Antithrombotic treatment strategies in patients with established coronary atherosclerotic disease

Abstract

Multiple guidelines and consensus papers have addressed the role of antithrombotic strategies in patients with established coronary artery disease (CAD). Since evidence and terminology continue to evolve, the authors undertook a consensus initiative to guide clinicians to select the optimal antithrombotic regimen for each patient. The aim of this document is to provide an update for clinicians on best antithrombotic strategies in patients with established CAD, classifying each treatment option in relation to the number of antithrombotic drugs irrespective of whether the traditional mechanism of action is expected to mainly inhibit platelets or coagulation cascade. With the aim to reach comprehensiveness of available evidence, we systematically reviewed and performed meta-analyses by means of both direct and indirect comparisons to inform the present consensus document.

Graphical Abstract

Algorithm for antithrombotic treatment in patients with established CAD. Treatment preferences within each box are shown from above to below, whereas treatments within the same line are sorted in alphabetical order. Panels A and B refer to non-high bleeding risk (HBR) and HBR patients, respectively. HBR is defined according to the ARC-HBR criteria or a PRECISE-DAPT score ≥25. * for patients at high ischaemic risk and very low bleeding risk. § if the patient is not eligible for above shown treatment options. Box colours indicate composition of antithrombotic regimens (light blue: SAPT; grey: DAPT; and red: DAT). Abbreviations: ARC, Academic Research Consortium; CABG, coronary artery bypass grafting; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; DAT, dual antithrombotic therapy; MI, myocardial infarction; PCI, percutaneous coronary intervention; SAPT, single antiplatelet therapy.

Antithrombotic treatment, Coronary artery disease, Percutaneous coronary intervention, Acute coronary syndrome, Chronic coronary syndrome

Introduction

Multiple guidelines and consensus papers have addressed the optimal use of antithrombotic medications for patients with established coronary artery disease (CAD).^1–6 However, evidence and terminology continue to evolve, and a single comprehensive, updated document aimed at supporting clinicians in deciding which antithrombotic regimen to select throughout the entire spectrum of patients with established CAD is missing. The remit of this initiative is to systematically review and perform meta-analysis of the available evidence by means of both direct and indirect comparisons (separate manuscript) to further inform a consensus document on antithrombotic treatment strategies for secondary or tertiary prevention in patients with established CAD. The management of patients requiring anticoagulation has been recently addressed by multiple European Society of Cardiology (ESC) guidelines^5,7 and American consensus documents⁸ and is therefore not addressed in this manuscript.

The 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes (CCSs)⁹ suggested using the term CCS instead of stable CAD to highlight the progressive and dynamic nature of the disease and described its multiple manifestations, including CCS patients who never experienced a prior acute coronary syndrome (ACS) as well as those with stabilized CCS at 12 months after ACS. In recognizing the fact that the need for antithrombotic strategies may vary among CCS patients based on the presence or absence of prior myocardial infarction (MI),^10,11 the interpretation of the evidence and clinical consensus statements have been provided separately for CCS patients with or without prior MI in this document. The present document distinguishes two types of CAD at onset, including ACS and CCS without prior MI, and discusses antithrombotic strategies stratifying patients based on revascularization modality [i.e. percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), or no revascularization] and bleeding risk. In CCS patients without prior MI at onset who develop an ACS, the latter form of CAD should drive decisions for antithrombotic strategies. Patients with ACS at onset, or a secondary form of CAD, who remain stable per an arbitrary period of 12 months transition towards CCS with prior MI.

An overview of all investigated antithrombotic strategies and corresponding randomized clinical trials in patients with established CAD^12–78 is shown in Table 1.

Table 1

Studies testing different antithrombotic strategies in patients with established coronary artery disease

