Curr Cardiol Rep (2015) 17: 61 DOI 10.1007/s11886-015-0618-4
INVASIVE ELECTROPHYSIOLOGY AND PACING (EK HEIST, SECTION EDITOR)
Cost-Effectiveness of Novel Oral Anticoagulants for Stroke Prevention in Non-Valvular Atrial Fibrillation Sheldon M. Singh 1 & Harindra C. Wijeysundera 1,2,3
Published online: 17 June 2015 # Springer Science+Business Media New York 2015
Abstract Recently, novel oral anticoagulants (NOACs) have been approved for stroke prevention in patients with atrial fibrillation (AF). Although these agents overcome some disadvantages of warfarin, they are associated with increased costs. In this review, we will provide an overview of the cost-effectiveness of NOACs for stroke prevention in AF. Our comments and conclusions are limited to studies directly comparing all available NOACs within the same framework. The available cost-effectiveness analyses suggest that NOACs are cost-effective compared to warfarin, with apixaban likely being most favorable. However, significant limitations in these models are present and should be appreciated when interpreting their results.
Keywords Anticoagulants . Atrial fibrillation . Cost-effectiveness analysis . Bleeding . Stroke
This article is part of the Topical Collection on Invasive Electrophysiology and Pacing * Sheldon M. Singh [email protected] 1
Schulich Heart Centre, Sunnybrook Health Sciences Centre, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
2
Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada
3
Institute for Clinical Evaluative Sciences (ICES), Toronto, ON, Canada
Introduction Atrial fibrillation (AF) is the most common arrhythmia worldwide. Over 2.5 million Americans currently experience AF [1] with 16 million Americans expected to develop AF by 2050 [2]. AF is of clinical importance as the rate of stroke is 5 times higher in patients with AF [3]. Not only is this rate higher, but AF strokes are more costly [4], debilitating [5], and fatal [6] compared to non-AF-related strokes. Given the expected increase in the prevalence of AF, AF-related stroke will become a greater public health issue. Oral antithrombotic and oral anticoagulation (OAC) may reduce the formation of thrombus within the left atrium thereby reducing the risk of stroke associated with AF. A metaanalysis of eight clinical trials demonstrated that, when compared to placebo, a 64 % reduction in AF-related stroke was associated with the use of warfarin and a 22 % reduction associated with the use of aspirin [7]. These findings have prompted recommendations by various guidelines societies for the use of oral anticoagulation in AF patients at risk for stroke. Currently, warfarin is the most commonly used oral anticoagulant in clinical practice [8]. However the need for monitoring, narrow therapeutic range, drug-drug and drug-food interactions, and risk of life-threatening bleeding have all resulted in a significant underuse of this agent [9]. More recently, novel oral anticoagulants (NOACs) have become available and aim to overcome the disadvantages of warfarin by minimizing bleeding, drug and food interactions, and not requiring monitoring. A meta-analysis [10••] of the four randomized trials [11–14] evaluating NOACs to warfarin demonstrated a risk reduction (RR) of 0.81 in stroke or systemic embolism, 0.48 for intracranial hemorrhage, and 0.90 for mortality in favor of NOACs [12]. It is quite possible that the use of these agents may result in significant health savings due to
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reductions in costs attributed to ischemic stroke and bleeding complications. The potential advantages of NOACs have resulted in a rapid increase in their use [8] and have prompted the Canadian Cardiovascular Society and European Society of Cardiology to preferentially recommend these agents over warfarin [15•, 16]. The benefits of NOACs come at an increased cost. Specifically, the monthly cost of warfarin in the USA is estimated to be $4 USD [17] compared to the lowest estimated costs of NOACs at approximately $250 USD [18]. In Canada, the cost for warfarin with its associated physician monitoring fees is $36 CDN [19] whereas the monthly cost of NOACs ranges between $85 and $100 CDN [20]. Given the chronic nature of AF with the need for lifelong OAC, significant long-term costs may be accrued with the use of these agents. Given the acquisition costs of these novel agents and current environment of fiscal restraint, a systematic assessment of their overall benefits is necessary to appreciate whether their advantages justify their costs when compared to warfarin. Cost-effectiveness analysis can provide the framework to balance the benefits and costs associated with each OAC thereby allowing for an indirect comparison of these agents. Such analyses are often used by Health Technology Assessment bodies such the Canadian Agency for Drugs and Technologies in Health (CADTH) and the UK National Institute for Health and Clinical Excellence (NICE) to guide decision-making. In general, cost-effectiveness analyses determine the gains in health relative to the costs associated with various health interventions. A conceptual model is outlined which contains the full range of clinical events related to the intervention being studied. In the case of AF such events include stroke syndromes, bleeding (intracranial, major, and minor), myocardial infarction, and death (Fig. 1). The probabilities of these events occurring and costs associated with each event are defined and the net cost of each intervention and subsequent health gain determined. The health gain is usually expressed in quality adjusted life-years (QALYs) gained which incorporates both quality of life (using a scale of 0 to 1 where 1 represents perfect health, 0 death, and values in between intermediate health states) and increases in length of life. The overall result of the analysis is expressed as the incremental cost-effectiveness ratio (ICER), a metric which expresses the difference in the cost of two therapies in relation to the difference in health gain (that is the difference in QALYs for each therapy). The accepted threshold one is willing to pay for an additional quality of life year (i.e., the threshold below which one considers a therapy to be cost-effective) varies based on local values. This value is reflected in the Bwillingness-to-pay^ threshold. In the USA, ICERs below $50,000U SD/QALY are considered cost-effective [21, 22] whereas this value ranges between $20,000–$100,000 CDN/QALY in Canada [23] and £20, 000–30,000/QALY in the UK [24].
