Heart disease remains the leading cause of death in the United States. Millions of patients undergo evaluation and treatment for heart disease each year. Understanding how to best treat patients who present with multiple cardiovascular comorbidities is of the utmost importance, particularly when it comes to balancing the risks and benefits to patients with indications for both antiplatelet therapy and oral anticoagulant (OAC) medications.

The efficacy and safety of triple therapy have been areas of key clinical interest. The question of how to ensure adequate thromboembolic protection while limiting the risk of bleeding, especially major bleeding, is critical. A series of trials has been published that examine the use of dual (OAC and P2Y12 inhibitor) or triple (OAC, aspirin, and P2Y12 inhibitor) therapy, specifically focusing on the incidence of bleeding. These data come from trials utilizing a variety of anticoagulants, including the following:

• Warfarin in the WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting) trial in 2013
• Rivaroxaban in PIONEER AF-PCI (An Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention) in 2016
• Dabigatran in RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) in 2017
• Apixaban in the AUGUSTUS (Antithrombotic Therapy After Acute Coronary Syndrome or PCI in Atrial Fibrillation) trial in 2019
• Edoxaban in the ENTRUST-AF PCI (Edoxaban-Based Antithrombotic Regimen in Patients With Atrial Fibrillation) trial in 2019

These studies predominantly focused on patients with atrial fibrillation (AF) and coronary artery disease, either stable ischemic heart disease (SIHD) or acute coronary syndrome (ACS), requiring percutaneous coronary intervention (PCI). Although these additions to the literature have provided much-needed insight, many providers are left wondering exactly what to do for complex patients they see in practice who might not exactly match the patient populations studied in these trials.

Fortunately, the 2020 ACC Expert Consensus Decision Pathway for Anticoagulant and Antiplatelet Therapy in Patients with Atrial Fibrillation or Venous Thromboembolism Undergoing Percutaneous Coronary Intervention or with Atherosclerotic Cardiovascular Disease was recently published by the American College of Cardiology (ACC).¹ This clinical decision pathway highlights four common clinical patient scenarios of patients requiring combination antiplatelet therapy and OAC:

