This document summarizes several key points regarding the management of NSTEMI and the use of ticagrelor vs clopidogrel: 1) ACS patients in the Gulf region are younger than in developed countries and often present late to the hospital. Mortality among NSTEMI patients is higher in those with multi-vessel disease. 2) The PLATO trial demonstrated that ticagrelor 90mg reduced cardiovascular mortality by 21% compared to clopidogrel and showed efficacy in NSTE-ACS patients with no increase in overall major bleeding. 3) The PRACTICAL study of over 45,000 real-world ACS patients found benefits of ticagrelor 90mg

1. IMPROVED
OUTCOMES
START HERE
NSTEMI
MVD
1041485.011
Veeva Activity ID: SA-3987

2. UNMET NEED IN STEMI MANAGEMENT
ACS PATIENTS IN THE GULF ARE A DECADE YOUNGER THAN THOSE IN
DEVELOPED COUNTRIES1-3
Adapted from:
1. Widimsky P. www.escardio.org/communities/councils/ccp/e-journal/volume5/Pages/voi5n40.aspx (accessed October 2011).
2. Scott IA, et al. Int J Qual Health Care 2004; 16:275-84. Tan WA. Unstable Angina. http://emedicine.medscape.com/article/159383-overview#a0156v (accessed October 2011)
3a. Gulf RACE II, Ann Saudi Med 2012;32920:9-18.
3b. Zubaid M, et al. Acta Cardiol 2009;64:439-46.

3. UNMET NEED IN STEMI MANAGEMENT6
ACS PATIENTS IN THE GULF ALSO PRESENT LATE TO THE HOSPITAL4-7
Adapted from:
4. Al Habib et al. Ann Saudi Med 2012; 32(2): 9-18.
5. Gibson et al. Am Heart J 2008; 156: 1035-44.
6. Eagle et al. Eur Heart J 2008; 29(5): 609-17.
7. Mandelzweig et al. Eur Heart J 2006; 27: 2285-2293
*Mediterranean Basin
MEDIAN TIME FROM SYMPTOMS ONSET TO HOSPITAL ARRIVAL FOR STEMI PATIENTS

4. Adapted from:
8. Fox K, et al. BMJ 2006; 33: 1091.
UNMET NEED IN STEMI MANAGEMENT
ST-DEPRESSION PATIENTS REMAIN AT SIGNIFICANT RISK OF DYING IN THE
FIRST 6 MONTHS AFTER AN ACS EVENT, SURPASSING THE RISK OF DEATH IN
STEMI PATIENTS
DEATH FROM HOSPITAL DISCHARGE TO 6 MONTHS8
Data from a prospective, multinational, observational study of 43,810 patients presenting with ACS without ST segment elevation enrolled in
the global registry of acute coronary events (GRACE) study between April 1999 and September 2005.

5. Adapted from:
9. Sorajja P, et al. Eur Heart J 2007; 28: 1709-1716.
CUMULATIVE INCIDENCE OF DEATH ACCORDING TO THE PRESENCE OF SINGLE-,
DOUBLE-, OR TRIPLE-VESSEL DISEASE9
UNMET NEED IN NSTEMI MANAGEMENT
MORTALITY AMONG NSTEMI PATIENTS IS HIGHER AMONG THOSE WITH
MULTI-VESSEL DISEASE COMPARED TO SINGLE-VESSEL DISEASE

6. Adapted from:
10. Stone GW, et al. N Engl J Med 2011; 364: 226-235.
PROSPECT: TIME-TO-EVENT CURVES FOR CV EVENTS* POST-MI
UNMET NEED IN NSTEMI MANAGEMENT
MORE THAN HALF OF SUBSEQUENT EVENTS IN STENTED PATIENTS
OCCUR IN NON-CULPRIT LESIONS10
*CV death, MI or stroke

7. PLATO: STUDY DESIGN
A LANDMARK CLINICAL TRIAL PROVING THE SUPERIORITY OF BRILINTA IN
REDUCING CV MORTALITY VS. CLOPIDOGREL ACROSS A BROAD RANGE OF
ACS PATIENTS11-13
Adapted from:
11. Brilinta. Summary of product characteristics.
12. Wallentin L, et al. N Engl J Med 2009; 1045-1057. Supplemental information.
13. Wallentin L, et al. N Engl J Med 2009; 1045-1057.

