1. Assessment of Cardiopulmonary Function in Patients With Stable Coronary Artery Disease Receiving Ticagrelor or Clopidogrel in the ONSET/OFFSET Study Robert F. Storey*, Kevin P. Bliden †, Shankar B. Patil*, Arun Karunakaran*, Rosemary Ecob*, Kathleen Butler ‡, Renli Teng ‡, Cheryl Wei ‡, Udaya S. Tantry †, Paul A. Gurbel † *Department of Cardiovascular Science, University of Sheffield, and NIHR Cardiovascular Biomedical Research Unit, Sheffield, UK; † Sinai Center for Thrombosis Research, Baltimore, MD, US; ‡ AstraZeneca Research and Development, Wilmington, DE, US. J Am Coll Cardiol 2010; 56: 185-93

2. 1 Wallentin L, et al. N Engl J Med. 2009;361:1045-1057. 2 Husted SE, et al. Eur Heart J. 2006;27:1038-104.. 3 Cannon CP, et al. J Am Coll Cardiol. 2007;50:1844-1851. Introduction Ticagrelor has been shown to reduce cardiovascular events more effectively than clopidogrel in patients with acute coronary syndromes 1 Some ticagrelor-treated patients develop dyspnea as a side effect of therapy 1-3 The ONSET/OFFSET study was conducted to characterize onset and offset of ticagrelor compared to clopidogrel in patients with stable coronary artery disease In addition, cardiopulmonary function was prospectively assessed

3. CAD = coronary artery disease; LVEF=left ventricular ejection fraction; NT-proBNP=N-terminal pro-brain natriuretic peptide. Methods 123 stable aspirin-treated CAD patients were randomized to receive one of three treatments for 6 weeks in a double-blind, double-dummy design (the ONSET/OFFSET study): –Ticagrelor (180 mg load then 90 mg bid [n=57]) –Clopidogrel (600 mg load then 75 mg qd [n=54]) –Placebo (n=12) Electrocardiography, echocardiographic assessment of LVEF, serum NT-proBNP, and comprehensive pulmonary function tests were performed at baseline and 6 weeks after drug administration and/or following development of dyspnea Proportions of patients with dyspnea were compared between treatment groups (Fisher’s exact test); percent change from baseline in cardiopulmonary function was analyzed by ANCOVA

4. Characteristic Ticagrelor (n=57) Clopidogrel (n=54) Placebo (n=12) Mean age, y (SD) Range 62 (9) 41-79 65 (8) 42-83 64 (8) 44-79 Female gender, n (%)14 (25%)14 (26%)2 (17%) Race, n (%) Caucasian Black/African American Other 51 (90) 4 (7) 2 (4) 48 (89) 5 (9) 1 (2) 9 (75) 3 (25) 0 (0) Dyslipidemia, n (%)54 (95)52 (96)12 (100) Hypertension, n (%)44 (77)39 (72)9 (75) Diabetes mellitus, n (%)12 (21)10 (19)5 (42) Ex smoker, n (%)29 (51)27 (50)7 (58) Concomitant medications, n (%) Statins Beta-blockers Diuretics CCB ACE inhibitors Organic nitrates PPI 49 (86) 39 (68) 20 (35) 17 (30) 10 (18) 6 (11) 16 (28) 50 (93) 42 (78) 18 (33) 9 (17) 8 (15) 12 (22) 16 (30) 11 (92) 9 (75) 4 (33) 2 (17) 0 (0) 3 (25) ACE = angiotensin converting enzymes; CCB = calcium channel blockers; PPI = proton pump inhibitor; SD = standard deviation. Baseline Demographics

5. Study Day * Ticagrelor Clopidogrel 1015202530354045505515 Study Drug Administration Period (42  3 days) Placebo Each line or symbol represents individual patient data and duration of event. Individual Profiles for Patients With Dyspnea Mild dyspnea Moderate dyspnea Mild dyspnea of  4 hours Moderate dyspnea lasting 5 minutes * Prematurely discontinued drug

6. Parameter Ticagrelor (n=57) Clopidogrel (n=54) Placebo (n=12) Baseline Mean (SD) Week 6 Mean (SD) Baseline Mean (SD) Week 6 Mean (SD) Baseline Mean (SD) Week 6 Mean (SD) Systolic BP (mmHg) 132 (17) 133 (16)132 (17)125 (20)121 (16) Diastolic BP (mmHg) 77 (10) 75 (10)74 (11)71 (9)70 (7) Heart rate (beats/min) 66 (11)66 (13)63 (10)63 (11)70 (11)65 (10) EF (%)58 (9)61 (8)62 (8)62 (7)60 (10)61 (10) NT-proBNP163 (184)140 (170)186 (227)214 (313)145 (145)141 (145) Cardiovascular Function Assessment P = not significant for all parameters. BP = blood pressure; EF = ejection fraction; NT-proBNP = N-terminal pro-brain natriuretic peptide; SD = standard deviation.

