Dabigatran versus rivaroxaban for the prevention of stroke and systemic embolism in atrial fibrillation in Canada

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1 672 Schattauer 2012 Blood Coagulation, Fibrinolysis and Cellular Haemostasis Dabigatran versus rivaroxaban for the prevention of stroke and systemic embolism in atrial fibrillation in Canada Comparative efficacy and cost-effectiveness Anuraag R. Kansal 1 ; Michael Sharma 2 ; Carole Bradley-Kennedy 3 ; Andreas Clemens 4 ; Brigitta U. Monz 4 ; Siyang Peng 1 ; Neil Roskell 5 ; Sonja V. Sorensen 1 1 United BioSource Corporation, Bethesda, Maryland, USA; 2 Division of Neurology University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; 3 Boehringer Ingelheim (Canada) Ltd., Burlington, Ontario, Canada; 4 Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany; 5 RTI Health Solutions, Manchester, UK Summary Canadian patients with atrial fibrillation (AF) in whom anticoagulation is appropriate have two new choices for anticoagulation for prevention of stroke and systemic embolism dabigatran etexilate (dabigatran) and rivaroxaban. Based on the RE-LY and ROCKET AF trial results, we investigated the cost-effectiveness of dabigatran (twice daily dosing of 150 mg or 110 mg based on patient age) versus rivaroxaban from a Canadian payer perspective. A formal indirect treatment (ITC) of dabigatran versus rivaroxaban was performed, using dabigatran clinical event rates from RE-LY for the safety-on-treatment population, adjusted to the ROCKET AF population. A previously described Markov model was modified to simulate anticoagulation treatment using ITC results as inputs. Model outputs included total costs, event rates, and quality-adjusted life-years (QALYs). The ITC found when compared to rivaroxaban, dabigatran had a lower risk of intracranial haemorrhage (ICH) (relative risk [RR] = 0.38; 95% confidence interval [CI] ) and stroke (RR = 0.62; 95%CI ). Over a lifetime horizon, the model found dabigatran-treated patients experienced fewer ICHs (0.33 dabigatran vs rivaroxaban) and ischaemic strokes (3.40 vs. 3.96) per 100 patient-years, and accrued more QALYs (6.17 vs. 6.01). Dabigatran-treated patients had lower acute care and long-term follow-up costs per patient ($52,314 vs. $53,638) which more than offset differences in drug costs ($7,299 vs. $6,128). In probabilistic analysis, dabigatran had high probability of being the most cost-effective therapy at common thresholds of willingness-to-pay (93% at a $20,000/QALY threshold). This study found dabigatran is economically dominant versus rivaroxaban for prevention of stroke and systemic embolism among Canadian AF patients. Keywords Anticoagulation, atrial fibrillation, cost-effectiveness, dabigatran, rivaroxaban, RE-LY, ROCKET AF Correspondence to: Anuraag Kansal United BioSource Corporation 7101 Wisconsin Avenue, Suite 600 Bethesda, MD 20814, USA Tel.: , Fax: anuraag.kansal@unitedbiosource.com Received: June 11, 2012 Accepted after minor revision: July 18, 2012 Prepublished online: August 17, 2012 doi: /th Thromb Haemost 2012; 108: Introduction The primary goal of the management of patients with atrial fibrillation (AF) is the prevention of stroke. Ischaemic stroke (IS) in the setting of AF results in death or disability in 80% of individuals and the one-year mortality approaches 50% (1, 2). Intracranial haemorrhages (ICH) in the setting of oral anticoagulation are larger and more likely to be fatal (3). Improvement in patients outcomes may be achieved by reductions in the occurrence of IS and ICH. Dabigatran etexilate (dabigatran), an orally active, reversible direct thrombin inhibitor, has been approved for the prevention of stroke and systemic embolism (SE) in AF patients in whom anticoagulation is appropriate (4). The RE-LY trial demonstrated that in the intent to treat (ITT) population, the rate of stroke or SE (the primary efficacy endpoint) was significantly lower with dabigatran 150 mg BID than adjusted-dose warfarin (relative risk [RR], 0.66; 95% CI, 0.53 to 0.82; p<0.001 for superiority), while dabigatran 110 mg twice daily (BID) was non-inferior for stroke and SE prevention, with fewer major bleeds in both dabigatran arms than adjusted-dose warfarin (5, 6). Based on these clinical results, many clinical guidelines now recommend dabigatran for patients with AF at moderate to high risk of stroke (7 9). Health Canada recommends dabigatran 150 mg BID for patients less than 80 years of age and 110 mg BID for those at least 80 years of age (4). Rivaroxaban, a direct inhibitor of factor (F)Xa, was recently approved by Health Canada for the prevention of stroke and SE in AF patients in whom anticoagulation is appropriate (10). The phase 3 clinical trial, ROCKET AF, was conducted to determine the efficacy and safety of rivaroxaban in to warfarin (11). This trial found that rivaroxaban was non-inferior to warfarin in the standard ITT population for prevention of stroke and SE (hazard ratio (HR), 0.88; 95% CI, 0.75 to 1.03; p<0.001 for non-inferiority; p = Thrombosis and Haemostasis 108.4/2012

