL/min), and severe (CrCl <30 mL/min) renal impairment, respectively. However, the peak concentration was less variable and the overall effect, even for those with severe renal impairment, was considered by the authors to be of moderate clinical relevance only (Table 2) . Nevertheless, clinical use of rivaroxaban must take into account renal function, and caution should be exercised in patients with moderate (CrCl 30–49 mL/min) renal impairment. In Europe, rivaroxaban may be used with caution in patients with severe renal impairment (CrCl 15–29 mL/min); however, in the United States rivaroxaban is not advised in these patients, except in those with AF. In all cases, rivaroxaban should be avoided in patients with a CrCl <15 mL/min [1, 2].
Mild (Child–Pugh A) hepatic impairment did not cause a clinically relevant alteration of rivaroxaban pharmacokinetics (15 % increase in AUC compared with healthy subjects), but moderate impairment led to a marked increase in exposure (Table 2) and pharmacodynamic effects (159 % increase in the effect–time curve AUC and significant prolongation of prothrombin time) . As such, rivaroxaban therapy is not recommended in patients with moderate to severe hepatic impairment, including hepatic disease associated with coagulopathy and clinically relevant bleeding risk, and in cirrhotic patients (Child–Pugh B and C) [1, 2].
2.3 Food Effects and Drug–Drug Interactions
Oral bioavailability was high (80–100 %) for a 10-mg dose regardless of food intake, but at higher doses of 15 or 20 mg in the absence of food, bioavailability and absorption rate were less than dose proportional [16, 25]. Without food, the bioavailability of a 20-mg dose of rivaroxaban was 66 % and the AUC was 1,447 μg·h/L. When this dose was given with food, the bioavailability was nearly 100 % with a 39 % increase in the AUC (2,048 μg·h/L) (Table 2) . Therefore, while taking rivaroxaban with food is necessary for optimal absorption, if food could not be administered for a single day due to the patient being NPO (nil by mouth), there is still about two thirds of the dose absorbed. Clinicians need to weigh the potential clinical impact of this change in absorption. The decreased absorption rate appears to be due to the limited aqueous solubility of rivaroxaban at higher doses, leading to a lower absolute oral bioavailability for the 20-mg tablet under fasting conditions compared with fed conditions . Rivaroxaban absorption was unaffected by changes in gastric pH due to ranitidine or antacid use , and pharmacokinetics were unaltered by digoxin or atorvastatin . Concomitant administration of other anticoagulants, non-steroidal anti-inflammatory drugs, or antiplatelet agents may increase bleeding risks, and potential interactions of rivaroxaban with these agents have been investigated in phase I studies. Co-administration with enoxaparin did not affect pharmacokinetics but led to an additive effect on anti-Factor Xa inhibition . Co-administration of naproxen with rivaroxaban did not prolong bleeding time to a clinically relevant extent, but there was evidence of a more pronounced response in some individuals . When co-administered with antiplatelet agents, the bioavailability and pharmacokinetics of a 15-mg dose of rivaroxaban were not affected by steady-state clopidogrel, although bleeding time increased to a clinically relevant extent . No clinically relevant pharmacokinetic or pharmacodynamic effects occurred with the combination of rivaroxaban and acetylsalicylic acid (ASA; 500 mg loading dose then 100 mg the next day plus rivaroxaban 15 mg) . Rivaroxaban is eliminated by multiple pathways, which include, among others, metabolic degradation by cytochrome P450 3A4 (CYP3A4) and it is a substrate for P-glycoprotein (P-gp)-dependent pathways [15, 32], and a relevant increase in rivaroxaban exposure was seen with co-administration of strong inhibitors of both CYP3A4 and P-gp (e.g., ketoconazole, ritonavir; Table 2) [1, 2, 15]. Because of the multiple routes of elimination, drugs that inhibit only one of these pathways and those that moderately inhibit both pathways did not have a clinically relevant effect on the pharmacokinetics of rivaroxaban. However, care must be taken with concomitant administration of moderate inhibitors in the setting of patients with chronic kidney disease (CrCl 30–49 mL/min) because the risk of bleeding may be increased [1, 2]. CYP3A4 inducers (e.g., rifampicin) have the potential to reduce rivaroxaban plasma concentrations to a significant degree, and concomitant therapy is not recommended because of the risk of reduced efficacy [1, 2].
