nut shell about antiplatelets

2. Back to Basics……
• Pharmacology of antithrombotic drugs
Jessica L Mega, Tabassome Simon
Lancet 2015; 386: 281–91

3. • Why we give loading dose ?
• Why ticlopidine was replaced with clopidogrel
• Advantage of prasugrel over clopidogrel ?
• Smoker paradox
• Non P2Y12 antagonist affects of ticagrelor ?
• Mechanism of dyspnoea with Ticagrelor ?
• High dose of Aspirin with ticagrelor ?
• Special groups for prasugrel and ticagrelor ?

4. Aspirin and P2Y12 receptor
antagonists
• Peak plasma concentration of aspirin is
obtained within 30 min after ingestion of
regular aspirin and up to 4 h after ingestion of
the enteric-coated formulation.
• Onset of clopidogrel antiplatelet action is
reported at 2 h after a 600 mg, compared with
after 30 min for prasugrel and ticagrelor

5. Do all P2Y12 inhibitors work the same
way?

6. 6
1. Capodanno D et al. Expert Rev Cardiovasc Ther 2010;8:151–158; 2. Cattaneo M et al. J Am Coll Cardiol 2014;63:2503–2509
Figure adapted from Dorsam RT & Kunapuli SP. J Clin Invest 2004;113:340–345
CPTP: Ticagrelor
Thienopyridines:
Clopidogrel
Prasugrel
CYP450
metabolism
• Prodrugs requiring
activation
• Covalently binding
(irreversible)
• Direct acting
• Reversibly binding
ENT-1
Active
metabolite
ADP
Adenosine
x
Platelet activation
P2Y12
A2A
x
x x
Inhibition of P2Y12 receptor1
‒Antiplatelet effect
Inhibition of ENT-1 transporter2
Enhanced local adenosine response may provide:
– Additional inhibition of platelet
aggregation/activation
– Vasodilation
Red blood cell
Recruitment of additional platelets
Potentiation of further ADP secretion Potentiation of procoagulant activity
Potentiation of aggregation
Platelet
Thrombus growth and stability
Image is used for educational purpose only. AstraZeneca is not responsible for data and copyrights.

7. Non P2Y12 antagonist affects of ticagrelor
•Adenosine has several properties including coronary
vasodilation, reduction of ischaemia and reperfusion injury,
inhibition of inflammatory responses to stress conditions,
negative chronotropic effects, reduction of glomerular
filtration
•stimulation of pulmonary vagal C fibres that might induce
dyspnoea.

9. How is ticagrelor different to the thienopyridines?
9
CPTP (ticagrelor)
Thienopyridines
(ticlopidine, clopidogrel, prasugrel)
Inhibition
of P2Y12
• Direct acting1,2
• 24-hour systemic exposure* to the
directly active compound (when dosed
twice daily)3
• Reversible binding to P2Y12 receptor4
• Prodrugsrequiring metabolic activation1,2,5
• 2–4 hours of systemic exposure* to the active
metabolite9
• Covalent, irreversible, binding to P2Y12 receptor1
Inhibition
of ENT-1
• Inhibition of ENT-1 providing an
enhanced endogenous adenosine
response6-9
• Currently no known effect
Ticagrelor has been documented to augment the following adenosine-induced effects in healthy subjects and in patients
with ACS: vasodilation (measured by coronary blood flow increases in healthy volunteers and ACS patients; headache),
inhibition of platelet function (in human whole blood in vitro) and dyspnoea. However, a link between the observed
increases in adenosine and clinical outcomes (e.g.: morbidity-mortality) has not been clearly elucidated10
*Measurement of active compound in plasma when administered as a maintenance dose
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10. Prasugrel over clopidogrel
• Due to its greater absorption and higher
active metabolite bioavailability rather than
due to differences between drug affinity for
the P2Y12 receptor.
• Diabetics

12. Landmark trials….
• Influenced current recommendations in DAPT
guidelines and lead to change in clinical
practice.

14. Landmark trials….
ISIS-2 (second international study of infarct
survival )- 17,187
Acute STEMI;
• Aspirin alone versus streptokinase alone
versus combination
• Combination reduced mortality Benefits
extended over 10 years
• Aspirin routinely administered in patients with
acute MI.

