Oral Antiplatelet Therapy in Patients with ACS: A Focus on Prasugrel and Ticagrelor Nicolas W. Shammas, MS, MD, FACC Coronary and Peripheral Interventionalist Cardiovascular Medicine, PC Research Director, Midwest Cardiovascular Research Foundation Adjunct Clinical Associate Professor, University of Iowa
Objectives Review the role of platelets in ACS Review Prasugrel (Effient) and Ticagrelor (Brilinta) with a focus on the PI label Discuss a proposed practical algorithm in patients with ACS
Conflict of Interest Educational grants from Sanofi/BMS, Astra Zeneca and Elli Lilly/Daichi to the Midwest Cardiovascular Research Foundation Speaker Bureau of Elli Lilly/Daichi, Astra, BMS/sanofi No stocks, bonds, options in any pharmaceutical or medical device company FDA ON LABEL industry slides will be shown but red flagged Full COI: www.mcrfmd.com Any off label discussion will be indicated during the talk
Mechanisms of Platelet Activation Prasugrel Ticagrelor
Efficacy of Antiplatelet Therapy:Antiplatelet Trialists Collaboration Category of trial No. of trials with data MI, stroke, or vascular death Anti- Adjusted platelet controls Odds ratio and confidence interval (Antiplatelet: control) % odds reduction (SD) Prior MI 11 1331/9677 1693/9914 25% (4) Acute MI 9 992/9388 1348/9385 29% (4) Prior stroke/ 18 1076/5837 1301/5870 22% (4) TIA Unstable angina 7 182/1991 285/2027 0 0.5 1.0 1.5 2.0 Antiplatelet therapy better Antiplatelet therapy worse TIA, transient ischemic attack Antiplatelet Trialists Collaboration BMJ 1994;308:81 106
Label Summary for Clopidogrel NSTEMI/UA: Clopidogrel + ASA whether PCI or no PCI performed STEMI: Clopidogrel + ASA. Benefit unknown in primary PCI Stable PAD patients: Clopidogrel or ASA but not combined Risks Major bleeding increased with Clopidogrel+ASA vs ASA Do not give in patients actively bleeding or at high risk of bleed Omeprazole may reduce effectiveness (CYP2C19 substrate) CYP2C19 genetic variation may reduce the effectiveness of clopidogrel
EFFIENT (Prasugrel)
Ticagrelor (Brilinta)
Ticagrelor (AZD 6140): an oral reversibly binding P2Y 12 antagonist Direct acting Not a pro-drug; does not require metabolic activation Rapid onset of inhibitory effect on the P2Y 12 receptor Greater inhibition of platelet aggregation than clopidogrel Reversibly bound Degree of inhibition reflects plasma concentration Faster offset of effect than clopidogrel HO N N HO O N S OH Functional recovery of circulating platelets within ~48 hours N N H N F F
PLATO study design NSTEMI ACS (moderate-to-high risk) or STEMI ACS (if primary PCI) (N=18,624) Clopidogrel-treated or -naive; randomized <24 hours of index event 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 months treatment Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding Recommendations for patients undergoing CABG: Study drugs withheld prior to surgery: 5 d for clopidogrel and 24 72 h for ticagrelor. Study drug be restarted as soon as possible after surgery and prior to discharge
Plato exclusion criteria Contraindication to clopidogrel Fibrinolytic therapy within 24 hours prior to randomization Need for oral anticoagulation therapy STEMI as acute complication of PCI or PCI performed before the first study dose Increased risk of bradycardic events (e.g. no pacemaker and known sick sinus syndrome, 2nd degree A-V block, 3 rd degree A-V block or previous documented syncope suspected to be due to bradycardia) Concomitant therapy with strong CYP3A inhibitors or inducers
