Cardiopatia ischemica: nuovi orizzonti nella terapia con antiaggreganti orali

Giancarlo Casolo

Genova, Hotel NH Marina21/22 Ottobre 2011

HEARTLINE HSM GenoaCardiology Meeting

NUOVI ORIZZONTI FARMACOLOGICI NELLA CARDIOPATIA ISCHEMICA

ESC Guideline 2010

Guidelines on myocardial revascularization

Guidelines on myocardial revascularization

PrasugrelTicagrelor

ESC Guideline 2011

STUDIO PLATO

STUDIO TRITON TIMI 38

Current Oasis 7

STUDIO TRITON TIMI 38

STUDIO PLATO

ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update

10

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.82.4

138 events

35 events

Balance of Balance of Efficacy and SafetyEfficacy and Safety

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167Adapted with permission from Wiviott SD et al NEJM 357:2007

TRITON: Results

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

ma

ry E

nd

po

int

(%)

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel

Loading Dose Maintenance Dose

Timing of BenefitTiming of Benefit(Landmark Analysis)(Landmark Analysis)

ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update

Principali risultati nello studio TRITON TIMI 38

TRITON: Previous STOKE or TIA (3.8%)

Wiviot SD et al. N Engl J Med 2007;357:2001-2015

PLATO study design

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)

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

James S et al. Am Heart J 2009;157:599-605

K-M estimate of time to first primary efficacy event (Composite of CV death, MI or stroke)

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

121110

9876543210

13C

um

ula

tive

inci

den

ce (

%)

9.8

11.7

8,219

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Clopidogrel

Ticagrelor

Completeness of follow-up 99.97% = five patients lost to follow-up

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

Wallentin L, Harrington R et al. New Engl J Med 2009;361 (10.1056/NEJMoa0904327).

Hierarchical testing of major efficacy endpoints

All patients*Ticagrelor(n=9,333)

Clopidogrel(n=9,291)

HR for ticagrelor(95% CI) P Value†

Primary objective, n (%)

CV death + MI + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77–0.92) <0.001

Secondary objectives, n (%)

Total death + MI + stroke

CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events

Myocardial infarction

CV death

Stroke

901 (10.2)

1,290 (14.6)

504 (5.8)

353 (4.0)

125 (1.5)

1,065 (12.3)

1,456 (16.7)

593 (6.9)

442 (5.1)

106 (1.3)

0.84 (0.77–0.92)

0.88 (0.81–0.95)

0.84 (0.75–0.95)

0.79 (0.69–0.91)

1.17 (0.91–1.52)

<0.001

<0.001

0.005

0.001

0.22

Total death 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) <0.001

*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 included fatal bleeding and only traumatic fatal bleeds were excluded from the CV death category; †By Cox regression analysis

Wallentin L, Harrington R et al. New Engl J Med 2009;361 (10.1056/NEJMoa0904327).

PLATO Conservative Arm

James et Al. BMJ 2011

Total major bleeding

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

13

TIMI major bleeding

Red cell transfusion *

PLATO life-threatening/

fatal bleeding

Fatal bleeding

TicagrelorClopidogrel

Major bleeding and major or minor bleeding according to TIMI criteria refer to nonadjudicated events analyzed with the use of a statistically programmed analysis in accordance with definition described in (Wiviott SD et al. NEJM. 357:2001-2015); *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

Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57

Dyspnoea

All patients

Ticagrelor

(n=9,235)

Clopidogrel

(n=9,186)

HR for

ticagrelor

(95% CI) P Value

Dyspnoea*, %

Any dyspnoea adverse event

Discontinued due to dyspnoea

13.8

0.9

7.8

0.1

1.84 (1.68–2.02) 6.12 (3.41–11.01)

<0.001

<0.001* Combined incidence of dyspnoea, dyspnoea at rest, dyspnoea exertional, dyspnoea paroxysmal nocturnal and nocturnal dyspnoea

Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57

Holter monitoring program

Holter monitor first weekTicagrelor(n=1,451)

Clopidogrel(n=1,415) P Value

Ventricular pauses ≥3 seconds, n (%)

Ventricular pauses ≥5 seconds, n (%)

84 (5.8)

29 (2.0)

51 (3.6)

17 (1.2)

0.01

0.10

Holter monitor at 30 days Ticagrelor(n= 985)

Clopidogrel(n=1,006)

P Value

Ventricular pauses ≥3 seconds, n (%)

Ventricular pauses ≥5 seconds, n (%)

21 (2.1)

8 (0.8)

17 (1.7)

6 (0.6)

0.52

0.60

Patients with Ventricular Pauses ≥3 seconds Ticagrelor

(n=89)

Clopidogrel

(n=62)

