Ranolazina e rivascolarizzazione coronarica: terapie complementari o competitive? Piera Angelica Merlini

Ranolazina e rivascolarizzazione coronarica: terapie complementari o competitive? Piera Angelica Merlini Key points: 1 Quale è l obbiettivo della terapia nella malattia coronarica stabile? 2 Che cosa aggiunge la rivascolarizzazione alla terapia medica ottimale? 3 Che cosa aggiunge la ranolazina alla terapia medica ottimale?

ACC/AHA Chronic Angina Guidelines: Basic Treatment / Education The initial treatment of the patient should include all elements: A. Aspirin and Antianginal therapy B. Beta blocker and Blood pressure C. Cigarette smoking and Cholesterol D. Diet and Diabetes E. Education and Exercise Gibbons RJ, et al. ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable Angina.

Supply and Demand Mismatch and Therapeutic Targets Vasospasm NTG, Calcium antagonist Thrombus ASA Atherosclerosis STATIN O 2 Supply O 2 Demand Afterload Calcium antagonist Heart rate Beta-blocker, Ivabradina Contractility Beta-blocker Preload (vascular) NTG Diastolic flow ( myocardial blood flow) Ischemia LVEDP ( diastolic tension) LV wall stiffness ( LV Preload) Adapted from Braunwald s Heart Disease 7 th Edition 2006; Brunton, et al. Goodman & Gilman s Pharmacological Basis of Therapeutics, 11 th Edition 2006.

Swedish Angina Pectoris Aspirin Trial Death or MI at 50 months follow-up Number of patients 150 125 100 75 50 P= 0.003 34% Risk Reduction 81 124 25 0 Jull-Muller S et al. Lancet 1992 340:1421-5 aspirin + sotalol placebo + sotalol

EUROPEAN SOCIETY OF CARDIOLOGY GUIDELINES MANAGEMENT OF STABLE ANGINA PECTORIS AVERT STUDY 341 patients with stable CAD and LDL > 115 mg/dl Cumulative Incidence (%) 25 20 15 10 5 Angioplasty Atorvastatin 0 0 6 12 18 Time since Randomization (months) The AVERT investigators NEJM 1999; 341: 70-6

Angiotensin II and Atherosclerosis HOPE Trial 0,2 Composite Outcome Placebo 0,15 Proportion of patients 0,1 0,05 P < 0.001 RR=0.78; 95% CI 0.70-0.86 Ramipril 0 0 500 1000 1500 2000 Days of Follow-up

EUROPEAN SOCIETY OF CARDIOLOGY GUIDELINES MANAGEMENT OF STABLE ANGINA PECTORIS Beta-blockers are effective in decreasing symtoms, increasing exercise tollerance and reducing nitrates consumption. Beta-blockers should be also recommended in all patients with previous MI and/or LV dysfunction CLASS I EVIDENCE A

ACC/AHA Chronic Angina Guidelines The goal of successful treatment the goal of treatment should be complete, or nearly complete, elimination of anginal chest pain and return to normal activities and a functional capacity of CCS class I angina with minimal side effects of therapy. Gibbons RJ et al, ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable Angina

Angina Symptoms Predict Total Mortality in Patients with Coronary Artery Disease Survival according to physical limition due to angina (SAQ score) - Prospective VA study 1.0 -> physical limitation due to angina, > mortality Mild limitation: 27% (HR 1.27 95%CI 0.98-1.64) Moderate limitation: 61% (HR 1.61 95%CI 1.27-2.05) Greatest limitation: 255% (HR 2.55 95%CI 1.97-3.30) - Greater symptoms of physical limitation due to angina were strongly predictive of poor survival Mozaffarian D. et al, Am Heart J. 2003; 146: 1015-1022 0.74 0 p < 0.001 for log-rank test for equality of survivor function 75-100 50-74 25-49 0-24 0 1 2 3 4 Years

Coronary Flow Reserve Coronary Flow Reserve 5 4 3 2 1 resting flow maximum flow 0 20 40 60 80 100 Diameter Narrowing %

EUROPEAN SOCIETY OF CARDIOLOGY GUIDELINES MANAGEMENT OF STABLE ANGINA PECTORIS PCI may be recommended for patients with stable angina who do not respond adequately to medical therapy or who wishes to remain physically active regardless of age and have significant coronary artery stenosis that are suitable with high likelihood of success CLASS I EVIDENCE C

