Cost Effectiveness of Oral Anticoagulants for Ischemic ...stroke.ahajournals.org/content/strokeaha/early/2016/04/21/STROKE... · Results—In the base case analysis, ... Cost Effectiveness

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Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. In 2010, the prevalence of AF was 5.2 mil-

lion, and the incidence of AF was 1.2 million.1 Chronic AF leads to a 5-fold increase in stroke risk.2 Strokes are associated with significant morbidity and mortality, with 5-year survival rates of 50%.3 The annual cost of stroke in the United States in 2010 was estimated to be $36.5 billion.4

Guidelines for the management of AF recommend anti-coagulation for stroke prevention in patients with moderate to high stroke risk.5 Although warfarin has been the standard therapy, it has a narrow therapeutic window and requires dietary control.6 The limitations of warfarin have complicated the management of AF and encouraged the development of newer oral anticoagulants (NOACs). Since 2010, the US Food and Drug Administration has approved dabigatran (Pradaxa), apixaban (Eliquis), rivaroxaban (Xarelto), and edoxaban (Savysa) for stroke prophylaxis among patients with AF.7 In their respective clinical trials, all the NOACs have shown at

least comparable efficacy and safety with warfarin.8–11 All the NOACs have substantially higher acquisition costs than war-farin. At present, there have been several cost effectiveness studies comparing dabigatran, apixaban, rivaroxaban, and edoxaban with warfarin individually.12–26 Fewer studies have compared dabigatran, apixaban, rivaroxaban, and warfarin with each other.27–32 To the best of our knowledge, no study has compared all the alternatives from a US payer perspec-tive to each other, and none have developed models that are reflective of the US commercial population. To address these knowledge gaps, this study sought to assess the cost effective-ness of all the 5 oral anticoagulants (OACs) available in the US market for stroke prophylaxis adopting a private payer’s perspective and a lifetime horizon.

MethodsWe developed a Markov model to evaluate the cost effectiveness of dabigatran (150 mg BID), rivaroxaban (20 mg QD), apixaban (5 mg

Background and Purpose—The objective of the study is to compare the cost effectiveness of oral anticoagulants among atrial fibrillation patients at an increased stroke risk.

Methods—A Markov model was constructed to project the lifetime costs and quality-adjusted survival (QALYs) of oral anticoagulants using a private payer’s perspective. The distribution of stroke risk (CHADS

2 score: congestive heart failure,

hypertension, advanced age, diabetes mellitus, stroke) and age of the modeled population was derived from a cohort of commercially insured patients with new-onset atrial fibrillation. Probabilities of treatment specific events were derived from published clinical trials. Event and downstream costs were determined from the cost of illness studies. Drug costs were obtained from 2015 National Average Drug Acquisition Cost data.

Results—In the base case analysis, warfarin was the least costly ($46 241; 95% CI, 44 499–47 874) and apixaban had the highest QALYs (9.38; 95% CI, 9.24–9.48 QALYs). Apixaban was found to be a cost-effective strategy over warfarin (incremental cost effectiveness ratio=$25 816) and dominated other anticoagulants. Probabilistic sensitivity analysis showed that apixaban had at least a 61% chance of being the most cost effective strategy at willingness to pay value of $100 000 per QALY. Among patients with CHADS

2 ≥3, dabigatran was the dominant strategy. The model was sensitive

to efficacy estimates of apixaban, dabigatran, and edoxaban and the cost of these drugs.Conclusions—All the newer oral anticoagulants compared were more effective than adjusted dosed warfarin. Our model

showed that apixaban was the most effective anticoagulant in a general atrial fibrillation population and has an incremental cost effectiveness ratio <$50 000/QALY. For those with higher stroke risk (CHADS

2≥3), dabigatran was the most cost-

effective treatment option. (Stroke. 2016;47:00-00. DOI: 10.1161/STROKEAHA.115.012325.)

Key Words: anticoagulants ◼ atrial fibrillation ◼ cost effectiveness ◼ quality-adjusted life years ◼ stroke

Cost Effectiveness of Oral Anticoagulants for Ischemic Stroke Prophylaxis Among Nonvalvular

Atrial Fibrillation PatientsAnuj Shah, BPharm; Anand Shewale, MS; Corey J. Hayes, PharmD, MPH;

Bradley C. Martin, PharmD, PhD

Received December 4, 2015; final revision received March 9, 2016; accepted March 15, 2016.From the Division of Pharmaceutical Evaluation and Policy, University of Arkansas for Medical Sciences, Little Rock.The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.

115.012325/-/DC1.Correspondence to Bradley C. Martin, PharmD, PhD, Division of Pharmaceutical Evaluation and Policy, University of Arkansas for Medical Sciences,

4301 W Markham St, Slot 522, Little Rock, AR 72205. E-mail [email protected]© 2016 American Heart Association, Inc.

Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.115.012325

Original Contribution

by guest on July 4, 2018http://stroke.ahajournals.org/

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2 Stroke June 2016

BID), edoxaban (60 mg QD), and adjusted dose warfarin. The cycle length for the model was 30 days with a lifetime horizon. The base-line model population consisted of persons with a CHADS

2 score

(congestive heart failure [1 point], hypertension [1 point], age ≥75 years [1 point], diabetes mellitus [1 point], stroke [2 points]) of ≥1. The distribution of CHADS

2 scores and their respective ages for the

baseline model population was derived from a nationally represen-tative sample of commercially insured patients with AF who were eligible to receive anticoagulant therapy.33

The model structure was adapted from the studies published by Lee et al14–16 (Figure 1). All the patients entered the model in the Well with atrial fibrillation state on an OAC and then transitioned to the other health states. We assumed that 28% of all the ischemic strokes were transient ischemic attacks, and the remaining could be 1 of 4 types: reversible, major, minor, or fatal. Intracranial hemorrhage (ICH) could be of 3 types: major, minor, and fatal. After a patient experienced an ICH or extracranial hemorrhage (ECH), anticoagu-lation was assumed to be discontinued and the patient switched to aspirin for the remainder of their lifetime. Consistent with Lee et al, we assumed that after 2 minor neurological events, patients would proceed to a major event health state and 2 major events would lead to death.14–16 To estimate net monetary benefits, we used a willing-ness to pay (WTP) threshold of $100 000 per quality-adjusted life year (QALY) based on the World Health Organization cost effective-ness guidances.34 Costs and utilities were discounted at a rate of 3% (range, 0%–5%).