17. Latest trial with antiplatelets ??

18. PLEASE NOTE THAT USE OF THESE MATERIALS IS SUBJECT TO LOCAL APPROVAL AND MUST BE SIGNED OFF BY
YOUR LOCAL NOMINATED SIGNATORY
Ticagrelor vs clopidogrel after thrombolytic therapy in
patients with ST-elevation myocardial infarction: A
randomized clinical trial
TREAT TRIALTREAT TRIAL
Disclaimer: This presentation contains information on the topic based on recent published literature & international guidelines. The user/presenter of this presentation
at his discretion may modify the contents as may be required. However, the modified version of the presentation shall be reviewed by AstraZeneca Medical Team,
before it can be presented in AstraZeneca driven CMEs. For product information, kindly refer to the full prescribing information.”
Doc No: IN-1545
Approval Date: 8/6/2018
Expiry Date: 8/6/2020

19. 19
OVERVIEW• Burden of the Disease
• Role of Fibrinolytics in STEMI
• Brief look into COMMIT and CLARITY TIMI 28 Trials
• TICAGRELOR – Guideline Recommendations
• TICAGRELOR – Evidence from Trials
• TREAT Trial
• Study rationale and design
• Baseline characteristics
• Selected procedures and other treatment
• Patient CONSORT diagram
• Ticagrelor was non-inferior to clopidogrel for major bleeding at 30 days
• Major bleeding did not differ between ticagrelor or clopidogrel in patients
randomized within 4 hours of fibrinolytic therapy
• Rates of ICH and fatal bleeding were similar between ticagrelor and clopidogrel
• MACE at 30 days was similar between ticagrelor- and clopidogrel-treated patients
• Conclusions
19

20. ST- Elevation Myocardial Infarction
Burden of Disease
20
• Patients with ST elevation myocardial infarction (STEMI)
represent 32% of patients with acute coronary syndrome (ACS)1
• In-hospital mortality ranges from 5% to 15% according to
geographic and baseline differences 1
1. André R, Bongard V, Elosua R, Kirchberger I, Farmakis D, Häkkinen U, et al. International differences in acute coronary syndrome patients’ baseline characteristics, clinical management and outcomes in Western Europe: the EURHOBOP
study. Heart Br Card Soc. 2014;100:1201–7 2. Zhao Z, Winget M. Economic burden of illness of acute coronary syndromes: medical and productivity costs. BMC Health Services Research. 2011;11:35–35.

21. • Fibrinolytic therapy remains an important initial reperfusion strategy in STEMI
when primary PCI cannot be offered within 2 hours of diagnosis (eg in
settings without 24-hour PCI capability or at too great a distance from PCI
facilities).
• Clopidogrel is currently the only P2Y12 inhibitor recommended following
fibrinolysis in the acute phase (within 48 hours following fibrinolysis), based on
data from the COMMIT1
and CLARITY-TIMI 282
trials
• Clopidogrel has limitations - relatively slow onset of effect3
and a variable
antiplatelet effect.4
• Fibrinolysis itself may promote platelet hyperactivity due to thrombin-mediated
platelet stimulation5
.
• A more potent and consistent antiplatelet inhibitor than clopidogrel may
therefore be particularly appropriate in this setting.
21
FIBRINOLYSIS IN STEMI PATIENTS
1. Chen ZM, Jiang LX, Chen YP et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomized placebo-controlled trial. Lancet 2005;366:1607–21 2. Sabatine MS, Cannon CP, Gibson CM et al. Addition of clopidogrel
to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352:1179–89 3. 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;120:2577–85 4. Storey RF, Angiolillo DJ, Patil SB et al. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in
patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy. J Am Coll Cardiol 2010;56:1456–62 5. Zeymer U, Mateblowski M and Neuhaus KL. Thrombin generation in patients with acute myocardial
infarction treated with front-loaded rt-PA and recombinant hirudin (HBW 023). J Thromb Thrombolysis 1998;5:203–7