ACME Study 212 patients with stable single vessel CAD Freedom from angina Patients without angina (%) 70 60 50 40 30 20 P< 0.01 at 6 months Medical Therapy PTCA 64 46 10 0 0 1 2 3 4 5 6 Parisi et al. For the ACME Investigators NEJM 1992; 326:10-16 Follow-up, months

High Risk Features Proximal LAD stenosis 25 5 Years mortality rate in medical treatment Without LAD disease P= 0.009 19,1% With LAD disease Patients percent P= 0.05 8,3 % 14,6 % 14,5 % 0 Yousuf et al. Lancet 1994:344;563-70 1 or 2 vessel disease 3 vessel disease

EUROPEAN SOCIETY OF CARDIOLOGY GUIDELINES MANAGEMENT OF STABLE ANGINA PECTORIS PCI may be considered for asymptomatic of mildly simptomatic patients in the category of high-risk ischemia and severe anatomic CAD if there is a high likelihood of success and a low risk of morbidity and mortality CLASS IIA EVIDENCE B

Stable CAD PCI vs Conservative Medical Management Meta-analysis of 11 randomized trials; N = 2,950 Favors PCI Favors Medical Management Death Cardiac death or MI Nonfatal MI CABG Katritsis DG et al. Circulation. 2005;111:2906-12. PCI 0 1 2 Risk ratio (95% Cl) P 0.68 0.28 0.12 0.82 0.34

Inclusion Criteria Men and Women 1, 2, or 3 vessel disease (> 70% visual stenosis of proximal coronary segment) Anatomy suitable for PCI CCS Class I-III angina Objective evidence of ischemia at baseline ACC/AHA Class I or II indication for PCI

Overall Survival 1.0 0.9 0.8 0.7 0.6 0.5 0.0 PCI + OMT OMT Hazard ratio: 0.87 95% CI (0.65-1.16) P = 0.38 Number at Risk 0 1 2 3 4 5 6 Years Medical Therapy 1138 1073 1029 917 717 468 302 38 PCI 1149 1094 1051 929 733 488 312 44 7

Survival Free of Death from Any Cause and Myocardial Infarction 1.0 Optimal Medical Therapy (OMT) 0.9 0.8 0.7 0.6 0.5 0.0 PCI + OMT Hazard ratio: 1.05 95% CI (0.87-1.27) P = 0.62 Number at Risk 0 1 2 3 4 5 6 Years Medical Therapy 1138 1017 959 834 638 408 192 30 PCI 1149 1013 952 833 637 417 200 35 7

Survival Free of Hospitalization for ACS 1.0 0.9 0.8 OMT PCI + OMT 0.7 0.6 0.5 Hazard ratio: 1.07 95% CI (0.84-1.37) P = 0.56 0.0 Number at Risk 0 1 2 3 4 5 6 Years Medical Therapy 1138 1025 956 833 662 418 236 127 PCI 1149 1027 957 835 667 431 246 134 7

Freedom from Angina During Long-Term Follow-up Characteristic PCI + OMT OMT CLINICAL Angina free no. Baseline 12% 13% 1 Yr 66% 58% 3 Yr 72% 67% 5 Yr 74% 72% The comparison between the PCI group and the medical-therapy group was significant at 1 year ( P<0.001) and 3 years (P=0.02) but not at baseline or 5 years.

Coronary revascularization vs medical therapy for overall mortality

CABG vs Medical Therapy -Mortality

PCI vs Medical Therapy-Mortality

Coronary revascularization vs medical therapy for Myocardial Infarction

EUROPEAN SOCIETY OF CARDIOLOGY GUIDELINES MANAGEMENT OF STABLE ANGINA PECTORIS CABG is highly effective in relieving the symptoms of stable angina and reduces the risk of death over the succeding 10 years in particular subgroups of patients, expecially if LV function is impaired: Left main stenosis Proximal LAD stenosis and three vessel desease Multivessel disease and diabetes CLASS I EVIDENCE A

Factors in the choice of intervention Stable coronary artery disease Not high risk patients Asymptomatic Symptomatic High risk patients : left main disease three vessels disease proximal LAD stenosis low EF Large area of ischemia Occupational risk Medical therapy Revascularisation + medical therapy

