A Comparison of the New Anticoagulants for Use in Atrial Fibrillation
Atrial fibrillation (AF) is the most common cardiac rhythm disorder, affecting at least 1% of the general population. After age 80 this increases to 10% of the population.1 In addition, the presence of AF is responsible for a 4- to 5-fold increase in the risk of ischemic stroke.2
Treatment for ischemic stroke prevention in the past has been limited to warfarin, a vitamin K antagonist, and aspirin. Use of warfarin requires ongoing anticoagulant monitoring and resultant dosage adjustments. However, Connolly et al found that even during randomized clinical trials patients were only within warfarin therapeutic range two-thirds of the time.3 Limitations of warfarin therapy include slow onset of action, a narrow therapeutic window, and multiple diet and drug interactions.4 In addition, warfarin use is associated with a risk of bleeding of 2% per year. Aspirin or aspirin with clopidogrel use leads to similar bleeding risk.5 Aspirin has been associated with a small reduction in stroke incidence.6
Recently the drug dabigatran was approved for stroke prevention in the AF population, followed closely by rivaroxaban. The drug apixaban is also currently undergoing FDA review. These three drugs approach anticoagulation via different mechanisms from warfarin, and the clinical trial results for each varies. In addition, therapy with these drugs does not require anticoagulant effect monitoring, and they render their effect at a fixed dose. The following is a summary of these new warfarin rivals.
Dabigatran etexilate, 150 mg twice daily, is a direct thrombin inhibitor, affecting factor IIa of the coagulation cascade (Figure 1). Pradaxa (dabigatran) received FDA approval in October 2010 for patients with non-valvular AF, at a dose of 150 mg twice a day.7
Dabigatran was studied in a variety of settings: orthopedic, stroke prevention in the AF population, and secondary prevention in acute coronary syndrome.
The RE-LY Trial
The pivotal trial for use in the AF population was the RE-LY (Randomized Evaluation of Long-term anticoagulation therapy) trial, a noninferiority study that compared dabigatran to warfarin.9 The goal of this study was stroke prevention, with secondary endpoints of myocardial infarction, pulmonary embolism, hospitalization, total mortality, and cardiovascular mortality. Patients were randomized to 110 or 150 mg of dabigatran b.i.d. or warfarin to maintain the INR at 2.0 to 3.0. The trial enrolled 18,113 AF patients. At the two-year follow-up, the stroke or embolism rate for the 110 mg group was equivalent to warfarin, and it was less often for those taking the 150 mg dose. Hemorrhagic stroke occurred less for both dose levels of dabigatran when compared to warfarin. The rate of major bleeding was comparable for high-dose dabigatran and warfarin but lower for low dose dabigatran (Table 2).
Contraindications, Interactions, and Adverse Events
Dabigatran is contraindicated with active pathological bleeding or hypersensitivity.
There were no reported significant rises in liver enzymes in the RE-LY study; there were no interactions with cytochrome P450 enzymes.
At steady-state with therapeutic doses, the drug increases aPTT 1.5-2 times control.
There is an increased risk of bleeding if the patient is on antiplatelet agents, heparin, fibrinolytic therapy, or takes NSAIDs chronically.
Dabigatran may be given with or without food. It should be given ≥ 2 hours before an antacid or proton pump inhibitor, as these drugs may decrease dabigatran concentration. Rifampin may decrease the effects of dabigatran. Dose adjustments are not required with ketoconazole, amiodarone, verapamil, clarithromycin, and quinidine. It is recommended that dabigatran be given ≥ 2 hours before giving these drugs. St. John’s wort may decrease dabigatran concentration.
There is an increased risk of stroke if the drug is discontinued.
Adverse GI effects include dyspepsia, gastritis, and bleeds within the first couple of months; histamine-2 receptor antagonists may help dyspepsia,7 but are prescribed cautiously. There was a higher rate of GI bleeds with dabigatran than with warfarin.7
Monitoring and Reversal
Drug therapy with dabigatran does not require regular monitoring. The level of anticoagulation can be assessed in cases of bleeding by measuring the thrombin clotting time or ecarin clotting time. Activated partial thromboplastin time does not give a totally accurate quantification of the level of anticoagulation, but may help determine if anticoagulation is excessive in an emergency situation.10
There is no antidote. It has been theorized that factor VIIa and activated prothrombin complex concentrates would be possible reversal agents; dialysis is also recommended.10 Once the drug enters the body, there is a low affinity for protein binding. Sixty percent of the drug is removed after 2–3 hours of dialysis. Activated charcoal may be administered within 1–2 hours of overdose, to decrease exposure.7 The best approach is thought to be use of fresh frozen plasma, mechanical compression, and surgical hemostasis.7 Maintenance of adequate diuresis is also important, as the drug is primarily excreted in the urine.
