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Back to Basicsā€¦ā€¦
ā€¢ Pharmacology of antithrombotic drugs
Jessica L Mega, Tabassome Simon
Lancet 2015; 386: 281ā€“91
ā€¢ Why we give loading dose ?
ā€¢ Why ticlopidine was replaced with clopidogrel
ā€¢ Advantage of prasugrel over clopidogrel ?
ā€¢ Smoker paradox
ā€¢ Non P2Y12 antagonist affects of ticagrelor ?
ā€¢ Mechanism of dyspnoea with Ticagrelor ?
ā€¢ High dose of Aspirin with ticagrelor ?
ā€¢ Special groups for prasugrel and ticagrelor ?
Aspirin and P2Y12 receptor
antagonists
ā€¢ 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.
ā€¢ Onset of clopidogrel antiplatelet action is
reported at 2 h after a 600 mg, compared with
after 30 min for prasugrel and ticagrelor
Do all P2Y12 inhibitors work the same
way?
6
1. Capodanno D et al. Expert Rev Cardiovasc Ther 2010;8:151ā€“158; 2. Cattaneo M et al. J Am Coll Cardiol 2014;63:2503ā€“2509
Figure adapted from Dorsam RT & Kunapuli SP. J Clin Invest 2004;113:340ā€“345
CPTP: Ticagrelor
Thienopyridines:
Clopidogrel
Prasugrel
CYP450
metabolism
ā€¢ Prodrugs requiring
activation
ā€¢ Covalently binding
(irreversible)
ā€¢ Direct acting
ā€¢ Reversibly binding
ENT-1
Active
metabolite
ADP
Adenosine
x
Platelet activation
P2Y12
A2A
x
x x
Inhibition of P2Y12 receptor1
ā€’Antiplatelet effect
Inhibition of ENT-1 transporter2
Enhanced local adenosine response may provide:
ā€“ Additional inhibition of platelet
aggregation/activation
ā€“ 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
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Non P2Y12 antagonist affects of ticagrelor
ā€¢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
ā€¢stimulation of pulmonary vagal C fibres that might induce
dyspnoea.
How is ticagrelor different to the thienopyridines?
9
CPTP (ticagrelor)
Thienopyridines
(ticlopidine, clopidogrel, prasugrel)
Inhibition
of P2Y12
ā€¢ Direct acting1,2
ā€¢ 24-hour systemic exposure* to the
directly active compound (when dosed
twice daily)3
ā€¢ Reversible binding to P2Y12 receptor4
ā€¢ Prodrugsrequiring metabolic activation1,2,5
ā€¢ 2ā€“4 hours of systemic exposure* to the active
metabolite9
ā€¢ Covalent, irreversible, binding to P2Y12 receptor1
Inhibition
of ENT-1
ā€¢ Inhibition of ENT-1 providing an
enhanced endogenous adenosine
response6-9
ā€¢ 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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Prasugrel over clopidogrel
ā€¢ Due to its greater absorption and higher
active metabolite bioavailability rather than
due to differences between drug affinity for
the P2Y12 receptor.
ā€¢ Diabetics
Landmark trialsā€¦.
ā€¢ Influenced current recommendations in DAPT
guidelines and lead to change in clinical
practice.
Landmark trialsā€¦.
ļ¶ISIS-2 (second international study of infarct
survival )- 17,187
Acute STEMI;
ā€¢ Aspirin alone versus streptokinase alone
versus combination
ā€¢ Combination reduced mortality Benefits
extended over 10 years
ā€¢ Aspirin routinely administered in patients with
acute MI.
Latest trial with antiplatelets ??
