2023 专家共识：确定冠心病患者抗血小板治疗的调节策略

CONSENSUS REPORTS

## Defining Strategies of Modulation of Antiplatelet Therapy in Patients With Coronary Artery Disease: A Consensus Document from the Academic Research Consortium

DavideCapodanno , MD, PhD; RoxanaMehran , MD; Mitchell W.Krucoff, MD; UsmanBaber, MD; Deepak L.Bhatt , MD, MPH; PieraCapranzano, MD, PhD; Jean-PhilippeCollet, MD, PhD; ThomasCuisset, MD, PhD; GiuseppeDe Luca , MD, PhD; LeonardoDe Luca , MD, PhD; AndrewFarb, MD; FrancescoFranchi , MD; C. MichaelGibson, MD; Joo-YongHahn , MD, PhD; Myeong-KiHong , MD, PhD; StefanJames , MD, PhD; AdnanKastrati , MD; TakeshiKimura , MD; Pedro A.Lemos , MD; Renato D.Lopes , MD, MHS, PhD; AdrianMagee, MD; RyosukeMatsumura, MD; ShuichiMochizuki , MD; Michelle L.O’Donoghue , MD; Naveen L.Pereira , MD; Sunil V.Rao , MD; FabianaRollini, MD; YukoShirai, MD; DirkSibbing, MD; Peter C.Smits , MD, PhD; P. GabrielSteg , MD; Robert F.Storey , MD; Jurrienten Berg , MD, PhD; MarcoValgimigli , MD, PhD; PascalVranckx , MD; HirotoshiWatanabe , MD; StephanWindecker , MD; Patrick W.Serruys , MD, PhD; Robert W.Yeh , MD, MBA; Marie-ClaudeMorice, MD; Dominick J.Angiolillo , MD, PhD

ABSTRACT: Antiplatelet therapy is the mainstay of pharmacologic treatment to prevent thrombotic or ischemic events in patients with coronary artery disease treated with percutaneous coronary intervention and those treated medically for an acute coronary syndrome. The use of antiplatelet therapy comes at the expense of an increased risk of bleeding complications. Defining the optimal intensity of platelet inhibition according to the clinical presentation of atherosclerotic cardiovascular disease and individual patient factors is a clinical challenge. Modulation of antiplatelet therapy is a medical action that is frequently performed to balance the risk of thrombotic or ischemic events and the risk of bleeding. This aim may be achieved by reducing (ie, de-escalation) or increasing (ie, escalation) the intensity of platelet inhibition by changing the type, dose, or number of antiplatelet drugs. Because de-escalation or escalation can be achieved in different ways, with a number of emerging approaches, confusion arises with terminologies that are often used interchangeably. To address this issue, this Academic Research Consortium collaboration provides an overview and definitions of different strategies of antiplatelet therapy modulation for patients with coronary artery disease, including but not limited to those undergoing percutaneous coronary intervention, and consensus statements on standardized definitions.

Key Words: acute coronary syndrome ◼ coronary artery disease ◼ percutaneous coronary intervention ◼ therapeutics

I nitial treatment with dual antiplatelet therapy (DAPT) including aspirin and a platelet receptor $\mathsf{P2Y}_{12}$ inhibitor is the standard of care for the prevention of atherothrombotic events in all patients undergoing percutaneous coronary intervention (PCI), as well as those treated medically for an acute coronary syndrome (ACS). 1,2 For patients with ACS undergoing PCI, guidelines from

Europe and the United States recommend that, in the absence of contraindications, the more potent prasugrel or ticagrelor be the $\mathsf{P2Y}_{12}$ inhibitor of choice for DAPT combinations, in preference to clopidogrel. 3–5 It is recommended that patients with PCI with a chronic coronary syndrome (CCS) receive aspirin in combination with clopidogrel. 5,6 DAPT is known to reduce the incidence

|Nonstandard Abbreviations and Acronyms|| |---|---| |ACC|American College of Cardiology| |ACS|acute coronary syndrome| |AHA|American Heart Association| |ARC|Academic Research Consortium| |CCS|chronic coronary syndrome| |DAPT|dual antiplatelet therapy| |ESC|European Society of Cardiology| |HBR|high bleeding risk| |MACE|major adverse cardiac events| |NACE|net adverse cardiac events| |PCI|percutaneous coronary intervention| |SAPT|single antiplatelet therapy| |SCAI| Society for Cardiovascular Angiography and Interventions |

of atherothrombotic events at the expense of increased bleeding, and therefore its duration needs to be carefully determined. The traditional approach recommended by current guidelines for PCI is that DAPT be maintained for at least 12 months after an ACS, and 6 months for CCS, unless concerns over bleeding prevail. 3–6 At the end of the minimum required DAPT period, all patients with PCI may be transitioned to a chronic regimen of single antiplatelet therapy (SAPT), usually aspirin. 3–6 Aspirin is the perceived standard of care for thrombotic prevention in patients with coronary artery disease in general, regardless of whether revascularization is performed. 7 Current recommendations for DAPT or SAPT after PCI are well-defined and represent an effective treatment strategy for most patients. Nevertheless, there are clinical circumstances in which physicians are particularly concerned about the risk of thrombotic events, the risk of bleeding events, or both. Bleeding or high thrombotic risk characteristics may lead a physician to prefer one among several potential types and durations of DAPT and SAPT for an individual patient.

When antiplatelet therapy after PCI is modified, the timing and antiplatelet strategy selected will reflect physician concern with relative bleeding versus thrombotic risk. 8 This practice has led to a proliferation of terms (eg, “short DAPT,” “de-escalation,” “escalation,” and “switch,” among others) that lack standardization and are sometimes used interchangeably. Lack of precision in terminology has resulted in confusion and misunderstanding on the use of antiplatelet medications after PCI. 9 Current guidelines have not clarified the terminology to be used when changing antiplatelet therapy after PCI, leaving physicians without a common understanding of which terms should be used to describe antiplatelet changes and clouding our communication around clinical practice decisions and the corresponding evidence used to guide them.

