MINERVA MEDICA COPYRIGHT. Aspirin is accepted as standard antiplatelet. Dual antiplatelet therapy for primary and secondary prevention

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1 This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies The concomitant use of aspirin and an ADP receptor (P2Y12) blocker, also known as dual antiplatelet therapy (DAPT), has been extensively investigated as a primary and secondary prevention strategy in an effort to reduce the risk of cardiovascular events. In this manuscript the authors review the current guideline recommendations for DAPT and discuss the scientific data that supports these recommendations. Reported are also the scientific knowledge gaps and how future studies are likely to delineate these issues. Incremental knowledge is not likely to be an alternative to individualized care provided by the astute clinician to his patient. In consideration for prescribing DAPT (drug, dosage and duration) the clinician will have to weigh the potential benefits (reduction in death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke) and risks (severe or life-threatening bleeding) for each and every patient. Key words: Platelet aggregation inhibitors - Secondary prevention - Primary prevention - Cardiovascular physiological processes. Aspirin is accepted as standard antiplatelet therapy in patients with coronary artery disease. The concomitant use of aspirin (ASA) and a platelet ADP receptor (P2Y12) inhibitor, known as dual antiplatelet therapy (DAPT), has been investigated as a primary and secondary prevention modality in MINERVA CARDIOANGIOL 2012;60: Dual antiplatelet therapy for primary and secondary prevention A. P., A. H. WALLER, S. DHRUVAKUMAR, V. MAZZA C. GERULA, J. MAHER, M. KLAPHOLZ, E. KALUSKI Division of Cardiology Department of Medicine, University Hospital and New Jersey Medical School, Newark, NJ, USA an effort to reduce the risk of cardiovascularevents. Current clinical-practice guidelines endorse the use of DAPT for secondary prevention following percutaneous coronary interventions (PCI), 1 acute coronary syndromes (ACS) 2-5 and in certain patient subsets with symptomatic peripheral arterial occlusive disease (PAOD). 6 Aim of this paper is to provide a comprehensive review of available literature that would enable a physician to decide on the appropriate use of DAPT in various clinical conditions encountered in daily clinical practice. Corresponding author: E. Kaluski, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Ave, MSB-I538, Newark, NJ, USA. kalusked@umdnj.edu Antiplatelet therapy in PAOD Primary prevention (asymptomatic PAOD) Most patients with PAOD have diffuse atherosclerotic disease, therefore exposing them to an increased risk of stroke, ACS and cardiovascular death. The estimated 5-year all-cause mortality of these patients is exceedingly high ( 30%). 7 Over a 10- year follow-up, patients with severe and symptomatic large-vessel peripheral arterial Vol No. 6 MINERVA CARDIOANGIOLOGICA 611

2 disease (PAD) had significantly higher relative risk (RR) of all-cause mortality (RR=3.1; 95% CI: ) and cardiovascular death (RR=6.6; 95% CI: ) than subjects without symptomatic PAOD. Several trials have established the benefit of aspirin in patients with PAD. The Antithrombotic Trialists Collaboration meta-analysis 8 demonstrated a 46% relative risk reduction in cardiovascular events with the use of aspirin for primary and secondary prevention. Absolute reductions of serious vascular event was 3.6% (36 per 1000 treated over 2 years) among patients with previous myocardial infarction (MI); 3.8% (38 per 1000) patients treated for one month among patients with acute MI; 3.6% (36 per 1000 treated for 2 years) among those with previous stroke or transient ischemic attack (TIA); 0.9% (9 per 1000 treated) for 3 weeks among those with acute stroke; and 2.2% (22 per 1000 treated for two years among other high risk patients. In each of these high-risk patient subsets the absolute benefits substantially outweighed the absolute risks of major extra-cranial bleeding. A similar benefit was observed in patients with claudication, peripheral artery bypass grafting and peripheral angioplasty. The efficacy and safety of clopidogrel in the prevention of cardiovascular events was first evaluated in the landmark clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial published in This trial randomized 19,185 patients with atherosclerotic vascular disease including: ischemic stroke, MI and symptomatic PAD, to receive clopidogrel (75 mg/day) or aspirin (325 mg/day aspirin). The event rate of the composite end point of ischemic stroke, MI, and vascular death was 5.32% and 5.83% for the clopidogrel and aspirin arms respectively (absolute risk reduction [ARR] of 0.51% and relative risk reduction [RRR] of 8.7%; P=0.043) for clopidogrel compared with aspirin. In the subgroup of CAPRIE patients with PAD, the mean annual event rate was 3.71% in the clopidogrel group compared with 4.86% in the aspirin group (ARR 1.15%, RRR 23.8%; P=0.0028). DUAL ANTIPLATELET therapy for PRIMARY and SECONDARY prevention Symptomatic PAOD The CHARISMA trial 10 compared lowdose aspirin ( mg/day) plus clopidogrel (75 mg daily) with low-dose aspirin plus placebo in patients with clinically evident cardiovascular disease defined as cerebrovascular disease, coronary disease, or symptomatic PAOD or multiple risk factors. The primary efficacy endpoint (composite of MI, stroke, and cardiovascular death) occurred in 6.8% and 7.3% among patients in the clopidogrel arm and placebo arm respectively. (RR 0.93; 95% CI: 0.83 to 1.05; P=0.22). Among the symptomatic patients, there was marginally significant reduction in primary efficacy end point with clopidogrel 6.9% vs. 7.9% (RR 0.88, P=0.046). However, in asymptomatic patients with multiple risk factors there was a non-significant 20% relative risk increase in among the clopidogrel arm (6.6% vs. 5.5%, P=0.20). A post-hoc analysis of the CHARISMA study 11 among patients with prior MI, ischemic stroke, or symptomatic PAD, the rate of cardiovascular death, MI, or stroke was significantly lower in the clopidogrel arm (7.3% vs. 8.8%, HR 0.83, 95% CI 0.72 to 0.96, P=0.01). Additionally, hospitalizations for ischemia were significantly decreased, 11.4% vs. 13.2% (HR 0.86, 95% CI 0.76 to 0.96, P=0.008). There was no significant difference in the rate of severe bleeding: 1.7% vs. 1.5% (HR 1.12, 95% CI 0.81 to 1.53, P=0.50); however moderate bleeding was significantly increased: 2.0% vs. 1.3% (HR 1.60, 95% CI 1.16 to 2.20, P=0.004). Results from these studies formed the basis for the class 2b recommendation for DAPT in patients with symptomatic lower extremity PAD by the 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease. 6 Dual antiplatelet therapy in ACS The 2011 clinical-practice guidelines for patients with ACS consisting of unstable angina or myocardial infarction without ST-segment elevation (NSTEACS) recom- 612 MINERVA CARDIOANGIOLOGICA December 2012

