Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses
BMJ 2011; 343 doi: https://doi.org/10.1136/bmj.d6333 (Published 31 October 2011) Cite this as: BMJ 2011;343:d6333
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Pink et al's brave economic analysis of the economics of dabigatran is a helpful pointer but is flawed by several real-world issues that are not considered:
1. The price of dabigatran is likely to fall in the medium term as competitive drugs are licensed.
2. The cost saving from not needing INR monitoring will depend upon whether warfarin clinics continue to run but at a lower workload, or close completely. In the former case their unit cost may well rise; in the latter the resource can be redeployed.
3. The need for some patients to continue on warfarin because of impaired renal function is not quantified.
4. Some patients failing to achieve therapeutic INR range on warfarin may be just as non-adherent with dabigatran (though the regimen is simpler to follow).
5. The authors do not indicate whether they have accounted for the cost of transport to clinics.
6. Many frailer patients refuse warfarin because they are unwilling to attend for monitoring; others with cognitive impairment cannot be trusted to adjust their dose in response to INR. These patients currently take aspirin, compared to which dabigatran is likely to be far superior for stroke prevention. It is problematic to deny these patients dabigatran.
7. There has never been a satisfactory mechanism in the NHS for transferring resource from secondary care to the primary care prescribing budget. Without this warfarin clinic resource is likely to disappear into the secondary care black hole.
8. The authors do not indicate any adjustment made for reduction of drug-related admissions.
9. Once sanctioned by NICE and publicised (as a breakthrough, perhaps correctly on this occasion!) by the Daily Mail, GPs will be overwhelmed by demand for dabigatran, because few patients enjoy regular monitoring.
Whilst it would be premature to recommend the wholesale closure of warfarin clinics before there are more long-term safety and efficacy data, we do not think the conclusion that dabigatran is 'unlikely to be cost effective in clinics able to achieve good INR control with warfarin' can be justified without considerable further refinement of the economic model.
Arnold Zermansky, GP and Senior Research Fellow, University of Leeds.
a.g.zermansky@leeds.ac.uk
Rani Khatib, Senior Pharmacist and Lecturer, University of Leeds.
Competing interests: No competing interests
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
Pink and colleagues note that their analysis "...counters the
concerns raised by NICE in its appraisal of the manufacturer's submission
[of dabigatran etexilate for stroke prevention in atrial fibrillation]".
They also imply that the reduced dose of dabigatran etexilate (110mg b.d)
"...is not a cost-effective option..." and that the higher dose (150mg
b.d) is cost-effective only in certain patient subgroups when considered
against the standard NICE threshold of ?20,000 per Quality-Adjusted Life
Year (QALY) gained.[1] However, these conclusions appear to have been
premature.
Whilst it must be conceded that the NICE Appraisal Committee did
raise some issues for clarification in their Appraisal Consultation
Document (ACD),[2] it is important to note that the ACD should be
regarded, as the name implies, as a document facilitating consultation and
that the Final Appraisal Determination (FAD) when published represents the
final conclusions of the NICE Appraisal Committee.
The FAD for this particular appraisal was published by NICE on
November 1st 2011, and the concerns noted by Pink and colleagues would
appear to have been resolved satisfactorily in the eyes of the Appraisal
Committee. The FAD proposes that dabigatran etexilate should be
recommended as an option within its licensed indication, without
restriction. [3] Subject to appeal, this will become final NICE guidance
in December 2011.
Within the FAD, the NICE Appraisal Committee note the following:
"[The Committee] accepted the manufacturer's [revised] approach and
concluded that the most plausible [incremental cost-effective ratios]
ICERs for the whole population eligible for dabigatran were within the
range normally considered a cost-effective use of NHS resources, being
less than ?20,000 per QALY gained." (Section 4.17)
"[The Committee] also accepted that it was not reasonable to expect
all patients to try warfarin first, with the associated risks, for the
purpose of selecting out a subgroup for whom dabigatran was less cost
effective." (Section 4.19)
"[The Committee] concluded that evidence for stratifying by INR
control was insufficient to exclude the minority of people with very good
control from the recommendation of dabigatran as a potential treatment
option, and that the ICER for the whole population should be the basis of
the recommendation." (Section 4.20)
This last conclusion is supported by a recent analysis of the UK
General Practice Research Database (GPRD) which estimated that the mean
time in therapeutic range (TTR) experienced by UK atrial fibrillation
patients treated with warfarin was approximately 63%.[4]
We would also query how Pink and colleagues have accounted for
intracranial haemorrhage (ICH) events in their analysis. The permanent
health state disutility associated with disability resulting from ICH
events is valued at 0.0524, less than one-quarter of the corresponding
value for stroke (0.233). Given the severity of ICH events, we find this
difficult to justify. Also it is unclear which cost value is attached to
ICH events. As demonstrated in another analysis of the same comparison,[5]
the results are likely to sensitive to these parameters meaning Pink and
colleagues may have underestimated the cost-effectiveness of dabigatran
etexilate.
