ANTIPLATELET THERAPY IN CAD

• ACRONYMS AND DEFINITIONS

• A fib - Atrial fibrillation
• ACC - American College of Cardiology
• ACCP - American College of Chest Physicians
• ACS - Acute coronary syndrome defined as myocardial infarction or unstable angina
• AHA - American Heart Association
• ASA - Acetylsalicylic acid, abbreviation for aspirin
• BMS - Bare metal stent
• CABG - Coronary artery bypass grafting
• CAD - Coronary artery disease
• CVD - Cardiovascular disease
• DES - Drug-eluting stent
• DAPT - Dual antiplatelet therapy (ASA + P2Y12 inhibitor)
• PCI - Percutaneous coronary intervention
• P2Y12 - P2Y12 inhibitors
• RCT - Randomized controlled trial
• STEMI - ST-Elevation myocardial infarction
• Triple therapy - DAPT + anticoagulant
• TT - Triple therapy (anticoagulant + DAPT)
• VKA - Vitamin K antagonist (e.g. warfarin)
• VTE - Venous thromboembolism (DVT and PE)

• PRIMARY PREVENTION

• See primary prevention of CAD with aspirin

• STABLE CAD

• Stable CAD is defined as one of the following:
• Asymptomatic CAD that has been detected through some type of imaging (e.g. CT angiography)
• Symptomatic CAD that has predictable symptoms that are not progressing
• Patient with CAD that is > 12 months from ACS, PCI, or CABG


• Treatment recommendations
• See antiplatelet therapy in the secondary prevention of CAD

• AHA DAPT RECOMMENDATIONS

• Duration of DAPT
• After coronary revascularization, dual antiplatelet therapy (aspirin + P2Y12 inhibitor) is recommended in most patients. DAPT helps prevent stent thrombosis and reduces ischemic events in patients who have undergone PCI, and it reduces vein graft occlusion in patients who received CABG. The drawback to DAPT is an increased risk of bleeding events. A number of studies have looked at different durations of DAPT in order to find the perfect balance between thrombosis prevention and bleeding risk (see DAPT studies below). Because these studies have varied greatly in design, it's difficult to apply their results across all patient populations.
• In 2016, the AHA issued recommendations for DAPT duration, and in 2021, they updated some of the guidelines. Those recommendations are presented in the illustration below.



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• DAPT score
• A clinical decision tool was developed based on a post-hoc analysis of the DAPT study. The tool can be used to help determine which patients may benefit the most from extended DAPT. Using the tool, patients are assigned a score based on a set of risk factors. The tool only applies to patients who have completed a year of DAPT without a major ischemic or bleeding event.
• In patients with a score ≥ 2, the benefits of extended DAPT (> 1 year) likely outweigh the risks. Based on their analysis, the authors concluded that in patients with a score ≥ 2, extended DAPT therapy confers an absolute risk reduction in myocardial infarction or stent thrombosis that is 8.2 times greater than the absolute risk increase in moderate or severe bleeding. In patients with a score < 2, extended DAPT causes an absolute increase in bleeding that is 2.4 times the absolute reduction in myocardial infarction or stent thrombosis. [4]
• The scoring criteria are presented below. It's important to note that the tool has not been validated in a randomized controlled trial.

• AHA DAPT RECOMMENDATIONS | Antiplatelet dosing

• Overview
• The AHA/ACC makes the following dosing recommendations for antiplatelet therapy in patients with coronary artery disease
• The recommended dose of aspirin during DAPT therapy is 81 mg once daily. After DAPT therapy is stopped, the recommended dose of aspirin is 75 - 162 mg once daily.


• PCI (BMS or DES)
• Aspirin - all patients should receive aspirin 162 - 325 mg loading dose, then 81 mg once daily during DAPT therapy
• P2Y12 inhibitor (one of the following)
• Clopidogrel 600 mg loading dose then 75 mg once daily
• Prasugrel^✝ 60 mg loading dose then 10 mg once daily
• Ticagrelor 180 mg loading dose then 90 mg twice daily [2]
• ^✝The AHA recommends prasugrel at the time of PCI, but not before PCI in patients with NSTEMI. In patients with STEMI, prasugrel is recommended as early as possible or at the time of PCI. See ACCOAST study below for more.


