A Review of Direct-acting Oral Anticoagulants and Their Use in Solid Organ Transplantation : Transplantation

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A Review of Direct-acting Oral Anticoagulants and Their Use in Solid Organ Transplantation

Rimsans, Jessica PharmD, BCPS1; Sylvester, Katelyn PharmD, BCPS, CACP1; Kim, Miae PharmD, MS, BCPS2; Connors, Jean M. MD3,4; Gabardi, Steven PharmD, BCPS4,5

Author Information
doi: 10.1097/TP.0000000000004195
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Abstract

For over 50 years, warfarin and low-molecular-weight heparins (LMWHs) were considered first-line anticoagulants for the prevention of stroke in nonvalvular atrial fibrillation (NVAF), as well as for the treatment and prevention of venous thromboembolism (VTE), and, more recently, a thromboembolic disease associated with the coronavirus infection1; however, because of the limitations of these older agents, such as the need for frequent monitoring, dose adjustments in renal dysfunction, and implementation of dietary restrictions, coupled with the risk of bleeding and difficulty with self-administering subcutaneous dosage forms, the direct-acting oral anticoagulants (DOACs) have begun to supplant the use of warfarin and LMWHs in the general population. In comparison with warfarin, DOACs do not require continual laboratory monitoring, have fewer drug and food interactions, and have a rapid onset and offset of pharmacologic effect but are dogged by their renal clearance and potential for drug–drug interactions.2 These pharmacologic characteristics would appear to be ideal for transplant candidates and recipients. The general clinical characteristics of the available DOACs are summarized in Table 1.

TABLE 1. - Direct-acting oral anticoagulant characteristics24
Apixaban Edoxaban Rivaroxaban Dabigatran
Trade name Eliquis Savaysa Xarelto Pradaxa
Mechanism of action Binds free and bound FXa Binds free and bound FXa Binds free and bound FXa Binds free and bound thrombin
Bioavailability 50% 62% 80%–100% 3%–7%
Protein binding 87% 55% 92%–95% 35%
Primary clearance 56% fecal 50% renal 67% renal 80% renal
Time to peak concentration 3–4 h 1–2 h 2–3 h 1.5–3 h
Half-life a 12 h 10–14 h 5–13 h 12–14 h
FDA-approved reversal agent Andexanet alfa None Andexanet alfa Idarucizumab
aRenal function dependent.
FDA, US Food and Drug Administration; FXa, oral factor Xa.

Data on the safety and efficacy of the DOACs in the solid organ transplant (SOT) population are limited, leaving clinicians to contemplate if these agents are best for their waitlist and/or posttransplant patients. Because of advances in medical therapy, such as extracorporeal circulatory life support and mechanical circulatory support, patients awaiting transplant are living longer with comorbid conditions, such as NVAF, that necessitate long-term anticoagulation. Other risk factors, such as prolonged immobility, presence of a central venous catheter, and cardiac implantable cardioverters, in conjunction with patient-specific factors, such as obesity, older age, and renal dysfunction, may all increase the risk for a VTE.3,4 Use of DOACs requires careful consideration for drug interactions, drug dosing based on renal or hepatic dysfunction, and transplant waitlist status. Managing anticoagulation in transplant patients receiving DOACs that require unplanned surgery and/or organ biopsy can be challenging. Reviews on DOACs in the nontransplant population have been published evaluating their pharmacology, pharmacokinetics, dosing, adverse event data, and pharmacoeconomics; therefore, these topics will not be included in this article. This review aims to appraise the available literature regarding anticoagulation use in SOT recipients, focusing on pre-, peri- and postoperative DOAC use.

LITERATURE SEARCH

In July and again in December 2021, a systematic search was completed to identify articles describing the safety and efficacy of the DOACs in SOT recipients. PubMed and EMBASE were searched for English-language articles using the search terms “direct-acting oral anticoagulant,” “DOAC,” “apixaban,” “dabigatran,” “edoxaban,” or “rivaroxaban,” along with “organ transplant,” “transplantation,” “transplant,” “kidney transplant,” “liver transplant,” “lung transplant,” “pancreas transplant,” and “heart transplant.”

PRETRANSPLANT CONSIDERATIONS

The appropriate selection of anticoagulation in SOT candidates is challenging for a multitude of reasons, including choosing the correct agent in the presence of coagulation abnormalities, evaluating the patient’s individual risk for bleeding, perceived waiting time of the individual transplant candidate, perioperative management of anticoagulation at the time of transplant, and heparin-induced thrombocytopenia (HIT), which may impact use of cardiopulmonary bypass (CPB). Patients awaiting SOT are often medically complex and at a higher risk of bleeding than the general atrial fibrillation (AF) population.5,6 In general, these patients may be malnourished, have disturbances in renal and hepatic drug clearance, and alterations in coagulation and hemostatic factors, such as thrombocytopenia, factor 7 deficiency, elevated international normalized ratio (INR), activated partial thromboplastin time (aPTT), or low von Willebrand factor.7,8 Lastly, sporadic availability of deceased donor organs has forced transplant practitioners to focus on the use of reversible anticoagulants, such as continuous infusion of unfractionated heparin (CI UFH), LMWH, or warfarin. Coagulation disturbances associated with severe liver dysfunction and critical illness or in sensitized patients receiving plasmapheresis and intravenous immunoglobulin therapy further complicate the anticoagulation management of the SOT candidate.

