Is There A LIfe for DES after discontinuation of Clopidogrel - ITALIC

Feb 16, 2018
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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:
Abbott Vascular Devices, Santa Clara, CA
Date Presented:
11/16/2014
Date Published:
06/19/2017
Date Updated:
02/16/2018
Original Posted Date:
11/16/2014
References

Contribution To Literature:

The ITALIC trial indicates that shorter durations of DAPT (6 months) are noninferior to prolonged durations of DAPT in patients undergoing DES PCI.

Description:

Current American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommend that dual antiplatelet therapy (DAPT) with aspirin and an ADP receptor antagonist 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 would be noninferior to 24 months in patients undergoing everolimus-eluting stent (EES) PCI.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Patients ages 18 years or over
  • Eligible for PCI with at least one Xience V DES implanted
  • Aspirin nonresistant
  • Pretreatment with aspirin + ADP receptor antagonist

    Number of screened applicants: 2,031
    Number of enrollees: 1,850
    Duration of follow-up: 1 year; 2 years 
    Mean patient age: 61.6 years
    Percentage female: 20%
    Ejection fraction: >50% in 54%, 31-50% in 17%

Exclusions:

  • PCI for acute MI
  • Left main trunk PCI
  • Use of abciximab during index PCI
  • Known platelet level <100,000/μl or known hemorrhagic diathesis
  • Oral anticoagulation therapy
  • Contraindications to aspirin or clopidogrel (prasugrel or ticagrelor)
  • Evidence of active gastrointestinal or urogenital bleeding
  • Severe liver failure; any surgery scheduled during the year after enrollment
  • Severe concomitant disease with <2 years’ life expectancy
  • Prior DES implantation within 1 year

Primary Endpoints:

  • Death, MI, emergency TVR, stroke or TIMI major bleeding at 12 months

Secondary Endpoints:

  • Death, MI, emergency TVR, stroke, or TIMI major bleeding at 24 months
  • Death, MI, emergency TVR, stroke, or TIMI major bleeding at 36 months
  • TIMI major bleeding at 12 months
  • TIMI minor bleeding at 12 months

Drug/Procedures Used:

Patients undergoing Xience V implantation and who were aspirin responsive were randomized in a 1:1 fashion to either 6 or 24 months of DAPT. Clopidogrel was the ADP receptor inhibitor of choice in 98.7% of patients.

Concomitant Medications:

Aspirin 75-325 mg

Principal Findings:

The trial was prematurely terminated due to slow recruitment. A total of 1,850 patients were randomized; 926 to 6 months of DAPT and 924 to 24 months. Baseline characteristics were fairly similar between the two arms. Approximately 37% had diabetes mellitus and 52% were smokers. Indication for PCI was stable angina in 41% and non–ST-segment elevation acute coronary syndrome (NSTE-ACS) in 23%. The vessel treated was left anterior descending in 73% and right coronary artery in 53%; nearly a third of patients had multivessel PCI. In the 6-month duration arm, 8.9% took DAPT for longer durations and 24.2% overall did not follow the prescribed 6-month duration. In the 24-month DAPT arm, 5.4% prematurely discontinued DAPT.

The primary major adverse cardiac event (MACE) was similar between the short- and long-term duration DAPT arms (1.5% vs. 1.6%, p for noninferiority = 0.0002, p for superiority = 0.85). Individual endpoints including all-cause mortality (0.9% vs. 0.8%, p = 0.8), MI (0.7% vs. 0.4%, p = 0.53), target vessel revascularization (0.5% vs. 0.2%, p = 0.27), and stent thrombosis (0.3% vs. 0%, p > 0.05) were all similar between the two arms. Major (0 vs. 0.3%) and minor (0.5% vs. 0.4%) bleeding were similar between the two arms as well.

Two-year results: MACE for short-term vs. long-term DAPT: 3.5% vs. 4.2%, p = 0.63; all-cause mortality: 1.0% vs. 2.2%, p = 0.19; MI: 1.8% vs. 1.5%, p = 0.75; definite/probable stent thrombosis: 1.3% vs. 0.7%, p = 0.48; major bleeding: 0% vs. 0.5%, p > 0.05.

Interpretation:

The results of the ITALIC trial indicate that shorter durations of DAPT (6 months) are noninferior to prolonged durations of DAPT in patients undergoing PCI with a second-generation DES in mostly low-risk patients. This trial was terminated early; thus, the results are likely underpowered. Moreover, although the randomization was to 24 months in the longer-duration arm, only 12-month results are presented here; thus, the current results represent a 6- versus 12-month duration of DAPT comparison.

Following concerns regarding late and very late stent thrombosis with first-generation DES, ACC/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. On the one hand, trials such as PRODIGY, RESET, ISAR-SAFE, and OPTIMIZE sought to assess shorter durations (3-6 months) of DAPT with at least 50% second-generation DES use in mostly stable patients. On the other hand, trials such as DES-LATE and EXCELLENT sought to assess if prolonged DAPT treatment would be superior to 12 months. The current trial extends to both sides of the spectrum, but does not provide any conclusive data. At this point, it may be best to follow current DAPT guidelines (12 months) for all patients undergoing DES-PCI, 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:

Didier R, Morice MC, Barragan P, et al. 6- Versus 24-Month Dual Antiplatelet Therapy After Implantation of Drug-Eluting Stents in Patients Nonresistant to Aspirin: Final Results of the ITALIC Trial (Is There a Life for DES After Discontinuation of Clopidogrel). JACC Cardiovasc Interv 2017;10:1202-10.

Gilard M, Barragan P, Noryani AA, et al. 6- Versus 24-Month Dual Antiplatelet Therapy After Implantation of Drug-Eluting Stents in Patients Nonresistant to Aspirin: The Randomized, Multicenter ITALIC Trial. J Am Coll Cardiol 2015;65:777-86.

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

Keywords: Acute Coronary Syndrome, Receptors, Purinergic P2, Angina, Stable, Drug-Eluting Stents, Ticlopidine, American Heart Association, Sirolimus, Aspirin, Platelet Aggregation Inhibitors, Purinergic P2Y Receptor Antagonists, Stents, Percutaneous Coronary Intervention, Thrombosis, Coronary Vessels, Diabetes Mellitus, AHA Annual Scientific Sessions


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