Cardiovascular Pharmacology: Open Access

DOACS: Direct Oral Anticoagulants; AFIB: Atrial Fibrillation; AXF: Anti-Xa Factor; DTI: Direct Thrombin Inhibitors; DI: Drug-drug Interactions; CHA2DS2: VASc Risk Score.

As the world population ages, the burden of AFib (atrial fibrillation) and venous thromboembolism disease is expected to increase, and prescriptions for long-term anticoagulation will climb [1- 3]. Anticoagulated patients are vulnerable to spontaneous, traumatic and perioperative bleeding. Warfarin is a vitamin K antagonist that has been used for decades to prevent and treat arterial and venous thromboembolism [4]. But due to the need of regular monitoring, non-vitamin K antagonists/oral anticoagulants are now widely used as alternatives to warfarin for stroke prevention in atrial fibrillation and management of venous thromboembolism. These are dabigatran etexilate (Pradaxa, Boehringer Ingelheim, Germany) [5], rivaroxaban (Xarelto, Bayer AG, Germany) [6], apixaban (Eliquis, Pfizer and Bristol-Myers Squibb, NY) [7] and edoxaban (Savaysa, Daiichi Sankyo Inc., Japan). DOACs are associated with comparable risk of stroke, systemic embolism, major bleeding and death compared with warfarin [8]. They have more predictable therapeutic effect, pharmacokinetic and pharmacodynamics properties, as well as do not require routine monitoring, have fewer potential drug-drug interactions and no restrictions on dietary [2].

In clinical practice there is still widespread uncertainty on how to manage patients on DOACs who have risk of bleeding. In addition, the lack of specific antidotes and measurement methods/assays, as well as the role of renal function are critical points for patients’ management with AFib.

Pharmacokinetics and pharmacodynamics of direct oral anticoagulants (DOACs)

The new oral anticoagulants differ in their pharmacology and pharmacokinetics (Table 1). Although their onset of action and half-life are quite similar, other properties such as their respective mechanism of action, bioavailability, metabolism and creatinine clearance are different (Boehringer Ingelheim Summary of Product Characteristics, 2017; Bayer Pharma AG Summary of Product Characteristics, 2017; Bristol- Myers Squibb Company Summary of Product Characteristics, 2017; Daiichi Sankyo Europe GmbH Summary of Product Characteristics, 2017). All agents have rapid onset of action, a wide therapeutic window, little or no interaction with food and other drugs, minimal interpatient variability, and similar pharmacokinetics in different patient populations. Since DOACs are substrates, co-administration with cytochrome P450 system isoenzymes and permeability glycoprotein (P-gp) inhibitors and inducers can result in substantial changes in plasma concentrations [2]. Clinicians should be aware and take into account before appointment of anticoagulative therapy.

Table 1: Pharmacology and pharmacokinetic properties.

Usually the pharmacokinetic profile of DOACs in healthy subjects is not substantially affected by age or sex. However, its profile is affected by mild impairment in hepatic function or extremes in bodyweight. In subjects with moderate hepatic impairment, the drug concentration is twofold higher than in controls, with an associated moderate increase of anti-coagulation and prolongation of prothrombin time [9]. In addition, patients with mild, moderate and severe renal impairment, the overall inhibition of coagulation cascade also could increase. Therefore, it is not expected to be dialyzable and their use are not recommended for patients with CrCl<15 ml/min [10].

Coagulation tests might be considered upon attainment of stable anticoagulation (1-2 weeks after initiation) to provide the level of anticoagulation achieved chronically. This information could be useful to interpret subsequent results.

Drug anticoagulative levels could be measured occasionally at the time of medical visits to assess adherence to treatment, to detect possible drug interactions and side effects. It should be realized that given the DOAC with short half-life (e.g. 8-15 hours), a dose missed a few days earlier that testing might not be detected in the laboratory.

Taking into account the CH2ADS2-VASc scale, individuals with extreme body weights may benefit from dose adjustment to avoid under- or over-anticoagulation (Table 2) [8].

Table 2: The effects of body weight, sex, age and co-morbidities on the anticoagulants pharmacokinetics.

The laboratory and direct oral anticoagulants

Although direct oral anticoagulants do not need laboratory testing for dose adjustment, there are instances when laboratory measurement of the drug anticoagulant effect may be useful. In addition, none of the standard coagulation tests constitutes a sensitive or accurate measure of their therapeutic activity. An assessment of the drug concentration or residual activity could be helpful for patients with low renal function or old age, before initiation of treatment, before surgical or invasive procedures, on occasion of hemorrhagic or thrombotic events, and whenever immediate reversal of anticoagulation is needed [11]. The comparative description of coagulation tests shown in Table 3.

Table 3: Coagulation tests that could be used to estimate plasma concentrations of DOACs.

Taking into account the different sensitivity and availability of coagulation tests in clinical practice, clinicians should be aware to reduce the risk of bleeding and stroke. However, the chromogenic anti-Xa assay and DTI assay are mostly appropriate tests to detect drug concentration and assess the safety of medical therapy and expected effect. Based on available data the coagulative laboratory testing is recommended for patients on high-risk groups, with CH2ADS2-VASc score ≥ 3 respectively [12,13].

The aim of this study was to define and assess the necessity of coagulation tests use in practice for patients with AFib in high-risk groups.

Quantitative, cross-sectional study was conducted at Pauls Stradins Clinical University Hospital, Latvia, in time from January 2013 to April 2015.

