Background: The clinical presentation of coronary artery disease can range from asymptomatic, through stable disease in the form of chronic coronary syndrome, to acute coronary syndrome. Chronic coronary syndrome is a frequent condition, and secondary prevention of ischaemic events is essential. Summary: Antithrombotic therapy is a key component of secondary prevention strategies, and it may vary in type and intensity depending on patient characteristics, comorbidities, and revascularisation modalities. Dual antiplatelet therapy is the default strategy in patients with chronic coronary syndrome and recent coronary stent implantation, while antiplatelet monotherapy is commonly prescribed for long-term prevention of cardiovascular events. Oral anticoagulation, in combination with antiplatelet therapy or alone, is used in patients with, e.g., concomitant atrial fibrillation or venous thromboembolism. Key Messages: This review provides an overview of antithrombotic treatment strategies in patients with chronic coronary syndrome. Key messages from current guidelines are conveyed, and we provide future perspectives on long-term antithrombotic strategies.

Coronary artery disease (CAD) is primarily caused by the deposition of atherosclerotic plaques in the coronary arteries. The nature of CAD is dynamic, ranging from asymptomatic to acute coronary syndrome (ACS) or established stable disease in the form of chronic coronary syndrome (CCS) [1]. In practice, CCS spans a wide spectrum of possible clinical presentations (Table 1). The diagnosis of CCS is a stepwise process based on clinical presentation, symptom evaluation, and the presence of modifiable as well as non-modifiable risk factors, including smoking, diabetes, hypertension, dyslipidaemia, age, sex, and family history of CAD [2]. The diagnostic process is supported by laboratory tests (lipid profile, glycated haemoglobin, glomerular filtration rate, and haemoglobin), resting electrocardiogram, and echocardiographic evaluation of left ventricular function and regional wall motion abnormalities suggestive of CAD. In patients with an increased likelihood of CAD, coronary imaging or, less frequently, stress testing is indicated. Most often, non-invasive imaging modalities such as coronary computed tomography angiography are recommended, while primary invasive coronary angiography is only recommended in patients with a high probability of CAD [1, 3].

Table 1.

Presentations of CCS in clinical practice according to ESC Guidelines [1]

Suspected CAD and “stable” anginal symptoms and/or dyspnoea 
II New onset of heart failure or left ventricular dysfunction and suspected CAD 
III Asymptomatic or symptomatic patients with stabilised symptoms <1 year after ACS or recent revascularisation 
IV Asymptomatic and symptomatic patients >1 year after initial diagnosis or recent revascularisation 
Patients with angina and suspected vasospastic or microvascular disease 
VI Asymptomatic subjects in whom CAD is detected at screening 
Suspected CAD and “stable” anginal symptoms and/or dyspnoea 
II New onset of heart failure or left ventricular dysfunction and suspected CAD 
III Asymptomatic or symptomatic patients with stabilised symptoms <1 year after ACS or recent revascularisation 
IV Asymptomatic and symptomatic patients >1 year after initial diagnosis or recent revascularisation 
Patients with angina and suspected vasospastic or microvascular disease 
VI Asymptomatic subjects in whom CAD is detected at screening 

ACS, acute coronary syndrome; CAD, coronary artery disease; CCS, chronic coronary syndrome; ESC, European Society of Cardiology.

Lifestyle modification and medical treatment both play a crucial role in reducing the risk of cardiovascular events and relieving anginal symptoms. Guideline-directed medical treatment includes anti-ischaemic drugs (e.g., β-blockers, calcium channel blockers, and long-acting nitrates) and antithrombotic drugs [4]. In patients undergoing elective revascularisation with percutaneous coronary intervention (PCI), dual antiplatelet therapy (DAPT) consisting of aspirin and clopidogrel is usually prescribed for 6 months as the standard approach, although this duration may be shortened (up to 1 month) or prolonged (>1 year) depending on the estimated risk of bleeding and ischaemic events. For decades, single antiplatelet therapy with aspirin has been the cornerstone of long-term antithrombotic treatment in patients with CAD. However, based on recent evidence from clinical trials and meta-analyses, novel antithrombotic strategies for secondary prevention have emerged as valid alternatives. In addition, specific considerations should be made for patients with atrial fibrillation or other medical conditions requiring chronic oral anticoagulation. This review provides a comprehensive overview of antithrombotic treatment in the setting of CCS.

Antithrombotic treatment with platelet inhibitors is essential in patients with CCS, whether or not they have undergone coronary revascularisation (Fig. 1). The type and duration of antithrombotic treatment depends on several factors, including patient comorbidity and procedure-related factors (Table 2). Focussing on mechanisms of action, the paragraphs below summarise key pharmacological information on the most frequently used antithrombotic drugs.

Fig. 1.

Key antiplatelet and anticoagulant pharmacological mechanisms of action. AA, arachidonic acid; ADP, adenosine diphosphate; PAR-4, protease-activated receptor 4; TXA2, thromboxane A2. (Created with BioRender.com)

Fig. 1.

Key antiplatelet and anticoagulant pharmacological mechanisms of action. AA, arachidonic acid; ADP, adenosine diphosphate; PAR-4, protease-activated receptor 4; TXA2, thromboxane A2. (Created with BioRender.com)

Close modal
Table 2.

Antithrombotic treatment of CCS according to risk and comorbidity [1]

Type of patientChoice of drugDosageDuration of treatment
Sinus rhythm Aspirina 75–100 mg q.d. Lifelong 
Sinus rhythm + moderate/high ischaemic risk without a high bleeding risk Aspirin plus rivaroxabanb, cor ticagrelor b 75–100 mg q.d. Lifelong 
2.5 mg b.i.d. 
60 mg b.i.d. 
Sinus rhythm + PCI Aspirin plus clopidogreld 75–100 mg q.d. Lifelong 
75 mg q.d. 6 months 
AFib, mechanical heart valve, VTE, or other reason for OAC DOAC/VKAe −/−f Lifelongg 
Afib, mechanical heart valve, VTE, or other reason for OAC + PCI Aspirinhplus clopidogrel plus DOAC/VKAe 75–100 mg q.d. Up to 1 month 
75 mg q.d. 6 months 
−/−f Lifelong 
AFib, mechanical heart valve, VTE, or other reason for OAC + CABG Aspirin/clopidogrel plus DOAC/VKAe 75 mg q.d 6 months 
−/−f Lifelong 
Type of patientChoice of drugDosageDuration of treatment
Sinus rhythm Aspirina 75–100 mg q.d. Lifelong 
Sinus rhythm + moderate/high ischaemic risk without a high bleeding risk Aspirin plus rivaroxabanb, cor ticagrelor b 75–100 mg q.d. Lifelong 
2.5 mg b.i.d. 
60 mg b.i.d. 
Sinus rhythm + PCI Aspirin plus clopidogreld 75–100 mg q.d. Lifelong 
75 mg q.d. 6 months 
AFib, mechanical heart valve, VTE, or other reason for OAC DOAC/VKAe −/−f Lifelongg 
Afib, mechanical heart valve, VTE, or other reason for OAC + PCI Aspirinhplus clopidogrel plus DOAC/VKAe 75–100 mg q.d. Up to 1 month 
75 mg q.d. 6 months 
−/−f Lifelong 
AFib, mechanical heart valve, VTE, or other reason for OAC + CABG Aspirin/clopidogrel plus DOAC/VKAe 75 mg q.d 6 months 
−/−f Lifelong 

