Ticagrelor is a reversible P2Y12 platelet inhibitor that was developed as an alternative to clopidogrel for dual antiplatelet therapy following acute coronary syndromes or percutaneous coronary interventions. The PLATO trial found that ticagrelor was more effective than clopidogrel at reducing the primary endpoint of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome, with no significant difference in major bleeding risks. However, ticagrelor was associated with higher rates of dyspnea and asymptomatic ventricular pauses. The PEGASUS trial showed that long-term use of ticagrelor on a background of aspirin reduced the risk of cardiovascular events in patients

1. TI CAGRELOR

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 2013:1941-9260
CYP3A4/5
Ketoconazole
Clarithromycin
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
throughCYP2C19 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
• Increasedfatal bleeding
• Dyspnea (14%)
• Ventricular pause
• Hyperuricemia
• Slight increasedCr

11. Adverse Effects
>10%
Dyspnoes (13.8&)
Bleeding (Continued…)
1-10%
Dizziness (4.5%)
Ventricular Pauses (6.0%)
Uricemia (2.4%)
Renal Dysfunction (2.1%)
Diarrhoea (3.7%)
Nausea (4.3%)

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

13. 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.

14. PLATO inclusion criteria
• Hospitalisation for STEMI or NSTEMI ACS, with onset during the
previous 24 hours
• With STEMI, the following two inclusion criteria were required
 Persistent STEMI or new LBBB
 Primary PCI planned
• With NSTEMI ACS, at least two of the following three were required
 ST-segment changes on ECG indicating ischaemia
 Positive biomarker indicating myocardial necrosis
 One of the following risk indicators
• ≥60 years of age
• Previous MI or CABG
• CAD with ≥50% stenosis in ≥2 vessels
• Previous ischaemic stroke, TIA, carotid stenosis (≥50%)
• Diabetes mellitus
• Peripheral artery disease
• Chronic renal dysfunction (creatinine clearance <60 mL/min)

15. Endpoints
 Primary endpoint: CV death + MI + Stroke
 Primary safety endpoint: Total major bleeding

16. K-M estimate of time to 1st primary efficacy
event (PLATO)
0 60 120
Days after randomisation
180 240 300 360
13
12
11
10
9
8
7
6
5
4
3
2
1
0
Cumulative
incidence
(%)
9.8
11.7
HR 0.84 (95% CI 0.77–0.92), p=0.0003
Clopidogrel
Ticagrelor
ARR 1.9%
NNT 53
Non CABG major bleeding:
4.5 vs 3.8%
NNH 143
No difference in fatal
bleeding

17. 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

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

19. 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

20. 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)

21. 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

22. 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

23. 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)

24. 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 withASA 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

25. 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.

26. PEGASUS TIMI- 54 Overall Results

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

28. 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

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

30. Basis
 Clopidogrel monotherapy shown to be more effective
than aspirin monotherapy in reducing CV events in
patients with PAD.
Hypothesis
 Monotherapy with ticagrelor would be superior to
clopidogrel in preventing CV events in patients with
symptomatic peripheral artery disease

31. 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

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

33. 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

34. Patients(Age≥ 18years and≤ 75years) withSTEMIwithin 24hand treatedwithfibrinolytic
therapy(N=3,799) (10countriesincludingChina)
Ticagrelor
180mgasearly aspossibleaftertheindexevent and
90mgtwicedailyfor 12months
Clopidogrel
300mgasearly aspossibleaftertheindexevent and
75mg/dayfor 12months
Followupvisits at hospitaldischarge or7thday,30days, 6and12months
Primarysafetyoutcome: TIMI MajorBleeding
Secondarysafetyoutcomes: Other bleedingevents(PLATOtrial, BARC,TIMI)
Exploratoryefficacyoutcomes: CVdeath, MI, or stroke
CV=cardiovascular; MI =Myocardialinfarction;TIA=transientischemicattack
TIMI=Thrombolysisin MyocardialInfarction; BARC=BleedingAcademicResearchConsortium
StudyDesign

35.  Contraindication to clopidogrel or ticagrelor
 Need for oral anticoagulation therapy
 Dialysis required
 Clinically important thrombocytopenia
 Clinically important anemia
 Pregnancy or lactation
Key Exclusion Criteria

36. Outcomesat30days
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(0.66to 1.47) 0.95
Exploratory Efficacy Outcomes

37.  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
hours, with comparable safety compared to clopidogrel.
Conclusions and Implications

38. SETFAST: The Safety and Efficacy of Ticagrelor
for Coronary Stenting Post Thrombolysis Trial.
Patients(Age≥ 18yearsand≤ 75years) withSTEMItreatedwithfibrinolytictherapyand
plannedforPCI
Ticagrelor
180mgasearly aspossibleaftertheindexevent and
90mgtwicedailyfor 12months
Clopidogrel
300mgasearly aspossibleaftertheindexevent and
75mg/dayfor 12months
RESULTS AWAITED

39. 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 Indian 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

40. Thank You..