2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS - Web Addenda

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1 European Heart Journal (2017) 00,1 23 doi:101093/eurheartj/ehx419 ESC GUIDELINES 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS - Web Addenda The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS) Authors/Task Force Members: Marco Valgimigli* (Chairperson) (Switzerland), Héctor Bueno (Spain), Robert A Byrne (Germany), Jean-Philippe Collet (France), Francesco Costa (Italy), Anders Jeppsson 1 (Sweden), Peter Jüni (Canada), Adnan Kastrati (Germany), Philippe Kolh (Belgium), Laura Mauri (USA), Gilles Montalescot (France), Franz-Josef Neumann (Germany), Mate Petricevic 1 (Croatia), Marco Roffi (Switzerland), Philippe Gabriel Steg (France), Stephan Windecker (Switzerland), and Jose Luis Zamorano (Spain) Additional Contributor: Glenn N Levine (USA) Document Reviewers: Lina Badimon (CPG Review Coordinator) (Spain), Pascal Vranckx (CPG Review Coordinator) (Belgium), Stefan Agewall (Norway), Felicita Andreotti (Italy), Elliott Antman (USA), Emanuele Barbato (Italy), Jean-Pierre Bassand (France), Raffaele Bugiardini (Italy), Mustafa Cikirikcioglu 1 (Switzerland), Thomas Cuisset (France), Michele De Bonis (Italy), Victora Delgado (The Netherlands), * Corresponding author: Marco Valgimigli, Cardiology, Inselspital, Freiburgstrasse 8, 3010 Bern, Switzerland Tel: þ , Fax: þ , marcovalgimigli@inselch ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in the Appendix 1 Representing the EACTS ESC entities having participated in the development of this document: Associations: Acute Cardiovascular Care Association (ACCA), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular Interventions (EAPCI) Working Groups: Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Coronary Pathophysiology and Microcirculation, Peripheral Circulation, Pulmonary Circulation and Right Ventricular Function, Thrombosis, Valvular Heart Disease The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only No commercial use is authorized No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC (journalspermissions@oxfordjournalsorg) Disclaimer The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient s caregiver Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations It is also the health professional s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription The article has been co-published with permission in the European Heart Journal [DOI: /eurheartj/ehx419] on behalf of the European Society of Cardiology and European Journal of Cardio-Thoracic Surgery [DOI /ejcts/ezx334] on behalf of the European Association for Cardio-Thoracic Surgery All rights reserved in respect of European Heart Journal, VC European Society of Cardiology 2017 The articles are identical except for minor stylistic and spelling differences in keeping with each journal s style Either citation can be used when citing this article For permissions, please journalspermissions@oupcom

2 2 ESC Guidelines Donna Fitzsimons (UK), Oliver Gaemperli (Switzerland), Nazzareno Galiè (Italy), Martine Gilard (France), Christian W Hamm (Germany), Borja Ibanez (Spain), Bernard Iung (France), Stefan James (Sweden), Juhani Knuuti (Finland), Ulf Landmesser (Germany), Christophe Leclercq (France), Maddalena Lettino (Italy), Gregory Lip (UK), Massimo Francesco Piepoli (Italy), Luc Pierard (Belgium), Markus Schwerzmann (Switzerland), Udo Sechtem (Germany), Iain A Simpson (UK), Miguel Sousa Uva 1 (Portugal), Eugenio Stabile (Italy), Robert F Storey (UK), Michal Tendera (Poland), Frans Van de Werf (Belgium), Freek Verheugt (The Netherlands), and Victor Aboyans (CPG Supervisor) (France) The disclosure forms of all experts involved in the development of this focused update are available on the ESC website The Full Text and Clinical Cases companion document of this focused update are available at: wwwescardio org/guidelines/clinical-practice-guidelines/2017-focused-update-on-dual-antiplatelet-therapy-dapt Keywords Guidelines Aspirin Clopidogrel Ticagrelor Prasugrel Dual antiplatelet therapy Acute coronary syndromes Coronary artery bypass grafting Coronary artery disease Drug-eluting stents Myocardial infarction Stent thrombosis Bleeding Percutaneous coronary intervention Recommendation Revascularization Risk stratification Stents Stable angina Stable coronary artery disease Oral anticoagulant Triple therapy DAPT score PRECISE-DAPT score Non-cardiac surgery Web Contents 2Introduction4 21 Short- and long-term outcomes after percutaneous coronaryintervention4 22 Risk of stent thrombosis in relation to stent type 6 23 Short- and long-term outcomes after coronary artery bypasssurgery11 24 Short- and long-term outcomes after medically managed acutecoronarysyndrome13 3 Efficacy and safety of dual antiplatelet therapy and risk stratificationtools14 31 Dual antiplatelet therapy for the prevention of stent thrombosis14 32 Dual antiplatelet therapy for the prevention of spontaneousmyocardialinfarction Dual antiplatelet therapy and mortality rate 17 34Safetyofdualantiplatelettherapy22 SupplementaryWebTableIA:25 SupplementaryWebTableIB:25 SupplementaryWebTableII:25 WebFigureI: 25 WebFigureII:25 References25 21 Short- and long-term outcomes after percutaneous coronary intervention Significant variation exists in rates of myocardial revascularization across European countries, which is related to varying incidence of the underlying disease condition as well as differences in local practices for diagnosis and treatment 1 However, across all countries, PCI is the dominant modality for myocardial revascularization, with a mean rate of >190 per population, compared with a mean rate of 53 per population for CABG surgery 2 Significant variation exists regarding the proportion of patients undergoing PCI presenting with stable or unstable disease, but ACS is the most frequent indication for revascularization across European countries In the United Kingdom, approximately 65% of interventions in 2015 were undertaken in patients with ACS 3 Short- and long-term results of PCI are governed by the clinical setting (stable CAD vs ACS), 4 the underlying disease complexity (left main and multivessel disease, chronic total occlusion, in-stent restenosis, diabetes, etc), 5 and operator/institutional experience Short-term outcomes after PCI (30 days): Registry data from England and Wales of patients treated with PCI between 2007 and 2011 reported a 30-day mortality of 17% (range 036% in elective PCI to 478% in emergency procedures) 6 In a more recent analysis from the National Cardiovascular Data Registry (NCDR) CathPCI database including PCI procedures performed between July 2009 and June 2011 at 1252 CathPCI Registry sites, in-hospital mortality was 14%, ranging from 02% among elective cases (451% of total cases) to 659% among patients with shock and recent cardiac arrest (02% of total cases) 7 The most important short-term, device-related complication is stent thrombosis, which is associated with MI or death in 50-70% of cases Early stent thrombosis (<30 days) occurs in 0-1% of cases and has been associated with patient, lesion, procedural, and device factors, as well as platelet and coagulation factors Patients with ACS