Curr Cardiol Rep (2015) 17: 61
In this review, we will summarize the cost-effectiveness data for the novel oral anticoagulants dabigatran, rivaroxiban, and apixaban in relation to warfarin. Our review will not include the NOAC endoxaban as this agent was recently approved (February 2015) in the USA for stroke prevention in AF, and, to date, no cost-effectiveness analysis has been published with this agent. As variations in the input parameters, model structure, and setting will make it challenging to perform cross-study comparisons, our review will focus on published cost-effectiveness analysis where all three NOACs were compared to warfarin within the same framework (Table 1; [25, 26•, 27•, 28, 29]).
Similarities and Differences in Cost-Effectiveness Analysis of NOACs for Stroke Prevention in AF Given the absence of clinical trials directly comparing the currently available NOACs, cost-effectiveness analyses allow for an indirect comparison of one NOAC to another. Five costeffectiveness analyses each evaluating dabigatran, rivaroxiban, apixaban, and warfarin within the same model have been published to date [25, 26•, 27•, 28, 29]—two were undertaken from a societal perspective within the US healthcare system [25, 26•], one from a Canadian provincial ministry perspective [27•], one from the perspective of the UK National Health Services [28], and one from the Italian National Health System perspective [29]. Similarities between these models include the use of a Markov model to simulate the expected clinical and economic outcomes with each NOAC, a base-case population with age of approximately 70 years, the inclusion of clinical events such as ischemic stroke, intracranial hemorrhage, major and minor bleeding and myocardial infarction, and modeling changes in health states between 1 and 3 months. No study included indirect costs such as those from loss of productivity. Important differences between each model must be highlighted given their potential impact on the observed results. First, the cost of apixaban was unavailable and thus approximated in two models [25, 26•]. Specifically, in one model from the perspective of the USA, Harrington [25] assumed that the price of apixaban in the USA would be similar to the pricing in the UK which in essence underestimated the direct cost of apixaban. Furthermore, the cost of all NOACs was also unknown in the Italian cost-effectiveness analysis, approximated for, and further assumed that all three cost the same [29]. Such assumptions are important to acknowledge as a lifelong time horizon will magnify these inaccurate prices on overall costs. Dyspepsia, a prominent symptom of dabigatran which occurred in approximately 11 % of patients in the RE-LY study compared to approximately 6 % of control (warfarin) patients [11], was included in only two of the five models—one
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Fig. 1 Typical model structure for cost-effectiveness analyses of oral anticoagulant use in non-valvular atrial fibrillation. Patients enter the model and can remain healthy or develop conditions such as ischemic stroke (fatal, major, minor, or transient ischemic attack [TIA]), intracranial
hemorrhage (ICH), myocardial infarction (MI), bleeding (major or minor), or die. Apart from death, patients may move from one state to another with each cycle of the model
explicitly modeling for its impact on quality of life and costs attributed to managing dyspepsia [25] whereas the second only accounted for costs related to dyspepsia [28]. Furthermore, NOAC discontinuation was accounted for in only one model [28]. Given the high discontinuation rates (between 14 and 20 %) of these agents in their respective clinical trials [11–13], and even higher discontinuation rates in clinical practice [30], failing to account for NOAC discontinuation may result in an overestimation of their benefits. The variation in dabigatran dosing across jurisdictions was apparent from these models. As the lower dabigatran dose
(110 mg) is not available in the USA, it is no surprise that only the 150-mg dose was evaluated in models from the perspective of the USA [25, 26•]. Sequential dabigatran dosing (150 mg twice daily until age 80 years then 110 mg twice daily) as recommended in the product monograph [31] was evaluated in the models constructed from Canadian and UK perspectives [27•, 28]. Knowledge of the dabigatran dose employed in the model is critical given its impact on bleeding and stroke. For example, while lower-dose dabigatran is less effective at stroke reduction, it is associated with less major bleeding and as such may result in a lower rate of drug
