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New Oral Anticoagulants for the Prevention of Thromboembolic Events in Patients with Atrial Fibrillation [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2012.

Cover of New Oral Anticoagulants for the Prevention of Thromboembolic Events in Patients with Atrial Fibrillation

New Oral Anticoagulants for the Prevention of Thromboembolic Events in Patients with Atrial Fibrillation [Internet].

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1EXECUTIVE SUMMARY

1.1. Background

Approximately 250,000 Canadians are affected by atrial fibrillation (AF).1 Stroke is a complication of AF, and Canadians with AF are five times more likely to have a stroke and are twice as likely to die than individuals without AF.1,2 AF and stroke are more common among the elderly.3,4

Preventing thromboembolic events such as stroke is an important part of managing AF patients. Antithrombotic strategies for AF patients include anticoagulant drugs, notably the coumadin class of vitamin K antagonists (VKAs), such as warfarin, and antiplatelet agents, such as aspirin. VKAs reduce the risk of stroke in patients with AF by more than 60% when compared with no treatment, and by 30% to 40% when compared with low-dose aspirin.5,6 However, VKA use is associated with some drawbacks, including a need for laboratory monitoring, an increased risk of bleeding complications, and several food and drug interactions. An improved understanding of how the blood clotting cascade works has led to the development of new oral anticoagulants (NOACs) that exhibit more predictable pharmacokinetics and pharmacodynamics, thereby obviating the need for laboratory monitoring. The NOACs that have either been approved, or are under review by regulators, for the prevention of thromboembolic events in AF patients include dabigatran, a direct thrombin inhibitor, and the direct Factor Xa (FXa) inhibitors, rivaroxaban, apixaban, and edoxaban. Ximelagatran, a direct thrombin inhibitor, was the first NOAC to be approved for use, but was withdrawn from the market in 2006 because of safety concerns.

While dabigatran, apixaban, and rivaroxaban have been demonstrated to be effective in preventing stroke/systemic embolism (SE) in AF patients, the relative effectiveness and associated bleeding risks of these NOACs, both among themselves and in comparison to warfarin, is not clear. Therefore, the aim of this project was to systematically review and analyze the safety and effectiveness of three NOACs – namely dabigatran, rivaroxaban, and apixaban – compared with warfarin in patients with non-valvular AF. In addition, the cost-effectiveness of the NOACs and warfarin was assessed using economic modelling.

1.2. Primary Research Questions

In patients with non-valvular AF:

  • What is the clinical effectiveness and safety of new oral anticoagulants compared with warfarin?
  • What is the cost-effectiveness of new oral anticoagulants compared to warfarin?
  • How do the new oral anticoagulants compare to optimal warfarin therapy when considering the time spent in the time in therapeutic range (TTR)?
  • How do the new oral anticoagulants compare to warfarin therapy in specific groups of patients with older age, other medical conditions, or who are taking other drug therapies?
  • What are the costs associated with warfarin when patients are stratified according to TTR? How do these compare with estimates for the new oral anticoagulants?
  • What is the cost-effectiveness of new oral anticoagulants compared to warfarin when stratified by age and CHADS2 score (CHADS2: C= congestive heart failure, H = hypertension, A = older than age 75 years, D = diabetes mellitus, S2 = prior stroke or history of transient ischemic attack).?

1.3. Methods

Clinical evidence was selected systematically according to a predefined protocol following accepted guidelines.7 Trials were selected for inclusion in the systematic review and subsequent analyses if they were carried out in AF patients, included treatment with one or more NOACs and warfarin, and included the following outcomes: all-cause stroke/SE (stroke/SE), major bleeding, intracranial bleeding, major gastrointestinal (GI) bleeding, all-cause mortality, and myocardial infarction (MI).

Next, randomized controlled trials (RCTs) for the NOAC identified in the systematic review were used for a mixed treatment comparison (MTC) that comprised a network meta-analysis for each of the aforementioned outcomes.

Finally, the results of the MTC were used to evaluate the cost-effectiveness of warfarin and the NOACs following standard procedures.8 The price of apixaban was assumed because this drug was not approved at the time that this report was prepared.

1.4. Results

1.4.1. Key clinical findings

The systematic review included five unique RCTs that each evaluated the non-inferiority of the three NOACs versus adjusted-dose warfarin.913 Three of these RCTs (ROCKET-AF, RE-LY, ARISTOTLE) were suitable for inclusion in the network meta-analysis.

