Rabih R. Azar, MD, MSc, FACCDirector of Cardiovascular ResearchHotel Dieu de France HospitalAssociate Professor of MedicineSaint Joseph University School of MedicineBeirut, LebanonNSTEMI: GPIIB/IIIA Inhibitors & Emerging Antiplatelets: Where Do We Stand?

Role of the Platelets in ThrombosisUA/NQMI: Partially-occlusive thrombus (primarily platelets)Intra-plaque thrombus (platelet dominated)Plaque coreST MI: occlusive thrombus (platelets, red blood cells, and fibrin)Intra-plaque thrombus (platelet dominated)Plaque coreSUDDEN DEATHAdapted from Davies MJ. Circulation. 1990; 82 (supl II): 30-46.

GP IIb/IIIa Receptor Activation PathwayASPIRINASPIRINHEPARINSASPIRINASPIRINASPIRINASPIRINGP IIb/IIIaGP IIb/IIIaThickness of line indicates strength of activator5HTPAFEpiThrombinADPTXA2ASPIRINVasopressinCollagenFibrinogenPLATELETPLATELETCLOPIDOGREL

Platelet-fibrinogen interaction

*Time after bolus (minutes)1530456012006080100abciximab plus infusiontirofiban 10 g/kg bolus plus infusion85%Inhibition of Light Transmission Aggregation Induced by 20 M ADP After Treatment with Tirofiban or AbciximabInhibition of Maximal Aggregation (%)TARGET DOSE

*Time after bolus (minutes)1530456012006080100abciximab plus infusiontirofiban 10 g/kg bolus plus infusiontirofiban 20 g/kg bolus plus infusiontirofiban 25 g/kg bolus plus infusion85%Inhibition of Light Transmission Aggregation Induced by 20 M ADP After Treatment with Tirofiban or AbciximabInhibition of Maximal Aggregation (%)TARGET DOSESHBD

EPIC: 3-year OutcomeJAMA 1997;278:478

*PRISM-PLUS: Study Design48 hPRISM-PLUS Study Investigators. N Engl J Med. 1998;338(21):1488-1497.

PRISM PLUS: ResultsNEJM 1998;338:1488

*

PRISM-PLUS: Outcomes in At-Risk ACS Patients With Elevated Troponin I at Baseline

P=.06

P=NS

n=21

n=27

n=34

n=28

Adapted from Januzzi JL, et al. J Thromb Thrombolysis. 2001;11(3):211-215.

Aggrastat + Heparin + ASA

Heparin + ASA

TpnI cut point >0.5 ng/mL; 56% of patients TpnI positive

Death/MI at 30 days

% of Patients

Chart1

11.19.5

20.63.6

Heparin + ASA

AGGRASTAT + heparin + ASA

20.6

11.1

3.6

9.5

Sheet1

Heparin + ASAAGGRASTAT + heparin + ASA

Troponin I-negative11.19.5

Troponin I-positive20.63.6

*

*

Slide 15 in Core Slide Deck

Page 213Col 1

Page 212Col 2

*

PRISM-PLUS: Outcomes in At-Risk ACS Patients With ST Changes at Baseline

% of Patients

n=479

n=440

n=92

n=104

PRISM-PLUS Study Investigators. N Engl J Med. 1998;338(21):1488-1497.

Death/MI/Refractory Ischemia at 7 Days

Chart1

21.716.6

17.47.7

Heparin

AGGRASTAT + heparin+ASA

Sheet1

HeparinAGGRASTAT + heparin+ASA

ST Depression21.716.6

ST Elevation17.47.7

*

*

Figure 2 p1494

Page 1494Fig 2

Brenner et al. Circulation 1998;98:734RAPPORT: Abciximab in primary PTCA reduces death/MI/urgent TVR at 30 days

Synergy between abciximab and stenting in primary angioplasty for acute MI. Event free suvival (death, acute coronary syndromes, TVR)Azar et al. J Am Coll Cardiol 1998;32:1996

GP IIb/IIIa Receptor Activation PathwayASPIRINASPIRINHEPARINSASPIRINASPIRINASPIRINASPIRINGP IIb/IIIaGP IIb/IIIaThickness of line indicates strength of activator5HTPAFEpiThrombinADPTXA2ASPIRINVasopressinCollagenFibrinogenPLATELETPLATELETCLOPIDOGREL

CURE

Study Design

Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients)

Placebo + ASA 75-325 mg q.d.*(6303 patients)

