Rivaroxaban (Xarelto) in the management of stroke and DVT Steve Chaplin MSc, MRPharmS, Victoria Haunton BM, DGM, MRCP, Thompson Robinson BMedSci, MD, FRCP and Catherine Bagot MD, FRCPath KEY POINTS is an oral direct factor Xa inhibitor newly licensed for the prevention of stroke and systemic embolism in adults with nonvalvular AF and one or more risk factors, and as treatment of DVT and prevention of recurrent DVT and PE following an acute DVT the dose for prevention of stroke or systemic embolism is mg once daily the dose for initial treatment of acute DVT is 15mg twice daily for the first three weeks, then mg once daily for continued treatment and prevention of recurrent DVT and PE available as 15mg and mg tablets; 15mg, 8= 58.8, = 88., 1= 1.; mg, 8= 58.8, 1= 1. in the prevention of stroke and systemic embolism (vs warfarin) and in the treatment of acute symptomatic DVT (vs enoxaparin, then warfarin/acenocoumarol), it was noninferior for efficacy with a similar overall risk of major and nonmajor clinically relevant bleeding events Rivaroxaban is now licensed for the prevention of stroke and the treatment and prevention of DVT. In our New products review, Steve Chaplin presents the clinical data for its efficacy and adverse events related to these new indications, and specialists comment on its likely place in therapy. it was superior to placebo in the prevention of recurrent DVT and PE with a small increase in the risk of major bleeding episodes there are few drug interactions and laboratory monitoring is not required there is no effective antidote or reliable laboratory assay the dose should be reduced in moderate to severe renal impairment and is contraindicated in hepatic disease in stroke prevention will provide an alternative treatment in patients who are unable to tolerate warfarin or remain in the thera - peutic range until more experience is gained, should only be considered in the short-term treatment and prevention of DVT Rivaroxaban (Xarelto) is an oral direct factor Xa inhibitor. It was licensed in 8 for prophylaxis of venous thromboembolism (VTE) after knee or hip replacement surgery at a dose of 1mg daily. It is now also licensed (as 15mg and mg tablets) for the prevention of stroke and systemic embolism in adults with nonvalvular atrial fibrillation (AF) and one or more risk factors (eg congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior stroke or transient ischaemic attack), and as treatment of deep vein thrombosis (DVT) and prevention of recurrent DVT and pulmonar y embolism (PE) following an acute DVT in adults. The National Institute for Health and Clinical Excellence (NICE) has recommended the use of in the prevention of stroke and systemic embolism in people with AF. 1 The recommended dose for prevention of stroke or systemic embolism is mg once daily. The dose for initial treatment of acute 1 Prescriber 5 September 1 www.prescriber.co.uk
Cumulative event rate (%) Figure 1. Cumulative rates of stroke or systemic embolism in the per-protocol population in patients with nonvalvular AF, vs warfarin; after reference Cumulative event rate for primary efficacy outcome (%) 6 5 3 1 3 1 warfarin 1 36 8 6 7 8 Days since randomisation DVT is 15mg twice daily for the first three weeks. If a dose is missed during this phase, it should be taken with the next dose to ensure a daily intake of 3mg. The dose for continued treatment and prevention of recurrent DVT and PE is mg once daily. Short duration of therapy (three months) should be based on transient risk factors, eg recent surgery, trauma, immobilisation, and longer durations should be based on permanent risk factors or idiopathic DVT. There is limited experience of treatment for more than a year. No dose adjustment is required for older people. The dose should be reduced in patients with moderate or severe renal impairment (see SPC for details). Rivaroxaban is contraindicated in patients with hepatic impairment. Rivaroxaban is metabolised by hepatic CYP3A enzymes; clinically enoxaparin/warfarin 3 6 9 1 15 18 1 7 3 33 36 Days Figure. Cumulative rates of symptomatic recurrent VTE during and after three months treatment of acute symptomatic DVT, vs enoxaparin/warfarin (p<.1 for noninferiority); after reference 3 significant interactions occur with drugs that inhibit or induce this system and by drugs that affect the P- glycoprotein transporter, eg some antifungals, macrolide antibiotics (see SPC for details). Clinical trials The key trials were ROCKET AF (Rivaroxaban Once daily oral direct factor Xa inhibitor Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fib ril - lation) for prevention of stroke and systemic embolism in patients with nonvalvular AF, and EINSTEIN DVT for initial and continued treatment of acute DVT and prevention of recurrent DVT and PE. 3 Prevention of stroke and systemic embolism ROCKET AF was a noninferiority trial comparing with warfarin in 1 6 patients with nonvalvular AF at moderate to high risk of stroke (9 per cent had previous thromboembolism or three or more risk factors). They were randomised to receive treatment with mg daily (15mg daily in those with moderate renal impairment) or warfarin with dose adjustment to international normalised ratio (INR). 3.. The primary end-point was a composite of ischaemic or haemorrhagic stroke and systemic embolism in the per-protocol population, ie those who received at least one dose and did not violate the protocol. Median patient age was 73; the commonest risk factors were hypertension (91 per cent), heart failure (63 per cent) and previous stroke, systemic embolism or transient ischaemic attack (55 per cent). In those taking warfarin, 55 per cent of INR values were within target range. About 35 per cent of patients also took aspirin at some stage during the trial. The median duration of treatment exposure was 16 Prescriber 5 September 1 www.prescriber.co.uk
