Angina Pectoris What to do when Standard Therapy Fails

1. Angina Pectoris � What to do when Standard Therapy Fails John C. Cedarholm, MD FACC Interventional Cardiologist Disclosures - None

2. Stable Coronary Artery Disease 6.4 million Americans with Stable CAD 400,000 new cases each year Previous MI Previous Acute Coronary Syndrome Stable Angina Pectoris CAD with Silent Ischemia

3. Angina Severity and Mortality

4. Stable CAD: Multiple treatment options

5. 55 yr old female with stable angina

6. Revascularization for Stable CAD 1 year after PCI or CABG 25 to 60% of patients still have ongoing angina Many patients are deemed �inoperable� Anatomy not suitable for PCI or CABG Co-morbidities make procedure too high risk

7. 82 year old with stable angina, but anatomy not ideally amenable to PCI

8. 70 yr old with severe refractory angina

9. 62 year old with CABG 5 years ago and severe refractory angina

10. Persistent Ischemia (Angina) Despite Optimal Revascularization

11. Stable CAD: Multiple treatment options

12. Chronic CAD � Conventional Medical therapy Decrease Myocardial Oxygen demand Decrease in HR (Beta blockers and some Calcium Channel Blockers) Decrease in Myocardial Contractility (BB and some CCBs) Increase Oxygen supply Long Acting Nitrates Calcium Channel Blockers

13. Chronic ischemic heart disease: Treatment gaps Many patients have relative intolerances to maximum doses of traditional antianginal agents (?-blockers, CCBs, and nitrates) Nitrates, beta-blockers, and calcium channel blockers (CCBs), the 3 major classes of antianginal/anti-ischemic agents, are the mainstay of angina treatment. However, many patients, particularly the elderly, cannot tolerate full doses of beta-blockers, calcium antagonists, or nitrates. Additionally, beta-blockers and many CCBs have similar (and, hence, additive) depressive effects on BP, heart rate, and atrioventricular conduction, limiting their use in combination to less-than-optimal doses. Nitrates, beta-blockers, and calcium channel blockers (CCBs), the 3 major classes of antianginal/anti-ischemic agents, are the mainstay of angina treatment. However, many patients, particularly the elderly, cannot tolerate full doses of beta-blockers, calcium antagonists, or nitrates. Additionally, beta-blockers and many CCBs have similar (and, hence, additive) depressive effects on BP, heart rate, and atrioventricular conduction, limiting their use in combination to less-than-optimal doses.

14. Understanding Angina at the Cellular Level Ischemia is associated with disruptions in cellular sodium and calcium homeostasis. An enhanced late sodium current is likely to contribute to the sodium overload observed in ischemia. Late phase sodium channels have been shown to remain open longer in ischemic conditions. Sodium overload may result from decreased efflux and increased influx during ischemia, with greater intracellular accumulation of sodium as the duration of ischemia increases. This is followed by an increase in intracellular Calcium through the Na/Ca exchanger on the myocyte wall. Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol. 1996;497 ( Pt 2):337-347. Murphy E, Perlman M, London RE, Steenbergen C. Amiloride delays the ischemia-induced rise in cytosolic free calcium. Circ Res. 1991;68:1250-1258. Jansen MA, van Emous JG, Nederhoff MG, van Echteld CJ. Assessment of myocardial viability by intracellular 23Na magnetic resonance imaging. Circulation. 2004;110:3457-3464. Ischemia is associated with disruptions in cellular sodium and calcium homeostasis. An enhanced late sodium current is likely to contribute to the sodium overload observed in ischemia. Late phase sodium channels have been shown to remain open longer in ischemic conditions. Sodium overload may result from decreased efflux and increased influx during ischemia, with greater intracellular accumulation of sodium as the duration of ischemia increases. This is followed by an increase in intracellular Calcium through the Na/Ca exchanger on the myocyte wall. Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol. 1996;497 ( Pt 2):337-347. Murphy E, Perlman M, London RE, Steenbergen C. Amiloride delays the ischemia-induced rise in cytosolic free calcium. Circ Res. 1991;68:1250-1258. Jansen MA, van Emous JG, Nederhoff MG, van Echteld CJ. Assessment of myocardial viability by intracellular 23Na magnetic resonance imaging. Circulation. 2004;110:3457-3464.