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.ā€
Doc No: IN-1545
Approval Date: 8/6/2018
Expiry Date: 8/6/2020
19
OVERVIEWā€¢ Burden of the Disease
ā€¢ Role of Fibrinolytics in STEMI
ā€¢ Brief look into COMMIT and CLARITY TIMI 28 Trials
ā€¢ TICAGRELOR ā€“ Guideline Recommendations
ā€¢ TICAGRELOR ā€“ Evidence from Trials
ā€¢ TREAT Trial
ā€¢ Study rationale and design
ā€¢ Baseline characteristics
ā€¢ Selected procedures and other treatment
ā€¢ Patient CONSORT diagram
ā€¢ Ticagrelor was non-inferior to clopidogrel for major bleeding at 30 days
ā€¢ Major bleeding did not differ between ticagrelor or clopidogrel in patients
randomized within 4 hours of fibrinolytic therapy
ā€¢ Rates of ICH and fatal bleeding were similar between ticagrelor and clopidogrel
ā€¢ MACE at 30 days was similar between ticagrelor- and clopidogrel-treated patients
ā€¢ Conclusions
19
ST- Elevation Myocardial Infarction
Burden of Disease
20
ā€¢ Patients with ST elevation myocardial infarction (STEMI)
represent 32% of patients with acute coronary syndrome (ACS)1
ā€¢ In-hospital mortality ranges from 5% to 15% according to
geographic and baseline differences 1
1. AndrĆ© R, Bongard V, Elosua R, Kirchberger I, Farmakis D, HƤkkinen U, et al. International differences in acute coronary syndrome patientsā€™ baseline characteristics, clinical management and outcomes in Western Europe: the EURHOBOP
study. Heart Br Card Soc. 2014;100:1201ā€“7 2. Zhao Z, Winget M. Economic burden of illness of acute coronary syndromes: medical and productivity costs. BMC Health Services Research. 2011;11:35ā€“35.
ā€¢ 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).
ā€¢ 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
ā€¢ Clopidogrel has limitations - relatively slow onset of effect3
and a variable
antiplatelet effect.4
ā€¢ Fibrinolysis itself may promote platelet hyperactivity due to thrombin-mediated
platelet stimulation5
.
ā€¢ 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;366:1607ā€“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;352:1179ā€“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;120:2577ā€“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;56:1456ā€“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;5:203ā€“7
ā€¢ For 28 days or until hospital discharge, patients in COMMIT were treated
with either
ā€¢ Clopidogrel 75 mg and aspirin 162 mg
ā€¢ Placebo and aspirin 162 mg
ā€¢ 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).
ā€¢ 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).
ā€¢ 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;366:1607ā€“21
ā€¢ 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.
ā€¢ Patients were treated with either:
ā€¢ Clopidogrel (300-mg loading dose,
followed by 75 mg once daily)
ā€¢ 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;352:1179ā€“89 Image is used for educational purpose only. AstraZeneca is not responsible for data and copyrights.
TICAGRELOR
EVIDENCE FROM THE TRIALSā€¦
24
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
ā€¢ 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.
ā€¢ 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
GAP IN THE
EVIDENCE?
Long-term use? After Fibrinolysis?
ā€¢ 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
ā€¢ The study demonstrated that the addition of ticagrelor 60 mg bid to low-
dose ASA in patients 1ā€“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;372:1791ā€“1800
Study rationale and design
27
1. Ibanez B et al. Eur Heart J 2018;39:119ā€“177; 2. Wallentin L et al. N Engl J Med 2009;361:1045ā€“1057; 3. Steg PG et al. Circulation 2014;123:2736ā€“2747; 4. Berwanger O et al. JAMA Cardiol 2018
doi:10.1001/jamacardio.2018.0612
ļ‚§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.
ļ‚§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
Study rationale and design
28
1. Ibanez B et al. Eur Heart J 2018;39:119ā€“177; 2. Wallentin L et al. N Engl J Med 2009;361:1045ā€“1057; 3. Steg PG et al. Circulation 2014;123:2736ā€“2747; 4. Berwanger O et al. JAMA Cardiol 2018 doi:10.1001/jamacardio.2018.0612
ļ‚§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
ļ‚§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
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;39:119ā€“177; 2. Wallentin L et al. N Engl J Med 2009;361:1045ā€“1057; 3. Steg PG et al. Circulation 2014;123:2736ā€“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 3ā€“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)
300ā€“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 18ā€“75 years, diagnosed with STEMI ā‰¤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.
