This document discusses antiplatelet treatment strategies in diabetic patients with acute coronary syndrome (ACS). It summarizes several clinical trials comparing different P2Y12 inhibitors in this population. The key points are: 1. Diabetic patients with ACS have higher mortality and morbidity than non-diabetic patients. Clopidogrel response is more variable in diabetics, with higher rates of non-response. 2. A head-to-head trial found ticagrelor reduced platelet reactivity more than prasugrel in diabetic ACS patients after loading doses, with fewer patients having high on-treatment platelet reactivity. 3. Clinical trials showed ticagrelor and prasug

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2. Diabetes and Acute Coronary SyndromeDiabetes and Acute Coronary Syndrome
Diabetic patients as compared to non-diabetics with acute
coronary syndrome (ACS) at 2 years showed a
1.8-fold increase in cardiovascular deaths
1.4-fold increase in myocardial infarctions (MI)
Patients with diabetes have higher mortality and morbidity
rates than non-diabetic patients after an acute MI.2
Because ACS is mainly a platelet-driven process, attention has
been recently given to high on-treatment platelet reactivity
(HPR) as a possible indicator of adverse cardiac events, which
could guide the individualization of antithrombotic strategies.1
1. Patti G et al. Circ J. 2014; 78: 33 – 41.
2. Malmberg K et al. Circ J. 2000;102: 1014-1019.

3. Diabetics Vs. Non-diabeticsDiabetics Vs. Non-diabetics
Malmberg K et al. Circ J. 2000;102: 1014-1019.

4. Mortality 1 Year Post-PCIMortality 1 Year Post-PCI
EPIC, EPILOG and EPISTENT - Meta-Analysis
Diabetes;
Non-Diabetics
0 50 100 150 200 250 300 350
0
1
2
3
4
Days of Randomization
3.3
2.1
; n = 5,072
n = 1,462
↑ 1.2%
p = 0.012
Mortality(%)
Bhatt DL et al. JACC 2000; 35:922-28.
Event Rates in Patients With and Without Diabetes

5. Anti-platelets in DiabeticAnti-platelets in Diabetic
ThrombocytopathyThrombocytopathy
What we already know?
Mainstay of treatment in ACS
DAPT role established beyond doubt
Balance efficacy v/s risk
Optimal duration of DAPT

6. Currently Available Anti-platelet AgentsCurrently Available Anti-platelet Agents
Inhibits TXA2
•Acetylsalicylic
acid (aspirin)
Thienopyridines
•Ticlopidine
•Clopidogrel
•Prasugrel
CPTPs
•Ticagrelor
Inhibits PDE
•Dipyridamole
•Cilastazol
Inhibits GPIIb/IIIa
•Eptifibatide
•Tirofiban
•Abciximab
Antiplatelet drugs
TXA2 Inhibitors
P2Y12
antagonists PDE Inhibitors GPIIb/IIIa
antagonists

7. AspirinAspirin
Benefit of aspirin has been consistently demonstrated in both NSTE-ACS
and STEMI trials
Still represents the first-line anti-platelet therapy for improving CV
outcome in all patients with acute or previous athero-thrombotic disease,
including those with DM
CURRENT-OASIS 7 study: High- (300–325 mg daily) vs. low-dose (75–100
mg daily) aspirin
 No significant differences in efficacy between high- and low-dose aspirin for the
primary outcome measure of 30-day MACE
 Significant increase in minor bleeding and gastrointestinal bleeding in the
higher-dose ASA group
A low response to aspirin has been also reported to be more common in
diabetic vs. non-diabetic patients
Patti G et al. Circ J 2014; 78: 33 – 41.

8. ClopidogrelClopidogrel
Irreversible P2Y12 Inhibitor
A prodrug requiring two step metabolic conversion
Slow onset of action
Low-moderate level IPA is only achieved
Individual variability and response
Excess of Bleeding during long term prescription
Incidence of clopidogrel resistance or non-responsiveness or
hypo-responsiveness noted
Composite endpoint driven primarily by reduction in MI
Gurbel PA, et al. Circulation. 2009;120:2577-2585; Plavix® [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals
Partnership;2010; Plavix [Summary of product characteristics] Paris, France: Sanofi Pharma Bristol-Myers Squibb SNC; 2010.