8. PLATO: STUDY DESIGN
A LANDMARK CLINICAL TRIAL PROVING THE SUPERIORITY OF BRILINTA IN
REDUCING CV MORTALITY VS. CLOPIDOGREL ACROSS A BROAD RANGE
OF ACS PATIENTS10-12,14-16
Adapted from:
10. Brilinta. Summary of product characteristics.
11. Supplementary Appendix to: Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045-1057.
doi: 10.1056/NEJMoa0904327.
12. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057.
14. Cannon CP, Harrington RA, James S, et al; PLATelet inhibition and patient Outcomes Investigators. Comparison of ticagrelor with clopidogrel in patients with a planned invasive
strategy coronary Syndrome(PLATO0: a randomised double-blind study. L ancet. 2010;375:283-293.
15 James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes :
rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2009;157:599-605.
16. James S, Roe MT, Cannon CP, et al; PLATO Study Group. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management:
substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial. BMJ.2011;342:d3527. doi:10.1136/bmj.d3527.
DEMONSTRATED EFFICACY IN A STUDY OF MORE THAN 18,000 ACS PATIENTS

9. PLATO: STUDY DESIGN
A LANDMARK CLINICAL TRIAL PROVING THE SUPERIORITY OF BRILINTA
IN REDUCING CV MORTALITY VS. CLOPIDOGREL ACROSS A BROAD
RANGE OF ACS PATIENTS
Adapted from:
12. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
James S et al. Circulation. 2012;125:2914-2921.

10. PLATO: EFFICACY & SAFETY RESULTS
BRILINTA 90MG ABSOLUTE RISK REDUCTION STARTS AS EARLY AS DAY
30 AND CONTINUES TO INCREASE THROUGHOUT THE 12 MONTHS11,13
Adapted from:
11. Brilinta. Summary of product characteristics.
13. Wallentin L, et al. N Engl J Med 2009; 1045-1057.
PRIMARY EFFICACY ENDPOINT: RISK REDUCTION AT 12 MONTHS

11. PLATO: EFFICACY & SAFETY RESULTS
BRILINTA 90MG DEMONSTRATED A 21% RRR IN CV MORTALITY VS.
CLOPIDOGREL
Adapted from:
12. Wallentin L, et al. N Engl J Med 2009; 36: 1045-1057.
SECONDARY EFFICACY ENDPOINT: CV MORTALITY AT 12 MONTHS12
Adapted from wallentin L et al. N Engl J Med 2009; 361: 1045-1057. supplementary information.1
All patients were on a background of aspirin therapy
months after randomisation
CV
MORTALITY
(KM%)
0
1
2
3
4
6
5
n=18,624
0 2 4 6 8 10 12
BRILINTA 90mg (n=9,333)
clopidogrel (n=9,291)
HR
0.79
95% CI
0.69-0.91
P=0.001
NNT=91

12. PLATO: EFFICACY & SAFETY RESULTS
IN THE NSTE-ACS SUBGROUP OF PLATO, BRILINTA 90MG REDUCED THE
COMPOSITE ENDPOINT OF CV DEATH, MI, OR STROKE VS. CLOPIDOGREL
WHERE THE ABSOLUTE BENEFIT INCREASES UP TO 12 MONTHS
Adapted from:
17. Lindholm D, et al. Eur Heart J 2014; 35: 2083-2093.
PLATO NSTE-ACS SUBGROUP

13. PLATO: EFFICACY & SAFETY RESULTS
BRILINTA 90MG DEMONSTRATED NO INCREASE IN OVERALL MAJOR
BLEEDING OR FATAL BLEEDING VS. CLOPIDOGREL13
Adapted from:
13. Wallentin L, et al. N Engl J Med 2009; 1045-1057.
Bleeding events
Major bleeding (PLATO)
Primary safety endpoint
Major bleeding (TIMI)
Bleeding requiring red cell transfusion
Life-threatening or fatal bleeding
Fatal bleeding
Non-intracranial fatal bleeding
Intracranial bleeding
Fatal
Non-fatal
Secondary safety endpoints
Non-CABG-related major bleeding
CABG-related major bleeding
Major or minor bleeding
BRILINTA 90 mg
n=9,235 KM %
11.6
7.9
8.9
5.8
0.3
0.1
0.3
0.1
0.2
4.5
7.4
16.1
clopidogrel
n=9,186 KM %
11.2
7.7
8.9
5.8
0.3
0.3
0.2
0.01
0.2
3.8
7.9
14.6
HR (95% CI)
1.04 (0.95 - 1.13)
1.03 (0.93 - 1.15)
1.00 (0.91 - 1.11)
1.03 (0.90 - 1.16)
0.87 (0.48 - 1.59)
–
1.87 (0.98 - 3.58)
–
–
1.19 (1.02 - 1.38)
0.95 (0.85 - 1.06)
1.11 (1.03 - 1.20)
P value
0.43
0.57
0.96
0.70
0.66
0.03
0.06
0.02
0.69
0.03
0.32
0.008

