1 Birmingham, Sandwell and Solihull Cardiac and Stroke Network Rivaroxaban or warfarin for treatment of Atrial Fibrillation: Position statement Introduction This guidance informs prescribers and commissioners regarding the implementation of NICE TAG 256 on Rivaroxaban for prevention of stroke and systemic embolism in AF within Birmingham, Sandwell and Solihull. It sets out the network position on: A. The on-going place of warfarin in therapy. B. The areas for special consideration in relation to the use of rivaroxaban C. The management of specific patient groups D. Who should initiate rivaroxaban. Specifically that it should only be initiated by clinicians who routinely initiate warfarin. It does not seek to compare dabigatran with rivaroxaban. However, the Network notes that due to the difference in baseline risk between the study populations in RE-LY and ROCKET-AF, comparison of the two drugs is a complex issue. Recommendations NICE TA 256 Atrial fibrillation Rivaroxaban states: The decision about whether to start treatment with rivaroxaban should be made after an informed discussion between the clinician and the person about the risks and benefits of rivaroxaban compared with warfarin. For people who are taking warfarin, the potential risks and benefits of switching to rivaroxaban should be considered in light of their level of international normalised ratio (INR) control A. The Birmingham, Sandwell and Solihull Cardiac and Stroke Network considers that warfarin remains a valuable treatment option in the management of Atrial Fibrillation 1. Warfarin is an effective therapy for stroke prevention in atrial fibrillation with long term safety and efficacy data derived from multiple trials and from real world experience. 2. Continuous monitoring of warfarin can be an aid to patient adherence and education with regular opportunities to assess safety issues when a patients clinical situation changes. 3. Warfarin s known efficacy for secondary prophylaxis in patients with arterial vascular disease (equivalent to an antiplatelet drug). 4. Warfarin can be used in patients with renal impairment. 5. Warfarin has well established protocols for reversal of anticoagulation with Vitamin K and Prothrombin Complex Concentrate.
2 B. The Birmingham, Sandwell and Solihull Cardiac and Stroke Network recognises the published clinical data on the use of rivaroxaban in prevention of stroke and systemic embolism, but notes the following concerns in relation to its use: 1. The methodology of the ROCKET-AF trial was complex, with data from different populations within the study used to calculate non-inferiority and superiority for the primary efficacy endpoint. The study was designed and powered to test the hypothesis that rivaroxaban would be non-inferior to warfarin for the prevention of stroke and systemic embolism in the per-protocol as-treated population. This was demonstrated. The study methodology then allowed for testing for superiority in the safety population - this demonstrated superiority for rivaroxaban over warfarin for the same endpoint. However, in the intention to treat population (ie including data from all patients from randomisation through to the end of the study), superiority of rivaroxaban over warfarin was not demonstrated. The ITT population is usually considered to be that which provides the most helpful information to the clinician, representing as it does the entire period from the decision to prescribe through to the end of follow up, including any period after discontinuation of the medication. 2. As a new medicine, there is a lack of long-term clinical safety data. Clinicians should be aware that due to the design of the ROCKET-AF study, the safety data pertains to patients who received at least one dose of the study drug, and were followed for events whilst they were receiving the assigned study drug or within two days of discontinuation. Unlike many trials, the safety data reported therefore does not include any longer term safety data, including possible effects emerging following discontinuation. 3. Plasma concentration is related to renal function. A reduced dose is recommended in patients with CrCl 15-49ml/min. 4. There is currently no specific antidote antagonising the effect of rivaroxaban. The SmPC states that if symptomatic treatment of excessive bleeding is inadequate, administration of a specific procoagulant reversal agent should be considered however, this is based on limited non-clinical studies and there is very limited clinical experience with the use of products such as PCC,APcc and r-fviia 5. Rivaroxaban must be taken with food. 6. As there is currently no data on the pharmacokinetic implications of crushing tablets, either for direct administration, or in the production of special liquid formulations, BSSCSN considers that rivaroxaban cannot be recommended for individuals who are unable to swallow the tablet. C. The Birmingham, Sandwell and Solihull Cardiac and Stroke Network has considered the position of rivaroxaban and warfarin in each of the groups outlined below: 1. Patients for whom there are stronger indications for consideration of rivaroxaban as an alternative to warfarin for atrial fibrillation. 2. Patients who request rivaroxaban as their preferred choice in terms of a favourable lifestyle in comparison to warfarin (e.g. in terms of dietary restrictions and inconvenience of INR monitoring). 3. Patients with a new diagnosis of atrial fibrillation.
