New anticoagulants in the treatment of Atrial Fibrillation: Update 2012 39thAnnual Conference of the Egyptian Society Cardiology Cardio Egypt, Cairo, Egypt March1st /2012

M. El. Shahawy, MD, MS, FACP,FESC ,FACC, FAHA,FSCCT Clinical Professor of Medicine Univ. of Florida and S. Florida Medical Director CVD Assessment Center, Sarasota, Florida

Disclosure of financial relationships: M. El Shahawy, MD, MS, FESC, FACC, FAHA Grant/Research Support: Abbot ,Amgen, Astra Zenka Boehringer, BMS, GSK, Myogen, Novartis, Sanofi-Aventis,Takeda Consultant:

Nitro med Inc; CVT

Speakers Bureau:

Abbot, Astra Zenka, Boehringer, Novartis; Pfizer.

Major stock shareholder: None Other:

None

Management of AF Stroke Prevention

Rate Control

Rhythm Control

Stoke prevention in NVAF Warfarin has been the standard medical therapy for stroke prevention in patients with atrial fibrillation for decades . However over the last few years we became more aware for the need for more efficient and safe alternative.

Objectives 1. Emphasize that Atrial fibrillation is the most common

cardiac arrhythmia and is associated with five fold increase in Stroke 2. Understand why the need for Novel alternative Anticoagulants for the prevention of stroke in NVAF beyond Warfarin 3. Emphasize the importance for the use of effective and safe alternative for warfarin

Continue Objectives 4. Familiarization with Novel anticoagulant for the treatment of atrial fibrillation with emphasis on factor X inhibitors and Direct Thrombin Inhibitors [DTI] 5. Appreciate Why in the long run novel oral anticoagulant , i.e. direct thrombin inhibitor and factor X inhibitor might be the best alternative to warfarin in all aspects including efficacy and safety

Objective #1

Emphasize that Atrial fibrillation is the most common cardiac arrhythmias and is associated with five fold increase of Stroke

Epidemiology of AF • Most common sustained cardiac arrhythmia • Currently affects nearly 2.3 million Americans, or 1% of population • Prevalence expected to increase by ≥2.5-fold by 2050 • Lifetime risk of developing AF: 1 in 4 for men and women ≥40 years of age AF = atrial fibrillation. Lloyd-Jones DM, et al. Circulation. 2004;110:1042-1046. Go AS, et al. JAMA. 2001;285(8):2370-2375.

Thromboembolic Events in Control Patients in NVAF Trials Cerebral* 49 (91%†)



Systemic* 5 (9%) *Number of events (% of total of 54 events in control patients); †Range in the studies: 86% to 94% Combined data for AFASAK, SPAF, and BAATAF shown. Adapted from: Albers et al. Ann Neurol 1991;30:511-518.

Thromboembolic Stroke

Courtesy of Peter Kowey, MD.

Risk of Stroke in AF according to The CHADS2 Scoring System • • • • •

C H A D S2

Congestive heart failure = 1 HTN (or treated HTN) =1 Age ≥75 years =1 Diabetes =1 Prior stroke or TIA =2 Total Score 0 1 2 3 4 5 6

Major bleeds on warfarin approximately 2% per year

Annual Risk of Stroke (%) 1.9 2.8 4.0 5.9 8.5 12.5 18.2

Hersi A, et al. Curr Probl Cardiol. 2005;30(4):175-233. Fuster V, et al. J Am Coll Cardiol. 2006;48(4):e149-e246. Gage BF, et al. Validation of clinical classification schemes for predicting stroke. JAMA. 2001;285:2864-2870.

Objective #2

2. Why there is a need for Novel Anticoagulants for the prevention of stroke in NVAF beyond Warfarin ?

Warfarin for AF

Adequacy of Anticoagulation in Patients With AF in Primary-Care Practice N=660

No Warfarin 65%

INR Above Target 6% INR in Target Range 15%

Sub-therapeutic INR 13% Samsa et al. Arch Intern Med. 2000;160:967-973.

Hence there is a need for an effective, safe and easy to use antithrombotic therapy for atrial fibrillation patients beyond Coumadin S0 what are the alternative ?

Alternatives to warfarin include: 1. New oral anticoagulants 2. Antiplatelet therapy and 3. Exclusion of the left atrial appendage (LAA) as a major embolic source

What the future of oral anticoagulation in Atrial fibrilation holds in store ? A number of newer oral anticoagulants has been recently released for stroke prevention in AF Including : 1. factor Xa inhibitors ,Rivaroxaban

2.Oral direct thrombin, Dabigtran This presentation will focus on summarizing the latest clinical trial data pertinent to this two new agents which currently in in use in USA

Objective #3 3. Familiarization with Novel oral anticoagulant

New Anticoagulants In A Fib New Oral Anticoagulants apixaban edoxaban rivaroxaban Extrinsic Pathway

Factor X

Intrinsic Pathway

direct Xa blockers

Activated Factor X (Xa)

Prothrombin (Factor II)

Thrombin (Factor IIa)

Fibrinogen

direct IIa blockers

Fibrin

dabigatran ximelagatran Verheugt FWA Nat Rev Cardiol 7:149-54, 2010

What the future of oral anticoagulation in Atrial Fibrillation holds in store ? Thrombin

Factor Xa

Apixaban Dabigatran

Quan ML et.al J Med Chem. 2005;48:1729-44.

A number of newer oral anticoagulants has been recently released for stroke prevention in AF Including : 1. Factor Xa inhibitors: Rivaroxaban 2. Oral direct thrombin: Dabigtran This presentation will focus on summarizing the latest clinical trial data pertinent to these two new agents, which are currently in in use in USA

PK/PD of 5 Novel Oral Agents Dabigatran

Rivaroxaba n

Apixaban

Edoxaban (DU-176b)

Betrixaban (PRT054021)

IIa (thrombin)

Xa

Xa

Xa

Xa

2

2-4

1-3

1-2

NR

None

32%

15%

NR

None

7%

80%

66%

>45%

34-47%

Transporters

P-gp

P-gp/BCRP

P-gp

NR

P-gp

Protein binding

35%

>90%

87%

55%

NR

12-14h

9-13h

8-15h

8-10h

19-20h

Renal elimination

80%

66%

25%

35%