NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Antithrombotic Agents for the Prevention of Stroke and Systemic Embolism in Patients With Atrial Fibrillation [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2013 Mar.

Cover of Antithrombotic Agents for the Prevention of Stroke and Systemic Embolism in Patients With Atrial Fibrillation

Antithrombotic Agents for the Prevention of Stroke and Systemic Embolism in Patients With Atrial Fibrillation [Internet].

Show details

EXECUTIVE SUMMARY

Context and Policy Issues

Atrial fibrillation (AF) is a common cardiac arrhythmia associated with increased morbidity and mortality.1,2 Patients with AF are at increased risk of systemic embolism (SE) and stroke, which can cause death, disability, and impaired quality of life.1 Antithrombotic therapies, such as oral anticoagulant and antiplatelet drugs, can reduce the risk for stroke and systemic thromboembolism and are recommended for most AF patients with risk factors for stroke.37 Antithrombotic therapies are also associated with a risk of bleeding, and their efficacy for stroke prevention should always be balanced against a patient’s risk of hemorrhage.37

Existing guidelines35 recommend antithrombotic therapy based on risk of stroke,35 and most patients with non-valvular AF benefit from some form of antithrombotic therapy with an anticoagulant or antiplatelet drug. However, each oral antithrombotic drug used for stroke prevention in AF has advantages and disadvantages. There are decades of experience with the use of the vitamin K antagonist (VKA) warfarin, as well as compelling evidence of efficacy with regard to stroke prevention.79 However, individualized dose adjustments and laboratory monitoring are required,1012 and warfarin remains the most common cause of drug-related emergency hospitalization in the elderly.13 Because there is less clinical experience with the new oral anticoagulant (NOAC) drugs apixaban, dabigatran, and rivaroxaban outside of randomized controlled trials, it is not yet clear whether the NOACs show increased real-world benefits compared with warfarin. Although less effective at stroke prevention than anticoagulant therapy in most risk categories,14 antiplatelet agents may still be the best choice for selected patients.35,7,15

Following individual recommendations for dabigatran and rivaroxaban in AF made by the Common Drug Review (CDR),16,17 the Canadian Agency for Drugs and Technologies in Health (CADTH) previously reviewed the clinical effectiveness and cost-effectiveness of the NOACs compared with warfarin for CDEC to develop recommendations for policy-makers regarding the NOACs and warfarin.18 At that time, apixaban was not approved for use in Canada, and was therefore not included in the CDEC recommendation; in addition, antiplatelet drugs were not included. The current review was undertaken to extend the previous review to allow CDEC to develop recommendations that include all the NOACs, as well as the antiplatelet drugs acetylsalicylic acid (ASA) and clopidogrel.

Objectives

  1. To conduct a systematic review and mixed treatment comparison (MTC) of the clinical evidence pertaining to antithrombotic agents for the prevention of morbidity and mortality in patients with non-valvular AF.
  2. To assess the impact of age, CHADS2 score, and time spent in the therapeutic range (TTR; relevant to warfarin only) on the clinical safety and efficacy of antithrombotic agents.
  3. To conduct a cost-effectiveness analysis of antithrombotic agents based on the results of the systematic review and MTC.

Methods

Active and placebo-controlled randomized controlled trials (RCTs) of antithrombotic agents for the prevention of stroke and other thromboembolic events in patients with AF were identified through electronic databases, grey literature, and stakeholder consultation. Two reviewers independently screened the titles and abstracts, and independently evaluated the full-text publications for final article selection. RCTs were considered for inclusion if they compared at least two of the antithrombotic strategies under review, in patients who were eligible for anticoagulant therapy, and reported outcomes related to patient safety or clinical efficacy, as pre-specified in the review protocol. Pairwise and Bayesian MTC network meta-analyses (NMA) were conducted to pool trial results, when appropriate. The results of the MTC were used to evaluate the cost-effectiveness of each intervention following standard procedures. This report was peer-reviewed by clinical experts.

Summary of Findings

The systematic review included 12 individual RCTs (28 publications)1946 in which the efficacy and safety of antithrombotic interventions were evaluated in patients with AF. Interventions included the NOACs apixaban, dabigatran, and rivaroxaban; warfarin; or ASA with or without clopidogrel.

Key Clinical Findings

While there were statistically significant differences between the NOACs and warfarin for some outcomes (details to follow), absolute risk differences (ARD) for the NOACs versus warfarin were small and were generally fewer than 10 events per 1,000 patients treated each year. Absolute risk differences were calculated versus warfarin and not among other treatment interventions.

