Antiplatlets controversy

1. Antithrombotic therapy between
clinical trials and guidelines
By
Ashraf Reda, MD, FESC
Prof and head of Card. Dep., Menofiya University
President of WGLVA

2. One of the big stories in the last few
years
• RE-LY:
• ROCKET:
• ARISTOTLE:
•
•
•
•
•
Dabigatran
Rivaroxaban
Apixaban
AF
Triology/TRITON : Prasugrel
DISPERSE?PLATO: Tecagrelor
ACS/PCI
ATLAS:
Rivaroxaban
Oasis
Fodaparinux
HORIZON-AMI
bivalirudin
Vit.K antagonist:
• Narrow therapeutic
range
• Drug &food
interaction
• Bleeding
•
•
•
•
Clopidogrel resistance
MACEs
Stent thrombosis
Variable response

3. ANTI THROMBOTICS IN ACS/PCI

5. OASIS
• Fondaparinux 2.5 mg bid Vs Enoxaparin 1mg/kg
bid
• Pts wit ACS
• Non inferiority DBRT
• Same protective effect
• Significantly less bleeding with fondaparinux
2.2% compared to Enoxaparin 4,15
• PCI thrombosis?

6. Bivalirudin:
Main Results From HORIZONS-AMI
Bonaca, M. P. et al. J Am Coll Cardiol 2009;54:969-984
Copyright ©2009 American College of Cardiology Foundation. Restrictions may apply.

8. ACC/ AHA guide lines
• Fonda is preferred only in:
• Conservative non invasive strategy
• Renal dysfunction

9. Antiplatelets

10. Anti platelets
• COX-1 inhibitors
Irreversible: aspirin
Reversible: indobufen, triflusal
• P2Y12 inhibitors
Irreversible: ticlopidine, clopidogrel, prasugrel
Reversible: Ticagrelor, cangrelora, elinogrela
• Phosphodiesterase inhibitors
Dipyridamole
Cilostazol
• GPIIb/IIIa blockers
Abciximab
Eptifibatide
Tirofiban
• Thromboxane receptor
(TP) antagonists
Terutrobana
• Thrombin receptor
(PAR-1) antagonists
Vorapaxara
Atopaxara

11. Current problems with anti platelet
drugs
•
•
•
•
•
Resistance
Bleeding
On treatment platelet reactivity
Drug interactions
Variable efficacy and liver enzyme genetic
variations
• Duration of therapy
• Preoperative management

13. Wiviott
SD, Braunw
ald
E, McCabe
CH, et al. N
Eng J Med
2007;
357:20012015.
TRITON-TIMI 38 results (ACS for PCI)
End point
Prasugrel
(%)
Clopidogrel
(%)
HR
(95% CI)
p
Cardiovascular
death/MI/
stroke*
9.9
12.1
0.81
(0.73–0.90)
<0.001
Cardiovascular
death
2.1
2.4
0.89
(0.70–1.12)
0.31
Nonfatal MI
7.3
9.5
0.76
(0.67–0.85)
<0.001
Nonfatal stroke
1.0
1.0
1.02
(0.71–1.45)
0.93
Death from any
cause
3.0
3.2
0.95
(0.78–1.16)
0.64
Urgent TVR
2.5
3.7
0.66
(0.54–0.81)
<0.001
Stent thrombosis
1.1
2.4
0.48
(0.36–0.64)
1.34
(1.11–1.63)
<0.001
Bleed requiring
4.0
3.0
CABG-related TIMI
major bleedb
13.4
3.2
*Primary end point
transfusion
4.73
(1.90–11.82)
<0.001
<0.001

14. Prasugrel
• Better prevention of MI and stent thrombosis
in ACS Pts under going PCI (More bleeding)
• For stent TH despite ASP/clopidogrel therapy
• High risk in the elderly, low body Wt. and HO
CVA
• TRIOLOGY 51 ( high risk medically managed
population/