The Academic Research Consortium (ARC) is an academic partnership initiated to help create consensus definitions and end points to help standardize the language around clinical care and evidence generation. In response to the antiplatelet use guidance gap, ARC came together to develop a consensus initiative to homogenize the language for antiplatelet therapy definitions. This initiative was undertaken by key leaders from North America, South America, Europe, and Asia with recognized expertise in the field of antiplatelet therapy. These experts, identified by the document chairs (D.C. and D.J.A.), reviewed the scientific literature on antiplatelet therapy modulation with input from representatives from the US Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency. All participants agreed to participate in the development of this document.

With regard to methodology, a blinded survey consisting of 14 statements grouped into 4 categories was first sent to the invited experts who were asked whether they agreed or disagreed with each statement and provided comments or advice. A virtual consensus meeting, coordinated by the Cardiovascular European Research Center (Massy, France), was held on November 21, 2022, to discuss the results of the survey, reach consensus on disagreements, and define the scope of the current document. The document is free from any type of industry support and represents the output of an academic collaboration among the identified experts who provided an overview and critique of different strategies of antiplatelet therapy modulation after PCI, resulting in consensus statements on standardized definitions for each potential antiplatelet strategy. Patients with a baseline indication for oral anticoagulation are not addressed in this document. Moreover, the document does not refer to those situations in which modulation of antithrombotic therapy is achieved by addition of an approved (eg, 2.5 mg of rivaroxaban) or investigational (eg, activated factor XI inhibitors asundexian or milvexian) anticoagulant in the absence of a preexisting reason for oral anticoagulation (eg, for venous thromboembolism, mechanical valve prosthesis, or atrial fibrillation). This consensus document is not intended to provide treatment recommendations for clinical practice. The consensus definitions in this document are intended to create a commonly understood lexicon to help the clinical and research communities describe antiplatelet strategies more precisely.

## DEFINITIONS, GUIDELINES, AND SUPPORTING EVIDENCE

Antiplatelet therapy can be modulated in 2 ways: by reducing (ie, de-escalation) or increasing (ie, escalation) the intensity of platelet inhibition. These terms refer to

the actions of reducing or increasing the antiplatelet effect by means of changes in the type, dose, or number of drugs used to inhibit platelets. For those treated with PCI or admitted with ACS, these actions may occur acutely (ie, within 24 hours), early (ie, within 30 days), late (ie, between 30 days and 1 year), or very late (ie, after 1 year). In the following paragraphs, de-escalation and escalation are discussed and categorized further (Figure1). For each strategy, we briefly summarize the available guidelines and supporting evidence and provide the ARC consensus statements.

Consensus Statements

• Modulation of antiplatelet therapy consists of changes in the antiplatelet effect by modification of the type, dose, or number of drugs aimed at decreasing or increasing the intensity of platelet inhibition. • Strategies of modulation of antiplatelet therapy include de-escalation and escalation. • De-escalation refers to the actions of reducing the antiplatelet effect by means of changes in the type, dose, or number of drugs used to inhibit platelets. • Escalation refers to the actions of increasing the antiplatelet effect by means of changes in the type, dose, or number of drugs used to inhibit platelets.

De-Escalation

De-escalation is intended to decrease bleeding complications of antiplatelet therapy at a time when their risk is perceived to be greater than the risk of thrombotic complications. Reduced bleeding risk may be achieved by switching to a drug with less anticipated antiplatelet effect (de-escalation by switching), reducing the dose (de-escalation by dose reduction), or removing an antiplatelet agent (de-escalation by discontinuation; Figure2). For DAPT, switching and dose reduction are usually confined to the $\mathsf{P2Y}_{12}$ inhibitor, although they are theoretically possible with aspirin (eg, switch to a better-tolerated aspirin formulation, or decrease the dose from 325 mg to 81 mg). Switch and dose reduction are also possible for $\mathsf{P2Y}_{12}$ inhibitor monotherapy. By discontinuation, which is also typically performed in the context of DAPT, we refer to the cessation by physician indication. Interruption because of surgery or disruption because of bleeding or nonadherence are other forms of treatment cessation that go beyond the scope of this document.

## De-Escalation by Switching

De-escalation by switching typically refers to changing from a $\mathsf{P2Y}_{12}$ antagonist with more potent platelet inhibition (ie, prasugrel or ticagrelor) to a $\mathsf{P2Y}_{12}$ antagonist with fewer expected potent effects (ie, clopidogrel). This is most likely to occur in patients with ACS treated

 Figure 1. Strategies of modulation of dual antiplatelet therapy. Modulation of dual antiplatelet therapy (DAPT) consists of changes in the type, dose, or number of antiplatelet agents aimed at decreasing or increasing the intensity of platelet inhibition. SAPT indicates single antiplatelet therapy.

 Figure 2. Strategies of de-escalation of antiplatelet therapy. There are 3 strategies of de-escalation of antiplatelet therapy. De-escalation of dual antiplatelet therapy (DAPT) by switch consists of switching the type of drug (eg, the $\mathsf{P2Y}_{12}$ inhibitors prasugrel or ticagrelor with the $\mathsf{P2Y}_{12}$ inhibitor clopidogrel). De-escalation of DAPT by dose reduction consists of reducing the dose (eg, the dose of the $\mathsf{P2Y}_{12}$ inhibitors prasugrel or ticagrelor as an alternative to the dose regimen initially planned). Discontinuation of DAPT, on the basis of physician recommendation, consists of stopping a drug (eg, the $\mathsf{P2Y}_{12}$ inhibitor or aspirin with transition to single antiplatelet therapy [SAPT] with aspirin or a $\mathsf{P2Y}_{12}$ inhibitor at a time that precedes the duration of DAPT initially planned). ACS indicates acute coronary syndrome.

