1. Nuove evidenze sull’impiego di antiaggreganti e anticoagulanti nello STEMI e nelle SCA NSTE Francesco Bovenzi
Dipartimento Cardio-Respiratorio
U.O. di Cardiologia, Ospedale “Campo di Marte” Lucca
LUCCA
CARDIOLOGIA

2. Milestones in ACS Management
Anti-Thrombin Rx
Anti-Platelet Rx
Treatment Strategy
Heparin
Aspirin
Conservative
LMWH
ESSENCE
Bivalirudin
REPLACE 2
OASIS-5
Fondaparinux
TRITON Timi 38
Prasugrel
PLATO
Ticagrenor
GP IIb/IIIa blockers
PRISM-PLUS
PURSUIT
CURE
Clopidogrel
TACTICS TIMI-18
Early invasive
ICTUS
ISAR-REACT 2
CURRENT OASIS-7
SYNERGY
ACUITY
1990
1994
1995
1996
1997
1997
1998
1999
2000
2001
2002
2003
2004
2005
The treatment of UA/NSTEMI has evolved considerably over the last decade. In the early 1990s, the “standard” of care was aspirin, unfractionated heparin, a conservative management strategy, and, if done, PCI involved primarily balloon angioplasty. Subsequently a number of management options (upper portion of the slide) as well as major trials (middle portion of the slide) have come forward. The clinical availability of GP IIb/IIIa blockers (green) in 1995, with trials such as PRISM-PLUS and PURSUIT (also in green) showing their efficacy in UA/NSTEMI patients, particularly those undergoing coronary intervention. The LMWH enoxaparin was studied in the mid-1990s in ESSENCE (in dark blue), and was released for use in unstable angina in Clopidogrel (in orange) released in 1998, was a mainstay of therapy for coronary intervention (particularly the rapidly-growing world of stents). It’s utility in UA/NSTEMI was confirmed in the large scale CURE trial. Bivalirudin also was approved (based on the REPLACE 2 trial) for use as procedural anticoagulation for PCI in about Finally, on the basis of trials such as TACTICS, the rapid invasive management strategy began to predominate, particularly in the US, in the late 1990s.
Newer data (gray boxes) have come forward (the trial names are color-coded to correspond to the agent and prior trials) that need to be assimilated into modern-day practice. Trials such as SYNERGY ( enoxaparin vs UFH in high-risk ACS patients managed with a rapid invasive management strategy), OASIS 5 (fondaparinux vs enoxaparin in higher-risk ACS), ICTUS (testing a rapid invasive strategy versus a selective invasive strategy in troponin (+) patients). ISAR-REACT 2 (assessing the utility of abciximab in ACS patients already pre-loaded with high doses of clopidogrel), and ACUITY(evaluating bivalirudin in rapidly invasively managed UA/NSTEMI) are going to help define the practice standards for the future.
In the bottom of the slide are schematic graphs of the general trends in bleeding and thrombotic (ischemic) events over this same period. The arrival of GP IIb/IIIa antagonists brought with it substantial increases in bleeding. Thienopyridines both reduced this rate (by substituting for IIb/IIIa antagonists in lower-risk patients) and worsened it (by further adding to the antithrombotic milieu. Enoxaparin had some issues in that it did not fit well with anticoagulation management (traditionally done with ACTs and UFH in the cath lab). The emerging early invasive strategy served to further highlight the importance of the transition to the cath lab. The arrival of bivalirudin brought with it an option for reducing the risk of bleeding complications. With time, better technologies, and better adjunctive therapies the clinical events rates have continued to fall, but this is to a large extent somewhat balanced by the emerging use of more sensitive markers for myocardial damage (such as troponin).
PCI
~ 5% stents
~85% stents
Drug-eluting stents
Ischemic risk
Bleeding risk

3. 80 different combinations!
The result is
80 different combinations!
Extreme attention should be paid to the use of drugs or drug combinations and dosages that may favour bleeding

4. Atalanta ACC 2010 Eugene Braunwald
“I più potenti inibitori delle piastrine sono stati studiati nel TRITON TIMI-38 e nel PLATO che hanno posto le basi per l’alba di una nuova era della terapia antipiastrinica.
Finora non c’è stato nulla di “free lunch”, perché quando interveniamo sulla coagulazione troveremo associato, in ogni modo, un eccesso di sanguinamento.
La nostra futura sfida sarà trovare uno “sweet spot” nella ricerca di bilanciare l’efficacia con la sicurezza.”