16. MARISA - Efficacy

17. RAN080 - Efficacy Reference: ISE Table 32, pg. 103; pg. 109Reference: ISE Table 32, pg. 103; pg. 109

18. CARISA: Ranolazine Increases Exercise Time, Time to Angina Onset, and Time to 1 mm ST Depression

19. ERICA

20. ERICA

21. Ranolazine � hemodynamic affects No affect of Blood Pressure or Heart Rate Can be added to Conventional Medical therapy, especially when BP and HR do not allow further increase in dose of BetaBlockers, Ca Channel blockers, and Long Acting Nitrates

22. ROLE: Long-term safety and tolerability in stable CAD patients Most common adverse events: Dizziness � 11.8% Constipation � 10.9% 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 The ROLE trial involved >80% of the patients who completed the MARISA or CARISA trials and voluntarily agreed to participate in an open-label extension program. The average exposure to the drug was 2.82 years. Of the 746 patients participating in the study, 571 (76.7%) completed 2 years of open-label therapy; only 9.7% of the 23.3% who did not complete 2 years of therapy stopped the study drug due to adverse effects. Aside from angina, the most common adverse effects were dizziness (11.8%) and constipation (10.9%). Adverse events rates were similar in patients who received ranolazine for the first time (n = 197 formerly in the placebo group), and 549 patients who had previously taken the drug. Electrophysiological complications were not a major determinant of study drug discontinuation. The ROLE trial involved >80% of the patients who completed the MARISA or CARISA trials and voluntarily agreed to participate in an open-label extension program. The average exposure to the drug was 2.82 years. Of the 746 patients participating in the study, 571 (76.7%) completed 2 years of open-label therapy; only 9.7% of the 23.3% who did not complete 2 years of therapy stopped the study drug due to adverse effects. Aside from angina, the most common adverse effects were dizziness (11.8%) and constipation (10.9%). Adverse events rates were similar in patients who received ranolazine for the first time (n = 197 formerly in the placebo group), and 549 patients who had previously taken the drug. Electrophysiological complications were not a major determinant of study drug discontinuation.

23. Chronic CAD � Medical Therapy Beta-Blocker, Ca Channel Blockers, LAN, and Ranolozine have not been shown to improve survival Beta-Blocker, Ca Channel Blockers, LAN, and Ranolozine have only been shown to reduce angina Only aggressive Risk factor treatment has been shown to improve survival

24. Stable CAD: Multiple treatment options

25. EECP = Enhanced External CounterPulsation

27. EECP � Sequential inflation of cuffs Retrograde aortic pressure wave Increased Coronary perfusion pressure Increased Venous Return Increased Preload Increased Cardiac Output

28. EECP -Simultaneous deflation of cuffs in late Diastole Lowers Systemic Vascular Resistance Reduced Preload Decreased Cardiac workload Decreased Oxygen Consumption

29. EECP 35 total treatments 5 days per week x 7 weeks 1 hour per day

31. MUST-EECP trial Only randomized, �blinded�, controlled trial 139 patients randomized to EECP or �sham� EECP CCS Class I, II, and III angina Evidence of CAD Positive ETT Arora RR, et al. JACC 1999;33(7):1833-1840

35. 2 Year Outcomes after EECP for Stable Angina

37. EECP - Indications Disabling stable angina (CCS Class III or IV) CAD not amenable to revascularization Anatomy not amenable to procedures High risk co-morbidities that create excessive risk May be beneficial in treatment of refractory CHF too, but generally this is not an approved indication for Medicare / Private Insurance

38. EECP � Contraindications and Precautions Arrhythmias that interfere with machine triggering Bleeding diathesis Active thrombophlebitis Severe lower extremity vaso-occlusive disease Presence of significant AAA Pregnancy

39. EECP Appears to reduce severity of Angina Has not been show to improve survival or reduce myocardial infarctions

40. Transmyocardial Laser Revascularization (TMLR) High power CO2 YAG and excimer laser conduits in myocardial to create new channels for blood flow Possible explanations for effect Myocardial angiogenesis Myocardial denervation Myocardial fibrosis with secondary favorable remodeling