3 Dual antiplatelet therapy for PRIMARY and SECONDARY prevention mend 3, 4 that clopidogrel (loading dose followed by daily maintenance dose) should be added to aspirin as soon as possible after admission and administered for at least 1 month (Level of Evidence [LOE]: A) and ideally up to 1 year (LOE: B). Patients with definite unstable angina ornon-st elevation myocardial infarction at medium or high risk and in whom an initial invasive strategy is selected should receive dual-antiplatelet therapy on presentation (LOE: A). The conventional loading doses are clopidogrel 600 mg, prasugrel 60 mg and ticagrelor 180 mg. Post-PCI either clopidogrel75 mg daily (LOE: A) prasugrel 10 mg daily (LOE: B) or ticagrelor 90 mg twice daily can be used. The duration and of DAPT in patients post- ACS related PCI, (clopidogrel 75 mg daily, prasugrel 10 mg daily, or Ticagrelor 90 mg twice (LOE B) 12 should be 12 months (LOE: B). If the risk of bleeding outweighs the anticipated benefits, earlier discontinuation should be considered (LOE: C). Clopidogrel maintenance dose of 150 mg daily for the initial 6 days post PCI and then 75 mg daily thereafter (LOE: B) is optional. Dual antiplatelet therapy in patients with ACS treated conservatively Evidence to support the use of clopidogrel in patients with ACS treated conservatively (no PCI or revascularization) comes exclusively from the clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial. 13 The CURE trial randomly assigned 12,562 patients who had presented within 24 hours after the onset of symptoms to receive clopidogrel (300 mg immediately, followed by 75 mg once daily) or placebo in addition to aspirin for 3 to 12 months. The use of clopidogrel plus aspirin provided a 20% relative risk reduction in the composite end point of CV death, MI, and stroke (11.4% vs. 9.3%, 95% CI , P<0.001). The beneficial effects of clopidogrel were seen in both subjects treated with PCI and those who did not undergo revascularization (73% of the CURE study population did not undergo any revascularization). Each of the components of the composite outcome (MI, stroke and cardiovascular death) was reduced (23%, 14%, and 7% RRR respectively). The beneficial effect of clopidogrel was seen within a few hours after randomization, with the rate of death from cardiovascular causes, nonfatal myocardial infarction, stroke, or refractory or severe ischemia significantly lower in the clopidogrel group by 24 hours after randomization (1.4% in the clopidogrel group vs. 2.1% in the placebo group; RR 0.66; 95% CI: 0.51 to 0.86). The rate of the first primary outcome was lower in the clopidogrel arm at 30 days (RR 0.79; 95% CI: 0.67 to 0.92) and at the end of the study (RR 0.82; 95% CI: 0.70 to 0.95). No mortality benefits from clopidogrel were demonstrated. Unfortunately, the clopidogrel arm had excess of major bleeding (HR 1.34, 95% CI 1.14 to 1.57; P<0.01), and minor bleeding. The recently published TRILOGY trial, 14 randomized 7243 patients <75 years presenting with NSTEACS and treated conservatively, to receive either 10 mg of prasugrel or 75mg daily of clopidogrel. In addition, 2083 patients >75 years were similarly randomized but with a lower dose of prasugrel 5mg. At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, MI or stroke among patients <75 years occurred in 13.9% of prasugrel group and 16.0% of the clopidogrel group (HR 0.91; 95% CI 0.79 to 1.05; P=0.21). Similar results were observed in the overall study population (HR 0.96, 95% CI: 0.86 to 1.07; P=0.45). Rates of severe and intra-cranial bleeding were similar between the two groups in all age groups (HR for prasugrel 1.31, 95% CI 0.81 to 2.11, P=0.27). There was no significant between-group difference in the frequency of non-hemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. Interestingly, after median follow up of 12 months, there was divergence in the curves for primary and component end points in favor of prasugrel. Reasons for this finding is unclear at this time and long term follow up results from the study may provide with more information. Clinical evidence to support the use of Vol No. 6 MINERVA CARDIOANGIOLOGICA 613

4 dual clopidogrel and aspirin therapy in patients with ST-elevation MI (STEMI) was derived from the CLARITY-TIMI 28 trial. 15 This study enrolled 3491 patients, 18 to 75 years of age, who presented within 12 hours after the onset of an ST-elevation myocardial infarction and randomly assigned them to receive clopidogrel (300-mg loading dose, followed by 75 mg once daily) or placebo. The primary efficacy end point, a composite of an occluded infarct-related artery on angiography or death or recurrent myocardial infarction before angiography, occurred in 21.7% in the placebo group and 15% in the clopidogrel group (ARR 6.7% 95% CI: 24% to 4%; P<0.001). At end of 30days, clopidogrel therapy reduced the odds of the composite end point of death from cardiovascular causes, recurrent MI, or recurrent ischemia leading to the need for urgent target lesion revascularization (TLR) by 20% (14.1% to 11.6%; P=0.03). The rates of major bleeding and intracranial hemorrhage were similar in the two groups. However, the follow-up period in CLARITY-TIMI 28 was limited to 30 days. Similarly, in COMMIT trial, patients were randomized within 24hrs of suspected acute-mi to clopidogrel 75mg or placebo in addition to aspirin and standard therapy. The primary composite end-point of death/mi/stroke was significantly lower in the clopidogrel group compared to placebo (9.2% vs. 10.1%, OR % CI 0.86 to 0.97, P=0.002). Most of this cohort was not subject to coronary revascularization. As with CLARITY-TIMI 28 trial, bleeding events were similar in both groups (0.58% vs. 0.55%, P=0.59). Dual antiplatelet therapy in patients with ACS treated with PCI The PCI-CURE, 17 a subset of the CURE study further