9. Diabetes & Clopidogrel induced Anti-plateletDiabetes & Clopidogrel induced Anti-platelet
EffectsEffects
Diabetes and Clopidogrel-Induced
Antiplatelet Effects
Loading Phase of Treatment1 Maintenance Phase of Treatment2
78%
14%
8%P = 0.04
Responders (Platelet inhibition ≥ 30%)
Low responders (Platelet inhibition 10-29%)
Non-responders (Platelet inhibition 10%)
56%
6%
38%
DM No DM
24h post 300 mg LD
0
20
40
60
80
PlateletAggregation(%)
P = 0.001
P < 0.0001
ADP 20 µmol/L ADP 6 µmol/L
T2DM No DM T2DM No DM
1Angiolillo DJ et al. Diabetes 2005;54:2430-2435
2Angiolillo DJ et al. J Am Coll Cardiol 2006;48:298-304
ADP=Adensine Diphosphate; DM=Diabetes Mellitus; LD=Loading Dose; MD=Maintenance Dose; T2DM=Type 2 Diabetes Mellitus
2-4h post 75 mg MD
52.9
43.0
41.5
31.8
Diabetes and Clopidogrel-Induced
Antiplatelet Effects
Loading Phase of Treatment1 Maintenance Phase of Treatment2
78%
14%
8%P = 0.04
Responders (Platelet inhibition ≥ 30%)
Low responders (Platelet inhibition 10-29%)
Non-responders (Platelet inhibition 10%)
56%
6%
38%
DM No DM
24h post 300 mg LD
0
20
40
60
80
PlateletAggregation(%)
P = 0.001
P < 0.0001
ADP 20 µmol/L ADP 6 µmol/L
T2DM No DM T2DM No DM
1Angiolillo DJ et al. Diabetes 2005;54:2430-2435
2Angiolillo DJ et al. J Am Coll Cardiol 2006;48:298-304
ADP=Adensine Diphosphate; DM=Diabetes Mellitus; LD=Loading Dose; MD=Maintenance Dose; T2DM=Type 2 Diabetes Mellitus
2-4h post 75 mg MD
52.9
43.0
41.5
31.8

10. PrasugrelPrasugrel
Irreversible P2Y12 Inhibitor
A prodrug requiring one step metabolic conversion
Faster onset of action compared to clopidogrel
Faster and greater mean IPA achieved
Lower individual variability and response
Increased bleeding risk and contra-indicated in >75yrs of age, <60kg
body weight and h/o stroke/TIA
Low prevalence of subjects who display resistance to prasugrel
No additional benefit in medical management
Composite endpoint driven primarily by reduction in MI
Effient ® [package insert]. Indianapolis, IN: Eli Lilly and Company; 2009; Efient [Summary of product characteristics]. Hampshire, UK: Eli
Lilly and Company Ltd Daiichi Sankyo UK Limited; 2009; NEJM 357: 2001-2015, 2007;

11. TRITON TIMI Diabetes Subgroup:TRITON TIMI Diabetes Subgroup:
Primary End Point Reduction (CV Death, NF MI or NF Stroke)Primary End Point Reduction (CV Death, NF MI or NF Stroke)
Insulin therapy was identified at time of randomization. CV=Cardiovascular; DM=Diabetes Mellitus; HR=Hazard Ratio; MI=Myocardial Infarction; NF=Nonfatal
Wiviott SD et al. Circulation2008;118:1626-1636.
HRPrasugrel Better Clopidogrel Better
Reduction
in Risk (%)
0.3 1.0 2.0
P-Value
30All DM
(n = 3,146)
< 0.001
26DM No Insulin
(n = 2,370)
0.009
37DM On Insulin
(n = 776)
0.009
14
Clopidogrel
(%)
17.0
15.3
22.2
10.6
Prasugrel
(%)
12.2
11.5
14.3
9.2No DM
(n = 10,462)
0.02

12. TRITON TIMI: Non-CABG TIMI Major or MinorTRITON TIMI: Non-CABG TIMI Major or Minor
Bleeding in Patients with DiabetesBleeding in Patients with Diabetes
P=0.002
P=0.029
Patients*
(%)
N=6716
3.4
N=1553
3.8
N=6716
1.7
N=1553
2.2
N=6741
4.5
N=1555
4.9
N=6741
2.2
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
All-ACS1
Diabetes2§
All-ACS1
Diabetes2§
Non-CABG TIMI Major†
or
Minor‡
Bleeding
Non-CABG TIMI
Major Bleeding
ClopidogrelPrasugrel
*Observed event rates.
†
Intracranial hemorrhage or clinically overt bleeding associated with a fall in hemoglobin ≥5 g/dL.
‡
Clinically overt bleeding associated with a fall in hemoglobin ≥3 g/dL but <5 g/dL.
§
P value not provided due to sample size limitations.
1. Effient Full Prescribing Information; 2. Data on file: #EFF20100129f. DSI/Lilly.