initially with a guideline-recommended DAPT regimen with prasugrel or ticagrelor. Because prasugrel and ticagrelor are known to increase the risk of major spontaneous bleeding at the doses tested in landmark clinical trials compared with clopidogrel, 10,11 the objective of switching is to improve safety (ie, less bleeding) at a time when there is perceived minimal trade-off in efficacy (ie, antithrombotic effects). De-escalation by switching may occur with (ie, guided) or without (ie, clinical judgment) tests to evaluate or predict responses to clopidogrel. Clopidogrel response is subject to broad interindividual response variability. The ${\approx}30\%$ of patients with impaired clopidogrel-induced platelet inhibition and persistent high platelet reactivity are at an increased risk of major adverse cardiac events (MACE) and stent thrombosis. 12 Tests to guide de-escalation by switching include platelet function testing (to identify patients with high residual platelet reactivity) and genotyping (to identify patients with CYP2C19 lossof-function alleles that predispose to high residual platelet reactivity). DAPT switching studies in patients with ACS include switching guided by clinical judgment alone (known as “unguided” switching), switching guided by platelet function testing, and switching guided by genotyping. The optimal time for switching is not stan

dardized. However, in unguided (ie, clinical judgment) switching studies, the change of $\mathsf{P2Y}_{12}$ inhibitor mostly occurred at 1 month (ie, when the bleeding risk was believed to surpass the thrombotic complication risk). In contrast, the change typically occurred at earlier time points, including immediately after PCI, in switching studies guided by platelet function and genetic testing. Of note, de-escalation by switching in the immediate peri-PCI period has been associated with an increase in thrombotic complications. 13–15

The strategy of DAPT de-escalation was first mentioned in a guideline in 2018 (guided de-escalation; class IIb). 16 The 2020 European Society of Cardiology (ESC) guidelines for ACS refined and expanded the recommendation by stating that de-escalation by switching is considered for an individual patient, especially for patients with ACS deemed unsuitable for potent platelet inhibition, on the basis of clinical judgment or guided by platelet function testing or CYP2C19 genotyping depending on the patient’s risk profile and availability of respective assays (class IIb). 3 The 2021 joint guidelines from the American College of Cardiology (ACC), the American Heart Association (AHA). and the Society for Cardiovascular Angiography and Interventions (SCAI) do not mention

de-escalation by switching among the options to reduce bleeding after PCI. 5

Two trials investigated strategies of unguided switching in ACS. In TOPIC (Timing of Platelet Inhibition After Acute Coronary Syndrome; $\mathord{\cap}{=}646.$ ), switching from prasugrel or ticagrelor to clopidogrel at 1 month was superior to standard DAPT with prasugrel or ticagrelor for the 1-year composite of cardiovascular events or major bleeding (ie, net adverse cardiac events [NACE]). 17 In TALOSAMI (Ticagrelor Versus Clopidogrel in Stabilized Patients With Acute Myocardial Infarction; $\mathord{\mathord{\cap}}\!\!=\!\!2697$ ), switching at 1 month from ticagrelor to clopidogrel was superior to standard DAPT for NACE between 1 and 12 months. 18 In both trials, the findings were driven by reduction in bleeding with switching. Two other trials investigated strategies of switching guided by platelet function testing. In ANTARCTIC (Tailored Antiplatelet Therapy Versus Recommended Dose of Prasugrel; n=877), switching was the most common strategy prompted by platelet function testing; treatment adjustment at 2 weeks and 1 month did not reduce 1-year NACE. 19 In TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment For Acute Coronary Syndromes Trial; $\mathord{\cap}{=}2610$ ), switching at 1 week was noninferior but not superior to standard DAPT for 1-year NACE. 20 Two trials investigated strategies, including switching guided by genotyping, at the time of the ACS diagnosis or PCI procedure. In PHARMCLO (Pharmacogenetics of Clopidogrel in Acute Coronary Syndromes; $\mathord{\cap}{=}888$ ; prematurely stopped), switching was one of the potential adjustment strategies, and treatment adjustment reduced 1-year NACE. 21 In POPULAR-GENETICS (Cost-Effectiveness of Genotype Guided Treatment With Antiplatelet Drugs in STEMI Patients: Optimization of Treatment; $\mathord{\mathsf{n}}{=}2488,$ ), switch was noninferior to standard DAPT for 1-year NACE and superior for bleeding. 22

Consensus Statements

• De-escalation by switching consists of changing an antiplatelet drug with another one with the intention to decrease the intensity of platelet inhibitory effect. • $\mathsf{P2Y}_{12}$ -specific de-escalation of DAPT by switching, generally in patients who experienced an ACS, consists of switching the $\mathsf{P2Y}_{12}$ inhibitor prasugrel or ticagrelor to the $\mathsf{P2Y}_{12}$ inhibitor clopidogrel. • De-escalation by switching may be guided by clinical judgment or by the results of platelet function testing or genotyping. • More data are needed on the comparative effectiveness and safety of guided versus unguided $\mathsf{P2Y}_{12}^{\phantom{\dagger}}$ specific de-escalation by switching, the specific subgroups that may or may not derive a clinical benefit from a $\mathsf{P2Y}_{12}$ -specific de-escalation strategy by switching, and the optimal timing of $\mathsf{P2Y}_{12}$ -specific de-escalation by switching.

De-Escalation by Dose Reduction

Pharmacokinetic data support the concept that reducing the dose of prasugrel or ticagrelor is associated with less systemic exposure of a drug, leading to reduced platelet inhibitory effects and thus reduced bleeding. 23,24 Reducing the dose of prasugrel or ticagrelor in DAPT combinations (eg, by using prasugrel doses of 3.75 or 5 mg once daily, or a ticagrelor dose of 60 mg twice daily) is a $\mathsf{P2Y}_{12}$ -specific de-escalation strategy that may be desired when concerns exist regarding high exposure to the active metabolite of more potent $\mathsf{P2Y}_{12}$ inhibitors (eg, in races such as East Asian). However, there are only limited effectiveness and safety data on these deescalation strategies during the first year after ACS. In the HOST-REDUCE-POLYTECH-ACS trial (Harmonizing Optimal Strategy for Treatment of Coronary Artery Diseases–Comparison of Reduction of Prasugrel Dose or Polymer Technology in ACS Patients; $\mathsf{n}\mathrm{=}\mathrm{2338},$ ), use of a halved dose of prasugrel (ie, 5 mg once daily) at 1 month reduced 1-year NACE. 25 Whereas the recommended maintenance dose of ticagrelor is 90 mg twice daily during the first year after an ACS event, after 1 year, a dosing regimen of 60 mg twice daily can be used on the basis of the PEGASUS-TIMI 54 trial (Prevention of Cardiovascular Events [eg, Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin). 26

Consensus Statements

• De-escalation by dose reduction consists of diminishing the dose of an antiplatelet drug with the intention to decrease the intensity of platelet inhibitory effects. • $\mathsf{P2Y}_{12}$ -specific de-escalation of DAPT by dose reduction consists of reducing the dose of the $\mathsf{P2Y}_{12}$ inhibitor compared with the standard dose. • More data are needed on the comparative effectiveness and safety of $\mathsf{P2Y}_{12}$ -specific de-escalation by switching versus de-escalation by dose reduction.

