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Pharmacologic Options in the Invasive Management of Acute Coronary Syndrome

Pharmacologic Options in the Invasive Management of Acute Coronary Syndrome. Ross J. Goodfellow , DO FACC FSCAI Health First Medical Group Cape Canaveral Hospital /Holmes Regional Medical Center Cocoa Beach & Melbourne, Florida. Disclosures. Speaker Astra Zeneca Zoll Medical.

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Pharmacologic Options in the Invasive Management of Acute Coronary Syndrome

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  1. Pharmacologic Options in the Invasive Management of Acute Coronary Syndrome Ross J. Goodfellow, DO FACC FSCAI Health First Medical Group Cape Canaveral Hospital/Holmes Regional Medical Center Cocoa Beach & Melbourne,Florida

  2. Disclosures • Speaker • Astra Zeneca • Zoll Medical

  3. Acute Coronary Syndrome (UA, NSTEMI, STEMI) • 2014 • Majority of patients undergo invasive strategy (cardiac cath within 24-48 hrs) • FRISC-II, RITA, ICTUS • Meta-analysis demonstrated 19% RRR in CV Death or MI in patients managed with early invasive strategy

  4. Risk Stratification: TIMI Risk Score • Age 65 or older • 3 or more CAD risk factors • DM, Smoking, HTN, HDL<40mg/dl, FamHx of premature CAD • Known CAD • ASA use in past 7 days • 2 or more anginal episodes in 24 hours • ST changes > 0.5mV • Positive cardiac biomarkers

  5. ACS Pharmacology: Invasive Strategy • Decrease myocardial demand/increase supply • Beta Blockers, Nitrates, Calcium Channel Blockers • Analgesics • Morphine • Oral Antiplatelet Agents • ASA, Clopidogrel, Prasugrel, Ticagrelor • Intravenous Antiplatelet Agents • IIb/IIIa Antagonists (Abciximab, Eptifibitide, Tirofiban) • Anticoagulants • Heparin, Bivalirudin, LMWH (Enoxaparin, Dalteparin)

  6. ADP/TXA2 • mediated • platelet • adhesion • Fibrin • Thrombin Sites of action of antiplatelet and anticoagulant medications1 • ANGIOMAX • GP IIb/IIIa inhibitors • Aspirin and Thienopyridines • Heparin • LMWH • AT • Fibrinogen • AT • Vessel Injury • FactorXa • Prothrombin • Collagen • Platelet activation • Plasma clotting factors • Platelet aggregation • Tissue factor • Please see important safety information and bleeding definitions on slides 64 and 65. Please see accompanying full Prescribing Information. • 1. Monroe DM et al. Arterioscler Thromb Vasc Biol 2002;22:1381-9

  7. Enoxaparin v. UFH • Meta-analysis of all trials demonstrates a 10% reduction in death or MI with enoxaparin over UFH • No significant differences in major bleedings • Meta-analysis included conservatively managed patients • Largest trial of invasively treated patients (SYNERGY) showed increased bleeding with enoxaparin

  8. Oral Antiplatelet Agents • ADP-P2Y12 interaction • Amplifies platelet activation • P2Y12 receptor antagonists • Thienopyridines • Ticlopidine • Clopidogrel (PLAVIX) • Prasugrel (EFFIENT) • CPTP (Cyclopentyltriazolopyrimidine) • Ticagrelor (BRILINTA)

  9. CURE Trial • Unstable angina/NSTEMI • ASA + Clopidogrel (300mg load/75mgqd) v. ASA alone • N=12,562 • 20% RRR in CV Death, MI, and Stroke in Clopidogrel group • Driven by decreased nonfatal MI • PCI-CURE • Clopidogrel pre-treatment (6 days) pre-PCI associated with 31% RRR in primary endpoint

  10. PCI-CURE

  11. CURRENT-OASIS 7 • Rationale • Attempt to address high on-treatment platelet reactivity seen in 10-30% pts. • Double-dose clopidogrel load/maintenance dose x 7 days v. standard dose in ACS pts. • 2 x 2 design also assessing ASA dose

  12. 1o endpoint: CV death, MI, Stroke • 2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic • Double-blind • ACS (STEMI or UA/NSTEMI) & Planned PCI • PRASUGREL • 60 mg LD/ 10 mg MD • CLOPIDOGREL • 300 mg LD/ 75 mg MD • Median duration of therapy - 12 months Study Design • Wiviott SD et al AHJ 152: 627,2006 • N= 13,600 • ASA

