Dabigatran Etexilate

Dabigatran EtexilateA Pharmacoeconomic Review of its Use in the Prevention of Strokeand Systemic Embolism in Patients with Atrial Fibrillation

Kate McKeage

Adis, Auckland, New Zealand

Various sections of the manuscript reviewed by:D.A. Hughes, Centre for Health Economics and Medicines Evaluation, Institute of Medical and Social CareResearch, Bangor University, Bangor, UK; H. Kamel, Department of Neurology and Neuroscience, WeillCornell Medical College, New York, NY, USA;G.Y. Lip, University of Birmingham Centre for CardiovascularSciences, City Hospital, Birmingham, UK; L. McCullagh, National Centre for Pharmacoeconomics, St James’sHospital, Dublin, Ireland.

Data Selection

Sources: Medical literature (including published and unpublished data) on ‘dabigatran etexilate’ was identified by searching databases(including MEDLINE and EMBASE) for articles published since 1996, bibliographies from published literature, clinical trialregistries/databases and websites (including those of regional regulatory agencies and the manufacturer). Additional information(including contributory unpublished data) was also requested from the company developing the drug.

Search strategy:MEDLINE search terms were ‘dabigatran’ and ‘atrial fibrillation’ and (‘economics’ or ‘health-policy’ or ‘quality-of-life’ or‘models-statistical’ or ‘health-planning’ or ‘epidemiology’ or ‘guideline in pt’ or ‘practice-guidelines in pt’). EMBASE search terms were‘dabigatran’ and (‘atrial fibrillation’ or ‘heart atrium fibrillation’) and (‘economics’ or ‘health economics’ or ‘economic evaluation’ or ‘healthstatus’ or ‘pharmacoeconomics’ or ‘drug cost’ or ‘drug utilization’ or ‘utilization review’ or ‘health survey’ or ‘practice guideline’ or ‘qualityof life’ or ‘treatment outcome’ or ‘cost’ or ‘cost benefit analysis’ or ‘cost control’ or ‘cost effectiveness analysis’ or ‘cost minimisationanalysis’ or ‘cost of illness’ or ‘cost utility analysis’). Searches were last updated 21 May 2012.

Selection: Economic analyses in patients with atrial fibrillation who received dabigatran etexilate. Inclusion of studies was based mainlyon the methods section of the trials. Relevant background data on epidemiology and cost of illness are also included.

Index terms: Dabigatran etexilate, atrial fibrillation, cost effectiveness, cost utility, pharmacoeconomics, therapeutic use.

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8421. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8422. Epidemiology and Cost-of-Illness Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8433. Clinical Profile of Dabigatran Etexilate in the Prevention of Stroke and Systemic Embolism in

Patients with Atrial Fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8433.1 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8443.2 Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846

4. Pharmacoeconomic Analyses of Dabigatran Etexilate in the Prevention of Stroke and SystemicEmbolism in Patients with Atrial Fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8484.1 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8484.2 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8484.3 Sensitivity Analyses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 850

4.3.1 Univariate Sensitivity Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8504.3.2 Probabilistic Sensitivity Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 851

4.4 Study Strengths and Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8515. Pharmacoeconomic Positioning of Dabigatran Etexilate in the Prevention of Stroke and

Systemic Embolism in Patients with Atrial Fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 852

ADIS PHARMACOECONOMIC DRUG EVALUATIONPharmacoeconomics 2012; 30 (9): 841-855

1170-7690/12/0009-0841/$49.95/0

Adis ª 2012 Springer International Publishing AG. All rights reserved.

Abstract This article provides an overview of the clinical profile of oral dabigatranetexilate (Pradaxa�, Pradax�) [hereafter referred to as dabigatran] when used forthe prevention of stroke and systemic embolism in patients with nonvalvularatrial fibrillation (AF), followed by a review of cost-utility analyses of dabigatranin this patient population.Dabigatran (110 or 150mg twice daily) demonstrated noninferiority versus

adjusted-dose warfarin with regard to the prevention of stroke and systemic em-bolism (primary endpoint) in patients with AF in the RE-LY trial, and the 150mgtwice-daily dosage was significantly more effective than warfarin for this end-point, as well as most other efficacy endpoints. The incidence of major bleedingwas generally similar in patients receiving dabigatran 150mg twice daily or war-farin, but was lower in patients receiving dabigatran 110mg twice daily. Withregard to other bleeding endpoints, dabigatran was generally associated withlower rates than warfarin, except for gastrointestinal major bleeding. Dabigatran(both dosages) was associated with a higher incidence of dyspepsia than warfarin.Results of modelled cost-utility analyses from several countries from the per-

spective of a healthcare payer over a lifetime (or 20-year) time horizon andprimarily based on data from the RE-LY trial were generally consistent. All butone analysis demonstrated that twice-daily dabigatran 150mg (or age-adjusted,sequential dosing) was cost effective with regard to the incremental cost perQALY gained relative to adjusted-dose warfarin in the prevention of stroke andsystemic embolism in AF patients, as the results were below generally acceptedcost-effectiveness thresholds. In contrast, the incremental cost per QALY gainedfor dabigatran 110mg twice daily versus warfarin exceeded cost-effectivenessthresholds in all studies except one.Sensitivity analyses suggested that the cost utility of dabigatran versus warfarin

was generally robust to variations in the majority of parameters. However, theincremental cost per QALY gained for dabigatran versus warfarin improvedwhen levels of international normalized ratio control in warfarin recipients de-creased and when the baseline level of risk of stroke increased.

1. Introduction

Atrial fibrillation (AF) is the most commoncardiac arrhythmia and it increases the risk ofseveral co-morbid conditions.[1] In particular, itis a major cause of ischaemic stroke, which isassociated with substantial disability and pro-longed periods of hospitalization.[1] Managementof AF is aimed at reducing symptoms and pre-venting thromboembolic complications, such asstroke.[2] Antithrombotic drugs and agents thatcontrol ventricular rate and concomitant cardiacdiseases are important therapies in the preventionof AF-related complications.[2]

Recommendations for antithrombotic therapyin patients with AF are based on the presence (orabsence) of risk factors for stroke or thrombo-

embolism.[2,3] The Congestive heart failure, Hy-pertension, Age, Diabetes mellitus, and priorStroke (doubled) or transient ischaemic attack[TIA] (CHADS2) risk stratification system is asimple initial means of assessing stroke risk.[2,3]