3 ESC Guidelines 3 have a higher risk of death and stent thrombosis within 30 days compared to patients with stable CAD 4 Mid-term outcomes after PCI (9 12 months): Mid-term clinical and angiographic outcomes of BMS and early- and new-generation DES were recently summarized in a systematic review of 158 randomized clinical trials with patients 8 In the subset of patients with three-vessel disease and/or left main CAD recruited in the Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) trial, the composite of all-cause death, stroke, or MI occurred in 76% of patients treated with PCI at 12 months 9 The most prevalent mid-term, device-related adverse event is target lesion revascularization owing to stent restenosis, which amounts to approximately 9-15% with BMS and <5% with new-generation DES within 12 months Predictors of target lesion revascularization include angiographic complexity, diabetes, and treatment of chronic total occlusion, in-stent restenosis, or ostial lesions 5 Rates of 12-month definite stent thrombosis are lowest among patients treated with new-generation DES (median 05%, 95% CI 03 07% per 100 person-years) followed by earlygeneration DES (median 07%, 95% CI 05 12% per 100 personyears) and BMS (median 11%, 95% CI 06 19% per 100 personyears) 8 Long-term outcomes after PCI (>1year):Beyond 1 year, there is a steady risk of late adverse events, which are related to either the failure of the original inserted coronary device(s) or the progression of underlying CAD 10 Device-related adverse events encompass very late stent thrombosis and target lesion revascularization, and have been related to delayed healing due to chronic inflammation and in-stent neoatherosclerosis following stent implantation Very late stent thrombosis has been reported with incidence rates of approximately 01, 02-08, and per 100 person-years with BMS, 11 early-generation DES, and new-generation DES, 12 respectively Late target lesion revascularization is associated with a continued increase in late lumen loss and is at least in part related to in-stent neoatherosclerosis The risk amounts to approximately 1%/year with BMS, %/year with early-generation DES, 14 and <1%/year with new-generation DES throughout 5 years More than 50% of late adverse events are not device-related and are secondary to disease progression at untreated segments In the 5-year follow-up of the SYNTAX trial, MACCE occurred in 373% of the PCI patients 15 The 5-year all-cause mortality was 139%, MI rate 97%, stroke rate 24%, and repeat revascularization rate 259% 15 In the DAPT trial, MI unrelated to the target lesion was more common than stent thrombosis-related MI, which occurred at an annual rate of approximately 1-15% Risk of stent thrombosis in relation to stent type Metallic stents: In the BMS era, early (ie within 30 days) stent thrombosis was the major concern while stent thrombosis occurring after 30 days was considered to be exceptionally rare In the pivotal studies designed for first-generation DES approval, DAPT was recommended for 2 or 3 months after sirolimus-eluting stent or 6 months after paclitaxel-eluting stent No safety issues were noted early on, up to at least 1 year, as compared to BMS First-generation DES were associated with higher risk of very late (ie after the first year) stent thrombosis as compared to BMS 20,21 This observation corroborated the perception of increased thrombogenicity of DES as compared to BMS and fuelled the longer the better notion for DAPT duration in DES-treated patients First-generation DES have been entirely replaced by newer-generation devices Evidence of superior safety with respect to stent thrombosis and target vessel MI has been generated for many of the newly introduced devices when compared to first-generation DES Importantly, most of these newer-generation stents were approved in non-inferiority trials, which compared first-generation to newer-generation DES Therefore, fewer studies have directly compared newer-generation DES with BMS The clinical Evaluation of the Xience-V stent in Acute Myocardial INfArcTION (EXAMINATION) all-comers trial was designed to compare clinical outcomes between cobalt chromium everolimus-eluting stent and BMS in 1498 STEMI patients At 5- year follow-up, the patient-oriented combined endpoint consisting of all-cause death, any recurrent MI, or any revascularization occurred in 159 (212%) patients in the everolimus-eluting stent group and in 192 (257%) patients in the BMS group (P = 003) This difference was mainly driven by a significant reduction in the rate of all-cause death and a trend towards a reduction in any revascularization 25 A pooled analysis of 4896 largely ACS patients showed a statistically significant reduction of definite stent thrombosis (HR 042, 95% CI ; P = 0006), MI (HR 071, 95% CI ; P = 001), and cardiac mortality (HR 067, 95% CI ; P = 001) with the use of everolimus-eluting stent, as compared to BMS 26 This treatment effect was shown to be consistent after adjustment for the duration of DAPT In the PRODIGY trial, which randomly allocated 2013 patients to everolimus-eluting stent, ZES, paclitaxel-eluting stent, or BMS at the time of PCI, both composite major cardiovascular events (everolimus-eluting stent 192%; ZES 278%; paclitaxel-eluting stent 262%; and BMS 321%; P = ) and definite/probable stent thrombosis (everolimuseluting stent 10%; ZES 14%; paclitaxel-eluting stent 46%; and BMS 36%; P = 00001) through 2 years were significantly higher among BMS patients vs newer-generation DES The DAPT trial compared major adverse events among patients treated with DES or BMS 30 Although not designed to address stent selection at the time of revascularization, the study demonstrated a higher rate of stent thrombosis through 33 months of follow-up for BMS compared with DES Moreover, compared with 12 months of DAPT, a 30-month DAPT regimen after BMS treatment was associated with a reduction in stent thrombosis, which appeared consistent as compared to that observed for patients treated with DES 30 In the ZEUS trial, patients fulfilling at least one pre-specified high bleeding risk criterion defined as a clinical indication for