COURAGE NUCLEAR SUBSTUDY 40 PCI - OMT (n=159) 40 OMT (n=155) Event free survival rate 30 20 10 30 20 10 0 Index 6-18 mo 0 Index 6-18 mo

COURAGE: Survival by residual ischemia 1.0 Cumulative event-free survival 0.8 0.6 0.4 0.2 0 % (n=23) 1% - 4.9% (n=141) 5% - 9.9% (n=88) 10% (n=62) 0 1.5 2 2.5 3 3.5 4 Time to Follow-up, y 4.5 5

COURAGE NUCLEAR SUBSTUDY 40 PCI - OMT (n=159) 40 OMT (n=155) Event free survival rate 30 20 10 30 20 10 0 Index 6-18 mo 0 Index 6-18 mo

Overview of the sodium channel Na + Na + Na + Resting closed Activated Inactivated [Na + ] = 140 mm [Na + ] ~10mM Na + Na + Na + Na + Na +Na+ in out out in Na + Na + /Ca 2+ Exchanger Ca 2+ Ca 2+ Ca Ca2+ 2+ Ca 2+ Ca 2+ Na + Ca 2+ 2/12/2010 4:50 PM AD-0363-07-WAT20.ppt Courtesy of L Belardinelli, 31 MD.

32 Myocardial ischemia causes enhanced late I Na Sodium current 0 Late Ischemia 0 Sodium current Late Peak Peak Enhanced late I Na appears to be a major contributor to increased intracellular Na + during ischemia Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14. 2/12/2010 4:50 PM AD-0363-07-WAT20.ppt

33 Oxygen Supply: Demand Ischemia Hypoxia, Ischemic metabolites, Ischemia acidosis, begets and ROSIschemia 33 MVO 2 O 2 Supply Contracture ( LVEDP) Contracture Ischemia Deleterious Positive Late I Na Feedback Cycle Ca ++ - overload Late I Na NCX [Na + ] i Arrhythmias Ca ++ Overload Modified from: Belardinelli et al. Eur Heart 8 (Suppl. A):A10-A13, 2006.

Selective Inhibition of Late Sodium Current by Ranolazine Therapeutic Range 2 to 8 μm A. Normal Late Sodium Current C. Human Cardiac NaCh in HEK293 Cells 34 I NaL Late I Na 100 Peak IC 50 = 428 µm Peak I Na Late I Na B. Enhanced Late Sodium Current % Inhibition Na + i 50 late IC 50 = 6.9 µm IC 50 Ca 2+ i IC 50 = 62-fold Ranolazine I NaL Late I Na 0 1E-3 0.01 0.1 1 10 100 C i f i ( ) Concentration of Ranolazine (mm) Peak I Na Belardinelli L et al. Eur Heart. 6 (Suppl. I):13-17, 2004. Wu L et al. Am J Physiol Heart Circ Physiol. 2009 Sept; 297:H1048 H105.

RANOLAZINE 35 Decreases Late Sodium Current (I Na ) Decreases Calcium Overload* Improves Relaxation (Positive Lusitropy) Ca i 2+ transient duration Relaxation Time Rate of relax. ( LV-dP/dt) LV IVRT Improves Electrical Stability Prolong APD Afterpotentials (EADs, DADs) Abnormal Automaticity ( DD) Disp. of Repolarization ( Reentry) 1. Anti-Ischemic (antianginal, LV function) Modified from Belardinelli L, et al. Heart 2006;92 (Suppl. IV):IV6-IV14. 2. Anti-Arrhythmic * [Na + ] i - dependent

Unique Therapeutic and Pharmacology of Ranexa Ranexa (Ranolazine) has anti-ischemic and antianginal effects with minimal or no changes in heart rate and arterial blood pressure. Ranexa does not a) slow heart rate (No bradycardia) b) decrease contractility (No depression of LV function) c) increase coronary or peripheral flow: not a vasodilator (No hypotension) d) slow AV nodal conduction (No PR prolongation) 36 Therapeutic concentrations are ~750-4,000 ng/ml (~2 to 8 µm)