16. PLATO: Patient disposition in the trial
Ticagrelor Versus Clopidogrel in Patients With ST-Elevation Acute Coronary Syndromes
Intended for Reperfusion With Primary Percutaneous Coronary Intervention
A Platelet Inhibition and Patient Outcomes (PLATO) Trial Subgroup Analysis
7544 STEMI
Steg P G et al. Circulation 2010;122:2131-2141
Copyright © American Heart Association

17. Time-related Kaplan–Meier estimates of the time to first occurrence of (A) the primary end
point (incidence of MI, stroke, or vascular death; HR, 0.87; 95% CI, 0.75 to 1.01; P=0.07) and
each of its components; B, cardiovascular death (HR, 0.83; 95% CI, 0.67...
Steg P G et al. Circulation 2010;122:2131-2141
Copyright © American Heart Association

18. Time-related Kaplan–Meier estimate for major bleeding according to the PLATO definition
(HR, 0.98; 95% CI, 0.83 to 1.14; P=0.76).
Steg P G et al. Circulation 2010;122:2131-2141
Copyright © American Heart Association

19. Clopidogrel

21. Glycoprotein (GP)IIb/IIIa blockers
• No routine up-stream
• For high risk PCI (=ve Troponin- Thrombus)
and low bleeding risk

23. Clopidogrel, Prasugrel, or Tecagrelor
A major across Atlantic differences

24. STEMI: 2013 ACCF/AHA guideline1
• A loading dose of a P2Y12 receptor inhibitor should be given as early as
possible or at time of primary PCI to patients with STEMI. Options include:
• Clopidogrel 600 mg (Level of Evidence: B); or
• Prasugrel 60 mg (Level of Evidence: B); or
• Ticagrelor 180 mg (Level of Evidence: B)
• P2Y12 inhibitor therapy should be given for 1 year to patients with STEMI who
receive a stent (bare metal stent or drug-eluting stent) during primary PCI,
using the following maintenance doses:
• Clopidogrel 75 mg daily (Level of Evidence: B); or
• Prasugrel 10 mg daily (Level of Evidence: B); or
• Ticagrelor 90 mg twice a day. (Level of Evidence: B)

25. UA/NSTEMI invasively or noninvasively 2012
ACCF/AHA guideline: Class I
•
For patients with definite UA/NSTEMI at medium or high risk and in whom an initial
invasive strategy is selected: Patients should receive dual antiplatelet therapy on
presentation. (Level of Evidence: A)
Aspirin should be initiated on presentation. (Level of Evidence: A)
The choice of a second antiplatelet therapy to be added to aspirin on presentation
includes 1 of the followinga:
Before PCI:
•
•
•
•
•
•
•
•
Clopidogrel (Level of Evidence: B); or
Ticagrelorb (Level of Evidence: B); or
An IV glycoprotein (GP) IIb/IIIa inhibitor (Level of Evidence: A)
At the time of PCI:
Clopidogrel if not started before PCI (Level of Evidence: A); or
Prasugrel (Level of Evidence: B); or
Ticagrelorb (Level of Evidence: B); or
An IV GP IIb/IIIa inhibitor (Level of Evidence: A

26. UA/NSTEMI conservative 2012 ACCF/AHA guideline:
Class I
• For UA/NSTEMI patients in whom an initial conservative (ie, noninvasive)
strategy is selected: Clopidogrel or ticagrelorb (loading dose followed by
daily maintenance dose) should be added to aspirin and anticoagulant
therapy as soon as possible after admission and administered for up to 12
months. (Level of Evidence B)
For UA/NSTEMI patients for whom PCI is plannedc:
A loading dose of P2Y12receptor inhibitor therapy is recommended.
One of the following regimens should be used:
• Clopidogrel 600 mg should be given as early as possible before or at the time
of PCI (Level of Evidence: B); or
• Prasugrel 60 mg should be given promptly and no later than 1 hour after PCI
once coronary anatomy is defined and a decision is made to proceed with PCI
(Level of Evidence: B); or
• Ticagrelorb 180 mg should be given as early as possible before or at the time of