In patients awaiting liver transplant and other SOT candidates with any degree of liver dysfunction, there are disturbances to all phases of hemostasis; therefore, careful consideration is needed in interpreting abnormal laboratory values in these patients.7,8 In the acute or periprocedural setting, patients may require a short-acting anticoagulant, such as CI UFH, which requires laboratory monitoring via aPTT or antifactor Xa. The aPTT may be prolonged at baseline; thus, the use of an antifactor Xa assay may be required.9 It has been shown that monitoring heparin anti-Xa levels may prove beneficial in decreasing the frequency of monitoring, reducing dose changes, and improving the time to therapeutic anticoagulation; however, no difference in clinical outcomes has been consistently demonstrated.10 If antifactor Xa monitoring is initiated, a therapeutic range of 0.3 to 0.7 IU/mL is generally acceptable; however, this should be correlated with a therapeutic heparin concentration within each institution.9

Although rates of bleeding with DOACs compared with vitamin K antagonists (VKA) were lower in the general population, the bleeding rates among SOT candidates taking a DOAC have not been well studied.11-18 In general, one can theorize that DOAC bleeding risks may be increased in pretransplant patients because of underlying alterations in drug clearance and the potential for drug–drug interactions, leading to higher than expected concentrations of these agents compared with those observed in the clinical trials.19 Despite these concerns, in a 2019 national survey of transplant pharmacists, 43 transplant programs (out of 115 unique respondents; 37.4%) allowed DOAC use in their waitlist patients.20 Solid-organ transplantation is considered a high-bleed risk surgical procedure; therefore, diligent management of patients receiving DOACs is required. A unique challenge associated with DOAC use in most organ transplants is the inability to plan for an exact surgical date. This is alleviated during a living donor transplant. The American College of Cardiology offers recommendations on DOAC discontinuation before a low- and high-bleed risk surgical procedure, which stratifies their recommendations based on specific agents and a patient’s degree of renal function.21,22 A summary of these recommendations can be seen in Table 2.

TABLE 2. - Recommendations for preprocedural DOAC discontinuation21,22
Apixaban, edoxaban, rivaroxaban – days before procedure to discontinue drug therapy Dabigatran – days before procedure to discontinue drug therapy
Low-bleed risk procedure High-bleed risk procedure Low-bleed risk procedure High-bleed risk procedure
CrCl >80 mL/min >1 d >2 d >1 d >2 d
CrCl 50–79 mL/min >1 d >2 d >1.5 d (36 h) >3 d
CrCl 30–49 mL/min >1 d >2 d >2 d >4 d
CrCl 15–29 mL/min >1.5 d (36 h) No data; consider DOAC-specific anti-Xa monitoring with discontinuation > 3 d >3 d >5 d
CrCl <15 mL/min No data; consider DOAC-specific anti-Xa monitoring with discontinuation >3 d No data; consider DOAC-specific anti-Xa monitoring with discontinuation >3 d No data; consider dilute thrombin time monitoring with discontinuation >4 d No data; no recommendation
CrCl, creatinine clearance; DOAC, direct-acting oral anticoagulant.

In patients on the deceased donor organ waitlist, delaying transplant surgery to allow for physiologic DOAC clearance is not possible because of the time constraints of organ viability. Thus, having a readily reversible anticoagulant is preferred. This is often the driving factor in many transplant centers requiring patients to be on warfarin or an LMWH, depending on their United Network for Organ Sharing waitlist category. Some institutions convert all patients on the deceased donor waitlist to warfarin or LMWH before being made active. Given that all anticoagulated patients waiting for SOT need urgent reversal before surgery, warfarin remains the preferred oral agent in this setting because of the availability and duration of reversal agents such as intravenous (IV) vitamin K and 4-factor prothrombin complex concentrate (4F-PCC). Some transplant centers may allow waitlisted patients to use a DOAC and delay the transition to warfarin depending on their waitlist status or the likelihood of an imminent organ transplant, but this comes with the risk of losing an opportunity for an available donor and canceling the surgery if the transition is not made in time or utilizing 4F-PCC to facilitate surgery. If all the other factors that affect the wait time (ie, blood type, body size, sensitization status, and accumulated wait time, etc) stay the same, wait time is expected to be correlated with their waitlist status23; however, it is difficult to predict when patients will be transplanted, and thus, DOAC use in the pretransplant population may be limited. For clinicians that encounter a pretransplant patient taking a DOAC at the time of the transplant, both dabigatran and the oral Xa inhibitors have Food and Drug Administration (FDA)-approved reversal agents. Idarucizumab is approved for dabigatran reversal before urgent/emergent surgery, and andexanet alfa is indicated for life-threatening or uncontrolled bleeding for patients on apixaban or rivaroxaban.24 Some literature exists describing the use of dabigatran in patients undergoing organ transplant after reversal with idarucizumab.25 Studies and case series outlining the efficacy of idarucizumab use before transplant are summarized in Table 3. Notwithstanding the availability of a reversal agent, dabigatran use among transplant candidates has declined because of its dependence on renal elimination and higher rates of bleeding than the oral factor Xa inhibitors.11,12,26-31 Anticoagulant reversal is further detailed in the section on the periprocedural period.

TABLE 3. - Data for reversal of anticoagulation with idarucizumab
Study Population DOAC Reversal strategy Outcomes
Rimsans et al, 2017 26 Heart transplant Dabigatran 150 mg twice daily – last dose morning of donor heart notification (6 h before reversal) Idarucizumab 2.5 grams ×2 Procedure uncomplicated, no blood products given
CPB time 98 min
Tralhao et al, 2017 27 Heart transplant Dabigatran 110 mg twice daily– last dose 12 h prior Idarucizumab 2.5 grams ×2 Transfusion: 4 units of FFP, 1u platelets were administered in the OR
CPB time 120 min
The postoperative period was uneventful; total CT output was 1125 mL after 3 d
Pollack et al, 2017 28 Bleeding and urgent surgery patients – 3 heart transplant included in the landmark trial Dabigatran Idarucizumab 2.5 grams ×2 Median time to the initiation of the intended procedure was 1.6 h; periprocedural hemostasis was assessed as normal in 93.4% of the patients
24 h sustained reversal
Jozwik et al, 2018 29 Pancreas and kidney transplant in HIT positive patient Dabigatran 150 mg – received dose morning of procedure Received an extra 3 h hemodialysis session. No idarucizumab given Notable tissue bleeding during surgery but did not impede procedure
TT returned to normal about 120 h after the last dose dabigatran
Received 2 units PRBC 24 h after procedure.
Herrera-Escandon et al, 2020 30 Heart transplant Dabigatran 150 mg twice daily – last dose 13 h before reversal idarucizumab 2.5 grams ×2 Received 3 u PRBC
Total CT output by 48 h was 1045 mL
Kalmanovich et al, 2021 31 10 patients undergoing heart transplant Dabigatran Idarucizumab 2.5 grams ×2
Harano et al, 2021 60 6 patients undergoing lung transplant Dabigatran Only 4 patients received idarucizumab 2.5 grams ×2 These 4 patients received a median of 3 units PRBC (range 0–4u) and had 450 mL blood loss
Crespo-Leiro et al, 2019 61 53 patients on dabigatran undergoing heart transplant Dabigatran Idarucizumab 2.5 grams ×2 7.5% required reoperation for bleeding
66% received blood transfusion
30 d survival was 92.4%
No data currently exists supporting andexanet alfa use in solid organ transplantation given limited experience and short half-life.
CPB, cardiopulmonary bypass; CT, chest tube; DOAC, direct-acting oral anticoagulant; FFP, fresh frozen plasma; HIT, heparin-induced thrombocytopenia; OR, operating room; PRBC, packed red blood cells; TT, thrombin time.