Table 1
Summary of cost-effectiveness analyses evaluating apixaban, dabigatran, rivaroxiban, and warfarin
Harrington Study et al. [25] author (ref. no.) Perspective Societal USA
Canestero et al. [26•]
Coyle et al. [27•]
Lip et al. [28]
Rognoni et al. [29]
Societal USA
Ontario, Canada
UK National Health Services
Italian National Health System
Age
70 years
72 years
70 years
71 years
70 years QALY Cost
Warfarin
7.97
Rivaroxiban 8.26
ICER
QALY Cost
ICER
QALY Cost
ICER
QALYb Costb ICERb QALYc Costc
ICERc
$77,813 Ref
5.87
$49,638 Ref
–
–
–
7.13
$78,738 $3190
6.18
$84,192 $111,465 6.54
$22,016 $55,757 –
–
–
7.58
$20,041 $13,063
6.48
$18,620 Ref
$14,115 Ref
Dabigatran
8.41a
$82,719 $11,150 6.15
$88,994 $140,557 6.62a
$20,797 $20,797 –
–
–
7.52
$18,813 $12,029
Apixaban
8.47
$85,326 $15,026 6.28
$87,794 $93,063
$21,966 $24,312 –
–
–
8.00
$18,224 $4723
a
6.62
Dabigatran 150 mg dosing
b
Cost, QALY, and ICER only available with apixaban comparisons to dabigatran and rivaroxiban
c
calculated for CHADS2 score >2
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discontinuation when compared to other NOACs. Given this, the model [29] where the higher-dose dabigatran was evaluated and treatment discontinuation not accounted for will likely overestimate the benefits attributed to dabigatran particularly in jurisdictions where differential dabigatran dosing is recommended based on explicit criteria. Finally, the survival benefit reported with apixaban during the 1.8-year follow-up period of the ARIS TOTLE trial [13] was specifically modeled for by Lip [28] but not by others [25, 26•, 27•, 29]—that is, an added survival benefit was included in the first 1.8 years of the lifetime horizon of the model by Lip. It is not clear whether this survival benefit should be explicitly modeled for as it may simply reflect an improvement in survival secondary to a reduction in clinical events which is already accounted for in the model. Should the observed survival benefit be due to the latter, then specifically including this survival advantage will provide an additional advantage to apixaban in this costeffective model. However, should the survival benefit be independent of the reduction in clinical events, then the benefits attributed to apixaban will be underestimated in other models not accounting for this [25, 26•, 27•, 29]. Furthermore, while a statistically significant improvement in survival was observed with apixaban in the ARISTOTLE trial (hazard ratio (HR) of death 0.89; 95 % confidence interval (CI) = 0.80–0.99, p value = 0.047) [13], a trend toward a survival benefit of similar magnitude was also observed with dabigatran 150 mg (HR = 0.88; 95 % CI = 0.77–1.00, p value = 0.051) and rivaroxiban (HR = 0.85; 95 % CI = 0.7–1.2, p value = 0.07) in the RE-LY and ROCKET-AF trials, respectively [11, 12]. Despite the lack of statistical significance with dabigatran and rivaroxiban, given the consistency of this observation among all NOACs, should one chose to incorporate a survival benefit in cost-effectiveness models, it likely should be applied to all NOACs.
Primary Findings of NOAC Cost-Effectiveness Analyses The analyses from all models consistently demonstrate that, compared to warfarin, NOACs cost more but are associated with greater QALYs gained. Furthermore, the ICER for all NOACs [25, 26•, 27•, 28, 29] predominantly falls within the accepted willingness-to-pay threshold for the respective jurisdictions. As such, NOACs are cost-effective relative to warfarin. Of all available NOACs, apixaban was consistently associated with the largest values for QALYs albeit with varying associated costs. Nonetheless, apixaban consistently appears to be the most cost-effective NOAC [25, 26•, 27•, 28].
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Rivaroxiban and dabigatran 110 mg was typically dominated by both apixaban and the high dose of dabigatran (150 mg). In other words, rivaroxiban and dabigatran 110 mg cost more per improvement in QALY, making these agents less favorable for stroke prevention in AF [26•, 27•].