De-Escalation by Discontinuation

Discontinuation refers to the practice of stopping 1 of the 2 antiplatelet agents and transitioning to SAPT (aspirin or a $\mathsf{P2Y}_{12}$ inhibitor). This practice is typically physician recommended and consistent with practice guidelines, and therefore is distinguished from other types of DAPT cessations. For example, discontinuation planned at the time of surgery or due to nonadherence 27 or bleeding carry different prognostic consequences and are more properly termed interruption and disruption, respectively. 28 With current-generation coronary stents, the time for discontinuation has been moved earlier after PCI than in the past. 1,2 In the following paragraphs, we refer to discontinuation of $\mathsf{P2Y}_{12}$ inhibitors or aspirin that occurs before

the period initially planned (ie, 6 months in CCS and 12 months in ACS). Current investigations of DAPT discontinuation in CCS include studies in which the $\mathsf{P2Y}_{12}$ inhibitor was stopped at 1 month or aspirin was stopped at 1 month or at the time of PCI. Investigations of DAPT discontinuation in ACS currently include studies in which the $\mathsf{P2Y}_{12}$ inhibitor was stopped at 3 to 6 months or aspirin was stopped at 1 to 3 months. These studies generally had a follow-up of 1 to 2 years, and therefore the best SAPT strategy for chronic therapy after this timeframe remains undefined.

$\boldsymbol{P}\boldsymbol{^{2}}\boldsymbol{Y}_{\mathfrak{j}\mathfrak{2}}$ Inhibitor Discontinuation. The 2019 guidelines from ESC for patients with CCS and sinus rhythm undergoing PCI recommend $\mathsf{P2Y}_{12}$ inhibitor (usually clopidogrel) discontinuation at 3 months (class IIa) or 1 month (class IIb) in patients at high bleeding risk (HBR). 6 The definition of HBR has been standardized as part of a dedicated ARC initiative. 29 In patients at HBR, the 2020 ESC guidelines for patients with an ACS without ST-segment elevation recommend $\mathsf{P2Y}_{12}$ inhibitor (usually prasugrel or ticagrelor) discontinuation at 3 months (class IIa). 3 The 2021 ACC/AHA/SCAI guidelines recommend $\mathsf{P2Y}_{12}$ inhibitor discontinuation at 3 months (class IIb) for patients with HBR with CCS and at 6 months for patients with HBR with ACS (class IIb). 5

There is a paucity of randomized controlled trials that compared early $\mathsf{P2Y}_{12}$ inhibitor discontinuation versus discontinuation at later times after PCI as recommended by current European and US guidelines. In the ONEMONTH DAPT trial (A Randomized Controlled Comparison Between One Versus More Than Six Months of Dual Antiplatelet Therapy After Biolimus A9-Eluting Stent Implantation; $\scriptstyle\bigcap=3020$ ), DAPT discontinuation at 1 month was noninferior to discontinuation at 6 to 12 months for 1-year NACE for patients with CCS or ACS (HBR and non-HBR) who underwent PCI for noncomplex lesions. 30 Three trials were conducted on patients with ACS (HBR and non-HBR): in SMART-DATE (Safety of 6-Month Duration of Dual Antiplatelet Therapy After Acute Coronary Syndromes; $\scriptstyle{\mathfrak{n}}=27\,1\,2$ ), discontinuation at 6 months was noninferior to discontinuation at 12 months for 1-year MACE, but there was an increase in myocardial infarction 31 ; in REDUCE-ACS (Randomised Evaluation of Short-Term Dual Antiplatelet Therapy in Patients With Acute Coronary Syndrome Treated With a New Generation Stent; n=1496), discontinuation at 3 months was noninferior to discontinuation at 12 months for 1-year NACE 32 ; in DAPT-STEMI (Randomized, Open Label Trial of 6 Months Versus 12 Months DAPT After Drug-Eluting Stent in STEMI; $\mathord{\mathsf{n}}{=}870$ ), discontinuation at 6 months was noninferior to discontinuation at 12 months for 2-year NACE in patients with ST-segment–elevation myocardial infarction. 33 The results of these trials, which used wide noninferiority margins, did not lead to a change in current ACS guidelines.

Aspirin Discontinuation. The 2019 ESC guidelines for CCS do not include a recommendation for aspirin discontinuation in patients with HBR. 6 The 2020 ESC guidelines for ACS recommend that aspirin be discontinued at 3 to 6 months, and the $\mathsf{P2Y}_{12}$ inhibitor continued, depending on ischemic versus bleeding risks (class IIa). 3 The 2021 ACC/AHA/SCAI guidelines for coronary revascularization recommend that aspirin be discontinued at 1 to 3 months (class IIa), and the $\mathsf{P2Y}_{12}$ inhibitor continued, regardless of bleeding risk and clinical presentation with ACS or CCS. 5

There are no randomized controlled trials that compared early aspirin discontinuation versus the 6-month standard DAPT regimen recommended by current guidelines for CCS. ASET (Acetyl Salicylic Elimination Trial: The ASET Pilot Study) was a single-arm trial with a stopping rule on the basis of the occurrence of definite stent thrombosis, for which aspirin discontinuation at the time of PCI with transition to prasugrel monotherapy was feasible and safe without stent thrombosis at 3 months. 34 Two trials compared early aspirin discontinuation versus the 12 months of DAPT recommended by current guidelines for ACS. In TICO (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation SirolimusEluting Stent for Acute Coronary Syndrome; $\mathord{\cap}\!\!=\!\!3056,$ ), discontinuation at 3 months with transition to ticagrelor monotherapy was superior for 1-year NACE. 35 In STOPDAPT-2 ACS (Short and Optimal Duration of Dual Antiplatelet Therapy-2 Study for the Patients With ACS; $\scriptstyle\bigcap=4\,1\,69.$ ), discontinuation at 1 to 2 months with transition to clopidogrel monotherapy was not noninferior for 1-year NACE. 36

