Effects of Ranolazine: from Angina to Cardiac Performance Iacopo Olivotto, MD Referral Center for Cardiomyopathies Careggi University Hospital Florence, Italy Referral Center for Cardiomyopathies Careggi University Hospital - Florence

Prospective study 8900 VA patients with CAD –Primary endpoint all-cause mortality –Seattle Angina Questionnaire (SAQ) –Over 2 years mean follow up Results –Avg age 67 years –98% male –~66% white –~25% diabetic –896 deaths Mozaffarian D, et al. Am Heart J Years Greater physical limitation due to angina “strongly associated with higher mortality” Angina Symptoms Predict Total Mortality in Patients with CAD

Referral Center for Cardiomyopathies Careggi University Hospital - Florence

β-blockers DHP CCBs Non-DHP CCBs Long-acting nitrates Drug class Coronary blood flow Arterial pressure Venous return Myocardial contractility Heart rate CCB = calcium channel blocker, DHP = dihydropyridine *Except amlodipine Boden WE et al. Clin Cardiol. 2001;24:73-9. Gibbons RJ et al. ACC/AHA 2002 Chronic Angina Guidelines. Kerins DM et al. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10 th ed. O 2 DemandO 2 Supply / * Antianginal Drugs

Sodium Current 0 Late Peak 0 Late Peak Sodium Current Na + ImpairedInactivationImpairedInactivation Remodeling Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;(8 suppl A):A Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7. Blocker: Ranolazine Mechanisms of action potential prolongation in chronic angina: late I Na Referral Center for Cardiomyopathies University Hospital of Careggi - Florence

Ranolazine: Mechanism of Action Ischemia Late I Na Na + Overload Diastolic relaxation failure (Increased diastolic tension) Extravascular compression Ca ++ Overload Ranolazine: Inhibits the late inward Na + current

Ju YK, et al. J Physiol Murphy E, et al. Circ Res Jansen MA, et al. Circulation  LV Diastolic Tension Ca 2+ i Overload  Na + i Ischemia The Cycle of Ischemia Ischaemia “begets” Ischaemia

Change from baseline, sec Pea k Trough *** ** *** ** * * * * * Exercise duration Time to angina Time to 1-mm ST depression Exercise duration Time to angina Time to 1-mm ST depression N = 791, ITT/LOCF; LS mean ± SE. *P <.05; **P ≤.01; ***P ≤.001 vs placebo Placebo Ranolazine 750 mg bid Ranolazine 1000 mg bid CARISA: Is Ranolazine effective on top of atenolol/amlodipine? Chaitman BR, et al. JAMA. 2004;291:

Baseline Peak HR = 142 bpm After RAN (3-4 wks) Peak HR = 142 bpm 25% 10% Effects of Ranolazine on Stress MPI RestExercise MPI Variables (n=21)BaselineAfter RANp Value Summed difference score Total perfusion defect size (PDS) Ischaemia PDS Reversible Perfusion Defect Size VenkataramanJ. A C C : C ardiovascular Imaging, V O L. 2, N O. 1 1,

MERLIN: components of the primary efficacy end-point Morrow D, et al. JAMA 2007;297: Recurrent ischaemia Days from randomisation Ranolazine 13.9% (n=3,279) Placebo 16.1% (n=3,281) HR 0.87 (95% CI 0.76 to 0.99) P= CV death or MI Ranolazine 10.4% Placebo 10.5% HR 0.99 (95% CI 0.85 to 1.15) P= Days from randomisation Clinical efficacy Placebo Ranolazine Cumulative percentage* *Kaplan-Meier cumulative incidence at 12 months

Hours from randomization Incidence (%) Ranolazine Placebo RR 0.63 ( ) P <.001 RR 0.67 P =.008 RR 0.65 P < % 5.3% MERLIN: Reduction in VT Lasting ≥ 8 beats Scirica BM et al. Circulation 2007;116;

Hours from randomization Incidence (%) Ranolazine Placebo RR 0.63 ( ) P <.001 RR 0.67 P =.008 RR 0.65 P < % 5.3% MERLIN: Reduction in VT Lasting ≥ 8 beats Scirica BM et al. Circulation 2007;116;

Referral Center for Cardiomyopathies Careggi University Hospital - Florence

Baseline BNP and Effect of Ranolazine on Primary Endpoint CV Death, MI, or Recurrent Ischemia (%) Days from Randomization *KM cumulative incidence (%) at 12 months BNP NEG p = BNP POS Placebo BNP POS Ranolazine P-interaction = 0.05 J Am Coll Cardiol 2010;55:1189– 96

Referral Center for Cardiomyopathies Careggi University Hospital - Florence

Referral Center for Cardiomyopathies Careggi University Hospital - Florence

Referral Center for Cardiomyopathies University Hospital of Careggi - Florence Circulation, 2012

Referral Center for Cardiomyopathies Careggi University Hospital - Florence 3 Birds with 1 Stone Ischemia Arrhythmias Diastolic Dysfunction RANOLAZINE