Uncertainty in NOAC Cost-Effectiveness Models While the results of the published cost-effectiveness analyses generally demonstrate that NOACs are cost-effective, it is apparent that uncertainty exists with this conclusion. Several different methods may be undertaken to determine how sensitive the primary result (that is the ICER) is to variations in the input parameters. One simple form involves altering the value of a specific input of interest and examining its impact on the ICER. This approach, known as a one-way sensitivity analysis, may allow an investigator to determine the influence of a single parameter on an outcome or determine a threshold at which the main conclusions of the model may change. Drug costs [25, 27•], rate of stroke, and intracranial bleeding with apixaban [25, 27•] were demonstrated to impact the findings of each published model. That is, the observed effects would be diminished if NOACs were less effective at reducing stroke, had higher rates of intracranial bleeding, or cost more. The threshold to reduce the benefits of each NOAC varies with each model and is related to the inputs in the model. A probabilistic sensitivity analysis also quantifies uncertainty in decision-analytic models. Rather than altering a single value as is done with one-way sensitivity analyses, a plausible distribution is assigned to each parameter within the model when performing a probabilistic sensitivity analysis. Each time the model is run, a value from within this distribution is selected. If the model is run a number of times (for example, 100,000 times), the variation that results will be recorded and used to create a cost-effectiveness acceptability curve which demonstrates the percentage of times an intervention is cost-effective. What is apparent from the probabilistic sensitivity analyses performed in the North American decision models evaluating NOACs [25, 26•, 27•] is that substantial uncertainty exists in the conclusions. Specifically, the probabilistic sensitivity analyses showed that there was less than a 50 % likelihood that we could be confident that our primary findings hold. This degree of uncertainty is an important limitation to cost-effective analysis of NOACs. The model parameters obtained from the literature are imperfect or have uncertainty [32]. This uncertainty can be substantial (that is have wide confidence intervals) when the available research into that particular parameter is sparse. As parameters for NOACs were derived from single trials evaluating each agent, it is not surprising that the confidence interval for key parameters is wide. This uncertainty will be propagated throughout the model and may result in an incorrect result [33]. Parameter uncertainty
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can be decreased with additional research to better define the parameter of interest. Furthermore, additional sophisticated analyses (i.e., value of information analyses) can help quantify the potential costs of uncertainty by determining the expected consequences of an incorrect decision based on uncertain data [32, 34, 35••].
Additional Limitations of NOAC Cost-Effectiveness Models Additional limitations of cost-effectiveness models must be appreciated [36••]. First, many model parameters such as utilities and event rates employed were derived from the 1990s and may not reflect contemporary practice or outcomes. Furthermore, not all health states are included in the current models (for example, dyspepsia related to dabigatran or pulmonary embolism) nor are responses to clinical events (i.e., the use of dual anti-platelets with myocardial infarction). This may result in underestimation of clinical events subsequently impacting survival and costs. Lone randomized trials of NOACs versus warfarin were also utilized for these models. Variation in the design of each trial including their patient population is not ideal when performing indirect comparisons. For example, the ROCKET-AF trial enrolled patients with higher CHADS2 score compared to the RE-LY and ARISTOTLE trials. It is not clear if the clinical events observed in the ROCKET-AF trial hold in patients with lower CHADS2 scores and thus can be applied to these patients in decision models. Additionally, it is unclear whether the findings from these studies, which were typically performed over a period of 1–2 years, will remain constant for the lifetime horizon of decision models. Differences in trial design may also impact the primary results of the large clinical trials resulting in inaccurate estimates input into these models. For example, in the RE-LY study, blinding was not performed between dabigatran and warfarin whereas this was achieved in the ROCKET-AF and ARISTOTLE trials. It is well known that trials with inadequate concealment yield larger estimates of treatment effects [37]. Should the treatment effect with dabigatran indeed be overestimated, it would impact the cost-effectiveness of dabigatran in our decision-models. As the advantages of NOACs are reduced compared to warfarin at centers with protocols that allow higher time in the warfarin therapeutic range [38, 39], it is important that the time in therapeutic range for the jurisdiction being studied be included in the cost-effectiveness model to provide results consistent with real-world practice. Finally, all published models utilize a base-case of a 70-year-old individual with AF. Given the need for anticoagulation from the time of diagnosis of AF, many times in individuals less than 70 years, we encourage the creation of models where base-case
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characteristics including baseline stroke risk, medication discontinuation rates (and time-in-therapeutic range for warfarin), bleeding risk, and real-world effectiveness of OAC are obtained from unselected real-world populations with AF requiring anticoagulation. Incorporation of these parameters will provide more clinically meaningful insight into the realworld cost-effectiveness of OAC for AF stroke prevention. It should also be noted that the cost-effectiveness of NOACs versus warfarin would vary in a model depending on baseline, patient-specific risk for ischemic stroke, and bleeding.