4 4 ESC Guidelines treatment with oral anticoagulants; recent bleeding episode(s) requiring medical attention; previous bleeding episode(s) which require hospitalization if the bleeding diathesis has not been completely resolved (ie surgical removal of the bleeding source); age >80; systemic conditions associated with increased bleeding risk [eg haematological disorders or any known coagulopathy determining bleeding diathesis, including history of or current thrombocytopenia defined as platelet count < /mm 3 (< /L)]; known anaemia defined as repeatedly documented haemoglobin <10 g/dl; and need for chronic treatment with steroids or non-steroidal antiinflammatory drugs were randomized to receive BMS or Endeavor ZES The study protocol mandated 30-day DAPT irrespective of the stent type The ZEUS study was the first RCT to compare DES vs BMS after mandating such a short course of DAPT 31,32 High bleeding risk patients derived benefits in terms of reductions of MACE (226% vs 29%; HR 075; P = 0033), MI (35% vs 104%; HR 033; P < 0001), target vessel revascularization (59% vs 114%; HR 050; P = 0005), and definite or probable stent thrombosis (26% vs 62%; HR 042; P = 0016) when treated with Endeavor ZES as compared to BMS, which is consistent with study results observed in the overall population 32 These findings have been duplicated in the LEADERS-FREE investigation, where 2466 high bleeding risk patients were allocated in a double-blind manner to drug-coated stent or the corresponding uncoated stent (Gazelle) 33 All patients received 1 month of DAPT At 390 days, the composite of cardiac death, MI, or stent thrombosis occurred in 112 patients (94%) in the drug-coated stent group and in 154 patients (129%) in the BMS group (071; P = 0005 for superiority) owing to a significant reduction of MI (61% vs 89%; HR 068; P = 001) 33 In the Norwegian Coronary Stent Trial (NORSTENT), 9013 patients, selected out of patients who underwent PCI during the recruitment phase, were randomly selected to receive DES (95% of which were newer-generation DES) or BMS 34 The primary outcome was a composite of death from any cause and non-fatal spontaneous MI after a median of 5 years of follow-up Secondary outcomes included repeat revascularization and stent thrombosis Eligible patients were men and women who were >_18 years of age and who presented with stable angina or ACS, had lesions in native coronary arteries or coronary artery grafts (all of which were amenable for implantation of either DES or BMS), had a Norwegian national identification number and were able to communicate in Norwegian, and provided informed consent Patients were excluded if they had previously been treated with a coronary stent; had a bifurcation lesion requiring treatment with a two-stent technique; had a serious medical condition other than CAD with a life expectancy of <5 years; were participating in another randomized trial; had intolerable side effects to any drug in use during PCI, contraindications to long-term DAPT, or had been prescribed warfarin; or were not able to follow the trial protocol, as judged by the investigator At 6 years, the rates of the primary outcome were 166% in the group receiving DES and 171% in the group receiving BMS (HR 098, 95% CI ; P = 066) The 6-year rates of any repeat revascularization were 165% in the group receiving DES and 198% in the group receiving BMS (HR 076, 95% CI ; P < 0001); the rates of definite stent thrombosis were 08% and 12%, respectively (P = 0049) Altogether, current evidence suggests an improved safety profile of many second-generation DES as compared to BMS under similar DAPT durations and provides a solid indication that a short DAPT duration does not justify the selection of BMS instead of second-generation DES Given the fact that second-generation DES have been largely approved in head-to-head studies vs first- or other second-generation DES based on relatively large non-inferiority margins, and none of them was powered for stent thrombosis, current evidence for each second-generation DES should be interpreted as being stentspecific Bioresorbable scaffolds: Unlike metallic stents, bioresorbable scaffolds have only recently been introduced into the market and limited evidence currently exists in comparison to metallic stent technologies In particular, limited information on long-term follow-up is currently available and little is known regarding the performance of bioresorbable scaffolds as compared to current-generation DES in unselected patient populations The first bioresorbable scaffold technology introduced into the market that gained CE mark and US Food and Drug Administration (FDA) approval is the Absorb bioresorbable vascular scaffold Meta-analyses show that patients who received a bioresorbable vascular scaffold had an increased risk of MI [43% vs 23%; odds ratio (OR) 163, 95% CI ; P < 001) and definite or probable scaffold thrombosis (13% vs 06%; OR 210, 95% CI ; P = 002) during the first year of follow-up as compared to corresponding non-bioresorbable stents 35,36 These results have also been confirmed at medium-term (ie 3 years) in the ABSORB II trial, which found an excess of target vessel MI among patients treated with bioresorbable vascular scaffold (6% vs 1%; P = 0012) 37 Moreover, bioresorbable vascular scaffold patients showed higher restenosis rate and no benefit on vasomotion compared to permanent metallic stents Increased scaffold strut thickness has been regarded as a putative explanation for the finding of increased stent thrombosis, and newer-generation bioresorbable scaffold technologies based on thinner stent struts are currently being developed No study exists with a focus on optimal DAPT type or duration after bioresorbable scaffold 23 Short- and long-term outcomes after coronary artery bypass surgery CABG was introduced in the 1960s The fundamental surgical technique, while progressively refined over time, has remained mainly unchanged since then, although outcomes after CABG have significantly improved 38,39 Short-term outcomes (30 days): The current 30-day overall mortality of CABG performed with or without the use of cardiopulmonary

