Cost-effectiveness of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation at high risk of bleeding and normal kidney function

Highlights

• We compared the cost-effectiveness of NOACs and warfarin from the US perspective.

• We modeled a cohort of atrial fibrillation patients at high-risk of bleeding.

• For CrCl between 50 and 95 ml/min, edoxaban was most cost-effective.

• Apixaban would be cost-effective if its price was reduced by 1.3%.

• For CrCl > 95 ml/min, apixaban was the most cost-effective treatment.

Abstract

Introduction

The comparative cost-effectiveness of all oral anticoagulants approved up to date has not been evaluated from the US perspective. The objective of this study was to compare the cost-effectiveness of edoxaban 60 mg, apixaban 5 mg, dabigatran 150 mg, dabigatran 110 mg, rivaroxaban 20 mg and warfarin in stroke prevention in atrial fibrillation patients at high-risk of bleeding (defined as HAS-BLED score ≥ 3).

Materials and methods

We constructed a Markov state-transition model to evaluate lifetime costs and quality-adjusted life years (QALYs) with each of the six treatments from the perspective of US third-party payers. Probabilities of clinical events were obtained from the RE-LY, ROCKET-AF, ARISTOTLE and ENGAGE AF-TIMI trials; costs were derived from the Healthcare Cost and Utilization Project, and other studies. Because edoxaban is only indicated in patients with creatinine clearance ≤ 95 ml/min, we re-ran our analyses after excluding edoxaban from the analysis.

Results

Treatment with edoxaban 60 mg cost $77,565/QALY gained compared to warfarin, and apixaban 5 mg cost $108,631/QALY gained compared to edoxaban 60 mg. When edoxaban was not included in the analysis, treatment with apixaban 5 mg cost $84,128/QALY gained, compared to warfarin. Dabigatran 150 mg, dabigatran 110 mg and rivaroxaban 20 mg were dominated strategies.

Conclusions

For patients with creatinine clearance between 50 and 95 ml/min, apixaban 5 mg was the most cost-effective treatment for willingness-to-pay thresholds (WTP) above $115,000/QALY gained, and edoxaban 60 mg was cost-effective when the WTP was between $75,000 and $115,000/QALY gained. For patients with creatinine clearance > 95 ml/min, apixaban 5 mg was the most cost-effective treatment for WTP thresholds above $80,000/QALY gained.

Introduction

Atrial fibrillation (AF) is the most prevalent type of arrhythmia and a leading cause of stroke [1], [2] – it is associated with a 5-fold increase in the risk of stroke, and around 15% of strokes in all age groups and 23.5% in elderly patients can be attributed to AF [3], [4]. The use of oral anticoagulation therapy has been found to reduce stroke risk by around 60%; [5] however, anticoagulation is associated with an increased risk of bleeding. For this reason, clinical guidelines recommend the assessment of the risk of stroke, as measured by the CHA2DS2-Vasc score, before the prescription of oral anticoagulation [6], [7]. There is solid evidence supporting the use of anticoagulation in patients with CHA2DS2-Vasc scores equal to or > 2, regardless of the risk of bleeding [5], [8], [9]. The risk of bleeding is measured by the HAS-BLED score; HAS-BLED scores equal to or > 3 indicate high risk of bleeding [10]. Representing around 40% of Medicare beneficiaries on oral anticoagulation [11], patients with HAS-BLED scores equal to or > 3 are usually at high risk of stroke too, because risk factors for bleeding events also increase the thromboembolic risk [10], [12], [13]. For this reason, the appropriate management of anticoagulation therapy in this subgroup of AF patients is especially relevant.

Before 2010, warfarin was the only oral anticoagulant approved for the prevention of stroke and systemic embolism in AF. In October 2010, dabigatran was the first non-vitamin K antagonist oral anticoagulant (NOAC) to reach market entry [14]. The approval of dabigatran was based on the results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, which showed that dabigatran 150 mg was superior to warfarin in the prevention of stroke and systemic embolism, but similar in the risk of bleeding [15]. The RE-LY trial also evaluated dabigatran 110 mg [15], an intermediate strength that was approved by the main international regulatory agencies except for the US Food and Drug Administration (FDA) for stroke prevention in patients with high risk of bleeding [16], [17], [18]. Since the approval of dabigatran in 2010, three new agents have gained the FDA approval for the prevention of stroke among AF patients with normal kidney function: rivaroxaban 20 mg in November 2011, apixaban 5 mg in December 2012 and edoxaban 60 mg in January 2015 [15], [19], [20], [21].

NOACs present certain advantages over traditional anticoagulation therapy with warfarin, such as fewer interactions and no requirement for routine monitoring of laboratory coagulation markers; however, drug acquisition costs are around 15 times higher for NOACs than warfarin [15], [19], [20], [21]. As a result, NOACs have garnered special attention regarding their cost-effectiveness. Specifically, three studies have simultaneously compared the cost-effectiveness of apixaban 5 mg, rivaroxaban 20 mg, dabigatran 150 mg and warfarin from the US perspective, finding that apixaban 5 mg was a cost-effective strategy compared to dabigatran 150 mg [22], [23], [24]. Because edoxaban was recently approved, few US-based cost-effectiveness studies have included this agent among the strategies compared [25], [26], [27]. In these studies, edoxaban 60 mg was found to be less expensive and more effective than rivaroxaban 20 mg, and less expensive and less effective than apixaban 5 mg [25], [28]. However, these studies did not specifically look at patients at high risk of bleeding. As a result, the comparative cost-effectiveness of five oral anticoagulants in the prevention of stroke among AF patients at high risk of bleeding remains unknown.

To address this evidence gap, we adopted a US perspective in comparing the cost-effectiveness of edoxaban 60 mg, apixaban 5 mg, dabigatran 150 mg, dabigatran 110 mg, rivaroxaban 20 mg and dose-adjusted warfarin in the prevention of stroke and systemic embolism in AF patients with high risk of bleeding, as defined by HAS-BLED score equal to or > 3 [29].