AFib, atrial fibrillation; b.i.d., twice daily; CABG, coronary artery bypass grafting; CCS, chronic coronary syndrome; DOAC, direct oral anticoagulant; q.d., once daily; OAC, oral anticoagulants; PCI, percutaneous coronary intervention; VKA, vitamin K antagonist; VTE, venous thromboembolism.

aClopidogrel if contraindication for aspirin.

bTreatment duration is decided by cardiologist.

cOne year after myocardial infarction or if multivessel coronary artery disease.

dPrasugrel or ticagrelor may be used as alternatives. Duration can be prolonged if high ischaemic risk.

ePatients with a mechanical heart valve, moderate to severe mitral stenosis, or severe renal insufficiency are treated with VKA.

fDose depends on choice of drug and INR (if treated with VKA).

gDuration depends on indication for OAC.

hCan be omitted if high bleeding risk.

Aspirin

Aspirin irreversibly blocks the cyclooxygenase-1 enzyme and thereby inhibits the conversion of arachidonic acid to thromboxane A2, which causes platelet activation/aggregation and vasoconstriction [5]. In patients with CAD, aspirin is commonly prescribed at low doses (75–100 mg), given its similar efficacy and better safety than high-dose regimens [6].

P2Y12 Inhibitors

P2Y12 inhibitors prevent platelet aggregation by antagonising the binding of adenosine diphosphate to the P2Y12 receptor. Contemporary oral P2Y12 inhibitors are clopidogrel, prasugrel, and ticagrelor. Clopidogrel and prasugrel are thienopyridine prodrugs that cause irreversible blockage of the P2Y12 receptor once activated, whereas ticagrelor exhibits direct reversible binding to the P2Y12 receptor [7]. Pharmacodynamic studies have shown some variability in inter-individual response to clopidogrel related to genetic and non-genetic factors; conversely, the newer, more potent P2Y12 inhibitors prasugrel and ticagrelor have a more predictable antiplatelet effect, which translates into a greater reduction in atherothrombotic events [8].

Clopidogrel is consistently prescribed at 75 mg once daily. The standard dose of prasugrel (which is not indicated in patients with CCS) is 10 mg once daily, but this maintenance dose should be reduced to 5 mg daily in patients ≥75 years of age or with a body weight <60 kg [9]. Ticagrelor is prescribed at 90 mg twice daily for up to 1 year in patients with ACS, while continued treatment after 1 year with a dose of 60 mg twice daily may be considered and, thus, may be used in some CCS patients with previous ACS [10]. Due to safety concerns, treatment with prasugrel is contraindicated in patients with previous stroke, transient ischaemic attack, or intracranial haemorrhage, whereas ticagrelor is contraindicated in patients with previous intracranial haemorrhage [11].

Anticoagulant Drugs

Direct oral anticoagulants (DOACs) inhibit activated factor X (rivaroxaban, apixaban, and edoxaban) or thrombin (dabigatran), whereas vitamin K antagonists (VKAs) inhibit the formation of vitamin K-dependent coagulation factors II, VII, IX, and X.

The risk of recurrent ischaemic events is particularly high in CCS patients with previous MI, stroke, multivessel CAD, peripheral arterial disease (PAD), older age, and comorbidities such as diabetes mellitus and chronic kidney disease [12]. Several tools have been proposed to provide a standardised definition of high ischaemic risk. The DAPT score is a risk stratification model to identify patients who may benefit from prolonged DAPT treatment beyond 12 months following revascularisation. The DAPT score, which was derived and validated based on the randomised DAPT study [13], includes nine procedural and clinical variables that are readily available in practice and can assist clinical decision-making [14].

The European Society of Cardiology (ESC) guidelines recently proposed several high-risk elements for stent-related recurrent events in PCI patients, including clinical features (e.g., chronic kidney disease, previous stent thrombosis), coronary anatomy (e.g., multivessel disease, complex lesions), and procedural factors (e.g., ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, chronic total occlusion, stenting of the last remaining patent coronary artery) [15]. These criteria were recently validated in a large PCI registry of patients with ACS and CCS, confirming their ability to stratify the risk of ischaemic cardiovascular events, but their overall predictive accuracy was modest, suggesting the need for improved tools to select patients who may benefit from extended DAPT duration [16].

The risk of bleeding after PCI can be estimated using risk scores or algorithms developed to guide the duration of DAPT. The Predicting Bleeding Complication in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score estimates the risk of spontaneous bleeding based on 5 items (age, creatinine clearance, haemoglobin, white blood cell count, and previous spontaneous bleeding) [17]. This score uses a cut-off of 25 points to identify patients at high bleeding risk who may benefit from a short DAPT duration. The PRECISE-DAPT score was derived from 8 multicentre randomised clinical trials and has been externally validated in large cohorts of PCI patients from randomised trials [18] and real-world registries [19], demonstrating reasonable discrimination and calibration.

Recently, the Academic Research Consortium for High Bleeding Risk (ARC-HBR) has proposed a set of clinical and laboratory risk criteria to standardise the definition of high bleeding risk patients undergoing PCI [20]. This framework, which requires the presence of 1 major criterion or ≥2 minor criteria to define high bleeding risk, has also been validated in a large population of patients undergoing PCI for CCS, showing good predictive ability [21].

Lifelong antiplatelet monotherapy with aspirin is recommended as a first-line strategy in patients with CCS (e.g., previous MI or remote revascularisation), and current guidelines also recommend clopidogrel monotherapy as a possible alternative to aspirin in patients with aspirin intolerance or in those with either PAD or cerebrovascular disease [1]. In CCS patients undergoing PCI, DAPT with aspirin and a P2Y12 inhibitor (preferably clopidogrel) is recommended with a standard duration of 6 months, although the DAPT phase may be shortened (to 1 month) or prolonged (>1 year) depending on the individual patient’s risk of bleeding or ischaemic complications [1]. In patients undergoing surgical revascularisation by coronary artery bypass grafting, aspirin monotherapy is recommended after the procedure (Table 2). Current recommendations for DAPT treatment are based on the trials outlined below (Table 3). Alternatively, long-term treatment with aspirin and low-dose rivaroxaban (dual pathway inhibition, DPI) may be considered in CCS patients at high risk of ischaemic events (Table 4).

Table 3.

