26.9.13 antiplatelet how to choose your bride among three sisters

Dr. Rajeev AgarwalaJaswant Rai Speciality Hospital, Meerut.

E-mail : [email protected]

HOW TO CHOOSE YOUR BRIDEAMONG THREE SISTERS

4. Plaque rupture, cholesterol content, inflammation (hs-CRP) (statins)

3. Platelet adhesion/ activation/aggregation (aspirin, clopidogrel, GP IIb/IIIa inhibitors)

2. Activation of clotting cascade – thrombin (heparin/LMWH)

1. Downstream from thrombus myocardial ischaemia/necrosis (-blockers, nitrates etc)

PlateletPlatelet

GP IIb/IIIaGP IIb/IIIareceptor receptor

FibrinogenFibrinogenThrombinThrombin

Fibrin Fibrin clotclot

Pathophysiology of ACS and potential pharmacological interventions

Central role of platelets in atherothrombosis and stent

thrombosis

Heart 2003;89:1273-1278

Pathways of Platelet Activation

http://heart.bmjjournals.com/content/vol89/issue10/images/large/ht318671.f4.jpeg

BRIDGING THE GAPBRIDGING THE GAP

BLEEDING

ISC

HEM

IADILEMMA

Trial

Indication

Duration

CHARISMA CURE CREDOPCI-CUREPCI-CLARITY

CLARITY COMMIT

Stable CVDMI Stroke PAD

ACSUA/NSTEMI

PCIStable CADUA/NSTEMISTEMI

STEMI

28 months 9 months 1-12 months 8-28 days

PIVOTAL TRIALS OF DUAL ORAL ANTIPLATELET THERAPY IN ACS

CURE (2001) N=12, 562

11.4% 9.3% P< .001

Primary Endpoint Reached

ASA + Placebo ASA + Clopidogrel

UA/NSTEMI

CLARITY TIMI-28

STEMI < 12 hrs

N=3491 21.7% 15.0% P< .001

STEMI

COMMIT93% STEMI or BBB + 24

hrs

N=45,852

10.1% 9.2% P= .002

Newer antiplatelet agents

TRITON TIMI-38: Study Design

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCIASA

PRASUGREL60 mg LD/ 10 mg

MD

CLOPIDOGREL300 mg LD/ 75 mg

MD

1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, UTVR Stent Thrombosis (ARC definite/probable) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic

Median duration of therapy - 12 months

N= 13,600

Wiviott SD et al. Am Heart J 2006;152:627-35

Net Clinical BenefitDeath, MI, Stroke, Major Bleed (non CABG)

0

5

10

15

0 30 60 90 180 270 360 450Days

En

dp

oin

t (%

)

HR 0.87P=0.004

13.9

12.2

Prasugrel

ClopidogrelITT= 13,608ITT= 13,608

-23

6

-25

-20

-15

-10

-5

0

5

10

Events per 1000 ptsEvents per 1000 pts

MIMI Major BleedMajor Bleed(non CABG)(non CABG)

++All CauseAll CauseMortalityMortalityClop 3.2%Clop 3.2%Pras 3.0 %Pras 3.0 %

P=0.64P=0.64

0

2

4

6

8

0 1 2 3

1

0

3060 90 180 270 360 450

HR 0.82P=0.01

HR 0.80P=0.003

5.6

4.7

6.9

5.6

Days

Pri

mary

En

dp

oin

t (%

)

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel

Loading Dose Maintenance Dose

Timing of BenefitTiming of Benefit

0

3

6

9

Days

CV

Death

, M

I, S

troke (

%)

No GP IIb/IIIa Inhibitor Used

GP IIb/IIIa Inhibitor Used

Benefit Benefit Regardless of GP Regardless of GP

IIb/IIIa UseIIb/IIIa Use

O’Donoghue M et al. JACC 2009;54:678-85

0 3015

Days0 3015

HR 0.76(0.64-0.90)P=0.001

HR 0.78(0.63-0.97)

P=0.026

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel

Diabetic Subgroup

0

2

4

6

8

10

12

14

16

18

0 30 60 90 180 270 360 450

HR 0.70P<0.001

Days

En

dp

oin

t (%

) CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 21

N=3146N=3146

17.0

12.2

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.6

2.5

Wiviott SD et al. NEJM 2007;357:2001-15

Prasugrel, in ACS patients with diabetes undergoing PCI, is

associated with significant reduction in primary endpoint compared to clopidogrel without increase in

bleeding events.

