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1 Off-Label Disclaimer Slides that include contain data that is not within the FDA approved package insert and have not otherwise been approved by the FDA 1

2 ASSESSMENT AND TREATMENT GOALS OF CHRONIC ANGINA Patient Profile: Hector Hector s History Hector had a PCI 1 year ago to relieve his angina Maybe not Hector goes home and has the neighbor continue to mow the grass because of his lack of energy and exertional arm pain Hector s Follow-up Physician: How are you feeling today? Patient: Fine Physician: Are you experiencing any chest pain or shortness of breath? Patient: No Physician: Good. I will see you in 6 months. PCI = percutaneous coronary intervention. 2

3 Prevalence (Millions) Chronic Angina Is Common Prevalence of Angina (Among Americans 20 Years of Age) M Men 5M Women Incidence of Angina (Thousands) New Cases of Stable Angina Per Year (Among Americans 45 Years of Age) ,000 Men 180,000 Women Median angina frequency is ~2 episodes per patient per week ~18 million episodes each week or ~30 episodes each second 500,000 Total Pepine CJ, et al. Am J Cardiol. 1994;74: Roger VL, et al. Circulation. 2012;125:e2-e220. Angina Often Persists Despite Revascularization Angina at baseline vs 1 year post-pci in patients randomized to receive PCI Patients With Angina, % Baseline ARTS COURAGE SYNTAX N = 600 Baseline, N = 1148 N = Year, N = 1031 * PCI was performed with bare metal stents. PCI was performed with bare metal stents except in 31 patients who received drug-eluting stents. PCI was performed with drug-eluting stents. 88 One year post- PCI 34 * Serruys PW, et al. N Engl J Med. 2001;344: Boden WE, et al. N Engl J Med. 2007;356: Cohen DJ, et al. N Engl J Med. 2011;364:

4 Angina Significantly Reduces Quality of Life SF- 36 Domain Score p = Comparison of QOL Domains of the SF Physical Functioning CAD With Angina 51 CAD = coronary artery disease; QOL = quality of life. p = CAD Without Angina p = General Health Social Functioning Mental Health 79 p = Marquis P, et al. Eur Heart J. 1995;16: Angina Is Categorized Into 4 Classes According to the Impact on Physical Activity Canadian Cardiovascular Society (CCS) Classifications CCS Class I CCS Class II CCS Class III CCS Class IV Ordinary physical activity such as walking or climbing stairs does not cause angina Angina occurs with strenuous, rapid, or prolonged exertion at work or recreation Slight limitation of ordinary activity Angina occurs on walking or climbing stairs rapidly, walking uphill, walking or stair-climbing after meals, in cold, in wind, under emotional stress, or only during the first few hours after awakening Angina occurs walking more than 2 blocks on the level and climbing more than 1 flight of ordinary stairs at a normal pace and in normal conditions Marked limitations of ordinary physical activity Angina occurs on walking 1 to 2 blocks on the level and climbing 1 flight of stairs in normal conditions and at a normal pace Inability to carry out any physical activity without discomfort Anginal symptoms may be present at rest Sangareddi V, et al. Coron Artery Dis. 2004;15:

5 ACC/AHA Goal for the Treatment of Chronic Angina Goal of Treatment From ACC/AHA Guidelines The committee agreed that for most patients, 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. This goal should be accomplished with minimal side effects of therapy. This definition of successful therapy must be modified in light of the clinical characteristics and preferences of each patient. Gibbons RJ, et al. Circulation. 2003;107(1): Physicians May Underestimate Their Patients Angina 80% 70% 60% 50% 40% 30% 20% 10% 0% Patient- Reported Outcomes and Physician Perceptions 56% 22% Patients have given up most physical activity due to angina Patients* (n = 500) Physicians (n = 394) 69% 43% Patients avoid activities that might cause angina 27% 53% Patients are able to enjoy life *Chronic angina patients experiencing at least 2 angina attacks per month. Data on file. Gilead Sciences, Inc., Foster City, CA. July 12, Data on file. Gilead Sciences, Inc., Foster City, CA. January 4,