5 ESC Guidelines 5 bypass is 1-3%, with higher mortality in patients operated on with ongoing MI, cardiogenic shock, and renal failure 40 CABG performed with or without cardiopulmonary bypass has comparable 30-day outcome as shown in the CABG Off or On Pump Revascularization Study (CORONARY) and the Veterans Affairs Randomized On/Off Bypass (ROOBY) trials 40,41 In the CORONARY trial, the primary outcome consisted of a composite of death, non-fatal stroke, nonfatal MI, or new renal failure requiring dialysis within 30 days 40 The primary outcome at 30 days occurred in 98% in the off-pump group and 103% in the on-pump group (P =059), 40 and the individual components of this composite outcome did not differ significantly between patients undergoing on- and off-pump surgery 40 Death occurred in 25% of patients in both the off-pump and on-pump groups; the MI rate was 67% and 72%, stroke occurred in 1% and 11% of patients, and new renal failure requiring dialysis occurred in 12% and 11% of patients undergoing off- and on-pump surgery, respectively 40 Mid- and long-term outcomes: Outcomes after the early post-operative period are best described in the SYNTAX trial In this trial, the primary endpoint was MACCE, a composite of death from any cause, stroke, MI, or repeat revascularization after 12 months In the CABG population, the primary outcome incidence at 12 months was 124%, and the rate of repeat revascularization was 59% 9 The rate of cardiac and non-cardiac death was 21% and 11%, respectively 9 Symptomatic, angiographically-confirmed graft occlusion rates were 03% at <_ 1 day, 03% within 2-30 days, and 25% within days 9 In the 5-year follow-up of the SYNTAX trial, MACCE occurred in 269% of the CABG patients 15 The 5-year all-cause mortality was 114%, MI rate 38%, stroke rate 37%, and repeat revascularization rate 137% 15 Constant development of surgical strategies may further improve outcome after CABG New and improved techniques may include arterial revascularization, bilateral mammary artery use, clampless/ anaortic approach, no-touch vein harvesting, and intraprocedural monitoring with epiaortic scanning and graft flow assessment A meta-analysis of seven pooled studies including single and 4693 bilateral internal mammary artery grafts demonstrated that bilateral internal mammary artery was associated with a reduced risk for death at 4-years follow-up (HR 081, 95% CI ) 42 However, this evidence was not confirmed in the 5-year follow-up of the Arterial Revascularisation Trial (ART), which randomized 3102 patients to a single or bilateral internal mammary artery graft, finding no difference in terms of mortality between these two strategies (HR 104, 95% CI ) 43 Apart from conduit selection and other technical and procedural considerations, further optimization of long-term outcomes after CABG can be achieved through improved secondary prevention including post-operative medication management Current evidence indicates that the benefits of DAPT in ACS are consistent in post- CABG patients as compared to patients who received PCI However, the use of DAPT after CABG is highly variable, and markedly lower than in PCI patients 9 DAPT after CABG has also been shown to possibly improve vein graft patency However, the quality of this evidence is weak 24 Short- and long-term outcomes after medically managed acute coronary syndrome Patients with ACS who are managed conservatively represent a heterogeneous population with a high prevalence of comorbidities 47 They are characterized by increased morbidity and mortality compared with those undergoing invasive strategies according to registries and clinical trials 47 In the PLATO trial, patients initially treated conservatively were older, more frequently women, and more frequently had diabetes, prior MI, congestive heart failure, and a TIMI NSTE-ACS risk score >2 compared with patients with intended invasive treatment 48 Patients assigned to a conservative treatment had an initially lower rate of cardiovascular death, MI, or stroke as compared to invasively managed individuals, but the event curves crossed at approximately 30 days and further separated over time in disfavour of patients who were initially conservatively managed 48 Overall mortality was higher in the intended conservative cohort than in the intended invasive cohort during the entire course of the study 48 Patients managed without revascularization might be further categorized into those who initially receive diagnostic angiography and those who do not Overall, this latter group carries a higher risk of subsequent ischaemic events and failure to undergo angiography during the initial hospitalization was a strong predictor of recurrent ischaemic events within 30 months follow-up 49 In the TRILOGY-ACS trial, patients with NSTE-ACS who were selected for management without revascularization were randomly assigned to clopidogrel or prasugrel 50 Among those <75 years, 3085 (426%) initially received coronary angiography with no revascularization and 4185 were directly assigned to a medical therapy without angiography Patients not receiving angiography at baseline were older, most frequently women, with a lower body weight, and were sicker (ie higher rate of Killip class II-III) at presentation 51 After adjustment, patients initially referred to coronary angiography showed a lower rate of cardiovascular death, MI, or stroke at 30 months (HR 063, 95% CI ), mostly driven by a significant reduction of cardiovascular death (HR 063, 95% CI ) Dual antiplatelet therapy for the prevention of stent thrombosis Stent thrombosis is one of the most serious complications of coronary stent implantation It is strongly associated with mortality and MI 52 It is defined as definite, probable, or possible 53 Stent thrombosis may occur any time from immediately after stent placement to several years thereafter 54 On the basis of timing of occurrence, it is categorized as early (<_30 days), which is further

