Antiplatelet Drugs in the Management of Coronary Artery Disease

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Antiplatelet Drugs in the Management of Coronary Artery Disease Jae Youn Moon and Dominick J. Angiolillo Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, FL, United States

INTRODUCTION 1017 ANTIPLATELET THERAPY IN THE MANAGEMENT OF STABLE CORONARY ARTERY DISEASE PATIENTS 1017 Historical Background of Antiplatelet Therapy for SCAD Patients With PCI 1017 DAPT in SCAD Patients With PCI 1018 Intravenous Antiplatelet Agents for SCAD Patients With PCI 1020 ANTIPLATELET THERAPY IN THE MANAGEMENT OF ACS PATIENTS 1020 History of Antiplatelet Therapy in ACS Patients 1020 Antiplatelet Therapy for ACS PCI Patients 1021 Antiplatelet Therapy for Medically Managed ACS Patients 1024 NEW STRATEGIES OF ANTITHROMBOTIC TREATMENT REGIMENS FOR SAFETY AND EFFICACY 1024 A Paradigm Shift: Dropping Aspirin 1024 De-Escalation Therapy and Personalized Antiplatelet Therapy 1025 Adjunctive Use of Oral Anticoagulation 1025 ANTIPLATELET THERAPY FOR PATIENTS WITH CAD IN SPECIFIC SETTINGS 1025 Patients Undergoing CABG 1025 Patients With Indication for Oral Anticoagulation 1026 REFERENCES 1026

INTRODUCTION Therapeutic inhibition of platelet activation is essential for the acute and long-term management of patients with coronary artery disease (CAD).1–3 For decades, aspirin has been the mainstay antiplatelet agent for CAD patients. However, the persistence of ischemic recurrences, particularly in high-risk subjects, despite aspirin therapy and the ever-growing knowledge of multiple platelet activation pathways leading to thrombus formation set the foundation for the development of other antiplatelet treatment regimens. In particular, the use of a platelet adenosine diphosphate (ADP) P2Y12 receptor inhibitor in addition to aspirin, also known as dual antiplatelet therapy (DAPT), has significantly contributed to the reduction of atherothrombotic events in patients with high risk for vascular events such as those with acute coronary syndromes (ACS) or undergoing percutaneous coronary interventions (PCI).4–7 The ischemic benefits associated with the use of a P2Y12 inhibitor have led to nearly two decades of clinical investigation in the field. In particular, clopidogrel largely replaced ticlopidine due to its more favorable safety profile.8 However, the Platelets. https://doi.org/10.1016/B978-0-12-813456-6.00056-4 Copyright © 2019 Elsevier Inc. All rights reserved.

nonuniform response profile of clopidogrel prompted the development of agents, such as prasugrel and ticagrelor, characterized by more prompt, potent, and predictable antiplatelet effects.9,10 In parallel to the advances in antithrombotic pharmacotherapy, there has also been great evolution in technologies, in particular stent designs, for the treatment of CAD.11 These advances have had an impact on many of the considerations surrounding intensity and duration of antiplatelet treatment regimens being used for prevention of recurrent ischemic events. Despite the undeniable benefits on reducing ischemic events, more intense and prolonged durations of antiplatelet therapy are associated with an increased risk of bleeding.12 Importantly, bleeding has important prognostic implications, including on survival.13–18 These observations underscore the need to identify antiplatelet treatment regimens that are efficacious at reducing ischemic recurrences while also safe in terms of bleeding risk profile. The present chapter focuses on the current guidelines as well as practical recommendations on antiplatelet treatment regimens for patients with different manifestations of CAD.

ANTIPLATELET THERAPY IN THE MANAGEMENT OF STABLE CORONARY ARTERY DISEASE PATIENTS Historical Background of Antiplatelet Therapy for SCAD Patients With PCI Stable coronary artery disease (SCAD) is defined as clinical evidence of ischemic heart disease attributed to the presence of atherosclerosis with no ACS event in the preceding 12 months. Aspirin has been used for a long time as the gold standard antiplatelet drug in SCAD. Many clinical trials have demonstrated the efficacy of aspirin therapy on reducing major adverse cardiovascular events (MACE) in patients with different CAD manifestations.19 In 1977, Andreas Gr€ untzig performed the first coronary balloon angioplasty in a 37-year-old man with CAD. At that time, aspirin was prescribed as an antiplatelet agent before the procedure, followed by warfarin for 6–9 months.20 Because the optimal pharmacotherapy to prevent failure and complications after PCI remained uncertain, early investigators recommended the use of warfarin as long-term adjunctive therapy after PCI. Accordingly, oral anticoagulation (OAC) therapy, such as vitamin K antagonists (VKA), were utilized in adjunct to aspirin after PCI for the prevention of thrombotic complications.21 However, because of the high bleeding risk and the limitations of VKA (i.e., drug-drug interactions, need for frequent monitoring, delayed onset/offset of action), other strategies were investigated. In 1996, the ISAR (Intracoronary Stenting and Antithrombotic Regimen) study demonstrated that DAPT with aspirin plus ticlopidine, a first generation thienopyridine, after coronary stenting decreased the rate of cardiac adverse events and hemorrhagic complications at 1 month compared with aspirin plus VKA therapy.22 In addition to identifying a safer strategy by using DAPT compared with VKA, these findings supported the importance

1017

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PART V Antiplatelet Therapy

of blockade of platelet activation pathways for the prevention of thrombotic complications after stent implantation setting the stage for many other investigations in the field. The subsequent STARS (Stent Anti-Thrombotic Regimen Study),23 FANTASTIC (Full Anticoagulation versus Aspirin and Ticlopidine),24 and MATTIS (Multicenter Aspirin and Ticlopidine Trial after Intracoronary Stenting)25 trials also demonstrated that a DAPT regimen using aspirin plus ticlopidine consistently reduced ischemic events with a favorable bleeding profile compared with the use of VKA. However, ticlopidine was associated with serious adverse effects including life-threatening hematological disorders.26 This has prompted the development of clopidogrel, a second-generation thienopyridine, which showed a better safety profile than ticlopidine as demonstrated in the CLASSICS (Clopidogrel Aspirin Stent International Cooperative Study) trial.8 The CREDO (Clopidogrel for the Reduction of Evens During Observation) trial then confirmed that 12-month DAPT with aspirin plus clopidogrel to be superior to aspirin monotherapy in PCI patients for the prevention of adverse ischemic events at 1 year.4 These observations contributed to the establishment of DAPT with aspirin plus a thienopyridine as a standard of care after stent implantation in SCAD patients.


6 months duration and long-term means 12 months of DAPT. Most of the short-term DAPT trials were designed to demonstrate a reduction in bleeding complications without any trade-off in efficacy. Indeed, these trials have been developed with the notion that major bleeding events with DAPT therapy increases mortality.32 Notably, the impact of a major bleeding event on mortality is the same or even greater than that of having a recurrent myocardial infarction (MI).15,16 The evolution in stent technology and the advent of these trials on short-term DAPT, have thus prompted a concept of minimum required duration of DAPT to prevent device-related thrombotic complications. On the other hand, trials of longterm DAPT were designed to demonstrate a reduction in adverse ischemic events after coronary stent implantation due to overall vascular events, in particular nonstent-related ischemic events.32 This concept was originally supported by post hoc analyses of RCTs demonstrating a reduction in overall ischemic events at the expense of an increased risk of bleeding.33 Indeed, a long-term DAPT strategy was tested prospectively in several trials, including the landmark DAPT (Dual Antiplatelet Therapy) and PEGASUS (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin.) trials.34,35

DAPT in SCAD Patients With PCI Coronary Stents and DAPT

Decision-Making on DAPT Duration and Risk Stratification

Coronary metal stents were developed to inhibit the recoiling process of coronary arteries and acute closure due to arterial dissection which limited the effectiveness of coronary balloon angioplasty.11 Early models of coronary stents were bare metal stents (BMS) which were effective for these issues. However, instent restenosis represented the main challenge with BMS, leading to the development of a new stent technology, known as drug-eluting stents (DES), characterized by slow release of antiproliferative agents to prevent intimal hyperplasia which is the main mechanism leading to in-stent restenosis.27,28 First generation DES had a polymer based technology releasing an antiproliferative drug which markedly reduced restenosis. However, this stent technology was associated with thrombotic complications, including very late thrombotic events (beyond 1 year), which emerged as critical issue with this stent type.29 The observation from the Bern–Rotterdam registry29 showing late stent thrombosis (ST) occurring at a rate of 0.6% per year up to 3 years after DES implantation led to a consensus recommendation, not supported by any randomized controlled trial (RCT), that DAPT should be maintained for at least 12 months after DES implantation.30 Moreover, several reports of very late ST have led to speculate that first generation DES would require clopidogrel therapy indefinitely. The increased risk of ST associated with first generation DES has been attributed to delayed endothelialization, polymer hypersensitivity reaction, and inflammation.31 This safety concern prompted the development of new alloys, polymers, drugs, and stent designs. The newer generation DES have indeed overcome the safety concerns of first generation DES, with markedly lower rates of thrombotic complications and nearly eliminated concerns of late thrombotic complications. This evolution in stent technology has allowed to reduce the minimum required duration of DAPT after coronary stent implantation.32

