Ticagrelor complete and concise information

1. TICAGRELOR

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.  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
Why newer P2Y12 antagonist were
needed
Postgraduate Medicine, Volume 125, Issue 4, July 2013:1941-9260

5. To present!
Since then, new P2Y12-ADP receptor
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)
OH
OH
O
O H
N
F
S
N
H
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
through CYP2C19
Yes
sensitive to polymorphisms
and drug interactions
Yes
less sensitive to polymorphisms
and drug interactions
No
Indications ACS, PCI, PAD, CVD PCI ACS, PCI
Loading/Maintenance
Dosing
300 mg /75 mg OD 60 mg/10 mg OD 180 mg/90 mg BID
Inhibition Irreversible Irreversible Reversible
Efficacy ++
• Further 2% ARR over ASA
monotherapy
+++
• Further 2% ARR over clopidogrel +
ASA
+++
• Further 2% ARR over
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. 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)

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

15. K-M estimate of time to 1st primary efficacy
event (PLATO)
Days after randomisation
0 60 120 180 240 300 360
12
11
10
9
8
7
6
5
4
3
2
1
0
13
Cumulativeincidence(%)
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

16. 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, %
Ventricular pauses ≥5 seconds, %
2.1
0.8
1.7
0.6
0.52
0.60
Bradycardia-related event, %
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186) p value
Pacemaker Insertion
Syncope
Bradycardia
Heart block
0.9
1.1
4.4
0.7
0.9
0.8
4.0
0.7
0.87
0.08
0.21
1.00

17. Other findings
All patients
Ticagrelor
(n=9,235)
Clopidogrel
(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

18. Other findings – laboratory parameters
All patients
Ticagrelor
(n=9,235)
Clopidogrel
(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

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

20. Total major bleeding
NS
NS
NS
NS
NS
0
K-Mestimatedrate(%peryear)
PLATO major
bleeding
1
2
3
4
5
6
7
8
9
10
12
11
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

21. 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

22. 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)

23. 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
RANDOMIZED
DOUBLE BLIND
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
N=21,162 (33 countries)
Follow up – 33 months

24. 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.

25. PEGASUS TIMI- 54 Overall Results

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

27. 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

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

29. 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

30. 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 groupsHiatt WR, et al. N Engl J Med 2017;376:32-40
Ticagrelor Clopidogrel
%
(p = 0.65)
10.8 10.6

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

32. 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

33. 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
TIMI = Thrombolysis in Myocardial Infarction; BARC = Bleeding Academic Research Consortium
Study Design

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

35. Outcomes at 30 days
Ticagrelor
(n=1,913)
Clopidogrel
(n=1,886)
Hazard Ratio
P Value
(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

36.  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

37. 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

38. 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

39. Thank You..