*2.1.1.4. Interactions*

• The coumarin anticoagulants: warfarin, acenocumarol, and phenprocoumon;

• Parenteral anticoagulant heparin and its derivatives.

unfractionated heparin (UFH), and fondaparinux [8].

**2. Oral anticoagulants**

*2.1.1.1. Mechanism of action*

**2.1. Old agents**

84 Anticoagulant Drugs

*2.1.1. Warfarin*

therapy.

*2.1.1.2. Indications*

*2.1.1.3. Pharmacokinetics*

• Direct oral anticoagulants (DOACs): dabigatran, rivaroxaban, apixaban, and edoxaban;

Warfarin is a racemic mixture of two optically active isomers, the R and S enantiomers, and it produces its anticoagulant effect by interfering with the cyclic interconversion of vitamin K and vitamin K-2,3-epoxide. Warfarin blocks vitamin K epoxide reductase (VKOR), and the consequent conversion of oxidized vitamin K epoxide into its reduced form, vitamin K hydroquinone [2]. However, warfarin also has a simultaneous procoagulant effect caused by blocking the activation of protein C and S, two endogenous anticoagulants. A rapid depletion of these proteins leads to a transient hypercoagulable state in the first 1 or 2 days of

Warfarin is prescribed for the treatment and prophylaxis of various thromboembolic diseases such as atrial fibrillation (AF), deep venous thrombosis (DVT), transient ischemic attacks (TIA), pulmonary embolism, and other thromboembolic disorders that may affect carriers of cardiac valvular prosthesis or patients who underwent electric cardioversion [3, 4]. The dose-response relationship of warfarin is influenced by genetic and environmental factors, including mutations in gene coding for cytochrome P (CYP) 450, the hepatic enzyme responsible for oxidative metabolism of warfarin, mutations in gene coding for VKOR [5], concomitant drugs, diet, and various disease states [6]. Although warfarin and other dicumarol derivatives cross the placenta and contribute to fetal bone and central nervous system abnormalities when mothers are treated with warfarin within the first-trimester of pregnancy, there is no evidence that warfarin directly affects bone metabolism when administered to children or adults [7]. Women who will be managed with therapeutic anticoagulation in pregnancy should be treated preferably with a parenteral agent, such as heparin and low-molecular-weight heparin (LMWH),

After oral intake, warfarin enantiomers are absorbed rapidly and almost completely from the gastrointestinal tract (100% of bioavailability) and reach their maximal plasma concentration in 90 minutes in healthy people. Racemic warfarin is extensively bound to plasma protein (mainly albumin, 99%) and has a plasma half-life of 36–42 hours [9]. Warfarin is extensively Drug interactions that alter the pharmacokinetics of warfarin may include alterations in absorption (e.g., cholestyramine), which would decrease the anticoagulant effect. Reduced plasmabinding because of the presence of excessively albumin-bound drugs causes an increase in free drug plasma concentration and therefore an increase in antithrombotic activity. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and large doses of penicillins inhibit platelet function, prolong bleeding time, and have the potential to increase the risk of warfarinassociated bleeding, especially upper gastrointestinal bleeding due to their gastric erosion effect. Many drug interactions with warfarin are caused by alterations in metabolism either by CYP2C9 enzyme induction [11], which increases warfarin clearance and thereby reducing antithrombotic activity (e.g., phenytoin, rifampin) [12], or stereoselective and nonselective enzyme inhibition (e.g., amiodarone, cimetidine, sulfamethoxazole, metronidazole) [13], which increases its antithrombotic effect (and the INR). Amiodarone is a potent inhibitor of the metabolic clearance of both the S-enantiomer and the R-enantiomer and potentiates warfarin anticoagulation [14]. The anticoagulant effect of warfarin is augmented by second-generation and third-generation cephalosporins, which inhibit the cyclic interconversion of vitamin K, by thyroxine, which increases the metabolism of coagulation factors, by clofibrate and by acetaminophen, by inhibition of VKOR through a toxic metabolite of the drug [2]. The effect of statins or fibrates on the risk of bleeding in patients on VKAs is controversial. The initiation of a fibrate or statin that inhibits CYP3A4 enzymes was reported to increase the risk of gastrointestinal bleeding, whereas statins that are mainly excreted unchanged were not found to be associated with such an increased risk [15, 16]. Furthermore, nutritional supplements and herbal products are particularly problematic in warfarin-treated patients, who often fail to inform physicians and use these products as self-medication. Fluctuating levels of dietary vitamin K derive predominantly from phylloquinones in plant material, i.e., green tea and *natto* [17, 18].