Prolonged Versus Short-Term DAPT Duration in PCI Patients Despite the evolution in stent technologies, the optimal duration of DAPT to meet the optimal efficacy and safety profile remains largely debated. To this extent, a large number of RCTs testing short-term versus long-term DAPT have been conducted. Generally short term DAPT after PCI means

The different bleeding and ischemic risk profile of individual patients makes it difficult to apply uniform decisions on DAPT duration to all patients. In fact, while some patients may benefit from prolonged DAPT, such as patients with diabetes, multiple stenting, complex PCI, others who have high risk of bleeding complication or low ischemic risk may derive harm from prolonged DAPT. Therefore, DAPT duration should be personalized based on a risk stratification model that takes into consideration the ischemic and bleeding risk profiles of the individual patient that easily identifies patients who will benefit or not from different DAPT durations (Fig. 56.1). To this extent, several scoring systems have been developed (Fig. 56.2).36–39 The PRECISEDAPT (PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy) score was developed to identify PCI patients at high risk of bleeding. This score predicts out-of-hospital bleeding using five parameters (age, creatinine clearance, white blood cell count, hemoglobin, and history of bleeding). Those at high bleeding risk (score 25) may benefit from short-term DAPT after DES implantation (3–6 months).38 On the other hand, the DAPT score allows the identification of patients who may receive benefit from prolonged DAPT duration using nine parameters. This score is useful for patients who already tolerated 12 months of DAPT after coronary stent implantation to select those eligible for long-term DAPT. Patients with a score 2 benefit from prolonged DAPT.37 Although none of these risk prediction scores has been prospectively tested in an RCT, the use of the PRECISE-DAPT and DAPT scores in decision making on DAPT duration may be considered in clinical practice (Class IIb, Level of evidence [LOE] B).40 It is important to note that although these risk scores are easy to follow and convenient to use, they are subject to limitations. Indeed, the risk of developing a bleeding complication is dynamic and changes over time. Thus the decisions from these scoring systems should not be considered as definitive and always needs to be integrated with clinical judgement and taking into consideration patient preference.41

Current Practice Recommendation of DAPT in SCAD Patients With PCI DAPT is the mainstay antiplatelet treatment regimen after PCI. However, DAPT is not indicated in medically managed patients with SCAD who have no history of PCI or prior MI. In fact, in

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Fig. 56.1 Optimal duration of DAPT after DES implantation. Minimal required duration of DAPT according to clinical presentation (ACS vs. SCAD) and indications for prolonged or shortened used according to ischemic and bleeding risk profile integrated with use of scoring systems. Abbreviations: ACS, acute coronary syndrome; CKD, chronic kidney disease; DAPT, dual antiplatelet therapy; MI, myocardial infarction; NSAID, nonsteroidal anti-inflammatory drugs; OAC, oral anticoagulants; SCAD; stable coronary artery disease. (Reproduced with permission from Prog Cardiovasc Dis 2017.32)

Fig. 56.2 Decision making on DAPT duration based on PRECISE-DAPT and DAPT scores. Variables included in the scores are associated with increased bleeding risk (red dot), increased ischemic risk (blue dot) or neutral effect (black dot). *In the validation study, short-term DAPT consisted of 3–6 months of therapy and standard DAPT consisted of at least 12 months of DAPT. (Reprinted from Gargiulo G, Valgimigli M, Capodanno D, Bittl JA. State of the art: duration of dual antiplatelet therapy after percutaneous coronary intervention and coronary stent implantation—past, present and future perspectives, EuroIntervention 2017;13(6):717–33, Copyright 2017, with permission from Europa Digital & Publishing.)

these patients aspirin remains the treatment of choice (Class I, LOE A). Patient with hypersensitivity or intolerance to aspirin should consider clopidogrel monotherapy (Class I, LOE B).42 To this extent, in this section, we will focus on the treatment recommendations for SCAD patients undergoing PCI. Current guideline recommendation from the European Society of Cardiology (ESC) and the American College of Cardiology (ACC)/ American Heart Association (AHA) for the antiplatelet therapy in patients with SCAD are summarized in Table 56.1.40,43,45 For all patients undergoing PCI, low-dose aspirin (81–325 mg daily) is indicated before elective stenting. If patients were not on aspirin therapy, nonenteric aspirin (150–325 mg) should be administered before PCI (Class I, LOE B). Clopidogrel (600 mg loading and 75 mg daily) is also a Class I indication for SCAD patients undergoing PCI (Class I, LOE A).

A multitude of studies investigating the safety of short-term DAPT duration in SCAD patients led to revision of the guidelines. Accordingly, the minimal required duration of DAPT after coronary stent implantation decreased from 12 to 6 months irrespective of stent type for SCAD patients. Indeed, the previous recommendation for 12 months of DAPT was based on empirical recommendations after emergence of the safety issues with first generation DES. In patients with SCAD who have tolerated DAPT and at low bleeding but high risk for thrombotic events, continuation of DAPT (duration from 6 to 30 months) may be considered (Class IIb). On the other hand, in patients at higher risk of bleeding complications or concomitant use of oral anticoagulant therapy, shortening of DAPT duration (3 months) may also be considered (Class IIa in ESC, Class IIb in ACC/AHA). In patients with a PRECISE-DAPT score 25, DAPT is recommended for 3 months in the ESC

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PART V Antiplatelet Therapy

TABLE 56.1 Summary of ACC/AHA and ESC Guidelines for the Management of Oral and Intravenous Antiplatelet Therapy in Patients With Stable Ischemic Heart Disease With PCI ACC/AHA43 Recommendations ORAL THERAPY Aspirin is indicated before elective stenting Patients not on aspirin therapy should be given nonenteric aspirin 150–325 mg before PCI Clopidogrel (600 mg loading dose, 75 mg daily dose) on top of aspirin is recommended in stable CAD patients undergoing coronary stent implantation Ticagrelor or prasugrel on top of aspirin may be considered instead of clopidogrel in stable CAD patients undergoing PCI, taking into account the ischemic (e.g., high SYNTAX score, prior stent thrombosis, location and number of implanted stents) and bleeding (e.g., according to PRECISE-DAPT score) risks DAPT DURATION In patients with stable CAD, DAPT with aspirin and clopidogrel is generally recommended for 6 months, irrespective of the stent type In patients with stable CAD considered at high bleeding risk (e.g., PRECISE-DAPT  25), DAPT for 3 months should be considered In patients with stable CAD in whom 3-month DAPT poses safety concerns, DAPT for 1 month may be considered In patients with stable CAD who have tolerated DAPT without a bleeding complication and who are at low bleeding but high thrombotic risk, continuation of DAPT with clopidogrel for >6 months and
30 months may be considered In patients with stable CAD treated with BVS, DAPT for at least 12 months should be considered INTRAVENOUS THERAPY In patients undergoing elective PCI treated with unfractionated heparin and not pretreated with clopidogrel, it is reasonable to administer a GPIs (abciximab, double-bolus eptifibatide, or high-bolus dose tirofiban) In patients undergoing elective PCI with stent implantation treated with unfractionated heparin and adequately pretreated with clopidogrel, it might be reasonable to administer a GPIs (abciximab, double-bolus eptifibatide, or high-bolus dose tirofiban) GPIs should be considered only for bail-out situation

ESC44

Class

Level

Class

Level

I I I

B B A

I I I

B C A

IIba

C

A

Ib

A

Ia

IIbb

C

IIaa

B

a

IIb IIba

C A

IIaa

C

IIa

C

IIbb

A

IIa

B

IIb

B

ACC, American College of Cardiology; AHA, American Heart Association; BID, twice a day; DAPT, dual antiplatelet therapy; ESC, European Society of Cardiology; BVS, bioresorbable vascular scaffolds; GPI, glycoprotein IIb-IIIa inhibitor; LD, loading dose; MD, maintenance dose; PCI, percutaneous coronary intervention. a

2017 ESC focus update on DAPT in CAD developed in collaboration with EACTS.40 2016 ACC/AHA Guideline focused update on duration of DAPT in patients with CAD.45

b

guidelines. Moreover, the updated ESC guidelines indicate that 1 month of DAPT may be considered if 3 months DAPT poses safety concerns in SCAD patients (Class IIb, LOE C). Afterwards, life-long single antiplatelet therapy, usually aspirin, is recommended. The routine use of potent P2Y12 inhibitor (prasugrel or ticagrelor) is not recommended in SCAD patients.