22. • For 28 days or until hospital discharge, patients in COMMIT were treated
with either
• Clopidogrel 75 mg and aspirin 162 mg
• Placebo and aspirin 162 mg
• Composite outcome of death, reinfarction, or stroke occurred at a
significantly lower rate in patients treated with clopidogrel added to aspirin
compared with patients treated with placebo added to aspirin (9.2% vs
10.1%, p=0.002).
• Outcome of death from any cause also occurred at a lower rate in patients
treated with clopidogrel added to aspirin compared with patients treated
with placebo added to aspirin (7.5% vs 8.1%, p=0.03).
• There was no statistically significant difference in the rates primary safety
end-point of life-threatening bleeding between the 2 treatment groups.
COMMIT TRIAL
.Chen ZM, Jiang LX, Chen YP et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomized placebo-controlled trial. Lancet 2005;366:1607–21

23. • 3,491 patients diagnosed with STEMI within 12 hours of receiving study medications
were also treated with a fibrinolytic agent and, when appropriate, heparin and were
scheduled for angiography in 2-8 days after start of the study medication.
• Patients were treated with either:
• Clopidogrel (300-mg loading dose,
followed by 75 mg once daily)
• Placebo
CLARITY TIMI 28 TRIAL
Major bleeding rates were
similar in the two
treatment groups.
Major bleeding rates were
similar in the two
treatment groups.
Sabatine MS, Cannon CP, Gibson CM et al. Addition of clopidogrel to aspirin and fibrinolytic
therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352:1179–89 Image is used for educational purpose only. AstraZeneca is not responsible for data and copyrights.

24. TICAGRELOR
EVIDENCE FROM THE TRIALS…
24

25. PLATO covered a broad ACS Patient Population
James S, et al. Am Heart J. 2009;157:599-605.
ACS
Patient
STEMI
NSTEMI
Primary PCI
Fibrinolytic
Rx
No Reperf
Early
Invasive Rx
Early Conservative
Rx
PCI
Medical Rx
CABG
PCI
Medical Rx
CABG
• PLATO was a randomised
controlled double-blind
multicentre study (n=18,624),
conducted between 2006
and 2008, which
demonstrated superiority of
the antiplatelet treatment
ticagrelor over clopidogrel in
reducing risk of several
cardiovascular events.
• In STE-ACS patients with
planned primary
percutaneous coronary
intervention (PCI), the effects
of ticagrelor were consistent
with those observed in the
overall PLATO trial.
James S, et al. Am Heart J. 2009;157:599-605.

26. 26
GAP IN THE
EVIDENCE?
Long-term use? After Fibrinolysis?
• PEGASUS-TIMI 54 is the first prospective, appropriately powered,
randomized controlled clinical trial to demonstrate the benefit of long-term
DAPT in a high-risk, post-MI patient population
• The study demonstrated that the addition of ticagrelor 60 mg bid to low-
dose ASA in patients 1–3 years after a MI significantly reduced the risk of
the primary endpoint, the composite of CV death, MI or stroke4
Bonaca MP et al. N Engl J Med 2015;372:1791–1800

27. Study rationale and design
27
1. Ibanez B et al. Eur Heart J 2018;39:119–177; 2. Wallentin L et al. N Engl J Med 2009;361:1045–1057; 3. Steg PG et al. Circulation 2014;123:2736–2747; 4. Berwanger O et al. JAMA Cardiol 2018
doi:10.1001/jamacardio.2018.0612
Whilst PCI is the preferred reperfusion strategy for patients with
STEMI,1
it is not always possible for patients to be treated at
hospitals with PCI capabilities in a timely manner, and as a result
many STEMI patients may receive fibrinolytic therapy.
PLATO demonstrated the superiority of ticagrelor 90 mg vs
clopidogrel for the prevention of major CV events over 12 months in
ACS patients,2
including in STEMI patients;3
however, PLATO did not
include patients who received fibrinolytic therapy in the
preceding 24 hours

