Article

PDF
Access to the PDF text
Advertising


Free Article !

Archives of cardiovascular diseases
Volume 106, n° 5
pages 271-273 (mai 2013)
Doi : 10.1016/j.acvd.2013.03.060
Received : 19 February 2013 ;  accepted : 29 Mars 2013
Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation
Durée optimale de la bithérapie anti-agrégante plaquettaire après stent actif
 

Gérard Helft
 Institute of Cardiology, GH Pitié-Salpétrière Hospital, AP–HP, boulevard Vincent-Auriol, 75013 Paris, France 

Fax: +33 1 42 16 30 34.

Keywords : Drug-eluting stent, Antiplatelet agent, Percutaneous coronary intervention, Guidelines, Randomized trial

Mots clés : Stent actif, Anti-agrégant plaquettaire, Procédure coronaire interventionnelle, Recommandations, Étude randomisée


Drug-eluting stents (DES) have become the standard in percutaneous coronary revascularization. Several pivotal clinical trials have shown that, compared with a bare-metal stent (BMS), the DES is associated with significant reductions in the risk of restenosis and the need for target-lesion revascularization [1, 2]. Drug-eluting stents are currently recommended as the first-choice option, especially when the risk of restenosis is high (i.e. in patients with diabetes, long lesions, chronic total occlusion, bifurcation lesions, restenotic lesions, small vessels). According to the latest guidelines on patients presenting with ST-segment elevation, if the patient has no contraindications to prolonged dual antiplatelet therapy (DAPT) (such as an indication for oral anticoagulation or estimated high long-term bleeding risk) and is likely to be compliant, DES should be preferred over BMS (class IIa, level A) [3].

The combination of aspirin and an adenosine diphosphate-receptor blocker such as clopidogrel, prasugrel or ticagrelor is mandatory after percutaneous coronary intervention (PCI). Usually, this DAPT includes aspirin 75–100mg/day per os plus clopidogrel 75mg/day. But, the optimal duration of DAPT after DES insertion is still debated. For example, the recommendations put forward by the American College of Cardiology/American Heart Association (AHA/ACCA) and those from the European Society of Cardiology (ESC) diverge slightly. According to the AHA/ACCA, in addition to aspirin, clopidogrel therapy should be continued for at least 12months after DES implantation, whereas the ESC guidelines recommend continuation for 6–12months [4, 5].

The main reason why an extended combination of DAPT therapy has been advocated is because early discontinuation of DAPT has been identified as a risk factor for late stent thrombosis in patients with a DES [6]. It was suggested that some late clinical events that occur later than 1year after DES implantation may be due to delayed arterial healing after implantation of DES. In the absence of randomized data, two independent observational registries have largely influenced the current recommendation to prolong clopidogrel therapy for12months or for 6–12months after DES implantation [7, 8]. The BASKET-LATE trial reported a>70% increase in rates of death or myocardial infarction in DES recipients who discontinued clopidogrel at 6months compared with patients treated with BMS [7]. Similarly, a 50% increase in rates of all-cause death or myocardial infarction was observed in the Duke Heart Center registry in patients treated with DES who discontinued clopidogrel at 6months compared with those who continued the treatment for 24months [8]. However, prolonged DAPT has been associated with higher severe bleeding rates compared with aspirin therapy alone: reported incidences of major bleeding ranged from 1.8% to 3.7% and from 1.7% to 5.1% for minor bleeding.

The question on the optimal duration of DAPT after DES is not only theoretical. More than 60,000 patients in France receive a DES every year. For each patient, the clinician has to make a decision. It is not surprising therefore that large clinical trials have been undertaken. Owing to the large number of DES implantations worldwide, the optimization of DAPT is important for both patient recovery and economic efficiency.

Recently, the results from four trials have suggested the possibility that a shorter duration of DAPT may be sufficient after DES implantation. The first randomized study on this issue analysed combined data from two multicentre trials: the REAL-LATE and ZEST-LATE trials [9]. This study found no significant benefit associated with continuing clopidogrel plus aspirin beyond 12months after DES implantation. No reduction in the incidence of myocardial infarction or death from cardiac causes was found. Moreover, the rates of composite outcomes (myocardial infarction, stroke, death) were higher with clopidogrel plus aspirin than with aspirin alone, although the difference was not statistically significant.

The results from the EXCELLENT study showed that, at 12months after DES implantation, patients treated with 12months or 6months of DAPT showed similar risks for target vessel failure, defined as the composite of cardiac death, myocardial infarction and ischaemia-driven target vessel revascularization [10]. However, the non-inferiority margin was wide, and the study was underpowered for death and myocardial infarction. Another study has shown that 24months of clopidogrel therapy in patients with DES or BMS was no more effective than a 6-month clopidogrel regimen for reducing the composite endpoint of death, myocardial infarction and cerebrovascular accident [11]. In that study, 2years of clopidogrel therapy resulted in an increase in bleeding episodes. The fourth study, the RESET trial, compared 3months of DAPT following zotarolimus-eluting stent implantation and 12months of DAPT following the other DES implantation. The investigators concluded that the first strategy was non-inferior to standard therapy [12].