2 Kansal et al. Dabigatran vs. rivaroxaban in stroke prevention for superiority). In a safety on treatment (SOT) population, rivaroxaban had an hazard ratio (HR) of 0.79 (95% confidence interval [CI]: 0.65 to 0.95) for stroke and SE. The safety on treatment population included patients who received at least one dose of a study drug and were followed for events, regardless of adherence to the protocol, while they were receiving the assigned study drug or within two days of discontinuation (11). Direct of outcomes between the RE-LY and ROCKET AF trials is made challenging by differences in the trial populations, study designs and primary analysis populations. The ROCKET AF trial enrolled patients with AF with a higher risk of stroke than those enrolled in the RE-LY trial, though the risk was still elevated in RE-LY. This difference is manifested in the mean CHADS 2 risk scores for the trial populations (2.1 in RE-LY vs. 3.1 in ROCKET AF) (5, 11). Additionally, the warfarin population in RE-LY achieved a better mean time in therapeutic range (TTR) of the international normalised ratio (INR) than the warfarin population in ROCKET AF (64.4% in RE-LY vs. 55.2% in ROCKET AF) (5, 11). Treatment discontinuation rates also differed between the trials. A previously published study examined the cost-effectiveness of dabigatran vs. warfarin using ITT estimates (12). As the anticoagulation landscape evolves in Canada, there is a need to understand the clinical and economic differences between the two new therapies. Direct of clinical outcomes, and thus economic implications, is confounded by the differences in trial populations previously described. We aimed to calculate comparable risk estimates of dabigatran vs. rivaroxaban by statistically correcting for differences between the trial populations and the performance of the warfarin arms in both studies using the same analysis set (i.e. SOT). Using these estimates as inputs, we compare the clinical and economic outcomes of dabigatran vs. rivaroxaban in a previously published model of stroke prevention in AF (12, 13). In a secondary analysis, these new agents are compared with warfarin. Methods Overview of cost-effectiveness model A Markov model was developed to estimate the cost-effectiveness of dabigatran in eligible patients with AF, details of which have been described previously (12). This model was modified to compare dabigatran, rivaroxaban and warfarin in an AF population that reflected the published ROCKET AF population. Dabigatran dosing in the model corresponded to the approved Canadian dosing, in which patients switch from the 150 mg BID dose to the 110 mg BID dose upon reaching age 80. The model followed AF patients over a lifetime horizon through the natural course of disease in three-month cycles, included all relevant clinical outcomes and incorporated health states stratified by treatment history, stroke history and disability level. Major clinical events included in the model were primary and recurrent IS, SE, transient ischaemic attack (TIA), acute myocardial infarc- tion (AMI), ICH including haemorrhagic stroke (HS), major extracranial haemorrhage (ECH), minor bleeding and death. HS and ICH were considered together as no data were available from ROCKET AF to separate those out as was previously done for dabigatran (12). IS and ICH could be disabling or non-disabling, with disabling events resulting in permanent functional deficits, as characterised by the modified Rankin Score (mrs) for IS and by the Glasgow Outcomes Scale (GOS) for ICH. All haemorrhagic events could result in discontinuation of current treatment. Patients could also discontinue for other reasons, including nonclinical reasons such as patient s decision. All patients who discontinued anticoagulant therapy due to ECH were assumed to switch to aspirin. A total of 70% of dabigatran- and rivaroxaban-treated patients (and 78% of warfarin treated patients in the secondary analysis) who discontinued due to other reasons were assumed to switch to aspirin as well. Patients who discontinued treatment without switching to a new therapy were assumed to permanently discontinue all treatment. The model included clinical and cost outcomes, along with incremental cost-effectiveness ratios (ICERs) and net monetary benefits (NMBs). An ICER represents the additional cost required to achieve an improved clinical outcome, most commonly, one additional quality-adjusted life-year (QALY; the equivalent of one year of totally healthy life). An ICER is formally computed as incremental cost in the dabigatran arm vs. the rivaroxaban arm divided by incremental QALYs. Where a treatment is both less costly and delivers better health outcomes, it is described as being economically dominant and no meaningful ICER can be computed (14). NMB was also included to address this formal limitation of ICERs. NMB translates both clinical and economic outcomes into costs based on a societal willingness-to-pay (WTP) threshold for the clinical outcome. This threshold is typically between at least $20,000 per QALY and $30,000 per QALY in Canada (15). NMB is computed by multiplying a WTP threshold with the incremental QALYs offered by a therapy and deducting the incremental cost of that therapy. A NMB greater than $0 indicates that the therapy is economically favourable, and the higher the NMB, the greater the cost-effectiveness. A baseline WTP threshold of CAN$30,000/QALY was used and was varied in sensitivity analyses. Patient population and baseline event rate A critical consideration in this assessment was ensuring that the treatments were compared taking account of the different performance (i.e. TTR) of the warfarin arms in the two studies (16) and the different underlying event risks due to enrolment of different patient populations (e.g. the mean CHADS 2 score was 2.1 in RE-LY vs. 3.1 in ROCKET AF). We chose to adjust the underlying event risk of the dabigatran clinical results from the RE-LY trial to the ROCKET AF trial population. Thus, the simulation population s age (73 years), gender ratio (60% male), and baseline event rates (see Table 1) were taken from the ROCKET AF trial (11, Schattauer 2012 Thrombosis and Haemostasis 108.4/2012

