Antithrombotic Therapy for Stroke Prevention in Atrial Fibrillation

To this variety of apoplexy those are most liable who lead an idle life, who are obese, whose face and hands are constantly livid and whose pulse constantly unequal. Wepfer, 1658

Left Atrial Appendage (LAA)

Thromboembolic Events Control Patients in AF Trials Cerebral 49 (91%) Systemic 5 (9%)

Severity of Ischemic Strokes in Atrial Fibrillation Fatal: 5 (10%) Moderate to severe: 23 (45%) Mild: 23 (45%) Number of events in 1,092 control patients

Age Distribution of People With AF Compared With U.S. General Population 30,00020,00010,0000 Arch Int Med. 1995;155:471. 5–95–9 Population with Atrial Fibrillation U.S. Population Age, years U.S. Population (x 1000) <5 10–14 15–19 20–24 25–29 30–34 35–39 40–44 50–54 60–64 70–74 80–84 90–94 45–49 55–59 65–69 75–79 85–89 >95 AF Population (x 10)

Efficacy of Warfarin Compared with Control in Five Studies AFASAK27811 BAATAF15922 CAFA14478 SPAF23508 SPINAF29972 Combined* No. of EventsPatient-years Warfarin Better Warfarin Worse Risk Reduction, % *Total risk reduction for all 5 studies combined is 68% studies combined is 68%

Patients Assigned to Warfarin in AF Trials Intensity of Anticoagulation When Stroke Occurred AFASAK SPAF I BAATAFSPINAFCAFA INR Ratio PT Ratio (ISI 2.4) ACCP recommendation: INR: 2.0– Target range for individual study

Efficacy of Aspirin Compared with Control AFASAK35807 SPAF EAFT Combined * No. of EventsPatient-years Aspirin Better Aspirin Worse Risk Reduction (%) *Total risk reduction for all 3 studies combined is 21%

SPAF III Study Atrial Fibrillation Clinical Assessment Echocardiography (TTE) Female > 75 years Systolic hypertension Systolic hypertension Impaired LV function Impaired LV function Prior thromboembolism Prior thromboembolism Low Risk Cohort Aspirin 325 mg/day Aspirin 325 mg/day High Risk Cohort WarfarinCombination INR 2–31–3 mg Warfarin + Monthly INR to325 mg Aspirin adjust dosefixed dose – +

SPAF III Results High Risk Cohort Lancet 1996; 348; Stroke or Systemic Embolism Major Bleeding IntracranialHemorrhage Aspirin Plus Fixed-Dose Warfarin Adjusted-Dose Warfarin (INR 2-3) Event Rate, % per Patient-year

SPAF III Study Atrial Fibrillation Clinical Assessment Echocardiography (TTE) Female > 75 years Systolic hypertension Systolic hypertension Impaired LV function Impaired LV function Prior thromboembolism Prior thromboembolism Low Risk Cohort Aspirin 325 mg/day Aspirin 325 mg/day High Risk Cohort WarfarinCombination INR 2–31–3 mg Warfarin + Monthly INR to325 mg Aspirin adjust dosefixed dose – +

SPAF III Non-Randomized Aspirin-Only Arm Low Stroke Risk Cohort * % per year95% CI% per year95% CI Stroke or syst.1.1%(0.6%–2.0%)3.6%(2.5%–5.2%) Stroke or syst.1.1%(0.6%–2.0%)3.6%(2.5%–5.2%) embolism embolism No History of Hypertension History of Hypertension No History of Hypertension History of Hypertension *Patients enrolled had none of these high risk features: female >75 years, impaired LV function, current SBP >160 mm Hg, prior thromboembolism prior thromboembolism

Risk Factors for Stroke and Efficacy of Antithrombotic Therapy in Atrial Fibrillation Archives of Internal Medicine July 11, 1994

Predicting Stroke Risk in AFWho Benefits Most? Multivariate Analysis of Pooled Data Clinical risk factors Relative risk Previous stroke or TIA2.5 x History of hypertension1.6 x Diabetes1.7 x Increasing age (per decade)1.4 x Adapted from Arch Intern Med 1994; 154:1454

Transthoracic Echocardiographic Predictors of Stroke in Patients with AF Atrial Fibrillation Investigators Combined databases from 3 randomized trials (N=1,066) Combined databases from 3 randomized trials (N=1,066) Moderate to severe LV dysfunction was the only independent predictor of stroke (RR 2.5, p<0.001) Moderate to severe LV dysfunction was the only independent predictor of stroke (RR 2.5, p<0.001) Left atrial size did not predict stroke risk Left atrial size did not predict stroke risk

Atrial Fibrillation Follow-up Investigation of Rhythm Management AFFIRM Multicenter, randomized clinical trial Multicenter, randomized clinical trial NHLBI-NIH supported NHLBI-NIH supported Patients with AF at high risk of stroke or death Patients with AF at high risk of stroke or death Randomized to either rate-control or rhythm- control strategy Randomized to either rate-control or rhythm- control strategy Primary endpoint: all-cause mortality Primary endpoint: all-cause mortality The AFFIRM Investigators. N Engl J Med. 2002;347:

AFFIRM Stroke Events P=.79 P=.73 P=.68 P=.93 The AFFIRM Investigators. N Engl J Med. 2002;347: Percent

7th ACCP Consensus Conference on Antithrombotic Therapy CHEST Supplement: 2004

ACCP Recommendations 2004 Risk Factors for Stroke Prior stroke, TIA, systemic embolism Prior stroke, TIA, systemic embolism Hypertension Hypertension Moderate or severely impaired LV systolic function and / or CHF Moderate or severely impaired LV systolic function and / or CHF Age >75 years Age >75 years Rheumatic mitral valve disease Rheumatic mitral valve disease Prosthetic heart valves Prosthetic heart valves Diabetes mellitus Diabetes mellitus Age Age Moderate Risk High Risk

ACCP 2004 Recommendations for Stroke Prevention in Atrial Fibrillation* Risk Factors Recommended Therapy Risk Factors Recommended Therapy Any High Risk Factor Warfarin Any High Risk Factor Warfarin (target INR 2.5, range )** (target INR 2.5, range )** Age years and Aspirin 325 mg qd Age years and Aspirin 325 mg qd No high risk factors or Warfarin No high risk factors or Warfarin (target INR 2.5, range )** (target INR 2.5, range )** No Risk Factors and age < 65 Aspirin 325 mg qd No Risk Factors and age < 65 Aspirin 325 mg qd *Applies to persistent (sustained or permanent) and paroxysmal (intermittent) AF **target INR > 2.5 for patients with mechanical heart valves

ACCP Recommendations 2004 Cardioversion Continuation of anticoagulation beyond 4 weeks after successful pharmacological or electrical cardioversion is based on whether the patient has experienced more than 1 episode of AF and on their risk factor status. Continuation of anticoagulation beyond 4 weeks after successful pharmacological or electrical cardioversion is based on whether the patient has experienced more than 1 episode of AF and on their risk factor status. Patients experiencing more than 1 episode of AF should be considered as having paroxysmal AF Patients experiencing more than 1 episode of AF should be considered as having paroxysmal AF

Warfarin for Atrial Fibrillation Limitations Lead to Under-treatment < % 58% 61% 57% 35% Age (years) Warfarin Use in Eligible Patients (%) 55% Overall Use Go A et al. Ann Intern Med 1999;131:927.

Warfarin for Atrial Fibrillation Limitations Lead to Inadequate Treatment Samsa GP, et al. Arch Intern Med 2000;160:967. INR above target 6% Subtherapeutic INR 13% INR in target range 15% No warfarin 65% Adequacy of Anticoagulation in Patients with AF in Primary Care Practice

Ximelagatran Oral Direct Thrombin Inhibitor Prompt onset and offset of anticoagulation Prompt onset and offset of anticoagulation Wider therapeutic margin than warfarin Wider therapeutic margin than warfarin Predictable pharmacokinetics Predictable pharmacokinetics Low potential for food and drug interactions Low potential for food and drug interactions No dose adjustment No dose adjustment No coagulation monitoring No coagulation monitoring Sarich TC, et al. J Am Coll Cardiol 2003;41:557. Eriksson H, et al. Drug Metab Disp 2003;31:294.

Stroke Prevention Using an ORal Direct Thrombin Inhibitor in Atrial Fibrillation The SPORTIF III and V Trials Fixed-doseXimelagatran (36 mg bid) Adjusted-doseWarfarin (INR 2-3) Patients with Nonvalvular AF and Risk Factors for Stroke n=7,320 SPORTIF III23 nationsopen-label (n=3,407) SPORTIF VUS, Canadadouble-blind(n=3,913)

SPORTIF Program Primary Analyses Intention-to-treat Analysis Difference in Absolute Event Rates (Ximelagatran – Warfarin) Ximelagatran BetterWarfarin Better012 SPORTIF III SPORTIF V p=0.10 p=0.13 PooledPooled-0.03 p=

SPORTIF V Hemorrhage Event Rate (% /year) p< p=0.16 p=NS

SPORTIF V Liver Enzyme Elevation ALT >3 x ULN Months Number of Patients Ximelagatran Warfarin Incidence (%) ALT >3x ULN p<0.001

ConclusionsConclusions Fixed oral dosing without coagulation monitoring Fixed oral dosing without coagulation monitoring Effectiveness non-inferior to well-controlled warfarin in preventing stroke and systemic embolic events Effectiveness non-inferior to well-controlled warfarin in preventing stroke and systemic embolic events Less bleeding than warfarin Less bleeding than warfarin Elevated liver enzymes in ~6% of patients Elevated liver enzymes in ~6% of patients A promising treatment option for prevention of thromboembolism A promising treatment option for prevention of thromboembolism In high-risk patients with atrial fibrillation, ximelagatran offers: