1. HEARTLINE HSM Genoa Cardiology Meeting
NUOVI ORIZZONTI FARMACOLOGICI NELLA CARDIOPATIA ISCHEMICA
Cardiopatia ischemica: nuovi orizzonti nella terapia con antiaggreganti orali
Giancarlo Casolo
Genova, Hotel NH Marina
21/22 Ottobre 2011

3. ESC Guideline 2010

4. Guidelines on myocardial revascularization

5. Prasugrel
Ticagrelor
Guidelines on myocardial revascularization

6. ESC Guideline 2011

7. STUDIO PLATO
STUDIO TRITON TIMI 38
Current Oasis 7

8. STUDIO TRITON TIMI 38
STUDIO PLATO

9. TRITON-TIMI 38: Study Design
Wiviott SD et al AHJ 152: 627,2006
Adapted with permission from E.Antman
TRITON-TIMI 38: Study Design
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
N= 13,600
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
Patients were candidates for the trial if they were moderate-high risk, had an acute coronary syndrome, and there was a plan to perform PCI.
A sample size of 13, 600 was considered necessary to provide at least 90 % power to test the primary hypothesis
All patients were to receive ASA.
Randomization was stratified by UA/NSTEMI vs STEMI
DB study drug therapy consisted either of - standard dosing with clopidogrel with a LD of 300 mg and MD of 75 mg
- OR prasugrel with a LD of 60 mg and MD of 10 mg
DB study drug was to be given for a median of at least 12 months with a minimum of 6 mos and maximum of 15 months
The primary composite EP was CV death, MI, or Stroke through the end of the study
Key secondary EPs are listed here and among these was Stent thrombosis Key safety Eps included: TIMI major (non CABG) bleeds, and life-threatening bleeds
Two key substudies are evaluating pharmacokinetics and genomics
1o endpoint: CV death, MI, Stroke
2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleeds Key Substudies: Pharmacokinetic, Genomic 9 9 9

10. Balance of Efficacy and Safety TIMI Major NonCABG Bleeds
TRITON: Results 15
138 events
Clopidogrel
HR 0.81 ( ) P=0.0004
12.1
CV Death / MI / Stroke
9.9 10
NNT = 46
Endpoint (%)
Prasugrel
This slide depicts the balance of efficacy and safety observed in the trial.
At the top is shown the significant reduction in the primary endpoint as presented a few moments ago. The number needed to treat to prevent one event was 46
At the bottom is the rate of TIMI major non CABG bleeds--a key safety endpoint-- which was 2.4% with prasugrel and 1.8% with clopidogrel—a 0.6% Absolute risk increase.
The excess of 35 major bleeds with prasugrel corresponded to an HR of 1.32 and P value of
The number of subjects who would need to be treated to result in one excess major bleed (NNH) was 167. 5
35 events
TIMI Major NonCABG Bleeds
Prasugrel
2.4
HR 1.32 ( ) P=0.03
1.8
Clopidogrel
NNH = 167 30 60 90
180
270
360
450
Adapted with permission from Wiviott SD et al NEJM 357:2007
Days 10 10 10

11. Timing of Benefit (Landmark Analysis)8
6.9
Clopidogrel
Clopidogrel 6
5.6
5.6
Primary Endpoint (%)
4.7 4
Prasugrel
Prasugrel
HR 0.82 P=0.01
HR 0.80 P=0.003 2 1 1 2 3 30 60 90
180
270
360
450
Days
Loading Dose
Maintenance Dose 11

12. CV Death, MI, Stroke Major Subgroups
TRITON TIMI-38
Reduction in risk (%) 18
UA/NSTEMI B 21
STEMI
Male 21
Female 12
<65 25
Age
65-74 14
>75 6
No DM 14 DM 30
BMS 20
DES 18
The beneficial effect of prasugrel on the primary end point was consistent across key prespecified major subgroups. Notable observations include:
A significant benefit in both the UA/NSTEMI and STEMI cohorts
There was a consistent reduction in events with prasugrel
in men and women,
pts with and without diabetes,
those treated with either a BMS or DES
whether or not a GPI was administered and regardless of the degree of renal function
All P values in tests for interaction for the subgroups described were negative.
Not depicted on the slide are the data showing a reduction in events with prasugrel regardless of the timing of the LD
GPI 21
No GPI 16 14
CrCl < 60 20
CrCl > 60 19
Pinter = NS
OVERALL
0.5
Clopidogrel Better
Prasugrel Better 1 2
Wiviott SD et al NEJM 357: 2001, 2007 HR 12 12 12