Cumulative event rate for primary efficacy outcome (%) 1 8 6 placebo 3 6 9 1 15 18 1 7 3 33 36 Days Figure 3. Cumulative rates of symptomatic recurrent VTE during and after 1 months prevention of DVT, vs placebo (p<.1 for superiority); after reference 3 59 days and the median follow-up period was 77 days. Stroke or systemic embolism occurred in 188 patients taking (1.7 per cent per year) and in 1 patients taking warfarin (. per cent per year; hazard ratio HR.79, 95% CI.66.96, p<.1 for noninferiority; see Figure 1). There were no differences between and warfarin according to time within the target INR range or in the rates of myocardial infarction or death (.9 per cent with vs 3.5 per cent). The rates of major and clinically relevant nonmajor bleeding with and warfarin were similar (1.9 vs 1.5 per cent per year). Decreased haemoglobin, transfusions and major gastrointestinal bleeding were more common with, whereas fatal bleeding and critical bleeding, eg intracranial, intraspinal, intraocular, were less frequent. Treatment of acute DVT and prevention of recurrent DVT and PE EINSTEIN DVT was a trial in 39 patients with acute symptomatic DVT. There were two phases: a threemonth acute noninferiority study compared (15mg twice daily for three weeks, then mg daily) with enoxaparin (Clexane) 1mg per kg twice daily initially followed by warfarin or acenocoumarol (Sinthrome). Enoxaparin was discontinued when INR. (median duration eight days) and the anti co - ag ulant dose was adjusted to maintain INR in the range. 3. (achieved for 58 per cent of the time). A continued-treatment superiority study compared mg daily with placebo in 1197 patients; of these, about two-thirds did not participate in the acutephase DVT study. The primary end-point in both phases was symptomatic recurrent VTE, defined as the composite of DVT or nonfatal or fatal PE. Mean patient age was 56 for the acute study and 58 for the continued-treatment study. Most (61 7 per cent) of DVTs or PEs were considered unprovoked; identified causes included surgery, trauma, immobilisation and oestrogen therapy. Previous VTE was known in 1 19 per cent of patients. In the acute phase, the primary end-point occurred in 36 (.1 per cent) of patients treated with and in 51 (3. per cent) of those taking enoxaparin/warfarin (HR.68, 95% CI. 1., p<.1 for noninferiority, p=.8 for superiority; see Figure ). The first major or clinically relevant nonmajor bleeding event occurred in 8.1 per cent of patients in both treatment groups. Significantly fewer patients taking had either a recurrent VTE or a major bleeding event (.9 vs. per cent with warfarin). There were no differences in efficacy or safety outcomes by treatment duration of 3, 6 or 1 months. In the continued-treatment study, the primary end-point occurred in eight patients (1.3 per cent) with and patients (7.1 per cent) in the placebo group (HR.18, 95% 1CI.9.39, p<.1; see Figure 3). Major bleeding occurred in.7 per cent of patients in the group and in none of those assigned to placebo. Signif - icantly fewer patients taking had a recurrent VTE or a major bleeding episode (. vs 7.1 per cent with placebo). There were no differences in the balance of risk and benefit in various subgroups and no differences in liver function tests between and warfarin or placebo in either study. References 1. NICE. Rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation. Technology appraisal TA56. May 1.. Patel MR, et al. N Engl J Med 11;365:883 91. 3. EINSTEIN Investigators. N Engl J Med 1;363:99 51. Steve Chaplin has undertaken paid writing work for several pharmaceutical companies. Steve Chaplin is a pharmacist who specialises in writing on therapeutics 18 Prescriber 5 September 1 www.prescriber.co.uk
Place in therapy stroke prevention The last two decades have seen significant and exciting developments in the field of stroke medicine. Nonetheless, stroke remains a devastating condition with high rates of mortality and morbidity. Indeed, stroke is currently the third largest cause of death and the single largest cause of adult disability in England. 1 Each year, approximately 11 people in England will have a first or recurrent stroke and more than 9 people are currently living with the effects of stroke, with half of these being dependent on others for help with everyday activities. The financial implications of stroke are substantial, with an estimated cost to the economy of 7 billion per year. 1 Warfarin AF, which is all too frequently asymptomatic, is associated with up to 15 per cent of ischaemic strokes in all ages and 3 per cent in persons over the age of 8. 3 When AF is detected, it is therefore vital that the opportunity to protect patients is not missed. Individual risk stratification, using the CHA DS -VASc score, and open and informed discussions with patients will guide anticoagulation decisions. When anticoagulation is indicated, warfarin offers excellent cost-effective stroke prevention with a relative risk reduction of 6 per cent (95% CI, 8 7 per cent) 5 and surprisingly low rates of significant However, fears regarding bleeding, multiple interactions and the need for frequent blood tests and dose adjustments lead to high rates of discontinuation. Indeed, it is estimated that only half of warfarin-eligible patients with AF actually receive anticoagulation. 