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Published on: February 28, 2012
Dronedarone exerts anticoagulant and antiplatelet effects independently of its antiarrhythmic actions
M Urooj Zafar1, Carlos G Santos-Gallego1, Donald A Smith1
1Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Insights
Dronedarone directly reduces blood clot formation and platelet aggregation in vitro, suggesting its benefits in preventing stroke may extend beyond its antiarrhythmic properties. These findings highlight potential alternative mechanisms for its therapeutic effects in atrial fibrillation patients.
Area of Science:
- Pharmacology
- Cardiovascular Medicine
- Hematology
Background:
- Dronedarone demonstrated stroke risk reduction in atrial fibrillation (AF) patients.
- The observed benefits may involve mechanisms beyond its antiarrhythmic effects.
- This study investigated dronedarone's direct impact on blood thrombogenicity.
Purpose of the Study:
- To assess the direct antithrombotic effects of dronedarone's active metabolite (SR35021A) on human blood.
- To determine if these effects are independent of its antiarrhythmic actions.
Main Methods:
- Human blood samples from cardiovascular disease patients were incubated with SR35021A at therapeutic concentrations.
- Thromboelastometry (Coagulation Time, Clot Formation Rate, Maximum Clot Firmness) was used.
- Whole blood platelet aggregation in response to agonists (ADP, collagen, TRAP) was measured.
Main Results:
- Dronedarone significantly prolonged Coagulation Time.
- Small but significant reductions in Clot Formation Rate and Maximum Clot Firmness were observed.
- Dronedarone reduced platelet aggregation induced by ADP and TRAP.
Conclusions:
- Dronedarone exhibits direct anticoagulant and antiplatelet effects in vitro.
- These antithrombotic actions are independent of its antiarrhythmic properties.
- The reduction in ischemic events may be partly attributed to these direct blood effects, warranting further clinical investigation.
Background And Aims:
Dronedarone reduced the rate of stroke and transient ischemic attack in patients with paroxysmal atrial fibrillation (AF) in the ATHENA trial. This cannot be explained by its antiarrhythmic effect alone and may involve alternative mechanisms. This study aimed to investigate any direct effect of dronedarone on blood thrombogenicity, independent of its antiarrhythmic effects.
Methods:
Blood samples from patients with cardiovascular disease (n = 30) taking no anticoagulant or antiplatelet medication except aspirin were incubated with dronedarone's active metabolite (SR35021A) at 66 ng/ml (am-L) and 119 ng/ml (am-H), i.e., minimum and maximum mean Cmax reported after repeated 400 mg BID dosing. A third aliquot of blood was incubated with vehicle (Control). Antithrombotic effects of dronedarone were assessed using Coagulation Time (CT), Clot Formation Rate (CFR) and Maximum Clot Firmness (MCF) in ThromboElastoMetry and whole blood platelet aggregation in response to ADP, collagen and TRAP.
Results:
Compared to Control, mean CT was prolonged by am-L and am-H (164 ± 25 s vs. 180 ± 22 and 182 ± 32 s, respectively, p<0.01 for both). Small but statistically significant reductions were observed in CFR (am-L and am-H) and MCF (am-H). Platelet aggregation induced by ADP and TRAP was also reduced (p<0.05 for both) by am-H.
Conclusions:
Dronedarone exerts direct anticoagulant and antiplatelet effects on human blood in vitro that are independent of its antiarrhythmic actions. This suggests the reductions in ischemic events reported with dronedarone may not be due to amelioration of AF itself. Additional clinical studies are required to further improve understanding of the mechanisms involved.
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