Baseline characteristics (1 of 2)
30
Characteristics Ticagrelor (N=1913) Clopidogrel (N=1886)
Median age, years (IQR) 59 (51.6ā€“65.2) 58.8 (51.6ā€“65.5)
Female sex, n/N (%) 433/1913 (22.6) 438/1886 (23.2)
Median body weight, kg (IQR) 76.5 (68.0ā€“88.0) [N=1911] 77.0 (67.0ā€“87.0) [N=1885]
Body weight <60 kg, n/N (%) 148/1911 (7.7) 150/1885 (8.0)
Median BMI, kg/mĀ² (IQR) 26.5 (24.0ā€“29.8) [N=1909] 26.5 (24.0ā€“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.
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.
Selected procedures and other
treatment*
32
Characteristics Ticagrelor (N=1913) Clopidogrel (N=1886)
Time from symptom to fibrinolytic administration, hours (IQR) 2.6 (1.5ā€“4.3) [N=1899] 2.6 (1.5ā€“4.4) [N=1870)
Time from fibrinolytic administration to randomization, hours (IQR) 11.4 (5.7ā€“18.1) [N=1899] 11.2 (5.8ā€“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 daysā€™ follow-up,ā€ 
n/N (%)
0ā€“80% 231/1907 (12.1) 205/1875 (10.9)
80ā€“90% 61/1907 (3.2) 64/1875 (3.4)
90ā€“100% 1615/1907 (84.7) 1606/1875 (85.7)
*Please refer to Table e1 of the publication for full details; ā€ 
Adherence to the study drug was defined as use of 0ā€“80%, 80ā€“90% and 90ā€“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.
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.
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 3ā€“5 bleeding
14 (0.73)
23 (1.20)
23 (1.20)
13 (0.69)
26 (1.38)
26 (1.38)
0.04 (-0.49ā€“0.58)
-0.18 (-0.89ā€“0.54)
-0.18 (-0.89ā€“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.
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.
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; ā€ 
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 (0.67ā€“1.25) 0.57
Death from vascular causes, MI, or
non-haemorrhagic strokeā€ 
70 (3.7) 77 (4.1) 0.90 (0.65ā€“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 (0.77ā€“1.35) 0.90
MI or deathā€ 
61 (3.2) 67 (3.6) 0.90 (0.63ā€“1.27) 0.54
MI or strokeā€ 
38 (2.0) 44 (2.3) 0.85 (0.55ā€“1.31) 0.47
Death from vascular causes 47 (2.5) 49 (2.6) 0.95 (0.63ā€“1.41) 0.79
MI 20 (1.0) 25 (1.3) 0.79 (0.44ā€“1.42) 0.43
Total stroke 18 (0.9) 20 (1.1) 0.89 (0.47ā€“1.68) 0.71
Death from any cause 49 (2.6) 49 (2.6) 0.99 (0.66ā€“1.47) 0.95
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;192:105ā€“112; 3. GuimarĆ£es LFC et al. Int J Cardiol 2017;230:204ā€“208;
4. Alexopoulos D et al. J Thromb Thrombolyis 2015;40:261ā€“267; 5. Ibanez B et al. Eur Heart J 2018;39:119ā€“177
ļ‚§ STEMI patients <75 years treated with fibrinolytic therapy ļƒØ ticagrelor non-inferior to
clopidogrel for major bleeding at 30 days1
ļ‚§ 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
ļ‚§ TREAT Results are consistent with smaller trials exploring ticagrelor use in patients
receiving fibrinolytic therapy2ā€“4
ļ‚§ 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
ļ‚§ 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
CONCLUSION
ā€¢ 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
ā€¢ 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;361:1045ā€“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;39:119ā€“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;67:1235ā€“50
Landmark trialsā€¦.