Conclusions Cost-effectiveness analyses of NOACs in relation to warfarin suggest that these new agents are indeed cost-effective. While variations in clinical events and costs do influence the costeffectiveness of one agent relative to another, apixaban consistently appears to be most cost-effective. Uncertainty in these models is present and may be ameliorated with improved parameter estimates through future research. It is likely that with ongoing use of these agents in clinical practice, realworld parameter estimates of safety and efficacy will become available thereby allowing for improved cost-effective modeling. Given the increase in AF burden with the aging population, importance of cost-effectiveness analysis on decisionmaking by payers, and evolving non-pharmacologic approaches for AF stroke prevention [40••], refining parameter estimates to reduce uncertainty within NOAC costeffectiveness models should be made a priority. Acknowledgments Dr. Wijeysundera is supported by a Heart & Stroke Foundation (H&SF) of Canada Distinguished Clinical Scientist Award. Compliance with Ethics Guidelines Conflict of Interest The authors declare that they have no competing interests. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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INVASIVE ELECTROPHYSIOLOGY AND PACING (EK HEIST, SECTION EDITOR)
Cost-Effectiveness of Novel Oral Anticoagulants for Stroke Prevention in Non-Valvular Atrial Fibrillation Sheldon M. Singh 1 & Harindra C. Wijeysundera 1,2,3
Published online: 17 June 2015 # Springer Science+Business Media New York 2015
Abstract Recently, novel oral anticoagulants (NOACs) have been approved for stroke prevention in patients with atrial fibrillation (AF). Although these agents overcome some disadvantages of warfarin, they are associated with increased costs. In this review, we will provide an overview of the cost-effectiveness of NOACs for stroke prevention in AF. Our comments and conclusions are limited to studies directly comparing all available NOACs within the same framework. The available cost-effectiveness analyses suggest that NOACs are cost-effective compared to warfarin, with apixaban likely being most favorable. However, significant limitations in these models are present and should be appreciated when interpreting their results.
Keywords Anticoagulants . Atrial fibrillation . Cost-effectiveness analysis . Bleeding . Stroke
This article is part of the Topical Collection on Invasive Electrophysiology and Pacing * Sheldon M. Singh [email protected] 1
Schulich Heart Centre, Sunnybrook Health Sciences Centre, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
2
Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada
3
Institute for Clinical Evaluative Sciences (ICES), Toronto, ON, Canada
Introduction Atrial fibrillation (AF) is the most common arrhythmia worldwide. Over 2.5 million Americans currently experience AF [1] with 16 million Americans expected to develop AF by 2050 [2]. AF is of clinical importance as the rate of stroke is 5 times higher in patients with AF [3]. Not only is this rate higher, but AF strokes are more costly [4], debilitating [5], and fatal [6] compared to non-AF-related strokes. Given the expected increase in the prevalence of AF, AF-related stroke will become a greater public health issue. Oral antithrombotic and oral anticoagulation (OAC) may reduce the formation of thrombus within the left atrium thereby reducing the risk of stroke associated with AF. A metaanalysis of eight clinical trials demonstrated that, when compared to placebo, a 64 % reduction in AF-related stroke was associated with the use of warfarin and a 22 % reduction associated with the use of aspirin [7]. These findings have prompted recommendations by various guidelines societies for the use of oral anticoagulation in AF patients at risk for stroke. Currently, warfarin is the most commonly used oral anticoagulant in clinical practice [8]. However the need for monitoring, narrow therapeutic range, drug-drug and drug-food interactions, and risk of life-threatening bleeding have all resulted in a significant underuse of this agent [9]. More recently, novel oral anticoagulants (NOACs) have become available and aim to overcome the disadvantages of warfarin by minimizing bleeding, drug and food interactions, and not requiring monitoring. A meta-analysis [10••] of the four randomized trials [11–14] evaluating NOACs to warfarin demonstrated a risk reduction (RR) of 0.81 in stroke or systemic embolism, 0.48 for intracranial hemorrhage, and 0.90 for mortality in favor of NOACs [12]. It is quite possible that the use of these agents may result in significant health savings due to
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reductions in costs attributed to ischemic stroke and bleeding complications. The potential advantages of NOACs have resulted in a rapid increase in their use [8] and have prompted the Canadian Cardiovascular Society and European Society of Cardiology to preferentially recommend these agents over warfarin [15•, 16]. The benefits of NOACs come at an increased cost. Specifically, the monthly cost of warfarin in the USA is estimated to be $4 USD [17] compared to the lowest estimated costs of NOACs at approximately $250 USD [18]. In Canada, the cost for warfarin with its associated physician monitoring fees is $36 CDN [19] whereas the monthly cost of NOACs ranges between $85 and $100 CDN [20]. Given the chronic nature of AF with the need for lifelong OAC, significant long-term costs may be accrued with the use of these agents. Given the acquisition costs of these novel agents and current environment of fiscal restraint, a systematic assessment of their overall benefits is necessary to appreciate whether their advantages justify their costs when compared to warfarin. Cost-effectiveness analysis can provide the framework to balance the benefits and costs associated with each OAC thereby allowing for an indirect comparison of these agents. Such analyses are often used by Health Technology Assessment bodies such the Canadian Agency for Drugs and Technologies in Health (CADTH) and the UK National Institute for Health and Clinical Excellence (NICE) to guide decision-making. In general, cost-effectiveness analyses determine the gains in health relative to the costs associated with various health interventions. A conceptual model is outlined which contains the full range of clinical events related to the intervention being studied. In the case of AF such events include stroke syndromes, bleeding (intracranial, major, and minor), myocardial infarction, and death (Fig. 1). The probabilities of these events occurring and costs associated with each event are defined and the net cost of each intervention and subsequent health gain determined. The health gain is usually expressed in quality adjusted life-years (QALYs) gained which incorporates both quality of life (using a scale of 0 to 1 where 1 represents perfect health, 0 death, and values in between intermediate health states) and increases in length of life. The overall result of the analysis is expressed as the incremental cost-effectiveness ratio (ICER), a metric which expresses the difference in the cost of two therapies in relation to the difference in health gain (that is the difference in QALYs for each therapy). The accepted threshold one is willing to pay for an additional quality of life year (i.e., the threshold below which one considers a therapy to be cost-effective) varies based on local values. This value is reflected in the Bwillingness-to-pay^ threshold. In the USA, ICERs below $50,000U SD/QALY are considered cost-effective [21, 22] whereas this value ranges between $20,000–$100,000 CDN/QALY in Canada [23] and £20, 000–30,000/QALY in the UK [24].
