Non-Vitamin K Antagonist Anticoagulants and Atrial Fibrillation
Non-Vitamin K Antagonist Anticoagulants and Atrial Fibrillation
Warfarin is relatively inexpensive and readily available, is partially reversible, and has well-understood interactions with other drugs. Warfarin is broadly indicated, and is suitable for patients with mechanical valves. Despite its proven effectiveness, there are several recognized disadvantages of warfarin, including a narrow therapeutic range, drug–drug interactions that can be delayed, food–drug interactions, slow dose-adjustment time, and genetic variability in the enzymes involved in its metabolism, all of which can affect INR. In addition, in order to assure that a therapeutic INR is maintained, frequent patient monitoring is required, which some patients may find burdensome. NOACs, which directly inhibit factor Xa (rivaroxaban, apixaban, and edoxaban) or thrombin (dabigatran), were developed to address some of the disadvantages of warfarin. NOACs have a predictable anticoagulant response, making regular laboratory monitoring unnecessary. Anticoagulation with NOACs is achieved quickly, reaching peak plasma concentrations 1–4 h following oral administration, in comparison with the delayed onset of warfarin ( Table 2 ). Half-lives of NOACs are shorter than that of warfarin, and range from 5 to 15 h. NOACs have fewer drug–drug and drug–food interactions than warfarin. Although rivaroxaban should be administered with food, the other NOACs can be administered without regard to food.
There are disadvantages associated with NOACs. Bleeding risks increase when NOACs are administered with other anticoagulants, platelet inhibitors, or non-steroidal anti-inflammatory drugs. NOACs are substrates of the P-glycoprotein (P-gp) transporter, and many rate-controlling and anti-arrhythmic drugs interact with P-gp. In addition, the NOACs, to varying degrees, are substrates of cytochrome P450 (CYP) isoenzyme 3A4. As such, co-administration of an NOAC with P-gp inducers or inhibitors and/or CYP3A4 inducers or inhibitors may impact exposure to the NOAC. This is related to the degree to which the NOAC depends on P-gp for transport or on CYP3A4 for metabolism. Thus, verapamil, diltiazem, quinidine, amiodarone, and dronedarone are associated with increased NOAC exposure, and use of these agents may require NOAC dose reduction or may be contraindicated in patients taking NOACs. The lack of laboratory monitoring for NOACs may also be a negative as it is difficult to determine the level of anticoagulation, and compliance can be assessed only by patient feedback and refill frequency.
Pharmacology of Non-vitamin K Antagonist Oral Anticoagulants (NOACs) Versus Warfarin
Warfarin is relatively inexpensive and readily available, is partially reversible, and has well-understood interactions with other drugs. Warfarin is broadly indicated, and is suitable for patients with mechanical valves. Despite its proven effectiveness, there are several recognized disadvantages of warfarin, including a narrow therapeutic range, drug–drug interactions that can be delayed, food–drug interactions, slow dose-adjustment time, and genetic variability in the enzymes involved in its metabolism, all of which can affect INR. In addition, in order to assure that a therapeutic INR is maintained, frequent patient monitoring is required, which some patients may find burdensome. NOACs, which directly inhibit factor Xa (rivaroxaban, apixaban, and edoxaban) or thrombin (dabigatran), were developed to address some of the disadvantages of warfarin. NOACs have a predictable anticoagulant response, making regular laboratory monitoring unnecessary. Anticoagulation with NOACs is achieved quickly, reaching peak plasma concentrations 1–4 h following oral administration, in comparison with the delayed onset of warfarin ( Table 2 ). Half-lives of NOACs are shorter than that of warfarin, and range from 5 to 15 h. NOACs have fewer drug–drug and drug–food interactions than warfarin. Although rivaroxaban should be administered with food, the other NOACs can be administered without regard to food.
There are disadvantages associated with NOACs. Bleeding risks increase when NOACs are administered with other anticoagulants, platelet inhibitors, or non-steroidal anti-inflammatory drugs. NOACs are substrates of the P-glycoprotein (P-gp) transporter, and many rate-controlling and anti-arrhythmic drugs interact with P-gp. In addition, the NOACs, to varying degrees, are substrates of cytochrome P450 (CYP) isoenzyme 3A4. As such, co-administration of an NOAC with P-gp inducers or inhibitors and/or CYP3A4 inducers or inhibitors may impact exposure to the NOAC. This is related to the degree to which the NOAC depends on P-gp for transport or on CYP3A4 for metabolism. Thus, verapamil, diltiazem, quinidine, amiodarone, and dronedarone are associated with increased NOAC exposure, and use of these agents may require NOAC dose reduction or may be contraindicated in patients taking NOACs. The lack of laboratory monitoring for NOACs may also be a negative as it is difficult to determine the level of anticoagulation, and compliance can be assessed only by patient feedback and refill frequency.
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