evaluated patients who underwent PCI following non-st elevation MI (NSTEMI) to determine whether prolonged DAPT was superior to short-term therapy. The primary endpoint of the PCI-CURE trial was a composite of MI, CV death, or urgent target-vessel revascularization within 30 days of PCI. Results showed that clopi- DUAL ANTIPLATELET therapy for PRIMARY and SECONDARY prevention dogrel use was associated with an overall relative risk reduction of 31% in CV death or MI compared with placebo (P=0.002), which included events that were prevented before and after PCI. The primary endpoint occurred in 4.5% of patients receiving clopidogrel and 6.4% of those in the placebo group (P=0.03). After PCI, long-term clopidogrel use was associated with a reduced rate of CV death or MI (P=0.047), as well as CV death, MI, or any revascularization (P=0.03). At follow-up, no significant difference in major bleeding was observed between the groups. In the CREDO trial, 18 patients were randomly assigned to receive a 300-mg clopidogrel loading dose (N.=1053) or placebo (N.=1063) 3 to 24 hours before PCI. Thereafter, all patients received clopidogrel 75 mg/d, through day 28. From day 29 through 12 months, patients in the loading-dose group received clopidogrel, 75 mg/d, and those in the control group received placebo. Both groups received aspirin throughout the study. At 1 year, long-term clopidogrel therapy was associated with a 26.9% relative risk reduction (RRR) in the combined risk of death, MI or stroke (95% CI 3.9% to 44.4%, P=0.02). Among the 893 patients receiving their loading dose of study medication 3 to less than 6 hours prior to PCI, no benefit of clopidogrel pretreatment was found (RRR, 13.4%: 95% CI, 29.8% to 83.3% P=0.60). On the other hand, in the 230 patients treated 6 to less than 12 hours prior to PCI and in the 621 patients treated 12 to 24 hours before PCI, the RRR in the combined end point was 35.5% (95% CI: 73.3% to 55.6%; P=0.32) and 40.1% (95% CI, 67.6% to 10.7%; P=.09), respectively. The risk of bleeding at 1 year was not statistically significant between the two groups (8.8% in clopidogrel compared to 6.7% in placebo, P=0.07). Pretreatment with clopidogrel for 15 h resulted in an endpoint rate of 3.5% and achieved a RRR of 58.5% (P=0.028) compared with the placebo arm. Patients treated with clopidogrel <15 h before procedure, or with placebo, had similar rates of occurrence of the endpoint (7.8 and 8.3%, respectively). Based on this 614 MINERVA CARDIOANGIOLOGICA December 2012

5 Dual antiplatelet therapy for PRIMARY and SECONDARY prevention data, patients should receive 300mg loading dose of clopidogrel (most patients receive 600 mg nowadays) at least 3 hours prior to PCI. However, in view of the brief time interval between undertaking the diagnostic coronary angiography and the PCI procedure this recommendation is not practical. Moreover, patients who receive the loading dose and require bypass surgery may be exposed to excessive risk of bleeding. Many physicians and institutions prefer to give 600mg of clopidogrel or new P2Y12 blockers just prior to PCI after completion of diagnostic coronary angiography, based on accumulating clinical evidence from trials in patients with ACS. Pretreatment dose of clopidogrel 300 mg vs. 600mg: does it matter? In the PRAGUE 8 study, patients due to undergo elective coronary angiography for suspected or proven coronary artery disease were randomized to receive clopidogrel 600 mg >6 hours before coronary angiography (mean duration between drug administration and coronary angiography was 20.6 hours), or to receive clopidogrel 600 mg after coronary angiography and prior to PCI, only where PCI was undertaken. There was no difference in the rate of the primary endpoint, which included death, periprocedural MI, stroke, TIA, or target vessel revascularization (TVR) within 7 days, between groups (0.8 vs. 1%; P=0.749) of non-selectively and selectively treated patients, respectively. However, significantly more bleeding complications occurred in non-selectively treated patients, compared with selectively treated patients (3.5 vs. 1.4%, respectively, P=0.027). The Antiplatelet therapy for Reduction of Myocardial Damage during Angioplasty (AR- MYDA-2) trial 20 evaluated the effect of a 300- mg versus a 600-mg loading dose of clopidogrel on the primary endpoint of MI, target vessel revascularization, or 30-day occurrence of death in patients undergoing PCI. The investigators observed antiplatelet effects by measuring creatine kinase MB, troponin I, and myoglobin levels at base- line and at 8 and 24 hours after clopidogrel administration. In this study, the primary endpoint occurred in 4% of patients receiving the higher clopidogrel loading dose compared with 12% of those receiving the conventional loading dose (P=0.041). These results were entirely due to the occurrence of periprocedural MIs (15 events in the 300-mg treatment group; 5 events in the 600-mg treatment group). Multivariate analysis demonstrated a 50% reduction in the risk of MI with the high loading-dose regimen (P=0.044). Through 30 days, target vessel revascularization occurred in one patient (600-mg group) and there were no deaths. In this study, high-dose clopidogrel was not associated with bleeding complications. The Clopidogrel Loading with Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) trial 21 evaluated the comparative efficacy of two different loading doses of clopidogrel (300-mg and 600-mg) alone and in combination with the glycoprotein (GP) IIb/IIIa inhibitor Eptifibatide to address the limitations observed with the 300-mg loading dose of clopidogrel. Clopidogrel was administered immediately after stenting. Results showed that the addition of eptifibatide to clopidogrel 600- mg produced a 2-fold increase in platelet inhibition at 3, 8, and hours following stenting compared with clopidogrel 600-mg alone (P<0.001), as measured by 5 mmol/l of ADP-induced aggregation. Treatment with 600 mg of clopidogrel produced better platelet inhibition than 300 mg of clopidogrel at all-time points (P<0.001). Maximum platelet inhibition induced by 600 mg of clopidogrel alone was observed at 8 hours after the procedure. The Clopidogrel optimal loading dose Usage to Reduce Recurrent Events-Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS) 7 study 22 evaluated the efficacy and safety of higher versus standard dosages of clopidogrel and aspirin in more than ACS patients with UA/NSTEMI (70.8%) and STE- MI (29.2%). These patients were managed with an early invasive strategy with intent for PCI as early as possible, but no later than 72 hours after randomization. This Vol No. 6 MINERVA CARDIOANGIOLOGICA 615