• Medical Therapy
• Aspirin - all patients should receive aspirin 162 - 325 mg loading dose, then 81 mg once daily during DAPT therapy
• P2Y12 inhibitor (one of the following)
• Clopidogrel 600 mg loading dose then 75 mg once daily
• Ticagrelor 180 mg loading dose then 90 mg twice daily [2]


• Fibrinolysis
• Aspirin - all patients should receive aspirin 162 - 325 mg loading dose, then 81 mg once daily during DAPT therapy
• P2Y12 inhibitor
• Clopidogrel 300 mg loading dose (if older than 75 years, do not give loading dose) then 75 mg once daily [2]


• PCI after fibrinolytic therapy
• Aspirin - all patients should receive aspirin 162 - 325 mg loading dose, then 81 mg once daily during DAPT therapy
• P2Y12 inhibitor
• Clopidogrel - if loading dose was given with fibrinolytic therapy, continue clopidogrel 75 mg once daily
• Clopidogrel - if loading dose was not given with fibrinolytic therapy, and PCI is to be performed ≤ 24 hours after fibrinolytic therapy, give 300 mg loading dose and continue at 75 mg once daily
• Clopidogrel - if loading dose was not given with fibrinolytic therapy, and PCI is to be performed > 24 hours after fibrinolytic therapy, give 600 mg loading dose and continue at 75 mg once daily [2]


• Urgent on-pump CABG
• Aspirin - do not stop aspirin before surgery
• P2Y12 inhibitor
• Clopidogrel - stop clopidogrel 24 hours before surgery if possible
• Ticagrelor - stop ticagrelor 24 hours before surgery if possible [2]


• Elective CABG
• Aspirin - do not stop aspirin before surgery
• P2Y12 inhibitor
• Clopidogrel - stop clopidogrel 5 days before surgery
• Ticagrelor - stop ticagrelor 5 days before surgery
• Prasugrel - stop prasugrel 7 days before surgery [3]

• AHA DAPT RECOMMENDATIONS | Periprocedural DAPT

• AHA 2016 periprocedural DAPT recommendations
• ACCP 2022 periprocedural DAPT recommendations

• DAPT STUDIES | DURATION

• DAPT duration
• DAPT prevents stent thrombosis while increasing the risk of major bleeding, and a number of studies have sought to determine the optimal duration of therapy that strikes a perfect balance between the two. The table below summarizes major DAPT studies that compared different lengths of treatment.

• DAPT STUDIES | THERAPIES

• DAPT therapies
• Clopidogrel, ticagrelor, and prasugrel are all approved for use in DAPT following ACS. Studies directly comparing their effects are detailed below.

• STUDY
  TALOS-AMI study - Ticagrelor vs Clopidogrel After 1 Month of Ticagrelor in Patients with MI Undergoing PCI, Lancet (2021) [PubMed abstract]
• Design: Randomized, open-label trial (N=2697 | length = 12 months) in patients with MI who had undergone PCI with drug-eluting stent placement and completed 1 month of DAPT with ticagrelor and aspirin without incident. Study was performed in South Korea.
• Treatment: Continue Ticagrelor vs Switch to Clopidogrel for 11 months
• Primary outcome: Net adverse clinical event, which is a composite of cardiovascular death, myocardial infarction, stroke, and bleeding type 2, 3, or 5 according to the Bleeding Academic Research Consortium (BARC) criteria, from 1 to 12 months after an index PCI
• Results:
• Primary outcome: Ticagrelor - 8.2%, Clopidogrel - 4.6% (p=0.0001, superiority)
• Composite of CV death, MI, or stroke: Ticagrelor - 3.1%, Clopidogrel - 2.1% (p=0.15)
• BARC 2, 3, or 5 bleeding: Ticagrelor - 5.6%, Clopidogrel - 3% (p=0.0012)
• Findings: In stabilized patients with acute myocardial infarction after index PCI, a uniform unguided de-escalation strategy significantly reduced the risk of net clinical events up to 12 months, mainly by reducing the bleeding events.

