University of Groningen
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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Vitamin K antagonists (VKAs) have been the standard of care for the treatment and prevention of thromboembolic events since their introduction in the 1950s [1]. It was only in 2008 that a new type of anticoagulant was introduced on the European market [2]. These ‘new’ anticoagulants were labelled ‘direct oral anticoagulants’ (DOACs), but they are also known as new- or non-vitamin K antagonist oral anticoagulants (both abbreviated as NOACs).
Various international studies have shown that DOACs can provide health benefits for a large number of patients [3–5]. Phase 3 clinical trials have shown that DOACs are at least as effective as the VKA warfarin [6–14]. However, DOACs have significantly better outcomes with regard to intracranial bleeding — a severe adverse event of anticoagulant therapy [15]. The DOACs apixaban (Eliquis®), dabigatran (Pradaxa®), edoxaban (Lixiana®), and rivaroxaban (Xarelto®) are currently registered for multiple indications in Europe.
VKAs require international normalised ratio (INR) monitoring because of unpredictable pharmacokinetics and pharmacodynamics, and they are also known for many food and drug interactions. DOACs, on the other hand, have a more direct inhibiting mechanism on the coagulation factors Xa (apixaban, edoxaban and rivaroxaban) or IIa (dabigatran), making INR monitoring unnecessary [16]. This, together with fewer food and drug interactions, make DOACs a more user-friendly treatment option.
Despite the benefits of DOAC treatment, it might not be the best choice for every patient. During the registration of DOACs, there was limited data concerning frail elderly patients and patients with severely impaired renal function. Therefore, it was advised that clinicians prescribe DOACs for these specific populations with caution. Furthermore, although DOACs have fewer interactions than VKAs, there are some pharmacokinetic interactions that physicians should consider when prescribing DOACs [17].
There were questions raised about the safety and costs of the drugs in many countries, including the Netherlands. Based on these questions, the Health Council of the Netherlands opted for a gradual and conservative introduction of the DOACs and recommended careful monitoring and documentation of bleeding and thrombotic complications [18]. Meanwhile, the Dutch government asked for the investigation of safety data and cost-effectiveness in the real-world situation as a complement to the available trial data. This, together with the involvement of many different parties with conflicting interests, resulted in conservative prescription dispensation and a slow increase in use of DOACs in the Netherlands.
This thesis focuses on the health economics of DOACs, specifically for the Netherlands, in two major populations: stroke prevention in patients with atrial fibrillation (part I) and patients requiring treatment and secondary prevention of venous thromboembolism (part II). Over the last few years, multiple cost-effectiveness models for both populations were developed. Typically, the initial models were all based on data from major clinical trials. In this thesis, cost-effectiveness analyses based on both clinical trials and real-world data are presented. Notably, it were the cost-effectiveness analyses based on real-world data that can be considered to validate the results found in the initial cost-effectiveness analyses based on randomised clinical trials. Furthermore, additional
cost-effectiveness analyses in specific subpopulations that may have been excluded from the large registration trials (e.g., cancer patients) but that may use DOACs in practice further explore the health economic consequences of real-world use of DOACs in the Netherlands. This thesis addresses the following research questions:
1. What is the cost-effectiveness of DOACs in patients with atrial fibrillation and
venous thromboembolism in the Netherlands?
2. Do the RWD-based cost-effectiveness analyses confirm the findings of the
trial-based cost-effectiveness analyses?
3. What are the limitations of using real-world data for validation of trial-based
cost-effectiveness results?
4. Are DOACs cost-effective in subgroups that may have been excluded from the
initial registration trials?
5. Was a conservative introduction of DOACs justified based on the argument of high
costs?
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia and is a major cause of ischaemic stroke, heart failure, and cardiovascular morbidity [19]. In the Netherlands, the prevalence in the total population is 1.6%, and this will increase even further throughout the coming decades [20]. It is predicted that by 2060 the number of adults aged 55 years and older with atrial fibrillation will constitute 3.2% of the total Dutch population [20].
Atrial fibrillation occurs when disorganised sinus stimuli lead to uncoordinated atrial activity, causing an irregular and fast heartbeat. This can cause symptoms like dizziness and shortness of breath; however, many patients are asymptomatic. The abnormal rhythm can cause blood stagnation in the atria, triggering blood clot formation. As a result, the risks of stroke and systemic embolism are increased.
