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Myocardial Ischemia Update

Myocardial Ischemia Update. Chronic Ischemic Heart Disease: Overview. Highly prevalent 6.5-16.5 million in the US Multifactorial etiology CAD, hypertension, hypertrophic cardiomyopathy, valvular heart disease High socioeconomic burden Depression Quality of life High costs of care.

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Myocardial Ischemia Update

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  1. MyocardialIschemia Update

  2. Chronic Ischemic Heart Disease: Overview • Highly prevalent • 6.5-16.5 million in the US • Multifactorial etiology • CAD, hypertension, hypertrophic cardiomyopathy, valvular heart disease • High socioeconomic burden • Depression • Quality of life • High costs of care Gibbons RJ et al. www.acc.org.

  3. Repeat revascularization is common post-PCI/CABG N = 18,240 who underwent elective PCI or CABG 50 46 40 30 30 Patients(%) 20 10 0 Recurrentangina 2nd revascularization Kempf J et al. Presented at ESC. 2007.

  4. Angina increases cost of care US managed care enrollees, n = 140,001 with asymptomatic CAD, n = 23,535 with angina Dx* Average yearly cost/patient $11,530 (asymptomatic CAD) vs $22,004 (angina) ED visits ED visits Hospitalizations Prior to diagnosis Following diagnosis Kempf J et al. Presented at Scientific Forum on Quality of Care and Outcomes Res in CV Disease. 2006. *And Rx nitrates and/or β-blockers and/or CCBs

  5. WISE: Landmark study in women Prospective cohort study conducted at 4 US sites Goals: • Improve diagnostic testing for ischemic heart disease in women • Study pathophysiologic mechanisms for ischemia in the absence of epicardial coronary artery stenoses • Evaluate the influence of menopausal status and reproductive hormone levels on diagnostic testing results Women’s Ischemia Syndrome Evaluation Bairey Merz CN et al. J Am Coll Cardiol. 1999;33:1453-61.

  6. WISE: Persistent chest pain in women predicts future CV events n = 673 WISE participants with chest pain at baseline 1 0.9 Without CAD HR 1.89 (1.06–3.39)P = 0.03 Event-freesurvival (%) 0.8 0.7 With CAD HR 1.17 (0.76–1.80)P = 0.49 0.6 0 1 2 3 4 5 6 Years from PChP diagnosis (at one year) Neither PChPNo CAD No PChPCAD Both PChP = persistent chest pain Johnson BD et al. Eur Heart J. 2006;27:1408-15.

  7. WISE: Persistent chest pain associated with diminished QOL *Adjusted P ≤ 0.04 †Range: 1 - 10 (best); ‡score = trait Johnson BD et al. Eur Heart J. 2006;27:1408-15. Bairey Merz CN et al. J Am Coll Cardiol. 1999;33:1453-61.

  8. WISE: CAD imposes an economic burden N = 883 women with angiographic CAD 80 70 * * * 60 * 50 Cumulative observed direct costs ($, thousands) 40 * 30 20 10 0 1 2 3 4 5 Follow-up (years) Nonobstructive CAD 1 vessel CAD 2 vessel CAD 3 vessel CAD *P < 0.0001 nonobstructive vs 1-3 vessel CAD Shaw LJ et al. Circulation. 2006;114:894-904.

  9. Contemporary clinical practice of ischemic heart disease Opportunity for early detection, risk stratification, and medical therapy Healthy population Revas = revascularization Adapted from Timmis AD et al. Heart. 2007;93:786-91.

  10. Examining the Science Underlying Myocardial Ischemia

  11. Severe obstruction (angina, no rupture) vs mild obstruction (no angina, likely to rupture) • Vulnerable plaque • Minor obstruction • Eccentric plaque • Lipid pool • Thin cap • Severe fibrotic plaque • Severe obstruction • No lipid • Fibrosis, Ca2+ • Plaque rupture • Acute MI • Unstable angina • Sudden death • Exertional angina • (+) ETT Revascularization Anti-anginal Rx Pharmacologic stabilization Early identification of high-risk? Courtesy of PH Stone, MD.

  12. Major cardiac events occur in non-target areas following successful PCI 20 15 Hazardrate (%) 10 Non-target lesion event 5 Target lesion event 0 1 2 3 Year 4 5 Substantial number of cardiac events could be prevented if non-obstructive, high-risk lesions were identified Cutlip DE et al. Circulation. 2004;110:1226-30.

  13. Local determinants of the natural history of individual coronary lesions Opportunities for identification and intervention Local factors Shear stress Quiescent, stable plaque No symptoms • Proliferation • Inflammation • Remodeling Quiescence Inflammation Thin cap Fibroatheroma MI, sudden death Proliferation Calcification Fibrotic/ scarred plaque Angina Courtesy of PH Stone, MD and R Gerrity, PhD.