3 Prevention of Venous Thromboembolism in Patients Undergoing Elective Hip or Knee Replacement Surgery
Patients undergoing major orthopedic surgery to replace hip or knee joints have an incidence of VTE of approximately 40–60 % if no thromboprophylaxis is given . As per international guidelines, acceptable options to reduce the risk of VTE include parenteral anticoagulation with unfractionated heparin, LMWH, or fondaparinux, or oral antithrombotic therapy with ASA, warfarin, or a TSOAC. Depending on the agent selected, therapy is started around the time of surgery and continued for 2–6 weeks . Although a lower-grade recommendation, LMWH therapy is still considered the preferred option given the amount of evidence available . However, in patients given parenteral agents, high rates of non-adherence to the recommended duration of anticoagulation have been reported, owing partly to the burden of self-injection . Rivaroxaban has a similarly rapid onset of action to the commonly used LMWH enoxaparin , which is important in this setting, and could be more convenient for patients (particularly after discharge) because of its once-daily administration and oral rather than injectable formulation.
Patients randomized (n)
Primary efficacy outcome
Principal safety outcome
Prevention of VTE in patients undergoing total hip or knee replacement
Multicenter, randomized, double-blind, superiority, pooled analysis
Rivaroxaban oral 10 mg vs enoxaparin s.c. 40 mg od
Rivaroxaban: 31–39 days (hip) or 10–14 days (knee) Enoxaparin: 10–40 days (hip) or 11–15 days (knee)
VTE plus all-cause mortality on treatment: 0.4 vs 0.8 %; p = 0.005
Major bleeding on treatment (14 days): 0.2 vs 0.2 %
Multicenter, randomized, double-blind, superiority, pooled analysis
Rivaroxaban oral 10 mg vs enoxaparin s.c. 40 mg od or 30 mg bid
Rivaroxaban: 31–39 days (hip) or 10–14 days (knee) Enoxaparin: 11–40 days (hip) or 10–15 days (knee)
Symptomatic VTE plus all-cause mortality on treatment: 0.5 vs 1.0 %; p = 0.001
Major bleeding on treatment (12 ± 2 days): 0.3 vs 0.2 %; p = 0.23 Clinically relevant bleeding on treatment (12 ± 2 days):a 2.8 vs 2.5 %; p = 0.19
Treatment and secondary prevention of VTE
Multicenter, randomized, open-label, non-inferiority
Rivaroxaban oral 15 mg bid for 3 weeks followed by 20 mg od vs standard enoxaparin/VKAb
3, 6, or 12 months
Symptomatic, recurrent VTE: 2.1 vs 3.0 % (p < 0.001 for non-inferiority)
Clinically relevant bleeding:a 8.1 vs 8.1 % (p = 0.77) Major bleeding: 0.8 vs 1.2 % (p = 0.21)
Multicenter, randomized, open-label, non-inferiority
3, 6, or 12 months
Symptomatic, recurrent VTE: 2.1 vs 1.8 % (p = 0.003 for non-inferiority)
Clinically relevant bleeding:a 10.3 vs 11.4 % (p = 0.23) Major bleeding: 1.1 vs 2.2 % (p = 0.003)
Multicenter, randomized, double-blind, superiority
Rivaroxaban oral 20 mg od or placebo
6 or 12 months
Symptomatic, recurrent VTE: 1.3 vs 7.1 % (p < 0.001)
Major bleeding: 0.7 vs 0.0 % (p = 0.11) Clinically relevant bleeding:a 6.0 vs 1.2 % (p < 0.001)
Prevention of stroke and systemic embolism in patients with non-valvular AF and risk factors for stroke
Multicenter, randomized, double-blind, non-inferiority
Rivaroxaban oral 20 mg odc or dose-adjusted warfarin
Median 590 days
Stroke or systemic embolism: 1.7 vs 2.2 % per year (p < 0.001 for non-inferiority; per-protocol population)
Clinically relevant bleeding:a 14.9 vs 14.5 % per year (p = 0.44) Major bleeding: 3.6 vs 3.4 % per year (p = 0.58) Intracranial bleeding: 0.5 vs 0.7 % per year (p = 0.02) Fatal bleeding: 0.2 vs 0.5 % per year (p = 0.003)
Prevention of cardiovascular events in patients with recent ACS
ATLAS ACS 2 TIMI 51
Multicenter, randomized, double-blind, superiority
Dual antiplatelet therapy plus either rivaroxaban oral 2.5 mg bid or 5 mg bid or placebo
Mean 31 months
Death from CV causes, MI or stroke: 8.9 vs 10.7 % (p = 0.008)
