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Cost-effectiveness of dabigatran etexilate for the primary prevention of venous thromboembolism in total hip and knee replacement in Portugal

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Cost-effectiveness of dabigatran etexilate for the primary prevention of venous thromboembolism in total hip and knee replacement in Portugal
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  New Technologies, Diagnostic Tools and Drugs Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: A Canadian payer perspective Sonja V. Sorensen 1 ;   Anuraag R. Kansal 1 ; Stuart Connolly 2 ; Siyang Peng 1 ; John Linnehan 1 ; Carole Bradley-Kennedy 3 ; Jonathan M. Plumb 4   1 United BioSource Corporation, Bethesda, Maryland, USA; 2 Population Health Research Institute, Hamilton, Ontario, Canada; 3 Boehringer Ingelheim (Canada) Ltd., Burlington, Ontario, Canada; 4 Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany Summary Oral dabigatran etexilate is indicated for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF) in whom anti-coagulation is appropriate. Based on the RE-LY study we investigated the cost-effectiveness of Health Canada approved dabigatran etexilate dosing (150 mg bid for patients <80 years, 110 mg bid for patients ≥ 80 years) versus warfarin and “real-world” prescribing (i.e. warfarin, as-pirin, or no treatment in a cohort of warfarin-eligible patients) from a Canadian payer perspective. A Markov model simulated AF patients at moderate to high risk of stroke while tracking clinical events [primary and recurrent ischaemic strokes, systemic embolism, transient is-chaemic attack, haemorrhage (intracranial, extracranial, and minor), acute myocardial infarction and death] and resulting functional disabil-ity. Acute event costs and resulting long-term follow-up costs incurred by disabled stroke survivors were based on a Canadian prospective study, published literature, and national statistics. Clinical events, sum- Correspondence to: Sonja V. Sorensen 7101 Wisconsin Avenue, Suite 600 Bethesda, MD 20814, USA Tel.: +1 301 654 9729, Fax: +1 301 654 9864 E-mail: sonja.sorensen@unitedbiosource.com marized as events per 100 patient-years, quality-adjusted life years (QALYs), total costs, and incremental cost effectiveness ratios (ICER) were calculated. Over a lifetime, dabigatran etexilate treated patients experienced fewer intracranial haemorrhages (0.49 dabigatran etex-ilate vs. 1.13 warfarin vs. 1.05 “real-world” prescribing) and fewer is-chaemic strokes (4.40 dabigatran etexilate vs. 4.66 warfarin vs. 5.16 “real-world” prescribing) per 100 patient-years. The ICER of dabigatran etexilate was $10,440/QALY versus warfarin and $3,962/QALY versus “real-world” prescribing. This study demonstrates that dabigatran et-exilate is a highly cost-effective alternative to current care for the pre-vention of stroke and systemic embolism among Canadian AF patients. Keywords Anticoagulation, dabigatran etexilate, warfarin, stroke, cost-effective-ness, atrial fibrillation Financial support: The project was funded by Boehringer Ingelheim Canada Ltd (BI). Received: February 9, 2011 Accepted after minor revision: March 14, 2011 Prepublished online: March 22, 2011 doi:10.1160/TH11-02-0089 Thromb Haemost 2011; 105: 908–919 Introduction Atrial fibrillation (AF) is a leading cause of stroke (1). Stroke in AF patients is associated with higher mortality and costlier hospital stays than stroke in patients without AF (2–4). Additionally, AF is associated with an increased risk of systemic embolism (SE) which may result in major damage to limbs and organs (e.g. embolism to the renal artery) (5). Clinical guidelines in Canada and elsewhere have traditionally recommended that patients with moderate to high risk of stroke receive long-term anticoagulation with vitamin K antagonists, such as warfarin with an international