2017esc focused updateondual antiplatelet therapy ... · the content of these european society of...
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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 arterydisease of the European Society of Cardiology (ESC) and of theEuropean Association for Cardio-Thoracic Surgery (EACTS)
Authors/Task Force Members: Marco Valgimigli* (Chairperson) (Switzerland),
Hector Bueno (Spain), Robert A. Byrne (Germany), Jean-Philippe Collet (France),
Francesco Costa (Italy), Anders Jeppsson1 (Sweden), Peter Juni (Canada),
Adnan Kastrati (Germany), Philippe Kolh (Belgium), Laura Mauri (USA),
Gilles Montalescot (France), Franz-Josef Neumann (Germany),
Mate Petricevic1 (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 ReviewCoordinator) (Belgium), Stefan Agewall (Norway), Felicita Andreotti (Italy), Elliott Antman (USA),Emanuele Barbato (Italy), Jean-Pierre Bassand (France), Raffaele Bugiardini (Italy), Mustafa Cikirikcioglu1
(Switzerland), Thomas Cuisset (France), Michele De Bonis (Italy), Victora Delgado (The Netherlands),
* Corresponding author: Marco Valgimigli, Cardiology, Inselspital, Freiburgstrasse 8, 3010 Bern, Switzerland. Tel: þ41 31 6323077, Fax: þ41 10 7035258, E-mail: [email protected].
ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in the Appendix.
1Representing 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 CardiovascularInterventions (EAPCI).
Working Groups: Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Coronary Pathophysiology and Microcirculation, Peripheral Circulation, Pulmonary Circulation andRight 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 ESCGuidelines 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 OxfordUniversity Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC ([email protected]).
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 avail-able 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 offi-cial recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Healthprofessionals 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 pre-ventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals tomake appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, thepatient’s caregiver. Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations orguidelines 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 ethicaland 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 ofprescription.
The article has been co-published with permission in the European Heart Journal [DOI: 10.1093/eurheartj/ehx419] on behalf of the European Society of Cardiology andEuropean Journal of Cardio-Thoracic Surgery [DOI 10.1093/ejcts/ezx334] on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved in respect ofEuropean 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 email [email protected].
European Heart Journal (2017) 00, 1–23 ESC GUIDELINESdoi:10.1093/eurheartj/ehx419
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Donna Fitzsimons (UK), Oliver Gaemperli (Switzerland), Nazzareno Galie (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 Uva1 (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 onthe ESC website http://www.escardio.org/guidelines.
The Full Text and Clinical Cases companion document of this focused update are available at: www.escardio.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 • Myocardialinfarction • Stent thrombosis • Bleeding • Percutaneous coronary intervention • Recommendation
• Revascularization • Risk stratification • Stents • Stable angina • Stable coronary artery disease • Oralanticoagulant • Triple therapy • DAPT score • PRECISE-DAPT score • Non-cardiac surgery
Web Contents
2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.1. Short- and long-term outcomes after percutaneous
coronary intervention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.2 Risk of stent thrombosis in relation to stent type. . . . . . . . . . . . . . . . . 6
2.3 Short- and long-term outcomes after coronary artery
bypass surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.4 Short- and long-term outcomes after medically managed
acute coronary syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3. Efficacy and safety of dual antiplatelet therapy and risk
stratification tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.1 Dual antiplatelet therapy for the prevention of stent
thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.2 Dual antiplatelet therapy for the prevention of
spontaneous myocardial infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
3.3 Dual antiplatelet therapy and mortality rate. . . . . . . . . . . . . . . . . . . . . 17
3.4 Safety of dual antiplatelet therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Supplementary Web Table IA: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Supplementary Web Table IB: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Supplementary Web Table II: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Web Figure I: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Web Figure II: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.1. Short- and long-term outcomes afterpercutaneous coronary interventionSignificant variation exists in rates of myocardial revascularizationacross European countries, which is related to varying incidence of
the underlying disease condition as well as differences in local practi-ces for diagnosis and treatment.1 However, across all countries, PCIis the dominant modality for myocardial revascularization, with amean rate of >190 per 100 000 population, compared with a meanrate of 53 per 100 000 population for CABG surgery.2
Significant variation exists regarding the proportion of patientsundergoing PCI presenting with stable or unstable disease, but ACS isthe most frequent indication for revascularization across Europeancountries. In the United Kingdom, approximately 65% of interven-tions in 2015 were undertaken in patients with ACS.3
Short- and long-term results of PCI are governed by the clinicalsetting (stable CAD vs. ACS),4 the underlying disease complexity(left main and multivessel disease, chronic total occlusion, in-stentrestenosis, diabetes, etc.),5 and operator/institutional experience.
