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Clinical Trial Update

Clinical Trial Update. Issues in chronic myocardial ischemia treatment. Implications for clinical trials. Pathophysiology of angina is complex; relationship of angina to ACS is unclear. Despite existing treatments, ischemic episodes frequently occur.

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Clinical Trial Update

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  1. Clinical Trial Update

  2. Issues in chronic myocardial ischemia treatment Implications for clinical trials Pathophysiology of angina is complex; relationship of angina to ACS is unclear Despite existing treatments, ischemic episodes frequently occur PCI is one approach to reduce angina frequency Trials of all proven noninterventional therapies alone and in combination are needed Bhatt AB, Stone PH. Curr Opin Cardiol. 2006;21:492-502.Boden WE et al. Am Heart J. 2006;151:1173-9.

  3. Stable CAD: Multiple treatment options Lifestyle intervention Medicaltherapy Reduce symptomsTreat underlying disease CABG PCI

  4. SAFE-LIFE: Evaluation of intensive lifestyle intervention N = 101 with CAD Advice on Mediterranean diet Stress management≥30 min daily Encouraged to physical activity 3-day nonresidential retreat Weekly 3-hr meetings x 10 weeks Biweekly 2-hr meetings x 9 months Control group received printed lifestyle advice only Michalsen A et al. Am Heart J. 2006;151:870-7.

  5. SAFE-LIFE: Reduction in angina at 1 year with intensive lifestyle intervention P = 0.015 P = 0.01 Michalsen A et al. Am Heart J. 2006;151:870-7.

  6. Chronic ischemic heart disease: Treatment gaps • Most patients have relative intolerances to maximum doses of traditional antianginal agents (-blockers, CCBs, and nitrates) • Patients continue to experience myocardial ischemia • -blockers and many CCBs have similar depressive hemodynamic and electrophysiologic effects • Antianginal drugs without these limitations are needed Pepine CJ et al. Am J Cardiol. 1994;74:226-31.Gibbons RJ et al. www.acc.org.

  7. Novel anti-ischemic strategy Development of ischemia Consequences of ischemia Ischemia O2 demand Ca2+ overload Heart rate Blood pressure Preload Contractility Electrical instability Myocardial dysfunction O2 supply Nitrates, β-blockers, CCBs Ranolazine (late Na+ current inhibition) Courtesy of PH Stone, MD and BR Chaitman, MD. 2006.

  8. Ranolazine clinical trial program MARISA CARISA ERICA Silent CAD Stable angina Unstable angina Myocardial infarction Heart failure Death NSTEMI STEMI MERLIN-TIMI 36 Courtesy of BR Chaitman, MD.

  9. Ranolazine clinical trial program in chronic stable angina Monotherapy Assessment of Ranolazine In Stable Angina Combination Assessment of Ranolazine In Stable Angina Efficacy of Ranolazine In Chronic Angina Chaitman BR et al. J Am Coll Cardiol. 2004.Chaitman BR et al. JAMA. 2004.Stone PH et al. J Am Coll Cardiol. 2006.

  10. MARISA, CARISA, ERICA main findings • As monotherapy, ranolazine improves exercise performance in the absence of clinically meaningful pathophysiologic effects • These studies provide evidence of additional antianginal and anti-ischemic efficacy in patients who remain symptomatic on standard therapies or maximal amlodipine therapy Chaitman BR et al. J Am Coll Cardiol. 2004.Chaitman BR et al. JAMA. 2004.Stone PH et al. J Am Coll Cardiol. 2006.

  11. Challenges in selected populations: Experience with ranolazine Women Ischemic heart disease Diabetes Elderly

  12. Antianginal efficacy by gender Improved exercise duration MARISA CARISA † 60 150 ‡ ‡ NS NS † NS NS NS 40 100 Exercise duration, sec(Δ from placebo) Exercise duration, sec(Δ from baseline) * 20 50 0 0 500 mg 1000 mg 1500 mg Placebo 750 mg 1000 mg Ranolazine Ranolazine Women Men *P = 0.014, †P < 0.001, ‡P ≤ 0.037 vs placebo Wenger NK et al. Am J Cardiol. 2007;99:11-8.

  13. Antianginal efficacy by gender Improved angina score NS 30 P = 0.016 20 SAQ angina frequency score (Δ from baseline) 10 0 Placebo + amlodipine Ranolazine + amlodipine Women Men ERICA studySAQ = Seattle Angina Questionnaire Wenger NK et al. Am J Cardiol. 2007;99:11-8.

  14. Antianginal efficacy by age P = 0.074 P = 0.15 Age <65 years Age ≥65 years Placebo + amlodipine Ranolazine + amlodipine ERICA study Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

  15. Antianginal efficacy by diabetes status Placebo Ranolazine 750 mg bid Ranolazine 1000 mg bid CARISA studyP = 0.81 (interaction between diabetes status and treatment effect) Timmis AD et al. Eur Heart J. 2006;27:42-8.