5. Primary Therapeutic Goal for ACS
Prevent the development of occlusive thrombus
Arrest procoagulant activity and inflammation
Attenuate platelet activation and aggregation
Promote platelet disaggregation
Facilitate perfusion 5

6. The Key Platelet Transmembrane Receptors
TRAP
ADP
TXA2
ADP
ADP
PGI2
P2X1
P2Y12
PAR TP
P2Y IP
TAX2 1 AA AC - +
PLC G G G q i S
COX Ca ++ +
ATP - Ca ++ +
cAMP
PGH2 IP 3 Ca ++
TAXS
Activation of GPIIb/IIIa
Binding of soluble fibrinogen
Aggregation

7. Conventional Antiplatelet Agents
Clopidrogel
Ticlopidina
TRAP
ADP
TXA2
ADP
ADP
PGI2
P2X1
P2Y12
PAR TP
P2Y IP
TAX2 1 AA AC - +
PLC G G G q i S
COX Ca ++ +
ATP - Ca ++ +
cAMP
PGH2 IP 3 Ca ++
ASA
TAXS
Activation of GPIIb/IIIa
Binding of soluble fibrinogen
Reopro
Tirofiban
Eptifibatide
Aggregation

8. Conventional Antiplatelet Agents
Clopidrogel
Ticlopidina
Prasugrel
Ticagrelor
Cangrelor
TRAP
ADP
TXA2
ADP
ADP
PGI2
P2X1
PAR TP
P2Y
P2Y12 IP
TAX2 1 AA AC - +
PLC G G G q i S
COX Ca ++ +
ATP - Ca ++ +
cAMP
PGH2 IP 3 Ca ++
ASA
TAXS
Activation of GPIIb/IIIa
Binding of soluble fibrinogen
Reopro
Tirofiban
Eptifibatide
Aggregation

9. Conventional Antiplatelet Agents
Clopidrogel
Ticlopidina
Prasugrel
Ticagrelor
Cangrelor
SCH530348
TRAP
ADP
TXA2
ADP
ADP
PGI2
P2X1
PAR TP
P2Y
P2Y12 IP
TAX2 1 AA AC - +
PLC G G G q i S
COX Ca ++ +
ATP - Ca ++ +
cAMP
PGH2 IP 3 Ca ++
TAXS
ASA
Activation of GPIIb/IIIa
Reopro
Tirofiban
Eptifibatide
Binding of soluble fibrinogen
Aggregation

10. P2Y12 inhibitors P2Y12 ATP Ticlopidine and clopidogrel
Prodrugs, converted in vivo by the hepatic cytochrome P-450 enzymatic pathway to active metabolites, 85% inactive metabolite
Irreversibly inhibiting the receptor
Because of the toxicity of ticlopidine (neutropenia, thrombotic thrombocytopenic purpura), ticlopidine has been almost completely replaced by clopidogrel in clinical practice.
P2Y12 AC - + i G
ATP
cAMP

11. P2Y12 inhibitors P2Y12 ATP Prasugrel Ticlopidine and clopidogrel
Prodrugs, Prasugrel is a thienopyridine with 10-fold more potent anti-P2Y12 receptor inhibitory activity than clopidogrel. Conversion to its active metabolite is less dependence on CYP enzymes than clopidogrel
Irreversibly inhibiting the receptor
More rapid and consistent inhibitory effects on platelet aggregation than Clopidogrel
Ticlopidine and clopidogrel
Prodrugs, converted in vivo by the hepatic cytochrome P-450 enzymatic pathway to active metabolites, 85% inactive metabolite
Irreversibly inhibiting the receptor
Because of the toxicity of ticlopidine (neutropenia, thrombotic thrombocytopenic purpura), ticlopidine has been almost completely replaced by clopidogrel in clinical practice.
P2Y12 AC - + i G
ATP
cAMP

