Is dabigatran considered a cost-effective alternative to warfarin treatment: a review of current economic evaluations worldwide

Figures & data

Table 1. Summed quality scores according to the CHEC-list and the level of evidence according to the Oxford model of included economic evaluations of dabigatran and warfarin treatment in the prevention of apoplexia and systemic embolism in patients with AF.

	González-Juanatey et al.20	You et al.12	Davidson et al.17	Kansal et al.13	Langkilde et al.16	Freeman et al.18	Kamel et al.19	Sorensen et al.14	Pink et al.15	Shah and Gage11	Total fulfillment*
Oxford model	2b	2b	2b	2b	2b	2b	2b	2b	2b	2b
CHEC-list
1. Is the study population clearly described?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	100%
2. Are competing alternatives clearly described?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	100%
3. Is a well-defined research question posed in answerable form?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	100%
4. Is the economic study design appropriate to the stated objective?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	100%
5. Is the chosen time horizon appropriate in order to include relevant costs and consequences?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	100%
6. Is the actual perspective chosen appropriately?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	100%
7. Are all important and relevant costs for each alternative identified?	No	No	No	No	No	No	No	No	No	No	0%
8. Are all costs measured appropriately in physical units?	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	90%
9. Are costs valued appropriately?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	100%
10. Are all important and relevant outcomes for each alternative identified?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	100%
11. Are all outcomes measured appropriately?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	100%
12. Are outcomes valued appropriately?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	100%
13. Is an incremental analysis of costs and outcomes of alternatives performed?	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	90%
14. Are all future costs and outcomes discounted appropriately?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	100%
15. Are all important variables, whose values are uncertain, appropriately subjected to sensitivity analysis?	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	No	80%
16. Do the conclusions follow from the data reported?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	100%
17. Does the study discuss the generalizability of the results to other settings and patient/client groups?	Yes	No	Yes	Yes	Yes	No	Yes	No	No	Yes	60%
18. Does the article indicate that there is no potential conflict of interest of study researcher(s) and funder(s)?	Yes	No	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	80%
Total fulfillment^†	94.4%	77.8%	94.4%	94.4%	88.9%	88.9%	83.3%	88.9%	88.9%	88.9%

AF, Non-valvular atrial fibrillation; CHEC-list, Consensus Health Economic Criteria list.

*Calculated as: Number of fulfilled criteria divided by total number of criteria multiplied by 100.

†Calculated as: Number of economic evaluations fulfilling the criteria in question divided by total number of economic evaluations multiplied by 100.

Figure 1. Flowchart of different steps in the systematic literature search.

Table 2. General characteristics of the included economic evaluations on dabigatran and warfarin treatment in prevention of apoplexia and systemic embolism in patients with AF.