Studies investigating DAPT or DPI and risk of ischaemic events in patients with CCS

TrialYearStudy populationSettingTreatmentFollow-upPrimary endpointResults
CHARISMA [222006 15,603 Patients with atherothrombotic risk factors, CCS, cerebrovascular disease, or PAD Clopidogrel 75 mg + aspirin versus placebo + aspirin 28 months Death, MI, or stroke Clopidogrel + aspirin versus placebo + aspirin: RR 0.93 95% CI [0.83–1.05] 
DAPT [132014 9,961 Patients treated with PCI with DES who completed 1 year of DAPT Aspirin + clopidogrel or prasugrel versus aspirin + placebo 33 months Stent thrombosis, major cardiac or cerebrovascular events (death, MI, stroke) Stent thrombosis: HR 0.29; 95% CI [0.17–0.48] 
Major cardiac or cerebrovascular events: HR 0.71; 95% CI [0.59–0.85] 
PEGASUS-TIMI 54 [102015 21,162 Patients with prior MI 1–3 years before inclusion Aspirin + ticagrelor 90 mg b.i.d. versus aspirin + ticagrelor 60 mg b.i.d. versus aspirin + placebo 33 months CV death, MI, or stroke Ticagrelor 90 mg versus placebo: HR 0.85; 95% CI [0.75–0.96] 
Ticagrelor 60 mg versus placebo: HR 0.84; 95% CI [0.74–0.95] 
COMPASS [232017 27,395 Patients with stable vascular disease (CCS and/or PAD Rivaroxaban 2.5 mg b.i.d. + aspirin versus rivaroxaban 5 mg b.i.d. versus aspirin 100 mg q.d 23 months CV death, MI, or stroke Rivaroxaban + aspirin versus aspirin: HR 0.76; 95% CI [0.66–0.86] 
Rivaroxaban versus aspirin: HR 0.90; 95% CI [0.79–1.03] 
GLOBAL LEADERS [242018 15,968 Patients with CCS or ACS undergoing PCI Aspirin + ticagrelor 90 mg b.i.d. for 1 month and monotherapy with ticagrelor for 23 months versus standard DAPT for 12 months followed by monotherapy with aspirin for 12 months 24 months All-cause mortality, or new Q-wave myocardial infarction Experimental versus control group: RR 0.87; 95% CI [0.75–1.01] 
THEMIS [112019 19,220 Patients with CCS and type 2 diabetes Aspirin + ticagrelor 60 mg b.i.d. versus aspirin + placebo 40 months CV death, MI, or stroke Ticagrelor versus placebo: HR 0.90; 95% CI [0.81–0.99] 
THEMIS-PCI [252019 11,154 Patients with CCS (58% with previous PCI) and type 2 diabetes Aspirin + ticagrelor 60 mg b.i.d. versus aspirin + Placebo 40 months CV death, MI, or stroke Ticagrelor versus placebo: HR 0.85; 95% CI [0.74–0.97] 
TWILIGHT [262019 7,119 Patients undergoing PCI and completing 3 months of DAPT Ticagrelor 90 mg b.i.d. + placebo versus ticagrelor 90 mg b.i.d. + aspirin 15 months BARC type 2, 3, or 5 bleeding Bleeding: HR 0.56; 95% CI [0.45–0.68] 
Death from any cause, non-fatal MI or non-fatal stroke Death, MI, or stroke: HR 0.99; 95% CI [0.78–1.25] 
STOPDAPT-2 [272019 3,009 Patients with CCS or ACS undergoing PCI 1-month DAPT followed by clopidogrel monotherapy versus standard DAPT for 12 months (aspirin + clopidogrel) 12 months CV death, MI, stroke, stent thrombosis, or major or minor bleeding At 12 months' follow-up, 1 months DAPT versus standard: HR 0.64; 95% Cl [0.42–0.98] 
SMART-CHOICE [282019 2,993 Patients undergoing PCI with drug-eluting stents Aspirin + P2Y12 inhibitor for 3 months, thereafter monotherapy with P2Y12 inhibitor versus DAPT for 12 months 12 months All-cause death, MI, stroke Between 3 and 12 months, DAPT for 3 months and thereafter monotherapy with P2Y12 inhibitor versus standard DAPT: HR 1.14; 95% Cl [0.67–1.93] 
COMPASS-PCI [292020 9,862 Patients with stable vascular disease and history of PCI Rivaroxaban 2.5 mg b.i.d. + aspirin versus aspirin 100 mg q.d 23 months CV death, MI, or stroke Rivaroxaban + aspirin versus aspirin in patients with history of PCI: HR 0.74; 95% CI [0.61–0.88] 
TrialYearStudy populationSettingTreatmentFollow-upPrimary endpointResults
CHARISMA [222006 15,603 Patients with atherothrombotic risk factors, CCS, cerebrovascular disease, or PAD Clopidogrel 75 mg + aspirin versus placebo + aspirin 28 months Death, MI, or stroke Clopidogrel + aspirin versus placebo + aspirin: RR 0.93 95% CI [0.83–1.05] 
DAPT [132014 9,961 Patients treated with PCI with DES who completed 1 year of DAPT Aspirin + clopidogrel or prasugrel versus aspirin + placebo 33 months Stent thrombosis, major cardiac or cerebrovascular events (death, MI, stroke) Stent thrombosis: HR 0.29; 95% CI [0.17–0.48] 
Major cardiac or cerebrovascular events: HR 0.71; 95% CI [0.59–0.85] 
PEGASUS-TIMI 54 [102015 21,162 Patients with prior MI 1–3 years before inclusion Aspirin + ticagrelor 90 mg b.i.d. versus aspirin + ticagrelor 60 mg b.i.d. versus aspirin + placebo 33 months CV death, MI, or stroke Ticagrelor 90 mg versus placebo: HR 0.85; 95% CI [0.75–0.96] 
Ticagrelor 60 mg versus placebo: HR 0.84; 95% CI [0.74–0.95] 
COMPASS [232017 27,395 Patients with stable vascular disease (CCS and/or PAD Rivaroxaban 2.5 mg b.i.d. + aspirin versus rivaroxaban 5 mg b.i.d. versus aspirin 100 mg q.d 23 months CV death, MI, or stroke Rivaroxaban + aspirin versus aspirin: HR 0.76; 95% CI [0.66–0.86] 
Rivaroxaban versus aspirin: HR 0.90; 95% CI [0.79–1.03] 
GLOBAL LEADERS [242018 15,968 Patients with CCS or ACS undergoing PCI Aspirin + ticagrelor 90 mg b.i.d. for 1 month and monotherapy with ticagrelor for 23 months versus standard DAPT for 12 months followed by monotherapy with aspirin for 12 months 24 months All-cause mortality, or new Q-wave myocardial infarction Experimental versus control group: RR 0.87; 95% CI [0.75–1.01] 
THEMIS [112019 19,220 Patients with CCS and type 2 diabetes Aspirin + ticagrelor 60 mg b.i.d. versus aspirin + placebo 40 months CV death, MI, or stroke Ticagrelor versus placebo: HR 0.90; 95% CI [0.81–0.99] 
THEMIS-PCI [252019 11,154 Patients with CCS (58% with previous PCI) and type 2 diabetes Aspirin + ticagrelor 60 mg b.i.d. versus aspirin + Placebo 40 months CV death, MI, or stroke Ticagrelor versus placebo: HR 0.85; 95% CI [0.74–0.97] 
TWILIGHT [262019 7,119 Patients undergoing PCI and completing 3 months of DAPT Ticagrelor 90 mg b.i.d. + placebo versus ticagrelor 90 mg b.i.d. + aspirin 15 months BARC type 2, 3, or 5 bleeding Bleeding: HR 0.56; 95% CI [0.45–0.68] 
Death from any cause, non-fatal MI or non-fatal stroke Death, MI, or stroke: HR 0.99; 95% CI [0.78–1.25] 
STOPDAPT-2 [272019 3,009 Patients with CCS or ACS undergoing PCI 1-month DAPT followed by clopidogrel monotherapy versus standard DAPT for 12 months (aspirin + clopidogrel) 12 months CV death, MI, stroke, stent thrombosis, or major or minor bleeding At 12 months' follow-up, 1 months DAPT versus standard: HR 0.64; 95% Cl [0.42–0.98] 
SMART-CHOICE [282019 2,993 Patients undergoing PCI with drug-eluting stents Aspirin + P2Y12 inhibitor for 3 months, thereafter monotherapy with P2Y12 inhibitor versus DAPT for 12 months 12 months All-cause death, MI, stroke Between 3 and 12 months, DAPT for 3 months and thereafter monotherapy with P2Y12 inhibitor versus standard DAPT: HR 1.14; 95% Cl [0.67–1.93] 
COMPASS-PCI [292020 9,862 Patients with stable vascular disease and history of PCI Rivaroxaban 2.5 mg b.i.d. + aspirin versus aspirin 100 mg q.d 23 months CV death, MI, or stroke Rivaroxaban + aspirin versus aspirin in patients with history of PCI: HR 0.74; 95% CI [0.61–0.88] 