41. TMLR � Direct Trial Only major blinded study 298 pts with low dose, high dose, or no laser channels No benefit to TMLR vs Med therapy to Patient survival Angina class Quality of life assessment Exercise duration Nuclear perfusion imaging Leon MB, et al. JACC 2005; 46:1812

42. TMLR High Surgical Risk (Mortality 5%) Mainly used as adjunct therapy during CABG to treat myocardial that cannot be bypassed

43. Chelation Therapy IV EDTA infusions 30 treatments over about 3 months Cost � about $3,000 Aggressive Marketing 500 to 1000 physicians offering this treatment

44. Chelation Therapy - claimed pathophysiologic affects Liberation of Calcium in plaque Lower LDL, VLDL, and Iron stores Inhibit platelet aggregation Relax vasomotor tone Scavenge �free radicals�

45. Chelation Therapy �Summary of trials Many case reports of benefit Only 2 small double blind placebo controlled trials of 9 and 16 patients each Both control and treatment groups showed similar subjective and physical performance improvements PLACEBO effect only ACC/AHA � Class III indication, with level C evidence

46. Stable CAD: Multiple treatment options

47. SAFE-LIFE: Evaluation of intensive lifestyle intervention Michalsen et al randomized 101 patients with established CAD to a 1-year lifestyle intervention program (n = 48) or to a group that received printed lifestyle advice only (n = 53). The lifestyle intervention program began with a 3-day nonresidential retreat, followed by weekly 3-hour meetings for 10 weeks, and finally 2-hour meetings every other week for 9 months. Participants in the lifestyle intervention program received advice on the Mediterranean diet in one-on-one sessions, group discussions, and cooking classes. Regular exercise and increased daily physical activity were strongly recommended. Subjects in this group also practiced various relaxation techniques according to personal choice, including mediation, guided imagery, and yoga. They also practiced techniques to reduce cognitive and affective components of stress. Michalsen et al randomized 101 patients with established CAD to a 1-year lifestyle intervention program (n = 48) or to a group that received printed lifestyle advice only (n = 53). The lifestyle intervention program began with a 3-day nonresidential retreat, followed by weekly 3-hour meetings for 10 weeks, and finally 2-hour meetings every other week for 9 months. Participants in the lifestyle intervention program received advice on the Mediterranean diet in one-on-one sessions, group discussions, and cooking classes. Regular exercise and increased daily physical activity were strongly recommended. Subjects in this group also practiced various relaxation techniques according to personal choice, including mediation, guided imagery, and yoga. They also practiced techniques to reduce cognitive and affective components of stress.

48. SAFE-LIFE: Reduction in angina at 1 year with intensive lifestyle intervention The severity of chest pain (as assessed by the 6-point Likert scale) decreased by 31% in the lifestyle intervention group and by 13% in the advice-only group (P = 0.015). Frequency of angina attacks decreased by 54% in the lifestyle intervention group and increased by 11% in the advice-only group (P = 0.01). This study provides further evidence for inclusion of comprehensive lifestyle modification in a CV prevention program. The severity of chest pain (as assessed by the 6-point Likert scale) decreased by 31% in the lifestyle intervention group and by 13% in the advice-only group (P = 0.015). Frequency of angina attacks decreased by 54% in the lifestyle intervention group and increased by 11% in the advice-only group (P = 0.01). This study provides further evidence for inclusion of comprehensive lifestyle modification in a CV prevention program.

49. Stable CAD: Multiple treatment options

50. Invasive Treatment of CAD Acute Coronary Syndrome and Acute MI Aggressive treatment unquestionably shown to save lives and reduce future MIs!! Stable Angina Pectoris What is the role of Coronary Revascularization?

51. Revasculariz ation for Stable CADSurvival Benefit? CABG better than Medical Therapy for LM disease (VA Coop Study) CABG better than Medical Therapy for 3 vessel CAD than involves Prox LAD (European Coronary Surgery Study) CABG better than Medical Therapy for 3 vessel CAD with low EF (CASS)

52. What is the definitive role of PCI in chronic angina and stable CAD? PCI improves angina and 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? While PCI relieves angina and improves exercise capacity in the short term, its long-term benefits are less certain. Its impact on disease progression and thromboembolic events is not known. In addition, PCI does not abolish the need for a second coronary revascularization procedure. While PCI relieves angina and improves exercise capacity in the short term, its long-term benefits are less certain. Its impact on disease progression and thromboembolic events is not known. In addition, PCI does not abolish the need for a second coronary revascularization procedure.