	Freeman et al.18	Pink et al.15	Kamel et al.19	Langkilde et al.16	Davidson et al.17
Year	2011	2011	2012	2012	2012
Country	US	UK	US	Denmark	Sweden
Journal	Annals of Internal Medicine	British Medical Journal	American Heart Association	Journal of Medical Economics	European Heart Journal
Design	Markov decision model Hypothetical cohort of 10,000 patients ≥65 years with non-valular AF, a CHADS2 score ≥1, and no contraindications	Markov model, reflected RE-LY patients Hypothetical cohort of 50,000 patients with a mean CHADS2 score of 2.1	Markov model Hypothetical cohort of 70-year-old patients with non-valvular AF, prior stroke or TIA, and no contraindications Cycles of 30 days	Adapted Markov model from Sorensen et al.16 Hypothetical cohort of 10,000 patients with AF and a mean age of 69 years Cycles of 3 months	Decision analytic model, Markov design Hypothetical cohort of patients >65 years with AF Cycles of 1 year
Compared alternatives	Adjusted-dose warfarin (target INR 2–3) Dabigatran 150 mg, twice daily Dabigatran 110 mg, twice daily	Warfarin Dabigatran, twice daily (150 mg < 80 years; 110 mg ≥ 80 years)	Adjusted-dose warfarin (target INR 2–3) Dabigatran 150 mg, twice daily	Dabigatran, twice daily (150 mg < 80 years; 110 mg ≥ 80 years) Warfarin (5 mg, target INR 2–3) Acetylsalicylic acid No treatment	Dabigatran, twice daily (150 mg < 80 years; 110 mg ≥ 80 years) Warfarin Acetylsalicylic acid No anticoagulation treatment
Time horizon	Lifetime (35 years or until death)	Expected lifetime	20 years or until death	Long-term (remaining lifetime)	Long-term (20 years)
Annual discount rate	3%	3.5%	3%	2%	3%
Health outcomes
Included adverse events	IS TIA MI Haemorrhage Death	Stroke ICH TIA MI Major bleeding Minor bleeding Pulmonary embolism	IS ICH TIA MI MEH Recurrent or combined stroke and/or ICH Mortality	IS ICH TIA AMI Other major haemorrhages Minor bleeds SE HS Death	IS MI Other major bleedings Minor bleeding GIB HS Death SE
Effect	Warfarin: 10.28 QALYs Dabigatran 110 mg: 10.70 QALYs Dabigatran 150 mg: 10.84 QALYs	Warfarin: 6.390 QALYs 10.851 Life-years Dabigatran 150 mg: 6.536 QALYs 11.051 Life-years Dabigatran 110 mg: 6.484 QALYs 10.940 Life-years	Warfarin: 3.91 QALYs Dabigatran: 4.27 QALYs	Warfarin: 8.32 QALYs 11.34 Life-years Dabigatran: 8.59 QALYs 11.61 Life-years	Warfarin: 8.31 QALYs 11.83 Life-years Dabigatran: 8.60 QALYs 12.11 Life-years
Costs
Perspective	Socio-economic	UK National Health service	Socio-economic	N/S*	Socio-economic
Currency	2008 USD($)	2009 GBP(£)	2010 USD($)	2011 Euro(€)	2012 Euro(€)