  16. Possible mechanisms: Insulin sensitivity Physical activity CARISA: Reductions in A1C (diabetes substudy) n = 131 with diabetes (n = 31 on insulin) AIC change from baseline Least squares mean(%) * * Placebo Ranolazine 750 mg bid Ranolazine 1000 mg bid Cooper-DeHoff R, Pepine CJ. Eur Heart J. 2006;27:5-6.Timmis AD et al. Eur Heart J. 2006;27:42-8. *P ≤ 0.008 vs placebo

  17. Summary: Ranolazine in challenging populations • Antianginal efficacy independent of: • Gender • Age • Diabetes status • Also associated with ↓A1C in patients with diabetes Wenger NK et al. Am J Cardiol. 2007.Stone PH et al. J Am Coll Cardiol. 2006.Timmis AD et al. Eur Heart J. 2006.

  18. ROLE: Long-term safety and tolerability in stable CAD patients N = 746 ranolazine patients who completed MARISA or CARISA • Adverse events: • Most common: dizziness (11.8%) and constipation (10.9%) • Discontinuation: dizziness (0.9%), constipation (0.6%) • Total of 72 patients (9.7%) discontinued due to adverse events • ECG findings: • Mean QTc prolongation 2.4 ms (P < 0.001 vs baseline) • QTc >500 ms in 10 patients (1.2%) • No cases of Torsades de Pointes 2.8-year mean follow-up; >80% entered open-label extension Ranolazine Open-Label Experience Koren MJ et al. J Am Coll Cardiol. 2007;49:1027-34.

  19. MERLIN-TIMI 36: Study design Patients with non-ST-elevation ACStreated with standard medical/interventional therapiesN = 6560 RandomizedDouble-blind IV/oral ranolazine Placebo Primary efficacy endpoint:CV death, MI, recurrent ischemia Safety endpoints:All-cause death, CV hospitalization, symptomatic documented arrhythmia, clinically significant arrhythmia on Holter during first 7 days Metabolic Efficiency with Ranolazine for Less Ischemia in Non-St-Elevation Acute Coronary Syndromes Morrow DA et al. JAMA. 2007;297:1775-83.

  20. MERLIN-TIMI 36: Effect on primary endpoint Ranolazine vs placebo within 48 hrs of ischemic symptom onset 30 CV death, MI, or recurrent ischemia (%) 20 HR 0.92(95% CI 0.83-1.02)Log-rank P = 0.11 10 0 0 180 360 540 Days Placebo Ranolazine No. at risk Placebo Ranolazine 3281 3279 2454 2450 1223 1223 268 269 Morrow DA et al. JAMA. 2007;297:1775-83.

  21. MERLIN-TIMI 36: Components of primary endpoint n = 3279 ranolazine group, n = 3281 placebo group CV death or MI Recurrent ischemia HR 0.99(95% CI 0.85-1.15)Log-rank P = 0.87 HR 0.87(95% CI 0.76-0.99)Log-rank P = 0.03 Placebo 16.1%* 20 20 Placebo 10.5%* 15 15 Cumulativepercentage 10 10 Ranolazine 13.9%* Ranolazine 10.4%* 5 5 0 0 0 180 360 540 0 180 360 540 Days *Event rates at 12 months Morrow DA et al. JAMA. 2007;297:1775-83.

  22. MERLIN-TIMI 36: Efficacy results in major subgroups Primary endpoint Subgroup Pinteraction n Favors ranolazine Favors placebo 0.12 Gender Men Women 4269 2291 0.80 Age <75 years ≥75 years 5406 1154 Diabetes No DM DM 4340 2220 0.39 TIMI Risk 0-3 4-7 3601 2959 0.16 Index event UA NSTEMI 3067 3342 0.85 0.23 STD ≥1 mm No Yes 4255 2304 Overall 6560 0.6 0.8 1.2 1.4 1.6 HR (95% CI) STD = ST-segment depression Morrow DA et al. JAMA. 2007;297:1775-83.

  23. MERLIN-TIMI 36: Primary arrhythmia endpoints SVT = supraventricular tachycardia Scirica BM et al. Circulation. 2007;116.

  24. MERLIN-TIMI 36: Reduction in VT lasting ≥8 beats 10 8.3% RR 0.65 P < 0.001 8 Placebo 5.3% RR 0.67 P = 0.008 Incidence(%) 6 4 Ranolazine 2 RR 0.63 (0.52-0.76) P < 0.001 0 0 24 48 72 96 120 144 168 Hours from randomization Scirica BM et al. Circulation. 2007;116.

