Preventionof Atrial Fibrillation Related Strokes and the Role of the New Oral Anticoagulants

Matt Dickinson, PharmD/MBA CandidateIdaho State University

Objectives• Define the risk factors, pathophysiology, and

treatment of atrial fibrillation (AFib)• Describe benefits of anticoagulation for stroke

prevention in atrial fibrillation and identify the population of patients at the greatest risk

• Compare the benefits and risks of the new oral anticoagulant therapies as well as their safety, efficacy, pharmacology, cost, and convenience

• Utilize available decision making tools to stratify the challenges and benefits of using new oral anticoagulants in patients with atrial fibrillation

Etiology and Risk Factors1-4

• Hypertension• Heart failure• Coronary artery

disease• Advanced age• Diabetes

• Electrolyte Imbalances

• Medications• Hyperthyroidism• COPD• Alcohol

Pathophysiology1-4

• Structural and/or electrophysiological abnormalities cellular hypertrophy and/or tissue fibrosis alterations in function & structure

• Ultimately leads to changes in the automaticity of the SA node

• Atria beat chaotically and out of coordination with ventricles

Clinical Presentation1-4

• Most commonlyo palpitations, tachycardia, dizziness, shortness

of breath, & weaknesso chest pain & worsening of heart failure

• Some patients are asymptomatic• 5x more likely to have a stroke

o 15% of all strokes are due to AFibo New oral anticoagulants may have better

stroke reduction & less of a bleed risk than warfarin

Treatment1-5

• Rate controlo beta-blockers, non-DHP Ca2+ channel blockers, digoxin,

amiodarone• Rhythm control

o Acute Conversion• ibutilide, flecainide, dofetilide, propafenone,

amiodaroneo Maintenance

• amiodarone, propafenone, flecainide, sotalol, dofetilide • Nonpharmacologic

o Ablation, pacemaker• Prevention of thromboembolism

o ASA, clopidogrel, warfarin, NOACs

Estimating Risk: CHADS2 score1-5

• Estimates stroke risk in patients with AFibo C = Congestive Heart Failure: 1pto H = Hypertension or treated for hypertension:

1pto A = Age >75 y/o: 1 pto D = Diabetes: 1 pto S2 = Prior stroke or TIA or thromboembolism:

2 pts

CHA2DS2-VASc Score1,5

• Supersedes CHA2D2 and provides better stratification of low risk patientso C = CHF: 1 pt o H = Hypertension: 1 pt

• BP > 140/90 or treated: 1 pto A2 = Age >75 years: 2 pts o D = Diabetes: 1 pt o S2 = Prior stroke or TIA or thromboembolism: 2 pts o V = Vascular disease: 1 pt – e.g., PAD, MIo A = Age 65-74 years: 1 pt o Sc = Female gender: 1 pt

Estimating Risk of Stroke: CHA2DS2-

VASc1, 5

Score Risk Anticoagulation Therapy

Considerations

0 Low No antithrombotic therapy or aspirin

Class IIa recommendation

1 Moderate Antithrombotic therapy is not necessary but an oral anticoagulant or aspirin may be considered

Class IIb recommendation

2 or higher

High Oral anticoagulant or warfarin at INR target of 2-3

Class I recommendation. If end-stage CKD, choose warfarin

New Oral Anticoagulants

(NOACs)• Direct thrombin (Factor IIa) inhibitor

o Dabigatran (Pradaxa) RE-LY trial• Direct Factor Xa inhibitors

o Rivaroxaban (Xarelto) ROCKET-AF trialo Apixaban (Eliquis) ARISTOTLE trialo Edoxaban (Savaysa) ENGAGE-AF trial

Characteristics of NOACs1,5,6-9

  Dabigatran Apixaban Rivaroxaban Edoxaban

Direct factor inhibition IIa Xa Xa XaBioavailability (Frel) 6 % 80 % 80 % 62 %

Peak action (tmax) 1–3 h 1–3 h 1–3 h 1-2 hProtein binding 35% 84% 92–95% 55%Renal clearance 80% 25% 33% 50%

Half life 13.8 h 15.1 h 9-12 h 10-14 h

Dosing 75-150 mg BID

2.5-5 mg BID 20 mg daily 30-60 mg

daily

Reversal agent Idarucizumab (Praxbind)