6 6 ESC Guidelines divided into acute (within the first 24 h) and subacute (days 2 30), late (between 31 days and 1 year), and very late (beyond 1 year) Several clinical, angiographic, and procedural factors are related to an increased risk of stent thrombosis 55 Their relative impact is largely dependent on the interval from the procedure Intravascular imaging with optical coherence tomography has shown that stent under-expansion, lack of stent strut apposition to the vessel wall, and edge dissection are more frequently associated with early stent thrombosis, while neoatherosclerosis plays an important role in very late stent thrombosis 56 Nevertheless, the longitudinal extension of malapposed and uncovered stents has been identified as the most important correlate of thrombus formation in very late stent thrombosis cases 57 This observation emphasizes the concept that suboptimal procedural results may have an impact on long-term outcomes Several dedicated randomized trials in the middle of the 1990s were able to show the ability of aspirin plus ticlopidine (later replaced by clopidogrel) to reduce both stent thrombosis and bleeding compared to oral anticoagulation, the initial standard adjunctive treatment after coronary stenting 58,59 The high effectiveness of DAPT provided additional proof of the key role of platelets in coronary stent thrombosis 60 Although DAPT was able to reduce the risk of stent thrombosis, it did not have an impact on the risk of in-stent restenosis, thus raising a question over the role of initial thrombus formation in the subsequent development of neointima 61 The lack of a relationship on clinical or imaging endpoints between platelet inhibition and neointima formation was subsequently confirmed with other antiplatelet agents 62 The newer P2Y 12 inhibitors prasugrel and ticagrelor have proven more efficacious than clopidogrel in the prevention of early and late stent thrombosis in patients with ACS, even if this comes at the cost of higher bleeding liability 63,64 The DAPT trial has unquestionably shown that a DAPT regimen is more effective than aspirin monotherapy in reducing the incidence of very late stent thrombosis 16 Therefore, current evidence suggests that DAPT mitigates the risk of stent thrombosis across the whole spectrum from acute to very late events 32 Dual antiplatelet therapy for the prevention of spontaneous myocardial infarction A primary goal of treatment of CAD is the prevention of first or recurrent coronary ischaemic events, including MI and related mortality The risk of MI is highest during the acute phase after an ACS (5% over 30 days) 65 This early risk declines as the index event becomes a more remote hazard 66 Nonetheless, a constant hazard of spontaneous MI remains in patients with CAD despite current optimal medical therapy 67 Following ACS, the risk of recurrent MI is 5-7% per year beyond 30 days to 12 months, 68,69 and 2-5% per year beyond 12 months 70 among patients treated with aspirin alone The addition of a P2Y 12 inhibitor is associated with significantly lower MI risk over both time periods Among patients who have remained stable for 1 year or more after PCI, there remains a residual risk of MI, the majority of which is unrelated to the stent itself, but rather related to disease progression and exacerbation outside the treated segment 71 In the DAPT trial, continued thienopyridine therapy with clopidogrel or prasugrel in addition to aspirin beyond 1 year after PCI was associated with a 20% absolute reduction in recurrent MI over 18 months (21% vs 41%; P < 0001); 55% of this treatment effect was not stent-related In patients treated with PCI for ACS, the benefits were greater in magnitude (30% absolute reduction; 22% vs 52%; P <0001) 16,72 In the PEGASUS-TIMI 54 trial, patients who were 1-3 years post MI and treated with ticagrelor in addition to aspirin experienced a 17% relative reduction of MI in comparison to those treated with placebo and aspirin (447% vs 525%; P = 0005); 70 in a prespecified analysis of those who had not discontinued P2Y 12 inhibitor therapy, or had only discontinued within 30 days, the benefit was greatest (28% relative reduction; 49% vs 62%; P = 00038) 73 Therefore, treatment with DAPT beyond 1 year after MI, or afterpci,exertsthemajorityofits benefit by reducing the rate of spontaneous MI, which is associated with mortality rates of 15% 74 Nonetheless, because continued antiplatelet therapy is also associated with increased bleeding risk, it is necessary to weigh this risk against potential benefit Therefore, compared with aspirin alone, DAPT beyond 1 year among stabilized highrisk patients with prior MI has the potential to decrease ischaemic events, including significant reductions in the individual endpoints of cardiovascular death, recurrent MI, and stroke Therefore, compared with aspirin alone, the benefit/risk ratio of DAPT beyond 1 year among stabilized PCI patients may largely be dependent on the indication for the procedure or prior cardiovascular history, with no evidence of reduced cardiovascular mortality and possible higher non-cardiovascular mortality rates in patients undergoing treatment for stable CAD 33 Dual antiplatelet therapy and mortality rate Most of the anticipated benefit of long-term DAPT would be expected to derive from prevention of MACCE and stent thrombosis, both of which potentially favourably impact cardiovascular mortality, whereas there would be no reason for prolonged DAPT to positively affect non-cardiovascular mortality On the other hand, there is concern that increased severe bleeding risk could potentially increase non-cardiovascular mortality Indeed, there is solid evidence that combination antiplatelet therapy increases bleeding, and the latter has a strong association with mortality, 75,76 both cardiovascular and non-cardiovascular So far, the evidence for a DAPT effect on mortality is uncertain and may reflect the intrinsic risk of future ischaemic events, largely depending on the presentation profile against the anticipated bleeding liability associated with a prolonged DAPT regimen,

