Ingo Ahrens*1 & Christoph Bode1 1 Clinic for Cardiology & Angiology I, University Heart Centre Freiburg – Bad Krozingen, Hugstetter Street 55, 79106 Freiburg, Germany *Author for correspondence: Tel.: +49 761 270 34010 n
[email protected]
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The occurrence of disabling stroke, the major fatal consequence of atrial fibrillation, can be reduced by almost two-thirds with warfarin oral anticoagulation. Recent estimates on the prevalence of atrial fibrillation in the USA suggest that approximately 3 million people suffer from this common cardiac arrhythmia, therefore the socioeconomic impact of adequate oral anticoagulation is enormous. Rivaroxaban, a direct orally available factor Xa inhibitor, is the first of a new class of drugs that target a central factor of the coagulation cascade upstream of thrombin. In the ROCKET AF clinical trial, rivaroxaban demonstrated noninferiority compared to warfarin for stroke prevention in patients with atrial fibrillation, while intracranial and fatal bleeding occurred less frequently with rivaroxaban treatment. Rivaroxban has recently been approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation by the US FDA and EMA. Very recently, rivaroxaban in addition to dual antiplatelet therapy, was shown to reduce mortality in patients with a recent acute coronary syndrome in the ATLAS ACS 2-TIMI 51 clinical trial. The clinical evaluation of rivaroxaban in cardiovascular disease and the results of the ROCKET AF study, the landmark clinical trial of rivaroxaban for stroke prevention, are discussed along with the unique pharmacological profile of rivaroxaban.
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Atrial fibrillation (AF) occurs in 1–2% of the population and represents the most common cardiac arrhythmia [1,2] . The prevalence increases with age up to 10% in patients older than 80 years [2–4] . Currently the prevalence of AF in the USA is estimated at approximately 3 million and projected to rise above 7 million people by 2050 [5] . Ischemic stroke is the major cardiovascular risk associated with AF and the left atrial appendage is the most common source of a thrombus that causes stroke or systemic embolism [6] . In the general population AF is associated with a fivefold risk of stroke [1] and according to novel risk stratification schemes like the CHA 2DS2VASc score, which pays respect to individual risk factors in patients with AF, the 5-year incidence for stroke in patients with a moderate risk (CHA 2DS2VASc score of 1) may be as high as 12.7% [7] . The use of warfarin anticoagulation in patients with AF reduces the risk for stroke by two-thirds [8,9] . This underlines the importance of the availability of adequate oral anticoagulation for patients with AF to prevent stroke, thereby reducing the socioeconomical impact of this disabling disease [10] . For decades, warfarin (clinical introduction in 10.2217/FCA.12.26 © 2012 Future Medicine Ltd
the 1950s) and its derivatives have been the sole oral anticoagulants for stroke prevention in AF [11] . After the 2010/2011 FDA/EMA approvals of dabigatran etexilate, an oral direct factor IIa (thrombin) inhibitor, and the 2011 US FDA/ EMA approvals of the oral direct factor Xa inhibitor rivaroxaban in patients with AF, a new era of oral anticoagulation for stroke prevention in AF has begun. The major advantages of the novel oral anticoagulants are that they do not require routine anticoagulation monitoring and that they do interfere at central steps (factor IIa or Xa) of the coagulation system. This leads to more predictable anticoagulation resulting in fewer fatal and critical bleeding events compared with warfarin [11,12] .
Drug Evaluation
Future Cardiology
Rivaroxaban for stroke prevention in atrial fibrillation and secondary prevention in patients with a recent acute coronary syndrome
Rivaroxaban
Rivaroxaban (Xarelto ®, Bayer HealthCare Berlin, Germany) is a small molecule direct factor Xa inhibitor with a high oral bioavailability [13,14] . The mechanism of binding to factor Xa is competitive with a dissociation constant (K i) of 0.4 nM [15] . Rivaroxaban has a >10,000-fold greater affinity to factor Xa compared with other serine proteases, thereby potently inhibiting Future Cardiol. (2012) 8(4), 1–xxx
Keywords ACS n anticoagulation atrial fibrillation n factor Xa n rivaroxaban n ROCKET AF n stroke
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ISSN 1479-6678
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Drug Evaluation
Ahrens & Bode
RECORD study program. RECORD1 and RECORD2 included a total of 7050 patients undergoing hip surgery, and in RECORD3 and RECORD4 5679 patients undergoing knee surgery were randomized to receive either rivaroxaban or enoxaparin [11,23] . Rivaroxaban was superior to enoxaparin in the prevention of venous thromboembolism throughout the RECORD Phase III clinical trial program [11,24–27] . The randomized, double-blind, dose-escalation clinical Phase II trial ATLAS ACS TIMI 46 assessed the safety and efficacy of rivaroxaban in addition to standard therapy in 3491 patients with acute coronary syndromes (ACSs) [28] . This trial also aimed to determine the most favorable dose and dosing regimen in patients with ACS. The patients were physician assigned to either stratum one (aspirin only; n = 761) or stratum two (aspirin plus clopidogrel; n = 2730). Within the strata, patients were randomized (1:1:1) to receive placebo, rivaroxaban q.d. or rivaroxaban b.i.d. The total daily doses for rivaroxaban were 5, 10 or 20 mg in stratum one and 5, 10, 15 or 20 mg in stratum two, respectively [28] . The primary safety end point was clinically significant bleeding and the primary efficacy end point was death, myocardial infarction, stroke or severe recurrent ischemia requiring revascularisation during the 6-month treatment period. There was a significant dose-dependent increase in clinically significant bleeding across the strata and q.d. or b.i.d. dosing groups compared to placebo [28] . The primary efficacy end point occurred in 5.6 versus 7% of the rivaroxaban and placebo-treated patients respectively (p = 0.10). This trend was driven by a significant reduction in death, myocardial infarction and stroke in the rivaroxaban versus placebotreated patients (3.9 vs 5.5%; p = 0.027) [28] . Interestingly, the rates of clinically significant bleeding and adverse cardiovascular events did not differ significantly between the q.d. versus b.i.d. doing groups. Based on pharmacokinetic and pharmacodynamic data lower peaks and higher troughs are suggested with b.i.d. versus q.d. dosing of rivaroxaban [28] . Based on these considerations, the favorable clinical outcome with rivaroxaban treatment, and the lower bleeding rates with the lowest rivaroxaban dosing regimens in ATLAS ACS TIMI 46, a 2.5-mg and 5-mg b.i.d. dosing regimen have been selected for the further clinical Phase III evaluation of rivaroxaban in patients with ACS (ATLAS ACS 2 TIMI 51) [29] .
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the conversion of prothrombin to thrombin, which occurs downstream of factor X activation within the coagulation cascade [11,13–15] . After oral intake, maximum inhibition of factor Xa occurs within 3 h corresponding to the maximum plasma concentrations achieved 3–4 h after oral administration [13] . Rivaroxaban has a dual mode of elimination, one-third is excreted unchanged via the kidneys and twothirds are metabolized to inactive metabolites by the liver [16] . Therefore patients with moderate impaired renal function (creatinine clearance: 30–49 ml/min) should receive reduced dosages of rivaroxaban. The mean terminal halflife after multiple oral doses is between 7 and 11 h [17] . Rivaroxaban is a substrate of CYP3A4 and P-gp. Therefore inhibitors of both CYP3A4 and P-gp (e.g., ketokonazole, itraconazole, voriconazole and posaconazole or ritonavir) may increase rivaroxaban plasma concentration significantly. The solubility of rivaroxaban in water is nearly 0% and in human plasma up to 95% of the drug is bound to serum albumin [14] . The anticoagulative effects of rivaroxaban in human plasma may be detected by the prothrombin time and the activated partial thromboplastin time (aPTT) [18] , but results are variable depending on the reagents used for the clotting assays and the timing of blood sampling after oral intake [19–21] . Pharmacokinetic and pharmacodynamic studies in patients enrolled in Phase IIb dose-ranging studies examining twice-daily (b.i.d.) or once-daily (q.d.) dosages of 5, 10 or 20 mg rivaroxaban demonstrated that the area under the plasma concentrationtime curve (identifying the maximum and the minimum plasma concentrations) were relatively equal (90% intervals overlapped) between the b.i.d. and the q.d. dosing regimens of rivaroxaban [22] . Based on the findings of this study, a 20 mg q.d. dose of rivaroxaban was suggested for the Phase III clinical trial of rivaroxaban in atrial fibrillation (ROCKET AF). The key pharmacological properties of rivaroxaban are summarized in Box 1. Clinical Phase II trials in cardiovascular disease
The successful clinical evaluation of rivaroxaban for the prevention of venous thromboembolism after major orthopedic surgery in the Phase III RECORD clinical study program set the stage for the further evaluation of rivaroxaban in clinical Phase II studies in patients with cardiovascular disease. A daily oral dose of 10 mg rivaroxaban was used throughout the 2
Future Cardiol. (2012) 8(4)
future science group
Rivaroxaban in patients with a recent acute coronary syndrome
Small molecule, direct competitive factor Xa inhibitor Maximum plasma concentrations reached 3–4 h after oral intake Terminal half-life: 7–11 h Dual mode of elimination: one-third renal excretion and two-thirds metabolized by the liver Low propensity for drug–drug interactions (except drugs with strong effects on p-gp and CYP3A4) and no food interactions
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secondary prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE). The EINSTEIN DVT trial was a randomized, open-label, event-driven study assessing rivaroxaban 15 mg b.i.d. for 3 weeks followed by 20 mg q.d. versus enoxaparin followed by a vitamin K antagonist (VKA) in 3449 patients with acute DVT [31] . Patients were treated for 3, 6 or 12 months, respectively. The primary efficacy outcome was venous thromboembolism, the principal safety outcome was major bleeding or clinically relevant non-major bleeding. In this noninferiority efficacy trial, rivaroxaban was noninferior compared to enoxaparin followed by VKA. The primary end point occurred in 2.1% of the rivaroxaban-treated patients versus 3.0% of the enoxaparin followed by VKAtreated patients (p
