**4. New oral anticoagulants**

1, is preferred to administer OACs (VKAs or NOACs) based upon an assessment of the risk of bleeding complications and patient preferences. If CHA2DS2-VASc score equal to or great‐ er than 2, the treatment is with OACs (VKAs or NOACs) is recommended, unless contrain‐ dicated. When the patients refuse the use of OACs (VKAs or NOACs), antiplatelet therapy should be considered (combination therapy with acetylsalicylic acid plus clopidogrel).

In patients with CHA2DS2-VASc score of 1, apixaban and both doses of dabigatran (110 mg twice daily and 150 mg twice daily) had a positive net clinical benefit while, in patients with CHA2DS2-VASc score ≥2, all three NOACs were superior to warfarin, with a positive net clinical benefit, irrespective of bleeding risk. The patients with CHA2DS2-VASc equal to 0 have a lower risk of stroke and could be left with acetylsalicylic acid or no treatment, prefer‐ ring the latter option, as it has not shown any benefit in this group without treatment.

When using dabigatran, the dose is 150 mg administered twice daily in patients with low risk of hemorrhage (HAS-BLED scale of 0 to 2) and 110 mg twice daily in patients with in‐ creased risk hemorrhage (HAS-BLED ≥ 3), elderly patients, concomitant use of interacting drugs and moderate renal impairment (creatinine clearance (CrCl) 30-49 mL/min) [12].When using rivaroxaban, the dose is 20 mg daily in the most patients and 15 mg daily en high bleeding risk (HAS-BLED ≥ 3) and moderate renal impairment (CrCl 30-49 mL/min) [13].

Anticoagulant therapy is recommended in patients with AF with risk factors for systemic em‐ bolism. The choice of treatment is based on the absolute risk of stroke, the risk of bleeding and the risk/benefit ratios for each patient [14]. The recent development of NOACs, with innova‐ tive mechanisms of action of therapeutic targets in the coagulation could change the current standard anticoagulant drug treatment [15]. The NOACs are orally administered drugs that di‐ rectly inhibit the coagulation steps defined by decreasing or inhibiting thrombin generation of the final enzyme, thrombin. Thrombin (factor IIa) is the end effector of the coagulation cascade that catalyzes the formation of fibrin from plasma fibrinogen. Is the most potent physiological agonist of platelet activation, so it is considered a key therapeutic target in the development of NOACs. The Factor Xa acts as a point of convergence of the intrinsic and extrinsic pathways of coagulation and catalyzes the conversion of prothrombin to thrombin [16,17]. A single mole‐ cule of factor Xa can generate more than 1.000 molecule of thrombin, as a consequence the in‐ hibition of factor Xa can block this process by reducing the activation of coagulation and platelet thrombin mediated. Whether the coagulation cascade is inhibited at the level of throm‐ bin and factor Xa, or even above the sequence, the net result is a decreased activity of thrombin. The NOACs are characterized by specific inhibition of one of the two key factors in the coag‐ ulation system, factor Xa and thrombin. Dabigatran, MCC977 and AZD0837 acts by directly inhibiting thrombin thus interfere with the first phase (initial phase) and late (amplification / propagation phase) the model based on the coagulation system. Rivaroxaban, apixaban, edoxaban, betrixaban, eribaxaban, LY517717, YM150, TAK-442 and bind to either factor Xa or factor Xa without bound in the prothrombinase complex thus blocking the conversion of

**3. Objectives of anticoagulant therapy**

210 Atrial Fibrillation - Mechanisms and Treatment

The search of ideal anticoagulant is one of the most active fields of investigation in lasts years. The ideal anticoagulant would be one that fulfilled the following characteristics: Oral administration, effective in the treatment of AF and low bleeding risk, predictable kinetics, which does not require monitoring of coagulation and platelet count, which is not necessary to adjust the dose, wide therapeutic range, low drug interaction, cost effective and availabili‐ ty of an effective antidote.

With these premises have been developed more specific inhibitors of coagulation factors: factor Xa and factor II (thrombin). In Table 5, inspired by Phillips and Ansell collected some of the most relevant pharmacological characteristics of NOACs (dabigatran, ribaroxaban and apixaban) compared with VKAs (warfarin and acenocoumarol) [18].


VKOR: vitamin K oxidase reductase; CYP: cytochrome P450; PCC: prothrombin complex concentrates; PPIs: proton pump inhibitors; P-gp: P-glycoprotein; h: hour.