3 674 Kansal et al. Dabigatran vs. rivaroxaban in stroke prevention Table 1: Patient distribution according to CHADS 2 scores and associated stroke rates. Patient population CHADS 2 % of patients % of patients with history of stroke Source for distribution, for stroke history Baseline event rate (dabigatran) Event Rate (per 100 Source patient-years) Ischaemic Calibrated based stroke on 11 and ITC (by CHADS 2) results Systemic embolism 0.09 Intracranial bleeding 0.17 Extracranial bleeding 2.19 Acute myocardial infarction ). Where published data from ROCKET AF were not adequate to specify the population completely, data from the RE-LY trial were used. For example, rates of disability following IS and ICH were assumed to be equal in the dabigatran and rivaroxaban arms and were taken from an analysis of the RE-LY trial data (as described previously in Sorensen et al [12]). The model population characteristics and baseline event rates are shown in Table 1. All patients were assumed to discontinue anticoagulation treatment if they experienced ICH, while the discontinuation rate following an ECH event was estimated to be 10%, based on the Food and Drug Administration (FDA) briefing summary for the ROCKET AF trial (17). Discontinuation rates for other causes were based on the overall rates reported in ROCKET AF, with dabigatran assumed to have an equal discontinuation rate to rivaroxaban. After two years, 23.7% of patients receiving dabigatran or rivaroxaban discontinued treatment for reasons other than bleeding, while 22.2% discontinued in the warfarin group (11). Since the probability of discontinuation varies by time, these rates were extrapolated to six years based on Weibull functions with a shape determined from analysis of the RE-LY trial discontinuation rates (Weibull shape = ; scale = 0.541) (12). As in the original model, patients that remained adherent to treatment for six years were assumed to discontinue thereafter only in the event of major bleeding. Health state utility values and quality of life decrements for clinical events were the same as those used in the previously published analysis of dabigatran in the Canadian AF population (12). Briefly, the baseline utility was 0.81 reflecting a population with AF (18). A one cycle disutility at the time of an event was applied: stroke (0.139), SE (0.120), ICH (0.181), ECH (0.181), TIA (0.103), AMI (0.125), and minor bleedings (0.004). A utility value corresponding to patient s functional status for independent with stroke history (0.65), moderately dependent (0.46), and totally dependent (0.30) was used (19). Similarly, event and disability management costs were equal to those published previously (provided in the Suppl. Material, available online at The daily price of dabigatran 150 mg BID and 110 mg BID was $3.20 (20). Rivaroxaban, however, was not included in that previous analysis, and its daily cost was set to $2.84 (21). A discount rate of 5% was applied to both costs and health outcomes, per the Canadian Agency for Drugs and Technologies in Health (CADTH) guidelines (22). treatment The relative risks (RR) of each type of clinical event in the model were computed using an ITC (23, 24) between dabigatran and rivaroxaban using standard methodologies such as those published by CADTH (25). These analyses were performed using data from the RE-LY and ROCKET AF trials with warfarin as the common comparator. In addition to an unadjusted ITC, two adjusted ITCs were performed for each endpoint. This was done to account for the observed differences in percent time in target INR range (TTR; INR target 2 3) for the warfarin group between the two trials. The dabigatran data included in these analyses combined selected data taken from the two respective RE-LY treatment arms, based on patient age at randomisation, to form one single dabigatran treatment group. Specifically, this set (n = 5,990) takes patients younger than 80 years from the dabigatran 150 mg BID group (n = 5,019/6,076) and patients aged 80 years and older from the dabigatran 110 mg BID group (n = 971/6,015) (Boehringer Ingelheim, data on file). On average, patients in the warfarin group in the RE-LY trial had higher TTR, with a mean of 64.4% (5), than those in the ROCKET AF trial (mean of 55.2% [11] or a RELY-adjusted mean of 57.7% [17]). The RELY-adjusted mean TTR for ROCKET AF was calculated by adjusting the ROCKET AF trial population to one that was similar to the RE-LY population (in terms of various demographic, disease-related and geographic factors). This recalculation was performed by the FDA Division of Biometrics. Warfarin treatment duration was longer in RE-LY vs. ROCKET AF (mean duration 647 [26] days compared to 580 days [17], respectively) and the warfarin discontinuation rate at year one was less in RE-LY vs. ROCKET AF, with 10.2% (5) compared to 21.1% (27), respectively. To investigate the relationship of TTR with the clinical outcomes, patient level warfarin data from the RE-LY trial were Thrombosis and Haemostasis 108.4/2012 Schattauer 2012

4 Kansal et al. Dabigatran vs. rivaroxaban in stroke prevention 675 analysed using logistic regression and odds ratios (OR) for a 10% change in TTR (similar as in Jones et al [28]). The residuals of the logistic link function were checked for adequacy of the TTRoutcome relationship. HRs (estimated using Cox proportional hazards models) of dabigatran, and separately, rivaroxaban vs. warfarin were used to form the unadjusted ITC for each endpoint. For the TTR adjusted ITCs, patient counts were used to form RRs for each endpoint for RE-LY and ROCKET AF. Prior to forming the RRs within ROCKET AF, the patient counts for the warfarin group were corrected to a hypothetical value, assuming the TTR for this trial had been the same as RE-LY by using the TTR effect OR estimates. Two separate TTR adjustments were performed to allow for a 9.2% (64.4% 55.2%; RELY ROCKET AF published TTR) and a 6.7% difference in TTR (64.4% 57.7%; RELY FDA-adjusted ROCKET AF TTR). The ITC analyses were performed for two patient populations, ITT and SOT according to data availability. For the RE-LY dataset, SOT results were calculated