Andaxanet (ANNEXA-R) in phase III trials

Andaxanet (ANNEXA-R) in phase III trials

Andaxanet (ANNEXA-R) in phase III trials

Atrial Fibrillation Studies10-14

Trial RE-LY ARISTOTLE ROCKET-AF ENGAGE-AFDesign Randomized,

open LabelN=18,113

Randomized, double blindN=18,209

Randomized, double blind &

dummyN=14,000

Randomized, double blind &

dummyN = 21,105

patientsMedian Age

71 70 73 72

Female 36 % 36 % 43 % 38 %Treatment

Dabigatran150 mg BID

Apixaban5 mg BID

Rivaroxaban20 mg daily

Edoxaban 60 mg daily

Comparator

Warfarin 2-3(67 % TTR)

Warfarin 2-3(66 % TTR)

Warfarin 2-3(57.8 % TTR)

Warfarin 2-3 (68 % TTR)

CHADS2 Scores

Average = 2.1 Average = 2.1 Average = 3.5 Average = 2.8

0-1 32 % 34 % 0 % 0 %

2 35 % 36 % 13 % 46 %3-6 33 % 30 % 87 % 54 %

Time in Therapeutic Range = TTR

Primary Endpoint – Stroke15

Primary Endpoint – Stroke10-15

Study NOAC VKA OutcomeRE-LY Dabigatran

1.1 %Warfarin1.7 %

RR 0.66 95% CI 0.53-0.82 P < 0.001 Superiority

ARISTOTLE Apixaban1.3 %

Warfarin1.6 %

HR 0.79 95% CI 0.66-0.95P < 0.001 Non-inferiority

P = 0.01 Superiority

ROCKET-AF Rivaroxaban1.7 %

Warfarin2.2 %

HR 0.79 95% CI 0.66-0.96P < 0.001 Non-inferiority

ENGAGE-AF

Edoxaban 1.18 %

Warfarin 1.5 %

HR 0.79 95% CI 0.63-0.99

P < 0.001 Non-inferiority

Major Bleeding15

Major Bleeding10-15

Study NOAC VKA Outcome

RE-LY Dabigatran3.3 %

Warfarin3.6 %

RR 0.9395% CI 0.81-1.07

P = 0.31

ARISTOTLE Apixaban2.1 %

Warfarin3.1 %

HR 0.6995% CI 0.60-0.8

P < 0.001

ROCKET-AF Rivaroxaban3.6 %

Warfarin3.4 %

HR 1.0495% CI 0.90-1.20

P = 0.58

ENGAGE-AF Edoxaban2.75 %

Warfarin3.34 %

HR 0.8095% CI 0.71-

0.91P < 0.001

Efficacy and Safety15

Intracranial Hemorrhage10-15

Study NOAC VKA Outcome

RE-LY Dabigatran0.3 %

Warfarin0.7 %

RR 0.4095% CI 0.27-0.60

P < 0.001

ARISTOTLE Apixaban0.3 %

Warfarin0.8 %

HR 0.4295% CI 0.30-0.58

P < 0.001

ROCKET-AF Rivaroxaban0.5 %

Warfarin0.7 %

HR 0.6795% CI 0.47-0.93

P = 0.02

ENGAGE-AF Edoxaban0.26 %

Warfarin0.47%

HR 0.5495% CI 0.38-

0.77P < 0.001

Dosing Schedules for AFib1,6-9

Agent Dosing RecommendationsDabigatran75mg, 150mg

CrCl > 30 mL/min: 150 mg BIDCrCl 15 to 30 mL/min: 75 mg BID* Avoid < 15 mL/min

Apixaban2.5mg, 5mg

CrCl > 15 mL/min: 5 mg BIDAny 2 ( > 80 yrs, < 60 kg, SCr > 1.5 mg/dL: 2.5 mg BID)Avoid < 15 mL/min

Rivaroxaban10mg, 15mg, 20mg

CrCl > 50 mL/min: 20 mg dailyCrCl 15-50 mL/min: 15 mg dailyAvoid CrCl < 15 mL/min

Edoxaban15mg, 30mg, 60mg

CrCl > 95 mL/min: use not recommended**CrCl 51-95 mL/min: 60 mg dailyCrCl 15-50 mL/min: 30 mg dailyAvoid CrCl < 15 mL/min

Which patients are good candidates for NOACs?

Patients who:• Find INR testing/monitoring burdensome

• Limited access to healthcare, unable to drive, etc.• Despite adherence to provider recommendations,

have low “time in therapeutic range”• Can afford (or arrange to get) the new drugs• Have moderate-normal renal function

If a patient has maintained a stable INR, the conservative approach is to continue current warfarin therapy.

