PALO ALTO, CA—For decades, patients prescribed warfarin to reduce the risk of stroke following a diagnosis of atrial fibrillation have made regular visits to pharmacist- or nurse-directed clinics to ensure their international normalized ratio (INR) remains within a very narrow therapeutic window. Similar monitoring was not considered necessary—nor has it generally been provided—for patients prescribed the less finicky direct-acting oral anticoagulants developed over the last 15 years.

A recent VA study suggested, however, that pharmacists can play a crucial role in ensuring patients on DOACs receive appropriate dosing. Monitoring appears to be particularly important for patients with chronic kidney disease, the researchers noted.

Proper dosing of DOACs for patients with reduced kidney function poses particular challenges, and getting it right has significant health implications for patients. 

“Direct oral anticoagulants (DOACs) are dependent on the kidneys to various degrees for elimination. Chronic kidney disease (CKD) will, therefore, increase serum DOAC concentrations and associated bleeding risk if the dose is not reduced,” said study co-author Mintu Turakhia, MD, chief of cardiac electrophysiology at the VA Palo Alto Healthcare System, associate professor of medicine at Stanford University and executive director of the Stanford Center for Digital Health.

While the U.S. Food and Drug Administration has established dosing guidelines for DOACs based on kidney function, “These dosing guidelines vary across DOACs and can be quite complex,” he said.

A previous study by Turakhia and colleagues published in the Journal of the American Medical Association, found that VA pharmacist management practices improve medication adherence and patient outcomes in other settings.

To see if the same benefits accrued to patient with reduced kidney function taking DOACs, they used data from The Retrospective Evaluation and Assessment of Therapies in AF (TREAT-AF) cohort study to identify 230,762 veterans with newly diagnosed atrial fibrillation and a DOAC prescription between 2003 and 2015. They then compared the DOAC doses prescribed to the dose recommended by the U.S. Food and Drug Administration. 

Of the patients who receive a DOAC within 90 days of diagnosis, 5,060 received dabigatran (77%) or rivaroxaban (22.7%). Of those, 1,312 had chronic kidney disease based on a recorded glomerular filtration rate of less than 60. 

The study’s finding that 93.6% of all veterans on DOACs and 83.2% of those with chronic kidney disease receive the appropriate dose “sharply contrast with previously published findings of substantially higher incorrect dosing from other (non-VA) fee-for-service and nonintegrated care systems,” 

“Underdosing in the general population and overdosing in patients with chronic kidney disease have been well documented in other healthcare systems including Medicare, U.S. commercial insurance, and outside of the U.S. (Canada),” he noted.

A retrospective study conducted using the OptumLabs Data Warehouse determined that 43% of patients with impaired renal function who would require a dose reduction received higher-than-recommended dosing, Turakhia told U.S. Medicine. In addition, 13.3% of patients without a renal indication were potentially underdosed. 

“In this context, specialized DOAC management as performed by the VA may reduce incorrect DOAC dosing and related adverse events, particularly in CKD,” he added.

Role of VA Anticoagulation Clinics

Since 2011, VA policy has recommended managing patients on DOACs through anticoagulation clinics, just like patients on warfarin. That policy likely explains the VA’s much higher rate of appropriate dosing, Turakhia said.

Anticoagulation clinics for patients on warfarin have a “mature reimbursement and care structure across a variety of payers and healthcare systems. In contrast, DOACs are generally not monitored in most healthcare systems, possibly owing to a lack of coverage and reimbursement for this service since DOACs were intended to circumvent the need to sustain costly care infrastructure,” he explained.

The VA takes a far more proactive approach to DOAC management. 

“The overwhelming majority of VA sites have specialized pharmacists review patient indications and suitability for DOACs, lead patient education on DOACs, monitor for adverse events, and follow patients receiving a DOAC prescription for at least several months,” Turakhia noted. 

A recent internal VA survey from the Pharmacy Benefits Management Services Clinical Pharmacy Practice Office indicated that 76% of sites routinely perform pharmacist-led management. About one-third of sites only manage initiation with monitoring for the first three to six months, while two-thirds provide ongoing management, according to data from co-author Lisa Longo, PharmD, of the VA Pharmacy Benefits Management Services.

The VA’s nationwide electronic health record system also might help ensure veterans receive the right DOAC dose.

“Other factors, such as electronic health record reminders, automated checks of eGFR in the order entry process and the integrated nature of the VA healthcare system may also contribute to higher rates of correct dosing,” Turakhia said.

Other healthcare providers and health plans could learn from the VA model, he noted.

“The conclusion of this study is that incorrect dosing of DOACs is substantially less prevalent across the VA system, when compared to studies of commercial payers and healthcare systems. The VA uses pharmacist-led DOAC management, which likely accounts for its better performance. Adoption of pharmacist-led management or similar interventions in other healthcare systems has the potential to improve appropriate dosing, particularly in CKD.”

1 Leef GC, Perino AC, Askari M, Fan J, Ho PM, Olivier CB, Longo L, Mahaffey KW, Turakhia MP. Appropriateness of Direct Oral Anticoagulant Dosing in Patients With Atrial Fibrillation: Insights From the Veterans Health Administration. J PharmPract. 2019 Feb  21:897190019828270. doi: 10.1177/0897190019828270. [Epub ahead of print]

2 Shore S, Ho PM, Lambert-Kerzner A, Glorioso TJ, Carey EP, Cunningham F, Longo L, Jackevicius C, Rose A, Turakhia MP. Site-level variation in and practices associated with dabigatran adherence. JAMA. 2015 Apr 14;313(14):1443-50. doi: 10.1001/jama.2015.2761.