Anticoagulants demonstrated consistently better outcomes compared with the antiplatelet treatments (see subsequent information).

Estimates of effect derived from the direct pairwise comparisons aligned closely with those obtained from NMA in both direction and magnitude. In no case was there a discrepancy in the statistical significance of the effect sizes between the direct pairwise comparisons and the NMA.

The results from the random-effects model were very similar to those of the fixed-effects model for all outcomes, although the confidence intervals (CIs) for each point estimate were wider for the random-effects model.

Reference Case

Stroke and Systemic Embolism
  • Apixaban 5 mg twice daily and dabigatran 150 mg twice daily were associated with statistically significantly lower rates of stroke and systemic embolism (SSE) compared with adjusted-dose warfarin. For apixaban, the odds ratio (OR) was 0.8 (95% CI, 0.7 to 0.95) and the ARD 95% CIs ranged from 1 to 6 fewer events per 1,000 patients treated per year. For dabigatran, the OR was 0.7 (95% CI, 0.5 to 0.8), with a range in ARD of 3 to 9 events per 1,000 patients treated per year.
  • Dabigatran 150 mg twice daily was associated with statistically significantly fewer SSEs versus dabigatran 110 mg twice daily (OR = 0.7 [95% CI, 0.6 to 0.9]).
  • Low-dose ASA and the combination of clopidogrel plus low-dose ASA were statistically significantly less effective at preventing SSE compared with all anticoagulants (OR = 1.9 [95% CI, 1.3 to 2.8] to 2.9 [95% CI, 2.0 to 4.3]).
  • No statistically significant differences in the OR for SSE were detected among each of the remaining interventions, including the comparison between rivaroxaban and warfarin or other NOACs.
Major Bleeding
  • Apixaban 5 mg twice daily and dabigatran 110 mg twice daily were associated with statistically significantly lower rates of major bleeding compared with warfarin (OR = 0.7 [95% CI, 0.6 to 0.8] and 0.8 [95% CI, 0.7 to 0.9], respectively). ARDs versus warfarin ranged from 6 to 13 fewer events per 1,000 patients treated per year with apixaban and from 2 to 11 fewer events per 1,000 patients treated per year with dabigatran 110 mg.
  • Dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily were associated with statistically significantly higher rates of major bleeding compared with apixaban 5 mg twice daily (OR = 1.3 [95% CI, 1.1 to 1.7] and 1.5 [95% CI, 1.2 to 1.8]) and dabigatran 110 mg twice daily (OR = 1.2 [95% CI, 1.0 to 1.4] and 1.3 [95% CI, 1.04 to 1.6]).
  • Clopidogrel plus low-dose ASA was associated with statistically significantly higher rates of major bleeding compared with apixaban (OR = 1.6 [95% CI, 1.2 to 2.2]).
  • No statistically significant differences in the OR for major bleeding were detected among each of the remaining interventions, including the comparison between rivaroxaban and warfarin.
All-Cause Mortality
  • Apixaban 5 mg twice daily was associated with statistically significantly less all-cause mortality compared with warfarin (OR = 0.9 [95% CI, 0.8 to 0.997], ARD = 0 to 8 fewer events per 1,000 patients treated per year).
  • No statistically significant differences in the OR for all-cause mortality were detected among each of the remaining interventions, including the comparisons among NOACs and versus warfarin.
Extracranial Hemorrhage
  • Apixaban 5 mg twice daily was associated with a statistically significantly lower rate of extracranial hemorrhage compared with warfarin (OR = 0.8 [95% CI, 0.7 to 0.9], ARD = 2 to 8 fewer events per 1,000 patients treated per year).
  • All of the following treatments were associated with statistically significantly higher rates of extracranial hemorrhage compared with apixaban: dabigatran 150 mg twice daily (OR = 1.4 [95% CI, 1.1 to 1.7]), rivaroxaban 20 mg OD (OR = 1.4 [95% CI, 1.1 to 1.8]), and medium-dose ASA (OR = 5.2 [95% CI, 1.2 to 39.8]).
Intracranial Hemorrhage
  • All NOACs were associated with statistically significant reductions in intracranial hemorrhage (ICH) compared with warfarin. Absolute risk reductions were similar between these interventions and ranged from 1 to 7 fewer events per 1,000 patients treated per year.
  • Dabigatran 110 mg twice daily was associated with a statistically significantly lower rate of ICH compared with rivaroxaban 20 mg OD (OR = 2.1 [95% CI, 1.2 to 3.8]). All other comparisons among NOACs did not reach statistical significance.
  • Clopidogrel plus low-dose ASA was associated with a statistically significantly higher rate of ICH compared with the NOACs (OR = 3.0 [95% CI, 1.4 to 7.0] to 6.5 [95% CI, 2.8 to 15.7]).
Myocardial Infarction
  • Dabigatran 150 mg twice daily was associated with a statistically significantly higher rate of myocardial infarction (MI) compared with warfarin (OR = 1.4 [95% CI, 1.02 to 2.0], ARD = 0 to 4 more events per 1,000 patients treated per year).
  • Dabigatran (110 mg and 150 mg twice daily ), medium-dose ASA, and the combination of clopidogrel plus low-dose ASA were both associated with statistically significantly higher rates of MI compared with apixaban 5 mg twice daily (OR = 1.6 [95% CI, 1.02 to 2.4], 1.6 [95% CI, 1.04 to 2.5], 1.8 [95% CI, 1.01 to 3.4] and 1.6 [95% CI, 1.2 to 2.2], respectively).
  • Medium-dose ASA was associated with a statistically significantly higher rate of MI compared with rivaroxaban 20 mg OD (OR = 2.0 [95% CI, 1.1 to 3.7]).