Day 1

6 m. Visit

9 m. Visit

12 m. or Final Visit

3 m. Visit

Discharge Visit

1 m. Visit

Patients withAcute Coronary Syndrome

(unstable angina or non-ST-segment elevation MI)

R

Placebo loading dose

R = Randomization * In combination with other standard therapy

The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

3 months double-blind treatment 12 months

Clopidogrel 300 mg loading dose

Patients were eligible for CURE if they were admitted to the hospital within 24 hours of an episode of chest pain suggestive of unstable angina or nonST-segment elevation MI. The average time between onset of pain and admission was 14 hours. Patients were randomized to one of two treatment arms: either clopidogrel (300 mg loading dose followed by 75 mg/day) or placebo, both in addition to aspirin (75-325 mg/day) and other standard therapy. Medications at time of randomization may include heparin or lowmolecular weight heparin, beta-blockers, ACE inhibitors, lipid-lowering agents, calcium channel blockers, and/or other therapies or interventions (PTCA, CABG) at physicians discretion. Treatment duration was for up to 1 year. The average duration of treatment was 9 months. Follow-up assessments were conducted at 1 and 3 months for all patients and at 6, 9 and 12 months for patients randomized early in the study.

For Educational Purposes Only. Not For Distribution.

CURE

Primary End Point - MI/Stroke/CV Death

Clopidogrel + ASA*

3

6

9

Placebo + ASA*

Months of Follow-Up

11.4%

9.3%

20% RRRP < 0.001N = 12,562

0

12

* In combination with standard therapyThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

Clopidogrel provided a 20% relative risk reduction in the composite outcome of MI, stroke or CV death (95% CI 0.72-0.90, P < 0.001). Overall there were 719 (11.4%) first events in the placebo group and 582 (9.3%) in the clopidogrel group. The hazard rate curves began to separate within the first few hours after therapy initiation and continued to diverge over the remainder of the trial.

For Educational Purposes Only. Not For Distribution.

Does Clopidogrel Eliminate the Need for GPIIb/IIIa Antogonists?

Treatment with AGGRASTAT provides greater flexibility for early surgical procedures, transfer, or dischargeAdapted from Kereiakes DJ et al. Am Coll Cardiol 1996;27(3):536-5420.560100% inhibitionFast-OnApproximate % plateletaggregation blockedFast-OffReturn to baseline of platelet functionHours of infusionHours postinfusion8040201224480601008040202480Endinfusion3567% inhibitionSlide 14

Clopidogrelprovided time-dependent and partial inhibition

Clopidogrel reached a maximum of only 44% IPA at 5 hours and declined to 24% at 48 hours Clopidogrel

AGGRASTATprovided rapid and excellent provided rapid and excellent inhibition

Nearly 90% inhibition of platelet aggregation (IPA) in the first 30 minutes of infusion1 Sustained IPA throughout entire 48-hour

Anti-platelet therapies in ACS - Early efficacy -

CURE, NEJM 2001 - PRISM-PLUS, NEM 1998

48h events

-18%

-66%

P=NS

P

EPISTENT: Effect of Thienopyridine PretreatmentPlacebo No PretreatPlacebo PretreatAbcix No PretreatAbcix Pretreat42% (P=0.028) 33% (P=0.033) Steinhubl S et al. Circulation 2001;103:1403-9

*

ISAR-REACT 2: At-Risk Patients

Kastrati A, et al. N Engl J Med. 2004;350(3):232-238.

*

*

*

Slide 30 in Core Slide Deck

*

*Tirofiban vs Placebo0246Death30 DaysDeath5 Months3.02.0OR= 0.66P

*Tirofiban vs Placebo051015Death30 DaysDeath/MI30 Days2.71.4OR= 0.50P=0.00512.28.5OR= 0.61P

Enough Data to Support the Use of GPIIb/IIIa Antagonists during High-Risk PCIGPIIb/IIIa antagonists:

Should be given for patients with high risk ACS undergoing PCI irrespective of the use of clopidogrel

Question is timing: upstream (as early as possible on admission) or downstream (in the cath lab at the time of PCI)

UpStream vs. Downstream GPIIb/IIIa InhibitorsACUITY Timing trial9207 patients with ACS

Upstream vs. downstream use of GPIIb/IIIa

Upstream: 98% received GPIIb/IIIa; mean duration 18.3 h

Downstream: 56% received GPIIb/IIIa; mean duration 13.1 h

Use of thienopyridines: 64% before angiography or PCI

UpStream vs. Downstream GPIIb/IIIa InhibitorsACUITY Timing trialP = 0.009P = NSStone et al. JAMA 2007;297:591-602

Chart1

7.17.9

6.14.9

11.711.7

upstream

downstream

Sheet1

upstreamdownstreamSeries 3

ischemic endpoints7.17.92

non CABG bleeding6.14.92

net clinical outcome11.711.73

Category 44.52.85

To resize chart data range, drag lower right corner of range.

