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Triple Antithrombotic Therapy

Prof. Bernadette Rodak of Indiana University forwarded a question about parallel anticoagulant and antiplatelet therapy from the ASCLS Consumer Web Forum. In the interest of confidentiality, I paraphrase the question:

“What should the international normalized ratio (INR) be when on simultaneous antiplatelet therapy (aspirin and clopidogrel) for percutaneous intervention (PCI) stent placement and anticoagulation therapy (Coumadin) for deep venous thrombosis (DVT) and pulmonary emboli (PE)? The patient has a heterozygous factor II mutation, prothrombin 20210, and heterozygous factor V Leiden mutation.”

Here is our initial response: The INR is unaffected by clopidogrel and aspirin therapy, and that the usual limits of 2–3 apply. However, the combination of Coumadin with aspirin and clopidogrel could raise the patient’s bleeding risk, so the patient should be told to watch for easy bruising, nosebleeds, or lengthy bleeding from cuts.

The questioner asked this follow-up: “The patient has decided to discontinue aspirin for safety. Is this a good choice?” Here is our follow-up response:

There seems to be no clear answer. Here is a somewhat inconclusive quote from Hylek EM, Palareti G, Ageno W, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141: 44S–88S.

Although there are no randomized controlled trials that have compared bleeding rates in patients receiving “triple therapy” (usually warfarin, aspirin, and clopidogrel) with either warfarin alone or with a “dual therapy,” a systematic review identified 12 reports involving 3,413 patients treated with oral anticoagulants who underwent percutaneous coronary intervention with stent insertion and subsequently received the combination of aspirin, clopidogrel, and warfarin. The rates of major bleeding in patients receiving triple therapy ranged from 0% to 21% (mean 7.4%) during up to 21 months of follow-up and 0% to 5.9% (mean 2.6%) during 30 days of follow-up. In a Danish nationwide registry of patients with AF, all combinations of warfarin, aspirin, and clopidogrel were associated with an increased risk of nonfatal and fatal bleeding, whereas dual or triple therapy carried a more than threefold higher bleeding risk than warfarin alone.”

The article provides no therapy recommendations for someone requiring both anticoagulant and antiplatelet therapy, however, a March 6 post, “A Dangerous Cocktail, Aspirin and Anticoagulants,” addresses this question and makes reference to the WOEST study, conducted in the Netherlands, that addresses the bleeding risk of aspirin in triple therapy. In particular, the linked audio comment by Dr. Samuel Goldhaber seems to settle the argument in favor of eliminating aspirin.

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