12. P2Y12 inhibitors P2Y12 ATP Prasugrel Ticlopidine and clopidogrel
Prodrugs, Prasugrel is a thienopyridine with 10-fold more potent anti-P2Y12 receptor inhibitory activity than clopidogrel. Conversion to its active metabolite is less dependence on CYP enzymes than clopidogrel
Irreversibly inhibiting the receptor
More rapid and consistent inhibitory effects on platelet aggregation than Clopidogrel
Ticlopidine and clopidogrel
Prodrugs, converted in vivo by the hepatic cytochrome P-450 enzymatic pathway to active metabolites, 85% inactive metabolite
Irreversibly inhibiting the receptor
Because of the toxicity of ticlopidine (neutropenia, thrombotic thrombocytopenic purpura), ticlopidine has been almost completely replaced by clopidogrel in clinical practice.
P2Y12 AC - + i G
ATP
cAMP
Ticagrelor
Not a prodrug
Rapid onset of inhibitory effect
Reversibly bound with faster offset of effect and functional recovery of all circulating platelets

13. P2Y12 inhibitors P2Y12 ATP Prasugrel
Prodrugs, Prasugrel is a thienopyridine with 10-fold more potent anti-P2Y12 receptor inhibitory activity than clopidogrel. Conversion to its active metabolite is less dependence on CYP enzymes than clopidogrel
Irreversibly inhibiting the receptor
More rapid and consistent inhibitory effects on platelet aggregation than Clopidogrel
Ticlopidine and clopidogrel
Prodrugs, converted in vivo by the hepatic cytochrome P-450 enzymatic pathway to active metabolites, 85% inactive metabolite
Irreversibly inhibiting the receptor
Because of the toxicity of ticlopidine (neutropenia, thrombotic thrombocytopenic purpura), ticlopidine has been almost completely replaced by clopidogrel in clinical practice.
P2Y12 AC - + i G
ATP
cAMP
Cangrelor
ATP analogue
Reversible binds to and inhibits the P2Y12 ADP receptor
Immediately active after i.v. infusion
Ticagrelor
Not a prodrug
Rapid onset of inhibitory effect
Reversibly bound with faster offset of effect and functional recovery of all circulating platelets

14. New P2Y12 inhibitors P2Y12 ATP Elinogrel
Direct-acting, reversible P2Y12 inhibitor that can be administered
both intravenously and orally
A Phase 2 Safety and Efficacy Study of Elinogrel a Novel Intravenous and Oral P2Y12 Inhibitor in Non-Urgent PCI (INNOVATE-PCI) is a multicenter, randomized, double-blind, triple-dummy,clopidogrel-controlled study of
intravenous and oral elinogrel
compared with clopidogrel in patients undergoing nonurgent (including elective) PCI. After diagnostic angiography, patients
scheduled for nonurgent PCI will be randomized to clopidogrel or 1 of 3 doses of elinogrel.
P2Y12 AC - + G i
ATP
The Early Rapid Reversal of Platelet Thrombosis With Intravenous Elinogrel Before PCI to Optimize Reperfusion
in Acute MI (ERASE-MI) is a randomized
trial evaluating the safety and tolerability of intravenous elinogrel (10, 20, 40,
and 60 mg) before PCI in patients with STEMI
cAMP

15. I ragionevoli dubbi con terapia anticoagulante e antiaggregante
Quale è il rischio e l’impatto degli eventi aterotrombotici nelle SCA?
Quale è il rischio e l’outcome dei sanguinamenti nelle SCA?
Esiste un compromesso clinico tra rischio emorragico e beneficio della doppia antiaggregazione?
Quanto incide la biodiversità sulle scelte?
Quale è il timing del rischio di sanguinamento
Come affrontare il rischio di sanguinamento correlato ad altre procedure invasive
Partiamo dalle evidenze dei tre ultimi grandi trial

16. ESC 2009
2007
2009
Factorial Randomized Trial (2X2) of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy with Intent For PCI
Non ancora pubblicato!
OASIS-7

17. Study Design, Flow and Compliance
25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)
Planned Early (<24 h) Invasive Management with intended PCI
Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)
Randomized to receive (2 X 2 factorial):
CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d)
ASA: High Dose ( mg/d) vs Low dose ( mg/d)
Angio 24,769
(99%)
PCI 17,232
(70%)
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 30
Stent Thrombosis at day 30
Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)
Key Subgroup: PCI v No PCI
Complete
Follow up
99.8%