Ongoing Tirofiban In Myocardial Infarction Evaluation

All-Cause Mortality 30 Daysopen label & double-blind, n = 1398

Ongoing Tirofiban In Myocardial Infarction Evaluation

All-Cause Mortality 1-YearP = 0.077open label & double-blind, n = 1398

Ongoing Tirofiban In Myocardial Infarction Evaluation

1 Year Survival: Patients with Primary PCIP = 0.007open label & double-blind, n = 1.155

EARLY-ACS trial9492 patients with non-ST elevation MIAll assigned to an invasive strategyRandomized to:Early eptifibatideEarly placebo with provisional use of eptifibatide in the cath lab (38% received eptifibatide in the cath lab)Primary end-point: death or MI or recurrent ischemia requiring urgent revascularization or thrombotic bailout5559 underwent PCI

EARLY-ACS trial: ResultsP = nsP = nsP = 0.015Guigliano RP et al. N Engl J Med 2009;360:2176-2190

Chart1

9.310

11.212.3

2.61.8

Early GPIIb/IIIa

provisional GPIIb/IIIa

Sheet1

Early GPIIb/IIIaprovisional GPIIb/IIIaSeries 3

composite9.3102

death or MI11.212.32

Major bleeding2.61.83

Category 44.52.85

To resize chart data range, drag lower right corner of range.

But We Have New Oral Anti-platelet Agents that are MORE POTENT than Clopidogrel

But We Have New Oral Anti-platelet Agents that are MORE POTENT than ClopidogrelWhat is the role of GPIIb/IIIa antagonists when those agents are used?

Patients included in TRITON were clopidogrel and prasugrel naives.

There was no PRE-TREATMENT with either of the 2 drug.

Clopidogrel or prasugrel were given on the cath table, immediately prior or during PCI

Eff-SK-2-MENA-07/10Eff-SK-2-MENA-07/10

Eff-SK-2-MENA-07/10Eff-SK-2-MENA-07/10

Eff-SK-2-MENA-07/10Eff-SK-2-MENA-07/10

Eff-SK-2-MENA-07/10Eff-SK-2-MENA-07/10

Did the use of GPIIb/IIIa inhibitor affect the outcome?

No data

PCI=Percutaneous Coronary Intervention; CABG=Coronary Artery Bypass Graft surgeryTRITON-TIMI 38: Index ProcedureWiviott SD et al. New Engl J Med 2007;357:2001-2015

Clopidogrel (n=6,795) %Prasugrel (n=6,813) %PCI9999CABG11Any Stent9594Bare-Metal Stent4748Drug-Eluting Stent4747Multivessel PCI1414Anticoagulant TherapyUnfractionated heparin6566Low Molecular Weight Heparin89Bivalirudin33GP IIb/IIIa- receptor antagonist5554

ODonoghue et al. JACC 2009No GP IIb/IIIa inhibitor+ GP IIb/IIIa inhibitorCV death, MI, stroke

Ticagrelor compared with clopidogrel in patients with acute coronary syndromes the PLATelet Inhibition and patient Outcomes trialOutcomes in patients with STEMI and planned PCIThe PLATO trial was funded by AstraZenecaSTEMIPh.Gabriel Steg*, Stefan James, Robert A Harrington, Diego Ardissino, Richard C. Becker, Christopher P. Cannon, Hkan Emanuelsson, Ariel Finkelstein, Steen Husted, Hugo Katus, Jan Kilhamn, Sylvia Olofsson, Robert F. Storey, Douglas Weaver, Lars Wallentin, for the PLATO study group

*Unit INSERM U-698Hpital Bichat Claude BernardUniversit Paris VII Denis Diderot

STEMI

Patient disposition18,758 patients enrolled in PLATOSTEMI: 8,430 patientsRandomized to ticagrelor: efficacy population N= 4,201 Randomized to clopidogrel: efficacy population N= 4,229 No intake of study medication: 36 patients No intake of study medication: 48 patients Safety population N=4,165Safety population N=4,181

