Ranexa™ for Chronic Angina An Unmet Need 2. Chronic Angina—An Unmet Need (CM) 4/13/2017 4:00 PM Ranexa™ for Chronic Angina An Unmet Need Eugene Braunwald, MD, FACC Harvard Medical School Brigham and Women’s Hospital

2. Chronic Angina—An Unmet Need (CM) 4/13/2017 4:00 PM CM-2 There is a strong disorder in the breast. The seat of it, and sense of strangling and anxiety with which it is attended, may make it not improperly be called angina pectoris.… Those who are afflicted with it, are seized, while they are walking with a painful and most disagreeable sensation in the breast, which seems as if it would take their life away, if it were to increase or to continue. Heberden. Medical Transaction, Royal College of Physicians of London. 1772;2:59-67.

Epidemiology of Chronic Angina 2. Chronic Angina—An Unmet Need (CM) 4/13/2017 4:00 PM Epidemiology of Chronic Angina AHA reports that at least 6.6 million Americans suffer with angina pectoris Despite therapeutic advances > 13 million episodes of angina a week in the US > 1000 episodes of angina every minute Growing prevalence of chronic angina due to reductions in cardiovascular mortality Improved treatment of angina is an important goal

Comorbid Conditions Complicate Therapy 2. Chronic Angina—An Unmet Need (CM) 4/13/2017 4:00 PM Comorbid Conditions Complicate Therapy Studies of VA patients with CAD demonstrate the following comorbidity incidence rates Diabetes: 26% to 31% COPD: 13% to 22% Peripheral vascular disease: 16% to 28% Congestive heart failure: 20% Rumsfeld, 1999.

Persistent Angina Despite Current Drug Therapy 2. Chronic Angina—An Unmet Need (CM) 4/13/2017 4:00 PM Persistent Angina Despite Current Drug Therapy Despite use of traditional anti-anginal agents (-blockers, CCBs, and nitrates), patients still reported an average of 2 anginal attacks/week† A significant percentage of patients have relative intolerance to full doses of -blockers, CCBs, and nitrates -blockers and many CCBs have similar depressive effects on BP, HR and/or AV nodal conduction It would be desirable to develop an anti-anginal drug without these limitations †Pepine, 1994.

Persistent Angina Despite Percutaneous Intervention (PCI) 2. Chronic Angina—An Unmet Need (CM) 4/13/2017 4:00 PM Persistent Angina Despite Percutaneous Intervention (PCI) Angina at 1-yr follow-up by events during or after initial PCI 1 yr after PCI for. . . Symptom relief (N = 1403) Treatment of acute myocardial infarction (N = 352) . . . the overall prevalence of angina was 26% Events, n Angina at follow-up, % Events occurring after post-PCI discharge only MI No 1576 25.2 Yes 44 38.6 CABG 1522 26.3 98 15.3 Repeat PCI 1370 24.1 250 34.0 Holubkov R, et al. NHLBI Dynamic Registry. Am Heart J. 2002;144:826-833.

Persistent Angina Despite Optimal Revascularization 2. Chronic Angina—An Unmet Need (CM) 4/13/2017 4:00 PM Persistent Angina Despite Optimal Revascularization 1 yr after optimal revascularization by stenting or surgery for relief of ischemia (ie, not to prolong survival) … TABLE 3. STATUS WITH RESPECT TO ANGINA AND MEDICATION USE AND QUALITY OF LIFE AMONG SURVIVING PATIENTS.* VARIABLE 12 MO AFTER INTERVENTION STENTING GROUP SURGERY GROUP P value Free of angina (%) 78.9 89.5 <0.001 Free of antianginal medication (%) 21.1 41.5 Free of angina and antianginal medication (%) 19.1 38.4 ~ 60% to 80% are still taking anti-anginal medications ~ 10% to 20% still have angina Serruys PW, et al. for the ARTS Study Group. N Engl J Med. 2001;344:1117-1124.

Self Rating of Health for Angina Patients 2. Chronic Angina—An Unmet Need (CM) 4/13/2017 4:00 PM Self Rating of Health for Angina Patients 100 Normal US population Angina patients 90 80 General health 70 Vitality 60 SF36 scores 50 40 30 20 10 Physical function Bodily pain Chen AY, et al. Med Decis Making. 1996;16:169-177.

Angina Frequency and Depression 2. Chronic Angina—An Unmet Need (CM) 4/13/2017 4:00 PM Angina Frequency and Depression 1957 patients completed SAQ 7 mo after ACS History of depression documented in 526 (26.7%) patients following ACS Strong correlation of angina frequency with depression 50 45 40 35 30 % depression 25 20 15 10 5 None Monthly Weekly Daily Angina frequency ACS = acute coronary syndrome SAQ = Seattle Angina Questionnaire Rumsfeld JS, et al. Am Heart J. 2003;145:492.

Unmet Need of Chronic Angina 2. Chronic Angina—An Unmet Need (CM) 4/13/2017 4:00 PM Unmet Need of Chronic Angina Angina continues in many patients despite medical therapy and mechanical revascularization The personal burden can deprive many patients of their functional independence, forcing them to downsize their lives The economic toll of angina places a huge burden on patients, their families, the healthcare system, and society

Unmet Need of Chronic Angina 2. Chronic Angina—An Unmet Need (CM) 4/13/2017 4:00 PM Unmet Need of Chronic Angina When angina cannot be eliminated by current drugs, it is often their additive effects on BP, HR, AV conduction, and other important side effects (depression, fatigue, sexual/sleep disorders, etc.) that preclude complete relief.

Novel Therapies Needed for a Growing Angina Burden 2. Chronic Angina—An Unmet Need (CM) 4/13/2017 4:00 PM Novel Therapies Needed for a Growing Angina Burden 6 4 Patients, millions 2 1900 2000

Angina—Evolution of Therapy 2. Chronic Angina—An Unmet Need (CM) 4/13/2017 4:00 PM Angina—Evolution of Therapy Nitrates  block CABG CCB PCI Ranexa™ TREATMENT 1880 1965 1969 1975 1977 2004 O2 demand + + + O2 supply + + ? + ATP/O2 + Likely mechanisms