Model Input ParametersKey model input parameters are provided in Table 1, and a complete list of all input parameters, their distributions, and sources are pro-vided Table I in the online-only Data Supplement.

CostsAll the costs were considered from a payer’s perspective, and we included only direct medical costs. The event costs of ICH, myo-cardial infarction (MI), stroke, and ECH and the follow-up costs of stroke, MI, and ICH were derived from AF-specific event and follow-up cost estimates.35 All event and follow-up costs were inflated using the medical component of the consumer price index to USD 2015.36 An alternate costing strategy was also used in which all the event and follow-up costs from the article of Lee et al15 were inflated to 2015 dollars.

Drug costs were estimated using the National Average Drug Acquisition cost as of April 2015 compiled by the US Medicaid program.37 To more accurately reflect a payers’ perspective in which

negotiated rebates are common when there are multiple branded products in a therapeutic category, we applied an average rebate of 23% to our National Average Drug Acquisition drug cost estimates.38 The variance estimates for drug costs were derived from the phar-macy claims of a commercial insurance database.

Health-Related Quality of Life and UtilitiesWe awarded utilities to each simulated patient to estimate QALY. Major or minor neurological events (major or minor, stroke, or ICH) were associated with a permanent disutility. ECH, MI, and minor bleed were assigned temporary disutilities. MI, ECH, and minor bleed were assigned a disutility of 30 days, 2 weeks, and 2 days, respectively.

ProbabilitiesThe stroke rates for patients on warfarin at each CHADS

2 score

were derived from the Anticoagulation and Risk Factors in Atrial Fibrillation cohort.39 Relative risks for an increase in ICH and stroke risk with every decade were based on systematic reviews and pooled analysis from clinical trials.40,41 The hazard ratios (HRs) with respect to warfarin for each of the events for the NOACs were derived from their respective clinical trials.8–11 The relative risk for each of the out-comes for aspirin in comparison with warfarin was based on a net-work meta-analysis.42

AnalysisModel development, implementation, and analysis were performed using TreeAge Pro 2015. Technical verification of the model was performed by 2 of the authors (Anuj Shah and Anand Shewale) inde-pendently constructing the initial model in TreeAge and replicating findings. For the base case analysis, we simulated a hypothetical cohort of 10 000 patients. A gamma distribution was used for all the costs, log-normal distribution for relative risk and HR, β distribution for utilities and probabilities, and a normal distribution for age.

Sensitivity AnalysesWe performed a 1-way sensitivity analysis on the influential model input parameters that were identified by visual inspection of tornado diagrams (Figures I–VIII in the online-only Data Supplement). We performed 2 probabilistic sensitivity analyses by generating 100 cohorts of 10 000 patients, 1 with the trial-based variances (base case) for NOAC efficacy and 1 with variance estimates inflated by 50% to account for potential patient heterogeneity of the NOACs pivotal trials. We also conducted a structural sensitivity analysis by making

Figure 1. Schematic representation of Mar-kov model. All patients with atrial fibrillation (AF) and increased stroke risk (CHADS2 score ≥1; congestive heart failure [1 point], hypertension [1 point], age ≥75 years [1 point], diabetes mellitus [1 point], stroke [2 points]) enter the model at varying ages depending on the age distribution of a com-mercially insured incident AF population. The cycle length is 30 d, and the model is ter-minated when 99% of the cohort dies. The transition probabilities into various health states depends on the prescribed therapy. *All patients start on an anticoagulant in well state but switch to aspirin in well state after an extracranial hemorrhage (ECH). †Myocardial infarction and ECH are tempo-rary health states. ICH indicates intracranial hemorrhage; and RIND, reversible ischemic neurological damage.


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Shah et al Cost Effectiveness of Oral Anticoagulants 3

the assumption that all patients who developed an MI after an ECH or ECH after MI would stay on aspirin but acquire the monthly fol-low-up cost of MI patients. We performed a sensitivity analysis by altering the costing strategy and inflating the costs used by Lee et al.15 To test the sensitivity of our model to cost estimates of NOACs, we assigned National Average Drug Acquisition cost (without rebate) and Medispan Average Wholesale Price as the mean cost estimates in 2 separate scenarios. In addition, we performed subgroup analy-ses among patients aged <65 and ≥65 years and among patients with CHADS

2 scores of 1, 2, and ≥3.

ResultsBase CaseIn the base case analysis, apixaban had the highest QALY (9.38; 95% CI, 9.24–9.48 QALYs) followed by dabiga-tran and was lowest for warfarin (9.02; 95% CI, 8.90–9.12 QALYs; Table 2). The costs were the lowest for warfarin ($46 241; 95% CI, $44 499–$47 874) and highest for rivaroxa-ban ($58 889; 95% CI, $57 467–$60 444). After eliminating edoxaban, rivaroxaban, and dabigatran (dominated strategies), the incremental cost effectiveness ratio (ICER) for apixaban relative to warfarin was $25 816/QALY. All the NOACs had an ICER <$100 000/QALY relative to the common compara-tor warfarin.

Sensitivity AnalysisThe 1-way sensitivity analysis showed dabigatran had the highest net monetary benefit using a threshold of 100 000/QALY under the following conditions: (1) when the HRs of ICH, MI, and stroke for apixaban were above 0.46, 1.05, and 0.99, respectively; (2) when the HRs of ICH, MI, ECH, and stroke for dabigatran were below 0.36, 1.17, 0.82, and 0.70, respectively; (3) when the annual stroke rate on warfa-rin was >0.02. Edoxaban had the highest net monetary benefit when the HRs of ICH and stroke for edoxaban were below 0.38 and 0.89. To become the preferred strategies at a WTP threshold of $100 000/QALY, monthly drug costs would have to be reduced by $63 and $30 for edoxaban and dabigatran, respectively. The probabilistic sensitivity analyses for the base case scenario and the scenario with the SDs of the efficacy estimates showed that apixaban was cost-effective in 98% and 61% of the iterations, respectively, at a WTP of $100 000/QALY(Figure 2).