Major bleeding:d 2.1 vs 0.6 % (p < 0.001) Intracranial bleeding: 0.6 vs 0.2 % (p = 0.009) Fatal bleeding: 0.3 vs 0.2 % (p = 0.66)
4 Treatment of Deep Vein Thrombosis and Pulmonary Embolism, and Prevention of Recurrent Venous Thromboembolism
Venous thromboembolism, comprising DVT and PE, is an established public health concern and is estimated to be responsible for almost half a million deaths in the European Union and approximately 300,000 fatalities in the United States annually [48, 49]. The standard treatment approach for all patients with VTE (specifically proximal DVT and PE, management of calf vein DVT is less established and varies by global region) includes therapeutic anticoagulation, and for patients not considered at high risk of immediate death, treatment usually starts with a parenteral anticoagulant such as a LMWH. An oral VKA is then added in parallel and the parenteral drug is discontinued after a minimum of 5 days of concomitant therapy and once the international normalized ratio (INR) is stable within the target range of 2.0–3.0 [50, 51]. All patients should receive a minimum of 3 months of therapeutic anticoagulation for the management of proximal DVT or PE, and many patients are candidates for longer durations of therapy to prevent recurrent events [50, 51]. This dual-drug paradigm (parenteral agent plus VKA) has been demonstrated to be very effective, but requires careful management, with patients subject to regular coagulation monitoring for the duration of their VKA treatment to keep the INR within the target range. By contrast, oral rivaroxaban can be used alone from the outset of treatment without the need for routine coagulation monitoring.
In the trial evaluating once-daily doses over the course of 3 months, the 20-, 30-, and 40-mg once-daily rivaroxaban regimens compared favorably with standard therapy in terms of reducing thrombus burden, with a similar incidence of major bleeding (Fig. 5b). Based on the outcomes of these two studies, the lowest effective daily dose for rivaroxaban in the treatment of VTE was identified as 20 mg daily. In addition, phase II results also raised the possibility that an initial twice-daily regimen may provide better clot resolution during the first 21 days of therapy. Utilization of a higher dose during initial therapy is also supported by other VTE trials that have shown that the highest risk of recurrent VTE occurs in the acute phase (initial 3–4 weeks) of treatment [54, 55]. Taking these considerations together, the EINSTEIN investigators chose a 15-mg twice-daily dose for 21 days, followed by transition to a 20-mg once-daily dose for the duration of therapy [56, 57, 58]. The EINSTEIN investigators did not discuss their selection of the 15 mg twice-daily dose in their methods paper as it was not studied in phase II testing . However, we might speculate they simply picked a dose between the 10- and 20-mg twice-daily dosing regimens that offered efficacy with the lowest risk of bleeding.
Two phase III studies of rivaroxaban for acute VTE treatment were conducted [57, 59]. EINSTEIN DVT recruited patients with symptomatic, confirmed DVT without PE , whereas EINSTEIN PE included patients with PE with or without concurrent DVT . PE was studied separately because it has a distinct clinical course to DVT and is also less common; therefore, trials involving a general VTE population may not recruit a sufficient proportion of patients with PE to confirm outcomes in this group. Both trials followed the same design, with patients randomized to receive 3, 6, or 12 months of treatment with rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily, or enoxaparin 1 mg/kg twice daily overlapping with and transitioning to a VKA (warfarin or acenocoumarol) with the dose adjusted to maintain an INR of 2.0–3.0 [57, 59].