				Primary efficacy endpoint		Primary safety endpoint
Study acronym; authors; year of publication	Characterization of study population	Study intervention (N)/control (N)	Key efficacy and safety endpoints	RRR	ARR	RRI	ARI
AMIS, Schoenberger et al. (1980)12	CCS with prior MI (>12 months)	Intervention: ASA (N = 2267)	Efficacy: death	−11.1%	−1.1%	Not applicable	Not applicable
		Control: placebo (N = 2257)	Safety: not available
ASCET, Pettersen et al. (2012)13	CCS and medical therapy without prior MI	Intervention: clopidogrel 75 mg (N = 499)	Efficacy: unstable angina, non-haemorrhagic stroke, MI, and death	−3.8%	−0.4%	54.9%a	5.6%a
		Control: ASA (N = 502)	Safety: any bleeding
APPRAISE-2, Alexander et al. (2011)24	ACS and PCI, ACS and medical therapy	Intervention: apixaban 5 mg b.i.d. + standard antiplatelet therapy (N = 3705)	Efficacy: CV death, MI, and ischaemic stroke	5.1%	0.4%	61.5%a	0.8%a
		Control: standard antiplatelet therapy (N = 3687)	Safety: TIMI major bleeding not related to CABG
ARCTIC, Collet et al. (2012)35	Phenotype-guided DAPT	Intervention: antiplatelet therapy guided by platelet function monitoring (N = 3705)	Efficacy: death, MI, stroke, TIA, urgent coronary revascularization, and ST	−11.3%	−3.5%	−30.3%	−1.0%
		Control: standard antiplatelet therapy (N = 3687)	Safety: STEEPLE major bleeding
ATLAS ACS2-TIMI 51, Mega et al. (2012)73	ACS and PCI, ACS and medical therapy, ACS and CABG	Intervention 1: rivaroxaban 2.5 mg twice daily + DAPT (ASA + clopidogrel) (N = 5114)	Efficacy: CV death, MI, or stroke	R2.5 mg b.i.d. + DAPT vs. DAPT: 15.0%a	R2.5 mg b.i.d. + DAPT vs. DAPT: 1.6%a	R2.5 mg b.i.d. + DAPT vs. DAPT: 200%a	R2.5 mg b.i.d. + DAPT vs. DAPT: 1.2%a
		Intervention 2: rivaroxaban 5 mg twice daily + DAPT (ASA + clopidogrel) (N = 5115)	Safety: TIMI major bleeding not related to CABG	R5 mg b.i.d. + DAPT vs. DAPT: 17.8%a	R5 mg b.i.d. + DAPT vs. DAPT: 1.9%a	R5 mg b.i.d. + DAPT vs. DAPT: 300%a	R5 mg b.i.d. + DAPT vs. DAPT: 1.8%a
		Control: DAPT (asprin + clopidogrel) (N = 5115)
CAPRIE, (1996)46	CCS with prior MI (>12 months)	Intervention: clopidogrel (N = 9599)	Efficacy: CV death, MI, and ischaemic stroke	8.7%a	1.6%a	11%	0.2%
		Control: ASA (N = 9586)	Safety: severe bleeding
CARDIFF-I, Elwood et al. (1974)57	ACS and medical therapy	Intervention ASA (N = 615)	Efficacy: death	21.8%	2.1%	Not applicable	Not applicable
		Control: placebo (N = 624)	Safety: not available
CARDIFF-II, Elwood et al. (1979)68	ACS and medical therapy	Intervention: ASA (N = 832)	Efficacy: death	16.9%	2.5%	Not applicable	Not applicable
		Control: placebo (N = 850)	Safety: Not available
CARS, (1997)76	ACS and medical therapy	Intervention 1: 1 mg warfarin + ASA (N = 2028)	Efficacy: CV death, non-fatal MI, and non-fatal ischaemic stroke	1 mgW + A vs. A: −28.7%a	1 mgW + A vs. A: −2.6%a	1 mgW + A vs. A: 45%	1 mgW + A vs. A: 0.4%
		Intervention 2: 3 mg warfarin + ASA (N = 3382)	Safety: major bleeding	3 mgW + A vs. A: 3.9%	3 mgW + A vs. A: 0.4%	3 mgW + A vs. A: 73.9%a	3 mgW + A vs. A: 0.7%a
		Control: ASA (N = 3393)
CASCADE, Kulik et al. (2010)77	CCS and CABG without prior MI	Intervention: ASA + clopidogrel 75 mg (N = 46)	Efficacy: SVG intimal hyperplasia; and MACE	MACE: 19.3%	MACE 1.7%	Not applicable	1.8%
		Control: ASA + (N = 46)	Safety: major bleeding
Chesebro et al. (1982)78	CCS and CABG without prior MI	Intervention: ASA + dipyridamole (N = 176)	Efficacy: vein graft occlusionSafety: not available	57.1%	7%	Not applicable	Not applicable
		Control: ASA + placebo (N = 184)
CDPA, (1974)14	CCS with prior MI (>12 months)	Intervention: ASA (N = 727)	Efficacy: death	30.1%	2.5%	Not applicable	Not applicable
		Control: placebo (N = 744)	Safety: not available
CHAMP, Fiore et al. (2002)15	ACS and medical therapy	Intervention: warfarin (INR target 1.5–2.5) + ASA (N = 2522)	Efficacy: death	−1.7%	−0.3%	77.8%a	0.6%a
		Control: ASA (N = 2537)	Safety: major bleeding
CHARISMA, Bhatt et al. (2006)16	CCS with prior MI (>12 months), CCS and medical therapy without prior MI	Intervention: clopidogrel 75 mg + ASA (N = 7802)	Efficacy: CV death, MI, and stroke	7%	0.5%	25%	0.3%
		Control: ASA (N = 7801)	Safety: GUSTO severe bleeding
COMPASS, Eikelboom et al. (2017)17	CCS with prior MI (>12 months), CCS and PCI without prior MI, CCS and CABG without prior MI, CCS and medical therapy without prior MI	Intervention 1: rivaroxaban 2.5 mg twice daily + ASA (N = 9152)	Efficacy: CV death, MI, and stroke	R 2.5 mg b.i.d. + A vs. A: 24.1%a	R 2.5 mg b.i.d. + A vs. A: 1.3%a	R 2.5 mg b.i.d. + A vs. A: 63.2%a	R 2.5 mg b.i.d. + A vs. A: 1.2%a
		Intervention 2: rivaroxaban 5 mg twice daily (N = 9117)	Safety: modified ISTH major bleeding	R 5 mg b.i.d. vs. A: 9.3%	R 5 mg b.i.d. vs. A: 0.5%	R 5 mg b.i.d. vs. A: 47.4%a	R 5 mg b.i.d. vs. A: 0.9%a
		Control: ASA (N = 9126)
CREDO, Steinhubl et al. (2002)18	CCS and PCI without prior MI	Intervention: clopidogrel 75 mg + ASA (N = 1053)	Efficacy: CV death, MI, and stroke	26.9%a	3.0%a	31.3%	2.1%
		Control: ASA (N = 1063)	Safety: TIMI major bleeding
CRYSSA, Mannacio et al. (2012)19	CCS and CABG without prior MI	Intervention: clopidogrel 75 mg + ASA (N = 150)	Efficacy: SVG failure; MACCE	SVG failure:43.5%a	SVG failure: 5.7%a	0%	0%
		Control: ASA (N = 150)	Safety: major bleeding	MACCE: 49.5%	MACCE: 4.6%
CURE, (2001)74	ACS and PCI, ACS and CABG, ACS and medical therapy	Intervention: clopidogrel 75 mg + ASA (N = 6259)Control: ASA (N = 6303)	Efficacy: CV death, non-fatal MI, and strokeSafety: major or minor bleeding	18.4%a	2.1%a	70%a	3.5%a
DACAB, Zhao et al. (2018)20	CCS and CABG without prior MI	Intervention 1: ticagrelor 90 mg b.i.d. + ASA (N = 168)Intervention 2: ticagrelor 90 mg b.i.d. (N = 166)Control: ASA (N = 166)	Efficacy: SVG patency; MACCESafety: non-CABG-related bleeding	T90 mg + A vs. A SVG patency: −15.9%a MACCE: 66.7%	T90 mg + A vs. A SVG patency: −12.2%a MACCE: 3.6%	T90 mg + A vs. A 237%a	T90 mg + A vs. A 21.4%a
				T90 mg vs. A SVG patency: −8.2%a MACCE: 55.6%	T90 mg vs. A SVG patency: −6.3%a MACCE: 3.0%	T90 mg vs. A 34.4%	T90 mg vs. A 3.1%
DAPT study, Mauri et al. (2014)21	CCS with prior MI (>12 months), CCS and PCI without prior MI, CCS and medical therapy without prior MI	Intervention: P2Y12i (clopidogrel or prasugrel) + ASA (N = 5020)Control: ASA (N = 4941)	Efficacy: ST; MACCE (death, MI, or stroke)Safety: GUSTO moderate or severe bleeding	ST: 71%a MACCE: 27.1%a	ST: 1%a MACCE: 1.6%a	56.3%a	0.9%a
DES-LATE, Lee et al. (2014)22	CCS with prior MI (>12 months), CCS and medical therapy without prior MI	Intervention: Clopidogrel + ASA (N = 2531)Control: ASA (N = 2514)	Efficacy: CV death, MI, or strokeSafety: TIMI major bleeding	8.3%	0.2%	−21.4%	−0.3%
Elderly-ACS 2, Savonitto et al. (2018)23	ACS and PCI	Intervention: prasugrel 5 mg + ASA (N = 2531)	Efficacy: death, MI, disabling stroke, or rehospitalization for CV causes or bleeding	−2.4%	−0.4%	48.5%	1.3%
		Control: clopidogrel 75 mg + ASA (N = 2514)	Safety: BARC 2, 3, or 5 bleeding
EXCELLENT, Gwon et al. (2012)25	ACS and PCI, CCS and PCI without prior MI	Intervention: 6-month DAPT (ASA + clopidogrel 75 mg) followed by ASA alone (N = 722)	Efficacy: TVF (CV death, MI, and TVR)Safety: TIMI major bleeding	−11.6%	−0.5%	−50.0%	−0.3%
		Control: 12-month DAPT (ASA + clopidogrel 75 mg) (N = 721)
Gao et al. (2009)26	CCS and CABG without prior MI	Intervention: clopidogrel + ASA (N = 95)	Efficacy: LIMA patencySafety: not available	−0.1%	−0.1%	Not applicable	Not applicable
		Control: ASA (N = 102)
GEMINI-ACS-1, Ohman et al. (2017)27	ACS and PCI, ACS and medical therapy	Intervention: rivaroxaban 2.5 mg b.i.d. + P2Y12i (clopidogrel 75 mg or ticagrelor 90 mg b.i.d.) (N = 1519)	Efficacy: CV death, MI, stroke, and definite STSafety: TIMI non-CABG clinically significant bleeding	−5.5%	−0.3%	8.0%	0.4%
		Control: ASA + P2Y12i (clopidogrel 75 mg or Ticagrelor 90 mg b.i.d.) (N = 1518)
GLASSY, Franzone et al. (2019)28	ACS and PCI, CCS with prior MI (>12 months), CCS and PCI without prior MI	Intervention: ticagrelor 90 mg b.i.d. + ASA for 1-month followed by ticagrelor monotherapy (N = 3794)	Efficacy: death, non-fatal MI, non-fatal stroke, urgent TVRSafety: BARC 3 or 5 bleeding	15.1%a	1.3%a	0%	0%
		Control: ticagrelor or clopidogrel + ASA for 12-month followed by ASA monotherapy (N = 3791)
GLOBAL LEADERS, Vranckx et al. (2018)29	ACS and PCI, CCS with prior MI (>12 months), CCS and PCI without prior MI	Intervention: ticagrelor 90 mg b.i.d. + ASA for 1-month followed by ticagrelor monotherapy (N = 7980)	Efficacy: death or new Q-wave MISafety: BARC 3 or 5 bleeding	12.8%	0.6%	−3.8%	−0.1%
		Control: ticagrelor or clopidogrel + ASA for 12-month followed by ASA monotherapy (N = 7988)
GRAVITAS, Price et al. (2011)30	Phenotype-guided DAPT	Intervention: high-dose clopidogrel + ASA (N = 1109)	Efficacy: CV death, non-fatal MI, or STSafety: GUSTO moderate or severe bleeding	0%	0%	−39.1%	−0.9%
		Control: standard-dose clopidogrel + ASA (N = 1105)
HOST-EXAM, Koo et al. (2021)97	CCS and PCI, CCS with prior (>12 months) MI	Intervention: clopidogrel 75 mg (N = 2710)Control: ASA (N = 2728)	Efficacy: cardiac death, MI, stroke, readmission due to ACS, or definite/probable ST	32.7%a	1.8%a	−40%a	−0.8%a
			Safety: BARC 3–5 bleeding
I-LOVE-IT 2, Han et al. (2016)31	ACS and PCI	Intervention: 6-month DAPT (ASA + clopidogrel 75 mg) followed by ASA alone (N = 909)	Efficacy: TLF (cardiovascular death, target vessel MI, or clinically indicated TLR)Safety: BARC ≥ 3 bleeding	−12.1%	−0.7%	71.4%	0.5%
		Control: 12-month DAPT (ASA plus clopidogrel 75 mg) (N = 920)
ISAR-REACT 5, Schüpke et al. (2019)32	ACS and PCI	Intervention: ticagrelor 90 mg b.i.d. + ASA (N = 2012)	Efficacy: death, MI, or strokeSafety: BARC 3, 4, or 5 bleeding	−34.8%a	−2.4%a	12.5%	0.6%
		Control: prasugrel 10 mg (5 mg in patients > 75yo or <60 kg) + ASA (N = 2006)
ISAR-SAFE, Schüpke et al. (2014)33	ACS and PCI CCS and PCI without prior MI	Intervention: 6-month of ASA plus placebo (a total length of 6-month DAPT) (N = 1997)	Efficacy: death, MI, definite or probable ST, stroke, or TIMI major bleedingSafety: TIMI major bleeding	6.3%	0.1%	−33.3%	−0.1%
		Control: 6-month of ASA + clopidogrel 75 mg (a total length of 12-month DAPT) (N = 2003)
ISIS-2, (1988)34	ACS and medical therapy	Intervention: ASA (N = 8587)	Efficacy: CV deathSafety: major bleeding	20.3%a	2.4%a	0%	0%
		Control: placebo (N = 8600)
ITALIC, Gilard et al. (2015)36	ACS and PCI; CCS with prior MI (> 12 months), CCS and PCI without prior MI	Intervention: 6-months DAPT (clopidogrel plus ASA) (N = 926)Control: 24-month DAPT (clopidogrel plus ASA) (N = 924)	Efficacy: death, MI, repeat emergency TVR, stroke, or TIMI major bleeding at 12 monthsSafety: TIMI major bleeding	−6.7%	−0.1%	Not applicable	−0.3%
IVUS-XPL, Hong et al. (2016)37	ACS and PCI	Intervention: 6-months DAPT (clopidogrel plus ASA) (N = 699)Control: 12-month DAPT (clopidogrel plus ASA) (N = 701)	Efficacy: the composite of cardiac death, MI, stroke, or TIMI major bleeding at 12 monthsSafety: TIMI major bleeding	−4.7%	−0.1%	−30%	−0.3%
LoWASA, Herlitz et al. (2004)38	CCS with prior MI (hospitalization for AMI within 42 days prior to randomization)	Intervention: ASA plus warfarin 1.25 mg (N = 1659)Control: ASA 75 mg (N = 1641)	Efficacy: (1) CV death, reinfarction, or stroke and (2) CV deathSafety: serious bleeding	CV death, reinfarction, and stroke: 2.4%CV death: 9.5%	CV death, reinfarction, and stroke: 0.7%CV death: 1.5%	120%a	1.2%a
MASTER DAPT, Valgimigli et al. (2021)91	ACS and PCI, CCS and PCI	Intervention: abbreviated DAPT (N = 2295)	Efficacy: death, MI, stroke, or BARC 3 or 5 bleeding	2.9%	0.2%	30.8%a	2.9%a