The structural sensitivity analysis resulted in edoxaban being extendedly dominated and dabigatran and rivaroxaban absolutely dominated. Apixaban had an ICER of $24 566 per QALY (Table 3) relative to warfarin. The alternate costing strategy based on Lee et al showed apixaban and dabigatran having an ICER <$100,000 per QALY and edoxaban and riva-roxaban were absolutely dominated (Table 3). When National Average Drug Acquisition cost and Average Wholesale Price based cost were used, apixaban dominated all other NOACs with an ICER <100 000 per QALY (Table 3).

Subgroup AnalysesIn the 2 cohorts of patients with incident AF above and below 65 years of age, all of the NOACs were absolutely or extend-edly dominated by apixaban (Table 3). For those with a CHADS

2 score of 1 or 2, apixaban was found to be cost effec-

tive at a WTP threshold of $50 000 per QALY dominating the other NOAC strategies (Table 3). For patients with a CHADS

2

score of ≥3, dabigatran dominated the other NOACs (Table 3).

DiscussionThe objective of this study was to compare and contrast the cost effectiveness of all the OACs available for stroke pro-phylaxis among patients diagnosed with atrial fibrillation in the United States. Our reference therapy was adjusted

Table 1. Key Model Input Parameters

Variable Base Case Range

Cost in 2015 monthly (US$)

Warfarin and international normalized ratio monitoring

39.00 6.00–61.00

Rivaroxaban 238.11 90.48–385.74

Dabigatran 234.28 127.59–340.98

Apixaban 234.87 124.01–345.74

Edoxaban 205.64 69.26–341.97

Rate of ischemic stroke on warfarin for different CHADS2 scores

CHADS2 score 1 0.72 NA




CHADS2 score 5 and 6 4.60 NA

Efficacy of NOACs

Hazard ratios for ischemic stroke, NOACs vs warfarin

Rivaroxaban 0.94 0.75–1.17

Dabigatran 0.76 0.60–0.98

Apixaban 0.92 0.74–1.13

Edoxaban 1.00 0.75–1.19

Hazard ratios for intracranial hemorrhage, NOACs vs warfarin



Apixaban 0.42 0.30–0.58

Edoxaban 0.47 0.34–0.63

Hazard ratios for extracranial hemorrhage, NOACs vs warfarin



Apixaban 0.79 0.68–0.93

Edoxaban 0.91 0.79–1.04

Hazard ratios for myocardial infarction, NOACs vs warfarin



Apixaban 0.88 0.66–1.17

Edoxaban 0.94 0.74–1.19

CHADS2 indicates congestive heart failure (1 point), hypertension (1 point),

age ≥75 years (1 point), diabetes mellitus (1 point), stroke (2 points); NA, not applicable; and NOAC indicates newer oral anticoagulant.


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4 Stroke June 2016

dose warfarin that has been identified as the standard ther-apy in AF management guidelines. Our model shows that all the NOACs are more effective than warfarin; however, the QALY difference between apixaban (most effective NOAC) and rivaroxaban (least effective NOAC) is a mod-est 50 days. In our base case scenario and across most of our sensitivity analyses, apixaban was determined to be the most cost effective strategy dominating all other strategies except warfarin. This finding was relatively robust in our base case probabilistic sensitivity analyses; however, the probabilistic sensitivity analyses that used inflated variance estimates from the pivotal trials showed considerably more uncertainty.

There are a few scenarios in which apixaban would not be the preferred anticoagulant, however. When the effective-ness of dabigatran increased or the effectiveness of apixaban decreased or the baseline rate of stroke increased, dabigatran became the most cost-effective. Similarly, the cost effec-tiveness of apixaban was also sensitive to the effectiveness estimates of edoxaban. Given the relatively modest QALY differences between NOACs and, in particular, between dabigatran, apixaban, and edoxaban, the preferred NOAC may change as more clinical data become available for the NOACs.

The prices of dabigatran and edoxaban also had a meaning-ful impact on the cost effectiveness results. If the monthly costs

Table 2. Base Case Costs, Quality-Adjusted Survival, NMB, and ICERs

Strategy

Therapies in the Order of CostWarfarin as the

Common Reference

Cost (95% CI) QALY (95% CI) ICER NMB (95% CI) ICER

Adjusted dose warfarin

$46 241 (44 499–47 874) 9.02 (8.90–9.12) 0 $856 092 (844 556–866 594) 0

Edoxaban $54 159 (52 670–55 702) 9.31 (9.16–9.40) Ext dom $876 817 (863 807–886 194) $27 643

Apixaban $55 455 (54 138–56 493) 9.38 (9.24–9.48) $25 816 $882 567 (870 327–892 217) $25 816

Dabigatran $56 425 (55 203–57 749) 9.35 (9.23–9.45) Abs dom $878 304 (867 159–887 641) $31 435

Rivaroxaban $58 889 (57 467–60 444) 9.24 (9.11–9.35) Abs dom $865 465 (853 044–875 853) $57 434

Abs dom indicates absolutely dominated; Ext dom, extendedly dominated; ICER, incremental cost effectiveness ratio; NMB, net monetary benefits; and QALY, quality-adjusted life years.

Figure 2. Cost effectiveness (CE) acceptability curve (probability that a treatment will be cost-effective at varying willingness-to-pay thresholds). The percentage of iterations that showed the particular therapy to be CE are plotted on the y-axis vs varying willingness to pay thresholds (plotted in terms of dollars a payer is willing to pay to achieve an additional quality-adjusted life-year for a patient) on the x-axis. A, Depicts the cost effectiveness acceptability curve for the base case scenario. B, The CE acceptability curve after inflating the standard deviations of the efficacy measures for the newer oral anticoagulants by 50%.


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of dabigatran and edoxaban was lowered by ≈13% and 30%, respectively, the ICER for apixaban exceeds $100 000/QALY. This finding is particularly relevant for those managing formu-laries in which rebates and discounts are often negotiated.

This is the first study from a US payer perspective to com-pare all 5 OACs available in the market. There is only 1 study from the UK perspective that compares all 5 OACs simulta-neously and our findings are similar to their findings, where they also found apixaban to be the preferred therapy.43 Our base case estimates show that apixaban and edoxaban are cost effective at a WTP of $50 000/QALY, but all NOACs are con-sidered rational choices at a WTP of $100 000/QALY when compared individually with warfarin. This is in contrast with other models from the US perspective that determined NOACs to be cost effective at a WTP of $50 000/QALY.14–16,18,19,21–23,31 This could possibly be because the fact that all the other mod-els look only at patients who are aged ≥65 years, who would have higher stroke risk.