6 Patient Profile: Donna Donna s History Her physician prescribed a beta-blocker to treat her chronic angina 6 months ago Donna s Follow-up Physician: How are you doing? Donna: I m good Physician: Are you having chest pains? Donna: No Physician: Good. Keep taking your medication and I will see you in 6 months. Maybe not Donna goes to Walmart on the way home and drives around for 15 minutes to find the closest parking spot because she gets some chest tightness and shortness of breath when she walks longer distances Chronic Angina Presents Differently Sites of pain Jaw Neck Chest Arm (Left or right) Shoulders Back Anginal chest pain is often described as: Burning sensation Pain Pressure Squeezing Tightness Angina symptoms other than pain may include: Fatigue Indigestion Lightheadedness Nausea Dyspnea Weakness Depre C, et al. In: Hurst's the Heart. 12th ed. 2008: Milner KA, et al. Am J Cardiol. 1999;84: Morrow DA, Gersh BJ. In: Braunwald s Heart Disease. 8th ed. 2008:

7 Angina Symptoms Other Than Chest Pain Are Common, Especially Among Women 60% Angina Symptoms Reported by Patients Referred for Catheterization Male (n = 2249) Female (n = 976) 50% 40% 55% 53% 30% 20% 10% 0% 28% Typical Symptoms 34% Atypical Symptoms p < 0.05 for comparison across sexes. Alexander KP, et al. J Am Coll Cardiol. 1998;32: Symptoms of Chronic Angina Impact Patient Activity Patients with angina may curtail activity to avoid anginal episodes Physical exertion and emotional stress are triggers for angina Many patients consider angina a warning to slow down Sedentary patients may have significant coronary artery disease (CAD), but may not report anginal symptoms because of their lack of activity Med Decis Making. 1996;16: Ann Intern Med. 2001;135:

8 An Increase in METs Can Impact Daily Living Iowa Cardiac Rehabilitation Guide: Exercise. internalmedicine/champs/metchart.html ACC/AHA Recommends Patients With Chronic Angina Remain Physically Active Physical activity of 30 to 60 minutes, 7 days per week (minimum 5 days per week) All patients should be encouraged to obtain 30 to 60 minutes of moderate-intensity aerobic activity, such as brisk walking, on most, preferably all, days of the week, supplemented by an increase in daily activities: Walking breaks at work Gardening Household work Fraker T, et al. Circulation. 2007;116;

9 OUTCOMES AND COSTS ASSOCIATED WITH ANGINA Physical Limitation From Angina Predicts Total Mortality Kaplan-Meier Survival According to Physical Limitation Due to Angina (Seattle Angina Questionnaire [SAQ] Score) (n = 8908) (27% increase in mortality) (61% increase in mortality) 0.74 p < for log-rank test for equality of survivor function 0 24 (250% increase in mortality) Years 3 4 Mozaffarian D, et al. Am Heart J. 2003;146:

10 Reduced Exercise Capacity Predicts Mortality Exercise Capacity and Mortality Among Men Referred for Exercise Testing METs Survivors p < With CV Disease (n = 3679) METs Nonsurvivors p < Without CV Disease (n = 2534) CV = cardiovascular; METs = metabolic equivalents. Myers J, et al. N Engl J Med. 2002;346: Chronic Angina Increases the Cost of CAD Care CAD Without Angina CAD With Angina $22,004 50% Average Annual Cost per Patient, US$ $11,530 Proportion of Patients 1-Year After Diagnosis, % 45% 40% 35% 30% 25% 20% 15% 10% 5% 12% 27% 10% 43% 0 Healthcare Costs 0% Emergency Department Visits Hospitalizations This claims-based analysis consisted of 140,001 managed-care patients with CAD and 25,535 patients with a diagnosis of angina and multiple prescriptions of antianginal medications. Kempf J, et al. Circulation. 2006;113:e810. Abstract P