Patients were involved based on following inclusion criteria:

➢ At least 18 years old.

➢Diagnosed non-valvular (as defined by European Society of Cardiology) AFib at least in one of the risk evaluation scores (CHA_2D2-VASc score more or equal to 2).

➢ Use DOACs more than 3 months.

➢ Have no life-dangerous, serious comorbidities, which can affect patients’ mortality (e.g. cancer).

➢ Agreed to participate in this research and confirmed it by signed informed consent form.

Main patients’ characteristics were collected, e.g. demographic data, comorbidies and used medicines. Laboratory assessments, diagnosis were defined during the interview and clarified with doctor if applicable. Patients demographic data, disease anamnesis, main comorbidies and used medicines was obtained. Laboratory test results, additional examinations were specified [14-18].

A total of 143 patients were included in this study, of whom 46.2% (n=66) were male. The mean age was 69.7 (SD ± 9.9) years. About 2/3 (73.1%) of all patients the AF were longer than 1 year. Almost half of patients (46.2%) used DOACs’, 16.1% dabigatran and 33.6% rivaroxaban respectively. The main characteristics are collected in Table 4.

Table 4: Baseline characteristics.

The mean CHA_2DS2-VASc score was 4.2 (SD ± 1.5), 3.8 in dabigatran group and 4.1 in rivaroxaban group respectively. From all patients the most common comorbidies were arterial hypertension (65.0%; 93), chronic heart failure (48.3%; 69), coronary artery disease (32.9%; 47), diabetes mellitus (24.5%; 35), and dyslipidemia (25.9%; 37).

Almost half of patients (46.2%; 66) used DOACs, 31.5% rivaroxaban and 14.7% dabigatran respectively; furthermore, 1.4% patients used DOACs’ with antiaggregants. 49.7% (71) patients had increased risk of possible drug-drug interactions, most frequently with proton pump inhibitors (16.8%; 24), amiodarone (24.5%; 35), anti-inflammatory drugs (49.0%; 70). Frequently used medicines are shown in Table 5.

Table 5: Most frequently used medicines and possible drug-drug interaction.

According to CHA2D2-VASc score, 60.2% patients were in highrisk group: score 3-23 (16.1%), score 4-22 (15.4%), score 5-20 (14.0%) and score 6-21 (14.7%). The use of DOACs and possible drug-drug interactions increases by risk score, reaching the maximum score 3 (16.1%; 23) and the mean frequent score 4.4 of 86 (60.1%) AF patients respectively. Based on CHA2D2- VASc score and clinically relevant possible drug-drug interactions, the DOACs’ concentration in plasma could be affected, in result of increased risk of bleeding and/or thrombotic events. Furthermore, analyzing data by HAS-BLED score, it is shown that 72.7% (104) patients had increased risk of bleeding. The most common comorbidies and their correlation with CHA2D2- VASc score is shown in Figure 1.

Figure 1: The most common comorbidies and their correlation with CHA₂D₂-VASc score.

To detect the possible drug-drug interactions, patients were divided into two risk groups-medium and high. In dabigatran group most frequent potential drug interactions were with amiodarone (16.7%) and proton pump inhibitors (13.8%), in rivaroxaban groupamiodarone (29.2%) and anti-inflammatory drugs (4.2%) respectively (Table 6). In addition, 1.4% patients used DOACs’ with antiagregants as triple therapy [19-21].

The use of DOACs without routine monitoring of anticoagulant effect is likely safe and effective treatment for non-valvular atrial fibrillation in many patients, but there are circumstances, such as treatment failure, bleeding, renal and/or hepatic failure and perioperative monitoring, in which reliable assays of DOAC activity are needed. DOAC dosing recommendations are currently based on patient characteristics rather than measurement of drug effect, and emerging data from the largest trials of DOACs support this strategy. However, specific coagulation assays, depending on the DOACs, should be used in order to provide the more reliable information on plasma concentrations. Standard assays, e.g. a PTT, PT, TT, of anticoagulation are generally insufficient for measuring DOAC activity, except in certain circumstances of extremely high or low drug levels and in the case of some factor Xa inhibitors. The use of calibrated chromogenic anti-Xa and DTI assays should be recommended for the assessment of DOACs, factor anti-Xa assay for rivaroxaban, apixaban and edoxaban, and DTI assay for dabigatran respectively. Unfortunately global coagulation tests, such PT and a PTT, are not useful at all and can lead to misinterpretation that could have clinical implications if the result is not fully understood (Lee, 2011) [12].

The use of dedicated assays may probably improve the benefitrisk profile of DOACs by identifying poor- and high- responders. Monitoring of therapies may be useful to provide guidance in case of bleeding, thrombosis recurrence, to assess the pharmacodynamics of high-risk groups responders, such as high age, low body weight, low renal function, before urgent surgery or procedure and for those with several co-morbidities. However, results should be interpreted with caution if responsiveness is unknown.

DOACs’ usage correlates with CHA2D2-VASc score with mean frequent score 4.4 of 86 (60.1%) AFib patients respectively. From all high-risk AFib patients (score ≥ 3) 47.7% had potentially moderate or major risk of drug-drug interactions. According to data by HASBLED score, it is shown that 72.7% (104) patients had increased risk of bleeding. In summary, for 60.2% AFib patients appropriate monitoring of anticoagulative therapy should be considered. Anticoagulative laboratory testing for patients on high-risk group could prevent safer anticoagulative therapy for patients with AFib.