Published on April 20, 2009
Antiplatelets in ACS and PCI : Antiplatelets in ACS and PCI Dr. RAJAGOPAL J What is the need for Antiplatelets in ACS? : What is the need for Antiplatelets in ACS? Slide 3: Rupture of unstable atherosclerotic plaque Disruption of protective endothelial layer Exposure of very prothrombotic subendothelial layer Slide 6: Platelet adhesion to area of injury Platelet activation exposure of Glycoprotein(GP) IIb/IIIa receptors Platelet aggregation Caused by fibrinogen binding to GP IIb/IIIa receptors Fibrin deposition - Platelet plug incorporates fibrin strands Slide 8: 1 2 3 4 Aspirin (ASA)/NSAIDS : Aspirin (ASA)/NSAIDS Irrev/Reversibly block COX 35%-50% RRR (ARR 2.5% NNT 40) in cardiovascular death/MI CLOPIDOGREL & TICLOPIDINE : CLOPIDOGREL & TICLOPIDINE Irreversibly inhibit ADP-induced platelet aggregation PLAVIX: Unstable angina, NSTEMI, PVD, 2° prevention AMI/CVA Consider for ASA hypersensitivity/GI intolerance Dyspepsia, rash, diarrhea TICLID: neutropenia, ITP, TTP Clopidogrel in ACS & PCI : Clopidogrel in ACS & PCI CLARITY-TIMI 28 (300mg loading dose in AMI) Primary endpoints: : CLARITY-TIMI 28 (300mg loading dose in AMI) Primary endpoints: Placebo Clopidogrel p=0.00000036 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds reduction CV death, MI, RI urgent revascularization : CV death, MI, RI urgent revascularization Days Percent with endpoint 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds ratio 0.80 (95% CI 0.65-0.97) p=0.026 20% Intravenous ANTIPLATELET AGENTS : Intravenous ANTIPLATELET AGENTS Glycoprotein IIb-IIIa receptor inhibitors Inhibits critical step in thrombus formation, by preventing binding of thrombin to activated platelets Indication Substantial benefit in those who undergo Percutaneous Coronary Intervention(PCI) 10%-27% RRR Modestly benefit those who are not routinely scheduled, but who may benefit from PCI Questionable benefit in patients who do not undergo PCI REOPRO (Abciximab) INTEGRILIN (Eptifibatide) AGGRASTAT (Tirofiban) Trials : Trials PRISM-PLUS (Tirofiban – prior to PCI) EPIC (Abciximab – prior to PCI) CAPTURE (Abciximab – prior to PCI) GUSTO IV-ACS (Abciximab – no PCI) PARAGON (Lamifiban – no PCI) PURSUIT (Eptifibatide -- no PCI) RESTORE (Tirofiban – no PCI) Abciximab : Abciximab Monoclonal Antibody: immunogenic Low dissociation from receptor Shown to be superior to Tirofiban and Eptifibatide in PCI Effects last for 10 hrs. or more Abciximab should be given for 12 hrs In ACS, Abciximab should be reserved for those patients in whom PCI is planned within 18-24 Hrs. Eptifibatide : Eptifibatide Synthetic Peptide Rapid receptor blockade and rapid dissociation Duration of action : 30 – 45 mins Should be continued for 18-24 hours Superior to Abciximab for upstream use Tirofiban : Tirofiban Non-Peptide Has not shown high benefit in PCI Useful in ACS patients not undergoing PCI also Lamifiban: Newer GP2b3a antagonist Oral 2b 3a inhibitors: OROFIBAN xemilofiban, lefradafiban, sibrafiban, roxifiban Approved Uses: : Approved Uses: PCI in unstable Angina and Acute MI patients Unstable Angina patients awaiting PCI Novel Uses: Post MI angina pts. not undergoing PCI Slow flow and no flow during PCI Facilitated Thrombolysis Antiplatelet treatment today : Antiplatelet treatment today Aspirin for all patients plus Clopidogrel in NSTE-ACS for 9-12 months Clopidogrel in STEMI for 1 month irrespective of the reperfusion strategy Clopidogrel after stent implantation (prolonged treatment in cases of DES implantation) Issues: Dosage of both ASA and clopidogrel Need for a rapid onset of action Too many non responder patients Cilastazol (Stiloz): : Cilastazol (Stiloz): Mechanism of action is not clear. It is an inhibitor of phosphodiesterase III (PDE III) enzyme Vasodilator and inhibitor of platelet aggregation Initially approved for Intermittent claudication Indicated for the reduction of events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent stroke, recent MI or established peripheral arterial disease. Why not Cilastazol ? : Why not Cilastazol ? Aspirin is effective in patients with a previous ACS or stroke but is not effective in patients with claudication Clopidogrel appears effective in all three groups. Cilastazol also is effective in all these patients Risks with Cilastazol: : Risks with Cilastazol: Causes a modest increase in heart rate (about 7 beats/minute) and a small increase in VPC rates (from 1/hour to 4/hour) - patients on cilostazol were also more likely to complain of palpitations. Cilostazol is a positive inotrope in animals at doses that inhibit platelet aggregation Same family of Milrinone / Amrinone Contraindicated in CHF patients May increase bleeding risks along with clopidogrel Unproven antiplatelets: : Unproven antiplatelets: Dipyridamole : alone or with aspirin has not been studied for acute coronary syndrome. Sulphinpyrazone New thienopyridines: Prasugrel : New thienopyridines: Prasugrel Prasugrel is more potent and with a more rapid onset of action than clopidogrel Greater inhibition of platelet aggregation with 60-mg dose of prasugrel than 300 mg of clopidogrel repeat dosing with 10 mg of prasugrel compared with 75mg of clopidogrel poor platelet aggregation response less frequent with a loading dose of 60 mg of prasugrel than 300 mg of clopidogrel Cangrelor : Cangrelor Intravenous P2Y12 Inhibitor Plasma half-life 3-5 minutes Full recovery of platelet function <60 minutes TRITON-TIMI 38 trial : TRITON-TIMI 38 trial Treatments clopidogrel LD of 300 mg followed by 75 mg daily prasugrel LD of 60 mg followed by 10 mg of maintenance dose Primary end-point time of first occurrence of any element of the composite of CV death, nonfatal MI, or nonfatal stroke Cangrelor with Clopidogrel : Cangrelor with Clopidogrel Storey RF, et al.,Thromb Haemost 2002; 88: 488-94 Cangrelor improves platelet inhibition in patients receiving chronic clopidogrel Cangrelor Clinical Data : Cangrelor Clinical Data Double-blind randomized trial in PCI Events up to 7-days SC931-5129 Part 2. Data on file, The Medicines Company 41%, p<.001. Cangrelor Anti-inflammatory Effects : Cangrelor Anti-inflammatory Effects 0 10 20 30 40 50 60 0.1 1 10 100 % conjugates Cangrelor control baseline ADP (mM) Storey RF, et al.,Thromb Haemost 2002; 88: 488-94 Effect of cangrelor on the formation of platelet – monocyte conjugates Thank you for All your Attention ! : Thank you for All your Attention !