AF patients with a CHADS2 score of ‡2 are con-sidered to be at high risk for thromboemboliccomplications, and chronic oral anticoagulation(OAC) therapy is indicated.[2,3] However, in pa-tients with a CHADS2 score of 0–1, a more com-prehensive stroke risk stratification system thatconsiders additional risk factors, the Congestiveheart failure, Hypertension, Age ‡75 years(doubled), Diabetes, Stroke (doubled), Vascular dis-ease, Age 65–75 years and Sex category (CHA2DS2-VASc), is recommended to identify those patientswho are likely to benefit from OAC therapy.[2]

842 McKeage

Adis ª 2012 Springer International Publishing AG. All rights reserved. Pharmacoeconomics 2012; 30 (9)

Indeed, the CHA2DS2-VASc system has demon-strated that some patients previously classified aslow risk (CHADS2 score of 0) are at substantialrisk of stroke.[4]

For many years, the standard OAC agent usedfor thromboprophylaxis in patients with AF hasbeen the vitamin K antagonist (VKA) warfarin.[1]

In addition to a well established efficacy in pre-venting ischaemic stroke in AF patients, warfarinis inexpensive.[1,5,6] However, several drawbacksare associated with warfarin treatment, includingthe need for regular monitoring of internationalnormalized ratio (INR) levels to ensure that pa-tients remain in the therapeutic range (2.0–3.0);variations in individual reactions to the drug, re-quiring dosage adjustments; and interactions withseveral foods, drugs and alcohol, requiring diet-ary precautions and strengthening the need forcoagulation monitoring.[7]

As a result of these drawbacks, alternativeantithrombotic agents or regimens have been in-vestigated. Antiplatelet therapy with aspirin (ace-tylsalicylic acid), or aspirin plus clopidogrel, is notas effective in preventing ischaemic stroke as war-farin, but may be indicated in some moderate-riskpatients for whom VKAs are unsuitable (althoughnot in those with a high bleeding risk).[2,3] More re-cently, dabigatran etexilate (Pradaxa�, Pradax�), aprodrug of the direct thrombin inhibitor dabiga-tran,[8,9] and rivaroxaban, a factor Xa inhibitor,[10]

have been approved for the prevention of stroke andsystemic embolism in adults with nonvalvular AF.

This article provides a brief summary of theclinical profile of oral dabigatran etexilate (here-after referred to as dabigatran) versus warfarin inthe prevention of stroke and systemic embolism inpatients with nonvalvular AF, and then focuses onpublished cost-utility analyses comparing the twoagents in this patient population.Dabigatran is alsoapproved for the prevention of venous thrombo-embolic events in adults undergoing orthopaedicsurgery,[8,9] but further discussion of this indicationis outside the scope of this review.

2. Epidemiology and Cost-of-Illness Data

AF is estimated to affect 1–1.5% of the pop-ulation in developed countries.[11] Prevalence in-

creases substantially with age, and in a WesternEuropean population followed throughout the1990s, prevalence was estimated at 0.7% in the55–59 year age group, rising to 18% in those aged‡85 years.[12] At 55 years of age, the lifetime riskof developing AF was estimated at 23.8% in menand 22.2% in women.[12]

The risk of embolic stroke is increased by almost5-fold in patients with nonvalvular AF comparedwith individuals without AF.[1] Ischaemic strokeassociated withAF is also likely to bemore severe innature and almost twice as likely to result in deaththan non-AF stroke.[13] Stroke ranks among the topfive causes of death in the US and is a principalcause of serious long-term disability.[14] Hospitali-zation rates associated with AF have steadily in-creased over recent decades, placing a large burdenon healthcare systemsworldwide. The burden ofAFis expected to increase further as populations age.[14]

A systematic review that evaluated costs asso-ciated with AF or atrial flutter (excluding acuteonset and post-operative) from 1990–2009 esti-mated that direct costs ranged from $US2000 to$US14200 per patient-year in the US and fromh450 to h3000 per patient-year in the EU.[15] Hos-pitalizations consistently represented the major costdriver (50–70% of total costs), and in theUS in 2005AF hospitalizations alone cost »$US6.65 billion.[15]

A recent, similar Canadian review estimatedthat overall AF-related direct costs ranged from$Can1632 to $Can21 099 (year 2010 values) perpatient-year and that the largest cost componentwas acute care, followed by outpatient, physicianthen medication-related costs.[16]

3. Clinical Profile of Dabigatran Etexilatein the Prevention of Stroke andSystemic Embolism in Patientswith Atrial Fibrillation

The clinical efficacy and tolerability of dabi-gatran in the prevention of stroke and systemicembolism in patients with AF has been reviewedin detail previously.[17] This section focuses on theRE-LY (Randomized Evaluation of Long-termanticoagulation therapY) study, the results ofwhich were incorporated into the modelled cost-utility analyses discussed in section 4.

Dabigatran Etexilate: A Pharmacoeconomic Review 843


RE-LY was a large (n = 18 113), multicentretrial of prospective, randomized, open-label,blinded-endpoint (PROBE) design that com-pared the efficacy of oral dabigatran 110 or150mg twice daily with that of oral warfarin ad-justed to an INR of 2.0–3.0 in patients with AFwho were at an increased risk for stroke; dabi-gatran dosages and the adjudication of eventswere blinded.[18] The study included adults withAF with at least one of the following character-istics: previous stroke or TIA; a left ventricularejection fraction of <40%; New York Heart As-sociation class II or higher heart-failure symp-toms within the past 6 months; age ‡75 years; orage 65–74 years with diabetes, coronary arterydisease or hypertension.[18] Stroke within 14 daysor severe stroke within 6 months, the presence ofa severe heart-valve disorder, a creatinine clear-ance (CLCR) of <30mL/minute or any conditionthat increased the risk of haemorrhage wereamong exclusion criteria.[18]

Patients were followed up for a median of2 years.[18] Concomitant use of aspirin (dosage<100mg/day) was permitted and was used con-tinuously in »20% of patients in all treatmentgroups. Quinidine was permitted in the initial2 years, but then prohibited based on its potentialto interact with dabigatran. Among warfarin re-cipients, the INR was within the therapeutic rangefor 64% (mean) of the study duration. Amongstudy participants, the mean age was 71.5 years,males accounted for 63.6%, about half had re-ceived prior long-term therapy with VKAs, andthe mean CHADS2 score was 2.1.[18] Results ofRE-LY were updated,[19] as several additionalefficacy and safety outcome events were identi-fied subsequent to the initial report.[18]