$\boldsymbol{P}\boldsymbol{^{2}}\boldsymbol{Y}_{\mathfrak{j}\mathfrak{2}}$ Inhibitor or Aspirin Discontinuation. In recent trials, the decision to discontinue the $\mathsf{P2Y}_{12}$ inhibitor or aspirin has been left to the discretion of the treating physician. DAPT discontinuation with transition to SAPT is now receiving greater attention than more precise characterization of $\mathsf{P2Y}_{12}$ inhibitor or aspirin discontinuation with transition to $\mathsf{P2Y}_{12}$ inhibitor or aspirin monotherapy. In the MASTER DAPT trial (Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated versus Standard DAPT Regimen; $\mathord{\cap}\!\!=\!\!4573)$ ), among patients at HBR, discontinuation of the $\mathsf{P2Y}_{12}$ inhibitor or aspirin (at the physician’s discretion) at 1 month was noninferior to their continuation for at least 2 additional months with respect to 1-year NACE or MACE, and was associated with reduced bleeding. 37

Consensus Statements

• Discontinuation of DAPT consists of stopping the $\mathsf{P2Y}_{12}$ inhibitor or aspirin on the basis of the physician’s recommendation.

• More data are needed on the effect and timing of $\mathsf{P2Y}_{12}$ inhibitor or aspirin discontinuation in CCS and ACS, the comparative effectiveness and safety of $\mathsf{P2Y}_{12}$ inhibitor or aspirin discontinuation leading to SAPT, and the best SAPT strategy for chronic management beyond the 1- to 2-year period investigated in trials of aspirin or $\mathsf{P2Y}_{12}$ inhibitor monotherapy.

Escalation

Antiplatelet therapy escalation is meant to decrease thrombotic or ischemic complications by increasing the intensity of platelet inhibition at a time when this risk is considered greater than the risk of bleeding complications. Escalation may be achieved by switching to a drug with higher anticipated platelet inhibitory effects (escalation by switching), increasing the dose (escalation by dose increase), or adding an antiplatelet drug (add-on escalation; Figure 3). In DAPT, switching and dose increase are usually confined to the $\mathsf{P2Y}_{12}$ inhibitor, but can be applied to aspirin as well (eg, dose increase from 81 mg to 325 mg). Switching and dose increase are also theoretically possible in the context of $\mathsf{P2Y}_{12}$ inhibitor monotherapy (eg, clopidogrel dose increase from 75 mg to 150 mg). By add-on escalation, we refer to escalation over the strategy initially planned by the physician.

Escalation by Switching

Escalation by switching typically refers to the practice of changing from a $\mathsf{P2Y}_{12}$ receptor inhibitor with moderate platelet inhibitory effects (ie, clopidogrel) to one with more potent platelet inhibitory effects (ie, prasugrel or ticagrelor). This is most likely to occur in patients with CCS undergoing elective PCI and treated with a guideline-recommended clopidogrel-based DAPT regimen. Prasugrel and ticagrelor were not shown to be more effective than clopidogrel among patients undergoing elective PCI in 2 trials that were not specific to escalation (SASSICAIA [Strategies of Loading With Prasugrel Versus Clopidogrel in PCI-Treated Biomarker Negative Angina], which was terminated prematurely; and ALPHEUS [Assessment of Loading With the $\mathsf{P2Y}_{12}$ Inhibitor Ticagrelor or Clopidogrel to Halt Ischemic Events in Patients Undergoing Elective Coronary Stenting], which was powered for periprocedural myocardial injury). 38,39 Therefore, the rationale for routine $\mathsf{P2Y}_{12}$ inhibitor-specific escalation is unproven. However, switching from clopidogrel to prasugrel or ticagrelor may be desired for selected patients with CCS due to several circumstances, including but not restricted to concern of low antithrombotic protection after complex PCI, evidence of on-clopidogrel high platelet reactivity, or known CYP2C19 loss-of-function genotype.

 Figure 3. Strategies of escalation of antiplatelet therapy. There are 3 strategies of escalation of antiplatelet therapy. Escalation of dual antiplatelet therapy (DAPT) by switch consists of switching the type of drug (eg, the $\mathsf{P2Y}_{12}$ inhibitor clopidogrel with the $\mathsf{P2Y}_{12}$ inhibitors prasugrel or ticagrelor). Escalation of DAPT by dose increase conceptually consists of increasing the dose (eg, of the $\mathsf{P2Y}_{12}$ inhibitor or aspirin), but such action has no currently approved recommendations. Add-on escalation consists of adding a drug (eg, $\mathsf{P2Y}_{12}$ inhibitor or aspirin) with transition to DAPT at a time when the patient is on single antiplatelet therapy (SAPT). CCS indicates chronic coronary syndrome.

Investigations of DAPT escalation by switching in CCS are mostly confined to this last category, and therefore include switching studies guided by platelet function and genetic testing. The optimal time for switching is not standardized, although in most of the available studies switching guided by platelet function testing and CYP2C19 loss-of-function genotype have changed the $\mathsf{P2Y}_{12}$ inhibitor as soon as the results of the test were available (typically close to the PCI procedure), as the risk of thrombotic or ischemic complications is believed to surpass the bleeding risk. Switching may also be considered a modification of the default strategy underscoring clopidogrel as a standard component of DAPT for CCS, rather than a true switching from clopidogrel to prasugrel or ticagrelor.

