Venous thromboembolism (VTE), the term for deep venous thrombosis (DVT) and pulmonary embolism (PE), affects nearly 1 million Americans each year, and 60,000 to 100,000 of those patients die.1 Long-term complications of DVT may lead to post-thrombotic syndrome, which includes persistent swelling, pain, and skin changes including ulceration of the affected limb.2 About one-third of patients will suffer additional VTE events within 10 years of the initial DVT or PE.1
Anticoagulation is the mainstay of drug therapy to prevent and treat VTE. Traditionally, oral therapy has included warfarin, a vitamin K antagonist. However, warfarin interacts with many foods and drugs, and its narrow therapeutic window means that patients need careful, individualized dosing and routine laboratory monitoring.3 Recently, direct oral anticoagulants (factor Xa inhibitors and direct thrombin inhibitors) have been approved for use in the United States for the treatment of VTE.
FACTOR XA INHIBITORS
Factor Xa inhibitors include rivaroxaban, apixaban, and edoxaban. These agents produce their anticoagulation effect by directly inhibiting the convergence point of the extrinsic and intrinsic coagulation pathways at a pivotal point in the cascade, rendering factor Xa ineffective to generate thrombin (Figure 1).4,5
Each of these agents has proven efficacious for the treatment of VTE compared with traditional anticoagulants, and have similar risks of bleeding complications.6-9 Apixaban and rivaroxaban are approved for the treatment and reduction of recurrent DVT and PE, along with prevention of VTE in patients undergoing elective total hip or knee arthroplasty.10,11 Edoxaban is approved for the treatment of VTE after initial therapy using parenteral anticoagulation for 5 to 10 days.12Table 1 reviews the clinical properties and dosing for these agents.
All of the factor Xa inhibitors have good bioavailability following oral administration, have rapid onset of action, and have predictable pharmacodynamic and pharmacokinetic properties permitting fixed-dose administration. With these properties, routine monitoring is not required as it is with warfarin. The half-lives of these agents range between 5 and 14 hours compared with 36 to 42 hours for warfarin.3,5 The rapid onset allows for a full anticoagulant effect quickly compared with the multiple doses of warfarin needed to achieve a goal protime. When the anticoagulant effect needs to be halted, the time to return to normal coagulation often is shorter with these agents (because of their short half-lives) than with warfarin.
Additionally, these agents (although each to a different extent) possess dual elimination pathways (renal and hepatic), thus reducing the magnitude of risk for drug accumulation in patients with renal impairment (Table 1).4 Reducing edoxaban dosages is recommended for patients with renal insufficiency when their creatinine clearance is between 15 and 30 mL/minute; patients with clearances below 15 mL/minute should not use this drug.12 Rivaroxaban is not recommended in patients with creatinine clearances less than 30 mL/min.11 Also avoid prescribing these drugs to patients with moderate to severe hepatic impairment (Child-Pugh class B or C).10-12
Factor Xa inhibitors have far fewer known drug-drug interactions than warfarin, but these agents do interact with medications involved with the P-glycoprotein transport protein.13 In patients taking a P-glycoprotein inhibitor, reduce the dose of edoxaban to 30 mg daily.12 Avoid prescribing rivaroxaban in patients who are taking P-glycoprotein inhibitors and strong cytochrome P450 (CYP) 3A4 inhibitors such as ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, conivaptan, and clarithromycin or drugs that are combined P-glycoprotein and strong CYP3A4 inducers (carbamazepine, phenytoin, rifampin, St. John's wort).11 Reduce the apixaban dose by half in patients also taking strong dual inhibitors of CYP3A4 and P-glycoprotein. If a patient is already on a reduced dose of apixaban due to risk factors listed in Table 1, avoid concomitant use of these agents.10
DIRECT THROMBIN INHIBITOR
Dabigatran is the only oral direct thrombin inhibitor approved in the United States for preventing recurrent VTE and for treating VTE after initial administration of parenteral anticoagulant for 5 to 10 days.14 Dabigatran binds to free and clot-bound thrombin and inactivates it, preventing conversion of fibrinogen to fibrin, a paramount step in coagulation (Figure 1).15
Like the factor Xa inhibitors, dabigatran possesses predictable pharmacodynamic and pharmacokinetic properties, so routine coagulation monitoring is not necessary.16 Dabigatran has a rapid onset—30 minutes to 2 hours.10 Unlike the factor Xa inhibitors, this drug has extensive renal elimination, and must be used cautiously in patients with renal impairment.