Intravenous Antiplatelet Agents for SCAD Patients With PCI Recent clinical trial did not show additional benefit from the use of glycoprotein IIb-IIIa inhibitors (GPIs) after a clopidogrel loading dose of 600 mg.46 According to the ESC guidelines, in elective PCI of SCAD patients, GPIs should be considered only for bail-out use (intra-procedure thrombus formation, slow flow, threatened vessel closure) (Class IIa, LOE C).44 However, the ACC/AHA PCI guidelines, which have not been updated since 2011, indicate that in patients undergoing elective PCI treated with unfractionated heparin and not pretreated with clopidogrel, it is reasonable to administer a GPI (abciximab, double-bolus eptifibatide, or high-bolus dose tirofiban) (Class IIa, LOE B), while a lower level of recommendation is provided for patients adequately pretreated with clopidogrel (Class IIb, LOE B).

ANTIPLATELET THERAPY IN THE MANAGEMENT OF ACS PATIENTS History of Antiplatelet Therapy in ACS Patients The key mechanism leading to an ACS is primarily based on arterial thrombosis which develops after rupture or erosion of an

atherosclerotic plaque.47 The processes of platelet activation and aggregation contribute to the development of pathological arterial thrombus and lead to vascular occlusion.47–49 ACS is a potentially lethal condition and has a high recurrence rate. For these reasons, long-term antiplatelet therapy is essential for the treatment and prevention of atherothrombotic complications in ACS patients. Aspirin has been the gold standard for many years. In the ISIS-2 (International Study of Infarct Survival-2) trial, which enrolled 17,187 acute myocardial infarction (AMI) patients, streptokinase alone and aspirin alone each produced a highly significant reduction (odds reduction of 25% and 23%, respectively) in 5-week vascular mortality compared with placebo and the combination of aspirin and streptokinase was significantly better than either agent alone.50 Subsequently, aspirin was established as the first-line therapy in ACS patients. The development of clopidogrel contributed towards improving the care of ACS patients. The benefit of the use of DAPT with aspirin and clopidogrel following an ACS was demonstrated by several landmark clinical trials.5–7 The superiority of 12 months of a DAPT regimen with aspirin and clopidogrel compared with aspirin alone in ACS patients was first shown in the CURE (Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events) trial.7 The superiority of DAPT was consistent among patients with ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytic therapy in the CLARITY (Clopidogrel as Adjunctive Reperfusion Therapy) trial.6 The COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) trial, conducted in patients with acute MI, showed that the adjunctive use of clopidogrel also had a survival benefit.5 These observations led DAPT with aspirin plus clopidogrel to be the standard of care in ACS patients.

Antiplatelet Drugs in the Management of Coronary Artery Disease

However, a considerable number of investigations have consistently revealed a broad variability in clopidogrel response and patients with poor clopidogrel response have a higher risk of thrombotic complications.51–53 These observations have prompted the development of prasugrel and ticagrelor which are newer generation oral P2Y12 receptor inhibitors characterized by more prompt, potent, and predictable pharmacodynamic profiles compared with clopidogrel.1 The TRITON (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel) TIMI 38 trial demonstrated a greater reduction is ischemic events compared with clopidogrel in high-risk ACS patients undergoing PCI.9 However, the reduction in ischemic events came at the expense of increased major bleeding, including life-threating and fatal bleeding. In patients with a history of cerebrovascular events there was a significant increase in adverse clinical events resulting in overall harm from the use of prasugrel (as compared with clopidogrel); this included a significant increase in intracranial hemorrhage in this cohort of patients. Therefore, prasugrel is contraindicated in these patients (Class III, LOE B). Two other important cohorts were patients 75 years of age or older and patients weighing less than 60 kg in whom there was an increased risk of bleeding ultimately leading to no net benefit from prasugrel. Therefore, prasugrel should be used with caution in these cohorts of patients. Although results of pharmacokinetic and pharmacodynamic investigations have suggested the use of lower maintenance dose regimens in these patients, these have not been tested in large-scale clinical investigations. In the PLATO (The Platelet Inhibition and Patient Outcomes) trial, ticagrelor also reduced ischemic events, including cardiovascular mortality, compared with clopidogrel in ACS patients.10 However, unlike the TRITON-TIMI 38 trial, which was conducted exclusively in ACS patients undergoing PCI, PLATO was conducted in ACS patients irrespective of type of management (invasive or noninvasive). These differences in trial design make ticagrelor use more versatile for the management of ACS patients compared with prasugrel. However, similarly to prasugrel, the decrease in ischemic recurrences was associated with an increase in bleeding complications, albeit not fatal. Moreover, ticagrelor was associated with an increased risk of nonbleeding side effects, in particular dyspnea.10 The persistence of ischemic recurrences despite the use of DAPT has set the foundation for identifying alternative targets. In particular, targeting the effects of thrombin on platelets has represented a key area of investigation given the central role of thrombin on platelet activation and thrombus formation.54 Vorapaxar is a direct PAR-1 inhibitor, which in addition to standard DAPT (mostly aspirin and clopidogrel) was associated with a reduction in ischemic events in patients with various vascular disease manifestations, including patients with a prior MI. However, this occurred at the expense of a significant increase in major bleeding complications, including ICH particularly among patients with a prior cerebrovascular event.55,56 Although vorapaxar is approved for clinical use, its uptake in clinical practice has been very limited and it is not recommended within practice guidelines.

Antiplatelet Therapy for ACS PCI Patients Current guideline recommendations on the use of antiplatelet therapy in patients with ACS from the ESC and ACC/AHA are summarized in Table 56.2.40,45,57–60 These recommendations consider DAPT as standard of care for both invasively and noninvasively managed ACS patients. Aspirin is recommended for all patients without contraindications and should be continued indefinitely. The initial oral loading dose is of 150–300 mg (for aspirin naive patients) and a maintenance dose of 75–100 mg/ day (Class I, LOE A). In patients presenting with an ACS, timely

1021

administration of antiplatelet therapy is critical. While there is consensus that aspirin should be used for all patients immediately at the time of presentation, timing of administration of the oral P2Y12 receptor inhibitors has been debated. Moreover, the availability of different P2Y12 inhibitors has prompted recommendations on drug selection. These aspects are described below.

Timing of P2Y12 Receptor Inhibitor Timing of administration of the oral P2Y12 receptor inhibitors has been debated. The term “pretreatment” of P2Y12 receptor inhibitors is defined as treatment administration before knowing coronary anatomy. Although guidelines have previously provided a class I recommendation for pretreatment with P2Y12 receptor inhibitor as soon as possible in ACS patients,61 the data to support this approach is very limited. The concept of pretreatment has been developed with the concept that early administration of a P2Y12 receptor inhibitor may protect the patient from ischemic recurrences prior to defining coronary anatomy and during the peri-PCI period. However, it cannot be excluded that this strategy in some patients may be unnecessary and in some cases be even harmful. For example, some patients may not have significant coronary artery stenosis warranting revascularization while others may require coronary artery bypass graft surgery (CABG).61 In the latter subjects prior exposure to P2Y12 inhibiting therapy increases the risk of surgical bleeding complications warranting patients to wait 5–7 days for wash-out of the drug effects. This indeed is associated with prolonging hospitalizations and increased costs (Fig. 56.3).62 The concept of pretreatment originated from the CURE study, in which patients were treated with clopidogrel 300 mg loading dose at the time of clinical presentation.63 However, this study was conducted in an era in which patients were conservatively managed and the median time to PCI was 10 days, which largely differs from current day practice in which patients are managed invasively and undergo PCI, if needed, more promptly. Importantly, a metaanalysis in patients with NSTE-ACS (n ¼ 37,814 from 15 clinical trials) found no differences in mortality between clopidogrel pretreatment and no pretreatment.64 Although the study design of PLATO, where all patients were pretreated supports the current practice of pretreatment of ticagrelor, the role of pretreatment versus no pretreatment with ticagrelor in patients with NSTEMI has not been tested in any RCT. On the other hand, this was specifically tested in the ACCOAST (Comparison of Prasugrel at the Time of PCI or as Pretreatment at the Time of Diagnosis in Patients with Non-ST Elevation Myocardial Infarction) trial which showed a threefold increase in non-CABG-related TIMI major bleeding without improvement in efficacy among NSTEMI patients pretreated with prasugrel versus those treated in the catheterization laboratory. For this reason, upstream treatment with prasugrel is contraindicated in NSTEMI patients.65 Similar to NSTEMI, pretreatment with oral P2Y12 receptor inhibitors is a broad practice in STEMI patients undergoing primary PCI, despite the lack of data from RCTs. In the STEMI subgroup of a large metaanalysis of patients undergoing PCI, pretreatment with clopidogrel was associated with an approximately 50% reduction in mortality.64 In the TRITON-TIMI 38 study, pretreatment was allowed only in STEMI patients undergoing primary PCI and showed favorable outcomes in this group. Thus, pretreatment with prasugrel in STEMI patients is allowed based on this observation. Although prehospital administration of ticagrelor in STEMI patients did not reduce the coprimary ischemic end points in the ATLANTIC (Administration of Ticagrelor in the Cath Laboratory or in the Ambulance for New ST-Segment-Elevation Myocardial Infarction to

