University of Groningen Health economics of direct oral anticoagulants in the Netherlands de Jong, Lisa

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Health economics of direct oral anticoagulants in the Netherlands

de Jong, Lisa

DOI:

10.33612/diss.129441687

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Publication date: 2020

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de Jong, L. (2020). Health economics of direct oral anticoagulants in the Netherlands. University of Groningen. https://doi.org/10.33612/diss.129441687

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L.A. de Jong E.P. Dvortsin K.J. Janssen M.J. Postma

Clin Ther 2017 Feb;39(2):288-302

analysis for apixaban in the acute

treatment and prevention of venous

thromboembolism in the Netherlands

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Abstract

Purpose: Low molecular weight heparin (LMWH) followed by vitamin K antagonists

(VKAs) are the current standard treatment of acute venous thromboembolism (VTE) and prevention of recurrent VTE. The direct oral anticoagulant apixaban was recently found to be noninferior in efficacy and superior in preventing major bleeding compared with LMWH/VKA in the AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis as First-Line Therapy) trial. The objective of this study was to calculate the cost-effectiveness of apixaban compared with LMWH/VKA in the treatment of acute VTE and prevention of recurrent VTE in the Netherlands.

Methods: A Markov model was designed to simulate a cohort of 1,000 VTE patients

receiving either apixaban or LMWH/VKA. Transition probabilities, costs, and utilities were obtained from the AMPLIFY trial and other literature. The incremental cost-effectiveness ratio (ICER) was calculated from the societal perspective, therefore, the model included both direct (inside and outside the healthcare sector) and indirect costs. In the univariate and probabilistic sensitivity analyses (PSAs) the robustness of the results was tested, and various additional scenario analyses were conducted.

Findings: In the base case analysis, apixaban saved €236 and 0.044 quality-adjusted life

years (QALYs) and 0.039 LYs were gained compared with LMWH/VKA. In the univariate sensitivity analysis, the model appeared to be robust. The results of 2,000 iterations in the PSA found that the probability of apixaban being cost-effective at a willingness-to-pay threshold of €20,000/QALY was 100% and cost-saving was 94%. The scenario of 18-months treatment duration was the only scenario not indicating cost-savings with an ICER of €425/QALY.

Implications: In acute anticoagulation use of apixaban was found to be cost-saving. A

longer anticoagulation period (18 months) resulted in a higher difference in drug costs, indicating a higher ICER. The cost-effectiveness of long-term or life-long use should be examined in future research.

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Introduction

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are collectively known as venous thromboembolism (VTE). DVT is a blood thrombus mostly seen in the calf veins, and PE is the result of a free clot causing obstruction in the pulmonary veins. Diagnosis of VTE is based on the symptoms and a D-dimer test, and risk factors (e.g. recent surgery, smoking) can confirm the suspicion [1].

In 2014 a total of approximately 60,000 VTE patients, including nearly 19,000 new patients, were monitored by the Dutch Thrombosis Service [2]. Of these patients 56% were treated for (recurrent) DVT and 44% for (recurrent) PE [2]. In general practice, the incidence of DVT and PE is respectively 0.5 to 1.5 and 0.2 per 1,000 patients per year [1]. The incidence of suspected PE, estimated by a survey among Dutch pulmonologists and internists, was 2.6 per 1,000 inhabitants per year, of which about 30% actually had PE [3]. The recurrence of VTE is 7% per year, and 30% of the patients experience a recurrent VTE (RecVTE) event within 8 years [1,4].

The occurrence of VTE imposes a decreased health-related quality of life and increased costs due to extending hospital stays, additional hospitalizations, and increased case-fatality and mortality rates in patients with PE [5,6]. Although VTE is treated as an acute event, it is associated with an increased risk of recurrence and chronic complications [1]. Post-thrombotic syndrome (PTS) can develop after chronic venous valve insufficiency caused by DVT. A rare delayed complication of PE is chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH is caused by arterial lung obstruction, which can induce heart failure [1].

The current treatment procedure of acute VTE in the Netherlands consists of a minimum of 5 days of low molecular weight heparin (LMWH), followed by at least 3 months of anticoagulation with a vitamin K antagonist (VKA; e.g. warfarin, acenocoumarol, phenprocoumon). Some high-risk patients receive anticoagulants as prophylaxis for a longer period [3]. Although the anticoagulation effect of VKA is considered strongly effective, the use is limited because of increased bleeding risks, a narrow therapeutic range, and the interactions with food and other drugs. Because of the narrow therapeutic range, monitoring of the international normalized ratio (INR) of the prothrombin time of the patients is required. In the Netherlands the INR range for VTE is 2.0 to 3.5, and the monitoring is conducted by specialized thrombotic services [1–3].

Lately, direct oral anticoagulants (DOACs) have been developed, which address most of these issues. Next to dabigatran, rivaroxaban, and edoxaban, apixaban is one of the representatives of this group of DOACs. Although VKAs inhibit several coagulation factors indirectly, apixaban is a specific factor Xa inhibitor, enabling a more predictable therapeutic effect [7]. Next to this, treatment with apixaban does not require INR monitoring and LMWH use. The AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) trial reported the effectiveness and safety profile of apixaban compared with warfarin in the acute (6 months) treatment of VTE [8]. The trial found noninferiority of apixaban to warfarin in the recurrence VTE or VTE-related death (VTEdie). Moreover, apixaban treatment was associated with a significant

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reduction of major bleeding (MB) and clinically relevant non-MB. In the AMPLIFY-EXT (for Extended Treatment of Venous Thromboembolism) trial an extended treatment of an additional 6 months of therapy of apixaban in two different doses (2.5 and 5.0 mg) was compared with placebo for the prevention of VTE [9]. Apixaban treatment was found to reduce the risk of RecVTE and VTEdie, without increasing bleeding risks.