Another important issue to evaluate in the pretransplant population receiving anticoagulation is the potential for HIT. Many patients, especially those awaiting cardiothoracic transplant, warrant anticoagulation therapy for NVAF or VTE before transplant and thus may have repeated or prolonged exposures to heparin products increasing the risk for developing HIT. Patients supported with a left ventricular assist system before heart transplant may also have significant pretransplant heparin exposure. Developing HIT before transplant is problematic because it complicates the use of heparin intraoperatively, which is required for CPB.32 HIT is a rare, life-threatening immune reaction associated with thrombocytopenia and both arterial and venous thromboembolic events.33 This complication occurs in 0.2% of the general medical and surgical population but can be seen in up to 5% of cardiothoracic patients.33,34 Generally following transplantation, the incidence of HIT appears to be very low.35 The management of those with a positive HIT antibody requires discontinuing all heparin products and utilizing alternative anticoagulation with an IV direct thrombin inhibitor (IV DTI), fondaparinux, or a DOAC.33 Data supporting the use of a nonheparin anticoagulant during CPB are limited, and concerns for reversibility and bleeding remain.36-38 One strategy for those patients who are United Network for Organ Sharing status 1 or 2 is to avoid heparin exposure and utilize bivalirudin or warfarin preoperatively to decrease the development of HIT antibodies that would complicate transplant surgery. For patients who develop HIT before transplant, options that have been described in the literature to remove or accelerate clearance of HIT antibodies temporarily are intravenous immunoglobulin, rituximab, or plasmapheresis immediately preoperatively, but these strategies still require approximately 2 months before re-exposure of UFH.39 Often a patient is inactivated from the transplant list until clearance of HIT antibodies occurs if heparin is required during transplant. HIT resolution can be monitored using both immunological and functional laboratory testing in addition to clinical characteristics. IgG platelet factor 4 (PF4) enzyme-linked immunosorbent assay is an immunoassay that detects anti-PF4/heparin antibodies that may or may not be pathological. Once detected, anti-PF4/heparin antibodies are typically cleared within 85 d (median), however, ranging from 3 months to up to 1 y. The serotonin release assay (SRA) is a functional assay that detects platelets activated caused by PF4/heparin antibodies. The SRA becomes negative after about 50 d (median).40 In the case that surgery cannot be delayed at least 3 months (ie, patients who are listed as status 1 or 2 on the heart/lung transplant list), surveillance of clinical-pathologic antibodies via the SRA is recommended to determine when patients can be reactivated on the transplant list and proceed with heparin intraoperatively.41

TIME OF TRANSPLANT CONSIDERATIONS

The anticoagulated patient awaiting SOT should have a plan in place for periprocedural anticoagulation management for when an organ becomes available (Figure 1). The plan for an anticoagulation reversal at the time of transplant will depend on the institution’s practice and available agents on formulary (ie, andexanet, idarucizumab, or 4F-PCC), timing of the surgery, the end-organ function of the recipient (for drug clearance), the type and duration of surgery, the need for anticoagulation during the surgery, and the anticoagulation regimen before surgery. In the case of a living donor transplant, a perioperative anticoagulation strategy should be devised with a multidisciplinary care team using approved organization protocols or guidelines. In general, a living donor transplant surgery can be timed, and the preoperative anticoagulation strategy can be coordinated, similar to other planned surgeries, to mitigate the risks of bleeding and thrombosis (Table 2). The plan should consider the recipient’s baseline thrombotic risk and indication for anticoagulation, the pharmacokinetics of the pretransplant anticoagulant, and the renal function of the recipient. Since SOT surgeries are classified as high-bleeding risk, they require normalization of coagulation parameters before surgery. In the event of a deceased donor transplant, the timing of surgery cannot be planned in advance, and an emergent reversal strategy is required. If available, coagulation laboratory values may be useful to guide management. Standard coagulation assays, such as the PT/INR and aPTT, do not offer significant insight perioperatively (Table 4).2,26,42-44

TABLE 4. - Nonspecific coagulation laboratory parameters2,42–44,103
Dabigatran Apixaban/edoxaban/rivaroxaban
Drug present TT Antifactor Xa (calibrated to LMWH/UFH)
*Other possible labs: possibly chromogenic antifactor Xa calibrated to each drug
Quantitative test dTT N/A
*Other possible labs possibly chromogenic antifactor Xa calibrated to each drug
Sensitivity: PT vs aPTT aPTT > PT/INR PT > aPTT
Anti-Xa calibrated to LMWH/UFH – not as predictable/accurate
aPTT, activated partial thromboplastin time; dTT, dilute thrombin time; INR, international normalized ratio; LMWH, low-molecular-weight heparin; N/A, not available; PT, prothrombin time; TT, thrombin time; UFH, unfractionated heparin.

F1
FIGURE 1.:
Considerations for anticoagulation before living donor or deceased donor transplant. 4F-PCC, 4-factor prothrombin complex concentrate; aPTT, activated partial thromboplastin time; CPB, cardiopulmonary bypass; DTI, direct thrombin inhibitor; Fxai, oral factor Xa inhibitor; Hep, heparin; INR, international normalized ratio; LMWH, low-molecular-weight heparin; TT, thrombin time; UFH, unfractionated heparin; VKA, vitamin K antagonist.