The increased thromboembolic risk can be mitigated by anticoagulation. VKAs have been the standard therapy to prevent strokes in patients with atrial fibrillation for decades, but the updated guidelines of the European Society of Cardiology (ESC) from 2012 state that NOACs offer better efficacy, safety, and convenience compared with VKAs, and therefore NOACs should be considered instead of VKAs for most patients with atrial fibrillation [21]. In the guideline update from 2016, a clear preference was expressed for DOACs over VKAs for stroke prevention in patients with atrial fibrillation. These guidelines are endorsed by the Dutch Society for Cardiology (NVVC, Nederlandse Vereniging voor Cardiologie). In September 2016, the Dutch College of General Practitioners (NHG, Nederlands Huisartsen Genootschap) issued a statement that anticoagulant treatment with DOACs is equivalent to VKAs [22]. However, there is still no mention of preferencing the use of DOACs over VKAs. Moreover, restrained use in frail elderly, patients with impaired renal function, and suspected poor compliance is advised.
Atrial fibrillation is a chronic disease; however, relatively new patients who suffer from symptoms that affect their daily activity can benefit from a restoration of heart rhythm. In the early stages of atrial fibrillation, symptomatic patients can undergo electrical cardioversion. This is a procedure in which a direct current electric shock is used to quickly and effectively restore the normal sinus rhythm. Though this procedure restores the heart rhythm, a temporary stasis of the blood around the time of the cardioversion strongly increases thromboembolic risk. Appropriate anticoagulation reduces the risk of these embolic events during and after the electric cardioversion procedure. Depending on the patient’s thromboembolic risk, the patient may discontinue anticoagulation after the cardioversion.
Venous thromboembolism
Deep vein thrombosis and pulmonary embolism are collectively known as venous thromboembolism. Deep vein thrombosis is a blood thrombus mostly seen in the calf veins and recognised by oedema and pain. Pulmonary embolism is the result of a blood clot obstructing in the pulmonary veins, which causes symptoms of dyspnoea, respiratory pain, tachypnoea, and tachycardia. Diagnosis of venous thromboembolism is based on the presence of symptoms and a D-dimer test, though the presence of risk factors can confirm the suspicion. The risk of thromboembolism strongly depends on age, and it can be exacerbated by risk factors like recent surgery, recent leg trauma, previous venous thromboembolism, immobilisation, malignancies, pregnancy, and oestrogen use. Where an event is not caused by any risk factor, it is known as an unprovoked or idiopathic venous thromboembolism. Although the expression of the disease is the same, idiopathic venous thromboembolism is characterised by a much higher recurrence rate than provoked venous thromboembolism (30% versus 3% within five years after the initial event, respectively) [23].
Although venous thromboembolism is treated as an acute event, it is associated with an increased risk of recurrence and chronic complications. Post-thrombotic syndrome can develop after chronic venous valve insufficiency caused by deep vein thrombosis and is characterized by oedema, pain, hyperpigmentation, itch, trophic disorders, and subcutaneous dilatation. A rare delayed complication of pulmonary embolism caused by arterial lung obstruction is chronic thromboembolic pulmonary hypertension, which can induce heart failure [23].
In general practice, the respective incidences of deep vein thrombosis and pulmonary embolism are 0.5–1.5 and 0.2 per 1,000 inhabitants per year. It is more frequent in women than in men, and incidence increases with age. The incidence of suspected pulmonary embolism (as estimated through a survey of Dutch pulmonologists and internists) was 2.6 per 1,000 inhabitants per year, of which about 30% actually had a pulmonary embolism [23].
The treatment of venous thromboembolism has long consisted of a minimum of five days of low-molecular weight heparin (LMWH) followed by at least three months of treatment with VKAs. Since 2015, the guidelines of the Dutch Internist Society (NIV) have adopted DOACs as the preferred treatment for patients experiencing venous thromboembolism. According to these guidelines, the first episode of provoked
thrombosis should be treated with at least three months of anticoagulation. Idiopathic venous thromboembolism should be treated with at least three months anticoagulation, potentially continued over a longer period based on recurrence and bleeding risks. Patients with malignancies who are experiencing thrombosis should be treated for six months with anticoagulation, and this should be continued as long as the malignancy is active. Any patient experiencing a recurring event (idiopathic or provoked) should receive extended anticoagulation, based on recurrence and bleeding risks [24].
