What’s New in Acute Coronary Syndromes? Claudia Bucci BScPhm, PharmD Clinical Coordinator,...

What’s New in What’s New in Acute Coronary Syndromes?Acute Coronary Syndromes?

What’s New in What’s New in Acute Coronary Syndromes?Acute Coronary Syndromes?

Claudia Bucci BScPhm, PharmDClaudia Bucci BScPhm, PharmDClinical Coordinator, Cardiovascular DiseasesClinical Coordinator, Cardiovascular Diseases

Sunnybrook Health Sciences CentreSunnybrook Health Sciences Centre

1313thth Annual Contemporary Therapeutic Issues Annual Contemporary Therapeutic Issues in Cardiovascular Diseasein Cardiovascular Disease

May 7, 2010May 7, 2010

ObjectivesObjectivesObjectivesObjectives

• To review recent evidence of To review recent evidence of antiplatelet therapies in the antiplatelet therapies in the management of ACSmanagement of ACS Clopidogrel (CURRENT/OASIS-7)Clopidogrel (CURRENT/OASIS-7) Prasugrel (TRITON-TIMI 38)Prasugrel (TRITON-TIMI 38) Ticagrelor (PLATO)Ticagrelor (PLATO)

• To provide an update on To provide an update on pharmacotherapeutic issues in the pharmacotherapeutic issues in the management of ACS.management of ACS.

Platelet CascadePlatelet CascadePlatelet CascadePlatelet Cascade

Platelet5HT

PAF

EPIADP Thrombin

Collagen

TXA2

Gp 2b/3a receptor

Platelet Aggregation

ClotClot

Clopidogrel PrasugrelTicagrelor

ASA

Platelet

AbciximabEptifibatide

Tirofiban

MedicationMedication In HospitalIn Hospital Long-TermLong-Term

AspirinAspirin 160mg to chew, 160mg to chew, followed by ECASA followed by ECASA

81mg daily81mg daily

ECASA 81mg daily ECASA 81mg daily indefinitelyindefinitely

ClopidogrelClopidogrel 300mg or 600mg X 1, 300mg or 600mg X 1, followed by 75mg followed by 75mg

dailydaily

75mg daily ≥ 1 75mg daily ≥ 1 yearyear

Minimum: 4 weeks Minimum: 4 weeks (BMS)(BMS)

3-6 months (DES)3-6 months (DES)

Use of Antiplatelets in ACS and PCIUse of Antiplatelets in ACS and PCIUse of Antiplatelets in ACS and PCIUse of Antiplatelets in ACS and PCI

Limitations of Current Limitations of Current Antiplatelet TherapyAntiplatelet Therapy


• Slow OnsetSlow Onset• Level of Platelet InhibitionLevel of Platelet Inhibition• Variability of ResponseVariability of Response

High on-treatment platelet reactivity leads to High on-treatment platelet reactivity leads to

increased risk of ischemic events. increased risk of ischemic events. Medication adherenceMedication adherence Patient factorsPatient factors P2Y12 receptor affinityP2Y12 receptor affinity Under-dosingUnder-dosing

CURRENT/OASIS-7CURRENT/OASIS-7CURRENT/OASIS-7CURRENT/OASIS-7

R

UA/NSTEMIor STEMI

ClopidogrelDay 1 = 600 mg LDDay 2 – 7 = 150 mg dailyDay 8-30 = 75 mg

ClopidogrelDay 1 = 300 mg LD + placeboDay 2 – 7 = 75 mg daily + placebo Day 8-30 75 mg daily

HIGH DOSE

STANDARD DOSE

All patients: ASA low dose (75-100mg) OR high dose (300-325mg)Up to 30 days

www.clinicaltrialresults.org

25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)

25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)

PCI 17,232(70%)

Angio 24,769(99%)

Angio 24,769(99%)

No PCI 7,855 (30%)