Prasugrel, in STEMI patients undergoing PCI, is associated with

significant reduction in primary endpoint compared to clopidogrel

without increase in bleeding events.

TRITON-TIMI 38: Major Efficacy End Points

Wiviott SD et al., N Engl J Med 2007

0.5

Prasugrel Better Clopidogrel BetterHR

0.4 0.6 0.7 0.8 0.9 1.1 1.2 1.3 1.41.0 1.5

Stent Thrombosis

Urgent traget vesell revasc.

All Cause Death

Nonfatal stroke

Nonfatal MI

CV Death

Primary Endpoint

Safety

Significant increase in serious bleeding(32% increase)

Avoid in pts with prior CVA/TIA

Efficacy

1. A significant reduction in: CV Death/MI/Stroke 19% Stent Thrombosis 52% uTVR 34%

MI 24%

2. An early and sustained benefit

3. Across ACS spectrum

Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD

ConclusionsHigher IPA to Support PCI

Net clinical benefit significantly favored PrasugrelNet clinical benefit significantly favored Prasugrel

Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balancebenefit : risk balance

Prasugrel in medically managed ACS patients

TRILOGY ACS Study Design

Medically Managed UA/NSTEMI PatientsMedically Managed UA/NSTEMI Patients

Clopidogrel1

75 mg MD

Clopidogrel1

75 mg MD

Prasugrel1

5 or 10 mg MD

Prasugrel1

5 or 10 mg MD

Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 monthsMinimum Rx Duration: 6 months; Maximum Rx Duration: 30 months

Primary Efficacy Endpoint: CV Death, MI, Stroke Primary Efficacy Endpoint: CV Death, MI, Stroke

Randomization Stratified by:Age, Country, Prior Clopidogrel Treatment(Primary analysis cohort — Age < 75 years)

Randomization Stratified by:Age, Country, Prior Clopidogrel Treatment(Primary analysis cohort — Age < 75 years)

Clopidogrel1

300 mg LD+

75 mg MD

Clopidogrel1

300 mg LD+

75 mg MD

Prasugrel1

30 mg LD+

5 or 10 mg MD

Prasugrel1

30 mg LD+

5 or 10 mg MD

Medical Management Decision ≤72 hrs(No prior clopidogrel given) — 4% of total

Medical Management Decision ≤72 hrs(No prior clopidogrel given) — 4% of total

Medical Management Decision ≤ 10 days(Clopidogrel started ≤ 72 hrs in-hospital OR

on chronic clopidogrel) — 96% of total

Medical Management Decision ≤ 10 days(Clopidogrel started ≤ 72 hrs in-hospital OR

on chronic clopidogrel) — 96% of total

1. All patients were on aspirin and low-dose aspirin (< 100 mg) was strongly recommended. For patients <60 kg or ≥75 years, 5 mg MD of prasugrel was given. Adapted from Chin CT et al. Am Heart J 2010;160:16-22.e1.

1. All patients were on aspirin and low-dose aspirin (< 100 mg) was strongly recommended. For patients <60 kg or ≥75 years, 5 mg MD of prasugrel was given. Adapted from Chin CT et al. Am Heart J 2010;160:16-22.e1.

