What is the interaction between Direct Oral Anticoagulant (DOAC) and dual antiplatelet therapy with Brilinta (Ticagrelor) and Plavix (Clopidogrel)?

From the Guidelines

Taking a direct oral anticoagulant (DOAC) together with both Brilinta (ticagrelor) and Plavix (clopidogrel) is generally not recommended due to the significantly increased risk of bleeding. This combination would involve three different medications that all reduce blood clotting through different mechanisms. According to the 2024 ESC guidelines for the management of chronic coronary syndromes 1, the use of ticagrelor or prasugrel is generally not recommended as part of triple antithrombotic therapy with aspirin and an OAC.

In patients with an indication for oral anticoagulation (OAC) who undergo percutaneous coronary intervention (PCI), initial low-dose aspirin once daily is recommended in addition to OAC and clopidogrel 1. However, the combination of a DOAC with both Brilinta and Plavix is not supported by the guidelines.

Some specific high-risk situations may require dual therapy with a DOAC and a single antiplatelet medication, such as after certain types of heart attacks or stent placements in patients who also have atrial fibrillation 1. Even in these cases, the duration of dual therapy should be limited, and the risk of bleeding carefully weighed against the potential benefits.

The risk of major bleeding complications with triple therapy can be life-threatening, and the benefit rarely outweighs this risk except in very specific clinical scenarios that require expert management 1. If you are currently taking this triple combination, you should contact your healthcare provider immediately to review your medication regimen.

Key points to consider:

• The use of ticagrelor or prasugrel is generally not recommended as part of triple antithrombotic therapy with aspirin and an OAC 1.
• Dual therapy with a DOAC and a single antiplatelet medication may be considered in specific high-risk situations, but the duration should be limited 1.
• The risk of major bleeding complications with triple therapy can be life-threatening, and the benefit rarely outweighs this risk except in very specific clinical scenarios that require expert management 1.

From the FDA Drug Label

In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and XARELTO (15 mg single dose) were coadministered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively The change in bleeding time was approximately twice the maximum increase seen with either drug alone. There was no change in the pharmacokinetics of either drug Neither enoxaparin nor warfarin affected the pharmacokinetics of rivaroxaban NSAIDs/Aspirin In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding.

The use of DOAC (Direct Oral Anticoagulant), such as rivaroxaban, with Brilinta (ticagrelor) and Plavix (clopidogrel) may increase the risk of bleeding due to their antiplatelet effects.

• Key points:
  • Increased bleeding time with concomitant use of clopidogrel and rivaroxaban
  • No change in pharmacokinetics of either drug
  • Aspirin use is an independent risk factor for major bleeding Based on the available data from the drug label 2, the concomitant use of rivaroxaban with Brilinta and Plavix may increase the risk of bleeding. However, the exact clinical implications of this combination are not explicitly stated in the label.

From the Research

Combination of DOAC with Brilinta and Plavix

• The combination of antiplatelet and anticoagulant therapy can be indicated in certain clinical situations, such as after coronary intervention in patients with atrial fibrillation 3.
• The use of low-dose rivaroxaban and aspirin has been shown to reduce major adverse cardiovascular events and major adverse limb events in patients with high-risk atherosclerosis 3.
• However, every combination of antiplatelet and antithrombotic drugs can increase bleeding risk, and a careful assessment of thrombotic versus bleeding risk is necessary for each patient 3, 4.

Risks and Benefits of Triple Therapy

• The combination of anticoagulant and antiplatelet therapy has been shown to be more effective than antiplatelet therapy alone for the initial and long-term management of acute coronary syndromes, but increases the risk of bleeding 4.
• The benefits of triple therapy, including the combination of DOAC, Brilinta (ticagrelor), and Plavix (clopidogrel), outweigh the risks in patients with atrial fibrillation and coronary stents, but requires evaluation in randomized trials 4, 5.
• Consensus guidelines recommend that patients with atrial fibrillation who undergo PCI or have an ACS event should be treated with triple antithrombotic therapy for 7 days or less, followed by double antithrombotic therapy for 6 to 12 months 5.

Bleeding Outcomes with DOAC and Antiplatelet Therapy

• Combined anticoagulant and antiplatelet use has been associated with increased bleeding risk without providing additional protection against thrombosis 6.
• The major bleeding rate and clinically relevant non-major bleeding rate were not significantly increased with the addition of antiplatelet therapy to DOAC therapy, but the sample size limits drawing conclusions about the safety of these regimens 6.