Included costs	Prices of drugs Adverse events INR-measurement	Prices of drugs Adverse events Costs of general practitioners Costs of district nurses’ visits Price of proton pump inhibitors (dyspepsia) Ward costs Inpatient and Outpatient costs	Prices of drugs Adverse events INR-measurements	Prices of drugs Adverse events INR-measurement Consultation Outpatient visits Dabigatran initiation (consultation and CrCl-test)	Prices of the drugs (including annual visits to primary care doctor) Warfarin monitoring visits Social services Outpatient care
Total costs	Dabigatran 110 mg: $164,576 Dabigatran 150 mg: $168,398 Warfarin: $143,193	Dabigatran 150 mg: £9,850 Dabigatran 110 mg: £10,529 Warfarin: £6,480	N/S*	Dabigatran: €18,752 Warfarin: €16,886	Dabigatran: €27,009 Warfarin: €24,797
	Gonzàlez-Juanatey et al.20	Shah and Gage11	You et al.12	Sorensen et al.14	Kansal et al.13
Year	2012	2012	2012	2011	2012
Country	Spain	US	China	Canada	UK
Journal	Revista Española de Cardiología	Circulation	Plos One	Thrombosis and Haemostasis	Heart
Design	Markov Model Hypothetical cohort of 10.000 patients with AF. Mean age was 69.1 years with initiation of model and had no disabilities Duration of a cycle was 3 months	Markov model Hypothetical cohort of 70-year-old patients with AF, moderate risk of stroke, and no contraindications Duration of a cycle was 1 month Intention-to-treat perspective	Markov model Hypothetical cohort of 65-year-old patients with AF and a CHADS2 score of 2 Duration of a cycle was 1 month	Markov model Hypothetical cohort of patients with AF matched that of RE-LY Duration of a cycle was 3 months	Markov model Two hypothetical cohorts of patients with AF (starting age <80 and ≥80 years) Duration of a cycle was 3 months
Compared alternatives	Scenario 1: Dabigatran, twice daily (150 mg ≥ 80 years; 110 mg < 80 years) Warfarin Scenario 2: Dabigatran, twice daily (150 mg ≥ 80 years; 110 mg < 80 years) Prescribing pattern in clinical practice (60% warfarin, 30% acetylsalicylic acid and 10% not treated)	Dabigatran, twice daily (150 mg ≥ 80 years; 110 mg < 80 years) Warfarin Clopidogrel/acetylsalicylic acid Acetylsalicylic acid No treatment	Dabigatran, twice daily (150 mg ≥ 80 years; 110 mg < 80 years) Warfarin (mean TTR 64%) Genotype-guided AC	Trial-like scenario: Dabigatran (sequential), twice daily Dabigatran, twice daily (150 mg ≥ 80 years) Dabigatran, twice daily (110 mg < 80 years) Warfarin Real-world scenario: Dabigatran (sequential), twice daily Anticoagulation treatment (receiving warfarin, acetylsalicylic acid, or no treated)	Age < 80: Dabigatran, twice daily warfarin (mean TTR 64%) Age ≥ 80: Dabigatran, twice daily warfarin (mean TTR 64%) Scenario analysis: Dabigatran, twice daily acetylsalicylic acid No treatment
Time horizon	Lifetime (maximum life expectancy 100 years)	Maximum of 20 years	Lifetime (maximum 25 years)	Lifetime (maximum life expectancy 100 years)	Lifetime (maximum life expectancy 100 years)
