Anticoagulation: How Do I Pick From All the Choices?

Jeffrey H. Neuhauser, DO, FACC BHHI Primary Care Symposium

February 28, 2014

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Atrial Fibrillation

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Atrial Fibrillation

• The most common arrhythmia encountered in clinical practice.

• The prevalence increases with age.• Risk factors include HPTN, valvular heart

disease, cardiomyopathy, obesity, sleep apnea, congenital heart disease, pulmonary disease, & hyperthyroidism.

• Classified as paroxysmal, persistent, or permanent.

• Major complications include CHF & stroke.

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LAA Thrombus

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AF - CASE STUDIES• 45 yr old male. No significant PMH. Develops AF while

training for a marathon. He presents to the ER & then spontaneously converts to SR after 6 hrs. Baseline ECG & Echo are normal.

• 76 yr old female with HPTN, NIDDM who presents to her PCP for an annual checkup is found to be in AF with a controlled ventricular response. She is completely unaware that she is in AF. She has a history of GI hemorrhage within the past year.

• 68 yr old male with previous CABG, CHF, HPTN, & AS presents to the ER with a 2 day history of palpitations. He is found to be in AF with a RVR. He is admitted to the hospital & started on IV diltiazem for rate control.

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CHADS2

Go AS, Hylek EM, Chang Y, et al. JAMA 2003; 290:2685

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CHA2DS2-VASc

Eur Heart J 2010; 31:2369

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CHA2DS2-VASc

Eur Heart J 2010; 31:2369

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Warfarin• Inhibits vit K dependent coagulation factors• Metabolism - Liver CYP450• 1/2 life 20-60h• Dose adjusted to INR 2-3• Many drug & food interactions• Common drugs that increase the INR - Quinolones,

Erythromycins, Tetracyclines antifungals, Isoniazid, Amio, Propafenone, Gemfibrizol, Niacin,Pantoprozole, Paroxitene, Rouvastatin

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Dabigatran (Pradaxa)

• Direct thrombin inhibitor• Indicated for the prevention of stroke &

thromboembolism in nonvalvular AF• No liver CYP 450 metabolism; Primarily

urine excretion• 1/2 life 12-17 hrs• CrCl >50 ml/min - dose 150mg bid• CrCl 30-50 ml/min - dose 75 mg bid

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Drugs that Increase Dabigatran Levels

• Cyclosporin• Dronedarone• Antifungal agents - Itraconazole & Ketoconazole• Quinidine• Verapamil

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Drugs That Decrease Dabigatran Levels

• Carbamazepine• Rifampin• St. John’s Wort

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RE-LY

• Comparison of Dabigatran (150 mg bid & 110 mg bid) with warfarin in pts with nonvalvular AF & risk of stroke.

• Randomized, blinded for dabigatran, unblinded for warfarin

• Primary outcome was stroke or systemic embolization

• Median duration of F/U - 2 yearsN Engl J Med 2009; 361:1139-1151

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RE-LY

• Efficacy outcomes according to treatment groupN Engl J Med 2009; 361:1139-1151

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RE-LY

• Cumulative hazard rates for stroke or systemic embolization according to treatment group.

N Engl J Med 2009; 361:1139-1151

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RE-LY

• Safety outcomesN Engl J Med 2009; 361:1139-1151

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Concomittant Use of Antiplatelet in the RE-LY Trial

Circulation. 2013;127:634-640.

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Periprocedural Bleeding in the RE-LY Trial

Circulation. 2012;126:343-348

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Periprocedural Bleeding in the RE-LY Trial

Circulation. 2012;126:343-348

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RE-ALIGN

• Dabigatran vs warfarin S/P AVR & MVR within 7 days & after 3 months.

• Dabigatran dose 150, 220, 300mg bid based on renal function.

• The trial was terminated prematurely due to an excess of thromboembolic & bleeding events in the dabigatran group.

N Engl J Med 2013;369:1206-14

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Rivaroxaban (Xarelto)

• Factor Xa inhibitor• Indicated for the prevention of stroke &

thromboembolism in nonvalvular AF. Also indicated for the prevention & tx of DVT/PE.

