Ticagrelor is a reversible P2Y12 antagonist that offers advantages over clopidogrel, including faster onset and greater platelet inhibition, leading to reduced ischemic events in acute coronary syndrome patients. Studies show that while ticagrelor reduces myocardial infarction and stent thrombosis, it may also increase bleeding risk, particularly in certain populations. The evidence supports ticagrelor as a superior alternative to clopidogrel, especially for patients undergoing percutaneous coronary intervention.

1. TICAGRELOR
A DRUG THAT HAS CHANGED TRENDS OF TREA
Dr .JEHANGIR ALI SHAH
ASSISTANT CATH LAB INCHARGE

2. Past...
 Clopidogrel remained the gold standard along
with aspirin for several years of DAPT
 Participated in the wide expansion of
percutaneous coronary intervention(PCI).

3. Why newer P2Y12 antagonist were needed

4. Why newer P2Y12 antagonist were
needed
 Stent thrombosis continued to occur, leading
investigators to suspect clopidogrel "resistance."
 Studies showed that clopidogrel,
• pro-drug
• short-lived active metabolite,
• mild potency,
• slow onset of action, and
• large inter-individual variability.
 These limitations were associated with adverse ischemic events
including stent thrombosis
Postgraduate Medicine, Volume 125, Issue 4, July 2013:1941-9260

5. To present!
receptor
Since then, new P2Y12-
ADP antagonists, have been
developed
• Prasugrel
• Ticagrelor and
• Cangrelor

6. Ticagrelor (AZD 6140):
an oral reversible P2Y12 antagonist
Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)
H O
H O
O
O H
N
F
S
H
N
N
N
N
N
F

7. Metabolism of P2Y12 Receptor
Antagonists
Schomig A. NEJM. 2009;361(11):1108-1111.
Postgraduate Medicine, Volume 125, Issue 4, July 2013:1941-
CYP3A4/5
Ketoconazole
Clarithromyci
n Nefazadone
ritonavir and
atazanavir
-
P-glycoprotein
CYP2C19

8.  Direct acting
• does not require metabolic activation
• Rapid onset of inhibitory effect (0.5 – 4 hrs) on the P2Y12 receptor than
clopidogrel (2 – 8 hrs)
• Greater inhibition of platelet aggregation (90%) than clopidogrel (60%)
 Reversibly bound
• Degree of inhibition reflects plasma concentration
• Faster offset of effect than clopidogrel
• Functional recovery of all circulating platelets
 Eliminated via hepatic metabolism T1/2 - 7.2 hrs, whereas active
metabolite via biliary excretion T1/2 8.5 hours.
Circulation. 2017;136:1955–1975. DOI: 10.1161/CIRCULATIONAHA.117.031164
Postgraduate Medicine, Volume 125, Issue 4, July 2013:1941-9260

9. Unique characteristic
• ability to increase adenosine levels; it being a
precursor of adenosine
o anti-inflammatory,
o cardioprotective,
o cerebroprotective,
o antisclerotic, and
o antifibrotic properties.
o coronary vasodilator.
Postgraduate Medicine, Volume 125, Issue 4, July 2013:1941-
9260

10. Properties of P2Y12 Receptor Antagonists
Clopidogrel Prasugrel Ticagrelor
Metabolic Activation Yes Yes No
through CYP2C19 sensitive to polymorphisms less sensitive to polymorphisms
and drug interactions and drug interactions
Indications ACS, PCI, PAD, CVD PCI ACS, PCI
Loading/Maintenance 300 mg /75 mg OD 60 mg/10 mg OD 180 mg/90 mg BID
Dosing
Inhibition Irreversible Irreversible Reversible
Efficacy ++
• Further 2% ARR over ASA
+++
• Further 2% ARR over clopidogrel +
+++
• Further 2% ARR over
monotherapy ASA clopidogrel + ASA
Bleeding risk + ++ ++
Issues • Rash
4.2% observed in clinical trials
leading to 0.5% drug
discontinuation
• Further increased bleeding risk
in: Prior Stroke / TIA
< 60 Kg
>75 yrs
• Increased fatal bleeding
• Dyspnea (14%)
• Ventricular pause
• Hyperuricemia
• Slight increased Cr

11. PLATO:Platelet Inhibition and Patient
Outcomes (Ticagrelor vs Clopidogrel)

12. Study design:
 Patients with high risk ACS(NSTE/STEMI) within 24
hrs.
 All patients received standard therapy, including ASA
 Excluded patients receiving fibrinolytics
 Randomized to ticagrelor 180 mg load followed by 90
mg bid or clopidogrel 300 mg load followed by 75 mg
daily
 n=18,624 (43 countries including India and China)
Wallentin L, et al. N Engl J Med. 2009;361(11):1045-1057.