14. PLATO: EFFICACY & SAFETY RESULTS
AT 12 MONTHS, BRILINTA SHOWED NO SIGNIFICANT INCREASE IN TOTAL
MAJOR BLEEDING VS. CLOPIDOGREL13
Adapted from:
13. Wallentin L, et al. N Engl J Med 2009; 1045-1057.

15. PLATO vs. TIMI BLEEDING DEFINITIONS
Adapted from:
11. Brilinta. Summary of product characteristics.

16. PLATO: EFFICACY & SAFETY RESULTS
NO SIGNIFICANT DIFFERENCE IN MAJOR BLEEDING SEEN WITH BRILINTA
Adapted from:
13. Wallentin L, et al. N Engl J Med 2009; 36: 1045-1057.
PLATO: MAJOR BLEEDING

17. PLATO: EFFICACY & SAFETY RESULTS
ACROSS ALL PATIENT SUBGROUPS, BRILINTA SHOWED NO SIGNIFICANT
INCREASE IN TOTAL MAJOR BLEEDING VERSUS CLOPIDOGREL, CONSISTENT
WITH THE OVERALL PLATO RESULTS12,18
Adapted from:
12. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Supplementary information.
18. James S, et al. Circulation 2010; 122-1056-1067.
Adapted from PLATO Primary publication

18. PLATO: EFFICACY & SAFETY RESULTS
DYSPNOEA
Adapted from:
1. Brilinta. Summary of product characteristics.
2. Wallentin L, et al. N Engl J Med. 2009:361: 1045-1057.
3. Storey RF, Bliden K, Patil SB, et al. Abstract 5768: The Effect of Ticagrelor on Cardiopulmonary Function in Patients With Stable Coronary Artery Disease.Circulation 2009: 120:S1145-a-.

19. PRACTICAL
EVALUATION OF OUTCOMES IN A LARGE POPULATION OF REAL-WORLD ACS
PATIENTS TREATED WITH BRILINTA 90MG OR CLOPIDOGREL19
Adapted from:
19. Sahlén A, et al. Eur Heart J 2016; pii: ehw284 [Epub ahead of print].
Due to BRILINTA 90mg 12 months license, only 12 months sensitivity analysis of the primary endpoints can be shared during this presentation
for efficacy analysis.
Data from PRACTICAL, an observational study of 45,073 patients prospectively enrolled into the SWEDEHEART registry, patients who were discharged on either BRILINTA 90mg or
clopidogrel were evaluated for the composite primary endpoints of death, MI or stroke.19

20. PRACTICAL
STUDY DESIGN
Adapted from:
19. Sahlén A, et al. Eur Heart J 2016; pii: ehw284 [Epub ahead of print].
Data from PRACTICAL, an observational study of 45,073 patients prospectively enrolled into the SWEDEHEART registry, patients who were
discharged on either BRILINTA 90mg or clopidogrel were evaluated for the composite primary endpoints of death, MI or stroke.

21. PRACTICAL
BRILINTA WAS RAPIDLY ADOPTED IN SWEDEN FOLLOWING ITS LAUNCH AND
INCLUSION IN ESC GUIDELINES19
Adapted from:
19. Sahlén A, et al. Eur Heart J 2016; pii: ehw284 [Epub ahead of print].
WITHIN 9 MONTHS OF LAUNCH BRILINTA HAS ACHIEVED ALMOST 50% SHARE IN DAPT MARKET19
Data from PRACTICAL, an observational study of 45,073 patients prospectively enrolled into the SWEDEHEART registry, patients who were
discharged on either BRILINTA 90mg or clopidogrel were evaluated for the composite primary endpoints of death, MI or stroke.