1. Patients with AF on an OAC in need of PCI:
   1. Continue OAC
   2. Recommend low-dose aspirin for the duration of the hospitalization (may consider up to 30 days of triple therapy)
   3. Initiate P2Y12 inhibitor:
      1. Time from PCI for SIHD (drug-eluting stent [DES]):
         1. 0-6 months: P2Y12 inhibitor + OAC
         2. 6-12 months: P2Y12 inhibitor or aspirin + OAC
         3. After 12 months: Stop antiplatelet therapy and continue OAC indefinitely
      2. Time from PCI for ACS (bare-metal stent [BMS] or DES):
         1. 0-12 months: P2Y12 inhibitor + OAC (BMS exception: 1 month P2Y12 inhibitor)
         2. After 12 months: Stop antiplatelet therapy and continue OAC indefinitely
      3. Reasonable to continue aspirin 81 mg daily or clopidogrel 75 mg daily after 12 months if perceived thrombotic risk is high and bleeding risk is low
2. Patients on antiplatelet therapy with new-onset AF requiring OAC:
   1. Start OAC; direct OAC (DOAC) preferred in all patients
   2. Stop antiplatelet therapy if primary reason for antiplatelet therapy is any of the following:
      1. Primary prevention of atherosclerotic cardiovascular disease (ASCVD)
      2. SIHD (no ACS) more than 12 months from PCI or coronary artery bypass grafting (DES/BMS)
      3. History of ACS and more than 12 months from event and/or PCI
      4. History of cerebrovascular disease with no intervention and prior event (transient ischemic attack, carotid endarterectomy, cerebrovascular accident) or carotid stenting (if completed recommended duration of antiplatelet therapy)
      5. History of peripheral arterial disease (PAD) without prior intervention, with prior surgical repair, or after endovascular intervention (if completed recommended duration of antiplatelet therapy)
   3. Stop aspirin and continue P2Y12 inhibitor for standard dual antiplatelet therapy period then stop P2Y12 inhibitor if any of the following apply:
      1. SIHD (no ACS) <6 months (DES) or <1 month (BMS) from PCI
      2. History of ACS ≤12 months from time of event +/- PCI
      3. History of carotid stenting or PAD with endovascular intervention (if recommended duration of antiplatelet therapy not completed)
   4. Continue aspirin or P2Y12 inhibitor until standard dual antiplatelet therapy period completed then stop antiplatelet therapy in patients with SIHD (no ACS) within 6-12 months (DES) or 1-12 months (BMS) from PCI
3. Patients with prior venous thromboembolism (VTE) receiving OAC in need of PCI:
   1. If urgent/emergent PCI or unable to defer elective PCI until after completion of OAC:
      1. Time limited OAC (3 months) after PCI:
         1. Replace OAC with aspirin once OAC therapy for VTE completed
         2. P2Y12 inhibitor for 1 month in ACS (BMS), 6 months in SIHD (DES), or 12 months in ACS (DES):
            1. After 1 month in ACS (BMS) or 6 months in SIHD (DES): Stop P2Y12 inhibitor and continue aspirin only
            2. After 12 months: Follow antiplatelet therapy per 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with Coronary Artery Disease²
      2. Indefinite OAC after PCI for SIHD (DES):
         1. Consider reduced DOAC dose after 6-12 months
         2. Time from PCI for SIHD:
            1. 0-6 months: P2Y12 inhibitor
            2. 6-12 months: Continue P2Y12 inhibitor or switch to aspirin and continue aspirin only
         3. Time from PCI for ACS (BMS/DES):
            1. 0-12 months: P2Y12 inhibitor (BMS exception: 1 month)
         4. After 12 months: Stop antiplatelet therapy and continue OAC, reassess need for indefinite anticoagulation annually
      3. After 12 months from PCI, consider continuation of aspirin with OAC for high-thrombotic-risk/low-bleeding-risk patients
4. Patients on antiplatelet therapy for ASCVD with a new VTE requiring OAC:
   1. Start OAC and stop antiplatelet therapy if any of the following apply:
      1. Primary prevention of ASCVD
      2. SIHD (no ACS) more than 12 months from PCI or coronary artery bypass grafting (DES/BMS)
      3. History of ACS and more than 12 months from event and/or PCI
      4. History of cerebrovascular disease with prior event, without intervention, or carotid stenting (if completed recommended duration of antiplatelet therapy)
      5. History of PAD without prior intervention, with prior surgical repair, or after endovascular intervention (if completed recommended duration of antiplatelet therapy)
   2. Start OAC, stop aspirin, and continue P2Y12 inhibitor if any of the following apply:
      1. SIHD (no ACS) and ≤6 months (DES) or <1 month (BMS) from PCI
      2. History of ACS and time from event and/or PCI ≤12 months
      3. History of carotid stent for cerebrovascular disease or PAD with endovascular intervention (if recommended duration of antiplatelet therapy not completed)
   3. Start OAC and continue aspirin or P2Y12 inhibitor if SIHD (no ACS) 6-12 months (DES) or 1-12 months (BMS) from PCI
   4. Start OAC and continue aspirin if <12 months post coronary artery bypass grafting

In all these clinical scenarios, DOACs are preferred over vitamin K antagonists (VKAs), and clopidogrel is the preferred P2Y12 inhibitor in most patients due to a higher risk of bleeding with ticagrelor and prasugrel. Patients on ticagrelor or prasugrel with new VTE requiring OAC should be switched to clopidogrel. If thrombotic risk is high and bleeding risk is low, adding aspirin 81 mg as part of a triple therapy regimen can be considered for a limited time (i.e., maximum of 30 days after PCI). For patients with AF on an OAC in need of PCI or patients with prior VTE receiving OAC in need of PCI at high risk of bleeding, consider antiplatelet therapy discontinuation at 3 months in SIHD (DES) or 6 months in ACS (DES).

