*citation from Havelock Ellis ‘Impressions and Comments’
Rivaroxaban is an oral direct factor Xa inhibitor belonging to the novel oral anticoagulants (NOACs) class. Concerning efficacy and tolerability, it has been reported to be more effective than enoxaparin in preventing venous thromboembolism in patients undergoing orthopaedic surgery,1,2 and was non-inferior to enoxaparin followed by warfarin in a study involving patients with established venous thrombosis.3 Its good bioavailability, rapid-action and a half-life of 5–13 h,4 associated with a highly reproducible anticoagulant activity and the same rate of bleeding complications as in patients on vitamin K antagonist (VKA) have led to its rapid uptake in clinical practice. The double-blind ROCKET-AF study established that rivaroxaban was non-inferior to warfarin for the primary end point of stroke and systemic embolism in 14,264 moderate-to-high-risk patients with non-valvular AF (NVAF) randomised to either (i) treatment with rivaroxaban 20 mg o.d. (15 mg daily for those with estimated creatinine clearance [CrCl] 30–49 ml/min) or (ii) warfarin.5 Of note, the study population had a considerably higher risk of stroke than those in other NOAC AF trials. There was no reduction in rates of mortality or ischaemic stroke, but a significant reduction in haemorrhagic stroke and intracranial haemorrhage for patients on rivaroxaban – although results showed an elevated risk of gastrointestinal bleeds.
Despite an atmosphere of suspicion related to the succession of health scandals, French doctors have widely adopted this new molecule as shown by a Conservatoire National des Arts et Métiers (CNAM) study showing a rise in the prescription of NOACs in the last quarter of 2012: among the 100,000 patients starting anticoagulant therapy, 57% were prescribed a first-line NOAC, and treatment was initiated by a cardiologist in 59% of cases. Therefore, NOACs have not replaced VKAs totally, but the key driver for the rapid uptake is that this innovation largely contributes to improving the care and quality of life for some patients. Unlike warfarin, rivaroxaban does not require laboratory monitoring, and to date, this is the only licensed molecule given once daily.
Despite some questions from patients (mostly related to anxiety brought about by information provided by the media and the internet), among the 368 patients who were switched from an anticoagulant agent to rivaroxaban, only five required a review of the treatment. Of these, three had developed digestive side effects, and two wished to return to their warfarin therapy despite good clinical tolerance. Major bleeding was rare, and in our clinical experience related to mistakes in the selection of patients. To reassure patients and their relatives, the pharmaceutical industry (XANTUS, XALIA studies) and health agencies have implemented unprecedented strategies to ensure proper use of the product and to identify possible side effects in a way that ensures real-world experience is as efficacious as clinical trial experience with these agents.
Furthermore, and to answer any questions that may arise with NOACs, the European Society of Cardiology (ESC) published a practical handbook on their use for stroke prevention in AF.6 Of course, the obvious classical restrictions to such drugs remain: first, potential drug interactions justify precaution and it is strongly suggested that clinicians implement a therapeutic educational programme, as is the case for VKA. Second, such therapeutic programmes require the rigorous screening of patients: in patients with valvular AF, or severe liver or renal impairment (CrCl less than 15 ml Cockcroft/min), VKAs are as yet the only oral anticoagulant therapy indicated. As a precaution, this rule could be extended to patients with CrCl between 15 and 30 ml/min. However, depending on the methodology used to assess CrCl, results can be very different. This can make a huge difference and lead to prescription errors. It must be remembered that all of the clinical studies on anticoagulants showed that elderly people, especially women with low body weight, were particularly at risk of major bleeding events.
However, in the Einstein trial with rivaroxaban, rates of recurrent venous thromboembolism and bleeding were similar in the two study groups regardless of age, sex, presence or absence of obesity, level of renal function, or extent of pulmonary embolism. Although other options, such as MDRD or CKD-EPI, are now recommended for the assessment of glomerular filtration rate and are considered better estimators of renal function, the Cockcroft–Gault (CG) strategy offers two key benefits: this formula has been used in studies to select patients and to adjust dosages (15 mg/day below 50 ml/min and 20 mg/day above 50 ml/min in AF). However, with the Cockcroft formula, CrCl values in patients older than 75 years are systematically lower than values obtained with the MDRD formula.
To date, the biggest concern I hear from clinicians using the new agents is that no dedicated reversal agents are currently available. However, a direct factor Xa inhibitor, andexanet alfa (PRT 4445) is in development. The clinical situation remains a challenge, especially concerning the management of scheduled surgery. Whatever the type of surgery, and the level of risk of bleeding, caution should be the guiding principle. In the absence of clinical experience and simple laboratory tests, the surgery should be carefully managed, and protected if necessary by a bridging treatment with parenteral anticoagulants, although the necessity of this treatment is by no means absolute. Indeed, the pharmacokinetics of rivaroxaban in different individuals is not perfectly predictable and it cannot be certain that the drug has been completely eliminated within four days in every patient.7
Rivaroxaban is a promising drug. A twice-daily low dose (2.5 mg) reduced overall and cardiovascular mortality, thus bringing new hope to acute coronary syndrome (ACS) patients.8
- Eriksson BI, Borris LC, Friedman RJ et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:2765–75. http://dx.doi.org/10.1056/NEJMoa0800374
- Lassen MR, Ageno W, Borris LC et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358:2776–86. http://dx.doi.org/10.1056/NEJMoa076016
- The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–510. http://dx.doi.org/10.1056/NEJMoa1007903
- Xarelto (rivaroxaban) Summary of Product Characteristics (SmPC) 2013.
- Patel MR, Mahaffey KW, Garg J et al.; ROCKET AF Investigators. Rivaroxaban vs.warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. http://dx.doi.org/10.1056/NEJMoa1009638
- Heidbuchel H, Verhamme P, Alings M et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013;34:2094–106. http://dx.doi.org/10.1093/eurheartj/eht134
- Kubitza D, Becka M, Wensing G et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939 – an oral, direct Factor Xa inhibitor – after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005;61:873–80. http://dx.doi.org/10.1007/s00228-005-0043-5
- Mega JL, Braunwald E, Wiviott SD et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9–19. http://dx.doi.org/10.1056/NEJMoa1112277