Mills-Peninsula Cardiovascular Symposium, September 2015 - Brad Angeja, MD FACC

1. Clinical Implications of
Oral Anti-Coagulants
Focus on Atrial Fibrillation
Brad Angeja, MD FACC
Palo Alto Medical Foundation

2. None
Disclosures

3. Relevant Advances in Atrial
Fibrillation
• Why anti-coagulate?
– Calculate stroke risk
• Data for warfarin
• Rationale for warfarin alternatives
– Data for the NOACs
– Idiosyncrasies of the NOACs
• Special topics
– Elderly, peri-operative, valves, reversal
Objectives

4. Clinical Uses of Anti-coagulation
• DVT, PE (discussed separately)
• Mechanical valves
• Atrial fibrillation
– 2.7 million American adults – and counting
– 12% 75 to 84 years of age
– >1/3 ≥80 years of age
– Lifetime risk after 40 years of age is about 25%
• Stroke in AF
– 15% of all strokes in the US can be attributed to AF,
– 5 fold increased risk of stroke and
– the results of stroke are worse 1 ,3
1. Nattel. Lancet 2006;367:262-272
2. Page. N Engl J Med 2004;351:2408-16
3. HRS guidelines 2014
Slide courtesy Chris Woods, MD

5. Stroke is caused by thromboembolic
disease in AF
5
90% of thrombi are
found in the
Left atrial appendage
Slide courtesy Chris Woods, MD

6. Transesophageal Echocardiogram of the
Appendage
6
Normal With Clot
Slide courtesy Chris Woods, MD

7. Slide courtesy Chris Woods, MD

8. Warfarin works
8

9. Narrow
Therapeutic
Window
9

10. Bleeding Risk: HAS-BLED
10
Clinical characteristics comprising the HAS-BLED Bleeding Risk Score
Letter Clinical characteristic* Points HAS-BLED score
Bleeds per 100 patient-yrs
H Hypertension (ie uncontrolled blood pressure) 1 0 1.13
A Abnormal renal and liver function (1 point each) 1 or 2 1 1.02
S Stroke 1 2 1.88
B Bleeding tendency or predisposition 1 3 3.74
L Labile INRs (for patients taking warfarin) 1 4 8.70
E Elderly (age greater than 65 years) 1 5 to 9 Insufficient data
D Drugs (aspirin or NSAIDs) or alcohol abuse (1 point each)
INR: international normalized ratio; NSAIDs: nonsteroidal anti-inflammatory drugs.

11. “There’s an app for that”
• Online and smartphone calculators
• https://itunes.apple.com/us/app/anticoagevaluato
r/id609795286?mt=8
11

12. 12

13. 13

14. Warfarin works, but…
• Bleeding risk
• Lab monitoring
• Drug interactions
• Food interactions
• Infrastructure
– Coumadin clinic
• Compliance
Enter: NOACs
• Novel Oral Anti-Coags
14

15. The Challenge for NOACs
• Must be
– better than warfarin, and/or
– safer than warfarin, and/or
– more convenient than warfarin
• At least enough to justify the cost
• For all it’s problems, warfarin sets a high bar
– 2/3 risk reduction
– Works for 2/3 of patients (INR at target)
– Cheap
15

16. 18,113
CHADS 2
Slide courtesy Chris Woods, MD

17. 17
N=14,266
CHADS 3.5
“As treated”
Slide courtesy Chris Woods, MD

18. 18,201
CHADS 2
Slide courtesy Chris Woods, MD

19. RE-LY
Dabigatran 110 mg 1.53% per year
Dabigatran 150 mg 1.11% per year
Warfarin 1.69% per year
ROCKET AF
Rivaroxaban 20mg 1.7% per year (2.1)
Warfarin 2.2% per year (2.4) (HR = 0.88) (P=0.12 ITT)
ARISTOTLE
Apixaban 5 mg 1.27% per year
Warfarin 1.60% per year
Primary Endpoint of Stroke or Systemic
Embolism: Non-inferiority Analysis
p<0.001
p<0.001
p<0.001
Non Inferiorirty
p vs warfarin
ITT Analysis
Modified ITT
No ITT analysis is available for non-inferiority in Rocket AF. An on treatment or per-protocol analysis is generally performed in the
assessment of non-inferiority. If numerous patients come off of study drug, this biases the trial towards a non-inferior result in an ITT
analysis. This is the basis for performing a per-protocol analysis in a non-inferiority assessment.
C. Michael Gibson, M.S., M.D.
p<0.001
ITT Analysis
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011
HR = 0.79
HR = 0.79
HR = 0.91
HR = 0.66
Slide modified from Chris Woods, MD

