Management of Nonvalvular Atrial Fibrillation and Acute Venous Thromboembolism with Novel Oral Anticoagulants

April 13, 2014
W. Todd Penberthy, PhD

Although they offer an alternative to warfarin for preventing stroke in patients with atrial fibrillation, effective use of the new anticoagulants requires careful patient selection.

Advances have recently been made in developing novel oral anticoagulants (NOACs) that are clinically superior to warfarin. NOACs work by direct target inhibition of either factor Xa (apixaban, edoxaban, and rivaroxaban) or factor IIa/thrombin (dabigatran, which is not yet FDA approved). Unlike warfarin, these agents do not inhibit vitamin K-dependent function.

At the American College of Physicians Internal Medicine 2014 annual meeting held in Orlando, FL, Amir K. Jaffer, MD, MBA, professor of medicine at Rush University and consultant to several pharmaceutical companies, presented clinical evaluations of NOACs risk analysis data.

Jaffer stressed that when selecting a therapy, clinicians must weigh the risk of thrombosis against the risk of bleeding. Renal function should also be evaluated prior to initiation of target therapy and reevaluated at least annually.

Most significantly, clinical trial data indicate that treatment with the NOACs apixaban and dabigatran results in significantly less stroke than does warfarin. However, more gastrointestinal bleeding adverse events were observed for NOACs than for warfarin.

Summary data indicate that NOACs are at least as good as warfarin, according to Jaffer. All NOACs were non-inferior to warfarin for prevention of stroke and systemic embolism.

Jaffer pointed out the unmet needs in using anticoagulants for treating atrial fibrillation. Atrial fibrillation confers a 5-fold greater risk for ischemic stroke, where recurrent stroke risk is increased by 2.4-fold in patients not treated by anticoagulants. Warfarin is the current recommended treatment, but in many cases it is not used. Moreover warfarin has a slow onset action with an unpredictable dose response.

All NOAC doses are set somewhat arbitrarily, with recommendations based on the dosing used in clinical trials, but dosing does depend on renal function. Jaffer cautioned that missed doses should never be doubled to make up for a lost dose and recommended the use of coagulation monitoring.

He said that it is also important to consider drug-drug interactions when using NOACs. This can get complicated, but generally they are “metabolized primarily by the cytochrome P450 3A4/5 (CYP3A4/5) enzyme (rivaroxaban and apixaban) and/or efflux transporter P-glycoprotein (P-gp) (dabigatran and edoxaban).” Thus, clinicians should aware of potential interactions between the NOACs and strong CYP3A or P-gp inhibitors or inducers. NOACs should also not be administered to patients who are on HIV1 protease inhibitors.

For managing bleeding events associated with NOACs, Jaffer recommended that the patient be withdrawn from therapy and aggressively clinically monitored. Red blood cell transfusions should be performed to prevent anticipated anemia. Currently, a bleeding antidote recombinant protein binder of factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban) is being examined in phase II clinical trials. These novel therapies may one day make otherwise too risky peri-operative procedures possible.

For patients that have undergone major surgery, it is recommended that they wait at least 2 days before treatment with NOACs, although Jaffer said the NOACs can be administered within 1 day post-surgery.

According to Jaffer, it is difficult to say which of the NOACs is the best, as there have not been any head-to-head comparisons to date. All trial data has made comparisons to warfarin controls.

In summary, the novel oral anticoagulants have superior performance in reducing strokes compared to warfarin. There is good evidence for using NOACs to treat patients with nonvalvular atrial fibrillation and acute venous thromboembolism. However, clinicians must always pay heightened attention to renal function in the elderly before dosing and adjust dose to avoid the drug altogether where indicated.