3 The following guidance is provided for clinicians within the BSSCSN in relation to each of these groups: 1. Patients for whom there are stronger indications for consideration of rivaroxaban as an alternative to warfarin for atrial fibrillation. The criteria below are a summary of suggestions by the steering committee of the West Midlands Thrombosis Forum as the strongest indications for consideration of rivaroxaban as an alternative to warfarin for atrial fibrillation. Allergic reaction/intolerance of coumarins (warfarin, phenindione, sinthrome) Patients with important and unavoidable drug interactions that favour rivaroxaban over warfarin e.g. chemotherapy in a patient at high risk of CVA where a clinician does not want to stop anticoagulation Patients in whom monitoring and/or coping with variable dose regimen is difficult but who are able to comply with a fixed dose drug regime. Previous significant bleed on warfarin in patients at high risk for stroke, if the bleed was associated with poor INR control in a patient who is believed to be adherent with prescribed medication. It should be noted that in the ROCKET-AF trial, Rivaroxaban was associated with a lower risk of intracranial bleeding than warfarin (approx 5 events per 1000 patients per year with rivaroxaban and approx 7 events per 1000 patient per year with warfarin), NNT = 500 Rivaroxaban was associated with a higher risk of major gastrointestinal bleeding than warfarin (approx 32 events per 1000 patient per year with rivaroxaban compared with approx 22 events per 1000 patient per year with warfarin), NNH = 100 Please note also that people with a condition which increased bleeding risk were excluded from the trial. Poor INR control (e.g. more than 2 INRs >8.0 or more than 3 INRs >5.0 in 6 months) Selection of patients based on time in treatment range (TTR) is complex. For patients with reduced TTR, a careful assessment of the contributory factors is essential. There is independent evidence that a TTR<40% could lead to an outcome worse than not being on warfarin at all. However, a lower TTR may indicate poor adherence with taking medications and therefore rivaroxaban would be unlikely to be advantageous in this situation. 2. Patients who request rivaroxaban as their preferred choice in terms of a favourable lifestyle in comparison to warfarin (e.g. in terms of dietary restrictions and inconvenience of INR monitoring). The BSSCSN Patient Clinician Discussion Guide, or the NICE Patient Decision Aid should be used to discuss the clinical benefits and risks. Absolute risk increases/decreases should be used wherever possible to allow the patient to set the risk in context (see Patient Clinician Discussion Guide). The concerns outlined in section B (above) should be carefully explored with the patient. Please see FAQs (Appendix 1) for further information on legal status of NICE guidance.