13. Principali risultati nello studio TRITON TIMI 38

14. TRITON: Previous STOKE or TIA (3.8%)
1414
L i n k 5 : T R I T O N T I M I 3 8
TRITON: Previous STOKE or TIA (3.8%)
Wiviot SD et al. N Engl J Med 2007;357:

15. PLATO study design
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)
Clopidogrel
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)
Ticagrelor
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)
6–12-month exposure
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 mortality
Primary safety: • Total major bleeding
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:

16. Cumulative incidence (%) Days after randomisation
K-M estimate of time to first primary efficacy event (Composite of CV death, MI or stroke)
Completeness of follow-up 99.97% = five patients lost to follow-up 13 12
Clopidogrel
11.7 11 10
9.8 9
Ticagrelor 8 7
Cumulative incidence (%) 6 5 4 3 2 1
HR 0.84 (95% CI 0.77–0.92), p=0.0003 60
120
180
240
300
360
Days after randomisation
No. at risk
Ticagrelor
9,333
8,628
8,460
8,219
6,743
5,161
4,147
Clopidogrel
9,291
8,521
8,362
8,124
6,743
5,096
4,047
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval
Wallentin L, Harrington R et al. New Engl J Med 2009;361 ( /NEJMoa ).

17. 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)
0.88 (0.81–0.95)
0.84 (0.75–0.95)
0.79 (0.69–0.91)
1.17 (0.91–1.52)
0.005
0.001
0.22
Total death
399 (4.5)
506 (5.9)
0.78 (0.69–0.89)
*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 ( /NEJMoa ).

18. Time to death/myocardial infarction/stroke13
12.3 12
Clopidogrel 11 10
10.2 9
Ticagrelor 8 7
K-M estimated rate (% per year) 6 5 4 3 2 1
HR 0.84 (95% CI 0.77–0.92), p=0.0001 60
120
180
240
300
360
Days after randomisation
No. at risk
Ticagrelor
9,333
8,628
8,460
8,219
6,743
5,161
4,147
Clopidogrel
9,291
8,521
8,361
8,124
6,650
5,096
4,047
Wallentin L, Harrington R et al. New Engl J Med 2009;361 ( /NEJMoa ).

19. Time to myocardial infarction7
6.9
Clopidogrel 6
5.8 5
Ticagrelor 4
K-M estimated rate (% per year) 3 2 1
HR 0.84 (95% CI 0.75–0.95), p=0.005 60
120
180
240
300
360
Days after randomisation
No. at risk
Ticagrelor
9,333
8,678
8,520
8,279
6,796
5,210
4,191
Clopidogrel
9,291
8,560
8,405
8,177
6,703
5,136
4,109
Wallentin L, Harrington R et al. New Engl J Med 2009;361 ( /NEJMoa ).

20. Time to cardiovascular death7 6
Clopidogrel 5
5.1 4
4.0
K-M estimated rate (% per year)
Ticagrelor 3 2 1
HR 0.79 (95% CI 0.69–0.91), p=0.001 60
120
180
240
300
360
Days after randomisation
No. at risk
Ticagrelor
9,333
8,294
8,822
8,626
7,119
5,482
4,419
Clopidogrel
9,291
865
8,780
8,589
7,079
5,441
4,364
Wallentin L, Harrington R et al. New Engl J Med 2009;361 ( /NEJMoa ).