Median Time to Enrollment = 4.5

Days

HR (95% CI) ≤ 1 Year:

0.99 (0.84, 1.16)

HR (95% CI) > 1 Year:0.72 (0.54, 0.97)

Primary Efficacy Endpoint to 30 Months

HR (95% CI):0.91 (0.79, 1.05)

P = 0.21

Interaction P = 0.07

Age<70years

Evaluation of All Ischemic Events Over Time*(Age < 75 years)

Prasugrel Clopidogrel

≥ 1 event 364 397

≥ 2 events 77 109

3–7 events 18 24

Lower risk multiple recurrent ischemic events Lower risk multiple recurrent ischemic events suggested with prasugrel using the pre-specified suggested with prasugrel using the pre-specified Andersen-Gill model Andersen-Gill model (HR = 0.85, 95% CI: 0.72–1.00, P=0.04)(HR = 0.85, 95% CI: 0.72–1.00, P=0.04)

Significant interaction with treatment and time (HR for Significant interaction with treatment and time (HR for > 12 mos = 0.64, 95% CI: 0.48–0.86, Interaction > 12 mos = 0.64, 95% CI: 0.48–0.86, Interaction P=0.02) P=0.02)

* Pre-specified evaluation of all CV death, MI, or stroke events by treatment

Primary Efficacy Endpoint and TIMI Major Bleeding Through 30 Months(Overall population)

HR (95% CI):0.96 (0.86,

1.07)P = 0.45

HR (95% CI):1.23 (0.84,

1.81)P = 0.29

Conclusions

In the largest trial to date of ACS patients managed medically without revascularization, prasugrel was not statistically different from clopidogrel during 2.5 years of follow-up among patients < 75 years of age

Further analyses of the primary endpoint yielded several important findings favoring prasugrel treatment• Trend for a time-dependent benefit after 1 year• Fewer total recurrent ischemic events, particularly

after 1 year No statistical differences in major, life-threatening,

or fatal bleeding with prasugrel vs. clopidogrel

PLATO study design

Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding

6–12-month exposure

ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)

Ticagrelor180 mg loading dose, then90 mg bid maintenance;(additional 90 mg pre-PCI)

NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)Clopidogrel-treated or -naive;randomised within 24 hours of index event (N=18,624)

PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,521

8,628

8,362

8,460

8,124

Days after randomisation

6,743

6,743

5,096

5,161

4,047

4,147

0 60 120 180 240 300 360

1211109876543210

13

Cu

mu

lati

ve in

cid

en

ce (

%)

9.8

11.7

8,219

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Clopidogrel

Ticagrelor

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Wallentin L et al. NEJM 2009;361:1045-57.

0 60 120 180 240 300 360

6

4

3

2

1

0

Clopidogrel

Ticagrelor

4.0

5.1

HR 0.79(95% CI 0.69–0.91)

P=0.001

7

5

9,291

9,333

8,865

8,294

8,780

8,822

8,589


7079

7119

5,441

5,482

4,364

4,4198,626

Cardiovascular deathC

um

ula

tive in

cid

en

ce (

%)

All-cause mortality4.5% vs. 5.9%

HR 0.78(0.69-0.89)

P<0.001

Wallentin L et al. NEJM 2009;361:1045-57.

8,688

8,763

0 10 20 30

8

6

4

2

0

Cu

mu

lati

ve in

cid

en

ce

(%)

Clopidogrel

Ticagrelor

4.775.43

HR 0.88 (95% CI 0.77–1.00), p=0.045

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,875

8,942

8,763

8,827


31 90 150 210 270 330

8

6

4

2

0

Clopidogrel

Ticagrelor

5.28

6.60

8,688

8,673

8,286

8,397

6,379

6,480

Days after randomisation*

HR 0.80 (95% CI 0.70–0.91), p<0.001

8,437

8,543

6,945

7,028

4,751

4,822

Cu

mu

lati

ve in

cid

en

ce

(%)

*Excludes patients with any primary event during the first 30 daysWallentin L et al. NEJM 2009;361:1045-57.