7 ESC Guidelines 7 which is consistent across the presentation profile (ACS vs stable CAD) ACS patients: The CURE trial established a benefit of DAPT combining clopidogrel and aspirin over aspirin and placebo in reducing MACE, but did not establish a survival benefit 68 Two subsequent trials compared DAPT using more novel oral P2Y 12 inhibitors The TRITON-TIMI 38 trial examined prasugrel vs clopidogrel in patients with ACS undergoing PCI, who were receiving aspirin, and found a reduction in MACE but no effect on mortality 77 The PLATO trial compared ticagrelor to clopidogrel in ACS patients and found a reduction in MACE, but also a reduction in total mortality (59% vs 45%; P < 0001) and cardiovascular mortality (51% vs 40%; P = 0001) 47 Post-MI patients: The CHARISMA trial compared clopidogrel to placebo in patients at risk of atherothrombosis due to a constellation of risk factors or in patients with established atherosclerotic disorders (CAD, cerebrovascular disease, or peripheral artery disease) The primary outcome of the trial was not reduced 78 A post hoc analysis focusing on patients with a history of prior events, including prior MI, identified a possible reduction in MACE, but there was no reduction in cardiovascular or all-cause mortality 79 More recently, the PEGASUS trial showed no reduction in overall mortality, although there was a borderline signal towards reduced cardiovascular mortality (when both doses were pooled) (HR 085, 95% CI ; P = 006), consistent with the reduction in nonfatal outcomes 70 A meta-analysis of randomized trials comparing >1 year of DAPT with aspirin alone in high-risk patients with a history of prior MI80 found that extended DAPT decreased the risk of MACE compared with aspirin alone (64% vs 75%; RR 078, 95% CI ; P = 0001) and reduced cardiovascular death (23% vs 26%; RR 085, 95% CI ; P = 003), with no increase in non-cardiovascular death (166% vs155%; RR 103, 95% CI ; P =076)The corresponding effect of DAPT on all-cause mortality yielded a nonsignificant RR of 092 (95% CI ; P = 013) Therefore, compared with aspirin alone, DAPT beyond 1 year among stabilized highrisk patients with prior MI has the potential to decrease ischaemic events, including significant reductions in the individual endpoints of cardiovascular death, recurrent MI, and stroke Post-PCI patients: The DAPT trial found a borderline increase in mortality with increased duration of DAPT; all-cause death rates were 20% in the group that continued thienopyridine therapy beyond 1 year and 15% in the placebo group (HR 136, 95% CI ; P = 005) 16 A further review of causes of death found that all-cause mortality rates were 19% vs 15% (continued thienopyridine vs placebo, P =007), cardiovascular mortality rates were 10% vs 10% (P = 097), and non-cardiovascular mortality rates were 09% vs 05% (P = 001) over the randomized period 81 Rates of fatal bleeding were 02% vs 01% (P = 081), and deaths related to any prior bleeding were 03% vs 02% (P = 036) Cancer incidence did not differ (20% vs 16%, P = 012) Cancer-related deaths occurred in 06% vs 03% (P = 002) and were rarely related to bleeding (01% vs 0%; P =025)After excluding those occurring in patients with cancer diagnosed before enrolment, rates were 04% vs 03% (P = 016) To tease out the exact implications of that finding, several meta-analyses have been conducted The first meta-analysis of the DAPT trial with other trials of prolonged (>6 months) DAPT in patients with various cardiovascular disorders (ie not restricted to post-pci patients) found no clear effect on mortality compared with aspirin alone or short duration DAPT (<_6 months), and continued treatment was not associated with a difference in all-cause mortality (HR 105, 95% CI ; P = 033) 82 Similarly, cardiovascular mortality (HR 101, 95% CI ; P = 081) and non-cardiovascular mortality (HR 104, 95% CI ; P = 066) were no different with extended duration vs short duration DAPT or aspirin alone A network meta-analysis of trials compared shorter (<_1 year) vs longer (>_1 year) DAPT durations following DES placement 83 : by frequentist pairwise meta-analysis, shorter DAPT was associated with lower all-cause mortality compared with longer DAPT (HR 082, 95% CI ; P = 002; NNT = 325), with no significant heterogeneity apparent across the trials The reduced mortality with shorter compared with longer DAPT was attributable to lower non-cardiac mortality (HR 067, 95% CI ; P = 0006; NNT = 347), with similar cardiac mortality (HR 093, 95% CI ; P = 052) The longer DAPT duration was associated with a reduction in MACE and in-stent thrombosis at the expense of increased all-cause mortality 83 Importantly, when the DAPT trial was excluded from that analysis, the effect of shorter vs longer DAPT duration on mortality was reduced, even if directionally consistent (HR 086, 95% CI ), suggesting that the mortality findings are not only influenced by the results of this single yet large RCT In November 2015, the FDA conducted its own review of the DAPT trial and other large, long-term clinical trials of clopidogrel with data available on rates of death, death from cancer, or cancer reported as an adverse event 84 It performed meta-analyses of other long-term clinical trials to assess the effects of clopidogrel on death rates from all causes The results indicate that long-term (>_12 months) DAPT with clopidogrel and aspirin does not appear to change the overall risk of death when compared to short-term (<_6 months) clopidogrel and aspirin, or aspirin alone Also, there was no apparent increase in the risks of cancer-related deaths or cancerrelated adverse events with long-term treatment In contrast, the meta-analyses by Giustino et al 85 (OR for all-cause mortality 082, 95% CI ) and by Navarese et al 86 (OR for all-cause mortality 077, 95% CI ) both suggested lower allcause mortality by shortened DAPT A more recent meta-analysis of 11 RCTs that enrolled patients who received predominantly newer-generation DES also provided weak evidence of increased mortality rate with prolonged DAPT 87

