Dual antiplatelet therapy after drug-eluting stent implantation ⁎editorials published in the journal of the american college of cardiology reflect the views of the authors and do not necessarily represent the views of jacc or the american college of cardiology.

Journal of the American College of Cardiology 2012 by the American College of Cardiology Foundation http://dx.doi.org/10.1016/j.jacc.2012.08.003 consistent lower rate of late or very late ST A recent network meta-analysis presented the provocative findingthat within 2 years, EES might have a lower risk of ST than BMS which, unlike common perception, might bebased on the possibility that polymeric coating could reduce stent thrombogenicity This lower rate of ST withnewer-generation DES might be attributable to better implantation technique, improved stent platform, thinnerstrut thickness, more biocompatible polymers, type and amount of antiproliferative drug, or a combination thereof.
Of note, in most contemporary DES trials, prolongedDAPT intake for at least 12 months was mandatory, although the optimal duration of DAPT is still lacking DAPT invariably increases the risk of major bleedings The bleeding risk correlates with the duration ofDAPT and bleeding events clearly have a negative Drug-eluting stents (DES) were introduced in interven- impact on outcomes of patients after PCI This raises tional practice more than 10 years ago and rapidly replaced 2 important questions, which are momentous for patients bare-metal stents (BMS) for treatment of coronary artery with a high likelihood for bleeding events, with the need for disease because of their superior capability to reduce the nondeferrable or unplanned noncardiac surgery or invasive need for restenosis-driven repeat intervention. Soon, it procedures, for elderly or fragile patients, and for patients became obvious that besides optimal stenting technique, with low drug adherence: First, are there certain conditions dual antiplatelet therapy (DAPT), which means the com- allowing us to safely shorten DAPT to Ͻ12 months after bination of aspirin and a P2Y12 platelet receptor inhibitor, DES implantation, and second, what are the consequences has to be established for a prolonged time after stent of DAPT discontinuation (temporary or permanent), in implantation in order to avoid potentially catastrophic stent thrombosis (ST). In the era of first-generation DES, it In this issue of the Journal, Kim et al. address the turned out that premature discontinuation of DAPT, which first question. In the RESET (REal Safety and Efficacy of means Ͻ3 months for sirolimus-eluting stents (SES) and 3-month dual antiplatelet Therapy following Endeavor Ͻ6 months for paclitaxel-eluting stents (PES), is a strong zotarolimus-eluting stent implantation) trial, 2,148 patients predictor of ST and this relationship is more pronounced with stable angina, unstable angina, or acute myocardial in patients with acute coronary syndromes receiving DES infarction (MI) undergoing elective PCI were enrolled, with As additional safety concerns arose from reports of an increased 1,059 randomized to the Endeavor (Medtronic, Santa Rosa, risk of late and very late (Ͼ1 year) ST events with first- California) zotarolimus-eluting stent (E-ZES) and 3 generation DES an attitude towards “the longer, the months of DAPT and 1,058 patients treated with standard better” DAPT therapy developed. This is reflected in current 12-month DAPT and other DES (Resolute [Medtronic] guidelines of the American societies recommending at least 12 zotarolimus-eluting stent [R-ZES], EES, or SES). Patients months of DAPT with clopidogrel after DES implantation with significant left main disease, in-stent restenotic lesions, and the European Society of Cardiology endorsing 6 to 12 chronic total occlusions, or patients with acute ST-segment months of DAPT treatment after DES implantation and 12 elevation MI (STEMI) were excluded from the trial. At 12 months for all patients after ACS, irrespective of revascular- months, the combined endpoint of cardiovascular death, ization strategy Meanwhile, second-generation DES with MI, ST, target vessel revascularization (TVR), or bleeding durable polymers such as everolimus-eluting stents (EES) or occurred in 4.7% of patients in both treatment arms (p Ͻ zotarolimus-eluting stents (ZES) and third-generation DES 0.001 for noninferiority). Overall, there was no significant with biodegradable polymers and abluminal coating such as difference in any of the individual components of the biolimus-eluting stents (BES) widely replaced first-generation primary endpoint. Definite or probable ST occurred in 2 DES because of improved stent deliverability while exhib- patients (0.2%) treated with E-ZES, both within the first iting equal or superior antiproliferative efficacy, and a month. Three patients (0.3%) had ST in the conventional12 months DAPT therapy arm, all of them between 3 and12 months. There was no significant difference in the *Editorials published in the Journal of the American College of Cardiology reflect theviews of the authors and do not necessarily represent the views of JACC or the primary endpoint in any of the subgroups, including pa- tients with diabetes mellitus and those with acute MI.
From the Department of Cardiology & Pulmonology, Charité–Campus Benjamin Considering the RESET trial, is it now a safe strategy to Franklin, Berlin, Germany. Dr. Witzenbichler has received lecture fees from AbbottVascular, Biotronik, Boston Scientific, and Medtronic.
implant E-ZES and limit DAPT to 3 months? Caution Early Discontinuation of Dual Antiplatelet Therapy should be advised in interpretation of the data. First, in their nonadherence can be based on disruption because of bleed- power calculations, the authors assumed a 10% incidence for ing events or noncompliance, on the recommendation of the primary endpoint at 12 months with a noninferiority physicians (medical decision) who have felt that the patients margin of 4%, where in fact the event rate was low with no longer need this therapy (usually permanent), or on a 4.7%. Therefore, statistically, a much larger sample size guided and recommended interruption because of a surgical would have been needed to prove the hypothesis. Second, or invasive procedure, usually temporary and not longer the low event rate is unexpected and might in part be than 14 days; it can be brief (Ͻ5 days), temporary or explained by the anatomic low-risk profile as defined in the permanent. The Spanish investigators prospectively col- inclusion/exclusion criteria of the trial, which makes it lected data on 1,622 all-comer patients undergoing implan- difficult to translate the findings to a broader all-comer tation of at least 1 DES. The major findings are as follows: population. Third, the investigators choose the E-ZES First, DAPT interruption for any reason was not infrequent because of a supposedly better safety profile. The phospho- and occurred in 10.6% of the patients, although in only 1 rylcholine polymer coating of the Endeavor stent accounts patient, ATD was observed within the first 4 weeks.