No Sig. CAD 3,616 CABG 1,809 CAD 2,430

Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30

Safety Outcomes: Bleeding

Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30

Safety Outcomes: Bleeding

CURRENT/OASIS-7CURRENT/OASIS-7CURRENT/OASIS-7CURRENT/OASIS-7


Clopidogrel: Double vs Standard Clopidogrel: Double vs Standard DoseDose

Clopidogrel: Double vs Standard Clopidogrel: Double vs Standard DoseDose

StandarStandardd

Double Double HRHR 95% CI95% CI PP Intn Intn

CV CV Death/MI/StrokeDeath/MI/Stroke

PCI (2N=17,232)PCI (2N=17,232) 4.54.5 3.93.9 0.850.85 0.74-0.990.74-0.99 0.0360.0360.0160.016

No PCI (2N=7855)No PCI (2N=7855) 4.24.2 4.94.9 1.171.17 0.95-1.440.95-1.44 0.140.14

Overall Overall (2N=25,087)(2N=25,087)

4.44.4 4.24.2 0.950.95 0.84-1.070.84-1.07 0.3700.370

MIMI

PCI (2N=17,232)PCI (2N=17,232) 2.62.6 2.02.0 0.780.78 0.64-0.950.64-0.95 0.0120.0120.0250.025

No PCI (2N=7855)No PCI (2N=7855) 1.41.4 1.71.7 1.251.25 0.87-1.790.87-1.79 0.230.23


2.22.2 1.91.9 0.860.86 0.73-1.030.73-1.03 0.0970.097

CV DeathCV Death

PCI (2N=17,232)PCI (2N=17,232) 1.91.9 1.91.9 0.960.96 0.77-1.190.77-1.19 0.680.681.01.0

No PCI (2N=7855)No PCI (2N=7855) 2.82.8 2.72.7 0.960.96 0.74-1.260.74-1.26 0.770.77


2.22.2 2.12.1 0.960.96 0.81-1.140.81-1.14 0.6280.628

StrokeStroke

PCI (2N=17,232)PCI (2N=17,232) 0.40.4 0.40.4 0.880.88 0.55-1.410.55-1.41 0.590.590.500.50

No PCI (2N=7855)No PCI (2N=7855) 0.80.8 0.90.9 1.111.11 0.68-1.820.68-1.82 0.670.67


0.50.5 0.50.5 0.990.99 0.70-1.390.70-1.39 0.9500.950


Days

Cu

mu

lati

ve H

azar

d

0.0

0.01

0.02

0.03

0.04

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel: Double vs Standard Dose Clopidogrel: Double vs Standard Dose Primary Outcome: PCI PatientsPrimary Outcome: PCI Patients

Clopidogrel Standard

Clopidogrel Double

HR 0.8595% CI 0.74-0.99

P=0.036

15% RRR15% RRR

CV Death, MI or StrokeCV Death, MI or Stroke


Stent ThrombosisStent Thrombosis

Days

Cu

mu

lati

ve H

azar

d

0.0

0.00

40.

008

0.01

2

0 3 6 9 12 15 18 21 24 27 30

C Standard, A Low

C Standard, A High

C Double, A Low

C Double, A High


CURRENT-OASIS 7 CURRENT-OASIS 7 ConclusionsConclusions

CURRENT-OASIS 7 CURRENT-OASIS 7 ConclusionsConclusions

• High Dose ClopidogrelHigh Dose Clopidogrel stent thrombosis and major CV stent thrombosis and major CV

events in PCI patients.events in PCI patients. ↑ ↑ CURRENT-defined major bleeds but CURRENT-defined major bleeds but

not TIMI major, ICH or fatal.not TIMI major, ICH or fatal.• High Dose ASAHigh Dose ASA

No significant difference in efficacy or No significant difference in efficacy or bleeding (with trends towards greater bleeding (with trends towards greater efficacy).efficacy).




• Slow OnsetSlow Onset• Level of Platelet InhibitionLevel of Platelet Inhibition• Variability of ResponseVariability of Response

High on-treatment platelet reactivity leads High on-treatment platelet reactivity leads to increased risk of ischemic events. to increased risk of ischemic events.

