Trough concentrations of dabigatran affect benefit/risk ratios in atrial fibrillation
The Effect of Dabigatran Plasma Concentrations and Patient Characteristics on the Frequency of Ischemic Stroke and Major Bleeding in Atrial Fibrillation Patients in the RE-LY Trial.
Reilly PA, Lehr T, Haertter S, et al.
J Am Coll Cardiol. 2013 Sep 26. doi: 10.1016/j.jacc.2013.07.104. [Epub ahead of print]
BackgroundThe Randomized Evaluation of Long-term Anticoagulation TherapY (RE-LY) trial showed that dabigatran etexilate (DE) was as effective (110 mg bid: DE 110) or more effective (150 mg bid: DE 150) than warfarin when given as a fixed dose for the prevention of stroke and systemic embolism in atrial fibrillation (AF) patients [1-3]. DE is a new, oral, direct thrombin inhibitor that does not need laboratory monitoring. Treatment with DE 150 as compared to DE 110 yielded a 39% reduction of strokes/systemic emboli, but at the cost of a 16% increase in major bleeding [1,2].
It is unknown how much the risk of stroke or bleeding varies across the plasma concentration range, which is known to depend on absorption, renal function and other patient factors [4-6]. It is unclear whether a single concentration range exists where the balance between thromboembolic events and bleeding events is optimal for all AF patients.
This pharmacokinetic analysis of the RE-LY trial aimed to explore the association between plasma concentrations and efficacy and safety outcomes, and to identify factors affecting the variability of plasma concentrations of dabigatran and their impact on outcome events in AF patients with an indication or oral anticoagulation.
- Geometric mean trough concentrations were 41% higher for the DE 150 dose compared to the DE 110 dose, and peak concentrations were 38% higher, indicating dose-proportionality. Peak-trough-ratios were about 1.9:1 for both doses. Data from both doses were pooled for subsequent analyses.
- Renal function (creatinine clearance) was a key determinant of plasma concentrations; moderate renal impairment (30-50 mL/min CrCl) was associated with a 2.29-fold higher trough concentrations than normal renal function (CrCl>80 mL/min).
- Patients >75 years old had 68% higher trough concentrations than patients younger than 65 years. Female subjects had higher (~30%) concentrations than males, and weight under 50 kg was also associated with geometric mean concentrations higher than in heavier subjects. Risk scores for stroke and bleeding were positively correlated with plasma dabigatran levels.
- Subjects who suffered from a major bleeding event had 55% and 36% higher median trough and post-dose concentrations, respectively than subjects without bleeding events. Dabigatran plasma levels were higher in subjects with hemorrhagic stroke than in subjects without. Median plasma levels did not differ between subjects with or without ischemic stroke or systemic embolic event (SEE).
- Multivariate logistic regression analysis of the relationship between major bleeding and trough plasma concentration gave a c-statistic of 0.715 (95%CI: 0.69-0.74) when including trough concentration, and a c-statistic of 0.68 when only considering the covariates age, aspirin use, diabetes, clopidogrel use, gender and CAD.
- An inverse relation was seen between dabigatran trough concentrations and the probability of an ischemic stroke/SEE event, with a c-statistic of 0.657 (95%CI: 0.61-0.71) when including trough concentration and 0.64 in a model without plasma trough dabigatran level.
ConclusionRisk of major bleeding and ischemic stroke/SEE after treatment with DE 110 or DE 150 in patients with AF is correlated to trough concentrations of dabigatran. Age, creatinine clearance, weight and gender significantly affect dabigatran plasma concentrations. No single plasma concentration range exists that gives optimal benefit for all patients.
The primary analyses of RE-LY suggests a wide therapeutic range. Nevertheless, some patients who are in the extremes of the concentration range, and who have additional risk factors such as old age, CrCl or low body weight, may benefit from adjusting the dose. The hypothesised benefits of lowering or increasing the dose to improve the risk-benefit ratio should be tested in a controlled trial.
1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361: 1139-51.
2. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363: 1875-6.
3. Ezekowitz MD, Connolly S, Parekh A, et al. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J. 2009; 157: 805-10.
4. Liesenfeld KH, Lehr T, Dansirikul C, et al. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost 2011; 9: 2168-2175.
5. Dansirikul C, Lehr T, Liesenfeld KH, et al. A combined pharmacometric analysis of dabigatran etexilate in healthy volunteers and patients with atrial fibrillation or undergoing orthopaedic surgery. Thromb Haemost 2012; 107: 775–785.
6. Stangier J Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47: 285-295