Our model improves on the previous models by mirror-ing the AF population in the United States. Other models assumed all patients start at a common age and CHADS

2

score,12,14–16,18,19,21–24,31 and we believe that our findings better represent the broad AF population that would be candidates for anticoagulation than previous studies. Another difference between our work and previous modeling studies is our cost-ing approach. The majority of previous studies have used HCUPnet and the study of Holloway et al44,45 to derive event costs of the cerebrovascular accidents (CVAs), MI, and ECH, and used the study of Leibson et al44 to derive the follow-up costs for the CVAs. These studies only consider national aver-ages and are not specific to the AF population; in addition, the studies by Leibson et al44 and Holloway et al45 were con-ducted in 1996, and the estimates based on these data are ≈20 years old and may not be reflective of current clinical care of a CVA. We used the estimates by Forrester et al35 to derive our cost estimates that report the incremental costs of CVAs

among an AF population. Forrester et al35 have used 2007 to 2011 Marketscan data that reflect the cost to private payers and would resemble more contemporary CVA management.

The results of this model should be interpreted while con-sidering the following limitations. First, the effectiveness esti-mates (probabilities and HRs) used in this model are based on clinical trials without head-to-head comparisons with durations much shorter than the lifetime horizon we modeled. To partially account for the indirect evidence from the piv-otal clinical trials, we ran a simulation with inflated variance estimates. Like previous modeling studies, we did not directly model changes in adherence for NOACs or time in therapeu-tic range for warfarin that may overestimate the QALY of all anticoagulants. The model also does not account for incident diabetes mellitus, congestive heart failure, and hypertension, which increases the CHADS

2 score over time and in turn

increases stroke risk. This may overstate QALY of all the anticoagulants, however, may differentially underestimate survival gains of anticoagulants that confer the greatest stroke risk reduction such as dabigatran. Finally, we did not make temporary states to model transitory increased risk of recur-rent events immediately after an event.

ConclusionsAll the NOACs we compared were more effective than adjusted dosed warfarin; however, the QALY among all NOACs was similar. Our model showed that apixaban had the highest QALY in a general AF population and has an ICER <$50 000/QALY. For those with higher stroke risk (CHADS

2≥3), dabi-

gatran had the highest QALY and an ICER <$50 000/QALY. Given the similarity of the QALY of most NOACs, the cost effectiveness of several strategies was sensitive to drug prices and efficacy estimates.

DisclosuresNone.

Table 3. Incremental Cost Effectiveness Ratios by Age, CHADS2 Scores, and Cost and Structural Sensitivity Analyses*

ScenarioPatients ≥

65 yPatients <65 y CHADS

2=1 CHADS

2=2 CHADS

2≥3

Alternate Costing

Scenario†AWP

Costs‡NADAC Costs§

Structural Sensitivity Analysis║

Strategies Incremental cost effectiveness ratios

Adjusted dose warfarin

… … … … … … … … …

Edoxaban Ext dom Ext dom Ext dom Ext dom Ext dom Abs dom Ext dom Ext dom Ext dom

Apixaban $13 662 $34 191 $31 580 $24 691 Abs dom $67 892 $65 332 $45 393 $24 566

Dabigatran Abs dom Abs dom Abs dom Abs dom $16 645 $1832 Abs dom Abs dom Abs dom

Rivaroxaban Abs dom Abs dom Abs dom Abs dom Abs dom Abs dom Abs dom Abs dom Abs dom

Abs dom indicates absolutely dominated; AWP, average wholesale price; CHADS2, congestive heart failure (1 point), hypertension (1 point), age ≥75

years (1 point), diabetes mellitus (1 point), stroke (2 points); Ext dom, extendedly dominated; MI, myocardial infarction; and NADAC, National Average Drug Acquisition Cost.

*For all scenarios in this table, except CHADS2 ≥3 and cost sensitivity analyses 1 therapies are in presented in increasing order of cost. For complete

cost, quality-adjusted survival and net monetary benefit information on all the scenarios please refer to the Table II in the online-only Data Supplement.†Deriving event costs by inflating costs of Lee et al.15

‡Using the Medispan AWP as mean drug cost estimates.§Using the NADAC as mean drug cost estimates.║Assigning MI follow-up costs to patients who get an MI in the post–extracranial hemorrhage phase as well.


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Anuj Shah, Anand Shewale, Corey J. Hayes and Bradley C. MartinNonvalvular Atrial Fibrillation Patients

Cost Effectiveness of Oral Anticoagulants for Ischemic Stroke Prophylaxis Among

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SUPPLEMENTAL MATERIAL

Title: Supplemental Data Tables for Cost effectiveness of Oral Anticoagulants for ischemic

stroke prophylaxis among patients with Nonvalvular Atrial Fibrillation.

Authors: Anuj Shah, B.Pharm*

Anand Shewale, MS*

Corey J. Hayes, PharmD, MPH*

Bradley C. Martin, PharmD, PhD*

Cover Title: Cost Effectiveness of Oral Anticoagulants

Indexing Terms: Cost-Effectiveness Atrial Fibrilation Stroke Anticoagulants Markov

model

Subject terms: Cost-Effectiveness Ischemic Stroke Anticoagulants

*Division of Pharmaceutical Evaluation and Policy, University of Arkansas for Medical Sciences

Supplemental Table I. Model parameters and ranges used in base model.