Cost-effectiveness analysis
An important part of the discussion around the introduction of DOACs has to do with their high drug costs compared to the very cheap VKAs and the worry about the concomitant high impact on the national healthcare budget. In a report from the Health Council of the Netherlands from 2012, it was estimated that the annual drug costs of the DOAC dabigatran were four times as high as the combined costs of acenocoumarol and INR monitoring (€1000 versus €225, respectively) [18]. With almost 450,000 patients treated with VKAs in 2012 [25], the budget impact of implementing DOACs in their place could be in the hundreds of millions. From a healthcare payer’s perspective, therefore, it remains a rather important question whether the increased cost of DOACs outweighs the INR monitoring, higher occurrence of adverse events, and other drawbacks of VKA treatment.
Cost-effectiveness analysis is a method that can be used to quantify the trade-off between the new DOACs and the previous standard-of-care, VKAs, in costs as well as health effects. In cost-effectiveness analyses, health effects are generally expressed in quality adjusted life-years (QALYs), with one QALY reflecting one year in perfect health. The main outcome of a cost-effectiveness analysis is the incremental cost-effectiveness ratio (ICER), which is calculated by dividing the incremental costs by the incremental QALYs. Cost-effectiveness analyses are used to aid reimbursement decisions but can also play a role in health policy decisions in the post-reimbursement phase.
To calculate the ICER, a cost-effectiveness model is designed to simulate a hypothetical cohort with the disease of interest. In the case of cardiovascular drugs, such as DOACs, Markov models are commonly used because they allow the possibility of modelling cost-effectiveness over a longer period. In a Markov model, the disease course is defined by health states, which often represent the stage of the disease and its associated complications. Health states can be identified based on clinical data, previous effectiveness models, input from clinical experts, and guidelines. Health states used in cost-effectiveness models for DOACs often represent the following: a stable or asymptomatic phase of the disease, thromboembolic events (e.g. stroke in atrial fibrillation, or deep vein thrombosis in venous thromboembolism), bleeding events, and chronic complications (e.g., post thrombotic syndrome). Clinical outcomes obtained from randomised clinical trials or real-world studies are combined with previously published data and used to calculate the probability that a patient will move to another health state.
According to Dutch guidelines for economic evaluations in healthcare, the ICER should be calculated from a societal perspective, which incorporates the direct and indirect costs both inside and outside the healthcare sector. We distinguish the following costs: drugs costs, direct medical costs (INR control, hospitalisation costs, outpatient and general practitioners visits), direct non-medical costs (travel costs), indirect medical costs (costs related to the occurrence of other diseases while preventing thromboembolic events), and indirect non-medical costs (productivity losses). As QALY measurement is often not included in randomised clinical trials or real-world studies, this is often collected from previously published data. When all data for costs and QALYs are identified, the total number of patients in each health state is multiplied by the cost and QALYs associated with that health state, ultimately resulting in the ICER.
Dutch guidelines recommend the use of a lifetime time horizon for cost-effectiveness modelling; however, the use of different types of data and assumptions means that extrapolating this to reflect a lifetime causes uncertainty in the model. Sensitivity and scenario analyses are used to calculate the effect of uncertainties on the ICER.
The introduction of DOACs in the Netherlands
Dabigatran was the first DOAC to obtain reimbursement in the Netherlands, at first for the primary prevention of venous thromboembolism in adults undergoing elective hip or knee replacements [26]. In June 2012, the reimbursement conditions were expanded to include the indication for stroke prevention in patients with atrial fibrillation. In that same year, rivaroxaban received reimbursement for two indications at the same time: 1) the prevention of stroke and systemic embolism in patients with atrial fibrillation, and 2) the treatment of deep vein thrombosis and pulmonary embolism in adults [27–29]. The year after, apixaban received reimbursement approval for stroke prevention in atrial fibrillation. The last reimbursement requests were approved in 2015, including edoxaban for stroke prevention in atrial fibrillation, and apixaban, dabigatran, and edoxaban for the treatment of venous thromboembolism.