18. Clopidogrel: Double vs Standard Dose Primary Outcome and ComponentsHR
95% CI P
Intn P
CV Death/MI/Stroke
PCI (2N=17,232)
4.5
3.9
0.85
0.036
0.016
No PCI (2N=7855)
4.2
4.9
1.17
0.14
Overall (2N=25,087)
4.4
0.94
0.370 MI
2.6
2.0
0.78
0.012
0.025
1.4
1.7
1.25
0.23
2.2
1.9
0.86
0.097
CV Death
0.96
0.68
1.0
2.8
2.7
0.77
2.1
0.628
Stroke
0.4
0.88
0.59
0.50
0.8
0.9
1.11
0.67
0.5
0.99
0.950

19. Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients
CV Death, MI or Stroke
Clopidogrel Standard
15% RRR
0.04
Clopidogrel Double
0.03
Cumulative Hazard
0.02
HR 0.85
95% CI
P=0.036
0.01
0.0 3 6 9 12 15 18 21 24 27 30
Days

20. Clopidogrel: Double vs Standard Dose
Definite Stent Thrombosis (Angio confirmed)
Clopidogrel Standard Dose
0.012
42%
RRR
0.008
Cumulative Hazard
Clopidogrel Double Dose
0.004
HR 0.58
95% CI
P=0.001
0.0 3 6 9 12 15 18 21 24 27 30
Days

21. Conclusions Clopidogrel Dose Comparison
Double-dose clopidogrel significantly reduced major CV events in PCI (CV death, MI or stroke) and stent thrombosis
In patients not undergoing PCI double dose clopidogrel was not significantly different from standard dose
There was a modest excess in CURRENT- defined major bleeds but no difference in severe: TIMI major bleeds, ICH, fatal bleeds or CABG-related bleeds

22. Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolisis in MI

23. TRITON-TIMI 38: Balance of efficacy and safety15
138 events
HR 0.81
( )
p=0.0004
NNT=46
(6795 pts)
12.1
9.9 10
(6813 pts) 5
35 events
HR 1.32
( )
p=0.03
NNH=167
2.4
1.8 30 60 90
180
270
360
450
Wiovitt SD et al. NEJM 2007

24. TIMI Major NonCABG Bleeds
Diabetic Subgroup
N=3146 18
Clopidogrel
17.0 16
CV Death / MI / Stroke 14
12.2 12
HR 0.70 P<0.001
Endpoint (%)
Prasugrel 10
NNT = 20 (46) 8 6
TIMI Major NonCABG Bleeds 4
Clopidogrel
2.6
2.5 2
Prasugrel 30 60 90
180
270
360
450
Days 24

25. Montalescot G et al. Lancet 2008;372:1-9; Wiviott SD, N Engl J Med 2007;357(20):2001-15

26. TRITON-TIMI 38: Timing of benefit2 4 6 8 1 3 30 60 90
180
270
360
450
Days
Loading Dose
Maintenance Dose
Primary Endpoint (%)
(6795 pts)
(6813 pts)
Wiovitt SD et al. NEJM 2007

27. TRITON-TIMI 38: Stent Thrombosis (ARC Definite + Probable)2
Endpoint (%) 1 30 60 90
180
270
360
450
Days
Wiovitt SD et al. NEJM 2007

28. TRITON-TIMI 38: Bleeding4
Events (%) 2
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
p=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
p=0.01
Non fatal
ARD 0.2%
p=0.23
Fatal
ARD 0.3%
p=0.002
ICH
ARD 0%
p=0.74
Wiovitt SD et al. NEJM 2007

29. TRITON-TIMI 38: Bleeding risk subgroups
Yes
+ 37
Prior Stroke / TIA
-16 No
Pint = 0.006 -1
>=75
Age
Pint = 0.18
-16
< 75
< 60 kg +3
Wgt
>=60 kg
Pint = 0.36
-14
-13
OVERALL
0.5 1 2
Prasugrel Better
Clopidogrel Better HR
Wiovitt SD et al. NEJM 2007

30. Higher IPA to Support PCI
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
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
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients
may help improve the benefit: risk balance

31. Bleeding Risk Subgroups Therapeutic Considerations
Reduced MD Guided by PK Age > 75 or Wt < 60 kg
Avoid Prasugrel Prior CVA/TIA
16% 4%
Significant Net Clinical Benefit with Prasugrel 80%
MD 10 mg
Antman EM, AHA 2007 31 31

