CVS

Dabigatran etexilate versus warfarin in managementof non-valvular atrial fibrillation in UK context:quantitative benefit-harm and economic analyses
د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2011

Atrial fibrillation is the most common sustained cardiac arrhythmia, with an estimated prevalence in the United Kingdom of 10% in patients aged 75 or over and an associated fivefold increase in the risk of ischaemic stroke.

Warfarin is the mainstay of oral thromboprophylactic

anticoagulation treatment. However, patients show considerable variability in their response to warfarin, which, coupled with anarrow therapeutic range, necessitates frequent monitoring and
adjustment of dosage to ensure optimal anticoagulation.Deviations outside the therapeutic range (internationalnormalised ratio (INR) 2.0-3.0) increase the risk of both strokes and haemorrhagic events.

Dabigatran etexilate is a new oral direct thrombin inhibitor that may provide an alternative to warfarin; it has the advantage of not requiring regular monitoring.

In the multinational,Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study, 18 113 patients with non-valvular atrial fibrillation and at least one risk factor for stroke were randomised to one of two doses of dabigatran (110 mg or 150mg, twice daily) or dose adjusted warfarin. After a median follow-up of two years, the rates of the primary outcome (stroke or systemic embolism) were similar to those for warfarin among patients assigned the lower dose but were lower among patients assigned the higher dose (1.11% v 1.71% per year; relative risk 0.66, 95% confidence interval 0.53 to 0.82; P=0.0001).

Compared with warfarin, the annual rate of major bleeding was lower among patients assigned dabigatran 110 mg (2.71% v 3.36%; relative risk 0.80, 0.69 to 0.93; P=0.003) but similar among those assigned 150 mg.
Dabigatran was associated with higher rates of myocardial infarction, but these were not statistically significant.


The US Food and Drug Administration (FDA) was satisfied of the positive benefit to harm balance of dabigatran but failed to identify a subgroup of patients in which the benefit-harm profile was superior for the 110 mg dose compared with the 150 mg dose and consequently approved only the higher dose. However, both doses have been approved by other regulatory authorities, including the European Medicines Agency, which specifies 150 mg twice daily for patients under 80 years of age and 110 mg twice daily for those aged 80 and over or as an option when the thromboembolic risk is considered to be low and the risk of bleeding is high.

Incidence of dyspepsia in the dabigatran groups—11.8% for 110 mg and 11.3% for 150 mg, compared with 5.8% for warfarin.

Clinical outcomes and net health benefit

In the base case analysis, dabigatran 110 mg and 150 mg twice daily extended life by 1.1 and 2.4 months compared with warfarin .

Lifetime incidences of stroke or systemic embolism were 12.5% lower with dabigatran 110 mg twice daily than with warfarin and 27.4% lower with dabigatran 150 mg twice daily. Incidences of major haemorrhagic events were lower for low dose dabigatran (by 4.0%) but higher for high dose dabigatran (by 8.8%). We found no discernible differences in lifetime
incidences of myocardial infarction between the two doses of
dabigatran, but these were about 19% higher than for warfarin.
Although age adjusted dabigatran dosing was associated with
lower bleeding rates, the higher rates of thrombotic events
resulted in it being inferior to the 150 mg dose with respect to
QALYs and life years gained.

Implications for practice and future research

Dabigatran has advantages over warfarin; the most important are that monitoring is not needed, that anticoagulation for a given dose is more predictable, and that fewer drug-drug interactions are likely.
However, it also has disadvantages.
Firstly, the lack of monitoring provides little ability to
objectively monitor adherence, which in the real world setting is likely to be worse with dabigatran given the need for twice daily dosing and its associated higher incidence of dyspepsia.


Secondly, if the patient has a serious bleed, no proven antidotes exist.
Thirdly, some uncertainty exists about dosing in certain clinical settings such as renal failure, old age, and concomitant intake of amiodarone, which may lead to either underdosing or overdosing given that no pharmacodynamic marker for monitoring exists.
Fourthly, the safety and efficacy of thrombin inhibitors in the longer term (beyond two years) are uncertain,
although the follow-up study of RE-LY patients should yield valuable information.

An important finding from the cost effectiveness analysis is that dabigatran is not cost effective when compared in patients whose INR is well controlled or in centres that achieve good INR control. Part of the reason for such variability in the time within the therapeutic range with warfarin is the presence of genetic polymorphisms in the CYP2C9 and VKORC1 genes. At least four randomised trials are running globally in which genotype guided prescribing of warfarin, which is predicted to improve the time within the therapeutic range, is being tested against current clinical care.

Whether dabigatran would be cost effective against genotype guided prescribing of warfarin is unclear and needs further evaluation. Furthermore, other competitors to dabigatran are due to be evaluated for licensing soon, such as rivaroxaban and apixaban, which have shown similar clinical effectiveness to warfarin but have not been tested against dabigatran. Thus, although the arrival of new anticoagulants should be welcomed, their place in the prevention of strokes in patients with atrial fibrillation in comparison with warfarin (perhaps genotype guided) needs further evaluation. In the end,a stratified approach may represent the best approach to maximise both the clinical effectiveness and cost effectiveness
of anticoagulation in patients with atrial fibrillation.

What is already known on this topic

Dabigatran etexilate is an alternative thromboprophylactic agent to warfarin for patients with non-valvular atrial fibrillation However, uncertainty exists about its dose, balance of benefits and harms, and cost effectiveness
Previous cost effectiveness analyses of dabigatran for this indication have shown conflicting results and have not used appropriate modelling approaches

What this study adds

Dabigatran was associated with positive incremental net benefits versus warfarin, but dabigatran 110 mg twice daily did not offer clinical or economic advantage over 150 mg twice daily in any subgroup .Dabigatran is unlikely to be cost effective in clinics, such as those in the UK, able to achieve good control of the (INR) with warfarin
Dabigatran 150 mg twice daily, and an age adjusted dosing regimen, will be cost effective only for patients at increased risk of stroke or for whom INR is likely to be less well controlled
BMJ 2011;343: 8 September