Review of Direct Oral Anticoagulants and Guide for Effective Drug Utilization

Tigran Khachatryan; Christopher Hauschild; Jason Hoff; Tahmeed Contractor; Arthur Khachatryan; Huyentran Tran; Bert Matsuo; Alan Jacobson; Anthony Hilliard

Disclosures

Am J Cardiovasc Drugs. 2019;19(6):525-539. 

In This Article

Direct Thrombin Inhibitors

Pharmacology

Dabigatran etexilate mesylate (Pradaxa®) is the only oral direct thrombin inhibitor approved in the USA. It is a prodrug that is converted to its active form, dabigatran, in the plasma and liver via a hydrolysis reaction.[11] Early single- and multiple-dose studies have indicated that dabigatran has a linear pharmacokinetic profile, with the maximum serum dabigatran concentration (Cmax) and area under the plasma concentration–time curve (AUC) increasing proportional to dabigatran dose. Furthermore, it has an apparent volume of distribution of 1430–2400 L in the terminal phase and total clearance ranging 1480–2430 mL/min. The rapid elimination of dabigatran means its concentration declines to around 30% of Cmax 8 h after reaching steady state, which led to the use of twice-daily dosing in clinical trials.[12,13] Early pharmacologic studies also demonstrated that dabigatran had a low bioavailability of approximately 3–7%, reaching Cmax 1 h after oral administration in the fasting state and approximately 2 h after a fatty meal, protein binding of 35%, and half-life of 12–17 h, with up to 80% eliminated via the kidneys.[12,13] Dabigatran kinetics are also affected by P-glycoprotein (P-gp) inducers and inhibitors, which are responsible for its many drug–drug interactions. P-gp inhibitors, including verapamil, amiodarone, dronedarone, ketoconazole, clarithromycin, ticagrelor, and quinidine, increase serum dabigatran concentrations, whereas P-gp inducers such as rifampin can reduce the anticoagulant effect (Table 4).[14–17] Dabigatran comes in a capsule formulation that should not be opened, crushed, or chewed since any of these actions will increase absorption by 75%, leading to an increased bleeding risk. The active metabolite produces its anticoagulant effects by reversibly binding to the active site of thrombin, which is responsible for the conversion of fibrinogen to fibrin.[11,12] Routine monitoring of dabigatran's anticoagulant effect is not required because of the relatively predictable pharmacology and fixed dosing. However, in some situations, testing is desirable and can guide clinical decision making, for instance, in patients needing urgent surgical intervention, in acute ischemic stroke requiring thrombolytic agents, and in patients who are bleeding or who experience thrombosis while receiving therapy. Nonetheless, in the USA, no standardized assays exist for this purpose despite a growing need. By virtue of its mechanism, dabigatran affects the coagulation function tests such as activated partial thromboplastin time (aPTT) and INR. It affects these parameters in a dose-dependent manner, which can be small, variable, and affected by other anticoagulants and reagents used for the test, making anticoagulation reversal challenging. Therefore, these tests are not generally useful in clinical practice. For instance, a normal aPTT will exclude supratherapeutic dabigatran concentrations but has no value for evaluation of therapeutic or subtherapeutic levels. Thrombin time (TT) can be useful in that a normal result will virtually exclude the presence of dabigatran, but the magnitude of the abnormal TT is not indicative of the anticoagulant effect. More accurate quantification methods include diluted thrombin time (dTT), which displays a direct linear relationship with drug concentration, and ecarin chromogenic assay, which provides a direct measure of dabigatran activity.[18–21] However, these tests are not widely available, standardized, or approved for serum dabigatran quantification. Mass spectroscopy is the gold standard for quantifying serum medication level but is complex and has a high turnaround time.[18]

