Risks Associated with Higher Residual Concentrations of Dabigatran in Seniors and Their Prevalence
Dabigatran is a direct thrombin inhibitor indicated for patients across the age spectrum. The benefit-risk assessment of anticoagulation is individual and depends on many factors. A Dutch observational pilot study examined residual concentrations of dabigatran in seniors of different ages with atrial fibrillation to clarify the relationship between study results and clinical practice.
Introduction
Patients over 75 years of age taking dabigatran are at significantly higher risk of gastrointestinal bleeding compared to those on warfarin. High residual concentrations of dabigatran present in the blood just before the administration of the next dose (the so-called trough concentration) have a significant impact on increasing the risk of bleeding.
Study Objectives and Methodology, Patient Population
In a Dutch pilot study, dabigatran concentrations were compared across three age categories: < 75 years (n = 25), 75–84 years (n = 25) and ≥ 85 years (n = 25). Patients with atrial fibrillation had been taking dabigatran for at least one week before being included in the study. Dosing was consistent with age and other clinical characteristics: 150 mg twice daily or 110 mg twice daily. Patients taking other anticoagulants, antithrombotics, or medications with pharmacokinetic interactions involving P-glycoprotein (P-gp) inhibition were excluded from the study. Other exclusion criteria included estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2, transaminase levels more than twice the upper limit of normal, current malignancy, and weight < 50 kg or > 110 kg.
Blood samples were taken from patients just before the next dabigatran dose, plasma samples were stored at -80°C, and later analyzed using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS).
Residual concentrations in the different age categories were compared using the Kruskal-Wallis test, and concentrations were further normalized to the dose taken. The prevalence of patients with absolute concentrations > 150 ng/ml was determined using Fisher's exact test. Regression analysis was used to examine the influence of renal function on differences between age groups.
Results
High residual concentrations of dabigatran (> 150 ng/ml) are considered a risk factor for gastrointestinal bleeding. The study found that 40% (n = 10) of observed patients over 85 years had residual concentrations exceeding this level, while the prevalence among patients < 75 years was 16% (n = 4; p = 0.059).
The median residual concentration of dabigatran was 9% higher in patients aged 75 to 84 years (median: 99 ng/ml; range: 29–214). Additionally, patients aged 85 years and older had 33% higher residual dabigatran levels (median: 132 ng/ml; range: 36–324) than patients under 75 years (median: 108 ng/ml; range: 33–327), despite generally lower dabigatran doses being used.
Median concentrations normalized to dose were 0.66 ng/ml/mg in the < 75 years age group, 0.83 ng/ml/mg in patients aged 75–84, and 1.20 ng/ml/mg in patients ≥ 85 years (p = 0.004).
Conclusion
The study conducted in a real-life elderly population revealed significantly higher residual concentrations of dabigatran in the oldest age category. Residual concentrations > 150 ng/ml were 2.5 times more common in patients aged ≥ 85 years. From a safety perspective, awareness of higher residual concentrations of dabigatran, which may persist in older patients despite dose reduction, is necessary to minimize bleeding risk.
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Sources:
1. Gommans E., Grouls R. J. E., Kerkhof D. et al. Dabigatran trough concentrations in very elderly patients. Eur J Hosp Pharm 2021; 28 (4): 231–233, doi: 10.1136/ejhpharm-2020-002456.
2. SPC Pradaxa. Available at: www.ema.europa.eu/en/documents/product-information/pradaxa-epar-product-information_cs.pdf
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