7. Parameter Ticagrelor (n=57) Clopidogrel (n=54) Placebo (n=12) Baseline Mean (SD) Week 6 Mean (SD) Baseline Mean (SD) Week 6 Mean (SD) Baseline Mean (SD) Week 6 Mean (SD) FEV 1 (L)2.8 (0.7) 2.7 (0.8) 2.9 (0.7)3.0 (0.7) FVC (L)3.7 (0.9) 3.7 (1.1)3.8 (1.0)4.0 (0.9) FEV 1 /FVC75.0 (7.1)74.7 (5.7)73.0 (6.8)72.8 (6.4)73.1 (7.2)74.3 (7.8) FEF 25-75 (%)2.9 (1.3)2.8 (1.3)2.7 (1.2) 2.5 (1.2)2.9 (1.4) V E (L/min)12.9 (4.0)13.7 (3.6)12.2 (3.6)13.1 (5.5)12.1 (4.1)11.5 (3.5) V T (L/min)0.96 (0.33)0.92 (0.26)0.89 (0.32)0.93 (0.39)0.89 (0.27)0.83 (0.33) P = not significant for all parameters. FEV 1 = forced expiratory volume in 1 second; FEF 25-75 = mean forced expiratory flow between 25% and 75% of the FVC; FVC = forced vital capacity; SD = standard deviation; V E = minute ventilation; V T = tidal volume. Pulmonary Function Assessment (1)

8. Parameter Ticagrelor (n=57) Clopidogrel (n=54) Placebo (n=12) Baseline Mean (SD) Week 6 Mean (SD) Baseline Mean (SD) Week 6 Mean (SD) Baseline Mean (SD) Week 6 Mean (SD) FRC (L)2.8 (0.9)2.7 (0.7)2.9 (0.9)2.8 (0.9)2.9 (0.7)2.8 (1.0) TLC (L)5.8 (1.3)5.7 (1.2)5.8 (1.4)5.9 (1.4)6.1 (1.0)6.0 (1.4) RV (L)1.9 (0.8)1.9 (0.6)2.0 (0.6) 1.9 (0.4)1.9 (0.8) RR (breaths/min) 15 (2)15 (3)14 (3)15 (2)16 (2)15 (1) D L CO SB (%)17 (9)16 (8)17 (11)17 (8)16 (6)16 (7) SpO 2 (%)97 (2)98 (1)97 (2)97 (1)98 (1)99 (1) P = not significant for all parameters. D L CO SB = single breath diffusing capacity for the lungs using carbon monoxide; FRC = forced residual capacity; FVC = forced vital capacity; RR = respiratory rate; RV = residual volume; SD = standard deviation; SpO 2 = blood oxygen saturation measured by pulse oximetry; TLC = total lung capacity. Pulmonary Function Assessment (2)

9. P = not significant for all parameters. EF=ejection fraction Boxes represent scatter plots of individual patient data; error bars show standard deviation Cardiovascular Parameters in Patients With Dyspnea: Ejection Fraction EF (%) Baseline Week 6 Baseline Week 6 TicagrelorClopidogrel 20 40 80 100 60 0

10. P = not significant for all parameters. V E = minute ventilation; V T = tidal volume. Boxes represent scatter plots of individual patient data; error bars show standard deviation Pulmonary Parameters in Patients With Dyspnea: V E and V T V E (L/min) Baseline Week 6 Baseline Week 6 TicagrelorClopidogrel 0 10 20 30 V T (L/min) Baseline Week 6 Baseline Week 6 Ticagrelor Clopidogrel 2 3 1 0

11. P = not significant for all parameters. FEV 1 = forced expiratory volume at 1 second; FVC = forced vital capacity. Boxes represent scatter plots of individual patient data; error bars show standard deviation Pulmonary Parameters in Patients With Dyspnea: FEV 1 and FVC FEV 1 (L) Baseline Week 6 Baseline Week 6 TicagrelorClopidogrel 5 0 1 2 3 4 Baseline Week 6 Baseline Week 6 TicagrelorClopidogrel FVC (L) 4 8 0 2 6

12. P = not significant. for all parameters RR = respiratory rate; TLC = total lung capacity. Pulmonary Parameters in Patients With Dyspnea: TLC and RR Boxes represent scatter plots of individual patient data; error bars show standard deviation Baseline Week 6 Baseline Week 6 TicagrelorClopidogrel TLC (L) 5 10 0 RR (breaths/min) Baseline Week 6 Baseline Week 6 TicagrelorClopidogrel 10 20 30 0

13. P = not significant for all parameters. D L CO SB = single breath diffusing capacity for the lungs using carbon monoxide; SpO 2 = blood oxygen saturation measured by pulse oximetry. Boxes represent scatter plots of individual patient data; error bars show standard deviation Pulmonary Parameters in Patients With Dyspnea: SpO 2 and D L CO SB SpO 2 (%) Baseline Week 6 Baseline Week 6 TicagrelorClopidogrel 100 75 80 85 90 95 D L CO SB (%) Baseline Week 6 Baseline Week 6 Ticagrelor Clopidogrel 10 40 20 30 0

14. Conclusions Dyspnea induced by ticagrelor therapy is not associated with any adverse change in cardiopulmonary function Dyspnea occurs as a relatively common side effect of ticagrelor but is usually mild or moderate in severity and often transient despite continued treatment