8 8 ESC Guidelines Overall, the totality of evidence suggests that after ACS, the benefits of prolonged DAPT in preventing ischaemic outcomes are likely not or only partially offset by an increased non-cardiovascular mortality 80 On the other hand, prolonged DAPT in patients with stable CAD does not reduce cardiovascular mortality and may increase overall mortality risk by increasing non-cardiovascular fatalities so that the benefit in preventing stent thrombosis and MACE is offset by bleeding Consistent with this interpretation, a sub-analysis of the DAPT trial showed that for the composite endpoint of MACCE, continued thienopyridine was associated with a similar directional benefit but greater magnitude reductions for patients with MI (39% vs 68%; HR 056, 95% CI ; P < 0001) compared with those without MI (44% vs 53%; HR 083, 95% CI ; P =008)withpositive interaction testing (P = 003) 72 Among patients with MI, the rates of all-cause death were 14% in the continued therapy group vs 16% in the placebo group (HR 087, 95% CI ; P =061)Among patients with no MI, the rates of death were 21% for the continued thienopyridine group vs 15% for placebo (HR 143, 95% CI ; P = 004; effect for MI vs no MI interaction P =013;P int = 012 for MI vs no MI) 72 Therefore, compared with aspirin alone, the benefit/risk ratio of DAPT beyond 1 year among stabilized PCI patients may largely be dependent on the indication for the procedure or prior cardiovascular history, with no evidence of reduced cardiovascular mortality and possible higher non-cardiovascular mortality rates in patients undergoing treatment for stable CAD 34 Safety of dual antiplatelet therapy Safety of DAPT when the duration of DAPT is shorter than a year: The 1- year duration of DAPT came first from the CURE trial, in which aspirin-treated patients with NSTE-ACS were randomized to clopidogrel treatment (300 mg loading dose followed by 75 mg/day) or placebo for 3-12 months 68 Average DAPT duration in the experimental arm was 9 months DAPT duration of up to 12 months was subsequently assessed in PCI-treated patients in the setting of the (CREDO trial, with 67% of the patients having ACS 69 At 1 year, there was a 10% absolute increase of major bleeding in CURE (37% vs 27%; P < 0001) and a 21% absolute increase of major bleeding in CREDO (88% vs 67%; P = 007) in patients treated with clopidogrel as compared to placebo on top of aspirin These two trials set 12 months of DAPT duration as reference therapy after ACS, which subsequently became the reference duration of DAPT therapy after DES, irrespective of clinical presentation at the time of PCI More recently, 10 randomized stent studies evaluated an abbreviated duration of DAPT (<_6 months) after stenting as compared to at least 12-month therapy Pooled analyses of seven trials, including patients, revealed that short-term DAPT as compared to 12-month DAPT was associated with a roughly 40% reduction in the odds of major bleeding according to each trial definition, with event rates of 035% (28/7975) and 061% (49/ 8020), respectively (OR 058, 95% CI ; P =002;I 2 = 0%); the corresponding NNT to prevent a major bleed was ,98 Results remained highly consistent when major bleeding according to the TIMI definition was appraised (OR 049, 95% CI ; P = 003; I 2 = 0%) More recently, the Evaluate Safety and Effectiveness of the Tivoli DES and the Firebird DES for Treatment of Coronary Revascularization (I-LOVE-IT 2) trial, which randomized 909 patients to 6-month and 920 patients to 12-month DAPT duration after DES implantation, observed an incidence of BARC >_3 bleeding of 07% and 12% (P = 021) at 1 year, respectively 95 Finally, a TIMI-defined major bleeding risk of, respectively, 07% vs 10% (P = 056) in the 6- and 12-month DAPT arms was reported by the Impact of Intravascular Ultrasound Guidance on Outcomes of XIENCE PRIME Stents in Long Lesions (IVUS XPL) trial 96 Safety of DAPT when the duration of DAPT is longer than a year: The CHARISMA trial found no significant reduction in ischaemic effects at a median follow-up of 28 months with DAPT, but it found a 04% absolute increase in severe bleeding (17% vs 13%; P = 009) and a 08% absolute increase in moderate bleeding (21% vs 13%; P < 0001) according to the GUSTO scale 78 Six randomized stent studies, consisting predominantly of patients treated with elective DES implantation, compared prolonged (18 48 months) DAPT with 6 12 months of DAPT 16,89,92, Prolonged or extended DAPT for an additional months in patients treated with DES resulted in a 1% absolute and 60% relative increase in major bleeding complications 87 In the largest of these six studies (the DAPT trial), prolonged DAPT was associated with a 02% and 07% absolute increase in GUSTO severe bleeding (P =015)andmoderate bleeding (P = 0004), respectively 16 The PEGASUS-TIMI 54 trial reported at 3 years follow-up that 60 mg ticagrelor bid resulted in 12% absolute risk and a two-fold relative risk increase of TIMI major bleeding vs placebo (HR 232, 95% CI ; P < 0001) 70 Therefore, current evidence suggests that the risk of bleeding in patients on DAPT is proportionally related to its duration both within and beyond 1 year of treatment duration Since the benefits of prolonged DAPT, especially for mortality endpoints, appear highly dependent on prior cardiovascular history (such as prior ACS/MI vs stable CAD), an individualized approach based on ischaemic vs bleeding risk assessment is warranted