#### *2.1.1.5. Therapy management*

Patients at low risk of thrombosis (i.e., AF) do not require heparin treatment at the beginning of warfarin therapy and a low initial dose regimen starting with 3 mg warfarin is recommended. The time taken to reach a therapeutic International Normalized Ratio (INR) is not critical; INR values should be monitored weekly on day 1 (baseline), day 8 and day 15, especially in older people who respond more slowly with changes to the INR. All patients who are sensitive to warfarin effects should monitor their INR more frequently (i.e., every 3–4 days). Patients at high risk of thrombosis (i.e., DVT) should be treated with heparin or LMWH when starting warfarin therapy for a minimum of 5 consecutive days. For initiation, a starting dose of 5 mg warfarin with daily INR monitoring for a minimum of 5 days is recommended. After day 4, clinicians should continue regular INR monitoring every 3 to 4 days until stabilized, and if the patient is still on heparin or LMWH, review the ongoing need for these additional anticoagulants. If INR values change of 0.5 over 3 days or 1.0 over 7 days, the INR is considered unstable. After INR stabilization, clinicians should adopt a maintenance dosing. The weekly dose can be prescribed using a range of dosing regimens (i.e., alternate day dosing or dose regimens with different doses for weekdays compared to the weekend).

bleeding occurs in the first 3 months of treatment [26]. In comparison, aspirin causes major bleeding in 1.3% of patients [26]. Absolute risk increases for intracranial hemorrhage with warfarin compared to aspirin is only 0.2% per year [27]. Risk of bleeding can be assessed using the HAS-BLED scoring system, where a bleeding risk score of equal to or greater than 3 indicates high risk. There

may identify reversible risks that can be managed prior to initiation of warfarin. In general, clinicians should be cautious and conduct regular review of the patient if initiating warfarin [24].

Like warfarin, acenocoumarol and phenprocoumon also exist as optical isomers that have different stereochemical characteristics. R-acenocoumarol has an elimination half-life of 9 h; it is primarily metabolized by CYP2C9 and CYP2C19 and is more potent than S-acenocoumarol. In fact, S-acenocoumarol has a faster clearance (elimination half-life of 0.5 h), it is primarily metabolized by CYP2C9 and undergoes extensive first pass metabolism. The treatment dose

Phenprocoumon is a much longer acting agent, with both the R- and the S-isomers with elimination half-lives of 5.5 days. Both are metabolized by CYP2C9, and S-phenprocoumon is 1.5–2.5 times more potent than R-phenprocoumon. It is administered in daily maintenance

As for warfarin, allelic variants of CYP2C9, CYP2C9\*2, and CYP2C9\*3 could lead to bleeding complications, especially if they code for enzymes with approximately 12 and 5% of the

Four non–vitamin K antagonist oral anticoagulants (NOACs), or direct oral anticoagulants (DOACs), are widely used as alternatives to warfarin: dabigatran etexilate, rivaroxaban, apixaban, and edoxaban. In contrast with warfarin, DOACs have a more predictable therapeutic effect, do not require routine INR monitoring, and have fewer potential drug-drug interactions and no restriction on dietary consumption of vitamin K–containing food [32].