28. Study rationale and design
28
1. Ibanez B et al. Eur Heart J 2018;39:119–177; 2. Wallentin L et al. N Engl J Med 2009;361:1045–1057; 3. Steg PG et al. Circulation 2014;123:2736–2747; 4. Berwanger O et al. JAMA Cardiol 2018 doi:10.1001/jamacardio.2018.0612
Current guidelines prefer ticagrelor over clopidogrel in the primary
PCI setting, as well as for maintenance therapy for at least 12
months post-STEMI, but clopidogrel is the only P2Y12 inhibitor
recommended for use following fibrinolytic therapy, with ticagrelor
initiated 36-48 hours after fibrinolytic treatment
Large scale RCTs exploring use of ticagrelor in STEMI patients
treated with fibrinolytic therapy have not been conducted, and there
remains a perceived concern about the risk of bleeding in this
population, necessitating evaluation of the safety of ticagrelor in this
setting

29. Study rationale and design
29
*Participating countries: Argentina, Australia, Brazil, Canada, China, Columbia, New Zealand, Peru, Russia and Ukraine
bid, twice-daily; CV, cardiovascular; ECG, electro-cardiogram; LD, loading dose; MI, myocardial infarction; qd, once-daily; TIA, transient ischaemic attack
1. Ibanez B et al. Eur Heart J 2018;39:119–177; 2. Wallentin L et al. N Engl J Med 2009;361:1045–1057; 3. Steg PG et al. Circulation 2014;123:2736–2747; 4. Berwanger O et al. JAMA Cardiol 2018
doi:10.1001/jamacardio.2018.0612
Primary safety endpoint: Time to TIMI-defined first major bleeding at 30 days
Secondary safety endpoints: PLATO major bleeding and BARC categories 3–5 bleeding; ICH; fatal
bleeding
Secondary efficacy endpoints: Composite of death from vascular causes, MI or stroke; composite
of death from vascular causes, MI, stroke, recurrent ischaemia, TIA or other arterial events; individual
components of these composites; all-cause mortality
Duration of follow-up: 12 months
Clopidogrel
(N=1886)
300–600 mg LD
then 75 mg qd
maintenance
Ticagrelor
(N=1913)
180 mg LD
then 90 mg bid
maintenance
LD administered as early as possible after index event and not >24 hours
post-event
All patients received ASA at hospitalization, continued at discharge
The TREAT study:4
Multinational*, open-label, randomized, Phase III trial to assess safety and efficacy of ticagrelor vs
clopidogrel in patients aged 18–75 years, diagnosed with STEMI ≤24 hours prior to randomization,
with documented cardiac ischaemic symptoms due to atherosclerosis >10 minutes duration at rest
and treated with pharmacological thrombolysis (N=3799)
Image is used for educational purpose only. AstraZeneca is not responsible for data and
copyrights.