		Control: standard DAPT (N = 2284)	Safety: BARC 2, 3, or 5 bleeding
Mangano et al. (2002)39	CCS and CABG without prior MI	Intervention: ASA (N = 2999)Control: no ASA (N = 2023)	Efficacy: fatal and non-fatal events occurring >48 h after surgery and during the index hospitalization	Death from any cause: 88%a	Death from any cause: 9.4%a	Not applicable	Not applicable
				MI: 48%	MI: 2.6%
NIPPON, Nakamura et al. (2017)40	ACS and PCI; CCS and PCI without prior MI	Intervention: 6-months DAPT (clopidogrel plus ASA) (N = 1654)Control: 18-month DAPT (clopidogrel plus ASA) (N = 1653)	Efficacy: NACCE (all cause death, MI, cerebrovascular events, and major bleeding events) from 6 to 18 months after DES implantation	−40%	−0.6%	0%	0%
			Safety: major bleeding (according to modified REPLACE-2 criteria)
One-month DAPT, Hong et al. (2021)131	CCS and PCI	Intervention: 1-month DAPT (clopidogrel + ASA) followed by ASA alone (N = 1507)	Efficacy: CV death, myocardial infarction, TVR, stroke, or STEEPLE major bleeding	10.8%	0.7%	32%	0.8%
		Control: 6- to 12-month DAPT (clopidogrel plus ASA) (N = 1513)	Safety: STEEPLE major bleeding
OPTIDUAL, Helft et al. (2016)41	CCS with prior MI (>12 months)	Intervention: clopidogrel plus ASA for a further 36 additional months (total treatment duration with DAPT: 48 + 3 months) (N = 695)	Efficacy: NACE (all-cause death, non-fatal MI, stroke, or ISTH major bleeding)	22.7%	1.7%	0%	0%
		Control: ASA plus placebo (N = 690)	Safety: ISTH major bleeding
OPTIMA-C, Lee et al. (2018)42	ACS and PCI; CCS and PCI without prior MI	Intervention: 6-months DAPT (clopidogrel plus ASA) (N = 683)	Efficacy: MACE (death, MI, and ischaemia-driven TLR) at 12-month follow-up	−100%	−0.6%	0%	0%
		Control: 12-months DAPT (clopidogrel plus ASA) (N = 684)	Safety: TIMI major bleeding
OPTIMIZE, Feres et al. (2013)43	ACS and PCI; CCS and PCI without prior MI	Intervention: 3-month DAPT (clopidogrel plus ASA) (N = 1605)	Efficacy: NACCE (all-cause death, MI, stroke, and major bleeding)	−3.4%	−0.2%	−33.3%	−0.3%
		Control: 12-month DAPT (Clopidogrel plus ASA) (N = 1606)	Safety: modified major REPLACE-2 and severe or life-threatening GUSTO bleeding
PEGASUS-TIMI 54, Bonaca et al. (2015)44	CCS with prior MI (>12 months)	Intervention 1: ticagrelor 90 mg b.i.d. (N = 7050)Intervention 2: ticagrelor 60 mg b.i.d. (N = 7045)Control: placebo (N = 7067) All pts treated with ASA	Efficacy: CV death, MI, or strokeSafety: TIMI major bleeding	T 90 mg vs. placebo: 13.1%aT 60 mg vs. placebo: 14%a	T 90 mg vs. placebo: 1.19%aT 60 mg vs. placebo: 1.27%a	T 90 mg vs. placebo: 145%aT 60 mg vs. placebo: 117%a	T 90 mg vs. placebo: 1.54%aT 60 mg vs. placebo: 1.24%a
PLATO, Wallentin et al. (2009)45	ACS and PCI; ACS and CABG; ACS and medical therapy	Intervention: ticagrelor 90 mg b.i.d. (N = 9333)Control: clopidogrel 75 mg (N = 9291)	Efficacy: death from vascular causes, MI, or strokeSafety: trial-defined major bleeding	16.2%a	1.9%a	3.6%	0.4%
POPular AGE, Gimbel et al. (2020)47	ACS and PCI; ACS and CABG; ACS and medical therapy	Intervention: clopidogrel 75 mg plus standard of care (N = 500)Control: ticagrelor 90 mg b.i.d. plus standard of care (N = 502)	Efficacy: net clinical benefit (all-cause death, MI, stroke, and PLATO major or minor bleeding)Safety: PLATO major or minor bleeding	15.6%	5%	−25%a	−6%a
POPular CABG, Willemsen et al. (2021)119	CCS and CABG without prior MI, ACS and CABG	Intervention: ticagrelor 90 mg b.i.d. + ASA (N = 249)	Efficacy: SVG occlusion at 1 yearSafety: BARC 3–5 bleeding	4.9%	0.5%	0%	0%
		Control: ASA (N = 247)
PRAGUE-18, Motovska et al. (2018)48	ACS and PCI	Intervention: prasugrel 10 mg + ASA (N = 634)	Efficacy: CV death, non-fatal MI, or stroke	−15.8%	−0.9%	−1.8%	−0.2%
		Control: ticagrelor 90 mg b.i.d. + ASA (N = 596)	Safety: any bleeding
PRASFIT-ACS, Saito et al. (2014)49	ACS and PCI	Intervention: prasugrel 3.75 mg (N = 685)Control: clopidogrel 75 mg (N = 678)	Efficacy: MACE (CV death, non-fatal MI, and non-fatal ischaemic stroke) at 24 weeks	20.3%	2.4%	−13.6%	−0.3%
			Safety: TIMI major bleeding
PRODIGY, Valgimigli et al. (2012)50	ACS and PCI, CCS with prior MI (>12 months), CCS and PCI without prior MI	Intervention: 24 months of DAPT (N = 987)Control: 6 months of DAPT (n = 983)	Efficacy: death, MI, and cerebrovascular accident at 2 yearsSafety: BARC type 2, 3, or 5 bleeding	−1%	0.1%	111% a	3.9%a
RACS, Bernardi et al. (2007)51	ACS and PCI, CCS and PCI without prior MI	Intervention: ASA + 6-month clopidogrel (N = 502)Control: ASA + 1-month clopidogrel (N = 502)	Efficacy: death, MI, and stroke at 6 monthsSafety: any bleeding (modified TIMI criteria)	66%a	3.3%a	−58%	−0.88%
REAL/ZEST-LATE, Park et al. (2010)52	CCS with prior MI (>12 months)	Intervention: clopidogrel 75 mg + ASA (N = 1357)	Efficacy: MI and death from cardiac causes	−50%	−0.6%	100%	0.1%
		Control: ASA(N = 1344)	Safety: TIMI major bleeding
REDUCE, De Luca et al. (2019)53	ACS and PCI	Intervention: 3 months of DAPT (N = 751)Control: 12 months of DAPT (N = 745)	Efficacy: all-cause mortality, MI, ST, stroke, TVR, and bleeding (BARC 2, 3, and 5) at 12 months	2.4%	0.2%	−16.7%	−0.5%
			Safety: BARC 2,3,5 bleeding
RESET, Kim et al. (2012)54	ACS and PCI, CCS and PCI without prior MI	Intervention: 3 months of DAPT with E-ZES (N = 1059)	Efficacy: CV death, MI, ST, ischaemia-driven TVR, or bleeding at 12 months	0%	0%	−50%	−0.5%
		Control: 12 months of DAPT with other DES (N = 1058)	Safety: TIMI major or minor bleeding
SAPAT, Juul-Moller et al. (1992)55	CCS and medical therapy without prior MI	Intervention: ASA (N = 1099)Control: placebo (N = 1026)	Efficacy: non-fatal or fatal MI (during hospitalization) or sudden deathSafety: major bleeding (trial-defined criteria)	33%a	4%a	58.3%	0.7%
SECURITY, Colombo et al. (2014)56	ACS and PCI, CCS and PCI without prior MI	Intervention: 6 months of DAPT (N = 682)	Efficacy: cardiac death, MI, stroke, definite or probable ST, or BARC type 3 or 5 bleeding at 12 months	−21.6%	−0.8%	−45.4%	−0.5%
		Control: 12 months of DAPT (N = 717)	Safety: BARC type 3 or 5 bleeding
SMART-CHOICE, Hahn et al. (2019)58	ACS and PCI, CCS and PCI without prior MI	Intervention: DAPT for 3 months followed by P2Y12 inhibitor monotherapy (N = 1495)	Efficacy: MACCE (all-cause death, MI, or stroke) at 12 months after the index procedure	−16%	−0.4%	−41%a	−1.4%a
		Control: DAPT for 12 months (N = 1498)	Safety: BARC 2–5 bleeding
SMART-DATE, Hahn et al. (2018)59	ACS and PCI	Intervention: 6-month DAPT (N = 1357)	Efficacy: All-cause death, MI, or stroke at 18 months	−12%	−0.5%	−30.7%	−1.2%
		Control: 12-month or longer DAPT(N = 1355)	Safety: BARC type 2–5 bleeding at 18 months
STOPDAPT-2, Watanabe et al. (2019)60	ACS and PCI, CCS and PCI without prior MI	Intervention: 1-month DAPT followed by clopidogrel monotherapy (N = 1523)Control: 12-month DAPT (ASA + clopidogrel) (N = 1522)	Efficacy: CV death, MI, ischaemic or haemorrhagic stroke, definite ST, TIMI major or minor bleeding at 12 monthsSafety: TIMI major or minor bleeding at 12 months	36.2%a	1.34%a	−73.4%a	−1.13%a
TALOS-AMI, Kim et al. (2021)132	ACS and PCI	Intervention: 1-month ASA + ticagrelor followed by 11-months ASA + clopidogrel (N = 1349)	Efficacy: CV death, MI, stroke, or BARC 2, 3, or 5 bleedingSafety: BARC 2, 3, or 5 bleeding	43.9%a	3.6%a	46.4%a	2.6%a
		Control: 12-month DAPT (ASA + ticagrelor) (N = 1348)
TAILOR-PCI, Pereira et al. (2020)61	Genotype-guided DAPT (ACS or CCS patients undergoing PCI with planned 12-month DAPT)	Intervention: genotype-guided DAPT (ASA + ticagrelor in CYP2C19 LOF carriers, ASA + clopidogrel in non-carriers) (N = 2652)Control: clopidogrel + ASA with genotyping after 12 months (N = 2650).	Efficacy: CV death, MI, stroke, ST, and severe recurrent ischaemia at 12 months in CYP2C19 LOF carriersSafety: TIMI major or minor bleeding in CYP2C19 LOF carriers	32.2%	1.9%	18.7%	0.3%
TenBerg et al. (2000)62	CCS and PCI without prior MI	Intervention: warfarin (started before PCI) + ASA (N = 530)Control: ASA (N = 528)	Efficacy: death, MI, TLR, and stroke at 1 yearSafety: major bleeding (leading to hospitalization and/or death), blood transfusion or surgical intervention, and vascular complications	29.5%a	6%a	220%a	2.2%a
THEMIS, Steg et al. (2019)63	CCS and PCI without prior MI, CCS and medical therapy without prior MI	Intervention: ticagrelor plus ASA (N = 9619)Control: placebo plus ASA (N = 9601)	Efficacy: CV death, myocardial infarction, or strokeSafety: TIMI major bleeding	9.4%a	0.8%a	120%a	1.2%a
TICAB, Schunkert et al. (2019)64	ACS and CABG, CCS and CABG without prior MI	Intervention: ticagrelor 90 mg b.i.d. (N = 946)Control: ASA (N = 947)	Efficacy: CV death, MI, repeat revascularization, and stroke 12 months after CABG	−18.2%	−1.5%	15.6%	0.5%
			Safety: BARC ≥ 4 for periprocedural and hospital stay-related bleedings or BARC ≥ 3 for post-discharge bleedings
TICO, Kim et al. (2020)65	ACS and PCI	Intervention: 3-month DAPT followed by ticagrelor monotherapy 90 mg b.i.d. (N = 1527).	Efficacy: NACE (major bleeding, death, MI, ST, stroke, or TVR) at 12 months	33.8%a	2%a	−43%a	−1.3%a
		Control: ticagrelor-based 12-month DAPT (N = 1529).	Safety: TIMI major bleeding
TREAT, Berwanger et al. (2019)66	ACS and PCI	Intervention: ticagrelor 90 mg b.i.d. (N = 1913)	Efficacy: CV mortality, MI, or stroke at 12 months	8.2%	0.6%	−16.6%	−0.2%
		Control: clopidogrel 75 mg (N = 1886)	Safety: TIMI major bleeding
TRILOGY-ACS, Roe et al. (2012)67	ACS and medical therapy	Intervention: ASA + prasugrel 10 mg (N = 3620)	Efficacy: MACE (CV death, non-fatal MI, or non-fatal stroke)	81.8%	0.9%	0%	0%
		Control: ASA + clopidogrel 75 mg (N = 3623)	Safety: GUSTO severe or life-threatening bleeding
TRITON-TIMI 38, Wiviott et al. (2007)75	ACS and PCI	Intervention: ASA + prasugrel (N = 6813)Control: ASA + clopidogrel (N = 6795)	Efficacy: CV death, MI, and strokeSafety: non-CABG related TIMI major bleeding	18.2%a	2.2%a	−33%a	−0.6%a
TROPICAL-ACS, Sibbing et al. (2017)69	Phenotype-guided DAPT	Intervention: 1-week prasugrel followed by 1-week clopidogrel and PFT-guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge; (N = 1304)	Efficacy: net clinical benefit (CV death, MI, stroke, or BARC bleeding grade 2 or higher at 1 year after randomization)Safety: BARC bleeding grade 2 or higher	−28.6%	−2%	20%	1%
		Control: prasugrel 10 mg (N = 1306)
TWILIGHT, Mehran et al. (2019)70	ACS and PCI, CCS with prior MI (>12 months), CCS and PCI without prior MI	Intervention: 3-month DAPT followed by ticagrelor + placebo (N = 3555)	Efficacy: death from any cause, non-fatal MI, or non-fatal stroke	0%	0%	−43.6%a	−3.1%a
		Control: ticagrelor + ASA (N = 3564)	Safety: BARC type 2,3,5 bleeding
VACS, Goldman et al. (1988)71	CCS and CABG without prior MI	Intervention 1: ASA, 325 mg daily (N = 154). Intervention 2: ASA, 325 mg three times daily (N = 155). Intervention 3: ASA and dipyridamole (325 mg and 75 mg, combination three times daily (N = 162). Intervention 4: sulfinpyrazone, 267 mg three times daily (N = 148)	Efficacy: angiographic graft patency (within 60 days)	Rates of graft patencyInt. 1: 93.5%Int. 2: 92.3%Int. 3: 91.9%Int. 4: 90.2%Comp: 85.2% (P < 0.05)	Not applicable	Not applicable	Not applicable
		Control: placebo (N = 153)
WARIS-II, Hurlen et al. (2002) 72	CCS with prior MI	Intervention 1: warfarin (N = 1216)Intervention 2: warfarin plus ASA 75 mg (N = 1208) %Control: ASA alone (N = 1206)	Efficacy: death, non-fatal MI, and thromboembolic strokeSafety: trial specific non-fatal major bleeding	A + W vs. A: 25%aW vs. A: 16.5%a	A + W vs. A: 5%aW vs. A: 3.3%a	A + W vs. A: 283%aW vs. A: 350%a	A + W vs. A: 1.7%aW vs. A: 2.1%a