22. PRACTICAL
BENEFITS OF BRILINTA 90MG IN PRACTICAL VS. CLOPIDOGREL SHOWED
CONSISTENCY WITH PLATO SECONDARY ENDPOINT IN A REAL-WORLD
SETTING AT 12 MONTHS12,18
Adapted from:
12. Wallentin L, et al. N Engl J Med 2009; 361: 1045-1057
18. Sahlén A, et al. Eur Heart J 2016; pii: ehw284 [Epub ahead of print].
BRILINTA 90MG WAS ASSOCIATED WITH A 0.85% HAZARD RATIO IN THE COMPOSITE OF ALL-CAUSE
DEATH, MI AND STROKE VS. CLOPIDOGREL AT 12 MONTHS12
*Graph adapted with 12-month sensitivity analysis data performed by PRACTICAL study team.
Data from PRACTICAL, an observational study of 45,073 patients prospectively enrolled into the SWEDEHEART registry. BRILINTA 90mg was associated
with a lower risk of all-cause death, MI or stroke vs. clopidogrel (crude rates 11.7% vs. 22.3%, respectively, with a multivariate risk adjusted HR 0.85, 95%
CI 0.78-0.93). Final values are adjusted for hospital and calendar time, age, sex, discharge medication, in-hospital course, presentation characteristics and
pre-existing comorbidities. As an observational study of real-world evidence, the data from this study are subject to potential confounding bias usually
associated with observational research. Data are for treatment at discharge and planned treatment duration only.18

23. PRACTICAL
BRILINTA 90MG DEMONSTRATED NO SIGNIFICANT INCREASE IN OVERALL
MAJOR BLEEDING VS. CLOPIDOGREL, CONSISTENT WITH RESULTS SEEN
IN PLATO
Adapted from:
12. Wallentin L, et al. N Engl J Med 2009; 36: 1045-1057. Supplemental information.
PRACTICAL PRIMARY SAFTEY END POINT (MULTIVARIATE RISK ADJUSTED) AT 12 MONTHS:
BLEEDING REQUIRING HOSPITALIZATION

33. GUIDELINES
FOR YOUR NSTEMI PATIENTS, MAJOR INTERNATIONAL GUIDELINES NOW
PREFER TICAGRELOR 90MG OVER CLOPIDOGREL FOR THE FIRST 12 MONTHS1-3
Adapted from:
1. Collet JP, et al.. 2020; 00, 1-79. DOI:10.1093/eurheartj/ehaa575.
2. Neumann FJ et al. Eur Heart J. 2019; 40(2):87-165 DOI:10.1093/eurheartj/ehy394.
3. Levine GN et al. Circulation 2016:DOI; 10.1161/CIR.00000000000000404.
LOE, Level of evidence; PCI = percutaneous coronary intervention; MM=medically managed; ACS=acute coronary syndrome; DAPT=dual antiplatelet
therapy; NSTE-ACS=non-ST elevated acute coronary syndrome; MM=medically managed
*Drug eluting stent or bare metal stent implantation
**Without revascularisation or fibrinolysis
aClass of recommendation.
bLevel of evidence

34. CONCLUSION
BRILINTA IS SIMPLE AND EFFECTIVE IN THE MANAGEMENT OF YOUR ACS
PATIENTS FOR UP TO 12 MONTHS*11,13
Adapted from:
11. Brilinta. Summary of product characteristics.
13. Wallentin L, et al. N Engl J Med 2009; 361: 1045-1057.
✝Unless contraindicated

35. CONCLUSION
BRILINTA IS SIMPLE TO USE WITHIN A BROAD RANGE OF ACS PATIENTS
Adapted from:
11. Brilinta. Summary of product characteristics.
BRILINTA LOADING IS NOT RESTRICTED BY11:

36. Adapted from:
11. Brilinta. Summary of product characteristics.
12. Wallentin L, et al. N Engl J Med 2009; 361: 1045-1057. Supplementary information
13. Wallentin L, et al. N Engl J Med 2009; 361: 1045-1057.
20. Roffi M, et al. Eur Heart J 2015; 36: 267-315.
21. Levine GN, et al. Circulation 2016; DOI; 10.1161
22. Jemberg T, et al. Eur Heart J 2015; 136: 1163-1170.
CONCLUSION
BRILINTA, IN COMBINATION WITH LOW DOSE ASA, PROTECTS YOUR MI
PATIENTS AGAINST SUBSEQUENT EVENTS FOR UP TO 12 MONTHS11

38. BRILINTA IS THE FIRST IN A NEW CHEMICAL CLASS OF
OAPS DIFFERENT FROM THIENOPYRIDINES
Adapted from:
1. Brilinta. Summary of product characteristics.
2. Husted S, et al. Cardio Ther 2009;27:259-274.

39. THE DUAL PATHWAY MEDIATES BOTH ANTI-PLATELETS
EFFECTS AND ENHANCED ADENOSINE RESPONSE
Adapted from:
1. Van Giezen JJJ, et al. J Thromb Haemost 2009;7:1556-1565.
2. Wallentin L. Eur Heart J 2009;30:1964-1977.
3. Nylander S. et al. J Thromb Haemost 2013;11:1867-1876.
4. Armstrong D. et al. J Cardiovasc. Pharmacol Ther; In press.
5. Van Giezen JJJ, et al. J Cardiovasc. Pharmacol Ther 2012;17;164-172.
6. Wang K. et al. Thromb Haemost 2010;104:609-17.
7. Wittfeldt A. et al. J Am CollCardiol 2013;61:723-727.

40. BRILINTA IS DIRECT ACTING; THIENOPYRIDINES
ARE PRO-DRUGS
Figure Adapted from Schoming A (2009) CYP, cytochrome P450. Schoming A. N Engl J Medicine 2009;361:1108-1111.

41. BRILINTA DELIVERS MORE RAPID PLATELET
INHIBITION VS. CLOPIDOGREL1,2
Adapted from:
1. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with
stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009;120:2577-2585.
2. Brilinta. Summary of product characteristics.

42. ONSET/OFFSET: INHIBITION OF PLATELETS
AGGREGATION
Adapted from:
1. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease:
the ONSET/OFFSET study. Circulation 2009;120:2577-2585.

43. ARE VARIABLE RESPONSES TO CLOPIDOGREL
TREATMENT ACCEPTABLE? 1-5
Adapted from:
1. Wallentin L. et al. N Engl J Med 2009;361:1045-1057.
2. Gurbel PA et al. Circulation 2009;120:2577-2585.
3. Ngugen TA et al. J Am Coll Cardiol 2005;45:1157-1164.
4. Mega JL. Et al. CYP-450 Polymorphism & response to clopidogrel N Eng J Med 2009;360:354-362.
5. Weerakkody GJ et al. Clopidogrel poor responders an objective definition based on Bayesian classification. Platelets 2007;18:435.

44. BRILINTA PROVIDES CONSISTANT RESULTS
REGARDLESS OF CYP2C19 GENOPTYPE1
Adapted from:
1. Wallentin L et al. Lancet 2010 Oct 16;376(9749):1320-8.

45. BRILINTA IS INDICATED FOR USE EITHER WHOLE,
OR AS CRUSHED TABLETS1,2
Adapted from:
1. Brilinta. Summary of product characteristics.
2. Teng R. Clin Pharmacokinet. 2015;54:1125-1138.
Administration of crushed 90mg tablets (orally or via nasogastric tube) resulted in higher ticagrelor plasma concentrations
at early timepoints (0.5 and 1 h) vs. whole tablets*2
*36 healthy subjects were randomized in this open-label, three-period, three-treatment crossover study

46. ACS PATIENTS RECEIVING BRILINTA HAD FEWER
DEFINITE STENT THROMBOSIS VS. PATIENTS
RECEIVING CLOPIDOGREL1,2
Adapted from:
1. Brilinta. Summary of product characteristics.
2. Wallentin L, Becker RC. Budaj A, et al. PLATO Investigators. Ticagrelor versus Clopidogrel in Patients with Acute Cornary Syndrome. N Engl J Med. 2009; 361 (11):1045-1057.
INCIDENCE OF STENT THROMBOSIS AT 12 MONTHS
With BRILINTA® vs clopidogrel, risk of definite stent thrombosis
was reduced by one third