21. End point primario nei pazienti dello studio PLATO
2121
Link 9: PLATO STEMI
End point primario nei pazienti dello studio PLATO
avviati all’angioplastica primaria
CV death, MI, stroke (%)
Steg G et al. Circulation. 2010;122:

22. PLATO Conservative Arm
James et Al. BMJ 2011

23. PLATO Major Bleeding* (STEMI)
2323
PLATO Major Bleeding* (STEMI)
Link 9: PLATO STEMI
* PLATO major bleeding was defined as significant disabling bleeding,
a fall in hemoglobin of ≥3 g/dL or a need for transfusion of ≥2 U red cells.
Steg G et al. Circulation. 2010;122:

24. K-M estimated rate (% per year) PLATO life-threatening/ fatal bleeding
Total major bleeding 13 NS
Ticagrelor
Clopidogrel 12
11.6
11.2 11 NS 10 NS
8.9
8.9 9
7.9 8
7.7 7 NS
K-M estimated rate (% per year)
5.8
5.8 6 5 4 3 2 NS 1
0.3
0.3
PLATO major bleeding
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 nonadjudicated events analyzed with the use of a statistically programmed analysis in accordance with definition described in (Wiviott SD et al. NEJM. 357: ); *Proportion of patients (%); NS = not significant
Wallentin L et al. N Engl J Med Sep 10;361(11):

25. Non-CABG and CABG-related major bleeding9 NS
Ticagrelor
Clopidogrel
7.9 8
7.4 7 NS
5.8 6
5.3
p=0.0264 5
4.5
K-M estimated rate (% per year) 4
3.8
p=0.0246
2.8 3
2.2 2 1
Non-CABG PLATO major bleeding
Non-CABG TIMI major bleeding
CABG PLATO major bleeding
CABG TIMI major bleeding
Wallentin L et al. N Engl J Med Sep 10;361(11):

26. 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
* Combined incidence of dyspnoea, dyspnoea at rest, dyspnoea exertional, dyspnoea paroxysmal nocturnal and nocturnal dyspnoea
Wallentin L et al. N Engl J Med Sep 10;361(11):

27. Holter monitoring program
Holter monitor first week
Ticagrelor
(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
(n= 985)
(n=1,006)
21 (2.1)
8 (0.8)
17 (1.7)
6 (0.6)
0.52
0.60
Patients with Ventricular Pauses ≥3 seconds
(n=89)
(n=62)
Patients with symptomatic pauses, n (%)
4 (4.5)
8 (12.9)
0.06
Wallentin L et al. N Engl J Med Sep 10;361(11):

28. Other findings
All patients
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186)
P Value*
Serum creatinine (% increase from baseline value), mean  SD
During treatment
Follow-up visit
10  22
8  21
<0.001
0.59
* P-values were calculated with the use of Fischer’s exact test
Wallentin L et al. N Engl J Med Sep 10;361(11):

29. Ticagrelor is a more effective alternative than clopidogrel
Conclusions
Reversible, more intense P2Y12 receptor inhibition for one year with ticagrelor in comparison with clopidogrel in a broad population with STEMI and NSTEMI ACS provides
Reduction in MI and stent thrombosis
Reduction in CV and total mortality
No change in the overall risk of major bleeding
Raised risk for non-procedure-related 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

30. Risultati principali TRITON morte CV, IM, CVA 9.9 vs 12.1%, RRR -19%
NNT 46
CABG related bleeding NNH 10
PLATO morte cause vascolari, IM,CVA
9.8 vs 11.7%, RRR -16%
NNT 53

31. Platelets and Coronary Thrombosis
Le piastrine hanno un ruolo chiave nella formazione del trombo in corrispondenza di una placca aterosclerotica vulnerabile che si e’ instabilizzata: La crescita rapida del trombo piastrinico all’interno di un’impalcatura fibrinica che lo stabilizza, puo’ condurre all’occlusione trombotica completa del vaso
Coronary plaque
Erosion/rupture
Thrombotic occlusion
Davies MJ. Am J Cardiol Aug 16;88(4A):2F-9F 31

32. Adesione piastrinica Lisman et Al. Frontiers in Bioscience ,2005
Schematic representation of adhesion and aggregation under flow conditions. A) Rolling of over -bound vWF mediated by GPIb. B) Firm attachment mediated by alpha(2)beta(1) and glycoprotein VI (GP VI) to , and by alpha(IIb)beta(3) to -bound vWF. C) , , and spreading. D) Aggregate formation.
Lisman et Al. Frontiers in Bioscience ,2005