Short-term outcomes after PCI (30 days): Registry data from Englandand Wales of 336 433 patients treated with PCI between 2007 and2011 reported a 30-day mortality of 1.7% (range 0.36% in electivePCI to 4.78% in emergency procedures).6 In a more recent analysisfrom the National Cardiovascular Data Registry (NCDR) CathPCIdatabase including 1 208 137 PCI procedures performed betweenJuly 2009 and June 2011 at 1252 CathPCI Registry sites, in-hospitalmortality was 1.4%, ranging from 0.2% among elective cases (45.1%of total cases) to 65.9% among patients with shock and recent cardiacarrest (0.2% of total cases).7
The most important short-term, device-related complication isstent thrombosis, which is associated with MI or death in 50 - 70% ofcases. Early stent thrombosis (<30 days) occurs in 0 - 1% of cases andhas been associated with patient, lesion, procedural, and device fac-tors, as well as platelet and coagulation factors. Patients with ACS
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..have a higher risk of death and stent thrombosis within 30 days com-pared to patients with stable CAD.4
Mid-term outcomes after PCI (9� 12 months): Mid-term clinical andangiographic outcomes of BMS and early- and new-generation DESwere recently summarized in a systematic review of 158 randomizedclinical trials with 108 839 patients.8 In the subset of patients withthree-vessel disease and/or left main CAD recruited in the SynergyBetween Percutaneous Coronary Intervention With Taxus andCardiac Surgery (SYNTAX) trial, the composite of all-cause death,stroke, or MI occurred in 7.6% of patients treated with PCI at12 months.9
The most prevalent mid-term, device-related adverse event is tar-get lesion revascularization owing to stent restenosis, which amountsto approximately 9 - 15% with BMS and <5% with new-generationDES within 12 months. Predictors of target lesion revascularizationinclude angiographic complexity, diabetes, and treatment of chronictotal occlusion, in-stent restenosis, or ostial lesions.5
Rates of 12-month definite stent thrombosis are lowestamong patients treated with new-generation DES (median 0.5%,95% CI 0.3–0.7% per 100 person-years) followed by early-generation DES (median 0.7%, 95% CI 0.5–1.2% per 100 person-years) and BMS (median 1.1%, 95% CI 0.6–1.9% per 100 person-years).8
Long-term outcomes after PCI (>1 year): Beyond 1 year, there is asteady risk of late adverse events, which are related to either thefailure of the original inserted coronary device(s) or the progres-sion of underlying CAD.10 Device-related adverse events encom-pass very late stent thrombosis and target lesion revascularization,and have been related to delayed healing due to chronic inflamma-tion and in-stent neoatherosclerosis following stent implantation.Very late stent thrombosis has been reported with incidence ratesof approximately 0.1, 0.2 - 0.8, and 0.1 - 0.2 per 100 person-yearswith BMS,11 early-generation DES, and new-generation DES,12
respectively. Late target lesion revascularization is associated witha continued increase in late lumen loss and is at least in partrelated to in-stent neoatherosclerosis. The risk amounts toapproximately 1%/year with BMS,13 1 - 2%/year with early-genera-tion DES,14 and <1%/year with new-generation DES throughout5 years.
More than 50% of late adverse events are not device-related andare secondary to disease progression at untreated segments. In the5-year follow-up of the SYNTAX trial, MACCE occurred in 37.3% ofthe PCI patients.15 The 5-year all-cause mortality was 13.9%, MI rate9.7%, stroke rate 2.4%, and repeat revascularization rate 25.9%.15 Inthe DAPT trial, MI unrelated to the target lesion was more commonthan stent thrombosis-related MI, which occurred at an annual rateof approximately 1 - 1.5%.16
2.2 Risk of stent thrombosis in relation tostent typeMetallic stents: In the BMS era, early (i.e. within 30 days) stent throm-bosis was the major concern while stent thrombosis occurring after30 days was considered to be exceptionally rare. In the pivotal
studies designed for first-generation DES approval, DAPT was rec-ommended for 2 or 3 months after sirolimus-eluting stent or6 months after paclitaxel-eluting stent. No safety issues were notedearly on, up to at least 1 year, as compared to BMS.17–19
First-generation DES were associated with higher risk of very late(i.e. after the first year) stent thrombosis as compared to BMS.20,21
This observation corroborated the perception of increased throm-bogenicity of DES as compared to BMS and fuelled the ‘longer thebetter’ notion for DAPT duration in DES-treated patients.
First-generation DES have been entirely replaced by newer-gener-ation devices. Evidence of superior safety with respect to stentthrombosis and target vessel MI has been generated for many of thenewly introduced devices when compared to first-generationDES.22–24 Importantly, most of these newer-generation stents wereapproved in non-inferiority trials, which compared first-generation tonewer-generation DES. Therefore, fewer studies have directly com-pared newer-generation DES with BMS.
