Re: Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses
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Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses
Re: Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses
Sir
We were heartened to read the analysis by Pink et al (1) published last week. This is obviously an important piece of work and we feel it should have a bearing on how clinicians consider the use of Dabigatran Etexilate in their practice. Though the actual point estimates of incremental cost effectiveness are different, the general principles highlighted are strikingly similar to work that was undertaken in West Yorkshire; that the effectiveness and therefore cost effectiveness is substantially linked to a patient’s time in therapeutic range. The West Yorkshire analysis (2) was influenced by the paper published by Wallentin and colleagues (3) and concluded that in currently warfarinised patients with good control Dabigatran is similar efficacy to warfarin but is markedly more expensive– therefore not cost effective within normal thresholds. In addition, the Wallentin study and the original RELY study both report comparative safety data (bleed and MI risk) that requires careful consideration among sub groups, defined by quartiles of therapeutic control.
In warfarinised patients with poor control (defined as <66% of time in therapeutic range) dabigatran is likely to be cost effective and in that cohort switching to dabigatran should be actively considered. This point was further reinforced when one reconsiders that the RELY cohort (4) cannot simply be generalised to UK clinical practice. The RELY cohort can be characterised as a generally lower risk population with poorer INR control (one third with CHADS2 >2 and warfarin was within therapeutic range 64% of the study period) compared to significant proportions of the UK AF population. In addition there are recent indications that Dabigatran Etilexate 110mg has a similar (as opposed to superior) safety profile to warfarin in elderly and renal impaired populations (5). This point about generalisability and risk of bias has also been highlighted by others (6)
Evidentially, it seems fair to say that there is insufficient evidence to shed light on the best strategy when considering antcoagulation in a newly incident patient or a prevalent patient naïve to warfarin. Obviously, given the high NNT to prevent one stroke with dabigatran compared to warfarin and the substantial net cost (up to £700 per patient per year, depending on the price paid for INR monitoring locally) the local consensus is that warfarin remains the drug of choice, and that dabigatran should only be considered in truly intolerant or patients whom, despite good concordance, are unable to get good therapeutic control. The implication of this consensus is that we do not agree that “dabigatran is the new warfarin”, it is not.
It seems clear that the Evidence Review Group made the point about clinical and cost effectiveness by TTR very strongly to the TA Committee considering this treatment (7). There is also recent publication from the manufacturer (8) highlighting the requirement for annual renal monitoring, this has an obvious bearing on the economic model that NICE may consider. As with all new medicines, we do not know the long term safety profile, there are some emerging signals (9), and it is of note that requiring INR monitoring could be seen to confer some benefits - clinicians can pick up that something is going wrong and adjust dose of warfarin; with no monitoring there will be no such opportunity with dabigatran. This might be a particular problem in elderly patients also treated with aspirin and or NSAIDs, although warfarin has similar issues.
We fear that the way this provisional TA recommendation will play out in the real world, especially when combined with significant media and patient pressure to switch from a drug that is often (poorly) characterised as rat poison, to this new medicine, will be that many patients with good therapeutic control will end up being treated with a medicine of similar efficacy but considerably more expensive. This would neither be a good choice for patients nor a rational use of scarce resources. The NICE Final Appraisal Determination does make points about patients manipulating their INR in order to "be switched", however there seems little available evidence of this, or intelligence that it is likely to happen..
We welcome the introduction of dabigatran, it truly does represent a step change in available anticoagulant treatments for a defined patient cohort. We recognise the danger of over stating the negative aspects of dabigatran, or over egging the risk benefit profile of warfarin. The judgements about absolute risk and benefit of both warfarin and dabigatran are highly nuanced and seem to vary within the currently warfarinised population (3) (5). Given these uncertainties in the current evidence base and how the evidence will develop over time we strongly urge clinicians to use this medicine carefully in those unable to maintain good control on warfarin.
Greg Fell, Consultant in Public Health, NHS Airedale, Bradford and Leeds Cluster
Matt Fay, GP, Westcliffe Medical Practice, Shipley, Bradford
(1) Pink J, Lane S, Pirmohamed M, Hughes DA. Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses. BMJ2011;343:d6333.
(3) Wallentin et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. The Lancet 2010; 376: 975–83
(4) Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. NEJM 2009;361
(5) Eikelboom J. W. et al. Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation. An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial. Circulation 2011, 123:2363-2372:
(6) Dabigatran for atrial fibrillation. Why we can not rely on RE-LY. Theraputics Initiative Neweletter, Jan – March 2011. www.ti.ubc.ca
(7) National Institute of Clinical and Health Excellence. Atrial fibrillation - dabigatran etexilate: final appraisal determination. http://guidance.nice.org.uk/TA/Wave21/10/FAD (accessed 8th November)
(8) Dear Healthcare professional letter, 27th Oct, Boeringer Ingleheim.