30. Baseline characteristics (1 of 2)
30
Characteristics Ticagrelor (N=1913) Clopidogrel (N=1886)
Median age, years (IQR) 59 (51.6–65.2) 58.8 (51.6–65.5)
Female sex, n/N (%) 433/1913 (22.6) 438/1886 (23.2)
Median body weight, kg (IQR) 76.5 (68.0–88.0) [N=1911] 77.0 (67.0–87.0) [N=1885]
Body weight <60 kg, n/N (%) 148/1911 (7.7) 150/1885 (8.0)
Median BMI, kg/m² (IQR) 26.5 (24.0–29.8) [N=1909] 26.5 (24.0–29.4) [N=1881]
Race, n/N (%)*
White 1100/1913 (57.5) 1077/1886 (57.1)
Black 73/1913 (3.8) 61/1886 (3.2)
Asian 631/1913 (33.0) 639/1886 (33.9)
Other 109/1913 (5.7) 109/1886 (5.8)
Cardiovascular risk factor, n/N (%)
Never smoked 629/1913 (32.9) 649/1886 (34.4)
Previous smoker 403/1913 (21.1) 359/1886 (19.0)
Habitual smoker 881/1913 (46.1) 878/1886 (46.6)
Hypertension 1072/1913 (56.0) 1071/1886 (56.8)
Dyslipidaemia 524/1913 (27.4) 525/1886 (27.8)
Diabetes Mellitus 332/1913 (17.4) 303/1886 (16.1)
Other medical history, n/N (%)
MI 178/1913 (9.3) 150/1886 (8.0)
Stroke 83/1913 (4.3) 84/1886 (4.5)
PCI 113/1913 (5.9) 100/1886 (5.3)
CABG 15/1913 (0.8) 13/1886 (0.7)
Congestive heart failure 38/1913 (2.0) 37/1886 (2.0)
Peripheral arterial disease 17/1913 (0.9) 16/1886 (0.8)
Atrial fibrillation 21/1913 (1.1) 24/1886 (1.3)
*Race was self-reported
BMI, body mass index; CABG, coronary artery bypass graft; IQR, interquartile range
Berwanger O et al. JAMA Cardiol 2018 doi:10.1001/jamacardio.2018.0612
Image is used for educational purpose only. AstraZeneca is not responsible for data and copyrights.

31. Baseline characteristics (2 of 2)
31
Characteristics Ticagrelor (N=1913) Clopidogrel (N=1886)
ECG findings at study entry, n/N (%)
ST-elevation (anterior alone) 638/1905 (33.5) 663/1878 (35.3)
ST-elevation (anterior and
inferior)
62/1905 (3.3) 59/1878 (3.1)
ST-elevation (inferior alone) 590/1905 (31.0) 567/1878 (30.2)
ST-elevation (other) 294/1905 (15.4) 301/1878 (16.0)
Left bundle block 20/1905 (1.0) 25/1878 (1.4)
Positive troponin I test at study
entry, n/N (%)
1542/1752 (88.0) 1506/1728 (87.2)
Killip class (II, III or IV), n/N (%) 152/1913 (7.9) 164/1886 (8.7)
Berwanger O et al. JAMA Cardiol 2018 doi:10.1001/jamacardio.2018.0612
Image is used for educational purpose only. AstraZeneca is not responsible for data and copyrights.