The clinical Evaluation of the Xience-V stent in AcuteMyocardial INfArcTION (EXAMINATION) all-comers trial wasdesigned to compare clinical outcomes between cobalt chromiumeverolimus-eluting stent and BMS in 1498 STEMI patients. At 5-year follow-up, the patient-oriented combined endpoint consist-ing of all-cause death, any recurrent MI, or any revascularizationoccurred in 159 (21.2%) patients in the everolimus-eluting stentgroup and in 192 (25.7%) patients in the BMS group (P = 0.03).This difference was mainly driven by a significant reduction in therate of all-cause death and a trend towards a reduction in anyrevascularization.25
A pooled analysis of 4896 largely ACS patients showed a statis-tically significant reduction of definite stent thrombosis (HR 0.42,95% CI 0.22–0.78; P = 0.006), MI (HR 0.71, 95% CI 0.55–0.92; P =0.01), and cardiac mortality (HR 0.67, 95% CI 0.49–0.91; P = 0.01)with the use of everolimus-eluting stent, as compared to BMS.26
This treatment effect was shown to be consistent after adjustmentfor the duration of DAPT. In the PRODIGY trial, which randomlyallocated 2013 patients to everolimus-eluting stent, ZES,paclitaxel-eluting stent, or BMS at the time of PCI, both compositemajor cardiovascular events (everolimus-eluting stent 19.2%; ZES27.8%; paclitaxel-eluting stent 26.2%; and BMS 32.1%; P =0.00029) and definite/probable stent thrombosis (everolimus-eluting stent 1.0%; ZES 1.4%; paclitaxel-eluting stent 4.6%; andBMS 3.6%; P = 0.0001) through 2 years were significantly higheramong BMS patients vs. newer-generation DES.27–29 The DAPTtrial compared major adverse events among 10 026 patientstreated with DES or BMS.30 Although not designed to addressstent selection at the time of revascularization, the study demon-strated a higher rate of stent thrombosis through 33 months offollow-up for BMS compared with DES. Moreover, comparedwith 12 months of DAPT, a 30-month DAPT regimen after BMStreatment was associated with a reduction in stent thrombosis,which appeared consistent as compared to that observed forpatients treated with DES.30
In the ZEUS trial,31 828 patients fulfilling at least one pre-specifiedhigh bleeding risk criterion—defined as a clinical indication for
ESC Guidelines 3
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..treatment with oral anticoagulants; recent bleeding episode(s)requiring medical attention; previous bleeding episode(s) whichrequire hospitalization if the bleeding diathesis has not been com-pletely resolved (i.e. surgical removal of the bleeding source); age>80; systemic conditions associated with increased bleeding risk [e.g.haematological disorders or any known coagulopathy determiningbleeding diathesis, including history of or current thrombocytopeniadefined as platelet count <100 000/mm3 (<100 � 109/L)]; knownanaemia defined as repeatedly documented haemoglobin <10 g/dL;and need for chronic treatment with steroids or non-steroidal anti-inflammatory drugs—were randomized to receive BMS or EndeavorZES. The study protocol mandated 30-day DAPT irrespective of thestent 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 reductionsof MACE (22.6% vs. 29%; HR 0.75; P = 0.033), MI (3.5% vs. 10.4%; HR0.33; P < 0.001), target vessel revascularization (5.9% vs. 11.4%; HR0.50; P = 0.005), and definite or probable stent thrombosis (2.6% vs.6.2%; HR 0.42; P = 0.016) when treated with Endeavor ZES as com-pared to BMS, which is consistent with study results observed in theoverall population.32
These findings have been duplicated in the LEADERS-FREE investi-gation, where 2466 high bleeding risk patients were allocated in adouble-blind manner to drug-coated stent or the correspondinguncoated stent (Gazelle).33 All patients received 1 month of DAPT.At 390 days, the composite of cardiac death, MI, or stent thrombosisoccurred in 112 patients (9.4%) in the drug-coated stent group and in154 patients (12.9%) in the BMS group (0.71; P = 0.005 for superior-ity) owing to a significant reduction of MI (6.1% vs. 8.9%; HR 0.68; P =0.01).33
In the Norwegian Coronary Stent Trial (NORSTENT), 9013patients, selected out of 20 663 patients who underwent PCI dur-ing the recruitment phase, were randomly selected to receiveDES (95% of which were newer-generation DES) or BMS.34 Theprimary outcome was a composite of death from any cause andnon-fatal spontaneous MI after a median of 5 years of follow-up.Secondary outcomes included repeat revascularization and stentthrombosis. 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 orBMS), had a Norwegian national identification number and wereable to communicate in Norwegian, and provided informed con-sent. Patients were excluded if they had previously been treatedwith a coronary stent; had a bifurcation lesion requiring treatmentwith a two-stent technique; had a serious medical condition otherthan CAD with a life expectancy of <5 years; were participating inanother randomized trial; had intolerable side effects to any drugin use during PCI, contraindications to long-term DAPT, or hadbeen prescribed warfarin; or were not able to follow the trial pro-tocol, as judged by the investigator. At 6 years, the rates of the pri-mary outcome were 16.6% in the group receiving DES and 17.1%
in the group receiving BMS (HR 0.98, 95% CI 0.88–1.09; P = 0.66).The 6-year rates of any repeat revascularization were 16.5% in thegroup receiving DES and 19.8% in the group receiving BMS (HR0.76, 95% CI 0.69–0.85; P < 0.001); the rates of definite stentthrombosis were 0.8% and 1.2%, respectively (P = 0.049).Altogether, current evidence suggests an improved safety profileof many second-generation DES as compared to BMS under simi-lar DAPT durations and provides a solid indication that a shortDAPT duration does not justify the selection of BMS instead ofsecond-generation DES.
Given the fact that second-generation DES have been largelyapproved in head-to-head studies vs. first- or other second-genera-tion DES based on relatively large non-inferiority margins, and noneof them was powered for stent thrombosis, current evidence foreach second-generation DES should be interpreted as being stent-specific.
Bioresorbable scaffolds: Unlike metallic stents, bioresorbable scaf-folds have only recently been introduced into the market and limitedevidence currently exists in comparison to metallic stent technolo-gies. In particular, limited information on long-term follow-up is cur-rently available and little is known regarding the performance ofbioresorbable scaffolds as compared to current-generation DES inunselected patient populations. The first bioresorbable scaffold tech-nology introduced into the market that gained CE mark and US Foodand Drug Administration (FDA) approval is the Absorb bioresorb-able vascular scaffold. Meta-analyses show that patients who receiveda bioresorbable vascular scaffold had an increased risk of MI [4.3% vs.2.3%; odds ratio (OR) 1.63, 95% CI 1.18–2.25; P < 0.01) and definiteor probable scaffold thrombosis (1.3% vs. 0.6%; OR 2.10, 95% CI1.13–3.87; P = 0.02) during the first year of follow-up as compared tocorresponding non-bioresorbable stents.35,36 These results have alsobeen confirmed at medium-term (i.e. 3 years) in the ABSORB II trial,which found an excess of target vessel MI among patients treatedwith bioresorbable vascular scaffold (6% vs. 1%; P = 0.012).37
Moreover, bioresorbable vascular scaffold patients showed higherrestenosis rate and no benefit on vasomotion compared to perma-nent metallic stents. Increased scaffold strut thickness has beenregarded as a putative explanation for the finding of increased stentthrombosis, and newer-generation bioresorbable scaffold technolo-gies based on thinner stent struts are currently being developed. Nostudy exists with a focus on optimal DAPT type or duration after bio-resorbable scaffold.