for a rapid release of zotarolimus within 2 weeks, resulting Second, in the majority of the patients with ATD, the in a reduced antiproliferative effect, reflected by early neo- interruption was temporary, and third, the composite end- intimal growth and higher late loss, which did not translate point of cardiac death or acute coronary syndrome occurred in clinical events in patients with a low-risk profile but in 5.4% of all patients, but only in a minority (8%) of those became evident in a more daily-practice population patients was ATD at any time before the event noted. In The hypothesis that this E-ZES–typical feature of early multivariate analysis, ATD was not found to be predictive neointimal growth would be protective against late ST was challenged by the SORT OUT III (Randomized Clinical The authors have to be acknowledged for their thorough Comparison of the Endeavor and the Cypher Coronary assessment of ATD, as most trials and registries simply Stents in Non-selected Angina Pectoris Patients) trial, collect data of patients being “on” or “off” DAPT, ignoring describing a 1.1% definite ST rate for E-ZES versus 0.3% the dynamic nature of drug intake. The extent of ATD for SES (p ϭ 0.048) at 12 months though the within the first year was high; however, in their analysis, incidence of very late ST (Ͼ12 months) was consistently overall premature ATD seemingly did not translate into low throughout the pivotal E-ZES trials Moreover, serious consequences. This may be explained by the follow- the follow-up time of 12 months in the RESET trial might ing issues: First, in 65% of the cases, ADT was temporary not be long enough to detect potential safety differences.
(median: 7 days), whereas it was shown that the median Fourth, industry has already reacted and replaced the interval from discontinuation of thienopyridine to ST was E-ZES by its successor, the Resolute-ZES (R-ZES) with a 13.5 days for the first 6 months Second, the temporal different slow-release polymer (BioLinx) and improved association between ATD and consecutive events beyond 6 antiproliferative activity. Therefore, in most catheterization months is known to be lenient and twice as many laboratories, the E-ZES has disappeared from the shelves patients in this study disrupted their DAPT at 6 to 12 and is replaced by the R-ZES. Fifth, in the control arm, a months. Third, because the event rates were low, the power mixture of first-generation (SES) and second-generation of the study is limited and the confidence intervals are wide.
DES (EES, R-ZES) was used instead of the E-ZES, Fourth, the authors were well advised to do simulations of hindering direct comparisons, and finally, 14% of the ATD in those patients who died of cardiac reasons. If in population in the trial presented with non–STEMI, the 18.8% of these cases DAPT had been interrupted before patient group probably having the most benefit from pro- death, the association between ATD and cardiac events longed DAPT by preventing future atherothrombotic would have been significant. As it is difficult to receive events regardless of the stent type implanted. The OPTI- detailed information from relatives on DAPT adherence of MIZE (Optimized Duration of Clopidogrel Therapy Fol- the deceased person, an even higher misclassification is quite lowing Treatment With the Endeavor Zotarolimus-Eluting conceivable. For these reasons, the data can only suggest Stent in the Real World Clinical Practice) trial that a brief interruption of DAPT does not have a large currently randomizing 3,120 patients to 3 impact on ischemic risk. For more information on different versus 12 months of DAPT after E-ZES implantation, will modes of nonadherence to DAPT, subsequent outcomes, probably give us a more robust insight into the safety of this and their relation to nonadherence, we have to await the approach, although the results cannot guide catheterization results of the observational PARIS (Patterns of Non- laboratories that have already abandoned the E-ZES.
Adherence to Dual Anti-Platelet Regimen In Stented The work of Ferreira-Gonza´les et al. in this issue of Patients) trial following more than 5,000 the Journal engages with the topic of antiplatelet therapy patients after stent placement over 2 years.
discontinuation (ATD) during the first 12 months. They Are these 2 reports now suggesting that the time has have extended their previous work on incidence and predic- come to slacken the reins in antiplatelet therapy after DES? tors of ATD in the same population, to the consecutive With newer-generation DES, 6 months DAPT might be risk for cardiac death and MI associated with it. DAPT sufficient, and 3 months not completely of the wall in Early Discontinuation of Dual Antiplatelet Therapy low-risk groups. Brief interruption of DAPT beyond 4 11. Kolandaivelu K, Swaminathan R, Gibson WJ, et al. Stent thrombo- weeks might not be associated with a dramatic risk increase.
genicity early in high-risk interventional settings is driven by stentdesign and deployment and protected by polymer-drug coatings.
However, the patient- and device-related criteria safely allowing early DAPT withdrawal or interruption still have 12. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK.
to be determined. Until then, we should be cautious and do Effects of clopidogrel in addition to aspirin in patients with acutecoronary syndromes without ST-segment elevation. N Engl J Med our best to avoid unplanned discontinuation of DAPT.
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therapy and long-term clinical outcome after coronary drug-eluting bichler, Department of Cardiology & Pulmonology, Charité– stent implantation: landmark analyses from the CREDO-Kyoto PCI/ Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, CABG Registry Cohort-2. Circ Cardiovasc Interv 2012;5:381–91.
14. Ndrepepa G, Berger PB, Mehilli J, et al. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropri-ateness of including bleeding as a component of a quadruple end point.
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