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Interventional Pharmacology: The Basics

Interventional Pharmacology: The Basics. Michael J. Cowley, FACC,FSCAI. Nothing to Disclose. Interventional Pharmacology. Heparin (UFH) GP IIb/IIIa Receptor Antagonists Low Molecular Weight Heparins Direct Thrombin Inhibitors Thienopyridines . Adjunctive Therapy for ACS / PCI.

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Interventional Pharmacology: The Basics

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  1. Interventional Pharmacology:The Basics Michael J. Cowley, FACC,FSCAI Nothing to Disclose

  2. Interventional Pharmacology • Heparin (UFH) • GP IIb/IIIa Receptor Antagonists • Low Molecular Weight Heparins • Direct Thrombin Inhibitors • Thienopyridines

  3. Adjunctive Therapy for ACS / PCI Anti Thrombins GP 2b3a Agents Abciximab Eptifibatide Tirofiban Heparin LMWH Bivalirudin + Clopidogrel pre-treatment how early? how much?

  4. Interventional Pharmacology Beneficial Agents UFH: Clinical Experience, Non-inferiority GP2b3a: Numerous studies (vs UFH alone) LMWH: ESSENCE, TIMI 11, INTERACT SYNERGY, STEEPLE Clopdiogrel: CURE, PCI-CURE, CREDO Bivalirudin: BAT, REPLACE 2, ACUITY

  5. Interventional Pharmacology

  6. Unfractionated Heparin

  7. Unfractionated Heparin Advantages Disadvantages • Multiple sites of action in coagulation cascade (IIa,Xa) • Long history of successful clinical use • Readily monitored by aPTT and ACT • Very inexpensive • Indirect thrombin inhibitor (does not inhibit clot-bound thrombin) • Nonspecific binding to: • Plasma proteins • Endothelial cells (variable anticoagulation level) • Inhibited by platelet factor 4 • reduced effect in ACS • Causes platelet aggregation • Risk of HIT Hirsh J, et al. Circulation. 2001;103:2994-3018

  8. ACC/AHA/SCAI PCI Guidelines Unfractionated Heparin • UFH should be given to pts under-going PCI (Level of Evidence: C) Class I:

  9. GP IIb / IIIa Receptor Antagonists

  10. GP IIb/IIIa Receptor Inhibition STEMI PCI ACSLysisPCI EPIC CAPTURE SPEED RAPPORT EPILOG PRISM TIMI 14 ADMIRAL RESTORE PRISM PLUS GUSTO 5 ISAR 2 IMPACT PURSUIT ASSENT 3 CADILLAC IMPACT 2 GUSTO 4 Impact AMI ACE EPISTENT ESPRIT TARGET

  11. GPIIb/IIIa Antagonists in PCI 30 Day Death / MI Trial N Placebo IIb/IIIa Risk Ratio & 95% CI EPIC 9.6% 6.6% 2,099 IMPACT-II 8.5% 7.0% 4,010 EPILOG 9.1% 4.0% 2,792 CAPTURE 9.0% 4.8% 1,265 6.3% 5.1% RESTORE 2,141 10.2% 5.2% EPISTENT 2,399 ESPRIT 10.2% 6.3% 2,064 0.62 (0.55, 0.71) p < 0.000000001 8.8% 5.6% Pooled 16,770 0 0.5 1 1.5 2 IIb/IIIa Antag Better Placebo Better

  12. Abciximab in PCI: Complex Lesions 30 day Events (D, MI, uTVR): EPIC and EPILOG % p=.047 p=.001 p=.001 p=.001 p=.078 p=.001 p=.001 p=.001 p=.001 365 452 761 961 380 799 2994 2312 1896 Ellis: JACC 1998; 32:1619

  13. Abciximab for Complex Lesions: EPISTENT 30 day D, MI, uTVR % p=0.17 p<0.001 230 267 517 468

  14. GP IIb/IIIa in Acute MI Abciximab PCI in Acute MI Trials 30 Day Endpoint (D, Re-MI, Urg TVR) % p<0.05 p=0.005 p=0.038 p=0.023 p=0.01 Stent N = 401 Stent N = 301 PTCA or Stent N = 2082 Stent N = 400 PTCA N = 483

  15. Anti-Platelet Therapy

  16. ASA in UA/NSTEMI Death or MI *p = .0005 *p = .012 *p = .008 * p<.0001 20 15 12 15 17.1 12.9 10.1 11.9 15 10 8 10 5.0* 6.2* Patients (%) 10 6.5* 4 5 5 3.3* 5 0 0 0 0 Placebo279 ASA276 Placebo118 ASA121 Placebo397 ASA399 Placebo 158 ASA 178 Cairns JA: NEJM 1985313:1369-1375 Lewis HD Jr: NEJM 1983309:396-403 Theroux P: NEJM 1988319:1105-1111 The RISC Group: Lancet 1990336:827-830

  17. 20% Relative RiskReduction 0.14 Placebo + Aspirin * (n=6303) 0.12 0.10 0.08 Clopidogrel + Aspirin * (n=6259) Cumulative Hazard Rate p < 0.001 N=12,562 0.06 0.04 0.02 0.00 0 3 6 9 12 Months of Follow-up CURE Primary End Point: MI/Stroke/CV Death * In addition to other standard therapies Yusuf S: N Engl J Med 2001;345:494-502