ACS, acute coronary syndrome; BARC, Bleeding Academic Research Consortium; b.i.d., twice daily; CI, confidence interval; CCS, chronic coronary syndrome; CV, cardiovascular; DAPT, dual antiplatelet therapy; DPI, dual pathway inhibition; HR, hazard ratio; MI, myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; PFT, platelet function test; q.d., once daily; RR, relative risk.

Table 4.

Antithrombotic strategies beyond 6 months following PCI in patients with CCS according to ESC Guidelines on CCS [15]

Class of recommendationLevel of evidenceTreatment optionIschaemic riskDose
Monotherapy Low to high Aspirin 75 mg q.d 
Aspirin 
IIa/IIb Prolonged DAPT Moderate to high* Clopidogrel 75 mg q.d. 
Aspirin + P2Y12 inhibitor Prasugrel 10 mg q.d. 
Ticagrelor 60 mg b.i.d. 
IIa/IIb Dual pathway inhibition Moderate to high* Aspirin 75 mg q.d. 
Aspirin + rivaroxaban Rivaroxaban 2.5 mg b.i.d. 
IIb Monotherapy Low to high  
P2Y12 inhibitor, as an alternative to aspirin 
Class of recommendationLevel of evidenceTreatment optionIschaemic riskDose
Monotherapy Low to high Aspirin 75 mg q.d 
Aspirin 
IIa/IIb Prolonged DAPT Moderate to high* Clopidogrel 75 mg q.d. 
Aspirin + P2Y12 inhibitor Prasugrel 10 mg q.d. 
Ticagrelor 60 mg b.i.d. 
IIa/IIb Dual pathway inhibition Moderate to high* Aspirin 75 mg q.d. 
Aspirin + rivaroxaban Rivaroxaban 2.5 mg b.i.d. 
IIb Monotherapy Low to high  
P2Y12 inhibitor, as an alternative to aspirin 

*If not at high bleeding risk.

b.i.d., twice daily; q.d., once daily.

Aspirin versus P2Y12 Inhibitors as Long-Term Monotherapy in CCS

Aspirin has historically been recognised as the cornerstone of secondary prevention in patients with CAD [30]; however, the primacy of aspirin as the standard long-term antiplatelet therapy has been challenged. First, the evidence supporting aspirin dates back several decades and may not be fully applicable to the contemporary practice of modern pharmaco-invasive strategies [31]. In addition, a non-negligible proportion of patients on chronic aspirin therapy experience adverse events, including recurrent ischaemic events, gastrointestinal bleeding, and intracranial haemorrhage, with a relevant impact on patient prognosis [31]. In light of this, several studies have compared aspirin with alternative long-term antithrombotic regimens in CAD patients, such as P2Y12 monotherapy.

The Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial was the first trial to directly compare aspirin (325 mg) and clopidogrel (75 mg) in the setting of broadly defined atherosclerotic disease (recent ischaemic stroke, MI, or symptomatic PAD). Overall, the study showed similar safety profiles and a modest reduction in cardiovascular events (ischaemic stroke, MI, or vascular death) with clopidogrel compared with high-dose aspirin (relative risk reduction of 8.7%; 95% confidence interval [CI]: 0.3–16.5; p = 0.043), most pronounced in patients with PAD [32]. Since the CAPRIE trial, which was conducted before the era of drug-eluting stents and high-intensity statins, a total of seven randomised trials have compared aspirin monotherapy with P2Y12 inhibitor monotherapy in different populations of patients with cardiovascular disease [33‒39]. The recent Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Extended Antiplatelet Monotherapy (HOST-EXAM) trial compared aspirin and clopidogrel monotherapy in patients who had tolerated DAPT (aspirin plus clopidogrel) for 6–18 months after PCI with drug-eluting stent implantation. At 24-months of follow-up, treatment with clopidogrel significantly reduced the rate of all-cause death, ischaemic events (non-fatal MI, stroke, and re-admission due to ACS), or major bleeding (hazard ratio [HR]: 0.73; 95% CI: 0.59–0.90; p = 0.0035) [34]. Importantly, the benefit of clopidogrel versus aspirin therapy was maintained after 5.8 years of follow-up in the HOST-EXAM Extended study (HR: 0.74; 95% CI: 0.63–0.86; p < 0.001) [40].

Gathering evidence from randomised trials comparing antiplatelet monotherapies in patients with CAD, a recent meta-analysis of individual patient data (P2Y12 Inhibitor or Aspirin Monotherapy as Secondary Prevention in Patients With Coronary Artery Disease, PANTHER) found that the incidence of ischaemic events was significantly reduced by 12% with P2Y12 inhibitor monotherapy compared with aspirin monotherapy. This benefit was mainly driven by a significant 23% relative reduction in MI and a numerically nonsignificant 16% relative reduction in stroke. No difference was observed in the risk of death between the two strategies. Furthermore, there was a significant reduction in bleeding events (gastrointestinal bleeding and haemorrhagic stroke) with P2Y12 inhibitor monotherapy compared with aspirin monotherapy, while major bleeding did not differ between treatment groups [41]. These findings clearly highlight the limitations of aspirin monotherapy as the default choice for long-term antithrombotic treatment. Outcomes in patients receiving DAPT or DPI are outlined below.

