Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation

INTRODUCTION Prediction Is Hard, Especially About the Future Coronary artery stenting has revolutionized percutaneous coronary interventions (PCI).1 The past 20 years have witnessed an impressive development of the field of coronary stents, with changes in scaffold materials and designs, and more recently in the addition of medications applied on the stent [drug-eluting stents (DES)] and released over time to prevent neointimal hyperplasia and in-stent restenosis, which had been the Achilles' heel of PCI.2 Limitations and Concerns Regarding Widespread Use of DES The advent of DES was, however, not without drawbacks. After the widespread introduction of the DES [mainly sirolimus- and paclitaxel-eluting stents (first generation DES)] into clinical practice, and at a time when >90% of implanted stents were DES, the United States of America Food and Drug Administration issued a warning regarding the risk of DES and subsequent thrombosis.3 Stent thrombosis (ST) represents indeed a catastrophic event associated with a high rate of acute myocardial infarction and death, and thus limiting the benefits of DES. Thankfully, ST is a rather rare event; and therefore, even if it is established that DES, a whole category, are associated with greater risk (nearly 2-fold) of ST than metal stents without drugs, bare-metal stents (BMS), the absolute risk increase is approximately 0.5% per year.4,5 This translates in an absolute risk reduction in the need for target vessel revascularization of approximately 25% with DES versus BMS (nearly 1 patient every 4) in exchange for an approximate 0.5% excess risk of ST (1 patient in every 200). Late ST: The Achilles' Heel of DES Prevention of ST after DES has therefore become an area of intensive research in PCI.4,5 The causes of ST are still incompletely understood. The prevailing hypothesis suggests a failure to provide a complete reendothelialization of the DES, which therefore remains “thrombogenic” for a longer period of time.6,7 The introduction of dual antiplatelet therapy (DAPT) shortly after the introduction of stenting has made the large growth of stenting possible. The initial concerns of early ST were abated with the introduction of DAPT (initially aspirin and ticlopidine) and allowed for the nearly complete abandonment of angioplasty without stenting. DAPT after BMS was mandated for 4 weeks, and ST during the initial 4 weeks or after DAPT cessation was rather rare. In patients receiving the first generation DES, the risk of ST is highest within the first 90–180 days after stenting but remains higher than BMS for several months and years, and an increase in ST after the first generation DES was documented after DAPT cessation.4,5,8 Prolonged DAPT After DES A Food and Drug Administration advisory statement and a consensus of the major professional societies few years ago recommended extension of the DAPT up to 12 months after DES to prevent earlier discontinuation of DAPT and excess risk of ST.3,9,10 Whether this strategy translated in better patient care or reduced ST events is object of debate. A meta-analysis of 4 randomized controlled trials (8158 patients) comparing a shorter duration of DAPT (3–6 months) with 1 of prolonged duration (>12 months) failed to demonstrate a reduction in death/myocardial infarction (MI) prolonging DAPT, whereas it showed potential arm in relation to an increased risk of major bleeding.11 Different types of DES (first vs. novel generation) and different indications for PCI (unstable vs. stable coronary disease) in the studies may however limit applicability of the results of the meta-analysis. In particular, the second-generation DES (everolimus and zotarolimus), and more recently the third generation DES (polymer-based DES) seem to be associated with lower risk of ST than sirolimus DES,5 thus raising the question of whether the extension to 12 months is justifiable with these DES, and whether an even shorter duration may be appropriate. In the last meta-analysis appearing in this issue of Journal, Liu and coll. address this important question.12 The analysis included 3 large randomized studies of 6679 patients published between 2012 and 2013, the durations of short-term DAPT were set as 3 months in 2 studies and 6 months in 1, whereas the long-term DAPT was set at 12 months. According the results, shortening the duration of DAPT after the second generation DES [zotarolimus-eluting (Endeavor, Medtronic Inc.) or everolimus-eluting (Xience, Abbott Vascular Inc.)] did not confer an increased risk of adverse cardiac events, yet showed a trend toward reduced risk of major bleeding, suggesting that routine prolongation of DAPT beyond 3–6 after everolimus or zotarolims DES is not necessary. Also, this analysis is limited; however, by the fact that <50% of patients enrolled were patients with unstable coronary artery disease. DAPT in Patients With Unstable Coronary Artery Disease In patients with unstable coronary artery disease (acute myocardial infarction and unstable angina), most of which were treated with PCI with exclusive use of BMS, the use of DAPT with aspirin and clopidogrel for up to 12 months led to a significant absolute reduction of 2.1% in cardiovascular events in the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial,12 and confirmed in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial13 (3.0% absolute reduction). A subgroup analysis of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) randomized controlled trial involving 9478 patients with previous acute myocardial infarction, previous stroke, or symptomatic peripheral arterial disease showed that prolonged use of DAPT (well beyond 12 months, median duration 28 months) led to an absolute risk reduction in adverse cardiovascular (1.5%, approximately 0.7% per year) without a significant increased risk of severe bleeding.14 Moreover, a recent meta-analysis showed that discontinuation of DAPT beyond 12 months after unstable coronary artery disease event was still associated with an increased risk of adverse events in patients with previous PCI (odds ratio = 1.19).15 These data suggest that in patients with unstable coronary artery disease, independent of the type of stent (BMS vs. DES), DAPT should be considered for at least 12 months. More recent studies including patients with unstable coronary artery disease most of which underwent PCI with large use of DES, support the use of novel inhibitors of the platelet P2Y12 receptor, ticagrelor, and prasugrel, instead of clopidogrel as the antiplatelet drug to be added to aspirin in DAPT.16,17 It therefore seems that prolonged DAPT after PCI in patients with unstable coronary artery disease is here to stay. Treatment Guidelines Recommendation from guidelines from the American Heart Association/American College of Cardiology/Society of Cardiac Angiography and Intervention updated in 2011 indicate an optimal duration of 12 months for DAPT for all patients receiving DES and for all patients receiving BMS for unstable coronary artery disease.18 The latest guidelines from the European Society of Cardiology updated in 2011 recommend an optimal duration of 6–12 months after DES and ask to take into consideration type of DES (second vs. first generation) and bleeding risk.19 “One Size Fits All” or Individualized Care? The risk of ST is not evenly distributed in the population of patients undergoing PCI. There are several risk factors for ST, some related to patients' clinical and angiographic characteristics others to the procedural details (Table 1). Based on such variables, each patient can be stratified in high, intermediate and low risk, and it is therefore foreseeable that 1 given strategy may prove effective in 1 risk group and not in another, this is however untested at the moment. The same applies to the risk of bleeding with DAPT, and an increased risk of major bleeding may shift the benefit/risk balance against prolonged DAPT in a given patient. In absence of randomized controlled trials addressing all the remaining questions, it is our opinion that prolonged DAPT (>3–6 months) seems unnecessary for routine treatment of patients undergoing second-generation DES, yet it seems to be indicated in selected patients as such those with unstable coronary artery disease and to be considered in patients perceived to be at high risk for ST and not at high risk for major bleeding.TABLE 1: Predictors of Stent Thrombosis After Drug-eluting Stent Implantation