Pharmacokinetics and pharmacodynamics of rivaroxaban and its effect on biomarkers of hypercoagulability in patients with chronic heart failure.
BACKGROUND
Heart failure (HF) is associated with a hypercoagulable state that predisposes to thromboembolism and anti-coagulation may improve clinical outcomes. The oral, direct Factor Xa inhibitor, rivaroxaban, has not been studied in patients with HF. We hypothesized that rivaroxaban would also reduce biomarkers of hypercoagulability in patients with HF.


METHODS
This study consisted of two cohorts: Cohort 1, open-label, actively controlled with enoxaparin 40 mg once daily, included 8 patients with acute decompensated HF; Cohort 2, double-blind and placebo-controlled, included 18 patients with stable, severe New York Heart Association Class III/IV HF.


RESULTS
The pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban were similar across both cohorts. Biomarker assessments were performed in Cohort 2; prothrombin fragment 1.2 (F1.2) mean concentration decreased by 2.7 ng/ml over 7 days with rivaroxaban, and increased by 11.6 ng/ml with placebo, an absolute difference of 14.3 ng/ml (p = 0.0009). A non-significant reduction in rate of increase of D-dimer (DD) and thrombin-anti-thrombin complex (TAT) levels with rivaroxaban was observed over 7 days (p = 0.31 and p = 0.77, respectively).


CONCLUSIONS
Rivaroxaban has similar PK/PD in patients with either acute or chronic HF. In vivo, hypercoagulability biomarkers appear to increase over time. Rivaroxaban reversed this trend for F1.2, and may reduce the rate of increase of DD and TAT in patients with stable, severe HF.
Gheorghiade
Mihai
M
Center for Cardiovascular Innovation, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA. m-gheorghiade@northwestern.edu
Thyssen
An
A
Zolynas
Robert
R
Nadar
Venkatesh K
VK
Greenberg
Barry H
BH
Mehra
Mandeep
M
Sun
Xiang
X
Tian
Hong
H
Plotnikov
Alexei N
AN
Burton
Paul
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000990:Antithrombin III; D015415:Biomarkers / Q000097:blood; D002908:Chronic Disease; D004311:Double-Blind Method; D017984:Enoxaparin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D006333:Heart Failure / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000097:blood*; D010447:Peptide Hydrolases / Q000097:blood*; D011516:Prothrombin; D000069552:Rivaroxaban; D013876:Thiophenes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019851:Thrombophilia / Q000097:blood*
D000925:Anticoagulants; D015415:Biomarkers; D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D005338:Fibrin Fibrinogen Degradation Products; D005343:Fibrinolytic Agents; D009025:Morpholines; D010446:Peptide Fragments; D013876:Thiophenes; C046193:antithrombin III-protease complex; C036309:fibrin fragment D; C045879:prothrombin fragment 1.2; D000990:Antithrombin III; D011516:Prothrombin; D000069552:Rivaroxaban; D010447:Peptide Hydrolases