Long-Term DAPT or DPI in Patients with CCS at High Ischaemic Risk

Several randomised trials have investigated the potential benefit of more intensive antithrombotic regimens to reduce the incidence of cardiovascular events in CCS patients at high ischaemic risk.

The Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial compared DAPT with aspirin and ticagrelor (either 90 mg or 60 mg twice daily (b.i.d.)) versus aspirin alone in 21,162 patients with recent MI (within 1–3 years). After a mean follow-up of 33 months, DAPT with ticagrelor 90 mg or 60 mg b.i.d. reduced the risk of cardiovascular death, stroke, or MI (HR for ticagrelor 90 mg: 0.85; 95% CI: 0.75–0.96; p = 0.008; HR for ticagrelor 60 mg: 0.84; 95% CI: 0.74–0.95; p = 0.004) [10]. The risk of bleeding was higher in patients treated with ticagrelor 90 mg compared with ticagrelor 60 mg twice daily. Given the similar efficacy and better safety profile, ticagrelor 60 mg twice daily in combination with aspirin is currently recommended for extended DAPT in patients with a history of MI and a high risk of recurrent ischaemic events.

In the open-label 12 or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents (DAPT) study, 9,961 patients with ACS or CCS who had received a drug-eluting stent and 12 months of standard DAPT treatment were randomly assigned to receive aspirin plus prasugrel, clopidogrel, or aspirin alone for 30 months. Extended DAPT with prasugrel or clopidogrel resulted in lower rates of stent thrombosis (0.4% vs. 1.4%; HR: 0.29; p < 0.001), MI (2.1% vs. 4.1%; HR: 0.47; p < 0.001), and the combined endpoint of major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%; HR: 0.71; p < 0.001), although this benefit occurred at the cost of excess moderate or severe bleeding events (2.5% vs. 1.6%; p = 0.001) and all-cause mortality (2.0% vs. 1.5%; p = 0.05).

The Ticagrelor in Patients with Stable Coronary Disease and Diabetes (THEMIS) trial randomised 19,220 patients with CCS and type 2 diabetes to receive DAPT with aspirin plus ticagrelor or aspirin alone. The median follow-up was 40 months. Treatment with ticagrelor plus aspirin was associated with reduced ischaemic cardiovascular events including cardiovascular death, MI, or stroke (7.7% vs. 8.5%; HR: 0.90; 95% CI: 0.81–0.99; p = 0.04), but with higher rates of major bleeding (2.2% vs. 1.0%; HR: 2.32; 95% CI: 1.82–2.94; p < 0.001) and intracranial haemorrhage (0.7% vs. 0.5%; HR: 1.71; 95% CI: 1.18–2.48; p = 0.005). A more favourable treatment effect was observed in a pre-specified secondary analysis of patients undergoing PCI (THEMIS-PCI), which showed that in patients with diabetes, stable CAD, and previous PCI, ticagrelor added to aspirin seems to reduce CV death, myocardial infarction, and stroke, although with increased major bleeding [25].

The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial was the first randomised trial to demonstrate the anti-ischaemic benefit of a novel DPI approach of aspirin plus low-intensity direct oral anticoagulation in patients with coronary or peripheral atherosclerosis [23]. The trial evaluated extended treatment with rivaroxaban in 27,395 patients with stable atherosclerotic disease in the form of CCS (91%) and/or PAD (27%). Patients were randomised to receive rivaroxaban (2.5 mg b.i.d.) plus aspirin (100 mg daily), rivaroxaban alone (5 mg b.i.d.), or aspirin alone (100 mg daily). Compared with aspirin alone, DPI with low-dose rivaroxaban plus aspirin yielded a significant 24% lower risk of cardiovascular death, stroke, or MI (HR: 0.76; 95% CI: 0.66–0.86; p < 0.001) at the cost of an increased risk of major bleeding (HR: 1.70; 95% CI: 1.40–2.05; p < 0.001) [23]. In the large subgroup of 16,560 patients with CCS (59.6% with previous PCI), DPI versus aspirin consistently reduced the risk of cardiovascular events regardless of prior revascularisation (PCI group, HR: 0.74; 95% CI: 0.61–0.88; no PCI group, HR: 0.76; 95% CI: 0.61–0.94; p-interaction = 0.85) [29].

DAPT versus P2Y12 Inhibitor Monotherapy Early after PCI in Patients with CCS

Over the past decade, several studies have explored a new paradigm in the management of patients undergoing PCI by testing the safety and efficacy of P2Y12 inhibitor monotherapy after a short course of DAPT (1–3 months) [42]. The ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months versus aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after Implantation of a Drug-eluting Stent (GLOBAL LEADERS) trial randomised 15,968 patients undergoing PCI for CCS or ACS to receive aspirin plus ticagrelor for 1 month, followed by ticagrelor monotherapy for 23 months, or standard treatment with DAPT (aspirin plus clopidogrel or ticagrelor) for 12 months, followed by aspirin monotherapy for 12 months [24]. The study found no difference between the experimental and control regimens in the primary endpoint of all-cause mortality or new Q-wave MI at 2 years (rate ratio: 0.87; 95% CI: 0.75–1.01; p = 0.073). No difference in major bleeding was observed, and the primary results were confirmed in patients who adhered to the study protocol [43]. Limitations include the open-label design, low event rate, and lack of central adjudication of adverse events [24].

The Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention (TWILIGHT) was a double-blind trial that compared ticagrelor monotherapy with ticagrelor plus aspirin from 3 months after PCI in 7,119 patients with ACS or CCS at high risk for bleeding or ischaemic events [26]. The incidence of the primary endpoint of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding was significantly reduced in patients receiving ticagrelor monotherapy than ticagrelor plus aspirin (HR: 0.56; 95% CI: 0.45–0.68; p < 0.001). Risk difference between the two groups was consistent for BARC type 3 or 5 bleeding (HR: 0.49; 95% CI: 0.33–0.74). The incidence of all-cause death, MI, or stroke was 3.9% in both study groups (HR: 0.99; 95% CI: 0.78–1.25; p < 0.001 for non-inferiority). These results indicated that, in high-risk patients who underwent PCI and completed 3-month DAPT, ticagrelor monotherapy reduced clinically relevant bleeding compared with DAPT, with no higher risk of fatal or ischaemic events [26].

To summarise the available evidence, a patient-level meta-analysis of 24,096 patients from 6 randomised trials comparing P2Y12 inhibitor monotherapy with standard DAPT after coronary revascularisation was performed [44]. The primary outcome of all-cause death, MI, and stroke occurred in 2.95% of patients on P2Y12 inhibitor monotherapy and 3.27% on DAPT in the per-protocol population (HR: 0.93; 95% CI: 0.79–1.09; p = 0.005 for non-inferiority; p = 0.38 for superiority). The risk of major bleeding was significantly lower with P2Y12 inhibitor monotherapy than with DAPT (0.89% vs. 1.83%; HR: 0.49; 95% CI: 0.39–0.63; p < 0.001). These results were confirmed in a pre-specified sub-analysis of the high-risk group of patients undergoing complex PCI, leading to the conclusion that stopping aspirin after 1–3 months of DAPT and continuing the P2Y12 inhibitor alone is safe and effective, regardless of PCI complexity [45].