Primary endpoint: CV death, MI or stroke 12 11 Clopidogrel 11.0 K-M estimated rate (% per year) 10 9 8 7 6 5 4 3 Ticagrelor 9.3 2 HR: 0.85 (95% CI = 0.74 0.97), p=0.02 1 0 No. at risk Ticagrelor Clopidogrel 0 1 2 3 4 5 6 7 8 9 10 11 12 Months 4,201 4,229 3,887 3,892 3,834 3,823 3,732 3,011 3,730 3,022 2,297 2,333 1,891 1,868
CV death/total MI 11 10 Clopidogrel 10.3 K-M estimated rate (% per year) 9 8 7 6 5 4 3 2 Ticagrelor 8.3 1 HR 0.81 (95% CI = 0.70 0.93), p=0.004 o. at risk icagrelor lopidogrel 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Months 4,201 3,912 3,862 3,759 3,038 2,321 1,914 4,229 3,908 3,841 3,751 3,043 2,350 1,881
All cause mortality 7 K-M estimated rate (% per year) 6 5 4 3 2 1 Clopidogrel Ticagrelor HR 0.82 (95% CI = 0.68 0.99), p=0.04 6.0 4.9 0 No. at risk Ticagrelor Clopidogrel 0 1 2 3 4 5 6 7 8 9 10 11 12 Months 4,201 4,005 3,962 3,876 3,150 2,413 1,993 4,229 4,029 3,989 3,912 3,195 2,471 1,980
PLATO main endpoints Primary efficacy endpoint CV death + MI + Stroke Primary safety endpoint Total major bleeding 13 15 K-M estimated rate (% per year) 12 11 10 9 8 7 6 5 4 3 2 1 Clopidogrel Ticagrelor HR 0.84 (95% CI 0.77 0.92), p=0.0003 11.7 9.8 K-M estimated rate (% per year) 10 5 Ticagrelor Clopidogrel HR 1.04 (95% CI 0.95 1.13), p=0.434 11.58 11.20 0 0 No. at risk Ticagrelor lopidogrel 0 2 4 6 8 10 12 Months 9,333 8,628 8,460 8,219 6,743 5,161 4,147 9,291 8,521 8,362 8,124 6,743 5,096 4,047 0 2 4 6 8 10 12 Months 9,235 7,246 6,826 6,545 5,129 3,783 3,433 9,186 7,305 6,930 6,670 5,209 3,841 3,479 Wallentin et al., New Eng J Med. 2009;361:1045 1057
Stent thrombosis (as per ARC definitions)* Ticagrelor (n=4,201) Clopidogrel (n=4,229) HR for ticagrelor (95% CI) p-value Definite 1.6 2.5 0.61 (0.42 0.87) 0.01 Probable or definite 2.5 3.6 0.69 (0.52 0.92) 0.01 Possible, probable, or definite 3.2 4.4 0.73 (0.56 0.94) 0.02 Time-at-risk is calculated from the date of first stent insertion in the study or date of randomization *Cutlip et. al., Circulation. 2007;115:2344 2351 By univariate Cox model
Total major bleeding K-M estimated rate (% per year) 12 11 10 9 8 7 6 5 4 3 2 1 0 9.0 NS 9.3 PLATO major bleeding 6.0 NS 6.4 TIMI major bleeding Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. New Eng J Med. 2007;357:2001 15; NS = not significant 7.3 NS 7.8 Transfusion Any blood product NS 4.5 4.9 PLATO lifethreatening/ fatal bleeding Ticagrelor Clopidogrel 0.3 NS 0.1 Fatal bleeding
Other findings All patients Ticagrelor (n=4,165) Clopidogrel (n=4,181) p-value * Dyspnoea, % Any 12.9 8.3 <0.0001 Requiring discontinuation of study treatment 0.5 0.1 0.0003 Bradycardia-related events, % Bradycardia 4.6 4.9 0.57 Pacemaker placement 1.2 1.0 0.35 Syncope 1.0 0.8 0.35 Heart block 1.0 0.9 0.82 * Fisher s exact test
Proposed Algorithm For Use of Different ADP Receptor Antagonists ACS Patients Non ACS patients No PCI PCI PCI No PCI Stroke or TIA No stroke : <60 kg or > 75 years. Yes No Ticagrelor Clopidogrel + ASA Ticagrelor Clopidogrel + ASA Ticagrelor Clopidogrel Prasugrel (if DM Prasugrel Ticagrelor Clopidogrel +ASA Clopidogrel + ASA Clopidogrel or ASA or prior STEMI) +ASA
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