3.1 Efficacy

The primary efficacy endpoint in RE-LY wasthe incidence of stroke or systemic embolism inthe intent-to-treat population, and the primaryanalysis was designed to evaluate the non-inferiority of dabigatran versus warfarin.[18] Bothdabigatran dosages (110 and 150mg twice daily)demonstrated noninferiority versus warfarin withregard to the primary endpoint, as the upper limit

of the one-sided 97.5% confidence interval (CI)for the relative risk (RR) was <1.46 (p < 0.001 forboth; figure 1).[19]

In subsequent superiority analyses, dabigatran150mg twice daily was significantly more effec-tive at preventing stroke and systemic embolismthan warfarin, reducing the RR by 35% (p< 0.001;figure 1).[19] Conversely, the risk reduction achievedwith dabigatran 110mg twice daily for the pri-mary endpoint was not significantly different tothat achieved with warfarin. In a comparison ofthe two dosages of dabigatran, the 150mg dosagewas significantly more effective with regard to theprimary endpoint than the 110mg dosage (RRreduction 28%; p = 0.004; figure 1).[19]

Dabigatran 150mg twice daily was associatedwith a significantly lower risk of most other effi-cacy endpoints than warfarin (figure 1). In con-trast, results associated with dabigatran 110mgtwice daily were generally not significantly dif-ferent to those associated with warfarin, exceptfor haemorrhagic stroke (figure 1) and hospitali-zation (RR 0.92; 95% CI 0.87, 0.97; p= 0.003),which both occurred less frequently with dabi-gatran 110mg.[19] In a comparison of the twodosages of dabigatran with regard to secondaryendpoints, the 150mg dosage was associated witha significantly lower risk of stroke, ischaemic orunspecified stroke, and disabling or fatal strokethan the 110mg dosage (figure 1).[19] Althoughthe difference between dabigatran and warfarintreatment groups in the incidence of myocardialinfarction did not reach significance in the updatedanalysis of the RE-LY trial,[19] a subsequent meta-analysis of randomized trials in a broad spectrumof patients indicated that dabigatran may beassociated with a slightly increased risk of myo-cardial infarction or acute coronary syndromecompared with various controls.[20]

The net clinical benefit outcome comprised acomposite of the incidence of stroke, systemicembolism, pulmonary embolism, myocardial in-farction, death or major haemorrhage.[18] TheRR of this composite endpoint was significantlyreduced with dabigatran 150mg twice daily ver-sus warfarin (0.90; 95% CI 0.82, 0.99; p= 0.02),but the risk reduction was not significantly dif-ferent between dabigatran 110mg twice daily

844 McKeage


Pulmonaryembolism

Myocardialinfarction

Death fromany cause

Death fromvascularcauses

Disabling/fatal stroke

Non-disablingstroke

Ischaemic/unspecified

stroke

Haemorrhagicstroke

Stroke (any)

Event rate per 100 person-years

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5

Relative risk (95% CI)

0.72 (0.58, 0.90) ††

0.90 (0.74, 1.10) NI0.65 (0.52, 0.81) NI ***

0.70 (0.56, 0.89) ††

0.91 (0.74, 1.12)0.64 (0.51, 0.81) ***

0.85 (0.39, 1.83)

0.31 (0.17, 0.56) ***0.26 (0.14, 0.49) ***

0.69 (0.54, 0.88) ††

1.11 (0.88, 1.39)0.76 (0.59, 0.97) *

0.72 (0.49, 1.07)

0.86 (0.61, 1.22)0.62 (0.43, 0.91) **

0.70 (0.53, 0.94) †

0.93 (0.72, 1.21)0.66 (0.50, 0.87) **

0.94 (0.79, 1.11)

0.90 (0.77, 1.06)0.85 (0.72, 0.99) *

0.97 (0.85, 1.11)

0.91 (0.80, 1.03)0.88 (0.77, 1.00)

0.98 (0.74, 1.30)

1.29 (0.96, 1.75)1.27 (0.94, 1.71)

1.27 (0.63, 2.56)

1.16 (0.54, 2.51)1.47 (0.71, 3.06)

DAB 150 mg vs DAB 110 mg

DAB 110 mg vs WAR

DAB 150 mgvs WAR

DAB 150 mg (n = 6076)DAB 110 mg (n = 6015)WAR (n = 6022)

Stroke orsystemic

embolism(primary

endpoint)

Fig. 1. Efficacy of dabigatran etexilate for the prevention of stroke and systolic embolism in patients with atrial fibrillation and at risk of stroke.The figure shows event rates and relative risk ratios (95% CI) in the updated analysis[19] of the randomized, open-label RE-LY study.[18]

Patients received oral dabigatran etexilate 110 or 150mg twice daily or oral warfarin adjusted to an international normalized ratio of 2.0–3.0over a median follow-up period of 2 years. Noninferiority of dabigatran etexilate versus warfarin was demonstrated for the primary endpoint(p< 0.001 for both doses); all other p-values refer to superiority tests. Stroke was defined as the sudden onset of a focal neurological deficit inthe area of amajor cerebral artery, which was classified as ischaemic, haemorrhagic or unspecified, and systemic embolism was defined as anacute vascular occlusion of an extremity or organ. Reproduced from Garnock-Jones KP. Dabigatran etexilate: a review of its use in theprevention of stroke and systemic embolism in patients with atrial fibrillation. Am J Cardiovasc Drugs 2011; 11 (1): 57-72 with permission fromSpringer International Publishing AG (ª Adis Data Information BV 2011. All rights reserved.). DAB =dabigatran etexilate; NI = noninferior;WAR =warfarin; * p <0.05, ** p £0.01, *** p <0.001 vs WAR; - p <0.05, -- p£ 0.01 vs DAB 110mg.



and warfarin, or between the two dabigatrandosages.[18]

Results of subgroup analyses were generallyconsistent with those of the total patient popula-tion.[18,19] Subgroups included previous long-termVKA therapy; aspirin, amiodarone or proton pumpinhibitor use at baseline; ethnic groups; base-line CLCR levels (<50mL/min, 50–79mL/min,‡80mL/min); CHADS2 score at baseline; symp-tomatic heart failure; diabetes; hypertension; andstroke or TIA.[18]

3.2 Tolerability

In the RE-LY trial, recipients of dabigatran110mg twice daily had a significantly lower in-cidence of major bleeding (primary safety out-come) than recipients of warfarin (p = 0.003) ordabigatran 150mg twice daily (p = 0.04), but theincidence of this event was not significantly dif-ferent between groups receiving dabigatran 150mgor warfarin (figure 2).[18]