Stent thrombosis

Ticagrelor

(n=5,640)

Clopidogrel

(n=5,649)

HR

(95% CI) p value

Stent thrombosis, n (%)

Definite

Probable or definite

Possible, probable, definite

71 (1.3)

118 (2.1)

155 (2.8)

106 (1.9)

158 (2.8)

202 (3.6)

0.67 (0.50–0.91)

0.75 (0.59–0.95)

0.77 (0.62–0.95)

0.009

0.02

0.01

(evaluated in patients with any stent during the study)

*Time-at-risk is calculated from first stent insertion in the study or date of randomisation

NS

NS

NS

NS

NS

0

K-M

esti

mate

d r

ate

(%

per

year)

PLATO major bleeding

1

2

3

4

5

6

7

8

9

10

12

11

13

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 (%); NS = not significant

11.611.2

7.9 7.7

8.9 8.9

5.8 5.8

0.3 0.3

TicagrelorClopidogrel


Non-CABG and CABG-related major bleeding

p=0.026

p=0.025

NS

NS

9K

-M e

stim

ate

d r

ate

(%

per

year)

Non-CABGPLATO majorbleeding

8

7

6

5

4

3

2

1

0Non-CABGTIMI major bleeding

CABGPLATO major bleeding

CABG TIMI major bleeding

4.5

3.8

2.8

2.2

7.4

7.9

5.3

5.8

TicagrelorClopidogrel

Conclusions Reversible, more intense P2Y12 receptor

inhibition for one year with 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

Thromb Haemost 2012; 108: 318-327

Efficacy comparison of High dose clopidogrel, prasugrel and ticagrelor strategies vs. standard clopidogrel therapy

OASIS-7 PCI (2010) TRITON TIMI-38 (2007) PLATO (2009)High dose clopidogrel

Standard clopidogrel

Risk reduction

Prasugrel Standard clopidogrel

Risk reduction

Ticagrelor Standard clopidogrel

Risk reduction

Primary endpoint

3.9% 4.5% 14% 9.9% 12.1% 19% 9.0% 10.7% 16%

All Cause Death

1.9% 2.1% 6% 3% 3.2% 5% 3.9% 5% 19%

Non-fatal MI 2% 2.6% 21% 7.3% 9.5% 14% 5.3% 6.6% 20%

Stent thrombosis

1.6% 2.3% 31% 1.1% 2.4% 52% 2.2% 3% 27%

Bleeding comparison of High dose clopidogrel, prasugrel and ticagrelor strategies vs. standard clopidogrel therapy

OASIS-7 PCI (2010) TRITON TIMI-38 (2007) PLATO (2009)High dose clopidogrel

Standard clopidogrel

HR Prasugrel Standard clopidogrel

HR Ticagrelor Standard clopidogrel

HR

Total Major Bleeding

1% 0.7% 1.36 2.5% 1.7% 1.46 7.9% 7.9% 1.0

Non-CABG related Major bleeding

0.8% 0.6% 1.34 2.4% 1.8% 1.32 2.8% 2.2% 1.23

Study Overview: Prasugrel / Ticagrelor

ST-Elevation Myocardial Infarction

Non ST-Elevation Acute Coronary Syndromes

Medically Managed Pts – NSTE ACS

Stable Angina

Diabetes mellitus

Chronic Kidney Disease

Limitations and Contraindications

Antiplatelet Therapies – The Dynamics

0

5

10

15

0 30 60 90 180 270 360 450

End

poin

t (%

)

Days

9.5%

6.5%

12.4%

10.0%

Clopidogrel

Prasugrel

CV death / MI / stroke

Efficacy of prasugrel in STEMIEfficacy of prasugrel in STEMI

Montalescot G et al., Lancet 2009

NNT = 42

P = 0.02

0

1

2

3

4

5

30 days 15 months

P=0.04 P=0.11

Incidence of death from any cause (%)

Lower early mortality with prasugrel in STEMILower early mortality with prasugrel in STEMI


Clopidogrel

Prasugrel

2.62.6

1.61.6

4.34.3

3.33.3

0

5

10

15

0 30 60 90 180 270 360 450

End

poin

t (%

)