ā€¢ NOAC with DAPT
ā€¢ The WOEST Trial: First randomised trial
comparing two regimens with and without
aspirin in patients on oral anticoagulant
therapy undergoing coronary stenting
ā€¢ Conclusions
ā€¢ 1.First randomized trial to address the optimal antiplatelet
therapy in patients on OAC undergoing coronary stenting
ā€¢ 2.Primary endpoint was met: as expected, OAC plus
clopidogrel causes less bleeding than triple antithrombotic
therapy, but now shown in a randomized way
ā€¢ 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
ā€¢ 4.Less all-cause mortality with dual therapy
PIONEER AF-PCI
ā€¢ 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
ā€¢ rivaroxaban-based strategies were associated
with improved safety compared with a
standard VKA-based triple therapy strategy in
patients with AF undergoing PCI
Study Design: Multicenter, randomized,
open-label trial following a PROBE
design
R
Randomization
ā‰¤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 2.0ā€“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 ā‰¤120 hrs post-PCI (ā‰¤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
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
ā€¢ Management of bleeding in patients treated
with dual antiplatelet therapy with or without
concomitant oral anticoagulation
Bleeding with NOAC
ā€¢ W/H anticoagulant and antiplatelet
ā€¢ Resuscitation with fluid and Blood products
eg. PTCC 50 U/kg, Factors VIIa
ā€¢ All patients should receive supportive measures, including
mechanical compression and endoscopic or surgical
hemostasis (if applicable).
ā€¢ 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.
ā€¢ Oral Activated charcoal-absorption in 4-6 hrs
ā€¢ HD- Dabigatran
ā€¢ Antidotes
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
Take home message
ā€¢ Non P2Y12 antagonist affects of ticagrelor
ā€¢ Post thrombolysis ticagrelor is non inferior to
clopidogrel
ā€¢ Landmark trials
ā€¢ Management of Bleeding with DAPT + OAC

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2017 dapt slide set2

  • 1.
  • 2. Back to Basicsā€¦ā€¦ ā€¢ Pharmacology of antithrombotic drugs Jessica L Mega, Tabassome Simon Lancet 2015; 386: 281ā€“91
  • 3. ā€¢ Why we give loading dose ? ā€¢ Why ticlopidine was replaced with clopidogrel ā€¢ Advantage of prasugrel over clopidogrel ? ā€¢ Smoker paradox ā€¢ Non P2Y12 antagonist affects of ticagrelor ? ā€¢ Mechanism of dyspnoea with Ticagrelor ? ā€¢ High dose of Aspirin with ticagrelor ? ā€¢ Special groups for prasugrel and ticagrelor ?
  • 4. Aspirin and P2Y12 receptor antagonists ā€¢ 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. ā€¢ 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;8:151ā€“158; 2. Cattaneo M et al. J Am Coll Cardiol 2014;63:2503ā€“2509 Figure adapted from Dorsam RT & Kunapuli SP. J Clin Invest 2004;113:340ā€“345 CPTP: Ticagrelor Thienopyridines: Clopidogrel Prasugrel CYP450 metabolism ā€¢ Prodrugs requiring activation ā€¢ Covalently binding (irreversible) ā€¢ Direct acting ā€¢ Reversibly binding ENT-1 Active metabolite ADP Adenosine x Platelet activation P2Y12 A2A x x x Inhibition of P2Y12 receptor1 ā€’Antiplatelet effect Inhibition of ENT-1 transporter2 Enhanced local adenosine response may provide: ā€“ Additional inhibition of platelet aggregation/activation ā€“ 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 ā€¢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 ā€¢stimulation of pulmonary vagal C fibres that might induce dyspnoea.
  • 8.
