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New oral anticoagulants
HANDS ON Oral Surgery New oral anticoagulants Background.—New orally administered anticoagulant agents (NOAs) are now available for patients whose conditions require the use of extended-duration anticoagulant therapy. Similar to the subcutaneous or intravenously administered low-molecular-weight heparin (LMWH) and in contrast to coumarin derivatives such as warfarin and acenocoumarol, these agents interfere with specific steps of the coagulation cascade. The new agents are dabigatran etexilate, a direct thrombin inhibitor (DTI), and the factor Xa inhibitors (FXaIs) rivaroxaban and apixaban. The characteristics of these agents and implications for dental practice were summarized. NOA Characteristics.—Dabigatran etexilate is a specific, reversible DTI given orally that is rapidly absorbed and converted into its active form (Table 2). It binds with the active site on free and clot-bound thrombin and reaches its peak plasma concentration within 30 minutes to 4 hours, so its onset of action is rapid. Half-life elimination is 12 to 14 hours in healthy patients, 14 to 17 hours in elderly persons, and up to 27 hours in patients with severe renal dysfunction. Compared to warfarin, a dabigatran dose of 150 mg twice a day was associated with lower rates of stroke and systemic embolism but similar rates of major bleeding. When 110 mg twice daily dabigatran and warfarin were compared, they had similar rates of stoke and systemic embolism, but dabigatran had significantly fewer cases of major bleeding. The rate of hemorrhagic stroke with dabigatran at both doses is less than a third that of warfarin and the protection against ischemic stroke is comparable. Generally dabigatran requires no regular monitoring. Thrombin clotting time (TT) and ecarin clotting time (ECT) are the most sensitive tests for quantifying anticoagulation rate in an emergency situation. Should reversal be required in an emergency situation or because of lifethreatening or uncontrolled bleeding, patients can be given idarucizumab, which has been shown to rapidly and completely reverse the anticoagulant activity of dabigatran in 88% to 98% of patients.
Rivaroxaban is a selective, reversible direct FXaI that binds with the part of factor XaI that catalyzes prothrombin activation. It has rapid onset and reaches peak plasma concentration in 2.5 to 4 hours, with a half-life of 5.7 to 9.2 hours in healthy persons (up to 12 or 13 hours in elderly patients). As an FXaI, rivaroxaban slightly prolongs prothrombin time (PT) and activated partial thromboplastin time (aPTT). No regular monitoring of rivaroxaban is needed, but in an emergency, anti factor Xa is the most effective anticoagulation measure. Compared to warfarin, rivaroxaban significantly reduces the number of strokes and systemic embolic events that occur in patients with atrial fibrillation. Reductions are also found in number of major bleeding episodes and intracranial hemorrhages compared to warfarin. Apixaban is a reversible FXaI whose therapeutic indications are similar to those for dabigatran and rivaroxaban. Peak plasma concentration is achieved in 1 to 3 hours and oral bioavailability is about 60%. The drug’s half-life is 12 hours. No specific reversal agent has been identified, but for emergency situations, recombinant factor VIIa, recombinant factor Xa, or activated thrombin complexes may be useful. For normal bleeding, patients can simply delay or skip the next dose of apixaban and that is usually sufficient. Implications for Dental Practice.—The various drugs differ in their rate and extent of digestive adsorption as well as their mechanism of action and rate of elimination. These factors are also governed by variables such as liver or renal function, sex, weight, age, genetic polymorphisms of the enzyme or efflux systems, and drug-drug interference. Therefore each patient presents a unique situation when it comes to determining the best approach to a dental situation. The dental practitioner should work closely with the patient’s primary care provider to estimate the patient’s thromboembolic and bleeding risk levels. Using this information, it should be determined if the anticoagulant should be interrupted or continued. Currently, these new agents have limited data comparing the relative benefits of