  13. Enrollment Criteria • Inclusion Criteria Planned PCI for : Mod-High Risk UA/NSTEMI (TRS > 3) STEMI: < 14 days (ischemia or Rx strategy) STEMI: Primary PCI • Major Exclusion Criteria: • Severe comorbidity • Increased bleeding risk • Prior hemorrhagic stroke or any stroke < 3 mos • Any thienopyridine within 5 days • No exclusion for advanced age or renal function • KnownAnatomy • Wiviott SD et al AHJ 152: 627,2006

  14. Primary EndpointCV Death,MI,Stroke • 15 • Clopidogrel • 12.1(781) • 9.9 (643) • 10 • Prasugrel • Primary Endpoint (%) • HR 0.81(0.73-0.90)P=0.0004 • HR 0.80P=0.0003 • HR 0.77P=0.0001 • 5 • NNT= 46 • LTFU = 14 (0.1%) • ITT= 13,608 • 0 • 0 • 30 • 60 • 90 • 180 • 270 • 360 • 450 • Days • Wiviott SD et al NEJM 357: 2001, 2007

  15. Components of Endpoints • Clopidogrel • Prasugrel • HR • 0.81 • 12.1 • 9.9 • CV Death, MI, Stroke • 0.89 • 2.1 • 2.4 • CV Death • 0.76 • 9.5 • 7.3 • Nonfatal MI • 1.02 • 1.0 • 1.0 • Nonfatal Stroke • 0.95 • 3.2 • 3.0 • All Cause Mortality • 0.66 • 3.7 • 2.5 • uTVR • Stent Thrombosis • 2.4 • 1.1 • 0.48 • 0.5 • 1 • 2 • Prasugrel Better • Clopidogrel Better • HR • Wiviott SD et al NEJM 357: 2001, 2007

  16. Balance of Efficacy and Safety • 15 • 138 events • Clopidogrel • HR 0.81(0.73-0.90)P=0.0004 • 12.1 • CV Death / MI / Stroke • 9.9 • 10 • NNT = 46 • Prasugrel • Endpoint (%) • 5 • 35 events • TIMI Major NonCABG Bleeds • Prasugrel • 2.4 • HR 1.32(1.03-1.68)P=0.03 • 1.8 • Clopidogrel • 0 • NNH = 167 • 0 • 30 • 60 • 90 • 180 • 270 • 360 • 450 • Days • Wiviott SD et al NEJM 357: 2001, 2007

  17. Bleeding EventsSafety Cohort(N=13,457) • ICH in Pts w Prior Stroke/TIA (N=518) • Clopidogrel • Prasugrel • Clop 0 (0) %Pras 6 (2.3)% (P=0.02) • % Events • ARD 0.6%HR 1.32P=0.03NNH=167 • ARD 0.5%HR 1.52P=0.01 • ARD 0.2%P=0.23 • ARD 0.3%P=0.002 • ARD 0%P=0.74 • Wiviott SD et al NEJM 357: 2001, 2007

  18. Events per 1000 pts Net Clinical BenefitDeath, MI, Stroke, Major Bleed (non CABG) • + • 15 • Clopidogrel • 13.9 • ITT= 13,608 • Major Bleed(non CABG) • MI • 12.2 • HR 0.87P=0.004 • Prasugrel • 10 • Endpoint (%) • All CauseMortality • 5 • Clop 3.2%Pras 3.0 %P=0.64 • 0 • 0 • 30 • 60 • 90 • 180 • 270 • 360 • 450 • Days • Wiviott SD et al NEJM 357: 2001, 2007

  19. CV Death, MI, StrokeMajor Subgroups • Reduction in risk (%) • 18 • UA/NSTEMI • B • 21 • STEMI • 21 • Male • 12 • Female • 25 • <65 • 14 • Age • 65-74 • 6 • >75 • 14 • No DM • 30 • DM • 20 • BMS • 18 • DES • 21 • GPI • 16 • No GPI • 14 • CrCl < 60 • 20 • CrCl > 60 • Pinter = NS • 19 • OVERALL • 0.5 • 1 • 2 • Prasugrel Better • Clopidogrel Better • HR • Wiviott SD et al NEJM 357: 2001, 2007

