Periprocedural antithrombotic therapy during PCI: Lessons from ISAR-REACT REACT 1234trials 1,2,3,4 Adnan Kastrati Deutsches Herzzentrum, Munich, Germany 1
First ISAR Trial 517 Patients Antiplatelet therapy Anticoagulant therapy 257 Pts 260 Pts Stent ISAR, NEJM 1996 30-day FU 2
First ISAR Trial Dual antiplatelet therapy vs. anticoagulant therapy Bleeding events Ischemic Events ASS+Ticlopidine ASS+Ticlopidine ISAR, NEJM 1996 3
The Difficult Balance Between Antiischemic and Pro Bleeding Effects 12,459 ISAR Patients Ndrepepa et al, Circulation 2012 4
Adjunct antithrombotic therapy during PCI 10 Year Experience: ~20,000 000 pts with CAD and PCI Ndrepepa et al, Cardiology 2009 ISAR-REACT 1 NEJM 2004 ADP-receptor antagonist loading 45% Stable AP 15% STEMI 16% NSTEMI Unstable AP 24% BRAVE 1 JAMA 2004 BRAVE 2 JAMA 2005, 2009 BRAVE 3 Circulation 2009 ISAR-REACT REACT 4 NEJM 2011 ISAR-REACT REACT 2 JAMA 2006 ISAR-REACT 3 NEJM 2008 5
Adjunct antithrombotic therapy during PCI ADP-receptor antagonist loading ISAR-REACT 1 NEJM 2004 45% Stable AP 16% NSTEMI Unstable AP 24% ISAR-REACT REACT 4 NEJM 2011 ISAR-REACT REACT 2 JAMA 2006 ISAR-REACT 3 NEJM 2008 All double blind, bli d placebocontrolled ll dti trials 6
Stable Angina ISAR REACT REACT (1) 2159 Patients pre treated with 600 mg clopidogrel Heparin+ Abciximab Double-blind Heparin+ Placebo 1079 Pts 1080 Pts PCI ISAR REACT, NEJM 2004 7
Death, MI, urg. TVR, % 5 Stable Angina ISAR REACT REACT (1) 4 4.2% 4.0% 3 2 1 0 Heparin+Abciximab i i b vs. Heparin+Placebo RR = 1.05 [95% CI, 0.69 1.59] 0 5 10 15 20 25 30 Days after randomization ISAR REACT, NEJM 2004 8
NSTE ACS ISAR REACT REACT 2 2022 patients with high riskacs Pre treated with 600 mg clopidogrel Abciximab Double-blind bli Placebo 1010 Pts 1012 Pts PCI ISAR REACT 2, JAMA 2006 9
Death/MI/UTVR, % 20 NSTE ACS ISAR REACT REACT 2 Trop(+) or NSTEMI: RR=0.71 [0.54-0.95] 15 10 Abciximab vs. Placebo 5 Trop(-) or Unstable Angina: RR=0.99 [0.56-1.76] 0 0 5 10 15 20 25 30 Days after randomization ISAR REACT 2, JAMA 2006 10
Stable and unstable angina ISAR REACT REACT 3 4,570 Patients pre treated with 600 mg clopidogrel Bivalirudin Double-blind Heparin 2,289 Pts 2,281 Pts PCI ISAR REACT 3, NEJM 2008 11
Stable and unstable angina ISAR REACT REACT 3 Death, MI, urg. TVR, major bleeding (%) 10 Heparin 8 Bivalirudin 6 4 2 RR=0.94 [95% CI, 0.77-1.15], P=0.57 0 0 5 10 15 20 25 30 Days after randomization ISAR REACT 3, NEJM 2008 12
Death, MI, urg. TVR (%) 10 Stable and unstable angina ISAR REACT REACT 3 8 6 4 Bivalirudin Heparin 5.9% 5.0% 2 RR=1.16 16 [95% CI, 0.91-1.49], 1 P=0.23 023 0 0 5 10 15 20 25 30 Days after randomization ISAR REACT 3, NEJM 2008 13
Stable and unstable angina ISAR REACT REACT 3 Bivalirudin Heparin Incidence (%) 12 % 10 P=0.008 P=0.0001 P=0.15 9.9 8 6 4 3.1 4.6 68 6.8 2 1.3 1.8 0 Major bleeding Minor bleeding Transfusion ISAR REACT 3, NEJM 2008 14
Incidence (%) 12 % 10 Stable and unstable angina ISAR REACT REACT 3&3A Reduced dose of UFH in 2505 pts 9.9 Bivalirudin Heparin Heparin red. dose 8 6 4.6 68 6.8 6.2 4 3.1 3.6 36 2 1.3 1.8 1 0 Major bleeding Minor bleeding Transfusion ISAR REACT 3A, Eur Heart J 2010 15
ISAR REACT 4 Trial flow chart 1,721 Pts with NSTEMI Pre treated with 600 mg of clopidogrel Double-blind (double-dummy dummy drug) 861 pts 860 pts Abciximab Bivalirudin Bolus of 0.25 mg/kg Infusion of 0.125 μg/kg/min for 12h Unfractionated heparin Bolus of 70 U/kg Bolus of 0.75 mg/kg Infusion of 1.75 mg/kg/hr for duration of PCI No PCI: 2 patients 2 patients 16
e Inciden nce (%) Cu umulativ 20 15 10 5 IR4: Primary endpoint Death, large MI, utvr, major bleeding Relative risk, 0.99 (95% CI, 0.74 1.32) P=0.94 09 Abciximab 10.9% Bivalirudin 11.0% 0 0 5 10 15 20 25 30 Days since Randomization ISAR REACT 4, NEJM 2011 17
Cu umulativ ve Inciden nce (%) 20 15 10 5 0 IR4: Secondary efficacy endpoint Death, any MI, utvr Relative risk, 0.96 (95% CI, 0.74 1.25) P076 P=0.76 Abciximab Bivalirudin Abciximab Bivalirudin Death, % 1.4 1.6 Any MI, % 12.0 11.4 utvr, % 0.8 1.3 0 5 10 15 20 25 30 Days since Randomization 12.8% 13.4% ISAR REACT 4, NEJM 2011 18
Cu umulativ ve Inciden nce (%) 20 15 10 5 IR4: Secondary safety endpoint Major bleeding Major bleeding Relative risk, 1.84 (95% CI, 1.10 3.07) P002 P=0.02 Abciximab 4.6% Bivalirudin 2.6% 0 0 5 10 15 20 25 30 Days since Randomization ISAR REACT 4, NEJM 2011 19
Major lessons from ISAR REACT 1,2,3&4 trials Early administration of an effective ADP receptor antagonist is of key importance in improving i the results of PCI Heparin without IIb/IIIa inhibitors is the most cost effective anticoagulant during elective PCI Bivalirudin is highly effective and the safest anticoagulant for PCI in patients with NSTEMI 20