  • 9. How is ticagrelor different to the thienopyridines? 9 CPTP (ticagrelor) Thienopyridines (ticlopidine, clopidogrel, prasugrel) Inhibition of P2Y12 ā€¢ Direct acting1,2 ā€¢ 24-hour systemic exposure* to the directly active compound (when dosed twice daily)3 ā€¢ Reversible binding to P2Y12 receptor4 ā€¢ Prodrugsrequiring metabolic activation1,2,5 ā€¢ 2ā€“4 hours of systemic exposure* to the active metabolite9 ā€¢ Covalent, irreversible, binding to P2Y12 receptor1 Inhibition of ENT-1 ā€¢ Inhibition of ENT-1 providing an enhanced endogenous adenosine response6-9 ā€¢ 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 Image is used for educational purpose only. AstraZeneca is not responsible for data and copyrights.
  • 10. Prasugrel over clopidogrel ā€¢ Due to its greater absorption and higher active metabolite bioavailability rather than due to differences between drug affinity for the P2Y12 receptor. ā€¢ Diabetics
  • 11.
  • 12. Landmark trialsā€¦. ā€¢ Influenced current recommendations in DAPT guidelines and lead to change in clinical practice.
  • 13.
  • 14. Landmark trialsā€¦. ļ¶ISIS-2 (second international study of infarct survival )- 17,187 Acute STEMI; ā€¢ Aspirin alone versus streptokinase alone versus combination ā€¢ Combination reduced mortality Benefits extended over 10 years ā€¢ Aspirin routinely administered in patients with acute MI.
  • 15.
  • 16.
  • 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.ā€ Doc No: IN-1545 Approval Date: 8/6/2018 Expiry Date: 8/6/2020
  • 19. 19 OVERVIEWā€¢ Burden of the Disease ā€¢ Role of Fibrinolytics in STEMI ā€¢ Brief look into COMMIT and CLARITY TIMI 28 Trials ā€¢ TICAGRELOR ā€“ Guideline Recommendations ā€¢ TICAGRELOR ā€“ Evidence from Trials ā€¢ TREAT Trial ā€¢ Study rationale and design ā€¢ Baseline characteristics ā€¢ Selected procedures and other treatment ā€¢ Patient CONSORT diagram ā€¢ Ticagrelor was non-inferior to clopidogrel for major bleeding at 30 days ā€¢ Major bleeding did not differ between ticagrelor or clopidogrel in patients randomized within 4 hours of fibrinolytic therapy ā€¢ Rates of ICH and fatal bleeding were similar between ticagrelor and clopidogrel ā€¢ MACE at 30 days was similar between ticagrelor- and clopidogrel-treated patients ā€¢ Conclusions 19
  • 20. ST- Elevation Myocardial Infarction Burden of Disease 20 ā€¢ Patients with ST elevation myocardial infarction (STEMI) represent 32% of patients with acute coronary syndrome (ACS)1 ā€¢ In-hospital mortality ranges from 5% to 15% according to geographic and baseline differences 1 1. AndrĆ© R, Bongard V, Elosua R, Kirchberger I, Farmakis D, HƤkkinen U, et al. International differences in acute coronary syndrome patientsā€™ baseline characteristics, clinical management and outcomes in Western Europe: the EURHOBOP study. Heart Br Card Soc. 2014;100:1201ā€“7 2. Zhao Z, Winget M. Economic burden of illness of acute coronary syndromes: medical and productivity costs. BMC Health Services Research. 2011;11:35ā€“35.
  • 21. ā€¢ 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). ā€¢ 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 ā€¢ Clopidogrel has limitations - relatively slow onset of effect3 and a variable antiplatelet effect.4 ā€¢ Fibrinolysis itself may promote platelet hyperactivity due to thrombin-mediated platelet stimulation5 . ā€¢ 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;366:1607ā€“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;352:1179ā€“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;120:2577ā€“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;56:1456ā€“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;5:203ā€“7
  • 22. ā€¢ For 28 days or until hospital discharge, patients in COMMIT were treated with either ā€¢ Clopidogrel 75 mg and aspirin 162 mg ā€¢ Placebo and aspirin 162 mg ā€¢ 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). ā€¢ 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). ā€¢ 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;366:1607ā€“21
  • 23. ā€¢ 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. ā€¢ Patients were treated with either: ā€¢ Clopidogrel (300-mg loading dose, followed by 75 mg once daily) ā€¢ 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;352:1179ā€“89 Image is used for educational purpose only. AstraZeneca is not responsible for data and copyrights.
