Effects of aliskiren, a renin inhibitor, on biomarkers of platelet activity, coagulation and fibrinolysis in subjects with multiple risk factors for vascular disease

Abstract

Aliskiren, an octanamide, is nonpeptide, low molecular weight, orally active renin inhibitor effectively preventing angiotensin and aldosterone release. This drug has been recently approved for the treatment of hypertension. Considering potential links between hypertension, platelets, the coagulation cascade and fibrinolysis we sought to evaluate the effect of aliskiren on human biomarkers of hemostasis. In vitro effects of whole blood preincubation with escalating concentrations of aliskiren (500, 1000 and 2000 ng ml À1) were assessed in 20 aspirin-naive volunteers with multiple risk factors for vascular disease. A total of 33 biomarkers were measured, of which 18 are related to platelet function, 12 to coagulation and 3 to fibrinolysis. Pretreatment of blood samples with aliskiren 500 ng ml À1 resulted in a significant increase of antithrombin-III (AT-III) activity (P ¼ 0.003). All other tested biomarkers were not significantly affected. Spiking whole blood with the higher aliskiren doses was associated with various trends in biomarker activity, where 1000 ng ml À1 concentration mostly decreased (7/33), and 2000 ng ml À1 mostly increased (6/33) some biomarkers. In the therapeutic concentration of 500 ng ml À1 aliskiren does not affect hemostatic biomarkers, except for a moderate but highly significant (P ¼ 0.003) increase of AT-III activity. Higher aliskiren doses were associated with more profound biomarker changes, but they are likely not to be clinically relevant since they show diverging (that is, both mild antiplatelet and platelet-activating) trends, and considering the 2-to 4-fold safety margin. It is suggested that antithrombotic properties of aliskiren be explored further in an ex vivo clinical setting.

Impact of aliskiren on some hemostatic parameters in experimental arterial thrombosis in rats

“…We measured standard coagulation parameters like APTT, PT or fibrinogen (Fg) level using routine laboratory methods and we did not found any changes after treatment with AL. These results are in accordance with Serebruany et al [43] who observed that AL in vitro did not change examined hemostatic biomarkers (PT, APTT, thrombin time (TT), Fg, Von Willebrand factor (vWF)). There is only one study demonstrating that AL may inhibit coagulation cascade.…”

Aliskiren: A novel, orally active renin inhibitor

“…In in vitro studies with whole human blood, the therapeutic concentration of 0.5 mg/ml of aliskiren did not affect hemostatic biomarkers, except for a significant increase in AT-III. [27] Thus, the antithrombotic properties of aliskiren should be further explored in clinical studies. Preliminary studies have shown that short-term administration of aliskiren has beneficial antialbuminuric effects in diabetic patients with chronic nephropathy and favorable neurohormonal effects in patients with chronic heart failure.…”

Επίδραση Ανταγωνιστών Αγγειοτασίνης II (Τελμισαρτάνη) Στη Θρομβογένεση Και Στη Μεταγευματική Υπερπηκτικότητα Σε Υπερτασικούς Ασθενείς

“…Σε αντίστοιχο πειραματικό μοντέλο η μονοθεραπεία με αναστολέα του μετατρεπτικού ενζύμου ή με εκλεκτικό ανταγωνιστή των υποδοχέων της αλδοστερόνης όπως η επλερενόνη, μερικώς μείωσαν την ενεργοποίηση των αιμοπεταλίων με επιπλέον μείωση σε συνδυασμένη θεραπεία [281]. Οι Serebruany et al 2008 [282] έδειξαν ότι σε θεραπευτικές δόσεις η αλισκιρένη, ένας αναστολέας της ρενίνης, δεν επιδρά στους αιμοστατικούς δείκτες in vitro και συνεπώς προτείνεται η περαιτέρω μελέτη των αντιθρομβωτικών ιδιοτήτων της αλισκιρένης σε ex vivo κλινικά εργαστήρια.…”