in order to match the ROCKET AF analysis. Additionally, endpoints were re-calculated to match the ROCKET AF definitions (e.g. IS excluding uncertain). For the RRs used in the cost-effectiveness model, the SOT population with a 6.7% difference in TTR was used in the base case, as this analysis provided most of the endpoints needed to populate the cost-effectiveness model (including major bleeding and ICH) which would not have been available in the ITT analysis. An analysis in which only the subgroup of RE-LY patients that had a CHADS 2 score of 2 or higher to correspond with the ROCKET AF trial population was considered in another ITC analysis. This analysis was used in model sensitivity analysis and no TTR adjustments were made. Results ITC results Table 2 presents the ITC results for dabigatran vs. rivaroxaban. For the unadjusted ITCs, dabigatran shows statistically significant benefit vs. rivaroxaban for the endpoints all stroke, HS, and ICH, and the composite endpoint all stroke and SE (ITT population only). Rivaroxaban shows statistically significant benefit vs. dabigatran for the AMI endpoint (SOT population only). As expected, reduced TTR was associated with increased events through the RE-LY warfarin patient-level data analysis. Most notably, a 10% decrease in TTR was associated with increased odds of death and all stroke or SE of 35% and 10%, respectively very comparable to the results by Jones et al. (2005) (28), with 29% for mortality and 12% for stroke and other thromboembolic events. Applying the TTR adjustment factors to the ROCKET AF data to make its warfarin arm more reflective of the RE-LY warfarin arm led to movement in all the ITC RR estimates in favour of dabigatran. This in turn led to potentially further significant (TTR adjustment and analysis population dependant) differences between dabigatran and rivaroxaban in the all-cause mortality, all stroke or SE, and major bleeding endpoints. The adjusted RRs and corresponding 95% CIs from the SOT analysis based on the FDA-reported difference in TTR for IS, SE, ICH, AMI, and major bleeds were entered into the cost-effectiveness model in the base case, as shown in Table 2. The ITC results for dabigatran 150 mg BID vs. rivaroxaban and dabigatran 110 mg BID that were used in sensitivity analyses are presented in the Suppl. Material (available online at sis-online.com). Model analyses Prior to performing the economic analyses, a validation on simulated outcomes was performed. In this test, clinical outcomes after two years with rivaroxaban or warfarin treatment generated from the model were compared to those reported for the ROCKET-AF trial. In particular, the model was used to simulate SOT results by excluding treatment discontinuation, and then to simulate ITT results by including treatment discontinuation. After this validation, the base case analyses then compared dabigatran and rivaroxaban to one another. A range of model parameters were tested in oneway deterministic sensitivity analyses. In addition, sensitivity analyses were performed considering patients treated with only dabigatran 150 mg BID or dabigatran 110 mg BID (regardless of age), or patients with a CHADS 2 score of 2 or higher. As secondary analysis that compared the new agents with warfarin was conducted. Finally, probabilistic sensitivity analysis (PSA) was undertaken varying all clinical, cost, and utility parameters in the model simultaneously considered dabigatran, rivaroxaban and warfarin in order to determine which drugs form the cost-effectiveness acceptability curve. Model results Validation Simulation of rivaroxaban vs. warfarin for a two-year time horizon closely reproduced the clinical event rates reported for the SOT population of the ROCKET AF study when discontinuation was excluded from the model (i.e. the model simulated only patients that remained on treatment). In particular, IS, ICH, AMI, and ECH event rates in the model were within 2% of the reported rates from ROCKET AF SOT population for both rivaroxaban and warfarin. Inclusion of discontinuation in the model closely reproduced the ITT rate of the primary endpoint for both rivaroxaban (1.72 vs events per 100 patient years for the model vs. the trial) and warfarin (1.86 vs events per 100 patient years), with deviations for both arms in the same direction and at comparable size. Base case In the base case, patients receiving dabigatran experienced fewer IS (3.40 dabigatran vs rivaroxaban), ICH (0.33 dabigatran vs. Schattauer 2012 Thrombosis and Haemostasis 108.4/2012

5 676 Kansal et al. Dabigatran vs. rivaroxaban in stroke prevention Table 2: treatment results: dabigatran vs. rivaroxaban. Outcome Relative Risk (95% CI) Odds Ratio (10% change in TTR) 5 RE-LY (DBG vs. Warfarin) 1,2 ROCKET AF (RIV vs. Warfarin) 1,3,4 Unadjusted ITC (DBG vs. RIV) Relative Risk (95% CI) FDA-TTR1 6 adjusted ITC (DBG vs.riv) TTR2 6 adjusted ITC (DBG vs.riv) Safety-on-treatment analyses All stroke 0.57 (0.44, 0.75) 0.85 (0.70, 1.03) 0.67 (0.48, 0.93) (0.45, 0.87) 0.61 (0.44, 0.85) Ischaemic stroke (0.53, 0.97) 0.94 (0.75, 1.17) 0.77 (0.53, 1.11) (0.49, 1.04) 0.70 (0.48, 1.02) Haemorrhagic stroke 0.16 (0.07, 0.37) 0.59 (0.37, 0.93) 0.27 (0.10, 0.70) (0.09, 0.63) 0.23 (0.09, 0.62) Systemic embolism 0.55 (0.25, 1.24) 0.23 (0.09, 0.61) 2.39 (0.69, 8.33) (0.56, 7.20) 1.91 (0.53, 6.85) All-cause mortality 0.80 (0.67, 0.95) 0.85 (0.70, 1.02) 0.94 (0.73, 1.22) (0.58, 0.98) 0.70 (0.54, 0.91) Intracranial haemorrhage (0.17, 0.45) 0.67 (0.47, 0.93) 0.42 (0.23, 0.76) (0.21, 0.67) 0.37 (0.20, 0.66) Acute myocardial infarction 1.33 (0.96, 1.85) 0.81 (0.63, 1.06) 1.64 (1.08, 2.50) (1.01, 2.34) 1.51 (0.99, 2.30) Vascular mortality 0.75 (0.61, 0.93) 0.89 (0.73, 1.10) 0.84 (0.63, 1.13) nd n/a n/a All stroke or systemic embolism 0.58 (0.45, 0.75) 0.79 (0.65, 0.95) 0.73 (0.53, 