P Value

Patients with symptomatic pauses, n (%) 4 (4.5) 8 (12.9) 0.06

Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57

Risultati principali

TRITON morte CV, IM, CVA9.9 vs 12.1%, RRR -19%NNT 46CABG related bleeding NNH 10

PLATO morte cause vascolari, IM,CVA

9.8 vs 11.7%, RRR -16%NNT 53

Platelets and Coronary Thrombosis

Davies MJ. Am J Cardiol. 2001 Aug 16;88(4A):2F-9F

Coronary plaque Erosion/rupture Thrombotic occlusion

Meccanismi di attivazione piastrinica

Wallentine L. Eur Heart J 2009

Slow onset of action (steady state platelet

inhibition: 4 - 5 hour after 300-600 mg load)

Modest inhibition of platelet aggregation

(steady state mean platelet inhibition 30 - 40%)

Slow offset of effect (at least 5 – 7 days)

Large interindividual variability in inhibition of platelet aggregation (poor platelet inhibition

response in 15 - 40% of pts)

Limitations of clopidogrel

Clopidogrel Response VariabilityBaseline - 2hr (5mol ADP)

∆ percent aggregationGurbel PA et al. Circulation 2003; 107:2908

Num

ber o

f pat

ient

s

0

4

8

12

16

20

24

≤ -30

-30, -20

-20, -10

-10, 0

0, 10

10, 20

20, 30

30, 40

40, 50

50, 60

60, 70

70, 80

> 80

Resistance = 63%

Attività piastrinica residua ed eventi cardiovascolari

Price M et Al. Circulation 2011

Kaplan Meier Survival Curves

Parodi G et Al. JAMA 2011Cardiac death, myocardial infarction, any urgent coronary revascularization, and stroke at 2-year follow up

14.6%

8.7% 9.7%

4.3%

1789 Pazienti consecutivi14% HRPP

Verify-nowLTA ADPWDA ADPPFA 100

ESC Guideline 2011

N

S

O

O

O

F

N

F

F

S N

O

O

N

NN

N

O

O

N

S

OCI

O

Ticagrelor

Prasugrel

Clopidogrel

ClopidogrelPrasugrelTicagrelor

Hydrolysisby esterase

CYP-dependentoxidation

CYP1A2CYP2B6

CYP2C19

CYP-dependentoxidationCYP2C19CYP3A4/5CYP2B6

Binding

P2Y12

CYP-dependentoxidationCYP3A4/5CYP2B6

CYP2C19CYP2C9CYP2D6

No in vivobiotransformation

Active compoud

Intermediate metabolite

Prodrug

Platelet

Antiplatelets Drug metabolism

Diverso meccanismo d’azione degli inibitori del recettore P2Y12

Becker RC, Gurbel PA Thromb Haemost 2010

New Antiplatelet Agents

Greater and More Consistent IPAwith AZD6140 than Clopidogrel

Final Extent

Mea

n pe

rcen

t inh

ibiti

on

Hours

AZD6140 100 mg bd

0

20

40

60

80

100

0 2 4 8 12 242 4 8 12Day 1 Day 14

Hours

Clopidogrel

0

20

40

60

80

100

0 2 4 8 12 242 4 8 12Day 1 Day 14

Circulation 2010

Onset

0

10

20

30

40

50

60

70

80

90

100

0 0.5 1 2 4 8 24 0 2 4 8 24 48 72 120 168 240

Onset and Offset of the Antiplatelet EffectsTicagrelor vs Clopidogrel

Time (hours)

Inhi

bitio

n of

Pla

tele

t Agg

rega

tion

(IPA

) per

cent

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

Ticagrelor (n=54)Clopidogrel (n=50)Placebo (n=12)

OffsetMaintenance

Loadingdose

Lastmaintenance

dose

6 weeks

Quale antiaggregante?

• Non esistono studi di confronto tra Prasugrel e Ticagrelor

• E’ possibile identificare una tipologia di paziente specifica per ciascun farmaco

Recent Meta-AnalysesAdjusted comparison of Prasugrel vs. Ticagrelor

Biondi-Zoccai G et al. Int J Cardiol 2010

Prasugrel

• Azione rapida, legame irreversibile

. soggetto “giovane”, nessuna storia di accidenti CV, peso > 60Kg,*

. paziente con STEMI avviato alla PCI

. ACS con anatomia coronarica nota eavviato alla PCI

*Non indizi di malattia che meriti BPAC

Ticagrelor

• Azione rapida , legame reversibile

. Paziente con ACS

. Quadro angiografico ignoto

. Clearance Creat >30 ml/min/1.73m2

Effetto dello switching tra farmaci

Gurbel et Al. Circulation,2010

Conclusioni

• Una moderna terapia antiaggregante dei pazienti con malattia coronarica consente di ridurre gli eventi ischemici e la mortalità nei pazienti con SCA

• I nuovi antiaggreganti sono più potenti, risentono poco o nulla delle differenze individuali, e sono più efficaci rispetto al clopidogrel

• Poiché si associano ad un rischio emorragico maggiore la selezione dei pazienti diventa molto importante nella scelta del farmaco da utilizzare e richiede un utilizzo giudizioso soppesando il rischio trombotico e quello emorragico

Eseguito con il WASP