Direct acting oral anticoagulants (DOACs).
Trials have shown these agents are noninferior to conventional therapy in the prevention of stroke and systemic embolism in atrial fibrillation, in the treatment of DVT, and as prophylaxis for venous thromboembolism after total knee and total hip arthroplasty.
DOACS are not prescribed for patients with mechanical heart valve, anti-phospholipid antibodies syndrome, for atrial fibrillation associated with rheumatic heart disease, for whom vitamin K antagonists are preferred.
Two distinct mechanisms of action exist for the DOAC’s: direct intervention of thrombin (dabigatran) and inhibition of Factor Xa (edoxaban, apixaban, and rivaroxaban).
DOACs efficacy and safety are affected by concomitant antiplatelet therapy.
Include: dabigatran (Pradaxa), Rivaroxaban (Xarelto),apixaban (Eliquis), and edoxaban (Lixiana).
Direct oral, anticoagulants (DOACs) including apixaban, rivaroxaban, edoxaban and danigatran are widely used anticoagulants ny approximately 4 million patients in the US currently using such therapy.
Approximately 20% of DOAC treated patients undergo an elective or urgent surgical procedure annually
Dabigatran blocks factor IIA in the clotting cascade, a direct thrombin inhibitor.
Dabigatran is a direct and competitive thrombin inhibitor.
Rivaroxaban, apixaban, and edoxaban block factor Xa.
DOACs have minimal interactions with food.
Rivaroxaban should be taken with the evening meal.
Absorption of dabigatran is delayed by approximately 2 hours if taken with a fatty meal.
Administered at fixed doses, act rapidly with peak activity in 3-4 hours.
Have reliable pharmacokinetics.
Not affected by vitamin K intake.
Unlike warfarin, they do not require coagulation test monitoring.
Have short half lives from 7-20 hours, which is an advantage relative to warfarin in emergency settings.
Elimination half lives of factor Xa inhibitors, apixaban, rivalroxaban, are 8 to 12 hours in patience with a creatinine clearance above 30 mm milliliters per minute.
Dabigatran is a higher dependence on kidney clearance so its elimination half-life is 10 to 14 hours and patience with creatinine clearance above 50 mL per minute and 18 to 24 hours and patience with creatinine clearance of 30 to 50 mL per minute.
Randomized control studies indicate above novel anticoagulant agents are as good as or better than warfarin for stroke prevention in patients with AF, DVT and pulmonary embolism.
Direct oral anticoagulants-Dabigatran, rivaroxaban, apixaban and edoxaban are recommended for stroke/system embolism prevention among patients with non-valvular atrial fibrillation and are associated with lower stroke/myocardial infarction and all-cause mortality rates compared with warfarin.
The concomitant use of direct oral anticoagulants with antiplatelet agents is associated with a similar risk of G.I. bleeding, and a lower risk of intracranial hemorrhage and other major bleeding than concomitant warfarin-antiplatelet use (Douros A).
Above drugs do not require monitoring of clotting parameters, or require dietary restrictions.
Currently there is no way to determine degree of anticoagulation produced by these agents.
Uncertainty remains about the optimum dose for specific patients, and there is also uncertainty about reasonable monitoring tests to determine the efficacy of NOACs.
These agents provide consistent anticoagulation in most patients.
DOACs are not recommended for use in pregnant or breast-feeding individuals because they cross the placenta and are present in breastmilk, and insufficient data exists for their safety for the fetus and newborn.
Direct acting oral anticoagulants demonstrate rapid onset of action after the initial dose.
In general these drugs are contraindicated if the creatinine clearance is less than 30 mL per minute and should be used with extreme caution if the creatinine is between 15 and 30 mL/minute.
Except for severe renal impairment with a creatinine clearance of less than 30 mL per minute for dabigatran and less than 15 mL per minute for a factor Xa inhibitors these agents use is not restricted in patients with renal dysfunction.
Direct acting oral anticoagulants have predictable offset related to the plasma half-life and there is lack of value of dose adjustment based on plasma level measurement beyond using clinical characteristics.
Above drugs have simplified dosing schedules.
DOAC dosing is reduced based on factors that affect DOAC clearance, including patient’s age of 80 years or older, weight less than 60 kg, creatinine clearance less than 50 mL per minute and potential DOAC – drug interactions.
Presently, no antidote exists to reverse anticoagulant effects if excessive bleeding occurs with novel agents.
Compared to warfarin novel agents have relatively short half-lives so stopping these agents have a short time to the return to normal coagulation.
Large trials suggest NOACs have similar bleeding complications to warfarin, and in some trials less catastrophic bleeding than warfarin, such as less cerebral hemorrhage.
The risk of intracranial hemorrhage overall is significantly reduced with novel agents and there may be a slightly increased risk of G.I. bleeding.
Such agents have been shown to reduce the risk of intracranial bleeding by approximately 50%.
NOACs associated with increased bleeding with concomitant use of anti platelet agents, and lower doses should be used.
Dose reduction is a recommended for patient with moderate kidney impairment, low bodyweight, and concomitant medications that may impact metabolism to the P-glycoprotein transport system or hepatic cytochrome P-450.
Often not necessary to stop NOACs for surgical procedures with moderate risk for bleeding, such as oral surgery or pacemaker implantation.
A meta-analysis by Chatterjee S et al reviewing NOACs dabigatran, apixaban, and Rivaroxaban are safer with regard to the incidence of intracranial hemorrhage.
The above meta-analysis confirmed that NOACS agents reduce the risk of intracranial hemorrhage compared with warfarin or aspirin and the reduction of ICH was not associateD with additional risk of stroke.
In addition the above study revealed that Dabigatran, apixaban or Rivaroxaban are not superior one to another in terms of ICH risk or stroke prevention.
Intracranial hemorrhage associated with NOACs is frequently life threatening and more than 50% of patients with such a process will die.
With direct oral antiicoagulants there is the risk of a major hemorrhage in older patients patients with renal insufficiency and these drugs should be avoided in this population.
Because of the short half-lives of direct oral anticoagulants the majority of direct oral anticoagulant associated bleeding complications can be managed by withholding the agent and providing supportive care.
Short half lives of direct oral anticoagulants facilitates the timing of elective surgery after withdrawl of the drug.
Dabigatran specific reversal agent is idarucizumab (Praxbind).
Rivaroxaban and epixaban reversal agent Andexanet alfa.
Patients treated with low dose DOAC’s are associated with the reduced effectiveness without a safety benefit in atrial fibrillation..
Direct oral anticoagulants are safe and effective for patients with venous thromboembolism and thrombophilia.
In patients with a confirmed diagnosis of inherited thrombophilia, including most severe and rare forms, direct oral anticoagulants showed an efficacy profile comparable to that of heparin/vitamin K antagonists.
Among patients with acute ischemic stroke treated with intravenous alteplase the use of NOACs within the preceding seven days, compared with no use of anticoagulants, was not associated with significantly increased risk of intracranial hemorrhage.