Variable Base Case Range Distributions Sources

Cost in 2015 (US$)

Total cost of warfarin and international normalized

ratio monitoring, monthly

39 6.00–61.00 Gamma 1

Rivaroxaban, monthly 238.11 90.48–385.74 Gamma 2,3

Dabigatran, monthly 234.28 127.59–340.98 Gamma 2,3

Apixaban, monthly 234.87 124.01–345.74 Gamma 2,3

Aspirin, monthly 0.60 0.15–6.00 Gamma 1

Edoxaban, monthly 205.64 69.26–341.97 Gamma 2,3

Event cost of minor stroke 19,007 16,891–21,124 Gamma 4

Monthly cost of minor stroke 813 212–1,414 Gamma 4

Event cost of moderate to severe stroke 30,046 26,700–33,392 Gamma 4

Monthly cost of moderate to severe stroke 1,285 334–2,235 Gamma 4

Event cost of reversible ischemic neurologic event 11,422 10,151–12,695 Gamma 4

Event cost of intracranial hemorrhage 46,252 33,150–59,356 Gamma 4

Monthly cost of intracranial hemorrhage 3,000 157–5,842 Gamma 4

Monthly cost of stroke and intracranial hemorrhage 3,809 200–7,419 Gamma 4

Event cost of extracranial hemorrhage 15,154 12,872–17,435 Gamma 4

Event cost of clinically relevant nonmajor bleeding 43 0–210 Gamma 1

Event cost of myocardial infarction 33,262 29,839–36,686 Gamma 4

Monthly cost of myocardial infarction 568 534–1,868 Gamma 4

Event cost of nonevent death 6,261 3,674–7,873 Gamma 1

Annual discount rate (%) 3 0–5 Beta Assumed

Utility

Healthy on warfarin (Annual) 0.987 0.940–1.000 Beta 5

Healthy on rivaroxaban, dabigatran, apixaban or

edoxaban (Annual)

0.994 0.975–1.000 Beta 6

Healthy on aspirin (Annual) 0.998 0.994–1.000 Beta 5

Major neurologic event (Annual) 0.390 0–1.000 Beta 5

Minor neurologic event (Annual) 0.760 0–1.000 Beta 5

Disutility of Non-ICH bleed event (Annual) -0.160 -0.300 to 0 Beta 7

Myocardial infarction (Annual) 0.840 0.500–1 Beta 8

Probabilities

Baseline rate of stroke on warfarin (%/year)

(CHADS2 score 1)

0.72 N/A* 9


(CHADS2 score 2)

1.27 N/A* 9


(CHADS2 score 3)

2.00 N/A* 9


(CHADS2 score 4)

2.35 N/A* 9


(CHADS2 score 5 & 6)

4.60 N/A* 9

Hazard ratio of stroke on rivaroxaban 0.94 0.75–1.17 Log-Normal 10

Hazard ratio of stroke on dabigatran 0.76 0.60–0.98 Log-Normal 11

Hazard ratio of stroke on apixaban 0.92 0.74–1.13 Log-Normal 12

Hazard ratio of stroke on Edoxaban 1.00 0.75–1.19 Log-Normal 13

Proportions of ischemic strokes with warfarin,

dabigatran, Apixaban, Edoxaban or rivaroxaban (%)

1,14–17

Fatal 8.20 8.20–10.10 Beta

Major 40.20 40.20–41.70 Beta

Minor 42.50 34.80–42.50 Beta

No residual deficit 9.10 9.10–13.30 Beta

Relative risk of stroke per 10 years of life 1.40 N/A 18

Relative risk of stroke for aspirin 2.08 1.59–2.70 Log-Normal 19

Proportions of ischemic strokes with aspirin (%) 1,14–16

Fatal 17.90 10.10–17.90 Beta

Major 30.00 30.00–41.10 Beta

Minor 41.00 34.80–41.00 Beta

No residual deficit 11.00 11.00–13.30 Beta

Baseline rate of intracranial hemorrhage on warfarin

(%/year)

0.70 0.59–0.90 Beta 10

Relative risk of intracranial hemorrhage per 10 years

of life

1.97 N/A* 20

Hazard ratio of intracranial hemorrhage on

Rivaroxaban

0.67 0.47–0.93 Log-Normal 10

Hazard ratio of intracranial hemorrhage on

Dabigatran

0.40 0.27 – 0.60 Log-Normal 11

Hazard ratio of intracranial hemorrhage on Apixaban 0.42 0.30–0.58 Log-Normal 12

Hazard ratio of intracranial hemorrhage on Edoxaban 0.47 0.34-0.63 Log-Normal 13

Relative risk of intracranial hemorrhage on aspirin 0.51 0.16–1.60 Log-Normal 21

Proportions of intracranial hemorrhage with

warfarin, rivaroxaban, dabigatran, apixaban,

Edoxaban and aspirin (%)

22

Fatal 36.40 28.30–45.20 Beta

Major 14.10 9.00–21.40 Beta

Minor 49.50 N/A*

Baseline rate of extracranial hemorrhage on warfarin

(%/year)

2.70 2.35–2.93 Beta 10

Hazard ratio of extracranial hemorrhage on

Rivaroxaban

1.04 0.90–1.20 Log-Normal 10


Dabigatran

1.07 0.78–1.25 Log-Normal 11

Hazard ratio of extracranial hemorrhage on Apixaban 0.79 0.68–0.93 Log-Normal 12


Edoxaban

0.91 0.79–1.04 Log-Normal 13

Relative risk of extracranial hemorrhage on aspirin 1.14 0.47–2.73 Log-Normal 21

Proportion of extracranial hemorrhage that are fatal

(%)

1.47 1.00–4.00 Beta 1

Baseline rate of clinically relevant nonmajor

bleeding on warfarin (%/year)

11.40 10.00–12.00 Beta 10

Hazard ratio clinically relevant nonmajor bleeding on

Rivaroxaban

1.04 0.96–1.13 Log-Normal 10


Dabigatran

0.91 0.85–0.97 Log-Normal 11


Apixaban

0.69 0.59–0.80 Log-Normal 12


Edoxaban

0.86 0.79–0.93 Log-Normal 13

Relative risk of clinically relevant nonmajor bleeding

on aspirin

0.63 0.32–1.22 Log-Normal 21

Baseline rate of myocardial infarction on warfarin

(%/year)

1.12 0.93–1.31 Beta 10

Relative risk of myocardial infarction per 10 years of

life

1.30 N/A* 1,14,16,17

Hazard ratio of myocardial infarction on

Rivaroxaban

0.81 0.63–1.06 Log-Normal 10

Hazard ratio of myocardial infarction on Dabigatran 1.31 0.89–1.91 Log-Normal 11

Hazard ratio of myocardial infarction on Apixaban 0.88 0.66–1.17 Log-Normal 12

Hazard ratio of myocardial infarction on Edoxaban 0.94 0.74–1.19 Log-Normal 13

Relative risk of myocardial infarction on aspirin 1.42 0.84–2.39 Log-Normal 21

Proportion of myocardial infarction that are fatal (%) 16.6 15.8–17.4 Beta 23

Relative risk of nonevent death with nonvalvular

atrial fibrillation

1.30 1.12–1.62 Log-Normal 24

Relative risk of nonevent death with nonvalvular

atrial fibrillation and stroke

2.30 1.30–3.00 Log-Normal 25

Age Distribution for CHADS2 scores 26

Age for CHADS2 score 1 62 18–98 Normal





Age for CHADS2 score 6 81 75–96 Normal * - Not Applicable

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Supplemental Table II. Projected Costs, Quality Adjusted Survival, Net Monetary Benefits

(NMB) and Incremental Cost Effectiveness Ratios (ICER) for all the scenarios.