Indications

The indications for dabigatran and DOACs are generally similar in the USA and Europe, with some notable differences (Table 5).[22–24] The US FDA-approved indications for dabigatran include reducing the risk of stroke or transient ischemic attack (TIA) in patients with NVAF, treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have already received parenteral anticoagulation for 5–10 days, reducing the risk of DVT and PE in previously treated patients, and prophylaxis of DVT and PE in patients after hip replacement surgery. The safety and efficacy of dabigatran for these indications was established by the RE-LY, RE-COVER, RE-MEDY, RE-SONATE, and RE-NOVATE trials, respectively.[1,25–27] The recommendation for parenteral run-in for patients with DVT and PE stems from trial design. Patients with VTE are at highest risk for thrombus propagation and poor outcomes in the first 5–10 days. Therefore, in the randomized controlled trial evaluating the efficacy of dabigatran for the treatment of VTE compared with warfarin (RE-COVER), investigators sought to mitigate this risk by designing the study with parenteral run-in, which would also be similar to the standard of therapy before DOACs.

Dabigatran should not be used in patients with mechanical heart valve.[14] The RE-ALIGN study evaluating dabigatran compared with warfarin in patients with mechanical aortic and mitral valves found higher rates of thromboembolic and bleeding events with dabigatran, leading to the early termination of the study.[28] The definition of valvular AF refers to AF in the setting of moderate to severe mitral stenosis or a mechanical heart valve.[7,8] Bioprosthetic valves and valve repairs had also been included in past classifications;[29] however, DOACs can be used safely in such patients.[30]

Dosing

Controversy of Dose Regimen. Dabigatran was extensively debated by regulators during its approval process for stroke prophylaxis in AF, and both the FDA and the European Medicines Agency (EMA) made very different regulatory decisions on how best to approve dabigatran for use. For the FDA, the primary deciding factor was to improve the efficacy of dabigatran in preventing stroke, and since the 150-mg dose resulted in a larger stroke reduction than the 110-mg dose, the decision was made to only approve the 150-mg dose, even though this higher dose was associated with a greater bleeding risk.[31] The decision to not approve the 110-mg dose did lead to two concerns: (1) that a lower dose would not be available for renally impaired patients, a population the FDA believed should have the opportunity to use this medication, and (2) that having only one strength available increased the chance of dispensing errors, since writing the dose on a prescription would no longer be necessary. To mitigate these concerns, the FDA requested the company also market the unstudied dose of 75 mg, which was already approved and marketed in Europe for DVT prophylaxis after knee or hip surgery, and that this dose be used in patients with AF with an estimated creatinine clearance (CrCl) of 15–30 mL/min.[32]

In contrast, the EMA focused more on the bleeding risk of dabigatran and not only approved the 110-mg dose but also recommended it for patients aged ≥ 75 years with additional risk factors for stroke, instead of the manufacturer's recommendation to use the 110-mg dose in all patients with AF aged ≥ 80 years. The EMA also requested blood concentration data, establishing a therapeutic concentration range of 48–200 ng/mL for dabigatran and ensuring that the Hemoclot direct thrombin inhibitor assay was validated to test for dabigatran levels. Even with this established therapeutic concentration, the EMA did not require blood monitoring testing for patients using dabigatran.[33]

Since the approval of dabigatran in both the USA and Europe, more data have demonstrated variability in blood level concentrations in patients receiving these fixed doses and the risks these variations pose. Postmarketing data from patients with serious and fatal bleeding demonstrated that most of these events happened in patients aged > 80 years, raising the concern that declining renal function and elevated blood concentrations were leading to these bleeding events. A dabigatran study looking at efficacy in patients with mechanical valves also revealed that 17% of patients in the original RE-LY trial had blood concentrations below the manufacturer's desired level of 50 ng/mL. Even when the dabigatran dose was increased to 300 mg, 7% of patients still did not reach the target blood concentration of 50 ng/mL.[32,33]

Both the FDA and the EMA have discussed making changes to the labeling of dabigatran in light of the new data but, to date, neither has decided to require blood level monitoring for dabigatran or changed the recommended dosing for patients with AF.