A Key Points to Remember article provides a summary of major takeaway points from the consensus decision pathway (Table 1):³

• Patients at high coronary thrombotic risk, such as those with prior myocardial infarction, complex lesions, extensive ASCVD, and low bleeding risk, may be considered for a short course of triple therapy.
• For patients at high thrombotic risk for whom a triple therapy regimen is chosen, it should be for the shortest period possible (i.e., 30 days maximum).
• Lower doses and intensities of antithrombotic therapies should be utilized when appropriate to minimize bleeding risk:
  • Clopidogrel is the preferred P2Y12 inhibitor in the majority of patients
  • Aspirin dose <100 mg
  • International normalized ratio (INR) goal of 2-2.5
  • Consider the off-label rivaroxaban dosing for patients with non-valvular AF as used in PIONEER AF-PCI (15 mg daily for patients with creatinine clearance ≥50 mL/min, 10 mg daily for patients with creatinine clearance <50 mL/min)
• Patients using 2 or more antithrombotic agents should start or continue a medication for gastrointestinal protection (e.g., proton pump inhibitor or H2 antagonist).

Table 1: Key Takeaways

Common Clinical Patient Scenarios (refer to text for details)	Patients with AF on an OAC in need of PCI Patients on antiplatelet therapy with new-onset AF requiring OAC Patients with prior VTE receiving OAC in need of PCI Patients on antiplatelet therapy for ASCVD with a new VTE requiring OAC
Minimize Bleeding Risk	Preferred OAC: DOACs (lower risk of major, intracranial, and fatal bleeding) Preferred P2Y12 inhibitor: Clopidogrel Limit aspirin doses to <100 mg Minimize duration of triple therapy (i.e., 30 days maximum) Utilize low-dose OAC when possible: INR goal: 2-2.5 Off-label rivaroxaban dose for non-valvular AF: Creatinine clearance ≥50 mL/min: 15 mg daily with dinner Creatinine clearance <50 mL/min: 10 mg daily VTE ≥6 months ago on indefinite anticoagulation consider either of the following: Rivaroxaban 10 mg daily Apixaban 2.5 mg twice daily
VKA	Consider switching to DOAC when possible. Consider bridging for high-thromboembolic-risk patients (e.g., within 3 months of a VTE, hypercoagulable state, left atrial or left atrial appendage thrombus, complete INR reversal or parenteral vitamin K administration prior to PCI). If not bridging, continue aspirin 81 mg daily until the INR is in the therapeutic range.
Cancer-Associated Thrombosis	DOAC (preferred overall), low molecular weight heparin (preferred over VKA), or VKA
Gastrointestinal Protection	Start a proton pump inhibitor or H2 antagonist for patients on ≥ 2 antithrombotic medications

Managing patients with indications for multiple antithrombotic therapies is a balancing act with a major goal of minimizing the risk of bleeding while maintaining efficacy for prevention of thromboembolic events. The combination of randomized clinical trials and a consensus decision pathway for common clinical scenarios provides practitioners with much-needed guidance to care for complex cardiovascular patients requiring antithrombotic therapy.

References

1. Kumbhani DJ, Cannon CP, Beavers CJ, et al. 2020 ACC Expert Consensus Decision Pathway for Anticoagulant and Antiplatelet Therapy in Patients With Atrial Fibrillation or Venous Thromboembolism Undergoing Percutaneous Coronary Intervention or With Atherosclerotic Cardiovascular Disease: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2021;77:629-58.
2. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;68:1082-115.
3. Barnes GD. 2020 ACC Expert Consensus Pathway for Anticoagulant and Antiplatelet Therapy (www.acc.org). December 18, 2020. Available at: https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2020/12/17/21/04/2020-acc-expert-consensus-anticoagulant-antiplatelet. Accessed January 4, 2021.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Cardiovascular Care Team, Invasive Cardiovascular Angiography and Intervention, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and ACS, Anticoagulation Management and Atrial Fibrillation, Anticoagulation Management and Venothromboembolism, Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Vascular Medicine

Keywords: Patient Care Team, Platelet Aggregation Inhibitors, Fibrinolytic Agents, Warfarin, Antithrombins, Drug-Eluting Stents, Anticoagulants, Aspirin, Atrial Fibrillation, Percutaneous Coronary Intervention, Coronary Artery Disease, Acute Coronary Syndrome, Ischemic Attack, Transient, Venous Thromboembolism, Peripheral Arterial Disease, Endarterectomy, Carotid, Consensus, Cardiovascular Diseases, Cause of Death, Hospitalization, Stroke, Vitamin K, Primary Prevention, Coronary Artery Bypass, Risk Assessment, Reference Standards

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