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TABLE 56.2 Summary of ACC/AHA and ESC Guidelines for the Management of Oral and Intravenous Antiplatelet Therapy in Patients With ACS ACC/AHA57 Recommendations ORAL THERAPY Nonenteric coated oral aspirin (150–325 mg) promptly after presentation (or 80–150 mg intravenously). Aspirin should be continued (75–100 mg/day) indefinitely A P2Y12 inhibitor is recommended in addition to aspirin, and maintained over 12 months unless there are contraindications: - Prasugrel (60 mg LD, 10 mg/daily MD) in patients in whom coronary anatomy is known and who are proceeding to PCI - Ticagrelor (180 mg LD, 90 mg BID MD) regardless of initial treatment strategy including those pretreated with clopidogrel - Clopidogrel (600 mg LD, 75 mg/day MD), only when prasugrel or ticagrelor are not available or are contraindicated Pretreatment with a P2Y12 inhibitor is generally recommended in patients in whom coronary anatomy is known and the decision to proceed to PCI is made as well as in patients with STEMI Pretreatment with prasugrel in patients in whom coronary anatomy not known is not recommended DAPT DURATION DAPT with P2Y12 inhibitor should be given for at least 12 months to patients with ACS (NSTE-ACS or STEMI) after BMS or DES implantation It may be reasonable to continue DAPT for > 12 months in ACS patients treated with coronary stent implantation who have tolerated DAPT without a bleeding complication and who are not at high bleeding risk (e.g., prior bleeding on DAPT, coagulopathy, oral anticoagulant use) Discontinuing P2Y12 inhibitor may be reasonable after 6 months in ACS patients treated with DAPT after DES implantation who develop a high risk of bleeding (e.g., treatment with oral anticoagulant therapy), are at high risk of severe bleeding complication, or develop significant overt bleeding In patients with MI and high ischemic risk who have tolerated DAPT without a bleeding complication, ticagrelor 60 mg BID for longer than 12 months on top of aspirin may be preferred over clopidogrel or prasugrel INTRAVENOUS THERAPY GPIs should be considered for bail-out situation or thrombotic complications Upstream use of GPIs in patients treated with an early invasive strategy and DAPT with intermediate/high-risk features In patients with NSTE-ACS and high-risk features (e.g., elevated troponin) not adequately pretreated with clopidogrel or ticagrelor, it is useful to administer a GPIs (abciximab, double-bolus eptifibatide, or high-dose bolus tirofiban) at the time of PCI In patients with NSTE-ACS and high-risk features (e.g., elevated troponin) treated with UFH and adequately pretreated with clopidogrel, it is reasonable to administer a GPIs (abciximab, double-bolus eptifibatide, or highbolus dose tirofiban) at the time of PCI In patients undergoing PCI, routine upstream use of GPIs is not recommended Cangrelor may be considered in P2Y12 inhibitor-naive patients undergoing PCI

ESC58

Class

Level

Class

Level

I

A

I

A

I

B

I

A

IIa

B

I

B

IIa

B

I

B

I

B a

A

IIIa

B

I

Ib

B

Ia

A

IIbb

A

IIba

A

IIbb

C

IIaa

B

IIba

B

IIa

C

III IIb

A A

IIb

A

I

A

IIa

B

Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; BID, twice a day; DAPT, dual antiplatelet therapy; ESC, European Society of Cardiology; GPI, glycoprotein IIb-IIIa inhibitor; LD, loading dose; MD, maintenance dose; PCI, percutaneous coronary intervention. a 2017 ESC focus update on DAPT in CAD developed in collaboration with EACTS.40 b 2016 ACC/AHA Guideline focused update on duration of DAPT in patients with CAD.45

Open the Coronary Artery) trial, rates of major bleeding were low and very similar between prehospital use and emergency room use, suggesting the safety of pretreatment with ticagrelor.66 The ESC guidelines have taken different positions over the years on their recommendations on pretreatment. This underscores the controversial nature of this topic with arguments that can be made both in favor and against pretreatment. While for many years the ESC guidelines where largely supportive of a pretreatment strategy, the 2015 guidelines for the first time indicated that no recommendation for or against pretreatment with ticagrelor or clopidogrel can be formulated because the optimal timing of administration for these agents in NSTEMI patients scheduled for an invasive strategy has not been adequately investigated.58 However, in the most recent 2017 update the ESC guidelines indicate that pretreatment of a P2Y12 receptor inhibitor with ticagrelor or clopidogrel is generally recommended in patients in whom coronary anatomy is known and the decision to proceed to PCI (Class I, LOE A).40 On the contrary, the current ACC/AHA guidelines are overall silent on their recommendations for pretreatment with ticagrelor or clopidogrel limiting to a description of how the drugs were used in the trials.57 In light of the ACCOAST trial, the ESC

guidelines do not recommended to administer prasugrel before knowing coronary anatomy in NSTEMI patients (Class III, LOE B).58 Similarly, prasugrel is not recommended for “upfront” therapy in patients with NSTEMI in the ACC/AHA guidelines.57 On the other hand, despite the lack of compelling data, pretreatment with a P2Y12 receptor inhibitor in STEMI is generally recommended in the ESC guidelines (Class I, LOE A).40 According to the ACC/AHA guidelines, a P2Y12 receptor inhibitor should be given as early as possible or at time of primary PCI to STEMI patients.67

P2Y12 Receptor Inhibitor Selection in ACS There are some differences between ESC and ACC/AHA recommendations on the selection of P2Y12 receptor inhibitor in ACS patients. The ESC guidelines indicate that58 ticagrelor (180 mg loading dose, 90 mg BID) is recommended, in the absence of contraindications (previous ICH or ongoing bleeds), for all patients at moderate-to-high risk of ischemic events (e.g., elevated cardiac troponins), regardless of initial treatment strategy, including those pretreated with clopidogrel (which should be discontinued when ticagrelor is started) (Class I, LOE B). Prasugrel (60 mg loading dose, 10 mg daily dose) is

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Fig. 56.3 Pros and cons of upstream versus downstream use of P2Y12 receptor inhibitors. (Reproduced with permission from Expert Rev Cardiovasc Ther 2016.62)

recommended in patients who are proceeding to PCI in the absence of contraindications (previous ICH, previous ischemic stroke or transient ischaemic attack or ongoing bleeds; prasugrel is generally not recommended for patients 75 years of age or with a body weight <60 kg) (Class I, LOE B). The ACC/AHA guidelines indicate that it is reasonable to choose ticagrelor over clopidogrel in patients with NSTE-ACS treated with an early invasive strategy and/or coronary stenting (Class IIa, LOE B).57 Moreover, they state that it is reasonable to choose prasugrel over clopidogrel in patients with NSTE-ACS who undergo PCI who are not at high risk of bleeding complications (Class IIa, LOE B). The ESC guidelines indicate that clopidogrel (300–600 mg loading dose and 75 mg daily maintenance dose) should be used only when both prasugrel and ticagrelor are contraindicated or for patients requiring oral anticoagulation therapy (triple therapy) (Class I, LOE B). However, there is no specific wording to this extent in the ACC/AHA guidelines.