6 Newer P2Y12 inhibitors To overcome this potential limitation of clopidogrel, new generation P2Y12 inhibitors were studied comparing their efficacies to clopidogrel. TRITON-TIMI randomly assigned 13,608 patients with moderate-tohigh-risk ACS with scheduled PCI to receive prasugrel (a 60-mg loading dose and a 10- mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal MI, or nonfatal stroke. The key safety end point was major bleeding. The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients relarge factorial study compared high-dose clopidogrel (600-mg loading dose followed by 150 mg/day on days 2-7, then 75 mg/ day) with the standard-dose regimen (300- mg loading dose followed by 75 mg/day) initiated as soon as possible and before PCI for preventing the composite of CV death, MI, or stroke at 30 days. The same composite endpoint was assessed in an evaluation of high-dose aspirin ( mg/day) versus a lower daily dosage ( mg/day). Among the 25,087 ACS patients enrolled in this study, 17,232 underwent PCI. In the overall population, the primary endpoint (PEP) defined as composite of CV death, MI, or stroke occurred in 4.2% of patients receiving high-dose clopidogrel therapy compared with 4.4% in the standard-dose group (P=0.370). However, in patients who underwent PCI, there was a 15% RRR and 0.6% ARR (HR 0.85, 95% CI ; P=0.036) in PEP among the subjects receiving high dose clopidogrelwith concordant reduction in MI rates (2% vs. 2.6%; P=0.012) and all stent thrombosis (2.5% vs. 3.5%, HR 0.72; 95% CI ; P=0.024). For aspirin therapy, no difference in outcome was observed with the use of high-dose aspirin compared with the lower-dose regimen, and this outcome was not affected by the use of PCI. Highdose clopidogrel was associated with an increase in major bleeding compared with standard-dose clopidogrel in the overall study population (2.5% vs. 2.0%; P=0.01), as well as in those who underwent PCI (1.6% versus 1.1%; P=0.006). An increase in severe bleeding was also observed in PCI patients receiving high-dose clopidogrel compared with those receiving the standard dose (1.1% versus 0.8%; P=0.034). No increase in TIMI major bleeding, CABG-related bleeding, or fatal bleeding events was observed. Limitations of clopidogrel In spite of modern treatment achievements, rates of recurrence and cardiovascular death remain high in patients who have experienced an ACS. In the CURE trial 582/6259 (9.3%) of patients experienced non-fatal MI, stroke, or death from cardio- DUAL ANTIPLATELET therapy for PRIMARY and SECONDARY prevention vascular causes during DAPT for up to 12 months. The incidence of recurrent events rose to 16.5% when refractory ischemia was also counted as an event. In such a clinical trial setting, recurrent events may be attributed to insufficient potency of the drug regimen. Recurrent cardiovascular events following ACS may also be caused by clopidogrel hypo-responsiveness. Indeed, there is marked individual variation in the degree of platelet inhibition achieved after administration of clopidogrel, and a clinically inadequate response has been shown to occur in between 4 and 30% of patients. In vitro studies 23 have demonstrated that responsiveness to clopidogrel is subject to inter-individual and intra-individual variability, which may result in the occurrence of ischemic events after stent placement, stent thrombosis, and periprocedural MI. The variable responsiveness with antiplatelet agents involves both pharmacokinetic and pharmacologic mechanisms, 24 and a combination of factors may influence the variability in response to clopidogrel. These factors include platelet function (i.e., increased sensitivity to collagen and ADP), genetic polymorphisms, reduced drug bioavailability (i.e., poor absorption, under-dosing, patient noncompliance, interactions with other drugs), and the presence of diabetes, hypercholesterolemia, high body mass index, or smoking. 616 MINERVA CARDIOANGIOLOGICA December 2012

7 Dual antiplatelet therapy for PRIMARY and SECONDARY prevention ceiving prasugrel (HR 0.81; 95% CI: 0.73 to 0.90; P<0.001). The difference between the treatment groups with regard to the rate of the primary end point was largely related to a significant reduction in myocardial infarction in the prasugrel group (9.7% in the clopidogrel group vs. 7.4% in the prasugrel group; HR 0.76; 95% CI, 0.67 to 0.85; P<0.001). When compared to clopidogrel, there was also significant reduction in urgent TLR (2.5% vs. 3.7% P<0.001), and stent thrombosis (ST) (1.1% vs. 2.4%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (HR 1.32; 95% CI: 1.03 to 1.68; P=0.03). The benefit tended to be greater among patients with diabetes (HR 0.70; 95% CI, 0.58 to 0.85; P<0.001) than among those without diabetes (HR 0.86; 95% CI, 0.76 to 0.98; P=0.02). There was no significant difference in primary end point if a bare metal stent (BMS) or a drug eluting stent (DES) was used (10% in prasugrel group vs. 12.2% in clopidogrel group and 9.4% in prasugrel group vs. 11.6% in clopidogrel group, respectively). In patients with a history of cerebrovascular events, no evidence of a clinical benefit was observed from prasugrel compared with clopidogrel. On contrary, there was significant harm with the use of prasugrel in these patients. Unlike thienopyridines, ticagrelor is a reversible P2Y12 inhibitor. The PLATO trial 26 compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 ACS patients. At 12 months, the primary end point, a composite of death from vascular causes, MI, or stroke occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (HR 0.84; 95% CI: 0.77 to 0.92; P<0.001). Predefined secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). Majority of patients in both groups who underwent PCI with stenting received BMS (66%) and fewer than 20% were treated with DES. Significant differences were also observed with the rate of death from vascular causes (5.1% with clopidogrel and 4% with ticagrelor, P=0.001) and MI alone (6.9% with clopidogrel and 5.8% with ticagrelor, P=0.005), but not with stroke alone. The rate of definite stent thrombosis was lower in patients receiving ticagrelor compared with clopidogrel (1.3% vs. 1.9%, P=0.009). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary artery bypass grafting (CABG) (4.5% vs. 3.8%, P=0.03). Dyspnea occurred more frequently with ticagrelor compared with clopidogrel5; therefore, it has been suggested that patients with known breathing difficulties are not good candidates for ticagrelor. Ticagrelor showed benefit over clopidogrel in patients who had previously received clopidogrel, patients with both planned invasive or noninvasive treatment, patients with STEMI referred for primary PCI, patients with non-stemi, and patients who underwent CABG. Type of stent use in acute coronary syndromes impact on DAPT In contemporary trials, DES have been proven to reduce the rate of restenosis by marked inhibition of neointimal hyperplasia. The culprit sites in ACS have large necrotic cores with a paucity of smooth muscle cells. In these lesions, penetration of the stent struts into the necrotic core is frequently observed after stent implantation. Pathologic observations have revealed that the lesions stented with DES frequently show greater delay in arterial healing than those treated with BMS. Thus, ACS culprit sites could be potentially at risk for thrombosis after DES implantation. Various trials Vol No. 6 MINERVA CARDIOANGIOLOGICA 617

8 have aimed to compare the effectiveness of DES to BMS in ACS patients. Patients with STEMI were excluded from the SIRIUS (Sirolimus-Eluting Stent in de Novo Native Coronary Lesions) and TAXUS IV (Paclitaxel-Eluting Stent) trials. SIRIUS 27 was a randomized, double-blind trial comparing a sirolimus-eluting stent (SES) with a BMS in 1058 patients in a native coronary artery. The primary end point was failure of the target vessel (a composite of death from cardiac causes, myocardial infarction, and repeated percutaneous or surgical revascularization of the target vessel) within 270 days. Before and after the index procedure, all patients received oral aspirin 325 mg daily and oral clopidogrel (a loading dose of 300 to 375 mg 24 hours before the procedure and then 75 mg daily for three months). The rate of failure of the target vessel was reduced from 21% with a standard stent to 8.6% with a SES (P<0.001). This was driven largely by a decrease in TLR (16.6% in the BMS group vs. 4.1% in the SES group, P<0.001). The frequency of neointimal hyperplasia within the stent was also decreased in the group that received SES, as assessed by both angiography and intravascular ultrasonography. Five-year results from this study showed that major adverse cardiovascular events (MACE) remained significantly lower in SES-treated patients than BMS-treated patients (20.3% vs. 33.5%; P<0.0001, respectively). MACE rates were driven almost entirely by the reduced rate of TLR (9.4% in the SES group as compared with 24.2% in the BMS group (P<0.0001). There were no significant differences in death, MI, non-target lesion revascularization, or stent thrombosis at five years. TAX- US IV trial 28 enrolled 1314 patients who were receiving a stent in a single, previously untreated coronary-artery stenosis in a prospective, randomized, double-blind study. A total of 652 patients were randomly assigned to receive a BMS and 662 patients to receive paclitaxel-eluting stent (PES). Before and after the index procedure, all patients received oral aspirin 325 mg daily and oral clopidogrel (a loading dose of 300 mg before the procedure and then 75 mg daily DUAL ANTIPLATELET therapy for PRIMARY and SECONDARY prevention for six months). The rate of ischemia-driven TLR at nine months was reduced from 12.0% with the implantation of a BMS to 4.7% with the implantation of a PES (RR 0.39; 95% CI: 0.26 to 0.59; P<0.001). There was TLR required in 3.0% of the group that received a PES, as compared with 11.3% of the group that received a BMS (RR 0.27; 95% CI 0.16 to 0.43; P<0.001). The rate of angiographic restenosis was reduced from 26.6% to 7.9% with PES (RR 0.30; 95% CI 0.19 to 0.46; P<0.001). The nine-month composite rates of death from cardiac causes or myocardial infarction (4.7% and 4.3%, respectively) and stent thrombosis (0.6% and 0.8%, respectively) were similar in the group that received a PES and the group that received a BMS. In contrast to SIRIUS which excluded patients with STEMI, the TYPHOON trial [29], was a single-blind, multicenter, prospectively randomized trial to compare SES with BMS in primary PCI for acute STEMI. The primary end point was target-vessel failure at 1 year after the procedure, defined as target-vessel-related death, recurrent MI, or TLR. The rate of the primary end point was significantly lower in the SES group than in the uncoated-stent group (7.3% vs. 14.3%, P=0.004). This reduction was driven by a decrease in the rate of TLR (5.6% and 13.4%, respectively; P<0.001). There was no significant difference between the two groups in the rate of death (2.3% and 2.2%, respectively; P=1.00), re-infarction (1.1% and 1.4%, respectively; P=1.00), or stent thrombosis (3.4% and 3.6%, respectively; P=1.00). The degree of neointimal proliferation, as assessed by the mean (±SD) in-stent late luminal loss, was significantly lower in the SES group (0.14±0.49 mm, vs. 0.83±0.52 mm in the BMS group; P<0.001). The mean duration of DAPT was 9.7 ± 2.9 in SES group and 9.5 ± 3.1 in BMS. The 4 year follow-up data 30 published showed that this difference was maintained with no late-catch up. In a similar study comparing SES vs. BMS in acute STEMI, the SESAMI trial, 31 the incidence of binary restenosis at 1 yr. was lower in the SES group than in the BMS group (9.3% vs. 21.3%, respectively; P=0.032), as were the rates of TLR (4.3% vs. 11.2%; 618 MINERVA CARDIOANGIOLOGICA December 2012