The 2019 ESC guidelines for CCS recommend switching to prasugrel or ticagrelor to be selectively considered as an alternative DAPT strategy, at least as initial therapy, in specific elective stenting high-risk situations (eg, suboptimal stent deployment or other procedural characteristics associated with a high risk of stent thrombosis, complex left main stem PCI, or multivessel stenting), with no comment on whether this practice should be on the basis of clinical judgment or guided by platelet function testing or CYP2C19 genotyping (class IIb). The 2021 ACC/AHA/SCAI guidelines do not mention escalation by switching among the options to reduce thrombotic or ischemic events after elective PCI. 5

One trial (PATH-PCI [Personalized Antiplatelet Therapy Guided by A Novel Detection of Platelet Aggregation Function in Stable Coronary Artery Disease Patients Undergoing Percutaneous Coronary Intervention]) investigated a strategy of switching from clopidogrel to ticagrelor, guided by platelet function testing in 2337 participants undergoing elective PCI for CCS. The study showed superiority for 6-month MACE associated with platelet function adjustment compared with standard treatment. 40 Another trial (TAILOR-PCI [Tailored Antiplatelet Therapy Following PCI]) investigated a strategy of ticagrelor versus clopidogrel in 1849 patients undergoing PCI for ACS or stable CAD with CYP2C19 loss-of-function variants on the basis of point-of-care genotyping; the study showed a non–statistically significant numeric reduction in 1-year MACE. 41

Consensus Statements

• Escalation by switching consists of changing an antiplatelet drug to another drug with the intention of increasing the intensity of platelet inhibitory effect compared with the initially planned treatment strategy. • $\mathsf{P2Y}_{12}$ -specific DAPT escalation by switching consists of switching the $\mathsf{P2Y}_{12}$ inhibitor clopidogrel to the $\mathsf{P2Y}_{12}$ inhibitor prasugrel or ticagrelor.

• $\mathsf{P2Y}_{12}$ -specific DAPT escalation by switching may be guided by clinical judgment or by the results of platelet function testing or genotyping. • More data are needed on the comparative effectiveness and safety of guided versus unguided $\mathsf{P2Y}_{12}.$ - specific escalation by switching and the optimal timing of $\mathsf{P2Y}_{12}.$ -specific escalation by switching.

Escalation by Dose Increase

Increasing the clopidogrel or aspirin dose in DAPT combinations is a strategy that is not currently supported by clinical guidelines for CCS. Doubling the maintenance dose of aspirin did not prove to be effective in the CURRENT-OASIS 7 trial (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions). 42,43 In the ARCTIC trial (Double Randomization of a Monitoring Adjusted Antiplatelet Treatment Versus a Common Antiplatelet Treatment for DES Implantation, and Interruption Versus Continuation of Double Antiplatelet Therapy; n=2440), including patients with ACS or CCS, platelet function testing used to guide the doubling of clopidogrel dose or the switch to prasugrel did not significantly reduce 1-year MACE. 44 In the GRAVITAS trial (Gauging Responsiveness with A VerifyNow assay: Impact on Thrombosis and Safety; $\scriptstyle{\mathfrak{n}}=22\,1\,4.$ ), among patients with high on-treatment platelet reactivity after PCI, the use of a doubled clopidogrel dose compared with standarddose clopidogrel also did not reduce the incidence of MACE. 45 In the ADAPTABLE trial (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term; $\mathord{\cap}=15\,076)$ ), there were no significant differences in cardiovascular events or major bleeding between patients assigned to 81 mg and those assigned to 325 mg of aspirin daily. 46

Consensus Statement

• Escalation by dose increase consists of increasing the dose of an antiplatelet drug with the intention to increase the intensity of platelet inhibitory effect.

Escalation by Add-On

Add-on escalation refers to the practice of adding a second antiplatelet agent to patients treated with SAPT. This strategy leads to DAPT when a second antiplatelet agent is added. DAPT was superior to SAPT with aspirin in reducing ischemic events in randomized trials, including patients with previous PCI (in both ACS and CCS after an event-free period of DAPT), 47 previous myocardial infarction, 26 or diabetes. 48

In 2019, the ESC guidelines for CCS introduced a recommendation for the addition of clopidogrel, ticagrelor, or prasugrel to aspirin for patients with CCS at high (class IIa) or moderate (IIb) risk of thrombotic or ischemic events and without HBR. 6 The 2020 ESC guidelines for ACS without ST-segment elevation included

these recommendations as DAPT extension after the first year following the ACS and provided criteria for identifying optimal candidates. 3 The 2021 ACC/AHA/ SCAI guidelines do not have add-on specific recommendations but recommend that DAPT be continued beyond 6 months in CCS and 12 months in ACS in selected patients who are not at HBR (class IIb). 5

Add-on of an antiplatelet agent to aspirin has been investigated in 2 trials. In PEGASUS-TIMI 54 (n=21162), for patients with previous myocardial infarction, DAPT with aspirin and ticagrelor (60 mg or 90 mg twice daily) was superior for MACE 26 at 3 years. In THEMIS (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study; $\scriptstyle\bigcap=19\,220$ ), for patients with type 2 diabetes without a previous acute cardiovascular event (previous myocardial infarction or cerebrovascular event), DAPT with aspirin and ticagrelor was superior for MACE at a median of 39.9 months. 47

Consensus Statements

• Add-on escalation consists of adding a $\mathsf{P2Y}_{12}$ inhibitor to aspirin (resulting in transitioning from SAPT to DAPT). • More data are needed on the effectiveness and safety of aspirin add-on for patients on chronic $\mathsf{P2Y}_{12}$ inhibitor monotherapy.

CONCLUSIONS

For patients with coronary artery disease without baseline indication for oral anticoagulation, particularly those undergoing PCI, modulation of antiplatelet therapy is a medical action that is frequently performed, considering the risk of thrombotic or ischemic events and the risk of bleeding, with the optimal intensity of platelet inhibition varying according to the stage and presentation of coronary artery disease and individual patient factors. This aim may be achieved by reducing (ie, de-escalation) or increasing (ie, escalation) the intensity of platelet inhibition in a number of different ways, including by changing the type, dose, or number of antiplatelet drugs.

ARTICLE INFORMATION

Received February 18, 2023; accepted April 24, 2023.

This article reflects the views of the authors and should not be construed to represent views or policies of the US Food and Drug Administration or the Japanese Pharmaceuticals and Medical Devices Agency.

