ISAR-REACT 3A: a study of reduced dose of unfractionated heparin in biomarker negative patients undergoing percutaneous coronary intervention.
OBJECTIVE
Although a 140 U/kg dose of unfractionated heparin (UFH) was comparable with bivalirudin in terms of net clinical outcome in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 3 trial, it was associated with a higher risk of bleeding. We designed this study to assess whether a reduction in the UFH dose from 140 to 100 U/kg is associated with improved net clinical outcome.


RESULTS
A total of 2505 biomarker negative patients undergoing percutaneous coronary intervention (PCI) after clopidogrel pre-treatment received a single bolus of 100 U/kg UFH. The primary endpoint was net clinical outcome-a quadruple endpoint of death, myocardial infarction, urgent target-vessel revascularization within 30 days, or in-hospital REPLACE 2 defined major bleeding. The primary comparison was with the historical UFH group of ISAR-REACT 3 (2281 patients). In a second analysis, we checked for non-inferiority against the historical bivalirudin arm of ISAR-REACT 3 (2289 patients). The incidence of the primary endpoint was 7.3% in the lower UFH dose group compared with 8.7% in the higher UFH dose group [hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.67-1.00; P = 0.045]. The incidence of major bleeding was 3.6% in the lower UFH dose group and 4.6% in the higher UFH dose group (HR 0.79; 95% CI 0.59-1.05; P = 0.11). The lower UFH dose met the criterion of non-inferiority compared with bivalirudin (P < 0.001).


CONCLUSIONS
In biomarker negative patients undergoing PCI after clopidogrel loading, a reduced dose of 100 U/kg UFH provided net clinical benefit compared with the historical control of 140 U/kg UFH in the ISAR-REACT 3 trial. The benefit was mostly driven by reduction in bleeding.


BACKGROUND
URL www.clinicaltrials.gov; Unique identifier NCT00735280.
Schulz
Stefanie
S
Deutsches Herzzentrum München, Technische Universität, Lazarettstr. 36, 80636 Munich, Germany. schulzs@dhm.mhn.de
Mehilli
Julinda
J
Neumann
Franz-Josef
FJ
Schuster
Tibor
T
Massberg
Steffen
S
Valina
Christian
C
Seyfarth
Melchior
M
Pache
Jürgen
J
Laugwitz
Karl-Ludwig
KL
Büttner
Hans-Joachim
HJ
Ndrepepa
Gjin
G
Schömig
Albert
A
Kastrati
Adnan
A
D000368:Aged; D000787:Angina Pectoris / Q000628:therapy*; D015906:Angioplasty, Balloon, Coronary; D000925:Anticoagulants / Q000008:administration & dosage*; D015415:Biomarkers; D000077144:Clopidogrel; D016757:Death, Sudden, Cardiac / Q000517:prevention & control; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006493:Heparin / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000517:prevention & control; D009204:Myocardial Revascularization; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage; D019106:Postoperative Hemorrhage / Q000517:prevention & control; D011446:Prospective Studies; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D016896:Treatment Outcome
D000925:Anticoagulants; D015415:Biomarkers; D010975:Platelet Aggregation Inhibitors; D006493:Heparin; D000077144:Clopidogrel; D013988:Ticlopidine