  14. Proposed classification scheme for atherosclerotic plaque Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.

  15. The spectrum of CAD Inner curvature:Low ESS region(atherosclerosis-prone) Physiologiccoronary artery Low ESS Early fibroatheroma 60% 20% 20% Fibroproliferation Microruptures Lower ESSVulnerabilityIntense inflammation Physiologic ESS Limited inflammation High ESS Quiescent plaque Stenotic plaque Thin cap fibroatheroma Erosion Rupture Asymptomatic Stable angina ACS ESS = endothelial shear stress Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.

  16. Ventricular arrhythmogenesis in ischemic myocardium • Risk factors • Age • Heredity • Gender • Smoking • Lipids • Hypertension • Diabetes • Obesity • Clinical or subclinical susceptibility • Structural substrate present High risk of transient acute ischemia reperfusion • Triggers • VPC • VT • Reentry • Substrate • Vulnerable ischemic zone • Intracoronary thrombus • Autonomic influence • Hemodynamic compromise Ventricular fibrillation + VPC = ventricular premature contraction VT = ventricular tachycardia Adapted from Luqman N et al. Int J Cardiol. 2007;119:283-90.

  17. Causes and consequences of myocardial ischemia: New understanding Development of ischemia Consequences of ischemia Ischemia O2 demand Na+ and Ca2+ overload Heart rate Blood pressure Preload Contractility Electrical instability Myocardial dysfunction O2 supply Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.

  18. Overview of the sodium channel Na+ Na+ Na+ Resting closed Inactivated Activated out Na+ Na+ in [Na+] Na+ [Na+] = 140 mM Na+ Na+ Na+ ~10mM Ca2+ Ca2+ in Ca2+ Ca2+ Na+ Ca2+ Ca2+ out Na+/Ca2+ Exchanger Na+ Ca2+ Courtesy of L Belardinelli, MD.

  19. During the plateau phase of the action potential, a small proportion of sodium channels either do not close, or close and then reopen These late channel openings permit a sustained Na+ current to enter myocytes during systole Origin of late INa 0 Sodiumcurrent Late Peak Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.

  20. Myocardial ischemia causes enhanced late INa 0 Sodiumcurrent Late Peak 0 Ischemia Sodiumcurrent Late Peak Enhanced late INa appears to be a major contributor to increased intracellular Na+ during ischemia Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.

  21. Role of altered ion currents in adverse consequences of myocardial ischemia Disease(s) and pathological states linked to imbalance of O2 supply/demand Late INa Na+ entry ([Na+]i) NCX Cytosolic Ca2+ • Electrical instability • Afterpotentials • Beat-to-beat APD • Arrhythmias (VT) • Mechanical dysfunction • Abnormal contraction and relaxation • Diastolic tension [Na+]i = intracellular [Na+]NCX = Na+/Ca2+ exchanger APD = action potential duration Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.

  22. Sustained contraction of ischemic tissue during diastole: Increases MVO2 Compresses intramural small vessels Reduces myocardial blood flow Diastolic relaxation failure adversely affects myocardial O2 supply and demand Exacerbates ischemia MVO2 = myocardial oxygen consumption Courtesy of PH Stone, MD.

  23. Late INa inhibition blunts Ca2+ accumulation 0.30 12 ATX-II RAN 0.25 Indo fluorescence(F405/F485 ratio) 8 * LV work(L/min per mm Hg) * 0.20 * 4 * 0.15 ATX-II RAN 0.10 0 0 10 20 30 40 50 0 10 20 30 40 50 Time of perfusion (min) ATX-II alone (n = 11) ATX-II + ranolazine 4 μM (n = 9) or 9 μM (n = 9) *P < 0.05 vs ATX-II aloneATX-II = sea anemone toxin (selectively late INa) Fraser H et al. J Mol Cell Cardiol. 2006;41:1031-8.

  24. Ranolazine blunts sotalol-induced action potential prolongation in dogs d-Sotalol + Ranolazine 5 uM + Ranolazine 10 uM Transmembrane action potentials (superimposed) Control 50 mV 1 sec Antzelevich C et al. Circulation 2004;110:904-10.

  25. 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.

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

  27. 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.

  28. 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.

  29. 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.

  30. 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.

  31. 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.

  32. 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.

  33. 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.

  34. 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.

  35. 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.

  36. 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.

  37. 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

  38. 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.

  39. 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.

  40. 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.

  41. 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.

  42. 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.

  43. 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.

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

  45. 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.

  46. 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.

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

  48. 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.

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

  50. 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.

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