Annual discount rate	Base case 3% Medication costs 7.5%	Base case 3%	Base case 3%	Base case 5%	Base case 3.5%
Health outcomes
Included outcomes	IS ICH TIA AMI Non-gastrointestinal haemorrhage Minor bleeding SE HS EH GIB Death	IS ICH TIA MI Major and minor non-cerebral haemorrhage Dyspepsia Death	IS ICH MI Major bleeding EH Dyspepsia Death	IS ICH TIA AMI Minor bleeding HS SE EH Death	IS TIA ICH AMI Minor bleeding HS SE EH Death
Effect	Scenario 1: Warfarin 8.45 QALYs Dabigatran 8.73 QALYs Scenario 2: Prescribing pattern in clinical practice 8.32 QALYs Dabigatran 8.73 QALYs	Warfarin: 8.40 QALYs Dabigatran 110 mg: 8.54 QALYs Dabigatran 150 mg: 8.65 QALYs Clopidogrel/acetylsalicylic acid: 8.32 QALYs Acetylsalicylic acid: 8.17 QALYs	Dabigatran 110 mg: 10.026 QALYs Dabigatran 150 mg: 10.065 QALYs Warfarin: 9.444 QALYs Genotype-guided AC: 9.554 QALYs	Trial-like scenario: Dabigatran (sequential): 7.29 QALYs Warfarin: 7.08 QALYs Dabigatran 150 mg: 6.86 QALYs Warfarin: 6.68 QALYs Dabigatran 110 mg: 6.82 QALYs Warfarin: 6.68 QALYs Real-world scenario: Dabigatran (sequential): 7.29 QALYs Warfarin: 7.01 QALYs	Age < 80: Warfarin: 7.82 QALYs Dabigatran: 8.06 QALYs Age ≥ 80: Warfarin: 4.04 QALYs Dabigatran: 4.11 QALYs Scenario analysis: Dabigatran: 8.06 QALYs Acetylsalicylic acid: 7.59 QALYs No treatment: 7.12 QALYs
Costs
Perspective	Spanish National Health System	Insurance company (or Medicare)	Healthcare payers	Canadian payer	N/S*
Currency	2010 Euro(€)	2010 USD($)	2012 USD($)	2010 CAD($)	2010 GBP(£)
Types of costs	Prices of drugs Adverse events INR-measurements Follow-up costs	Prices of drugs Adverse events INR-measurements Annual prophylaxis	Prices of drugs Adverse events INR-measurements Test of genotype	Prices of drugs Adverse events INR-measurements Follow-up costs	Prices of drugs INR-monitoring Adverse events Follow-up costs
Included costs	Scenario 1: Warfarin: €10,343 Dabigatran: €15,193 Scenario 2: Prescribing pattern in clinical practice: €9426 Dabigatran: €15,193	Dabigatran 150 mg: $43,700 Dabigatran 110 mg: $44,300 Warfarin: $23,000 Clopidogrel/acetylsalicylic acid: $34,000 Acetylsalicylic acid: $20,000	Dabigatran 110 mg: $102,536 Dabigatran 150 mg: $92,684 Warfarin: $90,481 Genotype-guided AC: $85,627	Trial-like scenario: Dabigatran (sequential): $45,124 Warfarin: $42,946 Dabigatran 150 mg: $41,824 Warfarin: $40,169 Dabigatran 110 mg: $44,379 Warfarin: $40,169 Real-world scenario: Dabigatran (sequential): $45,124 Warfarin: $44,020	Age < 80: Dabigatran: £19,645 Warfarin: £18.474 Age ≥ 80: Warfarin: £9,919 Dabigatran: £10,424 Scenario analysis: Dabigatran: £19,645 Acetylsalicylic acid: £18,561 No treatment: £20,475