11 Total Direct Costs of Patients Diagnosed With Chronic Angina Total Direct Costs 2004 Estimates: $1.9 $8.9 Billion (US)* Emergency Department, 12.1% Hospitalization, 16.3% Outpatient, 38.3% Prescription Drugs, 15.1% Home Health, 6.2% Nursing Home, 12.0% *Direct costs for angina $1.9 billion when it is the first-listed diagnosis and $8.9 billion when it is listed in any position. Adapted from Javitz H, et al. Am J Managed Care. 2004;10(11):S367. CHRONIC ANGINA TREATMENT OPTIONS 11

12 Angina Symptoms Occur at the End of the Ischemic Cascade Angina Magnitude of Ischemia Biochemical Alterations Relaxation Diastolic Filling Contraction ECG Δ Stress Duration ECG = electrocardiogram. Adapted from Kern MJ. In: Braunwald s Heart Disease. 7th ed Mismatched Oxygen Supply and Demand Leads to Cycle of Worsening Ischemia Vasospasm Heart rate Atherosclerosis O 2 Supply O 2 Demand Contractility Preload Microvascular Flow Ischemia Diastolic Wall Tension Impaired Diastolic Relaxation Belardinelli L, et. al. Heart. 2006;92(suppl 4):iv6-iv14. Canty JM Jr. In: Heart Disease. 2 vols. 8th ed. 2008:

13 Classes of Antianginal Drugs Therapeutic Class Beta-blockers Calcium channel blockers* Nitrates Other Class Description Decrease myocardial oxygen demand by blocking inotropic and chronotropic effects of catecholamines, and by decreasing blood pressure Vasodilation; decrease myocardial oxygen demand, increase oxygen supply Vasodilation; decrease myocardial oxygen demand, increase oxygen supply Late sodium current inhibition (ranolazine) ATP-sensitive potassium channel (KATP) opener (nicorandil) Sinus node inhibition (ivabradine) *Actions of the individual drugs in this class vary. Not approved for treatment in the United States. ATP = adenosine triphosphate. Dellegrottaglie S, et al. In: Hurst's the Heart. 12th ed Vadnais DS, Wenger NK. Clin Med Ther. 2009;1: Class of Recommendations Class I Class IIa Class IIb Class III Benefit >>> Risk Procedure/Treatment SHOULD be performed/administered Benefit >> Risk Additional studies with focused objectives needed IT IS REASONABLE to perform procedure/administer treatment Benefit Risk Additional studies with broad objectives needed; additional registry data would be helpful Procedure/Treatment MAY BE CONSIDERED Risk Benefit Procedure/Treatment should NOT be performed/ administered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL Fihn SD, et al. J Am Coll Cardiol Dec 18;60(24):e44-e

14 Level of Evidence Level A Level B Level C Multiple populations evaluated Data derived from multiple randomized clinical trials or meta-analyses Limited populations evaluated Data derived from a single randomized trial or nonrandomized studies Very limited populations evaluated Only consensus opinion of experts, case studies, or standard of care Fihn SD, et al. J Am Coll Cardiol Dec 18;60(24):e44-e164. Medical Therapy for Relief of Symptoms Section 4.4.3: Class I Class IIa LOE A Ranolazine in combination with beta blockers can be useful when prescribed for relief of symptoms when initial treatment with beta blockers is not successful in patients with SIHD (LOE: A) Beta blockers should be prescribed as initial therapy for relief of symptoms in patients with SIHD (LOE: B) Treatment with a long-acting nondihydropyridine calcium channel blocker (verapamil or diltiazem) instead of a beta blocker as initial therapy for relief of symptoms is reasonable in patients with SIHD (LOE: B) LOE B Calcium channel blockers or long-acting nitrates should be prescribed for relief of symptoms when beta blockers are contraindicated or cause unacceptable side effects in patients with SIHD (LOE: B) Calcium channel blockers or long-acting nitrates, in combination with beta blockers, should be prescribed for relief of symptoms when initial treatment with beta blockers is unsuccessful in patients with SIHD (LOE: B) Sublingual nitroglycerin or nitroglycerin spray is recommended for immediate relief of angina in patients with SIHD (LOE: B) Ranolazine can be useful when prescribed as a substitute for beta blockers for relief of symptoms in patients with SIHD if initial treatment with beta blockers leads to unacceptable side effects or is ineffective or if initial treatment with beta blockers is contraindicated (LOE: B) SIHD = stable ischemic heart disease; LOE = level of evidence Fihn SD, et al. J Am Coll Cardiol Dec 18;60(24):e44-e

