Stroke prevention in atrial fibrillation Prof. Mirza Dilić, MD, PhD, FESC, FACC Clinical Center Sarajevo Director Internal Clinics and Departments

Epidemiological data ~15% of all strokes affected patients with AFib Risk of stroke in AFib patients who do not receive OAC or ATT is ~ 5% per year Prevalence of AFib is about 10% in patients age 80 yrs Patients of 75 yrs with AF have risk of thromboembolism > 4% AF povećava Mb i Mt starijih i sa komorbiditetom. AF enlarges Mb and Mt of elderly and of people with co-morbidity References Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983–988 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly; the Framingham Heart Study. Arch Intern Med 1987;147:1561–1564 Benjamin EJ et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998;98:946–952 Hart RG et al. Prevention of stroke in patients with nonvalvular atrial fibrillation. Neurology 1998;51:674–681 6

Atrial fibrillation is an independent risk factors for stroke. Several factors increased the risk for stroke in elderly patients with AFib. Non-valvular AFib is associated with an increased risk of stroke.

In the USA and Europe, about 20% of all hospital admissions have an AFib either primary or secondary diagnosis. Patients with AFib may present with variety of symptoms, including; palpitations, exercise intolerance, heart failure, chest pain, sincope, dissiness, and stroke.

Loss of atrial systolic function results in sluggish blood flow in the atrium Disturbed atrial endothelial function and activation of coagulation factors, Cloth formation in the atrium.

Therapy of AFib, therefore, involve measures: to control ventricular rates, to restore and maintain sinus rhythm, to prevent thromboembolic complications

ACC / AHA / ESC Guidelines 2001 11

ACCP Guidelines 2008 12

CHADS2 scoring system is used as basis for risk stratification of thromboembolic events CHADS2 Cardiac failure Hypertension Age, Diabetes Stroke (doubled)

In CHADS2 - 1 point is given for following clinical variables: Recent CHF Age over 75, Hypertension, Diabetes. Prior Stroke – 2 points

CHADS2 score of 0 – should not require antithrombotic therapy. CHADS2 score of 1 – may be treated with Aspirin or Warfarin. CHADS2 score of 2 or more - should be treated with Warfarin with a target INR of 2.0 to 3.0

Class I (Level of Evidence A) Antithrombotic th. recommended in all pts with AF, except those with lone Afib, age < 65 yrs, or contraindications. Antithrombotic agent should be chosen balansing - absolutes risk of stroke and bleeding and relative risk and benefit for given patient. Warfarin (target INR 2.0 – 3.0) for patients with CHADS risk of 2 is recommended unless contraindicated.

Class I (Level of Evidence A) Patients with 1 “clinically non-major” risk factors are at intermediate risk and, OAC therapy or, Aspirin 75-325 mg Patients with mechanical valve prosthesis OAC therapy, maintaining INR of at least 2.5 (mitral) or 2.0 (aortal). (Level of Evidence B).

Class IIa (Level of Evidence A,B) Most patients with 1 “clinically relevant non-major” risk factor, should be considered for warfarin, rather than aspirin therapy. (A) Patients with no risk factors, < 65 yrs, lone AF, none of the risk factors, no antithrombotic therapy should be considered, rather than aspirin. (B)

Class IIa (Level of Evidence B,C) Dual therapy with aspirin + clopidogrel in patients with contraindication to warfarin or refusal to use warfarin.(B) In patients who are not at high risk and do not have mechanical valve prosthesis and going to procedure, interruption of OAC should be considered to up 48 hrs without bridging with heparin.(C)

Class IIb (Level of Evidence C) In patients who are at high risk and have mechanical valve prosthesis and going to procedure, bridging anticoagulation with LMWH or UH should be considered. (C) If it is necessary to interrupt therapy for 1 week, in high risk patients, LMWH or UFH my be given.

