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Risk/Benefit AssessmentRisk/Benefit Assessment

Jeremy N. Ruskin, M.D.Jeremy N. Ruskin, M.D.Director, Cardiac Arrhythmia ServicesDirector, Cardiac Arrhythmia Services

Massachusetts General HospitalMassachusetts General Hospital

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AF PopulationAF PopulationBaseline CharacteristicsBaseline Characteristics

Parameter, no. (%)All Patients

(n=773)AFFIRM Study

(n=4060)

Euro Heart Survey

(n=3662)

Male 526 (68.0) 2466 (60.7) 2141 (58.5)

Age years (Mean ± SD) 63.2 ± 13.2 69.7 ± 9.0 ~ 65

Medical history

CHF 115 (14.9) 939 (23.1) 997 (27.2)

Valvular heart disease 53 (6.8) 198 (4.9) 766 (20.9)

Coronary artery disease 187 (24.2) 1059 (26.1) 1161 (31.7)

Cardiomyopathy 194 (4.8) 328 (9.0)

Hypertension 402 (52.0) 2063 (50.8) 2334 (63.7)Nieuwlaat R et al. Eur Heart J. 2005; 26:2422-34Nieuwlaat R et al. Eur Heart J. 2005; 26:2422-34The AFFIRM Writing Group N Engl J Med, 2002;347:1825-33The AFFIRM Writing Group N Engl J Med, 2002;347:1825-33

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Risks of Vernakalant InjectionRisks of Vernakalant Injection0-24 Hours – 0-24 Hours – All PatientsAll Patients

Risk Estimate 95% CL*

TdP 1/773 (0.13%) 0.61%

Hypotension† 10/773 (1.29%) 2.18%

Bradycardia† 13/773 (1.68%) 2.66%

** Based on Exact Methodology, 1-sided 95% confidence intervalBased on Exact Methodology, 1-sided 95% confidence interval†† SAE or discontinuation of study drug due to hypotension or bradycardiaSAE or discontinuation of study drug due to hypotension or bradycardia

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Risks of Vernakalant InjectionRisks of Vernakalant Injection

• QT prolongation – moderate, transientQT prolongation – moderate, transient• TdP – 1 event within 24 hours of vernakalant TdP – 1 event within 24 hours of vernakalant

infusion and immediately following infusion infusion and immediately following infusion of ibutilideof ibutilide

• Hypotension – peri-infusional, generally Hypotension – peri-infusional, generally transient, usually responds to saline and transient, usually responds to saline and positioning positioning

• Bradycardia – associated with cardioversionBradycardia – associated with cardioversion

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Risks of Vernakalant Injection Risks of Vernakalant Injection By History of CHFBy History of CHF

PlaceboHx CHF

Vernakalant InjectionHx CHF

Vernakalant Injection

No Hx CHF

Efficacy 0%(0/16)

27%(7/26)

54%(111/205)

AE hypotension*

3.7%(2/54)

14.5%(16/110)

5.3%(33/627)

SBP <90 mmHg*

11.1%(6/54)

18.2%(20/110)

5.6%(35/627)

** Based on events occurring within 0-24 hour time periodBased on events occurring within 0-24 hour time period

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Benefits of Vernakalant InjectionBenefits of Vernakalant Injection

52.9%51.0% 51.2%

47.0%50.9%

48.3%50.0%

14.0%

24.0%

28.6%

3.6%5.3% 4.0%

CRAFT ACT I ACT III ACT II ACT IV ACT I ACT III

Vernakalant Placebo

Patients withoutPatients withoutAF SymptomsAF Symptoms

at Min. 90 (AF >3h - ≤7d)at Min. 90 (AF >3h - ≤7d)Consistent Conversion RatesConsistent Conversion Rates

All PatientsAll Patients

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Benefits of Vernakalant InjectionBenefits of Vernakalant Injection• Maintenance of sinus rhythm at 24 hours - 97% Maintenance of sinus rhythm at 24 hours - 97%

• Can be administered with background rate (72%) or Can be administered with background rate (72%) or rhythm control (20%) medicationsrhythm control (20%) medications

• Electrical cardioversion is effective in non-responders Electrical cardioversion is effective in non-responders (vernakalant - 88%; placebo - 90%) (vernakalant - 88%; placebo - 90%)

• Safe and effective in patients with common Safe and effective in patients with common co-morbidities, including:co-morbidities, including:

– Hypertension (52% of patients in P2/3 studies)Hypertension (52% of patients in P2/3 studies)– History of ischemic heart disease (24% of patients in P2/3 History of ischemic heart disease (24% of patients in P2/3

studies)studies)

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Risk/Benefit of Vernakalant InjectionRisk/Benefit of Vernakalant InjectionProfile of ventricular arrhythmias within Profile of ventricular arrhythmias within the first 24 hoursthe first 24 hours– Ventricular Fibrillation – 2/773 (0.26%) Ventricular Fibrillation – 2/773 (0.26%) – Torsade de Pointes (TdP) – 1/773 (0.13%)Torsade de Pointes (TdP) – 1/773 (0.13%)– Ventricular TachycardiaVentricular Tachycardia

Ventricular Tachycardia

PlaceboN=315

Vernakalant InjectionN=737

Unsustained monomorphic

30 (9.5%) 58 (7.9%)

Unsustained polymorphic

14 (4.4%) 24 (3.3%)

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Vernakalant Injection Vernakalant Injection Risk/Benefit SummaryRisk/Benefit Summary

• Effective for the rapid conversion of AF Effective for the rapid conversion of AF to sinus rhythm with reduction of AF to sinus rhythm with reduction of AF symptomssymptoms

• An important treatment alternative for An important treatment alternative for patients with acute symptomatic atrial patients with acute symptomatic atrial fibrillation, including post-cardiac fibrillation, including post-cardiac surgery patientssurgery patients