STEMI

Primary endpoint: CV death, MI or stroke01234567891011121211109876543210MonthsHR: 0.85 (95% CI = 0.740.97), p=0.02No. at riskClopidogrelTicagrelor4,2294,2013,8923,8873,8233,8343,7303,0223,0112,3332,2971,8681,8913,73211.09.3ClopidogrelTicagrelorK-M estimated rate (% per year)

Proposed Algorithm for Initial Management of NSTEMIST depression or + troponin ?- clopidogrel (class I) or ticagrelor(class I) and early cath lab. If PCI: Tirofiban in cath lab (class I). If CABG: WAIT 5 DAYS OR

Tirofiban (class I ACC/ Iia ESC) and early cath lab. If PCI prasugrel (class I) (or clopidogrel) on the table. If CABG, do it same or next dayAspirin + Hep or EnoxaparinNOConservative therapy: No indication for GPIIb/IIIa antagonists YES

Proposed Algorithm for Initial Management of STEMIPossibility of Primary PCI?NO

YesAspirin + clopidogrel or prasugrel or ticagrelor* (class I)IIb/IIa antagonist- pre cath: IIb- During PCI: IIaFibrinolysis

ESC Guidelines for GPIIb/IIIa Inhibitors in NSTEMI

RecommendationClassLevel of evidenceAmong patients on DAPT, if PCI is high risk (+trop; visible thrombus), add GPIIb/IIIaIBIf high-risk patient not treated with P2Y12 inhibitor, add GPIIb/IIIa prior to angiographyIIaCIf high-risk patient treated with DAPT, add GPIIb/IIIa prior to PCI if on going ischemia and low bleeding riskIIbCGPIIb/IIIa routinely prior to angiographyIIIIAGPIIb/IIIa in patients on DAPT treated conservativelyIIIIA

ACC/AHA Guidelines for GPIIb/IIIa Inhibitors in NSTEMI

RecommendationClassLevel of evidenceMedium or high-risk patients clopidogrel or (upstream) GPIIb/IIIa in addition to ASA prior to PCIIAMedium or high-risk patients: GPIIb/IIIa at the time of PCI (downstream)IAUpstream GPIIb/IIIa in high-risk patients already on DAPT who are selected for an invasive approach and who are not at high risk of bleedingIIbBLow risk ischemia patients or patients at high risk of bleeding and who are receiving DAPTIIIB

Non ST-Elevation Acute Coronary SyndromesPercent Requiring In-hospital CABG

14.2

23

17.5

19.7

13

15.8

Percentage (%)

Pursuitn = 10,948

Prism-Plusn = 1,370

PRISMn = 3,232

TIMI-18 INVn = 1,114

TIMI-18 CONn = 1,106

Averagen = 17,970

# of patients 17,970# of patients requiring CABG 2,855

Need for Reexploration Secondary to Bleeding

Need for Reexploration

% of Patients

Swarup, oral at AHA 2000

Yende, Crit Care Med 2001

P

Coronary Artery Bypass Graft Bleedings -

% In Hospital Mortality

Dacey, Archive Surgery 1998

3 Times Higher

Mortality Related to Reexploration Secondary to Bleeding

P

Treatment with AGGRASTAT provides greater flexibility for early surgical procedures, transfer, or dischargeAdapted from Kereiakes DJ et al. Am Coll Cardiol 1996;27(3):536-5420.560100% inhibitionFast-OnApproximate % plateletaggregation blockedFast-OffReturn to baseline of platelet functionHours of infusionHours postinfusion8040201224480601008040202480Endinfusion3567% inhibitionSlide 14

Keys Points in Anti-Platelet Therapy in NSTEMIDuring PCI: GPIIb/IIIa antogonists are class I indication in both ESC and ACC/AHA guidelines on top of aspirin and thienopyridines

Dual anti-platelet therapy as early as possible in high-risk patients (asa + clopidogrel or ticagrelor; class I) or (asa + GPIIb/IIIa class I in ACC and class IIa in ESC)I favor GPIIb/IIIa antagonists rather than thienopyridines because safer if surgery (allows surgery sooner)

Routine triple anti-platelet therapy in high-risk patients prior to PCI is class IIb indication in the ACC/AHA guidelines and class III indication in ESC guidelines (but it becomes class IIb if recurrent ischemia)

