The dissertation is dedicated to the prediction of safety and optimization of
anticoagulant therapy in atrial fibrillation (AF) by studying clinical features,
indicators of plasma and platelet hemostasis and personalized warfarin (WF)
dosing taking into account polymorphisms of the CYP2C9, CYP4F2, VKORC1
genes.
For the first time, based on the
results of a one-time cross-sectional study, it was established that in Zaporizhzhia
region polymorphisms of the CYP4F2 and VКORC1 genes are the most common,
while the prevalence of CYP2C9*2 and CYP2C9*3 polymorphisms is much
lower; it was specified that this distribution of genotypes is comparable to
European and all-Ukrainian populations.
Scientific data regarding frequency of CYP2C9, CYP4F2, VKORC1 gene
polymorphisms in patients with AF have been expanded. The difference in the
daily dose of WF depending on the genotypes has been clarified. It was found that
with the empirical selection method in patients with AF, the presence of the A
allele of the VKORC1 gene is likely to increase the probability of WF dose of less
than 5 mg by 7.00 times, while the mutant T allele of the CYP4F2 gene increases
the probability of WF dose greater than the median by 6.26 times. At the same
time, the contribution of allelic polymorphisms of the CYP2C9 gene to the dosage
of WF has not been established. Scientific data regarding the relationship of
clinical and genetic factors with the stability of anticoagulation and the
development of hemorrhagic complications in patients with AF and empirical WF
dosing method have been added. For the first time, it was established that the
polymorphism of the VKORC1 gene exerts a reliable influence on the
development of the cumulative end point, which included episodes of excessive
hypocoagulation and bleeding, in patients with AF and empirical WF dosing
method.
For the first time, the state of platelet and coagulation hemostasis in patients
with AF was assessed depending on the method of WF dosing, and it was
established that in the group of the pharmacogenetic dosing, the degree, time, and
speed of ADP-induced platelet aggregation were significantly lower in 30 seconds
and a decrease in the proportion of patients with an increased level of D-dimer was
observed compared to the group of traditional dose adjustment.
For the first time, it was found that in patients with AF, the frequency and
risk of development of the cumulative endpoint significantly decreased with the
pharmacogenetic method of WF dosing compared to the empirical WF dosing. The
advantages of the pharmacogenetic method of WF dosing in terms of reduction of
the number and risk of episodes of excessive hypocoagulation have been clarified.
For the first time, the leveling of the influence of endo- and exogenous factors
during the individualized WF dosing has been proven, as evidenced by the absence
of a relationship between TTR, episodes of excessive hypocoagulation, and
hemorrhagic complications with clinical and genetic factors in patients with AF on
the background of anticoagulant therapy with WF with pharmacogenetic dosing, in
contrast to groups of patients with empirical dosing. For the first time, it was found
that the risk factors for the development of the cumulative end point, which
includes episodes of excessive hypocoagulation and hemorrhagic complications in
patients with AF using the pharmacogenetic method of WF dosing during a year of
observation, are female gender and obesity in the absence of the influence of the
VKORC1 gene mutation.
It is recommended that patients with AF should be assessed using the SAMe-TT2R2 scale when selecting
the dose of WF using empirical method for prediction of the unsatisfactory INR
control (TTR < 70%), however the SAMe-TT2R2 scale for this purpose should be
considered impractical in case of pharmacogenetic WF dosing method. It is
proposed in clinical practice to take into account the concomitant use of
amiodarone, which increases the risk by 1.83 times and to determine the
polymorphism of the VKORC1 gene, which increases the risk by 2.14 times, for
the purpose of predicting episodes of excessive hypocoagulation (INR > 4) when
selecting the dose of WF using an empirical method. It is proposed to determine
the polymorphism of the VKORC1 gene in patients with AF when selecting the
dose of WF using the empirical method to predict the risk of developing
hemorrhagic complications, which increases by 2.14 times in the presence of a
mutant allele.
The expediency of the pharmacogenetic WF dosing method in patients with
AF under conditions of dynamic long-term observation in the anticoagulation
monitoring office with the determination of indicators of platelet and coagulation
hemostasis in order to reduce episodes of excessive hypocoagulation and the risk
of bleeding was substantiated and introduced into clinical practice.