FDA-Approved Dosing. Dabigatran is prescribed at a dose of 150 mg twice daily for all indications in patients with CrCl > 30 mL/min except for DVT prophylaxis after hip replacement surgery, where the recommended initial dose is 110 mg administered 1–4 h after surgery then 220 mg daily for 28–35 days.[14] For patients with NVAF and CrCl 15–30 mL/min or those with CrCl 30–50 mL/min and receiving the P-gp inhibitors dronedarone or ketoconazole, dabigatran 75 mg twice daily should be prescribed. No dose adjustment is needed for the P-gp inhibitors amiodarone, quinidine, ticagrelor, verapamil, or clarithromycin.[14] Dabigatran for patients with CrCl < 30 mL/min or with CrCl < 50 mL/min who are also receiving P-gp inhibitors is not recommended for all other indications and should generally be avoided for patients receiving P-gp inducers (Table 1 and Table 4).[14,16,34]

Making the Switch

Regiments when converting from other anticoagulants to dabigatran will vary according to the anticoagulant and the indication. For patients with NVAF receiving warfarin, dabigatran can be started once the INR is < 2. For other oral or parenteral anticoagulants, dabigatran can be given at the next scheduled dose time. For patients receiving continuous parenteral anticoagulation, dabigatran can be started 0–2 h after the parenteral medication is stopped. For patients with DVT or PE who have been treated for 5–10 days with parenteral anticoagulation, dabigatran should be started as soon as unfractionated heparin is discontinued or 0–2 h before the next dose of low-molecular-weight heparin would be administered.[14]

Periprocedural Recommendations and Reversal

It is generally recommended that dabigatran be held even for procedures with low bleeding risk because data on the safety of uninterrupted DOAC use are limited. The ACC consensus statement recommendation for patients at low procedural bleeding risk is to hold dabigatran ≥ 24 h for CrCl ≥ 80 mL/min, ≥ 36 h for CrCl 50–79 mL/min, ≥ 48 h for CrCl 30–49 mL/min, and ≥ 75 h for CrCl 15–29 mL/min and to consider measuring dTT or holding dabigatran ≥ 96 h for CrCl ≤ 15 mL/min. In patients for whom the procedural bleeding risk is uncertain, intermediate, or high, dabigatran should be held ≥ 48 h for CrCl ≥ 80 mL/min, 72 h for CrCl 50–79 mL/min, ≥ 96 h for CrCl 30–49 mL/min, and ≥ 120 h for CrCl 15–29 mL/min and to consider dTT measurement for CrCl ≤ 15 mL/min to facilitate decision making.[21]

Considerations for reinitiating dabigatran after a procedure should be similar to that with parenteral anticoagulants, focusing on the procedural and patient-specific bleeding risk. In general, dabigatran may be reinitiated postprocedure once adequate hemostasis is achieved. A study evaluating the preprocedural management of dabigatran found major bleeding risk to be 1.8% and thromboembolic risk to be 0.2% when the medication was restarted at 75 mg the night after a low-bleeding-risk procedure, with the full dose the next day, and the full dose after 48–72 h following a high-bleeding-risk procedure.[35] No bridging is required before reinitiation of this agent because of its fast onset of effect. Furthermore, bridging may confer harm. A substudy of the RE-LY trial found bridging with parenteral anticoagulation with dabigatran conferred a significant increase in the bleeding risk.[36] Therefore, the ACC consensus statement recommends restarting a DOAC without bridging the day following a low-bleeding-risk procedure and 48–72 h after a high-bleeding-risk procedure.[37]

In cases of bleeding complications, management will depend on the presentation. Holding the anticoagulant will usually resolve the issue in nonmajor bleeding. In cases of major bleeding where the patient is hemodynamically unstable, hemoglobin drop is ≥ 2 g/dL, or the patient requires blood transfusions, additional intervention will be needed to achieve hemostasis. The ACC consensus statement recommends the use of idarucizumab (Praxbind®) to reverse the effects of dabigatran. Four-factor prothrombin complex concentrate (4F-PCC) or activated prothrombin complex concentrate (aPCC) can be used for life-threatening bleeding if idarucizumab is not available.[21] Idarucizumab is a monoclonal antibody fragment developed for the reversal of dabigatran's anticoagulant effect. In the RE-VERSE AD clinical trial, intravenous idarucizumab 5 g showed efficacy in rapid reversal of dabigatran's anticoagulant effect as measured by dTT and ecarin clotting time.[38] Hemodialysis is also an option for removing the drug from systemic circulation.[39]

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