• Metabolism - Liver CYP450; Urinary excretion 66%

• 1/2 life 5-9 hrs; 11-13 hrs in the elderly• CrCl >50 ml/min - dose 20 mg daily• CrCl 15-50 ml/min - dose 15 mg daily

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Drugs That Increase Rivaroxaban Levels

• Amiodarone, Dronedarone• Erythromycins• Cyclosporine• Diltiazem• Antifungal agents - Itraconazole & Ketoconazole• Phenytoin• Ranolazine• Tamoxifen• Verapamil

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Drugs That Decrease Rivaroxaban Levels

• Carbamazepine• Phenytoin• Rifampin• St. John’s Wort

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ROCKET AF

• Comparison of Rivaroxaban (20 mg daily) vs warfarin (INR 2-3) in pts with nonvalvular AF.

• Randomized, double blind design.• Primary endpoint - stroke or systemic

embolization.N Engl J Med 2011;365:883-91

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ROCKET AF

• The Rivaroxaban group had 21% reduction in stroke & systemic embolization.

• Incidence of major bleeding was similar -Rivaroxaban (14.9%) vs warfarin (14.5%).

• The Rivaroxaban group had significantly less intracranial hemorrhage (0.5% vs 0.7%) & fatal hemorrhage (0.2% vs 0.5%).

N Engl J Med 2011;365:883-91

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ROCKET AF

N Engl J Med 2011;365:883-91

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ROCKET AF

N Engl J Med 2011;365:883-91

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ROCKET AF

J Am Coll Cardiol 2013;61:651–8

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ROCKET AF

• The mean time in therapeutic range in the warfarin group was 55.2%.

• The mean time with an INR <2 was 29.1%.• The mean time with an INR >3 was 15.7%.

J Am Heart Assoc. 2013;2:e000067 doi 10.1161/JAHA.112.000067

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Apixaban (Eliquis)

• Factor Xa inhibitor• Indicated for the prevention of stroke &

thromboembolism in nonvalvular AF• Metabolism - Liver CYP450; Urine

excretion 27%• 1/2 life 12 hrs• Dose 5 mg bid• Creat >1.5, age >80, wt <60 kg - dose 2.5

mg bid

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Drugs That Decrease Apixaban Levels

• Dexamethasone• Nafcillin• Phenobarbital• Phenytoin• Rifampin• St. John’s Wort

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ARISTOTLE

• Apixaban vs Warfarin in pts with AF• Randomized, double blind trial design• Pts had at least 1 additional RF for stroke• Primary outcome: stroke or systemic

embolization• Median duration of F/U - 1.8 years

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ARISTOTLE

N Engl J Med 2011;365:981-92

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ARISTOTLE

N Engl J Med 2011;365:981-92

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AVERROES

• Apixaban vs ASA in pts with AF• Double blind, randomized design• Mean F/U 1.1 years• The primary outcome was stroke or

systemic embolizationN Engl J Med 2011;364:806-17

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AVERROES

N Engl J Med 2011;364:806-17

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AVERROES

N Engl J Med 2011;364:806-17

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LAA Occlusion Devices

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PROTECT AF• Comparison of a LAA closure device (Watchman) with

warfarin for the prevention of stroke & systemic embolization in pts with nonvalvular AF & at least 1 risk factor.

• After device implantation, pts received warfarin for 45 days, followed by clopidogrel for 4.5 months & then life long ASA.

• Mean F/U 2.3 yrs.• Composite endpoint - stroke, systemic embolization, &

CV death. • Primary composite endpoint in the Watchman group

(3%) was equivalent to the warfarin group (4.3%).Circulation.2013;127:720-729

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PROTECT AF

Circulation.2013;127:720-729

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ASAP Study

• Evaluation of the Watchman LAA closure device in pts with nonvalvular AF ineligible for warfarin.

• 150 pts with nonvalvular AF & CHADS2 score at least 1

• Primary efficacy end point was the combined events of ischemic stroke, hemorrhagic stroke, systemic embolization, CV / unexplained death.

J Am Coll Cardiol 2013;61:2551–6

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ASAP Study• Pts with LVEF <30%, intracardiac thrombus, dense

spontaneous echo contrast on TEE, PFO, significant mitral stenosis, pericardial effusion >3 mm, mobile plaque in the ascending aorta or aortic arch were excluded.

• Following implant, pts received 6 months of clopidogrel or ticlopidine followed by life long ASA.

• The mean CHADS2 score was 2.8.• Mean f/u 14.4 months.

J Am Coll Cardiol 2013;61:2551–6

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ASAP Study

•The expected rate of ischemic stroke for pts treated only with ASA was 7.3%.

J Am Coll Cardiol 2013;61:2551–6

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THE WATCHMAN LAA OCCLUSION DEVICE

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Cryoablation for AF