Intravenous Antiplatelet Agents for ACS Patients With PCI The use of a GPI is a treatment option in high-risk ACS patients undergoing PCI. These agents block the final pathway of platelet aggregation, and provide rapid and potent antiplatelet effects.68 However, the role of GPIs in clinical practice has been downgraded because of their high rates of bleeding complications, as well as the development of novel alternative treatment options with a more favorable safety profile. Indeed, available data support their selective rather than routine use in ACS patients undergoing PCI. There are some differences between the ESC and ACC/ AHA guidelines. In the ESC guidelines, the use of GPIs during PCI should only be considered for bailout situations (high thrombus burden, stent thrombosis) or thrombotic complications (Class IIa, LOE C). Routine upstream use of GPIs is not recommended before PCI (Class III, LOE A). However, according to

the ACC/AHA guidelines, the upstream use of small molecule GPIs (eptifibatide or tirofiban) may be considered in addition to DAPT in NSTEMI with high-risk features (Class IIa, LOE B). At the time of PCI, the ACC/AHA guidelines recommend the use of GPIs (abciximab, double-bolus eptifibatide, or high-dose bolus tirofiban) in NSTEMI patients with high-risk features (e.g., elevated troponin) not adequately pretreated with clopidogrel or ticagrelor (Class I, LOE A). In NSTEMI patients treated with unfractionated heparin and adequately pretreated with clopidogrel, the ACC/AHA guidelines indicate that it is reasonable to administer a GPI (Class IIa, LOE B). Cangrelor is the only intravenous P2Y12 receptor inhibitor currently available. The drug was approved for clinical use based on the results of the CHAMPION PHOENIX (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition PHOENIX) trial.69 The ESC guidelines state that the drug may be considered in P2Y12 receptor inhibitor naive patients undergoing PCI (Class IIb, LOE A). The ACC/ AHA guidelines have not been updated since approval of cangrelor, thus no recommendations are available. Although cangrelor has been tested as a bridging strategy for patients with CAD requiring surgery,70 the drug has not been approved for this indication.

DAPT Duration in ACS Patients According to both the ESC and AHA/ACC guidelines, in ACS patients DAPT with aspirin plus P2Y12 inhibitor is recommended for 12 months irrespective of management (invasive vs. noninvasive), type of revascularization (percutaneous vs. surgical), or type of intracoronary device (BMS vs. DES) (Class I, LOE B).40,45 A shorter duration of DAPT (i.e., 6 months) can be considered in ACS patient at high bleeding risk (Class IIa, LOE B in ESC guidelines; Class IIb, LOE C in ACC/AHA

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guidelines). On the contrary, in patients at high ischemic risk who have tolerated DAPT without bleeding complications, continuation of DAPT for longer than 12 months may be considered (Class IIb, LOE A). The ESC guidelines further expand on this recommending ticagrelor 60 mg BID for >12 months on top of aspirin over clopidogrel or prasugrel (Class IIb, LOE A). This recommendation is based on the results of the PEGASUS35 and DAPT34 trials, both of which evaluated the efficacy and safety of long-term (>12 months) DAPT with aspirin plus a P2Y12 inhibitor. The DAPT trial showed a benefit of prolonged DAPT (12–30 months after PCI) compared to 12 months DAPT. There was a significant reduction in the rates of ST, MI, and MACE in patients on prolonged DAPT. However, there was an increased risk of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding with long-term DAPT.34 The PEGASUS trial assessed the long-term efficacy of ticagrelor in addition to aspirin among patients with a prior (1–3 years) spontaneous MI.35 In this study two dosing regimens of ticagrelor were tested (90 mg bid and 60 mg bid). Both regimens of ticagrelor significantly reduced the risk of adverse ischemic events to a similar extent compared with placebo. This occurred at the expense of an increased risk of TIMI major bleeding, albeit no differences in fatal bleeds or ICH. The 60 mg regimen had an overall more favorable safety profile compared with the 90 mg regimen, hence the specific recommendations in the ESC guidelines.

Antiplatelet Therapy for Medically Managed ACS Patients For medically managed ACS patients, despite guideline recommendations and clinical trial evidence, DAPT is less frequently used compared to patients treated with PCI.71 The CURE study showed a clinical benefit of 9 months DAPT (3–12 months) including aspirin and clopidogrel as compared to 1 month therapy in NSTE-ACS patients, irrespective of management strategy.7 In the subgroup analysis of the PLATO trial, medically managed NSTE-ACS patients had consistent benefit, including reduced mortality, from ticagrelor 90 mg twice daily as compared to clopidogrel.72 In the PEGASUS trial, which enrolled patients with a prior history of spontaneous MI, 4271 patients had no prior history of coronary stenting and showed consistent outcomes compared to patients with prior coronary stenting.35 However, prasugrel treatment in medically managed ACS patients is not recommended based on the result of TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial, in which there were no differences between prasugrel and clopidogrel on the primary ischemic end point.73 The evidence in support of DAPT regimen in patients with medically managed STEMI or prior fibrinolytic therapy is limited to 1 month of DAPT.5,6 The CLARITY trial, which was conducted in STEMI patients treated with fibrinolytic therapy, showed DAPT with aspirin and clopidogrel was associated with a reduction in ischemic events compared to aspirin monotherapy.6 However, the majority of these patients would undergo coronary intervention and 12 months of DAPT therapy is still recommended in the medically managed ACS patients including STEMI.

NEW STRATEGIES OF ANTITHROMBOTIC TREATMENT REGIMENS FOR SAFETY AND EFFICACY A Paradigm Shift: Dropping Aspirin The observations that stacking antithrombotic therapies, even with the use of newly developed agents, systematically increases bleeding risk has led to the investigation of new strategies that may be potentially safer than a conventional DAPT

regimen. To this end, there are several investigations evaluating whether dropping aspirin, particularly when more potent adjunctive therapies are being utilized, can reduce bleeding.74 This strategy is indeed considered to be a paradigm shift particularly considering that aspirin represents the gold standard antiplatelet drug for secondary prevention in patients with atherothrombotic diseases. In the CAPRIE (a randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events) trial, which showed that long-term administration of clopidogrel in patients with various atherosclerotic vascular disease manifestations to be more effective than aspirin in reducing the combined risk of ischemic events, aspirin contributed to the increased risk of bleeding complications, particularly gastrointestinal bleeding.75 In the MATCH (Aspirin and clopidogrel compared with clopidogrel alone after recent ischemic stroke or transient ischemic attack in high-risk patients) adding aspirin to clopidogrel in high-risk patients with recent ischemic stroke or transient ischemic attack was associated with a nonsignificant difference in reducing major vascular events and an increased risk of life-threatening or major bleeding.76 These observations have suggested that aspirin may contribute to the increased risk of bleeding. However, it may also be argued that adding a P2Y12 inhibitor may also be responsible for the increased risk of bleeding as studies of adjunctive P2Y12 inhibiting therapy have consistently shown an increased risk of bleeding particularly in lower risk settings.77 Overall, this data would suggest that the risk of bleeding may be more attributed to the additive antiplatelet effects rather than to a specific agent. Although observations from in vitro investigations have suggested that aspirin only offers minimal adjunctive antithrombotic effects in the presence of potent P2Y12 receptor inhibitor,78 this is not supported by other investigations conducted ex vivo.79 In line with these observations, a number of trials have evaluated the feasibility of dropping aspirin therapy as an approach to reduce bleeding complications without loss of efficacy. The first trial to evaluate the impact of dropping aspirin was the WOEST (What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing) study, which was conducted in patients treated with OAC undergoing PCI.80 This study compared triple therapy (OAC combined with aspirin and clopidogrel) with dual therapy (OAC and clopidogrel) and demonstrated that maintaining dual therapy was associated with a significant reduction in bleeding complications. Importantly, there was no tradeoff in efficacy and a reduction in mortality. The safety of dropping aspirin in atrial fibrillation (AF) patients undergoing PCI and maintaining therapy with a novel oral anticoagulant (NOAC) and a P2Y12 inhibitor was recently shown in the PIONEER (Prevention of bleeding in patients with atrial fibrillation undergoing PCI) AF-PCI 81 and REDUAL-PCI (Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention)82 trials, with rivaroxaban and dabigatran, respectively. Several trials of dropping aspirin, characterized by a short-term DAPT therapy followed by potent P2Y12 receptor inhibitor monotherapy without aspirin are ongoing. The two largest studies are the GLOBAL LEADERS (The Clinical Study Comparing Two Forms of Antiplatelet Therapy After Stent Implantation, NCT01813435) and TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention, NCT 02270242). The GLOBAL LEADERS trial recently completed enrollment of 16 000 patients and is comparing the outcomes between ticagrelor monotherapy after 1 month of DAPT and conventional standard DAPT (aspirin plus clopidogrel/ticagrelor) in all-comers patients undergoing PCI with a biolimus-eluting stent. Study results are anticipated be presented in 2019.83 The TWILIGHT study is evaluating the

Antiplatelet Drugs in the Management of Coronary Artery Disease

effectiveness and safety of ticagrelor monotherapy after 3 months of DAPT, compared to DAPT (aspirin plus ticagrelor) in reducing ischemic adverse events and bleeding complications among high-risk PCI patients.84 The study has recently completed enrollment of 9000 patients. It is also important to note that neither of these studies included an arm of aspirin alone.