Clinical Development Studies of Ranolazine in Patients with CAD 37 4 Key Randomized, Placebo-Controlled Trials MARISA = monotherapy (X-over) (n=191) CARISA = combination (parallel) (n=823) ERICA = comb. max dose (parallel) (n=565) MERLIN-TIMI 36 = acute-to-chronic Rx in pts with high-risk NSTE ACS (n=6,550) Pooled data comprise 8,129 patients more extensively studied than any agent in stable CAD

RAN080: La ranolazina è efficacie come il betabloccante? 460 Time to onset of angina Time to 1-mm ST-depression Exercise duration P <.001 P =.006 P <.04 440 P <.001 P =.18 LS mean ± SE, sec 420 400 380 360 340 320 P <.001 P <.001 P =.86 P <.001 300 All patients analysis, N = 142 Placebo Ranolazine IR 400 mg tid Atenolol 100 mg qd Rousseau MF, et al. Am J Cardiol. 2005;95:311-316.

CARISA: La ranolazina aggiunge qualcosa alla terapia medica ottimale? Change from baseline, sec 150 100 50 Trough * * Exercise Time * * Placebo Ranolazine 750 mg bid Ranolazine 1000 mg bid Time to 1-mm *** Exercise * Peak ** ** Time *** ** Time to 1-mm duration to angina ST depression duration to angina ST depression N = 791, ITT/LOCF; LS mean ± SE. *P <.05; **P.01; ***P.001 vs placebo Tolerance to ranolazine did not develop after 12 weeks of therapy and rebound angina, as measured by exercise duration, has not been observed. Chaitman BR, et al. JAMA. 2004;291:309-316.

CARISA: La ranolazina migliora la classe di angina? Mean number of angina attacks/week 5 4 3 2 1 3.3 2.1* 36% Reduction in Angina Frequency P <.001 Placebo + background therapy Ranolazine 1000 mg twice daily plus background therapy Mean number of angina attacks/wk at baseline Placebo + background therapy Ranolazine 1000 mg twice daily + background therapy 0 Double-blind Chaitman BR, et al. JAMA. 2004;291:309-316. Ranexa (ranolazine extended-release tablets) PI. March 2009. Gilead data on file RAN00253-2. 4.6 4.5

ERICA: La ranolazina aggiunge qualcosa nei pazienti refrattari in terapia medica ottimale Average weekly angina attacks over 6-week study period 5 Mean number of angina attacks per week 4 3 2 1 0 4.3 Placebo Modified from Stone P, et al. J Am Coll Cardiol. 2006;48(3):566-575. 3.3 Ranolazine 23% Reduction In Angina Frequency P =.028

42 Myocardial Perfusion Imaging in Patients with Coronary Artery Disease Treated with Ranolazine Exploratory study in 20 patients with CAD and angina Before Ranolazine PDS* = 25% of LV Peak HR = 142 bpm After Ranolazine PDS* = 11% of LV Peak HR = 142 bpm Ischemia Perfusion Defect Size (%) 30 20 10 0 Baseline P = 0.003 RAN N= 14 Treadmill exercise time increased by 32 seconds (p=0.017, n=20) Angina reduced in 15 patients (75%) after ranolazine treatment. Improvement in the extent and severity of ischemia was noted in 14 patients (70%). Among these patients, ischemia PDS (% LV) decreased from 16 + 10 to 8 + 6 (p=0.003, n=14) Among the 15 patients with reduced angina, 11 (73%) had an improvement in perfusion. Venkataraman R, et al. JACC Imaging 2009 (in press); Courtesy of Ami Iskandrian, MD *PDS: perfusion defect size

MERLIN: Efficacy and Safety in Patients with Chronic Angina 3565 patients with prior history of angina (54%) Mean duration of chronic angina 5.2 years. Prior PCI or CABG (33%) Baseline: 41% in CCS Class 2; 32% in CCS Class 3 Evidenced-based therapy ASA (95%) Statins (77%) Beta-blockers (89%) Ace-I (79%) CCB (30%) LAN (40%) Coronary revascularization (49.9%) CCS = Canadian Cardiovascular Society Wilson SR, et al. J Am Coll Cardiol. 2009;53;1510-1516.