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In this review, we will summarize the cost-effectiveness data for the novel oral anticoagulants dabigatran, rivaroxiban, and apixaban in relation to warfarin. Our review will not include the NOAC endoxaban as this agent was recently approved (February 2015) in the USA for stroke prevention in AF, and, to date, no cost-effectiveness analysis has been published with this agent. As variations in the input parameters, model structure, and setting will make it challenging to perform cross-study comparisons, our review will focus on published cost-effectiveness analysis where all three NOACs were compared to warfarin within the same framework (Table 1; [25, 26•, 27•, 28, 29]).
Similarities and Differences in Cost-Effectiveness Analysis of NOACs for Stroke Prevention in AF Given the absence of clinical trials directly comparing the currently available NOACs, cost-effectiveness analyses allow for an indirect comparison of one NOAC to another. Five costeffectiveness analyses each evaluating dabigatran, rivaroxiban, apixaban, and warfarin within the same model have been published to date [25, 26•, 27•, 28, 29]—two were undertaken from a societal perspective within the US healthcare system [25, 26•], one from a Canadian provincial ministry perspective [27•], one from the perspective of the UK National Health Services [28], and one from the Italian National Health System perspective [29]. Similarities between these models include the use of a Markov model to simulate the expected clinical and economic outcomes with each NOAC, a base-case population with age of approximately 70 years, the inclusion of clinical events such as ischemic stroke, intracranial hemorrhage, major and minor bleeding and myocardial infarction, and modeling changes in health states between 1 and 3 months. No study included indirect costs such as those from loss of productivity. Important differences between each model must be highlighted given their potential impact on the observed results. First, the cost of apixaban was unavailable and thus approximated in two models [25, 26•]. Specifically, in one model from the perspective of the USA, Harrington [25] assumed that the price of apixaban in the USA would be similar to the pricing in the UK which in essence underestimated the direct cost of apixaban. Furthermore, the cost of all NOACs was also unknown in the Italian cost-effectiveness analysis, approximated for, and further assumed that all three cost the same [29]. Such assumptions are important to acknowledge as a lifelong time horizon will magnify these inaccurate prices on overall costs. Dyspepsia, a prominent symptom of dabigatran which occurred in approximately 11 % of patients in the RE-LY study compared to approximately 6 % of control (warfarin) patients [11], was included in only two of the five models—one
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Fig. 1 Typical model structure for cost-effectiveness analyses of oral anticoagulant use in non-valvular atrial fibrillation. Patients enter the model and can remain healthy or develop conditions such as ischemic stroke (fatal, major, minor, or transient ischemic attack [TIA]), intracranial
hemorrhage (ICH), myocardial infarction (MI), bleeding (major or minor), or die. Apart from death, patients may move from one state to another with each cycle of the model
explicitly modeling for its impact on quality of life and costs attributed to managing dyspepsia [25] whereas the second only accounted for costs related to dyspepsia [28]. Furthermore, NOAC discontinuation was accounted for in only one model [28]. Given the high discontinuation rates (between 14 and 20 %) of these agents in their respective clinical trials [11–13], and even higher discontinuation rates in clinical practice [30], failing to account for NOAC discontinuation may result in an overestimation of their benefits. The variation in dabigatran dosing across jurisdictions was apparent from these models. As the lower dabigatran dose
(110 mg) is not available in the USA, it is no surprise that only the 150-mg dose was evaluated in models from the perspective of the USA [25, 26•]. Sequential dabigatran dosing (150 mg twice daily until age 80 years then 110 mg twice daily) as recommended in the product monograph [31] was evaluated in the models constructed from Canadian and UK perspectives [27•, 28]. Knowledge of the dabigatran dose employed in the model is critical given its impact on bleeding and stroke. For example, while lower-dose dabigatran is less effective at stroke reduction, it is associated with less major bleeding and as such may result in a lower rate of drug
