title: ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting.
abstract: BACKGROUND
  In patients receiving aspirin, the optimal duration of clopidogrel therapy after drug-eluting stent (DES) implantation remains unclear.
  
  
  METHODS
  This multicentre, randomized, double-blind, placebo-controlled trial tested the hypothesis that in patients undergoing DES implantation, 6 months of clopidogrel is non-inferior to 12 months in terms of clinical outcomes. At 6 months after DES implantation, patients on clopidogrel were randomly assigned to either a 6-month period of placebo or an additional 6-month period of clopidogrel. The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, and thrombolysis in myocardial infarction major bleeding at 9 months after randomization.
  
  
  RESULTS
  Owing to slow recruitment and low event rates, the trial was stopped prematurely after enrolment of 4005 of 6000 planned patients. Of 4000 patients included in the final analysis, 1997 received 6 months of clopidogrel and 2003 received 12 months. The primary endpoint occurred in 29 patients (1.5%) assigned to 6 months of clopidogrel and 32 patients (1.6%) assigned to 12 months, observed difference -0.1%, upper limit of one-sided 95% confidence interval (CI) 0.5%, limit of non-inferiority 2%, Pfor noninferiority <0.001. Stent thrombosis was observed in five patients (0.3%) assigned to 6 months of clopidogrel and three patients (0.2%) assigned to 12 months; hazard ratio (HR) 1.66, 95% CI: 0.40-6.96, P = 0.49. Thrombolysis in myocardial infarction major bleeding was observed in 4 patients (0.2%) assigned to 6 months clopidogrel and 5 patients (0.3%) assigned to 12 months; HR 0.80, 95% CI: 0.21-2.98, P = 0.74.
  
  
  CONCLUSIONS
  In the present trial, characterized by low event rates, we did not observe a significant difference in net clinical outcome between 6 and 12 months of clopidogrel therapy after DES implantation. However, the results of the trial must be considered in view of its premature termination and lower than expected event rates. The trial is registered with ClinicalTrials.gov, Identifier: NCT00661206.
authors.affiliation: ISAResearch Center, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany DZHK, Partner Site Munich Heart Alliance, Munich, Germany schulzs@dhm.mhn.de.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schulz-Schüpke
authors.affiliation: ISAResearch Center, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Byrne
authors.affiliation: St Antonius Hospital, Nieuwegein, Netherlands.
authors.forename: Jurrien M
authors.initials: JM
authors.lastname: Ten Berg
authors.affiliation: Universitäts-Herzzentrum Freiburg - Bad Krozingen, Bad Krozingen, Germany.
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Neumann
authors.affiliation: Shenyang Northern Hospital, Shenyang, China.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Han
authors.affiliation: University Hospital Leuven, Leuven, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Adriaenssens
authors.affiliation: Herzzentrum der Segeberger Kliniken Gruppe, Bad Segeberg, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Tölg
authors.affiliation: Helios Klinikum Wuppertal, Witten/Herdecke University, Wuppertal, Germany.
authors.forename: Melchior
authors.initials: M
authors.lastname: Seyfarth
authors.affiliation: Aarhus University Hospital, Aarhus N, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Maeng
authors.affiliation: Krankenhaus Landshut-Achdorf, Landshut, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zrenner
authors.affiliation: Universitätsklinikum Goettingen, Goettingen, Germany.
authors.forename: Claudius
authors.initials: C
authors.lastname: Jacobshagen
authors.affiliation: Klinikum Neuperlach, Muenchen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Mudra
authors.affiliation: MediClin Herzzentrum Lahr/Baden, Lahr, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: von Hodenberg
authors.affiliation: Universitaetsklinikum Ulm, Ulm, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Wöhrle
authors.affiliation: University of Florida College of Medicine-Jacksonville, Jacksonville, FL, USA.
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
authors.affiliation: ISAResearch Center, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: von Merzljak
authors.affiliation: ISAResearch Center, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany.
authors.forename: Nonglag
authors.initials: N
authors.lastname: Rifatov
authors.affiliation: ISAResearch Center, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kufner
authors.affiliation: ISAResearch Center, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Morath
authors.affiliation: ISAResearch Center, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany.
authors.forename: Antonia
authors.initials: A
authors.lastname: Feuchtenberger
authors.affiliation: 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Tareq
authors.initials: T
authors.lastname: Ibrahim
authors.affiliation: St Antonius Hospital, Nieuwegein, Netherlands.
authors.forename: Paul W A
authors.initials: PW
authors.lastname: Janssen
authors.affiliation: Universitäts-Herzzentrum Freiburg - Bad Krozingen, Bad Krozingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Valina
authors.affiliation: Shenyang Northern Hospital, Shenyang, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: University Hospital Leuven, Leuven, Belgium.
authors.forename: Walter
authors.initials: W
authors.lastname: Desmet
authors.affiliation: Herzzentrum der Segeberger Kliniken Gruppe, Bad Segeberg, Germany.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdel-Wahab
authors.affiliation: Helios Klinikum Wuppertal, Witten/Herdecke University, Wuppertal, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Tiroch
authors.affiliation: ISAResearch Center, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany DZHK, Partner Site Munich Heart Alliance, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.affiliation: 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Isabell
authors.initials: I
authors.lastname: Bernlochner
authors.affiliation: Universitätsklinikum Regensburg, Regensburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Fischer
authors.affiliation: ISAResearch Center, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany DZHK, Partner Site Munich Heart Alliance, Munich, Germany.
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.affiliation: DZHK, Partner Site Munich Heart Alliance, Munich, Germany 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Karl-Ludwig
authors.initials: KL
authors.lastname: Laugwitz
authors.affiliation: ISAResearch Center, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Schömig
authors.affiliation: DZHK, Partner Site Munich Heart Alliance, Munich, Germany Klinikum der Universität München; Medizinische Klinik I, Munich, Germany.
authors.forename: Julinda
authors.initials: J
authors.lastname: Mehilli
authors.affiliation: ISAResearch Center, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany DZHK, Partner Site Munich Heart Alliance, Munich, Germany.
authors.forename: Adnan
authors.initials: A
authors.lastname: Kastrati
mesh_terms: D000368:Aged; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000401:mortality / Q000628:therapy*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D054855:Drug-Eluting Stents; D005260:Female; D006083:Graft Occlusion, Vascular / Q000209:etiology / Q000401:mortality; D006470:Hemorrhage / Q000139:chemically induced / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology / Q000401:mortality; D062645:Percutaneous Coronary Intervention / Q000379:methods / Q000401:mortality; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D011475:Prosthesis Failure / Q000209:etiology; D020521:Stroke / Q000209:etiology / Q000401:mortality; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: Clopidogrel; Double-blind; Drug-eluting stent; Dual antiplatelet therapy; Randomized trial; Stent thrombosis