In EINSTEIN PE, the first 400 patients included in the study were evaluated separately to confirm that the dose regimen, which had been selected based on outcomes in patients with symptomatic DVT without symptomatic PE, was efficacious and safe for patients with PE. Based on the incidence of the composite of symptomatic recurrent VTE and asymptomatic deterioration on repeat lung imaging at 3 weeks, the regimen was deemed to be appropriate . In both EINSTEIN DVT and EINSTEIN PE, rivaroxaban was non-inferior to enoxaparin/VKA for the prevention of recurrent, symptomatic VTE (Table 3). There was also no difference between the regimens in the incidence of major plus non-major clinically relevant bleeding [57, 59]. However, in EINSTEIN PE, rivaroxaban provided a 51 % relative risk reduction in the incidence of major bleeding (Table 3). Outcomes were consistent in subpopulations of patients such as the elderly, those with renal impairment, and patients with high or low body weight, suggesting that the rivaroxaban regimen would be appropriate without the need for adjustment in this setting. It is important to note that patients with an estimated CrCl <30 mL/min were excluded from the EINSTEIN trials, and that patients receiving thrombolytic therapy were also excluded from the EINSTEIN PE trial [57, 59]. An extension study of long-term rivaroxaban treatment to prevent recurrent VTE, EINSTEIN EXT, was also conducted. Patients who had been successfully treated for an initial VTE, but for whom the decision to continue or stop anticoagulation was uncertain, received either rivaroxaban 20 mg once daily or placebo for a further 6 or 12 months . Rivaroxaban was superior to placebo for the prevention of recurrent VTE, without a significant increase in major bleeding (Table 3) .
5 Prevention of Stroke and Systemic Embolism in Patients with Non-Valvular Atrial Fibrillation
AF is the most common dysrhythmia that occurs in clinical practice and is responsible for approximately 500,000 hospitalizations in the United States alone . Conservative estimates suggest that 2.7 million patients in the United States and 4.5 million in the European Union have AF [60, 61]. These numbers are expected to at least double in the next 30 years because of the aging population . Patients with AF have an approximately five-fold increase in the risk of stroke compared with the general population . Patients with AF are routinely prescribed oral anticoagulant therapy such as warfarin or another VKA. The limitations of VKA therapy have been well described, and the use of an oral anticoagulant that does not require dose adjustment (fixed dose) or lifetime therapeutic monitoring would be a significant advantage in the management of these patients. Whereas dabigatran and apixaban are both administered twice daily for the reduction of risk of stroke in patients with AF, rivaroxaban is taken once daily. This adds to the simplicity of the regimen and may improve adherence .
The suitability of the aforementioned dose was confirmed in the randomized, double-blind, double-dummy, phase III trial, 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 total of 14,264 patients with non-valvular AF at moderate to high risk of stroke were randomized to rivaroxaban, dosed as above, or dose-adjusted warfarin (managed to an INR of 2.0–3.0). In the intention-to-treat analysis, the primary endpoint of stroke or systemic embolism occurred at a rate of 2.1 % per year in patients receiving rivaroxaban and 2.4 % per year in patients receiving warfarin. This 12.5 % relative risk reduction with rivaroxaban met the criteria for non-inferiority (p < 0.001), but not superiority (p = 0.12). The primary analysis of the trial was designed to be the per-protocol, as-treated population. In this group, a benefit of rivaroxaban was demonstrated compared with warfarin (hazard ratio 0.79; 95 % CI 0.66–0.96; Table 3). Among patients in the on-treatment safety population, rivaroxaban was superior to warfarin (p = 0.01). Rates of clinically relevant bleeding and major bleeding were similar between the treatment arms (Table 3). However, rivaroxaban use led to a significant decrease in intracranial hemorrhage (p = 0.02) and fatal bleeding (p = 0.003), although the incidence of gastrointestinal bleeding was higher in the rivaroxaban arm (p < 0.001) . Pharmacokinetic analysis of 161 patients in ROCKET AF supported the predictions of the modeling work, and confirmed that parameters for patients with moderate renal impairment (who were given rivaroxaban 15 mg once daily) were similar to those with normal renal function who received 20 mg twice daily . Therefore, ROCKET AF demonstrated that rivaroxaban provides comparable efficacy to warfarin, with less intracranial and fatal bleeding at a cost of more gastrointestinal bleeding.
