Intracoronary Stenting and Antithrombotic Regimen: Safety and Efficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting - ISAR-SAFE

Mar 05, 2015
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Deutsches Herzzentrum Muenchen
Date Presented:
11/16/2014
Date Published:
01/23/2015
Date Updated:
03/05/2015
Original Posted Date:
11/16/2014
References

Description:

Current guidelines recommend that dual antiplatelet therapy (DAPT) with aspirin and an ADP receptor inhibitor be continued for a minimum of 12 months following drug-eluting stent (DES) percutaneous coronary intervention (PCI). The optimal duration, however, remains unclear. This trial sought to investigate if 6 months of DAPT was superior to 12 months in patients undergoing DES PCI.

Contribution to the Literature: The ISAR-SAFE trial showed that 6 months of DAPT may be noninferior to 12 months of DAPT in patients undergoing DES PCI, with a trend toward lower bleeding.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Patients on clopidogrel at 6 months after DES implantation
  • Number of enrollees: 4,000
  • Duration of follow-up: 15 months following initial screening
  • Mean patient age: 67.2 years
  • Percentage female: 19%
  • Ejection fraction: Reduced left ventricular ejection fraction in 25%

Exclusions:

  • Clinical symptoms or signs of ischemia and/or angiographic lesions requiring revascularization
  • Active bleeding; bleeding diathesis; history of intracranial bleeding
  • STEMI and NSTEMI during the last 6 months after DES
  • Previous stent thrombosis
  • DES in left main coronary artery at index intervention
  • Oral anticoagulation
  • Planned major surgery within the next 6 months with a need to discontinue antiplatelet therapy

Primary Endpoints:

  • Composite of death, MI, stent thrombosis, stroke, or TIMI major bleeding at 9 months after randomization (15 months after index DES implantation)

Secondary Endpoints:

  • All-cause mortality at 9 months (15 months after index DES implantation)
  • MI at 9 months (15 months after index DES implantation)
  • Stent thrombosis at 9 months (15 months after index DES implantation)
  • Stroke at 9 months (15 months after index DES implantation)
  • TIMI major bleeding at 9 months (15 months after index DES implantation)

Drug/Procedures Used:

Patients with DES PCI received 6 months of open-label DAPT with aspirin and clopidogrel. At 6 months, they were randomized in a 1:1 fashion to receive an additional 6 months of DAPT or aspirin alone.

Principal Findings:

The trial was terminated early due to a lower than anticipated event rate. At this time, a total of 4,000 patients were randomized, 2,003 to 12 months of DAPT and 1,997 to 6 months of therapy. Baseline characteristics were fairly similar between the two arms. Approximately 24% had diabetes mellitus and 15% were smokers. Indication for PCI was stable angina in 48%, ST-segment elevation myocardial infarction (STEMI) in 8% and NSTE-acute coronary syndrome (NSTE-ACS) in 32%. Multivessel disease was observed in 62%, with the target vessl being left anterior descending in 40% and right coronary artery in 33%. The mean number of lesions treated was 1.7, with approximately 1.45 stents/patient. Reference vessel diameter was 3.0 mm. Stent type was everolimus-eluting stent (EES) in 49%, zotarolimus-eluting stent (ZES) in 15%, biolimus in 8%, newer-generation sirolimus-eluting stent (SES) in 16% and bare-metal stent (BMS) in 0.4%.

The primary major adverse cardiac event (MACE) endpoint was similar between the 6- and 12-month DAPT arms (1.5% vs. 1.6%, p for noninferiority < 0.001). The composite of death, MI, stroke, and stent thrombosis was also similar (1.3% vs. 1.5%, p = 0.59). Individual endpoints including mortality (0.4% vs. 0.6%, p = 0.37), MI (0.7% vs. 0.7%, p = 0.85), stent thrombosis (0.3% vs. 0.2%, p = 0.74), and stroke (0.4% vs. 0.3%, p = 0.57) were similar between the two arms, respectively. TIMI major or minor bleeding was numerically lower with 6 months of DAPT (0.3% vs. 0.7%, p = 0.12), wherease BARC ≥class 2 bleeding was significantly reduced (1% vs. 2%, p = 0.01).

Interpretation:

The results of the ISAR-SAFE trial indicate that 6 months of DAPT may be noninferior to 12 months of DAPT in patients undergoing DES PCI, with a trend toward lower bleeding. However, this trial had to be terminated early due to a significantly lower event rate than anticipated (actual: 1.6%; anticipated: 10%); thus, the results must be viewed within this context.

Following concerns regarding late and very late stent thrombosis with first-generation DES, American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommended a minimum duration of 12 months of DAPT following DES PCI. However, the optimal duration remains unknown and trials have sought to study both sides of the duration spectrum. Trials assessing shorter durations include PRODIGY, RESET, OPTIMIZE, and now ISAR-SAFE. At least 50% of patients in these trials received a second-generation DES, and the majority of patients in these trials were low-risk (PCI for non-ACS indication).

Since none of these trials were individually powered to demonstrate a difference, it may be best to follow current DAPT guidelines (12 months) for all patients undergoing DES-PCI at this time, with the knowledge that if a low-risk patient with a second-generation DES requires premature DAPT cessation at 3-6 months (for example, need for noncardiac surgery), the outcome may not be significantly different than if the patient had completed 12 months of DAPT.

References:

Schulz-Schüpke S, Byrne RA, Ten Berg JM, et al., on behalf of the Intracoronary Stenting and Antithrombotic Regimen: Safety And EFficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) Trial Investigators. ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 versus 12 months of clopidogrel therapy after drug-eluting stenting. Eur Heart J 2015;Jan 23:[Epub ahead of print].

Presented by Dr. Stefanie Schüpke at the American Heart Association Scientific Sessions, Chicago, IL, November 16, 2014.

 

Keywords: Myocardial Infarction, Stroke, Acute Coronary Syndrome, Follow-Up Studies, Receptors, Purinergic P2, Angina, Stable, Drug-Eluting Stents, Ticlopidine, American Heart Association, Sirolimus, Aspirin, Stents, Percutaneous Coronary Intervention, Thrombosis, Stroke Volume, Coronary Vessels, Diabetes Mellitus, AHA Annual Scientific Sessions


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