In kidney transplant recipients (KTRs) it reaches 7.3% within 36 months from the procedure in comparison to 2% in the general population ^[1][2][3][1,2,3]. RWesearchers are going to focus on the use of NOACs in post-transplant treatment and compare them with the commonly used vitamin K antagonists (VKA), primarily warfarin, in terms of effective anticoagulation and safety of use, including the risk of bleeding, incidence of thromboembolic events and drug-to-drug interactions (DDI). The use of NOACs in KTRs is not strictly contraindicated but requires renal function assessment and therapeutic drug monitoring of immunosuppressive drugs, considering their predominant renal excretion and possible pharmacokinetic interactions between the two groups [4]. NOACs are successfully used as a prevention of thromboembolic events in patients with AF and treatment of such as deep vein thrombosis (DVT) and pulmonary embolism (PE) in the general population as they have a wider therapeutic window, lower frequency of intracranial bleeding and do not require routine monitoring. Atrial fibrillation increases the risk of ischemic stroke 5-fold [3] and is found in 24% of patients during the acute phase of ischemic stroke. Stroke risk is 43% greater in patients suffering from CKD without atrial fibrillation in comparison to the general population [5]. Among patients with CKD, AF increases the risk of stroke between 1.5-fold and 2.5-fold depending on the stage of kidney dysfunction and albuminuria [6]. History of atrial fibrillation among KTRs is associated with an increased risk of graft failure and post-transplant mortality, as well as a 37% higher risk of ischemic stroke [7].

2. Oral Anticoagulants

2.1. Warfarin

Warfarin, a commonly used vitamin K antagonist (VKA), has been proven to decrease the risk of ischemic stroke for both patients with CKD and KTRs. Warfarin-based anticoagulation among patients with CKD provided a decrease in stroke risk from 26% to 9% [8], which is comparable with the relative reduction in stroke risk in the general population [9], while KTR studies have shown a trend towards a decrease in composite endpoints of death, stroke and gastrointestinal bleeding [10]. On the other hand, warfarin-based anticoagulant therapy significantly enhances the risk of major bleeding events. Studies show that the safety of warfarin use strongly depends on maintaining the INR level within the therapeutic norms (2–3) without presenting strong dependence on the GFR level. In a prospective cohort study of 1273 long-time warfarin users it was demonstrated that compared with patients with a GFR of >60 mL/min per 1.73 m², those with a GFR of 30–44 mL/min per 1.73 m² and those with a GFR < 30 mL/min per 1.73 m² had 2.2-fold and 5.8-fold higher risks, respectively, of major bleeding events at an INR value > 4, but the same study showed that GFR did not modify the risk of hemorrhage for INR values < 4 [11]. Importantly, KTRs receiving warfarin-based OAC require stricter monitoring and lower doses of anticoagulants in order to maintain the safety of treatment [12]. For many years the world has not been presented with an alternative oral anticoagulant, until 2010, when the Food and Drugs Administration approved dabigatran as a new option for the therapy. Since then, three other oral agents: rivaroxaban, apixaban and edoxaban have been approved. Even though the pharmacokinetic features of NOACs are dependent on renal clearance to some degree, they have been commonly prescribed for patients with kidney diseases suffering from atrial fibrillation and increased thromboembolic event risks with good effects and a low risk of bleeding (Table 1).

 

* Decreased dose of 2.5 mg orally twice a day is administered in patients with two out of three of the following criteria: age ≥ 80 years, body weight ≤ 60 kg, creatinine concentration ≥ 1.5 mg/dL. ** As well as in patients with a high risk of bleeding. *** Intended uses of NOAC activity reversing drugs include: unplanned emergency surgeries or procedures and uncontrolled life-threatening bleeding episodes. **** Recommended dose of idarucizumab is 5 g—the dose may be repeated in case of recurrence of bleeding or indications for a second emergency procedure. No dose adjustments are required for patients with renal impairment.