Medication adherenceMedication adherence Patient factorsPatient factors P2Y12 receptor affinityP2Y12 receptor affinity Under-dosingUnder-dosing

ClopidogrelClopidogrel

(Plavix(Plavix®)®)PrasugrelPrasugrel

(Effient(Effient®)®)TicagrelorTicagrelor

(Brilinta(Brilinta®)®)

EvidenceEvidence CURECURE

PCI-CUREPCI-CURETRITON-TIMI TRITON-TIMI

3838PLATOPLATO

DoseDose 300-600mg X 300-600mg X 11

75 mg od 75 mg od (150mg X 7d)(150mg X 7d)

60mg X 1,60mg X 1,

10mg od10mg od180mg X 1180mg X 1

90mg bid90mg bid

Approved Approved IndicationsIndications**

• MI, stroke, MI, stroke, PAD (secondary PAD (secondary prev’n)prev’n)• ACS +/- PCIACS +/- PCI

NSTEMI/STEMI NSTEMI/STEMI with PCIwith PCI

--

AvailabilityAvailability** YesYes June 2010June 2010 --

CostCost $2.58/day$2.58/day ?? ??

Update: Antiplatelet Agents in ACS and Update: Antiplatelet Agents in ACS and PCIPCI

Update: Antiplatelet Agents in ACS and Update: Antiplatelet Agents in ACS and PCIPCI

*as of May 2010

ClopidogrelClopidogrel

(Plavix(Plavix®)®)PrasugrelPrasugrel

(Effient(Effient®)®)TicagrelorTicagrelor

(Brilinta(Brilinta®)®)

MechanismMechanism IrreversibleIrreversible IrreversibleIrreversible ReversibleReversible

Inhibitory Inhibitory effecteffect

++ ++++ ++++

OnsetOnset 2 h2 h < 30 min< 30 min 1-2 h1-2 h

Peak Peak responseresponse

2-5 h2-5 h 2-4 h2-4 h 1-3 h1-3 h

MetabolismMetabolism ProdrugProdrug(CYP 2C19, 3A, (CYP 2C19, 3A,

2B6, 1A2)2B6, 1A2)

ProdrugProdrug(3A4, 2B6, 2C9, (3A4, 2B6, 2C9,

2C19)2C19)

Not a Not a prodrugprodrug

DurationDuration 5-7 days5-7 days 5-7 days5-7 days 24 – 48 h24 – 48 h

Comparison of Antiplatelet Agents in Comparison of Antiplatelet Agents in ACSACS

Comparison of Antiplatelet Agents in Comparison of Antiplatelet Agents in ACSACS

N Engl J Med 2009; 361:1108

Inhibition of Platelet AggregationInhibition of Platelet Aggregation(IPA) at 24 Hours (Healthy (IPA) at 24 Hours (Healthy

Volunteers)Volunteers)

Inhibition of Platelet AggregationInhibition of Platelet Aggregation(IPA) at 24 Hours (Healthy (IPA) at 24 Hours (Healthy

Volunteers)Volunteers)

-20.0-20.0

0.00.0

20.020.0

40.040.0

60.060.0

80.080.0

100.0100.0

Inhi

bitio

n of

Pla

tele

t Agg

rega

tion

(%)

Inhi

bitio

n of

Pla

tele

t Agg

rega

tion

(%)

Response to Response to PrasugrelPrasugrel

Response to Response to ClopidogrelClopidogrel

Clopidogrel ResponderClopidogrel Non-responder

*Responder = *Responder = 25% IPA at 4 and 24 25% IPA at 4 and 24 hh

Inte

rpat

ien

t Va

ria

bilit

y

Interp

atient

Va

riab

ility

Brandt, Payne, Wiviott et al AHJ 2007

TRITON-TIMI 38TRITON-TIMI 38TRITON-TIMI 38TRITON-TIMI 38

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCI

ASA

PRASUGREL60 mg LD/ 10 mg MD

CLOPIDOGREL300 mg LD/ 75 mg MD

1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch

CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic

Median duration of therapy - 12 months

N= 13,600

Wiviott SD et al. New Engl J Med 2007;357:2001-2015

10

15

Days

0

5

0 30 60 90 180 270 360 450

Prasugrel

Clopidogrel

Intent To Treat: n=13,608; Lost to Follow-Up: n=14 (0.1%)