Days

TIMI major non-CABG bleeds

Clopidogrel

Prasugrel 2.4%

2.1%

Safety of prasugrel in STEMISafety of prasugrel in STEMI


NNH = 333

P = 0.65

Steg PG et al., Circulation 2010

Benefit of ticagrelor in STEMIBenefit of ticagrelor in STEMI

0

2.5

5.0

7.5

8 months

P=0.05

Incidence of death from any cause (%)

Lower all-cause mortality with ticagrelor in STEMILower all-cause mortality with ticagrelor in STEMI

Clopidogrel

Ticagrelor6.16.1

5.05.0



Safety of ticagrelor in STEMISafety of ticagrelor in STEMI

Similar efficacy and safety in STEMI

TRITON: Prasugrel1° efficacy endpointAll cause mortality 1° safety endpoint

PLATO: Ticagrelor1° efficacy endpointAll cause mortality 1° safety endpoint

Hazard ratio for 1° endpoint(95 % - confidence limit)

0.5 1 1.5

Study drug better Clopidogrel better

Montalescot G et al., Lancet 2009; Steg PG et al., Circulation 2010




Stable Angina

Diabetes mellitus




Similar efficacy of prasugrel in STEMI and UA/NSTEMI

15-month incidence of death/MI/stroke (%)

0

2

4

6

8

10

12

14

16

12.4

10.0

p=0.02

STEMINNT = 42

12.0

9.9

p=0.03

UA/NSTEMINNT = 47


Clopidogrel

Prasugrel

Favorable risk-benefit ratio of prasugrel in UA/NSTEMI

Clopidogrel

Prasugrel


15-month incidence (%)

0

2

4

6

8

10

12

14

16

12.0

9.9

p=0.03

death/MI/stroke

NNT = 47

1.72.4

p=0.01

major non-CABG bleed

NNH = 142

TRITON: All cause mortality in NSTE-ACS vs. STEMI

Wiviott SD et al., J Am Cardiol 2010

STEMI

NSTE-ACS

Hazard ratio for all cause mortality(95 % - confidence limit)

0.5 1 1.5

Prasugrel better Clopidogrel better

Pint = 0.11Pint = 0.11

Favorable risk-benefit ratio of ticagrelor in UA/NSTEMI

Clopidogrel

Ticagrelor

Wallentin L et al., N Engl J Med 2009, Steg PG et al., Circulation 2010

15-month incidence (%)

0

2

4

6

8

10

12

14

16

11.5

9.6

P = 0.001

death/MI/stroke

NNT = 52

7.8 8.2

P = 0.41

TIMI major bleed

NNH = 233

Differential efficacy in NSTE-ACS

Wiviott SD et al., J Am Cardiol 2010 & N Engl J Med 2007; Wallentin L et al., N Engl J Med 2009

TRITON1° endpoint All cause mortality

PLATO1° endpoint

All cause mortality


0.5 1 1.5


New P2Y12 inhibitors superior to high-dose clopidogrel

Non-selected ACS

PLATO (ticagrelor)

OASIS-7 (high-dose clopidogrel)

ACS undergoing PCI

TRITON (prasugrel)

OASIS-7 PCI (high-dose clopidogrel)

Hazard ratio for 30-day 1° endpoint(95 % - confidence limit)

0.5 1 1.5

study treatment better

normal-dose clopidogrelbetter

P = 0.045

P = 0.30

P < 0.001

P = 0.039

Wallentin L et al., N Engl J Med 2009OASIS-7 investigators, N Engl J Med 2010Mehta SR et al., Lancet 2010




Medically Managed Pts – NSTE ACS

Stable Angina

Diabetes mellitus




Superior net clinical benefit of prasugrel in

diabetics

Days

0

2

4

6

8

10

12

14

16

18

0 30 60 90 180 270 360 450

HR 0.70P < 0.001

En

dpo

int (

%)