With increasing importance of cost-effectiveness in decision making, the consequences for the quality of life and costs associated with apixaban compared with LMWH/VKA need to be considered. This is in particular the case in Western countries, such as the Netherlands [10]. The aim of this study is to estimate the cost-effectiveness of apixaban compared with LMWH/VKA in the acute treatment and secondary prevention of VTE in the Netherlands.

Methods

Decision Model

The cost-effectiveness of apixaban compared with the current standard treatment of LMWH/VKA was calculated using a cohort-based Markov model designed in Excel (Microsoft, Redman, Washington; 2013) [11,12]. A cohort of 1,000 patients who had just experienced a VTE event was followed in the model. The population had an average starting age of 57 years and 59% were male, based on the patient characteristics of the AMPLIFY trial (see Table A1) [8].

In the Markov model, the patients move through 12 health states: index DVT, index PE, RecVTE (RecPE or RecDVT), VTEdie, MB, clinically relevant non-major bleeding (CRNMB), CTEPH, PTS, treatment discontinuation (TxDiscontinue), other death, and no event. The pathways that specify the transitions among the different health states are detailed in Figure 1. A cycle length of 3 months was used, and in each cycle only one event was allowed to occur. The model used half-cycle corrections [11]. Specific event probabilities were based on the AMPLIFY and AMPLIFY-EXT trials and previously published articles [8,9]. In these trials, warfarin, which is the worldwide most used VKA, was compared with apixaban. In the Netherlands the most used VKAs are acenocoumarol and phenprocoumon. Because the Dutch reimbursement authorities presume the efficacy and safety profile of warfarin is similar to acenocoumarol and phenprocoumon, these risks found in these trials could also be applied in a model specific for the Netherlands.

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Figure 1. Schematic structure of the cohort-based Markov model. Abbreviations: CRNMB, clinically relevant non-major bleed; CTEPH, chronic thromboembolic pulmonary hypertension; DVT, deep vein thrombosis; EC, extracranial, IC, intracranial; MB, major bleed; PE, pulmonary embolism; Rec, recurrent; TxDiscontinue, treatment discontinuation; VTEdie, venous thromboembolism-related death.

Patients who just experienced a PE or DVT entered the model in the state index PE or index DVT. The distribution over PE and DVT was based on the AMPLIFY trial [8]. Shortly after entering the index state, patients received an initial treatment of 6 months of anticoagulation with either apixaban or 7 days of LMWHs, followed by VKA [8]. Subsequently, the patients were exposed to risks of RecVTE events, bleeding events, chronic consequence CTEPH, TxDiscontinue, and death from other causes (background mortality). On the recurrence of VTE during the initial anticoagulation treatment, the current treatment was extended by 6 months. In case RecVTE occurred after the initial treatment, the patients were signed up for a 6-month treatment with LMWH/VKA in the model [9].

RecVTE was divided into VTEdie, non-fatal RecPE, and non-fatal RecDVT because of differing effects on health outcomes, costs, and rates of mortality [1,4]. After a RecPE or RecDVT, patients move to the states index PE and index DVT, respectively. Consequences associated with PE on health outcomes and costs are considered more serious than those of DVT [1,3,4]. Therefore, patients who had experienced a PE in the past return to the state index PE after a RecVTE, regardless of the origin (PE or DVT). As a result, patients who experienced both DVT and PE have assigned risks of CTEPH and PTS in the model.

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Once patients developed the chronic complication CTEPH, they moved to a post-CTEPH state with higher mortality risks and could not move to other states except death. MB could be fatal or non-fatal. In the case of non-fatal MB, a patient had either an intracranial (IC) bleeding or an extracranial (EC) bleeding. On the occurrence of an IC bleeding, patients moved to a post-IC bleeding state with higher mortality risks and could not move to other states, similar to the post-CTEPH state. After patients experienced a non-fatal non-IC bleeding or a CRNMB, they returned to the initial index state.

Next to the TxDiscontinue due to non-fatal EC bleeding (Figure 1), TxDiscontinue

unrelated to bleeding events was modelled explicitly. Because of TxDiscontinue patients move to VTE off treatment, in which their risks were updated to no treatment [9]. A second-line treatment, for example with aspirin, is not specified by clinical guidelines in the Netherlands; therefore, it was not included in the model [1,3].

The outcome of the economic evaluation is the incremental cost-effectiveness ratio (ICER) of apixaban compared with LMWH/VKA for acute treatment and prevention of VTE. The effectiveness measures are expressed in terms of the numbers of avoided VTE or bleeding events, life years (LYs), and quality-adjusted LYs (QALYs).