Observations in Patients with History of Angina 44 Placebo Ranolazine HR P value N=1776 N = 1789 Primary endpoint 29.4 25.2 0.86 p = 0.017 CV death or MI 12.5 11.9 0.97 p = 0.71 Recurrent ischemia 21.1 16.5 0.78 p = 0.002 Severe recurrent ischemia** Prompting revascularization 14.4 11.9 0.81 p = 0.026 6.4 4.5 0.66 p = 0.006 Worsening angina*** 8.2 5.6 0.77 p = 0.048 *KM Cumulative Incidence at 12 months; ** Ischemia with ECG changes, prompting rehospitalization, or revascularization *** 1 CCS Class and requiring intensification of anti-anginal Rx Data shown are % Wilson S et al. J Am Coll Cardiol 2009;53:1510 6

Observations of Exercise Performance at 8 Months in Patients with History Chronic Angina 45 RANOLAZINE PLACEBO Duration (Seconds) 520 510 500 490 480 470 460 482 514 508 509 477 476 450 Exercise Duration Time to 1 mm ST dep Time to Angina P = 0.002 P = 0.003 P = 0.002 Wilson S et al. J Am Coll Cardiol 2009;53:1510 6

SAQ Angina Frequency SAQ angina frequency scores 87 86 85 84 83 82 81 80 P = 0.002 P < 0.001 P = 0.002 4 months 8 months 12 months Placebo Ranolazine i.v. to 1,000 mg b.i.d. p.o. Circ Cardiovasc Qual Outcomes 2008;1:107-115

SAQ QoL Estimated effect of Ranolazine vs placebo (95% CI) 6 4 2 0 0 * P = 0.05 SAQ QoL P 0.05 * P 0.05 * P<0.001 4 8 12 * Follow-up Time (months) Circ Cardiovasc Qual Outcomes 2008;1:107-115

Risk for SCD in Patients With or Without Prior History of MI 48 A. Placebo B. Ranolazine RR (95% CI): 1.87 (1.15, 3.05); p=0.01 RR (95% CI): 1.46 (0.86, 2.47); p=0.16 Sudden Cardiac Death MI Sudden Cardiac Death MI No MI No MI Days After Randomization Days After Randomization No. At Risk No. At Risk Data on file, Gilead Sciences, Inc.

Risk for SCD in Patients With or Without Low LVEF 49 A. Placebo B. Ranolazine RR (95% CI): 3.84 (2.13, 6.95); p<0.01 RR (95% CI): 2.43 (1.13, 5.21); p=0.018 Sudden Cardiac Death LVEF < 40% LVEF > 40% Sudden Cardiac Death LVEF < 40% LVEF > 40% Days After Randomization Days After Randomization Modified from Scirica B, et al. Circulation. 2007;116:1647-1652. Data on file, Gilead Sciences, Inc.

Risk for SCD in Patients with Prolonged QTc at Randomization 50 A. Placebo B. Ranolazine 10% Placebo QTc >= 470 Placebo QTc < 440 RR (95% CI): 2.93 (1.52, 5.64); p<0.001 RR (95% CI): 1.77 (0.86, 3.66); p=0.12 Sudden Cardiac Death 8% 6% 4% 2% Relative Risk (95% CI): 2.93 (1.52, 5.64); p<0.001 QTc > 470 Sudden Cardiac Death QTc > 470 0% No. At Risk QTc >= 470 278 QTc < 440 2358 QTc < 440 0 90 180 270 360 450 540 Days After Randomization Days after Randomization 257 232 179 127 65 23 2251 2064 1621 1125 630 265 Days after Randomization QTc < 440 Prokopczuk E, et al. HR 2009 (abstract) Data on file, Gilead Sciences, Inc. In patients with QTc > 500 msec, 4 (placebo) and 1 (ranolazine) died of SCD

Estimated Incidence of Sudden Cardiac Death vs. Baseline QTc 51 6% SCD RR (95%CI) increase per 10 msec increase in QTc Estimated Incidence of SCD 5% 4% 3% 2% 1% Treatment by QTc Interaction p = 0.25 0% 350 370 390 410 430 450 470 490 510 530 550 Baseline QTc (msec) Placebo 8.4% (2.2%, 15.0%) p = 0.007 Ranolazine 2.9% (-3.9%, 10.1%) p = 0.412 Prokopczuk E, et al. HR 2009 (abstract) Data on file, Gilead Sciences, Inc.

