Digoxin concentration linked to platelet activation in AFib patients

Monitoring digoxin concentration and platelet activation in atrial fibrillation (AF) patients treated with vitamin K antagonists could be important for reducing those patients’ inherently elevated risk for CVD, according to a study published in the Journal of the American Heart Association Nov. 15.

Digoxin, an antiarrhythmic commonly sold under the brand names Lanoxin and Digox, is widely used to control heart rate and blood pressure in patients with AF, Daniele Pastori, MD, PhD, and colleagues at Sapienza University of Rome wrote in JAHA—but the news isn’t all positive.

“Recent studies raised concerns on the use of digoxin in AF because of a putative increased risk of cardiovascular and all-cause mortality in patients given digoxin,” Pastori et al. said. “However, current evidence on this issue is still controversial given the lack of a randomized trial specifically aimed at testing digoxin safety in AF. Furthermore, the biologic mechanism underlying such an association is still elusive.”

Pastori and her team hypothesized digoxin use, as measured by serum digoxin concentration (SDC), might elevate cardiovascular risk by increasing platelet activation in the body. They recruited hundreds of anticoagulated patients with AF for their study, 132 of whom were digoxin users and 388 of whom were nonusers.

The researchers measured participants’ platelet activation through urinary excretion of 11-dehydro-thromboxane B2 (TxB2) and their SDC levels using Abbott’s AxSYM analyzer. They then performed in vitro experiments in both healthy subjects and AF patients, whose platelets were incubated with scalar doses of digoxin with or without pre-stimulation with collagen.

Median 11-dehydro-TxB2 levels in the study population were 105 ng/mg creatinine, and average SDC hovered around 0.65 ng/mL, the authors reported. After a post hoc analysis, they found the two were correlated. Among the team’s findings:

  • Patients in the upper tertile of SDC had higher 11-dehydro-TxB2 compared to non-digoxin users

  • Patients with AF saw increased basal platelet activation compared to healthy patients

  • 2.4 ng/mL of digoxin induced calcium mobilization, PAC-1 and platelet aggregation in AF patients, but not in healthy patients

  • After pre-treatment with a sub-threshold of collagen, digoxin induced calcium mobilization, arachidonic acid release, TxB2 biosynthesis, PAC-1 and soluble platelet selectin expression and platelet aggregation

“We found that SDCs exceeding the therapeutic range (>1.2 ng/mL) favor in vitro activation only in primed platelets, indicating the need of sub-stimulated platelets to obtain extensive aggregation,” Pastori and co-authors wrote. “This finding reinforces the importance of keeping patients in the therapeutic range of SDCs to avoid not only proarrhythmic side effects related to digoxin but also an increase in platelet activation that may lead to thrombotic complications. Indeed, our findings provide novel insight into the increased risk of cardiovascular disease observed in AF with an SDC of more than 1.2 ng/mL.”

The authors said their study was limited in its sample population—all patients were white—and that they can’t exclude the notion that other pathways might be involved in digoxin-related platelet activation. Still, the connection they found between SDC and urinary TxB2 was significant.

“Digoxin induced in vitro platelet TxB2 formation via calcium mobilization, PLA2 phosphorylation and eventually arachidonic acid release,” Pastori and colleagues said. “Monitoring digoxin concentration and platelet activity may be relevant to reduce the cardiovascular risk in patients with AF.”