**Table 5.** Summary of pharmacokinetics and pharmacodynamics of VKAs and NOACs

The following describes the characteristics of each one of them:

#### **4.1. Dabigatran**

It is a potent, selective and reversible thrombin [19]. Has been authorized, among other indi‐ cations, in preventing stroke and systemic embolism in adult patients with non-valvular AF with one or more risk factors: stroke, transient ischemic attack or previous systemic embo‐ lism, left ventricular ejection fraction <40 %, symptomatic heart failure class ≥ 2 scale New Cork Heart Association (NYHA), age ≥ 75 years, age ≥ 65 years associated with diabetes mel‐ litus, coronary artery disease or hypertension.

tion of thrombin, is dose dependent, meaning that high doses could compromise coagula‐ tion. Has a dual route of elimination: 1/3 of the drug is eliminated via the kidney and 2/3 of the drug has hepatic metabolism. No interaction was observed with drugs such as acetylsali‐ cylic acid, aluminum hydroxide and magnesium, ranitidine or naproxen. Its bioavailability increases with inhibitors of CYP3A4 and P-gp, such as ketoconazole and ritonavir, and di‐

New Oral Anticoagulants in Atrial Fibrillation

http://dx.doi.org/10.5772/53614

213

It is an oral potent inhibitor reversible and highly selective direct factor Xa [21]. Has greater affinity for factor Xa attached to clot which is free. Inhibits and delays the generation of thrombin without significantly affecting platelet aggregation. The oral bioavailability is ap‐ proximately 50%. Rapidly absorbed and reaches peak concentrations at 3-4 hours after in‐ gestion. Food intake does not affect the area under the curve or maximum concentration, and can be taken with or without food. The binding to plasma proteins is 87%. The half-life is 12 hours and is metabolized with CYP3A4/5. It is also a substrate binding proteins, P-gp. Not recommended for use with potent CYP3A4 inhibitors and P-gp and that may increase exposure to apixaban twice. With the administration of inductors opposite happens. Aproxi‐ mately 25% of the drug is excreted in the urine and more than 50% in the feces. The multiple elimination pathways suggest that even patients with moderate hepatic or renal impairment

Currently, there are other investigational drugs: direct thrombin inhibitor (AZD0837 and MCC977), direct inhibitors of factor Xa (betrixaban, YM150, edoxaban, eribaxaban,

The NOACs not require routine monitoring. However, there are situations where it is advis‐ able to monitor selected patients as those with extreme weights, kidney failure or those who

As a result of the occurrence of serious adverse effects, including severe gastrointestinal bleeding (81 cases) and deaths (260 cases) of bleeding in patients treated with dabigatran were published safety ratings by the rating agencies worldwide drug advising monitoring of renal function in patients with moderate renal impairment (30-50 mL/min) receiving dabi‐ gatran and in patients over 75 years. Rivaroxaban is contraindicated if CrCl <15 mL/min,

Monitoring is also useful to evaluate the adherence to treatment (the omission of one or more doses puts the patient at risk of complications at an early stage) or when the patient needs to undergo an invasive procedure. When subjecting a patient to an invasive proce‐

minishes with rifampicin. The bioavailability increases only marginally with food.

may be suitable for this anticoagulant. No need to monitor renal function.

**4.4. Oral anticoagulants under investigation**

**5. Monitoring of NOACs**

LY517717, TAK-442, otamixaban (parenteral) [22].

suffer thrombotic complications being treated with these drugs.

and should be used with caution if is 15-30 mL/min.

**4.3. Apixaban**

It is administered orally as a prodrug (dabigatran etexilate), which is rapidly transformed by intestinal bioconversion by esterases to its active form. With a bioavailability of 6.5% for ad‐ equate absorption requires an acidic microenvironment, provided by multiple tartaric acid microspheres present in the composition of the capsules. It reaches its peak plasma concen‐ tration 2 hours after administration, with slight delays in the presence of food (up to 4 hours) or in the postoperative period (up to 6 hours). Elimination half life is about 12-14 hours. Approximately 20% of the drug is metabolized in the liver and excreted by the biliary system, independent of cytochrome P450. Most of dabigatran (about 80%) is eliminated re‐ nally as unchanged, so that his administration is contraindicated in patients with severe re‐ nal impairment (CrCl <30 mL/min), requiring administered with caution (setting dose) in patients with CrCl 30-49 mL/min. No other adjustments are required, except in patients over 75 years, which should decrease the dose. Administration is not recommended if liver en‐ zymes are elevated (transaminases 2 times baseline). Are recommended a baseline measure‐ ment before starting treatment, in patients with severe renal impairment (CrCl <30 mL/min) or in cases of concomitant quinidine. The main adverse event of dyspepsia is related to the pharmaceutical formulation. Dabigatran need a daily oral dose and fixed (in two doses), in‐ dependent of age, weight and race, with predictable effects and constant, without significant interactions with food or other drugs without coagulation controls. The absorption of dabi‐ gatran administration is reduced by approximately 25% with the co-administration of pro‐ ton pump inhibitors. Dabigatran is contraindicated if the patient is treated with systemic ketoconazole, cyclosporine, itraconazole and tacrolimus, and should be used with caution if the patient is receiving other potent inhibitors of P-glycoprotein (P-gp): amiodarone, quini‐ dine or verapamil.