15 Considerations for Prescribing Antianginal Therapies: Beta-Blockers Proposed Mechanism of Action Decreases myocardial oxygen demand by decreasing heart rate, blood pressure and myocardial contractility May increase myocardial perfusion by prolonging diastole Attributes Clinical challenges Useful in stable and unstable angina Useful in SVT and HTN Data shows improved outcomes only in patients s/p MI Bradycardia AV block Sick sinus syndrome Peripheral vascular disease Asthma/Emphysema/Chronic bronchitis Diabetes mellitus Depression AV = atrioventricular HTN = hypertension MI = myocardial infarction s/p = status post SVT = supraventrlcular tachycardia Gibbons RJ, et al. J Am Coll Cardiol. 2003: Dvir D. Cardiovasc Drugs Ther. Published online July 24, 2010 Guideline Recommendations: Beta Blockers Section : Recommended as initial agents to relieve symptoms in most patients Reduce myocardial oxygen consumption by reducing heart rate, myocardial contractility, and afterload Long-term treatment well tolerated Reduces ischemic burden and threshold Improves survival in patients with LV dysfunction or history of MI Worsening of symptoms in patients with significant depressive illness or peripheral artery disease observed rarely in clinical practice Adherence can be influenced by adverse effects such as fatigue, lethargy, sexual dysfunction, or sleep disturbance SIHD = stable ischemic heart disease; LOE = level of evidence Fihn SD, et al. J Am Coll Cardiol Dec 18;60(24):e44-e

16 Considerations for Prescribing Antianginal Therapies: Calcium Channel Blockers* Proposed Mechanism of Action Attributes Clinical challenges Increase myocardial oxygen supply by vasodilatation Decrease myocardial oxygen demand by decreasing heart rate and also by vasodilatation which decreases afterload Effective for exercise-induced angina Useful in variant angina (Prinzmetal s angina) Useful in SVT and HTN Bradycardia AV block Sick sinus syndrome Reduced LV ejection fraction Decompensated heart failure *Actions of the individual drugs in this class vary AV = atrioventricular HTN = hypertension LV = left ventricular SVT = supraventricular tachycardia. Gibbons RJ, et al. J Am Coll Cardiol. 2003:1-126; Dvir D. Cardiovasc Drugs Ther. Published online July 24, 2010 Guideline Recommendations: Calcium Channel Blockers Section : Recommended if adverse effects or contraindications limit the use of BBs Not recommended for routine treatment in patients with heart failure and a reduced LVEF Useful in variant angina (Prinzmetal s angina) Negative inotropic effects, cardiac pacemaker depression, slowing conduction and smooth muscle relaxation Reduce anginal episodes, increase exercise duration, reduce use of sublingual nitroglycerin Adverse effects: Dihydropyridines: vasodilatation and systemic hypotension, including headache, dizziness, palpitations and flushing; peripheral edema Verapamil can cause constipation that can be severe, particularly in the elderly BB = beta blocker; LVEF = left ventricular ejection fraction Fihn SD, et al. J Am Coll Cardiol Dec 18;60(24):e44-e

