Low-dose apixaban may be safe anti-stroke option for dialysis patients

By Joan Stephenson

NEW YORK (Reuters Health) - Low-dose apixaban achieves blood levels that appear to be safe and might be a “reasonable alternative” to warfarin for preventing stroke in patients with atrial fibrillation who are on hemodialysis, new research suggests.

The single-center, open-label cohort study of seven patients with advanced chronic kidney disease found that “apixaban should be avoided in dialysis patients at the currently recommended dose of 5 mg twice daily, but may be considered at the reduced dose of 2.5 mg twice daily,” first author Dr. Thomas Mavrakanas, told Reuters Health by email.

Atrial fibrillation affects nearly 20% of patients on hemodialysis, and these patients are also at increased risk of ischemic or hemorrhagic stroke compared with the general population. It’s not clear whether warfarin, the most widely prescribed anticoagulant, is protective or harmful for patients with end-stage renal disease (ESRD) and atrial fibrillation.

“Therefore, the potential role of alternative anticoagulants has to be investigated further,” explained Dr. Mavrakanas, currently a research fellow at Brigham and Women’s Hospital and Harvard Medical School in Boston.

A team led by Dr. Mavrakanas and Dr. Mark Lipman at the McGill University-affiliated Jewish General Hospital in Montreal sought to determine apixaban pharmacokinetics at steady state, where the rates of the drug’s input and elimination would be roughly equivalent, in stable hemodialysis patients.

Apixaban is a direct oral anticoagulant agent that inhibits the coagulation factor Xa. In the initial drug labeling approved by the U.S. Food and Drug Administration in 2012, the drug was not recommended for patients with creatinine clearance < 25 ml per minute.

In 2014, U.S. (but not European or Canadian) labeling was amended to include patients with advanced or end-stage chronic kidney disease, a recommendation based on a study of eight dialysis patients that reported pharmacokinetic and pharmacodynamic data for a single 5 mg dose.

Because that data suggested to the authors of the current study that the standard twice-daily 5 mg dose would expose ESRD patients to excessive levels of the drug, they tested a lower dose of 2.5 mg twice daily for eight days in seven patients (mean age 62).

Blood levels showed significant accumulation of the drug over the eight days, the researchers reported in the Journal of the American Society of Nephrology (JASN), online March 16. On day 9, apixaban levels were measured hourly in six patients after a 2.5 mg dose was given, and only 4% of the drug was removed by dialysis.

The reduced dose of 2.5 mg twice daily “resulted in drug exposure that was comparable to (levels from previous studies reflecting) the standard dose in patients with preserved renal function,” the authors wrote.

After a five-day washout period, five of the patients received the currently recommended dose, 5 mg apixaban, twice daily. The patients experienced a substantial increase in exposure to the drug, above the 90th percentile for this dose in patients with normal kidney function.

It is likely that ESRD patients “could be overexposed by at least 36%” with the standard 5 mg twice-daily dose, which “should be avoided in this population,” the researchers cautioned.

Based on these findings, the authors “strongly recommend” against the use of the full 5 mg twice-daily regimen in dialysis patients, to avoid major bleeding events.

“We were anticipating that the full dose of apixaban would probably lead to very high (supratherapeutic) drug levels in the blood and were hoping that the reduced dose would result in drug exposure comparable with that of the standard dose in patients with preserved kidney function,” Dr. Mavrakanas noted. “Our results confirmed these hypotheses.”

“Regulatory authorities across different countries may consider revising dose recommendations for apixaban in dialysis patients,” he added.

Although the current study provides useful information about safety, a randomized prospective trial is necessary to prove efficacy of apixaban at the reduced dose of 2.5 mg twice daily in dialysis patients, he noted.

“The paper on apixaban in the JASN is very important,” Dr. Frieder Keller, of University Hospital in Ulm, Germany, told Reuters Health in an email.

The study shows that 2.5 mg twice daily is the right dose in patients with advanced chronic kidney disease, said Dr. Keller, a nephrologist who has studied pharmacokinetics of drugs in patients with chronic kidney disease.

If indicated, a loading dose of 5 mg twice daily on the first day might be needed, noted Dr. Keller, who was not involved with the study.

SOURCE: http://bit.ly/2mO1DQO

J Am Soc Nephrol 2017.

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