• STUDY
  Ticagrelor vs Clopidogrel after NSTEMI-ACS in Patients ≥ 70 Years Old, Lancet (2020) [PubMed abstract]
• Design: Randomized open-label trial (N=1002 | length = 12 months) in patients ≥ 70 years old presenting with NSTEMI-ACS
• Treatment: Ticagrelor 90 mg twice daily vs Clopidogrel 75 mg once daily for 12 months. All patients were given loading doses of their respective treatment. Low-dose aspirin was recommneded in all patients.
• Primary outcomes: Co-primary net clinical benefit outcome consisted of all-cause death, myocardial infarction, stroke, PLATO major and minor bleeding
• Results:
• Primary outcome: Ticagrelor - 32%, Clopidogrel - 28% (p=0.11)
• Cardiovascular death, myocardial infarction, stroke: Ticagrelor - 11%, Clopidogrel - 12% (p=0.71)
• PLATO major or minor bleeding: Ticagrelor - 24%, Clopidogrel - 18% (p=0.02)
• Drug discontinuation: Ticagrelor - 47%, Clopidogrel - 22%
• Interventions received during initial hospitalization: PCI - 47%, CABG - 17%
• Findings: In patients aged 70 years or older presenting with NSTE-ACS, clopidogrel is a favourable alternative to ticagrelor, because it leads to fewer bleeding events without an increase in the combined endpoint of all-cause death, myocardial infarction, stroke, and bleeding. Clopidogrel could be an alternative P2Y12 inhibitor especially for elderly patients with a higher bleeding risk.

• STUDY
  ISAR-REACT trial - Ticagrelor vs Prasugrel After ACS, NEJM (2019) [PubMed abstract]
• Design: Randomized, open-label trial (N=4018 | length = 1 year) in patients hospitalized with ACS who were scheduled to undergo coronary angiography
• Treatment: Ticagrelor 180 one time followed by 90 mg twice daily vs Prasugrel 60 mg one time followed by 10 mg once daily. All patients were also to receive aspirin.
• Primary outcome: Composite of death, myocardial infarction, or stroke at 1 year after randomization
• Results:
• Primary outcome: Ticagrelor - 9.3%, Prasugrel - 6.9% (p=0.006)
• BARC 3, 4, or 5 bleeding: Ticagrelor - 5.4%, Prasugrel - 4.8% (p=0.46)
• Interventions received: PCI - 84.1%, CABG - 2.1%
• Findings: Among patients who presented with acute coronary syndromes with or without ST-segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel than among those who received ticagrelor, and the incidence of major bleeding was not significantly different between the two groups.

• STUDY
  Reducing Prasugrel to 5 mg vs Continuing 10 mg One Month after PCI, Lancet (2020) [PubMed abstract]
• Design: Randomized open-label trial (N=2338 | length = 1 year) in patients with ACS undergoing PCI
• Treatment: Prasugrel 10 mg once daily for 1 month followed by 5 mg once daily for 11 months (reduction group) vs Prasugrel 10 mg once daily for 12 months (standard group). All patients received aspirin 100 mg once daily.
• Primary outcome: Net adverse clinical events (all-cause death, non-fatal myocardial infarction, stent thrombosis, repeat revascularization, stroke, and bleeding events of grade 2 or higher according to BARC criteria) at 1 year
• Results:
• Primary outcome: Reduction - 7.2%, Standard - 10.1% (p=0.012)
• Cardiac death, MI, stent thrombosis, and ischemic stroke: Reduction - 1.4%, Standard - 1.8% (p=0.40)
• BARC grade ≥ 2 bleeding: Reduction - 2.9%, Standard - 5.9% (p<0.0007)
• Overall mortality: Reduction - 0.9%, Standard - 1.2% (p=0.41)
• Findings: In east Asian patients with acute coronary syndrome patients receiving PCI, a prasugrel-based dose de-escalation strategy from 1 month after PCI reduced the risk of net clinical outcomes up to 1 year, mainly driven by a reduction in bleeding without an increase in ischemia.

• TRIPLE THERAPY

• Overview
• In some cases, indications may arise in the same patient for dual antiplatelet therapy (P2Y12 inhibitors + aspirin) and anticoagulation (e.g. factor Xa inhibitors). A common scenario would be PCI with heart stent placement in someone with atrial fibrillation. The stent placement is an indication for dual antiplatelet therapy, and atrial fibrillation is an indication for anticoagulation. In this example, an anticoagulant, aspirin, and a P2Y12 inhibitor would all be indicated based on the separate diagnoses. This triple antithrombotic regimen greatly increases a person's risk of bleeding, and this may cause the risks of therapy to outweigh the benefits. Because of this, specific recommendations for this subset of patients have been published.
• The AHA published recommendations for TT in A fib in 2019. The ACC published recommendations for TT in A fib and VTE in 2020. Both sets of recommendations along with studies that have compared triple therapy to other regimens are reviewed below.