AF, Non-valvular atrial fibrillation; AMI, Acute myocardial infarction; CHADS2 score, Congestive heart failure, hypertension, age >75, diabetes mellitus, and two points for the factor prior stroke or transient ischemic attack; CrCl, Creatine clearance; TTR, Mean time in the therapeutic range; EH, Extracranial haemorrhage; Genotype-guided AC, Genotype-guided anticoagulation care; GIB, Gastrointestinal bleedings; HS, Haemorrhagic stroke; ICH, Intracranial haemorrhage; INR, International normalized ratio; IS, Ischaemic stroke; MEH, Major extracranial haemorrhage; mg, milligrams; MI, Myocardial infarction; QALYs, Quality-adjusted life years; RE-LY, The Randomized Evaluation of Long-term Anticoagulant Therapy trial; SE, Systemic embolism; TIA, Transient ischemic attack.

*Not stated.

Table 3. Results of the included economic evaluations of dabigatran and warfarin treatment in the prevention of apoplexia and systemic embolism in patients with AF.

	Freeman et al.18	Pink et al.15	Kamel et al.19	Langkilde et al.16	Davidson et al.17
Cost-effectiveness
WTP threshold	$50,000 per QALY gained	£20,000–30,000 per QALY gained	$50,000 per QALY gained	€30,000 per QALY gained	€50,000 per QALY gained
ICER	Dabigatran 110 mg: $51,229 per QALY gained Dabigatran 150 mg: $45,372 per QALY gained	Dabigatran 150 mg: £23,082 per QALY gained Dabigatran 110 mg: £43,074 per QALY gained Ad hoc sub-group analysis: £24,340 per QALY gained Full RE-LY data: £27,940 per QALY gained	Dabigatran: $25,000 per QALY gained	Dabigatran: €6950 per QALY gained	Dabigatran: €7699 per Life-year gained €7742 per QALY gained
Sensitivity analysis
One-way	Key parameters influencing cost-effectiveness: Drug cost (dabigatran 110 mg not cost-effective >$9.36 per day. Dabigatran 150 mg not cost-effective >$13.70 per day) Risk of IS and ICH for dabigatran and warfarin Age (ICER decreased with age) Utility of dabigatran and warfarin Costs after ICH Utility after MI	Dabigatran 150 mg was cost-effective at the highest WTP threshold for all sub-groups except in very well-regulated patients (TTR ≥ 65.5%)	Key parameters influencing cost-effectiveness: Monthly costs of stroke and/or ICH (if >$5000 dabigatran dominated) Starting age of the cohort (if ≤81 years dabigatran dominated) Difference in RR of stroke between Dabigatran and warfarin (if ≥0.92 dabigatran dominated) Costs of dabigatran (if <$320 dabigatran dominated) Average CTTR (if CTTR <73% dabigatran dominated) Utility of mild IS	Key parameters influencing cost-effectiveness: Annual costs of INR-measurements (if >€744 dabigatran dominated) Dabigatran is cost-effective to warfarin irrespective of the range in quality of warfarin treatment	Key parameters influencing cost-effectiveness: Compared to well-controlled warfarin treatment the ICER increased to €12,449 per QALY gained, still below WTP threshold CHADS2 scores = 3–6 generated a better cost-effectiveness of dabigatran than lower scores If only transitions within the RE-LY time frame were included, the ICER increased to €10,287 per gained QALY, still below WTP threshold
Multi-way	Dabigatran 150 mg was the preferred choice unless patients had a low risk of stroke and a high risk of IH	Dabigatran 110 mg exceeded the highest WTP threshold in all cases	–	Higher levels of stroke risk were associated with lower incremental costs of dabigatran and higher QALY gained The ICER stayed below €18,000 per QALY gained in all cases	–
Probabilistic	10,000 first-order Monte Carlo simulations: Dabigatran 150 mg was cost-effective in 53% of cases compared to warfarin Dabigatran 110 mg was cost-effective in 30% of cases compared to warfarin	2,000 first-order Monte Carlo simulations: Warfarin had the highest probability of being cost-effective at threshold ≤£24,400 per QALY gained dabigatran 150 mg was most cost-effective in 68% of cases (at a CHADS2 score of ≥3)	10,000 first-order Monte Carlo simulations: Dabigatran was cost-effective in 57% of cases	–	1000 first-order Monte Carlo simulations: In all cases, the ICER was <€50,000 per QALY gained
Conclusions	Dabigatran was likely to be a cost-effective alternative to warfarin in the US, especially in patients with increased risk for IS and IH and highly dependent on pricing Dabigatran 110 mg was more cost-effective than dabigatran 150 mg in patients with low risk of IS	Dabigatran 150 mg was cost-effective at the lowest WTP threshold for patients with a low-quality INR-control or a high risk of stroke in the UK. Dabigatran offered a positive benefit-to-harm ratio when compared with warfarin	Dabigatran was likely to be a cost-effective alternative to warfarin in the US, but might not apply with excellent INR-control	Dabigatran represented a cost-effective alternative to warfarin in Denmark	Dabigatran was expected as a cost-effective treatment in Sweden, as the ICER was below the WTP threshold in all cases
