Regular ArticlePatient-reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of pulmonary embolism; results from the EINSTEIN PE trial☆
Introduction
Pulmonary embolism (PE) is a life-threatening manifestation of venous thromboembolism (VTE) [1], [2], [3], [4]. The estimated annual incidence of PE is approximately 69 per 100,000 and the associated mortality risk is greater than 20%, with 65% of deaths occurring within 1 hour [3], [5], [6]. The risk of mortality may persist at a rate of 5% for up to 12 months [7]. Although the incidence of deep vein thrombosis (DVT) is approximately twice that of PE, PE accounts for the majority of the 30-day case fatality rate in patients with VTE [1]. In addition to a high rate of mortality, PE can be associated with recurrent VTE or secondary complications [5], [7]. Rates of recurrent VTE are equally high for both PE and proximal DVT, particularly in the first 6–12 months after diagnosis (hazard rate of ~ 20 per 1,000 person-days) [8]. However, recurrent VTE typically presents as PE after an initial PE (in ~ 60% of cases) and as DVT after an initial DVT (~ 80%); therefore, recurrent VTE after an initial PE is associated with a two- to threefold increased risk of mortality compared with recurrent VTE after DVT [7]. Secondary complications after PE include chronic thromboembolic pulmonary hypertension, which in some cases can lead to progressive right ventricular failure [9]. Considering the potential for serious complications and the risk of mortality with recurrent PE, it is unsurprising that PE patients may be treated for longer than DVT patients [10], [11], even though guideline recommendations suggest equal treatment lengths [12].
Standard therapy for PE in haemodynamically stable patients consists of treatment with low molecular weight heparin (LMWH) overlapping with and followed by a dose-adjusted vitamin K antagonist (VKA), such as warfarin [12]. Limitations with VKA treatment include the need for regular monitoring of the anticoagulation effect, drug–drug interactions and dietary restrictions, and the initial parenteral administration of LMWH can delay discharge of patients from hospital or increase healthcare utilisation [13], [14], [15], [16]. Given the link between patient treatment satisfaction and adherence, the limitations associated with standard therapy may impact upon adherence to therapy [17]. As the patient perspective becomes increasingly recognised for its importance and impact on outcomes, further examination of the treatment experience from the patient perspective is warranted [17], [18].
Non-VKA oral anticoagulants (NOACs) may overcome some of the limitations observed with the current standard of care. Rivaroxaban and apixaban are direct Factor Xa inhibitors approved in the EU and US for the treatment of acute DVT and PE and the prevention of recurrent VTE in adults [19], [20], [21], [22]. Dabigatran, a direct thrombin inhibitor, is also approved in the EU and US for this indication in adult patients who have been treated with a parenteral anticoagulant for 5–10 days [23], [24]. The direct Factor Xa inhibitor edoxaban has completed phase III testing for VTE treatment in patients who had initially received heparin [25], and has received its first approval for this indication in Japan [26]. Recently, the updated European Society of Cardiology (ESC) guidelines recommended rivaroxaban, dabigatran and apixaban as alternatives to parenteral/VKA anticoagulation for acute-phase treatment of patients at an intermediate-low risk of early mortality from PE (Class I, Level B). Rivaroxaban, dabigatran and apixaban are also recommended as alternatives to conventional therapy for patients who require extended anticoagulation (> 3 months) (Class IIa, Level B) [27].
In contrast to the trials examining dabigatran, apixaban and edoxaban [25], [28], [29], [30], which included combined DVT and PE patient populations, the EINSTEIN PE trial of rivaroxaban focused on a specific population of patients with PE (with or without DVT) [31]. The results from EINSTEIN PE demonstrated that fixed-dose monotherapy with rivaroxaban was non-inferior to standard therapy (enoxaparin overlapping with and followed by a VKA) for the primary efficacy endpoint of symptomatic recurrent VTE (2.1% vs 1.8% in the rivaroxaban and standard therapy groups, respectively; hazard ratio [HR] 1.12; P = 0.003), and had similar rates of major or non-major clinically relevant bleeding (10.3% vs 11.4%, respectively; HR = 0.90; P = 0.23) and adverse events [31]. Rivaroxaban therapy was associated with a significantly lower rate of major bleeding compared with standard therapy (1.1% vs 2.2%, respectively; HR = 0.49; P = 0.003) [31]. In addition to offering a favourable safety profile, rivaroxaban does not require dietary modifications, routine measurement of anticoagulant effect, dose adjustments or bridging with heparins [31], [32], [33].