  20. Net Clinical BenefitBleeding Risk Subgroups • Post-hoc analysis • Risk (%) • + 54 • Yes • Prior Stroke / TIA • -16 • No • Pint = 0.006 • -1 • >=75 • Age • -16 • Pint = 0.18 • < 75 • +3 • < 60 kg • Wgt • Pint = 0.36 • -14 • >=60 kg • -13 • OVERALL • 0.5 • 1 • 2 • Prasugrel Better • Clopidogrel Better • HR • Wiviott SD et al NEJM 357: 2001, 2007

  21. August 30, 2009 at 08.00 CET

  22. Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP) • H • O • N Ticagrelor (AZD 6140): an oral reversible P2Y12 antagonist • N • N • H • H • O • N • F • O • N • N • F • S • O • H • Direct acting • Not a prodrug; does not require metabolic activation • Rapid onset of inhibitory effect on the P2Y12 receptor • Greater inhibition of platelet aggregation than clopidogrel • Reversibly bound • Degree of inhibition reflects plasma concentration • Faster offset of effect than clopidogrel • Functional recovery of all circulating platelets

  23. 6–12-month exposure • Primary endpoint: CV death + MI + Stroke • Primary safety endpoint: Total major bleeding • 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) PLATO study design • NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) • Clopidogrel-treated or -naive; • randomised within 24 hours of index event • (N=18,624) • Ticagrelor • 180 mg loading dose, then • 90 mg bid maintenance; • (additional 90 mg pre-PCI) • PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack

  24. K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) • 13 • 12 • 11.7 • Clopidogrel • 11 • 10 • 9.8 • 9 • Ticagrelor • 8 • 7 • 6 • Cumulative incidence (%) • 5 • 4 • 3 • 2 • HR 0.84 (95% CI 0.77–0.92), p=0.0003 • 1 • 0 • 0 • 60 • 120 • 180 • 240 • 300 • 360 • Days after randomisation • No. at risk • Ticagrelor • 9,333 • 8,628 • 8,460 • 8,219 • 6,743 • 5,161 • 4,147 • Clopidogrel • 9,291 • 8,521 • 8,362 • 8,124 • 6,743 • 5,096 • 4,047 • K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

  25. Hierarchical testing major efficacy endpoints • The percentages are K-M estimates of the rate of the endpoint at 12 months.

  26. Secondary efficacy endpoints over time • Cardiovascular death • Myocardial infarction • 7 • 7 • 6.9 • Clopidogrel • 6 • 6 • 5.8 • Clopidogrel • 5.1 • 5 • 5 • Ticagrelor • 4.0 • 4 • 4 • Ticagrelor • 3 • Cumulative incidence (%) • Cumulative incidence (%) • 3 • 2 • 2 • 1 • 1 • HR 0.84 (95% CI 0.75–0.95), p=0.005 • HR 0.79 (95% CI 0.69–0.91), p=0.001 • 0 • 0 • 0 • 60 • 120 • 180 • 240 • 300 • 360 • 0 • 60 • 120 • 180 • 240 • 300 • 360 • Days after randomisation • Days after randomisation • No. at risk • 9,333 • 8,294 • 8,822 • 8,626 • 7119 • 5,482 • 4,419 • Ticagrelor • 9,333 • 8,678 • 8,520 • 8,279 • 6,796 • 5,210 • 4,191 • 9,291 • 8,865 • 8,780 • 8,589 • 7079 • 5,441 • 4,364 • Clopidogrel • 9,291 • 8,560 • 8,405 • 8,177 • 6,703 • 5,136 • 4,109

  27. Stent thrombosis • (evaluated in patients with any stent during the study) • *Time-at-risk is calculated from first stent insertion in the study or date of randomisation

  28. Time to major bleeding – primary safety event • 15 • Ticagrelor • 11.58 • 11.20 • 10 • Clopidogrel • K-M estimated rate (% per year) • 5 • HR 1.04 (95% CI 0.95–1.13), p=0.434 • 0 • 0 • 60 • 120 • 180 • 240 • 300 • 360 • Days from first IP dose • No. at risk • Ticagrelor • 9,235 • 7,246 • 6,826 • 6,545 • 5,129 • 3,783 • 3,433 • Clopidogrel • 9,186 • 7,305 • 6,930 • 6,670 • 5,209 • 3,841 • 3,479

