1. Atrial Fibrillation Warfarin and its newer alternatives
Dr Mark Abelson
Cardiologist
Somerset West

9. Association of AF
and Stroke
MM00453 (01) Intl 06/09

11. Occluded Left ICA-T Pre and Post Embolectomy
54y M, “Wake up” >4h,NIHSS=32
90 d

12. Carotid Embolectomy

13. AF and Stroke Atrial Fibrillation and Stroke
3 million in US and 4.5 million in the EU have AF
2/3 of AF population are at high-risk of stroke
AF is responsible for 15-20% of ischemic strokes
AF Incidence increases with age
% in general population
% of yrs of age
% of >60 yrs of age
-- 10% of > 80 yrs of age

14. Relationship of AF and Stroke

15. Annual Stroke Risk for Patients with AF
Risk Stratification and Annual Stroke Risk for Patients with AF
Annual Stroke Risk for Patients with AF
By CHADS(2) Score
CHADS(2) Score
CHADS
Congestive heart failure +1
Hypertension
Age 75>
Diabetes Mellitus
Stroke or History of Cerebral Ischemia +2
F GAGE et al., 2004; 110:

16. The CHA2DS2-VASc score predicts clinical risk of stroke and thromboembolism in atrial fibrillation[1].
Congestive Heart Failure 1
Hypertension 1
Age ≥ 75 years 2
Age between 65 and 74 years 1
Stroke/TIA/TE 2
Vascular disease (previous MI, peripheral arterial disease or aortic plaque) 1
Diabetes mellitus 1
Female 1
Before bleeding risk evaluated score of 0 recommends no antithrombotic therapy and 2 or more antithrombotic therapy. A score of 1 recommends either antithrombotic or antiplatelet therapy.

17. Clot Prevention Currently Available Management Options
Medical Management: Anticoagulant
Effective: 67% stoke risk reduction(1)
Narrow therapeutic window for proper dose
Contraindicated in 14-47% of patients at risk of stroke (2)
Major complication: bleeding
Surgical Excision (Appendectomy)
Residual shunt: 10% (3)
Inconsistent outcomes due to incomplete exclusion;
Can create pouch with stagnant blood flow (4,5)
High invasiveness
Transcatheter Device Closure
Minimally invasive nature
Designed for percutaneous closure of the LAA in
prevention of clot embolization that may form in the
LAA
Intended as an alternative to warfarin therapy for
patients with non-valvular atrial fibrillation

18. Warfarin Therapeutic Window - INR of 2 to 3
A small window:
difficult to achieve
a well controlled
therapeutic range

19. AF Patients On Warfarin% 
Only 55% of AF patients with no contraindications have evidence of warfarin use in previous 3 months
Other studies cite warfarin use in AF patients from 17-50%
Elderly patients with increased absolute risk least likely to be taking warfarin
Contraindications 30-40%
Ann Int Med 131(12), 1999

20. INR Control – Not Good Low INR <1.6 Therapeutic INR 2-3
Efficacy  4-fold
Therapeutic INR 2-3
High INR >3.2 %
Bungard: Pharmacotherapy 20:1060, 2001

21. New Warfarin Alternatives
NO INR monitoring
- Dabigatran ( Pradaxa) – direct thrombin inhibitor
- Rivaroxaban (Xarelto) – F10a inhibitor
Aspirin plus clopidogrel
Aspirin (reduces stroke risk by 20%)

23. Rely Trial
Background
Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. Conclusions
In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT )

24. Risk of Stroke or Embolism
Figure 1. Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group.
Connolly SJ et al. N Engl J Med 2009;361:

25. Relative Risk of the Primary Outcome of Stroke or Systemic Embolism with Dabigatran versus Warfarin, According to Subgroup.
Figure 2. Relative Risk of the Primary Outcome of Stroke or Systemic Embolism with Dabigatran versus Warfarin, According to Subgroup. Ethnic group was self-reported. Long-term therapy with a vitamin K antagonist (VKA) denotes a total lifetime use of a VKA of 61 days or more. The body-mass index is the weight in kilograms divided by the square of the height in meters. The CHADS2 score is a measure of the risk of stroke in which congestive heart failure, hypertension, an age of 75 years or older, and diabetes mellitus are each assigned 1 point and previous stroke or transient ischemic attack is assigned 2 points; the score is calculated by summing all the points for a given patient. 12 Creatinine clearance was calculated according to the Cockcroft–Gault method. The squares with horizontal lines are hazard ratios and corresponding 95% confidence intervals; the sizes of squares are proportional to the sizes of the subgroups. PPI denotes proton-pump inhibitor.
Connolly SJ et al. N Engl J Med 2009;361:

26. Rivaroxaban
Xarelto® is the first oral, once-daily direct Factor Xa inhibitor for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery
Atrial Fibrillation

27. ROCKET AF TRIAL (Stroke Prevention Using the Oral Direct Factor Xa Inhibitor Rivaroxaban Compared With Warfarin in Patients with Nonvalvular Atrial Fibrillation)
The trial showed that the experimental factor Xa inhibitor rivaroxaban was as effective as warfarin in preventing stroke in 14,264 AF patients and did not increase their risk of bleeding. In the per protocol analysis, the rate of stroke and embolism was lower in the rivaroxaban group than in the warfarin group (p<0.001 for non-inferiority, p=0.018 for superiority). Major bleeding complications occurred at a similar rate (p=0.576).
Rate of stroke and embolism:
Rivaroxaban: 1.71 events per 100 patient-years
Warfarin: 2.16 events per 100 patient-years
Major bleeding complications:
Rivaroxaban: 3.60 events per 100 patient-years
Warfarin: 3.45 events per 100 patient-years
However, in the full intention-to-treat analysis, the superiority of rivaroxaban over warfarin did not achieve statistical significance (p=0.177). Intracerebral hemorrhage occurred in 55 patients on riveroxaban and 84 on warfarin (p=0.019).
“The main implication is that we have an alternative to warfarin,” said Robert Califf, M.D., co-principal investigator of the study, in an AHA press release. “Equally important, there was no increase in bleeding, so we have a drug you can take once a day, without monitoring, that is at least as good as warfarin and carries no additional risk.”

28. Can’t Take Warfarin?? Frail, falls GI bleeds Cerebral bleeds
Stroke despite therapeutic warfarin
Non-compliant / labile INR
(Do not want warfarin)

29. 90% of clots in appendage

30. Left Atrial Appendage Occluders
Transcatheter Occlusion of the LAA
Currently available in limited markets
AMPLATZER® Cardiac Plug WATCHMAN®

35. Device Event Rate (95% CI) Control Event Rate (95% CI)
WATCHMAN®
PROTECT – AF: Updated Data (Bayesian sequential design)
Primary Safety Results
End Point
Device Events (n)
Device Rate (95% CI)
Control Event (n)
Control Rate (95% CI)
Relative Risk (95% CI)
900 pts-yr cohort 48
8.7 ( ) 13
4.2 ( )
2.08 ( )
Primary Efficacy Results
End Point
Device Events (n)
Device Rate (95% CI)
Control Event (n)
Control Rate (95% CI)
Relative Risk (95% CI)
900 pts-yr cohort 20
3.4 ( ) 16
5.0 ( )
0.68 ( )
All Stroke, HS, and IS by Intervention
End Point
Device Event Rate (95% CI)
Control Event Rate (95% CI)
Relative Risk (95% CI)
All Stroke
2.6 ( )
3.5 (1.7 – 5.7)
0.74 (0.36 – 1.76) IS
2.4 (1.3 – 3.9)
1.6 (0.5 – 3.1)
1.53 (0.654 – 5.43) HS
0.2 ( )
1.9 (0.7 – 3.7)
0.09 (0.00 – 0.45)
Holmes DR: ACC & i2 Summit 2009

36. Protect AF – 21month F/U

37. Vergelegen Experience
7 patients – all elderly men with Chads>2
Significant GI bleeds on warfarin
Warfarin stopped – 2 had small strokes
One INR very labile due to recurrent UTI (antibiotics. Suprapubic catheter)
All discharged next day – ASA and plavix for 1 month then ASA alone.