De-Escalation Therapy and Personalized Antiplatelet Therapy The observation that ischemic events most commonly occur early (first weeks/months) after the index event (ACS/PCI) and that bleeding complications accrue over time, has led to an emerging concept of de-escalation of P2Y12 inhibiting therapy from a more potent to a less potent agent.85 The SCOPE (Switching from Clopidogrel to New Oral Antiplatelet Agents during PErcutaneous Coronary Intervention) registry86 demonstrated switching from prasugrel/ticagrelor to clopidogrel in the early phases of an ACS presentation was associated with an increase in adverse clinical events. However, in the TOPIC (Timing of platelet inhibition after acute coronary syndrome) study, de-escalation 1 month after an ACS event was superior to maintaining DAPT with a potent P2Y12 receptor inhibitor to prevent bleeding complications without an increase in ischemic events.87 However, the small sample size of the study and definition of the primary outcome measure, which did not include MI, have questioned the validity of these findings. In addition, there have been concerns that some patients who switched to clopidogrel may have an increased ischemic risk if they have inadequate response to clopidogrel suggesting the need for a guided approach using either platelet function or genetic testing.88 The TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for ACS) trial showed that a strategy of de-escalation of P2Y12 inhibiting therapy guided by platelet function testing was noninferior compared with standard treatment with prasugrel in ACS patients undergoing PCI on clinical outcomes (combined ischemic and bleeding events).89 In this study, there was a trend towards a reduction in bleeding complications without any increase in ischemic events. Indeed, more studies are warranted to better support the safety and efficacy of deescalation. A number of ongoing studies, many using rapid bedside genetic testing are currently ongoing to support this hypothesis which to date are mostly limited to registry data or small randomized studies.90 The ESC and ACC/AHA guidelines are consistent in their recommendations on the use of platelet function and genetic testing in clinical practice. In particular, platelet function testing may be considered in patients at high risk for poor clinical outcomes (Class IIb, LOE C) while routine use of platelet function testing to screen patients treated with clopidogrel is not recommended (Class III, LOE C).43,44 Similarly, genetic testing for CYP2C19 loss of function alleles in high risk patients undergoing PCI is considered a Class IIb recommendation, while routine genotyping is not recommended (Class III, LOE C).40,43–45 These issues are discussed in more detail in Chapter 36.

Adjunctive Use of Oral Anticoagulation Although the use of DAPT with aspirin and a P2Y12 receptor inhibitor reduces the risk of ischemic events, the risk of ischemic recurrences in ACS patients remains high. These observations may be attributed to the persistence of thrombin generation after an ACS event.91,92 This pathophysiological consideration underscores how inhibition of both platelets and coagulation factors are important for secondary prevention of adverse event in ACS patients. This also prompted investigators to reevaluate the benefit of long-term OAC therapy in ACS

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patients. Indeed, the introduction of the NOACs, which have an enhanced safety profile and ease of use compared with VKA, have stimulated several investigations of NOACs with DAPT in ACS patients. Among the various NOACs, only rivaroxaban successfully completed phase III clinical investigation meeting its primary efficacy endpoint. In particular, the ATLAS ACS 2 (Anti-Xa Therapy to Lower cardiovascular events in addition to Aspirin with or without thienopyridine therapy in Subjects with Acute Coronary Syndrome 2)-TIMI 51 study enrolled 15 526 patients with a recent ACS and showed that triple therapy including low-dose rivaroxaban, 2.5 mg twice a day (BID) regimen, aspirin and clopidogrel reduced recurrent cardiovascular events, including mortality, compared to DAPT with aspirin and clopidogrel, at the expense of a threefold increase in major bleeding, including ICH, but without increase in fatal bleeding.93 These observations contributed to the approval for clinical use of very low-dose rivaroxaban in most parts of the world (not in the United States) for ACS patients. However, despite of the survival benefit observed with triple therapy including low dose rivaroxaban 2.5 mg BID, aspirin, and clopidogrel, the use of NOACs for the ACS indication has been limited because of the increased bleeding risk. As mentioned above, a current trend of investigations is evaluating whether withdrawing aspirin therapy may represent a potential option to reduce bleeding risk while maintaining efficacy. The GEMINI-ACS-1 (A study to compare the safety of rivaroxaban versus acetylsalicylic acid in addition to either clopidogrel or ticagrelor therapy in participants with acute coronary syndrome-1) trial also suggested that the use of dual therapy including low-dose rivaroxaban and ticagrelor without aspirin was associated with an acceptable safety profile compared with DAPT with aspirin and ticagrelor in ACS patients.94 The addition of low-dose rivaroxaban (2.5 mg BID for one year) is now considered within the ESC guidelines on NSTEACS and STEMI.58,59 In particular, in NSTEMI patients without a history of prior stroke/transient ischemic attack and at high ischemic risk as well as low bleeding risk receiving aspirin and clopidogrel, low-dose rivaroxaban (2.5 mg BID) may be considered after discontinuation of parenteral anticoagulation (Class IIb, LOE B);58 in selected STEMI patients who receive aspirin and clopidogrel, low-dose rivaroxaban (2.5 mg BID) may be considered if the patient is at low bleeding risk (Class IIb, LOE B).59 However, rivaroxaban has not been approved by the Food and Drug Administration (FDA) for the ACS indication due to concerns regarding missing data in the pivotal trial. While the GEMINI-ACS-1 trial demonstrated the benefit of very low dose rivaroxaban combined with a P2Y12 receptor inhibitor in ACS patients, the COMPASS trial (Cardiovascular OutcoMes for People using Anticoagulation StrategieS trial) was conducted to evaluate the role of very low-dose of rivaroxaban for secondary prevention in patients with stable CAD or peripheral artery disease.95 In this trial, patients were randomized to three groups: rivaroxaban (2.5 mg BID) plus aspirin 100 mg, rivaroxaban (5 mg BID) or aspirin alone (100 mg once daily). The rivaroxaban plus aspirin group was associated with better cardiovascular outcomes, including reduced mortality, than with aspirin monotherapy. Although major bleeding events occurred in more patients in the rivaroxaban-plus aspirin group compared with aspirin alone, very low-dose of rivaroxaban with aspirin showed benefit for secondary prevention in stable CAD or peripheral artery disease.

ANTIPLATELET THERAPY FOR PATIENTS WITH CAD IN SPECIFIC SETTINGS Patients Undergoing CABG The optimal antiplatelet treatment regimen in patients undergoing CABG has been largely debated. However, a number of

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studies have shown DAPT to reduce ischemic recurrences among ACS patients undergoing CABG. In the CURE trial, which was conducted in NSTE-ACS patients, the outcome in the CABG subpopulation was consistent with the overall study results.96 In the CABG substudies of the TRITON-TIMI 38 and the PLATO trials, prasugrel and ticagrelor were more effective than clopidogrel in preventing adverse events.97,98 Although there is limited evidence in patients with ACS undergoing CABG, current guidelines recommend DAPT in all ACS patients, independent of revascularization strategy. Management of antiplatelet therapy in patients with CAD undergoing surgery is better established. Continuation of aspirin until CABG is associated with a significant reduction in the risk of perioperative MI with a moderately increased risk of bleeding complication.99 Thus, in patients on aspirin who undergo CABG, it is recommended to continue aspirin throughout the perioperative period (Class I, LOE C).40 Recent findings from the POISE-2 (PeriOperative ISchemic Evaluation-2) study suggest that patients with a prior PCI also derive benefit from not withholding aspirin during noncardiac surgery.100 On the contrary, P2Y12 inhibitors should be discontinued prior to surgery in order to reduce the risk of bleeding.96–98 Therefore, it is recommended that the P2Y12 inhibitor be discontinued whenever possible before elective surgery: at least 3 days after discontinuation of ticagrelor, at least 5 days after clopidogrel, and at least 7 days after prasugrel (Class IIa, LOE B) in the ESC guidelines.40 Similar recommendations are given in the ACC/AHA guidelines for clopidogrel (5 days, Class I, LOE B) and prasugrel (7 days, Class I, LOE C), although 5 days of treatment discontinuation are recommended for ticagrelor (Class I, LOE B).101