4 3. Patients with a new diagnosis of Atrial Fibrillation Patients awaiting cardioversion: This cohort of patients was excluded from ROCKET-AF, and no other clinical data is available. BSSCSN therefore cannot recommend the use of rivaroxaban in this patient group. Warfarin remains a reasonable option prior to cardioversion. For all other patients the BSSCSN Patient Clinician Discussion Guide, or the NICE Patient Decision Aid, should be used to discuss the clinical benefits and risks. Timing of discussions Other than in exceptional circumstances, it is not necessary for clinicians to actively seek out patients for consideration of rivaroxaban. For patients meeting the criteria in section C part 1, clinicians should consider initiating a discussion regarding rivaroxaban at the next routine appointment. Patients in group 2 will self-present. Discussion with patients in group 3 will be integral to the overall management planning. D. Network position on Initiation The Birmingham, Sandwell and Solihull Cardiac and Stroke Network recommends that discussions of the risks and benefits of rivaroxaban in comparison with warfarin should be undertaken by clinicians who routinely initiate warfarin. In many cases this will necessitate referral to the anti-coagulation service. The first prescription for rivaroxaban must be provided by the service initiating the medication. Prescribing may then be transferred to the patient s GP with a standardised clinical letter containing the following information Confirmation that the patient meets the NICE criteria Confirmation that an informed discussion the benefits and risks of rivaroxaban compared with warfarin has taken place Monitoring requirements Criteria for discontinuation
5 APPENDIX 1 Rivaroxaban FAQs Does this position statement refer to all use of rivaroxaban? No it refers only to the use of rivaroxaban in AF in accordance with NICE TAG 256, which states Rivaroxaban is recommended as an option for the prevention of stroke and systemic embolism within its licensed indication, that is, in people with nonvalvular atrial fibrillation with one or more risk factors such as: congestive heart failure hypertension age 75 years or older diabetes mellitus, prior stroke or transient ischaemic attack. Separate NICE guidance is available regarding use of rivaroxaban for prevention of VTE in patients following THR or TKR (TA157), and for the treatment of DVT and prevention of recurrent VTE and PE (TA261). Other potential indications are currently off-label, and have not been considered by NICE or local Formulary committees. Rivaroxaban is therefore not currently recommended for use in these indications, other than via exceptional circumstances processes. What is the legal position regarding a NICE TAG? Commissioners are legally required to provide funding for the provision of NICE approved medicines within 3 months of the publication date of the TAG. There is no legal requirement on the prescriber to prescribe it in all circumstances, and the TAG does not override the decision making or clinical responsibility of the prescriber for any individual patient, nor does it over-ride usual medico-legal principles. Does the NICE TAG mean that clinicians have to prescribe rivaroxaban for all patients who ask for it? No. The TAG clearly states that rivaroxaban is recommended as an option (see above) It goes on to state: The decision about whether to start treatment with rivaroxaban should be made after an informed discussion between the clinician and the person about the risks and benefits of rivaroxaban compared with warfarin. For people who are taking warfarin, the potential risks and benefits of switching to rivaroxaban should be considered in light of their level of international normalised ratio (INR) control This implies that the decision should be shared by the patient and the clinician, and not dominated by either party. Supporting the patient in understanding the benefits and risks of both warfarin and rivaroxaban, by presenting them in a way which puts them into a meaningful context will be an important part of the discussion. The NICE +/- BSSCSN resources for discussing risks and benefits are commended for this purpose. What about the NHS Constitution? The NHS Constitution states: You have a right to the drugs and treatments that have been recommended by NICE for use in the NHS, if your doctor says they are clinically appropriate for you. Please note in this TAG the recommendation is that rivaroxaban is an option.
6 Rivaroxaban checklist Item Indication Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age >75 years, diabetes mellitus, prior stroke or transient ischaemic attack. Contraindications: Patients with creatinine clearance <15 ml/min; clinically significant active bleeding; hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C; pregnancy and breast feeding; patients receiving azole-antifungals (e.g. ketoconazole, itraconazole, voriconazole, posaconazole) or HIV protease inhibitors; patients receiving dronedarone (lack of data); hypersensitivity to the active substance or to any of the excipients. Cautions: Increased bleeding risk; concomitant use of other anticoagulants; creatinine clearance <30ml/min; strong CYP 3A4 inducers (e.g. rifampicin); NSAIDS; antiplatelet drugs. Discussed Benefits/risks Rivaroxaban i compared with dose-adjusted warfarin. Stroke/systemic embolism No benefit for either rivaroxaban or warfarin (difference not statistically significant) Major bleeding No benefit for either rivaroxaban or warfarin (difference not statistically significant) Intracranial bleeding Favours rivaroxaban 2 fewer events per 1,000 patients per year Gastrointestinal (upper,lower and rectal) bleeding Favours warfarin 10 fewer events per 1,000 patients per year Mortality No benefit for either rivaroxaban or warfarin (difference not statistically significant) Summary Rivaroxabani is about as good as warfarin in preventing stroke and blood clots, and has a similar risk of major bleeding. Side effects/tolerability Overall No benefit for either rivaroxaban or warfarin (difference not statistically significant) Epistaxis Favours warfarin (10.1% rivaroxaban vs 8.6% warfarin) Study withdrawal Comparable with both rivaroxaban and warfarin (23.7% rivaroxaban vs 22.2% warfarin)
