PHARMACOLOGY REVIEW:
Comparison of the Efficacy and Safety
of New Oral Anticoagulants with Warfarin
in Patients with Atrial Fibrillation-
A Meta-analysis of Randomised Trials
Presented by: Khairunnisa Zamri
OUTLINE
1. Definition
2. Epidemiology and prognosis
3. Pathophysiology
4. Management of thromboembolism
5. Mechanism of action of warfarin
6. Justification of study
7. Aim
8. Methodology
9. Results
10. Interpretation
11. Conclusion
12. References
DEFINITION
Atrial fibrillation (AF): is an atrial tachyarrhythmia
characterized by uncoordinated atrial activation with
consequent deterioration of atrial mechanical function 1
1 CPG on Management of Atrial Fibrillation (2012)
EPIDEMIOLOGY AND PROGNOSIS
In Malaysia, information on AF is scarce.
Hospital practice data may give a biased view of the clinical epidemiology of AF, since only one-third of patients with AF may actually have been admitted to hospital.
Data from Western populations, estimated prevalance of AF is 0.4% to 1% in the general populations and doubles with each decade of age, from 0.5% (age 50-59 years) to ~9% (age 80-89 years).
AF is associated with prothrombotic state leads to stroke and thromboembolism- only ANTITHROMBOTHIC therapy has been shown to reduce AF-related deaths 2.
2 Hylek EM et al. (2003)
PATHOPHYSIOLOGY
Symptoms of AF
Breathlessness
Angina
Palpitations
Dizziness
MANAGEMENT-PREVENTION OF
THROMBOEMBOLISM
Risk stratification for stroke- allows the clinician to
consider anticoagulant treatment for those people who
are at increased risk of stroke.
MECHANISM OF ACTION OF WARFARIN
Background of study
Atrial fibrillation: 3 is a supraventricular tachyarrhythmia
characterized by uncoordinated atrial activation with
consequent deterioration of mechanical function.
the most common sustained cardiac arrhythmia, predisposes
patients to an increased risk of embolic stroke and has a higher
mortality than sinus rhythm. 4
Four new oral anticoagulants (Dabigatran, rivaroxaban, apixaban and
edoxaban) compare favourably with warfarin for stroke prevention in patients
with atrial fibrillation
3 American Heart Association (2011)
4 Camm AJ et al. (2010)
Justification of study
Warfarin and other Vit. K antagonist are
highly effective in prevention of
thromboembolism but have narrow therapeutic index
Requiring frequent
monitoring and dose
adjustments
Resulting in substantial risk
and inconvenience
Other limitation:
-poor patient adherence
-systematic underuse of vitamin K
antagonists for
stroke prevention 3,4
3 Birman-Deych E et al. (2006)
4 Hylek EM et al. (2007)
Justification of study
New oral anticoagulants have been developed that dose-
dependently inhibit thrombin or activated factor X (factor
Xa) and offer potential advantages over vitamin K
antagonists, eg:
rapid onset and offset of action
absence of an effect of dietary vitamin K intake on their
activity
fewer drug interactions
Cont…
Dabigatran, rivaroxaban and apixaban have been approved
by regulatory authorities
Edoxaban has completed late-stage clinical assessment.
New oral anti coagulants are at least as safe and effective
as warfarin for prevention of stroke and systemic
embolism in patients with atrial fibrillation 5-8
5 Connoly et al. (2009)
6 Patel MR et al. (2011)
7 Granger CB et al. (2011)
8 Giugliano RP et al. (2013)
Aim
To assess the relative benefit of new oral anticoagulants in
key subgroups and the effects on important secondary
outcomes.
To offer clinicians a more comprehensive picture of the
new oral anticoagulants as a therapeutic option to reduce
the risk of stroke in patients with atrial fibrillation.
Methodology
Study selection
undertook a prespecified analysis of the four phase 3, randomised trials comparing the efficacy and safety of new oral anticoagulants with warfarin for stroke prevention in patients with atrial fibrillation:
1) Randomized Evaluation of Long Term Anticoagulation Therapy
(RE-LY; dabigatran)
2) Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF)
3) Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)
4) ENGAGE AF–TIMI 48 study (edoxaban)
Statistical analysis
calculated relative risks (RRs) and corresponding 95% CIs for each outcome and trial separately and checked findings against published data for accuracy.
assessed the appropriateness of pooling of data across studies with use of the Cochran Q statistic and I2 test for heterogeneity.
assessed comparative efficacy and safety for stroke or systemic embolic events and for major bleeding (the primary efficacy and safety outcomes)
analyses with Comprehensive Meta-Analysis software (version 2)
Results
Stroke or systemic embolic events
Secondary efficacy and safety outcomes
Major bleeding
Interpretation
New oral anticoagulants had a favourable risk–benefit profile, with
significant reductions in stroke, intracranial haemorrhage, and mortality, and
with similar major bleeding as for warfarin
But increased gastrointestinal bleeding.
The relative efficacy and safety of new oral anticoagulants was consistent
across a wide range of patients.
The findings offer clinicians a more comprehensive picture of the new oral
anticoagulants as a therapeutic option to reduce the risk of stroke in this
patient population.
Conclusion
The new oral anticogulants show a favourable balance
between efficacy and safety compared with warfarin,
which is consistent across a wide range of patients with
atrial fibrillation known to be at high risk for both
ischaemic and bleeding events.
References 1. Clinical Practice Guidelines on Management of Atrial Fibrillation (2012)
2. American Heart Association, 2011
3. Camm AJ, Kirchhof P, Lip GY, et al, and the European Heart Rhythm Association, and the European
Association for Cardio-Thoracic Surgery. Guidelines for the management of atrial fibrillation: the
Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC).
Eur Heart J 2010; 31: 2369–429.
4. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and
mortality in atrial fibrillation. N Engl J Med 2003; 349: 1019–26.
5. Birman-Deych E, Radford MJ, Nilasena DS, Gage BF. Use and effectiveness of warfarin in Medicare
beneficiaries with atrial fibrillation. Stroke 2006; 37: 1070–74.
6. Connolly SJ, Ezekowitz MD, Yusuf S, et al, and the RE-LY Steering Committee and Investigators.
Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139–51.
7. Patel MR, Mahaff ey KW, Garg J, et al, and the ROCKET AF Investigators. Rivaroxaban versus
warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883–91.
8. Granger CB, Alexander JH, McMurray JJ, et al, and the ARISTOTLE Committees and Investigators.
Apixaban versus warfarin in patients with atrial fi brillation. N Engl J Med 2011; 365: 981–92.
9. Giugliano RP, Ruff CT, Braunwald E, et al. Once-daily edoxaban versus warfarin in patients with atrial
fibrillation. N Engl J Med 2013; 369: 2093–104.
Thank you