Disclosures Dr Scirica has received Dr Scirica has received honoraria for educational presentations (modest) from CV Therapeutics The study was supported through a research grant (major) from CV Therapeutics.

September 5 th, 2007 Vienna The Effect of Ranolazine on the Incidence of Arrhythmias in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome: Results from the MERLIN-TIMI 36 Trial

Ranolazine in Ischemic Heart Disease Background New antianginal agent –Anti-ischemic action without clinically significant effect on HR or BP Novel mechanism of action –Inhibition of late I Na (Late phase of sodium current) Approved for treatment of chronic angina –  exercise time,  angina in selected pts Persistent concern b/c prolongation of QT –2-6 msec with approved doses –Theoretical risk of ventricular tachycardia

Relation Between Peak and Late I Na and Ventricular Action Potential Sodium Current (I Na ) nA Action Potential mV Background Late Peak 0 Twitch Normal Late I Na Augmented Late I Na (delayed or incomplete inactivation) Late Peak 0 Twitch Early after- depolarization

Consequences of Increased Consequences of Increased Late I Na Na + Overload Ischemia Heart Failure Genetic defects Drugs Na +- Ca 2+ Exchanger Ca 2+ Overload  Late I Na Electrical Dysfunction Afterpotentials (e.g., EAD and DAD) Transmural Dispersion of Repolarization (TDR) Prolonged Action Potential Ranolazine Arrhythmias

Background Sotalol, 100 µM Ranolazine Antzelevitch C., et al. Circ 2004; 110: No ↑ in Transmural Dispersion of Repolarization (TDR) Effects of Ranolazine in Experimental Models on Pro-Arrhythmic Substrate and Triggers However, the potential anti-arrhythmic actions of ranolazine have yet to be evaluated in humans TDR (msec) Concentration (µM) ↓ Early Afterdepolarization (EAD) Control Action Potential EAD Sotalol + Ranolazine 10 µM

UA/NSTEMI (Moderate-High Risk) Ranolazine IV to PO Placebo Matched IV/PO RANDOMIZE (1:1) Double-blind HolterContinuous 7-day recording Long-term Follow-up (Median 348 Days) Standard Therapy N = 6560

Primary Endpoint Results CV Death or MI (%)Recurrent Ischemia (%) Days from Randomization Ranolazine 13.9%* (N=3,279) Placebo 16.1%* (N=3,281) HR 0.87 (95% CI 0.76 to 0.99) P = Ranolazine 10.4%* Placebo 10.5%* HR 0.99 (95% CI 0.85 to 1.15) P = Days from Randomization *KM Cumulative Incidence (%) at 12 months Primary Endpoint - CV Death, MI, or Recurrent Ischemia 21.8% for Ranolazine vs. 23.5% for Placebo HR 0.92 (95% CI 0.83 to 1.02), P = 0.11 Morrow DA et al, JAMA 2007;297(16):

7-day Continuous ECG (Holter) monitoring7-day Continuous ECG (Holter) monitoring –Started at randomization (mean duration 6.3 d) –Customized monitors and analysis software (DelMar Reynolds / Spacelabs) –Evaluated in TIMI Core Laboratory blinded to treatment and clinical outcome Sudden Cardiac Death through entire clinical follow-up (mean 12 months)Sudden Cardiac Death through entire clinical follow-up (mean 12 months) –Adjudicated by blinded Clinical Events Committee Methods Study Design

Clinically Significant ArrhythmiaClinically Significant Arrhythmia –VT >3 beats –SVT >120 bpm lasting >4 beats –New onset a-fib –Bradycardia 2.5 s Further ClassificationFurther Classification –Ventricular Tachycardia Non-sustained VT >8 beatsNon-sustained VT >8 beats Sustained VT (lasting >30 seconds)Sustained VT (lasting >30 seconds) Mono or Poly-morphicMono or Poly-morphic –Ventricular Pauses >3 s Arrhythmia Endpoints Analysis Study Design

Baseline Characteristics RANOLAZINE (n=3,162) PLACEBO (n=3,189) Age (yrs, median) Female (%) Prior MI (%) Prior heart failure (%) Prior vent arrhythmia (%) EF <40% (%) NSTEMI on admission (%) Beta-blocker (%) Holter Cohort 6,351 pts (97% of entire trial) Results

Primary Arrhythmia Endpoints Results RANOLAZINE (%) PLACEBO (%) P value Ventricular Events VT > 3 beats <0.001 Supraventricular Events SVT >4 beats <0.001 New-onset atrial fib Bradycardic Events Brady 2.5s <0.001 Pause > 3 sec

First Occurrence of Ventricular Tachycardia Lasting > 8 Beats Results Hours from randomization Incidence of VT > 8 beats (%) RANOLAZINE PLACEBO RR %CI 0.52, 0.76 p<0.001 RR 0.67 p=0.008 RR 0.65 p< % 5.3%

Incidence of VT >8 Beats in Subgroups Results RR 0.72 p<0.001 RR 0.53 p=0.001 RR 0.53 p=0.013 RR 0.66 p<0.001 Ejection Fraction >40%<40% Baseline QT c (msec) <450>450 Ranolazine Placebo

No Ischemia on cECG Ischemia on cECG RANOLAZINE (%) PLACEBO (%) p value < Relative Risk (95% CI) Incidence of VT >8 Beats in High-risk Subgroups Results TRS 0-4 TRS 5-7 No Prior HF Prior HF < < EF > 40% EF < 40% QTc <450 msec QTc > 450 msec < P values for interaction >0.05

Ventricular Tachycardia Events Results RANOLAZINE (%) PLACEBO (%) P value Polymorphic VT > 8 beats Sustained VT (> 30s) Monomorphic VT Polymorphic VT

Sudden Cardiac Death Through Follow-up (mean 12 months) Results RANOLAZINE (%) PLACEBO (%) P value Overall EF >40% EF <40% QTc <450 msec QTc >450 msec TRS TRS No Prior HF Prior HF P values for interaction >0.05

Among patients with ACS, ranolazine, an inhibitor of late I Na, has anti-arrhythmic effects as assessed by Holter monitoringAmong patients with ACS, ranolazine, an inhibitor of late I Na, has anti-arrhythmic effects as assessed by Holter monitoring In particular, patients treated with ranolazine had fewer episodes of VT > 8 beats, SVT, and ventricular pauses > 3 secondsIn particular, patients treated with ranolazine had fewer episodes of VT > 8 beats, SVT, and ventricular pauses > 3 seconds Consistent effect in several high-risk sub- groupsConsistent effect in several high-risk sub- groups Conclusions Conclusions

This is the 1 st clinical report of potential anti- arrhythmic actions of ranolazine and supports anti-arrhythmic findings in experimental modelsThis is the 1 st clinical report of potential anti- arrhythmic actions of ranolazine and supports anti-arrhythmic findings in experimental models There was no evidence for a significant excess risk of polymorphic ventricular tachycardia or sudden cardiac deathThere was no evidence for a significant excess risk of polymorphic ventricular tachycardia or sudden cardiac death Studies specifically designed to evaluate the potential role of ranolazine as an anti- arrhythmic agent are warrantedStudies specifically designed to evaluate the potential role of ranolazine as an anti- arrhythmic agent are warranted Conclusions (cont.) Conclusions