ISAR-REACT 2: Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2

Luis Gruberg, MD, FACC

Disclosures

July 20, 2006

Editorial Collaboration

Medscape &

"Of interest, diabetic patients did not derive the benefit we expected from the combination of clopidogrel pretreatment and abciximab as was shown in other studies."

Presenter: Adnan Kastrati, MD (Deutsches Herzzentrum Munich, Germany)

The issue of adequate platelet inhibition in patients undergoing percutaneous coronary intervention (PCI) with stents has become more important than ever with the advent of drug-eluting stents. Furthermore, high-risk, acute coronary syndrome (ACS) patients may need more potent antiplatelet therapy because of enhanced platelet activation and aggregation compared with patients with stable coronary artery disease.

Previous studies have shown that pretreatment with 600 mg of clopidogrel may circumvent this limitation. However, there are no specifically designed studies to assess the value of the glycoprotein (GP) IIb/IIIa inhibitor, abciximab, in high-risk patients undergoing PCI after pretreatment with 600 mg of clopidogrel.

The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2)[1,2] trial was a randomized, multicenter, double-blind, placebo-controlled study designed to assess whether abciximab provides additional protective effects on top of those provided by a 600-mg loading dose of clopidogrel in high-risk patients with non-ST elevation ACS undergoing PCI.

Study Design Primary Efficacy Endpoint
  • Composite of death, myocardial infarction (MI), or urgent target vessel revascularization (TVR) within the first 30 days after PCI

Safety Endpoints
  • Major and minor in-hospital bleeding complications

  • Profound thrombocytopenia

  • Need for blood transfusions

Patients were treated with clopidogrel 600 mg at least 2 hours prior to the procedure. Aspirin and heparin (70 U/kg bolus) were administered in routine manner. Patients were then randomized to either abciximab (0.25-mg bolus followed by 0.125 mcg/kg/min for 12 hours) or to placebo with an additional 70 U/kg bolus of heparin followed by a 12-hour placebo infusion. Clopidogrel 75 mg twice daily was administered until discharge and then 75 mg daily for at least 4 weeks.

Inclusion Criteria
  • Rest angina episodes in the last 48 hours with either elevated troponin levels or ST-segment depression

Exclusion Criteria
  • ST-segment elevation MI

  • Hemodynamic instability

  • Pericarditis

  • Increased risk for bleeding

  • Known allergic reaction

  • Pregnancy

Results

A total of 2022 patients were enrolled in the study and randomized to abciximab (n = 1012) or placebo (n = 1010). All patients underwent PCI, 49% received a drug-eluting stent, 48% were treated with a bare-metal stent, and 3% of patients underwent plain balloon angioplasty. Baseline characteristics are shown in the following table.

Table 1. ISAR-REACT 2: Baseline Characteristics
Abciximab
(n = 1012)
Placebo
(n = 1010)
Age (yrs) 66 67
Male (%) 77 74
Diabetes (%) 25 28
Hypercholesterolemia (%) 62 60
Hypertension (%) 63 64
Current smoker (%) 23 22
Multivessel disease (5) 74 74
S/P MI (%) 24 24
S/P CABG (%) 10 11
Elevated troponin (%) 51 53
Culprit vessel
LAD (%) 42 40
LCx (%) 24 26
RCA (%) 28 26
LMCA (%) 2.4 2.2
Bypass graft (%) 4 5
Complex (B2-C) lesion (%) 80 81
DES (%) 50 49
Bare metal stent (%) 48 48
CABG = coronary artery bypass graft; DES = drug-eluting stent; LAD = left anterior descending; LCx = left circumflex; LMCA = left main coronary artery; MI = myocardial infarction; RCA = right coronary artery; S/P = status-post

The safety analysis was similar in both groups, with identical rates of major bleeding complications and similar minor bleeding complications (Figure 1). However, the incidence of the trial's primary endpoint (composite of death, MI, and urgent TVR at 30 days) was significantly higher in the placebo group compared with patients randomized to abciximab (11.9% vs 8.9%, respectively; P < .05). In addition, the rates of death/MI and MI were also significantly higher in the placebo group (Figure 2). According to subset analysis, troponin-negative and diabetic patients did not seem to derive any benefit from abciximab treatment.

Figure 1. ISAR-REACT 2: safety analysis.
Figure 2. ISAR-REACT 2: efficacy analysis.
Conclusions
  1. Abciximab reduces the risk of adverse events in high-risk ACS patients undergoing PCI after pretreatment with 600 mg of clopidogrel.

  2. The benefit provided by abciximab appears to be confined to patients presenting with an elevated troponin level.

Viewpoint

The ISAR studies are simple, well-designed trials that evaluated complex issues and yielded excellent quality of data. In ISAR-REACT 2, the investigators assessed GP IIb/IIIa inhibitor therapy in addition to a high loading dose of clopidogrel in patients with ACS undergoing PCI. There was a significant reduction in the primary combined endpoint of the study, mainly driven by a reduction in 30-day MI (definition was not presented) and almost no impact on mortality or urgent TVR. As always, this was achieved at the expense of higher rates of minor bleeding complications and thrombocytopenia. Of interest, diabetic patients did not derive the benefit we expected from the combination of clopidogrel pretreatment and abciximab as was shown in other studies. Further subgroup analysis, such as evaluation of the outcomes of patients treated with drug-eluting stents, will yield additional interesting observations.

References
  1. Kastrati A, Mehilli J, Neumann F-J, et al. Prospective, randomized, double blind, placebo controlled trial of glycoprotein IIb/IIIa inhibition with abciximab in patients with acute coronary syndromes undergoing stenting after pretreatment with a high loading dose of clopidogrel. Program and abstracts from the American College of Cardiology 55th Annual Scientific Session, March 11-14, 2006, Atlanta, Georgia. Abstract 411-10.

  2. Kastrati A, Mehilli J, Neumann F-J, et al; for the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) Trial Investigators. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA. 2006;295:1531-1538.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....