17 Considerations for Prescribing Antianginal Therapies: Nitrates Proposed Mechanism of Action Attributes Clinical challenges Decrease myocardial oxygen demand and increase myocardial oxygen supply through vasodilatation Short-acting formulas useful for immediate symptom relief Long-acting formulas for chronic daily dosing* Long history of use with accepted safety and efficacy Hypotension Left ventricular outflow tract obstruction Reflex tachycardia Co-administration with PDE5 inhibitors Development of drug tolerance PDE5 = phosphodiesterase type 5 *To prevent tolerance 8-12 hour doasge-free period recommended Gibbons RJ, et al. J Am Coll Cardiol. 2003:1-126 Guideline Recommendations: Long-acting Nitrates Section : Recommended for treatment of angina when initial therapy with a BB or nondihydropyridine CCB is contraindicated or poorly tolerated or when additional therapy to control angina is necessary Relaxes vascular smooth muscles in the systemic arteries Improves exercise tolerance, time to ST-segment depression, and time to onset of angina in patients with SIHD Titration of dose is important to gain adequate anginal control Necessary to maintain a daily nitrate-free interval of hours to avoid development of nitrate tolerance Common side effects: headache, flushing, and hypotension Coadministration with phosphodiesterase inhibitors should be strictly avoided within 24 hours of nitrate administration; risk of profound hypotension CCB = calcium channel blocker Fihn SD, et al. J Am Coll Cardiol Dec 18;60(24):e44-e

18 Considerations for Prescribing Antianginal Therapies: Ranolazine Proposed Mechanism of Action Inhibition of late sodium current Decrease in subsequent intracellular calcium overload May increase myocardial perfusion 1 Inhibition of Ikr QTc prolongation (mean 6msec for 1000mg BID dose) Attributes Indicated for chronic stable angina No clinically significant effect on blood pressure or heart rate No dose adjustment required for patients with diabetes or heart failure Clinical challenges Contraindicated in patients with cirrhosis Contraindicated in conjunction with strong CYP3A inhibitors / strong CYP3A inducers Limited data available on high doses or use with QT interval-prolonging drugs Ranexa (ranolazine) Prescribing Information, July Venkataraman R, et al. J Am Coll Cardiol Img. 2009;2: Guideline Recommendations: Ranolazine Section : May be used in combination with BBs, nitrates, dihydropyridine CCBs, ACE inhibitors, ARBs, and antiplatelet and lipid-lowering therapy Inhibits the late inward sodium current, indirectly reducing the sodium-dependent calcium current during ischemic conditions and leading to improvement in ventricular diastolic tension and oxygen consumption Minimal changes in mean heart rate (<2 beats/min) and systolic BP (<3 mmhg) in controlled studies An alternative for patients with bradycardia or low BP Reduces frequency of angina, improves exercise performance, and delays the development of exercise-induced angina and ST-segment depression Among patients with ACS, ranolazine did not reduce the incidence of MI or death, but did reduce recurrent ischemia in the postinfarction period In patients with preexisting angina, it was superior to placebo in improving patients angina and quality of life ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; BP = blood pressure; ACS = acute coronary syndrome; MI = myocardial infarction Fihn SD, et al. J Am Coll Cardiol Dec 18;60(24):e44-e

19 Guideline Recommendations: Ranolazine Section : Ranolazine could exert a beneficial effect on glycemic control and has demonstrated consistent reductions in HbA1c in patients with diabetes mellitus in 2 studies No dose adjustment for age, sex, NYHA Class I-IV heart failure, or diabetes mellitus Plasma concentrations of ranolazine are increased by up to 50% in patients with CrCl <30 ml/min Contraindicated in patients with clinically significant hepatic impairment Contraindicated in combination with potent inhibitors of the CYP3A4 pathway Most common adverse effects are constipation, nausea, dizziness, and headache Ranolazine prolongs the QTc interval in a dose-related manner In a large trial with ACS patients (MERLIN), there was no increased risk of proarrhythmia or sudden death NYHA = New York Heart Association; CrCl = creatinine clearance Fihn SD, et al. J Am Coll Cardiol Dec 18;60(24):e44-e164. Revascularization Is an Important Part of Angina Treatment Attributes and Challenges of Revascularization Attributes Clinical challenges Can contribute to effective treatment of chronic stable angina Revascularization can improve quality of life and morbidity Restenosis/acute coronary occlusion Not feasible for some patients Diffuse disease and/or poor distal target vessels Contrast-induced nephropathy/renal toxicity Gibbons RJ, et al. Circulation. 2003;107(1): Levine GN, et al. Ann Intern Med. 2003;139(2):