6 Furthermore, warfarin s efficacy is powerfully dependent on the time spent in the therapeutic range and there are a significant number of patients who do not achieve this. 7 A number of alternatives to warfarin are becoming available for some patients where anticoagulation is clinically indicated and safe. Rivaroxaban Following on from the RE-LY (Randomized Evaluation of Long term anticoagulant therapy) study, 8 which demonstrated the superiority (15mg twice-daily dose) and noninferiority (11mg twice-daily dose) of the direct thrombin inhibitor dabigatran (Pradaxa), the ROCKET-AF study 9 has demonstrated the noninferiority of the factor Xa inhibitor to warfarin in the prevention of stroke and systemic embolism in patients with AF, with similar rates of Rivaroxaban has few inter - actions and needs no laborator y monitoring. However, there are some important considerations. Although bleeding rates are similar to warfarin, the study did show an increase in haemoglobin reduction, transfusion requirements and major GI bleeding in the group. Furthermore, in keeping with the other warfarin alternatives, has no established antidote and no reliable laboratory assay. It also requires caution in renal failure and is absolutely contraindicated in hepatic failure. While war farin is likely to remain the mainstay of treatment for most patients with AF, direct Prescriber 5 September 1 www.prescriber.co.uk
thrombin and factor Xa inhib - itors are a significant and exciting development in the field of stroke medicine. It is likely that they will be initially reser ved for patients who cannot tolerate war farin, who struggle to remain in the therapeutic range or where there are concerns regarding compliance and drug interactions in patients with multiple comorbidities, but in whom stroke risk outweighs the risk of major References 1. Mant J, et al. Health care needs assessment: stroke. In: Stevens A, et al, eds. Health care needs assessment: the epidemiologically based needs assessment reviews. First series, nd ed. Oxford: Radcliffe Medical Press, ;11.. National Audit Office. Reducing brain damage: faster access to better stroke care. (HC 5 Session 5 6). London: The Stationery Office, 5. 3. Wolf PA, et al. Arch Intern Med 1987; 17:1561.. Camm AJ, et al. Europace 1; 1:136. 5. Fuster V, et al. Circulation 6; 11:e57 e35. 6. Glazer NL, et al. Arch Intern Med 7; 167:6 5. 7. Samsa GP, et al. Arch Intern Med ; 16(7):967 73. 8. Conolly SY, et al. New Eng J Med 9; 361(1):1139 51. 9. Patel MR, et al. New Eng J Med 11;365(1):883 91. Dr Haunton, none to declare; Professor Robinson has received educational grants and honoraria in respect of advisory boards from Boehringer Ingelheim. Dr Haunton is clinical research fellow and honorary specialist registrar, and Thompson Robinson is professor of stroke medicine, Ageing and Stroke Medicine, Department of Cardiovascular Sciences, University of Leicester Place in therapy DVT treatment and prevention Rivaroxaban appears to be an attractive alternative to warfarin in the treatment of acute DVT and the secondary prevention of DVT and PE for a number of reasons: no routine monitoring of anticoagulation is required; there is minimal risk of erroneous anticoagulation; there is limited interaction with diet and medication; and the repeated administration of low-molecularweight heparin (LMWH) injections at the commencement of warfarin therapy is unnecessary is effective immediately. Concerns However, caution is required when considering these benefits. Firstly, patient education must not be neglected: it will still be essential that patients are informed of the risk of bleeding and the action that needs to be taken should it occur. Furthermore, the omission of even a single dose of could lead to a more significant period of underanticoagulation compared to warfarin due to its shorter half-life. Patients will therefore need to understand the importance of regular, sustained compliance with. Perhaps of greatest concern to those involved in anticoagulation management is the lack of an effective antidote to, a complete contrast to warfarin. Animal models provide only limited data that replacement with either prothrombin complex concentrates (in the active or inactive form) or recombinant VIIa might be effective. Therefore, if a patient requires urgent surgery or is admitted with major haemorrhage, there is currently no reliable reversal strategy. This is not helped by the inability of current laboratory techniques to give little more than a qualitative indication of the presence or absence of the drug. Conclusion Overall, has the potential to enhance the management of acute DVT and secondary prevention of venous thrombosis as it has been shown to be as effective as warfarin for these indications. However, there is limited evidence on the use of beyond 1 months. It might therefore be prudent that, until further experience is accrued, is only used in patients who are anticipated to require short-term anti - coagulation for three to six months and not in those who require longterm treatment for secondary prevention. In the meantime, there must be strict data collection of the realworld experience with to monitor the frequency, management and outcome of bleeding episodes in patients using this drug. Ongoing development of laboratory methods for accurately detecting drug plasma concentrations is crucial. Finally, hospitals will need to formulate protocols to manage bleeding episodes, and the education of patients in drug compliance and reporting of bleeding will be essential. None to declare. Dr Bagot is a consultant haematologist at Glasgow Royal Infirmary www.prescriber.co.uk Prescriber 5 September 1 3