Main study results are presented as relative and absolute risk reduction (RRR and ARR) for the efficacy and relative and absolute risk increase (RRI and ARI) for the primary safety endpoint, as previously described by Bodemer et al. (Med Decis Making 2014; 34:615–626). Relative and absolute risk reductions or increases are presented as positive or negative numbers based on the risk of the outcome of interest. Specifically, positive ARR and RRR indicate that the risk of that outcome is reduced by study intervention, while negative ARR and RRR indicate that the active treatment arm increased the risk of the outcome. Conversely, positive RRI and ARI indicate that the risk of that outcome is increased by study intervention, while negative values indicate the active treatment is safer than the comparator.

^aStatistically significant.

ACS, acute coronary syndrome; ARD, absolute risk difference; ASA/A, aspirin; b.i.d. , bis in die; BARC, Bleeding Academic Research Consortium; CABG, coronary artery bypass grafting; CI, confidence interval; CCS, chronic coronary syndrome; CV, cardiovascular; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; E-ZES, endeavor zotarolimus-eluting stent; GUSTO, Global Use of Strategies to Open Occluded Arteries; Hb, haemoglobin; HR, hazard ratio; INR, International Normalized Ratio; ISTH, International Society on Thrombosis and Haemostasis; LOF, loss of function; LIMA, Left Internal Mammary Artery; MACCE, major adverse cardiac and cerebrovascular events; MACE, major adverse cardiac events; MI, myocardial infarction; NACCE, net adverse clinical and cerebrovascular events; NACE, net adverse clinical events; P2Y12i, P2Y12 inhibitor; PCI, percutaneous coronary intervention; PLATO, Platelet Inhibition and Patient Outcomes; REPLACE-2, Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events; R, rivaroxaban; RR, rate ratio; ST, stent thrombosis; STEEPLE, Safety and Efficacy of Enoxaparin in PCI Patients; an International Randomized Evaluation; SVG, saphenous vein graft; T, ticagrelor; TIA, transient ischaemic attack; TIMI, thrombolysis in myocardial infarction; TLF, target lesion failure; TVF, target vessel failure; TLR, target lesion revascularization; TVR, target vessel revascularization; W + A, warfarin + aspirin.

Antithrombotic therapies have been traditionally classified based on the principal thrombotic target, either platelets (antiplatelet agents) or coagulation factors (anticoagulant agents). However, platelets and coagulation mutually influence each other. Anticoagulants, at lower than the standard dosing that is traditionally used to achieve conventional anticoagulation effects, prevent CAD-related ischaemic and fatal events not solely via an anticoagulation effect but likely by concomitantly modulating thrombin-mediated platelet activation.⁷⁹

Against this background, multiple combinations of antiplatelet agents or antiplatelet and anticoagulant drugs, using various regimens, have been tested for the prevention of thrombotic events in patients with established CAD. Although some treatment combinations have lowered ischaemic risk compared with simpler regimens, combination therapy usually increases bleeding and always increases prescribing complexity. To better address this issue, the present document classifies each treatment option in relation to the number of antithrombotic drugs irrespective of whether the traditional mechanism of action is expected to mainly inhibit platelets or coagulation cascade. This document does not address antithrombotic treatments in primary prevention or in patients with incidental finding of non-obstructive CAD or with a high calcium score detected at coronary computed tomography for whom the risk/benefit of an antithrombotic therapy has never been clearly investigated. In this document, high bleeding risk (HBR) is defined based on Academic Research Consortium (ARC)-HBR criteria^80,81 or PRECISE-DAPT score^82,83 ≥25. Given the need for continuous monitoring of treatment tolerance and adherence together with the possible evolution of ischaemic and bleeding risks over time, active involvement of the primary care physician at the time of treatment implementation is warranted for shared decision-making and follow-up of these patients. An overview of consensus statements endorsed by this document regarding antithrombotic treatment strategies in patients with established coronary atherosclerotic disease after PCI, CABG or in medically managed patients, with or without HBR is provided in the graphical abstract.

Coronary and peripheral arterial diseases

A substantial and often underdiagnosed proportion of patients with CAD have peripheral artery disease (PAD).^84,85 These patients, often described as having ‘polyvascular’ disease, are at increased risk of thrombotic events.⁸⁶ This document includes the management of this subset of patients, while comorbidities other than PAD are not addressed in this document. Most data on concomitant PAD in patients with CAD are limited to a clinical history of the former. However, even subclinical PAD is a marker of increased risk in CAD patients particularly after revascularization.⁸⁷ CAD patients with concomitant PAD [diagnosed by a low ankle-brachial index (ABI) even in the absence of symptoms] are at increased risk of adverse cardiovascular events, and they have a larger absolute net benefit from intensified antithrombotic therapies than CAD patients without concomitant PAD.^17,88 Hence, the identification of subclinical PAD (e.g. by ABI measurement) can help to better stratify CAD patients and select the most suitable antithrombotic strategies. To better disseminate routine ABI measurement in cardiology practice, automated multi-cuff devices, which have been shown to have a high degree of correlation with the standard Doppler method,⁸⁹ can be considered as a first-line approach for subclinical PAD diagnosis. In the presence of an abnormal ABI, further confirmatory vascular work-up is suggested.

Consensus statements endorsed by this document regarding patients with CAD and PAD are provided in Table 2.

Table 2

Clinical consensus statements for PAD patients with established CAD

The presence of PAD in patients with CAD prompts considering an intensified antithrombotic treatment (e.g. clopidogrel instead of aspirin if single antiplatelet therapy is preferrable or aspirin and rivaroxaban 2.5 mg b.i.d or aspirin and ticagrelor 60 mg b.i.d. instead of single antiplatelet therapy with aspirin in patients not at high bleeding risk).

ABI, ankle-brachial index; b.i.d., bis in die; CAD, coronary artery disease; PAD, peripheral arterial disease.

Acute coronary syndrome managed by percutaneous coronary intervention

Evidence-based treatment options are shown in Figure 1 and the corresponding summary of evidence in the Supplemental material.

Figure 1

ACS managed by PCI. Treatment options for ACS patients managed by PCI, depending on bleeding and ischaemic risks. For detailed consensus statements, see Table 3. Box colours indicate composition of antithrombotic regimens (light blue: SAPT; grey: DAPT). Abbreviations: ACS, acute coronary syndrome; DAPT, dual antiplatelet therapy; PCI, percutaneous coronary intervention; SAPT, single antiplatelet therapy.

Single antithrombotic therapy

Aspirin monotherapy following PCI has been investigated mainly from 6 months onwards after dual antiplatelet therapy (DAPT)⁹⁰ among patients who were not deemed to be at HBR. Among HBR patients, aspirin monotherapy after a short course of DAPT is associated with lower bleeding risk compared with more prolonged DAPT, but it remains unclear if it preserves ischaemic risk as this treatment option has been investigated in a limited patient/selected population.^91–95 Among ACS patients at either low or unselected bleeding risk, aspirin monotherapy is associated with greater ischaemic risk than DAPT.^11,59,96 Clopidogrel monotherapy, compared with aspirin monotherapy after at least 6 months of DAPT without clinical events, is associated with greater net clinical benefit,⁹⁷ supporting the preference of the former over the latter treatment option. This evidence was generated in the context of an open-label trial (the HOST EXAM study) conducted in East Asian patients and generalizability to Western population remains to be established. However, an extended follow-up of this study confirmed a greater benefit of clopidogrel over aspirin monotherapy for up to 5 years.⁹⁸

P2Y₁₂ inhibitor monotherapy following 1–3 months of DAPT has been investigated after PCI compared with DAPT prolongation.^{28,29,70,99,100} Aggregate data meta-analyses of these studies are available¹⁰¹ but suffer from limitations in quantifying the risks and benefits of aspirin withdrawal compared with DAPT. This is due to the inclusion of events occurring during the initial DAPT phase, which consisted of an identical treatment regimen in both experimental and control regimens. These limitations were addressed in two individual patient data meta-analyses that censored events occurring during the initial DAPT period, therefore appraising only the events that occurred during the experimental phase (i.e. when the two treatments started to diverge).^99,100 In the SIDNEY Collaboration, which included 14 628 patients, BARC 3 or 5 bleeding occurred less frequently with ticagrelor monotherapy than DAPT [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.41–0.75; P < 0.001].⁹⁹ The composite of all-cause death, MI, or stroke occurred in a similar number of patients in the ticagrelor monotherapy and DAPT-treated groups (HR 0.92, 95% CI 0.76–1.10; P < 0.001 for non-inferiority). In analyses of individual endpoints, ticagrelor was associated with lower risks of all-cause mortality (HR 0.71, 95% CI 0.52–0.96; P = 0.027) and cardiovascular mortality (HR 0.68, 95% CI 0.47–0.99; P = 0.044), possibly due to lower bleeding, taking into account the fact that the rates of MI, stent thrombosis, and stroke did not differ.⁹⁹ The treatment effect was consistent in ACS patients (P_interaction = 0.51), which represented slightly less than two-thirds of the study population. In the SIDNEY-2 Collaboration, consisting of data from 24 096 patients, the composite of all-cause death, MI, or stroke did not differ with P2Y₁₂ inhibitor monotherapy, including any of the three oral P2Y₁₂ inhibitors, or DAPT (HR 0.93, 95% CI 0.79–1.09; P = 0.005 for non-inferiority).¹⁰⁰ The treatment effect was consistent across all subgroups, including ACS (13 966 or 60%), but there was an interaction with sex (P_interaction = 0.019), suggesting that P2Y₁₂ inhibitor monotherapy is associated with a lower rate of all-cause death, MI, or stroke in females (HR 0.64, 95% CI 0.46–0.89), irrespective of the choice of P2Y₁₂ inhibitor monotherapy.¹⁰⁰ However, ticagrelor and prasugrel were over- and under-represented, respectively, among the newer P2Y₁₂ inhibitors, and clopidogrel monotherapy was only tested in Asian populations in comparison with the combination of aspirin and clopidogrel.¹⁰⁰ The STOPDAPT2-ACS trial enrolled 3008 ACS patients from Japan who were then combined with ACS patients included in the parent STOPDAPT2 trial (n = 1161). In the 4169 ACS patient cohort, non-inferiority for the composite of cardiovascular death, MI, definite stent thrombosis, and stroke of 1-month DAPT with aspirin and clopidogrel followed by clopidogrel monotherapy was not shown compared with 1-year DAPT (HR 1.14, 95% CI 0.80–1.62; P for non-inferiority = 0.06) due to a significant excess of MI in the monotherapy arm (HR 1.91, 95% CI 1.06–3.44). However, the rate of BARC 3 or 5 bleeding was lower in the monotherapy arm (HR 0.41, 95% CI 0.20–0.83). The Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated vs. Standard DAPT Regimen (MASTER DAPT) trial recruited 4579 HBR patients, including 2211 (48.3%) patients with ACS who underwent 1-month DAPT after sirolimus-eluting biodegradable polymer stent implantation, followed by single antiplatelet therapy (clopidogrel in 53.9% of the patients, aspirin in 28.8%, ticagrelor in 13.6%, and prasugrel in 1.2%) or a more prolonged DAPT regimen of at least 3 months.⁹¹ Non-inferiority for both net and major adverse cardiac and cerebral event endpoints was shown for the abbreviated DAPT arm, which was also associated with a lower risk of major or clinically relevant non-major bleeding (HR 0.68, 95% CI 0.55–0.84) and with consistent results among ACS patients.⁹¹

Evidence from the network meta-analysis (NMA), including PCI and/or ACS patients, focusing on 12-month treatment effects, suggests that ticagrelor monotherapy is associated with lower risks of mortality (HR 0.68, 95% CI 0.52–0.89) and MI (HR 0.69, 95% CI 0.50–0.95) compared with aspirin.¹⁰² In comparison with 12-month DAPT with aspirin and clopidogrel, ticagrelor monotherapy is associated with a lower risk of mortality (HR 0.70, 95% CI 0.55–0.89) and a similar risk of MI and bleeding,¹⁰² whereas clopidogrel monotherapy is associated with similar death or MI rates but lower bleeding (HR 0.62, 95% CI 0.40–0.96).¹⁰²