9 Dual antiplatelet therapy for PRIMARY and SECONDARY prevention P=0.02), target vessel revascularization (5% vs. 13.1; P=0.015), MACE (6.8% vs. 16.8%; P=0.005), and target vessel failure (8.7% vs. 18.7%; P=0.007). The incidence of angiographically documented stent thrombosis was 1.2% (N.=2) in the SES group and 0.6% (N.=1) in the BMS group. The duration of DAPT was 12 months. The 5-year survival rate free from TVF and TLR was significantly higher in the SES than in the BMS group (85% vs. 76% P=0.038; 92% vs. 85% P=0.045, respectively). The lower incidence of adverse events was achieved in the first year of follow-up. The cumulative incidence of MACE, death or non-fatal MI and ST was comparable in the 2 groups at 5-year follow-up. 32 Predictors of death or MI during 5-year follow-up were TLR within 1year (OR 3.4, 95% CI ; P=0.04) and small vessels treatment (OR % CI ; P=0.002). The STRATEGY 33 trial randomized 175 patients presenting with acute STEMI to single high-dose bolus tirofiban regimen plus SES(N.=87) vs. standard-dose abciximab plus BMS (N.=88). The primary end point was a composite of death, nonfatal myocardial infarction, stroke, or binary restenosis at 8 months. Secondary outcomes included freedom, at day 30 and month 8, from major cardiac or cerebrovascular adverse events (composite of death, re-infarction, stroke, and repeat TLR). All patients received aspirin ( mg orally as a loading dose and then mg/d orally indefinitely) and clopidogrel (300 mg orally as a loading dose and then 75 mg/d for at least 3 months). Cumulatively, 14 of 74 patients (19%; 95% CI, 10% to 28%) in the tirofiban plus SES group and 37 of 74 patients (50%; 95% CI: 44% to 56%) in the abciximab plus BMS group reached the primary end point (HR 0.33; 95% CI: 0.18 to 0.60; P<0.001). The cumulative incidence of death, re-infarction, stroke, or TLR was significantly lower in the tirofiban plus SES group (18%) compared to the abciximab plus BMS group (32%) (HR 0.53; 95% CI: 0.28 to 0.92; P=0.04), predominantly reflecting a reduction in the need for TLR. Binary restenosis was present in 6 of 67 (9%; 95% CI 2% to 16%) and 24 of 66 (36%; 95% CI 26% to 46%) patients in the tirofiban plus SES and abciximab plus BMS groups, respectively (P=0.002). The PASSION 34 trial randomized 619 patients presenting with an acute STEMI to receive either a PES or a BMS. The primary end point was a composite of death from cardiac causes, recurrent myocardial infarction, or target-lesion revascularization at 1 year. There was a trend toward a lower rate of serious adverse events in the PES group than in BMS group (8.8% vs. 12.8%; adjusted RR 0.63; 95% CI 0.37 to 1.07; P=0.09). A non-significant trend was also detected in favor of the PES group, as compared with the BMS group, in the rate of death from cardiac causes or recurrent MI (5.5% vs. 7.2%, P=0.40) and in the rate of TLR (5.3% vs. 7.8%, P=0.23). The incidence of stent thrombosis during 1 year of followup was the same in both groups (1.0%). PASSION trial had patients with more complex lesions and an unexpectedly low event in the BMS group. In HORIZONS-AMI trial, patients presenting with acute STEMI were randomized to receive either PES or BMS. Aspirin (324 mg administered in chewable form or 500 mg administered intravenously) was given in the emergency room, after which 300 to 325 mg was given orally every day during the hospitalization and 75 to 81 mg every day thereafter indefinitely. A loading dose of clopidogrel (either 300 mg or 600 mg, at the discretion of the investigator) was administered before catheterization, followed by 75 mg orally every day for at least 6 months (with a recommendation of 1 year or longer). DAPT was continued in 94.7% patients in SES group and 87.5% in BMS at 6 months and 73.1% in SES group and 63.9% in BMS at 1year. Patients who received PES, as compared with those who received BMS, had significantly lower 12-month rates of ischemia-driven TLR (4.5% vs. 7.5%; HR 0.59; 95% CI 0.43 to 0.83; P=0.002) and TLR (5.8% vs. 8.7%; HR 0.65; 95% CI 0.48 to 0.89; P=0.006), with non-inferior rates of the composite safety end point (8.1% vs. 8.0%; HR 1.02; 95% CI, 0.76 to 1.36; absolute difference, 0.1% point; 95% CI, 2.1 to 2.4; P=0.01 for non-inferiority; P=0.92 for superiority). Patients treated Vol No. 6 MINERVA CARDIOANGIOLOGICA 619

10 First generation DES Premature discontinuation of DAPT has been shown to be an independent predictor for stent thrombosis after DES implantation. 38 Independent predictors of ST were premature DAPT discontinuation (HR]89.78; 95% CI: to ; P<0.001), renal failure (HR 6.49; 95% CI: 2.60 to 16.15; P<0.001), bifurcation lesions (HR 6.42; 95% CI: 2.93 to 14.07; P<0.001), diabetes (HR 3.71; 95% CI: 1.74 to 7.89; P=0.001), and a lower left ventricular ejection fraction (EF) (HR 1.09; 95% CI: 1.05 to 1.36; p <0.001 for each 10% decrease). Tables I, II summarize the MACE events in contemporary PCI studies. In one study consecutive patients were successfully treated DES and discharged with DAPT (aspirin and clopidogrel) for a period of 12 months; 119 patients (8.8%) had discontinued one or both antiplatelet agents within the first 12 months ( early discontinuation) and 65 patients (4.8%) had discontinued aspirin after 1 year ( late discontinuation). Patients with early discontinuation experienced a greater incidence of MACE (28.6% vs. 13.7%, P<0.001) and ST (7.6% vs. 3.4%, P=0.038). All-cause mortality (13.4% vs. 4.7%, p <0.001) and cardiovascular death (5% vs. 1.2%, P=0.007) were significantly more frequent among patients with early discontinuation. This data was similar to that from EVENT registry, 40 which showed that non-cardiac surgery in the year after DES implantation is frequent and a strong predictor of cardiac death, MI and stent thrombosis (HR 27.3, 95% CI: 10.0 to 74.2, P<0.001). At the same time, this registry also showed that the risk for adverse events after DAPT discontinuation decreases in a time-dependwith PES and those treated with BMS had similar 12-month rates of death (3.5% and 3.5%, respectively; P=0.98) and ST (3.2% and 3.4%, respectively; P=0.77). The 13-month rate of binary restenosis was significantly lower with PES than with BMS (10.0% vs. 22.9%; HR 0.44; 95% CI 0.33 to 0.57; P<0.001). In a meta-analysis of 14 randomized clinical trials 36 of DES vs. BMS in acute myocardial infarction, there was no difference in the hazard of death or recurrent myocardial infarction (HR 0.91; 95% CI 0.75 to 1.09) between patients treated with DES versus patients treated with BMS. Treatment with DES resulted in a significant reduction in the hazard of re-intervention (HR 0.41; 95% CI 0.32 to 0.52). The hazards of death (HR 0.90; 95% CI 0.71 to 0.15), MI (HR 0.81; 95% CI 0.63 to 1.04), ST (HR 0.84; 95% CI 0.61to1.17) were not significantly different between patients treated with drug eluting stents versus patients treated with bare-metal stents. The duration of DAPT ranged from 3 months to 12 months. Recently published, BASE-ACS trial 37 randomized 827 patients presenting with ACS (NSTEMI and STEMI) to receive either everolimus-eluting stents (EES) or a titanium-nitride-oxide-coated bioactive