  25. MERLIN-TIMI 36: Incidence of VT ≥8 beats in high-risk subgroups Ranolazine (%) Placebo (%) P EF ≥40% 5.3 7.3 0.011 EF <40% 8.8 16.6 0.005 QTc ≤450 msec 7.8 <0.001 5.2 QTc >450 msec 10.5 0.002 5.6 TRS 0-4 8.2 <0.001 5.5 TRS 5-7 8.9 0.001 4.4 No prior HF 8.1 <0.001 5.2 Prior HF 9.3 0.013 5.4 No ischemia on cECG 8.3 <0.001 5.0 Ischemia on cECG 8.3 0.12 6.3 1 10 0.1 RR (95% CI) TRS = TIMI risk scorecECG = continuous ECG Scirica BM et al. Circulation. 2007;116.

  26. MERLIN-TIMI 36: Ventricular tachycardia events Scirica BM et al. Circulation. 2007;116.

  27. MERLIN-TIMI 36: Major safety outcomes *VT ≥3 beats, SVT ≥120 bpm, new AF, bradycardia <45 bpm, CHB, or pulse >2.5 sec Morrow DA et al. JAMA. 2007;297:1775-83.

  28. MERLIN-TIMI 36: Sudden cardiac death by subgroup Scirica BM et al. Circulation. 2007;116.

  29. MERLIN-TIMI 36: Summary and implications • In patients with ACS, ranolazine added to standard therapy was associated with • No difference in: • Composite efficacy endpoint of CV death, MI, recurrent ischemia • Safety endpoints of all-cause death, all-cause death or CV hospitalization, symptomatic documented arrhythmia • Significant reduction in arrhythmias detected by Holter monitoring during first 7 days Findings do not support use of ranolazine in ACS but add to previous safety data and provide additional support for ranolazine as antianginal therapy in stable CAD Morrow DA et al. JAMA. 2007;297:1775-83.

  30. Stable CAD: Multiple treatment options Lifestyle intervention Medicaltherapy Reduce symptomsTreat underlying disease CABG PCI

  31. ACIP: Study design Angiographic CAD (≥50% stenosis in≥1 major vessel or branch) suitable for revascularization + ischemia during exercise or pharmacologic stress testing and ≥1 asymptomatic episode during 48-hr AECG Angina-guided strategy(n = 183) Ischemia-guided strategy(n = 183) Revascularization strategy(n = 192) Primary outcome: Absence of ischemia at 12 weeksSecondary outcomes: Death, MI, recurrent hospitalization for cardiac disease, nonprotocol revascularization at 1 and 2 years Pepine CJ et al. J Am Coll Cardiol. 1994:24:1-10.Davies RF et al. Circulation. 1997;95:2037-43. Asymptomatic Cardiac Ischemia Pilot

  32. ACIP: Baseline characteristics Davies RF et al. Circulation. 1997;95:2037-43.

  33. ACIP: Two-year cumulative all-cause mortality rates for the treatment strategies 8 6.6% Angina guided 6 P = 0.34 4.4% Ischemia guided P < 0.005 Percent 4 P < 0.05 2 1.1% Revascularization 0 0 4 8 12 15 20 24 Follow-up (months) Davies RF et al. Circulation. 1997;95:2037-43.

  34. SWISSI II: Study design Recent first MI with asymptomatic myocardial ischemia on exercise testing and 1- or 2-vessel coronary disease suitable for PCI Randomized, unblinded PCI (n = 96) Anti-ischemic therapy*(n = 105) Primary outcomes: Cardiac death, nonfatal MI, symptom-driven revascularization Follow-up: 10.2 years (mean) *Nitrates, β-blockers, CCBs All patients also received aspirin and statin Swiss Interventional Study on Silent Ischemia Type II Erne P et al. JAMA. 2007;297:1985-91.

  35. SWISSI II: Baseline characteristics Erne P et al. JAMA. 2007;297:1985-91.

  36. SWISSI II: Treatment effect on primary outcome Cardiac death, nonfatal MI, symptom-driven revascularization 1.00 PCI 0.75 Event-free survival 0.50 Drug therapy 0.25 P < 0.001* 0 0 5 10 15 Time from randomization (years) No. at risk PCI 96 7 7 54 Anti-ischemic drug therapy 105 6 4 37 *Log-rank Erne P et al. JAMA. 2007;297:1985-91.

  37. ACIP, SWISSI II: Summary and implications • ACIP: In patients with documented CAD + symptomatic and asymptomatic ischemia, PCI compared with anti-ischemic or antianginal therapy reduced 2-year risk of major CV events • SWISSI II extended these finding to post-MI patients with asymptomatic ischemia and a longer 10-year follow-up • Data reported after ACIP and SWISSI II began suggest that risk factor management in these trials was not optimal Davies RF et al. Circulation. 1997;95:2037-43. Erne P et al. JAMA. 2007;297:1985-91.

