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Diabetes and Acute Coronary SyndromeDiabetes and Acute Coronary SyndromeDiabetic patients as compared to non-diabetics with

acute coronary syndrome (ACS) at 2 years showed a1.8-fold increase in cardiovascular deaths1.4-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.

Diabetics Vs. Non-diabeticsDiabetics Vs. Non-diabetics

Malmberg K et al. Circ J. 2000;102: 1014-1019.

Mortality 1 Year Post-PCIMortality 1 Year Post-PCIEPIC, EPILOG and EPISTENT - Meta-Analysis

Diabetes;

Non-Diabetics

0 50 100 150 200 250 300 3500

1

2

3

4

Days of Randomization

3.3

2.1

; n = 5,072

n = 1,462

1.2%p = 0.012

Mor

talit

y (%

)

Bhatt DL et al. JACC 2000; 35:922-28.

Event Rates in Patients With and Without Diabetes

Anti-platelets in Diabetic ThrombocytopathyAnti-platelets in Diabetic Thrombocytopathy

What we already know?Mainstay of treatment in ACSDAPT role established beyond doubtBalance efficacy v/s riskOptimal duration of DAPT

Currently Available Anti-platelet AgentsCurrently Available Anti-platelet Agents

Inhibits TXA2

•Acetylsalicylicacid (aspirin)

Thienopyridines•Ticlopidine•Clopidogrel•Prasugrel

CPTPs•Ticagrelor

Inhibits PDE

•Dipyridamole•Cilastazol

Inhibits GPIIb/IIIa

•Eptifibatide•Tirofiban•Abciximab

Antiplatelet drugs

TXA2 Inhibitors P2Y12antagonists PDE Inhibitors GPIIb/IIIa

antagonists

AspirinAspirinBenefit of aspirin has been consistently demonstrated in both

NSTE-ACS and STEMI trialsStill 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.

ClopidogrelClopidogrelIrreversible P2Y12 InhibitorA prodrug requiring two step metabolic conversionSlow onset of actionLow-moderate level IPA is only achievedIndividual variability and responseExcess of Bleeding during long term prescriptionIncidence of clopidogrel resistance or non-

responsiveness or hypo-responsiveness notedComposite 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.

Diabetes & Clopidogrel induced Anti-platelet Diabetes & Clopidogrel induced Anti-platelet EffectsEffects

Diabetes and Clopidogrel-Induced Antiplatelet EffectsLoading 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

Plat

elet

Agg

rega

tion

(%)

P = 0.001P < 0.0001

ADP 20 mol/L ADP 6 mol/L

T2DM No DM T2DM No DM

1Angiolillo DJ et al. Diabetes 2005;54:2430-24352Angiolillo 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

43.041.5

31.8

PrasugrelPrasugrelIrreversible P2Y12 InhibitorA prodrug requiring one step metabolic conversionFaster onset of action compared to clopidogrelFaster and greater mean IPA achievedLower individual variability and responseIncreased bleeding risk and contra-indicated in >75yrs of

age, <60kg body weight and h/o stroke/TIALow prevalence of subjects who display resistance to

prasugrelNo additional benefit in medical managementComposite endpoint driven primarily by reduction in MIEffient ® [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;

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=NonfatalWiviott SD et al. Circulation2008;118:1626-1636.

HRPrasugrel Better Clopidogrel Better

Reductionin 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

TRITON TIMI: Non-CABG TIMI Major or Minor TRITON TIMI: Non-CABG TIMI Major or Minor Bleeding in Patients with DiabetesBleeding in Patients with Diabetes

P=0.002

P=0.029

Pati

ents

* (%

)

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

0.00.51.01.52.02.53.03.54.04.55.05.5

All-ACS1 Diabetes2§ All-ACS1 Diabetes2§

Non-CABG TIMI Major† or Minor‡ Bleeding

Non-CABG TIMI Major Bleeding

Clopidogrel Prasugrel

*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.

TicagrelorTicagrelorFirst in class cyclo-pentyl-triazolo-pyrimidine (CPTP)Reversible non-competitive P2Y12 InhibitorNot a prodrug, but directly acting drug not requiring metabolic

activationFaster onset of action compared to clopidogrelHigher and more consistent mean IPA achievedActive in systemic circulation throughout dosing intervalReturn of platelet function is quicker with functional recovery of

almost all circulating plateletsComposite endpoint driven primarily by reduction in MI and CV deathBroad 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.

PLATO Diabetes:PLATO Diabetes:Primary Composite EndpointPrimary Composite Endpoint

Days after randomisation

CV

deat

h, M

I, or

str

oke

(%)

14.1%

16.2%

8.4%

10.2%

DiabetesTicagrelor (n=2326)Clopidogrel (n=2336)HR (95% CI) = 0.88(0.76–1.03)

No diabetesTicagrelor (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.

PLATO Diabetes: PLATO Diabetes: Major bleedingMajor bleeding

14.1%14.8%

10.8%10.0%

DiabetesTicagrelor (n=2305)Clopidogrel (n=2316)HR (95% CI) = 0.95(0.81–1.12)

No diabetesTicagrelor (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

Maj

or b

leed

ing

(%)

p for interaction = 0.21

James S, et al. Eur Heart J 2010;31:3006–3016.

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

ACS Patients with Diabetes

Prasugrel 60 mg LD

n=50

Ticagrelor 180 mg LDn= 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 an Ticagrelor versus Prasugrel in Diabetic Patients with an ACS : A pharmacodynamic studyACS : A pharmacodynamic study

Laine M et al. Thromb Haemost 2014; 111: 273–278.

ObjectiveTo compare the level of PR inhibition achieved by Prasugrel and Ticagrelor LD in diabetic ACS patients undergoing PCI

The primary endpoint was significantly lower in the Ticagrelor group The 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.

The number of patients with HTPR was lower in the The 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 Comparison of platelet reactivity between the two groupsgroups

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.

High on- treatment platelet reactivity (HTPR) following P2Y12-ADP receptor antagonist LD is associated with recurrent thrombotic events

HTPR is more prevalent in diabetic patientsTicagrelor 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?

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 FORM90 mg - Round, biconvex, yellow, film-coated tablets. The tablets are marked with “90” above “T” on one side and plain on the otherMechanism 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 USAGEBRILINTA 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 riskAs 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.

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.ContraindicationsHyper-sensitivity to ticagrelor or any of the excipients.Active pathological bleedingHistory of intracranial haemorrhageSevere hepatic impairmentADVERSE 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 300C. Pack size: refer to outer carton BRILINTA is a trademark of the AstraZeneca group of companies.For Further Information Contact:AstraZeneca Pharma India LimitedAvishkar”, Off Bellary road, Hebbal,BANGALORE – 560 024, Date of revision of text: October 2013.V1: 08/10/2013For more information refer full prescribing information For the use of a Cardiologist and Internal Medicine Specialities or a Hospital or a Laboratory only.