Scenarios may arise where assessing the anticoagulation effect of a DOAC may be warranted. The use of coagulation laboratory assays in DOACs is controversial but may be helpful in select scenarios, such as in patients who are extremely obese, with severely impacted renal or hepatic function in conjunction with known drug–drug interactions, and those undergoing a surgical procedure or in assessing absorption or adherence. Standard coagulation assays, such as the PT/INR or the aPTT, are unable to quantify the level of anticoagulation intensity from the DOACs, as the significant anticoagulant effect may still be present despite normal or near-normal results.25,45 Other assays, such as the antifactor Xa assay, calibrated to LMWH/UFH, can detect the presence of an oral factor Xa inhibitor but do not quantify the intensity. This test may be useful if a calibrated assay to the specific factor Xa inhibitor is not available. Often, the lower limit of normal, <0.1 U/ml, has been used as a marker of normal coagulation status and is acceptable to proceed with surgery.45 Although not readily available in most hospitals in the United States, the antifactor Xa assays calibrated to either apixaban or rivaroxaban can be used to quantify the concentration of the anticoagulant in the sample and may provide greater insight into the degree of anticoagulation (Table 5).42-44 The reference ranges listed are observed peak and trough levels from the landmark clinical trials of each DOAC based on the indication and have not been validated for safety and efficacy. Given this, these levels are not considered to target therapeutic ranges but should only be used for reference.

TABLE 5. - Observed concentration levels for the direct-acting oral anticoagulants.2,12-18,42-45,103
Apixaban Edoxaban Rivaroxaban Dabigatran
NVAF peak (ng/mL) 91–321 12–245 184–343 117–275
NVAF trough(ng/mL) 41–230 19–62 12–137 61–143
VTE treatment peak (ng/mL) 59–302 N/A 22–535 117–275
VTE treatment trough (ng/mL) 22–177 N/A 6–239 61–143
FDA-approved reversal agent Andexanet alfa None Andexanet alfa Idarucizumab
The references ranges in this table are observed peak and trough levels from the landmark clinical trials and have not been validated for safety and efficacy. These levels should be used with caution depending on the clinical scenario.
FDA, US Food and Drug Administration; N/A, not available; NVAF, nonvalvular atrial fibrillation; VTE, venous thromboembolism.

The Subcommittee on Control of Anticoagulation of the International Society on Thrombosis and Haemostasis recommends, based on expert opinion, that patients on apixaban or rivaroxaban requiring an emergent surgery that is associated with a high risk of bleeding be considered for a reversal agent if the antifactor Xa level exceeds 30 ng/mL.21,46 As these cutoff levels are estimates based off retrospective analyses and expert opinion, the clinical utility of an elevated measurement remains unknown, and clinicians are advised to proceed with caution.21,42,46

Risk Stratification for Anticoagulation Interruption

For patients at low-to-moderate risk of thromboembolism, interruption of anticoagulation for a duration, based on estimated drug clearance may be adequate. For patients on therapeutic doses of warfarin, a 5-d hold is generally sufficient to achieve an INR of <1.3 and proceed to surgery; however, a longer hold may be required for patients with liver dysfunction, older age, smaller dose requirements, and preoperative supratherapeutic INR.21 Before surgery, an INR should be checked to ensure it is within an acceptable range. If the INR is still elevated, a small dose of IV vitamin K may be required to normalize the INR.46 For patients on DOACs, the duration of hold before surgery ranges from 2 to 5 d (Table 2) depending on the pharmacokinetics of the agent and the renal function of the transplant recipient.21,46,47

Patients at a high risk of thromboembolism during interruption of anticoagulation may either require a transition from an oral to a parenteral anticoagulant as an outpatient using LMWH or may require admission to the hospital for IV CI UFH before surgery.48,49 For patients on a DOAC, bridging with a parenteral agent is generally not required because of the short half-lives of the agents.49 Some examples of high thromboembolic risk categories include recent VTE within the last 3 months, mechanical mitral valve, AF with a CHA2DS2-VASc score of 7 or 8, a recent stroke or transient ischemic stroke within 3 months, and severe thrombophilia.45,48,49 If a parenteral bridge is required, it should be stopped before surgery with adequate time to allow the coagulation parameters to normalize. For CI UFH, the infusion should generally be stopped 4 to 6 h before surgery, and for LMWH, the last dose should be approximately 24 h from the time of surgery. An IV DTI such as bivalirudin or argatroban may be considered to avoid the development of HIT antibodies or in patients with a previous diagnosis of HIT, or in those with heparin resistance. The infusion should be stopped 4 to 6 h before surgery, and an aPTT should be assessed before proceeding with surgery to ensure anticoagulation has been cleared.46

Warfarin Reversal

For patients on warfarin at the time an organ becomes available, anticoagulation should be reversed with a combination of vitamin K and a 4F-PCC to provide immediate and sustained reversal.21,24,46,50,51 Warfarin has a long half-life, approximately 40 h, and inhibits the synthesis of vitamin K dependent clotting factors II, VII, IX, and X. To restore the function of these clotting factors, vitamin K can be administered by either oral or IV routes to allow for the synthesis of functional clotting factors. The time to correction of the INR after IV vitamin K is much more rapid than following oral administration; however, even with IV administration, the onset of action is around 6 h.51 Because of the delay in onset/peak effect of IV vitamin K, factors II, VII, IX, and X should also be administered along with IV vitamin K for immediate effect. There are multiple formulations of concentrated clotting factors available including 4F-PCC (contains adequate concentrations of factors II, VII, IX, and X in an inactivated form), 3F-PCC (contains adequate concentrations of factors II, IX, and X and trace amounts of VII in an inactivated form), and activated PCC (aPCC) (contains adequate concentrations of factors II, IX, and X in an inactivated form and factor VII in an activated form).24 Administration of plasma has many limitations, including the need to be thawed and obtained from the blood bank, potential transmission of blood-borne pathogens, transfusion reactions, and the large volume required for adequate concentrations of clotting factors.52,53 In a study by Sarode et al,53 which compared the effect of 4F-PCC and plasma on INR reversal and hemostasis, effective hemostasis was achieved in approximately 70% of patients in each group; however, INR reduction was achieved in 62.2% of patients receiving 4F-PCC versus 9.6% receiving plasma. The safety profile of the 2 strategies was similar in this study with 7.8% of the patients experiencing a thromboembolic event in the 4F-PCC group compared with 6.4% in the plasma group.53