Transition Probabilities

The transition probabilities in the model for patients treated with apixaban or LMWH/ VKA in the first 6 months were obtained from the AMPLIFY trial [8] and previously published articles (Table 1) [13,14]. The risks of VTEdie and RecVTE, MB, and clinically relevant non-MB were considered to be time dependent, with risks presented for 3-month intervals. The distribution of RecPE, RecDVT, and VTEdie was based on pooled estimates of the clinical trials (AMPLIFY and AMPLIFY-EXT) and was assumed to be equal across treatments [8,9]. After treatment cessation, lifetime risk of RecVTE was calculated from the cumulative 10-year incidence at 39.9% found by Prandoni et al. [14].

The absolute risks of MB were obtained from the AMPLIFY trial [8]. The distribution of the nature of the bleeding was based on a study by Linkins et al. [15]: 13.46% of the MBs were fatal and 13.97% were IC bleedings. The residual MBs were assumed to be EC, but no distinction was made in the origin of the EC bleedings. Patients with non-fatal IC bleeding moved to a post-IC bleeding state and were assigned higher mortality rates [16]. EC bleeding was assumed to have no effect on patients’ rate of mortality.

Only patients in the health state PE were exposed to the risk of CTEPH, which is assumed to be equal across treatments. Once a patient moved to the post-CTEPH state, they discontinued the treatment permanently and were assigned higher mortality rates [17]. The risk of PTS, obtained from a prospective study by Prandoni et al. [18], was applied to patients in index DVT and patients in index PE who had experienced a DVT. The model assumed a 5-year risk of severe PTS of 8.1% among patients with DVT. Only the incidence of severe PTS was applied to the model, because it was assumed that mild PTS did not affect the costs and health outcomes of the patients.

The background mortality was obtained from Statistics Netherlands [19]. Patients in the index, post-IC bleeding, and post-CTEPH states were assigned higher mortality

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rates by applying corresponding hazard ratios obtained from previously published articles [13,16,17].

Table 2. Base-case transition probabilities per specific time period with the associated ranges and distributions used in the probabilistic sensitivity analysis.

Transition probability Value (95% CI/range) Distribution Source

Recurrent VTE and VTE-related death

Apixaban 0-3 months 0.0171 (0.01220-0.02200) Beta Agnelli et al. [8]

LMWH/VKA 0-3 months 0.0214 (0.01600-0.02690) Beta Agnelli et al. [8]

LMWH/VKA 3-6 months 0.0048 (0.00220-0.00750) Gamma Agnelli et al. [8]

Distribution of PE, DVT and VTE related death 0-6 months

VTE related death 0.2154 Fixed Agnelli et al. [8]

Recurrent PE 0.3769 Fixed Agnelli et al. [8]

Recurrent DVT 0.4077 Fixed Agnelli et al. [8]

Cumulative incidence of risk recurrent VTE post-treatment cessation

0-1 years 0.0110 (0.0950-0.1250) Beta Prandoni et al. [14]

Major bleeding

Apixaban 3-6 months 0.0015 (0.00003-0.00296) Gamma Agnelli et al. [8]

Proportion of fatal major bleeding among major bleeding, and non-fatal IC bleeding among non-fatal major bleeding

Fatal major bleeding 0.1346 (0.1128-0.1580) Beta Linkins et al. [15]

Non-fatal IC bleeding 0.1397 (0.1160-0.1652) Beta Linkins et al. [15]

Risk of CRNMB

Bleeding risk adjustment factor major bleeding and CRNMB (per decade)

1.970 (1.7900-2.1600) Log normal Ariesen et al. [20]

Risk of treatment interruption after non-IC bleeding (14 days)

0.4727 0.3434-0.6039) Beta Agnelli et al. [8]

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Table 2. Base-case transition probabilities per specific time period with the associated ranges and distributions used in the probabilistic sensitivity analysis. (continued)

Transition probability Value (95% CI/range) Distribution Source

Risk of treatment

interruption after CRNMB (2 days)

1.0000 Fixed Assumption

Risk of other treatment discontinuation (unrelated to discontinuation due to the events modelled)

Annual risk of CTEPH in PE patients

0.0125 (0.0003-0.0246) Beta Miniati et al. [21]

5-year risk of severe PTS in DVT patients

0.0810 (0.5000-1.0000) Beta Prandoni et al [18]

Hazard ratios mortality risks

Index DVT (HR) 4.41 (3.63-5.36) Gamma Flinterman et al. [16]

Index PE (HR) 4.41 (3.63-5.36) Gamma Flinterman et al. [16]

Post-IC bleeding (HR) 2.60 (2.20-5.60) Gamma Prandoni et al. [17]

Post-CTEPH (HR) 1.30 (0.98-1.73) Gamma Ng et al. [13]

Abbreviations: CI, confidence interval; CRNMB, clinically relevant non-major bleeding; CTEPH, chronic thromboembolic pulmonary hypertension; DVT, deep vein thrombosis; HR, hazard ratio; IC, intracranial; LMWH, low molecular weight heparin; PE, pulmonary embolism; PTS, post-thrombotic syndrome; VKA, Vitamin K Antagonist; VTE, venous thromboembolism.

Utilities

The utilities used in the Markov model are shown in Table A2, with the corresponding systematic literature review in a PRISMA (Transparent Reporting of Systematic Reviews and Meta-Analyses) flow diagram shown in Figure A1 [5,22–26]. All patients were assigned a baseline utility, which was updated on the occurrence of a non-fatal IC bleeding or CTEPH. Utility decrements associated with PE, DVT, non-IC bleeding, CRNMB, and severe PTS were subtracted from the baseline utility. The decrement durations, specific to each event, were based on previously published articles [26–28]. While on treatment, utility decrements reflecting the use of apixaban or LMWH/VKA were applied.