Therapies in the order of cost

Subgroup Analysis for >=65

Strategy Cost QALY ICER ICER with

Warfarin

as common

Baseline

NMB

(95% CI)

Adjusted dose

warfarin

$38,406

(34,460 – 42,780)

5.79

(0.20 – 16.04)

- - $540,611

(514,055 – 570,922)

Edoxaban $42,017

(38,572 – 45,822)

6.04

(0.20 – 16.62)

Ext.

Dom

$14,533 $561,845

(536,361 – 591,999)

Apixaban $42,479

(39,273 – 45,321)

6.09

(0.20 – 16.64)

$13,662 $13,662 $566,348

(546,390 – 594,081)

Dabigatran $43,670

(40,208 – 46,685)

6.09

(0.20 – 16.72)

Abs

Dom

$17,796 $564,928

(538,037 – 592,446)

Rivaroxaban $46,134

(42,793 – 50,105)

5.98

(0.20 – 16.47)

Abs

Dom

$41,054 $551,706

(527,365 – 579,913)

Subgroup Analysis for 65<

Strategy Cost

(95% CI)

QALY

(95% CI)

ICER ICER with

Warfarin

as common

Baseline

NMB

(95% CI)

Adjusted dose

warfarin

$55,715

(50,445 – 61,487)

12.85

(12.46 – 13.18)

- - $1,229,467

(1,190,535 – 1,265,604)

Edoxaban $68,338

(63,890 – 72,904)

13.19

(12.81 – 13.59)

Ext.

Dom

$37,375 $1,250,617

(1,209,837 – 1,289,875)

Apixaban $70,640

(65,964– 75,234)

13.29

(12.86 – 13.67)

$34,191 $34,191 $1,258,194

(1,219,084 – 1,293,411)

Dabigatran $71,711

(67,292 – 76,659)

13.21

(12.87 – 13.61)

Abs

Dom

$44,799 $1,249,177

(1,216,443 – 1,286,747)

Rivaroxaban $74,165

(69,280 – 79,625)

13.12

(12.72 – 13.51)

Abs

Dom

$69,958 $1,237,390

(1,195,829 – 1,275,333)

Subgroup Analysis for CHADS2 = 1

Strategy Cost

(95% CI)

QALY

(95% CI)

ICER ICER with

Warfarin

as common

Baseline

NMB

(95% CI)

Adjusted dose

warfarin

$47,600

(42,225 – 53,459)

10.85

(10.42 – 11.34)

- - $1,037,165

(993,627 – 1,085,820)

Edoxaban $57,607

(53,066 –62,480)

11.16

(10.72 – 11.69)

Ext

Dom

$31,749 $1,058,679

(1,017,393 – 1,108,091)

Apixaban $59,880

(55,966 – 64,009)

11.24

(10.73 – 11.79)

$31,580 $31,580 $1,063,770

(1,013,460 – 1,117,603)

Dabigatran $61,027

(8,612 – 252,859)

11.17

(10.71 – 11.66)

Abs

Dom

$41,395 $1,056,174

(1,012,266 – 1,101,950)

Rivaroxaban $63,043

(57,568 –67,883)

11.09

(10.61 – 11.60)

Abs

Dom

$63,563 $1,046,018

(995,136 – 1,095,686)

Subgroup Analysis for CHADS2 = 2

Strategy Cost

(95% CI)

QALY

(95% CI)

ICER ICER with

Warfarin

as common

Baseline

NMB

(95% CI)

Adjusted dose

warfarin

$45,154

(40,560 – 50,302)

8.31

(7.90 – 8.70)

- - $786,340

(746,823 – 823,419)

Edoxaban $52,405

(46,914 –57,769)

8.59

(8.21 – 9.00)

Ext

Dom

$26,191 $806,773

(770,537 – 848,391)

Apixaban $53,713

(49,134 – 57,657)

8.66

(8.26 – 9.03)

$24,691 $24,691 $812,445

(776,922 – 848,128)

Dabigatran $54,507

(50,566 – 59,202)

8.64

(8.17 – 9.05)

Abs

Dom

$28,569 $809,726

(763,273 – 848,528)

Rivaroxaban $57,017

(52,673 – 61,603)

8.52

(8.13 – 8.91)

Abs

Dom

$56,850 $795,344

(757,987 – 832,107)

Subgroup Analysis for CHADS2 >= 3

Strategy Cost

(95% CI)

QALY

(95% CI)

ICER ICER with

Warfarin

as common

Baseline

NMB

(95% CI)

Adjusted dose

warfarin

$44,558

(40,436 –48,116)

6.20

(5.96 – 6.48)

- - $575,203

(552,518 – 605,677)

Edoxaban $49,291

(45,254 – 54,296)

6.44

(6.20 – 6.73)

Ext.

Dom

$19,592 $594,628

(570,183 – 622,739)

Apixaban $49,903

(46,113 – 53,852)

6.51

(6.26 – 6.79)

Ext.