2.3 Short- and long-term outcomes aftercoronary artery bypass surgeryCABG was introduced in the 1960s. The fundamental surgical techni-que, while progressively refined over time, has remained mainlyunchanged since then, although outcomes after CABG have signifi-cantly improved.38,39
Short-term outcomes (30 days): The current 30-day overall mortalityof CABG performed with or without the use of cardiopulmonary
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..bypass is 1 - 3%, with higher mortality in patients operated on withongoing MI, cardiogenic shock, and renal failure.40 CABG performedwith or without cardiopulmonary bypass has comparable 30-day out-come as shown in the CABG Off or On Pump RevascularizationStudy (CORONARY) and the Veterans Affairs Randomized On/OffBypass (ROOBY) trials.40,41 In the CORONARY trial, the primaryoutcome consisted of a composite of death, non-fatal stroke, non-fatal MI, or new renal failure requiring dialysis within 30 days.40 Theprimary outcome at 30 days occurred in 9.8% in the off-pump groupand 10.3% in the on-pump group (P = 0.59),40 and the individual com-ponents of this composite outcome did not differ significantlybetween patients undergoing on- and off-pump surgery.40 Deathoccurred in 2.5% of patients in both the off-pump and on-pumpgroups; the MI rate was 6.7% and 7.2%, stroke occurred in 1% and1.1% of patients, and new renal failure requiring dialysis occurred in1.2% and 1.1% of patients undergoing off- and on-pump surgery,respectively.40
Mid- and long-term outcomes: Outcomes after the early post-opera-tive period are best described in the SYNTAX trial. In this trial, theprimary endpoint was MACCE, a composite of death from any cause,stroke, MI, or repeat revascularization after 12 months. In the CABGpopulation, the primary outcome incidence at 12 months was 12.4%,and the rate of repeat revascularization was 5.9%.9 The rate of car-diac and non-cardiac death was 2.1% and 1.1%, respectively.9
Symptomatic, angiographically-confirmed graft occlusion rates were0.3% at <_ 1 day, 0.3% within 2 - 30 days, and 2.5% within 31 - 365days.9 In the 5-year follow-up of the SYNTAX trial, MACCEoccurred in 26.9% of the CABG patients.15 The 5-year all-cause mor-tality was 11.4%, MI rate 3.8%, stroke rate 3.7%, and repeat revascula-rization rate 13.7%.15
Constant development of surgical strategies may further improveoutcome after CABG. New and improved techniques may includearterial revascularization, bilateral mammary artery use, clampless/anaortic approach, “no-touch” vein harvesting, and intraproceduralmonitoring with epiaortic scanning and graft flow assessment. Ameta-analysis of seven pooled studies including 11 269 single and4693 bilateral internal mammary artery grafts demonstrated thatbilateral internal mammary artery was associated with a reduced riskfor death at 4-years’ follow-up (HR 0.81, 95% CI 0.70–0.94).42
However, this evidence was not confirmed in the 5-year follow-up ofthe Arterial Revascularisation Trial (ART), which randomized 3102patients to a single or bilateral internal mammary artery graft, findingno difference in terms of mortality between these two strategies (HR1.04, 95% CI 0.81–1.32).43
Apart from conduit selection and other technical and proceduralconsiderations, further optimization of long-term outcomes afterCABG can be achieved through improved secondary preventionincluding post-operative medication management. Current evidenceindicates 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 mark-edly lower than in PCI patients.9 DAPT after CABG has also been
shown to possibly improve vein graft patency.44–46 However, thequality of this evidence is weak.