13. TicagrelorTicagrelor
First in class cyclo-pentyl-triazolo-pyrimidine (CPTP)
Reversible non-competitive P2Y12 Inhibitor
Not a prodrug, but directly acting drug not requiring metabolic activation
Faster onset of action compared to clopidogrel
Higher and more consistent mean IPA achieved
Active in systemic circulation throughout dosing interval
Return of platelet function is quicker with functional recovery of almost all
circulating platelets
Composite endpoint driven primarily by reduction in MI and CV death
Broad spectrum anti-platelet drug that can be used irrespective of whether
the patient is undergoing PCI or medical management or CABG
Does not require dose adjustment across ACS patient population including
age (18years and above) and weight
van Giezen JJJ. Eur Heart J. 2008;10 (Suppl D):D23-D29; Husted S, et al. Eur Heart J. 2006;27:1038-1047; Gurbel PA, et al. Circulation. 2009;120:2577-2585;
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057; James S, et al. Am Heart J. 2009;157:599–605.

14. PLATO Diabetes:PLATO Diabetes:
Primary Composite EndpointPrimary Composite Endpoint
Days after randomisation
CVdeath,MI,orstroke(%)
14.1%
16.2%
8.4%
10.2%
Diabetes
Ticagrelor (n=2326)
Clopidogrel (n=2336)
HR (95% CI) = 0.88(0.76–1.03)
No diabetes
Ticagrelor (n=6999)
Clopidogrel (n=6952)
HR (95% CI) = 0.83(0.74–0.93)
0 60 120 180 240 300 360
20
15
10
5
0
p for interaction = 0.49
James S, et al. Eur Heart J 2010;31:3006–3016.

15. PLATO Diabetes:PLATO Diabetes: Major bleedingMajor bleeding
14.1%
14.8%
10.8%
10.0%
Diabetes
Ticagrelor (n=2305)
Clopidogrel (n=2316)
HR (95% CI) = 0.95(0.81–1.12)
No diabetes
Ticagrelor (n=6928)
Clopidogrel (n=6870)
HR (95% CI) = 1.08(0.97–1.20)
Days after randomisation
0 60 120 180 240 300 360
15
10
5
0
Majorbleeding(%)
p for interaction = 0.21
James S, et al. Eur Heart J 2010;31:3006–3016.

16. Summary of Various Clinical TrialsSummary of Various Clinical Trials
Patti G et al. Circ J 2014; 78: 33 – 41. Image used for Academic purpose only. AstraZeneca is not responsible for copyright

17. ACS Patients with Diabetes
Prasugrel 60 mg LD
n=50
Ticagrelor 180 mg
LD
n= 50
Exclusive Criteria
Fulfillment (n=36)
Refuse to participate
(n=2)
Prasugrel 10 mg/day Ticagrelor 90 mg bid
PR assessed by the VASP index
(Completed study n= 100)
Randomization
Ticagrelor versus Prasugrel in Diabetic Patients with anTicagrelor versus Prasugrel in Diabetic Patients with an
ACS : A pharmacodynamic studyACS : A pharmacodynamic study
Laine M et al. Thromb Haemost 2014; 111: 273–278.
Objective
To compare the level of PR inhibition achieved by Prasugrel and Ticagrelor LD in
diabetic ACS patients undergoing PCI
Objective
To compare the level of PR inhibition achieved by Prasugrel and Ticagrelor LD in
diabetic ACS patients undergoing PCI

18. The primary endpoint was significantly lower in the Ticagrelor groupThe primary endpoint was significantly lower in the Ticagrelor group
compared to the Prasugrel group after the LDcompared to the Prasugrel group after the LD
(VASP: 17.3 ± 14.2 % vs 27.7 ± 23.3 %; p=0.009)
Individual platelet reactivity following the loading dose in the
Ticagrelor and Prasugrel groupLaine M et al. Thromb Haemost 2014; 111: 273–278.