33. Meccanismi di attivazione piastrinica
Wallentine L. Eur Heart J 2009

35. Limitations of clopidogrel
Slow onset of action (steady state platelet inhibition: hour after mg load)
Modest inhibition of platelet aggregation (steady state mean platelet inhibition %)
Slow offset of effect (at least 5 – 7 days)
Large interindividual variability in inhibition of platelet aggregation (poor platelet inhibition response in % of pts)
Come tutti ben sappiamo, il clopidogrel è una delle pietre angolari nella prevenzione dell’aterotrombosi. Sfortunatamente il clopidogrel, che insieme all’aspirina è il farmaco più utlizzato in questo settore, ha delle importanti limitazioni:
Problema nelle prime ore delle sindromi coronariche acute quando il rischio trombotico è più alto
Efficacia antiapiastrinica non elevata e soprattutto con notevole variabilità interindividuale
Questo preoccupa nei pazienti ad elevato rischio di sanguinamento

36. Clopidogrel Response Variability Baseline - 2hr (5mol ADP)
Resistance = 63%
Number of patients
≤ -30
-20, -10
0, 10
20, 30
40, 50
60, 70
> 80
-30, -20
-10, 0
10, 20
30, 40
50, 60
70, 80
∆ percent aggregation
Gurbel PA et al. Circulation 2003; 107:2908

37. Major pathways leading to the formation of thienopyridine active metabolites
Wallentine L. Eur Heart J 2009

38. Genetic effects on pharmacokinetic responses to clopidogrel
Percent difference in AUCo-t
162 healthy subjects
-32.4
-6.8
-15.7
5.6
11.2
p value
<0.001
0.59
0.03
0.45
CYP2C19
CYP2C9
CYP2B6 CYP3A5
CYP1A2
-50
-40
-30
-20
-10 10 20 30
Relative Percent Difference
Mega J L et al, N Engll J Med 2009; 360:

39. Cytochrome P450 2C 19 polymorphism
Time course of ex-vivo platelet aggregation in response to 10 μM ADP
Clopidogrel 75 mg/d 90 80 70
ADP 10 μmol/L-induced
Platelet aggregation (%) 60
P <0.003 50
CYP2C19 genotype *1/*1
CYP2C19 genotype *1/*2 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Time (Days)
Hulot et al. Blood 2006; 108:

40. CYP2C19*2 polymorphism in young MI patients treated with clopidogrel
The AFIJI Multicentre Registry (n= 259)
Kaplan Maier estimates of the rates of first cardiovascular event at 5years of follow-up 1
0.9
0.8
0.7
HR 3.69 (95% CI ) p=0.0005
0.6
Cumulative event- free survival (%)
0.5
Non carriers
Carriers
0.4 1 2 3 4 5
Follow-up duration (years)
Collet JP, et al, Lancet 2009; 373:

41. Cytochrome P450 2C19 polymorphism and stent thrombosis
2485 patients undergoing PCI and treated with clopidogrel
p=0.002
30-day incidence of stent thrombosis (%)
CYP2C19
*1/*1
CYP2C19
*1/*2
CYP2C19
*2/*2
Sibbing et al, Eur Heart Journal 2009; 30:

42. Attività piastrinica residua ed eventi cardiovascolari
prospective observational studies using the Accumetrics VerifyNow P2Y12 assay
Price M et Al. Circulation 2011

43. Kaplan Meier Survival Curves
1789 Pazienti consecutivi
14% HRPP
14.6%
8.7%
9.7%
4.3%
Cardiac death, myocardial infarction, any urgent coronary revascularization, and stroke at 2-year follow up
Parodi G et Al. JAMA 2011

44. Two-year clinical outcome
Parodi G et Al. JAMA 2011

45. Analisi dei risultati
Parodi G et Al. JAMA 2011

46. Verify-now
LTA ADP WDA ADP
PFA 100

47. ESC Guideline 2011

48. Antiplatelets Drug metabolismF S O
Ticagrelor N S O F
Prasugrel
Clopidogrel N S O CI
No in vivo
biotransformation
Active compoud
Intermediate metabolite
Prodrug
CYP-dependent
oxidation
CYP3A4/5
CYP2B6
CYP2C19
CYP2C9
CYP2D6
Binding
Ticagrelor
Hydrolysis
by esterase
Platelet
Prasugrel
P2Y12
Clopidogrel
CYP-dependent
oxidation
CYP1A2
CYP2B6
CYP2C19
CYP-dependent
oxidation
CYP2C19
CYP3A4/5
CYP2B6