Although 4F-PCC has been FDA-approved for reversal of warfarin for emergent surgery since 2013, limited data exist supporting the optimal dosing strategy for both bleeding management and reversal for surgery. The US label instructions for 4F-PCC provide a variable weight-based dose that escalates based on the presenting INR.24 A number of studies have published data using this INR-based approach, as well as fixed-dose strategies and step-wise approach strategies.54 Because of the risk of thrombotic complications associated with 4F-PCC, as well as the surgery itself, recent guidelines have advocated for the step-wise approach starting with 12.5 units/kg and administering the second dose if laboratory or clinical variables suggest inadequate reversal.54 Notably, in the cardio/thoracic population, transplant surgeries require anticoagulation during CPB; levels of coagulation factors may vary, thus, of the optimal dose of 4F-PCC, and its extent of factor repletion is unknown.55

Despite its rapid onset of action within 30 min, the duration of reversal by 4F-PCC is limited to the half-lives of the clotting factors.24 Because of the long half-life of warfarin, vitamin K must be administered along with 4F-PCC if sustained reversal of anticoagulation is required. The use of 4F-PCC in combination with IV vitamin K to reverse warfarin before transplant has been reported as both safe and effective by multiple transplant centers.56-58

Dabigatran Reversal

For patients on dabigatran at the time of the transplant, the FDA-approved reversal agent, idarucizumab, can be utilized. Idarucizumab is a human monoclonal antibody fragment that binds free and thrombin-bound dabigatran without binding to other anticoagulants or substrates of thrombin.24 Idarucizumab is FDA approved for reversal both in cases of life-threatening bleeding and to facilitate an urgent surgery or intervention.24 In the surgery arm of the REVERSE-AD trial, periprocedural hemostasis was assessed as normal in 93.4% of the patients.28 Notably, no patients underwent SOT surgery during the trial. At 90 d, 7.4% of patients in the surgery group had a thromboembolic event, and the mortality rate in that group was 18.9%.28 The pharmacokinetic half-life of idarucizumab is around 45 min, but the bound dabigatran-idarucizumab complex is renally excreted, extending the duration of effect to 12 to 24 h.24,54,59 The reduction of dabigatran plasma concentration in the REVERSE-AD trial was observed for at least 24 h.28 Some real-world data have been published supporting the use of idarucizumab to reverse the anticoagulant effects of dabigatran during heart and lung transplant cases.26,60-62 An alternative option for a nonspecific dabigatran reversal agent if idarucizumab is not available is aPCC; however, there are no published data supporting this approach in transplant patients, as most transplant centers have idarucizumab on formulary and are approved for this use.25,63,64

Factor Xa Inhibitor Reversal

As discussed previously, andexanet alfa is currently available and indicated for life-threatening or uncontrolled bleeding for patients on apixaban or rivaroxaban.24 Emerging data have been published evaluating its use in patients on edoxaban.65 Andexanet alfa has not been studied in a prospective clinical trial for patients undergoing major surgery. The ANEXXA-4 trial included patients requiring minimally invasive procedures indicated for diagnostic or therapeutic reasons but excluded patients expected to undergo surgery in <12 h.66 There are some small retrospective cases of use in surgery reported in the literature; however, there are none at this time in transplant surgery. In all but 2 of these cases, hemostasis was documented as achieved.67-70 Thrombotic events were observed in 10% of the population in the ANNEXA trial up to 30 d postadministration (bleeding patients), compared with 7.4% in the surgical population in the REVERSE-AD trial (up to 90 d postadministration) and up to 9% with 4F-PCC (in-hospital events).28,59,71

Although there are some data supporting the use of andexanet alfa in surgery and even more data supporting the use in reversal for bleeding patients, some important considerations need to be evaluated when using this strategy in the SOT subgroup. Unlike idarucizumab, andexanet alfa has a short pharmacodynamic half-life of about 1 h requiring an initial bolus followed by a 2-h infusion.24 In the ANNEXA-4 trial, antifactor Xa activity returned to levels anticipated from physiological clearance approximately 2 h after completion of continuous infusion; however, thrombin generation was sustained for about 24 h.66 It is unclear at this time how these surrogate laboratory markers correlate with surgical bleeding and hemostasis. One possible strategy would be to extend the duration of the continuous infusion, but there are currently no data to support the safety and efficacy of that approach. Depending on the time of the last dose of the anticoagulant, renal function of the transplant recipient, and duration of surgery, the duration of effect for andexanet alfa may not cover the entire duration of the surgery, as well as the immediate postoperative time period.

Another consideration when administering andexanet alfa before invasive surgery is the interaction with andexanet alfa and heparin, an indirect factor Xa inhibitor. Andexanet alfa inhibits both direct and indirect Xa inhibitors.24 This is particularly relevant to lung and heart transplant surgeries that may require heparinization during CPB. Multiple published analyses have demonstrated a dose-dependent reversal of the anticoagulation effects of heparin in the presence of andexanet alfa.71-74 For patients requiring therapeutic anticoagulation during transplant surgery, there are a few options to consider. If andexanet alfa is the preferred reversal agent, either high doses of unfractionated heparin can be used to overcome the inhibition or andexanet alfa can be used in conjunction with a DTI, such as bivalirudin, for anticoagulation.74,75 Use of DOACs in this situation is not advised.

