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