Dual antithrombotic therapy

Since the publication of the PCI-CURE study,¹⁰³ DAPT has been the mainstay of antithrombotic treatment after PCI in patients with ACS. The TRITON-TIMI 38⁷⁵ and PLATO⁴⁵ trials established the superiority of prasugrel and ticagrelor over clopidogrel in aspirin-treated patients in terms of ischaemic outcomes. Both studies showed a similar reduction in the primary composite endpoint of cardiovascular death, MI, or stroke and a comparable increase in major non-CABG-related bleeding as compared with clopidogrel. In the TRITON-TIMI study, there was a slight, yet significant, excess of fatal bleeding with prasugrel, which led the Food and Drug Administration (FDA) to issue a black box warning on bleeding risk with prasugrel. The PLATO study found a significant reduction in cardiovascular mortality with ticagrelor.⁴⁵ In the PRAGUE-18, no significant differences in the primary composite net endpoint at 7 days were found among aspirin-treated ACS patients treated with prasugrel or ticagrelor.¹⁰⁴ The ISAR-REACT 5 is the largest head-to-head comparison of 1-year DAPT strategy with ticagrelor (administered ‘upstream’, before coronary angiography) as compared with DAPT with prasugrel (administered ‘downstream’, only after coronary anatomy was known) in patients with ACS treated with an invasive management.³² In this study, prasugrel was associated with a reduction in the composite endpoint of cardiovascular death, MI, or stroke as compared with ticagrelor (HR 0.74, 95% CI 0.59–0.92), which was driven by a reduction in MI (HR 0.61, 95% CI 0.44–0.85).³² Mortality and bleeding rates were similar between the two groups. Some aspects of this trial have been criticized, such as its open-label design and adherence to treatment assignment.¹⁰⁵ A NMA does not provide clear evidence of the superiority of prasugrel over ticagrelor.¹⁰⁶ DAPT duration should not exceed 1 month in HBR patients, irrespective of concomitant high-risk features, such as patients who underwent complex intervention^91,107,108 and should be preferably followed by P2Y₁₂ inhibitor monotherapy instead of aspirin.^97,99

Triple antithrombotic therapy

In patients with a recent ACS, low-dose rivaroxaban [2.5 mg bis in die (b.i.d.)] for a mean of 13 months and up to 31 months was associated with lower risk of cardiovascular death, MI, or stroke (HR 0.84, 95% CI 0.72–0.97) compared with placebo in the ATLAS ACS 2- TIMI 51 trial, where most patients were on DAPT with aspirin and clopidogrel or ticlopidine.⁷³ The potential benefit of rivaroxaban with respect to ischaemic outcomes should be weighed against the increased risk of major (HR 3.46, 95% CI 2.08–5.77) and intracranial bleeding (HR 2.83, 95% CI 1.02–7.86).⁷³ Apixaban 5 mg b.i.d., mostly in combination with DAPT, was not associated with lower risk of cardiovascular death, MI, or ischaemic stroke (HR 0.95, 95% CI 0.80–1.11) but greater than two-fold major bleeding risk (HR 2.59, 95% CI 1.50–4.46) in the APPRAISE-2 trial, leading to premature study termination.²⁴ The NMA provides evidence that triple therapy with rivaroxaban 2.5 mg, aspirin, and clopidogrel is associated with lower mortality risk compared with aspirin and 12-month clopidogrel (HR 0.68, 95% CI 0.53–0.87), but with higher bleeding risk (HR 2.49, 95% CI 1.54–4.03).¹⁰²

Consensus statements endorsed by this document regarding antithrombotic therapy in ACS patients undergoing PCI are provided in Table 3.

Table 3

Clinical consensus statements for ACS managed by PCI (without baseline indications for OAC)

Single antithrombotic therapy

Compared with 12-month DAPT, aspirin withdrawal after 1-to-3-month DAPT and continuation with P2Y12 inhibitor in the form of:• ticagrelor monotherapy provides net benefit with reduced bleeding complications without increased risk of non-fatal or fatal ischaemic events;• prasugrel monotherapy has not been investigated and cannot, therefore, be supported;• clopidogrel monotherapy is associated with greater MI risk among patients who were not selected for being at HBR (e.g. based on ARC-HBR criteria or PRECISE-DAPT ≥ 25).a

Compared with ≥12-month DAPT, P2Y12 inhibitor withdrawal after 3- or 6-month DAPT and continuation of aspirin is associated with greater MI risk among patients who were not selected for being at HBR (e.g. based on ARC-HBR criteria or PRECISE-DAPT ≥ 25).

Dual antithrombotic therapy

During the first year after PCI in ACS, DAPT with a newer P2Y12 inhibitor (prasugrel or ticagrelor) is superior to DAPT with clopidogrel in terms of ischaemic outcomes and is therefore warranted.

Long-term DAPT, instead of P2Y12 inhibitor monotherapy, remains justifiable in patients at high risk of recurrent ischaemic eventsb in whom the bleeding risk does not pose concerns.

One-month DAPT duration is warranted in HBR patients (e.g. based on ARC-HBR criteria or PRECISE-DAPT ≥ 2583).c

The combination of rivaroxaban 2.5 mg b.i.d. and a P2Y12 inhibitor cannot be supported as a routine strategy without additional investigation.

The combination of rivaroxaban 2.5 mg b.i.d. with clopidogrel or ticagrelor may be justifiable following PCI in aspirin-intolerant patients who are not HBR.

Triple antithrombotic therapy

Triple antithrombotic therapy with rivaroxaban 2.5 mg b.i.d. in combination with aspirin and clopidogrel remains a therapeutic option in selected patients at high risk of thrombotic complications and low risk of bleeding.d

ACS, acute coronary syndrome; ARC, Academic Research Consortium; b.i.d., bis in die; DAPT, dual antiplatelet therapy; HBR, high bleeding risk; MI, myocardial infarction; OAC, oral anticoagulation; PADs, peripheral arterial diseases; PCI, percutaneous coronary intervention.

^aThis evidence was generated in patients who underwent durable polymer everolimus-eluting stent implantation; consequently, these results may not extend to patients who receive other stent types.

^bHigh ischaemic risk is defined as diffuse multivessel coronary artery disease with at least one of the following: diabetes mellitus requiring medication, recurrent MI, peripheral arteria disease, or chronic kidney disease with estimated glomerular filtration rate 15–59 mL/min/1.73 m².

^cThis evidence was generated in patients who underwent biodegradable polymer sirolimus-eluting stent implantation; consequently, these results may not extend to patients who receive other stent types.

^dSuch as patients in whom the use of ticagrelor and prasugrel is not an option, those with recurrent ischaemic events on prior use of ticagrelor or prasugrel in whom adherence to these drugs has been established, or patients in whom the early transition towards dual therapy with aspirin and rivaroxaban is envisioned.

Acute coronary syndrome managed by coronary artery bypass grafting

Evidence-based treatment options are shown in Figure 2 and summary of evidence in the Supplemental material.

Figure 2

ACS managed by CABG. Treatment options for ACS patients managed by CABG, depending on bleeding risk. For detailed consensus statements, see Table 4. Box colours indicate composition of antithrombotic regimens (light blue: SAPT; grey: DAPT). Abbreviations: ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; DAPT, dual antiplatelet therapy; SAPT, single antiplatelet therapy.

Single antithrombotic therapy

Uninterrupted, low-dose aspirin reflects current best practice in most ACS patients while waiting for CABG and shortly (generally 24 h) after surgery.¹ Clopidogrel was associated with a lower risk of vascular death, MI or ischaemic stroke (HR 0.64, 95% CI 0.47–0.87) compared with aspirin in patients with prior CABG in the CAPRIE trial.¹⁰⁹ The prematurely interrupted TICAB trial, which included 31% of patients with ACS, failed to show superiority of ticagrelor monotherapy over aspirin monotherapy within 1 year after CABG.⁶⁴ Ticagrelor, clopidogrel, and prasugrel should be stopped 3, 5, and 7 days before CABG, respectively.

Dual antithrombotic therapy

The available evidence for dual antithrombotic therapy in ACS-CABG patients comes from subgroup analyses of ACS trials, which showed results consistent with the overall findings. The CURE trial first supported starting a second antiplatelet drug (clopidogrel) at hospital admission in addition to aspirin in ACS patients for the reduction of cardiovascular death, MI, or stroke [rate ratio (RR) 0.80, 95% CI 0.72–0.90],⁷⁴ including those undergoing CABG (RR 0.89, 95% CI 0.71–1.11), (P_interaction = 0.53).¹¹⁰ The PLATO trial showed a significant reduction in all-cause mortality (HR 0.49, 95% CI 0.32–0.77) and cardiovascular mortality (HR 0.52, 95% CI 0.32–0.85) with ticagrelor compared with clopidogrel in aspirin-treated patients undergoing CABG,¹¹¹ supporting the use of ticagrelor over clopidogrel in addition to aspirin for the first 6–12 months following surgery.

Triple antithrombotic therapy

In the ATLAS ACS 2-TIMI 51 trial, 60% of the overall ACS cohort underwent PCI or CABG.⁷³

The treatment effects of rivaroxaban, when mainly added to aspirin and clopidogrel, among CABG patients have not been separately reported.

Consensus statements endorsed by this document regarding antithrombotic therapy in ACS patients undergoing CABG are provided in Table 4.

Table 4

Clinical consensus statements for ACS managed by CABG (no baseline indications for OAC)

Single antithrombotic therapy

Single antithrombotic therapy does not represent the current standard of care unless it is justified by intolerance or contraindications to dual antiplatelet therapy, such as HBR (e.g. based on ARC-HBR criteria or PRECISE-DAPT ≥ 25).

If single antithrombotic therapy is selected, then clopidogrel is preferable over aspirin or ticagrelor.

Dual antithrombotic therapy

Dual antiplatelet therapy for up to 12 months provides greater ischaemic protection than aspirin alone, and represents the current standard of care, unless concerns over HBR prevail (e.g. based on ARC-HBR criteria or PRECISE-DAPT ≥ 2583).

The use of aspirin and ticagrelor provides greater ischaemic protection than aspirin and clopidogrel

Triple antithrombotic therapy

The treatment effects of rivaroxaban 2.5 mg b.i.d. on top of aspirin and clopidogrel in patients who underwent CABG are unknown.

ACS, acute coronary syndrome; b.i.d., bis in die; CABG, coronary artery bypass grafting; HBR, high bleeding risk; OAC, oral anticoagulation.

Acute coronary syndrome managed by medical therapy alone

Evidence-based treatment options are shown in Figure 3 and summary of evidence in the Supplemental material.

Figure 3

ACS managed by medical therapy alone. Treatment options for ACS patients managed by medical therapy alone, depending on bleeding risk. For detailed consensus statements, see Table 5. Box colours indicate composition of antithrombotic regimens (light blue: SAPT; grey: DAPT). § DAPT with aspirin and prasugrel is justifiable if clopidogrel and ticagrelor are not indicated, such as in patients receiving strong CYP3A inhibitors among patients with CAD confirmed by angiography. Abbreviations: ACS, acute coronary syndrome; DAPT, dual antiplatelet therapy; SAPT, single antiplatelet therapy.

