clinical implications of oral anti-coagulants
TRANSCRIPT
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Clinical Implications of Oral Anti-Coagulants
Focus on Atrial Fibrillation
Brad Angeja, MD FACC Palo Alto Medical Foundation
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None
Disclosures
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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
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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
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Stroke is caused by thromboembolic disease in AF
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90% of thrombi are found in the Left atrial appendage
Slide courtesy Chris Woods, MD
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Transesophageal Echocardiogram of the Appendage
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Normal With Clot Slide courtesy Chris Woods, MD
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Slide courtesy Chris Woods, MD
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Warfarin works
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Narrow Therapeutic
Window
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Bleeding Risk: HAS-BLED
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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.
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“There’s an app for that”
• Online and smartphone calculators • https://itunes.apple.com/us/app/anticoagevaluato
r/id609795286?mt=8
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Warfarin works, but…
• Bleeding risk • Lab monitoring • Drug interactions • Food interactions • Infrastructure
– Coumadin clinic • Compliance Enter: NOACs • Novel Oral Anti-Coags
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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
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18,113 CHADS 2
Slide courtesy Chris Woods, MD
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N=14,266 CHADS 3.5 “As treated”
Slide courtesy Chris Woods, MD
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18,201 CHADS 2
Slide courtesy Chris Woods, MD
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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
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All Cause Stroke
Ischemic Stroke
Hemorrhagic stroke
Slide courtesy Chris Woods, MD
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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
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Efficacy • Eliquis • Pradaxa • Xarelto
Convenience • Xarelto • Eliquis • Pradaxa
Safety • Eliquis • Xarelto • Pradaxa
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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…
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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
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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
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Efficacy • Eliquis • Pradaxa • Xarelto
Convenience • Xarelto • Eliquis • Pradaxa
Safety • Eliquis • Xarelto • Pradaxa
I favor Eliquis unless: • Once-daily preferred • Formulary requires
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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”
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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
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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
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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
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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