Dom

$17,064 $601,182

(577,134 – 629,052)

Dabigatran $50,130

(46,532 – 53,556)

6.53

(6.26 – 6.82)

$16,645 $16,645 $603,108

(579,012 – 630,616)

Rivaroxaban $51,024

(46,547 – 55,756)

6.39

(6.14 – 17.68)

Abs

Dom

$34,213 $587,637

(562,490 – 616,946)

Structural Sensitivity Analysis assigning MI follow up costs to patients who get MI after ECH and

vice versa

Strategy Cost QALY ICER ICER with

Warfarin

as common

Baseline

NMB

(95% CI)

Adjusted dose

warfarin

$47,525

(42,257 – 53,634)

9.01

(8.58 – 9.40)

- - $853,474

(814,519 – 893,393)

Edoxaban $55,329

(51,467 – 60,666)

9.30

(8.90 – 9.69)

Ext.

Dom

$26,687 $874,914

(835,425 – 913,462)

Apixaban $56,450 9.37 $24,566 $24,566 $880,081

(52,394 –61,827) (8.98 – 9.77) (841,019 – 920,551)

Dabigatran $58,261

(54,309 – 62,114)

9.34

(8.89 – 9.74)

Abs

Dom

$32,785 $875,485

(832,600 – 913,308)

Rivaroxaban $60,365

(55,415 – 66,130)

9.23

(8.84 – 9.61)

Abs

Dom

$57,512 $862,960

(824,471 – 902,205)

Alternate Costing Scenario 1 - Using Inflated Costs of Lee et al

Strategy Cost

(95% CI)

QALY ICER ICER with

Warfarin

as common

Baseline

NMB

(95% CI)

Adjusted dose

warfarin

$71,195

(59,713 – 82,260)

9.04

(8.71 – 9.35)

- - $833,126

(795,355 –862,584)

Dabigatran $71,775

(62,760 – 80,065)

9.36

(8.98 – 9.65)

$1,832 $1,832 $864,195

(826,276 –893,543)

Apixaban $74,234

(65,190 – 85,677)

9.40

(9.03 – 9.76)

$67,892 $8,617 $865,358

(828,164 –906,741)

Edoxaban $79,696

(7,865 – 91,392)

9.33

(8.97 – 9.67)

Abs

Dom

$29,884 $853,071

(818,076 - 890,758)

Rivaroxaban $80,474

(71,504 – 91,183)

9.26

(8.90 – 9.58)

Abs

Dom

$42,746 $845,554

(812,315 – 875,000)

Alternate Costing Scenario 2 – Using NADAC costs for NOACs

Strategy Cost

(95% CI)

QALY

(95% CI)

ICER ICER with

Warfarin

as common

Baseline

NMB

(95% CI)

Adjusted dose

warfarin

$46,196

(41,460 –50,799)

9.05

(8.58 – 9.48)

-

- $859,092

(818,302 – 901,625)

Edoxaban $59,757

(53,083 – 63,670)

9.34

(8.91 – 9.74)

Ext.

Dom

$46,912 $874,438

(832,651 – 912,631)

Apixaban $62,452

(57,401 – 66,818)

9.41

(8.92 – 9.81)

$45,393 $45,393 $878,647

(836,725 – 917,308)

Dabigatran $62,774

(58,493 – 66,553)

9.37

(8.94 – 9.80)

Abs

Dom

$51,570 $874,660

(833,873 – 915,034)

Rivaroxaban $65,416

(60,053 – 69,672)

9.28

(8.84 – 9.74)

Abs

Dom

$85,999 $862,221

(821,171 – 906,534)

Alternate Costing Scenario 3 – Using AWP costs for NOACs

Strategy Cost

(95% CI)

QALY

(95% CI)

ICER ICER with

Warfarin

as common

Baseline

NMB

(95% CI)

Adjusted dose

warfarin

$46,196

(41,460 – 50,799)

9.05

(8.58 – 9.48)

-

- $859,092

(818,302 – 901,625)

Edoxaban $65,977

(60,547 – 69,583)

9.34

(8.92 – 9.74)

Ext

Dom

$68,384 $868,237

(827,662 – 906,881)

Dabigatran $69,544 9.37 Ext $72,630 $867,890

(64,989 – 73,509) (8.94 – 9.80) Dom (827,331 – 907,890)

Apixaban $69,592

(64,269 – 74,186)

9.41

(8.92 – 9.81)

$65,332 $65,332 $871,507

(829,754 – 909,648)

Rivaroxaban $71,685

(66,033 – 75,883)

9.28

(8.84 – 9.74)

Abs

Dom

$114,049 $855,952

(815,197 – 900,082)

Ext Dom – Extendedly Dominated

Abs Dom – Absolutely Dominated

Supplemental Figure I

Tornado diagram for one-way sensitivity analyses. Vertical bar represent the changes in the

model parameters. Horizontal axis represents the net monetary benefit expected by varying the

model parameters.

WAR – Adjusted Dose Warfarin

DAB – Dabigatran

API – Apixaban

EDO – Edoxaban

ICH – Intracranial Hemorrhage

ECH – Extracranial Hemorrhage

MI – Myocardial Infarction

HR – Hazard Ratio

Supplemental Figure II

Tornado diagram for one-way sensitivity analyses of all utility parameters. We had programmed

some of the utility parameters as disutilities (Bleed event other than ICH, MI, minor and major

neurologic events) derived as 1-utility. Hence for these parameters our tornado diagram

represents disutilities and not utilities.




NOACs – Newer Oral Anticoagulants

Supplemental Figure III

Tornado diagram for one-way sensitivity analyses of all the cost inputs.


DAB – Dabigatran

API – Apixaban

EDO – Edoxaban




RIND – Reversible Ischemic Neurologic Damage

Supplemental Figure IV

Tornado diagram for one-way sensitivity analyses for all probabilities related to Extracranial

Hemorrhage.


DAB – Dabigatran

API – Apixaban

EDO – Edoxaban


HR – Hazard Ratio

RR – Relative Risk

Supplemental Figure V

Tornado diagram for one-way sensitivity analyses for all probabilities related to Intracranial

Hemorrhage.


DAB – Dabigatran

API – Apixaban

EDO – Edoxaban


HR – Hazard Ratio


Supplemental Figure VI

Tornado diagram for one-way sensitivity analyses for all probabilities related to Myocardial

Infarction.


DAB – Dabigatran

API – Apixaban

EDO – Edoxaban


HR – Hazard Ratio


Supplemental Figure VII

Tornado diagram for one-way sensitivity analyses for all probabilities related to clinically

relevant non-major bleeding (minor bleed).


