SNOWMASS, COLO. – All four Food and Drug Administration–approved novel oral anticoagulants offer impressive safety advantages over the traditional strategy of low-molecular-weight heparin bridging to warfarin for treatment of acute venous thromboembolism, Dr. Patrick T. O’Gara observed at the Annual Cardiovascular Conference at Snowmass.
He highlighted a European analysis of six phase III clinical trials totaling more than 27,000 patients with venous thromboembolism (VTE) in which dabigatran (Pradaxa), rivaroxaban(Xarelto), apixaban (Eliquis), or edoxaban (Savaysa) was compared to the traditional strategy of unfractionated or low-molecular-weight heparin (LMWH) bridging to warfarin or another vitamin K antagonist. All four NOACs proved statistically noninferior to the traditional strategy in terms of efficacy as defined by prevention of recurrent VTE. Efficacy of NOACs and warfarin was similar regardless of body weight, chronic kidney disease, age, cancer, and pulmonary embolism versus deep venous thrombosis.
Dr. Patrick T. O’Gara
In terms of safety, it was no contest: The NOACs were collectively associated with a 39% lower risk of major bleeding, a 64% lower risk of fatal bleeding, and a 63% reduction in intracranial bleeding compared to LMWH/warfarin (Blood 2014 Sep 18;124[12]:1968-75).
“This is a big-ticket winner for the novel oral anticoagulants in the longer-term management of patients who have venous thromboembolic disease – not inferior to a strategy of low-molecular-weight heparin bridging to warfarin and much better with respect to serious consequences of a safety nature,” said Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.
The pivotal trials for NOACs in VTE were generally structured statistically as noninferiority trials, with one exception: edoxaban has been shown to be superior to warfarin in a prespecified subgroup with submassive pulmonary embolism.
Further strengthening the case for routine use of NOACs in treating acute VTE is the emergence of fast-acting antidotes to the drugs in the event a patient develops a bleeding complication. Idarucizumab (Praxbind) received FDA approval last October as a reversal agent for dabigatran. Many experts think andexanet alpha will likely receive regulatory approval later this year as a universal antidote to all the factor Xa inhibitors, he noted.
It’s estimated that 70% of patients with pulmonary embolism can be classified as low risk and thus eligible for consideration for early hospital discharge and home treatment, provided their social situation is suitable. Pulmonary embolism patients are categorized as low risk if they are hemodynamically stable, don’t require supplemental oxygen, don’t show right ventricular dilatation on CT imaging in the emergency department, and lack serum biomarker evidence of right ventricular strain or injury.
In making decisions about outpatient therapy for VTE, a point worth considering is that two NOACs, rivaroxaban and apixaban, possess the practical advantage of being single-agent therapy. That is, they don’t require a heparin bridge prior to their introduction, as established in the EINSTEIN trial for rivaroxaban and in the AMPLIFY study for apixaban. However, a loading dose is necessary. Rivaroxaban is given at 15 mg b.i.d. for 3 weeks before dropping down to 20 mg once daily. Apixaban has a loading dose of 10 mg b.i.d. for the first 7 days followed by 5 mg b.i.d. thereafter.
“You’ll note that you give a higher loading dose for these particular agents for events that occur on the venous side of the circulation compared with the management of patients who have nonvalvular atrial fibrillation,” Dr. O’Gara said.
In contrast, both dabigatran and edoxaban require either unfractionated or LMWH as bridge before switching to oral therapy.
Dr. O’Gara reported having no financial conflicts of interest regarding his presentation.