32. Selected procedures and other
treatment*
32
Characteristics Ticagrelor (N=1913) Clopidogrel (N=1886)
Time from symptom to fibrinolytic administration, hours (IQR) 2.6 (1.5–4.3) [N=1899] 2.6 (1.5–4.4) [N=1870)
Time from fibrinolytic administration to randomization, hours (IQR) 11.4 (5.7–18.1) [N=1899] 11.2 (5.8–18.2) [N=1870]
Fibrinolytic therapy, n/N (%)
Tenecteplase 757/1911 (39.6) 750/1884 (39.8)
Alteplase 377/1911 (19.7) 362/1884 (19.2)
Reteplase 322/1911 (16.8) 313/1884 (16.6)
Prourokinase 134/1911 (7.0) 141/1884 (7.5)
Urokinase 131/1911 (6.9) 135/1884 (7.2)
Streptokinase 109/1911 (5.7) 106/1884 (5.6)
Other 81/1911 (4.2) 77/1884 (4.1)
Clopidogrel administered before randomization, n/N (%)
No or less than 300 mg 195/1898 (10.3) 202/1876 (10.8)
300 mg 1652/1898 (87.0) 1614/1876 (86.0)
More than 300 mg 51/1898 (2.7) 60/1876 (3.2)
In-hospital ASA treatment, n/N (%) 1890/1913 (98.8) 1865/1886 (98.9)
Invasive procedure performed during index hospitalization, n/N (%)
PCI 1084/1913 (56.7) 1048/1886 (55.6)
DES 653/1913 (34.1) 623/1886 (33.0)
Within 24 hours after randomization 811/1913 (42.4) 792/1886 (42.0)
Cardiac surgery during hospitalization 32/1913 (1.7) 39/1886 (2.1)
Within 24 hours after randomization 0/1913 (0) 3/1886 (0.2)
Within 7 days after randomization 9/1913 (0.5) 9/1886 (0.5)
Adherence to study drug at 30 days’ follow-up,†
n/N (%)
0–80% 231/1907 (12.1) 205/1875 (10.9)
80–90% 61/1907 (3.2) 64/1875 (3.4)
90–100% 1615/1907 (84.7) 1606/1875 (85.7)
*Please refer to Table e1 of the publication for full details; †
Adherence to the study drug was defined as use of 0–80%, 80–90% and 90–100% of the study medication during each interval between visits,
as assessed by the site investigator DES, drug eluting stent
Berwanger O et al. JAMA Cardiol 2018 doi:10.1001/jamacardio.2018.0612 Image is used for educational purpose only. AstraZeneca is not responsible for data and copyrights.

33. Patient CONSORT diagram
33
* Plus low-dose ASA
TREAT patients
N=3799
1913 randomized to ticagrelor*
- 1908 received intervention as
randomized
- 5 did not receive intervention as
randomized (did not receive a
dose) [0.3%]
1886 randomized to clopidogrel*
- 1880 received intervention as
randomized
- 6 did not receive intervention as
randomized (did not receive a
dose) [0.3%]
1913 included in
primary safety analysis
1886 included in
primary safety analysis
2 withdrew consent [0.1%]
- 1 vital status known
- 1 vital status unknown
3 lost to follow-up [0.2%]
5 withdrew consent [0.3%]
- 2 vital status known
- 3 vital status unknown
2 lost to follow-up [0.1%]
Berwanger O et al. JAMA Cardiol 2018 doi:10.1001/jamacardio.2018.0612 Image is used for educational purpose only. AstraZeneca is not responsible for data and copyrights.

34. clopidogrel for major bleeding at 30
days (TIMI, PLATO and BARC
definitions)
34
Safety end point at 30 daysTicagrelor (N=1913)Clopidogrel (N=1886) Difference in percentage
points (95% CI)
P value
TIMI major bleeding
PLATO major bleeding
BARC type 3–5 bleeding
14 (0.73)
23 (1.20)
23 (1.20)
13 (0.69)
26 (1.38)
26 (1.38)
0.04 (-0.49–0.58)
-0.18 (-0.89–0.54)
-0.18 (-0.89–0.54)
<0.001
0.001
0.001
-1.0 -0.5 0.0 0.5 1.0 1.5
Ticagrelor better Clopidogrel better
Berwanger O et al. JAMA Cardiol. doi:10.1001/jamacardio.2018.0612 Published online March 11, 2018.
Image is used for educational purpose only. AstraZeneca is not responsible for data and copyrights.

35. Rates of ICH and fatal bleeding
were similar between ticagrelor and
clopidogrel
35
End point at 30 days Ticagrelor (N=1913) Clopidogrel (N=1886)
P value for
noninferiority
ICH, % 0.42 0.37 0.82
Fatal bleeding, % 0.16 0.11 0.67
Berwanger O et al. JAMA Cardiol 2018 doi:10.1001/jamacardio.2018.0612
Image is used for educational purpose only. AstraZeneca is not responsible for data and copyrights.