Single antithrombotic therapy

Aspirin reduces the odds of serious vascular events—defined as vascular death, MI, or stroke—by 25% as compared with no treatment in patients with prior MI.¹¹² The CAPRIE trial demonstrated greater ischaemic protection from clopidogrel than aspirin, without higher bleeding risk.⁴⁶

Dual antithrombotic therapy

Among ACS patients who are medically managed without revascularization, the combination of aspirin and clopidogrel reduces the risk of cardiovascular death, MI, or stroke (RR 0.80, 95% CI 0.69–0.92) but increases the risk of major bleeding (RR 1.75, 95% CI 1.25–2.36) compared with aspirin alone.¹¹⁰ The combination of ticagrelor and aspirin was associated with lower risk of cardiovascular death, MI, or stroke compared with aspirin and clopidogrel in the PLATO trial,⁴⁵ which was consistent in the medically managed population (HR 0.85, 95% CI 0.73–1.00; P_interaction = 0.88)¹¹³ and across all ages.¹¹⁴ The overall bleeding risks did not differ between ticagrelor and clopidogrel in medically managed ACS patients (HR 1.17, 95% CI 0.98–1.39; P_interaction = 0.12),¹¹³ although observational data suggest that ticagrelor should be used cautiously in octogenarians.¹¹⁵

When low-dose rivaroxaban is combined with either clopidogrel or ticagrelor for the treatment of ACS patients who were, however, predominately treated with PCI, the risk of clinically significant bleeding is similar to the risk with aspirin and a P2Y₁₂ inhibitor without evidence of greater ischaemic protection.²⁷

Triple antithrombotic therapy

ACS was managed medically in 55, 20, and 40% of the patients included in the APPRAISE-2,²⁴ ATLAS ACS-TIMI 46,¹¹⁶ and ATLAS ACS 2-TIMI 51⁷³ trials, respectively. In the ATLAS ACS 2-TIMI 51, the use of low-dose rivaroxaban (2.5 mg b.i.d.) added to aspirin and clopidogrel was associated with a lower risk of cardiovascular death, MI, or stroke but considerably higher bleeding in the overall population.⁷³ However, the risks and benefits of triple therapy with rivaroxaban 2.5 mg b.i.d. in medically managed ACS patients have not been separately appraised in the published literature.

Consensus statements endorsed by this document regarding antithrombotic therapy in ACS patients managed by medical treatment alone are provided in Table 5.

Table 5

Clinical consensus statements for ACS managed by medical therapy alone (no baseline indications for OAC)

Single antithrombotic therapy

Single antithrombotic therapy does not represent the current standard of care unless it is justified by intolerance or contraindications to dual antiplatelet therapy, such as HBR (e.g. based on ARC-HBR criteria or PRECISE-DAPT ≥ 2583).

Aspirin provides greater ischaemic protection than no aspirin following acute MI.

Clopidogrel provides net benefit compared with aspirin.

Dual antithrombotic therapy

The combination of aspirin and ticagrelor for up to 12 months is warranted instead of aspirin and clopidogrel unless concerns over the bleeding risk prevail (e.g. based on ARC-HBR criteria or PRECISE-DAPT ≥ 2583).

The treatment duration of aspirin and ticagrelor or clopidogrel depends on treatment tolerance, side effects, and assessment of ischaemic vs. bleeding risks.

The combination of aspirin and prasugrel is justifiable if clopidogrel and ticagrelor are not indicated, such as in patients receiving strong CYP3A inhibitors if CAD has been confirmed by angiography.

The combination of rivaroxaban 2.5 mg b.i.d. with clopidogrel or ticagrelor requires further investigation.

Triple antithrombotic therapy

Triple antithrombotic therapy with rivaroxaban 2.5 mg b.i.d., aspirin, and clopidogrel has limited evidence in medically managed ACS patients.

ACS, acute coronary syndrome; b.i.d., bis in die; CAD, coronary artery disease; HBR, high bleeding risk; MI, myocardial infarction; OAC, oral anticoagulation; PCI, percutaneous coronary intervention.

Chronic coronary syndrome with prior (>12 months) myocardial infarction

Evidence-based treatment options are shown in Figure 4 and summary of evidence in the Supplemental material.

Figure 4

CCS with prior MI. Treatment options for CCS patients with prior MI (>12 months), depending on bleeding and ischaemic risks. For detailed consensus statements, see Table 6. Box colours indicate composition of antithrombotic regimens (light blue: SAPT; grey: DAPT; red: DAT). Abbreviations: CCS, chronic coronary syndrome; DAPT, dual antiplatelet therapy; DAT, dual antithrombotic therapy; MI, myocardial infarction; SAPT, single antiplatelet therapy.

Single antithrombotic therapy

Remote studies evaluated monotherapy with aspirin, clopidogrel, or warfarin in the context of CCS and prior MI are now historical. A 1994 meta-analysis showed that aspirin therapy, among ≈20 000 patients with a prior history of MI, reduced the odds of serious vascular events, defined as vascular death, MI, or stroke, by 25% as compared with no treatment.¹¹⁷ A wide range of aspirin dosing regimens were evaluated and proved equally effective. In a comparison of clopidogrel vs. aspirin in the CAPRIE trial, among 8446 (44%) patients with prior MI, the relative risk reduction of vascular death, MI, or ischaemic stroke was 7.4% (95% CI −5.2 to 18.6%) with clopidogrel.⁴⁶ In that trial, the presence of polyvascular disease was associated with an increased benefit from clopidogrel over aspirin. In the WARIS-II trial,⁷² though warfarin monotherapy showed benefit compared with aspirin in terms of a composite of death, non-fatal reinfarction, or thromboembolic cerebral stroke (RR 0.81, 95% CI 0.69–0.95), the warfarin strategy was associated with a four-fold higher annual rate of non-fatal major bleeding. In the more contemporary GLOBAL LEADERS trial (34% of patients with AMI at presentation and 23% of patients with prior MI before index procedure), ticagrelor monotherapy from 12 to 24 months after PCI was associated with borderline reduction of all-cause death or new Q-wave MI compared with aspirin.²⁹ A post-hoc landmark analysis of the GLOBAL LEADERS trial showed that ticagrelor monotherapy resulted in lower rates of the composite endpoint of all-cause death, any MI, or any stroke (HR 0.74, 95% CI 0.58–0.96), mainly driven by >40% lower MI risk at both unadjusted and adjusted analyses (HR 0.54, 95% CI 0.36–0.82).¹¹⁸ The benefits with ticagrelor were consistent in patients with or without ACS at index PCI (P for interaction = 0.22). The rates of major bleeding were significantly higher with ticagrelor in the adjusted analyses (HR 1.89, 95% CI 1.03–3.45) but not in the unadjusted analyses (HR 1.80, 95% CI 0.99–3.30) and derived entirely from patients with PRECISE DAPT < 25. In the Global Leaders Adjudication Substudy (GLASSY), an independent clinical event committee adjudicated investigator-reported and eventually unreported events of 7585 patients from the 20 top-enrolling participating sites. The 2-year co-primary efficacy endpoint occurred in 271 (7.14%) and in 319 (8.41%) patients in the experimental and conventional groups, respectively (RR 0.85, 95% CI 0.72–0.99; P for non-inferiority < 0.001; P for superiority = 0.0465).²⁸

A landmark analysis of GLASSY showed that MI risk was significantly reduced with ticagrelor compared with aspirin from 12 to 24 months after PCI (HR 0.54, 95% CI 0.33–0.88), with consistent findings in patients with or without ACS at presentation, whereas major bleeding did not differ.

In the recent HOST-EXAM trial, 5530 patients, mainly after ACS (72%), were randomized to stop DAPT after a median duration of 382 days and continue with aspirin or clopidogrel.⁹⁷ The composite of all-cause death, MI, stroke, readmission due to ACS or major bleeding was reduced with clopidogrel (HR 0.73, 95% CI 0.59–0.90), mainly due to lower rates of the last two primary endpoint components.⁹⁷

In the NMA, ticagrelor 90 mg monotherapy was associated with lower risk of MI (HR 0.54, 95% CI 0.32–0.92) compared with aspirin without higher bleeding risk.¹⁰²

Dual antithrombotic therapy

The benefit of DAPT (P2Y₁₂ inhibitor plus aspirin) or a combination of aspirin with oral anticoagulation beyond 1 year after ACS was investigated in 11 trials, but interpretation of the accumulated evidence remains controversial. Several studies (CHARISMA,¹⁶ DAPT,²¹ DES-LATE,²² ITALIC,³⁶ OPTIDUAL,⁴¹ PRODIGY,⁵⁰ and REAL-ZEST LATE⁵²) investigated the effectiveness of DAPT with clopidogrel, whereas only one trial tested DAPT using ticagrelor (PEGASUS-TIMI 54⁴⁴); prasugrel was tested in a subset of patients in a trial (DAPT study)²¹ (Supplemental material). One trial assessed a new oral anticoagulant (NOAC) in the management of CCS patients (COMPASS,¹⁷ rivaroxaban). LoWASA³⁸ and WARIS-II⁷² analysed an antiplatelet plus reduced-dose anticoagulant approach with coumadin.

The DAPT trial showed a significant reduction of stent thrombosis (HR 0.29, 95% CI 0.17–0.48) and major adverse cardiovascular and cerebrovascular events (HR 0.71, 95% CI 0.59–0.85) with DAPT compared with aspirin therapy alone.²¹ The DAPT trial did not report the net impact of ischaemic outcomes and major bleeding (summation of these events does not show net benefit), and the first-generation drug-eluting stents (DES) were largely used in this trial.²¹

In the PEGASUS-TIMI 54 trial, twice-daily treatment with ticagrelor 90 mg (HR 0.85, 95% CI 0.75–0.96) or 60 mg (HR 0.84, 95% CI 0.74–0.95) in addition to aspirin 1–3 years after an MI reduced the risk of cardiovascular death, MI, or stroke⁴⁴; however, the rates of major bleeding were more than two-fold higher with ticagrelor 90 mg (HR 2.69, 95% CI 1.96–3.70) or ticagrelor 60 mg (HR 2.32, 95% CI 1.68–3.21).⁴⁴ This therapeutic approach is justified for patients with a high ischaemic risk if at low risk of bleeding.

The data from the combination therapy of warfarin and aspirin should be interpreted with caution,^38,72 as NOACs have largely replaced warfarin, new generations of DES are routinely used, and the overall risk of coronary events has fallen in recent years.

The COMPASS trial assessed two strategies (rivaroxaban 2.5 mg b.i.d. plus aspirin or rivaroxaban 5 mg b.i.d. alone) compared with aspirin alone in patients with CCS and/or PAD (62% with a history of prior MI).¹⁷ Among patients with CAD, rivaroxaban 2.5 mg and aspirin significantly reduced major adverse cardiac events (HR 0.76, 95% CI 0.66–0.86) vs. aspirin alone, at the cost of significantly increased risk of major bleeding (HR 1.70, 95% CI 1.40–2.05). There was a favourable net clinical benefit (HR 0.80, 95% CI 0.70–0.91), and all-cause deaths were numerically lower (HR 0.82, 95% CI 0.71–0.96) with rivaroxaban and aspirin dual therapy vs. aspirin alone. Subgroup analysis showed similar results in CAD patients with or without a history of MI (P_interaction 0.93), irrespective of timing of prior MI. Patients with CAD and PAD had numerically higher absolute benefits from rivaroxaban and aspirin compared with aspirin alone. This trial showed no benefit of rivaroxaban 5 mg b.i.d. alone vs. aspirin alone.

In the NMA, the combination of aspirin and rivaroxaban 2.5 mg was associated with a large benefit for stroke reduction (HR 0.58, 95% CI 0.38–0.88) and ranked as the first treatment option for stroke prevention among the contemporary options to mitigate this endpoint.¹⁰²

Consensus statements endorsed by this document regarding antithrombotic therapy in CCS patients with prior (>12 months) MI are provided in Table 6.

Table 6

Clinical consensus statements for CCS with prior (>12 months) MI (no baseline indications for OAC)

Single antithrombotic therapy

Aspirin therapy decreases the risk of ischaemic events compared with no aspirin.

Based on both direct and indirect evidence (ref. NMA), ticagrelor 90 mg b.i.d. decreases the risk of MI compared with aspirin.

