**1. Introduction**

Hemostasis is the physiologic process for the prevention of hemorrhage and bleeding in response to blood vessel damage, while physiologic inhibition of coagulation ensures the fluidity of blood. The ways in which these factors all balance each other can be the difference between hemostasis and thrombosis [1]. Alteration of this balance in favor of coagulation results in thrombosis, a pathological process characterized by the formation of a platelet or fibrin clot, which could occlude both arterial and venous vessels.

This chapter reviews the agents commonly used for controlling blood fluidity, including in particular:

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


metabolized in the liver by different CYP enzymes: CYP3A4 and CYP1A2 primarily metabolize the R-enantiomer, whereas the S-enantiomer is mainly metabolized by CYP2C9. The inac-

Real-World Safety of Anticoagulants http://dx.doi.org/10.5772/intechopen.78023 85

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].

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

tive metabolites are excreted with the urine and stool [10].

*2.1.1.4. Interactions*

*2.1.1.5. Therapy management*

• Parenteral anticoagulant heparin and its derivatives.