Table 1
Summary of cost-effectiveness analyses evaluating apixaban, dabigatran, rivaroxiban, and warfarin
Harrington Study et al. [25] author (ref. no.) Perspective Societal USA
Canestero et al. [26•]
Coyle et al. [27•]
Lip et al. [28]
Rognoni et al. [29]
Societal USA
Ontario, Canada
UK National Health Services
Italian National Health System
Age
70 years
72 years
70 years
71 years
70 years QALY Cost
Warfarin
7.97
Rivaroxiban 8.26
ICER
QALY Cost
ICER
QALY Cost
ICER
QALYb Costb ICERb QALYc Costc
ICERc
$77,813 Ref
5.87
$49,638 Ref
–
–
–
7.13
$78,738 $3190
6.18
$84,192 $111,465 6.54
$22,016 $55,757 –
–
–
7.58
$20,041 $13,063
6.48
$18,620 Ref
$14,115 Ref
Dabigatran
8.41a
$82,719 $11,150 6.15
$88,994 $140,557 6.62a
$20,797 $20,797 –
–
–
7.52
$18,813 $12,029
Apixaban
8.47
$85,326 $15,026 6.28
$87,794 $93,063
$21,966 $24,312 –
–
–
8.00
$18,224 $4723
a
6.62
Dabigatran 150 mg dosing
b
Cost, QALY, and ICER only available with apixaban comparisons to dabigatran and rivaroxiban
c
calculated for CHADS2 score >2
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discontinuation when compared to other NOACs. Given this, the model [29] where the higher-dose dabigatran was evaluated and treatment discontinuation not accounted for will likely overestimate the benefits attributed to dabigatran particularly in jurisdictions where differential dabigatran dosing is recommended based on explicit criteria. Finally, the survival benefit reported with apixaban during the 1.8-year follow-up period of the ARIS TOTLE trial [13] was specifically modeled for by Lip [28] but not by others [25, 26•, 27•, 29]—that is, an added survival benefit was included in the first 1.8 years of the lifetime horizon of the model by Lip. It is not clear whether this survival benefit should be explicitly modeled for as it may simply reflect an improvement in survival secondary to a reduction in clinical events which is already accounted for in the model. Should the observed survival benefit be due to the latter, then specifically including this survival advantage will provide an additional advantage to apixaban in this costeffective model. However, should the survival benefit be independent of the reduction in clinical events, then the benefits attributed to apixaban will be underestimated in other models not accounting for this [25, 26•, 27•, 29]. Furthermore, while a statistically significant improvement in survival was observed with apixaban in the ARISTOTLE trial (hazard ratio (HR) of death 0.89; 95 % confidence interval (CI) = 0.80–0.99, p value = 0.047) [13], a trend toward a survival benefit of similar magnitude was also observed with dabigatran 150 mg (HR = 0.88; 95 % CI = 0.77–1.00, p value = 0.051) and rivaroxiban (HR = 0.85; 95 % CI = 0.7–1.2, p value = 0.07) in the RE-LY and ROCKET-AF trials, respectively [11, 12]. Despite the lack of statistical significance with dabigatran and rivaroxiban, given the consistency of this observation among all NOACs, should one chose to incorporate a survival benefit in cost-effectiveness models, it likely should be applied to all NOACs.
Primary Findings of NOAC Cost-Effectiveness Analyses The analyses from all models consistently demonstrate that, compared to warfarin, NOACs cost more but are associated with greater QALYs gained. Furthermore, the ICER for all NOACs [25, 26•, 27•, 28, 29] predominantly falls within the accepted willingness-to-pay threshold for the respective jurisdictions. As such, NOACs are cost-effective relative to warfarin. Of all available NOACs, apixaban was consistently associated with the largest values for QALYs albeit with varying associated costs. Nonetheless, apixaban consistently appears to be the most cost-effective NOAC [25, 26•, 27•, 28].
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Rivaroxiban and dabigatran 110 mg was typically dominated by both apixaban and the high dose of dabigatran (150 mg). In other words, rivaroxiban and dabigatran 110 mg cost more per improvement in QALY, making these agents less favorable for stroke prevention in AF [26•, 27•].