Patients with Concurrent Atrial Fibrillation

The prevalence of non-valvular atrial fibrillation increases with age and is approximately 25–35% in patients with CCS [46, 47]. These patients are at particularly high risk of thromboembolic events, including ischaemic stroke. In patients treated with PCI, short-term triple antithrombotic therapy (aspirin, clopidogrel, and an anticoagulant drug) is recommended for up to 1 week as the default strategy and up to 1 month in patients at high risk of ischaemic events [15]. DOACs are preferred over VKAs as they reduce the risk of major bleeding events and are easier to use in practice. In recent years, 4 randomised trials have examined antithrombotic treatment strategies including DOACs in patients with atrial fibrillation undergoing PCI. The trials differed in terms of patient selection and treatment regimens, but results were pooled in a meta-analysis, concluding that DOAC-based dual therapy reduced the risk for bleeding compared with VKA-based triple therapy, although the studies were not powered to assess differences in risks of all-cause death and ischaemic outcomes (myocardial infarction, stroke, stent thrombosis, and cardiovascular death) [48].

Despite optimal adherence to DAPT, some patients develop recurrent ischaemic events, including MI and stent thrombosis. Adequate platelet inhibition is of paramount importance to reduce the risk of cardiovascular events in patients with CCS. However, there is currently no conclusive evidence to support that routine platelet function testing is beneficial for guidance on the choice, dose, or duration of antiplatelet therapy. Cardiovascular events occurring despite DAPT may be explained, at least in part, by genetic predisposition causing insufficient activation of clopidogrel to its active metabolite (low responders). Up to 30% of Caucasian patients may be low responders to clopidogrel because of genetic variations in the hepatic cytochrome P2C19 (CYP2C19) enzyme, which is responsible for clopidogrel activation [49, 50]. Consequently, there may be a role for genetic testing in selected patients to guide P2Y12 inhibitor treatment. Although the majority of trials exploring genetically tailored P2Y12 inhibitor treatment were conducted in patients receiving DAPT, such research may also benefit patients considered for long-term clopidogrel monotherapy. Improved treatment benefit with clopidogrel will further challenge the current preference in clinical practice for aspirin as single antiplatelet therapy compared to clopidogrel, thus adding novel data to the evidence provided by the above-mentioned PANTHER meta-analysis [41].

In the setting of ACS, the ongoing Dan-DAPT trial (NCT05262803) is a randomised study investigating whether individualised choice of (prasugrel/ticagrelor vs. clopidogrel) and duration (6 vs. 3 months) of DAPT based on genetic testing of clopidogrel responsiveness can reduce the bleeding risk compared to standard of care treatment in patients with ACS at high risk of bleeding (PRECISE-DAPT score ≥25). More studies exploring genetically tailored antiplatelet therapy will likely be initiated, also in the setting of CCS.

Patients with CCS have a substantial risk of thrombotic events that can be mitigated by the use of antithrombotic drugs. Currently, most patients are treated with long-term aspirin monotherapy, but the available evidence supports alternative strategies, including P2Y12 inhibitor monotherapy, extended DAPT or DPI, to reduce ischaemic risk. Weighing the benefits against the risk of bleeding is important, and identifying subsets of patients with the most favourable trade-off between ischaemic and bleeding risk is therefore essential. More studies are needed to better guide clinicians on how to evaluate thrombotic and bleeding risk to improve the selection of patients who are likely to benefit from shortened or extended treatment with intensified antithrombotic therapy.

M.W., P.C., and F.G. have nothing to disclose. M.P. has received advisory board honorarium from AstraZeneca, Janssen-Cilag, and Novo Nordisk; grant support from the Danish Cardiovascular Academy, funded by the Novo Nordisk Foundation and the Danish Heart Foundation (grant number: CPD5Y-2022004-HF); and speaker honorarium from AstraZeneca, Bayer, Boehringer Ingelheim, and Janssen-Cilag. ELG has received speaker honoraria or consultancy fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Novo Nordisk Organon, and Lundbeck Pharma. He is an investigator in clinical trials sponsored by AstraZeneca, Idorsia, and Bayer and has received unrestricted research grants from Boehringer Ingelheim. K.P. is an investigator in clinical trials sponsored by AstraZeneca, Idorsia, Bayer, Janssen-Cilaq, and Bristol-Myers Squibb.

This study was not supported by any sponsor or funder.

Erik Lerkevang Grove made the first outline of the paper, which was mainly written by Archana Kulasingam. Erik Lerkevang Grove, Manan Pareek, Felice Gragnano, Morten Würtz, and Kasper Pryds also contributed to the writing of the paper. Archana Kulasingam, Manan Pareek, Felice Gragnano, Morten Würtz, Kasper Pryds, Paolo Calabrò, and Erik Lerkevang Grove critically reviewed and approved the final version of the manuscript.