With regard to other bleeding endpoints, thedabigatran 110 and 150mg twice-daily dosageswere associated with significantly lower rates oflife-threatening major bleeding, minor bleeding,major or minor bleeding, and intracranial bleed-ing than warfarin (figure 2). In contrast, the rateof gastrointestinal major bleeding was higher inthe dabigatran 150mg twice-daily group than inthe warfarin or dabigatran 110mg twice-dailygroups. The higher dosage of dabigatran wasalso associated with a higher incidence of minorbleeding, and major or minor bleeding than thelow-dosage dabigatran group.[18]

Further analysis of intracranial haemorrhageevents in the RE-LY trial was carried out tocompare clinical outcomes between treatmentgroups.[21] In the absence of an antidote for da-bigatran, it has been suggested that intracranialhaemorrhages with dabigatran could have aworse prognosis than those associated with war-farin. However, the clinical spectrum of intra-cranial haemorrhage was similar in dabigatranand warfarin recipients, and there were fewerabsolute rates at all sites (intracerebral, subdural,subarachnoid) [p < 0.001 for both dosages], fewerfatal (p < 0.01 for both) and fewer traumatic

(p< 0.05 for both) intracranial haemorrhages withdabigatran than with warfarin.[21] Aspirin use priorto haemorrhage was themost importantmodifiablerisk factor for intracranial haemorrhage.[21]

In a subgroup analysis of the RE-LY trial,there was a significant treatment-by-age inter-action for the primary safety endpoint, and bothdabigatran dosages versus warfarin were asso-ciated with an increasing RR of major bleedingwith increasing age.[22] In patients aged <75 years,twice-daily dabigatran 110mg (1.89% vs 3.04%per year; RR 0.62; 95% CI 0.50, 0.77) and 150mg(2.12% vs 3.04% per years; RR 0.70; 95%CI 0.57,0.86) were both associated with a lower risk ofmajor bleeding than warfarin (p < 0.001 for both).However, in patients aged ‡75 years, the risk ofmajor bleeding was not significantly differentbetween the low-dose dabigatran and warfaringroups (4.43% vs 4.37%; RR 1.01; 95% CI 0.83,1.23), but was numerically higher in the higher-dose dabigatran group than in the warfarin group(5.10% vs 4.37%; RR 1.18; 95% CI 0.98, 1.42;p = 0.07). The level of significance for interactionfor both analyses was p < 0.001.[22] The inter-action between treatment and age was evidentwith extracranial bleeding but not intracranialbleeding, with both dosages of dabigatran beingassociated with a lower incidence of intracranialbleeding than warfarin irrespective of age.

In further subgroup analyses, there were nosignificant interactions observed between ran-domized treatment and CLCR, sex, bodyweight,or concomitant use of amiodarone or protonpump inhibitors.[22]

With regard to nonbleeding-related safetyoutcomes in the RE-LY study, dabigatran 110and 150mg twice daily were generally as welltolerated as warfarin in patients with AF at riskof stroke.[18] The only adverse event for whichthere was a significant difference in incidencebetween treatment groups was dyspepsia, whichoccurred more often with dabigatran 110 and150mg twice daily than with warfarin (11.8% and11.3% vs 5.8%; p< 0.001 for both). Significantlymore patients in the dabigatran groups than thewarfarin group had discontinued treatment at2 years as a result of serious adverse events (2.7%and 2.7% vs 1.7%; p< 0.001 for both).[18]

846 McKeage


0 2 4 6 8 10 12 14 16 18 20

Extracranialbleeding

Intracranialbleeding

Major or minorbleeding

Minor bleeding

Gastrointestinalmajor bleeding

Non-life-threatening

major bleeding

Life-threateningmajor bleeding

Any majorbleeding

(primary safetyoutcome)

Event rate per 100 person-years

1.16 (1.00, 1.34) †

0.80 (0.70, 0.93) **0.93 (0.81, 1.07)

1.21 (0.97, 1.50)

0.67 (0.54, 0.82) ***0.80 (0.66, 0.98) *

1.13 (0.94, 1.36)

0.96 (0.80, 1.15)1.08 (0.90, 1.30)

1.36 (1.09, 1.70) ††

1.08 (0.85, 1.38)1.48 (1.18, 1.85) †††

1.16 (1.09, 1.24) †††

0.79 (0.74, 0.84) ***0.91 (0.86, 0.97) **

1.39 (0.85, 2.28)

0.30 (0.19, 0.45) ***0.41 (0.28, 0.60) ***

1.16 (1.09, 1.23) †††

0.78 (0.73, 0.83) ***0.91 (0.85, 0.96) **

1.14 (0.98, 1.33)

0.94 (0.81, 1.10)1.07 (0.92, 1.24)

DAB 150 mg (n = 6076)DAB 110 mg (n = 6015)WAR (n = 6022)

Relative risk (95% CI)

DAB 150 mg vs DAB 110 mg

DAB 110 mg vs WAR

DAB 150 mgvs WAR

Fig. 2. Bleeding outcomes associated with dabigatran etexilate in patients with atrial fibrillation and at risk of stroke. The figure shows eventrates and relative risk ratios (95% CI) in the updated analysis[19] of the randomized, open-label RE-LY study.[18] Patients received oraldabigatran etexilate 110 or 150mg twice daily or oral warfarin adjusted to an international normalized ratio of 2.0–3.0 over a median follow-upperiod of 2 years. The primary safety endpoint was major bleeding, which was defined as a reduction in the haemoglobin level of ‡20g/L, therequirement for a transfusion of ‡2 units of blood or symptomatic bleeding in a critical area or organ. Life-threatening major bleeding(a subgroup of major bleeding) consisted of fatal bleeding, symptomatic intracranial bleeding, or bleeding causing a decrease in haemoglobinof ‡50 g/dL, requiring transfusion of ‡4 units of blood or inotropic agents, or requiring surgery.[18] Reproduced from Garnock-Jones KP.Dabigatran etexilate: a review of its use in the prevention of stroke and systemic embolism in patients with atrial fibrillation. Am J CardiovascDrugs 2011; 11 (1): 57-72 with permission from Springer International Publishing AG (ª Adis Data Information BV 2011. All rights reserved.).DAB = dabigatran etexilate; WAR =warfarin; * p <0.05, ** p £0.01, *** p < 0.001 vs WAR; - p< 0.05, -- p £ 0.01, --- p £0.001 vs DAB 150mgtwice daily.