Before the approval of andexanet alfa, nonspecific reversal agents such as 4F-PCC were used for emergent reversal of the oral Xa inhibitors. Guidelines recommend 4F-PCC as an alternative to andexanet alfa in patients with life-threatening bleeding on a factor Xa inhibitor when andexanet alfa is not available; however, most guidelines do not address reversal for emergent surgery.46 In a survey of 115 transplant programs, only 17 reported using a reversal agent for the factor Xa inhibitors at the time of transplant, and of those, 82.4% reported using 4F-PCC (andexanet alfa had only been widely available for about 6 months at that time).20 In a retrospective chart review evaluating the safety and efficacy of 2000 units of 4F-PCC in emergency surgery for reversal of apixaban or rivaroxaban in 21 patients, hemostasis was noted to be good by the surgeon in 85.7% of the cases, and no thromboembolic events were noted.76 In another small case series of 3 patients requiring emergency cardiac surgery while on an oral Xa inhibitor who were treated with 25 units/kg of activated PCC, they reported no bleeding complications intraoperatively and no thromboembolic complications intraoperatively or postoperatively. One of the 3 patients (type A aortic dissection) did have postoperative pericardial bleeding. One of the patients in this case series was on apixaban 5 mg BID and was reversed with aPCC (FEIBA) to undergo a heart transplant.77 Because of the potential of increased thrombotic risk with activated PCC, guidelines recommend 4F-PCC over aPCC for reversal when andexanet alfa is not available or not approved for use.63,78

POSTTRANSPLANT CONSIDERATIONS

Challenges in anticoagulation management continue to be highly variable and persist posttransplant, as patients may have new-onset AF or VTE, altered pharmacokinetics while awaiting organ recovery, postoperative hemostasis, drug–drug interactions, presence of chest tubes or central lines (eg, tunneled dialysis catheters and atrial pacing wires), postoperative allograft biopsy, thoracentesis, or other procedures and may be nutritionally impaired because of nausea, vomiting, and diarrhea associated with immunosuppressive agents. Rates of VTE are high posttransplant, ranging from 3% to5% in liver transplant, 2% to 14% in renal transplant, 8% to 29% in lung transplant, and 7% to 26% in heart transplant; thus, patients frequently require prolonged anticoagulation posttransplant and will require monitoring and interruption before surgical procedures, including tissue biopsies.79 A recent meta-analysis concluded that DOAC use was associated with decreased risk of composite bleed [relative risk (RR), 0.49; 95% confidence interval (CI), 0.32-0.76; P = 0.002] in comparison with warfarin80; however, there were no differences seen in the rates of major bleeding episodes (RR, 0.55; 95% CI, 0.20-1.49; P = 0.24) and development of VTE (RR, 0.65; 95% CI, 0.25-1.70; P = 0.38) between the 2 groups. Below we will briefly discuss the individual SOT studies that were included in this meta-analysis.80

Heart Transplant

Henricksen et al81 evaluated 51 heart transplant recipients receiving DOAC therapy and compared them to 22 patients receiving warfarin.81 The patient characteristics and length of follow-up were similar between the groups with the exception of more warfarin patients being maintained on renal replacement therapies (22.7% versus 3.9%; P = 0.01). During this analysis, 2 recurrent VTE episodes occurred in patients taking a DOAC. It was noted that both of these patients were taking reduced-dose apixaban because of concomitant use of itraconazole. Bleeding occurred in 5 DOAC-treated patients (10%) and 5 warfarin-treated patients (23%; P = 0.08). The DOACs were also associated with a lower rate of bleeding necessitating a blood transfusion (P = 0.04). The authors concluded that DOAC use was associated with a trend toward lower rates of bleeding complications in comparison with warfarin.81

Kidney Transplant

Leon et al82 studied DOAC (n = 52) versus VKA (n = 50) in 50 renal transplant recipients. Patients with an eGFR <30 mL/min/1.73m2 or those with a mechanical valve were excluded. The primary efficacy endpoints were the development of arterial thromboembolic events or VTE, with bleeding events being the primary safety outcome measure. Patients in the VKA group had a higher hypertension, abnormal renal and liver function, stroke, bleeding, labile INR, elderly, drugs or alcohol score, a closer time to the transplant date, and lower baseline hemoglobin. Within the DOAC group, 25 patients (48%) were receiving reduced doses. The authors noted that there were no differences in VTE (0% versus 8%; P = 0.054), but there was a lower rate of bleeding events associated with DOAC therapy (13% versus 42%; P = 0.003). The authors determined that the DOACs are safe and effective in renal transplant recipients with stable allograft function.82

Bixby et al evaluated DOACs (n = 99) versus warfarin (n = 98) in renal transplant recipients with the primary outcome being the incidence of major bleeding.83 Over the course of this analysis, major bleeding episodes occurred at a rate of 7.2% per year among patients taking DOACs and 11.4% per year in patients receiving warfarin (Mantel-Cox P = 0.15). There were no differences in stroke (1.0% versus 5.1%; P = 0.13) or VTE (2.0% versus 3.1%; P = 0.50) between either group. Of note, when the authors stratified the risk of major bleeding by the individual agent administered, the lowest incidence was among patients treated with apixaban versus all other agents (6.7% versus 19.0%; P = 0.027). The authors concluded that further research is warranted to define the role of DOACs as an alternative to warfarin in renal transplant recipients.83

In single-center cohort analysis, Parker et al84 reviewed 31 adult renal transplant recipients receiving rivaroxaban or apixaban. The authors demonstrated that 94% of DOAC peak and trough levels were within the expected range. There were no thromboembolic events but 4 bleeding episodes, with 2 considered major bleeds and 2 considered clinically relevant nonmajor bleeds; however, the overall bleeding rate was 6.9/100 patient-years at risk. The authors concluded that calcineurin inhibitors had no major impact on the exposure of the DOACs and that these anticoagulants appear to be safe and effective in the renal transplant population.84