CV death / MI / stroke

TIMI major non-CABG bleeds

NNT = 21

17.0%

12.2%

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.6%

2.5%

Wiviott SD et al. Circulation 2008

Wiviott SD et al., Circulation 2008

Superior efficacy of prasugrel in diabetics:1° endpoint


Potent effect of prasugrel in diabetics:Stent thrombosis


Safety of prasugrel in diabetics:TIMI major non CABG bleeding

No interaction with diabetes in PLATO: 1° endpoint

Pint = 0.49Pint = 0.49

James S et al., Eur Heart J 2010

No interaction with diabetes in PLATO: Mortality

Pint = 0.66Pint = 0.66

James S et al., Eur Heart J 2010

Interaction with diabetes mellitus

Wiviott SD et al., Circulation 2008; James S et al., Eur Heart J 2010

TRITONNo diabetesDiabetes

PLATONo diabetes

Diabetes


0.5 1 1.5


Pint = 0.49Pint = 0.49

Pint = 0.09Pint = 0.09




Stable Angina

Diabetes mellitus




Different interaction with renal function

Wiviott SD et al., N Engl J Med 2007; James S et al., Circulation 2010

TRITON 1° endpointCrCl < 60 mL/min CrCl > 60 mL/min

Hazard ratio(95 % - confidence limit)

0.5 1 1.5


Pint n.s.Pint n.s.Pint n.s.Pint n.s.

PLATO 1° endpointCrCl < 60 mL/min CrCl > 60 mL/min

Pint = 0.13Pint = 0.13

12.1 %

3.1 %3.3 %

10.0 %

ticagrelor

ticagrelor

clopidogrel

clopidogrel

Creatinine clearance > 60 ml/minCreatinine clearance > 60 ml/min

Creatinine clearance < 60 ml/minCreatinine clearance < 60 ml/min

Cumulative incidence of all-cause deathCumulative incidence of all-cause death

Days since randomization

No survival benefit of ticagrelor in normal creatinine clearanceNo survival benefit of ticagrelor in normal creatinine clearance

James S et al., Circulation 2010




Stable Angina

Diabetes mellitus




0.5 1 2

OVERALL

Prasugrel Better Clopidogrel Better

No

YesPrior Stroke / TIA Pint = 0.006

<75

≥75Age

Pint = 0.18

≥60 kg

<60 kgWeight

Pint = 0.36

www.timi.org – Accessed on July 16, 2008

Contraindication with history of cerebro-vascular event

Hazard Ratio for net clinical outcome

Dyspnoea on Ticagrelor

Any dyspnoea With discontinuation of study treatment

Incidence (%)

P < 0.001

7.7

0.1

13.8

0.9

Clopidogrel

0

5

15

10Ticagrelor

P < 0.001

Wallentin L et al., N Engl J Med 2009

Exclusion criterion: Increased risk of bradycardia

≥ 3 sec

Incidence of ventricular pauses during 1st week (%)

P = 0.01

3.6

1.2

5.8

2.0

Clopidogrel

0

2

6

4Ticagrelor

P = 0.10

Wallentin L et al., N Engl J Med 2009

3

5

1

≥ 5 sec

P2Y12-Blockers in PCI

STEMI ACS - UA Elective PCI

Non STEMI

Prasugrel Ticagrelor Clopidogrel

Diabetes Mellitus Normal Renal Function CKD

Ticagrelor over Prasugrel: <60 kg, Over 75 Yrs, Previous Stroke or TIAPrasugrel over Ticagrelor: Bradycardia

STEMI ACS - UA Elective PCI

Non STEMI

Prasugrel Ticagrelor Clopidogrel

Diabetes Mellitus Normal Renal Function CKD

Ticagrelor over Prasugrel: <60 kg, Over 75 Yrs, Previous Stroke or TIAPrasugrel over Ticagrelor: Bradycardia

TICAGRELOR180 mg loading dose,

then 90 mg bid for

1 year (ASA < 100)