1.
Knuuti
J
,
Wijns
W
,
Saraste
A
,
Capodanno
D
,
Barbato
E
,
Funck-Brentano
C
, et al
.
2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes
.
Eur Heart J
.
2020
;
41
(
3
):
407
77
. .
2.
SCORE2 working group and ESC Cardiovascular risk collaboration
;
Pennells
L
,
Ojeda
F
,
Kaptoge
S
,
Kuulasmaa
K
,
de Vries
T
.
SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe
.
Eur Heart J
.
2021
;
42
(
25
):
2439
54
. .
3.
De Bruyne
B
,
Pijls
NHJ
,
Kalesan
B
,
Barbato
E
,
Tonino
AL
,
Piroth
Z
, et al
.
Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease
.
N Engl J Med
.
2012
;
367
(
11
):
991
1001
. .
4.
Belsey
J
,
Savelieva
I
,
Mugelli
A
,
Camm
AJ
.
Relative efficacy of antianginal drugs used as add-on therapy in patients with stable angina: a systematic review and meta-analysis
.
Eur J Prev Cardiol
.
2015
;
22
(
7
):
837
48
.
5.
Grove
EL
,
Würtz
M
,
Thomas
MR
,
Kristensen
SD
.
Antiplatelet therapy in acute coronary syndromes
.
Expert Opin Pharmacother
.
2015
;
16
(
14
):
2133
47
. .
6.
Jones
WS
,
Mulder
H
,
Wruck
LM
,
Pencina
MJ
,
Kripalani
S
,
Muñoz
D
, et al
.
Comparative effectiveness of aspirin dosing in cardiovascular disease
.
N Engl J Med
.
2021
;
384
(
21
):
1981
90
. .
7.
Würtz
M
,
Lordkipanidzé
M
,
Grove
EL
.
Pharmacogenomics in cardiovascular disease: focus on aspirin and ADP receptor antagonists
.
J Thromb Haemost
.
2013
;
11
(
9
):
1627
39
. .
8.
Galli
M
,
Franchi
F
,
Rollini
F
,
Angiolillo
DJ
.
Role of platelet function and genetic testing in patients undergoing percutaneous coronary intervention
.
Trends Cardiovasc Med
.
2023
;
33
(
3
):
133
8
. .
9.
Valgimigli
M
,
Bueno
H
,
Byrne
RA
,
Collet
JP
,
Costa
F
,
Jeppsson
A
, et al
.
2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS)
.
Eur Heart J
.
2018
;
39
(
3
):
213
60
. .
10.
Bonaca
MP
,
Bhatt
DL
,
Cohen
M
,
Steg
PG
,
Storey
RF
,
Jensen
EC
, et al
.
Long-term use of ticagrelor in patients with prior myocardial infarction
.
N Engl J Med Overseas Ed
.
2015
;
372
(
19
):
1791
800
. .
11.
Steg
PG
,
Bhatt
DL
,
Simon
T
,
Fox
K
,
Mehta
SR
,
Harrington
RA
, et al
.
Ticagrelor in patients with stable coronary disease and diabetes
.
N Engl J Med
.
2019
;
381
(
14
):
1309
20
. .
12.
Neumann
FJ
,
Sousa-Uva
M
,
Ahlsson
A
,
Alfonso
F
,
Banning
AP
,
Benedetto
U
, et al
.
2018 ESC/EACTS Guidelines on myocardial revascularization
.
Eur Heart J
.
2019
;
40
(
2
):
87
165
. .
13.
Mauri
L
,
Kereiakes
DJ
,
Yeh
RW
,
Driscoll-Shempp
P
,
Cutlip
DE
,
Steg
PG
, et al
.
Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents
.
N Engl J Med
.
2014
;
371
(
23
):
2155
66
. .
14.
Yeh
RW
,
Secemsky
EA
,
Kereiakes
DJ
,
Normand
SLT
,
Gershlick
AH
,
Cohen
DJ
, et al
.
Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 Year after percutaneous coronary intervention
.
JAMA
.
2016
;
315
(
16
):
1735
49
. .
15.
Byrne
RA
,
Rossello
X
,
Coughlan
JJ
,
Barbato
E
,
Berry
C
,
Chieffo
A
, et al
.
2023 ESC Guidelines for the management of acute coronary syndromes
.
Eur Heart J
.
2023
;
44
(
38
):
3720
826
. .
16.
Spirito
A
,
Cao
D
,
Sartori
S
,
Sharma
A
,
Smith
KF
,
Vogel
B
, et al
.
Predictive value of the thrombotic risk criteria proposed in the 2023 ESC guidelines for the management of ACS: insights from a large PCI registry
.
Eur Heart J Cardiovasc Pharmacother
.
2024
;
10
(
1
):
11
9
. .
17.
Costa
F
,
van Klaveren
D
,
James
S
,
Heg
D
,
Räber
L
,
Feres
F
, et al
.
Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials
.
Lancet
.
2017
;
389
(
10073
):
1025
34
. .
18.
Gragnano
F
,
Heg
D
,
Franzone
A
,
McFadden
EP
,
Leonardi
S
,
Piccolo
R
, et al
.
PRECISE-DAPT score for bleeding risk prediction in patients on dual or single antiplatelet regimens: insights from the GLOBAL LEADERS and GLASSY
.
Eur Heart J Cardiovasc Pharmacother
.
2022
;
8
(
1
):
28
38
. .
19.
Munafò
AR
,
Montalto
C
,
Franzino
M
,
Pistelli
L
,
Di Bella
G
,
Ferlini
M
, et al
.
External validity of the PRECISE-DAPT score in patients undergoing PCI: a systematic review and meta-analysis
.
Eur Heart J Cardiovasc Pharmacother
.
2023
;
9
(
8
):
709
21
. .
20.
Urban
P
,
Mehran
R
,
Colleran
R
,
Angiolillo
DJ
,
Byrne
RA
,
Capodanno
D
, et al
.
Defining high bleeding risk in patients undergoing percutaneous coronary intervention
.
Circulation
.
2019
;
140
(
3
):
240
61
. .
21.
Gragnano
F
,
Spirito
A
,
Corpataux
N
,
Vaisnora
L
,
Galea
R
,
Gargiulo
G
, et al
.
Impact of clinical presentation on bleeding risk after percutaneous coronary intervention and implications for the ARC-HBR definition
.
EuroIntervention
.
2021
;
17
(
11
):
e898
909
. .
22.
Bhatt
DL
,
Fox
KAA
,
Hacke
W
,
Berger
PB
,
Black
HR
,
Boden
WE
, et al
.
Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events
.
N Engl J Med
.
2006
;
354
(
16
):
1706
17
. .
23.
Eikelboom
JW
,
Connolly
SJ
,
Bosch
J
,
Dagenais
GR
,
Hart
RG
,
Shestakovska
O
, et al
.
Rivaroxaban with or without aspirin in stable cardiovascular disease
.
N Engl J Med Overseas Ed
.
2017
;
377
(
14
):
1319
30
. .
24.
Vranckx
P
,
Valgimigli
M
,
Jüni
P
,
Hamm
C
,
Steg
PG
,
Heg
D
, et al
.
Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial
.
Lancet
.
2018
;
392
(
10151
):
940
9
. .
25.
Bhatt
DL
,
Steg
PG
,
Mehta
SR
,
Leiter
LA
,
Simon
T
,
Fox
K
, et al
.
Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial
.
Lancet
.
2019
;
394
(
10204
):
1169
80
. .
26.
Mehran
R
,
Baber
U
,
Sharma
SK
,
Cohen
DJ
,
Angiolillo
DJ
,
Briguori
C
, et al
.
Ticagrelor with or without aspirin in high-risk patients after PCI
.
N Engl J Med
.
2019
;
381
(
21
):
2032
42
. .
27.
Watanabe
H
,
Domei
T
,
Morimoto
T
,
Natsuaki
M
,
Shiomi
H
,
Toyota
T
, et al
.