4. Pharmacoeconomic Analyses ofDabigatran Etexilate in the Prevention ofStroke and Systemic Embolism in Patientswith Atrial Fibrillation

This section summarizes data from fully pub-lished, cost-utility analyses that compared dabi-gatran and warfarin in the prevention of strokeand systemic embolism in patients with AF; threestudies were performed in the US,[6,23,24] threein the UK,[5,25,26] one in Canada[27] and one inDenmark.[28]

4.1 Methods

All analyses reported incremental costs perQALY gained with dabigatran versus warfarin,and results can be interpreted based on generallyaccepted cost-utility thresholds, such as h20 000–50 000, $US50 000 or d20 000–30 000 per QALYgained.[29-32] Decision models used a Markovdesign[6,23-28] to predict treatment strategies andoutcomes, or a discrete-event simulation modelthat considered individual patients and theirclinical events and outcomes over time.[5] Eachanalysis was performed from the perspective ofa healthcare provider and, accordingly, only di-rect fixed and variable healthcare costs wereconsidered, with annual discounting applied tocosts and outcomes. Sensitivity analyses wereperformed to examine the effects of incorporat-ing plausible ranges of values for key inputassumptions.[5,6,23-28]

The primary source of input data in all modelswas the RE-LY trial (section 3), supplementedwith other clinical trial data, and relevant evi-dence reflective of local healthcare costs and util-ity values. The hypothetical patient populationgenerally matched that of the RE-LY trial, inwhich patients were diagnosed with AF and hadat least one other risk factor for stroke or embo-lism (section 3).[18] One US study specified thatthe hypothetical cohort included patients withAF and prior stroke or TIA.[24] Patient data wereextrapolated over the remaining lifetime[5,6,25-28]

or for 20 years.[23,24] The US studies specified thatpatients started treatment aged ‡65 years[6] or70 years.[23,24] Some studies used an age-adjusted,

sequential dosing plan, whereby, among patientsrandomized to dabigatran, those aged <80 yearsreceived the 150mg twice-daily dosage and thoseaged ‡80 years received the 110mg twice-dailydosage, with patients switching to the lower dosewhen they reached 80 years.[25-28] Age-adjusted,sequential dosing with dabigatran was also eval-uated in a secondary analysis in one study.[5]

Health states in the Markov model analysesincluded no disability, TIA, ischaemic stroke,systemic embolism, intracranial haemorrhage,stroke and intracerebral haemorrhage, myo-cardial infarction and death.[6,23-28] Each of theseevents was defined according to definitions fromthe RE-LY trial.[18] Where stated, cycle lengthswere 1[23] or 3[25-28] months. Utilities (and utilitylosses) and costs were applied to each outcomeover its expected duration, the risk of adverseevents and discontinuation rates were generallycalculated from RE-LY data, and country-specificmortality rates were adjusted for age.[5,6,23-28] Theyear of costing was 2008,[6] 2009,[5] 2010[23-25,27]

or 2011,[28] or was not reported.[26]

4.2 Results

Based on the incremental costs per QALYgained, which were below generally acceptedcost-effectiveness thresholds, twice-daily dabiga-tran 150mg (or age-adjusted, sequential dosing)was considered to be cost effective relative towarfarin in the prevention of stroke and systemicembolism in patients with AF in all but one[23] ofthe cost-utility analyses (table I).[5,6,24-28] In con-trast, incremental costs per QALY gained fordabigatran 110mg twice daily versus warfarin didnot usually fall below generally accepted cost-effectiveness thresholds, except for the UK studyreported by the National Institute for Health andClinical Excellence (NICE) [table I];[26] in one USstudy,[6] the incremental cost was only just abovethe threshold.

While the incremental cost per QALY gainedfor dabigatran 150mg versus warfarin was belowthe cost-effectiveness threshold in the UK studyby Pink et al.,[5] the overall conclusion was thatin the UK context, where INR control is gen-erally good (see section 4.3 for further discussion),

848 McKeage


dabigatran was not expected to be cost effectiverelative to warfarin.[5] Similarly, in the US studyby Shah and Gage,[23] in which the base-case in-cremental cost per QALY gained for dabigatran150mg versus warfarin exceeded the threshold of

$US50 000 (table I), the overall conclusion wasthat dabigatran 150mg would be cost effectiveversus warfarin in AF patients with a high risk ofstroke or haemorrhage, unless the INR control inwarfarin recipients was excellent. One possible

Table I. Cost utility of dabigatran etexilate relative to warfarin for the prevention of stroke and systemic embolism in patients with nonvalvular

atrial fibrillation at risk of stroke. Analyses were performed from a healthcare payer perspective and were modelled over a lifetime[5,6,25-28] or

20-year time horizon.[23,24] Cycle lengths in Markov models were 1[23] or 3[25-28] months. Efficacy and other input data were primarily derived

from the RE-LY trial.[18,19] Patient cohorts commenced treatment aged 65,[6] 70,[23,24] or 71.5 years (RE-LY mean age)[5,25-28]

Study (country) Year of costing;

annual discount

ratea

Treatmentb Total cost per pt Total QALYs

per pt

Incremental cost per QALY gained

Markov model

Freeman et al.[6]

(US)

2008; 3% DAB 110mg $US164 576 10.70 $US51 229 vs WAR

DAB 150mg $US168 398 10.84 $US45 372 vs WARc

WAR $US143 193 10.28

Kamel et al.[24]

(US)

2010; 3% DAB 150mg NR 4.27 $US25 000 vs WAR

WAR NR 3.91

Kansal et al.[25]

(UK)

2010; 3.5% DABd £19 645 8.06 In pts starting therapy aged <80 y: £4831vs WAR, £3457 vs ASP; in pts starting

therapy aged ‡80 y: £7090 vs WARWAR £18 474 7.82

ASP £18 561 7.59

No treatment £20 475 7.12 Dominated by DAB in pts starting

therapy aged <80 y

Langkilde et al.[28]

(Denmark)

2011; 2% DABd h18 752 8.59 h6950 vs WAR

WAR h16 886 8.32

NICE appraisal[26]

(UK)

NR; 3.5% DAB 110mg NR NR £18691 vs WAR

DAB 150mg NR NR £6264 vs WAR

DABd NR NR In pts starting therapy aged

<80 y: £7314 vs WAR; in pts starting

therapy aged ‡80 y: £7873 vs WARWAR NR NR

Shah and Gage[23]

(US)

