Author + information
- Claudia Stöllberger, MD∗ ( and )
- Josef Finsterer, MD, PhD
- ↵∗Krankenanstalt Rudolfstiftung, Steingasse 31/18, A-1030 Vienna, Austria
With interest we read the report by Reilly et al. (1) in a recent issue of the Journal regarding the effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in patients with atrial fibrillation. We have the following comments and concerns.
Dabigatran is a substrate of the P-glycoprotein system (P-gp). Many drugs are known to inhibit or induce the activity of P-gp (2). Was there any association between comedication of drugs affecting P-gp activity and plasma concentrations of dabigatran? It is known that P-gp activity is dependent on polymorphisms (3). Did the authors investigate the prevalence of P-gp polymorphisms and its association with dabigatran levels?
Because metabolization of a substance also depends on diurnal rhythms, it would be interesting to know if the samples were all taken at the same time of the day. Renal function may deteriorate over time, especially in elderly patients, due to comorbidities. Did the authors observe an increase of plasma dabigatran levels in patients whose renal function deteriorated over time? Were the plasma levels of dabigatran correlated with renal function? What was the optimal range of dabigatran to prevent both ischemia and bleeding?
Table 2 in the report by Reilly et al. (1) shows that dabigatran plasma concentrations were higher in patients 75 years of age or older, but no data are given for patients older than 80 years of age. Because many patients with atrial fibrillation are older than 80 years of age, it would be interesting to analyze the results in this subgroup of patients more precisely.
What was the time interval between measurement of the dabigatran level and occurrence of the bleeding or ischemic event? Did patients with higher levels develop bleeding earlier than patients with lower levels, and did patients with low levels develop ischemic events earlier than patients with higher levels? Were there any patients in whom plasma dabigatran levels were investigated at the time when the bleeding or ischemic event occurred? Was the volume of the bleeding or the size of the ischemic stroke correlated with the dabigatran levels?
The authors report only the association of plasma dabigatran levels with major bleeding. It would be of interest to know if this association was also found in patients with minor bleeding.
In the discussion, it is mentioned that an assay of dabigatran concentration is not yet available. When will this assay be available?
The RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study was published in 2009. Since that time, the drug has been used in thousands of patients, and many bleeding and ischemic episodes have been reported outside clinical trials (4). Why were the results of the present study not reported sooner than 5 years after publication of the RE-LY study? Knowledge of the importance of dabigatran levels would have saved some of these patients.
Overall, this study provides evidence that prevention of ischemic stroke by dabigatran is dependent on the plasma concentration of the drug and cannot be managed simply by using 2 different types of dosages. There is a strong need to determine the dose of this drug according to the plasma concentration and to find the optimal plasma concentration that best prevents the recurrence of stroke but also the occurrence of a bleeding event.
- American College of Cardiology Foundation
- Reilly P.A.,
- Lehr T.,
- Haertter S.,
- et al.
- Wessler J.D.,
- Grip L.T.,
- Mendell J.,
- Giugliano R.P.