normalised ratio (INR) tar-get of 2.0 to 3.0 (6–8). In clinical practice, however, warfarin has significant drawbacks. Its variable pharmacokinetic profile leads to wide inter- and intra-patient response variability. Due to this and multiple drug-drug and drug-food interactions, warfarin-treated patients require regular INR monitoring and dose adjustments. The safety and effectiveness of warfarin is dependent on maintain-ing patients within therapeutic INR range (9, 10); patients are at increased risk of ischaemic stroke (IS) when INR values are below the therapeutic INR range, and at risk of major bleed events (e.g. intracranial haemorrhage [ICH]) when INR values rise above therapeutic range. Although randomised controlled trials have demonstrated that warfarin is effective at preventing strokes in pa-tients with AF (11), the percentage of time spent in therapeutic INR range seen in clinical trials has not been achieved in commu-nity practice outside of specialised anticoagulation clinics (12, 13), likely due to a lack of protocol-driven management. This might partially explain the reduced performance that has been observed with warfarin in the naturalistic primary care setting (14). Exacer-bating this issue is the observation that many warfarin-eligible pa-tients with AF in Canada receive only aspirin or no anticoagulation Thrombosis and Haemostasis 105.5/2011 908 © Schattauer 2011  © Schattauer 2011 Thrombosis and Haemostasis 105.5/2011 909 Sorensen et al. Cost-effectiveness of dabigatran etexilate for stroke prevention therapy of any type due to physicians’ concerns of the risks of being outside therapeutic INR range (15, 16). A need therefore exists for a safer and more efficacious stroke prevention therapy that presents less monitoring burden on pa-tient and physician. Dabigatran etexilate – an oral direct thrombin inhibitor recently approved in Canada for stroke prevention in AF (17) – has predictable and stable pharmacokinetics and a wide therapeutic margin without the need for the continuous INR monitoring and frequent dose adjustments required by warfarin (18). Indeed, the new Canadian Cardiovascular Society (CCS) clinical guidelines indicate dabigatran etexilate or warfarin for pa-tients with AF, with some preference given to dabigatran due to its increased efficacy (8). In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, the efficacy and safety of two doses of dabigatran etexilate (150 mg bid and 110 mg bid) were compared with adjusted-dose warfarin for stroke pre-vention in AF patients (n=18,113) (19, 20). Results of the RE-LY trial show that the primary outcome, the time to first stroke or SE, was significantly better with dabigatran etexilate 150 mg bid than warfarin (1.11% vs. 1.71% per year; relative risk [RR] 0.65; 95% confidence interval [CI] 0.52–0.81) with a mean therapeutic time in range of 64.4% (median 67%). Dabigatran etexilate 110 mg bid was non-inferior for stroke/SE prevention. Dabigatran etexilate 150 mg bid had similar rates of major bleeds; there were fewer major bleeds with the dabigatran etexilate 110 mg bid dose. Sec-ondary outcomes, particularly ICH and haemorrhagic stroke (HS), were significantly less likely with both doses of dabigatran et-exilate compared with warfarin (19, 20). Although both doses of dabigatran etexilate have been approved, Health Canada recom-mends the 150 mg bid dose for patients under the age of 80 and the 110 mg bid dose for patients aged 80 and older (17). To assess the cost-effectiveness of dabigatran etexilate, a model was developed to quantify comparisons with current care for stroke prevention in AF in Canada. In accordance with Health Ca-nada approved dosing, the model evaluated dabigatran etexilate in a sequential dosing approach, with patients under 80 years of age receiving 150 mg bid and patients 80 years and over receiving 110 mg bid. In the base case, this sequential dosing