PRASUGREL60 mg loading dose,

then 5-10 mg PO daily

for 1 year

CLOPIDOGREL600 mg PO loading dose, then 150 mg daily 1-4 weeks,

then 75 mg daily for 1 year

•R/O Contraindications•PCI ( Clop naïve )

• STEMI • Diabetic • Stent Thrombosis

• Clopidogrel NR

•Irrespective of strategy• Mod to High Risk ACS/ NSTEMI (On or Off C)• Unknown coronary anatomy; CABG likely•Clopidogrel NR

• All others, especially if high-risk for bleeding• Lung and renal disease• Already on Clopidogrel but no ischemic event

10-15% 40-50% 30-40%

Choice of Oral Antiplatelet Therapy in ACS/PCI Patients

Antiplatelet Therapy in ACS

Placebo APTC CURE TRITON-TIMI 38Single Antiplatelet Rx

Dual Antiplatelet Rx

Higher IPA

ASAASA + Clopidogrel ASA +

Prasugrel

- 22%

- 20%

- 19%

+ 60% + 38% + 32%

Reduction inIschemicEvents

- 21%

PLATO

ESC 2011 Antiplatelet guidelines for ACS patients presenting ST segment elevation

Current Research Questions Head to head comparison of APS.

Short term / reversibility may increase the incidence of stent thrombosis.

Is aspirin still necessary in modern DAPT.

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Results: MACE

Non significant 6% reduction in MACE

with high dose clopidogrel in overall study population

Significant 14% reduction in MACE in PCI

subgroup with high dose

clopidogrel

Significant 19% reduction in MACE

with prasugrel after 15 months


with prasugrel after 30 days of

FU


with ticagrelor after 12 months of

FU


with ticagrelor after 30 days of

FU

Significant 16% reduction in MACE with ticagrelor in

invasive only subgroup

MACE: Clopidogrel high dose vs. standard dose

Significant 26% risk reduction in MACE with high dose clopidogrel strategy compared to

standard dose clopidogrel therapy

Other Adverse EventsTicagrelor

(n=9,235)

Clopidogrel

(n=9,186) p value

Ventricular pauses ≥3 sec on Holter, %

In 1st week (n=2866 w/ Holter)

At 30 days (n=1991 w/ Holter)

5.8

2.1

3.6

1.7

0.01

0.52

Bradycardia-related event, %

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

Dyspnea, %

Any

Leading to d/c of study treatment

13.8

0.9

7.8

0.1

<0.001

<0.001


Dyspnea Associated with Ticagrelor

Usually mild to moderate

Observed within 1st 7 days, median time 23 days, mostly resolves spontaneously

Patients with baseline cardiopulmonary disease were not at an increased relative risk of dyspnea

No measured changes in pulmonary function/ BNP levels

Benefit of ticagrelor is maintained in patients at risk for dyspnea and those who experience dyspnea

Patient with mild to moderate dyspnea should be encouraged to continue with Ticagrelor considering consistency of benefit

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057

Key Messages Diabetes

Overall PEP consistent with PLATO Main results Driven by MI and CVD like PLATO main results No Increase in PLATO Major, LT, Non-CABG

Major Bleeds. Benefit of PLATO trial design

PLATO hierarchical testing of major efficacy endpoints

*The percentages are K-M estimates of the rate of the endpoint at 12 months. Patients could have had more than one type of endpoint. Death from CV causes and fatal bleeding, as only traumatic fatal bleeds were excluded from the CV death category.†By Cox regression analysis using treatment as factor.