Clopidogrel provides net clinical benefit compared with aspirin.

Dual antithrombotic therapy

Long-term DAPT, including the combination of aspirin and clopidogrel or aspirin and ticagrelor 90 mg, has not provided evidence of net clinical benefit in comparison with aspirin.

Long-term DAPT with aspirin and ticagrelor 60 mg b.i.d. is a therapeutic option for non-HBR patients (e.g. no ARC-HBR criterion or PRECISE-DAPT < 25) who are deemed at increased risk of ischaemic events, especially recurrent MI.a

Following completion of DAPT, a dual antithrombotic regimen consisting of aspirin + rivaroxaban 2.5 mg b.i.d. is a therapeutic option for patients with high ischaemic riska who are non-HBR (e.g. no ARC-HBR criterion or PRECISE-DAPT < 2583) and is warranted especially among patients in whom the long-term risk of stroke prevails over the risk of recurrent MI, such as patients with prior stroke, or concomitant PAD or additional risk factors including diabetes, renal dysfunction, and heart failure, who did not experience recurrent coronary events over the last year(s).

ARC-HBR, Academic Research Consortium-high bleeding risk; b.i.d., bis in die; CCS, chronic coronary syndrome; DAPT, dual antiplatelet therapy, HBR, high bleeding risk; MI, myocardial infarction; OAC, oral anticoagulation.

^aHigh ischaemic risk is defined as diffuse multivessel CAD with at least one of the following: diabetes mellitus requiring medication, recurrent MI, peripheral arteria disease, or chronic kidney disease with estimated glomerular filtration rate 15–59 mL/min/1.73 m².

Chronic coronary syndrome managed by percutaneous coronary intervention without prior myocardial infarction

Evidence-based treatment options are shown in Figure 5 and summary of evidence in the Supplemental material.

Figure 5

CCS managed by PCI without prior MI. Treatment options for CCS patients managed by PCI, depending on bleeding and ischaemic risks. For detailed consensus statements, see Table 7. Box colours indicate composition of antithrombotic regimens (light blue: SAPT; grey: DAPT; red: DAT). § After 1–3 month(s) of DAPT, if aspirin is continued in non-high bleeding risk patients in prevision of adding rivaroxaban 2.5 mg b.i.d at a later time point, an earlier administration of rivaroxaban in combination with aspirin after DAPT cessation is reasonable. Abbreviations: b.i.d, bis in die; CCS, chronic coronary syndrome; DAPT, dual antiplatelet therapy; DAT, dual antithrombotic therapy; MI, myocardial infarction; PCI, percutaneous coronary intervention; SAPT, single antiplatelet therapy.

Single antithrombotic therapy

The SIDNEY-2 collaboration included 22 974 (99%) patients who underwent PCI and compared oral P2Y₁₂ monotherapy after a 1-to-3-month course of DAPT with DAPT continuation for at least 12 months.¹⁰⁰ A total of 9339 (40.1%) patients had CCS, 13 966 (59.9%) had ACS, and overall prior MI was noted in 19.0% of the population. The composite of all-cause death, MI, or stroke occurred with similar rates in patients allocated to P2Y₁₂ monotherapy or DAPT at 1 year among CCS patients, which was consistent with the treatment effect observed among ACS patients (P_interaction = 0.51). Results remained consistent when clopidogrel monotherapy or monotherapy with newer P2Y₁₂ inhibitors, consisting of ticagrelor in 99% of the patients, was compared with DAPT. P2Y₁₂ monotherapy was associated with consistently lower risk of BARC 3 or 5 bleeding among CCS (HR 0.72, 95% CI 0.48–1.07) or ACS (HR 0.40, 95% CI 0.29–0.54) patients (P_interaction = 0.057).¹⁰⁰ However, the use of clopidogrel monotherapy was investigated exclusively in Asian patients in whom the use of intravascular imaging modalities was high. Recently, the HOST-EXAM trial enrolled patients who maintained DAPT without clinical events for 6–18 months after PCI with DES. Patients were subsequently randomized to clopidogrel or aspirin monotherapy for 24 months. The study showed greater net benefit with clopidogrel than aspirin, mainly driven by lower rehospitalization for ACS and bleeding.⁹⁷ For long-term (>12 months) secondary prevention, the NMA suggests that ticagrelor (HR 0.54, 95% CI 0.32–0.92) but not clopidogrel monotherapy almost halved the risk of MI without a bleeding risk trade-off compared with aspirin monotherapy.¹⁰²

Dual antithrombotic therapy

Most trials of DAPT duration included a mixed population of patients (CCS and ACS presentations), and a variable proportion had prior MI. Multiple studies have compared a shorter vs. a longer DAPT regimen, including ISAR-SAFE,³³ ITALIC,³⁶ NIPPON,⁴⁰ OPTIMA-C,⁴² OPTIMIZE,⁴³ PRODIGY,⁵⁰ RESET,⁵⁴ SECURITY,⁵⁶ SMART CHOICE,⁵⁸ EXCELLENT,²⁵ OPTIDUAL,⁴¹ and DAPT.²¹ Overall, extended DAPT increased major bleeding about two-fold. In the DAPT trial (9961 patients), the benefits of reduced MI and stent thrombosis were approximately matched by the excess in major and fatal bleeding (the trend for excess mortality appears to be non-cardiovascular).²¹ Net benefit (cardiovascular death/MI/stroke and major bleeding) has not been shown for prolonged DAPT. In summary, prolonged DAPT after PCI for non-ACS patients may only be justified for a selected population who received complex intervention in whom the ischaemic outweighs the bleeding risks.

THEMIS compared ticagrelor vs. placebo in aspirin-treated diabetic patients without prior MI.⁶³ The primary endpoint (CV death, MI, or stroke) was marginally lower in ticagrelor-treated patients (HR 0.90, 95% CI 0.81–0.99). There was no difference in cardiovascular death, but there was excess TIMI-major bleeding (HR 2.32, 95% CI 1.82–2.94), and the calculation of irreversible harm did not show benefit for ticagrelor in the trial as a whole.

COMPASS included patients with chronic vascular disease (CCS and/or PAD) and markers of increased vascular risk.¹⁷ Rivaroxaban 2.5 mg b.i.d. plus aspirin significantly reduced the primary endpoint of CV death/MI/stroke (HR 0.76, 95% CI 0.66–0.86) compared with aspirin alone and demonstrated a net-clinical benefit (composite of CV death, MI, stroke, fatal bleeding, or symptomatic bleeding into a critical organ: HR 0.80, 95% CI 0.70–0.91). All-cause mortality was reduced using the nominal 0.05 statistical significance but did not meet the pre-defined alpha level of 0.0025 after correcting for multiplicity. In contrast to the findings with DAPT, the benefits seen with rivaroxaban were independent of prior MI. The patients that entered long-term trials of DAPT had tolerated DAPT without major bleeding complications. In contrast, patients in COMPASS had tolerated single antiplatelet therapy. Therefore, rivaroxaban 2.5 mg plus aspirin is an appealing treatment over aspirin alone in higher risk chronic vascular patients, independent of prior MI. These benefits have not been shown with full anticoagulation plus aspirin in patients with prior stenting,¹¹⁹ nor with rivaroxaban 5 mg without aspirin. It is unknown whether reduced dosage of other NOACs will show similar benefits. In the NMA, the combination of aspirin and rivaroxaban 2.5 mg was associated with a large benefit for stroke reduction (HR 0.58, 95% CI 0.38–0.88) and ranked as the first treatment option for stroke prevention among the contemporary options to mitigate this endpoint.¹⁰²

Consensus statements endorsed by this document regarding antithrombotic therapy in CCS patients treated with PCI (no prior MI) are provided in Table 7.

Table 7

Clinical consensus statements for CCS managed by PCI (no baseline indications for OAC)

Single antithrombotic therapy

Compared with 12-month DAPT, aspirin withdrawal after 1-to-3-month DAPT and continuation with P2Y12 inhibitor in the form of ticagrelor or clopidogrel monotherapy provides net benefit with reduced bleeding complications and similar risk of non-fatal or fatal ischaemic events.

Compared with ≥12-month DAPT, P2Y12 inhibitor withdrawal after 6-month DAPT and continuation of aspirin is associated with net benefit with reduced bleeding complications and similar risk of non-fatal or fatal ischaemic events.

Longer than 6-month DAPT duration remains justifiable in patients at high risk of recurrent ischaemic eventsa in whom the bleeding risk does not pose concerns.

Clopidogrel, after completion of DAPT, provides net clinical benefit compared with aspirin based on both direct and indirect comparisons.

The use of ticagrelor 90 mg b.i.d. monotherapy beyond 1 year is associated with lower risk of MI and similar bleeding compared with aspirin (based on direct and indirect comparisons).

Dual antithrombotic therapy

One-to-six-month DAPT followed by single antiplatelet therapy is the default approach following PCI. In HBR patients (e.g. ARC-HBR criteria or PRECISE-DAPT ≥ 2583), 1-month DAPT duration is warranted followed by single antiplatelet therapy.

Following completion of DAPT, the combination of aspirin and rivaroxaban 2.5 mg b.i.d. provides net clinical benefit in those with high ischaemic riska who do not have a high bleeding risk and is especially warranted for those deemed at high risk for stroke (unless they have an indication for higher-dose anticoagulation such as atrial fibrillation), such as patients with prior stroke, or concomitant PAD or additional risk factors including diabetes, renal dysfunction, and heart failure.

ARC-HBR, Academic Research Consortium-high bleeding risk; b.i.d., bis in die; CCS, chronic coronary syndrome; DAPT, dual antiplatelet therapy; HBR, high bleeding risk; MI, myocardial infarction; OAC, oral anticoagulation; PCI, percutaneous coronary intervention.

^aHigh ischaemic risk is defined as diffuse multivessel CAD with at least one of the following: diabetes mellitus requiring medication, recurrent MI, peripheral arteria disease, or chronic kidney disease with estimated glomerular filtration rate 15–59 mL/min/1.73 m².

Chronic coronary syndrome managed by coronary artery bypass grafting without prior myocardial infarction

Evidence-based treatment options are shown in Figure 6 and summary of evidence in the Supplemental material.

Figure 6

CCS managed by CABG or medical therapy alone (no prior MI). Treatment options for CCS patients managed by CABG, depending on bleeding risk. For detailed consensus statements, see Table 8. Box colours indicate composition of antithrombotic regimens (light blue: SAPT; red: DAT). Abbreviations: CABG, coronary artery bypass grafting; CCS, chronic coronary syndrome; DAT, dual antithrombotic therapy; MI, myocardial infarction; SAPT, single antiplatelet therapy.

Single and dual antithrombotic therapy

Focusing on graft patency as the primary endpoint, the majority of studies showed aspirin monotherapy to be effective and safe.^39,71,78 In contrast, DAPT studies included small study populations and reported heterogeneous results. Clopidogrel was associated with a lower risk of vascular death, MI or ischaemic stroke (HR 0.64, 95% CI 0.47–0.87) compared with aspirin in patients with prior CABG in the CAPRIE trial. The DACAB study, which assessed the effects of a combination of ticagrelor/aspirin on SVG patency, documented a significant increase in graft patency compared with aspirin alone (RR 0.48, 95% CI 0.31–0.74).²⁰ However, the results were not confirmed in the POPULAR CABG trial.¹²⁰ In the pre-specified COMPASS-CABG sub-study the combination of aspirin and rivaroxaban 2.5 mg b.i.d. did not affect graft patency compared with aspirin alone, but the treatment effect on reducing CV death/MI/stroke was consistent with the benefits shown in COMPASS overall.¹²¹

Consensus statements endorsed by this document regarding antithrombotic therapy in CCS patients treated with CABG (no prior MI) are provided in Table 8.

Table 8

Clinical consensus statements for CCS managed by CABG (no baseline indications for OAC)

Single antithrombotic therapy

Clopidogrel provides net benefit compared with aspirin.