Costs

The costs included in the Markov model are summarized in Table 2. A PRISMA flow diagram for the systemic cost data collection is presented (see Figure A2). After the first year, costs and health outcomes were discounted by 4% and 1.5% per annum, respectively [10]. Direct costs inside the health care sector included drug, administration, monitoring, and event-related costs. Drug costs for LMWH, VKA, and apixaban were derived from the official Dutch pricelist (Z-index) [29]. Costs of apixaban were based on a 7-day introduction dose

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of 20 mg, a long-term dose of 10 mg/d during the first 6 months after dose introduction, and an extended dose of 2.5 mg [1,29]. The price of LMWH was based on the price of nadroparin, because this is the most used LMWH in the Netherlands [2]. For nadroparin, the dose was assumed at 171 IE/mL per kilogram [30]. For a mean weight of 84.6 kg the 0.8 mL 19,000 IE/mL syringe was closest to this recommended daily dosage [30]. The price of VKA was based on the average use of acenocoumarol and phenprocoumon (77.1% and 22.9%, respectively) in the Netherlands [2,31]. The 7-day introduction and long-term dosing consisted of 3.2 mg and 2.2 mg, respectively [1,3].

The administration and monitoring costs for the LMWH/VKA treatment were based on information provided in the annual medical report of the Dutch Federation for Thrombotic Services of 2014 [2]. For the administration of LMWH, the costs of patient education were added for the 6.7% of the patients who were trained to self-inject. For the remaining 93.3% of the patients, the cost of 30 minutes of home care was applied for 7 days [10]. The cost of the INR monitoring visits was based on the annual cost of €230 divided by the average number of 20.8 visits [2,10].

Event-related acute care costs were obtained from previous publications [32– 35] and Dutch prices. Long-term costs were assigned to patients surviving PTS, CTEPH, or IC-bleeding. Hospital costs were calculated with the assumption that 40% of the patients were treated in general hospitals and 60% in academic hospitals; 8% of the DVT patients and 85% of the PE patients were treated as inpatients (Key Opinion Leader) [36]. The Key Opinion Leader is a medical professor in one of the University Medical Centers in the Netherlands with >20 years of experience in the diagnosis and treatment of VTE. Because most PE patients are treated as an inpatient for a duration of 3.5 days, the number of days in the hospital was subtracted from the number of days they needed help with injections.

Direct costs outside the health care sector were included for travel expenses to the hospital or thrombosis center and were calculated based on a distance of 14 km (7 km one way), according to the Dutch Cost Manual [10]. Travel expenses were calculated as the mean of transportation costs by taxi, public transport, and car. Indirect costs included productivity losses due to the burden of VTE. The friction cost method was used to calculate the indirect costs, by applying a friction period of 23 weeks as described in the Dutch costs manual [10]. Costs were analysed from a societal perspective and therefore the model included both direct (inside and outside the health care sector) and indirect costs. The indirect costs included productivity losses and traveling expenses. All relevant costs from a societal perspective were included and were corrected for inflation to August 2015 [10,12].

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Table 3. Costs applied in the Markov model.

Resources Average cost

(€, 2015)

Range (€) Source

Medication Apixaban (daily)

Introduction period (20 mg/day) Long-term period (10 mg/day) Extended treatment (2.5 mg/day)*

4.60 2.30 2.15 Fixed Fixed Fixed Z-index [29] Z-index [29] Z-index [29] LMWH: nadroparin 19000 IU/ml, 0.8ml (daily) 9.37 Fixed Z-index [29] VKA (daily) Introduction period (3.2 mg) Long-term period (2.2 mg) 0.06 0.04 Fixed Fixed Z-index [29] Z-index [29]

Administration and monitoring costs Patient education/instruction to self-inject 71.32 53.49-89.15 NZA [31] LMWH administration by homecare nurse 19.05 14.29-23.81 NZA [31]

INR monitoring visit 11.58 8.69-14.48 FNT [2],

Event related costs PE/DVT inpatients

Diagnosis and treatment (day admission)

566.23 424.67-707.79 NZA [31]

PE/DVT outpatients

Doppler ultrasound 41.09 30.82-51.36 NZA [31]

CT angiography 204.25 153.19-255.31 NZA [31]

Echocardiogram 41.09 30.82-51.36 NZA [31]

D-Dimer test 2.45 1.84-3.06 NZA [31]

GP visit 29.20 21.90-36.50 NZA [31]

Other event related costs IC bleeding

Acute care 20,489 14,907-28,161 Stevanovic et al. [34]

Long term maintenance 591,70 430.42-813.46 Stevanovic et al. [34]

CTEPH Acute care (Diagnosis and 56.8% of patients pulmonary endarterectomy surgery) 4,271 2,136-6,407 NICE [32,33]

Long term maintenance 253.01 126.51-379.53 NICE [32,33]

Non-IC major bleeding 5,036 3,664-6,921 Ten Cate-Hoek et al. [35]

CRNMB (one GP visit) 30.72 23.04-38.40 Ten Cate-Hoek et al. [35]