In a recent retrospective, single-center analysis by Zaitoun et al,85 8 renal transplant recipients maintained on a DOAC were compared with matched patients receiving warfarin (n = 8). There were no thromboembolic events or bleeding events in patients treated with a DOAC, whereas there were no thromboembolic events but 3 episodes of bleeding in the warfarin-treated patients. In terms of the impact of the DOACs on calcineurin inhibitor levels, there were no statistically significant changes. The authors concluded that, compared with warfarin, DOACs are well tolerated and effective at preventing and managing thromboembolic events among renal transplant recipients.85

Liver Transplant

Santeusanio et al86 evaluated 27 liver transplant recipients receiving DOACs compared with 20 matched controls receiving warfarin. The primary study endpoint was the incidence of clinically relevant bleeding, both major and nonmajor. More patients receiving warfarin experienced a bleeding episode (45% versus 15%; P = 0.01). There were no clinically relevant major bleeds in the DOAC group compared with 4 in warfarin-treated patients. The authors also noted that there were no differences in thrombotic event frequency (20% versus 15%; P = 0.67). Univariate analysis revealed that warfarin use, a baseline eGFR <30 mL/min, or total bilirubin ≥3 mg/dl was associated with clinically relevant bleeding. The authors concluded that DOAC use among liver transplant recipients was relatively safe in comparison with warfarin.86 In the general population, it appears that DOACs are safe in patients with mild to moderate liver disease.87

Lung Transplant

In the previously discussed organ transplant sections, the trials evaluated compared a DOAC to therapy with a VKA. This type of data is not available with lung transplant, as there are only single-arm analyses available in this population. In a retrospective review by Reininger et al,88 28 lung transplant recipients who received apixaban for atrial arrhythmias or VTE treatment were evaluated. The primary outcome was a composite of breakthrough stroke or thromboembolic events and bleeding episodes. The authors noted that there was 1 breakthrough DVT during follow-up and only 1 clinically relevant nonmajor bleeding episode. This led the authors to conclude that apixaban may be safe to use in lung transplant recipients but that a prospective, comparator arm study was needed to truly understand the safety and efficacy of DOACs in this population.88

Comparison Among DOACs in SOT Recipients

The available literature suggests that the DOACs are associated with a lower risk of bleeding than warfarin in SOT recipients; however, there is a dearth of data comparing one DOAC to another with respect to bleeding in the SOT population. Salerno et al89 conducted a single-center, retrospective analysis evaluating the use of apixaban (n = 70) versus nonapixaban DOACs (rivaroxaban or dabigatran, n = 36) among kidney, heart, lung, and liver transplant recipients. The primary outcome evaluated was the incidence of bleeding, whereas secondary outcomes included the frequency of major bleeding episodes and thromboembolic events. Apixaban-treated patients had a lower cumulative rate of bleeding than rivaroxaban/dabigatran-treated patients at both 90 d (4.9% versus 16.1%) and 180 d (11.4% versus 24.9%; P = 0.034). Major bleeding and thrombotic events were similar between the 2 groups. The authors concluded that apixaban demonstrated similar efficacy but improved safety compared with the nonapixaban DOACs in transplant recipients.89

General Considerations of Postoperative DOAC Use

Generally, when indicated, DOACs should be started in the posttransplant patient when the end-organ function has recovered and hemostasis has been achieved. The use of DOAC posttransplant requires caution because of potential drug–drug interactions and overexposure related to labile kidney function after transplant. Dabigatran is often not a preferred agent to use after SOT, partially because of the greater renal clearance, higher gastrointestinal tolerance issues, and higher incidence of bleeding events among DOACs.24,25 In fact, a single-center experience described the use of DOAC in patients who received a cardiac transplant, and they found a numerically higher rate of major bleeding with dabigatran than with rivaroxaban or apixaban, although it was not clear if this was due to drug–drug interactions or renal dysfunction.90

Drug–drug Interactions

Despite the DOACs having less drug interactions than warfarin, some interactions remain. Apixaban and rivaroxaban are both metabolized by cytochrome P450 3A4 (CYP3A4) isozymes, and all of the DOACs are substrates of P-glycoprotein (P-gp).24 Cyclosporine (CsA) and tacrolimus (TAC) are known substrates of both CYP3A4 and P-gp as well as inhibitors of P-gp. CsA, only, is an inhibitor (moderate) of CYP3A4.24 Given these facts, in theory, either calcineurin inhibitor could interact with the DOACs and theoretically increase the risk of bleeding.24,91,92

Several case series have documented the potential for calcineurin inhibitor coadministration increasing exposure in patients maintained on rivaroxaban; however, the existence of confounding variables, such as poor renal function, was noted in most of the cases.82,93,94 Wannhoff et al94 explored the impact of CsA and TAC on trough levels of rivaroxaban in 9 liver transplant recipients. Although rivaroxaban trough levels varied widely, a mean rivaroxaban trough level in patients receiving CsA was >6 times higher than that of patients receiving TAC. Patients who received CsA had a numerically higher rate of any bleeding; however, kidney function was worse in the CsA group, even though the authors did not find any correlation between rivaroxaban trough and renal dysfunction.94 In a healthy volunteer study, Brings et al95 evaluated the impact of coadministration of CsA and CsA plus fluconazole on rivaroxaban exposure. Twelve patients received rivaroxaban (20 mg) alone, in combination with CsA, and in combination with CsA plus fluconazole. Compared with rivaroxaban alone, CsA increased rivaroxaban overall exposure by 47% and maximal concentration after administration (Cmax) by 104%. When combined with fluconazole, CsA increased rivaroxaban overall exposure by 86% and Cmax by 115% (83%–153%).95 This analysis clearly demonstrates the impact that moderate (CsA) and strong (fluconazole) inhibitors of the CYP3A4 isozymes have on rivaroxaban exposure. Unfortunately, the clinical impact of this increased exposure was not evaluated.