The evidence for ticagrelor monotherapy is inconclusive.

Dual antithrombotic therapy

The benefits for DAPT after CABG have not been demonstrated.

The effect of aspirin and ticagrelor compared with aspirin monotherapy for preserving bypass patency remains unclear.

The combination of rivaroxaban 2.5 mg b.i.d. and aspirin, compared with aspirin monotherapy, is associated with lower ischaemic and higher bleeding risks and is therefore a reasonable treatment in patients in whom concerns over ischaemic events prevail over bleeding.

The combination of rivaroxaban 2.5 mg b.i.d. and aspirin compared with aspirin monotherapy has not been shown to preserve graft patency.

b.i.d., bis in die; CABG, coronary artery bypass grafting; CCS, chronic coronary syndrome; DAPT, dual antiplatelet therapy; MI, myocardial infarction; OAC, oral anticoagulation.

Chronic coronary syndrome managed by medical therapy alone without prior myocardial infarction

Evidence-based treatment options are shown in Figure 6 and summary of evidence in the Supplemental material.

Single antithrombotic therapy

The SAPAT trial supports the use of low-dose aspirin in symptomatic patients with stable angina who do not have a history of prior MI.⁵⁵ It is uncertain whether aspirin provides net benefit in lower risk CCS patients, such as those with incidental detection of non-obstructive CAD on imaging. Although the evidence is inconclusive, it is reasonable to use clopidogrel in CCS patients who are intolerant of aspirin on the basis of the CAPRIE trial⁴⁶ and experience in patients with prior MI. Based on the same trial, the coexistence of PAD in these patients would then prioritize clopidogrel over aspirin if single antiplatelet therapy is considered rather than dual antithrombotic therapy. Rivaroxaban 5 mg b.i.d did not reduce the composite of CV death, MI, and stroke compared with aspirin monotherapy and was associated with greater bleeding risk (HR 1.51, 95% CI 1.25–1.84).¹⁷

Dual antithrombotic therapy

A DAPT regimen consisting of aspirin and clopidogrel has not proved more beneficial than aspirin alone in this population, whereas results appeared more favourable with DAPT among patients with prior MI (CHARISMA¹⁶). In the THEMIS trial, among the 20% of medically managed patients, there was no evidence of benefit or net benefit with aspirin and ticagrelor compared with aspirin alone.⁶³ Rivaroxaban 2.5 mg plus aspirin significantly reduced the risk of CV death, MI, or stroke (HR 0.76, 95% CI 0.66–0.86), principally driven by reduced stroke,¹⁷ and a significant net benefit was shown (HR 0.80, 95% CI 0.70–0.91).¹⁷ Total mortality was reduced at a nominal P-value of 0.05, even if it did not reach predefined statistical significance. Findings were independent of the presence of prior MI.

Consensus statements endorsed by this document regarding antithrombotic therapy in CCS patients treated with medical therapy alone (no prior MI) are provided in Table 9.

Table 9

Clinical consensus statements for CCS managed by medical therapy alone (no baseline indications for OAC)

Single antithrombotic therapy

Clopidogrel or alternatively aspirin monotherapy is warranted in symptomatic patients although the net benefit is uncertain in asymptomatic patients.

Rivaroxaban 5 mg b.i.d. monotherapy does not seem to provide benefit and confers a higher bleeding risk compared with aspirin monotherapy.

Dual antithrombotic therapy

The current evidence does not support the use of DAPT.

Long-term dual antithrombotic therapy (rivaroxaban 2.5 mg b.i.d. plus aspirin) provides net benefit in patients at high ischaemic riska and low bleeding risk (e.g. no ARC-HBR criterion or PRECISE-DAPT < 2583).

ARC-HBR, Academic Research Consortium-high bleeding risk; b.i.d., bis in die; CCS, chronic coronary syndrome; DAPT, dual antiplatelet therapy; MI, myocardial infarction; OAC, oral anticoagulation.

a

High ischaemic risk is defined as diffuse multivessel CAD with at least one of the following: diabetes mellitus requiring medication, recurrent MI, peripheral arteria disease, or chronic kidney disease with estimated glomerular filtration rate 15–59 mL/min/1.73 m².

Genotype- and phenotype-guided DAPT

In the POPULAR GENETICS trial,¹²² including patients undergoing primary PCI, a CYP2C19 genotype-guided strategy for selection of the P2Y₁₂ inhibitor was non-inferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to a composite of thrombotic and bleeding events (P-value for non-inferiority < 0.001) and reduced the incidence of mostly minor bleeding (HR 0.78, 95% CI 0.61–0.98). However, a prior genetic sub-study of PLATO suggested superiority of ticagrelor over clopidogrel irrespective of the presence or absence of CYP2C19 loss-of-function alleles.¹²³ Conversely, among CYP2C19 loss-of-function allele carriers with ACS or CCS undergoing PCI, genotype-guided selection of DAPT did not reduce the incidence of combined thrombotic events compared with conventional clopidogrel therapy without point-of-care genotyping in patients with ACS and those with CCS.⁶¹

Despite initial promising data from observational¹²⁴ and small randomized studies,^125–128 no adequately powered randomized clinical trial demonstrated that the routine use of platelet function testing for guiding P2Y₁₂ inhibitor treatment improves clinical outcomes in patients with ACS or CCS undergoing PCI.^30,35,69,129 In the TROPICAL-ACS study, a guided de-escalation of antiplatelet treatment using platelet function testing was non-inferior to standard treatment with prasugrel at 1 year after PCI in terms of net clinical benefit.⁶⁹ Although the results of meta-analysis show favourable safety and efficacy outcomes associated with a guided selection of antiplatelet therapy by means of platelet function or genetic testing,¹³⁰ it remains unclear if these findings are reproducible outside the research setting, considering that routine use of platelet function testing for tailoring DAPT is not implemented in clinical practice.¹³¹

Consensus statements endorsed by this document regarding genotype- and phenotype-guided DAPT are provided in Table 10.

Table 10

Clinical consensus statements for genotype-/phenotype-guided dual antiplatelet therapy

Genotype-based guidance

The current evidence does not support the routine selection of P2Y12 receptor inhibitor treatment based on rapid genotype testing (e.g. de-escalation from prasugrel or ticagrelor to clopidogrel in non-carriers of loss-of-function alleles).

Phenotype-based guidance

The current evidence does not support the routine use of platelet function testing to guide antiplatelet therapy.

Funding

None.

Disclaimer

In view of the short time interval between publication of the final version of this manuscript and the expected publication of the [2023 ACS Guidelines], which will largely overlap with the topics in this manuscript, EAPCI, ACVC and EAPC have decided that the manuscript will be published without the document subtitle of the unedited manuscript.

Relationship with industries and other entities

The views expressed in this manuscript are those of the authors and do not reflect the positions of the European Society of Cardiology nor its Associations. M.V. reports grants and/or personal fees from AstraZeneca, Terumo, Alvimedica/CID, Abbott Vascular, Daiichi Sankyo, Bayer, CoreFLOW, Idorsia Pharmaceuticals Ltd, Universität Basel Department Klinische Forschung, Vifor, Bristol Myers Squib SA, Biotronik, Boston Scientific, Medtronic, Vesalio, Novartis, Chiesi, and PhaseBio, outside the submitted work. V.A. reports speakers honoraria from Amgen, Novartis, and Pfizer and is consultant/advisory board for Bayer Healthcare, Novo Nordisk, Sanofi, AstraZeneca, Boehringer Ingelheim, and BMS, outside the submitted work. D.J.A. declares that he has received consulting fees or honoraria from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company and has received payments for participation in review activities from CeloNova and St Jude Medical, outside the present work. D.J.A. also declares that 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. D.C. declares that he has received consulting and speaking fees from Amgen, Boehringer Ingelheim, Biotronik, Daiichi Sankyo, and sanofi-aventis outside the present work. S.H. has received speaking fees from Boehringer Ingelheim, BMS, Pfizer, and Sanofi, outside the submitted work. S.J. reported grants from AstraZeneca outside the submitted work. P.J. serves as an unpaid steering committee member of trials funded by Abbott Vascular, AstraZeneca, Biotronik, Biosensors, St Jude Medical, Terumo, and The Medicines Company; receives institutional research grants from Appili Therapeutics, AstraZeneca, Biotronik, Biosensors International, Eli Lilly, and The Medicines Company; and receives institutional honoraria for participation in advisory boards or consulting from Amgen, Ava, and Fresenius, but has not received personal payments by any pharmaceutical company or device manufacturer. V.K. has received personal fees/honoraria from Bayer, AstraZeneca, Abbott, Amgen, and Daiichi Sankyo, all outside the submitted work. S.L. reports grants and personal fees from AstraZeneca, Daiichi Sankyo, Bayer, Pfizer/BMS, ICON, Chiesi, and Novo Nordisk, all outside the submitted work. R.M. reports institutional research grants from Abbott, Abiomed, Applied Therapeutics, Arena, AstraZeneca, Bayer, Biosensors, Boston Scientific, Bristol Myers Squibb, CardiaWave, CellAegis, CERC, Chiesi, Concept Medical, CSL Behring, DSI, Insel Gruppe AG, Medtronic, Novartis Pharmaceuticals, OrbusNeich, Philips, Transverse Medical, and Zoll; personal fees from ACC, Boston Scientific, California Institute for Regenerative Medicine (CIRM), Cine-Med Research, Janssen, WebMD, and SCAI; consulting fees paid to the institution from Abbott, Abiomed, AM-Pharma, Alleviant Medical, Bayer, Beth Israel Deaconess, CardiaWave, CeloNova, Chiesi, Concept Medical, DSI, Duke University, Idorsia Pharmaceuticals, Medtronic, Novartis, and Philips; equity,1% in Applied Therapeutics, Elixir Medical, STEL, and CONTROLRAD (spouse); Scientific Advisory Board for AMA and Biosensors (spouse), all outside the submitted work. G.M. reports institutional research funds or fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cell Prothera, CSL Behring, Europa, Idorsia, IRIS-Servier, Medtronic, MSD, Novartis, Pfizer, Quantum Genomics, and Sanofi, outside the submitted work. E.P.N. reports research grants from Abbott and Amgen and lecture fees/honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron, outside the submitted work.

R.F.S. reports institutional research grants/support from AstraZeneca, Cytosorbents, and GlyCardial Diagnostics; consultancy fees from AstraZeneca, Bayer, Bristol Myers Squibb/Pfizer, CSL Behring, Cytosorbents, GlyCardial Diagnostics, Hengrui, Idorsia, Novartis, PhaseBio, Portola, sanofi-aventis, and Thromboserin; and honoraria from AstraZeneca, Bayer, Bristol Myers Squibb/Pfizer, Intas Pharmaceuticals, and Medscape, all outside the submitted work. P.V. reports personal fees from Bayer, personal fees from Daiichi Sankyo, and personal fees from CLS Behring, outside the submitted work. S.W. reports research and 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 & Dohm, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pfizer, Polares, Regeneron, sanofi-aventis, Servier, Sinomed, Terumo, Vifor, and V-Wave. S.W. serves as an unpaid advisory board member and/or unpaid 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, but has not received personal payments by pharmaceutical companies or device manufacturers. He is also a member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. K.A.A.F. has received grants and personal fees from Bayer/Janssen and AstraZeneca and personal fees from Sanofi/Regeneron and Verseon, outside the submitted work.

The other authors report no relationships relevant to the contents of this paper to disclose.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

Author notes

Twitter handles: @vlgmrc (Marco Valgimigli)

Twitter handles: @antoniolandii (Antonio Landi)

Twitter handles: @DFCapodanno (Davide Capodanno)

Twitter handles: @Drroxmehran (Roxana Mehran)

Twitter handles: @elianonavarese (Eliano Navarese).