Avoid dabigatran for VTE indications in patients with a creatinine clearance of less than 30 mL/minute or those on dialysis. The half-life varies based on the patient's creatinine clearance, ranging between 12 and 17 hours in healthy patients to longer in patients with renal impairment. Avoid using dabigatran and P-glycoprotein inhibitors in patients with creatinine clearances less than 50 mL/minute.14
Although no routine monitoring is needed with these agents, monitoring may be needed in the periprocedural period or if the patient has a hemorrhage. Unfortunately, routine coagulation assays are not reliable for assessing these drugs' anticoagulation activity. Of the commonly available tests, prothrombin time appears to have some sensitivity for the qualitative anticoagulation effect of the factor Xa inhibitors, although to a lesser extent for apixaban.11,12 For dabigatran, activated prothrombin time appears to be sensitive. The reagents used in these tests cause variability of the results.17
Other tests available in some US laboratories may provide more insight on the effect of these agents on the coagulation cascade. For the factor Xa inhibitors, chromogenic anti-Xa assays can be used. Drug-specific calibration is only available for rivaroxaban, making the test less reliable with apixaban and edoxaban. Thrombin time, through direct assessment of thrombin activity, is a sensitive test for dabigatran and is available in the United States.18,19
TRANSITIONING ANTICOAGULATION AGENTS
Before prescribing a direct anticoagulant, talk to the patient to determine the best anticoagulation strategy given the risks and benefits of the new drugs compared with traditional anticoagulants. Consider out-of-pocket expense, availability of reversal agents in case of bleeding complications, drug interactions, need for monitoring, administration schedule, increased risk of thrombotic events if a direct oral anticoagulant is abruptly stopped, and patient medical conditions that would affect drug elimination pathways.
Clinicians may need to transition patients from one anticoagulant to another. Due to the rapid onset of direct oral anticoagulants, overlapping administration with other anticoagulants is not necessary. Table 2 outlines the procedure for switching agents. In general, patients switching between two direct oral anticoagulants can stop the old agent and start the new one at their next scheduled dose. For patients on warfarin, remember that direct anticoagulants may alter the result of the international normalized ratio, and caution should be used in its interpretation.19
Until recently, one of the biggest downsides of the new agents was the lack of specific reversal agents. Idarucizumab has been approved to reverse dabigatran; andexanet alfa is under investigation as a reversal agent for apixaban, rivaroxaban, enoxaparin, and edoxaban (see Which antidotes are available for the novel oral anticoagulants? in the July 2016 issue of JAAPA).
Antidotes are needed to restore a normal coagulation cascade before procedures or during hemorrhage. Due to their short half-lives, discontinuing the new anticoagulants may be enough to return the patient's coagulation profile to normal.20 However, abrupt discontinuation of these agents when a patient still requires therapy increases the risk of thrombotic complications, so alternative anticoagulation should be used periprocedurally.10-12,14 Hemorrhage may be controlled with direct pressure or procedures that can stop bleeding, such as endoscopic or radiologically guided embolization. Dialysis can speed the elimination of dabigatran, which is primarily excreted renally, but dialysis is time-consuming and requires vascular access, which poses the risk of bleeding.16,21
In patients with life-threatening hemorrhage, reversal strategies include using nonspecific procoagulant agents. Most studies evaluating the use of nonspecific reversal agents are very limited, involve healthy subjects or animals, and sometimes yield conflicting results.21 Use of nonspecific reversal agents for hemorrhage associated with direct oral anticoagulants is off-label; because of the risk of thrombosis, evaluate the risks and benefits and exercise extreme caution.13,22
Prothrombin complex concentrates appear to be the most effective agents for reversing life-threatening hemorrhage. These concentrates contain varying amounts of active and inactive clotting factors.22,23 For life-threatening hemorrhage in patients taking factor Xa inhibitors, four-factor prothrombin complex concentrate (50 IU/kg) containing nonactivated factors II, VII, IX, X is weakly preferred.13,20 If idarucizumab is unavailable, activated four-factor prothrombin complex concentrate (80 IU/kg) is weakly preferred for treating life-threatening hemorrhage in patients taking dabigatran.13,20
Over the past several years, additional oral anticoagulation options have emerged for the prevention and treatment of VTE. These agents' reliable pharmacologic properties make them easier to use for patients. In clinical trials, the direct oral anticoagulants have similar risks of bleeding events compared with warfarin or low-molecular-weight heparin (LMWH). Unfortunately, when bleeding complications arise, a specific reversal agent is available only for dabigatran.
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Keywords:Copyright © 2016 American Academy of Physician Assistants
venous thromboembolism; direct oral anticoagulants; rivaroxaban; apixaban; edoxaban; dabigatran