Thirty days only double antiplatelet therapy after drug-eluting stenting: could a 'short-term' treatment be advantageous?

Abstract

Introduction Dual antiplatelet therapy (DAPT) with aspirin and an ADP receptor antagonist is the foundation to prevent stent thrombosis and the duration of DAPT after coronary stenting has been extensively studied during the last decades.1 Initially, patients were treated with a short course (15–30 days) of DAPT after bare-metal stenting (BMS). Afterward, drug-eluting stents (DES) were approved on the basis of randomized controlled trials (RCTs) in which DAPT was used for 3–6 months (only 2 months in the seminal RAVEL trial).1 Few years later, it was recognized that the tremendous restenosis benefit of DES was associated with a higher risk of myocardial infarction (MI) and death presumably due to late stent thrombosis.2 This 2.75 higher risk of late stent thrombosis as compared with BMS was attributed to the delayed stent endothelialization of DES.1,2 After this evidence, in 2006 the US Food and Drug Administration (FDA) consensus recommendation supported prolonged (at least 12 months) DAPT after DES implantation to prevent late stent thrombosis, and this warning was rapidly incorporated in the International guidelines. However, this recommendation was not based on any prospective RCT's evidence. On the contrary, such prolonged DAPT enhances the risk of bleeding. Thus, in clinical practice in which numbers of high bleeding risk patients are substantial, the less effective BMS are preferred in this setting due to the shortened DAPT regimen needed. However, several RCTs comparing prolonged and short DAPT therapy after implantation of mainly new-generation DES have been planned during the last few years. These studies largely conclude that in stable patients, a short-duration (3–6 months) DAPT results in similar rates of stent thrombosis, MI, and death but reduced bleeding risk, when compared with a longer (12–24 months) one.1,3 Significantly, a recent RCT lowered the bar even further and demonstrated that in patients at high risk of bleeding, treated with a shortened (30 days) course of DAPT, a polymer-free DES could offer better results than BMS stenting without increasing the risk of stent thrombosis.4 Thus, recent data highlight the increasing bleeding risk of patients after stenting and cast doubts on the cost-effectiveness of the former recommendation of routinely prolonging DAPT after DES. The balance between the risk of bleeding and the risk of late stent thrombosis Among patients undergoing percutaneous coronary intervention (PCI), it is estimated that 15% or more are at high risk for bleeding due to older age, comorbidities, needs of concomitant oral anticoagulants, or others.5 Even in these cases, prolonging DAPT after PCI reduces ischemic and thrombotic risk, but it carries an inherent risk of bleeding that increases further over time. Notably, in patients with stable vascular disease or at risk of atherothrombotic events, prolonged DAPT did not provide significant protection against ischemic events while it was associated with a significant 60% excess of moderate bleeding and a nonsignificant excess of severe or fatal bleeding complications.6 In addition, in the recent DAPT trial, extending clopidogrel from 12 to 30 months reduced ischemic events but increased the relative risk of major bleeding by 56% vs. placebo.7 Furthermore, a recent meta-analysis demonstrated that for every stent thrombosis event averted with longer DAPT, about two major bleedings are estimated to occur.8 Moreover, all bleedings, whether they are insignificant, life threatening or fatal, may seriously affect morbidity and mortality.5 In fact, the Italian MANTRA Registry observed that unselected patients with acute coronary syndrome (ACS) who bleed have a higher risk of death or MI, and these negative events occur a few days after the hemorrhage.9 In addition, 4–7% of patients undergoing PCI will require noncardiac surgery in each year after the procedure, and this need of surgery could force physicians to interrupt DAPT earlier.1 Therefore, the identification of patients deemed at risk of bleeding with prolonged DAPT duration is an important component of any PCI planning. On the other hand, patients after PCI are at risk of coronary thrombotic events that can be classified as stent and nonstent related.10 DAPT confers protection on both types of thrombotic events through suppression of platelet reactivity and aggregability. Physicians are particularly concerned of stent-related events, in particular stent thrombosis, due to its association with a higher risk of MI and death. Not surprisingly, early cessation of DAPT has emerged as a strong, consistent, and independent risk factor for stent thrombosis with BMS or first-generation DES. Thus, it could be easy to understand why in 2006 both FDA and the cardiologic community rapidly recommended prolonged DAPT (at least 12 months) although at that time the level of evidence of such indication was below the accepted limits. Later on, further studies observed that for some stable patients DAPT extension beyond 3 months confers no additional