There was substantial heterogeneity among the three RCTs, including differences in trial design (blinded warfarin use versus open label), populations (specifically in baseline risk of stroke), definitions of major end points (bleeding), and duration and type of follow-up. In addition, data for the ROCKET-AF trial were not reported consistently (intention-to-treat versus as-treated data), with the exception of all-cause stroke/SE and mortality. These limitations should be borne in mind when interpreting the clinical results:

  • Dabigatran 150 mg and apixaban, but not rivaroxaban or dabigatran 110 mg, significantly reduced all-cause stroke/systemic embolism compared with adjusted-dose warfarin. The absolute difference in all-cause stroke/SE for the NOACs versus warfarin ranged from two to six fewer events per 1,000 patients treated each year. Except for apixaban (1 less death per 1,000 patients), none of the NOACs significantly reduced all-cause mortality. None of the NOACs reduced the risk of MI relative to adjusted-dose warfarin.
  • Apixaban and dabigatran 110 mg significantly reduced the risk of major bleeding relative to adjusted-dose warfarin. The absolute difference in major bleeding for all the NOACs versus warfarin ranged from one to eight fewer events per 1,000 patients treated each year. All of the NOACs significantly reduced the risk of intracranial bleeding relative to adjusted-dose warfarin, and the absolute difference versus warfarin ranged from three to five fewer events per 1,000 patients treated each year. By contrast, none of the NOACs significantly reduced the risk of major GI bleeding relative to adjusted-dose warfarin, and dabigatran 150 mg and rivaroxaban were associated with a significant increase in the risk of a major GI bleed versus warfarin. The absolute difference in GI bleeding for all the NOACs versus warfarin ranged from one fewer to eight more events per 1,000 patients treated each year.

Similar subgroup data were reported for all-cause stroke/SE and major bleeding but not consistently reported or available for other outcomes. Results from subgroup analyses are hypothesis-generating and revealed the following:

  • For TTR < 66%, 150 mg dabigatran reduced the risk of stroke/SE versus warfarin, whereas 110 mg dabigatran, 150 mg dabigatran, and 150 mg apixaban reduced the risk of major bleeding versus warfarin. For TTR ≥ 66%, none of the NOACs reduced the risk of stroke/SE versus warfarin, whereas apixaban was the only NOAC that reduced the risk of major bleeding versus warfarin.
  • For patients younger than 75-years-old, 150 mg dabigatran reduced the risk of stroke/SE versus warfarin, whereas 110 and 150 mg dabigatran and apixaban reduced the risk of major bleeding versus warfarin. For patients 75 years and older, 150 mg dabigatran, apixaban and rivaroxaban reduced the risk of stroke/SE versus warfarin, whereas apixaban was the only NOAC that reduced the risk of major bleeding versus warfarin.
  • For lower risk patients (CHADS2 < 2), 150 mg dabigatran was the only NOAC that reduced the risk of stroke/SE versus warfarin, whereas 110 mg dabigatran and apixaban reduced the risk of major bleeding versus warfarin. For high-risk patients (CHADS2 ≥ 2), 150 mg dabigatran and apixaban reduced the risk of stroke/SE versus warfarin, whereas apixaban was the only NOAC that reduced the risk of major bleeding versus warfarin.

1.4.2. Key economic findings

In the base-case analysis for the whole patient population, dabigatran 150 mg twice daily was the optimal treatment assuming a decision-maker is willing to pay $17,525 for each quality-adjusted life-year (QALY) gained. Dabigatran 110 mg twice daily, rivaroxaban, and apixaban were more effective and more costly than warfarin. However, they were more costly and less effective than dabigatran 150 mg.

The cost of apixaban was assumed to be the same as that of dabigatran. If the cost of apixaban was 20% less per day than dabigatran, apixaban would be the optimal treatment assuming a willingness to pay of $11,742 per QALY. The base result was very uncertain regarding the relative cost-effectiveness of apixaban and dabigatran 150 mg. The probability that dabigatran 150 mg is optimal given a willingness to pay of $50,000 per QALY was 68.1%, whereas the probability that apixaban is optimal was 29.0%.

The results of the analysis of specific patient subgroups were very sensitive to the patient population under consideration. Dabigatran 150 mg was the most cost-effective treatment option irrespective of risk of stroke (CHADS2 score). Apixaban was most cost-effective in patients 80 years old, while dabigatran 150 mg was the most cost-effective treatment option in younger patients (60 or 70 years old). In centres where the TTR was < 66%, dabigatran 150 mg was the most cost-effective treatment option, whereas apixaban was the most cost-effective treatment option where the TTR was ≥ 66%. None of the NOACs were likely to be considered cost-effective for patients with a previous major stroke.

1.5. Strengths of Review

  • Clinical results have been presented using relative and absolute effect measures.
  • Attempts were made to adjust for heterogeneity by formally comparing results from subgroups as versus the alternative — an informal comparison.
  • Results presented at the study level and using a Bayesian and frequentist network meta-analysis.
  • Robustness of the cost-effectiveness results was demonstrated through extensive sensitivity analyses.