32. Study of Platelet Inhibition and Patient Outcomes: PLATO Study Design

33. PLATO: Primary efficacy endpoint (CV death,MI or stroke)
11.7 12
(9.291 pts) 10
9.8 8
(9.333 pts)
Cumulative incidence (%) 6 4 2 60
120
180
240
300
360
Days after randomisation
Wallentin L et al. NEJM 2009

34. PLATO: Secondary efficacy endpoints
Myocardial Infarction
Cardiovascular death 7 7 6 6 5 5 4 4
Cumulative incidence (%)
Cumulative incidence (%) 3 3 2 2 1 1 60
120
180
240
300
360 60
120
180
240
300
360
Days after randomization
Days after randomization
Wallentin L et al. NEJM 2009

35. PLATO: Primary safety event (total major bleeding)60
120
180
240
300
360 5 10 15
(9.235 pts)
(9.186 pts)
K-M estimated rate (% per years)
Days from first IP dose
Wallentin L et al. NEJM 2009

36. PLATO: Non CABG and CABG major bleeding9 8 7 6 5
K-M estimated rate (% per years) 4 3 2 1
Non-CABG
PLATO major bleeding*
Non-CABG
TIMI major bleeding
CABG
PLATO major bleeding*
CABG
TIMI major bleeding
*Bleeding with clinically significant disability or associated with hemoglobin declive at least 3.0 g/dl but less 5.0 g/dl trasfusion of
2 to 3 units
Wallentin L et al. NEJM 2009

37. PLATO-invasive Myocardial infarction Cardiovascular death8 8
Clopidogrel
6.6 6 6
5.3
Cumulative incidence (%)
Cumulative incidence (%)
Clopidogrel
Ticagrelor
4.3 4 4
3.4
Ticagrelor 2 2
HR 0.80 (95% CI = 0.69–0.92), p=0.002
HR 0.82 (95% CI = 0.68–0.98), p=0.025 60
120
180
240
300
360 60
120
180
240
300
360
Days after randomization
Days after randomization
No. at risk
Ticagrelor
6,732
6,268
6,173
6,010
4,924
3,766
3,078
6,732
6,439
6,375
6,241
5,141
3,591
3,233
Clopidogrel
6,676
6,157
6,062
5,917
4,849
3,706
2,987
6,676
6,376
6,332
6,209
5,114
3,917
3,164
Cannon PC et al. Lancet 2010

38. K-M estimated rate (% per year) GUSTO severe bleeding*
PLATO-invasive: Non-CABG and CABG-related major bleeding 13 NS
Ticagrelor
Clopidogrel 12
11.5
11.6 11
4.7 10 NS 9
4.1
Non-CABG
8.0
8.0 8 7
K-M estimated rate (% per year)
2.3
2.8 6 5 NS 4
CABG
3.2
2.9 3
1.7 2
1.9 1
PLATO major bleeding*
TIMI major bleeding
GUSTO severe bleeding*
*Bleeding with clinically significant disability or associated with hemoglobin declive at least 3.0 g/dl but less 5.0 g/dl trasfusion of
2 to 3 units
Cannon PC et al. Lancet 2010

39. Luci e ombre della bivaliridina2 1
Trombina
Trombina
Sito catalitico
Sito esterno
Trombina
Trombina
Bivalirudina
Fibrina
- Inibisce in modo diretto la trombina legata al coagulo e
circolante con uno specfico legame bivalente ai due siti
- Non richiede la presenza dell'antitrombina
Inibisce la trombina mediata dall'attivazione piastrinica
Ha un'emivita plasmatica di 25 minuti
- Non richiede monitoraggio
Bivalirudina può interagire con la trombina legata, spiazzando la fibrina. La trombina legata al coagulo è una importante fonte di estensione del coagulo e di attivazione piastrinica.