was compared to warfarin under “trial-like” INR control (i.e. patients spent the same proportion of time within, above, and below therapeutic INR range as measured in the RE-LY trial), as well as to a “real-world” prescribing scenario that accounts for stroke prophylaxis in warfa-rin-eligible Canadian patients with AF as observed in actual clini-cal practice (15, 16), meaning patients could be receiving prophy-laxis with warfarin, aspirin, or no treatment at all. Methods Model design Patients with AF were followed in three-month cycles for their re-maining lifetime using a Markov model approach. Treatment pat-terns and costs were reflective of a Canadian provincial health care system (Ministry of Health). The primary source of model input data was the RE-LY trial; in situations where the data from RE-LY were insufficient, alternative sources of evidence were used. Patient population The patient population in the model matched that of the RE-LY trial (19, 20). Patients were either diagnosed with AF plus at least one additional risk factor for stroke or embolism (as defined by the CHADS 2  score risk stratification scheme) or were diagnosed with AF plus impaired left ventricular ejection fraction; all patients had to be eligible for anticoagulation treatment. Patients could be anti-coagulation treatment-naïve or experienced, but were assumed not to be on any concomitant anticoagulation medication. For the purpose of the economic analysis and to match the approved label in Canada, the RE-LY population was stratified into those <80  years of age and those ≥ 80 years of age. Patients had CHADS 2  scores ranging from 0 to 6. The mean CHADS 2  score in the model patient population was 2.1, with roughly two-thirds of patients having a CHADS 2  score of 2 or higher. At baseline, approximately 20% of patients had a history of previous stroke or transient ischaemic attack (TIA). The mean age of the patient cohort entering the base case model (i.e. the cohort below age 80) was 69 and 65% were men. Model structure The conceptual framework of the model has been published pre-viously (21). The clinical events considered included primary and recurrent IS, TIA, SE, acute myocardial infarction (AMI), ICH ex-cluding HS, HS, major extracranial haemorrhage (ECH), minor bleeding, and death. Each of these events was defined in accord-ance with the clinical definitions from the RE-LY trial (19, 20). In particular, ECH was defined as all extracranial bleeding resulting in a reduction in the haemoglobin level of at least 20 g per litre, transfusion of at least two units of blood, or symptomatic bleeding in a critical area or organ with any other extracranial bleeding de-fined as a “minor bleed”. ICH consisted of subdural or subarach-noid haemorrhage. The key consequences of the clinical events were disability as defined by modified Rankin Score (strokes) or Glasgow Outcomes Scale (ICH), mortality, reductions in quality of life, changes in the underlying risk of future events, and changing treatment status (i.e. switching treatment as well as temporary or permanent treatment discontinuation). A simplified model dia-gram is presented in  Figure 1. During any model cycle, patients could experience a clinical event (which could be fatal in all cases except for TIA and minor bleeds), death from other causes, or remain unchanged in their current health state. A three-month cycle length was used because it was unlikely that patients experienced more than one major event during any three-month period. In addition, this timeframe  Thrombosis and Haemostasis 105.5/2011 © Schattauer 2011 910 Sorensen et al. Cost-effectiveness of dabigatran etexilate for stroke prevention reflected the typical duration of temporary drug discontinuation due to ECH. Model scenarios In the base case, dabigatran etexilate with sequential dosing was compared with “trial-like” warfarin and “real-world” prescribing (i.e. warfarin, aspirin, or no treatment in a cohort of warfarin-eli-gible patients). “Trial-like” warfarin reflected warfarin control (as measured by INR) as observed in the RE-LY trial. In the RE-LY study, the mean percentage of patient time spent within the target INR range of 2.0–3.0 was 64% (19, 20). It was similar for patients <80 and ≥ 80 years of age (65% and 64%, respectively). Patients <80 years spent 22% of their time below 2.0 and 13% of their time above 3.0, while these values were 22% and 14%, respectively, among patients ≥ 80 years. Because the level of patient monitoring and care as well as ad-herence to treatment guidelines in clinical trials is often better than in clinical practice, the model also evaluated the cost-effectiveness of sequential dosing of dabigatran etexilate in a “real-world” pre-scribing scenario. This scenario accounted for the fact that INR control among patients receiving warfarin was not as tight in a “real-world” setting as compared to a clinical trial environment, and that AF patients who are eligible for warfarin often received suboptimal anticoagulation therapy with aspirin or no treatment at all. The proportion of time spent within and outside of thera-peutic INR range in routine clinical practice in Canada was based on the results of a published retrospective study of warfarin-treated AF patients (n=10,020) in Eastern Ontario (22). This study estimated that INR values were within target range 59% of the time, below target 27% of the time, and above target range 14% of the time. To account for aspirin treatment or no treatment among warfarin eligible patients, a weighted average of this “real-world” warfarin control, aspirin, and no treatment was calculated based on a study by Parkash et al. in the Canadian setting, which reported that 83% of warfarin eligible patients were on warfarin, 11% were on aspirin, and 6% received no treatment at all (15). Model assumptions As long as patients remained adherent to treatment (i.e. remained anticoagulated), efficacy was assumed to be constant over time for dabigatran etexilate, warfarin, and aspirin. Patients who discon-tinued treatment due to bleeding were assumed to receive no further clinical benefit because coagulation returns to untreated values after discontinuation of therapy (23). Strokes in AF patients are more severe than in the general population and are often as-sociated with long-term disability (24–26). As a conservative as-sumption, patients could not improve to a better functional status than the one they were in prior to an event like IS, HS, and ICH; but status quo or a worsening of functional status was allowed (e.g. moderate to dependent disability levels, but not vice versa) for Figure 1: Simplified Markov Model diagram.  DL: dis-ability level (as measured by mRS or GOS); IS: is-chaemic stroke; ICH: in-tracranial haemorrhage; HS: haemorrhagic stroke; ECH: extracranial haem-orrhage; SE: systemic embolism; TIA: transient ischaemic attack; AMI: acute myocardial infarc-tion. Patients who experi-ence at least one IS or TIA or SE will be rec-orded as having a pre-vious stroke which may subsequently change their risk of recurrent stroke.  © Schattauer 2011 Thrombosis and Haemostasis 105.5/2011 911 Sorensen et al. Cost-effectiveness of dabigatran etexilate for stroke prevention both first-time and recurring events. Mortality directly resulting from stroke was assumed to be independent of a patient’s history of prior strokes (27). After a non-fatal ECH, 50% of patients were as-sumed to permanently stop treatment. Patients off treatment could still experience ischaemic or haemorrhagic events at the ob-served rate of AF patients without anticoagulation (28, 29). Data inputs Risk of clinical events Annual probabilities of events in the warfarin arm and the relative risks (RR) in the dabigatran etexilate arm as compared to warfarin were obtained from the RE-LY trial. These values were calculated separately for patients <80 years that were receiving dabigatran et-exilate 150 mg bid, and for patients ≥ 80 years that were receiving dabigatran etexilate 110 mg bid (  Table 1). The probabilities of primary and recurrent IS were dependent on stroke history and CHADS 2  score (30). The proportion of the cohort starting at each Table 1: Annual probabilities and relative risk of clinical events for sequential dosing*.   