Affiliations

Azienda Ospedaliero-Universitaria Policlinico $^{\mathrm{u}}\mathrm{G}$ . Rodolico-San Marco,” University of Catania, Italy (D.C., P.C.). Zena and Michael A. Wiener Cardiovascular Institute (R.M.) and Mount Sinai Heart (D.L.B.), Icahn School of Medicine at Mount Sinai, New York, NY. Duke University Medical Center, Durham, NC (M.W.K., R.D.L.). University of Oklahoma Health Sciences Center, Oklahoma City (U.B.). Sorbonne Université, ACTION Study Group, Institut de Cardiologie, Hôpital Pitié-Salpêtrière (APHP), Paris, France (J.-P.C.). Interventional Cardiology Unit and Cathlab, Department of Cardiology, University Hospital, La Timone, Marseille, France (T.C.). Division of Cardiology, Azienda Ospedaliero-Universitaria Policlinico $^{4}\mathrm{G}$ Martino,”

University of Messina, Italy (G.D.L.). Division of Cardiology, IRCCS Hospital Galeazzi-Sant'Ambrogio, Milan, Italy (G.D.L.). Department of Cardio-Thoracic and Vascular Medicine and Surgery, Division of Cardiology, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy (L.D.L.). UniCamillus-Saint Camillus International University of Health Sciences, Rome, Italy (L.D.L.). US Food and Drug Administration, Silver Spring, MD (A.F., A.M.). Division of Cardiology, University of Florida College of Medicine, Jacksonville (F.F., F.R., D.J.A.). Baim Institute for Clinical Research, Boston, MA (C.M.G.). Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (J.-Y.H.). Division of Cardiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea (M.-K.H.). Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Sweden (S.J.). Deutsches Herzzentrum München, Technische Universität München, Munich, Germany (A.K.). Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK; German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (A.K., D.S.). Department of Cardiology, Hirakata Kohsai Hospital, Osaka, Japan (T.K.). Hospital Israelita Albert Einstein, São Paulo, Brazil (P.A.L.). Pharmaceuticals and Medical Devices Agency, Tokyo, Japan (R.M., S.M., Y.S.). TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (M.L.O.). Department of Cardiovascular Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN (N.L.P.). NYU Langone Health System, New York, NY (S.V.R.). Ludwig-Maximilians University München, Munich, Germany (D.S.). Privatklinik Lauterbacher Mühle am Ostsee, Seeshaupt, Germany (D.S.). Department of Cardiology, Maasstad Hospital, Rotterdam, the Netherlands (P.C.S.). Université Paris-Cité, AP-HP, Paris, France (P.G.S.). INSERM U-1148/ LVTS, Paris, France (P.G.S.). Institut Universitaire de France, Paris (P.G.S.). Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, UK (R.F.S.). Cardiovascular Research Institute Maastricht (CARIM), School for Cardiovascular Diseases, Maastricht University Medical Center, the Netherlands (J.t.B.). Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands (J.t.B.). Department of Cardiology, University Medical Center Maastricht, the Netherlands (J.t.B.). Cardiocentro Institute, Ente Ospedaliero Cantonale, Università della Svizzera Italiana (USI), Lugano, Switzerland (M.V.). Department of Cardiology, Bern University Hospital, Inselspital (S.W.), University of Bern, Switzerland (M.V.). Department of Cardiology and Critical Care Medicine, Jessa Ziekenhuis, Hasselt, Belgium (P.V.). Faculty of Medicine and Life Sciences, University of Hasselt, Belgium (P.V.). Department of Cardiology, Hirakata Kohsai Hospital, Osaka, Japan (H.W.). Department of Cardiology, University of Galway, Ireland (P.W.S.). Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (R.W.Y.). ICPS and CERC, Massy, Paris, France (M.-C.M.).

Sources of Funding

None.

Disclosures

Dr Capodanno reports speaker or consulting fees from Amgen, Arena, Daiichi Sankyo, Sanofi, and Terumo; and institutional fees from Medtronic. Dr Mehran reports institutional research payments from Abbott, Abiomed, Alleviant Medical, Amgen, AM-Pharma, Arena, AstraZeneca, Atricure, Bayer, Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, CSL Behring, Cytosorbents, Daiichi Sankyo, Element Science, Faraday, Filterlex Medical, Humacyte, Idorsia Pharmaceuticals, Janssen, Mediasphere, Medtelligence, Medtronic, Novartis, OrbusNeich, Penumbra, PhaseBio, Philips, PiCardia, PLx Pharma, Protembis, RenalPro, RM Global, Shockwave, Vivasure, and Zoll; personal fees from Cine-Med Research, Ionis Pharmaceuticals, Novartis, Novo Nordisk, Vectura, and WebMD; equity ${<}1\%$ in Applied Therapeutics, Elixir Medical, Stel, and ControlRad (spouse); and roles with the American Medical Association (Scientific Advisory Board, JAMA Cardiology Associate editor), American College of Cardiology (board of trustees member, member clinical trials research program), and Society for Cardiovascular Angiography & Interventions (Women in Innovations committee member; faculty Cardiac Research Foundation; no fee). Dr Baber discloses honoraria from Amgen, AstraZeneca, Boston Scientific, and Abbott Vascular. Dr Bhatt discloses the following relationships: advisory board: Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; board of directors: Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS. LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TobeSoft; chair: inaugural chair, American Heart Association Quality Oversight Committee; consultant: Broadview Ventures and Hims; data monitoring committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for PORTICO [Portico Re-sheathable Transcatheter Aortic Valve System US IDE Trial], funded by St Jude Medical, now Abbott), Boston Scientific (chair, PEITHO