DAB – Dabigatran

API – Apixaban

EDO – Edoxaban

HR – Hazard Ratio


Supplemental Figure VIII

Tornado diagram for one-way sensitivity analyses for all probabilities related to ischemic stroke.


DAB – Dabigatran

API – Apixaban

EDO – Edoxaban

HR – Hazard Ratio


OAC – Oral Anticoagulants (Warfarin, Dabigatran, Apixaban, Rivaroxaban and Edoxaban)

RIND – Reversible Ischemic Neurologic Damage

Abstract 25

非弁膜症性心房細動患者の虚血性脳卒中予防における経口抗凝固薬の費用対効果

Cost-Effectiveness of Oral Anticoagulants for Ischemic Stroke Prophylaxis Among Nonvalvular Atrial Fibrillation Patients

Anuj Shah, BPharm; Anand Shewale, MS; Corey J. Hayes, PharmD, MPH, et al.Division of Pharmaceutical Evaluation and Policy, University of Arkansas for Medical Sciences, Little Rock

背景および目的：本研究の目的は，脳卒中リスクが高い心房細動患者において経口抗凝固薬の費用対効果を比較することである。方法：Markov モデルを構築し，民間保険業者の観点から経口抗凝固薬の生涯費用および質調整生存年（QALY）を推定した。営利保険に加入する新規発症心房細動患者のコホートから脳卒中リスク（CHADS2 スコア：うっ血性心不全，高血圧症，高齢，糖尿病，脳卒中）およびモデル化した集団における年齢の分布を求めた。公表された臨床試験から治療特異的イベントの発生率を求めた。疾病費用に関する研究からイベントおよび発症後の費用を求めた。薬剤費は 2015 年の National Average Drug Acquisition Costデータから得た。結果：ベースケース分析で費用が最も低い薬剤はワルファリンであり（$46,241，95％ CI：44,499 ～ 47,874），QALYが最も高い薬剤はアピキサバンであった（9.38，95％ CI：9.24 ～ 9.48 QALY）。アピキサバンは，ワルファ

リンよりも費用対効果に優れた治療法であることが明らかになり（増分費用対効果比＝ $25,816），また，他の抗凝固薬よりも優位であった。確率的感度分析から，支払意思額をQALYあたり $100,000 とした場合，アピキサバンは少なくとも 61％の確率で最も費用対効果に優れた治療法であることが明らかになった。CHADS2 ≧ 3 の患者では，ダビガトランが優位な治療法であった。本モデルはアピキサバン，ダビガトラン，エドキサバンの有効性およびこれらの薬剤の費用の影響を受けた。結論：比較したすべての新しい経口抗凝固薬は用量で調節後のワルファリンよりも有効であった。本モデルから，アピキサバンは一般的な心房細動集団において最も効果的な抗凝固薬であり，増分費用対効果比は $50,000/QALY未満であることが明らかになった。脳卒中リスクが高い集団（CHADS2 ≧ 3）では，ダビガトランが最も費用対効果に優れた治療選択肢であった。

Stroke. 2016; 47: 1555-1561. DOI: 10.1161/STROKEAHA.115.012325.

Abstract

表2　ベースケースの費用，質調整生存年，NMB，ICER

治療法（費用順）ワルファリン

（共通の基準群）

治療法費用（95% CI） QALY（95% CI） ICER NMB（95% CI） ICER

ワルファリン（用量調節後）

$46,241 (44,499‒47,874) 9.02 (8.90‒9.12) 0 $856,092 (844,556‒866,594) 0

エドキサバン $54,159 (52,670‒55,702) 9.31 (9.16‒9.40) Ext dom $876,817 (863,807‒886,194) $27,643

アピキサバン $55,455 (54,138‒56,493) 9.38 (9.24‒9.48) $25,816 $882,567 (870,327‒892,217) $25,816

ダビガトラン $56,425 (55,203‒57,749) 9.35 (9.23‒9.45) Abs dom $878,304 (867,159‒887,641) $31,435

リバーロキサバン $58,889 (57,467‒60,444) 9.24 (9.11‒9.35) Abs dom $865,465 (853,044‒875,853) $57,434

Abs dom：絶対的に優位，Ext dom：広く優位，ICER：増分費用対効果比，NMB：純金銭便益，QALY：質調整生存年。

表3　年齢，CHADS2 スコア，費用別の増分費用対効果比および構造的感度分析 *

シナリオ 65歳以上の患者 65歳未満の患者 CHADS2＝ 1 CHADS2＝ 2 CHADS2≧ 3 別の費用シナリオ† AWP費用‡ NADAC費用§ 構造的感度分析‖

治療法増分費用対効果比

ワルファリン（用量調節後）

… … … … … … … … …

エドキサバン Ext dom Ext dom Ext dom Ext dom Ext dom Abs dom Ext dom Ext dom Ext dom

アピキサバン $13,662 $34,191 $31,580 $24,691 Abs dom $67,892 $65,332 $45,393 $24,566

ダビガトラン Abs dom Abs dom Abs dom Abs dom $16,645 $1,832 Abs dom Abs dom Abs dom

リバーロキサバン Abs dom Abs dom Abs dom Abs dom Abs dom Abs dom Abs dom Abs dom Abs dom

Abs dom：絶対的に優位，AWP：平均卸売価格，CHADS2：うっ血性心不全（1点），高血圧症（1点），年齢 75歳以上（1点），糖尿病（1点），脳卒中（2点），Ext dom：広く優位，MI：心筋梗塞，NADAC：National Average Drug Acquisition Cost。*CHADS2≧ 3 および費用感度分析を除く本表のすべてのシナリオの治療法は費用の昇順で提示した。すべてのシナリオの完全な費用，質調整生存年，純金銭便益に関する情報については，オンラインデータ補遺の表 II を参照のこと。†Lee ら（文献 15）の増大費用別にイベント費用を算出。‡Medispan AWPを平均薬剤費の推定値として使用。§NADACを平均薬剤費の推定値として使用。‖MI の経過観察費用を頭蓋外出血期のMI を発症した患者にも割り当てる。

STR-J_11-3_Ab10_main.indd 25STR-J_11-3_Ab10_main.indd 25 10/26/2016 7:24:10 PM10/26/2016 7:24:10 PM

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