Why can't ticagrelor (P2Y12 inhibitor) and rivaroxaban (factor Xa inhibitor) be used together in a patient with atrial fibrillation (AF) and ST-elevation myocardial infarction (STEMI), particularly in those with advanced heart failure (HF)?

From the Guidelines

Combining ticagrelor and rivaroxaban is not recommended due to the significantly increased risk of bleeding, and instead, clopidogrel should be used as the P2Y12 inhibitor in combination with aspirin and an anticoagulant like rivaroxaban for patients with atrial fibrillation (AF) and ST-elevation myocardial infarction (STEMI), particularly those with advanced heart failure (HF). Both medications are potent antithrombotic agents that work through different mechanisms: ticagrelor is a P2Y12 inhibitor that prevents platelet aggregation, while rivaroxaban is a direct oral anticoagulant (DOAC) that inhibits factor Xa in the coagulation cascade. For a patient with both AF and STEMI who also has advanced HF, medication management becomes particularly challenging.

Key Considerations

• The use of triple therapy (aspirin, P2Y12 inhibitor, and anticoagulant) should be minimized to reduce bleeding risk, often limited to 1-6 months depending on the patient's specific thrombotic and bleeding risks 1.
• After this period, dual therapy with a P2Y12 inhibitor and anticoagulant is typically continued, with clopidogrel being the preferred P2Y12 inhibitor due to its lower bleeding risk compared to ticagrelor 1.
• For patients with advanced HF, careful monitoring of renal function is essential as it affects dosing of rivaroxaban, and these patients may experience fluctuations in renal function that could increase bleeding risk.

Bleeding Risk

• The combination of an oral anticoagulant (OAC) plus dual antiplatelet therapy (DAPT) leads to an increased bleeding risk, and major bleeding is associated with earlier mortality 1.
• Double antithrombotic therapy (OAC plus P2Y12 receptor inhibitor, mostly clopidogrel) after a 1–4 week period of triple antithrombotic therapy in chronic coronary syndrome (CCS) patients with AF undergoing percutaneous coronary intervention (PCI) is recommended to reduce the risk of bleeding without a significant increase in ischemic events 1.

Medication Management

• Ticagrelor or prasugrel should generally not be used as part of triple antithrombotic therapy, while ticagrelor, and possibly prasugrel, may be considered as part of double antithrombotic therapy 1.
• The choice of anticoagulant and antiplatelet therapy should be individualized based on the patient's specific thrombotic and bleeding risks, as well as their renal function and other comorbidities.

From the FDA Drug Label

Concomitant use of other drugs that impair hemostasis increases the risk of bleeding These include aspirin, P2Y 12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7. 4)] , selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.

The use of ticagrelor (a P2Y12 inhibitor) and rivaroxaban (a factor Xa inhibitor) together may increase the risk of bleeding due to their combined effect on impairing hemostasis. This is particularly concerning in patients with atrial fibrillation (AF) and ST-elevation myocardial infarction (STEMI), especially those with advanced heart failure (HF), as they may already be at a higher risk of bleeding complications.

• The concomitant use of these medications may lead to an increased risk of serious or fatal bleeding.
• It is essential to weigh the risk of thrombotic events against the risk of bleeding when considering the use of these medications together.
• Patients should be monitored frequently for signs or symptoms of bleeding, and the need for blood replacement should be considered promptly if bleeding occurs 2.

From the Research

Background

The use of ticagrelor (P2Y12 inhibitor) and rivaroxaban (factor Xa inhibitor) together in patients with atrial fibrillation (AF) and ST-elevation myocardial infarction (STEMI) is a complex issue.

Risks Associated with Combination Therapy

• The combination of ticagrelor and rivaroxaban may increase the risk of bleeding complications, as both drugs have antithrombotic properties 3, 4.
• Patients with AF and STEMI are already at high risk of bleeding due to the use of anticoagulant and antiplatelet therapy 5, 6.
• The addition of rivaroxaban to ticagrelor may further increase this risk, as seen in the GEMINI-ACS-1 phase II study, which compared the safety of rivaroxaban vs aspirin in addition to either clopidogrel or ticagrelor in acute coronary syndrome 7.

Clinical Outcomes

• The RT-AF study aimed to evaluate the safety and efficacy profile of the combination of rivaroxaban and ticagrelor in patients with AF and coronary artery disease undergoing percutaneous coronary intervention 4.
• The study found that the primary endpoint of major or clinically relevant non-major bleeding events at 12 months was higher in the dual therapy group (rivaroxaban and ticagrelor) compared to the triple therapy group (warfarin, clopidogrel, and aspirin).
• Another study found that patients with STEMI who developed new-onset transient AF had higher rates of major bleeding when treated with vitamin K antagonist (VKA) and dual antiplatelet therapy (DAPT) compared to DAPT alone 6.

Advanced Heart Failure

• Patients with advanced heart failure (HF) are at higher risk of bleeding and thrombotic complications due to their underlying condition 5.
• The use of ticagrelor and rivaroxaban together in these patients may further increase this risk, and therefore, requires careful consideration and monitoring.

Current Evidence

• There is limited evidence on the use of ticagrelor and rivaroxaban together in patients with AF and STEMI, particularly in those with advanced HF 3, 4, 5, 6, 7.
• Further studies are needed to determine the safety and efficacy of this combination therapy in this patient population.