Secondary Prevention Goal: Prevention of recurrent events Life style changes – exercise, smoking, weight Hypertension Diabetes Aspirin ACE/ARB Influenza vaccine LIPID LOWERING - CONTROVERSIAL Angina 2012 1

Lipid Lowering in the Elderly Ref: Electronic Publication. Braunwald’s Heart Disease Angina 2012 2

Limitations of Lipid Control Benefits in most trials did not start for 3-5 years TNT – excluded patients above the age of 75 High dose statins may be associated with more myopathy: CKD, old age, Frailty, Multisystem disease, Drug interactions ? Use the lowest effective dose. TREATING TO NEW TARGETS N ENGL J MED 2005; 352: 1425 Angina 2012 3

Pharmacologic Therapy NITROGLYCERIN BETA BLOCKER CALCIUM CHANNEL IMPROVE SUPPLY ++ - + LOWER DEMAND ++++ ACUTE BENEFIT +++ CHRONIC BENEFIT +/- +++++ Angina 2012 4

Nitrates Mechanism: NO contributor, vasodilate Physiology: Reduce preload, afterload, Dilate collaterals, counteract spasm Action: Rapid onset Administration: iv, sl, buccal, topical, (PO) Limitations Tachyphylaxis rapidly develops Hypotension, tachycardia MAINSTAY FOR ALL PATIENTS WITH ANGINA Angina 2012 5

Pitfalls of nitrates in elderly Postural hypotension Rapid absorption with Isosorbide dinitrate Interaction with alpha blockers (BPH in men) Bradycardia Volume depletion Approaches Isosorbide mononitrate Topical nitrates Angina 2012 6

Beta Blockers Mechanism: Competitive inhibition at beta 1 and beta 2 receptors Physiology: Reduce demand through slower heart rate, lower BP, and reduced contractility Action: Variable onset, usually slow Angina 2012 7

BETA Blockers Pitfalls in Elderly Titrate to resting heart rate – sick sinus syndrome ? Role of pacemaker for therapy Inadequate doses to achieve reduced contractility Short actions of drugs – metoprolol, atenolol – multiple dosing. CNS penetration – lipophilic Favor nadolol, atenolol Only anti-anginal with evidence for prolonging life in patients post MI Angina 2012 8

Calcium Channel Blockers Mechanism: Vascular Smooth muscle relaxation and reduced contractility Physiology: Demand reduced by reducing BP, contractility, and heart rate (for some) Supply improved by blocking spasm Action: Duration longer, rapid onset Angina 2012 9

Calcium Channel Blockers Limitations in elderly Dihydropyridines induce reflex tachycardia Contraindicated in low EF patients post MI Edema formation (venous insufficiency) Sick sinus syndrome – non dihydropyridines, combinations with beta blockers Constipation Postural hypotension Role: “triple therapy” Angina 2012 10

Dose: 500 mg bid increasing to 1000 mg bid Added to existing antianginals Contraindications: • With pre-existing QT prolongation • With hepatic impairment (Child-Pugh Classes A [mild], B [moderate] or C [severe]) • On QT prolonging drugs • On potent and moderately potent CYP3A inhibitors, including diltiazem Angina 2012 11

Ranolazine: Most recenta Anti-anginal Piperazine derivative Anti-ischemic effect without effect on heart rate or blood pressure Inhibits late Ina (slowly inactivating component of sodium current) = reduce intracellular calcium and sodium overload Angina 2012

Effects of Ranolazine With Atenolol, Amlodipine, or Diltiazem on Exercise Tolerance and Angina Frequency in Patients With Severe Chronic Angina Randomized, 3-group parallel, double-blind, placebo-controlled trial of 823 eligible adults. Patients received twice-daily placebo or 750 mg or 1000 mg of ranolazine Treadmill exercise 12 hours (trough) and 4 hours (peak) after dosing was assessed after 2, 6 (trough only), and 12 weeks of treatment. Trough exercise duration increased by 115.6 seconds … vs 91.7 seconds in the placebo group (P = .01). The increases did not depend on changes in blood pressure, heart rate, or background antianginal therapy and persisted throughout 12 weeks. JAMA. 2004;291:309-316 Angina 2012