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Table 3. Costs applied in the Markov model. (continued)

Resources Average cost

(€, 2015) Range (€) Source

Fatal major bleeding 20,489 14,907-28,161 Assumption: costs are

equal to acute care costs

Fatal event due to CTEPH 4,271 2,136-6,407 Assumption: costs are

VTE related death 566.23 396.36-736.10 Assumption: costs are

Direct costs outside health care Travel expenses due to administration/monitoring visit/ hospital visit for IC bleed, CTEPH, PE or DVT event

14.76 3.09-34.78 Cost manual [10]

Indirect costs outside health care Expected hourly wages

Male Female 41.2930.60 Fixed Fixed Dutch Statistics [37] Dutch Statistics [37]

Probability of employment (based on age 55-65 years) Male Female 71.0% 52.4% Fixed Fixed Dutch Statistics [37] Dutch Statistics [37]

Productivity loss due to

PE 8.4 days Fixed Guanella et al., CDEC [38,39]

DVT 11.3 days Fixed Guanella et al. [38]

IC bleeding 160 days 32-288 Assumption, friction cost

method

CTEPH 160 days 32-288 Assumption, friction cost

method

Death 160 days 32-288 Assumption, friction cost

method

* This parameter was only used in the scenario analysis. Abbreviations: CRNMB, clinically relevant non-major bleeding; CT, computed tomography; CTEPH, chronic thromboembolic pulmonary hypertension; DVT, deep vein thrombosis; GP, general practice; IC, intracranial; INR, international normalized ratio; LMWH, low molecular weight heparin; PE, pulmonary embolism; PTS, post-thrombotic syndrome; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Sensitivity Analysis

Sensitivity analyses were performed on key input variables of the model such as patient characteristics, transition probabilities, utilities, and costs. In the univariate sensitivity analysis the variables were individually varied over their 95% CI, and when the 95% CI was unavailable, the variables were assumed to follow a log-normal distribution with a relative SD of 0.25 [11]. The distributions used for the variables in the model were β and

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γ for the transition probabilities, log normal, or β or γ for relative risks (RRs), β for QALYs, and γ or log normal for costs. The impact of these varying variables on the incremental costs and QALYs were presented in tornado diagrams. A total of 87 uncertain variables were validated, and only the 15 most influencing variables were presented in the tornado diagrams, because the other variables had no observed difference in costs or QALYs.

PSAs, from societal and health care payer perspectives, were conducted to account for variability in outcomes due to uncertainty in input variables. The ICER was repeatedly calculated while variating the key input variables simultaneously within their ranges. The results of 2,000 calculated ICERs were plotted in a cost-effectiveness plane.

Scenario Analyses

In total 6 scenarios were conducted to determine the effect on the ICER of relevant differing circumstances. Dutch guidelines state a treatment of 3 to 6 months for patients with an acute VTE event, and patients with RecVTE can receive treatment extension based on an expert’s opinion [1,3,10]. In scenario 1 a treatment period of 3 months was applied to the model, and in scenario 2 the treatment consisted of 6 months of anticoagulation plus an extended anticoagulation period of 12 months. In scenario 3 the treatment-specific bleeding distributions (fatal/non-fatal IC) were based on the results found in the AMPLIFY trial [8]. The average time in therapeutic range (TTR) in the AMPLIFY trial was 61% [8]. Because of strictly carried out INR monitoring by specific Dutch thrombotic services, the TTR for Dutch patients who just received VKAs was 60.6% to 68.2% [2]. In the scenario analysis the RRs for LMWH/VKA of the third quartile of the AMPLIFY population (INR, 59.1%–68%) were used (scenario 4). Scenario 5 excluded the disutilities associated with anticoagulation use. Finally, scenario 6 reflected the ICER from a health care payers’ perspective. Input variables used in the scenario analyses are summarized (see Table A3).

Results

In a cohort of 1,000 VTE patients, apixaban treatment averted 2 RecVTEs/VTEdies, 12 MBs, 38 CRNMB, and 7 cases of TxDiscontinue compared with LMWH/VKA treatment (Table 3). The number of observed CTEPH and PTS events are comparable for both treatments. Averted events result in a health gain of 0.044 QALYs and 0.039 LYs per patient for apixaban treatment compared with LMWH/VKA. Apixaban treatment increases anticoagulation and administration costs, and decreases the total event-related costs compared with LMWH/ VKA. The treatment with apixaban was found to be cost-saving compared with LMWH/ VKA treatment (€8,178 vs €8,414) (Table 4).

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Table 4. Outcomes of the simulation of the hypothetical cohort of 1,000 patients diagnosed with index PE or DVT receiving apixaban or VKA: number of VTE, bleeding, and other events and the related costs per patient (discounted).