Limitations	Did not include genotype-guided warfarin treatment or patient self-testing approaches, which might be a more cost-effective alternative Costs of dabigatran patient management were not included Productivity losses were not estimated	Had no access to data of individual patients Costs of dabigatran patient management were not included Productivity losses were not estimated Data of acetylsalicylic acid came from another study A 2-year trial was extrapolated to life-time Assumptions of utility decrements for AF patients were made Widespread of dabigatran might affect the quality of treatment in clinics	Costs of dabigatran patient management were not included Productivity losses were not estimated	Productivity losses were not estimated Did not include a PSA taking all variable uncertainties into account Limitations in the extrapolation to Danish settings Assumptions were made about dabigatran treatment, e.g., healthcare contact and treatment adherence High rate of AF patients treated despite recommendations not included	Productivity losses were not estimated Other complications were assumed to only affect costs and quality-of-life in the year in which they occurred. Transitions between CHADS2 scores occurred only according to age and stroke and no switch in choice of drug could occur (simplifications)
	Gonzàlez-Juanatey et al.20	Shah and Gage11	You et al.12	Sorensen et al.14	Kansal et al.13
Cost-effectiveness
WTP threshold	€30,000 per QALY gained	$50,000 per QALY gained	$50,000 per QALY gained	$30,000 per QALY gained	£20,000–£30,000 per QALY gained
ICER	Scenario 1: €17,581 per QALY gained Scenario 2: €14,118 per QALY gained	Warfarin: Dabigatran 150 mg $86,000 per QALY gained Dabigatran 110 mg $150,000 per QALY gained Clopidogrel/acetylsalicylic acid dominated Acetylsalicylic acid: Dabigatran 150 mg $50,000 per QALY gained Dabigatran 110 mg $66,000 per QALY gained Warfarin $12,500 per QALY gained Clopidogrel/acetylsalicylic acid $99,000 per QALY gained	Dabigatran 110 mg was by dominated Dabigatran 150 mg Dabigatran 150 mg $13,810 per QALY gained compared to Genotype-guided AC Warfarin was dominated by Genotype-guided AC	Trial-like scenario: Dabigatran (sequential): $10,440 per QALY gained Dabigatran 150 mg $9041 per QALY gained Dabigatran 110 mg $29,994 per QALY gained Real-world scenario: Dabigatran (sequential): $3962 per QALY gained	Before age of 80: Dabigatran compared to warfarin: £4831 per QALY gained At age 80 years and above: Dabigatran compared to warfarin: £7090 per QALY gained Scenario analysis: Dabigatran compared to acetylsalicylic acid: £3457 per QALY gained Dabigatran compared to no treatment: Dominated
Sensitivity analysis
One-way	Key parameters influencing cost-effectiveness: Time horizon Discount rate Patients ≥80 years (dabigatran 110 mg) Mean TTR Analysis perspective Degree of INR-control Reduction of risk of stroke Cost for INR-measurements Decrease in degree of disability when treated with dabigatran Scenario 1: The ICER ranged from €14,651–€57,719 per QALY gained Scenario 2: The ICER ranged from €11,519–€52,160 per QALY gained	Key parameters influencing cost-effectiveness: IS and major bleeds (if CHADS2 score = 2 and annual risk of haemorrhage >6% dabigatran 150 mg dominated. If CHADS2 score ≥3 dabigatran 150 mg dominated) Cost of dabigatran (if <$1800 per year then dabigatran 150 mg dominated)	Key parameters influencing cost-effectiveness: Mean TTR in Genotype-guided AC (dabigatran dominated Genotype-guided AC unless when TTR >98%) Utility of warfarin and dabigatran (dabigatran dominated warfarin unless the utility of warfarin ≥0.99 or dabigatran ≤0.95) Difference in risk of stroke in dabigatran 150 mg and warfarin treatment (ICER ranged between $10,000–$38,000) Risk of stroke with warfarin in INR target range	Key parameters influencing cost-effectiveness: Degree of INR-control (varying the fraction of patients in INR-range from 40–80% then the ICER increased from $1716 to $23,263 per QALY gained) Difference in RR and rate of long-term disability of IS in dabigatran and warfarin treatment (ranging RR in dabigatran 110 mg and 150 mg between 0.51 and 0.58 to 1.33 and 1.03, respectively, then the ICER was between $4186–$30,521 per QALY gained) Cost of long-term follow-up care for patients with disabilities Time horizon (a 10-year time horizon increased the ICER to $23,555 per QALY gained) Varying incremental clinical costs and parameters from 20–30% resulted in an ICER ranging from $13,130–$30,521 per QALY gained	Key parameters influencing cost-effectiveness: Degree of INR-control (dabigatran dominated unless TTR was 91–97% (<80 years) and 80–83% (≥80 years)) Costs of INR-measurements Difference in RR and overall rates of IS, ICH, and HS between dabigatran and warfarin treatment (using the upper limit of 95% CI for the RR of IS, ICH, or HS increased the calculated ICERS to £13,353, £10,013, and £8,420 per QALY gained) Long-term cost of follow-up care on disability Time horizon (a 10-year time horizon increased the ICER to £11,898 per QALY gained)
