Download Dabigatran instead of warfarin in AF

From www.gp‐update.co.uk – one day courses for GPs, by GPs Dabigatran instead of warfarin in AF In March 2012 NICE approved dabigatran for use as thromboprophylaxis in atrial fibrillation (AF), as an alternative to warfarin. Dabigatran has also been approved for use in Scotland. About dabigatran •
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Dabigatran is a direct coagulation inhibitor; it inhibits thrombin activity. Unlike warfarin, dabigatran requires no monitoring. Dabigatran is taken twice daily and there are two doses, 110mg and 150mg. The lower dose (110mg twice daily) should be used in those aged 80 or over, because of the higher risk of bleeding in this age group. There is more on dosing by age in the box summarising the NICE guidance (below) (BMJ 2011;343:d6333). If monitoring costs are included, warfarin is estimated to cost around £426/year, about half that of dabigatran (£920) (DTB 2011;49(10):114). As far as I can tell, there is no antidote if rapid reversal is required (e.g. for emergency surgery). No dietary restrictions are required for dabigatran (NICE 2012, TA 249). It is contraindicated in renal and liver impairment (NICE 2012, TA 249). Nausea, diarrhoea, dyspepsia and abdominal pain are common side effects, as well as anaemia/bleeding from the GI or GU tract (NICE 2012, TA 249). What does NICE guidance say? NICE on dabigatran NICE 2012, TA 249. • Dabigatran is ‘an option’ for the prevention of stroke and systemic emboli in those with non‐valvular AF if they have one or more of the following risk factors: o Aged 75 or over o Age 65 or over with either diabetes, coronary artery disease or hypertension o Previous CVA, TIA or systemic emboli o LV ejection fraction of <40% o Symptomatic heart failure (NYHA class 2 or worse= anyone with any limitation in activities). • It is not recommended for those with valvular AF. • Dose depends on age. o For those aged 80 or over a dose of 110mg twice daily should be used. o For those under 80 a dose of 150mg twice daily should be used. o However for those aged 75‐80, it is at the clinician’s discretion as to whether 110 or 150mg dosing should be used! o The lower dose can also be used in patients where the bleeding risk is high and the embolic risk is low (one wonders whether aspirin might not be better in these individuals…?) • The higher dose of dabigatran (150mg) is more effective than the lower dose or warfarin. The lower dose of dabigatran (110mg twice daily) is as effective as warfarin. • This guidance applies to those already diagnosed with AF as well as those newly diagnosed with it. o So patients with newly diagnosed AF do not need a trial of warfarin first, but can, if suitable, be offered dabigatran as a first line therapy. o All those currently on warfarin should be reviewed to assess the risks and benefits of continuing warfarin or swapping to dabigatran. 1 From www.gp‐update.co.uk – one day courses for GPs, by GPs So what is the evidence for dabigatran? So NICE says dabigatran is ‘an option’ for those with one or more risk factors listed above, but who exactly should we offer it to? Everyone who meets the above criteria? Only some of those meeting the criteria? And in which case who? Exactly which people we might use it in is discussed after an overview of the evidence base behind the NICE decision. The main trial of dabigatran is the RE‐LY trial. The RE‐LY trial took 18 000 patients with non‐valvular AF and randomised them to either: Dabigatran 110mg twice daily Dabigatran 150mg twice daily Warfarin. RE‐LY excluded people for whom warfarin was contraindicated (NEJM 2011;363:1875). RE‐LY was a non‐inferiority trial, so asked the question ‘Are these drugs any worse than warfarin at reducing strokes in AF?’ The trial did not test superiority (‘Is dabigatran better than warfarin?’) Despite this, conclusions were drawn in the NEJM paper and NICE about superiority, and I report these conclusions here. Outcomes of the RE‐LY trial Here I am mainly summarising data from the published RE‐LY trial (NEJM 2011;363:1875), but I do also include some data from the NICE technology appraisal, and this in indicated by (NICE) after the statement. Follow up over two years showed: •
Higher dose dabigatran offered greatest stroke protection. o Stroke risk on high dose dabigatran (150mg bd) was 1.1%/year. o Stroke risk on warfarin or low dose dabigatran was 1.71%/year That gives an NNT of 164 over 12m for high dose dabigatran versus warfarin/low dose dabigatran (that is, you have to treat 164 people for 12m with high dose dabigatran to prevent one stroke that would have occurred if the patient had been on low dose dabigatran or warfarin). o Benefits were the same whether patients were under or over 80y, although higher doses are not licensed in those aged 80 or over (NICE). •