13. Holter monitoring & Bradycardia related events
Holter monitoring at first week
Ticagrelor
(n=1,451)
Clopidogrel
(n=1,415) p value
Ventricular pauses ≥3 seconds, %
Ventricular pauses ≥5 seconds,
%
5.8
2.0
3.6
1.2
0.01
0.10
Holter monitoring at 30 days
Ticagrelor
(n= 985)
Clopidogrel
(n=1,006) p value
Ventricular pauses ≥3 seconds, % 2.1 1.7 0.52
Ventricular pauses ≥5 seconds, % 0.8 0.6 0.60
Bradycardia-related event, %
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186) p value
Pacemaker Insertion 0.9 0.9 0.87
Syncope 1.1 0.8 0.08
Bradycardia 4.4 4.0 0.21
Heart block 0.7 0.7 1.00

14. Other findings
All patients
Ticagrelor Clopidogrel
(n=9,235)
(n=9,186)
p value*
Dyspnoea, %
Any
With
discontinu
ation of
study
treatment
13.8
0.9
7.8
0.1
<0.001
<0.001
*p values were calculated using Fischer’s exact
test

15. Other findings – laboratory parameters
All patients
Ticagrelor Clopidogrel
(n=9,235)
(n=9,186)
p value*
% increase in creatinine from baseline
At 1 month
At 12 months
Follow-up visit
10 
22
11 
22
10 
22
8 
21
9 
22
10 
22
<0.001
<0.001
0.59
% increase in uric acid from baseline
At 1 month
At 12 months
Follow-up visit
14 
46
15 
52
7 
43
7 
44
7 
31
8 
48
<0.001
<0.001
0.56
Values are mean %  SD; *p values were calculated using Fisher’s exact
test

16. Time to major bleeding – primary safety event
0 60 120 180 240
Days from first IP dose
300 360
10
5
0
15
Clopidogrel
Ticagrelor 11.58
11.20
No. at risk
Ticagrelor 9,235 7,246 6,826 6,545 5,129 3,783 3,433
Clopidogrel 9,186 7,305 6,930 6,670 5,209 3,841 3,479
HR 1.04 (95% CI 0.95–1.13), p=0.434
K-M
estimated
rate
(%
per
year)

17. Total major bleeding
NS
NS
NS
NS
NS
K-M
estimated
rate
(%
per
year)
PLATO major
bleeding
12
11
10
9
8
7
6
5
4
3
2
1
0
TIMI major
bleeding
Red cell
transfusion*
PLATO life-
threatening/
Fatal bleeding
fatal bleeding
Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically
programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15;*Proportion of patients (%);
11.6
11.2
7.9
7.7
8.9 8.9
5.8 5.8
0.3 0.3
Ticagrelor
Clopidogrel

18. Conclusions (PLATO)
• Ticagrelor in comparison with clopidogrel in a
broad population with ST- and non-ST-elevation
ACS provides
 Reduction in myocardial infarction and stent
thrombosis
 Reduction in cardiovascular and total mortality
 No change in the overall risk of major bleeding
Ticagrelor is a more effective alternative than clopidogrel for the
continuous prevention of ischaemic events, stent thrombosis and death in
the acute and long-term treatment of patients with ACS

19. Prevention of Cardiovascular Events in Patients with
Prior Heart Attack Using Ticagrelor Compared to
Placebo on a Background of Aspirin–TIMI 54
(PEGASUS-TIMI 2015)

20. Design of PEGASUS-TIMI 54
Stable pts with history of MI 1-3 yrs prior
+ 1 additional atherothrombosis risk
factor*
Ticagrelor
90 mg
bid
Placebo
Follow-up Visits
Q4 mos for 1st yr, then Q6 mos
Planned treatment with ASA 75 – 150 mg
& Standard background care
* Age >65 yrs, diabetes, 2nd prior MI,
multivessel CAD, or chronic non-end stage
renal dysfunction (Crcl <60ml/min)
Minimum 1 year follow-up
Event-driven trial
Ticagrelor
60 mg
bid
RANDOMIZED
DOUBLE BLIND
N=21,162 (33
countries) Follow up –
33 months

21. Exclusion criteria
• Planned use of a P2Y12 receptor antagonist
(dipyridamole, cilostazol) or anticoagulant therapy
• bleeding disorder
• H/o ischemic stroke or intracranial bleeding,
• CNS tumor,
• intracranial vascular abnormality
• GI bleeding within 6 months or
• major surgery within 30 days.

22. PEGASUS TIMI- 54 Overall Results

23. Safety End Points as 3-year Kaplan-Meier Estimates

24. Addition of ticagrelor, at a dose of 90 mg twice daily or 60
mg twice daily, to low-dose aspirin reduced the risk of
cardiovascular death, myocardial infarction, or stroke and
increased the risk of TIMI major bleeding among patients
who had MI 1 to 3 years earlier.
Conclusion

25. Examining Use of Ticagrelor in Peripheral
Artery Disease (EUCLID) - 2016
This article was published on November 13, 2016, at NEJM.org.

