[GDF-15 and the risk of bleeding in patients with stable CAD receiving multicomponent antithrombotic therapy: the results of the prospective REGATA register].

AIM: To evaluate the prognostic value of GDF-15 in relation the development of bleeding and events in stable CAD patients, receiving combined antithrombotic therapy. MATERIALS AND METHODS: The data was obtained from the prospective registry REGATA, 343 CAD patients (249 males), median age 68 [IQR 62; 75] years) were enrolled. Patients with sinus rhythm and concomitant PAD received acetylsalicylic acid in combination with rivaroxaban 2.5 mg bid (31.8%) or clopidogrel (24.8%). Other 43.4% with concomitant atrial fibrillation (AF) received direct oral anticoagulants in combination with antiplatelet therapy after elective percutaneous coronary interventions. Median follow-up was 12 months [IQR 9.0; 18.0]. The safety end point was major and clinically relevant bleedings (type 2-5) according to the BARC classification. Plasma samples for GDF-15 identification were taken at the inclusion and analyzed using ELISA assay. RESULTS: Frequency of BARC 2-5 bleedings was 16% (BARC 2 - 46; BARC 3 - 9; BARC 4-5 - 0), median GDF-15 level was 1185.0 pg/ml [850.0; 1680.0]. In patients with AF and concomitant MFA, the level of GDF-15 was significantly higher than in the subgroups of patients with only AF or MFA (p=0.0022). According to the quintile analysis, GDF-15 values in the top three quintiles of distribution (cut-off value >943 pg/ml) were associated with higher frequency of bleeding events: 23.2% versus 5.1%; p=0.0001. The multivariable logistic regression model demonstrated that bleeding events were independently associated with GDF-15 level>943 pg/ml (OR 2.65, 95% CI 1.11-6.30; p=0.0275), AF (OR 2.61, 95% CI 1.41-4.83; p=0.0023) and chronic kidney disease (OR 1.92, 95% CI 1.03-3.60; p=0.0401). Clinical factors determining the risk of bleeding events also determined a GDF-15 elevation. CONCLUSION: Assessment of GDF-15 level may improve bleeding risk stratification in CAD patients with concomitant AF and/or PAD receiving combined antithrombotic therapy.

Chronic Kidney Disease is a Predictor of Recurrent Bleeding in Patients With Atrial Fibrillation After Resuming Anticoagulant Therapy (based on REGistry of Long-term AnTithrombotic TherApy (REGATA-2).

AIM: Patients with atrial fibrillation (AF) at high risk of thromboembolic complications who have had bleeding should strive to resume anticoagulant therapy. Existing traditional scales for assessing the risk of hemorrhagic complications are not highly specific for the risk of recurrent bleeding. Thus, searching is needed for clinical and laboratory predictors to identify patients who require a personalized monitoring regimen. The aim of the study was to assess the incidence rate and predictors of recurrent major and clinically significant bleeding in patients with AF after resumption of the anticoagulant therapy, as well as the contribution of changing the anticoagulant to the treatment safety. MATERIAL AND METHODS: Based on a 5-year follow-up of 95 patients with AF who have had major and clinically significant bleeding, the incidence and clinical factors determining the recurrence of hemorrhagic complications were assessed.Results According to the data of the 5-year follow-up, the recurrence rate of major/clinically significant bleeding was 16.9/100 patient-years. Changing the oral anticoagulant significantly reduced the risk of relapse after clinically significant bleeding and did not affect the risk of recurrence of major bleeding. The predictor for relapse of major/clinically significant bleeding during the therapy resumption was chronic kidney disease with a decrease in creatinine clearance to less than 60 ml/ min, which increased the risk of relapse 2.27 times (95% confidence interval: 1.1253-4.6163; p=0.0221). CONCLUSION: The development of serious bleeding in a patient at high risk of thrombotic complications always requires a reassessment of risk factors and an adequate choice and dosage of the anticoagulant. Development of a unified protocol for the management of AF patients receiving anticoagulants and having a high risk of bleeding is essential and will reduce the risk of adverse outcomes.

[Resumption of anticoagulant therapy after major bleeding and the risk of negative events in patients with atrial fibrillation (based on REGistry of Long-term AnTithrombotic TherApy-2 - REGATA)].