9 ESC Guidelines 9 Supplementary Web Table 1A Studies testing different P2Y 12 inhibitors or different DAPT durations In order to provide a clear and comparable outlook of the available evidence, we selected clinical trials testing comparing different P2Y 12 inhibitors or different DAPT durationswithin each trial randomly allocated arm, we defined a weaker and a stronger antiplatelet treatment strategy, based on the expected higher or lower efficacy of the randomized treatment We present relative risks for the composite ischaemic endpoint, the bleeding endpoint and mortality relative to a stronger as compared to a weaker antiplatelet treatment Clinical endpoints were obtained from previously published data or directly from the study authors and selected in order to homogenize endpoint definition among clinical trials (definition of ischaemic and bleeding endpoints used are provided in the companion table) The impact of each trial strategy is presented using number needed to treat This was calculated directly from the relative risk estimate, taking into consideration the background event rate of each population as previously described by Smeeth et al (BMJ 1999;318: ) In order to extend these results to high and low risk populations, we defined by consensus standard background event rates at one year as follows: high vs low risk of ischaemia at one year (low risk of ischaemia 5 2%/year; high risk of ischaemia 5 10%/year), high vs low risk of bleeding at one year (low risk of bleeding 5 05%/year; high risk of bleeding 5 25%/year), and high vs low risk of mortality at one year (low risk of death 5 1%/year; high risk of death 5 3%/year) As such, the number needed to treat calculated with these standardized event rates represent the theoretical effect of each investigated strategy among high/low risk populations ACS = acute coronary syndrome; EES = everolimus-eluting stent; MI = myocardial Infarction For explanation of trial names please see list of abbreviations and acronyms in the main guidelines Green colour represents benefit from a stronger as compared to a weaker antiplatelet treatment Red colour represents harm from a stronger as compared to a weaker antiplatelet treatment Bold numbers represent significant impact of a stronger as compared to a weaker antiplatelet treatment within each trial NIPPON and IVUS-XPL trials were not included because no information regarding pure ischaemic endpoint was available at the time of manuscript drafting a Defined as the composite of cardiac/cardiovascular/vascular or all cause death, myocardial infarction or stroke In a single trial (ARCTIC-Interruption) this was defined as all cause death, any acute coronary syndrome, stroke or transient ischaemic attack b Defined as TIMI (Thrombolysis In Myocardial Infarction) major or minor, TIMI major or other moderate or severe bleeding event

10 10 ESC Guidelines Supplementary Web Table 1B Studies testing different P2Y12 inhibitors on top of aspirin or long-term DAPT regimen versus no DAPTor a shorter DAPT regimen Continued

11 ESC Guidelines 11 Continued

12 12 ESC Guidelines Continued

13 ESC Guidelines 13 Continued

14 14 ESC Guidelines Continued

15 ESC Guidelines 15 Continued

16 16 ESC Guidelines ABI = ankle brachial index; ACS = acute coronary syndrome; ALT = alanine aminotransferase; ASA = acetylsalicylic acid; AST = aspartate aminotransferase; CABG = coronary artery bypass graft surgery; CAD = coronary artery disease; CCS = Canadian Cardiovascular Society; CNS = central nervous system; COX-2 = cyclo-oxygenase 2; CrCl = creatinine clearance; DAPT = dual antiplatelet therapy; DES = drug eluting stent; GP = glycoprotein; ICH = intracranial haemorrhage; LM = left main coronary artery; LVEF = left ventricular ejection fraction; MI = myocardial infarction; NSAIDs = non-steroidal anti-inflammatory drugs; NSTE-ACS = non-st-elevation acute coronary syndrome; NSTEMI = non-st-elevation myocardial infarction; NYHA = New York Heart Association; OAC = oral anticoagulants; PCI = percutaneous coronary intervention; RVD = reference vessel diameter; SBP = systolic blood pressure; STEEPLE = Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention (PCI) Patients, an International Randomized Evaluation; STEMI = ST-segment elevation myocardial infarction; TIA = transient ischaemic attack; TIMI = Thrombolysis in Myocardial Infarction; UA = unstable angina; ULN = upper limit of normality For explanation of trial names please see list of abbreviations and acronyms in the main article NIPPON and IVUS-XPL trials were not included because no information regarding pure ischaemic endpoint was provided in the publications