53. ACIP: Two-year cumulative all-cause mortality rates for the treatment strategies At 2 years, all-cause mortality rates were 6.6%, 4.4%, and 1.1% in the angina-guided, ischemia-guided, and revascularization strategies, respectively. The revascularization strategy was significantly different from the other two strategies. There was no significant difference in all-cause mortality between the angina-guided and ischemia-guided strategies. At 2 years, all-cause mortality rates were 6.6%, 4.4%, and 1.1% in the angina-guided, ischemia-guided, and revascularization strategies, respectively. The revascularization strategy was significantly different from the other two strategies. There was no significant difference in all-cause mortality between the angina-guided and ischemia-guided strategies.

54. SWISSI II: Treatment effect on primary outcome During the 10.2-year mean follow-up, the primary endpoint occurred in 28% and 64% of the PCI and anti-ischemic therapy groups, respectively (adjusted HR 0.33, 95% CI 0.20-0.55, P < 0.001). During the 10.2-year mean follow-up, the primary endpoint occurred in 28% and 64% of the PCI and anti-ischemic therapy groups, respectively (adjusted HR 0.33, 95% CI 0.20-0.55, P < 0.001).

55. COURAGE: Treatment effect on primary outcome As an initial management strategy in patients with stable CAD, PCI added to optimal medical therapy did not reduce the primary composite endpoint of death and nonfatal MI, or reduce major cardiovascular events, as compared with optimal therapy alone during follow-up. The primary outcome (a composite of death from any cause and nonfatal MI) occurred in 211 patients in the PCI group and 202 patients in the medical therapy group. The estimated 4.6-year cumulative primary-event rates were 19.0% in the PCI group and 18.5% in the medical-therapy group (unadjusted HR for the PCI group 1.05, 95% CI 0.87-1.27, P = 0.62). As an initial management strategy in patients with stable CAD, PCI added to optimal medical therapy did not reduce the primary composite endpoint of death and nonfatal MI, or reduce major cardiovascular events, as compared with optimal therapy alone during follow-up. The primary outcome (a composite of death from any cause and nonfatal MI) occurred in 211 patients in the PCI group and 202 patients in the medical therapy group. The estimated 4.6-year cumulative primary-event rates were 19.0% in the PCI group and 18.5% in the medical-therapy group (unadjusted HR for the PCI group 1.05, 95% CI 0.87-1.27, P = 0.62).

56. COURAGE: Treatment effect on angina Both treatment groups had a substantial reduction in the prevalence of angina during follow-up. The only significant difference between the 2 treatment strategies was a reduced prevalence of angina in the PCI group at 1 and 3 years; however, by 5 years there was no significant difference between groups in freedom from angina. Most of the increase in freedom from angina in the medical-therapy group took place at 1 year, with a further improvement at 5 years. Both treatment groups had a substantial reduction in the prevalence of angina during follow-up. The only significant difference between the 2 treatment strategies was a reduced prevalence of angina in the PCI group at 1 and 3 years; however, by 5 years there was no significant difference between groups in freedom from angina. Most of the increase in freedom from angina in the medical-therapy group took place at 1 year, with a further improvement at 5 years.

57. COURAGE: Change in quality-of-life scores Assessments of quality of life were based on questionnaires, with data collected at 1, 3, 6, and 12 months, then annually thereafter. Results of the SAQ pointed to a slight advantage of PCI over optimal medical therapy out to 3 years of follow-up, with similar results thereafter. Assessments of quality of life were based on questionnaires, with data collected at 1, 3, 6, and 12 months, then annually thereafter. Results of the SAQ pointed to a slight advantage of PCI over optimal medical therapy out to 3 years of follow-up, with similar results thereafter.

58. 60 year old banker with 4 months of stable angina

59. Revascularization with PCI and CABG Acute Coronary Syndrome and Acute MI Clearly shown to improve survival Chronic Stable Angina Goal may be to just reduce symptoms and improve quality of life �INOPERABLE� or �Not a Candidate� for PCI � these are relative terms

60. 64 year old with refractory anginaPre and post Stenting

61. 60 year old plumber with stable angina

62. Stable CAD: Multiple treatment options