Apixaban LMWH/VKA

Variable Events, n Costs/Patient, € Events, n Costs/Patient, €

Index VTE 1,000 929 1,000 329

Recurrent VTE and VTE-related death

VTE-related death 77 438 77 443 Non-fatal recurrent PE 159 1692 160 1,697 Non-fatal recurrent DVT 393 207 394 207 Total 629 630 Major bleeding Fatal 18 12,970 19 14,031 Non-fatal IC bleeding 16 19,823 17 21,899 Non-fatal EC bleeding 99 3,203 107 3,387 Total 132 144 CRNMB 664 20 682 20 CTEPH 34 7,976 34 7,963 Treatment discontinuation 49 - 56

-Anticoagulant and administration costs - 509 - 285

Monitoring costs - 59 - 199

Abbreviations: CRNMB, clinically relevant non-major bleeding; CTEPH, chronic thromboembolic pulmonary hypertension; DVT, deep vein thrombosis; IC, intracranial; LMWH, low molecular weight heparin; PE, pulmonary embolism; PTS, post-thrombotic syndrome; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Table 5. Outcomes per patient: incremental costs, QALYs, LYs, and the ICER.

Variable Apixaban LMWH/VKA

Outcomes per patient

Total QALYs 10.373 10.330

Total LYs 12.739 12.700

Total costs, € 8,178 8,414

Incremental results apixaban

ΔQALYs 0.044

ΔLYs 0.039

ΔCosts, € -236

ICER (per QALY gained) Cost-saving

ICER (per LY gained) Cost-saving

Abbreviations: ICER, incremental cost-effectiveness ratio; LMWH, low molecular weight heparin; LY, life year; QALY, quality-adjusted life year, VKA, vitamin K antagonist.

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Sensitivity Analysis

The results of the univariate sensitivity analysis are presented in the tornado diagrams in Figures 2 and 3, reflecting the impact of the uncertainties of the key input variables of the incremental costs and QALYs, respectively. The uncertainty around apixaban unit cost and the rate of MB of LMWH/VKA and apixaban in the first 3 months of treatment show the highest influence on the incremental costs. The variables with the highest impact on the incremental QALYs are the starting age, baseline utility value, and the risk of RecVTE in both treatment arms in the first cycle of the model. In all the univariate analyses the ICER remains cost-saving.

Figure 2. Tornado diagram illustrating the impact on the incremental costs from the univariate sensitivity analyses. The tornado diagram represents the impact of the 15 most influential variables on the incremental costs calculated in the univariate sensitivity analysis. The dark grey bars represent the high value of the 95% CI range of the variables, whereas the light gray bars represent the low value. The solid vertical line in the middle of the graph represents the base-case incremental costs. Abbreviations: EC, extracranial; IC, intracranial; HR, hazard ratio; LMWH, low molecular weight heparin; MB, major bleed; P, probability; VKA, vitamin K antagonist.

Results of the PSAs from the societal and health care payer perspective are shown in the effectiveness planes in Figure 4 and Figure A3, respectively. Apixaban is 100% cost-effective compared with LMWH/VKA at a willingness to pay of €20,000/QALY, and 94% of the simulations indicate cost-savings.

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Figure 3. Tornado diagram illustrating the impact on the incremental QALYs from the univariate sensitivity analyses. The tornado diagram represents the impact of the 15 most influential parameter uncertainty on the incremental QALYs calculated in the univariate sensitivity analysis. The dark grey bars represent the high value of the 95% CI range of the variables, whereas the light grey bars represent the low value. The solid vertical line in the middle of the graph represents the base-case incremental QALYs. Abbreviations: DVT, deep vein thrombosis; HR, hazard ratio; IC, intracranial; LMWH, low molecular weight heparin; MB, major bleed; QALYs, quality-adjusted life years; rVTE, recurrent venous thromboembolism; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Figure 4. Cost-effectiveness plane showing the results of the probabilistic sensitivity analysis of apixaban versus LMWH/VKA in the treatment and prevention of VTE from a societal perspective. Abbreviations: LMWH, low-molecular weight heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism.

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Scenario Analyses

The results of the scenario analyses are shown in Table 5. In all scenarios, except one, the ICER remains cost-saving. When treatment is extended to 18 months (scenario 2), the ICER is not cost-saving. The costs of apixaban compared with LMWH/VKA increase, but apixaban remains more effective, resulting in an ICER of €425/QALY. Similarly, a shorter treatment duration (scenario 1) saves more costs compared with the base-case analysis and is thereby still cost-saving. When anticoagulation-specific distribution of severity of the bleeding (scenario 3), obtained from the AMPLIFY trial, were applied to the model, the incremental costs were less, but the ICER was still cost-saving. Scenarios 4 and 5 have mainly influence on the incremental QALYs. Scenario 4 increases the health gain associated with apixaban treatment, whereas scenario 5 shows a decrease of the incremental QALYs. If applying the health care payer’s perspective (scenario 6), the incremental costs decrease, but the ICER remains cost-saving.

Table 5. Incremental costs, incremental QALYs, and the ICER in the scenario analyses. Scenario Incremental costs, € Incremental QALYs ICER, €/QALY

1. 3-month treatment duration -387.51 0.041 Cost-saving

2. 18-month treatment duration 53.82 0.127 424.56

3. Treatment-specific bleeding distribution vs LMWH/VKA

-131.39 0.054 Cost-saving

4. LMWH/VKA RRs from third quartile of INR control

-237.82 0.047 Cost-saving

5. No treatment disutilities -236.23 0.038 Cost-saving

6. Healthcare payer’s perspective -48.27 0.044 Cost-saving

Abbreviations: ICER, incremental cost-effectiveness ratio; INR, international normalized ratio; LMWH, low molecular weight heparin; QALY, quality-adjusted life years; RR, relative risk; VKA, vitamin K antagonist.