#### **4.2. Rivaroxaban**

It is a potent and selective inhibitor of factor Xa [20], having peak plasma levels approxi‐ mately 3 hours after oral ingestion. As dabigatran, is indicated for the prevention of stroke and systemic embolism in adult patients with non-valvular AF, with one or more risk fac‐ tors: congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or attack transient ischemic. Bioavailability is 80-100% for the dose of 10 mg. Rapidly absorbed and reaches peak concentrations at 2-4 hours after ingestion. Its plasma half-life is 5 to 9 hours but increases markedly in people over 75 years from 9 to 13 hours. Not recommended for use in patients with CrCl <15 mL/min. The intensity of inhibition and, therefore, the genera‐ tion of thrombin, is dose dependent, meaning that high doses could compromise coagula‐ tion. Has a dual route of elimination: 1/3 of the drug is eliminated via the kidney and 2/3 of the drug has hepatic metabolism. No interaction was observed with drugs such as acetylsali‐ cylic acid, aluminum hydroxide and magnesium, ranitidine or naproxen. Its bioavailability increases with inhibitors of CYP3A4 and P-gp, such as ketoconazole and ritonavir, and di‐ minishes with rifampicin. The bioavailability increases only marginally with food.

#### **4.3. Apixaban**

The following describes the characteristics of each one of them:

litus, coronary artery disease or hypertension.

It is a potent, selective and reversible thrombin [19]. Has been authorized, among other indi‐ cations, in preventing stroke and systemic embolism in adult patients with non-valvular AF with one or more risk factors: stroke, transient ischemic attack or previous systemic embo‐ lism, left ventricular ejection fraction <40 %, symptomatic heart failure class ≥ 2 scale New Cork Heart Association (NYHA), age ≥ 75 years, age ≥ 65 years associated with diabetes mel‐

It is administered orally as a prodrug (dabigatran etexilate), which is rapidly transformed by intestinal bioconversion by esterases to its active form. With a bioavailability of 6.5% for ad‐ equate absorption requires an acidic microenvironment, provided by multiple tartaric acid microspheres present in the composition of the capsules. It reaches its peak plasma concen‐ tration 2 hours after administration, with slight delays in the presence of food (up to 4 hours) or in the postoperative period (up to 6 hours). Elimination half life is about 12-14 hours. Approximately 20% of the drug is metabolized in the liver and excreted by the biliary system, independent of cytochrome P450. Most of dabigatran (about 80%) is eliminated re‐ nally as unchanged, so that his administration is contraindicated in patients with severe re‐ nal impairment (CrCl <30 mL/min), requiring administered with caution (setting dose) in patients with CrCl 30-49 mL/min. No other adjustments are required, except in patients over 75 years, which should decrease the dose. Administration is not recommended if liver en‐ zymes are elevated (transaminases 2 times baseline). Are recommended a baseline measure‐ ment before starting treatment, in patients with severe renal impairment (CrCl <30 mL/min) or in cases of concomitant quinidine. The main adverse event of dyspepsia is related to the pharmaceutical formulation. Dabigatran need a daily oral dose and fixed (in two doses), in‐ dependent of age, weight and race, with predictable effects and constant, without significant interactions with food or other drugs without coagulation controls. The absorption of dabi‐ gatran administration is reduced by approximately 25% with the co-administration of pro‐ ton pump inhibitors. Dabigatran is contraindicated if the patient is treated with systemic ketoconazole, cyclosporine, itraconazole and tacrolimus, and should be used with caution if the patient is receiving other potent inhibitors of P-glycoprotein (P-gp): amiodarone, quini‐

It is a potent and selective inhibitor of factor Xa [20], having peak plasma levels approxi‐ mately 3 hours after oral ingestion. As dabigatran, is indicated for the prevention of stroke and systemic embolism in adult patients with non-valvular AF, with one or more risk fac‐ tors: congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or attack transient ischemic. Bioavailability is 80-100% for the dose of 10 mg. Rapidly absorbed and reaches peak concentrations at 2-4 hours after ingestion. Its plasma half-life is 5 to 9 hours but increases markedly in people over 75 years from 9 to 13 hours. Not recommended for use in patients with CrCl <15 mL/min. The intensity of inhibition and, therefore, the genera‐

**4.1. Dabigatran**

212 Atrial Fibrillation - Mechanisms and Treatment

dine or verapamil.

**4.2. Rivaroxaban**

It is an oral potent inhibitor reversible and highly selective direct factor Xa [21]. Has greater affinity for factor Xa attached to clot which is free. Inhibits and delays the generation of thrombin without significantly affecting platelet aggregation. The oral bioavailability is ap‐ proximately 50%. Rapidly absorbed and reaches peak concentrations at 3-4 hours after in‐ gestion. Food intake does not affect the area under the curve or maximum concentration, and can be taken with or without food. The binding to plasma proteins is 87%. The half-life is 12 hours and is metabolized with CYP3A4/5. It is also a substrate binding proteins, P-gp. Not recommended for use with potent CYP3A4 inhibitors and P-gp and that may increase exposure to apixaban twice. With the administration of inductors opposite happens. Aproxi‐ mately 25% of the drug is excreted in the urine and more than 50% in the feces. The multiple elimination pathways suggest that even patients with moderate hepatic or renal impairment may be suitable for this anticoagulant. No need to monitor renal function.

#### **4.4. Oral anticoagulants under investigation**

Currently, there are other investigational drugs: direct thrombin inhibitor (AZD0837 and MCC977), direct inhibitors of factor Xa (betrixaban, YM150, edoxaban, eribaxaban, LY517717, TAK-442, otamixaban (parenteral) [22].