2.4 Short- and long-term outcomes aftermedically managed acute coronarysyndromePatients with ACS who are managed conservatively represent a het-erogeneous population with a high prevalence of comorbidities.47
They are characterized by increased morbidity and mortality com-pared with those undergoing invasive strategies according to regis-tries and clinical trials.47
In the PLATO trial, patients initially treated conservatively wereolder, 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 lowerrate of cardiovascular death, MI, or stroke as compared to inva-sively managed individuals, but the event curves crossed atapproximately 30 days and further separated over time in disfa-vour of patients who were initially conservatively managed.48
Overall mortality was higher in the intended conservative cohortthan in the intended invasive cohort during the entire course ofthe study.48
Patients managed without revascularization might be furthercategorized into those who initially receive diagnostic angiographyand those who do not. Overall, this latter group carries a higherrisk of subsequent ischaemic events and failure to undergo angiog-raphy during the initial hospitalization was a strong predictor ofrecurrent ischaemic events within 30 months’ follow-up.49 In theTRILOGY-ACS trial, patients with NSTE-ACS who were selectedfor management without revascularization were randomlyassigned to clopidogrel or prasugrel.50 Among those <75 years,3085 (42.6%) initially received coronary angiography with norevascularization and 4185 were directly assigned to a medicaltherapy without angiography. Patients not receiving angiographyat baseline were older, most frequently women, with a lowerbody weight, and were sicker (i.e. higher rate of Killip class II-III) atpresentation.51 After adjustment, patients initially referred to cor-onary angiography showed a lower rate of cardiovascular death,MI, or stroke at 30 months (HR 0.63, 95% CI 0.53–0.75), mostlydriven by a significant reduction of cardiovascular death (HR 0.63,95% CI 0.49–0.83).51
3.1 Dual antiplatelet therapy for theprevention of stent thrombosisStent thrombosis is one of the most serious complications of cor-onary stent implantation. It is strongly associated with mortalityand MI.52 It is defined as definite, probable, or possible.53 Stentthrombosis may occur any time from immediately after stentplacement to several years thereafter.54 On the basis of timing ofoccurrence, it is categorized as early (<_30 days), which is further
ESC Guidelines 5
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..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 relatedto an increased risk of stent thrombosis.55 Their relative impact islargely dependent on the interval from the procedure.Intravascular imaging with optical coherence tomography hasshown that stent under-expansion, lack of stent strut appositionto the vessel wall, and edge dissection are more frequently associ-ated with early stent thrombosis, while neoatherosclerosis playsan important role in very late stent thrombosis.56 Nevertheless,the longitudinal extension of malapposed and uncovered stentshas been identified as the most important correlate of thrombusformation in very late stent thrombosis cases.57 This observationemphasizes the concept that suboptimal procedural results mayhave an impact on long-term outcomes.
Several dedicated randomized trials in the middle of the 1990swere able to show the ability of aspirin plus ticlopidine (later replacedby clopidogrel) to reduce both stent thrombosis and bleeding com-pared to oral anticoagulation, the initial standard adjunctive treat-ment after coronary stenting.58,59 The high effectiveness of DAPTprovided additional proof of the key role of platelets in coronarystent thrombosis.60 Although DAPT was able to reduce the risk ofstent thrombosis, it did not have an impact on the risk of in-stentrestenosis, thus raising a question over the role of initial thrombusformation in the subsequent development of neointima.61 The lack ofa relationship on clinical or imaging endpoints between platelet inhibi-tion and neointima formation was subsequently confirmed with otherantiplatelet agents.62 The newer P2Y12 inhibitors prasugrel and tica-grelor have proven more efficacious than clopidogrel in the preven-tion of early and late stent thrombosis in patients with ACS, even ifthis comes at the cost of higher bleeding liability.63,64 The DAPT trialhas unquestionably shown that a DAPT regimen is more effectivethan aspirin monotherapy in reducing the incidence of very late stentthrombosis.16
Therefore, current evidence suggests that DAPT mitigates the riskof stent thrombosis across the whole spectrum from acute to verylate events.
3.2 Dual antiplatelet therapy for theprevention of spontaneous myocardialinfarctionA primary goal of treatment of CAD is the prevention of first orrecurrent coronary ischaemic events, including MI and relatedmortality. The risk of MI is highest during the acute phase after anACS (�5% over 30 days).65 This early risk declines as the indexevent becomes a more remote hazard.66 Nonetheless, a constanthazard of spontaneous MI remains in patients with CAD despitecurrent optimal medical therapy.67 Following ACS, the risk ofrecurrent MI is 5 - 7% per year beyond 30 days to 12 months,68,69
and 2 - 5% per year beyond 12 months70 among patients treatedwith aspirin alone. The addition of a P2Y12 inhibitor is associated
with significantly lower MI risk over both time periods. Amongpatients who have remained stable for 1 year or more after PCI,there remains a residual risk of MI, the majority of which is unre-lated to the stent itself, but rather related to disease progressionand exacerbation outside the treated segment.71 In the DAPTtrial, continued thienopyridine therapy with clopidogrel or prasu-grel in addition to aspirin beyond 1 year after PCI was associatedwith a 2.0% absolute reduction in recurrent MI over 18 months(2.1% vs. 4.1%; P < 0.001); 55% of this treatment effect was notstent-related. In patients treated with PCI for ACS, the benefitswere greater in magnitude (3.0% absolute reduction; 2.2% vs.5.2%; P < 0.001).16,72 In the PEGASUS-TIMI 54 trial, patients whowere 1 - 3 years post MI and treated with ticagrelor in addition toaspirin experienced a 17% relative reduction of MI in comparisonto those treated with placebo and aspirin (4.47% vs. 5.25%; P =0.005);70 in a prespecified analysis of those who had not discontin-ued P2Y12 inhibitor therapy, or had only discontinued within 30days, the benefit was greatest (28% relative reduction; 4.9% vs.6.2%; P = 0.0038).73
Therefore, treatment with DAPT beyond 1 year after MI, orafter PCI, exerts the majority of its benefit by reducing the rate ofspontaneous MI, which is associated with mortality rates of�15%.74 Nonetheless, because continued antiplatelet therapy isalso associated with increased bleeding risk, it is necessary toweigh this risk against potential benefit. Therefore, comparedwith aspirin alone, DAPT beyond 1 year among stabilized high-risk patients with prior MI has the potential to decrease ischae-mic events, including significant reductions in the individual end-points of cardiovascular death, recurrent MI, and stroke.Therefore, compared with aspirin alone, the benefit/risk ratio ofDAPT beyond 1 year among stabilized PCI patients may largelybe dependent on the indication for the procedure or prior cardi-ovascular history, with no evidence of reduced cardiovascularmortality and possible higher non-cardiovascular mortality ratesin patients undergoing treatment for stable CAD.