[Pulmonary Embolism Thrombolysis Study]), Cleveland Clinic (including for ExCEED [Centera THV System in Intermediate Risk Patients Who Have Symptomatic, Severe, Calcific, Aortic Stenosis], funded by Edwards), Contego Medical (chair, PERFORMANCE 2 [Protection Against Emboli During Carotid Artery Stenting Using the Neuroguard IEP System]), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for ENVISAGE [Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrillation], funded by Daiichi Sankyo; for ABILITY-DM [Randomized Comparison of Abluminus DES+ Sirolimus-Eluting Stents Versus Everolimus-Eluting Stents in Coronary Artery Disease Patients with DiabetesMellitus], funded by Concept Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health–funded MINT [Myocardial Ischemia and Transfusion]); honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News , ACC.org; chair, American College of Cardiology Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI [Evaluation of Dual Therapy With Dabigatran vs Triple Therapy With Warfarin in Patients With Atrial Fibrillation That Undergo a PCI With Stenting] clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II [Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome] executive committee funded by CSL Behring), Belvoir Publications (Editor-inChief, Harvard Heart Letter ), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for PRONOUNCE [A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease], funded by Ferring Pharmaceuticals), HMP Global (editor-in-chief, Journal of Invasive Cardiology ), Journal of the American College of Cardiology (guest editor; associate editor), K2P (co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (course director, Comprehensive Review of Interventional Cardiology ), Piper Sandler, Population Health Research Institute (for the COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies] operations committee, publications committee, steering committee, and US national coleader, funded by Bayer), Slack Publications (chief medical editor, Cardiology Today’s Intervention ), Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (continuing medical education steering committees), and Wiley (steering committee); other: Clinical Cardiology (deputy editor), National Cardiovascular Data Registry–ACTION Registry Steering Committee (chair), and VA CART (Cardiovascular Assessment, Reporting, and Tracking) Research and Publications Committee (chair); patent: sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital, assigned to Lexicon; neither the author nor Brigham and Women’s Hospital receives any income from this patent); research funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; royalties: Elsevier (editor, Braunwald’s Heart Disease ); site coinvestigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; trustee: American College of Cardiology; and unfunded research: FlowCo and Takeda. Dr Capranzano reports speaker fees from Daiichi Sankyo, Amgen, and Bayer. Dr Collet reports grants for the institution, honoraria, or research fees from BMS Pfizer, Medtronic, Boston Scientific, and AstraZeneca. Dr Cuisset reports consulting and lecture fees from Abbott Vascular, Boston Scientific, Edwards, Europa Organisation, Medtronic, Terumo, and Sanofi, and shares from CERC, a health care company. Dr L. De Luca has received consulting fees or honoraria from Amgen, Aspen, AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, Daiichi Sankyo, Eli Lilly, Menarini, Pfizer/Bristol Myers Squibb, Sanofi, Servier, and The Medicines Company, outside the present work. Dr Farb has received payment as an individual for consulting fee or honoraria from AstraZeneca, Bayer, and Sanofi and institutional payments for grants from PLx Pharma and The Scott R. MacKenzie Foundation. Dr Gibson reports grant support paid to the institution and consulting fees from Johnson & Johnson, Bristol Myers Squibb, CeleCor, Daiichi Sankyo, and Merck. Dr Hahn reports an institutional research grant from the National Evidence-based Healthcare Collaborating Agency, Ministry of Health & Welfare, Korea, and from Abbott Vascular, Biosensors, Boston Scientific, Daiichi Sankyo, Donga-ST, Hanmi Pharmaceutical, and Medtronic Inc. Dr James repots grants to the institution from Amgen, Novartis, Janssen, and AstraZeneca. Dr Lemos reports institutional research funding, unpaid advisory board membership,

unpaid membership of the steering/executive/data safety and monitoring group of trials, and unpaid interventional proctorship by Abbott, Corindus, Scitech, Boston Scientific, and Flouit but has not received personal payments by pharmaceutical companies or device manufacturers; being part of Argonauts, an innovation facilitator; and partial support by a grant from The National Council for Scientific and Technological Development (CNPq), Brazil (grant 306677/2019-9). Dr Lopes reports research support from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, and Pfizer and consulting fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, and Portola. Dr Morice reports being chief executive officer and a shareholder of CERC and a minor shareholder of Electroducer. Dr O’Donoghue reports grants through the hospital from Amgen, Novartis, Janssen, Merck, and AstraZeneca, and honoraria from Amgen, Novartis, AstraZeneca, and Janssen. Dr Serruys reports consultancy fees from SMT, Philips, Novartis, Merillife, and Xeltis. Dr Smits reports institutional research grants from Abbott Vascular and SMT and speaker or consulting honoraria from Abbott Vascular, Microport, and Terumo. Dr Steg reports research grants from Amarin, Bayer, Sanofi, and Servier; he is a speaker or consultant for Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers-Squibb, Janssen, Kowa, Idorsia, Lexicon, Merck, Novartis, Novo Nordisk, PhaseBio, Pfizer, Regeneron, Sanofi, and Servier; he is senior associate editor of Circulation . Dr Storey reports institutional research grants/support and personal fees from AstraZeneca, Cytosorbents, GlyCardial Diagnostics, and Thromboserin and personal fees from Alnylam, Bayer, Bristol Myers Squibb/Pfizer, Chiesi, CSL Behring, Daiichi Sankyo, Hengrui, Idorsia, Intas Pharmaceuticals, Novartis, PhaseBio, and Sanofi Aventis. Dr Valgimigli reports grants and personal fees from Terumo and personal fees from AstraZeneca, Alvimedica/CID, Abbott Vascular, Daiichi Sankyo, Bayer, CoreFLOW, Idorsia Pharmaceuticals Ltd, Universität Basel, Dept Klinische Forschung, Vifor, Bristol Myers Squib SA, Biotronik, Boston Scientific, Medscape, Medtronic, Vesalio, Novartis, Chiesi, ECRI, and PhaseBio. Dr Vranckx received personal fees from Daiichi Sankyo, Bayer AG, CSL Behring, Novartis, and PfizerBristol Meyers Squibb alliance. Dr Windecker reports research, travel, or educational grants to the institution from Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Corflow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Janssen-Cilag, Johnson & Johnson, Medicure, Medtronic, Merck Sharp & Dohme, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pfizer, Polares, Regeneron, Sanofi-Aventis, Servier, Sinomed, Terumo, Vifor, and V-Wave; serves as an advisory board member or member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, SINOMED, Terumo, V-Wave, and Xeltis, with payments to the institution but no personal payments; and is a member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without effect on his personal remuneration. Dr Yeh reports research grants or consulting fees from Abbott Vascular, Boston Scientific, and Medtronic; and consulting fees from Cathworks, Elixir Medical, Shockwave, and Zoll. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura, outside the present work; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. The other authors have nothing to disclose.

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