36. MACE at 30 days were similar
between ticagrelor- and
clopidogrel-treated patients
36
Note: These are selected data, please refer to Table 3 of the publication for full details
Secondary efficacy outcomes were exploratory in nature
12 month outcomes are yet to be reported
Berwanger O et al. JAMA Cardiol 2018 doi:10.1001/jamacardio.2018.0612
Image is used for educational purpose only. AstraZeneca is not responsible for data and copyrights.
*Calculated by Cox regression analysis; †
Post-hoc analysis
End point at 30 days
Ticagrelor (N=1913),
n (%)
Clopidogrel (N=1886),
n (%)
Difference, % (95% CI) P value*
Death from vascular causes, MI, or
stroke
76 (4.0) 82 (4.3) 0.91 (0.67–1.25) 0.57
Death from vascular causes, MI, or
non-haemorrhagic stroke†
70 (3.7) 77 (4.1) 0.90 (0.65–1.24) 0.50
Death from vascular causes, MI,
stroke, severe recurrent ischaemia,
recurrent ischaemia, TIA, or other
arterial thrombotic event
98 (5.1) 95 (5.0) 1.02 (0.77–1.35) 0.90
MI or death†
61 (3.2) 67 (3.6) 0.90 (0.63–1.27) 0.54
MI or stroke†
38 (2.0) 44 (2.3) 0.85 (0.55–1.31) 0.47
Death from vascular causes 47 (2.5) 49 (2.6) 0.95 (0.63–1.41) 0.79
MI 20 (1.0) 25 (1.3) 0.79 (0.44–1.42) 0.43
Total stroke 18 (0.9) 20 (1.1) 0.89 (0.47–1.68) 0.71
Death from any cause 49 (2.6) 49 (2.6) 0.99 (0.66–1.47) 0.95

37. SUMMARY
37
1. Berwanger O et al. JAMA Cardiol 2018 doi:10.1001/jamacardio.2018.0612; 2. Dehghani P et al. Am Heart J 2017;192:105–112; 3. Guimarães LFC et al. Int J Cardiol 2017;230:204–208;
4. Alexopoulos D et al. J Thromb Thrombolyis 2015;40:261–267; 5. Ibanez B et al. Eur Heart J 2018;39:119–177
 STEMI patients <75 years treated with fibrinolytic therapy  ticagrelor non-inferior to
clopidogrel for major bleeding at 30 days1
 Rates of fatal and intracranial bleeding were similar between ticagrelor and clopidogrel;
however rates of minor, minimal and total bleeding events were numerically higher with
ticagrelor1
 TREAT Results are consistent with smaller trials exploring ticagrelor use in patients
receiving fibrinolytic therapy2–4
 Given that current STEMI guidelines recommend ticagrelor should only be initiated after 36-
48 hours following fibrinolysis,5
this trial adds new and important information to practicing
physicians
 The majority of patients received clopidogrel pre-randomization, and based on the results,
STEMI patients aged <75 years who initially receive clopidogrel can be safely switched to
ticagrelor in the first 24 hours after fibrinolysis

38. CONCLUSION
• PLATO provided the evidence for the Class IA guideline
recommendations and preferential use of ticagrelor 90 mg*
over clopidogrel* in patients with STEMI undergoing primary
PCI.1-3
• Together with PLATO, TREAT provides evidence that ticagrelor
can be used in STEMI regardless of the reperfusion strategy
38
1. Wallentin L, Becker RC, Budaj A et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57
2. Ibanez B, James S, Agewall S et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2018;39:119–77
3. Levine GN, Bates ER, Blankenship JC et al. 2015 ACC/AHA/SCAI focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI
guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. J Am Coll Cardiol 2016;67:1235–50

39. Landmark trials….
• NOAC with DAPT

40. • The WOEST Trial: First randomised trial
comparing two regimens with and without
aspirin in patients on oral anticoagulant
therapy undergoing coronary stenting