Interactions between apixaban and calcineurin inhibitors have also been studied in 12 healthy volunteers who were administered apixaban (10 mg) alone or in combination with either CsA (100 mg) or TAC (5 mg).96 Concomitant use of CsA and apixaban resulted in enhanced overall exposure to apixaban by 120% and Cmax by 143%. Conversely, coadministration of apixaban and TAC resulted in reductions in apixaban overall exposure (78%) and Cmax (87%). Despite these changes in exposure, the authors felt that these observations were within the range of apixaban seen during its clinical development, thereby recommending no need for apixaban dose adjustment when given with either calcineurin inhibitor.96

Parasrampuria et al97 evaluated the impact of ketoconazole, erythromycin, and CsA on endoxaban exposure in healthy volunteers. Ketoconazole, erythromycin, and CsA coadministration enhanced edoxaban Cmax by 89%, 68%, and 74%, respectively, and overall exposure by 87%, 85%, and 73%, respectively. The authors noted no change in exposure to M4, the major active metabolite of edoxaban, when given with ketoconazole or erythromycin; however, when edoxaban was coadministered with CsA, M4 concentrations were increased 6.9-fold. The authors concluded that administration of CYP3A4 inhibitors increases edoxaban exposure by <2-fold, but the clinical significance is unknown.97

Through competition for both CYP3A4 and P-gp, DOACs could also, theoretically, impact the exposure of either CsA or TAC. Vanhove et al98 published a single-center retrospective analysis of 39 SOT recipients who were coadministered either rivaroxaban (n = 29) or apixaban (n = 10) with their calcineurin inhibitors. Dose-corrected calcineurin inhibitor trough concentrations (C0/D) before and after the addition of the DOAC were evaluated. Overall, the pre-DOAC therapy and post-DOAC therapy average C0/D was not significantly different. Subgroup analysis revealed that there was a significant effect of rivaroxaban on tacrolimus C0/D (9.2% increase; P = 0.042). DOAC administration was considered an independent predictor of CsA C0/D (12.1% increase; P = 0.020). This study demonstrated that the DOACs have a minor impact on raising calcineurin inhibitor trough concentrations and recommended that clinicians monitor levels after starting and stopping a DOAC but felt that preemptive calcineurin inhibitor dose reductions were not necessary.98

In a similar study, Scheibner et al99 retrospectively evaluated 50 SOT recipients receiving TAC with either rivaroxaban (n = 18) or apixaban (n = 32) for changes in TAC trough levels and doses. The median dose-adjusted TAC trough and total daily dose were not statistically different pre-DOAC use and post-DOAC use. The authors concluded that it was unlikely that rivaroxaban or apixaban have an impact on the exposure of TAC in SOT recipients.99

Triazole antifungals are commonly administered in SOT recipients for prophylaxis against or treatment of invasive fungal infections. Azoles are considered moderate (fluconcazole) to strong (ie, ketoconazole, itraconazole, posaconazole, and voriconazole) CYP3A4 inhibitors. Several studies above noted an interaction between an azole and the DOACs.95,97 Frost et al100 also demonstrated the impact that ketoconazole and diltiazem had on apixaban exposure. In this healthy volunteer study, ketoconazole increased apixaban exposure by 2-fold, and diltiazem increased it by 1.4-fold.100 In a large, retrospective analysis of the Taiwan National Health Insurance database of >90 000 patients with atrial fibrillation using a DOAC, Chang et al101 demonstrated that fluconazole coadministration increased the risk of major bleeding events. The FDA labeling for rivaroxaban recommends avoiding coadministration with P-gp and strong CYP3A4 inhibitors, whereas the dabigatran warns against concomitant use of P-gp inhibitors in patients with poor renal function.24 Apixaban product labeling calls for a 50% reduction in dosing when it is coadministered with ketoconazole or itraconazole24; however, there is no guidance given on the use of apixaban specifically with posaconazole, voriconazole, or isavuconazole. Some centers use unvalidated dosing regimens of DOACs to mitigate potentially supratherapeutic DOAC concentrations due to drug–drug interactions. A retrospective study described their experience of using DOACs in the thoracic transplant population.6 The authors used doses of DOACs that were lower than the FDA-approved doses for patients receiving azoles antifungals (as low as rivaroxaban 7.5 mg daily or apixaban 1.25 mg twice daily for treatment). Two out of 37 patients, however, had breakthrough VTE, and 8 (37%) had bleeding events.6

Bridging

Frequently after SOT, patients require an interruption to their anticoagulation regimen. Historically, perioperative anticoagulation management included holding warfarin and bridging with LMWH or CI UFH and restarted warfarin when hemostasis was achieved. Although this option remains, rates of bleeding and thrombosis are still present. It is reported that 3.2% of patients experience bleeding when using IV/SQ bridging in the Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation trial of AF patients; thus, it is not recommended to bridge in most clinical situations.49 Alternatively, clinicians may choose to forgo using a bridging agent and use a DOAC because of their lack of routine monitoring and fast onset/offset of action, which may facilitate procedures. The fast onset/offset that is advantageous with DOACs is often altered in the SOT population; thus, holding 24 to 48 h before a procedure may not be sufficient. In 80 heart transplant patients, more bleeding with warfarin therapy than with DOACs was observed with no overall difference in bleeding complications following endomyocardial biopsy (odds ratio, 4.55; CI, 1.2-16.2).102 Further study is needed to firmly evaluate the risk of bleeding with DOACs versus VKA in tissue biopsies in SOT recipients.

CONCLUSION

The use of therapeutic anticoagulation in the SOT population, both pretransplant and posttransplant, continues to be challenging. In the general population, the DOACs provide anticoagulation that is more convenient for patients and provides improved safety and efficacy in comparison with historical vitamin K antagonists; however, these advantages must be weighed against the dearth of literature to support their use in SOT patients and, for pretransplant patients, the lack of data on the reversal at the time of transplant. In retrospective, small observational trials in SOT patients, the DOACs have been shown to be safe and effective alternatives to warfarin, heparin and, LMWHs. The biggest barrier to DOAC use is the reversal of these agents to allow for transplant surgery, organ biopsies, or other surgical procedures posttransplantation. Although reversal agents are available for the DOACs, reversal agents for the oral factor Xa inhibitors are limited to use for life-threatening bleeds and are not routinely used to facilitate surgery or biopsy. The DOACs have provided clinicians with an advancement in anticoagulation for their patients. Judicial use of these agents pre–organ transplantation and post–organ transplantation should be considered.

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