These four studies are interesting and could provide a paradigm shift in the management of DAPT after DES implantation. Interestingly, none of these studies investigated the same course of DAPT duration: 12months versus 24months for LATE, 6months versus 12months for EXCELLENT, 6months versus 24months for PRODIGY, and 3months versus 12months for RESET. These data suggest the possibility that a shorter duration of DAPT may be sufficient after implantation of new generation DES. They do not rule out the possibility that prolonging the clopidogrel plus aspirin treatment might result in a reduction of major adverse cardiac events. As stated by the authors themselves, the studies were limited by a short follow-up and the exclusion of very high-risk patients.

Importantly, other clinical trials are currently ongoing to investigate optimal treatment duration after DES insertion. The DAPT study aims to compare the benefits and risks of 12months versus 30months of DAPT in patients undergoing PCI, and it has the largest number of subjects enrolled to date. Over 20,000 subjects have been enrolled at approximately 220 international clinical study sites. Most of the patients (>15,000) have received a DES. Interestingly, in that prolonged combined antiplatelet therapy, patients receive either clopidogrel or prasugrel, a new thienopyridine. Another ongoing trial (ISAR-SAFE) aims to assess whether discontinuation of clopidogrel plus aspirin at 6months after DES implantation is non-inferior to routine 1-year treatment. Not surprisingly, French trials have also investigated this important question, including ARCTIC, ITALIC and OPTIDUAL [13]. It would, however, probably have been wiser to perform one large trial rather than three smaller ones.

In patients at high risk of bleeding, the LEADERS FREE trial will assess the shortest course of DAPT ever used (1month) with an active stent devoid of polymer.

Before appealing for a reduction in the duration of DAPT after DES implantation, and while awaiting the results of the ongoing trials, it has to be kept in mind that few patients with an acute coronary syndrome have been included in these four clinical trials. In patients with an acute coronary syndrome, pending the results of ongoing trials, 9–12months of DAPT is recommended, with a strict minimum of 1month for patients who have received a BMS and 6months for those with a DES [1].

In conclusion, according to recent studies, a shorter course of DAPT than recommended by the guidelines may be considered, especially with new-generation everolimus and zotarolimus DES, polymer-free DES, and polymer-biodegradable DES, in the absence of ACS at the time of implantation. On the other hand, no sound evidence is available to support prolongation of DAPT beyond 12months, although such a strategy may be considered in specific patient subsets (e.g. those with left main disease or the last remaining vessel stenting receiving DES). Lastly, it remains very important to inform patients and their physicians about the need to avoid premature discontinuation of DAPT. In the meantime, it is not unreasonable to await the results of ongoing trials before changing our practice.

Disclosure of interest

The author has received grants from Cordis, Boston, Medtronic, Terumo and Biotronik.

References

Moses J.W., Leon M.B., Popma J.J., and al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery N Engl J Med 2003 ;  349 : 1315-1323 [cross-ref]
Stone G.W., Ellis S.G., Cox D.A., and al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease N Engl J Med 2004 ;  350 : 221-231 [cross-ref]
Task Force on the management of STseamiotESoCSteg P.G., James S.K., and al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation Eur Heart J 2012 ;  33 : 2569-2619
King S.B., Smith S.C., Hirshfeld J.W., and al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines J Am Coll Cardiol 2008 ;  51 : 172-209 [cross-ref]
Wijns W., Kolh P., Danchin N., and 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 ;  31 : 2501-2555
Park D.W., Park S.W., Park K.H., and al. Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during long-term follow-up Am J Cardiol 2006 ;  98 : 352-356 [inter-ref]
Pfisterer M., Brunner-La Rocca H.P., Buser P.T., and al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents J Am Coll Cardiol 2006 ;  48 : 2584-2591 [cross-ref]
Eisenstein E.L., Anstrom K.J., Kong D.F., and al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation JAMA 2007 ;  297 : 159-168 [cross-ref]
Park S.J., Park D.W., Kim Y.H., and al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents N Engl J Med 2010 ;  362 : 1374-1382 [cross-ref]
Gwon H.C., Hahn J.Y., Park K.W., and al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study Circulation 2012 ;  125 : 505-513 [cross-ref]
Valgimigli M., Campo G., Monti M., and al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial Circulation 2012 ;  125 : 2015-2026 [cross-ref]
Kim B.K., Hong M.K., Shin D.H., and al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation) J Am Coll Cardiol 2012 ;  60 : 1340-1348 [cross-ref]
Helft G., Le Feuvre C., Georges J.L., and al. Efficacy and safety of 12 versus 48months of dual antiplatelet therapy after implantation of a drug-eluting stent: the OPTImal DUAL antiplatelet therapy (OPTIDUAL) trial: study protocol for a randomized controlled trial Trials 2013 ;  14 : 56 [cross-ref]



© 2013  Published by Elsevier Masson SAS.
EM-CONSULTE.COM is registrered at the CNIL, déclaration n° 1286925.
As per the Law relating to information storage and personal integrity, you have the right to oppose (art 26 of that law), access (art 34 of that law) and rectify (art 36 of that law) your personal data. You may thus request that your data, should it be inaccurate, incomplete, unclear, outdated, not be used or stored, be corrected, clarified, updated or deleted.
Personal information regarding our website's visitors, including their identity, is confidential.
The owners of this website hereby guarantee to respect the legal confidentiality conditions, applicable in France, and not to disclose this data to third parties.
Close
Article Outline
You can move this window by clicking on the headline