HR 0.81 (0.73-0.90)P<0.001

ARR=2.2% NNT=46

12.1(n=781)

9.9 (n=643)

HR 0.77 (0.67-0.88)

P<0.001

HR 0.80 (0.71-0.90)

P<0.001

CV

Dea

th/M

I/S

tro

ke

(%)

TRITON-TIMI 38: CV Death, MI, TRITON-TIMI 38: CV Death, MI, StrokeStroke


Prasugrel

Clopidogrel

TRITON-TIMI 38TRITON-TIMI 38TRITON-TIMI 38TRITON-TIMI 38

5

10

15

00 30 60 90 180 270 360 450

Days After Randomization

En

d P

oin

t (%

)

120

1.8 (n=111)

2.4(n=146)

Non-CABG TIMI Major Bleeds

CV Death, MI, Stroke

P=0.03

P<0.001↓138 events

↑ 35 events

12.1(n=781)

9.9 (n=643)

Prasugrel

Clopidogrel


TRITON-TIMI 38: TRITON-TIMI 38: Non-CABG TIMI Major Non-CABG TIMI Major

BleedsBleeds

TRITON-TIMI 38: TRITON-TIMI 38: Non-CABG TIMI Major Non-CABG TIMI Major

BleedsBleeds

Pat

ien

ts (

%)

Non-CABGTIMI Major

Through day 3 At study endAfter day 3 to study end

(n=6,716)

(n=6,741)

Life Threatening Bleeds

1.8%

0.4%0.3%

1.0%

0.6%

n=111

2.4%n=146

0.9%n=56

1.4%n=85

P=0.03

P=0.26

P=0.03

P=0.01


P=0.002

Odds Ratio 4.73P<0.001

TIMI Major or Minor

CABG-related TIMI Major Bleeding

Requiring Transfusion

P<0.001

At risk 6/189

At risk 24/179

(n=6,716)

(n=6,741)

Pat

ien

ts (

%)

3.2%

13.4%

n=244n=182

n=231

n=3033.8%5.0%

3.0%4.0%

TRITON-TIMI 38: TRITON-TIMI 38: Other TIMI BleedsOther TIMI BleedsTRITON-TIMI 38: TRITON-TIMI 38: Other TIMI BleedsOther TIMI Bleeds


0.5 1.5 2.5 3.5 4.5 5.5 6.51.0 2.0 3.0 4.0 5.0 6.0

Prasugrel Better Clopidogrel BetterHR

P* value

P**interaction

0.06 -

0.08 0.22

0.10 -

0.17 0.64

TRITON-TIMI 38: Non-TRITON-TIMI 38: Non-CABG TIMI Major BleedCABG TIMI Major BleedTRITON-TIMI 38: Non-TRITON-TIMI 38: Non-

CABG TIMI Major BleedCABG TIMI Major Bleed

History of stroke or TIA

Yes

No

Any of the following:

Age >75 y, Body wt. <60 kg, History stroke/TIA

Yes

No

*Tests HR=1.0 within subgroups; **Tests equality HR between subgroups*Tests HR=1.0 within subgroups; **Tests equality HR between subgroups


Ticagrelor versus Clopidogrel in ACS Ticagrelor versus Clopidogrel in ACS (PLATO)(PLATO)

Primary endpoint: • CV death + MI + Stroke Key secondary: • CV death + MI + Stroke in patients intended for invasive management • Total mortality + MI + Stroke • CV death + MI + Stroke + recurrent ischaemia + TIA + arterial thrombotic events • MI alone / CV death alone / Stroke alone / Total mortalityPrimary safety: • 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, then

90 mg bid maintenance;(additional 90 mg pre-PCI)

UA/NSTEMI (moderate-to-high risk) STEMI (if primary PCI)All receiving ASA; clopidogrel-treated or naive;

randomised within 24 hours of index event (N=18,624)

NEJM 2009;361:1045-57.