Patients With Indication for Oral Anticoagulation It is known that approximately 6%–8% of patients undergoing PCI have an indication for long-term OACs due to various reason such as having AF, mechanical valves, or venous thromboembolism (VTE). Triple therapy (DAPT plus OAC therapy) results in at least a two- to three-fold increase in bleeding complications compared with OAC monotherapy.102,103 Therefore, several strategies to reduce bleeding complication should be applied. First, careful assessment of the ischemic and bleeding risk of the patient, including with validated risk scores, should occur. DAPT duration should be as short as possible with clopidogrel as the P2Y12 inhibitor of choice. A NOAC is generally preferred over a VKA. According to the ESC guidelines, in patients treated with coronary stent implantation, triple therapy with aspirin, clopidogrel, and OAC should be considered for 1 month, irrespective of the type of stent used (Class IIa, LOE B).104 Triple therapy for 1–6 months should be considered in patients with high ischemic risk due to ACS or other anatomical/procedural characteristics that outweigh the bleeding risk (Class IIa, LOE B). Dual therapy (clopidogrel 75 mg plus OAC) should be considered as an alternative to 1 month triple therapy in patients in whom the bleeding risk outweighs the ischemic risk (Class IIa, LOE B). Currently, the use of ticagrelor or prasugrel is not recommended as part of triple therapy with aspirin and OAC (Class III LOE C). The 2018 North American focused update on the antithrombotic management of patients with AF undergoing PCI also recommends that a NOAC be preferred over a VKA as the OAC of choice in the absence of contraindications. However, on the contrary to the ESC recommendation, this most recent North American update recommends the use of a doubletherapy regimen (OAC plus single antiplatelet therapy with a P2Y12 inhibitor, preferably clopidogrel) by the time of hospital discharge for most patients (aspirin should still be used in all patients in the peri-PCI period). Extending the use of

aspirin beyond hospital discharge (i.e., triple therapy) should be considered only for selected patients at high ischemic/ thrombotic and low bleeding risks and for a limited period of time. REFERENCES 1. Angiolillo DJ. The evolution of antiplatelet therapy in the treatment of acute coronary syndromes: from aspirin to the present day. Drugs 2012;72(16):2087–116. 2. Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. Nat Rev Cardiol 2015;12(1):30–47. 3. Franchi F, Rollini F, Angiolillo DJ. Antithrombotic therapy for patients with STEMI undergoing primary PCI. Nat Rev Cardiol 2017;14(6):361–79. 4. Steinhubl SR, Berger PB, Mann 3rd JT, Fry ET, DeLago A, Wilmer C, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288(19):2411–20. 5. Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366(9497):1607–21. 6. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with STsegment elevation. N Engl J Med 2005;352(12):1179–89. 7. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345(7):494–502. 8. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH, Investigators C. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000;102(6):624–9. 9. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357 (20):2001–15. 10. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361(11):1045–57. 11. Serruys PW, Rutherford JD. The birth, and evolution, of percutaneous coronary interventions: a conversation with Patrick Serruys, MD, PhD. Circulation 2016;134(2):97–100. 12. Bittl JA, Baber U, Bradley SM, Wijeysundera DN. Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;68(10): 1116–39. 13. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006;114(8):774–82. 14. Rao SV, O’Grady K, Pieper KS, Granger CB, Newby LK, Van de Werf F, et al. Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol 2005;96(9):1200–6. 15. Pocock SJ, Mehran R, Clayton TC, Nikolsky E, Parise H, Fahy M, et al. Prognostic modeling of individual patient risk and mortality impact of ischemic and hemorrhagic complications: assessment from the Acute Catheterization and Urgent Intervention Triage Strategy trial. Circulation 2010;121(1):43–51. 16. Mehran R, Pocock S, Nikolsky E, Dangas GD, Clayton T, Claessen BE, et al. Impact of bleeding on mortality after percutaneous coronary intervention results from a patient-level pooled analysis of the REPLACE-2 (randomized evaluation of PCI linking angiomax to reduced clinical events), ACUITY (acute catheterization and urgent intervention triage strategy), and HORIZONSAMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trials. JACC Cardiovasc Interv 2011;4(6):654–64.

Antiplatelet Drugs in the Management of Coronary Artery Disease 17. Suh JW, Mehran R, Claessen BE, Xu K, Baber U, Dangas G, et al. Impact of in-hospital major bleeding on late clinical outcomes after primary percutaneous coronary intervention in acute myocardial infarction the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial. J Am Coll Cardiol 2011;58(17):1750–6. 18. Genereux P, Giustino G, Witzenbichler B, Weisz G, Stuckey TD, Rinaldi MJ, et al. Incidence, predictors, and impact of postdischarge bleeding after percutaneous coronary intervention. J Am Coll Cardiol 2015;66(9):1036–45. 19. Antithrombotic TC. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324 (7329):71–86. 20. Gruntzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979;301(2):61–8. 21. De Caterina R, Husted S, Wallentin L, Andreotti F, Arnesen H, Bachmann F, et al. Vitamin K antagonists in heart disease: current status and perspectives (Section III). Position paper of the ESC Working Group on Thrombosis—Task Force on Anticoagulants in Heart Disease. Thromb Haemost 2013;110(6):1087–107. 22. Schomig A, Neumann FJ, Kastrati A, Schuhlen H, Blasini R, Hadamitzky M, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334(17):1084–9. 23. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339(23):1665–71. 24. Bertrand ME, Legrand V, Boland J, Fleck E, Bonnier J, Emmanuelson H, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (fantastic) study. Circulation 1998;98(16):1597–603. 25. Urban P, Macaya C, Rupprecht HJ, Kiemeneij F, Emanuelsson H, Fontanelli A, et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the multicenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS). Circulation 1998;98(20): 2126–32. 26. Love BB, Biller J, Gent M. Adverse haematological effects of ticlopidine. Prevention, recognition and management. Drug Saf 1998;19(2):89–98. 27. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’Shaughnessy C, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349(14):1315–23. 28. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JT, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350 (3):221–31. 29. Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet 2007;369(9562):667–78. 30. Grines CL, Bonow RO, Casey Jr DE, Gardner TJ, Lockhart PB, Moliterno DJ, et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation 2007;115(6):813–8. 31. Finn AV, Nakazawa G, Joner M, Kolodgie FD, Mont EK, Gold HK, et al. Vascular responses to drug eluting stents: importance of delayed healing. Arterioscler Thromb Vasc Biol 2007;27(7): 1500–10. 32. Moon JY, Franchi F, Rollini F, Angiolillo DJ. Evolution of coronary stent technology and implications for duration of dual antiplatelet therapy. Prog Cardiovasc Dis 2017;. 33. Bhatt DL, Flather MD, Hacke W, Berger PB, Black HR, Boden WE, et al. Patients with prior myocardial infarction, stroke, or

34.

35. 36.

37.

38.

39.

40.

41. 42.

43.

44.

45.

46.

47. 48. 49. 50.

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symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007;49(19):1982–8. Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371(23): 2155–66. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372(19):1791–800. Gargiulo G, Valgimigli M, Capodanno D, Bittl JA. State of the art: duration of dual antiplatelet therapy after percutaneous coronary intervention and coronary stent implantation—past, present and future perspectives. EuroIntervention 2017;13(6):717–33. Yeh RW, Secemsky EA, Kereiakes DJ, Normand SL, Gershlick AH, Cohen DJ, et al. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016;315 (16):1735–49. Costa F, van Klaveren D, James S, Heg D, Raber L, Feres F, et al. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials. Lancet 2017;389(10073):1025–34. Baber U, Mehran R, Giustino G, Cohen DJ, Henry TD, Sartori S, et al. Coronary thrombosis and major bleeding after PCI with drug-eluting stents: risk scores from PARIS. J Am Coll Cardiol 2016;67(19):2224–34. Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: 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). Eur Heart J 2018;39(3):213–60. Capodanno D, Angiolillo DJ. Tailoring duration of DAPT with risk scores. The Lancet 2017;389(10073):987–9. Task Force M, Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34(38):2949–3003. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, et al. 2011 ACCF/AHA/SCAI Guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation 2011;124(23):e574–651. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, et al. ESC/ EACTS Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for CardioThoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014 2014;35(37):2541–619. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;68(10):1082–115. Kastrati A, Mehilli J, Schuhlen H, Dirschinger J, Dotzer F, ten Berg JM, et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004;350(3):232–8. Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013;368(21):2004–13. Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007;357(24):2482–94. Angiolillo DJ, Ueno M, Goto S. Basic principles of platelet biology and clinical implications. Circ J 2010;74(4):597–607. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2(8607):349–60.