19. The number of patients with HTPR was lower in theThe number of patients with HTPR was lower in the
Ticagrelor group as compared to Prasugrel groupTicagrelor group as compared to Prasugrel group
Comparison of platelet reactivity between the two groupsComparison of platelet reactivity between the two groups
Laine M et al. Thromb Haemost 2014; 111: 273–278.
Ticagrelor
group (n=50)
Prasugrel
group (n=50)
P value
VASP Index (%) 17.3 +_ 14.2 27.7 +_ 23.2 0.009
HTPR (> 50%) 3 (6%) 8 (16%) 0.2
HTPR (>61%) 1 (2%) 6 (12%) 0.1
LTPR (16%) 30 (60%) 27 (54%) 0.3
LD : Loading Dose; PR : Platelet Reactivity; vasodilator-stimulated phosphoprotein phosphorylation (VASP) assay.

20. High on- treatment platelet reactivity (HTPR) following P2Y12-ADP
receptor antagonist LD is associated with recurrent thrombotic events
HTPR is more prevalent in diabetic patients
Ticagrelor and Prasugrel are biologically and clinically superior to
Clopidogrel in ACS patients
We demonstrated that Ticagrelor loading dose is superior to Prasugrel to
block the P2Y12- ADP receptor in diabetics suffering of ACS
The rate of patients with HTPR tends to be lower in the Ticagrelor group
The rate of patients with low on-treatment platelet reactivity was similar
in both groups
What is Known about this Topic?What is Known about this Topic?
Laine M et al. Thromb Haemost 2014; 111: 273–278.
What does this paper add?What does this paper add?

21. Abbreviated Prescribing Information
Ticagrelor Tablets
Brilinta® 90 mg
Composition:
Each film coated tablets contains:
Ticagrelor 90mg
Colors: Ferric oxide Yellow USP-NF & Titanium Dioxide I.P.
PHARMACEUTICAL FORM
90 mg - Round, biconvex, yellow, film-coated tablets. The tablets are marked with “90” above “T” on one side and plain on the other
Mechanism of action: BRILINTA contains ticagrelor a member of the chemical class Cyclo Pentyl Triazolo Pyrimidines (CPTP), which is a selective and reversible adenosine diphosphate (ADP)
receptor antagonist acting on the P2Y12
ADP-receptor that can prevent ADP-mediated platelet activation and aggregation. Ticagrelor is orally active, and reversibly interacts with the platelet
P2Y12
ADP receptor. Ticagrelor does not interact with the ADP binding site itself, but its interaction with platelet P2Y12
ADP-receptor prevents signal transduction.
INDICATIONS AND USAGE
BRILINTA is indicated for the prevention of thrombotic events (cardiovascular death, myocardial infarction and stroke) in patients with Acute Coronary Syndromes ([ACS] unstable angina, non ST
elevation Myocardial Infarction [NSTEMI] or ST elevation Myocardial Infarction [STEMI]) including patients managed medically, and those who are managed with percutaneous coronary
intervention (PCI) or coronary artery by-pass grafting (CABG).
DOSAGE AND ADMINISTRATION: BRILINTA treatment should be initiated with a single 180 mg loading dose (two tablets of 90 mg) and then continued at 90 mg twice daily.
For oral use: BRILINTA can be taken with or without food. Patients taking BRILINTA should also take ASA daily unless specifically contraindicated. Following an initial dose of ASA, BRILINTA
should be used with a maintenance dose of ASA of 75 150 mg. Lapses in therapy should be avoided. A patient who misses a dose of BRILINTA should take one 90 mg tablet (their next dose) at its‑
scheduled time.
Physicians who desire to switch patients from clopidogrel to BRILINTA should administer the first 90 mg dose of BRILINTA 24 hours following the last dose of clopidogrel. Treatment is
recommended for at least 12 months unless discontinuation of BRILINTA is clinically indicated. In patients with Acute Coronary Syndromes (ACS), premature discontinuation with any antiplatelet
therapy, including BRILINTA, could result in an increased risk of cardiovascular death, or myocardial infarction due to the patient’s underlying disease.
Special warnings and special precautions for use
Bleeding risk
As with other antiplatelet agents, the use of BRILINTA in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of thrombotic events. If
clinically indicated, BRILINTA should be used with caution in the following patient groups:
Consideration should be given to the following:
Patients with a propensity to bleed (e.g. due to recent trauma, recent surgery, active or recent gastrointestinal bleeding, or moderate hepatic impairment). The use of BRILINTA is
contraindicated in patients with active pathological bleeding and in those with history of intracranial haemorrhage, and severe hepatic impairment. Patients with concomitant administration of
medicinal products that may increase the risk of bleeding (e.g. non-steroidal anti-inflammatory drugs (NSAIDS), oral anticoagulants and/or fibrinolytics within 24 hours of BRILINTA dosing). No
data exist with BRILINTA regarding a haemostatic benefit of platelet transfusions; circulating BRILINTA may inhibit transfused platelets. Since co administration of BRILINTA with desmopressin
did not decrease template bleeding time, desmopressin is unlikely to be effective in managing clinical bleeding events.
Anti-fibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa may augment haemostasis. BRILINTA may be resumed after the cause of bleeding has been
identified and controlled.
Surgery:
If a patient requires surgery, physicians should consider each patient's clinical profile as well as the benefits and risks of continued antiplatelet therapy when determining when discontinuation
of BRILINTA treatment should occur. Because of the reversible binding of BRILINTA, restoration of platelet aggregation occurs faster with BRILINTA compared to clopidogrel. In the OFFSET study,
mean Inhibition of Platelet Aggregation (IPA) for BRILINTA at 72 hours post-dose was comparable to mean IPA for clopidogrel at 120 hours post-dose. The more rapid offset of effect may predict
a reduced risk of bleeding complications, e.g, in settings where antiplatelet therapy must be temporarily discontinued due to surgery or trauma.
In PLATO patients undergoing CABG, BRILINTA had a similar rate of major bleeds compared to clopidogrel at all days after stopping therapy except Day 1 where BRILINTA had a higher rate of
major bleeding.
If a patient is to undergo elective surgery and antiplatelet effect is not desired, BRILINTA should be discontinued 5 days prior to surgery.