2010; 3% DAB 110mg $US44 300 8.54 $US150 000 vs WAR

DAB 150mg $US43 700 8.65 $US86 000 vs WAR

WAR $US23 000 8.40

ASP +CLO $US34 000 8.32 Dominated by WAR

ASP $US20 000 8.17

Sorensen et al.[27]

(Canada)

2010; 5% DABd $Can45 124 7.29 $Can10 440 vs WAR

WAR $Can42 946 7.08

Discrete-event simulation model

Pink et al.[5]

(UK)

2009; 3.5% DAB 110mg £10 529 6.48 £43 074 vs WAR

DAB 150mg £9850 6.54 £23 082 vs WAR

WAR £6480 6.39

a Applied to costs and outcomes.

b DAB was administered as 110 or 150mg bid and the dosage of oral WAR was adjusted to an international normalized ratio of 2.0–3.0.

c A revised incremental cost per QALY gained of $US12 386 was estimated based on the cost of DAB subsequent to US FDA approval

(»$US8/day), which was lower than the estimated price used in the initial analysis ($US13/day) prior to approval.[33]

d Age-adjusted, sequential dosing plan. Among pts receiving DAB, those aged <80 y received 150mg bid and those aged ‡80 y received

110mg bid, with pts switched to the lower dose when they reached 80 y.

ASP = aspirin (acetylsalicylic acid); bid = twice daily; CLO = clopidogrel; DAB = dabigatran etexilate; NICE =National Institute for Health and

Clinical Excellence; NR= not reported; pt(s) = patient(s); WAR =warfarin.



contributing factor to the higher incremental costper QALY gained for dabigatran versus warfarinin this study[23] comparedwith other US studies[6,24]

is the specific inclusion of dyspepsia associatedwith dabigatran in the decision model; the rateof dyspepsia was significantly higher with dabi-gatran than with warfarin in the RE-LY trial(section 3.2).[23]

Overall, in base-case analyses, compared withwarfarin, twice-daily dabigatran 150mg (or age-adjusted, sequential dosing) was associated withhigher total QALYs gained and higher total costs(table I). While costs associated with clinicalevents and follow-up (including INRmonitoring)were numerically lower with dabigatran thanwarfarin, the higher drug cost of dabigatran re-sulted in a higher overall cost. For example, ina recently published study from the perspectiveof the UK NHS (table I), differences in clinicalevent rates resulted in 0.24 incremental QALYsgained at an incremental cost of d1171 per patientover a lifetime with dabigatran versus warfa-rin.[25] These results equate to an incremental costper QALY gained of d4831 with dabigatran ver-sus warfarin in patients initiating therapy aged<80 years (table I).[25] In this analysis, drug costsaccounted for 35% of total dabigatran costs ver-sus 17% of total warfarin costs; the greatest pro-portion of costs was attributed to follow-up care(47% for dabigatran and 61% for warfarin).[25]

In the Canadian study by Sorensen et al.,[27]

the base-case analysis included a comparison be-tween dabigatran and ‘trial-like’ warfarin (table I)and ‘real-world’ prescribing. In a real-world setting,the level of patient monitoring and adherence totreatment guidelines is not usually as precise as ina clinical trial setting. For example, in the RE-LYstudy, the mean percentage of time warfarin re-cipients spent within the target INR range of2.0–3.0 was 64%, whereas in routine clinical prac-tice in Canada, the mean percentage of time wasestimated at 59%.[27] Furthermore, in clinicalpractice, AF patients eligible for warfarin often re-ceive suboptimal anticoagulation with aspirin orno treatment.[27] When dabigatran age-adjusted,sequential dosing was compared with real-worldwarfarin prescribing (outcome differences wereestimated from the RE-LY trial adjusted based

on a study in AF patients in the US[34]), the in-cremental cost per QALY gained for dabigatranversus warfarin was reduced to $Can3962.

In addition to the base-case analysis (table I),age-adjusted, sequential dabigatran dosing wascompared with dabigatran 150mg twice daily inthe UK study by Pink et al.[5] The study found thatdabigatran 150mg twice daily dominated dabi-gatran age-adjusted, sequential dosing.

4.3 Sensitivity Analyses

4.3.1 Univariate Sensitivity Analyses

Univariate sensitivity analyses performed inthe cost-utility studies found that the cost effec-tiveness of dabigatran versus warfarin was gen-erally robust to variations in the majority ofparameters.[5,6,23-28] The parameters that had thegreatest effect on cost effectiveness were the drugcost of dabigatran,[6,23,24] risk of stroke or intra-cranial haemorrhage associated with each treat-ment[5,6,23-27] and risk at baseline,[6,23,26,28] INRcontrol in warfarin recipients,[23-25,27,28] cost oflong-term follow-up care for patients with dis-ability,[6,25,27] the time horizon analysed[25-27] andolder age (>75 years; probably as a result of an in-creased risk of stroke).[6]

The US study by Freeman et al.[6] used therelatively high estimated (dabigatran was notavailable in the US at the time of the analysis)price of $US13.00 per day for dabigatran 150mgtwice daily in the base case. When the drug pricewas varied, the incremental cost per QALYgained of dabigatran 150mg twice daily versuswarfarin reached the cost-effectiveness thresholdof $US50 000 once the price of dabigatran wasincreased to $US13.70 per day.[6] Subsequent tothe approval of dabigatran 150mg twice daily bythe US FDA, the actual drug price was sub-stantially lower (»$US8.00 per day), resulting in arevised incremental cost per QALY gained versuswarfarin of $US12 386 (table I).[33]

Several studies observed that as the mean timethat warfarin recipients spent in the therapeuticINR range increased, the cost effectiveness ofdabigatran versus warfarin decreased.[23,25,27,28]

For example, in the UK study by Kansal et al.,[25]

incremental costs per QALY gained reached the

850 McKeage


thresholds of d20 000 and d30 000 for dabigatran(age-adjusted, sequential dosing) when warfarinrecipients were maintained in the therapeutic INRrange for an average of about 91% and 97% of thetime, respectively, in patients starting therapyaged <80 years, and 80% and 83%, respectively, inpatients starting therapy aged ‡80 years. Simi-larly, in the Canadian study,[27] varying the pro-portion of time warfarin recipients spent in thetherapeutic INR range from 40% to 80% resultedin a shift in the incremental cost per QALY gainedfor dabigatran versus warfarin from $Can1716 to$Can23263.