40. Study Design – Patient Flow
ACUITY
Study Design – Patient Flow
Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy
UFH/Enox
+ GP IIb/IIIa
(N=4,603)
Bivalirudin
(N=4,604)
Alone
(N=4,612) R*
GPI upstream (N=2294)
GPI CCL for PCI (N=2309)
GPI upstream (N=2311)
GPI CCL for PCI (N=2293)
Aspirin in all
Clopidogrel
dosing and timing
per local practice
Moderate-
high risk
ACS
The ACUITY trial involved 13 819 patients with moderate- to high-risk ACS who all underwent cardiac catheterization within 72 hours; percutaneous or surgical revascularization was performed when appropriate. Patients were randomized to one of three arms: UFH or enoxaparin plus routine GP IIb/IIIa inhibition; bivalirudin plus routine GP IIb/IIIa inhibition; or bivalirudin alone, with GP IIb/IIIa inhibition only given as bailout (in this arm, around 7% of patients actually received a bailout GP IIb/IIIa blocker).
A second part of the trial involves a 2x2 randomization in the groups receiving routine GP IIb/IIIa blockers and looks at whether these are better started early (on presentation) or late (just before the patient goes to the cath lab).

41. Primary Endpoint Measures (ITT)
ACUITY
Primary Endpoint Measures (ITT)
UFH/Enoxaparin + GPI vs. Bivalirudin Alone
11,7%
7,3%
5,7%
3,0%
10,1%
7,8%
Net clinical
outcome
Ischemic
composite
Major bleeding
30 day events (%)
UFH/Enoxaparin+GPI (N=4603)
Bivalirudin alone (N=4612)
PNI <0.0001
PSup = 0.015
PNI = 0.011
PSup = 0.32
PSup <0.0001
For the main part of the trial, the primary study end point is the composite of death, myocardial infarction, unplanned revascularization for ischemia, and major bleeding at 30 days. Results were presented for each bivalirudin arm separately compared with the UFH/enoxaparin arm.
When bivalirudin alone was compared with heparin/enoxaparin plus a GP IIb/IIIa blocker, there was a slight but nonsignificant increase in ischemic events; these results fell within the prespecified levels for noninferiority. However, the bivalirudin group showed significantly less major bleeding.
Stone GW et al. N Engl J Med. 2006;355:2203–2216.

43. 3602 randomized pts undergoing primary PCI
HORIZONS AMI Trial
3602 randomized pts undergoing primary PCI
Anti-thrombotic
therapy
Hypothesis: Bivalirudin compared to UFH + routine IIb/IIIa will reduce the composite rate of death, reinfarction, TVR, stroke and major bleeding at 30-days
Randomize 1:1
UFH +
IIb/IIIa
inhibitor
Bivalirudin +
bail-out
IIb/IIIa
Target vessel
stenting
TAXUS
stent
Bare metal
Express stent
Randomize 3:1
Hypothesis: Use of the polymer-based slow-release paclitaxel-eluting TAXUS stent will safely reduce the 1-year rate of ischemia-driven TLR

44. 3602 pts with STEMI Randomized 30 day FU* ITT population UFH +
Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI R
1:1
UFH +
GP IIb/IIIa
N=1802
Bivalirudin
Monotherapy
N=1800
Randomized 9 15
• • • Withdrew • • •
• • • Lost to FU • • • 10 13
N=1778
(98.7%)
N=1777
(98.7%)
30 day FU*
ITT population
N=1802
N=1800
* Range ±7 days

45. Primary Outcome Measures
Diff = -2.9% [-4.9, -0.8]
RR = 0.76 [0.63, 0.92]
PNI ≤
Psup = 0.006
Diff = -3.3% [-5.0, -1.6]
RR = 0.60 [0.46, 0.77]
PNI ≤
Psup ≤
Diff = 0.0% [-1.6, 1.5]
RR = 0.99 [0.76, 1.30]
Psup = 1.00
1 endpoint
1 endpoint
Stone GW, et al. N Engl J Med. 2008;358(21):

46. Conclusioni
- I nuovi farmaci che bloccano il recettore P2Y12 (prasugrel, ticagrelor) sono risultati più efficaci del clopidogrel grazie ad una migliore farmacocinetica e farmacodinamica. Ad essi si associa tuttavia un certo grado di rischio emorragico.
L’analisi di efficacia e di rischio in particolari sottogruppi di pazienti con SCA potrà permettere di utilizzare il farmaco più vantaggioso per quel dato contesto clinico.
- La bivalirudina riduce i sanguinamenti locali e d’organo nei pazienti con SCA sottoposti a PCI, soprattutto in quelli a maggior rischio emorragico (anziani), ma per un’efficace copertura anti-ischemica deve essere associata ad un regime di doppia anti-aggregazione piastrinica.