49. Diverso meccanismo d’azione degli inibitori del recettore P2Y12
Il ticagrelor e’ un potente inibitore reversibile del recettore P2Y12, con un meccanismo diverso da quello delle tienopiridine. Il farmaco infatti non impedisce l’interazione tra ADP e recettore, ma disattiva il recettore medesimo, rendendo impossibile quella modificazione conformazionale che lo associa ad una serie di azioni pro-aggreganti all’interno della piastrina. Nel momento in cui il prodotto si dissocia dal recettore quest’ultimo ripristina le sue piene funzioni. Ticagrelor appartiene alla classe farmacologica delle nuove pirimidine ciclopentiltiazolo.
Il ticagrelor raggiunge la massima antiaggregazione piastrinica prodotta dal farmaco (50-60%) dopo 2 h dall’assunzione di una dose di carico di 180 mg e questo livello di inibizione si mantiene con la somministrazione di 90 mg x 2/die
Becker RC, Gurbel PA Thromb Haemost 2010 49

50. New Antiplatelet Agents

51. I nuovi antiaggreganti piastrinici
Steady state
Aggregazione
3-7 gg
3gg
2-3gg
rapida
Inizio anti-
Aggreg.
2 h
30min
rapida
Grado di
inibizione
30-50%
70-80% SI
Legame
reversibile NO SI
Offset
5gg
4-5gg
36-48h --
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor

52. Prasugrel farmacodinamica
clopidogrel
Jernberg et al, Eur Heart J 2006;27;

54. Ticagrelor Pharmacodynamics
AZD mg od
AZD mg bd
AZD mg bd
% IPA Final
AZD mg bd
Clopidogrel 75mg od
IPA: Inibition of Platelet Aggregation

55. Greater and More Consistent IPA with AZD6140 than Clopidogrel
Final Extent
AZD mg bd
Clopidogrel
100
100 80 80 60 60
Mean percent inhibition 40 40 20 20 2 4 8 12 2 4 8 12 24 2 4 8 12 2 4 8 12 24
Day 1
Day 14
Day 1
Day 14
Hours
Hours

56. Circulation 2010

57. Onset and Offset of the Antiplatelet Effects
Ticagrelor vs Clopidogrel 10 20 30 40 50 60 70 80 90
100
0.5 1 2 4 8 24 48 72
120
168
240
Loading
dose
Last
maintenance
dose
Ticagrelor (n=54)
Clopidogrel (n=50)
Placebo (n=12)
Inhibition of Platelet Aggregation (IPA) percent
6 weeks
Onset
Maintenance
Offset
Time (hours)
Gurbel PA et al, Circulation 2009; 120:

58. Quale antiaggregante?
Non esistono studi di confronto tra Prasugrel e Ticagrelor
E’ possibile identificare una tipologia di paziente specifica per ciascun farmaco

59. Recent Meta-Analyses Link 11: Montalecot JACC 2010 Meta-analysis
5959
Link 11: Montalecot JACC 2010 Meta-analysis
Recent Meta-Analyses
Montalescot G et al. J Am Coll Cardiol 2010

60. Recent Meta-Analyses Adjusted comparison of Prasugrel vs. Ticagrelor
L i n k 1 2 : I n t J C a r d i o l
L i n k 1 3 : C o m p a r i s o n o f t h e C h a r a c t e r i s t i c s ( P r a s u g r e l v s . T i c a g r e l o r )
6060
Recent Meta-Analyses
Adjusted comparison of Prasugrel vs. Ticagrelor
Biondi-Zoccai G et al. Int J Cardiol 2010

61. 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 e
avviato alla PCI
*Non indizi di malattia che meriti BPAC

62. Ticagrelor Azione rapida , legame reversibile . Paziente con ACS
. Quadro angiografico ignoto
. Clearance Creat >30 ml/min/1.73m2

64. P2Y12 reaction units (PRU) as assessed by the VerifyNow P2Y12 assay by protocol time and treatment
Gurbel PA et al, Circulation 2009; 120:

65. Effetto dello switching tra farmaci
Gurbel et Al. Circulation,2010

66. 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

68. Eseguito con il WASP

69. Reversibilità della inibizione e vantaggi potenziali
Becker RC, Gurbel PA Thromb Haemost 2010