Subgroup Analyses

CHADS2 < 2
SSE
  • No statistically significant differences were observed between warfarin and each evaluated NOAC for SSE.
  • Dabigatran 150 mg twice daily was associated with a statistically significantly lower rate of SSE versus dabigatran 110 mg twice daily (OR = 0.6 [95% CI, 0.4 to 0.996]).
  • Low-dose ASA and the combination of clopidogrel plus low-dose ASA were statistically significantly less effective at preventing SSE compared with the anticoagulants (OR ranging from 2.2 [95% CI, 1.03 to 4.9] to 3.6 [95% CI, 1.6 to 8.3] with low-dose ASA and from 3.2 [95% CI, 1.2 to 9.1] to 5.2 [95% CI, 2.0 to 15.2] with the combination of clopidogrel plus low-dose ASA).
Major Bleeding
  • Apixaban 5 mg twice daily and dabigatran 110 mg twice daily were associated with statistically significantly lower rates of major bleeding compared with warfarin (OR = 0.6 [95% CI, 0.4 to 0.8] and OR = 0.7 [95% CI, 0.5 to 0.9], respectively). ARDs versus warfarin ranged from 6 to 17 fewer events per 1,000 patients treated per year with apixaban and from 3 to 17 fewer events per 1,000 patients treated per year with dabigatran 110 mg. The combination of clopidogrel plus low-dose ASA was associated with statistically significantly higher rates of major bleeding compared with apixaban 5 mg twice daily and dabigatran (110 mg and 150 mg twice daily ) (OR = 2.6 [95% CI, 1.4 to 4.8], 2.3 [95% CI, 1.3 to 4.4] and 2.0 [95% CI, 1.1 to 3.7], respectively).
CHADS2 ≥ 2
SSE
  • Dabigatran 150 mg twice daily and apixaban 5 mg twice daily were associated with statistically significantly lower rates of SSE compared with warfarin (OR = 0.7 [95% CI, 0.5 to 0.9] and 0.8 [95% CI 0.6 to 0.95], respectively). ARDs versus warfarin ranged from 3 to 10 fewer events per 1,000 patients treated per year with dabigatran 150 mg and from 1 to 7 fewer events per 1,000 patients treated per year with apixaban.
  • Low-dose ASA and the combination of clopidogrel plus low-dose ASA were statistically significantly less effective at preventing SSE compared with the NOACs (OR ranging from 2.4 [95% CI, 1.03 to 6.0] to 3.2 [95% CI, 1.3 to 8.0] with low-dose ASA and from 2.0 [95% CI, 1.4 to 3.0] to 2.7 [95% CI, 1.8 to 4.1] with the combination of clopidogrel plus low-dose ASA).
Major Bleeding
  • Apixaban 5 mg twice daily was associated with a statistically significantly lower rate of major bleeding compared with warfarin (OR = 0.7 [95% CI, 0.6 to 0.9], ARD = 5 to14 fewer events per 1,000 patients per year), as well as compared with dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily (OR = 1.4 [95% CI, 1.1 to 1.7] and 1.3 [95% CI], respectively).
Age and Time in Therapeutic Range
SSE
  • In patients 75 years old or older, dabigatran 150 mg twice daily and apixaban 5 mg twice daily were associated with a statistically significantly lower rate of SSE compared with warfarin, and all anticoagulant drugss were significantly superior to low-dose ASA. In patients younger than 75 years, low-dose ASA and the combination of clopidogrel plus low-dose ASA were statistically significantly less effective at preventing SSE compared with warfarin, and dabigatran 150 mg twice daily was associated with statistically significantly fewer SSE versus warfarin, dabigatran 110 mg twice daily, and rivaroxaban 20 mg once daily.
  • In centres with poor INR control (TTR < 66%), dabigatran 150 mg twice daily was associated with a statistically significantly lower rate of SSE compared with warfarin and rivaroxaban 20 mg once daily. In centres with good INR control (TTR ≥ 66%), there were no statistically significant differences among treatments.
Major Bleeding
  • In patients 75 years old or older, apixaban 5 mg twice daily was associated with statistically significantly lower rates of major bleeding compared with the other anticoagulant drugs. In patients younger than 75 years, dabigatran 110 mg and 150 mg and apixaban were associated with statistically significantly lower rates of major bleeding compared with warfarin.
  • In centres with poor INR control (TTR < 66%), apixaban 5 mg twice daily and dabigatran 110 mg and 150 mg twice daily were all associated with statistically significantly lower rates of major bleeding compared with warfarin. In centres with good INR control (TTR ≥ 66%), apixaban was associated with statistically significantly lower rates of major bleeding compared with warfarin.
  • Apixaban 5 mg twice daily was associated with statistically significantly lower rates of major bleeding compared with dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily irrespective of the degree of INR control.