Effect of 1-month dual antiplatelet therapy followed by clopidogrel vs 12-month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving PCI: the STOPDAPT-2 randomized clinical trial
.
JAMA
.
2019
;
321
(
24
):
2414
27
. .
28.
Hahn
JY
,
SongOh
YJH
,
Chun
WJ
,
Park
YH
,
Jang
WJ
,
Im
ES
, et al
.
Effect of P2Y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients undergoing percutaneous coronary intervention: the SMART-CHOICE randomized clinical trial
.
JAMA
.
2019
;
321
(
24
):
2428
37
. .
29.
Bainey
KR
,
Welsh
RC
,
Connolly
SJ
,
Marsden
T
,
Bosch
J
,
Fox
KAA
, et al
.
Rivaroxaban plus aspirin versus aspirin alone in patients with prior percutaneous coronary intervention (COMPASS-PCI)
.
Circulation
.
2020
;
141
(
14
):
1141
51
. .
30.
Grove
EL
.
Antiplatelet effect of aspirin in patients with coronary artery disease
.
Dan Med J
.
2012
;
59
(
9
):
B4506
.
31.
Gragnano
F
,
Capolongo
A
,
Calabrò
P
.
P2Y12 Inhibitor or Aspirin Monotherapy in Patients with Coronary Artery Disease: is it Time for a Paradigm Shift
.
Curr Vasc Pharmacol
.
2023
. .
32.
CAPRIE Steering Committee
.
A randomised, blinded, trial of Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE)
.
Lancet
.
1996
;
348
(
9038
):
1329
39
..
33.
Pettersen
AR
,
Seljeflot
I
,
Abdelnoor
M
,
Arnesen
H
.
High on-aspirin platelet reactivity and clinical outcome in patients with stable coronary artery disease: results from ASCET (aspirin nonresponsiveness and clopidogrel endpoint trial)
.
J Am Heart Assoc
.
2012
;
1
(
3
):
e000703
. .
34.
Koo
BK
,
Kang
J
,
Park
KW
,
Rhee
TM
,
Yang
HM
,
Won
KB
, et al
.
Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOST-EXAM): an investigator-initiated, prospective, randomised, open-label, multicentre trial
.
Lancet
.
2021
;
397
(
10293
):
2487
96
. .
35.
Schunkert
H
,
Boening
A
,
Von Scheidt
M
,
Lanig
C
,
Gusmini
F
,
DeWaha
A
, et al
.
Randomized trial of ticagrelor vs. aspirin in patients after coronary artery bypass grafting: the TiCAB trial
.
Eur Heart J
.
2019
;
40
(
29
):
2432
40
. .
36.
Franzone
A
,
McFadden
E
,
Leonardi
S
,
Piccolo
R
,
Vranckx
P
,
Serruys
PW
, et al
.
Ticagrelor alone versus dual antiplatelet therapy from 1 Month after drug-eluting coronary stenting
.
J Am Coll Cardiol
.
2019
;
74
(
18
):
2223
34
. .
37.
Woodward
M
,
Lowe
GDO
,
Francis
LMA
,
Rumley
A
,
Cobbe
SM
,
Bain
R
, et al
.
A randomized comparison of the effects of aspirin and clopidogrel on thrombotic risk factors and C-reactive protein following myocardial infarction: the CADET trial
.
J Thromb Haemost
.
2004
;
2
(
11
):
1934
40
. .
38.
Zhao
Q
,
Zhu
Y
,
Xu
Z
,
Cheng
Z
,
Mei
J
,
Chen
X
, et al
.
Effect of ticagrelor plus aspirin, ticagrelor alone, or aspirin alone on saphenous vein graft patency 1 year after coronary artery bypass grafting: a randomized clinical trial
.
JAMA
.
2018
;
319
(
16
):
1677
86
. .
39.
Johnston
SC
,
Amarenco
P
,
Albers
GW
,
Denison
H
,
Easton
JD
,
Evans
SR
.
Ticagrelor versus aspirin in acute stroke or transient ischemic attack
.
N Engl J Med
.
2016
;
375
(
1
):
35
43
. .
40.
Kang
J
,
Park
KW
,
Lee
H
,
Hwang
D
,
Yang
HM
,
Rha
SW
, et al
.
Aspirin versus clopidogrel for long-term maintenance monotherapy after percutaneous coronary intervention: the HOST-EXAM extended study
.
Circulation
.
2023
;
147
(
2
):
108
17
. .
41.
Gragnano
F
,
Cao
D
,
Pirondini
L
,
Franzone
A
,
Kim
HS
,
von Scheidt
M
, et al
.
P2Y12 inhibitor or aspirin monotherapy for secondary prevention of coronary events
.
J Am Coll Cardiol
.
2023
;
82
(
2
):
89
105
. .
42.
Capodanno
D
,
Baber
U
,
Bhatt
DL
,
Collet
JP
,
Dangas
G
,
Franchi
F
, et al
.
P2Y12 inhibitor monotherapy in patients undergoing percutaneous coronary intervention
.
Nat Rev Cardiol
.
2022
;
19
(
12
):
829
44
. .
43.
Gragnano
F
,
Zwahlen
M
,
Vranckx
P
,
Heg
D
,
Schmidlin
K
,
Hamm
C
, et al
.
Ticagrelor monotherapy or dual antiplatelet therapy after drug-eluting stent implantation: per-protocol analysis of the GLOBAL LEADERS trial
.
J Am Heart Assoc
.
2022
;
11
(
10
):
e024291
. .
44.
Valgimigli
M
,
Gragnano
F
,
Branca
M
,
Franzone
A
,
Baber
U
,
Jang
Y
, et al
.
P2Y12 inhibitor monotherapy or dual antiplatelet therapy after coronary revascularisation: individual patient level meta-analysis of randomised controlled trials
.
BMJ
.
2021
;
373
:
n1332
. .
45.
Gragnano
F
,
Mehran
R
,
Branca
M
,
Franzone
A
,
Baber
U
,
Jang
Y
, et al
.
P2Y12 inhibitor monotherapy or dual antiplatelet therapy after complex percutaneous coronary interventions
.
J Am Coll Cardiol
.
2023
;
81
(
6
):
537
52
. .
46.
Ruff
CT
,
Giugliano
RP
,
Braunwald
E
,
Hoffman
EB
,
Deenadayalu
N
,
Ezekowitz
MD
, et al
.
Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials
.
Lancet
.
2014
;
383
(
9921
):
955
62
. .
47.
Weng
LC
,
Preis
SR
,
Hulme
OL
,
Larson
MG
,
Choi
SH
,
Wang
B
, et al
.
Genetic predisposition, clinical risk factor burden, and lifetime risk of atrial fibrillation
.
Circulation
.
2018
;
137
(
10
):
1027
38
. .
48.
Khan
SU
,
Osman
M
,
Khan
MU
,
Khan
MS
,
Zhao
D
,
Mamas
MA
, et al
.
Dual versus triple therapy for atrial fibrillation after percutaneous coronary intervention: a systematic review and meta-analysis
.
Ann Intern Med
.
2020
;
172
(
7
):
474
83
. .
49.
Winter
MP
,
Grove
EL
,
De Caterina
R
,
Gorog
DA
,
Ahrens
I
,
Geisler
T
, et al
.
Advocating cardiovascular precision medicine with P2Y12 receptor inhibitors
.
Eur Heart J Cardiovasc Pharmacother
.
2017
;
3
(
4
):
221
34
. .
50.
Claassens
DMF
,
Vos
GJA
,
Bergmeijer
TO
,
Hermanides
RS
,
van ’t Hof
AWJ
,
van der Harst
P
, et al
.
A genotype-guided strategy for oral P2Y 12 inhibitors in primary PCI
.
N Engl J Med
.
2019
;
381
(
17
):
1621
31
. .