PALO ALTO, CA — Ten years ago choosing an anticoagulation therapy boiled down to warfarin or—warfarin. Today, physicians and patients in the VA and elsewhere have more anticoagulant choices than ever. and those newer options have largely displaced warfarin for many indications.

In 2010, the U.S. Food and Drug Administration approved the first direct oral anticoagulant, dabigatran etexilate mesylate, an oral direct thrombin inhibitor. Rivaroxaban gained approval in 2011, followed by apixaban in 2012, edoxaban in 2015, and betrixaban in 2017.

All four of the “xabans” are oral, selective factor Xa inhibitors. warfarin is a vitamin K antagonist that inhibits the synthesis of vitamin K-dependent clotting factors II, VII, IX, and X as well as two anticoagulant proteins.

“Across almost every healthcare system and payer, including the VA, DOACs have seen a tidal rise of use,” said Minang Turakhia, MD, MAS, director of cardiac electrophysiology at the VA Palo Alto, CA, Health Care System and executive director of the Center for Digital Health at Stanford University.

Between 2013 and 2014, the use of DOACs nationwide and within the VA and DoD tripled. By late 2016, the new drugs accounted for two-thirds of all new prescriptions for anticoagulants and nearly half of all anticoagulant prescriptions overall at the VA.1

Today, about 217,000 veterans take a DOAC and 86,000 are on warfarin, according to Heather L. Ouorth, PharmD, national program manager for Clinical Pharmacy Practice Program and Outcomes Assessment, VA Pharmacy Benefits Management. “That’s double the 2011 number, when 150,000 veterans were on warfarin,” she said.

“The VA has done a great job responding to this change and thought about systemwide implementation and usage early on,” Turakhia told U.S. Medicine. Right from the start, the VA adapted existing warfarin clinics to support DOAC initiation (see Article 3) and offered educational programs and materials for providers about the new drugs.

The most common indications for DOACs are for stroke prevention in patients with atrial fibrillation and for the prevention of venous thromboembolism.

The 2019 American Heart Association/American College of Cardiology/Heart Rhythm Society Guidelines recommend DOACs over warfarin for patients with atrial fibrillation except in those with moderate to severe mitral stenosis or a mechanical heart valve.

Switching to DOACs

“Where we are today, if someone comes in for a new indication for atrial fibrillation, we’re more likely to recommend a DOAC unless they’re in a special population,” Turakhia said. Special cases include patients with valvular atrial fibrillation or with mechanical valves, for whom DOACs have not been approved, and some patients with chronic kidney disease.

“What we had not seen until recently is conversion from patients on warfarin to a DOAC.”

But that’s changing. “First, patients with not great [international normalization ratio] INR control transitioned, now, even if a patient is well-managed on warfarin, we discuss the potential benefits of switching,” he noted.

Several factors have driven the rapid adoption of DOACs. “Major randomized controlled trials showed that DOACs are as good or superior to warfarin in stroke prevention in patients with atrial fibrillation and intracranial hemorrhage is lower with DOACs, while time in therapeutic range is higher,” Turakhia said.

“There are also advantages for patients. They don’t need ongoing INR monitoring and dosing adjustments; there’s a simple dosing strategy and they are more convenient,” he added. Unlike warfarin, the DOACs have few interactions with other drugs or food.

No head-to-head trials have directly compared the DOACs to each other, so choosing between them varies by facility, physician preference, indication and patient characteristics.

While the drugs have many similarities, administration differs in important ways between them.

“With dabigatran, you have to have a certain amount injected first, and most people prefer not having to use injection. Some of the others can be used as monotherapy, without an injection,” said Tracy Minichiello, MD, chief of the anticoagulation and thrombosis services in the division of hematology at the San Francisco VAMC and clinical professor medicine at the University of California San Francisco. “For atrial fibrillation, rivaroxaban can be dosed once a day, which may be best for patients with compliance issues.”

National Criteria

The VA’s Pharmacy Benefit Management team “has done an exceptional job creating national criteria for use,” that guide physicians’ choice in specific situations, Turakhia said.

The VA’s drug class review summarizes the clinical trials supporting each indication for the drugs and the results for special populations, including pregnant or nursing patients and the very old, and discusses drug interactions. The guidance also notes which drugs can be put in pillboxes and which have to stay in original packaging as well as whether the drugs can be crushed, mixed with food or administered via feeding tubes.

“VA has been really proactive with anticoagulant use and guidance to help clinicians. It’s done a great job of providing evidence or expert-based guidance,” Minichiello said in an interview with U.S. Medicine.

The support is particularly valuable when trying to achieve the delicate balance needed for many patients who require a blood thinner. “Anticoagulation is a risky business. These are great, incredibly effective medications, but they have risk,” she added.

The DOACs have a lower rate of major bleeds than warfarin, but some patients and physicians have been particularly concerned about the risk of bleeds in the absence of a specific reversal agent for the drugs. The FDA approval of reversal agents for dabigatran in 2015 and factor Xa inhibitors in 2018 may put some of those concerns to rest and increase DOAC use, Minichiello noted. (See Article 2.)

Other factors could drive down DOAC use over time. Compared to 10 or 20 years ago, “warfarin is better managed; DOACs are better understood; patients have better blood pressure control and physicians are better about prescribing aspirin to only patients who need it,” Turakhia explained.

“Anticoagulation may not be the right choice for every patient with atrial fibrillation. They may be getting atrial fibrillation at the end of life,” he said. “We have amazing therapies to maintain normal sinus rhythm, so do all patients still need to be on anticoagulants for life? New trials are looking to see if we can have periods when patients don’t need anticoagulation when they are not having atrial fibrillation. That’s the flip side of undertreating—we may be deimplementing for some patients.”


  1. Rose AJ, Goldberg R, McManus DD, Kapoor A, Want V, Liu W, Yu H. Anticoagulant prescribing for non-valvular atrial fibrillation in the Veterans Health Administration. J Am Heart Assoc. 2019 Sep 3; 8(17):e012646. doi:10.1161/JAHA.119.012646. Epub 2019 Aug 23.