Rapid Response:
Re: Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses
Sir
We were heartened to read the analysis by Pink et al (1) published last week. This is obviously an important piece of work and we feel it should have a bearing on how clinicians consider the use of Dabigatran Etexilate in their practice. Though the actual point estimates of incremental cost effectiveness are different, the general principles highlighted are strikingly similar to work that was undertaken in West Yorkshire; that the effectiveness and therefore cost effectiveness is substantially linked to a patient’s time in therapeutic range. The West Yorkshire analysis (2) was influenced by the paper published by Wallentin and colleagues (3) and concluded that in currently warfarinised patients with good control Dabigatran is similar efficacy to warfarin but is markedly more expensive– therefore not cost effective within normal thresholds. In addition, the Wallentin study and the original RELY study both report comparative safety data (bleed and MI risk) that requires careful consideration among sub groups, defined by quartiles of therapeutic control.
In warfarinised patients with poor control (defined as <66% of time in therapeutic range) dabigatran is likely to be cost effective and in that cohort switching to dabigatran should be actively considered. This point was further reinforced when one reconsiders that the RELY cohort (4) cannot simply be generalised to UK clinical practice. The RELY cohort can be characterised as a generally lower risk population with poorer INR control (one third with CHADS2 >2 and warfarin was within therapeutic range 64% of the study period) compared to significant proportions of the UK AF population. In addition there are recent indications that Dabigatran Etilexate 110mg has a similar (as opposed to superior) safety profile to warfarin in elderly and renal impaired populations (5). This point about generalisability and risk of bias has also been highlighted by others (6)
Evidentially, it seems fair to say that there is insufficient evidence to shed light on the best strategy when considering antcoagulation in a newly incident patient or a prevalent patient naïve to warfarin. Obviously, given the high NNT to prevent one stroke with dabigatran compared to warfarin and the substantial net cost (up to £700 per patient per year, depending on the price paid for INR monitoring locally) the local consensus is that warfarin remains the drug of choice, and that dabigatran should only be considered in truly intolerant or patients whom, despite good concordance, are unable to get good therapeutic control. The implication of this consensus is that we do not agree that “dabigatran is the new warfarin”, it is not.
It seems clear that the Evidence Review Group made the point about clinical and cost effectiveness by TTR very strongly to the TA Committee considering this treatment (7). There is also recent publication from the manufacturer (8) highlighting the requirement for annual renal monitoring, this has an obvious bearing on the economic model that NICE may consider. As with all new medicines, we do not know the long term safety profile, there are some emerging signals (9), and it is of note that requiring INR monitoring could be seen to confer some benefits - clinicians can pick up that something is going wrong and adjust dose of warfarin; with no monitoring there will be no such opportunity with dabigatran. This might be a particular problem in elderly patients also treated with aspirin and or NSAIDs, although warfarin has similar issues.
We fear that the way this provisional TA recommendation will play out in the real world, especially when combined with significant media and patient pressure to switch from a drug that is often (poorly) characterised as rat poison, to this new medicine, will be that many patients with good therapeutic control will end up being treated with a medicine of similar efficacy but considerably more expensive. This would neither be a good choice for patients nor a rational use of scarce resources. The NICE Final Appraisal Determination does make points about patients manipulating their INR in order to "be switched", however there seems little available evidence of this, or intelligence that it is likely to happen..
We welcome the introduction of dabigatran, it truly does represent a step change in available anticoagulant treatments for a defined patient cohort. We recognise the danger of over stating the negative aspects of dabigatran, or over egging the risk benefit profile of warfarin. The judgements about absolute risk and benefit of both warfarin and dabigatran are highly nuanced and seem to vary within the currently warfarinised population (3) (5). Given these uncertainties in the current evidence base and how the evidence will develop over time we strongly urge clinicians to use this medicine carefully in those unable to maintain good control on warfarin.
Greg Fell, Consultant in Public Health, NHS Airedale, Bradford and Leeds Cluster
Matt Fay, GP, Westcliffe Medical Practice, Shipley, Bradford
Campbell Cowan, Consultant Cardiologist, Leeds Teaching Hospitals Trust.
(1) Pink J, Lane S, Pirmohamed M, Hughes DA. Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses. BMJ2011;343:d6333.
(2) Economic Appraisal of Dabigatran Etexilate 150 mg Compared to Warfarin or Aspirin in Patients with Atrial Fibrillation. http://www.yorksandhumberhearts.nhs.uk/upload/WYCN/Dabigatran/YHEC%20Dab...
(3) Wallentin et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. The Lancet 2010; 376: 975–83
(4) Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. NEJM 2009;361
(5) Eikelboom J. W. et al. Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation. An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial. Circulation 2011, 123:2363-2372:
(6) Dabigatran for atrial fibrillation. Why we can not rely on RE-LY. Theraputics Initiative Neweletter, Jan – March 2011. www.ti.ubc.ca
(7) National Institute of Clinical and Health Excellence. Atrial fibrillation - dabigatran etexilate: final appraisal determination. http://guidance.nice.org.uk/TA/Wave21/10/FAD (accessed 8th November)
(8) Dear Healthcare professional letter, 27th Oct, Boeringer Ingleheim.
(9) Dabigatran: Australia issues bleeding warning. http://www.tga.gov.au/safety/alerts-medicine-dabigatran-111005.htm (accessed Nov 11)
Competing interests: No competing interests