Class IIb (Level of Evidence C) Following coronary revascularisation in patients with AF, warfarin may be interrupted, but resumed as soon as possible, with target INR. Aspirin may be given in hiatus. For patients underwent PCI, clopidogrel 75 mg + warfain should be maintenance. In BMS clopidogrel at least 1 month, sirolimus-eluting stents up to 3 months, and paclitaxel-eluting stent up to 6 months.

For cardioverson of acute episodes that are of less than 48 hours’ duration, anticoagulation is not required. For episode that are of greater than 48 hours’ duration, or when duration is uncertain, 3 to 4 weeks of warfarin anticolgulation before cardioversion is recommended. In patients without risk factors for stroke, anticolagulation is maintained for at least 4 weeks after conversion.

ACCP Guidelines 2012 30

CHEST 2012 9 ed. Executive Summary Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Guyatt GH, MD, FCCP,  Aki EA, MD, PhD, MPH, Crowther M, MD, Gutterman DD, MD, FCCP, Schuemann HJ, MD, PhD, FCCP, and for the American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel*

Antithrombotic Therapy for Atrial Fibrillation Nonrheumatic Atrial Fibrillation (AF) For patients with AF, including those with paroxysmal AF, who are at low risk of stroke (eg, CHADS2 [congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischemic attack] score = 0), we suggest no therapy rather than antithrombotic therapy (Grade 2B). For patients who do choose antithrombotic therapy, we suggest aspirin (75 mg to 325 mg once daily) rather than oral anticoagulation (Grade 2B) or combination therapy with aspirin and clopidogrel (Grade 2B).

AF and intermediate risk of stroke For patients with AF, including those with paroxysmal AF, who are at intermediate risk of stroke (eg, CHADS2 score = 1), we recommend oral anticoagulation rather than no therapy (Grade 1B). We suggest oral anticoagulation rather than aspirin (75 mg to 325 mg once daily) (Grade 2B) or combination therapy with aspirin and clopidogrel (Grade 2B). For patients who are unsuitable for or choose not to take an oral anticoagulant (for reasons other than concerns about major bleeding), we suggest combination therapy with aspirin and clopidogrel rather than aspirin (75 mg to 325 mg once daily) (Grade 2B). .

AF and high risk of stroke For patients with AF, including those with paroxysmal AF, who are at high risk of stroke (eg, CHADS2 score = 2), we recommend oral anticoagulation rather than no therapy (Grade 1A), aspirin (75 mg to 325 mg once daily) (Grade 1B), or combination therapy with aspirin and clopidogrel (Grade 1B). For patients with AF, including those with paroxysmal AF, for recommendations in favor of oral anticoagulation we suggest dabigatran 150 mg twice daily rather than adjusted-dose VKA therapy (target INR range, 2.0-3.0) (Grade 2B).

Patients With AF and Mitral Stenosis For patients with AF and mitral stenosis, we recommend adjusted-dose VKA therapy (target INR range, 2.0-3.0) rather than no therapy, aspirin (75 mg to 325 mg once daily), or combination therapy with aspirin and clopidogrel (all Grade 1B). For patients with AF and mitral stenosis who are unsuitable for or choose not to take adjusted-dose VKA therapy (for reasons other than concerns about major bleeding), we recommend combination therapy with aspirin and clopidogrel rather than aspirin (75 mg to 325 mg once daily) alone (Grade 1B).

Aspirin In ACC /AHA / ESC guideline 75 - 325 mg/day ACCP guideline 75 -100 mg/day ESC/ACCP/ACC/AHA Opie et al.

Aspirin Aspirin + warfarin Aspirin + clopidogrel + warfarin Aspirin 50 mg Warfarin with target INR of 1.8 -2.0

Novel antithrombotics

FDA approval Anti-thrombin – Dabigatran 150 mg. twice daily. By intention-to-treat, rivaroxaban was non-inferior to warfarin but did not achieve superiority.

FDA approval Anti Xa - Rivaroxaban once daily. By intention-to-treat, rivaroxaban was non-inferior to warfarin.

Safety Similar rates of bleeding and adverse events Less CVI and fatal bleeding

The key for optimal therapy is risk stratification. Appropriate balansing between benefit and risk of bleeding.