Ranolazine: MERLIN-TIMI 36 JAMA. 2007;297:1775-1783 6560 patients over 442 sites (17 countries) 2004-2006 ACS, TIMI > 3 Placebo v IV then po ranolazine (1000 mg bid) Endpoint: Occurrence of Death, MI, Recurrent Ischemia Result: No Difference Median follow: 348 days Context Ranolazine is a novel antianginal agent that reduces ischemia in patients with chronic angina but has not been studied in patients with acute coronary syndromes (ACS). Objective To determine the efficacy and safety of ranolazine during long-term treatment of patients with non–ST-elevation ACS. Design, Setting, and Patients A randomized, double-blind, placebo-controlled, multinational clinical trial of 6560 patients within 48 hours of ischemic symptoms who were treated with ranolazine (initiated intravenously and followed by oral ranolazine extended-release 1000 mg twice daily, n=3279) or matching placebo (n=3281), and followed up for a median of 348 days in the Metabolic Efficiency With Ranolazine for Less Ischemia in Non−ST-Elevation Acute Coronary Syndromes (MERLIN)-TIMI 36 trial between October 8, 2004, and February 14, 2007. Main Outcome Measures The primary efficacy end point was a composite of cardiovascular death, myocardial infarction (MI), or recurrent ischemia through the end of study. The major safety end points were death from any cause and symptomatic documented arrhythmia. Results The primary end point occurred in 696 patients (21.8%) in the ranolazine group and 753 patients (23.5%) in the placebo group (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.83-1.02; P=.11). The major secondary end point (cardiovascular death, MI, or severe recurrent ischemia) occurred in 602 patients (18.7%) in the ranolazine group and 625 (19.2%) in the placebo group (HR, 0.96;95%CI, 0.86-1.08; P=.50). Cardiovascular death or MI occurred in 338 patients (10.4%) allocated to ranolazine and 343 patients (10.5%) allocated to placebo (HR, 0.99; 95% CI, 0.85-1.15; P=.87). Recurrent ischemia was reduced in the ranolazine group (430 [13.9%]) compared with the placebo group (494 [16.1%]; HR, 0.87; 95% CI, 0.76-0.99; P=.03). QTc prolongation requiring a reduction in the dose of intravenous drug occurred in 31 patients (0.9%) receiving ranolazine compared with 10 patients (0.3%) receiving placebo. Symptomatic documented arrhythmias did not differ between the ranolazine (99 [3.0%]) and placebo (102 [3.1%]) groups (P=.84). No difference in total mortality was observed with ranolazine compared with placebo (172 vs 175; HR, 0.99;95%CI, 0.80-1.22; P=.91). Conclusions The addition of ranolazine to standard treatment for ACS was not effective in reducing major cardiovascular events. Ranolazine did not adversely affect the risk of all-cause death or symptomatic documented arrhythmia. Our findings provide support for the safety and efficacy of ranolazine as antianginal therapy. Trial Registration clinicaltrials.gov Identifier: NCT00099788 JAMA. 2007;297:1775-1783 www.jama.com Angina 2012 14

Ranolazine: Limitations in Elderly Side effects more common Dizziness Constipation, Nausea, dyspepsia, abdominal pain Asthenia Headache QT prolongation due to drug interactions Angina 2012

Dr. MS: Referred for Angiography ABNORMAL CORONARY CIRCULATION Proximal LAD: 99 % stenosis, site of prior stent. ·Mid LAD: 80 % stenosis. ·D1: 80 % stenosis. ·D2: 99 % stenosis. ·Mid circumflex: 40 % stenosis. ·Mid RCA: 99 % stenosis. ·Distal RCA: 60 % stenosis. RPDA: 90 % stenosis. Angina 2012 16

Non-medical Therapies All therapy requires lifestyle changes and drugs for secondary prevention of ischemic events Revascularization Surgical (1968) Percutaneous (1978) PCI v. Surgery Medical v. Intervention Angina 2012 17

Percutaneous Coronary Interventions Lesion angioplasty POBA Atherectomy and occluded vessels Adjunctive Platelet Therapies Stenting – BMS, DES Bare Metal Drug Eluting Efficacy: Equivalent to surgical intervention in short term relief Angina 2012

Coronary Bypass Graft Surgery Indications Symptomatic – refractory to medical therapy Prognostic Left main stenosis > 50% Three vessel disease +/- impaired LV function Two vessel disease with LAD involvement Risks – Mortality 1-2%, increased by gender, emergency surgery, LV function, reoperation Advances – Off Pump, Limited access, Arterial Conduits Comparisons – anti-anginal effect long term 85% Angina 2012 19

STS Database for CABG Only 1997-2000 J Am Coll Surg 2003;197:347–357 Angina 2012 20

Survival and Comorbidities Table 3. Independent Risk Factors for 4-Year Mortality in the Development Cohort in the Multivariable Analysis Lee, S. J. et al. JAMA 2006;295:801-808 Copyright restrictions may apply.

TIME: One Year results JAMA 2003 289:1117 Switzerland Patients over 75 Chronic stable angina 148 optimized Med 153 invasive Similar outcomes for symptoms, QOL, Death or Nonfatal Infarction Angina 2012 23

COURAGE N Engl J Med 2007;356:1503-16. Chronic Stable Angina Average age 61 85% Male 86% White Angina 2012

Alternative Therapies of Angina Vitamin E Garlic Gingko Biloba Salmon oil Red Algae Chelation Therapy Angina 2012

Dr. MS Decision: PCI of LAD Readmitted emergently with severe pain and palpitations – RCA ischemia and atrial fibrillation Converted to NSR, RCA revascularized Referred for cardiac rehab – completely asymptomatic 2 years later – recurrent angina then ACS – new RCA lesion. Angina 2012 26

Angina pectoris is a classic syndrome of ischemia Conclusions: Angina pectoris is a classic syndrome of ischemia Evaluation depends on a history – 95% specific; In the elderly it often has reduced sensitivity Clinical assessment focuses on stability and high risk cases Therapy always involves secondary prevention, but not all is proven for elderly patients Drug therapy can be effective with caution. Interventional therapies work well. They do NOT always offer survival benefit. Drug therapy should be mastered for those in whom intervention carries risks Angina 2012 27