  • 24. TICAGRELOR EVIDENCE FROM THE TRIALSā€¦ 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 ā€¢ 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. ā€¢ 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? ā€¢ 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 ā€¢ The study demonstrated that the addition of ticagrelor 60 mg bid to low- dose ASA in patients 1ā€“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;372:1791ā€“1800
  • 27. Study rationale and design 27 1. Ibanez B et al. Eur Heart J 2018;39:119ā€“177; 2. Wallentin L et al. N Engl J Med 2009;361:1045ā€“1057; 3. Steg PG et al. Circulation 2014;123:2736ā€“2747; 4. Berwanger O et al. JAMA Cardiol 2018 doi:10.1001/jamacardio.2018.0612 ļ‚§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. ļ‚§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;39:119ā€“177; 2. Wallentin L et al. N Engl J Med 2009;361:1045ā€“1057; 3. Steg PG et al. Circulation 2014;123:2736ā€“2747; 4. Berwanger O et al. JAMA Cardiol 2018 doi:10.1001/jamacardio.2018.0612 ļ‚§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 ļ‚§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;39:119ā€“177; 2. Wallentin L et al. N Engl J Med 2009;361:1045ā€“1057; 3. Steg PG et al. Circulation 2014;123:2736ā€“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 3ā€“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) 300ā€“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 18ā€“75 years, diagnosed with STEMI ā‰¤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 (51.6ā€“65.2) 58.8 (51.6ā€“65.5) Female sex, n/N (%) 433/1913 (22.6) 438/1886 (23.2) Median body weight, kg (IQR) 76.5 (68.0ā€“88.0) [N=1911] 77.0 (67.0ā€“87.0) [N=1885] Body weight <60 kg, n/N (%) 148/1911 (7.7) 150/1885 (8.0) Median BMI, kg/mĀ² (IQR) 26.5 (24.0ā€“29.8) [N=1909] 26.5 (24.0ā€“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 (1.5ā€“4.3) [N=1899] 2.6 (1.5ā€“4.4) [N=1870) Time from fibrinolytic administration to randomization, hours (IQR) 11.4 (5.7ā€“18.1) [N=1899] 11.2 (5.8ā€“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 daysā€™ follow-up,ā€  n/N (%) 0ā€“80% 231/1907 (12.1) 205/1875 (10.9) 80ā€“90% 61/1907 (3.2) 64/1875 (3.4) 90ā€“100% 1615/1907 (84.7) 1606/1875 (85.7) *Please refer to Table e1 of the publication for full details; ā€  Adherence to the study drug was defined as use of 0ā€“80%, 80ā€“90% and 90ā€“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 3ā€“5 bleeding 14 (0.73) 23 (1.20) 23 (1.20) 13 (0.69) 26 (1.38) 26 (1.38) 0.04 (-0.49ā€“0.58) -0.18 (-0.89ā€“0.54) -0.18 (-0.89ā€“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; ā€  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 (0.67ā€“1.25) 0.57 Death from vascular causes, MI, or non-haemorrhagic strokeā€  70 (3.7) 77 (4.1) 0.90 (0.65ā€“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 (0.77ā€“1.35) 0.90 MI or deathā€  61 (3.2) 67 (3.6) 0.90 (0.63ā€“1.27) 0.54 MI or strokeā€  38 (2.0) 44 (2.3) 0.85 (0.55ā€“1.31) 0.47 Death from vascular causes 47 (2.5) 49 (2.6) 0.95 (0.63ā€“1.41) 0.79 MI 20 (1.0) 25 (1.3) 0.79 (0.44ā€“1.42) 0.43 Total stroke 18 (0.9) 20 (1.1) 0.89 (0.47ā€“1.68) 0.71 Death from any cause 49 (2.6) 49 (2.6) 0.99 (0.66ā€“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;192:105ā€“112; 3. GuimarĆ£es LFC et al. Int J Cardiol 2017;230:204ā€“208; 4. Alexopoulos D et al. J Thromb Thrombolyis 2015;40:261ā€“267; 5. Ibanez B et al. Eur Heart J 2018;39:119ā€“177 ļ‚§ STEMI patients <75 years treated