Multi-way	–	If TTR was <57.1% and a CHADS2 score ≥2 then dabigatran 150 mg dominated	If warfarin utility was between 0.95–1.00 and TTR 77–98% then Genotype-guided AC dominated If utility of warfarin was the same as or higher than dabigatran then Genotype-guided AC dominated	–	–
Probabilistic	10,000 Monte Carlo simulations: Scenario 1: Dabigatran was cost-effective in 96.4% of cases compared to warfarin Scenario 2: Dabigatran was cost-effective in 99.9% of cases compared to prescribing pattern in clinical practice Sub-group analysis: Dabigatran was cost-effective in 99.4% of cases compared to warfarin with poor INR-control Dabigatran was cost-effective in 99.3% of cases compared to warfarin with good INR-control	–	10,000 Monte Carlo simulations: Dabigatran was cost-effective in 51.6% of cases, whereas Genotype-guided AC was in 46.2% of cases warfarin was cost-effective in 0.6% of cases and dabigatran 110 mg in 1.6% of cases	10,000 Monte Carlo simulations: Trial-like scenario: Dabigatran (sequential) was cost-effective in 82% of cases compared to warfarin Dabigatran 150 mg was cost-effective in 81% of cases compared to warfarin Dabigatran 110 mg was cost-effective in 42% of cases compared to warfarin Real-world scenario: Dabigatran (sequential) was cost-effective in 99% of cases compared to warfarin	5000 Monte Carlo simulations: At the low WTP threshold dabigatran was cost-effective in 98% of cases compared to warfarin in patient <80 years and 100% compared to acetylsalicylic acid as well as no treatment At the low WTP threshold dabigatran were cost-effective in 63% of cases compared to warfarin in patient ≥80 years
Conclusions	Dabigatran was a cost-effective alternative to warfarin in Spain	Dabigatran 150 mg was a cost-effective alternative to warfarin only in patients with a CHADS2 score of three or higher or in patients with a CHADS2 score of two as well as a poor INR-control	Dabigatran was the most cost-effective alternative compared to warfarin if TTR ≤ 64% If warfarin was the same as or higher than dabigatran utility and TTR was >77% then Genotype-guided AC cost-effective	Dabigatran was a highly cost-effective alternative in all comparisons conducted	Dabigatran was likely to be cost-effective in all comparisons conducted and recommended as a first-line drug
Limitations	Costs of dabigatran patient management were not included Productivity losses were not estimated Data on utilities extrapolated from UK settings The first line drug in Spain is acenocoumarol not warfarin	Costs of dabigatran patient management were not included Productivity losses were not estimated Warfarin administration in RE-LY was not blinded Did not include a PSA taking all variable uncertainties into account	Costs of dabigatran patient management were not included Productivity losses were not estimated RE-LY based on a 2-year period whereas the Markov model was based on lifetime	Costs of dabigatran patient management were not included Productivity losses were not estimated Did not consider rehabilitation Discontinuation rates were based on RE-LY RR were used over the whole time horizon	Costs of dabigatran patient management were not included Productivity losses were not estimated Limited data available of costs of long-term disability Assuming that the decision to treat with anticoagulation is life long

AF, Atrial Fibrillation; CHADS2 score, Congestive heart failure, hypertension, age >75, diabetes mellitus, and two points for the factor prior stroke or transient ischemic attack; TTR, mean time in the therapeutic range; Genotype-guided AC, Genotype-guided anticoagulation care; HS, Haemorrhagic stroke; ICER, Incremental cost-effectiveness ratio; ICH, Intracranial haemorrhage; INR, International normalized ratio; IS, Ischaemic stroke; mg, milligrams; MI, Myocardial infarction; QALYs, Quality-adjusted life years; RE-LY, The Randomized Evaluation of Long-term Anticoagulant Therapy trial; RR, relative risk; WTP, Willingness-to-pay.

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