56

1028

PART V Antiplatelet Therapy

51. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007;49(14):1505–16. 52. Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC, et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPTDES): a prospective multicentre registry study. Lancet 2013;382 (9892):614–23. 53. Tantry US, Bonello L, Aradi D, Price MJ, Jeong YH, Angiolillo DJ, et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 2013;62(24):2261–73. 54. Angiolillo DJ, Capodanno D, Goto S. Platelet thrombin receptor antagonism and atherothrombosis. Eur Heart J 2010;31(1): 17–28. 55. Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, Dalby AJ, Fish MP, et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012;366(15):1404–13. 56. Tricoci P, Huang Z, Held C, Moliterno DJ, Armstrong PW, Van de Werf F, et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 2012;366(1):20–33. 57. Amsterdam EA, Wenger NK, Brindis RG, Casey Jr DE, Ganiats TG, Holmes Jr DR, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;64(24):e139–228. 58. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: task force for the management of acute coronary syndromes in patients presenting without persistent STsegment elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37(3):267–315. 59. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39 (2):119–77. 60. O’Gara PT, Kushner FG, Ascheim DD, Casey Jr DE, Chung MK, de Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;127(4):529–55. 61. Capodanno D, Angiolillo DJ. Pretreatment with antiplatelet drugs in invasively managed patients with coronary artery disease in the contemporary era: review of the evidence and practice guidelines. Circ Cardiovasc Interv 2015;8(3). e002301. 62. Capodanno D, Angiolillo DJ. Reviewing the controversy surrounding pre-treatment with P2Y12 inhibitors in acute coronary syndrome patients. Expert Rev Cardiovasc Ther 2016;14(7): 811–20. 63. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358(9281):527–33. 64. Bellemain-Appaix A, O’Connor SA, Silvain J, Cucherat M, Beygui F, Barthelemy O, et al. Association of clopidogrel pretreatment with mortality, cardiovascular events, and major bleeding among patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. JAMA 2012;308 (23):2507–16. 65. Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay JF, et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med 2013;369 (11):999–1010. 66. Montalescot G, van ‘t Hof AW, Lapostolle F, Silvain J, Lassen JF, Bolognese L, et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med 2014;371 (11):1016–27.

67. American College of Emergency P, Society for Cardiovascular A, Interventions, O’Gara PT, Kushner FG, Ascheim DD, et al. ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013 2013;61(4):e78–e140. 68. Muniz-Lozano A, Rollini F, Franchi F, Angiolillo DJ. Update on platelet glycoprotein IIb/IIIa inhibitors: recommendations for clinical practice. Ther Adv Cardiovasc Dis 2013;7(4):197–213. 69. Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med 2013;368(14):1303–13. 70. Angiolillo DJ, Firstenberg MS, Price MJ, Tummala PE, Hutyra M, Welsby IJ, et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA 2012;307(3):265–74. 71. Prami T, Khanfir H, Deleskog A, Hasvold P, Kyto V, Reissell E, et al. Clinical factors associated with initiation of and persistence with ADP receptor-inhibiting oral antiplatelet treatment after acute coronary syndrome: a nationwide cohort study from Finland. BMJ Open 2016;6(11). e012604. 72. James SK, Roe MT, Cannon CP, Cornel JH, Horrow J, Husted S, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial. BMJ 2011;342:d3527. 73. Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 2012;367(14):1297–309. 74. Capodanno D, Mehran R, Valgimigli M, Baber U, Windecker S, Vranckx P, et al. Aspirin-free strategies in cardiovascular disease and cardioembolic stroke prevention. Nat Rev Cardiol 2018;15 (8):480–96. 75. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348 (9038):1329–39. 76. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebocontrolled trial. Lancet 2004;364(9431):331–7. 77. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354(16):1706–17. 78. Kirkby NS, Leadbeater PD, Chan MV, Nylander S, Mitchell JA, Warner TD. Antiplatelet effects of aspirin vary with level of P2Y(1)(2) receptor blockade supplied by either ticagrelor or prasugrel. J Thromb Haemost 2011;9(10):2103–5. 79. Scavone M, Femia EA, Caroppo V, Cattaneo M. Inhibition of the platelet P2Y12 receptor for adenosine diphosphate does not impair the capacity of platelet to synthesize thromboxane A2. Eur Heart J 2016;37(44):3347–56. 80. Dewilde WJM, Oirbans T, Verheugt FWA, Kelder JC, De Smet BJGL, Herrman J-P, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. The Lancet 2013;381(9872):1107–15. 81. Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016;375 (25):2423–34. 82. Cannon CP, Bhatt DL, Oldgren J, Lip GYH, Ellis SG, Kimura T, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med 2017;377(16):1513–24. 83. Vranckx P, Valgimigli M, Windecker S, Steg PG, Hamm C, Juni P, et al. Long-term ticagrelor monotherapy versus standard dual antiplatelet therapy followed by aspirin monotherapy in patients undergoing biolimus-eluting stent implantation: rationale and design of the GLOBAL LEADERS trial. EuroIntervention 2016;12 (10):1239–45. 84. Baber U, Dangas G, Cohen DJ, Gibson CM, Mehta SR, Angiolillo DJ, et al. Ticagrelor with aspirin or alone in high-risk patients after coronary intervention: rationale and design of the TWILIGHT study. Am Heart J 2016;182:125–34.

Antiplatelet Drugs in the Management of Coronary Artery Disease 85. Angiolillo DJ, Rollini F, Storey RF, Bhatt DL, James S, Schneider DJ, et al. International expert consensus on switching platelet P2Y12 receptor-inhibiting therapies. Circulation 2017;136(20):1955–75. 86. De Luca L, D’Ascenzo F, Musumeci G, Saia F, Parodi G, Varbella F, et al. Incidence and outcome of switching of oral platelet P2Y12 receptor inhibitors in patients with acute coronary syndromes undergoing percutaneous coronary intervention: the SCOPE registry. EuroIntervention 2017;13(4):459–66. 87. Cuisset T, Deharo P, Quilici J, Johnson TW, Deffarges S, Bassez C, et al. Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study. Eur Heart J 2017;38(41):3070–8. 88. Rollini F, Franchi F, Angiolillo DJ. Switching P2Y12-receptor inhibitors in patients with coronary artery disease. Nat Rev Cardiol 2016;13(1):11–27. 89. Sibbing D, Aradi D, Jacobshagen C, Gross L, Trenk D, Geisler T, et al. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet 2017;390(10104):1747–57. 90. Moon JY, Franchi F, Rollini F, Rivas Rios JR, Kureti M, Cavallari LH, et al. Role of genetic testing in patients undergoing percutaneous coronary intervention. Expert Rev Clin Pharmacol 2017;1–14. 91. Ardissino D, Merlini PA, Bauer KA, Galvani M, Ottani F, Franchi F, et al. Coagulation activation and long-term outcome in acute coronary syndromes. Blood 2003;102(8):2731–5. 92. Merlini PA, Bauer KA, Oltrona L, Ardissino D, Cattaneo M, Belli C, et al. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 1994;90(1):61–8. 93. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366(1):9–19. 94. Ohman EM, Roe MT, Steg PG, James SK, Povsic TJ, White J, et al. Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial. Lancet 2017;389(10081):1799–808. 95. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377(14): 1319–30. 96. Fox KA, Mehta SR, Peters R, Zhao F, Lakkis N, Gersh BJ, et al. Benefits and risks of the combination of clopidogrel and aspirin in

97.

98.

99. 100.

101.

102.

103.

104.

1029

patients undergoing surgical revascularization for non-STelevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004;110(10):1202–8. Held C, Asenblad N, Bassand JP, Becker RC, Cannon CP, Claeys MJ, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol 2011;57(6):672–84. Smith PK, Goodnough LT, Levy JH, Poston RS, Short MA, Weerakkody GJ, et al. Mortality benefit with prasugrel in the TRITON-TIMI 38 coronary artery bypass grafting cohort: riskadjusted retrospective data analysis. J Am Coll Cardiol 2012;60 (5):388–96. Hastings S, Myles P, McIlroy D. Aspirin and coronary artery surgery: a systematic review and meta-analysis. Br J Anaesth 2015;115(3):376–85. Graham MM, Sessler DI, Parlow JL, Biccard BM, Guyatt G, Leslie K, et al. Aspirin in patients with previous percutaneous coronary intervention undergoing noncardiac surgery. Ann Intern Med 2017;. Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG, et al. ACCF/AHA guideline for coronary artery bypass graft surgery. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011 2011;58(24):e123–210. Sorensen R, Hansen ML, Abildstrom SZ, Hvelplund A, Andersson C, Jorgensen C, et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 2009;374(9706):1967–74. Hansen ML, Sorensen R, Clausen MT, Fog-Petersen ML, Raunso J, Gadsboll N, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010;170(16):1433–41. Angiolillo DJ, Goodman SG, Bhatt DL, Eikelboom JW, Price MJ, Moliterno DJ, et al. Antithrombotic Therapy in Patients with Atrial Fibrillation Treated with Oral Anticoagulation Undergoing Percutaneous Coronary Intervention: A North American Perspective – 2018 Update. Circulation 2018;138:527–36.

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