1.6. Limitations of Review

  • The validity of indirect comparisons is determined by the extent of clinical and methodological trial similarity, so that differences in study populations, interventions, and outcome definitions are potential sources of incomparability.
  • Heterogeneity of patient populations in the included RCTs is a key limitation, and the small number of trials available in the published literature limited the ability to adjust for this heterogeneity during analysis.
  • The small number of trials in the published literature limited the modelling that could be considered primarily to fixed effects models and, as a result, study variability could not be fully incorporated.
  • Not all outcomes were comprehensively or consistently reported across the three RCTs included in the network meta-analysis.
  • Trial design is a potential source of bias. The open-label design RE-LY trial may have led to performance, ascertainment, or adjudication bias, when compared with the ROCKET-AF and ARISTOTLE trials, which both employed a double dummy design.
  • ROCKET-AF did not report results using ITT data for many outcomes, whereas RE-LY and ARISTOTLE used ITT. As a result, only analyses for stroke/SE and all-cause mortality use for rivaroxaban use ITT data throughout.
  • While outcome definitions for efficacy end points are similar across the included trials, definitions of bleeding events, especially minor bleeding, differed substantially.
  • All studies included in the network meta-analysis were multinational, which could impact the generalizability to the Canadian health care system.
  • The limited follow-up (maximum median of two yrs) from the three RCTs and the sensitivity of the results to the duration of treatment effect leads to uncertainty around whether the included NOACs will be cost-effective in the long term.

1.7. Conclusions

The results of this report highlight the paucity of clinical evidence available to definitively compare the efficacy and safety of the NOACs as a thromboprophylaxis in AF patients. There were three large, well-designed and properly conducted studies available for analysis, each comparing NOACs and warfarin. However, there was heterogeneity across the three RCTs and, with only three studies handling this, heterogeneity was limited. This should be borne in mind when interpreting the results.

Compared with adjusted-dose warfarin, dabigatran 150 mg and apixaban produced statistically significant reductions in stroke/SE, whereas rivaroxaban and dabigatran 110 mg did not. Apixaban and dabigatran 110 mg were associated with significantly less major bleeding versus adjusted-dose warfarin, whereas there was no association with major bleeding with dabigatran 150 mg and rivaroxaban. All treatments were associated with a significant reduction in intracranial bleeding relative to adjusted-dose warfarin, whereas no treatments were associated with a significant reduction in MI relative to adjusted-dose warfarin. No treatments were associated with a significant reduction in GI bleeding relative to adjusted-dose warfarin, but dabigatran 150 mg and rivaroxaban were associated with a significant increase. Apixaban was associated with a significant reduction in all-cause mortality relative to adjusted-dose warfarin. Even though some differences were statistically significant between treatments for some outcomes, the absolute differences for the NOACs versus warfarin where statistical significance was achieved ranged from two to a maximum of eight fewer events per 1,000 patients.

The results of the subgroup analyses were further limited by a paucity of data, but suggested that there may be subpopulations for which the use of NOACs may be more or less beneficial. In patients where warfarin treatment is well-controlled (TTR ≥ 66%), the use of NOAC may be rather less favourable — the absolute risk increase of a major bleed exceeded the absolute risk reduction of stroke/SE. In elderly patients (≥ 75 years old), the NOACs may be more favourable for preventing thromboembolic events than warfarin, but are associated with a greater risk of major bleeding. Indeed, for dabigatran 150 mg and rivaroxaban, the absolute risk of major bleeding exceeded or approached the absolute risk of stroke/SE, respectively, in this population. For low to moderate risk patients (CHADS2 < 2), the NOACs were less favourable than warfarin for preventing stroke/SE, but were preferable to warfarin for reducing the absolute risk of major bleeding.

In addition to the limitations imposed by the clinical data, the results of the analysis of cost-effectiveness of the NOACs and warfarin were limited by the uncertainty regarding the pricing of the NOACs. Analysis of the base case suggested that either dabigatran 150 mg or apixaban would be the most cost-effective treatment option. Analysis of subpopulations suggested that dabigatran 150 mg was the most cost-effective treatment option in younger patients (< 80 years old), and in centres where the TTR is < 66%, whereas apixaban was the most cost-effective treatment option in older patients (80 years old) and in centres where the TTR was ≥ 66%. None of NOACs were likely to be considered cost-effective for patients with a previous major stroke. However, the results of the cost-effectiveness analysis were highly sensitive to the patient population under consideration, reinforcing the need for tailoring the treatment of individual patients according to individual characteristics that affect treatment outcomes(includes the degree of control of which warfarin therapy (TTR), age, risk of stroke, and history of thromboembolic events).

In conclusion, the limited number of RCTs available for analysis and heterogeneity in several important features of these RCTs means that there is uncertainty regarding the comparative clinical or cost-effectiveness of the NOACs and warfarin. To fully elucidate the comparative effectiveness of these agents and facilitate the identification of subpopulations within which the NOACs might be more beneficial than warfarin, rigorously conducted comparative RCTs or network meta-regression analyses of patient-level data are required.

Copyright © 2012 CADTH.
Bookshelf ID: NBK169802
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