  29. Total major bleeding • 13 • NS • Ticagrelor • Clopidogrel • 12 • 11.6 • 11.2 • 11 • NS • 10 • NS • 8.9 • 8.9 • 9 • 7.9 • 7.7 • 8 • NS • 7 • 5.8 • 5.8 • K-M estimated rate (% per year) • 6 • 5 • 4 • 3 • 2 • NS • 1 • 0.3 • 0.3 • 0 • PLATO major bleeding • TIMI major bleeding • Red cell transfusion* • PLATO life-threatening/fatal bleeding • Fatal 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. NEJM 2007;357:2001–15; *Proportion of patients (%); NS = not significant

  30. Non-CABG and CABG-related major bleeding • 9 • Ticagrelor • Clopidogrel • NS • 7.9 • 8 • 7.4 • 7 • NS • 5.8 • 6 • 5.3 • p=0.026 • 5 • K-M estimated rate (% per year) • 4.5 • 3.8 • 4 • p=0.025 • 2.8 • 3 • 2.2 • 2 • 1 • 0 • Non-CABGPLATO majorbleeding • Non-CABGTIMI major bleeding • CABGPLATO major bleeding • CABG TIMI major bleeding

  31. Holter monitoring & Bradycardia related events

  32. Other findings • *p values were calculated using Fischer’s exact test

  33. Ticagrelor is a more effective alternative than clopidogrel • for the continuous prevention of ischaemic events, stent thrombosis and death in the acute and long-term treatment of patients with ACS Conclusions • Reversible, more intense P2Y12 receptor inhibition for one year with ticagrelor in comparison with clopidogrel in a broad population with ST- and non-ST-elevation ACS provides • Reduction in myocardial infarction and stent thrombosis • Reduction in cardiovascular and total mortality • No change in the overall risk of major bleeding

  34. IIb/IIIa Antagonists • Inhibit >80% of platelet aggregration • Early studies demonstrated short and long term event reduction in ACS patients compared with heparin alone • Driven by reduction in peri-procedural MI • Increased bleeding • Recent Trials • ISAR-REACT 2, EARLY ACS, ACUITY

  35. ACUITY Study Design – First Randomization • UFH/Enox • + GP IIb/IIIa • (n=4,603) • Bivalirudin • + GP IIb/IIIa • (n=4,604) • Bivalirudin • Alone† • (n=4,612) • CABG • Medical • management • Moderate- • and high- • Risk ACS • (n=13,819) • PCI • Moderate- and high-risk unstable angina or NSTEMI undergoing an early invasive strategy (N=13,819) • Angiography within 72h • R* • Aspirin in all • clopidogrel; • dosing and timing • per local practice • *Stratified by pre-angiography thienopyridine use or administration • †ANGIOMAX alone (with GP IIb/IIIa inhibition reserved for severe breakthrough ischemia and procedural complications during PCI) • The safety and effectiveness of ANGIOMAX have not been established in patients with acute coronary syndromes (ACS) who are not undergoing PTCA or PCI. • Stone GW et al. N Engl J Med. 2006;355:2203-2216 • 11

  36. Overall ACUITY Management Strategy (N=13,819) • Bivalirudin + GP IIb/IIIa • N = 2,609 • UFH/Enox + GP IIb/IIIa • N = 2,561 • Bivalirudin alone • N = 2,619 • Medical Rx (n=4,491) • CABG (n=1,539) • 32.5% • 11.1% • 56.4% • PCI (n=7,789) • Stone GW et al. N Engl J Med. 2006;355:2203-2216 • 12

  37. P=.32 • P<.001 • P=.16 • P=.45 • P=.10 Primary Results – 30 Days • P=.057 • UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone • Stone GW et al. Lancet. 2007;369:907-919. • Please refer to important ANGIOMAX safety information on slide 28 and see full Prescribing Information • 16

  38. 30-day • Estimate • 1-year Early and Late Mortality • P • (log rank) • P • (log rank) • Estimate • 3.1% • — • UFH/Enoxaparin + IIb/IIIa • 0.9% • — • 0.70 • 2.4% • 0.45 • Bivalirudin + IIb/IIIa • 1.2% • 0.48 • 2.2% • 0.63 • Bivalirudin alone • 1.1% • UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone • p=0.78 • Mortality (%) • Days from Randomization • Data on file, The Medicines Company, Parsippany, NJ. • Please refer to important ANGIOMAX safety information on slide 28 and see full Prescribing Information • 19

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