1. Effects of Ranolazine: from Angina to Cardiac Performance Iacopo Olivotto, MD Referral Center for Cardiomyopathies Careggi University Hospital Florence, Italy olivottoi@aou-careggi.toscana.it Referral Center for Cardiomyopathies Careggi University Hospital - Florence

2. 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. 2003. Years Greater physical limitation due to angina “strongly associated with higher mortality” Angina Symptoms Predict Total Mortality in Patients with CAD

3. Referral Center for Cardiomyopathies Careggi University Hospital - Florence

4. 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

5. 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):A10-13. 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

6. 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

7. Ju YK, et al. J Physiol. 1996. Murphy E, et al. Circ Res. 1991. Jansen MA, et al. Circulation. 2004.  LV Diastolic Tension Ca 2+ i Overload  Na + i Ischemia The Cycle of Ischemia Ischaemia “begets” Ischaemia

8. Change from baseline, sec Pea k Trough *** ** *** ** * * * * * 50 100 150 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;291:309-316.

9. 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 score7.2 + 54.7 + 40.006 Total perfusion defect size (PDS) 24 + 1617 + 150.003 Ischaemia PDS 16 + 11 8 + 5 0.005 Reversible Perfusion Defect Size VenkataramanJ. A C C : C ardiovascular Imaging, V O L. 2, N O. 1 1, 2 0 0 9

11. MERLIN: components of the primary efficacy end-point Morrow D, et al. JAMA 2007;297:1775-83 Recurrent ischaemia Days from randomisation Ranolazine 13.9% (n=3,279) Placebo 16.1% (n=3,281) 0180360540 HR 0.87 (95% CI 0.76 to 0.99) P=0.030 0 5 10 15 20 CV death or MI 0 5 10 15 0180360540 Ranolazine 10.4% Placebo 10.5% HR 0.99 (95% CI 0.85 to 1.15) P=0.87 20 Days from randomisation Clinical efficacy Placebo Ranolazine Cumulative percentage* *Kaplan-Meier cumulative incidence at 12 months

12. 0 2 4 6 8 10 024487296120144168 Hours from randomization Incidence (%) Ranolazine Placebo RR 0.63 (0.52- 0.76) P <.001 RR 0.67 P =.008 RR 0.65 P <.001 8.3% 5.3% MERLIN: Reduction in VT Lasting ≥ 8 beats Scirica BM et al. Circulation 2007;116;1647-1652.

13. 0 2 4 6 8 10 024487296120144168 Hours from randomization Incidence (%) Ranolazine Placebo RR 0.63 (0.52-0.76) P <.001 RR 0.67 P =.008 RR 0.65 P <.001 8.3% 5.3% MERLIN: Reduction in VT Lasting ≥ 8 beats Scirica BM et al. Circulation 2007;116;1647-1652.

14. Referral Center for Cardiomyopathies Careggi University Hospital - Florence

15. Baseline BNP and Effect of Ranolazine on Primary Endpoint CV Death, MI, or Recurrent Ischemia (%) Days from Randomization *KM cumulative incidence (%) at 12 months 0 5 10 15 20 25 30 0180360 BNP NEG p = 0.009 BNP POS Placebo BNP POS Ranolazine P-interaction = 0.05 J Am Coll Cardiol 2010;55:1189– 96

16. Referral Center for Cardiomyopathies Careggi University Hospital - Florence

17. Referral Center for Cardiomyopathies Careggi University Hospital - Florence

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

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