1.01) (0.49, 0.93) 0.66 (0.48, 0.90) Major bleeds 0.90 (0.78, 1.05) 1.04 (0.90, 1.20) 0.87 (0.70, 1.06) (0.65, 0.97) 0.77 (0.63, 0.94) Intent-to-treat analyses Ischaemic stroke (0.61, 1.01) 0.99 (0.82, 1.20) 0.79 (0.57, 1.08) (0.56, 1.07) 0.76 (0.55, 1.06) Haemorrhagic stroke 0.22 (0.11, 0.44) 0.58 (0.38, 0.89) 0.38 (0.17, 0.86) (0.15, 0.81) 0.35 (0.15, 0.79) Systemic embolism 0.62 (0.31, 1.23) 0.74 (0.42, 1.32) 0.84 (0.34, 2.05) (0.28, 1.85) 0.66 (0.26, 1.69) All-cause mortality 0.87 (0.77, 0.99) 0.92 (0.82, 1.03) 0.95 (0.80, 1.12) (0.67, 0.94) 0.74 (0.63, 0.88) Acute myocardial infarction 1.28 (0.95, 1.74) 0.91 (0.72, 1.16) 1.41 (0.96, 2.07) (0.93, 2.04) 1.36 (0.92, 2.01) Vascular mortality 0.81 (0.69, 0.96) 0.94 (0.81, 1.08) 0.86 (0.69, 1.07) nd n/a n/a All stroke or systemic embolism 0.65 (0.52, 0.81) 0.88 (0.74, 1.03) 0.74 (0.56, 0.97) (0.54, 0.92) 0.69 (0.52, 0.90) nd = not done; n/a = not applicable; DBG = dabigatran; RIV = rivaroxaban, TTR = Time in therapeutic range; IS = ischaemic stroke; HS = haemorrhagic stroke; SE = systemic embolism; ICH = intracranial haemorrhage; AMI =acute myocardial infarction. 1 Relative risks estimated using Cox proportional hazards ratios. 2 RE-LY results are data on file with Boehringer Ingelheim for the combined dabigatran arms to reflect the Canadian label (i.e. 150 mg BID below the age of 80 and 110 mg BID at age 80 or above). 3 ROCKET AF results for the SOT population (all endpoints) and ITT (all cause mortality and all stroke and SE) were obtained from the ROCKET AF trial publication (11). The remaining ITT results were obtained from ROCKET AF presentation at the 2010 AHA conference (40). 4 ROCKET AF SOT results exclude data from one non-gcp compliant site, except for the safety endpoints, ICH and major bleeds which included their data (11). 5 The TTR odds ratio for IS was calculated on IS including unclassified strokes rather than the data we present here (excluding uncertain). A significant linear relationship between TTR and the following endpoints was established: all stroke or SE, SE, ICH, and major bleeds. A linear relationship (though not significant) between TTR and endpoint was established for: all stroke, IS, HS, and acute myocardial infarction. A significant linear relationship (with 75% truncation on the data) between TTR and endpoint was established for: all cause mortality. Warfarin population of RE-LY (Boehringer Ingelheim, data on file). 6 TTR1 and TTR2 present ITC results adjusted for a 6.7%, and 9.2%, difference in TTR, respectively. The source numbers and derivations in these calculations are available from the authors upon request. 7 IS excludes unclassified strokes to correspond to definitions in ROCKET AF (11). 8 ICH includes HS rivaroxaban), and ECH (2.99 dabigatran vs rivaroxaban) per 100 patients-years. Patients receiving dabigatran experienced more AMI (2.13 dabigatran vs rivaroxaban) and SE events (0.30 dabigatran vs rivaroxaban). Overall, patients receiving dabigatran had more life-years (8.85 vs. 8.68) and quality-adjusted life years (6.167 vs ). Total costs for dabigatran were lower than those for rivaroxaban ($59,613/patient vs. $59,766/patient). Use of dabigatran resulted in lower per patient costs than rivaroxaban for management of acute clinical events ($7,198 vs. $8,029) and lower long-term follow-up costs ($45,116 vs. $45,609). These lower management costs more than offset the difference in drug costs ($7,299 vs. $6,128). In the base case, dabigatran dominated rivaroxaban yielding more QALYs at lower total cost. Assuming a $30,000/QALY WTP threshold, QALY gained on dabigatran of and an incremental cost of approximately -$153 of dabigatran vs. rivaroxaban, the NMB of dabigatran was $4,717 per patient; that is, dabigatran is preferred to rivaroxaban. Secondary analysis vs. warfarin Patients receiving dabigatran had more incremental life-years compared to warfarin (0.233 dabigatran vs rivaroxaban) and incremental quality-adjusted life years (0.229 dabigatran vs rivaroxaban). Incremental costs for dabigatran were lower than that for rivaroxaban if each was compared to warfarin ($1,579/patient dabigatran vs. $1,732 per patient rivaroxaban). Thrombosis and Haemostasis 108.4/2012 Schattauer 2012

6 Kansal et al. Dabigatran vs. rivaroxaban in stroke prevention 677 Dabigatran vs. warfarin led to an ICER of $6,889, whereas rivaroxaban vs. warfarin led to an ICER of $22,475. Assuming a $30,000/QALY WTP threshold, the NMB of dabigatran was $5,297 per patient; whereas the NMB of rivaroxaban was $580 per patient. Probabilistic sensitivity analyses These cost-effectiveness results were consistent when exploring the uncertainty in the clinical parameters in the PSA of a three-way of dabigatran, rivaroxaban, and warfarin. The likelihood of rivaroxaban being the most cost-effective option was below 13% regardless of WTP and below 1% for WTP thresholds greater than $10,000/QALY. For WTP thresholds greater than $8,000/QALY, dabigatran had the greatest probability of being the most cost-effective option, with a 93% probability of being most cost-effective at a $20,000/QALY WTP threshold, and a 98% probability at a $30,000 WTP threshold ( Fig. 1) For lower WTP thresholds (<$8,000/ QALY), warfarin was likely to be the most cost-effective option. Sensitivity analyses Table 3 presents the impacts of varying model input parameters on the base case findings. The most significant driver of cost-effectiveness was the relative risk of IS, with NMB ranging from $1915 to $8648 when varied from the lower to upper 95% confidence limits with a higher NMB indicating greater cost-effectiveness for dabigatran vs. rivaroxaban. Similarly, variation from the upper limit to the lower limit of the CI around the relative risk of ICH yielded a range of NMB from $2,583 to $8,381. The results were only minimally sensitive to the baseline risk of IS or ICH. The model NMB results did not noticeably change for analysis around ECH, including varying the RR of ECH and baseline rate of ECH, increasing the assumptions on the cost of bleed, or changing assumptions on post-ech discontinuation. The NMB also only minimally changed by increasing substantially the utility and cost impacts of AMI. Finally, the NMB changed minimally when restricting to patients with CHADS 2 scores of 2 or higher. The NMB was sensitive to discounting of health outcomes, with no discounting of health outcomes resulting in a NMB of $8,382, but not to discounting of costs, with no cost discounting resulting in a NMB of $4,607. The NMB accrues relatively steadily over time, with a NMB of $834 after a five-year time horizon and $2,327 after a 10-year horizon. Considering a 50% price discount on rivaroxaban and no price discount on dabigatran decreased the NMB to $1,656. A younger cohort starting age of 65 years of age rather than the base case 73 years of age, yielded a higher NMB benefit (NMB $6,116). This NMB decreased for an older cohort (starting age 78 NMB $3,596). Without a TTR adjustment to the clinical estimates, the NMB decreased to $3,759. However, considering a TTR adjustment based on the RELY ROCKET AF published TTR difference, rather than the FDA reported difference, yielded a NMB of $5,051. The of the single dose dabigatran 150 mg BID vs. rivaroxaban yielded an NMB of $4,557 which is very close to that of the integrated dabigatran dose cohort used in the base case. The NMB of dabigatran 110 mg BID was $512. In all sensitivity analyses performed, dabigatran had a positive NMB at a WTP of $30,000 per QALY, thus remaining the preferred treatment option. Discussion Using ITC estimates, it was possible to use the previously developed model of anticoagulation treatment in AF patients with relatively Figure 1: Cost-effectiveness acceptability curves. Schattauer 2012 Thrombosis and Haemostasis 108.4/2012

7 678 Kansal et al. Dabigatran vs. rivaroxaban in stroke prevention Table 3: Sensitivity analysis results cost-effectiveness. Parameter Baseline value Alternate value NMB of dabigatran vs. rivaroxaban 1 Base case 4,717 98% CHADS2 distribution ROCKET CHADS2 CHADS2 = 2 5, % distribution CHADS2 = 5 3,725 95% Baseline IS rate per 100 patient years CHADS2 =2, 0.59 CHADS2 = 3, 0.82 CHADS2 = 4 5, 1.30 CHADS2 = 6, 1.77 CHADS2 =2, 0.48 CHADS2 = 3, 0.66 CHADS2 = 4 5, 1.04 CHADS2 = 6, 1.42 CHADS2 =2, 0.71 CHADS2 = 3, 0.98 CHADS2 = 4 5, 1.55 CHADS2 = 6, , % 4,286 99% Patients with CHADS 2 score of 2 2 4, % Baseline ECH rate per , % 100 patient years , % Baseline ICH rate per 100 patient years ,279 4, % 99% RR of IS , % (rivaroxaban vs. dabigatran) ,648 99% RR of ICH ,583 99% (rivaroxaban vs. dabigatran) ,381 99% RR of ECH , % (rivaroxaban vs. dabigatran) , % Post ECH 10% 0% 4, % discontinuation 50% 4, % Discontinuation rate of dabigatran 23% 19% 5, % by end of 2 year period 28% 3,881 99% Disutility for dabigatran , % Disutility of AMI , % Disutility and cost of AMI disutility cost $7,351 7,535 Dabigatran dosing in patients with CHADS2 score of 2 2 disutility cost $22,054 22,605 3,789 99% Rivaroxaban price discount 0% 50% 1,656 93% Cost of GI bleed $ $ , % Cost of renal function test 0 $7.75 per year 4, % for dabigatran Starting age , % 78 3, % Health discount rate 5% 0% 8, % Cost discount rate 5% 0% 4,607 94% Time horizon life time 5 years % 10 years 2,327 96% TTR adjustment FDA TTR adjustment no TTR adjustment 3, % TTR2 adjustment 5,051 99% Dabigatran dosing 3 Combined dabigatran dabigatran 150 mg bid 4, % dabigatran 110 mg bid % dabigatran 150 mg bid 3, % dabigatran 110 mg bid % Probability of dabigatran being most cost-effective at WTP threshold $30,000 4 AMI: acute myocardial infarction, GI: gastrointestinal, ECH: extracranial haemorrhage, ICH: intracranial haemorrhage, IS: ischemic stroke, NMB: net monetary benefit, TTR: time in therapeutic range, WTP: willingness to pay; 1 A NMB > $0 indicates dabigatran is economically favourable vs. rivaroxaban; a higher NMB indicates greater economic benefit. 2 ITC analysis of the RE-LY patients with CHADS 2 scores of 2 or higher, not adjusted for warfarin TTR. 3 ITC results that were used in dabi - gatran single dose scenarios are presented in table A1 and table A2 and described in the respective text (see Suppl. material online at com). 4 Probability of dabigatran being most cost-effective at a WTP threshold of $30,000/QALY is subject to small fluctuations (1 2%) due to random sampling. Thrombosis and Haemostasis 108.4/2012 Schattauer 2012

8 Kansal et al. Dabigatran vs. rivaroxaban in stroke prevention 679 small modifications to evaluate the cost-effectiveness of dabigatran, rivaroxaban, and warfarin. This evaluation found that dabigatran was economically dominant (i.e. more effective and less costly) vs. rivaroxaban. As in previous analyses vs. warfarin (12), the cost-effectiveness is driven both by the prevention of IS and avoidance of ICH. Dabigatran was found to have lower risk of both IS and ICH than rivaroxaban in the ITC, and these advantages form the basis of the economic dominance of dabigatran vs. rivaroxaban. That both IS and ICH events are, roughly, equally important was evidenced by the comparable ranges of NMB achieved when setting the RR for each of these events to the limits of its 95% CIs in the sensitivity analysis. Other clinical endpoints had a much smaller overall impact on the difference between dabigatran and rivaroxaban as they are less frequent and/or have fewer long-term consequences, especially AMI. The relative benefits of dabigatran accrue steadily over time, as stroke and ICH substantially affect patients quality of life and follow-up care costs over their remaining lifetime. It is important