  18. PCI- CURE PCI Substudy 0.10 N = 2,658 Placebo 0.08 0.06 Clopidogrel Cumulative Hazard Rates 0.04 31% RRR p = 0.002 0.02 0.00 0 100 200 300 400 Days of Follow-Up The CURE Investigators: Lancet August 2001

  19. CREDO: 1 Year Primary Outcome Death, MI or Stroke 15 Placebo N=1063 % 11.5% 10 8.5% Clopidogrel N=1053 5 27% RRR p = 0.02 0 0 3 6 9 12 Months

  20. Circulation 2005; 112:2946-2950

  21. ISAR-CHOICE Platelet Aggregation 4h after Clopidogrel Loading 5 µmol/L ADP 20 µmol/L ADP B A p = 0.001 p = 0.001 120 100 80 60 40 20 0 120 100 80 60 40 20 0 ADP (20 µmol/L)-Induced Aggregation (%) ADP (5 µmol/L)-Induced Aggregation (%) p = .01 p = .59 p = 0.01 p = .59 300 mg 600 mg 900 mg 300 mg 600 mg 900 mg n = 20 n = 20 n = 20 n = 20 n = 20 n = 20 Circles represent single measurements; bars denote mean ± SD von Beckerath N, et al: Circulation 2005;112:2946-2950

  22. ARMYDA-2 Trial Primary Endpoint: death, MI, or TVR at 30 days 255 patients with stable CAD or NSTEMI prior to PCI 13% GP IIb/IIIa inhibitors 20% DES 14% 12% 12% p=0.041 Randomized 4-8 hrs Pre-PCI 10% 8% 6% Clopidogrel Loading Dose 600 mg Pre-PCI Clopidogrel Loading Dose 300 mg Pre-PCI 4% 4% 2% 0% High Dose Standard Dose Patti G et al:. Circulation 2005;111:2099-2106

  23. CREDO Study: Timing of Loading Dose and 28-Day Endpoint Timing N Pretreat No Pretreat 3–<6 h 893 7.9 7.0 ≥6–24h 851 5.8 9.4 RRR: –13.4% p=0.60 RRR: 38.6% p=0.05 RRR: 18.5% P=.23 CREDO Overall 0.4 0.6 0.8 1.0 1.2 Hazard Ratio (95% CI) Steinhubl SR, et al: JAMA.2002;288:2411-2420

  24. Clopidogrel with PCI Summary • Pre-treatment effective if started > 6 hr before PCI • No advantage to load dose >600 mg • Beneficial effects evident out to 1 yr • Optimal duration with DES unknown

  25. LMWH with PCI

  26. Advantages of LMWH vs UFH • No platelet activation • Inhibits von Willebrand factor release • Augments TFPI release • Inhibits thrombin generation • No rebound hypercoagulability

  27. Enoxaparin in the Cath Lab Transition to Cath Lab In Cath Lab NICE 1 NICE 4 ELECT Choussat Carnendran STEEPLE Collet PEPCI PK study NICE 3 SYNERGY

  28. LMWH vs UFH in PCI Trials Pooled Results (15 studies) Borentain, Montalescot: ESC 2003

  29. Enoxaparin in PCI Trials Pooled Results Borentain, Montalescot: ESC 2003

  30. STEEPLE Trial 3528 pts with non-emergent single or multi-vessel PCI ACT – adjusted UFH Target ACT 200-300 With GP IIb/IIIa Target ACT 300-350 if no GP IIb/IIIa n=1230 IV enoxaparin 0.75 mg/kg n=1228 IV enoxaparin 0.5 mg/kg n=1070 Primary Endpoint: Major / minor bleeding (non-CABG) at 48 hrs post-PCI Secondary Endpoints: - Percent reaching target anticoagulation levels at start and end of PCI - Composite of major bleed (48 hrs), mortality, MI, Urg TVR at 30 days Montalescot: NEJM 2006;355:1006-1017

  31. STEEPLE Trial: Primary Endpoint Non-CABG Major or Minor Bleeding at 48 hrs p=0.052 vs UFH p=0.014 vs UFH Lower bleeding rate was observed overall and in the GP IIb/IIIa subgroup Montalescot: NEJM 2006;355:1006-1017

  32. STEEPLE Trial Analysis of Major Bleeding p=0.007 vs UFH p=0.005 vs UFH 57% lower with Enoxaparin Montalescot: NEJM 2006;355:1006-1017

  33. STEEPLE Trial: Secondary Endpoint Patients reaching target anticoagulation levels at the start and end of procedure p<0.001 vs Enox Montalescot: NEJM 2006;355:1006-1017

  34. STEEPLE Trial Summary • Reduced dose enoxaparin had less major or minor bleeding at 48 hrs than UFH • Lower dose IV enoxaparin for PCI offers a safety advantage over ACT-guided UFH