As mentioned, the introduction of DOACs in the Netherlands has given rise to an ongoing discussion. Some have pointed out the uncertainties around the real-life safety, the lack of an antidote, and the efficacy for patients in the Netherlands who, unlike patients in other countries, benefit from a very well organised thrombosis service to control INR. Others felt that the randomised clinical trials gave no reason to doubt the efficacy or safety of DOACs. That is, not more than usual when translating randomised clinical trial data to a real-world situation. Too much caution could lead to the unnecessary undertreatment of patients who could have otherwise benefitted from a DOAC.
Cost-effectiveness of DOACs in the Netherlands
Throughout the years, many cost-effectiveness analyses of DOACs have been published, some of them for reimbursement purposes. Table 1 provides an overview
of the cost-effectiveness analyses of DOACs in patients with atrial fibrillation or venous thromboembolism published in the Netherlands before the first publication included in this thesis. For both indications, dabigatran and rivaroxaban were assessed for reimbursement purposes based on cost-effectiveness by the health technology assessment agency Zorginstituut Nederland [28–30]. For apixaban and edoxaban this was not required because they could be “clustered” with dabigatran and rivaroxaban. In a report from the Health Council of the Netherlands, the cost-effectiveness of dabigatran was assessed in four different models. All other cost-effectiveness analyses were published in peer-reviewed scientific journals.
The majority of the analyses were for the indication for atrial fibrillation, which can be explained by the earlier market access and reimbursement approvals. The ICER for stroke prevention in patients with atrial fibrillation was higher overall (€1,875 to €34,248 per QALY) compared to the treatment of patients with venous thromboembolism (dominant to €5,896 per QALY). This can be explained by the longer treatment duration for atrial fibrillation. Two of the three cost-effectiveness analyses for the venous thromboembolism indication appeared to result in a dominant ICER; this means that treatment with the DOAC saves money while increasing the patient’s health when compared with treatment with the VKA.
In the Netherlands, there is no official threshold to determine if an ICER is cost-effective or not. However, the current guidelines for economic evaluation in healthcare suggest a threshold of €20,000 per QALY for diseases with a disease burden with a proportional shortfall of 0.1–0.4, such as atrial fibrillation and venous thromboembolism [31]. If we compare the above ICERs to this threshold, only 4 of the 16 analyses are not considered cost-effective. There is, however, more data needed to explain the differences found between the analyses.
T ab le 1 . O ve rv ie w o f c o st -e ff ec ti ve ne ss s tu di es p ub lis he d b ef o re t he p ub lic at io n o f t he fi rs t p ro je ct i n t hi s t he si s. A ut hor [ re f] Int er ve nt ion C o m pa rat o r P erspe ct iv e T re at me nt d ur at ion T im e ho ri zon ∆c o st s* ∆ Q A LY s* IC E R (€ /Q A LY ) A tr ia l fi br illa ti o n H ea lth C ou nc il o f t he N et he rla nd s [1 8] 1 5-20 12 dabi ga tr an VK A H eal thc ar e pay er Co nt in uo us Li fe tim e €3 ,0 57 0. 26 0 €11 ,7 58 a €3 ,080 0. 26 0 €11 ,8 46 b €4 ,4 01 0. 220 €2 0, 37 5 c €3 ,37 0 0.1 50 €2 3, 082 d Z IN [ 29 ] 6 -6 -2 01 2 dabi ga tr an VK A So cie ta l Co nt in uo us Li fe tim e €2 ,111 0.1 58 €13 ,3 32 Z IN [ 28 ] 2 6-10 -2 01 2 riv ar ox ab an VK A So cie ta l Co nt in uo us Li fe tim e €2 ,1 02 0.1 84 €11 ,3 96 Le e t a l. [ 32 ] 2 2-10 -2 01 3 ap ix ab an VK A H eal thc ar e pay er Co nt in uo us Li fe tim e €3 ,74 6 0. 30 0 €12 ,4 88 dabi ga tr an €3 ,76 5 0. 