Discussion

Our economic evaluation shows the cost-effectiveness of apixaban compared with LMWH/ VKA for the acute treatment of VTE and the prevention of RecVTE in the Netherlands. The evaluation was done using a Markov model simulating 1,000 VTE patients receiving either apixaban or LMWH/VKA and was performed from a societal perspective. We found that the use of apixaban increases LYs/QALYs and reduces costs compared with LMWH/ VKA; hence, apixaban is dominant over LMWH/VKA. The beneficial effect of apixaban on the health gain is mostly driven by the reduction in MB and CRNMB but also by a small reduction (statistically not significant) in RecVTE events as observed in the AMPLIFY trial [8]. Consequently, costs associated with these averted events may be prevented.

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The impact of the uncertainties in key input variables in the model on the robustness of the outcomes was assessed in several sensitivity and scenario analyses. The PSA found that apixaban is 100% cost-effective compared with LMWH/VKA at a willingness-to-pay threshold of €20,000/QALY; moreover, apixaban appeared to be cost-saving in 94% of the simulations. The univariate analyses found that apixaban unit costs and the rate of MB had the most impact on the incremental costs, whereas the starting age and baseline utility value indicated the most impact on the incremental QALYs. The scenario analyses found that in all except one scenario apixaban remains cost-saving compared with LMWH/VKA.

The scenario in which the treatment was extended up to 18 months was the only not cost-saving scenario. It found that, although treating with apixaban is obviously associated with additional costs mainly due to the drug costs, it also results in an increase in QALYs. This resulted in an ICER of €425/QALY. It is plausible that the longer the treatment, the less cost-effective apixaban becomes compared with LMWH/VKA. In the base-case analysis the distribution of the severity of MB (fatal/non-fatal) were equal for both treatments. In a scenario analysis this distribution was adapted to treatment-specific distributions found in the AMPLIFY trial. The equal distribution used in the base-case analysis can lead to an underestimation of the ICER, although in the scenario analysis the ICER was still cost-saving.

To address the concern that the time in the therapeutic INR range in the Netherlands may be better than in the AMPLIFY study population (61%), a scenario analysis was based on the relative risks of the third quartile (TTR, 59.1%–68.0%) of the AMPLIFY patients receiving VKA [2,8]. Although this third quartile indicated a lower RR of VTEs and VTEdies, the RR of MBs increased compared with the original study population. MBs are associated with very high event costs; therefore, apixaban was, again, cost-saving compared with LMWH/VKA. Annual medical reports of the Dutch Thrombotic Services suggest that the TTR may be even higher than 68% [2]. Contrarily, the target INR range in the Netherlands (2.0–3.5) is wider than the target INR range used in the trials (2.0–3.0), causing an overestimation of the TTR in the Netherlands [2,8]. Although lower VTE and MB rates in the subgroup TTR > 68% (fourth quartile) were expected, this was not found in the trial; therefore, this scenario was not conducted [8].

Finally, the scenario analysis from the health care payer perspective was also cost-saving. The most recent update of the Dutch guidelines for pharmacoeconomic evaluations states that all indirect costs have to be included in the economic model [10]. However, currently these costs are not often included. In this study we therefore investigated 2 perspectives, namely the societal and the health care payer perspective. Note that this is not applicable on a more market-based system, such as in the United States.

Next to the uncertainties and limitations tested in the sensitivity and scenario analyses, the model had some other limitations. First, it is assumed that all patients with an IC bleeding and none of the non-MB patients discontinued anticoagulation therapy. In practice this is decided on the patient’s individual characteristics. Furthermore, switching to other treatment is often seen in practice, but this was not included in the model. These assumptions can both lead to overestimation and underestimation of the ICER.

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To our knowledge this is the first cost-effectiveness analysis of apixaban for the treatment and prevention of VTE in the Netherlands. Previously, a Canadian study estimated the economic benefits of the extended treatment for the treatment and prevention of VTE with apixaban compared with LMWH/VKA. The analysis was based on the results of the AMPLIFY and AMPLIFY-EXT trials and resulted in an ICER of $4,828 per QALY gained [40]. The economic evaluation also found the cost-effectiveness of apixaban compared with other DOACs, which is mostly driven by the reduction of bleeding associated with apixaban use. Same results were found in an evaluation from the US payer perspective by Amin et al. [41], who compared the incremental medical costs of apixaban, dabigatran, rivaroxaban, and edoxaban with LMWH/VKA in VTE patients. Apixaban appeared to have the greatest reduction of medical costs, also driven by the bleeding reduction found in the AMPLIFY trial. Jurgin et al. [42] compared the cost-effectiveness of dabigatran and rivaroxaban for the treatment and extended anticoagulation in settings in the United Kingdom, showing dabigatran to be dominant over rivaroxaban due to higher clinical benefits and lower treatment costs. The international literature seems in line with our findings. Differences are expected across different studies because some country-specific data can slightly alter model preferences and subsequently the results.

Conclusions

Apixaban was found to be cost-saving in the base-case, univariate sensitivity and most of the scenario analyses. The only not cost-saving scenario, in which an 18-month treatment duration was applied, is still highly cost-effective. The PSA found that apixaban is cost-saving in 94% of the simulations, compared with LMWH/VKA. In conclusion, the economic evaluation shows that apixaban is a cost-effective alternative compared with the current standard of care of LMWH/VKA for the treatment of VTE and prevention of RecVTE in the Netherlands.