NOACs, including rivaroxaban, have the potential to reduce treatment burden and improve overall patient satisfaction. Indeed, in the EINSTEIN DVT study [34], a study of identical design to EINSTEIN PE that enrolled patients with DVT without concurrent PE, rivaroxaban was associated with significantly greater treatment satisfaction than standard therapy [35]. This study employed the use of the Anti-Clot Treatment Scale (ACTS), a 15-item, patient-reported instrument of satisfaction with anticoagulant treatment [36]. As in EINSTEIN DVT, treatment satisfaction was a predefined outcome in the EINSTEIN PE study, and here we compare the burdens and benefits of rivaroxaban as an oral fixed-dose regimen, versus dual-drug standard of care in patients with PE enrolled in the EINSTEIN PE study.
Section snippets
Materials and Methods
We investigated patient-reported treatment satisfaction in the EINSTEIN PE study [31], a randomised, open-label, event-driven, non-inferiority study including patients who had acute symptomatic PE with or without DVT. Rivaroxaban (15 mg twice daily for 21 days, and 20 mg once daily thereafter) was compared with enoxaparin (1.0 mg/kg twice daily for ≥ 5 days) overlapping with and followed by dose-adjusted VKA (target international normalised ratio 2.0–3.0). The intended treatment duration–3, 6 or 12
Patients and Baseline Characteristics
Of the 4,833 patients randomised in the EINSTEIN PE study [31], 2,397 participated in the patient satisfaction substudy, of whom 1,200 patients received rivaroxaban and 1,197 patients received enoxaparin/VKA (Fig. 1). Patients in this substudy were representative of the overall global EINSTEIN PE population with, for example, a mean age of approximately 58 years in both groups, with male patients comprising 55.9% of the patients in the rivaroxaban arm and 52.6% in the enoxaparin/VKA arm (Table 1
Discussion
This study demonstrates improved patient-reported satisfaction with rivaroxaban compared with enoxaparin/VKA treatment. Patients with acute, symptomatic PE enrolled in the EINSTEIN PE study reported a lower burden and greater perceived benefit with rivaroxaban compared with traditional dual-drug therapy, as measured by both the anticoagulation-specific ACTS scale and the widely validated TSQM II score.
The open-label design of EINSTEIN PE enabled patients to report directly on treatment
Conclusion
Long-term anticoagulant treatment is important for the prevention of recurrent VTE. The improved patient satisfaction seen with rivaroxaban compared with enoxaparin/VKA treatment could have implications for patient adherence and persistence, and ultimately patient outcomes. As well as being of clinical relevance in VTE treatment, the potential for improved adherence with rivaroxaban may impact on other indications that also require long-term treatment, for example stroke prevention in patients
Conflicts of Interest Statement
MH Prins has acted as a consultant for Bayer HealthCare, Sanofi-aventis, Boehringer Ingelheim, GlaxoSmithKline, Daiichi Sankyo, Leo Pharma, Thrombogenics and Pfizer. L Bamber, AWA Lensing and MY Wang are employees of Bayer Pharma AG. R Bauersachs has received honoraria for lectures or consultancies from Novartis, LEO, Bayer Pharma AG, Boehringer Ingelheim and Bristol-Myers Squibb. SJ Cano was supported in part through a grant from Bayer Pharma AG and has received honoraria for lectures or
Acknowledgements
The study was supported by Bayer Pharma AG. The authors would like to acknowledge Hayley Dawson, who provided editorial support with funding from Bayer HealthCare Pharmaceuticals
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Financial support: The study was supported by Bayer Pharma AG.