31 0 €12 ,14 6 riv ar ox ab an €5 ,0 66 0. 210 €24 ,124 St ev an ov ic e t a l. [3 3] 5 -8 -2 01 4 ap ix ab an VK A H eal thc ar e pay er Co nt in uo us Li fe tim e €1 ,8 52 0.1 80 €1 0, 576 Ve rh oe f e t a l. [3 4] 1 8-12 -2 014 ap ix ab an VK A H eal thc ar e pay er Co nt in uo us Li fe tim e €4 ,7 54 0. 365 €13 ,0 24 dabi ga tr an €5 ,4 65 0. 374 €1 4, 62 6 riv ar ox ab an €5 ,6 81 0.1 66 €3 4, 24 8 V enou s th ro m bo em bolism Z IN [ 28 ] 2 6-10 -2 01 2 riv ar ox ab an LMWH /VK A Soc iet al* * 3– 12 m on th s* ** Li fe tim e €3 00 0. 05 1 €5 ,8 96 Z IN [ 30 ] 8 -6 -2 01 5 dabi ga tr an LMWH /VK A So cie ta l 24 m on th s Li fe tim e €-1 ,9 96 0. 058 D om in ant va n L ee nt e t a l. [3 5] 4 -8 -2 01 5 dabi ga tr an LMWH /VK A So cie ta l 6 m on th s 6 m on th s €-1 8. 90 0. 04 1 D om in ant * p er p at ie nt ; * * E xc lu di ng in di re ct n on -m ed ic al c os ts ; * ** B as ed o n t he E IN ST EI N tr ia l, th e p at ie nt s w er e tr ea te d f or e ith er 3 , 6 , o r 12 m on th s. T hi s d ist rib ut io n w as u se d t he calc ul at e the c os t-eff ec tiv eness; a B as ed o n N L m od el ; b B as ed o n m od el R E-LY ; c B as ed o n m od el R E-LY /P in k e t a l.; d B as ed o n P in k e t a l. A bb re vi at io ns : I C ER , i nc re m en ta l c os t-eff ec tiv en es s r at io ; L M W H , l ow -m ol ec ul ar w ei gh t h ep ar in ; Q A LY , q ua lit y-ad ju st ed li fe y ea rs ; V K A , v ita m in K a nt ag on ist ; Z IN , Z or gi ns tit uu t N eder la nd .
Aim of this thesis
This thesis aims to demonstrate the economic consequences of the broad implementation of DOACs in the Netherlands. This will be done by using real-world data to validate the outcomes of cost-effectiveness analyses that compared DOACs with VKAs in the general atrial fibrillation and venous thromboembolism populations using trial data, as well as modelling specific subgroups that may have been excluded in the initial registration trials. With this, we aim to address the question of whether the conservative introduction of DOACs based on the argument of high costs was justified.
Thesis outline
Figure 1 provides an outline of the thesis chapters. It includes an overview of the studies (registration studies, subgroup and real-world analyses) that have been used as the basis for the design of the cost-effectiveness models described in the chapters. Part I of the thesis focuses on the cost-effectiveness analysis for patients with atrial fibrillation. Multiple trial-based cost-effectiveness analyses have been published before this thesis (Table 1). Real-world-data-based cost-effectiveness analyses of rivaroxaban (chapter 2) and apixaban (chapter 3) were performed to see whether the results of the trial-based analyses can be confirmed. The cost-effectiveness of rivaroxaban treatment in the subgroup assessed in the X-Vert trial (patients with atrial fibrillation undergoing elective electrical cardioversion) is assessed in chapter 4. Reimbursement of the indication for venous thromboembolism came around the time of the start of this thesis; consequently, there had not been many trial-based cost-effectiveness analyses published yet. Therefore, part II of this thesis includes two trial-based cost-effectiveness analyses (chapters 5 and 6), followed by an analysis of patients requiring extended (more than three months) anticoagulation with apixaban based on the AMPLIFY-EXT trial (chapter 7), a real-world cost-effectiveness analysis of rivaroxaban (chapter 8), and an analysis of cancer patients experiencing venous thromboembolism (chapter 9).
Fi gu re 1 . O ut lin e o f t he t he si s. A bb re vi at io ns : B I, b ud ge t i m pa ct ; C EA , c os t-eff ec tiv en es s a na ly sis ; E M A , E ur op ea n M ed ic in es A ge nc y.
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