7 Item Monitoring and convenience Warfarin - Frequency of blood tests/ dose adjustments Rivaroxaban may require initial renal function test to determine dose Routine health checks required in case of unexplained bleeding Drug interactions Discussed Dosing and administration Warfarin not suitable for dosette boxes (due to variable dose) Rivaroxaban may not be suitable for people with swallowing difficulties as no data available on crushing tablets Antidotes There may be a need to reverse anticoagulation if Serious bleeding following a fall or accident, Serious bleeding without external cause Urgent requirement for surgery INR (warfarin) too high due to dietary change, drug interaction Vit K / PCC for warfarin There is no specific antidote to rivaroxaban. Consideration may be given to use of procoagulant products such as PCC, but this recommendation is largely based on limited non-clinical data as there is very limited clinical data relating to use. Areas of uncertainty Limited patient exposure and lack of long-term safety data for rivaroxaban End Note i Rivaroxaban 20mg o.d., or 15mg o.d. in patients with creatinine clearance of 30 to 49ml per minute (ROCKET-AF population)
8 Rivaroxaban Patient Clinician Discussion Guide What did NICE say 1? Rivaroxaban is recommended as an option for the prevention of stroke and systemic embolism within its licensed indication, that is, in people with nonvalvular atrial fibrillation with one or more risk factors such as: congestive heart failure hypertension age 75 years or older diabetes mellitus, prior stroke or transient ischaemic attack. The decision about whether to start treatment with rivaroxaban should be made after an informed discussion between the clinician and the person about the risks and benefits of rivaroxaban compared with warfarin. For people who are taking warfarin, the potential risks and benefits of switching to rivaroxaban should be considered in light of their level of international normalised ratio (INR) control Does this mean my doctor has to prescribe it for me if I want it? Some people cannot take rivaroxaban because of other health conditions. In this case, their doctor would not prescribe it for them, even if they met the NICE criteria above. You should not take rivaroxaban if: You have an allergy to rivaroxaban or a component of the tablet You have extremely poor kidney function You have another illness causing significant bleeding You have liver disease associated with clotting problems and bleeding risk You need to take ketoconazole or similar drugs, dronedarone or HIV medication, You are pregnant or breast-feeding. If you have an increased risk of bleeding, your doctor will need to consider the risks of rivaroxaban particularly carefully. Some people take warfarin for conditions other than to reduce the risk of stroke due to atrial fibrillation. This NICE guidance does not apply to those conditions. If you meet the NICE criteria, then you and your doctor (or nurse or pharmacist) should have a discussion about whether rivaroxaban or warfarin is better for you. This means thinking about the possible benefits, and possible problems, associated with taking rivaroxaban compared with warfarin. This guide is to help you and your doctor to go through what we know about the positives and negatives about rivaroxaban, compared with warfarin, and to highlight some of the things that we don t know about it yet. End Note 1 If you do not meet at least one of the criteria in the NICE guidance then you would only be considered for rivaroxaban in exceptional circumstances.
9 What do I need to consider? Important information about clinical trials, benefits and harms Every medicine has good points (benefits) and bad points (harms, or side effects ). These are worked out on a large scale by doing trials of the medicine in lots of people, so we can get an idea of how many people will get the benefit, and how many will experience a side effect. The big trial that compared rivaroxaban with warfarin in patients with atrial fibrillation was called ROCKET-AF. Of course, not everyone will actually get a benefit many people would not have had a bad event like a stroke whether they took the medicine or not - and sadly some people will still have the bad event even if they do take the medicine. However, out of all the people who take the medicine, a small number of people will be prevented from having the bad event. Similarly, most people will not suffer harm, such as dangerous bleeding, from taking the medicine. A small number of people would have suffered harm whether they took the medicine or not. However, out of all the people who take a medicine, a small number of people will suffer harm who would not have done if they had not taken that medicine. We can t tell beforehand which person will fall into which category, so we can t tell you specifically whether you will be someone for whom taking rivaroxaban (rather than warfarin) prevents a bad event, someone in whom it causes a dangerous or unpleasant side effect, or someone in whom it has neither a positive nor a negative effect. It s important to note that some people were not allowed to take part in the study e.g. if they had just had a stroke or mini-stroke, if they were at high risk of bleeding, or had severe kidney or liver problems, a severe heartvalve disorder, uncontrolled hypertension or were pregnant. People for whom cardioversion was planned were also excluded from the trial. If you have one of these conditions, then either rivaroxaban may not be suitable for you, or the balance of benefits and risks may be different. The information from clinical trials involves thinking about some numbers, so everything in this section is presented in terms of considering benefits and harms/side effects per 1,000 people treated for one year.