22. Patients with moderate hepatic impairment:
Caution is advised in patients with moderate hepatic impairment because BRILINTA has not been studied in these patients. Use of BRILINTA is contraindicated in patients with severe hepatic
impairment.
Patients at risk for bradycardiac events:
Due to observations of mostly asymptomatic ventricular pauses in an earlier clinical study, patients with an increased risk of bradycardiac events (e.g. patients without a pacemaker who have
sick sinus syndrome, 2nd or 3rd degree AV block or bradycardiac-related syncope) were excluded from the main study evaluating the safety and efficacy of BRILINTA. Therefore, due to the
limited clinical experience in these patients, caution is advised.
Dyspnoea:
Dyspnoea, usually mild to moderate in intensity and often resolving without need for treatment discontinuation, is reported in patients treated with BRILINTA (approximately 13.8% ). The
mechanism has not yet been elucidated. If a patient reports new, prolonged or worsened dyspnoea this should be investigated fully and if not tolerated, treatment with BRILINTA should be
stopped.
Other:
Based on a relationship observed in PLATO between maintenance ASA dose and relative efficacy of ticagrelor compared to clopidogrel, co-administration of ticagrelor and high maintenance
dose ASA (>300 mg) is not recommended.
Renal impairment:
No dosing adjustment is needed in patients with renal impairment. No information is available concerning treatment of patients on renal dialysis.
Pregnancy and lactation:
No clinical study has been conducted in pregnant or lactating women. Limited clinical data on exposure to BRILINTA during pregnancy are available. BRILINTA should be used during pregnancy
only if the potential benefit to the mother justifies any potential risks to the foetus.
Contraindications
Hyper-sensitivity to ticagrelor or any of the excipients.
Active pathological bleeding
History of intracranial haemorrhage
Severe hepatic impairment
ADVERSE REACTIONS:
The most commonly reported adverse events in patients treated with ticagrelor were dyspnoea, headache, and epistaxis and these events occurred at higher rates than in the clopidogrel
treatment group. During the treatment period, the BRILINTA group had a higher incidence of discontinuation due to adverse events than clopidogrel (7.4% vs. 5.4%).
List of excipients:
Tablet core: Mannitol, Dibasic calcium phosphate, Magnesium stearate, Sodium starch glycolate, Hydroxypropyl cellulose.
Tablet Coat : Talc, Titanium dioxide, Ferric oxide yellow, Polyethylene glycol 400, Hypromellose.
Incompatibilities: Not applicable.
Shelf life: refer outer pack.
Storage: Do not store above 300
C.
Pack size: refer to outer carton
BRILINTA is a trademark of the AstraZeneca group of companies.
For Further Information Contact:
AstraZeneca Pharma India Limited
Avishkar”, Off Bellary road, Hebbal,
BANGALORE – 560 024,
Date of revision of text: October 2013.
V1: 08/10/2013
For more information refer full prescribing information
For the use of a Cardiologist and Internal Medicine Specialities or a Hospital or a Laboratory only.