3.3 Dual antiplatelet therapy andmortality rateMost of the anticipated benefit of long-term DAPT would beexpected to derive from prevention of MACCE and stent thrombo-sis, both of which potentially favourably impact cardiovascular mor-tality, whereas there would be no reason for prolonged DAPT topositively affect non-cardiovascular mortality. On the other hand,there is concern that increased severe bleeding risk could potentiallyincrease non-cardiovascular mortality. Indeed, there is solid evidencethat combination antiplatelet therapy increases bleeding, and the lat-ter has a strong association with mortality,75,76 both cardiovascularand non-cardiovascular.
So far, the evidence for a DAPT effect on mortality is uncertainand may reflect the intrinsic risk of future ischaemic events, largelydepending on the presentation profile against the anticipatedbleeding liability associated with a prolonged DAPT regimen,
6 ESC Guidelines
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.which is consistent across the presentation profile (ACS vs. stableCAD).
ACS patients: The CURE trial established a benefit of DAPT com-bining clopidogrel and aspirin over aspirin and placebo in reducingMACE, but did not establish a survival benefit.68 Two subsequent tri-als compared DAPT using more novel oral P2Y12 inhibitors. TheTRITON-TIMI 38 trial examined prasugrel vs. clopidogrel in patientswith ACS undergoing PCI, who were receiving aspirin, and found areduction in MACE but no effect on mortality.77 The PLATO trialcompared ticagrelor to clopidogrel in ACS patients and found areduction in MACE, but also a reduction in total mortality (5.9% vs.4.5%; P < 0.001) and cardiovascular mortality (5.1% vs. 4.0%; P =0.001).47
Post-MI patients: The CHARISMA trial compared clopidogrel toplacebo in patients at risk of atherothrombosis due to a constellationof risk factors or in patients with established atherosclerotic disor-ders (CAD, cerebrovascular disease, or peripheral artery disease).The primary outcome of the trial was not reduced.78 A post hoc analy-sis focusing on patients with a history of prior events, including priorMI, identified a possible reduction in MACE, but there was no reduc-tion in cardiovascular or all-cause mortality.79
More recently, the PEGASUS trial showed no reduction in overallmortality, although there was a borderline signal towards reducedcardiovascular mortality (when both doses were pooled) (HR 0.85,95% CI 0.71–1.00; P = 0.06), consistent with the reduction in non-fatal outcomes.70
A meta-analysis of randomized trials comparing >1 year of DAPTwith aspirin alone in high-risk patients with a history of prior MI80found that extended DAPT decreased the risk of MACE comparedwith aspirin alone (6.4% vs. 7.5%; RR 0.78, 95% CI 0.67–0.90; P =0.001) and reduced cardiovascular death (2.3% vs. 2.6%; RR 0.85,95% CI 0.74–0.98; P = 0.03), with no increase in non-cardiovasculardeath (1.66% vs.1.55%; RR 1.03, 95% CI 0.86–1.23; P = 0.76). Thecorresponding effect of DAPT on all-cause mortality yielded a non-significant RR of 0.92 (95% CI 0.83–1.03; P = 0.13). Therefore, com-pared with aspirin alone, DAPT beyond 1 year among stabilized high-risk patients with prior MI has the potential to decrease ischaemicevents, including significant reductions in the individual endpoints ofcardiovascular death, recurrent MI, and stroke.
Post-PCI patients: The DAPT trial found a borderline increase inmortality with increased duration of DAPT; all-cause death rateswere 2.0% in the group that continued thienopyridine therapybeyond 1 year and 1.5% in the placebo group (HR 1.36, 95% CI1.00–1.85; P = 0.05).16
A further review of causes of death found that all-cause mortalityrates were 1.9% vs. 1.5% (continued thienopyridine vs. placebo, P=0.07), cardiovascular mortality rates were 1.0% vs. 1.0% (P = 0.97),and non-cardiovascular mortality rates were 0.9% vs. 0.5% (P = 0.01)over the randomized period.81 Rates of fatal bleeding were 0.2% vs.0.1% (P = 0.81), and deaths related to any prior bleeding were 0.3%vs. 0.2% (P = 0.36). Cancer incidence did not differ (2.0% vs. 1.6%,
P = 0.12). Cancer-related deaths occurred in 0.6% vs. 0.3% (P = 0.02)and were rarely related to bleeding (0.1% vs. 0%; P = 0.25). Afterexcluding those occurring in patients with cancer diagnosed beforeenrolment, rates were 0.4% vs. 0.3% (P = 0.16).
To tease out the exact implications of that finding, severalmeta-analyses have been conducted. The first meta-analysis of theDAPT trial with other trials of prolonged (>6 months) DAPT inpatients with various cardiovascular disorders (i.e. not restrictedto post-PCI patients) found no clear effect on mortality comparedwith aspirin alone or short duration DAPT (<_6 months), and con-tinued treatment was not associated with a difference in all-causemortality (HR 1.05, 95% CI 0.96–1.19; P = 0.33).82 Similarly, cardi-ovascular mortality (HR 1.01, 95% CI 0.93–1.12; P = 0.81) andnon-cardiovascular mortality (HR 1.04, 95% CI 0.90–1.26; P =0.66) were no different with extended duration vs. short durationDAPT or aspirin alone.