Major bleeding risk for warfarin and high dose dabigatran were similar at 3.36%/year. o Major bleeding risk on low dose dabigatran was 2.71%/year. However, dabigatran (compared to warfarin) had significantly lower rates of intracranial haemorrhage and haemorrhagic stroke, but higher incidence of gastrointestinal haemorrhage (NICE 2012 TA 249). • Those with poorest INR control got the most benefit from dabigatran. In those with good INR control, little or no additional benefit was gained from dabigatran, in terms of stroke benefits/bleeding risks, but those on dabigatran do benefit from not needing regular INR monitoring (NICE). Cost effectiveness of dabigatran Subsequently the researchers did a cost‐effectiveness analysis, based on 50 000 simulated patients, using data from the RE‐LY trial (BMJ 2011;343:d6333). They did this for both doses of dabigatran (110mg and 150mg). On the basis of this they concluded that: • Dabigatran would only be cost effective in those for whom tight INR control was not achieved or if the stroke risk was particularly high. 2 From www.gp‐update.co.uk – one day courses for GPs, by GPs So what does this mean in practice? The DTB reviewed the evidence on dabigatran (DTB 2011;49(10)114). They concluded that warfarin should currently remain the first line therapy for anticoagulation in atrial fibrillation. Dabigatran should be reserved for: o those in whom INR monitoring is difficult, but who are at high risk of stroke o those in whom anticoagulation control is poor o those at high risk of drug interactions. Certain patients immediately spring to mind who may well benefit from dabigatran (the man who NEVER comes for his INR, or the woman whose INR yo‐yos all over the place for no obvious reason and despite good compliance), but for the rest of our population, I still think the decision is not that clear cut. I have no doubt there will be a proliferation of local guidelines on this topic! Dabigatran for atrial fibrillation •
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Dabigatran has recently been approved by NICE as an option instead of warfarin for thromboprophylaxis in AF. NICE recommends its use only in those with one or more risk factors (outlined above). The DTB conclude its role should be reserved for those with poor INR control but who are at high risk of stroke, those for whom monitoring is difficult, or those at high risk of drug interactions. There are going to be some who will clearly benefit – but whether everyone else should give it a try is much less clear. No doubt there will be a proliferation of local guidance on this topic! 3 From www.gp‐update.co.uk – one day courses for GPs, by GPs The GP Update Course – A one day course for GPs and GP Registrars, by GPs. We trawl through all the journals and do all the legwork to bring you up to speed on the latest issues, research and guidelines in General Practice. We set all this in the context of the consulting room and the requirements of revalidation. We focus on actions ‐ getting the literature into practice and ensuring it counts towards revalidation. We make it entertaining too, without compromising the content! Course delegates receive a copy of The GP Update Handbook, a 400 page book outlining the results of the most important research relevant to primary care over the last 5 years, access to GP Update Handbook Online from the date of booking to a year after the course. We will also give you a copy of the GP Update Revalidation Action Pack which contains step by step guidance on audits, reflective practice and service developments related to the course, so that you have documented evidence of improved care for your next appraisal and for revalidation. We’ve included lots of material for locums too. The GP Update Course is completely free from pharmaceutical company sponsorship. This means that you can be totally reassured that there will be no biasing of the information presented to you and that there will be no reps there on the day! Summer 2012 dates: Exeter ‐ Wednesday May 16 Bristol ‐ Thursday May 17 London ‐ Friday May 18 London ‐ Saturday May 19 Newcastle ‐ Wednesday May 23 Sheffield ‐ Thursday May 24 Manchester ‐ Friday May 25 Birmingham ‐ Saturday May 26 Norwich ‐ Tuesday May 29 London ‐ Wednesday May 30 Autumn 2012 dates: Oxford ‐ Friday September 28 Southampton ‐ Saturday September 29 Leeds ‐ Wednesday October 3 Liverpool ‐ Thursday October 4 Manchester ‐ Friday October 5 Birmingham ‐ Saturday October 6 Cardiff ‐ Wednesday October 10 Exeter ‐ Thursday October 11 London ‐ Friday October 12 London ‐ Saturday October 13 Cambridge ‐ Tuesday October 16 Nottingham ‐ Wednesday October 17 Inverness ‐ Wednesday November 7 Edinburgh ‐ Thursday November 8 Glasgow ‐ Friday November 9 GPs £195, ST1, 2 & 3 and Nurses £150. For more details see www.gp‐update.co.uk We make every effort to ensure the information in these pages is accurate and correct at the date of publication, but it is of necessity of a brief and general nature, and this should not replace your own good clinical judgement, or be regarded as a substitute for taking professional advice in appropriate circumstances. In particular check drug doses, side effects and interactions with the British National Formulary. Save insofar as any such liability cannot be excluded at law, we do not accept any liability for loss of any type caused by reliance on the information in these pages. GP Update Limited and Primary Care Education LLP April 2012 4