  38. COURAGE: Defining optimal care Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation Intensive lifestyle intervention Intensive medicaltherapy Reduce symptomsTreat underlying disease Revascularization?

  39. What is the definitive role of PCI in chronic angina and stable CAD? • PCI improves angina and short-term exercise capacity • However, compared to optimal medical therapy, does PCI • Prolong survival? • Reduce risk of subsequent MI? • Reduce hospitalization for unstable angina? • Decrease need for subsequent CABG? • Improve quality of life? Courtesy of WE Boden, MD.

  40. Patient expectations about elective PCI for stable CAD N = 52 consecutive patients scheduled for first elective PCI; semi-structured questionnaire completed prospectively Holmboe ES et al. J Gen Intern Med. 2000;15:632-7.

  41. COURAGE: Study design AHA/ACC Class I/II indications for PCI, suitable coronary artery anatomy + ≥70% stenosis in ≥1 proximal epicardial vessel + objective evidence of ischemia (or ≥80% stenosis + CCS class III angina without provocation testing) Optimal medical therapy* + PCI (n = 1149) Optimal medical therapy*(n = 1138) Randomized Primary outcomes: All-cause mortality, nonfatal MI Secondary outcomes: Death, MI, stroke; ACS hospitalization Follow-up: Median 4.6 years *Intensive pharmacologic therapy + lifestyle interventionCCS = Canadian Cardiovascular Society Boden WE et al. Am Heart J. 2006;151:1173-9. Boden WE et al. N Engl J Med. 2007;356:1503-16.

  42. Smoking cessation Exercise program ≥30 min moderately intensive exercise 5x/week Nutrition counseling Total dietary fat <30% of calories Saturated fat <7% of calories Dietary cholesterol <200 mg/day Weight control BMI <25 kg/m2 (if baseline BMI 25.0-27.5) 10% relative weight loss (if baseline BMI >27.5) LDL-C (mg/dL) 60-85 HDL-C (mg/dL) ≥40 Triglycerides (mg/dL) <150 BP (mm Hg) <130/85 <130/80 if diabetes or renal disease present A1C (%) <7.0 COURAGE: Lifestyle intervention and risk factor goals Boden WE et al. Am Heart J. 2006;151:1173-9.

  43. Antiplatelet Aspirin Clopidogrel in accordance with established practice standards Dyslipidemia Simvastatin ± ezetimibe, ER niacin, or fibrates ACEI, ARB, or diuretic Lisinopril or losartan -blocker ER metoprolol Calcium channel blocker Amlodipine Nitrate Isosorbide 5-mononitrate COURAGE: Pharmacologic therapy Boden WE et al. Am Heart J. 2006;151:1173-9. Boden WE et al. N Engl J Med. 2007;356:1503-16.

  44. COURAGE: Baseline angiographic data *Patients who underwent previous CABG†P = 0.01 Boden WE et al. N Engl J Med. 2007;356:1503-16.

  45. COURAGE: Baseline angina Boden WE et al. N Engl J Med. 2007;356:1503-16.

  46. COURAGE: Inducible ischemia at baseline Boden WE et al. N Engl J Med. 2007;356:1503-16.

  47. COURAGE: Treatment effect on primary outcome All-cause death, MI 1.0 0.9 0.8 Survival free of primary outcome HR 1.05 (0.87-1.27) P = 0.62* 0.7 0.6 0.5 0 0 1 2 3 4 5 6 7 Years Medical therapy PCI + medical therapy No. at risk Medical therapy 1138 1017 959 834 638 408 192 30 PCI 1149 1013 952 833 637 417 200 35 *Unadjusted, log-rank Boden WE et al. N Engl J Med. 2007;356:1503-16.

  48. COURAGE: Treatment effect on angina NS P = 0.02 P < 0.001 Angina-free(%) NS Years Boden WE et al. N Engl J Med. 2007;356:1503-16.

  49. COURAGE: Treatment effect in CV and diabetes subgroups Baseline characteristics PCI better Medical therapy better Myocardial infarction Yes No Extent of CAD Multivessel disease Single-vessel disease Diabetes Yes No Angina CCS 0-I CCS II-III Ejection fraction ≤50% >50% Previous CABG No Yes 0.25 0.50 1.00 1.50 1.75 2.00 Hazard ratio (95% CI) Boden WE et al. N Engl J Med. 2007;356:1503-16.

  50. COURAGE:Change in quality-of-life scores After 1 year, both strategies associated with comparable improvement 90 85 80 75 SAQ QOL score 70 65 60 55 50 Baseline 6 24 48 Time (months) PCI + medical therapy Medical therapy WS Weintraub, MD. Presented at ACC. 2007.

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