• AHA 2019 recommendations in patients with A fib and ACS
• Acute treatment
• Urgent direct-current cardioversion of new-onset AF in the setting of ACS is recommended for patients with hemodynamic ischemia, or inadequate rate control
• Intravenous beta blockers are recommended to slow a rapid ventricular response to AF in patients with ACS who do not display HF, hemodynamic instability, or bronchospasm
• Administration of amiodarone or digoxin may be considered to slow a rapid ventricular response in patients with ACS and AF associated with severe LV dysfunction and heart failure or hemodynamic instability
• Administration of nondihydropyridine calcium antagonists may be considered to slow a rapid ventricular response in patients with ACS and A fib only in the absence of significant HF or hemodynamic instability
• Antithrombotic regimens
• For patients with ACS and A fib at increased risk of systemic thromboembolism (based on CHA₂DS₂-VASc risk score ≥ 2), anticoagulation is recommended unless the bleeding risk exceeds the expected benefit
• If triple therapy (oral anticoagulant, aspirin, and P2Y12 inhibitor) is prescribed for patients with A fib at increased risk of stroke (based on CHA₂DS₂-VASc risk score of ≥ 2) who have undergone PCI with stenting for ACS, it is reasonable to choose clopidogrel in preference to prasugrel
• In patients with A fib at increased risk of stroke (based on CHA₂DS₂-VASc risk score ≥ 2) who have undergone PCI with stenting for ACS, double therapy with a P2Y12 inhibitor (clopidogrel or ticagrelor) and dose-adjusted vitamin K antagonist is reasonable to reduce the risk of bleeding as compared with triple therapy (see WOEST study below)
• In patients with A fib at increased risk of stroke (based on CHA₂DS₂-VASc risk score ≥ 2) who have undergone PCI with stenting for ACS, double therapy with P2Y12 inhibitors (clopidogrel) and low-dose rivaroxaban 15 mg daily is reasonable to reduce the risk of bleeding as compared with triple therapy (see PIONEER study below)
• In patients with A fib at increased risk of stroke (based on CHA₂DS₂-VASc risk score ≥ 2) who have undergone PCI with stenting for ACS, double therapy with a P2Y12 inhibitor (clopidogrel) and dabigatran 150 mg twice daily is reasonable to reduce the risk of bleeding as compared with triple therapy (see RE-DUAL PCI study below)
• Triple therapy duration
• If triple therapy (oral anticoagulant, aspirin, and P2Y12 inhibitor) is prescribed for patients with A fib who are at increased risk of stroke (based on CHA₂DS₂-VASc risk score ≥ 2) and who have undergone PCI with stenting (drug eluting or bare metal) for ACS, a transition to double therapy (oral anticoagulant and P2Y12 inhibitor) at 4 to 6 weeks may be considered (see ISAR-TRIPLE trial below) [9]

• ACC 2020 triple therapy recommendations
• The ACC published a paper in 2020 that contains a number of algorithms for determining antithrombotic regimens in patients with A fib or VTE who are undergoing PCI. A link to a pdf version of the paper along with a guide to pertinent pages is provided below.
• ACC 2020 Recommendations for Triple Therapy [pdf]
• A fib
• Patient with A fib undergoing PCI [page 9]
• Patient on antiplatelet therapy with new A fib diagnosis [page 12]
• VTE
• Patient with prior VTE undergoing PCI [page 15]
• Patient with VTE on anticoagulant who has undergone PCI [page 16]
• Patient on antiplatelet therapy with new VTE [page 18]
• Periprocedural management
• Periprocedural management of patient on anticoagulant undergoing PCI [page 10]

