and readily absorbed orally. These agents inhibit specific activated Ridaforolimus enzymes of the coagulation system, whereas warfarin and other vitamin K antagonists reduce the production of the coagulation proenzymes, and heparin or low molecular weight heparin require antithrombin III to inhibit their respective target enzymes. Dabigatran, rivaroxaban, and apixaban are direct anticoagulants in that they do not require the presence of a cofactor, such as antithrombin III, for function. Formally, Pradaxa is dabigatran etexilate, a prodrug. In vivo, dabigatran etexilate is rapidly converted to dabigatran by esterases in the blood and liver.4 The metabolism of dabigatran, rivaroxaban, and apixaban involves cytochrome P450 3A4, P glycoprotein, or both.
4 The medical literature is not yet sufficiently mature to provide full guidance on whether and how to modify the use of the new anticoagulants based on the coadministration of drugs that modify activity of cytochrome P450 3A4 or P glycoprotein. The rivaroxaban product information cautions against its use with combined P glycoprotein Raltegravir MK-0518 and strong cytochrome P450 3A4 inhibitors or inducers. The dabigatran product information also cautions to avoid its use in the presence of concomitant use of P glycoprotein inducers, such as rifampin. Although some P glycoprotein inhibitors have been shown to not require adjustment of the dabigatran dose, not all P glycoprotein inhibitors are known to be acceptable. Development/Clinical Trials The new oral anticoagulants have followed similar paths to development.
They were studied in thrombosis prophylaxis for high risk orthopedic patients, nonvalvular atrial fibrillation, Fulvestrant ICI 182780 and treatment and secondary prophylaxis for venous thromboembolic disease. More recent studies have included acute coronary syndrome, and extended thrombosis prophylaxis in medical patients. The studies were designed with fixed doses of the drug and did not incorporate therapeutic efficacy monitoring or dose titration. Most of the studies were powered for noninferiority. Nonvalvular Atrial Fibrillation Dabigatran was the first of the new oral anticoagulants to be approved by the FDA to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 4 This was based on the impressive results of the RE LY trial.
5 Patients with nonvalvular atrial fibrillation and a risk for stroke were randomly assigned to 150 mg twice daily or 110 mg twice daily of dabigatran or to dose adjusted warfarin. Both buy Marbofloxacin doses of dabigatran were noninferior to warfarin for the primary efficacy end point introspection of stroke or systemic embolism and the primary safety end point of major bleeding.5,6 The higher dose of dabigatran resulted in a relative risk of stroke or systemic embolism of 0.66 compared with dose adjusted warfarin. This was significant for superiority, without a significant difference in bleeding rates.5,6 The 110 mg twice daily dose of dabigatran was noninferior to warfarin for stroke or systemic embolism but significantly safer for major and all bleeding episodes. Of note, both the 150 mg and the 110 mg doses of dabigatran were associated with significantly lower rates of intracerebral and subdural hemorrhage than warfarin. In a controversial move, the FDA approved 150 mg .