Age<80 Age ≥ 80 Ischaemic stroke Annual risk for warfarin by CHADS 2  score 0 0.62% N/A 1 0.79% 0.42% 2 0.88% 1.54% 3† 1.55% 2.48% 4† 1.55% 2.48% 5† 2.77% 4.72% 6† 2.77% 4.72% RR of vs. warfarin dabigatran etexilate 150 mg bid 0.77 (0.58 – 1.03) dabigatran etexilate 110 mg bid 0.82 (0.51 – 1.33) aspirin‡ 1.62 (0.99 – 2.65) 1.62 (0.99 – 2.65) no treatment§ 3.35 (2.23 – 5.03) 3.35 (2.23 – 5.03) Systemic embolism Annual risk for warfarin 0.15% 0.31% RRs vs. warfarin dabigatran etexilate 150 mg bid 0.66 (0.30 – 1.47) dabigatran etexilate 110 mg bid 0.51 (0.13 – 2.06) aspirin‡ 1.77 (0.66 – 4.77) 1.77 (0.66 – 4.77) no treatment§ 4.44 (1.78 – 11.08) 4.44 (1.78 – 11.08) Haemorrhagic stroke Annual risk for warfarin 0.33% 0.63% RRs vs. warfarin dabigatran etexilate 150 mg bid 0.21 (0.09 – 0.47) dabigatran etexilate 110 mg bid 0.26 (0.07 – 0.91) aspirin‡ 0.84 0.84 no treatment§ 0.33 0.33 Transient ischaemic attack Annual risk for warfarin 0.73% 1.41% RRs vs. warfarin dabigatran etexilate 150 mg bid 0.92 (0.66 – 1.29) dabigatran etexilate 110 mg bid 0.45 (0.23 – 0.89) aspirin‡ 1.56 (0.86 – 2.83) 1.56 (0.86 – 2.83) no treatment§ 1.23 (0.59 – 2.58) 1.23 (0.59 – 2.58) Acute myocardial infarction Annual risk for warfarin 0.59% 0.89% RRs vs. warfarin dabigatran etexilate 150 mg bid 1.26 (0.89 – 1.78) dabigatran etexilate 110 mg bid 1.39 (0.74 – 2.60) aspirin‡ 1.42 (0.84 – 2.39) 1.42 (0.84 – 2.39) no treatment§ 1.57 (0.67 – 3.69) 1.57 (0.67 – 3.69)  Age<80 Age ≥ 80 dabigatran etexilate 110 mg bid 0.91 (0.78 –1.07) aspirin‡ 0.63 ( 0.32 – 1.22) 0.63 ( 0.32 – 1.22) no treatment§ 0.55 (0.38 – 0.80) 0.55 (0.38 – 0.80) * RE-LY database, Boehringer Ingelheim, data on file. † Due to small sample sizes, CHADS 2  scores 3 and 4 and scores 5 and 6 were grouped. Unpublished update of network meta-analyses by Roskell et al. (Thromb Haemost 2010). ‡ Used when patients switched from or discontinued the first line treatment. § Used when patients discontinued all anti-thrombotic therapy. ¶ Minor bleeds: bleeding that is non-fatal and where no blood transfusion was necessary or no substantial decrease in haemoglobin was noted. Intracranial haemorrhage Annual risk for warfarin 0.35% 0.73% RRs vs. warfarin dabigatran etexilate 150 mg bid 0.48 (0.27 – 0.85) dabigatran etexilate 110 mg bid 0.29 (0.10 – 0.88) aspirin‡ 0.51 (0.16 – 1.60) 0.51 (0.16 – 1.60) no treatment§ 0.33 0.33 Extracranial haemorrhage Annual risk for warfarin 2.71% 3.50% RRs vs. warfarin dabigatran etexilate 150 mg bid 0.93 (0.78 – 1.11) dabigatran etexilate 110 mg bid 1.44 (1.05 – 1.97) aspirin‡ 1.14 (0.47 – 2.73) 1.14 (0.47 – 2.73) no treatment§ 0.61 (0.10 – 3.78) 0.61 (0.10 – 3.78) Minor bleeds¶ Annual risk for warfarin 16.06% 17.98% dabigatran etexilate 150 mg bid 0.86 (0.80 – 0.93) RRs vs. warfarin  912 Sorensen et al. Cost-effectiveness of dabigatran etexilate for stroke prevention Thrombosis and Haemostasis 105.5/2011 © Schattauer 2011 CHADS 2  score was based on the distribution within RE-LY and was further stratified by patients with and without a history of stroke. A first-ever stroke resulted in an increment of two points to the patient’s baseline CHADS 2  score, whereas the CHADS 2  score remained unchanged after a recurrent stroke. Similarly, the CHADS 2  score increased by one point when patients passed age 75. The risk of ECH doubled once a patient surpassed 70 years of age (28). Of the patients with an ECH, 46% on dabigatran etexilate 