• STUDY
  AUGUSTUS study - Triple therapy vs VKA or Apixaban + P2Y12 Inhibitor in Patients with A fib and Recent PCI, NEJM (2019) [PubMed abstract]
• Design: Randomized, 2-factorial, placebo-controlled trial (N=4614 | length = 6 months) in patients with A fib who had ACS or recent PCI
• Treatment groups:
• P2Y12 + Apixaban + ASA
• P2Y12 + Apixaban + Placebo
• P2Y12 + VKA + ASA
• P2Y12 + VKA + Placebo
• Primary outcome: Major or clinically relevant nonmajor bleeding
• Results:
• There were no significant interactions between the two randomization factors on the primary or secondary outcomes
• Primary outcome: Apixaban - 10.5%, VKA - 14.7% (p<0.001)
• Primary outcome: ASA - 16.1%, Placebo - 9% (p<0.001)
• Death or ischemic event: Apixaban - 6.7%, VKA - 7.1% (HR 0.93 [0.75–1.16])
• Death or ischemic event: ASA - 6.5%, Placebo - 7.3% (HR 0.89 [0.71–1.11])
• Findings: In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both

• STUDY
  PIONEER study - VKA + DAPT vs Rivaroxaban 15 mg once daily + P2Y12 inhibitor vs Rivaroxaban 2.5 mg twice daily + DAPT, NEJM (2016) [PubMed abstract]
• Design: Randomized, multi-factorial, controlled trial (N=2124 | length = 12 months) in patients with A fib who had PCI with stents
• Treatment: Rivaroxaban 15 mg once daily + P2Y12 inhibitor for 12 months vs Rivaroxaban 2.5 mg twice daily + DAPT for 1, 6, or 12 months vs VKA + DAPT for 1, 6, or 12 months
• Primary outcome: Clinically significant bleeding (TIMI major or minor bleeding)
• Results:
• Primary outcome: Rivaroxaban 15 mg - 16.8%, Rivaroxaban 2.5 mg - 18%, VKA - 26.7% (1 or 2 vs 3 p<0.001)
• CVD events: Rivaroxaban 15 mg - 6.5%, Rivaroxaban 2.5 mg - 5.6%, VKA - 6% (all comparisons nonsignificant)
• Findings: In participants with atrial fibrillation undergoing PCI with placement of stents, the administration of either low-dose rivaroxaban plus a P2Y12 inhibitor for 12 months or very-low dose rivaroxaban plus DAPT for 1, 6, or 12 months was associated with a lower rate of clinically significant bleeding than was standard therapy with a VKA plus DAPT for 1, 6, or 12 months. The three groups had similar efficacy rates, although the observed broad confidence intervals diminish the surety of any conclusions regarding efficacy.

• STUDY
  ENTRUST study - VKA + P2Y12 + ASA vs Edoxaban + P2Y12 in Patients with A fib and Recent PCI, Lancet (2019) [PubMed abstract]
• Design: Randomized, open-label, controlled trial (N=1506 | length = 12 months) in patients with A fib who had recent PCI for stable CAD or ACS
• Treatment: Edoxaban 60 mg once daily + P2Y12 inhibitor vs VKA + P2Y12 inhibitor + ASA 100 mg once daily
• Primary outcomes:
• Safety: Composite of major or clinically relevant non-major bleeding
• Efficacy: Composite of cardiovascular death, stroke, systemic embolic events, myocardial infarction, and definite stent thrombosis
• Results:
• Primary outcome (safety): Edoxaban - 17%, VKA - 20% (p=0.1154)
• Primary outcome (efficacy): Edoxaban - 7%, VKA - 6% (HR 1.06, 95%CI [0.71 - 1.69])
• Findings: In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events

• BLEEDING RISK FACTORS

• Bleeding risk factors differ among recommendations and trials. The factors listed below are from the AHA DAPT recommendations and the MASTER DAPT study.

• ISCHEMIC/STENT THROMBOSIS RISK FACTORS

• Risk factor for ischemia and stent thrombosis that may favor a longer duration of DAPT are presented in the table below

• OTHER STUDIES

• BIBLIOGRAPHY

• 1 - PMID 27026020 - AHA 2016 DAPT recommendations
• 2 - PMID 23247304 - AHA GL on STEMI
• 3 - PMID 22800849 - AHA GL on non-ST MI
• 4 - PMID 27022822 - DAPT analysis/tool
• 5 - PMID 16908781 AHA 2006 A fib GL
• 6 - PMID 22315257 ACCP GL on thrombosis
• 7 - PMID 23247304 - 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction
• 8 - PMID 22800849 - 2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction
• 9 - PMID 30686041 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation
• 10 - PMID 34449185 - Dual Antiplatelet Therapy after PCI in Patients at High Bleeding Risk, NEJM (2021)