Stroke and Systemic Embolism versus Major Bleeding

Reference Case

The overall comparative benefit/risk profile based on the results for SSE (benefit) and major bleeds (risk) for the nine interventions suggests that the benefit/risk of the NOACs was positive compared with warfarin (decrease in SSE and/or major bleeding) and largely similar among one another. Even where statistically significant differences existed for the OR for the NOACs versus warfarin, the ARD associated with these differences were small and were generally fewer than 10 events per 1,000 patients treated each year.

Comparison of all anticoagulant treatment (including warfarin) to ASA with or without clopidogrel suggests that antiplatelet drugs have a less favourable benefit/risk profile than the NOACs.

Subgroups

For patients with a CHADS2 score < 2, the overall benefit/risk of the NOACs was positive compared with warfarin and closer to the benefit/risk of warfarin than the ASA treatments; whereas the NOACs (except rivaroxaban, which was not included in this analysis) decrease the risk of SSE and major bleeding, antiplatelet drugs had a less favourable benefit/risk profile.

For patients with a CHADS2 score ≥ 2, the benefit/risk of the NOACs was positive compared with warfarin and very similar to the benefit/risk of warfarin. Low-dose ASA had a less favourable benefit/risk profile than the NOACs; however, the benefit/risk profile for clopidogrel plus low-dose ASA appears to be close to the anticoagulants in this subgroup. The level of confidence in this observation is considerably lower than for the anticoagulant drugs, as the estimated effect sizes for clopidogrel plus low-dose ASA were derived from a single RCT with substantially fewer patients.

Comparison of all overall benefit/risk of the anticoagulant treatments versus the antiplatelet drugs suggests that antiplatelet drugs have a less favourable benefit/risk profile than the NOACs irrespective of stroke risk, age, or the degree of INR control.

Key Economic Findings

For patients with CHADS2 < 2, dabigatran 150 mg twice daily was likely the optimal treatment, with an incremental cost per quality-adjusted life-year (QALY) gained versus warfarin of $20,845.

For patients with CHADS2 ≥ 2, dabigatran 150 mg twice daily and apixaban 5 mg twice daily were the most cost-effective treatments among the NOACs, and the incremental cost per QALY gained for both apixaban and dabigatran 150 mg versus warfarin was $17,795. Apixaban 5 mg twice daily was likely optimal, as it dominated dabigatran 150 mg twice daily in probabilistic analyses, but the difference between these two treatments is marginal.

The antiplatelet treatments were all dominated by one or more of the anticoagulants, irrespective of stroke risk (CHADS2 score), age, or degree of INR control (TTR). Therefore, compared with anticoagulant drugs, antiplatelet therapy was never optimal in any of the subgroups analyzed. However, the paucity of data for patients with a CHADS2 score = 0 suggests that these findings cannot be generalized to patients with a low risk of stroke, and must be limited to patients with a moderate or high risk of stroke (CHADS2 score > 0).