Volume 61
Issue 5
2016
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Table 2.—Principal characteristics of new oral anticoagulants (NOAs)
NOAs
Class
Dabigatran etexilate
Direct thrombin inhibitor
Indications
Prevention of cerebrovascular complications in non-valvular atrial fibrillation; hip and knee replacement surgery; venous thromboembolism prophylaxis and management Rivaroxaban Direct Prevention of inhibitor cerebrovascular of factor Xa complications in non-valvular atrial fibrillation; venous thromboembolism prophylaxis and management Apixaban Direct Prevention of inhibitor cerebrovascular of factor Xa complications in non-valvular atrial fibrillation; venous thromboembolism prophylaxis and management
Dosage
Time to peak plasma concentration
Half life
Routes of elimination
Monitoring of coagulation
110 mg- 150 mg 2–4 h twice daily
80 % renal, Not needed 12–14 h; 14–17 h 20 % in elderly; 15–18 h hepatic in moderate renal impairment; up to 28 h in advanced renal impairment
20 mg daily
5–10 h; 12–13 h in patients > 75 years
66 % renal, Not needed 28 % in feces
10–14 h
25 % renal, Not needed 55 % intestinal, remnant hepatic
2.5–4 h
5 mg twice daily 1–3 h
(Courtesy of Costantinides F, Rizzo R, Pascazio L, et al: Managing patients taking novel oral anticoagulants (NOAs) in dentistry: A discussion paper on clinical implications. BMC Oral Health 16:5, 2016.)
continuing anticoagulation versus interrupting it, so clinical judgment will be the determining factor. Dental procedures are generally considered low-risk for bleeding, so most patients can continue to take their FOAs. However, if the procedure is surgical and considered to be associated with a high risk for bleeding, the agent can be discontinued. Examples of procedures with a high risk of surgical bleeding include multiple extractions, surgery lasting more than 45 minutes, head and neck cancer operations, or extensive oral and maxillofacial surgery in patients with comorbid conditions. If a very high or high risk for thromboembolism exists, anticoagulant cessation should be as brief as possible. Bridging with LMWH may not be required because of the shorter half-lives of the new agents and the recent development of the DTI reversal agent.
steps in the coagulation cascade. Only one has a specific reversal agent available, so dental surgery must be carefully planned for patients taking these drugs. For simple surgery, it appears that no interruption in administration is required. For extensive surgical procedures, any interruption is determined by considering patient factors as well as procedural concerns. No evidence-based guidelines have yet been developed, so clinical prospective studies are needed to establish bleeding risks and hemostasis requirements for these patients undergoing dental surgery.
Costantinides F, Rizzo R, Pascazio L, et al: Managing patients taking novel oral anticoagulants (NOAs) in dentistry: A discussion paper on clinical implications. BMC Oral Health 16:5, 2016
Clinical Significance.—The NOAs that have been developed are targeted to very specific
e118
Dental Abstracts
Reprints available from F Costantinides; e-mail: f.costantinides@ fmc.units.it
Rivaroxaban is a selective, reversible direct FXaI that binds with the part of factor XaI that catalyzes prothrombin activation. It has rapid onset and reaches peak plasma concentration in 2.5 to 4 hours, with a half-life of 5.7 to 9.2 hours in healthy persons (up to 12 or 13 hours in elderly patients). As an FXaI, rivaroxaban slightly prolongs prothrombin time (PT) and activated partial thromboplastin time (aPTT). No regular monitoring of rivaroxaban is needed, but in an emergency, anti factor Xa is the most effective anticoagulation measure. Compared to warfarin, rivaroxaban significantly reduces the number of strokes and systemic embolic events that occur in patients with atrial fibrillation. Reductions are also found in number of major bleeding episodes and intracranial hemorrhages compared to warfarin. Apixaban is a reversible FXaI whose therapeutic indications are similar to those for dabigatran and rivaroxaban. Peak plasma concentration is achieved in 1 to 3 hours and oral bioavailability is about 60%. The drug’s half-life is 12 hours. No specific reversal agent has been identified, but for emergency situations, recombinant factor VIIa, recombinant factor Xa, or activated thrombin complexes may be useful. For normal bleeding, patients can simply delay or skip the next dose of apixaban and that is usually sufficient. Implications for Dental Practice.