All Patients*All Patients* Ticagrelor Ticagrelor (n=9333)(n=9333)

Clopidogrel Clopidogrel (n=9291)(n=9291)

HR for HR for ticagrelor ticagrelor (95% CI)(95% CI)

PP value value††

Primary objective, n (%/year)

CV death + MI + stroke 864 (9.8) 1014 (11.7) 0.84 (0.77–0.92) 0.0003

Secondary objectives, n (%/yr)

Total death + MI + stroke 901 (10.2) 1065 (12.3) 0.84 (0.77–0.92) 0.0001

CV death + MI + stroke + severe + recurrent

ischemia + TIA + arterial thrombus

1290 (14.6) 1456 (16.7) 0.88 (0.81–0.95) 0.0006

MI 504 (5.8) 593 (6.9) 0.84 (0.75-0–95) 0.0045

CV death 353 (4.0) 442 (5.1) 0.79 (0.69–0.91) 0.0013

Stroke 125 (1.5) 106 (1.3) 1.17 (0.91–1.52) 0.2249

Total death 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) 0.0003

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057

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Clop

Efficacy Across Patient Subgroups

AgeAge

Overall Treatment Effect

SexSex

Body WeightBody Weight

Prior Non-hemorrhagic Stroke /TIA

Prior Non-hemorrhagic Stroke /TIA

FemaleFemale 13.213.213.213.2

MaleMale 11.111.111.111.1

≥ 75 years≥ 75 years 18.318.318.318.3

< 75 years< 75 years 10.410.410.410.4

< 65 years< 65 years 8.58.58.58.5

11.711.711.711.7

< 60 kg< 60 kg 17.317.317.317.3

≥ 60 kg≥ 60 kg 11.211.211.211.2

NoNo 20.820.820.820.8

YesYes 11.111.111.111.1

Diabetes MellitusDiabetes MellitusYesYes 16.216.216.216.2NoNo 10.210.210.210.2

OtherOther 14.714.714.714.7

STEMISTEMI 10.110.110.110.1Final DiagnosisFinal Diagnosis NSTEMINSTEMI 13.913.913.913.9

Uns. AnginaUns. Angina 9.19.19.19.1

0.5 1.0 2.0

TotalPatients Tic HR (95% CI)

KM% at Month 12

Characteristic

11.211.211.211.2

9.29.29.29.2

16.816.816.816.8

8.68.68.68.6

7.27.27.27.2

9.89.89.89.8

13.113.113.113.1

9.59.59.59.5

19.019.019.019.0

9.29.29.29.2

14.114.114.114.18.48.48.48.4

9.19.19.19.18.58.58.58.5

11.411.411.411.48.68.68.68.6

0.83 (0.71, 0.97)0.83 (0.71, 0.97)

0.85 (0.76, 0.95)0.85 (0.76, 0.95)

0.94 (0.78, 1.12)0.94 (0.78, 1.12)

0.82 (0.74, 0.91)0.82 (0.74, 0.91)

0.85 (0.74, 0.97)0.85 (0.74, 0.97)

0.84 (0.77, 0.92)0.84 (0.77, 0.92)

0.75 (0.56, 0.99)0.75 (0.56, 0.99)

0.86 (0.78, 0.94)0.86 (0.78, 0.94)

0.87 (0.66, 1.13)0.87 (0.66, 1.13)

0.84 (0.76, 0.93)0.84 (0.76, 0.93)

0.88 (0.76, 1.03)0.88 (0.76, 1.03)0.83 (0.74, 0.92)0.83 (0.74, 0.92)

0.58 (0.34, 1.00)0.58 (0.34, 1.00)

0.84 (0.72, 0.98)0.84 (0.72, 0.98)

0.83 (0.73, 0.94)0.83 (0.73, 0.94)

0.96 (0.75, 1.22)0.96 (0.75, 1.22)

52885288

1333613336

28782878

1574415744

1064310643

1862418624

13121312

1725617256

11521152

1746217462

466246621396213962

489489

70267026

79557955

31123112

InteractionP-value

0.81820.8182

0.21660.2166

0.36150.3615

0.83510.8351

0.48820.4882

0.40850.4085

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

Tic Better

Clop Better

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Health & Medicine

interaction p

primary pci clopidogrel

md clopidogrel

time hr

pci asa prasugrel

risk clopidogrel ticagrelor

days endpoint

cv death