44. • Conclusions
• 1.First randomized trial to address the optimal antiplatelet
therapy in patients on OAC undergoing coronary stenting
• 2.Primary endpoint was met: as expected, OAC plus
clopidogrel causes less bleeding than triple antithrombotic
therapy, but now shown in a randomized way
• 3.Secondary endpoint was met: with dual therapy there is
no excess of thrombotic/thromboembolic events: stroke,
stent thrombosis, target vessel revascularisation, myocardial
infarction or death
• 4.Less all-cause mortality with dual therapy

45. PIONEER AF-PCI

46. • Rivaroxaban 15 mg OD plus single antiplatelet
therapy was associated with a 41% risk
reduction versus VKA plus DAPT treatment
16.8% and rivaroxaban 2.5 mg BID plus DAPT
was associated with a 37% risk reduction
• rivaroxaban-based strategies were associated
with improved safety compared with a
standard VKA-based triple therapy strategy in
patients with AF undergoing PCI

48. Study Design: Multicenter, randomized,
open-label trial following a PROBE
design
R
Randomization
≤120 hours
post-PCI* 6-month minimum treatment duration with visits every 3 months for the first year, then
visits and telephone contact alternating every 3 months and a 1-month post-
treatment visit
Patients
with AF
undergoing
PCI with
stenting
Dabigatran 150 mg BID + P2Y12
inhibitor
Dabigatran 110 mg BID + P2Y12
inhibitor
Warfarin (INR 2.0–3.0) + P2Y12 inhibitor + ASA
N=27
25
Mean duration of
follow-up:
~14 months
Dabigatran (110 or 150 mg) P2Y12 inhibitor
Warfarin P2Y12 inhibitor
1 month of ASA (BMS) 3 months of ASA (DES)
*Study drug should be administered 6 hours after sheath removal and no
later than ≤120 hrs post-PCI (≤72 hrs is preferable). PROBE, prospective,
randomized, open, blinded end-point; R, randomization; BMS, bare metal
stent; DES, drug-eluting stent. ClinicalTrials.gov: NCT02164864; Cannon et al.
Clin Cardiol 2016

49. Conclusions
In patients with AF who have undergone
PCI:
Dual therapy with dabigatran and a P2Y12 antagonist significantly reduced
the risk of bleeding versus warfarin triple therapy, with non-inferiority for
overall thromboembolic events
Absolute risk reductions with dabigatran dual therapy were 11.5% and 5.5% in
ISTH major or clinically relevant non-major bleeding at the 110 mg and
150 mg doses, respectively, compared with warfarin triple therapy

50. • Management of bleeding in patients treated
with dual antiplatelet therapy with or without
concomitant oral anticoagulation

56. Bleeding with NOAC
• W/H anticoagulant and antiplatelet
• Resuscitation with fluid and Blood products
eg. PTCC 50 U/kg, Factors VIIa
• All patients should receive supportive measures, including
mechanical compression and endoscopic or surgical
hemostasis (if applicable).
• Following a major gastrointestinal bleeding event, NOACs
should be restarted as early as feasible (usually 4-7 days) if
the risk of stroke persists and outweighs the risk of
recurrent bleeding.
• Oral Activated charcoal-absorption in 4-6 hrs
• HD- Dabigatran
• Antidotes

57. Antidote Structure Site of action Mech. Of
Action
Dose
Idarucizumab Humanised
Antibody
Fragemnt
Dabigatran Binds with High
Affinity
5 mg IV in two
doses no more
than 15
minutes apart.
Andexaneata
alfa
Recombinant
Human Factor
Xa
Universal for all
Xa Inhibtiors
Competes with
Xa Inhibitors
400mg iv
bolus,2h
infusion at
4mg/min
Cirapantag/
Aripazine
Water soluble
cation
Dabigatran,
Edoxaban
Competes 100-300mg iv
single dose

58. Take home message
• Non P2Y12 antagonist affects of ticagrelor
• Post thrombolysis ticagrelor is non inferior to
clopidogrel
• Landmark trials
• Management of Bleeding with DAPT + OAC