2.2. Apixaban

Apixaban is a direct Xa factor inhibitor indicated to prevent and treat VTE and decrease the risk of a stroke in individuals suffering from non-valvular atrial fibrillation (NVAF). In the Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial (n = 5.599 subjects), patients with AF were randomized to apixaban 5 mg twice a day and aspirin. A reduced dose of apixaban 2.5 mg twice per day was given to patients who met at least two of the following criteria: serum creatinine between 1.5 and 2.5 mg/dl, age ≥ 80 years, and body weight ≤ 60 kg. The study indicated apixaban’s superiority over aspirin in preventing stroke and systemic embolization [13]. Open-label extension of the study presented data supporting the safety and efficacy in the long-term use of apixaban in patients suffering from AF [14]. In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation study (ARISTOTLE), apixaban has been shown to be superior to warfarin in preventing stroke and systemic embolism, while also reducing the risk of bleeding and mortality [15]. The ARISTOTLE study showed that in CKD stage G4, apixaban might reduce the risk of stroke (1.27 vs. 1.6% per year) and major bleeding (2.13 vs. 3.09% per year) in comparison with warfarin during a median follow-up of 1.8 years; however, the study only included a small number of participants in this CKD stage (3%, 270 individuals) ^[15][16][15,16]. Pharmacodynamic features of apixaban result from factor Xa inhibition and even though the regular control of an anticoagulant effect is most often unnecessary during therapy, major changes in screening plasma coagulation tests (mostly APTT and PT) have been observed. However, neither APTT nor PT can be used for the laboratory control of NOAC activity in order to adjust the dose and ensure that a therapeutic effect is obtained. Studies showed different results of screening plasma coagulation tests in various individuals receiving the same dose of NOAC therapy ^[17][18][17,18]. Furthermore, Apixaban, along with other NOACs, exerts anti-Xa activity, which can be used to assess the concentration of the drug (Rotachrom Heparin anti-Xa assay). Such dose adjustments are however inadvisable since the therapeutic range of NOACs remains unknown [19]. Nevertheless, as stated by Baglin et al., in the recommendation on measuring oral direct inhibitors of thrombin and factor Xa, it is advised to monitor the anticoagulant effect in specific clinical scenarios, such as bleeding incidents, prior to surgery and perioperatively, in patients who take other drugs which may cause pharmacokinetic interactions or who may benefit from dose adjustments due to extreme body weight. Other indications include patients with decreased renal function, suspicion of overdose, necessity for reversal of anticoagulation and compliance monitoring [20]. Apixaban’s absorption occurs primarily in the upper gastrointestinal tract reaching maximal plasma concentration (Cmax) usually after 3 to 4 h. It is bound by plasma proteins in ~93% of healthy subjects, which is comparable to patients with ESRD. Absolute bioactivity of the drug is approximately 50% and it indicates dose-proportional increases in AUC for oral doses up to 10mg. In humans, apixaban is approximately 87% bound to plasma proteins and the volume of distribution (Vss) is approximately 21L. Apixaban is mainly metabolized by CYP3A4/5; however, in human plasma, it occurs mainly in the unchanged form and studies have not detected any active metabolites in the bloodstream. The renal excretion of apixaban accounts for approximately 27% of the total body clearance, followed by 50% eliminated through biliary and intestinal secretion into the feces [17]. Based on low-quality evidence, apixaban appears to be the preferred agent in patients with renal insufficiency, but further studies are warranted [21].

2.3. Rivaroxaban

Rivaroxaban is also a direct Xa inhibitor indicated in the prevention of VTE and CV incidents in atherosclerotic cardiovascular disease (ASCVD), prevention of stroke and systemic embolism in NVAF and treatment of VTE. In ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), a randomized controlled trial of 14,264 patients with AF at a moderate to high risk for stroke (mean CHADS2 score 3.5 ± 0.9), all of whom had CrCl > 30 mL/min, rivaroxaban had similar effects to warfarin in preventing stroke and systemic embolism [22]. Moreover, according to the study, major bleeding occurrence was not significantly different between the two groups. The FDA approved a 20 mg once-daily rivaroxaban dose in November 2011. The label consisted of recommendations of 15 mg once-daily dose for patients with CrCl between 15 and 50 mL/min. Rivaroxaban is not recommended for use in patients with CrCl < 15 mL/min or those undergoing dialysis. Absolute bioavailability is dose dependent where almost complete absorption (80 to 100%) is achieved at the 10 mg dose but reduced to 66% for the 20 mg dose. Absorption occurs primarily in the proximal small intestine with peak concentrations observed 2 to 4 h following oral intake. In humans, rivaroxaban is extensively bound to plasma proteins, approximately 92–95%, mainly albumin. The volume of distribution is moderate with a steady-state volume of distribution (Vss) of approximately 50 liters. Approximately 2/3 of the rivaroxaban dose is metabolized, half of which is eliminated via the kidneys and the other half via the feces. The remaining 1/3 of the administered rivaroxaban dose is excreted by the kidneys in the urine in an unchanged form mainly through active renal secretion. Unchanged rivaroxaban is the most important compound in human plasma; no active circulating metabolite is present. The elimination of rivaroxaban from the plasma occurs with a terminal half-life of 5 to 9 h in young individuals and a terminal half-life of 11 to 13 h in the elderly. Rivaroxaban affects the clotting times by, most importantly, prolonging the PT and aPTT, the latter with a curvilinear concentration–response relationship. aPTT is prolonged 1.5- to 2-fold at peak plasma concentration with normalization all the way through. However, in patients with CrCl < 50 mL/min, the measurements appear to be less sensitive. PT measurement can be used to determine the approximate degree of anticoagulation, with normal PT corresponding with its unsatisfying level. Measurement of plasma rivaroxaban concentration may be useful in situations where DOAC-related bleeding must be excluded and the contribution of oral anticoagulants to the bleeding event must be assessed. In patients requiring an emergency surgical intervention the plasma drug level measurement may also be useful [23].