A network meta-analysis of trials compared shorter (<_1 year)vs. longer (>_1 year) DAPT durations following DES placement83:by frequentist pairwise meta-analysis, shorter DAPT was associ-ated with lower all-cause mortality compared with longer DAPT(HR 0.82, 95% CI 0.69 –0.98; P = 0.02; NNT = 325), with no signif-icant heterogeneity apparent across the trials. The reduced mor-tality with shorter compared with longer DAPT was attributableto lower non-cardiac mortality (HR 0.67, 95% CI 0.51–0.89; P =0.006; NNT = 347), with similar cardiac mortality (HR 0.93, 95%CI 0.73–1.17; P = 0.52). The longer DAPT duration was associatedwith a reduction in MACE and in-stent thrombosis at the expenseof increased all-cause mortality.83 Importantly, when the DAPTtrial was excluded from that analysis, the effect of shorter vs. lon-ger DAPT duration on mortality was reduced, even if directionallyconsistent (HR 0.86, 95% CI 0.69–1.06), suggesting that the mor-tality findings are not only influenced by the results of this singleyet large RCT.
In November 2015, the FDA conducted its own review of theDAPT trial and other large, long-term clinical trials of clopidogrelwith data available on rates of death, death from cancer, or cancerreported as an adverse event.84 It performed meta-analyses of otherlong-term clinical trials to assess the effects of clopidogrel on deathrates from all causes. The results indicate that long-term(>_12 months) DAPT with clopidogrel and aspirin does not appear tochange the overall risk of death when compared to short-term(<_6 months) clopidogrel and aspirin, or aspirin alone. Also, there wasno apparent increase in the risks of cancer-related deaths or cancer-related adverse events with long-term treatment.
In contrast, the meta-analyses by Giustino et al85 (OR for all-causemortality 0.82, 95% CI 0.67–1.01) and by Navarese et al86 (OR forall-cause mortality 0.77, 95% CI 0.60–0.98) both suggested lower all-cause mortality by shortened DAPT. A more recent meta-analysis of11 RCTs that enrolled 33 051 patients who received predominantlynewer-generation DES also provided weak evidence of increasedmortality rate with prolonged DAPT.87
ESC Guidelines 7
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..Overall, the totality of evidence suggests that after ACS, the bene-fits of prolonged DAPT in preventing ischaemic outcomes are likelynot or only partially offset by an increased non-cardiovascular mor-tality.80 On the other hand, prolonged DAPT in patients with stableCAD does not reduce cardiovascular mortality and may increaseoverall mortality risk by increasing non-cardiovascular fatalities sothat the benefit in preventing stent thrombosis and MACE is offset bybleeding. Consistent with this interpretation, a sub-analysis of theDAPT trial showed that for the composite endpoint of MACCE, con-tinued thienopyridine was associated with a similar directional benefitbut greater magnitude reductions for patients with MI (3.9% vs. 6.8%;HR 0.56, 95% CI 0.42–0.76; P < 0.001) compared with those withoutMI (4.4% vs. 5.3%; HR 0.83, 95% CI 0.68–1.02; P = 0.08) with positiveinteraction testing (P = 0.03).72 Among patients with MI, the rates ofall-cause death were 1.4% in the continued therapy group vs. 1.6% inthe placebo group (HR 0.87, 95% CI 0.50–1.50; P = 0.61). Amongpatients with no MI, the rates of death were 2.1% for the continuedthienopyridine group vs. 1.5% for placebo (HR 1.43, 95% CI1.02–2.00; P = 0.04; effect for MI vs. no MI interaction P = 0.13; Pint =0.12 for MI vs. no MI).72
Therefore, compared with aspirin alone, the benefit/risk ratio ofDAPT beyond 1 year among stabilized PCI patients may largely bedependent on the indication for the procedure or prior cardiovascu-lar history, with no evidence of reduced cardiovascular mortality andpossible higher non-cardiovascular mortality rates in patients under-going treatment for stable CAD.
3.4 Safety of dual antiplatelet therapySafety 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 whichaspirin-treated patients with NSTE-ACS were randomized to clopi-dogrel treatment (300 mg loading dose followed by 75 mg/day) orplacebo for 3 - 12 months.68 Average DAPT duration in the experi-mental arm was 9 months. DAPT duration of up to 12 months wassubsequently 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 1.0% absolute increase of major bleeding in CURE (3.7%vs. 2.7%; P < 0.001) and a 2.1% absolute increase of major bleeding inCREDO (8.8% vs. 6.7%; P = 0.07) in patients treated with clopidogrelas compared to placebo on top of aspirin.
These two trials set 12 months of DAPT duration as referencetherapy after ACS, which subsequently became the reference dura-tion of DAPT therapy after DES, irrespective of clinical presentationat the time of PCI.
More recently, 10 randomized stent studies evaluated an abbre-viated duration of DAPT (<_6 months) after stenting as compared
to at least 12-month therapy.88–97 Pooled analyses of seven trials,including 15 378 patients, revealed that short-term DAPT as com-pared to 12-month DAPT was associated with a roughly 40%reduction in the odds of major bleeding according to each trialdefinition, with event rates of 0.35% (28/7975) and 0.61% (49/8020), respectively (OR 0.58, 95% CI 0.36–0.92; P = 0.02; I2 = 0%);the corresponding NNT to prevent a major bleed was 385.86,98
Results remained highly consistent when major bleeding accordingto the TIMI definition was appraised (OR 0.49, 95% CI 0.26–0.94;P = 0.03; I2 = 0%).