—The various drugs differ in their rate and extent of digestive adsorption as well as their mechanism of action and rate of elimination. These factors are also governed by variables such as liver or renal function, sex, weight, age, genetic polymorphisms of the enzyme or efflux systems, and drug-drug interference. Therefore each patient presents a unique situation when it comes to determining the best approach to a dental situation. The dental practitioner should work closely with the patient’s primary care provider to estimate the patient’s thromboembolic and bleeding risk levels. Using this information, it should be determined if the anticoagulant should be interrupted or continued. Currently, these new agents have limited data comparing the relative benefits of
Volume 61
Issue 5
2016
e117
Table 2.—Principal characteristics of new oral anticoagulants (NOAs)
NOAs
Class
Dabigatran etexilate
Direct thrombin inhibitor
Indications
Prevention of cerebrovascular complications in non-valvular atrial fibrillation; hip and knee replacement surgery; venous thromboembolism prophylaxis and management Rivaroxaban Direct Prevention of inhibitor cerebrovascular of factor Xa complications in non-valvular atrial fibrillation; venous thromboembolism prophylaxis and management Apixaban Direct Prevention of inhibitor cerebrovascular of factor Xa complications in non-valvular atrial fibrillation; venous thromboembolism prophylaxis and management
Dosage
Time to peak plasma concentration
Half life
Routes of elimination
Monitoring of coagulation
110 mg- 150 mg 2–4 h twice daily
80 % renal, Not needed 12–14 h; 14–17 h 20 % in elderly; 15–18 h hepatic in moderate renal impairment; up to 28 h in advanced renal impairment
20 mg daily
5–10 h; 12–13 h in patients > 75 years
66 % renal, Not needed 28 % in feces
10–14 h
25 % renal, Not needed 55 % intestinal, remnant hepatic
2.5–4 h
5 mg twice daily 1–3 h
(Courtesy of Costantinides F, Rizzo R, Pascazio L, et al: Managing patients taking novel oral anticoagulants (NOAs) in dentistry: A discussion paper on clinical implications. BMC Oral Health 16:5, 2016.)
continuing anticoagulation versus interrupting it, so clinical judgment will be the determining factor. Dental procedures are generally considered low-risk for bleeding, so most patients can continue to take their FOAs. However, if the procedure is surgical and considered to be associated with a high risk for bleeding, the agent can be discontinued. Examples of procedures with a high risk of surgical bleeding include multiple extractions, surgery lasting more than 45 minutes, head and neck cancer operations, or extensive oral and maxillofacial surgery in patients with comorbid conditions. If a very high or high risk for thromboembolism exists, anticoagulant cessation should be as brief as possible. Bridging with LMWH may not be required because of the shorter half-lives of the new agents and the recent development of the DTI reversal agent.
steps in the coagulation cascade. Only one has a specific reversal agent available, so dental surgery must be carefully planned for patients taking these drugs. For simple surgery, it appears that no interruption in administration is required. For extensive surgical procedures, any interruption is determined by considering patient factors as well as procedural concerns. No evidence-based guidelines have yet been developed, so clinical prospective studies are needed to establish bleeding risks and hemostasis requirements for these patients undergoing dental surgery.
Costantinides F, Rizzo R, Pascazio L, et al: Managing patients taking novel oral anticoagulants (NOAs) in dentistry: A discussion paper on clinical implications. BMC Oral Health 16:5, 2016
Clinical Significance.—The NOAs that have been developed are targeted to very specific
e118
Dental Abstracts
Reprints available from F Costantinides; e-mail: f.costantinides@ fmc.units.it