Finally, whilst it may be of academic interest for the 150mg b.d and
110mg b.d doses to be compared directly, the relevance of these
conclusions to the UK setting is unclear. As noted in the NICE ACD,[3]
only an analysis that mirrors the approved UK licensed indication of
dabigatran etexilate is relevant for decision making. That is, patients
aged at least 80 years are not eligible for the 150 mg b.d dose under the
approved label. Therefore any conclusions drawn from a comparison of the
two doses in this subgroup of patients is not relevant to UK clinical
practice.
Yours Sincerely
Jane Griffin
Director
Paul Robinson
Heath Economics Team Manager
Dr Ray Gani
Senior Health Economist
Market Access, Pricing and Outcomes Research Dept.
Prescription Medicine
Boehringer Ingelheim Ltd.
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. BMJ
2011;343:d6333.
2. National Institute for Health and Clinical Excellence. Single
Technology Appraisal: Atrial fibrillation - dabigatran etexilate.
Appraisal Consultation Document. August 2011. Available at:
http://guidance.nice.org.uk/TA/Wave21/10/Consultation/Latest
3. National Institute for Health and Clinical Excellence. Single
Technology Appraisal: Atrial fibrillation - dabigatran etexilate. Final
Appraisal Determination. November 2011. Available at:
http://guidance.nice.org.uk/TA/Wave21/10/FAD
4. Gallagher AM; Setakis E, Plumb JM; Clemens A; van Staa T-P. Risks
of stroke and mortality associated with suboptimal anticoagulation in
atrial fibrillation patients. Thromb Haemost 2011; 106 (published online
ahead of print, September 8th 2011)
5. Sorensen SV, Kansal AR, Connolly S. Cost-effectiveness of
dabigatran etexilate for the prevention of stroke and systemic embolism in
atrial fibrillation: a Canadian payer perspective. Thromb Haemost
2011;105:908-15.
Competing interests: Jane Griffin, Paul Robinson and Ray Gani are employees of Boehringer Ingelheim Ltd, the manufacture of dabigatran etexilate.
Re: Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses
Zermansky et al raise a number of points regarding our economic evaluation of dabigatran. In line with accepted health economic methods [1], we used the current list price of dabigatran. While the availability of generics significantly affects future pricing, new entrants have little if any effect on the price of the first to market [2]. We assumed dabigatran would have no impact on anticoagulation clinics. The marginal cost of INR monitoring will only fall in the unlikely event of dabigatran displacing warfarin. Should there be wholesale closure of anticoagulation clinics, these resources would presumably be redeployed in other cost-effective ways. We agree that not all poorly adherent patients will be better with dabigatran, but made no such assumption in our analysis. Warfarin’s longer elimination half life makes it more forgiving in the face of missed doses. There is no basis, at present, to assume a reduction in drug-related hospital admissions. Warfarin is the third highest cause of such admissions [3] but differences in major bleeding event rates between warfarin and dabigatran 150mg bid were not statistically significant in the RE-LY study [4]. Our analysis adopted an NHS costing perspective and therefore correctly ignored costs to patients, such as clinic attendance for INR monitoring. We made no provisions for renally compromised patients to remain on warfarin but as with the case of switching current aspirin users to dabigatran, there were insufficient data to inform the analysis. NICE’s endorsement of dabigatran should be viewed cautiously. While it is undoubtedly effective, evidence on its safety in the real world setting is lacking and its cost-effectiveness is questionable. The 256 spontaneous case reports of bleeding-related deaths [5] warrant careful balancing of benefits against harms. This is likely to be optimised in centres (and hence patients) who are least well controlled with warfarin.
1. Hughes DA, Tilson L, Drummond M. Estimating drug costs in economic evaluations in Ireland and the UK: an analysis of practice and research recommendations. Pharmacoeconomics. 2009;27(8):635-43.
2. Office of Fair Trading. The Pharmaceutical Price Regulation Scheme. An OFT market study. February 2007. http://www.oft.gov.uk/shared_oft/reports/comp_policy/oft885.pdf
3. Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, Farrar K, Park BK, Breckenridge AM. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ. 2004;329(7456):15-9.
4. Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, Oldgren J, Yang S, Alings M, Kaatz S, Hohnloser SH, Diener HC, Franzosi MG, Huber K, Reilly P, Varrone J, Yusuf S. 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(21):2363-72.
5. European Medicines Agency. European Medicines Agency updates on safety of Pradaxa. 18 November 2011. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2011/...
Competing interests: No competing interests