  35. Superior Yield of the New strategy of Enoxaparin, Revascularization & GlYcoprotein IIb/IIIa Inhibitors • 10,027 ACS patients with 2 out of 3 high-risk criteria: • Age > 60 • (+) biomarkers • (+) ECG s • Randomized to enoxaparin vs UFH • Invasive management strategy • GP IIb/IIIa antagonists encouraged • Primary endpoint : Death / MI at 30 days The Synergy Investigators: JAMA 2004; 292: 45-54

  36. SYNERGY Efficacy at 30 days % p=0.396 p=0.135 p=0.705 The Synergy Investigators: JAMA 2004; 292: 45-54

  37. SYNERGYOutcomes with Consistent Therapy* p=0.0039 RRR = 16.4% p=0.0029 RRR = 17.9% % p=ns p=ns n=3398 n=2740 n=3010 n=2627 Intent-to-treat Per Protocol * Consistent therapy = no pre-randomized therapy, or randomized to the same therapy they had been receiving The Synergy Investigators: JAMA 2004; 292: 45-54

  38. Bivalirudin

  39. Direct Thrombin Inhibitors Advantages Disadvantages • Predictable anticoagulant response • Inhibits soluble and fibrin-bound thrombin • Inhibits thrombin-induced platelet aggregation • No HIT • Needs continuous infusion • No antidote • Cost Xiao Z, Theroux P: Circulation 1998;97:251-256

  40. Direct Thrombin Inhibitors Bivalirudin REPLACE – 2 ACUITY

  41. REPLACE - 2 Primary Endpoint % p=0.324 p=0.43 p<0.001 p=0.255 p=0.435

  42. REPLACE - 2 Outcomes % p<0.001 p=ns p=ns p=ns p=ns cytopenia

  43. REPLACE - 2 Conclusions • Non-inferior to heparin + GP 2b3a receptor inhibitors • Superior to heparin • Reduced bleeding, transfusion, and thrombocytopenia • Reduced time of treatment

  44. Medical management UFH or enox+ GP IIb/IIIan=4603 PCI Bivalirudin + GP IIb/IIIan=4604 Angiography within 72 h R* Bivalirudin alonen=4,612 CABG ACUITY Study Design:First Randomization Moderate- to high-risk patients with UA or NSTEMIundergoing an invasive strategy (N = 13,819) Moderate-to high- risk ACS Aspirin in all; Clopidogrel dosing and timing per local practice *Stratified by pre-angiography thienopyridine treatment Stone GW, et al: Am Heart J 2004; 148:764–775

  45. ACUITY: Primary End Point Measures* UFH/Enoxaparin + GP IIb/IIIa vs Bivalirudin + GP IIb/IIIa P value(noninferior)(superior) UFH/Enox + IIb/IIIa Primary end point Risk ratio ±95% CI Bival + IIb/IIIa RR (95% CI) <.001 .93 Net clinical outcome 11.8% 11.7% 1.01 (0.90-1.12) .015 .39 Ischemic composite Upper boundary non-inferiority 7.7% 7.3% 1.07 (0.92-1.23) <.001 .38 Major bleeding 5.3% 5.7% 0.93 (0.78-1.10) *ITT population Bivalirudin + GP IIb/IIIa better UFH/Enox + GP IIb/IIIa better Stone GW, et al: Presented at: 55th ACC Annual Meeting March 2006

  46. ACUITY: Primary End Point Measures* UFH/Enoxaparin + GP IIb/IIIa vs Bivalirudin alone P value(noninferior)(superior) UFH/Enox + IIb/IIIa Primary end point Risk ratio ±95% CI Bival alone RR (95% CI) <.001 .015 Net clinical outcome 10.1% 11.7% 0.86 (0.77-0.97) .02 .32 Ischemic composite 7.8% 7.3% 1.08 (0.93-1.24) Upper boundary non-inferiority <.001 <.001 Major bleeding 3.0% 5.7% 0.53 (0.43-0.65) *ITT population Bivalirudin alone better UFH/Enox + IIb/IIIa better Stone GW et al: Presented at: 55th ACC Annual Meeting March 2006

  47. ACUITY-PCINet Clinical Outcomes % 15 p=0.001 10 Estimate p(log rank) Heparin* + IIb/IIIa (N=2561) 13.5% 5 Bivalirudin + IIb/IIIa (N=2609) 15.1% 0.10 Bivalirudin alone (N=2619) 11.7% 0.049 0 0 5 10 15 20 25 30 35 Days from Randomization Stone GW: Presented at TCT; October 2006

  48. ACUITY- PCIComposite Ischemia p (log rank) % Estimate Heparin* + IIb/IIIa (N=2561) 8.4% 15 Bivalirudin + IIb/IIIa (N=2609) 9.4% 0.15 Bivalirudin alone (N=2619) 0.45 8.9% 10 p=0.36 5 0 0 5 10 15 20 25 30 35 Days from Randomization Stone GW. Presented at TCT; October 2006

  49. Anti-Thrombins for PCI Summary • UFH is effective for PCI, especially when used with GP2b3a inhibition • LMWH (enoxaparin) is safe and effective with PCI • Bivalirudin is superior to heparin and non-inferior to heparin + GP 2b3a Rx

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