20. 20
All Cause Stroke
Ischemic Stroke
Hemorrhagic stroke
Slide courtesy Chris Woods, MD

21. All Cause Mortality favors NOAC
Dabigatran 110 mg 3.75% / yr 0.91 0.35
Dabigatran 150 mg 3 .64% / yr 0.88 0.051
Warfarin 4.13% / yr
HR ITT
p-value
Rivaroxaban 20 mg 4.52% / yr 0.92 0.152*
Warfarin 4.91% / yr
ROCKET
RELY
C. Michael Gibson, M.S., M.D.
*In an on treatment analysis in Rocket AF mortality rates were 1.87% / yr for rivaroxaban and 2.21% / yr for
warfarin, p=0.073. No on treatment analysis is available from RE-LY.
Apixaban 5 mg 3.52% / yr 0.89 0.01
Warfarin 3.94% / yr
ARISTOTLE
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011
95% CI 0.89 (0.80, 0.998)
N=448 events planned, 480 in trial
Slide courtesy Chris Woods, MD

22. 22
Efficacy
• Eliquis
• Pradaxa
• Xarelto
Convenience
• Xarelto
• Eliquis
• Pradaxa
Safety
• Eliquis
• Xarelto
• Pradaxa

23. 23

24. 24

25. 25

26. Safety concerns re: Pradaxa
• GI side effects in 25-35%
– Including significantly more GI bleeding
• Not advised in patients over 80
• 75 mg “dose adjustment” for renal dysfunction
– Not validated in Re-Ly!
– Generally avoid this agent if CrCl is under 30
• Small increase in MI risk?
– Did not reach statistical significance
– But – I have seen 2 cases…
26

27. Fewer safety concerns re: Xarelto
• No GI side effects
• Acceptable in patients over 80
• Dose adjustment for renal dysfunction
– 15mg daily if CrCl is 15-50
– Must calculate Cockcroft-Gault!
• Estimated GFR from lab varies from CrCl
27

28. Fewest safety concerns re: Eliquis
• No GI side effects
• Acceptable in patients over 80
• Dose adjustment if any 2 of 3 are present:
– Renal dysfunction (Cr > 1.5)
• Including ESRD (although still consider warfarin)
• No need to calculate Cockcroft-Gault
– Weight under 60kg
– Age > 80
28

29. 29
Efficacy
• Eliquis
• Pradaxa
• Xarelto
Convenience
• Xarelto
• Eliquis
• Pradaxa
Safety
• Eliquis
• Xarelto
• Pradaxa
I favor Eliquis unless:
• Once-daily preferred
• Formulary requires

30. Special Considerations: Peri-operative
• Low-bleed risk
– Continue if possible
• Intermediate risk
– Stop the day prior
• High bleed risk
– Stop 2 days prior
• Refer to manufacturer
recommendations
• Ask us!
• Warfarin, Eliquis,
Xarelto, plavix, ASA,
prasugrel…
• No “one size fits all”
for pre-op!
– Old standard:
• “Stop blood thinners 1
week prior”
– In 2015:
• “Please consult with the
prescribing physician”
30

31. Special Considerations: Bleeding
• “Warfarin can be reversed, NOACs cannot”
– How effective is plasma and Vit K anyway?
– Short half-life – NOACs “wear off” quickly
– No antidote in the clinical trials of NOACs, and they
were equal to or better than warfarin bleed risk!
– Reversal agents are on the way
31

32. Special Considerations: Warfarin only
• Valvular AF
– In particular when the AF is related to the valve (mitral)
– Less strict if the valve is dissociated from the AF (AS)
• Mechanical valves
• “Triple Therapy”
– AF with high CVA risk PLUS recent ACS or stent
– Aspirin, plavix, warfarin – best determined by
interventional cardiologist
32

33. Making the switch
• Warfarin to NOACs
– Stop warfarin
– INR drifts down; intend to start NOAC when INR < 2
• Measure every day, or
• Typically skip 2 days if INR has been predictable 2.5
• NOACs to warfarin
– More complicated
– Generally requires enoxaparin to replace the NOAC
while warfarin gets to INR > 2
• NOACs can affect INR
33

34. Relevant Advances in Atrial
Fibrillation
• Anti-coagulation reduces stroke risk in AF
– CHADS-VASC and HAS-BLED
– “There’s an app for that”
• Warfarin is very good – NOACs are better
– Eliquis > Xarelto > Pradaxa
– Except valves and “triple therapy”
• Peri-op – tailor the “holiday” to the agent!
Summary