6 Prevention of Cardiovascular Events in Patients with Recent Acute Coronary Syndrome
An ACS event is a common complication of coronary heart disease and is associated with more than 1.2 million hospitalizations in the United States and close to 3 million hospitalizations worldwide annually [60, 69]. ACS comprises unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI), with UA and NSTEMI commonly grouped together as non-ST-segment elevation ACS (NSTE ACS). Standard chronic management of patients who have had an ACS event includes treatment with dual antiplatelet therapy consisting of ASA and a P2Y12 inhibitor. Despite this aggressive antiplatelet strategy, the rate of recurrent cardiovascular events remains high (~10 %) [70, 71]. There is evidence of sustained coagulation activation after an ACS event [72, 73], and previous studies have shown that the addition of an oral anticoagulant (e.g., warfarin) to antiplatelet therapy can further reduce recurrent cardiovascular events but increases the risk of bleeding [74, 75].
In the randomized phase III ATLAS ACS 2 TIMI 51 study, rivaroxaban 2.5 or 5 mg twice daily added to standard antiplatelet therapy (ASA ± a thienopyridine) was assessed against antiplatelets alone in patients with a recent ACS event . The addition of rivaroxaban at either dose significantly reduced the incidence of death from cardiovascular causes, MI, or stroke (Table 3) but, unlike the higher dose, the 2.5-mg twice-daily dose led to significantly reduced rates of death from cardiovascular causes (p = 0.002) and any cause (p = 0.002). Rivaroxaban was associated with an increased incidence of major bleeding not related to coronary artery bypass grafting (1.8 % for the 2.5-mg dose and 2.4 % for the 5-mg bid dose vs 0.6 %; p < 0.001 for both rivaroxaban doses combined vs placebo) and intracranial bleeding (0.4 % for the 2.5-mg bid dose and 0.7 % for the 5-mg bid dose vs 0.2 %; p = 0.009 for both rivaroxaban doses combined vs placebo), but fatal bleeding was not increased (0.3 vs 0.2 %; p = 0.66). The lower dose resulted in a lower rate of fatal bleeding than the higher dose (0.1 vs 0.4 %; p = 0.04) . Based on these data, the 2.5-mg twice-daily dose was approved in Europe as an adjunct to antiplatelet therapy, but only in patients with a recent ACS event and elevated cardiac biomarkers, suggesting a high likelihood of recurrence. Rivaroxaban is currently not approved in the United States for this indication, as the FDA has raised concerns with trial results and data management.
7 Implications for Daily Clinical Practice
The rivaroxaban clinical study program, including phase I pharmacokinetic and pharmacodynamic investigations, phase II dose-finding studies, and randomized phase III clinical trials, as well as pharmacokinetic modeling and simulation work, provide a body of evidence to support the doses that are now used in each approved clinical indication (Table 1). Despite a half-life that would suggest the need for twice-daily dosing (5–9 h in healthy young subjects, 11–13 h in healthy elderly patients), once-daily doses are appropriate in many situations based on positive results from phase II and III clinical trials for patients with AF, patients who have undergone hip or knee replacement surgery, and those receiving long-term treatment for the prevention of recurrent VTE. In addition, it is important to consider that similar to what has been observed for LMWHs, the pharmacodynamic effects for rivaroxaban exceed the pharmacokinetic half-life. As such, the duration of pharmacodynamic effect (anti-Xa activity) should be the main determinant of the daily dosing schedule. Nevertheless, it is important to consider clinical circumstances in which daily dosing is not the case, namely the initial 3 weeks of twice-daily rivaroxaban treatment for acute DVT or PE and for patients with ACS; (Table 1). The clinical pharmacology of rivaroxaban supports a once-daily dosing regimen for VTE prophylaxis after hip and knee replacement surgery (10 mg) and the prevention of recurrent VTE and stroke (20 mg) because of a long-lasting effect on thrombin generation and trough plasma drug concentrations sufficient to provide an effective antithrombotic effect for 24 hours or longer [10, 11, 21, 40, 56].