PLATO: CV Death, MI or PLATO: CV Death, MI or StrokeStroke

PLATO: CV Death, MI or PLATO: CV Death, MI or StrokeStroke

Days after randomisation

0 60 120 180 240 300 360

121110

9876543210

13C

um

ula

tive

inci

den

ce (

%)

9.8

11.7

P<0.001

HR 0.84 (95% CI 0.77–0.92)

RRR = 16%, ARR = 1.87%, NNT = 54

Clopidogrel

Ticagrelor

NEJM 2009;361:1045-57.

PLATO: Major BleedingPLATO: Major BleedingPLATO: Major BleedingPLATO: Major Bleeding

Days from first IP dose

0 60 120 180 240 300 360

10

5

0

15

Clopidogrel

Ticagrelor

11.211.6

HR 1.04 (95% CI 0.95–1.13), p=0.43

K-M

est

imat

ed r

ate

(% p

er y

ear)

NEJM 2009;361:1045-57.

PLATO Total Major PLATO Total Major BleedingBleeding

PLATO Total Major PLATO Total Major BleedingBleeding

NS

NS

NS

NS

NS

0

K-M

est

ima

ted

rat

e (%

per

ye

ar)

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

TicagrelorClopidogrel

11.611.2

7.9 7.7

8.9 8.9

5.8 5.8

0.3 0.3

NEJM 2009;361:1045-57.

PLATO Non-CABG and PLATO Non-CABG and CABG-related Major CABG-related Major

BleedingBleeding

PLATO Non-CABG and PLATO Non-CABG and CABG-related Major CABG-related Major

BleedingBleeding

p=0.03

p=0.03

NS

NS

K-M

est

imat

ed r

ate

(%

per

yea

r)

Non-CABGPLATO major

bleeding

8

7

6

5

4

3

2

1

0Non-CABGTIMI major bleeding

CABGPLATO major

bleeding

CABG TIMI major bleeding

TicagrelorClopidogrel

4.5

3.8

2.8

2.2

7.4

7.9

5.3

5.8

NEJM 2009;361:1045-57.

PLATO: SafetyPLATO: SafetyTicagrelorTicagrelor

N=9333N=9333Clopidogrel Clopidogrel

n=9291n=9291pp

DyspneaDyspnea

Dyspnea Dyspnea requiring requiring discontinuationdiscontinuation

13.8%13.8%

0.9%0.9%7.8%7.8%

0.1%0.1%<0.001<0.001

<0.001<0.001

Ventricular Ventricular Pauses Pauses ≥ 3 sec≥ 3 sec

≥ ≥ 5 sec5 sec5.8%5.8%

2.0%2.0%3.6%3.6%

1.2%1.2%0.010.01

0.100.10

Increase in SrCr Increase in SrCr (%)(%)

1month1month

12 month12 month

End of TxEnd of Tx

1010±22±22

11±2211±22

1010±22±22

88±21±21

99±22±22

1010±22±22

<0.001<0.001

<0.001<0.001

0.590.59NEJM 2009;361:1045-57.

These slides have been provided, on request, by the AstraZeneca Medical AffairsThese slides have been provided, on request, by the AstraZeneca Medical Affairs

LastMaintenance

Dose

Loading Dose

Onset Maintenance Offset

100

90

80

70

60

50

40

30

20

10

0

IPA

%Ticagrelor (n=54)

Clopidogrel (n=50)

Placebo (n=12)

0 .5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240

*

*

* * *

*

*

*

*

‡

†

†

20 µM ADP- Final Extent 20 µM ADP- Final Extent

Gurbel PA, et al Circulation. 2009 ;120:2577-2585.

Intensive Statin Therapy in Intensive Statin Therapy in PCIPCI

Intensive Statin Therapy in Intensive Statin Therapy in PCIPCI

JACC 2009;54:2290-5.

What’s New in Acute Coronary Syndromes? Claudia Bucci BScPhm, PharmD Clinical Coordinator,...

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