BMS (BAS). The primary endpoint was a composite of cardiac death, non-fatal MI or ischemia-driven TLR at 12-month follow-up. Patients were pre-treated with aspirin at a loading dose of 250 mg orally or mg intravenously during the procedure, and continued thereafter at a daily dose of at least mg indefinitely. Oral clopidogrel was initiated at a loading dose of at least 300 mg before or immediately after the procedure, and continued thereafter at a daily dose of 75 mg. DAPT was continued for a minimum of six to maximum of 12 months, according to the operator s discretion. On follow up, about 99.3% of patients in the EES group were maintained on clopidogrel therapy at six months and 68.3% at 12 months (in the BAS group, 89.7% and 51.3%, respectively, p value for comparison with the EES group <0.001 for both). At end of 12-months, the primary composite endpoint occurred in 9.6% of patients in the BAS DUAL ANTIPLATELET therapy for PRIMARY and SECONDARY prevention group and 9.0% of those in the EES group (HR 1.04, 95% CI: 0.81 to 1.32, P=0.81, P for non-inferiority =0.001). Non-fatal MI was significantly less frequent in the BAS as compared with the EES group (2.2% vs. 5.9%, P=0.007). However, the individual rates of cardiac death and ischemia-driven TLR were similar between the two groups (1.9% vs. 1.0%, P=0.39, and 6.5% vs. 4.9%, P=0.37, respectively). 620 MINERVA CARDIOANGIOLOGICA December 2012

11 Dual antiplatelet therapy for PRIMARY and SECONDARY prevention Table I. Frequency of MACE in contemporary PCI studies. Study Follow up duration ACS Death ent manner. The incidence of acute coronary events was found to be 12% in those who discontinued DAPT within 3 months of stent implantation compared to 4.9% in patients who suspended DAPT after 3 months. In a prospective observation cohort study that included 6,816 patients who underwent CV Death Nonfatal MI Stent Thrombosis DES implantation, discontinuation of clopidogrel was associated with ST in the first 6 months only (P<0.0001). During that period, the median time interval from clopidogrel discontinuation to ST was 9 days (interquartile range [IQR] 5.5 to 22.5) while thereafter it was days (IQR 7.4 to 294.8). The Vol No. 6 MINERVA CARDIOANGIOLOGICA 621 TVR Non -TVR COMPARE Patients receiving PCI at a single center randomized to PES vs. EES with one year follow-up (N.=1797) 45 EES (N.=897) 1 year 541 (60) 43 (8.3) 7 (0.8) 18 (2) 2 (0.2) 5 (0.6) - PES (N.=903) 1 year 534 (59) 6 (0.7) 6 (0.7) 28 (3) 15 (2) 19 (2) - DES.DE (N.=4962) 55 Observational study of patients in the DES.DE registry comparing PES, SES, and BMS for one-year clinical outcomes SES (N.=2137) 1 year 837 (39) 88 (4.1) - 68 (3.2) 77 (3.6) 222 (10.4) - PES (N.=2740) 1 year 1146 (42) 104 (3.8) - 88 (3.2) 104 (3.8) 285 (10.4) - BMS (N.=485) 1 year 296 (61) 16 (5.2) (6) 21 (4.3) 73 (14.9) - GERSHWIN Patients with CAD for elective PCI treated with SES or BMS and 18 month clinical follow-up (N.=952) 56 SES (N.=658) 1.5 years 175 (27) (1.2) 51 (8) 105 (16) BMS (N.=294) 1.5 years 85 (29) (0.3) 41 (17) 38 (13) REALITY (N.=1386) 42 Patients with de novo coronary artery lesions randomized to SES versus PES with one-year clinical follow-up SES (N.=684) 1 year - 16 (2.3) 10 (1.5) 35 (5.1) 5 (0.7) 14 (2.0) - PES (N.=669) 1 year - 9 (1.3) 7 (1.0) 40 (6.0) 13 (1.9) 12 (1.8) - SIRIUS (N.=1058) 27 SES (N.=533) 5 years 432 (81) 43 (8.3) 21 (3.8) (0.4) 123 (23) 112 (21) (20.1; 8.8 TVR) BMS (N.=524) 5 years 456 (87) 44 (8.4) 26 (5) 31 (5.7; 3.4 TVR) 4 (0.8) 225 (43) 110 (21) SPIRIT III (N.=951) 57, 58 Patients with 2 de novo coronary artery lesions randomized to EES versus PES with two-year clinical follow-up EES (N.=642) 2 years - 13 (2.0) 7 (1.1) 21 (3.3) 6 (1.0) 65 (10.1) - [TLR 39 (6.1)] PES (N.=309) 2 years - 8 (2.6) 4 (1.3) 18 (5.9) 5 (1.7) 43 (13.9) [TLR-35 (11.3)] - SPIRIT IV (N.=3687) 59 Patients with 2 de novo coronary artery lesions randomized to EES versus PES with five-year clinical follow-up EES (N.=2416) 5 years - 24 (1) 97 (0.4) 46 (1.9) 7 (0.29) 101 (4.2) - PES (N.=1195) 5 years - 16 (1.3) 48 (0.4) 37(3.1) 13 (1.06) 81 (6.8) - TAXUS IV N.=1294) 60 Patients with single de novo coronary artery lesion randomized to BMS versus PES with five-year follow-up TAXUS (N.=651) 5 years 432 (66) 65.1 (10) 29 (4.4) 47 (7.2) 23 (3.5) 110 (16.9) 59 (9.1) BMS (N.=643) 5 years 402 (63) 72 (11.2) 29 (4.5) 48 (7.4) 22 (3.4) 176 (27.4) 67 (10.4) Metanalysis (N.=1228) 61 Combined data from three randomized control trials (ASCENT, NIRVANA, SMART) comparing postintervention outcomes at one year with those at five years Post-PCI at 5 year 488 (39.7) 11 (0.90) 9 (0.73) 104 (8.5) - Total TVR (8.9) 1Year Post-PCI at 5 Years (15) 5 year 488 (39.7) 89 (8.2) 53 (5) 180 (16) - Total TVR 270 (23) 242 (22)

12 Table II. Cumulative clinical outcomes by stent type over time. Follow up duration Death latter finding suggests that events occurring after 6 months are most likely not due to the discontinuation of clopidogrel. In an observational study, 41 2-year outcomes were assessed in patients undergoing SES implantation. Incidences of definite ST were 0.34% at 30 days, 0.54% at 1 year, and 0.77% at 2 years. Thienopyridine use was maintained in 97%, 62%, and 50% of patients at 30 days, 1 year, and 2 years, respectively. Patients who discontinued both thienopyridine and aspirin had a significantly higher rate of stent thrombosis than those who continued both for <6 months, 6 to 12 months, and 12 to 24 months after stent implantation (1.76% vs. 0.1%, P<0.001; 0.72% vs. 0.07%, P=0.02; and 2.1% vs. 0.14%,P=0.004, respectively). When discontinuation of aspirin was taken into account, patients who discontinued thienopyridine only did not have an excess of stent thrombosis in any of the time intervals studied. Although grouped together DES vary in their drugs (including drug kinetics), and design (stent material, surface coating, structure, and polymer). These design variations have been associated with clear and consistent differences in clinical outcomes. Two randomized trials, Sirolimusversus Paclitaxel-eluting Stents in de novo Coronary Artery Lesions (REALITY) and Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization (SIR- DUAL ANTIPLATELET therapy for PRIMARY and SECONDARY prevention CV Death Nonfatal MI Stent Thrombosis 1 year EES (N.=897) 43 (4.8) 7 (0.78) 18 (2.0) 2 (0.22) 5 (0.56) PES (N =4312) 113 (2.6) 13 (0.30) 156 (3.6) 132 (3.1) 316 (7.3) SES (N.