27. 2 more problems
• Pre operative management
• Triple therapy

28. The Safety and Efficacy Of Cangrelor, a Short
Acting, IV, Reversible, Platelet P2Y12 Inhibitor In
Patients Awaiting Cardiac Surgery:
Results Of the BRIDGE Trial
Dominick J. Angiolillo MD, PhD, Michael S. Firstenberg MD, Matthew J. Price
MD, Pradyumna E. Tummala MD, Martin Hutyra MD, Ian J. Welsby MD,
Michele D. Voeltz MD, Harish Chandna MD, Chandrashekhar Ramaiah MD,
Miroslav Brtko MD, PhD, Louis Cannon MD, Cornelius Dyke MD Tiepu Liu MD, PhD, Gilles
Montalescot MD, Steven V. Manoukian MD, Jayne Prats PhD, Eric J. Topol MD for the
BRIDGE Investigators
28

29. Unmet need & rationale
•
Surgery is frequent in patients presenting with an ACS or treated with stents (1-2)
– 10–15% of patients presenting with ACS have to undergo CABG
– 5% to 25% of patients have to undergo non-cardiac surgery
•
Oral P2Y12 therapy following ACS and coronary stenting is Guideline-recommended
for up to 12 months (3-4)
•
Continue or stop P2Y12 therapy? (5-10)
– Continuation puts patients at ∼35% incidence of bleeding. Bleeding and transfusion are
associated with increased risk of mortality
– Preoperative discontinuation of anti-platelet therapy is associated with ∼20% incidence of
ischemic events
•
No proven and efficacious alternative solution for bridging to surgery is currently
available (11-12)
1. Vicenzi MN, et al. Br J Anaesth 2006; 96: 686–693; 2. Ebrahimi R., et al. J ACC 2009; 53: 1965–19724;3. King, S.B., 3rd, et al. JACC 2008; 51: 172–209; 4. Patrono C, et al.
Chest 2008; 133: 199S-233S; 5. Berger JS, et al. JACC 2008; 52: 1693–1701; 6. Kaluza GL, et al. JACC 2000; 35: 1288–1294; 7. Berger PB, et al. JACC Cardiovasc Interv 2010;
3:.920-7; 8. Rao SV, et al. Eur Heart J 2007; 28: 1193–1204; 9. Hajjar LA, et al. J Am Med Assoc 2010; 304: 1559–1567; 10. Murphy GJ, et al. Circulation 2007; 116: 2544–255;
11.Hamm C et al Eur Heart J 2011 Sep 21. [Epub ahead of print]; 12. Anderson J et al. Circulation. 2011;123:e426-e579.
29

30. BRIDGE Conclusions
• The results of the BRIDGE trial support the hypothesis
that IV cangrelor is a feasible and safe management
strategy in patients who require prolonged platelet P2Y12
inhibition after thienopyridine discontinuation prior to
cardiac surgery.
• Larger patient samples are warranted to more
definitively assert the safety and efficacy of cangrelor as
a bridging therapy in patients with ACS or treated with
coronary stents who require surgery.
30

31. TOAT (triple oral antithrombotic therapy)
• DAPT: ACS, PCI
• OAC: AF, prosthetic valves, venous thromboembolism (VTE)
• Risk of bleeding with TOAT against risk of stent thrombosis or
stroke
• 5-10% of Pts scheduled for PCI are on OAC
• Population aging with more prevalence of AF increase the need
to consider TOAT
• Should we decrease the dose of OAC?
• Should we avoid new agents with high bleeding risk as
Prasugrel?
• Could we consider Clopidogrel + OAC without ASP?

32. THANK YOU
ASRAF REDA, MD, FESC