150 mg bid and 33% on warfarin experienced a gastrointestinal (GI) tract bleed among patients <80 years, and 45% on dabigatran etex-ilate 110 mg bid and 41% on warfarin experienced a GI tract bleed among patients ≥ 80 years, and therefore temporarily discontinued anticoagulation for three months. Efficacy and safety data A network meta-analysis of up to 20 trials, depending on the spe-cific outcome measure, was used to estimate the RR of events ver-sus warfarin for patients who receive aspirin or no treatment (31). These RRs were applied irrespective of whether the treatment op-tion was utilised first-line, second-line, or following treatment dis-continuation. As this analysis was not stratified by age (due to lack of data), the RRs were applied in both age groups of the base case model. Age-adjusted, all-cause mortality was obtained from Cana-dian national statistics (32, 33). The proportion of deaths due to IS, SE, AMI, ICH/HS, and ECH were excluded from all-cause mortal-ity rates to avoid double counting. The proportions for the Cana-dian population were assumed to be similar to those in the UK population due to lack of specific data (34). To estimate the outcome differences between warfarin in the base case and in the “real-world” prescribing scenario on the risk of stroke/SE and bleeds, the risks observed in the RE-LY trial were ad- justed based on a study of 116,969 AF patients and their pattern of anticoagulant use and incidences of stroke, ICH, and SE (35). For each type of clinical event, the Walker et al. data was used to calcu-late the RR for below target (i.e. <2.0), within target (i.e. 2.0–3.0), and above target INR (>3.0), separately. These risks were then weighted based on the INR distribution to create RRs for the “real-world” prescribing scenario versus the warfarin arm of the RE-LY trial. Disability following IS and ICH/HS Post-stroke disability was graded using the modified Rankin scale (mRS) (27). Non-fatal stroke disability was stratified as indepen-dent (mRS ≤ 2), moderately dependent (mRS = 3–4), and totally dependent (mRS = 5). The rates of disabling events three months following IS for warfarin- and dabigatran etexilate-treated patients were calculated separately using RE-LY data for all ages as well as the two age subgroups (  Table 2) (RE-LY database, Boehringer Ingelheim, data on file). Aspirin and no treatment RRs versus war-farin for each disability level and fatal stroke were obtained from a Table 2: Rate of disability and mortality following IS, ICH, and HS for sequential dosing.   Independent (events/100 patient-years) Moderate disability (events/100 patient-years) Totally dependent (events/100 patient-years) Fatal events (events/100 patient-years) Ischaemic Stroke Disability* Age <80 (mRS ≤ 2) (mRS = 3 or 4) (mRS = 5) Warfarin† 0.58 0.22 0.04 0.24 Dabigatran etexilate 150 mg bid† 0.48 0.12 0.03 0.19 Aspirin (27)‡ 1.14 0.40 0.16 0.54 No treatment (27)§ 1.48 0.69 0.29 1.16 Ischaemic Stroke Disability* Age ≥ 80 Warfarin† 0.86 0.31 0.20 0.60 Dabigatran etexilate 110 mg bid 0.43 0.51 0.05 0.61 Aspirin (27)‡ 1.32 0.44 0.47 0.91 Dabigatran etexilate 110 mg bid§ 0.01 0.01 0.03 0.05 Aspirin (36)‡ 0.03 0.03 0.08 0.05 No treatment (36)§ 0.02 0.02 0.05 0.03 mRS: modified Rankin Scale; GOS: Glasgow Outcome Scale. * Based on CHADS 2  score distribution in RE-LY. †RE-LY database, Boehringer Ingelheim, data on file. ‡ Used when patients switched from or discontinued the first line treatment. § Used when patients discontinued all antithrombotic therapy. # Assumed distribution of post-event disability for dabigatran etexilate is the same as trial-like warfarin. No treatment (27)§ 2.22 0.98 1.11 2.22 Intracranial Haemorrhage and Haemorrhagic Stroke Disability (GOS = 5) (GOS = 4) (GOS ≤ 3) Warfarin (36) #  0.03 0.03 0.11 0.18 Dabigatran etexilate 150 mg bid§ 0.01 0.02 0.05 0.09
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