Many patients receiving dual antiplatelet therapy for ACS or after receiving a stent may also require anticoagulant therapy for stroke prevention, leading to increased usage of triple antithrombotic therapy (clopidogrel, aspirin, and warfarin). “But although triple therapy can prevent both thromboembolism and stent thrombosis, it is also associated with significant bleeding hazards,” write David Holmes and colleagues in a JACC White Paper on combining atiplatelet and anticoagulant therapies. “Furthermore, when bleeding events do occur, the challenge of balancing the risk of stent thrombosis or stroke and the need for hemostasis requires considerable expertise.”

Following a review of currently available drugs and indications, the authors go on to review the potential impact on triple therapy of new agents, including the factor Xa antagonists, third generation thienopyridines such as prasugrel, and PAR-1 antagonists. Of the factor Xa antagonists, Homes et al write: “although these novel agents might eventually replace warfarin, available data suggest that when they are administered in combination with antiplatelet therapies, bleeding risk will be increased.”

In their conclusion, the authors notes that triple antithrombotic therapy “is associated with an increase in bleeding complications that might range from mild or moderate to severe or life-threatening.” Therapy should “be limited to the time necessary for stent endothelialization in patients at high risk for bleeding events” since “risk increases with the duration of therapy.”

“Before committing a patient to triple therapy for an indefinite period, the physician should carefully consider approaches that might not require prolonged dual antiplatelet therapy in conjunction with warfarin. For patients who require triple therapy, careful follow-up is indicated, with low-dose (<100 mg) ASA, conventional dose (75 mg) clopidogrel, a lower target INR (approximately 2.0), and consideration of prophylactic proton-pump inhibition.”

Sanjay Kaul sent the following comment to CardioBrief:

“I agree with the overall recommendations for triple therapy: low-dose aspirin (less than 100mg), 75 mg clopidogrel, and target INR of approximately 2.0. However, given the potential interaction between clopidogrel and PPIs, it is prudent to avoid routine prophylactic use of PPIs.”

“It is important to keep in mind the lack of high-quality evidence that informs these recommendations. We do not know the dose of aspirin that has an optimal benefit-risk profile either when administered alone or in combination with other antithrombotic agents. The optimal time and dose for clopidogrel pretreatment or the duration of treatment post-stenting is also not clear. Finally, the target INR which maximizes the adjunctive effect of warfarin and minimizes its bleeding complications is also not known. Thus, we need to interpret the data with caution and apply them with prudence when making clinical decisions.”