20 Section 5.3: Revascularization to Improve Symptoms Class I Class IIa CABG or PCI is beneficial in patients with 1 or more significant ( 70% diameter) coronary artery stenosis amenable to revascularization and unacceptable angina despite GDMT (LOE: A) CABG or PCI is reasonable in patients with 1 or more significant ( 70% diameter) coronary artery stenosis and unacceptable angina for whom GDMT cannot be implemented because of medication contraindications, adverse effects, or patient preferences (LOE: C) PCI is reasonable in patients with previous CABG, 1 or more significant ( 70% diameter) coronary artery stenosis associated with ischemia, and unacceptable angina despite GDMT (LOE: C) It is reasonable to choose CABG over PCI in patients with complex 3- vessel CAD (eg, SYNTAX score >22), with or without involvement of the proximal LAD artery, who are good candidates for CABG (LOE: B) CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention; GDMT = guideline directed medical therapy; CAD = coronary artery disease; LOE = level of evidence Fihn SD, et al. J Am Coll Cardiol Dec 18;60(24):e44-e164. Revascularization to Improve Symptoms Class IIb CABG might be reasonable for patients with previous CABG, 1 or more significant ( 70% diameter) coronary artery stenoses not amenable to PCI, and unacceptable angina despite GDMT (LOE: C) TMR performed as an adjunct to CABG may be reasonable in patients with viable ischemic myocardium that is perfused by arteries that are not amenable to grafting (LOE: B) Class III CABG or PCI should not be performed in patients who do not meet anatomic ( 50% diameter left main or 70% non-left main stenosis diameter) or physiological (eg, abnormal FFR) criteria for revascularization (LOE: C) CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention; GDMT = guideline directed medical therapy; LOE = level of evidence; TMR = transmyocardial revascularization; FFR = fractional flow reserve Fihn SD, et al. J Am Coll Cardiol Dec 18;60(24):e44-e

21 Heart Team Approach And Patient Preference Heart Team Approach: A collaborative assessment of revascularization options, or the decision to treat with GDMT without revascularization, involving an interventional cardiologist, a cardiac surgeon, and (often) the patient s general cardiologist, followed by discussion with the patient about treatment options, is optimal. Vital Importance of Involvement by an Informed Patient: Recommendation Class I Choices about diagnostic and therapeutic options should be made through a process of shared decision making involving the patient and provider, with the provider explaining information about risks, benefits, and costs to the patient (LOE: C) GDMT = guideline directed medical therapy; LOE = level of evidence Fihn SD, et al. J Am Coll Cardiol Dec 18;60(24):e44-e164. TIPS AND TOOLS FOR MANAGING ANGINA 21

22 Patient Checklists Can Help Your Patients Understand the Impact of Chronic Angina Available at A Symptom Tracker Can Help You Assess the Progress of Your Patient s Chronic Angina Patients log data about each angina episode to show at their next office visit Available at 22

23 Questions for Assessing Chronic Angina Has your activity level changed since your last visit? Are you as active as you would like to be? Do you have the energy you think you should have? Are there any symptoms, such as shortness of breath or fatigue, you are experiencing that limit your activity or concern you? What are you doing to make your symptoms go away? Developed by a panel of cardiac nurse practitioners and physician assistants. SUMMARY 23

24 What Have We Learned? Chronic angina is associated with decreased QOL and increased mortality and healthcare costs Patients may continue to suffer from chronic angina because of incomplete assessment Despite multiple treatment options and available tools, chronic angina remains undertreated, in part because we are not asking the appropriate questions 24