Uncertainty in NOAC Cost-Effectiveness Models While the results of the published cost-effectiveness analyses generally demonstrate that NOACs are cost-effective, it is apparent that uncertainty exists with this conclusion. Several different methods may be undertaken to determine how sensitive the primary result (that is the ICER) is to variations in the input parameters. One simple form involves altering the value of a specific input of interest and examining its impact on the ICER. This approach, known as a one-way sensitivity analysis, may allow an investigator to determine the influence of a single parameter on an outcome or determine a threshold at which the main conclusions of the model may change. Drug costs [25, 27•], rate of stroke, and intracranial bleeding with apixaban [25, 27•] were demonstrated to impact the findings of each published model. That is, the observed effects would be diminished if NOACs were less effective at reducing stroke, had higher rates of intracranial bleeding, or cost more. The threshold to reduce the benefits of each NOAC varies with each model and is related to the inputs in the model. A probabilistic sensitivity analysis also quantifies uncertainty in decision-analytic models. Rather than altering a single value as is done with one-way sensitivity analyses, a plausible distribution is assigned to each parameter within the model when performing a probabilistic sensitivity analysis. Each time the model is run, a value from within this distribution is selected. If the model is run a number of times (for example, 100,000 times), the variation that results will be recorded and used to create a cost-effectiveness acceptability curve which demonstrates the percentage of times an intervention is cost-effective. What is apparent from the probabilistic sensitivity analyses performed in the North American decision models evaluating NOACs [25, 26•, 27•] is that substantial uncertainty exists in the conclusions. Specifically, the probabilistic sensitivity analyses showed that there was less than a 50 % likelihood that we could be confident that our primary findings hold. This degree of uncertainty is an important limitation to cost-effective analysis of NOACs. The model parameters obtained from the literature are imperfect or have uncertainty [32]. This uncertainty can be substantial (that is have wide confidence intervals) when the available research into that particular parameter is sparse. As parameters for NOACs were derived from single trials evaluating each agent, it is not surprising that the confidence interval for key parameters is wide. This uncertainty will be propagated throughout the model and may result in an incorrect result [33]. Parameter uncertainty
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can be decreased with additional research to better define the parameter of interest. Furthermore, additional sophisticated analyses (i.e., value of information analyses) can help quantify the potential costs of uncertainty by determining the expected consequences of an incorrect decision based on uncertain data [32, 34, 35••].
Additional Limitations of NOAC Cost-Effectiveness Models Additional limitations of cost-effectiveness models must be appreciated [36••]. First, many model parameters such as utilities and event rates employed were derived from the 1990s and may not reflect contemporary practice or outcomes. Furthermore, not all health states are included in the current models (for example, dyspepsia related to dabigatran or pulmonary embolism) nor are responses to clinical events (i.e., the use of dual anti-platelets with myocardial infarction). This may result in underestimation of clinical events subsequently impacting survival and costs. Lone randomized trials of NOACs versus warfarin were also utilized for these models. Variation in the design of each trial including their patient population is not ideal when performing indirect comparisons. For example, the ROCKET-AF trial enrolled patients with higher CHADS2 score compared to the RE-LY and ARISTOTLE trials. It is not clear if the clinical events observed in the ROCKET-AF trial hold in patients with lower CHADS2 scores and thus can be applied to these patients in decision models. Additionally, it is unclear whether the findings from these studies, which were typically performed over a period of 1–2 years, will remain constant for the lifetime horizon of decision models. Differences in trial design may also impact the primary results of the large clinical trials resulting in inaccurate estimates input into these models. For example, in the RE-LY study, blinding was not performed between dabigatran and warfarin whereas this was achieved in the ROCKET-AF and ARISTOTLE trials. It is well known that trials with inadequate concealment yield larger estimates of treatment effects [37]. Should the treatment effect with dabigatran indeed be overestimated, it would impact the cost-effectiveness of dabigatran in our decision-models. As the advantages of NOACs are reduced compared to warfarin at centers with protocols that allow higher time in the warfarin therapeutic range [38, 39], it is important that the time in therapeutic range for the jurisdiction being studied be included in the cost-effectiveness model to provide results consistent with real-world practice. Finally, all published models utilize a base-case of a 70-year-old individual with AF. Given the need for anticoagulation from the time of diagnosis of AF, many times in individuals less than 70 years, we encourage the creation of models where base-case
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characteristics including baseline stroke risk, medication discontinuation rates (and time-in-therapeutic range for warfarin), bleeding risk, and real-world effectiveness of OAC are obtained from unselected real-world populations with AF requiring anticoagulation. Incorporation of these parameters will provide more clinically meaningful insight into the realworld cost-effectiveness of OAC for AF stroke prevention. It should also be noted that the cost-effectiveness of NOACs versus warfarin would vary in a model depending on baseline, patient-specific risk for ischemic stroke, and bleeding.
Conclusions Cost-effectiveness analyses of NOACs in relation to warfarin suggest that these new agents are indeed cost-effective. While variations in clinical events and costs do influence the costeffectiveness of one agent relative to another, apixaban consistently appears to be most cost-effective. Uncertainty in these models is present and may be ameliorated with improved parameter estimates through future research. It is likely that with ongoing use of these agents in clinical practice, realworld parameter estimates of safety and efficacy will become available thereby allowing for improved cost-effective modeling. Given the increase in AF burden with the aging population, importance of cost-effectiveness analysis on decisionmaking by payers, and evolving non-pharmacologic approaches for AF stroke prevention [40••], refining parameter estimates to reduce uncertainty within NOAC costeffectiveness models should be made a priority. Acknowledgments Dr. Wijeysundera is supported by a Heart & Stroke Foundation (H&SF) of Canada Distinguished Clinical Scientist Award. Compliance with Ethics Guidelines Conflict of Interest The authors declare that they have no competing interests. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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