with fibrinolytic therapy ļƒØ ticagrelor non-inferior to clopidogrel for major bleeding at 30 days1 ļ‚§ 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 ļ‚§ TREAT Results are consistent with smaller trials exploring ticagrelor use in patients receiving fibrinolytic therapy2ā€“4 ļ‚§ 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 ļ‚§ 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 ā€¢ 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 ā€¢ 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;361:1045ā€“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;39:119ā€“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;67:1235ā€“50
  • 40. ā€¢ The WOEST Trial: First randomised trial comparing two regimens with and without aspirin in patients on oral anticoagulant therapy undergoing coronary stenting
  • 41.
  • 42.
  • 43.
  • 44. ā€¢ Conclusions ā€¢ 1.First randomized trial to address the optimal antiplatelet therapy in patients on OAC undergoing coronary stenting ā€¢ 2.Primary endpoint was met: as expected, OAC plus clopidogrel causes less bleeding than triple antithrombotic therapy, but now shown in a randomized way ā€¢ 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 ā€¢ 4.Less all-cause mortality with dual therapy
  • 46. ā€¢ 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 ā€¢ rivaroxaban-based strategies were associated with improved safety compared with a standard VKA-based triple therapy strategy in patients with AF undergoing PCI
  • 47.
  • 48. Study Design: Multicenter, randomized, open-label trial following a PROBE design R Randomization ā‰¤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 2.0ā€“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 ā‰¤120 hrs post-PCI (ā‰¤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. ā€¢ Management of bleeding in patients treated with dual antiplatelet therapy with or without concomitant oral anticoagulation
  • 51.
  • 52.
  • 53.
  • 54.
  • 55.
  • 56. Bleeding with NOAC ā€¢ W/H anticoagulant and antiplatelet ā€¢ Resuscitation with fluid and Blood products eg. PTCC 50 U/kg, Factors VIIa ā€¢ All patients should receive supportive measures, including mechanical compression and endoscopic or surgical hemostasis (if applicable). ā€¢ 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. ā€¢ Oral Activated charcoal-absorption in 4-6 hrs ā€¢ HD- Dabigatran ā€¢ 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 ā€¢ Non P2Y12 antagonist affects of ticagrelor ā€¢ Post thrombolysis ticagrelor is non inferior to clopidogrel ā€¢ Landmark trials ā€¢ Management of Bleeding with DAPT + OAC

Editor's Notes

  1. PEGASUS TIMI 54 helped us establish that in patients who had prior MI 1-3 years earlier, ticagrelor (90 mg or 60 mg, twice daily) in combination with ASA significantly reduced the risk of cardiovascular death, MI, or stroke.
  2. In STEMI patients &amp;lt;75 years old treated with fibrinolytic therapy, ticagrelor was non-inferior to clopidogrel for major bleeding at 30 days1 Importantly, 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 The results of TREAT are consistent with smaller trials exploring ticagrelor use in patients receiving fibrinolytic therapy2ā€“4 Given that current STEMI guidelines recommend ticagrelor should only be initiated after 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 &amp;lt;75 years who initially receive clopidogrel can be safely switched to ticagrelor in the first 24 hours after fibrinolysis