Relative cost-effectiveness was influenced by the following:

  • Willingness-to-pay threshold (λ): The probability that dabigatran 150 mg twice daily is the most cost-effective NOAC in CHADS2 < 2 increases as the λ increases. Similarly, the probability that apixaban 5 mg twice daily is optimal in patients with a CHADS2 score ≥ 2 increases as the λ increases.
  • Age: Dabigatran 150 mg twice daily was optimal in younger patients (60 or 70 years old), whereas apixaban 5 mg twice daily was optimal in older patients (80 years old). None of the antiplatelet agents was optimal irrespective of age.
  • Degree of INR control: In centres with poor INR control (TTR < 66%), dabigatran 150 mg twice daily was optimal, while apixaban 5 mg twice daily was optimal in centres with good INR control (TTR ≥ 66%), although there was little difference in cost-effectiveness for both therapies.

Key Limitations

A major limitation of conclusions made in the current report is heterogeneity among the included trials, both for patient characteristics (e.g., differences in baseline patient characteristics of the included studies that may be important predictors of treatment effects, such as stroke risk, differences in the degree of INR control) and trial methodology (e.g., population sizes, definitions, and reporting of outcomes). We also observed variability in definitions (e.g., bleeding) and methodological rigour; indeed, most trials evaluating ASA with or without clopidogrel or placebo/no treatment were substantially smaller, older, and of lower quality than the NOACs trials. Due to the relatively small number of trials available for each individual therapy in the published literature, the limited ability to adjust for such heterogeneity reduces the degree of certainty associated with the results of our analyses.

Other important limitations are presented here:

  • There are no direct comparisons of the NOACs available, and indirect comparisons were used to compare the different treatments. This method has inherent limitations, but in the absence of head-to-head trial data, this is the only alternative at present to compare different antithrombotic therapies.
  • Data were not available for all outcomes for all treatments in all subpopulations of interest. In particular, there were very few patients for all interventions at low risk of stroke (CHADS2 score = 0). Therefore, our findings cannot be generalized to patients who have a low risk of stroke.
  • Limitations based on the comparison of clinical efficacy and safety necessarily apply to the confidence in the results of pharmacoeconomic analyses.

Conclusions and Implications for Decision- or Policy-Making

The results of the current review revealed that there were statistically significant differences in clinical outcomes in AF patients between the NOACs and warfarin, although it is unclear whether the ARD associated with these differences translate into clinically meaningful benefits in practice. The pharmacoeconomic analyses suggested that NOACs may be cost-effective alternatives to warfarin for preventing SSE in AF patients. More specifically, if it is assumed that the λ is $50,000, then among the NOACs, dabigatran 150 mg twice daily is likely the optimal therapy in patients who have a moderate risk of stroke (CHADS2 = 1), or are relatively young (≤ 70 years old), or who cannot maintain an adequate INR control (TTR < 66%); apixaban 5 mg twice daily would likely be the optimal NOAC therapy in patients who have a high risk of stroke (CHADS2 score ≥ 2) or are relatively old (≥ 80 years old).

The current review extends our previous report by demonstrating that anticoagulant therapy is superior to ASA, both regarding clinical benefit and cost-effectiveness, irrespective of whether ASA is co-administered with clopidogrel. Anticoagulant therapy would appear to be a superior treatment option for preventing SSE in patients with non-valvular AF in patients with a moderate or high risk of stroke (CHADS2 score ≥ 1). The superiority of the anticoagulant drugs versus the antiplatelet drugs was consistent irrespective of age and the degree of INR control (TTR). There was, however, insufficient evidence to compare anticoagulant drugs to antiplatelet drugs in patients with a low risk of stroke (CHADS2 score = 0).

These results must be considered in the light of several limitations that create uncertainty, most notably the reliance on indirect comparison methodology to compare the different treatments.

Copyright © CADTH February 2013.

You are permitted to make copies of this document for Non-commercial purposes provided it is not modified when reproduced and appropriate credit is given to CADTH. You may not otherwise copy, modify, translate, post on a website, store electronically, republish or redistribute any material from the website in any form or by any means without the prior written permission of CADTH.

Please contact CADTH’s Vice-President of Corporate Services at ac.htdac@secivresetaroproc with any inquiries about this notice or other legal matters relating to CADTH’s services.

Bookshelf ID: NBK168992
PubReader format: click here to try

Views

Other titles in this collection

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...