Elsevier

The Lancet

Volume 384, Issue 9954, 1–7 November 2014, Pages 1577-1585
The Lancet

Articles
Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial

https://doi.org/10.1016/S0140-6736(14)60612-7Get rights and content

Summary

Background

Optimum duration of dual antiplatelet treatment (DAPT) after coronary stenting remains uncertain, with an unknown efficacy to safety ratio of extended treatment leading to discrepancies between international guidelines and clinical practice. We assessed whether DAPT continuation beyond 1 year after coronary stenting is beneficial.

Methods

This analysis was a planned extension of the previously published ARCTIC-Monitoring trial, in which we randomly allocated 2440 patients to a strategy of platelet function testing with antiplatelet treatment adjustment or a conventional strategy after coronary stenting with drug-eluting stent (DES). We recruited patients (aged 18 years or older) scheduled for planned DES implantation at 38 centres in France. After 1 year of follow-up, patients without contraindication to interruption of DAPT were eligible for a second randomisation to this second phase of the study (ARCTIC-Interruption). Using a computer-generated randomisation sequence (1:1; stratified by centre), we allocated patients to a strategy of interruption of DAPT where the thienopyridine was interrupted and single aspirin antiplatelet treatment was maintained (interruption group) or a strategy of DAPT continuation for 6–18 months (continuation group). The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularisation, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00827411.

Findings

Between Jan 4, 2011, and March 3, 2012, 1259 eligible patients were randomly allocated to treatment in ARCTIC-Interruption: 624 to the interruption group and 635 to the continuation group. After a median follow-up of 17 months (IQR 15–18), the primary endpoint occurred in 27 (4%) patients in the interruption group and 24 (4%) patients in the continuation group (hazard ratio [HR] 1·17 [95% CI 0·68–2·03]; p=0·58). STEEPLE major bleeding events occurred more often in the continuation group (seven [1%] patients) compared with the interruption group (one [<0·5%] patient; HR 0·15 [0·02–1·20]; p=0·073). Major or minor bleedings were also more common in the continuation group compared with the interruption group (12 [2%] patients vs three [1%] patients; HR 0·26 [0·07–0·91]; p=0·04).

Interpretation

Our finding suggests no apparent benefit but instead harm with extension of DAPT beyond 1 year after stenting with DES when no event has occurred within the first year after stenting. No conclusion can be drawn for high-risk patients who could not be randomised. The consistency between findings from all trials of such interruption suggests the need for a reappraisal of guidelines for DAPT after coronary stenting towards shorter duration of treatment.

Funding

Allies in Cardiovascular Trials Initiatives and Organized Networks (ACTION Study Group), Fondation de France, Sanofi-Aventis, Cordis, Medtronic, Boston Scientific, Fondation SGAM.

Introduction

The recommended duration of dual antiplatelet treatment (DAPT) for elective coronary implantation of a bare-metal stent is at least 1 month on the basis of observational data.1 Concerns about a potential increased risk of stent thrombosis with drug-eluting stents (DESs)2, 3, 4 led to extension of DAPT from 2 months to 6–12 months.5, 6 However, new analyses of data from randomised trials7 and data from studies of the newer generations of DESs have not substantiated any increased risk, but have instead shown a lower risk of stent thrombosis in higher risk clinical situations such as in ST-elevation myocardial infarction.8, 9, 10

Findings from several randomised studies and large observational registries have challenged the recommendation of 6–12 months of DAPT treatment after implantation of a DES in stable patients, although duration in the control groups of these studies was variable and not always reflecting the 12-month recommendation of DAPT duration after DES implantation.11, 12, 13, 14, 15, 16, 17, 18, 19, 20

The ARCTIC (Assessment by a double Randomisation of a Conventional antiplatelet strategy versus a monitoring-guided strategy for drug-eluting stent implantation and, of Treatment Interruption versus Continuation 1 year after stenting)-Interruption trial is the second phase of the previously published ARCTIC-Monitoring study,21, 22 in which we randomly allocated 2440 patients to either platelet function testing with antiplatelet treatment adjustment or conventional antiplatelet treatment after coronary stenting with a DES. After 1 year of follow-up, we invited patients without major events and who were treated with clopidogrel or prasugrel in addition to aspirin to enrol in a second randomisation to either interruption of DAPT as recommended by international guidelines or continuation of DAPT for a further 6–18 months.6, 23 All patients participated in the first phase of the ARCTIC study, which served as a screening log book for the second randomisation 1 year later to assess this second hypothesis about DAPT duration.

Section snippets

Study design and population

ARCTIC was a multicentre, prospective open-label study with parallel trial arms and double randomisation. Between Jan 26, 2009, and Jan 5, 2011, we recruited patients (aged ≥18 years) scheduled for planned DES implantation at 38 centres in France.21 We excluded patients with primary percutaneous coronary intervention for ST-elevation myocardial infarction, planned use of glycoprotein IIb/IIa inhibitors, chronic anticoagulation treatment, or bleeding diathesis. Results from the first phase

Results

Of the 2440 patients originally enrolled in the ARCTIC-TRIAL, 1259 were enrolled into the ARCTIC-Interruption study, of whom 624 were assigned to the interruption group and 635 were assigned to the continuation group (figure 1). The baseline risk of the non-randomised study population (n=1181) differed from the ARCTIC-Interruption population with a higher proportion of diabetes (469 [40%] of 1181 patients vs 420 [33%] of 1259 patients; p=0·0011), peripheral artery disease (167 [14%] patients vs

Discussion

Findings from ARCTIC-Interruption show no benefit with DAPT continuation beyond 1 year after coronary stenting, rather a harm of continued DAPT, with patients in the continuations group having more major or minor bleeding. They also show that 1 year after stenting, only half of patients are eligible for randomisation to thienopyridine interruption or continuation leading to the selection of a low risk population, and that strict adherence to the open-label treatment assignment of both single

References (34)

  • EL Eisenstein et al.

    Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation

    JAMA J Am Med Assoc

    (2007)
  • M-C Morice et al.

    A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization

    N Engl J Med

    (2002)
  • W Wijns et al.

    Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)

    Eur Heart J

    (2010)
  • A Kastrati et al.

    Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents

    N Engl J Med

    (2007)
  • G Sarno et al.

    Lower risk of stent thrombosis and restenosis with unrestricted use of ‘new-generation’ drug-eluting stents: a report from the nationwide Swedish Coronary Angiography and Angioplasty Registry (SCAAR)

    Eur Heart J

    (2012)
  • F Airoldi et al.

    Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment

    Circulation

    (2007)
  • S Schulz et al.

    Stent thrombosis after drug-eluting stent implantation: incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4-year period

    Eur Heart J

    (2009)
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