A recently published study looked at the cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation.11 The outcome measures for this study were quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios. The study concluded that for the ≥ 65-year-old population at increased risk for stroke, dabigatran may be a cost-effective alternative to warfarin depending on the drug pricing of dabigatran.
Dabigatran has been available now for a little over one year. A few issues related to therapy with the drug have been identified:12
- The cost of dabigatran is ~$7 per day vs. warfarin $0.22 per day. For those who pay out of pocket, this is excessive. For those whose medications are purchased through copay, it is thought the insurers will review the data related to the decreased stroke incidence with this drug and consider the ultimate savings.
- There is a 6% rate of major GI bleeds during each year of treatment with dabigatran plus an increase in the incidence of gastritis; coadministration of antiplatelet drugs may contribute to this, and care providers need to be aware of this.
- There is no antidote.
- Twice a day dosing tends to decrease compliance levels.
- The drug blister pack cannot be opened days in advance due to drug potency loss. This prevents patients from lining up their meds for a week at a time, a maneuver that increases compliance.
A medication guide is available to give to the patient when the medication is prescribed.
Xa inhibition prevents prothrombin from being generated from thrombin, and inhibits the generation of tissue factor-induced thrombin.13 Apixaban, betrixaban, edoxaban, and rivaroxaban are the drugs that inhibit factor Xa (Figure 1). This discussion includes rivaroxaban and apixaban.
Rivaroxaban (Xarelto, Bayer/Johnson & Johnson)
Xarelto (rivaroxaban) was approved by the FDA in November 2011 for use in patients with non-valvular atrial fibrillation. It was approved in July 2011 for use after knee or hip replacement surgery, to reduce the risk of blood clots, DVT, and pulmonary embolism. The FDA has required that patients getting the drug must receive a medication guide describing the risks and adverse reactions associated with the drug. The drug should be taken once a day with the evening meal to ensure complete absorption.
Rivaroxaban is 80% bioavailable. Maximal plasma concentrations are reached after 3–4 hours14 and rivaroxaban has a plasma half-life of 7 to 11 hours. Two-thirds of the drug is metabolized by the liver; one-third goes unchanged through renal excretion (Table 1).15
The ROCKET AF Study
Rivaroxaban was first studied in the orthopedic population. The ROCKET AF study was conducted from December 2006 to May 2010.16 This was a double-blind trial design in which computer-generated sham INR values were generated for rivaroxaban patients to eliminate treatment bias. The Phase III ROCKET AF study enrolled 14,264 patients and was conducted in 45 countries. Patients with nonvalvular AF and a history of stroke or two additional independent risk factors for stroke were randomized to 20 mg of rivaroxaban daily (15 mg daily if creatinine clearance is 30 to 49 ml/min) or warfarin with the dose adjusted to maintain the INR at 2.0 to 3.0.17 For this study, the primary efficacy endpoint was new stroke or systemic embolism, and the safety endpoint was a major bleeding event or clinically relevant nonmajor bleeding event. Secondary efficacy endpoints were all-cause death, vascular death, and MI.
Rivaroxaban was found to be noninferior to warfarin for stroke or systemic embolism prevention. Major bleeding incidence was equivalent, but intracranial and fatal bleeding occurred less frequently in rivaroxaban (Table 2).
Contraindications, Interactions, and Adverse Events
The drug is not recommended for those receiving ketoconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, conivaptan, HIV protease inhibitors, rifampin, itraconazole, voriconazole, or posaconazole.
Avoid use with moderate and severe hepatic impairment or with any hepatic disease associated with coagulopathy.
There are no reported food-drug interactions and little drug-drug interaction potential.
Phenytoin, phenobarbital, carbamazepine, rifampin, and St. John’s wort may reduce rivaroxaban concentration. Aspirin, clopidogrel, naproxen, erythromycin, fluconazole, and clarithromycin use may increase bleeding. Use anticoagulants, NSAIDs/aspirin, and clopidogrel concomitantly with caution.
If creatinine clearance is between 15–50 mL/min, rivaroxaban should be used with caution with amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, and erythromycin.
A boxed warning states that sudden discontinuation increases the risk of stroke.
The most common adverse reactions were bleeding complications.
Monitoring and Reversal
In case of overdose, dialysis is not thought to be of benefit. There is no antidote available. However, activated charcoal may be used to reduce absorption.18