to note that, while this analysis was conducted primarily to understand the economic differences between riva - roxaban and dabigatran, the difference it found between dabigatran and rivaroxaban is primarily a clinical one. The incremental cost savings with dabigatran ($153/patient) is small compared to the NMB ($4,717/patient), which shows that the cost differences are small compared to the total clinical benefit difference. In fact, even assuming a price of rivaroxaban discounted by 50% resulted in a favourable NMB ($1,656/patient) for dabigatran. The indirect between dabigatran and rivaroxaban enabled us to compare these two important additions to the treatment options for stroke prevention in AF. ITC methods are fairly simplistic and cannot easily adjust for differences between patient populations. Clearly a major difference between RE-LY and ROCKET AF was the time spent in target INR range for the warfarin arms. The ROCKET AF warfarin treatment arm spent 6.7% more time out of the target INR range than patients in the warfarin arm of RE-LY, which may have resulted in a more favourable risk for rivaroxaban compared to warfarin. It is difficult to estimate just how much impact this difference would make in reality, however. We have therefore presented unadjusted ITC results alongside ad- Table 4: treatment estimates for dabigatran vs. rivaroxaban published to date, for selected endpoints. Stroke/systemic embolism (primary endpoint) Dabigatran 150 mg bid vs. Rivaroxaban Kansal et al (0.56, 0.97) 1 CADTH 0.74 ( ) 1 Lip et al ( ) 1 Mantha 0.74 and Ansell ( ) 1 Testa et al ( ) 6 Dabigatran 110 mg bid vs. Rivaroxaban Kansal et al (0.79, 1.32) 1 CADTH 1.03 ( ) 1 Lip et al ( ) 1 Mantha 1.03 and Ansell ( ) 1 Testa et al ( ) 6 All-cause mortality 0.96 (0.80, 1.14) ( ) ( ) ( ) ( ) (0.83, 1.17) ( ) ( ) ( ) ( ) 4 AMI Major ICH Reported bleeding type of estimate 1.40 (0.95, 2.05) ( ) ( ) ( ) ( ) (0.97, 2.08) ( ) ( ) ( ) ( ) (0.75, 1.13) ( ) ( ) ( ) ( ) 4, (0.63, 0.96) ( ) ( ) ( ) ( ) 4, (0.27, 0.84) ( ) ( ) 4, ( ) 4 Hazard ratio Odds ratio Hazard ratio Odds ratio Type of Bayesian MTC (fixed effects) NA Odds ratio 0.36 (0.20, 0.65) ( ) ( ) 4, ( ) 4 Hazard ratio Odds ratio Hazard ratio Odds ratio Bayesian MTC (fixed effects) NA Odds ratio Ref. Table A Table A2 3 1 Intention to treat populations for both, dabigatran and rivaroxaban. 2 Safety on treatment populations for both, dabigatran and rivaroxaban. 3 Supplementary online material available at 4 Intention to treat population for dabigatran; safety on treatment population for rivaroxaban. 5 Did not use the updated RE-LY data from [6], but only the results as reported in [5]. 6 From the event numbers reported in the publication for RE-LY, it appears that the authors re-defined the primary endpoint and subtracted haemorrhagic stroke from the composite endpoint. However, the published event rates for rivaroxaban could not be derived applying this method. 7 Reported as extracranial major bleeding, excluding intracranial haemorrhage. MTC: mixed treatment, NA: not available, AMI: acute myocardial infarction, ICH: intracranial haemorrhage Schattauer 2012 Thrombosis and Haemostasis 108.4/2012

9 680 Kansal et al. Dabigatran vs. rivaroxaban in stroke prevention justed ITC results to present a range of possible differences between dabigatran and rivaroxaban and used those in sensitivity analyses for the cost-effectiveness analysis. The NMB of dabigatran based on the unadjusted ITC was $3,759 vs. an NMB of $4,717 using ITC adjusted from the FDA analysis. There are a number of differences between the ROCKET AF and RE-LY trials including the enrolled population, the degree of INR control achieved in the warfarin arm and study designs, and the ITC cannot fully adjust for all possible confounding effects. We acknowledge these limitations of our methods of adjustment, and of ITC in general, but feel these analyses present important investigations into the sensitivity of the treatment s. This also enabled us to compare like with like, in this context, ITT and SOT analysis endpoints, especially as many different analyses have been reported for rivaroxaban. Despite a different methodological approach, the ITC results of dabigatran vs. rivaroxaban in this study are largely consistent with the conclusions drawn by the network meta-analyses performed by CADTH in their evaluation of anticoagulation (29) and by the analyses of other researchers (30 32) ( Table 4), if the same analysis populations were used (i.e. ITT for both, dabigatran and rivaroxaban); they were different if mixed analysis populations (i.e. ITT for dabigatran and SOT for rivaroxaban) were used, or when endpoints have been redefined (32). Only in the indirect presented here was it possible to compare findings either in the ITT or SOT populations, whereas the other researchers had to rely on published estimates, which created for example for bleeding events this mixture of analysis populations. We furthermore were able to create an analysis population reflecting the Canadian label and to mirror the way the ROCKET AF trial was analysed, where patients with a reduced rivaroxaban dose were contributing to the overall study findings. This study has a number of other strengths. The model used for this evaluation has undergone extensive computational and clinical validation. The model was able to closely reproduce the reported ITT rates of the primary endpoint in the ROCKET AF study for both rivaroxaban and warfarin. Furthermore, this model has undergone peer-review through the publication process (12, 33) and through the assessments by a number of health authorities as part of reimbursement decisions for dabigatran (e.g. CADTH, NICE) (8, 34). An additional strength of this is that it relies on a model with a design specified before the results of