2.4. Dabigatran

Dabigatran is a direct thrombin (factor IIa) inhibitor also recommended in the primary prevention and treatment of VTE and prevention of stroke and systemic embolism in NVAF. According to the RE-LY study, dabigatran-based treatment in patients with NVAF, in comparison to warfarin, has been associated with a noninferior reduction in stroke risk with a lower risk of bleeding, while administered in doses of 110 mg twice a day, and a superior reduction in stroke risk, but a similar risk of bleeding while being administered in doses of 150 mg twice a day [24]. Moreover, studies on the pharmacokinetic profile of dabigatran have shown that, in patients with CrCl of 15–30 mL/min, a twice daily regimen of 75 mg dose could be applied, achieving a similar exposure to the drug. However, patients with even moderate renal dysfunction (CrCl 50–80 mL/min) who converted from warfarin to dabigatran have a three times higher risk of bleeding in comparison to patients who did not undergo treatment conversion [25]. Dabigatran is administered orally in the form of a prodrug, dabigatran etexilate, with a mean bioavailability of 6.5%. It is completely converted by nonspecific hydrolases to the active product, reaching peak concentration at around 1.5–3 h after administration—the distribution volume equals 50–70 L. Dabigatran undergoes rapid distribution within the body tissues, resulting in a rapid decrease in plasma concentration to <30% Cmax within 4–6 h from administration, followed by an elimination phase. The plasma half-life of dabigatran averages 12–14 h and is dose independent. Studies with radiolabeled dabigatran show that ~35% of the drug is bound to plasma proteins. Importantly, dabigatran etexilate is not metabolized by CYP enzymes and does not induce or inhibit their activity ^[26][27][26,27]. Elimination of dabigatran occurs mostly through the kidneys (80%) in an unchanged form, while 20% of the drug is conjugated by glucuronosyltransferases to pharmacologically active glucuronide compounds, which remain pharmacologically active and can be detected in urine ^[26][27][26,27]. There is a dose-dependent effect of dabigatran on laboratory clotting tests. The aPTT is sensitive to dabigatran, showing a curvilinear concentration–response relationship, with a steep increase at low concentrations and linearity above a dabigatran concentration of 400 ng/mL. In patients taking 150 mg twice daily, the median peak aPTT ratio is approximately two times higher than the peak observed in controls, and the median trough aPTT is 1.5 times higher than median observed in the controls [28]. Above 100 ng/mL, the aPTT is substantially prolonged [29]. As said before, the aPTT is useful as an easily available method for determining the relative degree of anticoagulation but should not be used to determine the plasma drug level. On the other hand, in comparison to aPTT, PT is insensitive to dabigatran. At 100 ng/mL, the PT is usually within the normal range. [29] Similarly to aPTT, TT is sensitive to the antithrombin effect of dabigatran. The sensitivity of this parameter is presenting itself with a linear concentration–response relationship over the therapeutic range of the drug. A normal TT correlates with subtherapeutic (low or even undetectable plasma concentration of dabigatran ^[20][28][29][20,28,29]. Moreover, in comparison to aPTT, the measurement of TT and diluted thrombin time (dTT) is more sensitive at lower plasma dabigatran concentrations—normal TT/dTT is not observed at therapeutic plasma drug concentrations in contradt to aPTT ^[30][31][30,31]. Although the monitoring of NOAC-based treatment could be based on plasma drug concentration, therapeutic ranges have not yet been set. However, in the studies focused on pharmacokinetics and pharmacodynamics of NOACs, it was able to determine that administering fixed doses of the drugs corresponds to stable and predictable clinical effect, even though the plasma concentration ranges were wide ^[32][33][32,33]. As the novel oral anticoagulants show a stable profile of therapeutic outcomes, it is necessary to determine how the profile changes in specific populations, such as KTRs.