Direct oral anticoagulant considerations in solid organ transplantation: A review

Abstract

For more than 60 years, warfarin was the only oral anticoagulation agent available for use in the United States. In many recent clinical trials, several direct oral anticoagulants (DOACs) demonstrated similar efficacy with an equal or superior safety profile, with some other notable benefits. The DOACs have lower inter- and intrapatient variability, much shorter half-lives, and less known drug-drug and drug-food interactions as compared to warfarin. Despite these demonstrated benefits, the use of DOACs has not gained uniform acceptance because of lack of supportive data in special patient populations, including recipients of solid organ transplants maintained on immunosuppression. This review describes the properties of several novel DOACs including their pharmacology and mechanisms of action as they relate to use among solid organ transplant recipients. We have particularly focused on (i) dosing in patients with impaired renal and hepatic function; (ii) considerations for drug-drug interactions with immunosuppressive medications; and (iii) management of the anticoagulated patients at the time of unplanned surgery. The risks and benefits of the use of DOACs in solid organ transplant recipients should be carefully evaluated prior to the introduction of these agents in this highly distinct patient population.

Safety of direct‐acting oral anticoagulants relative to warfarin in a matched cohort of liver transplant recipients

“…Patients prescribed DOACs were matched with warfarin controls based on 7 discrete clinical parameters chosen by investigator consensus and review of previous literature, using an exact greedy matching algorithm: type of transplant (orthotopic, living donor, or simultaneous liver/kidney), age (<65 or ≥65), history of hepatocellular carcinoma, indication for anticoagulation (atrial fibrillation or current/prior thromboembolism), HAS‐BLED score, timing of anticoagulant prescription (≤30 days post‐transplant or >30 days post‐transplant), and duration of anticoagulation (≤1 year or >1 year) . DOAC‐treated patients who could not be matched with a warfarin control were still included in the descriptive analysis of DOAC prescribing, but were not considered in any of the head‐to‐head comparisons or multivariable modeling (Figure ).…”

“…Thrombotic diseases can occur both arterially (acute coronary syndromes, ischemic stroke, hepatic artery thrombosis) and in the venous system (deep vein thrombosis, pulmonary embolism, portal vein thrombosis), with incidence rates ranging from 2% to 10% following liver transplantation . A variety of surgical thrombotic risk factors including release of tissue factor, ischemia reperfusion injury, venous stasis due to immobility and surgical clamping, and platelet hyper‐reactivity can potentiate thrombus formation . Patient‐specific risk factors can also contribute to overall thrombotic risk peri‐transplant as a number of the etiologies of chronic liver disease are associated with an increased risk for systemic thrombosis including Budd‐Chiari syndrome, hepatocellular carcinoma, primary sclerosing cholangitis, and primary biliary cirrhosis …”

“…A variety of surgical thrombotic risk factors including release of tissue factor, ischemia reperfusion injury, venous stasis due to immobility and surgical clamping, and platelet hyper‐reactivity can potentiate thrombus formation . Patient‐specific risk factors can also contribute to overall thrombotic risk peri‐transplant as a number of the etiologies of chronic liver disease are associated with an increased risk for systemic thrombosis including Budd‐Chiari syndrome, hepatocellular carcinoma, primary sclerosing cholangitis, and primary biliary cirrhosis …”

“…While these agents present an attractive therapeutic option for patients and providers owing to their relative ease of administration and reduced rates of major bleeding in large randomized trials, concerns still remain regarding the use of these medications in the liver transplant population . Each of these agents is at least partially metabolized or excreted via P‐glycoprotein (Pgp) or the cytochrome P450 (CYP450) enzyme system which can be altered by calcineurin inhibitor‐based immunosuppression . Pharmacokinetic studies have also demonstrated altered CYP450 enzymatic activity following liver transplantation when compared with healthy controls, suggesting that even in a functioning transplant allograft enzyme activity does not return entirely to baseline .…”

“…Pharmacokinetic studies have also demonstrated altered CYP450 enzymatic activity following liver transplantation when compared with healthy controls, suggesting that even in a functioning transplant allograft enzyme activity does not return entirely to baseline . Variable renal and hepatic function post‐transplant can also serve as sources of inter‐ and intra‐patient pharmacokinetic variability, and lack of routine access to timely therapeutic drug monitoring presents potential safety concerns . These factors, in combination with the relative paucity of data describing the use of DOACs following liver transplantation, have thus far limited DOAC uptake in the liver transplant population …”