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Eight Years Later: How Comfortable Are We Really With Target Specific Oral Anticoagulants (TSOACs) After Cardiothoracic Transplant


Derek Owen, PharmD
Dowen@houstonmethodist.org

Kyle Dawson, PharmD, MBA, BCPS
KLDawson@HoustonMethodist.org
Houston Methodist
Houston, TX, USA



Following dabigatran's approval by the European Medicines Agency in 2008 and by the US Food and Drug Administration in 2010, TSOACs are being prescribed with increasing frequency in the general population to reduce the risk of stroke in patients with atrial fibrillation and to treat venous thromboembolism (VTE) [1]. Three other TSOACs have since been approved including rivaroxaban, apixaban, and edoxaban. Without listing all of the potential benefits of these medications, the ease of use around biopsies and procedures due to their rapid onset/elimination may be appealing for clinicians. While these newer agents are now recommended ahead of warfarin for the treatment of VTE in the general population, comfort with their use in solid organ transplant patients is still growing amongst clinicians [2].

There are many reasons for a potential lack of comfort in using these agents in the transplant population. First and foremost, therapeutic drug monitoring recommendations are not available for the TSOACs. While laboratory monitoring tests do exist, there are not universally accepted therapeutic ranges for these assays. Imagine the difficulty of dosing tacrolimus without the ability to monitor or interpret levels. While not as drastic, the TSOACs share many similarities with tacrolimus in terms of factors that impact AUC and clinical effects.

Many of the TSOACs are substrates of the CYP3A4 enzyme and/or the P-glycoprotein (P-gp) transporter and are therefore subject to drug interactions with medications commonly used in transplant patients. Dose reductions for these agents may depend not only the strength of 3A4 inhibition, but also the presence of P-gp inhibition. For instance, the azole antifungals (eg. fluconazole, voriconazole, posaconazole, itraconazole, and isavuconazonium) all have different degrees of 3A4 and P-gp inhibition and could possibly lead to varying dose adjustments. Additionally, the unpredictable nature of episodes of acute renal or hepatic dysfunction provide another instance where therapeutic drug monitoring would be helpful. It is difficult to know exactly how changes in organ function correlate to drug exposure, clinical efficacy, or risk of bleeding.

Lastly, recommendations for the management of bleeding in patients taking TSOACs are lacking, and with the exception of dabigatran, there are no approved reversal agents for the TSOACs. Evidence is available for the use of 4-factor prothrombin complex concentrates for reversal, however this is not an approved indication [3]. A novel agent, andexanet alfa, is currently being investigated. The combination of these concerns in transplant patients can create a hesitancy to utilize TSOACs that may not be seen in the general population.

Key considerations for the TSCOACs in transplant patients:

There are many options for anticoagulation in transplant patients, including warfarin, LMWHs, and TSOACs. Regimens should be chosen based on patient specific factors, such as need/availability of therapeutic drug monitoring, drug interactions, and the risk/benefit profile of the individual agents. The TSOACs may not replace warfarin or low molecular weight heparin for all cardiothoracic transplant patients, however for the right patient they may provide a safe and effective mode of anticoagulation. ■

Disclosure Statement: The authors have no conflicts of interest to disclose.


References:

  1. Desai, NR, Krumme, AA, Schneeweiss, S. et al. Patterns of initiation of oral anticoagulants in patients with atrial fibrillation-quality and cost implications. Am J Med. 2014;127(11):1075-82.
  2. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy For VTE Disease: Chest Guideline And Expert Panel Report. Chest 2016;149(2):315-352.
  3. Lazo-Langner A, Lang ES, Douketic J. Clinical review: Clinical management of new oral anticoagulants: a structured review with emphasis on the reversal of bleeding complications. Critical Care 2013;17:230.
  4. Pradaxa® (dabigatran) package insert. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc.; 2015 November.
  5. Praxbind (idarucizumab) package insert. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc. ; 2015 October.
  6. Xarelto® (rivaroxaban) package insert. Titusville, NJ. Janssen Pharmaceuticals Inc.; 2016 May.
  7. Eliquis® (abixaban) package insert. Princeton, NJ. Bristol-Myers Squibb Company; 2016 July.
  8. Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016;56(5):628-36.
  9. Savaysa® (edoxaban) package insert. Parsippany, NJ. Daiichi Sankyo, Inc.; 2015 May.



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