More recently, the Evaluate Safety and Effectiveness of the TivoliDES and the Firebird DES for Treatment of CoronaryRevascularization (I-LOVE-IT 2) trial, which randomized 909 patientsto 6-month and 920 patients to 12-month DAPT duration after DESimplantation, observed an incidence of BARC >_3 bleeding of 0.7%and 1.2% (P = 0.21) at 1 year, respectively.95 Finally, a TIMI-definedmajor bleeding risk of, respectively, 0.7% vs. 1.0% (P = 0.56) in the 6-and 12-month DAPT arms was reported by the Impact ofIntravascular Ultrasound Guidance on Outcomes of XIENCE PRIMEStents in Long Lesions (IVUS XPL) trial.96
Safety of DAPT when the duration of DAPT is longer than a year: TheCHARISMA trial found no significant reduction in ischaemic effects ata median follow-up of 28 months with DAPT, but it found a 0.4%absolute increase in severe bleeding (1.7% vs. 1.3%; P = 0.09) anda 0.8% absolute increase in moderate bleeding (2.1% vs. 1.3%;P < 0.001) according to the GUSTO scale.78
Six randomized stent studies, consisting predominantly ofpatients treated with elective DES implantation, compared pro-longed (18–48 months) DAPT with 6–12 months ofDAPT.16,89,92,99–101 Prolonged or extended DAPT for an addi-tional 18–36 months in patients treated with DES resulted in a�1% absolute and 60% relative increase in major bleeding compli-cations.87 In the largest of these six studies (the DAPT trial), pro-longed DAPT was associated with a 0.2% and 0.7% absoluteincrease in GUSTO severe bleeding (P = 0.15) and moderatebleeding (P = 0.004), respectively.16
The PEGASUS-TIMI 54 trial reported at 3 years’ follow-up that60 mg ticagrelor b.i.d. resulted in 1.2% absolute risk and a two-foldrelative risk increase of TIMI major bleeding vs. placebo (HR 2.32,95% CI 1.68–3.21; P < 0.001).70
Therefore, current evidence suggests that the risk of bleeding inpatients on DAPT is proportionally related to its duration bothwithin and beyond 1 year of treatment duration. Since the benefits ofprolonged DAPT, especially for mortality endpoints, appear highlydependent on prior cardiovascular history (such as prior ACS/MI vs.stable CAD), an individualized approach based on ischaemic vs.bleeding risk assessment is warranted.
8 ESC Guidelines
Supplementary Web Table 1A Studies testing different P2Y12 inhibitors or different DAPT durations. In order toprovide a clear and comparable outlook of the available evidence, we selected clinical trials testing comparing differ-ent P2Y12 inhibitors or different DAPT durations.Within each trial randomly allocated arm, we defined a weaker anda stronger antiplatelet treatment strategy, based on the expected higher or lower efficacy of the randomized treat-ment. We present relative risks for the composite ischaemic endpoint, the bleeding endpoint and mortality relative toa stronger as compared to a weaker antiplatelet treatment. Clinical endpoints were obtained from previously pub-lished data or directly from the study authors and selected in order to homogenize endpoint definition among clinicaltrials (definition of ischaemic and bleeding endpoints used are provided in the companion table). The impact of eachtrial 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 (BMJ1999;318:15481551). In order to extend these results to high and low risk populations, we defined by consensus stand-ard background event rates at one year as follows: high vs. low risk of ischaemia at one year (low risk of ischaemia 52%/year; high risk of ischaemia 5 10%/year), high vs. low risk of bleeding at one year (low risk of bleeding 5 0.5%/year;high risk of bleeding 5 2.5%/year), and high vs. low risk of mortality at one year (low risk of death 5 1%/year; high riskof death 5 3%/year). As such, the number needed to treat calculated with these standardized event rates representthe 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 themain 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.aDefined 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 allcause death, any acute coronary syndrome, stroke or transient ischaemic attack.bDefined as TIMI (Thrombolysis In Myocardial Infarction) major or minor, TIMI major or other moderate or severe bleeding event.
ESC Guidelines 9
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ESC Guidelines 13
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14 ESC Guidelines
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ESC Guidelines 15
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16 ESC Guidelines
Supplementary Web Table 2 Standardized bleeding definitions commonly used in clinical trials
BARC = Bleeding Academic Research Consortium; CABG = coronary artery bypass graft surgery; TIMI = Thrombosis In Myocardial Infarction; GUSTO = Global Utilization ofStreptokinase and Tissue plasminogen activator for Occluded coronary arteries.
ESC Guidelines 17
Web Figure 1 Case example for PRECISE-DAPT score calculation.
18 ESC Guidelines
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73. Bonaca MP, Bhatt DL, Steg PG, Storey RF, Cohen M, Im K, Oude Ophuis T,Budaj A, Goto S, Lopez-Sendon J, Diaz R, Dalby A, Van de Werf F, ArdissinoD, Montalescot G, Aylward P, Magnani G, Jensen EC, Held P, Braunwald E,Sabatine MS. Ischaemic risk and efficacy of ticagrelor in relation to time fromP2Y12 inhibitor withdrawal in patients with prior myocardial infarction: insightsfrom PEGASUS-TIMI 54. Eur Heart J 2016;37:1133–1142.
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.74. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR,
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22 ESC Guidelines
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