GPIIb/IIIa antagonists are not recommended for low risk patients

Clinical manifestations of arterial thrombosisThe clinical manifestation of coronary thrombosis depends on the extent and duration of thrombotic occlusion. Unstable angina and non-Q-wave MI are characterized by mural, platelet-rich thrombi, which do not completely block coronary blood flow and therefore cause ischemia of relatively short duration. The aggregated platelets can serve as a substrate for further thrombus propagation, leading to formation of an occlusive red thrombus formed by entrapment of red blood cells within the fibrin mesh. This complete occlusion results in abrupt and persistent ischemia that clinically manifests as ST-segment elevation MI. Left untreated, occlusion of the coronary arteries can lead to sudden cardiac death.**Slide I.13The combined effect of platelet adhesion and platelet recruitment by agonists such as thrombin exposes the integrin platelet glycoprotein IIb/IIIa receptor,13,15 which is present in as many as 50,000 copies on the surface of each platelet.32 Like other members of the integrin family, platelet glycoprotein IIb/IIIa receptors are specific for the amino-acid sequence arginine-glycine-aspartic acid, or RGD.32 Thus, adhesive proteins, such as fibrinogen, that contain an RGD sequence can bind to the glycoprotein IIb/IIIa receptor.23 Indeed, the primary function of this receptor is to provide a binding site for fibrinogen. Activated platelets form aggregates by cross-linking through fibrinogen's multiple glycoprotein IIb/IIIa receptor binding sites.23Once platelets begin cross-linking with fibrinogen, they rapidly join together into doublets, triplets, and multiple groups. These aggregates enlarge at the site of vessel damage.33 Following atherosclerotic plaque rupture, large platelet aggregates can potentially lead to a critical occlusion of the diseased vessel.16 Elucidation of the pathophysiology of thrombus formation has shown that the binding of fibrinogen to the platelet glycoprotein IIb/IIIa receptor is the final, obligatory pathway to platelet aggregation.15By preventing the binding or interaction of the receptor with fibrinogen, glycoprotein IIb/IIIa receptor antagonists help prevent platelet aggregation and subsequent thrombus formation.15****PRISM-PLUS Study Investigators. N Engl J Med. 1998;338(21):1488-1497.1488/2/2; 1489/1/1-2,4; 1489/2/3; 1490/Table1**Slide 14AGGRASTAT has a rapid onset of action and rapid recovery of platelet function. In patients with UA, a two-staged intravenous infusion regimen of AGGRASTAT (loading infusion of 0.4 g/kg/min for 30 minutes followed by 0.1 g/kg/min for up to 48 hours in the presence of heparin and aspirin) produced approximately 90% inhibition of ex vivo ADP-induced platelet aggregation at 30 minutes.10 The rapid blockade of platelet aggregation allows for rapid restoration of coronary flow. Because AGGRASTAT has a short half-life of 1.9 to 2.2 hours, the effects on platelet function and hemostasis are rapidly reversible. By 1.5 hours after the cessation of infusion with AGGRASTAT, 50% of platelet function returned to baseline.10 Recovery in platelet function that provides hemostasis can be expected within four hours.22 Nearly 100% of platelet function returned to baseline within eight hours. This rapid return of normal hemostasis and platelet function provides potentially better control of bleeding.Ref 10,Source A,p 14ASource E,pp C-43A, C-44A

Source A,p 13A

Ref 10,Source E,p C-45A

Ref 22,pp 539A, 540A

*****THIS SLIDE HAS BEEN THROUGH QUALITY REVIEWDOI link website: http://dx.doi.org/10.1056/NEJMoa0706482

*******Slide 14AGGRASTAT has a rapid onset of action and rapid recovery of platelet function. In patients with UA, a two-staged intravenous infusion regimen of AGGRASTAT (loading infusion of 0.4 g/kg/min for 30 minutes followed by 0.1 g/kg/min for up to 48 hours in the presence of heparin and aspirin) produced approximately 90% inhibition of ex vivo ADP-induced platelet aggregation at 30 minutes.10 The rapid blockade of platelet aggregation allows for rapid restoration of coronary flow. Because AGGRASTAT has a short half-life of 1.9 to 2.2 hours, the effects on platelet function and hemostasis are rapidly reversible. By 1.5 hours after the cessation of infusion with AGGRASTAT, 50% of platelet function returned to baseline.10 Recovery in platelet function that provides hemostasis can be expected within four hours.22 Nearly 100% of platelet function returned to baseline within eight hours. This rapid return of normal hemostasis and platelet function provides potentially better control of bleeding.Ref 10,Source A,p 14ASource E,pp C-43A, C-44A

Source A,p 13A

Ref 10,Source E,p C-45A

Ref 22,pp 539A, 540A