Cost Analysis16 Incremental medical costs to a US health payer of

an AFib patient experiencing a clinical event during 1 year following the event were obtained from published literature and adjusted for inflation. Medical costs, excluding drug costs, were evaluated and compared for each NOAC vs Warfarin.

In a patient year, the medical cost reduction associated with NOAC usage instead of Warfarin was estimated to be $179 for Dabigatran $89 for Rivaroxaban $485 for Apixaban

Differences in Yearly Medical Costs of AFib Patients Treated with NOAC vs

Warfarin17

PBM Management• Allow a fixed number of preauthorized PAs

o Prior authorizations cost the health care system about $50 each

• Quantity limit of 60 tablets per month• Sample Prior Authorization Criteria for Eliquis for Afib

o Does the patient have a mechanical heart valve?o Does the patient live > 70 miles from A healthcare facility?o Does the patient have a CrCl > 15 mL/min?o Has the patient failed warfarin due to intolerance or

contraindication?• Is there documented evidence that the patient’s TTR has

been < 50%

Conclusion• Patient selection for use is critical

o All NOACs show better results in bleeding and stroke risk in patients with non-valvular atrial fibrillation than warfarin

• excluding GI bleeding o NOACs provide a safe and efficacious alternative to

warfarin• Well managed warfarin will remain an option

o There are many challenges to anticoagulation therapy with warfarin

• Pharmacists and physicians must work together to individualize anticoagulant therapy for each patient.

References1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2014 Dec 2;130(23):e199-267 PDF2. Camm AJ, Kirchhof P, Lip GY, et al; European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010 Oct;31(19):2369-429 full-text3. Healey JS, Parkash R, Pollak T, Tsang T, Dorian P; CCS Atrial Fibrillation Guidelines Committee. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: etiology and initial investigations. Can J Cardiol. 2011 Jan-Feb;27(1):31-7 4. Camm AJ, Lip GY, De Caterina R, et al; ESC Committee for Practice Guidelines (CPG). 2012 focused update of the ESC Guidelines for the management of atrial fibrillation. Eur Heart J 2013 Mar;34(10):790 full-text.

References cont. 5. Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3):453-60. Pub Med PMID: 22537354.6. Dabigatran Etexilate Mesylate Drug Facts and Comparisons. Facts and Comparisons [database online]. Clinical Drug Information, LLC.; From http://online.factsandcomparisons.com7, Rivaroxaban Drug Facts and Comparisons. Facts and Comparisons [database online]. Clinical Drug Information, LLC.; From http://online.factsandcomparisons.com 8. Apixaban Drug Facts and Comparisons. Facts and Comparisons [database online]. Clinical Drug Information, LLC.; From http://online.factsandcomparisons.com 9. Edoxaban Drug Facts and Comparisons. Facts and Comparisons [database online]. Clinical Drug Information, LLC.; From http://online.factsandcomparisons.com

References cont. 10. Warfarin Sodium Drug Facts and Comparisons. Facts and Comparisons [database online]. Clinical Drug Information, LLC.; From http://online.factsandcomparisons.com11. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, et al.; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51. 12. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, et al.; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91.13. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, et al.; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981-92.

14. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JD et. Al. Edoxaban versus Warfarin in Patients with Atrial Fibrillation. N. Engl. J. Med. 2013, 369, 2093-2104. 15. Jia, B, Lynn HS, Rong F, Zhang W. Meta-analysis of Efficacy and Safety of the New Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation. J. Cardiovasc. Pharmacol. 2014, 64. 16. Deitelzweig S, Amin A, Jing Y, Makenbaeva D, Wiederkehr D, Lin J, and Graham J. “Medical cost reductions associated with the usage of novel oral anticoagulants vs warfarin among atrial fibrillation patients, based on the RE-LY, ROCKET-AF, and ARISTOTLE trials” J Med Econ. 2012;15(4):776-85. 17. Amin A, Lingohr-Smith M, Bruno A, Trocio J, Lin J (2015) Economic Evaluations of Medical Cost Differences: Use of Targeted-Specific Oral Anticoagulants vs. Warfarin among Patients with Nonvalvular Atrial Fibrillation and Venous Thromboembolism in the U.S. J Hematol Thrombo Dis 3:209. doi: 10.4172/2329-8790.1000209

References cont.

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