Clinical Implications of Oral Anti-Coagulants

Focus on Atrial Fibrillation

Brad Angeja, MD FACC Palo Alto Medical Foundation

None

Disclosures

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

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

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

Transesophageal Echocardiogram of the Appendage

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Normal With Clot Slide courtesy Chris Woods, MD

Slide courtesy Chris Woods, MD

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.

“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

18,201 CHADS 2

Slide courtesy Chris Woods, MD

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

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

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