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Appendix

Table A1. Patient characteristics of the AMPLIFY trial [8], used in the Markov model. Characteristic Value Age (years) 56.9 Male sex (%) 58.7 Weight Mean (kg) 84.6 Distribution (%) ≤ 60 kg 8.8 60 - 100 kg 71.7 ≥ 100 kg 19.3 Data missing 0.2 DVT (%) 65.8 PE (%) 34.2

Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism

Table A2. Utilities applied in the Markov model.

Utilities Value Source

Baseline utility 0.825 [22]

Post-IC bleeding state 0.330 [23]

Post-CTEPH state 0.650 [24]

Utility decrements Value Duration

PE -0.320 30 days [23]

DVT -0.110 30 days [23]

Non-IC bleeding -0.300 30 days [23]

CRNMB -0.005 2 days [25]

Severe PTS -0.070 Throughout [26]

Anticoagulation

Apixaban -0.002 Whilst on treatment [5]

LMWH/VKA -0.013 Whilst on treatment [5]

Abbreviations: CRNMB, clinically relevant non-major bleeding; CTEPH, chronic thromboembolic pulmonary hypertension; DVT, deep vein thrombosis; IC, intracranial; PE, pulmonary embolism; PTS, post-thrombotic syndrome; LMWH, low molecular weight heparin; VKA, vitamin K antagonist.

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Figure A1. PRISMA flow diagram summarizing the systematic literature search for utility scores. Different combinations of the search terms ‘utility’, ‘venous thromboembolism’, ‘quality of life’, ‘apixaban’ and ‘EQ-5D’ were used.

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Figure A2. PRISMA flow diagram summarizing systematic literature search. In the electronic search we used various combinations of the terms ‘cost’, ‘kosten’, ‘NOAC’, ‘cost-effectiveness’, ‘apixaban’, ‘VKA’, ‘veneuze tromboembolie’ and ‘venous thromboembolism’.

Table A3. Overview of scenario analyses. Scenario 1: treatment duration 3 months

Difference to base case: transition probabilities between 3-6 months disregarded and costs of 3 months treatment (versus 6 months in base case)

Scenario 2: treatment duration 12 months Sources

Risk of recurrent VTE and VTE related death

Apixaban 6-9 months 0.0048 (0.0001-0.0094) [9] Apixaban 9-12 months 0.0059 (0.0007-0.0111) [9]

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Table A3. Overview of scenario analyses. (continued)

No treatment 6-9 months 0.0277 (0.0166-0.0389) [9] No treatment 9-12 months 0.0265 (0.0156-0.0375) [9] Distribution of PE, DVT and VTE related death > 6 months

VTE related death 0.1188 [9]

Recurrent PE 0.2475 [9]

Recurrent DVT 0.6337 [9]

Risk of major bleeding

Apixaban > 6 months 0.0024 (0.0000-0.0057) [9] No treatment > 6 months 0.0048 (0.0001-0.0096) [9] Risk of CRNMB

Apixaban > 6 months 0.030 (0.0182-0.0412) [9] No treatment > 6 months 0.023 (0.0128-0.0332) [9] Risk of other treatment discontinuation (unrelated to discontinuation due to the events modelled)

Apixaban > 6 months 0.0667 (0.0498-0.0835) [9] No treatment > 6 months Not applicable

Scenario 3: treatment specific distribution of fatal major bleeding and non-fatal IC bleeding

% Fatal major bleeding

Apixaban 0.0667 [8]

LMWH/VKA 0.0408 [8]

% Non-Fatal IC bleeding

Apixaban 0.2143 [8]

LMWH/VKA 0.1224 [8]

Scenario 4: Efficacy and safety from third quartile of INR control (RR LMWH/VKA vs apixaban)

RR recurrent VTE 1.33 (versus 1.19 in base case) [8] RR major bleeding 3.02 (versus 3.33 in base case) [8]

Scenario 5: No decrements for LMWH/VKA or apixaban treatment

Difference to base case: decrements -0.013 for LMWH/VKA and -0.002 for apixaban treatment

Scenario 6: Health care payer perspective

Difference to base case: travel expenses and productivity excluded from the analysis

Abbreviations: CRNMB, clinically relevant non-major bleeding; DVT, deep vein thrombosis; IC, intracranial; INR, international normalized ratio; LMWH, low molecular weight heparin; PE, pulmonary embolism; RR, relative risk; VKA, vitamin K antagonist; VTE, venous thromboembolism. References refer to the main body text.

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Figure A3. Cost-effectiveness plane showing the results of the probabilistic sensitivity analysis of apixaban versus LMWH/VKA in the treatment and prevention of VTE from a healthcare payer perspective. Abbreviations: LMWH, low-molecular weight heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Acknowledgements

We thank Mark Rozenbaum from Pfizer NL for his input during this research. This study was funded by Bristol-Myers Squibb. M.J. Postma has received various research grants from various pharmaceutical companies, including but not limited to Pfizer, Bristol-Myers Squibb, GSK, Roche, and Novartis. The authors have indicated that they have no other conflicts of interest regarding the content of this article. The authors declare that the study results were not influenced by Bristol-Myers Squibb’s funding.

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