benefit in terms of reduction in stent thrombosis, while it was associated with more bleedings.10 These findings are not surprising as the pathophysiology of stent thrombosis is multifactorial and could extend from patient-related to procedural-related, or even stent-related factors. Significantly, a substantial improvement in stent endothelialization and strut thrombogenicity has been achieved with second-generation DES. Data from new technology DES (mainly with durable fluorinated polymer) show that the greatest risk of stent thrombosis is within the first 30 days and that following this period, this risk does not differ between patients on-DAPT or off-DAPT.11 Thus, we may argue that better stent bioengineering with thinner struts, more biocompatible polymers, and more effective drugs could have affected the risk of stent thrombosis with second-generation DES. Today, new technologic updates like abluminal drug coating, polymer-free or bioresorbable polymers, better elution of drug, or improvements in their antirestenotic properties could offer further advantages and eliminate triggers for late or very late stent thrombosis. Finally, physicians should consider that from a clinical perspective, thrombotic/ischemic and bleeding risks are not constant over time. In fact, although stent thrombosis or recurrent ischemic events tend to peak early after PCI and substantially decrease or stabilize thereafter, the bleeding risk after a mild, early increase remains constant over time (Fig. 1). Thus, finding the sweet spot between these opposed bleeding and thrombotic risk is of paramount importance at the time of PCI.Fig. 1: Time-related differences between stent thrombosis and bleeding risk after stenting. Mandatory double antiplatelet therapy regimen represents the minimum time after percutaneous coronary intervention during which cessation of double antiplatelet therapy results in an unacceptably high risk for thrombotic events.The LEADERS-FREE trial In patients at high risk of bleeding, current guidelines favor the use of either a second-generation DES with a 3–6-month DAPT or a BMS stent followed by 1 month of DAPT.12 The latter strategy is associated with a higher risk of restenosis and reintervention than that observed with the use of DES. These recommendations are the background of the LEADERS-FREE trial, a randomized, double-blind study, that compared the umirolimus (biolimus A9)-coated, polymer-free, and carrier-free stent with a very similar BMS in 2466 patients with a high risk of bleeding who underwent PCI.4 This high bleeding predisposition was mainly described by older age (65% of patients aged more than 75 years) and concomitant anticoagulation (35%). All patients received 1 month of DAPT, mainly clopidogrel. The primary safety end point, tested for both noninferiority and superiority, was a composite of cardiac death, MI, or stent thrombosis. The primary efficacy end point was clinically driven target-lesion revascularization. On day 390, the primary safety end point had occurred in 112 patients (9.4%) in the polymer-free BA9-coated stent group and in 154 patients (12.9%) in the BMS group [estimated absolute risk difference, −3.6 percentage points; 95% confidence interval (CI), −6.1 to −1.0; P < 0.001 for noninferiority]. This result was driven mainly by a lower rate of MI. On day 390, the primary efficacy end point had occurred in 59 patients (5.1%) in the polymer-free BA9-coated stent group and in 113 patients (9.8%) in the BMS group [estimated risk difference, −4.8 percentage points; 95% CI, −6.9 to −2.6; hazard ratio, 0.50 (95% CI: 0.37–0.69) P < 0.001] (Fig. 2a). Rates of definite or probable stent thrombosis [polymer-free BA9-coated stent 2.0% vs. BMS 2.2%, hazard ratio, 0.91 (95% CI: 0.53– 1.59) P = 0.75] were high in this study, and more than half the stent thrombosis in both groups occurred during the first 30 days, when patients were still taking DAPT. The high rates of stent thrombosis observed were impressive, although similar to those reported in other trials of unselected patients treated with DES, or in registries of triple therapy. However, these high rates of stent thrombosis may be a consequence of the evenly high risk of bleeding among the patients enrolled that is associated with a higher risk for stent thrombosis as well.Fig. 2: Cumulative percentage of patients with the primary safety endpoint (a composite of cardiac death, myocardial infarction, or stent thrombosis) or the primary efficacy end point (clinically driven target-lesion revascularization). (a) For the LEADERS-FREE trial and (b) for the LEADERS-FREE ACS substudy. BMS, bare-metal stent; DCS, drug-coated stent. Modified from 5,12.In addition, the LEADERS-FREE trial included a prespecified substudy (LEADERS-FREE ACS) that addressed its ACS population, a true clinical challenge due to the imbalance of the opposing risks. Of these, 659 ACS patients were included in this analysis (polymer-free BA9-coated stent 330 patients, BMS 329 patients, respectively).13 At a 12-month follow-up, treatment with the polymer-free BA9-coated stent was more effective (clinically driven target-lesion revascularization 