Using a shorter time horizon reduced the costeffectiveness of dabigatran versus warfarin. In twostudies that reduced the time horizon to 10 years,the incremental cost per QALY gained wasd11 898[25] and $Can23 555[27] (versus base-casevalues over a lifetime horizon of d4831[25] and$Can10 440[27]). Similarly, reducing the durationof benefit from dabigatran over time reduced itscost effectiveness versus warfarin.[5]

The RR of stroke with dabigatran versus war-farin had a marked impact on cost effectiveness inseveral studies,[5,6,24,25,27] as did the baseline riskof stroke (based on CHADS2 score).[5,6,23,28] Inthe US study by Shah and Gage,[23] treatmentwith dabigatran 150mg twice daily was cost ef-fective versus warfarin (i.e. the incremental costper QALY gained was reduced to £$US50 000) inhigh-risk patients (i.e. CHADS2 score of ‡3) or inmoderate-risk patients (CHADS2 score of 1 or 2)if the risk of haemorrhage was >6% per year. Inanother US study,[24] the incremental cost perQALY gained for dabigatran 150mg twice dailyversus warfarin exceeded $US50 000 when theRR of stroke with dabigatran versus warfarinexceeded 0.92 (95% CI 0.52, 1.11).

The cost effectiveness of dabigatran versuswarfarin was also reduced when the cost of amajor bleeding event with dabigatran was in-creased to reflect the lack of a reversal agent andthe potential need for prothrombin complexconcentrates.[5]

4.3.2 Probabilistic Sensitivity Analyses

The results of probabilistic sensitivity analysesthat each ran simulations varying all variables si-

multaneously found that dabigatran 150mg twicedaily was cost effective relative to warfarin in themajority of simulations.[5,6,24,25] In two US studies,using a cost-effectiveness threshold of $US50000per QALY gained, dabigatran 150mg twice dailywas cost effective in 53%[6] and 57%[24] of simu-lations. Using a cost-effectiveness threshold of$Can30 000 per QALY gained, dabigatran (age-adjusted, sequential dosing) was cost effectiveversus trial-like warfarin in 82% of simulations inthe Canadian study by Sorensen et al.[27]

In the UK study by Kansal et al.,[25] using acost-effectiveness threshold of d20000 per QALYgained, the probability of dabigatran (age-adjusted,sequential dosing) being cost effective in patientsinitiating therapy aged <80 years was 98% versuswarfarin and 100% versus aspirin or no treat-ment. At the same cost-effectiveness threshold,the probability of dabigatran being cost effectivein patients initiating therapy at 80 years of agewas 63% versus warfarin.[25] Dabigatran 150mgtwice daily had the highest probability of beingcost effective versus warfarin at thresholds ofd24 400 or higher in the UK study by Pink et al.,[5]

whereas warfarin was the most likely to be costeffective at thresholds below that value.[5]

4.4 Study Strengths and Limitations

The modelled cost-utility analyses of dabigatranversus warfarin in patients with AF were generallywell conducted.[5,6,23-28] Model structures were jus-tified and data sources were appropriate for eachcountry. The primary source of data regardingefficacy, tolerability and treatment discontinuationwas the large head-to-head RE-LY trial.[18]

Some studies[25,27,28] facilitated optimal esti-mates of clinical outcomes by using patient-leveldata in the RE-LY trial rather than publisheddata. This also allowed disability levels after astroke to be stratified according to observedseverity. Several studies also used age-adjusted,sequential dosing of dabigatran in the base-caseanalysis, which enabled the EU-approved stratifica-tion of the two dosages (110 and 150mg twice daily)to be reflected in the correct populations.[5,25-28]

Because the level of INR control in warfarinrecipients tends to be worse in real-world conditions



than in the setting of a clinical trial, the Canadianstudy by Sorensen et al.[27] also compared dabigatranwith warfarin in a ‘real-life’ prescribing scenario.Based on the level of INR control achieved in thereal world, costs associated with warfarin thatwere derived from efficacy results in the RE-LYtrial could be considered as conservative. Warfarindiscontinuation rates due to the burden of INRtesting also tend to be higher in real-life practicethan in a clinical trial. However, it is also truethat, as yet, the real-world performance of dabi-gatran is unknown.

The UK study by Pink et al.[5] used a discrete-event simulation method that effectively modelsa large number of potential health states and re-moves the need to define additional structuralparameters (such as cycle length). A discrete-eventsimulation also operates in continuous rather thandiscrete time, thereby allowing more accurate es-timation of patients’ histories.[5]

As with all modelled analyses, a number oflimitations exist in the cost-utility analyses in-cluded in this review,[5,6,23-28] the primary onesbeing that results are influenced by assumptionsand that efficacy and adverse event data weremostly derived from a single study. A wide vari-ety of sources were used to obtain utility values,which has the potential to introduce bias. WhileRE-LY provided a reliable source of comparativedata, input data from a clinical trial may not beentirely applicable to real-life practice. For ex-ample, only about one-third of patients in theRE-LY trial had a baseline CHADS2 score of ‡3.Furthermore, clinical trials tend to achieve betterlevels of treatment adherence than those observedin real-life practice.[27] The RE-LY trial design wasopen label, which has the potential to introducebias, although dabigatran dosages and the ad-judication of events were blinded.

The generalizability of RE-LY data to specificcountries may be somewhat limited where onlypublished data (i.e. not patient-level data) wereused.[5,6,23,24] Another limitation with all analysesis that the average age in the RE-LY trial was71.5 years, so results may not be entirely appli-cable to more elderly groups, such as octogenar-ians. Four[25-28] of the eight cost-utility analyseswere funded by the manufacturer of dabigatran.

5. Pharmacoeconomic Positioning ofDabigatran Etexilate in the Prevention ofStroke and Systemic Embolism in Patientswith Atrial Fibrillation

As the prevalence of AF increases with theaging of populations in developed countries, sotoo will the economic burden resulting fromthromboembolic complications and treatmentcosts.[1] OAC therapy is indicated in a substantialproportion of AF patients, based on the risk ofcomplications, and therapy is generally requiredfor life.[2,3] Warfarin has been the mainstay oftherapy for several decades, but treatment is com-plicated by several drawbacks associated with thedrug (section 1). Dabigatran was the first alter-native OAC agent to warfarin to be approved forthe prevention of stroke and systemic embolismin patients with AF in several countries, includingthe US[9] and EU member states,[8] and it is nowrecommended as an option in current treatmentguidelines.[2,26,35]