10 What did the ROCKET-AF trial show? Efficacy and safety Looking at the numbers of people who had a stroke or a blood clot: There was no difference 2 in the risk of having a stroke or blood clot with rivaroxaban compared with warfarin Looking at the numbers of people who had major bleeding: There was no difference 2 in the risk of having a major bleed with rivaroxaban compared with warfarin Looking at the people who had bleeding in the brain For every 1,000 people treated for one year Number of bleeds in the brain with rivaroxaban 5 Number of bleeds in the brain with warfarin 7 Number of bleeds in the brain prevented by using rivaroxaban 2 per 1,000 people Risk of dying Overall, the risk of dying was the same for people taking rivaroxaban as people taking warfarin. In summary - Rivaroxaban is about as good as warfarin in preventing stroke and blood clots, and has a similar risk of major bleeding. Side effects and tolerability The rate of most side effects was the same whether people were taking rivaroxaban or warfarin. However, more people experienced epistaxis (nose-bleed) with rivaroxaban than with warfarin For every 1,000 people (rounded figures) Epistaxis (nose-bleed) with rivaroxaban 101 Epistaxis (nose-bleed) with warfarin 86 Additional cases of epistaxis (nose-bleed) with rivaroxaban 15 per 1,000 people End Note 2 no difference is used to indicate that the difference in the point estimates was not statistically significant
11 Overall, about the same number of people stopped taking the medicine and withdrew from the study with rivaroxaban as did with warfarin. So what else might I need to think about? Monitoring and convenience Unlike warfarin, rivaroxaban does not need regular blood tests and dose adjustments, and there are no special dietary requirements. There are fewer drug interactions. A person who is considering rivaroxaban may be asked to have a test before starting it to check how well their kidneys are working. Any person taking a blood thinning medicine should have regular health checks in case of unexplained bleeding. Remembering to take the medicine Warfarin is taken once a day. It is not suitable for dosette boxes and similar systems, as there may be a need to change the dose. Rivaroxaban is also taken once a day. It is important to be confident that you will be able to remember to do this, especially as there is no monitoring to give you regular feedback on your blood levels. We do not have any information on whether it is safe to crush tablets, so rivaroxaban may not be suitable for people with swallowing difficulties. Antidote Sometimes there may be a need to reverse the blood-thinning (anticoagulation) effect e.g. INR (warfarin) too high due to dietary change, drug interaction Blood level ( rivaroxaban) too high e.g. due to gradual or sudden reduction in kidney function. Serious bleeding following a fall or accident, Serious bleeding without external cause Urgent requirement for surgery The effect of warfarin can be reversed using a Vitamin K antidote, and various blood products can be used to help to reduce or stop bleeding. There is currently no known antidote to rivaroxaban, so there are few options for controlling excessive bleeding. Certain treatments might reduce bleeding, but there is limited clinical experience with this. Some areas of uncertainty Because warfarin has been used for many years, the side effects are well known, and doctors and nurses are familiar with dealing with them. Rivaroxaban is a very new drug, so we know much less about it than we do about warfarin. It is not uncommon for more information about side effects to become apparent once more people start using a medicine outside the carefully controlled circumstances of a clinical trial. Sometimes these may not emerge until after several years of use, and sometimes they may be serious. It may be helpful to be aware that in the past ten years there have been examples of new drugs where no serious concerns have emerged, and others where concerns have been so great that the drug has been withdrawn for safety reasons. At this stage it is not possible to tell what the future holds for rivaroxaban.