Incidence of Non-Sustained Ventricular Tachycardia in the MERLIN - TIMI 36 Trial 52 p < 0.001 30 30 Placebo Ranolazine Incidence (%) 20 10 21 p < 0.001 p < 0.001 p < 0.001 8.3 0 5.2 5.7 3.4 2.5 1.3 1.3 p = 0.075 0.9 4 8 10 15 20 Non-Sustained VT (No. of Beats) Scirica et al. Circulation. 2007;116:1449-1457.

Incidence of Sudden Cardiac Death: MERLIN- TIMI 36 53 Incidence of SCD (%) 8 6 4 2 0 3.1 Placebo Ranolazine 1.3 3.4 1.6 6.3 _ > 4 _ > 8 _ > 15 1.6 Non-sustained VT (No. of Beats) Scirica et al. JACC. 2009;53 (10) (Suppl A):A121 (abstract).

Primary Arrhythmia Endpoints Results Ventricular Events RANOLAZINE( %) PLACEBO( %) P value VT > 3 beats 52.1 60.6 <0.001 Supraventricular Events SVT >4 beats 44.7 55.0 <0.001 New-onset atrial fib 1.7 2.4 0.08 Bradycardic Events Brady <45 bpm, CHB, or pause >2.5s 39.8 46.6 <0.001 Pause > 3 sec 3.1 4.3 0.01 Scirica BM et al. Circulation 2007

55 CARISA: Reductions in A1C (diabetes substudy) n = 131 with diabetes (n = 31 on insulin) AIC change from baseline 0-0.02 Least squares mean (%) -0.2-0.4-0.6-0.5 * Possible mechanisms: Insulin sensitivity Physical activity -0.8-0.72 * Placebo Ranolazine 750 mg bid Ranolazine 1000 mg bid *P 0.008 vs placebo Cooper-DeHoff R, Pepine CJ. Eur Heart J. 2006;27:5-6. Timmis AD et al. Eur Heart J. 2006;27:42-8. 2/12/2010 4:50 PM AD-0363-07-WAT20.ppt

56 MERLIN-TIMI 36: Effect of ranolazine on HbA1c 0.4 Diabetes Mellitus Month of Follow-up 0 4 8 12 16 0.4 No Diabetes Month of Follow-up 0 4 8 12 16 0.2 0.2 Change in HbA1c 0-0.2 0-0.2-0.4-0.4-0.6-0.6-0.8 Placebo Ranolazine P-value N = 770 N = 707 <0.001 N = 598 N = 535 <0.001 N = 122 N = 112 = 0.13-0.8 N = 1428 N = 1401 <0.001 N = 1113 N = 1113 = 0.002 N = 260 N = 266 = 0.025 Placebo Ranolazine Morrow DA et al. Circulation. 2007; 116: II-540 2/12/2010 4:50 PM AD-0363-07-WAT20.ppt

MERLIN TIMI-36 Results in Women Women (n = 2291) vs men (n = 4269) Older, with higher rates of DM, HTN HF Prior angina ST BNP However, lower rates of Stenosis > 50% Troponin Greater burden of ischemia on Holter monitoring and Seattle anginal questionnaire P < 0.001 for all comparisons 1 Year event rate (%) 30 25 20 15 10 RRR P-value 5 0 11.3 Outcomes in Women Placebo Ranolazine 11 CV Death or MI 3% 0.82 18.2 13 Recurrent Ischemia 29% 0.002 25.8 21.8 Primary EP 17% 0.03 Mega JL et al. Presented at AHA. 2007.

Ranolazina e rivascolarizzazione coronarica: terapie complementari o competitive? Piera Angelica Merlini Key points: 1 Quale è l obbiettivo della terapia nella malattia coronarica stabile? 2 Che cosa aggiunge la rivascolarizzazione alla terapia medica ottimale? 3 Che cosa aggiunge la ranolazina alla terapia medica ottimale?

Anti-ischemic Strategies in Stable CAD Initial therapy Drug therapy PCI CABG Persistent / Recurrent ischemia Antianginal drug therapy (uptitrate/add additional agents) Repeat revascularization (if possible) Gibbons RJ et al, ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable Angina