26. EUCLID
• CV death, MI, or ischemic stroke:
10.8% - ticagrelor vs 10.6% - clopidogrel (p = 0.65)
• Acute limb ischemia:
1.7% - ticagrelor vs 1.7% with clopidogrel
• Major bleeding:
1.6% with ticagrelor vs. 1.6% with clopidogrel
• Dyspnea resulting in drug discontinuation:
4.8% - ticagrelor vs 0.8% - clopidogrel (p < 0.001)
Trial design: Patients with peripheral arterial disease (PAD) randomized to
ticagrelor 90 mg BID (n = 6,930) vs. clopidogrel 75 mg QD (n = 6,955). (28
countries)
Results
Conclusions
• In patients with symptomatic PAD, ticagrelor was
not superior to clopidogrel in preventing MACE
• Acute limb ischemia and major bleeding were
also
similar between treatment groups
Hiatt WR, et al. N Engl J Med 2017;376:32-40
Ticagrelor Clopidogrel
%
(p = 0.65)
10.8 10.6

27. TREAT: (2018)
Ticagrelor Versus Clopidogrel After
Thrombolytic Therapy In Patients With
St-elevation Myocardial Infarction

28. Available at jama.com and on The JAMA Network Reader
at mobile.jamanetwork.com
The Writing Committee for the
TREAT Study Group
Ticagrelor vs Clopidogrel After
Fibrinolytic Therapy in Patients With
ST-Elevation Myocardial Infarction:
A Randomized Clinical Trial
Published online March 11,
2018

29. Patients (Age ≥ 18 years and ≤ 75 years) with STEMI with in 24h and treated with
fibrinolytic therapy (N=3,799) (10 countries including China)
Ticagrelor
180 mg as early as possible after the index
event and 90 mg twice daily for 12 months
Clopidogrel
300 mg as early as possible after the index
event and 75 mg/day for 12 months
Follow up visits at hospital discharge or 7th day, 30 days, 6 and 12
months
Primary safety outcome: TIMI Major Bleeding
Secondary safety outcomes: Other bleeding events (PLATO trial, BARC,
TIMI)
Exploratory efficacy outcomes: CV death, MI, or stroke
CV = cardiovascular ; MI = Myocardial infarction; TIA = transient ischemic attack
Study
Design

30. Outcomes at 30 days
Ticagrelor
Clopidogrel Hazard Ratio P Value
(n=1,913) (n=1,886) (95% CI)
Death from vascular causes, MI, or
stroke
4.0 4.3 0.91 (0.67 to
1.25)
0.57
Death or MI 3.2 3.6 0.90 (0.63 to
1.27)
0.54
MI or stroke 2.0 2.3 0.85 (0.55 to
1.31)
0.47
Death (from vascular causes) 2.5 2.6 0.95 (0.63 to
1.41)
0.79
Total MI 1.0 1.3 0.79 (0.44 to
1.42)
0.43
Total stroke 0.9 1.1 0.89 (0.47 to
1.68)
0.71
Other arterial thrombotic events 0.1 0.2 0.33 (0.03 to
3.16)
0.34
Death (from any cause) 2.6 2.6 0.99 (0.66 to 1.47) 0.95
Exploratory Efficacy Outcomes

31.  Patients aged ≤ 75 yrs with STEMI, administration of ticagrelor after
fibrinolytic therapy was noninferior to clopidogrel for TIMI major
bleeding at 30 days.
 Total bleeding was increased with ticagrelor and there was
no
benefit on exploratory efficacy outcomes.
 Ticagrelor is a reasonable option for patients ≤ 75 years who have
received fibrinolytic therapy (and clopidogrel) within the past 24
Conclusions and Implications

32. SETFAST: The Safety and Efficacy of Ticagrelor
for Coronary Stenting Post Thrombolysis Trial.
Patients (Age ≥ 18 years and ≤ 75 years) with STEMI treated with fibrinolytic therapy
and planned for PCI
Ticagrelor
180 mg as early as possible after the index
event and 90 mg twice daily for 12 months
Clopidogrel
300 mg as early as possible after the index
event and 75 mg/day for 12 months
RESULTS AWAITED

33. Summary
 Dual antiplatelet therapy improves outcomes for
patients with ACS
 Strong evidence for replacing clopidogrel with
ticagrelor in patients with ACS undergiong PCI comes
from PLATO study.
 The above statement also holds true for south Asiam
population.
 Replacing clopidogrel with either ticagrelor or
prasugrel improves outcomes to similar magnitude
BUT at a cost of increased bleeding
 Patient characteristics and revascularization method
affect drug choice

34. Thank
You..