DOACs act through direct inhibition of thrombin or inhibition of activated factor X (factor Xa). Dabigatran etexilate mesylate is a competitive direct thrombin inhibitor. Rivaroxaban, apixaban, and edoxaban inhibit factor Xa and prothrombinase activity, thus inhibiting the

DOACs indications comprehend thromboembolic prevention in patients with nonvalvular atrial fibrillation (AF), DVT, and pulmonary embolism. For each one of these conditions, dose regimen has to be adjusted. Creatinine clearance (CrCl) values should be checked for dose management.

conversion of prothrombin to thrombin and decreasing thrombus formation.

may vary between patients up to 10-fold, ranging from 1 to 9 mg daily [28, 29].

enzymatic activity of the wild type genotype CYP2C9\*1 [31].

HAGES [23]. Assessment

Real-World Safety of Anticoagulants http://dx.doi.org/10.5772/intechopen.78023 87

are other bleeding risk assessment tools available including HEMORR2

*2.1.2. Acenocoumarol and phenprocoumon*

doses of 0.75–9 mg [29, 30].

**2.2. Novel oral anticoagulants**

*2.2.1. Direct oral anticoagulants*

*2.2.1.1. Mechanism of action*

*2.2.1.2. Indications*

Dose modification should be taken into account following the INR monitoring:


For INR values greater than or equal to 5, there is a significantly increased risk of bleeding and vitamin K administration should be evaluated. Patients have to cease warfarin therapy and restart with a reduced dose, when INR is minor than 5 [19].

In case of switch to another anticoagulant agent and in particular to a direct oral anticoagulant agents (DOACs) in patients with atrial fibrillation, INR should be strictly monitored. Apixaban and dabigatran should be started when INR < 2, rivaroxaban when INR < 3, and edoxaban when INR ≤ 2.5 [20].

### *2.1.1.6. Real-world safety aspects*

Vitamin K antagonists reduce stroke and systemic embolism by 64% and all-cause mortality by 26%, compared to placebo in patients with atrial fibrillation [21]. However, as already mentioned above, VKAs have many drug and food interactions and require routine INR monitoring, and these limitations result in under-treatment for 30–50% of AF patients [22].

The CHADS2 scoring system [23] is a simple system that can be used to assess the annual risk of stroke in AF. In the CHADS2 scoring system, each point increases the annual risk of stroke by a factor of 1.5. Treatment with warfarin is recommended for a CHADS2 or CHA2 DS2 VASc scores of equal to or greater than 2. While the CHADS2 score is simple, it does not include many common stroke risk factors. The CHA2 DS2 VASc score is inclusive of the most common stroke risk factors in everyday clinical practice and has been validated in multiple cohorts; the accumulated evidence shows that CHA2 DS2 VASc is better at identifying "truly low-risk" patients with AF and is as good as, and possibly better than, scores such as CHADS2 in identifying patients who develop stroke and thromboembolism [24]. Direct comparison between the effects of warfarin and aspirin has been undertaken in several studies, demonstrating that warfarin was significantly superior, with a relative risk (RR) reduction of stroke of 39%.

In clinical practice, the risk of stroke should be weighed against the risk of bleeding to assess appropriateness of anticoagulant therapy. Warfarin causes major bleedings in 1–2% of people treated and intracranial bleeding in 0.1–0.5% of patients each year of treatment [25]. The highest rate of major bleeding occurs in the first 3 months of treatment [26]. In comparison, aspirin causes major bleeding in 1.3% of patients [26]. Absolute risk increases for intracranial hemorrhage with warfarin compared to aspirin is only 0.2% per year [27]. Risk of bleeding can be assessed using the HAS-BLED scoring system, where a bleeding risk score of equal to or greater than 3 indicates high risk. There are other bleeding risk assessment tools available including HEMORR2 HAGES [23]. Assessment may identify reversible risks that can be managed prior to initiation of warfarin. In general, clinicians should be cautious and conduct regular review of the patient if initiating warfarin [24].