either trial were available (13). Furthermore, this analysis included an analysis pooling all patients in RE-LY who were treated according to the approved Canadian label, thus, facilitating a cost-effectiveness analysis integrating both doses of dabigatran and comparing it with the labelled dose for rivaroxaban. Other strengths are the inclusion of SOT results from both the RE-LY and ROCKET AF trials. Comparing the same analysis population in both studies removes a key element of discrepancy between the results reported. In addition, the use of the SOT populations for the clinical outcomes while on treatment is an improvement over the previous, conservative approach of using the ITT population, which doublecounted the effects of treatment discontinuation in the economic model, as discontinuation was applied as model event on top of clinical results reported from RE-LY on the ITT population (12). The results of this evaluation are consistent with those of CADTH in their evaluation of anticoagulation in the Canadian market (29). That evaluation similarly found that dabigatran dominates rivaroxaban and is preferred to warfarin, as well as apixaban, at common WTP thresholds. The CADTH evaluation, however, compared dabigatran outcomes based on the ITT population in RE-LY and rivaroxaban outcomes based on the ITT and SOT population in ROCKET AF, whereas the evaluation presented here uses consistently the SOT populations from both trials. As such, the outcomes from this evaluation and the CADTH evaluation cannot be quantitatively compared, though both evaluations reach similar qualitative conclusions. Along with addition of rivaroxaban as a comparator, this evaluation includes SOT data for dabigatran, a patient population at higher risk of stroke due to the adaptation to the ROCKET AF trial characteristics for the sake of comparability, and an updated estimate of treatment discontinuation relative to the prior evaluation of the cost-effectiveness of dabigatran vs. warfarin in Canada (12). Several prior evaluations have found the cost-effectiveness of dabigatran treatment is influenced by the patient population (35 38), with dabigatran being more cost-effective as the risk of IS or ICH increases (36 38). This has several limitations. The most important is the lack of direct head-to-head data comparing dabigatran and rivaroxaban. The ITC adjusts for differences between trials, but cannot replace head-to-head data. When selecting an anticoagulant in clinical practice, also considerations beyond those reflected in any ITC are relevant, such as the patient s concomitant medications and comorbidities as well as previous anticoagulation. Examples can be found in Pengo et al. (39). In addition, for the cost-effectiveness analysis, not all clinical parameters (notably discontinuation rates) could be adjusted for differences in population and design between RE-LY and ROCKET AF to allow a like with like. Where this was the case, ROCKET AF data were used if available (as it was decided that the modelled population should reflect this trial population), with RE-LY data used elsewhere. These parameters were also tested in sensitivity analysis to ensure their uncertainty did not substantially alter the findings (most notably the discontinuation rate). However, for none of those parameters did the conclusions change qualitatively. Increasing the negative impact of AMI by increasing the utility impact and costs, given that rivaroxaban shows statistically significant benefit vs. dabigatran for the AMI endpoint (SOT population only), did not alter the conclusions (NMB decreased by less than $1000). Conclusions Overall, this study found that dabigatran appears to offer clinical advantages vs. rivaroxaban when compared within the same population and analysis set. Analysing these differences in an economic model found dabigatran to be economically dominant compared to rivaroxaban in the Canadian setting, yielding more total QALYs at a lower total cost. That finding was robust in one way and probabilistic sensitivity analyses. Major determinants of this finding Thrombosis and Haemostasis 108.4/2012 Schattauer 2012

10 Kansal et al. Dabigatran vs. rivaroxaban in stroke prevention 681 What is known about this topic? Dabigatran has been found to be cost-effective relative to warfarin for stroke prevention in patients with atrial fibrillation. Rivaroxaban has become available and the relative effectiveness of those two new oral anticoagulants needs to be understood. What does this paper add? This study reports safety-on-treatment results from the RE-LY trial to facilitate to rivaroxaban. This study also estimates the relative clinical efficacy and safety of dabigatran and rivaroxaban based on a formal indirect treatment using standard methodology, common populations and analysis sets. We report a cost-effectiveness analysis that shows that dabigatran is both, more effective and less costly than rivaroxaban in this indication and that those results were very robust over a wide range of sensitivity analyses. were the better stroke prevention and lower intracranial bleeding rates observed with dabigatran. Acknowledgements The authors would like to thank Herbert Noack (statistician at Boehringer Ingelheim) for providing analyses of the RE-LY trial data used as inputs to the ITC and model, most notably the SOT analyses, the calculation of the TTR adjustment factors from the warfarin arm of RE-LY and all analyses for re-defined endpoints to match the ROCKET AF definitions. Conflicts of interest The project was funded by Boehringer Ingelheim International GmbH. Anuraag Kansal, Siyang Peng, Sonja Sorensen and Neil Roskell acted as paid consultants on this project. Carole Bradley- Kennedy, Andreas Clemens, and Brigitta U. 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