Routine dose reduction for renal impairment is recommended at this time only for patients with AF who are receiving rivaroxaban for stroke prevention and who have moderate (CrCl 30–49 mL/min) or severe (CrCl 15–29 mL/min) renal impairment. In these patients, a 15-mg once-daily dose is recommended instead of the normal 20-mg once-daily dose [1, 2]. This dose reduction was as effective as standard therapy when clinically tested in patients with renal impairment in ROCKET AF . By contrast, patients receiving rivaroxaban for long-term secondary prevention of recurrent VTE, for whom the same 20-mg once-daily dose is recommended, should not routinely be given a reduced dose if they have renal impairment (CrCl 15–50 mL/min), as they did not receive such a dose in the phase III EINSTEIN trials [57, 59]. The rationale is that VTE patient populations are generally younger and have fewer co-morbidities than AF populations and are, therefore, less susceptible to drug accumulation. As previously stated, pharmacokinetic modeling for this patient population did not indicate a large variation in plasma concentrations accompanying changes in either age or renal function . In addition, clinical trial results support this approach. In a combined pooled analysis of both the EINSTEIN DVT and PE trials, it was found that in patients with a calculated creatinine clearance <50 mL/min, rivaroxaban demonstrated a lower risk of bleeding as compared with patients receiving LMWH/warfarin with a similar effect on efficacy. Similar favorable results with safety were also seen in patients >75 years of age, or who weighed less than 60 kg. These results further support maintaining patients at a dose of 20 mg once daily down to a creatinine clearance of 30 mL/min . Although these results stem from a secondary analysis of the EINSTEIN trials, it is important to note that the subpopulation for reduced renal function totaled 649 patients, a sample size that is far larger than exists for any other anticoagulant in this patient population. Regardless, the European Summary of Product Characteristics states that a 15-mg once-daily dose may be considered in patients receiving long-term rivaroxaban for prevention of secondary VTE if the risk of bleeding is high and outweighs the evaluated risk for recurrent VTE . However, this recommendation is not included in the US Prescribing Information . In general, with the exception of ROCKET AF, few of the dose reductions recommended for TSOACs have actually been tested in clinical trials. It is important that patients with a CrCl <15 min/mL should not receive rivaroxaban for any of the approved indications because of the risk of drug accumulation.
Rivaroxaban is appropriate for a broad population of patients because its pharmacokinetic and pharmacodynamic properties generally do not vary to a clinically relevant degree with variations in gender, age, body weight, ethnicity, and mild or moderate renal and mild hepatic impairment [39, 56, 77]. However, there are circumstances and patient groups in which these agents are either not appropriate or relatively untested. Critically ill patients with PE who have shock and/or hypotension and require urgent thrombolytic therapy or thromboectomy fall into this category, and there are no data on the use of TSOACs in this setting. There are also no data on the use of these drugs during pregnancy, in patients aged <18 years, or in patients with a CrCl <15 mL/min; therefore, use of rivaroxaban is not recommended in these patients [1, 2]. Use in patients with moderate or severe hepatic disease (Child–Pugh B or C) is also not recommended because of a clinically relevant increased risk of bleeding. In general, more data are needed in patients with moderate renal impairment and those with cancer, relatively few of whom have been included in the phase III trials of the TSOACs, and also in patients with severe renal impairment (CrCl 15–29 mL/min), who were excluded from phase III studies because of their high bleeding risk. Although risk of major bleeding appears to be comparable to other anticoagulants, it is important to note that a small number of patients on rivaroxaban will experience a bleeding event and further guidance is needed with regards to effective reversal strategies in the case where bleeding may be life-threatening.
Rivaroxaban is increasingly used by clinicians in a broad range of thromboembolic disorders. Use of the specific dose regimen for each indication is vital to optimize therapeutic benefit and minimize risk of bleeding.
Acknowledgments and disclosures
The authors would like to acknowledge Stephen Purver, who provided editorial support, with funding from Bayer HealthCare Pharmaceuticals and Janssen Scientific Affairs, LLC.
Conflicts of interest
TT serves as a consultant for Boehringer-Ingelheim, Janssen, and BMS/Pfizer. PPD serves as a consultant for Janssen, AstraZeneca, and BMS/Pfizer.
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