3.9 vs. 9.0%, P = 0.009) and safer (cumulative incidence of cardiac death, MI, or definite or probable stent thrombosis 9.3 vs. 18.5%, P = 0.001), driven by significantly lower rates of cardiac mortality (3.4 vs. 6.9%, P = 0.049) and MI (6.9 vs. 13.8%, P = 0.005) (Fig. 2b). These findings did not depend on the postprocedural DAPT scheme, the oral anticoagulation regimen, or imbalances at baseline. Thus, the LEADERS-FREE investigators provocatively concluded that in patients at high risk of bleeding, the use of BMS should no longer be recommended as a second-generation polymer-free DES offers superior results even in patients treated with a shortened (30 days) course of DAPT. Other experiences However, given the inherent limitation of this seminal study, these provocative conclusions of the LEADERS-FREE investigators should be reinforced by other data before their wide application in clinical practice. To date, few studies with a low level of evidence already reported favorable results with less than 3 months of DAPT after DES. In a pooled population of patients receiving a resolute zotarolimus-eluting stent, in which DAPT was prescribed for 6–12 months,14 the association between DAPT interruption and the rates of stent thrombosis and major cardiac events was retrospectively analyzed. Three groups were identified: no interruption, interruption during the first month, and interruption between more than 1 and 12 months. There were 1069 (21.8% of the pooled population) patients with a DAPT interruption and among the 166 patients who interrupted therapy in the first month, six definite/probable stent thrombosis events occurred (3.6%; all were long DAPT interruptions). Among the 903 patients in the >1–12-month (60% occurred between 6 and 12 months) interruption group, only one stent thrombosis event occurred (0.1%; it was a 2-day long DAPT interruption). On the other hand, among patients with no DAPT interruption, 32 stent thrombosis events occurred (0.8%). Rates of major cardiac events were 6.8% in the 1-month long interruption group, 1.4% in the 1–12-month interruption group, and 4.1% in patients who continued DAPT without interruptions. Thus, this subanalysis showed that in second-generation DES, only DAPT interruptions within 1 month are associated with a high risk of stent thrombosis or adverse outcomes, whereas DAPT interruptions between 1 and 12 months were associated with low rates of stent thrombosis and adverse cardiac outcomes as well. Recently, Ariotti et al.15 reported a prespecified analysis of the ZEUS trial, in which 828 high bleeding risk patients were implanted with Endeavor-zotarolimus-eluting stent (E-ZES) or a thin-strut BMS and treated with a protocol-mandated 30-day DAPT regimen. The primary composite (death, MI, and target vessel revascularization) end point at 1 year occurred in 22.6% of E-ZES as compared with 29% of BMS patients [hazard ratio: 0.75 (95% CI: 0.57–0.98) P = 0.033]. Again, definite or probable stent thrombosis at 1 year occurred in 2.6% of E-ZES as compared with 6.2% of BMS patients (hazard ratio: 0.419, P = 0.016). Thus, the authors conclude that in patients at high risk of bleeding E-ZES as compared with conventional BMS followed by 30-day DAPT regimen provides superior efficacy and safety.15 Significantly, similar results have been reported by Kinnaird et al.16 that compared 249 patients, operator-defined at high bleeding risk (mainly older age, anemia, and warfarin therapy) implanted with the polymer-free BA9-coated stent with a contemporary DES cohort. To note, DAPT was prescribed for 3 months among polymer-free BA9-coated stent patients (56.7% for 30 days) as opposed to 12 months among the control DES group.16 Thus, these preliminary data seem to support the use of shortened DAPT after new-generation DES, but these results should be confirmed with adequately designed studies (Table 1).Table 1: Planned or ongoing studies on shortened double antiplatelet therapy regimen after drug-eluting stentsConclusion Although the duration of DAPT after DES stenting has been extensively studied during the last decades, physicians still lack a firm ‘mandatory’ duration of DAPT after new-generation DES.17 Prolonged DAPT reduces late stent thrombosis and MI, but at the expenses of more hemorrhages. On the contrary, this could affect prognosis as well. Thus, in patients at high risk of bleeding, the less effective BMS could be preferred to DES due to the shortened DAPT needed. However, new studies with a low level of evidence and a landmark RCT question these recommendations. They suggest that new DES technologies carry a lower risk of stent thrombosis that could allow a shortened (30 days) DAPT regimen after the procedure. Thus, it becomes an ethical must to define the minimum time after PCI during which cessation of DAPT results in an unacceptably high risk for thrombotic events. Beyond this timeframe, physicians need to go back to their clinical attitude and base the decision to continue or discontinue DAPT on an individual, clinical assessment of the trade-off between ischemic and bleeding risk. Acknowledgements Conflicts of interest There are no conflicts of interest.