Dabigatran acts rapidly, has few interactionswith food or other drugs, is not metabolized viathe cytochromeP450 pathway, and has a predictablepharmacodynamic effect without requirementfor regular monitoring.[17] Thus, dabigatran hassome specific advantages compared with warfa-rin and, in particular, a quality-of-life advantagefor patients, as they can forego regular INR moni-toring. However, some limitations are associatedwith this class of agent, including a lack of long-term safety data and, as yet, there is no specificantidote. Furthermore, as there is no pharmaco-dynamic marker for monitoring, unlike warfarin,it is difficult to objectively monitor adherence.[5]

Exposure to dabigatran is increased in patientswith renal failure and, as such, there is someuncertainty about optimal dosages in this pa-tient group.[36] The dosage of dabigatran shouldbe reduced in patients with moderate (CLCR

30–50mL/min) [EU recommendation][8] or severe(CLCR 15–30mL/min) [US recommendation][9]

renal impairment.Dabigatran (110 and 150mg twice daily)

demonstrated noninferiority versus warfarin withregard to the prevention of stroke and systemicembolism (primary endpoint) in the RE-LY trial

852 McKeage


(section 3.1), and the 150mg twice-daily dosage(but not the 110mg twice-daily dosage) was sig-nificantly more effective than warfarin for thisendpoint as well as most other efficacy endpoints.Based on results from the RE-LY trial, the FDAapproved only the dabigatran 150mg twice-dailydosage (reduced to 75mg twice daily in patientswith severe renal impairment).[37]

The incidence of major bleeding in the RE-LYtrial was generally similar in patients receivingdabigatran 150mg twice daily or warfarin, butwas lower in patients receiving dabigatran 110mgtwice daily (section 3.2). With regard to otherbleeding endpoints, dabigatran was generallyassociated with lower rates than warfarin, exceptfor gastrointestinal major bleeding. Dabigatran(both dosages) was also associated with a higherincidence of dyspepsia and a higher rate oftreatment discontinuation than warfarin.

The potential economic impact of the wide-spread use of dabigatran in favour of warfarin inthe prevention of stroke and systemic embolismin AF patients is far reaching. Results of mod-elled cost-utility analyses from the perspective ofa healthcare payer over a lifetime (or 20-year)time horizon and primarily based on data fromthe RE-LY trial were generally consistent (sec-tion 4.2). All but one trial[23] demonstrated thattwice-daily dabigatran 150mg (or age-adjusted,sequential dosing) was cost effective comparedwith warfarin with regard to the incremental costper QALY gained in the prevention of stroke andsystemic embolism in AF patients, as results werebelow generally accepted cost-effectiveness thresh-olds; incremental costs per QALY gained asso-ciated with dabigatran 110mg twice daily versuswarfarin exceeded cost-effectiveness thresholds inall[5,6,24,25,27,28] but one study.[26]

A common finding in base-case analyses wasthat the relatively high drug cost of dabigatranwas offset to some degree by warfarin monitoringcosts and costs associated with complications dueto over- and under-anticoagulation associated withwarfarin.[5,6,24,25,27,28] Not surprisingly, medicalcentres or practices that consistently achieve highlevels of INR control have lower resource-usecosts than centres where warfarin dosing is notmanaged well. Sensitivity analyses support this

finding (section 4.3), although incremental costsper QALY gained of dabigatran versus warfaringenerally remained below cost-effectiveness thres-holds when levels of INR control were well abovethose generally observed in clinical practice(55–60% of patients[38]). In contrast, a subgroupanalysis in the UK study by Pink et al.[5] foundthat in centres where INR was maintained withinthe therapeutic range for a mean of ‡65.5% of thetime, the incremental costs per QALY gained ofdabigatran versus warfarin (d42 386) exceededgenerally accepted thresholds.

Several studies demonstrated that dabigatranbecame more cost effective relative to warfarin asthe risk of ischaemic stroke increased (section4.3), suggesting that its use is particularly costeffective compared with warfarin in patients athigh risk (e.g. CHADS2 score ‡3).[5,6,23]

It is worthy of note that reliance on RE-LYtrial data in the cost-utility analyses means thatpatients were assumed to be willing to receivewarfarin (if not assigned to dabigatran). In reallife, many AF patients refuse to take warfarin ortake it irregularly, thereby increasing their risk ofstroke.[34,39] The Canadian study by Sorensenet al.[27] demonstrated the substantial impact thatreal-world versus trial-like warfarin prescribingand adherence has on the incremental cost utilityof dabigatran versus warfarin (section 4.2).

Based on evidence that the cost effectivenessof dabigatran versus warfarin varies in certainscenarios, several commentators have suggestedthat a stratified approach to AF treatment mayachieve the greatest cost effectiveness of OACtherapy in patients at risk of stroke, until furthertrial data become available.[5,40,41] Factors suchas the level of INR control, potential adverse ef-fects and baseline risk of stroke can impact costeffectiveness, and treatment decisions should bebased on individual assessments. Indeed, the re-cent guidance from NICE recommends that thedecision to commence dabigatran be made afteran informed discussion between the clinician andpatient with respect to the comparative risks andbenefits versus warfarin.[26]

Other possible OAC agents for use in AF nowinclude the recently approved rivaroxaban. Riv-aroxaban was noninferior to warfarin with regard



to stroke prevention in patients with AF andwas associated with a similar or reduced risk ofmost bleeding endpoints.[42] As yet, the drug hasnot been compared with dabigatran in a head-to-head trial, and which agent will prove the mostcost effective in this patient population remainsto be determined.

In conclusion, dabigatran 150mg twice daily(or age-adjusted, sequential dosing) was a cost-effective alternative to adjusted-dose warfarin forthe prevention of stroke and systemic embolismin patients with AF in all but one of the cost-utility analyses from several countries. Overall,incremental costs per QALY gained for dabiga-tran 150mg versus warfarin were below generallyaccepted cost-effectiveness thresholds, whereasincremental costs per QALY gained for dabiga-tran 110mg twice daily versus warfarin exceededcost-effectiveness thresholds in all studies exceptone. Sensitivity analyses suggested that the in-cremental cost per QALY gained for dabigatranversus warfarin improved when levels of INRcontrol in warfarin recipients decreased and whenthe baseline level of risk of stroke increased.

Disclosure

The preparation of this review was not supported by anyexternal funding. During the peer review process, the manu-facturer of the agent under review was offered an opportunityto comment on this article. Changes resulting from commentsreceived were made by the author on the basis of scientific andeditorial merit.

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Correspondence: Kate McKeage, Adis, 41 Centorian Drive,Private Bag 65901, Mairangi Bay, North Shore 0754, Auck-land, New Zealand.E-mail: [email protected]



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