=2821) 104 (3.7) 10 (0.35) 103 (3.7) 82 (2.9) 236 (8.4) BMS (N.=485) 16 (3.3) - 29 (6.0) 21 (4.3) 73 (15) ALLª (N.=9743) 287 (2.9) 39 (0.40) 410 (4.2) 237 (2.4) 815 (8.4) 1-4 years EES (N.=642) 13 (2.0) 7 (1.1) 21 (3.3) 6 (0.93) 65 (10) PES (N =309) 8 (2.6) 4 (1.3) 18 (5.8) 5 (1.6) 43 (14) SES (N.=658) (1.2) 51 (7.8) BMS (N.=294) (3.1) 41 (14) ALL (N.=1903) 21 (1.1) 11 (0.58) 39 (2.1) 28 (1.5) 200 (11) 5 years PES (N =1846) 81 (4.4) 77 (4.2) 84 (4.6) 34 (1.8) 191 (10) SES (N.=533) 43 (8.1) 21 (3.9) 107 (20) 2 (0.38) 112 (21) BMS (N.=1167) 116 (9.9) 55 (4.7) 79 (6.8) 26 (2.2) 401 (34) ALLª (N.=4034) 329 (8.2) 206 (5.1) 450 (11) 62 (1.5) 974 (24) TAX) assessed whether differences might exist between SES and PES when tested in the more complex patients and lesion types encountered in routine practice, in contrast to the early SIRIUS and TAXUS IV trials which relatively had low risk patients and simple lesions. In the REALITY trial, 42 the typical difference in late loss was observed in favor of SES but did not translate into a difference in the primary end point of binary angiographic restenosis at 8 months or any of the secondary clinical end points at 1 year. In this study, Aspirin 100 mg daily was administered indefinitely to all patients. Clopidogrel, 75 mg once daily, was administered for 6 months or more In the PES group and for 2 months or more in the SES group. In contrast, the SIRTAX trial 43 showed a significant reduction in the clinical primary end point of MACE at 9 months for SES, with most of the difference resulting from a 44% reduction in TLR. In a meta-analysis of 16 trials (including 8,695 patients), 44 compared with PES, SES significantly reduced the risk of re-intervention (HR 0.74; 95% CI: 0.63 to 0.87, P<0.001) and ST (HR 0.66; 95% CI: 0.46 to 0.94, P=0.02) without significantly impacting on the risk of death (HR 0.92; 95% CI: 0.74 to 1.13, P=0.43) or MI (HR 0.84; 95% CI: 0.69 to 1.03, P=0.10). Minimum duration of DAPT treatment in these trials was 6 months (range 6 to 12 months). 622 MINERVA CARDIOANGIOLOGICA December 2012 TVR

13 Dual antiplatelet therapy for PRIMARY and SECONDARY prevention Second generation DES Clinical experience has shown that endothelialization of a first-generation DES is incomplete in humans with atherosclerosis, leaving stent struts exposed to the arterial lumen months to years after stent implantation, and that thrombi formed at the exposed sites. It has been reported that rate of late and very late ST is less frequent with second generation DES. Results from the Spanish registry ESTROFA-2, which included 4768 patients (2549 treated with ZES, and 2219 with EES) showed that the cumulative incidence of definite/probable ST for ZES was 1.3% at 1 year and 1.7% at 2 years and for EES 1.4% at 1 year and 1.7% at 2 years (P=0.8). The increment of definite thrombosis between the first and second year was 0.2% and 0.25%, respectively. In COMPARE trial, patients were randomized to either the XIENCE-V or the TAXUS-LIBERTE DES and followed up to one year. The primary composite end point of all death, nonfatal MI, and TVR occurred in 9.0% of EES patients and 13.7% of PES patients (RR: 0.66; 95% CI: 0.50 to 0.86) driven by a lower rate of MI (3.9% vs. 7.5%; RR 0.52; 95% CI: 0.35 to 0.77) and target vessel revascularization (3.2% vs. 8.0%; RR: 0.41; 95% CI: 0.27 to 0.62), and a lower rate of definite or probable ST (0.9% vs. 3.9%; RR 0.23; 95% CI: 0.11 to 0.49). Similar results were seen in the SPIRIT IV trial. However, the COMPARE trial included a more complex patient population than SPIRIT IV, including 25% acute-mi patients, 23% STEMI patients, and relatively high proportions of patients with calcified lesions, bifurcations, multi-vessel disease, and diabetes. The EES are associated with a similar incidence of ST both in acute and chronic patients (0.7%), whereas the PES had an incidence of ST dramatically higher in patients with ACS compared with stable patients (2.9% vs. 1.8%). In recently published data from Swedish registry, SCAAR 46 showed a statistically significant lower risk of restenosis in the new generation DES compared with BMS (adjusted HR 0.29; 95% CI: 0.25 to 0.33) and older generation DES (HR 0.62; 95% CI: 0.53 to 0.72). A lower risk of definite ST was found in the new generation DES compared with BMS (HR 0.38; 95% CI: 0.28 to 0.52) and old generation DES (HR 0.57; 95% CI: 0.41 to 0.79). The risk of death was significantly lower in new generation DES compared with older generation DES (adjusted HR: 0.77; 95% CI: 0.63 to 0.95) and BMS (adjusted HR: 0.55; 95% CI: 0.46 to 0.67). The Kaplan-Meier curves continued to separate at end of 2 years. Recently, the RESOLUTE all-comers study reported TLR rates of 4.4% with the ZES resolute and 4.0% with EES in complex lesions; no significant differences in TLR rates were reported between ZES and EES in simple lesions (3.0% ZES vs. 2.1% EES, P=NS). The Clopidogrel Use and Long-Term Safety After Drug-Eluting Stents Implantation (ZEST- LATE) trial and the Correlation of Clopidogrel Therapy Discontinuation in Real-World Patients Treated With Drug-Eluting Stent Implantation and Late Coronary Arterial Thrombotic Events (REAL-LATE) trial 47 randomized patients who had been event free after 12 to 18 months of DAPT following stent implantation to continue aspirin and clopidogrel or aspirin alone. Most patients received SES, with about a quarter receiving paclitaxel-eluting stents PES and < 20% receiving zotarolimus eluting stents (ZES). The incidence of death or myocardial infarction was similar among the groups (ZES vs. SES vs. PES, 5.8% vs. 6.9% vs. 7.6%, respectively, P=0.31). The incidence of stent thrombosis was significantly lower in the SES group (ZES vs. SES vs. PES, 0.7% vs. 0% vs. 0.8%, respectively, P=0.02). In PRODIGY trial, patients (74% with acute coronary syndromes and 26% with stable angina) who underwent stenting were randomized to six or 24 months of dual antiplatelet treatment (clopidogrel plus aspirin). The primary end point was all-cause mortality, nonfatal MI, or stroke at two years. Results showed that the overall risk of the primary end point was almost identical between the two groups (10.0% in 6 month group vs in 12 month group, HR 0.98; 95% CI: 0.74 to 1.29, p = 0.91). The individual risks of death, MI, stroke, or stent thrombosis also did not differ between the two groups. In the trial, patients Vol No. 6 MINERVA CARDIOANGIOLOGICA 623