BACKGROUND: It is necessary to strive to resume anticoagulants for patients with atrial fibrillation who have a high risk of thrombosis after the development of large bleeding. Due to the fact that death in these patients is caused not by a recurrence of fatal bleeding, but by the development of stroke in case of refusal of anticoagulant therapy. AIM: To evaluate the effect of the resumption of anticoagulant therapy on the risk of recurrence of major bleeding, thrombosis and death in patients with atrial fibrillation who have suffered major bleeding. MATERIALS AND METHODS: To evaluate the frequency of bleeding, thrombosis and death in patients with atrial fibrillation after major bleeding according to prospective follow-up data for one year. RESULTS: The recurrence rate of major bleeding after the resumption of therapy was 21.7% per year. The frequency of fatal bleeding was 2.2%. In the anticoagulant withdrawal group, the incidence of thrombotic complications (ischemic stroke and myocardial infarction) was significantly higher compared to patients who resumed therapy. The frequency of death from all causes was significantly higher in the group of patients who did not resume anticoagulant therapy. Half of the deaths were due to cardiovascular causes. The presence of more than 5 points of the Charlson Comorbidity Index was a predictor of the development of the sum of all adverse events. CONCLUSION: The resumption of anticoagulant therapy after the development of major bleeding in patients with atrial fibrillation reduces the risk of thrombosis and death at a cost, while increasing the risk of recurrence of non-fatal bleeding.

[Severe gastrointestinal bleeding in patients with atrial fibrillation receiving oral anticoagulants (based on REGistry of long-term AnTithrombotic TherApy - REGATTA)].

BACKGROUND: The rate of major bleeding in patients with atrial fibrillation receiving oral anticoagulants is 25% per year. Gastrointestinal bleedings are at least a half of major hemorrhagic complications. Currently, there is no optimal scale to calculate the risk of bleeding, and therefore the search for clinical predictors of gastrointestinal bleeding remains relevant. AIM: To assess the frequency and structure of large gastrointestinal bleeding, as well as to identify clinical predictors of their development based on long-term prospective observation of patients with atrial fibrillation receiving oral anticoagulants. MATERIALS AND METHODS: Data were obtained from single center prospective REGistry of long-term AnTithrombotic TherApy (REGATTA NCT043447187). Investigation based on a 20-year follow-up with 510 patients with atrial fibrillation with a high thromboembolic risk (median CHA2DS2-VASc was 4 points). The REGATTA registry assessed the frequency and structure of major gastrointestinal bleeding. Predictors of the development of 32 large gastrointestinal bleeding were identified based on the analysis of pairs with univariate and multivariate analyses. RESULTS: The frequency of major gastrointestinal bleeding in patients with atrial fibrillation receiving oral anticoagulants at 1 year was 1.42 per 100 patients; the predominant localization was upper gastrointestinal tract. Predictors of the development of major gastrointestinal bleeding according to multiple regression data analysis were hemoglobin level 14.55 g/dL, body mass index 28.4 kg/m2, gastrointestinal ulcer or erosive lesion and major hemorrhagic complications in history of disease. In 1/2 cases the sourse of bleeding remained unclear. CONCLUSION: Searching for clinical predictors of gastrointestinal bleeding can identify patients receiving oral anticoagulants who is need of intensive monitoring risk factors to prevent the development of life-threatening bleeding and to provide with adequate anticoagulant therapy.

[Resumption of anticoagulant therapy after major bleeding and recurrence of hemorrhagic complications in patients with atrial fibrillation with a high risk of stroke and thromboembolism (based on the results of 20 years of observation)].

AIM: To analyze the frequency of resumption of anticoagulant therapy (ACT) after major and clinically significant bleeding among AF patients who received oral anticoagulants and were observed in the Department of clinical problems of atherothrombosis from 1999 to 2019 within the retro-prospective register Regata-2, and to search for clinical factors associated with recurrence of hemorrhagic complications among patients who resumed anticoagulant therapy after a bleeding episode. MATERIALS AND METHODS: In cohort study of patients with high-risk AF with absolute indications for ACT we enrolled 290 AF patients (130 women and 160 men) aged 32 to 85 years (the average age was 65.188.89 years). During the follow-up period, 92 patients developed hemorrhagic complications, and 73 of them resumed ACT. 35 of the 73 patients who resumed ACT developed a relapse of major/clinically significant bleeding. RESULTS: The frequency of resuming ACT after the first hemorrhagic complication increased over time from 75% in the period from 19992003 to 90% in the period 20152019. We were not able to establish an exact relationship between the presence of concomitant pathology and the decision to resume the ACT after bleeding. The only reliable reason for refusing to resume the ACT was the patients categorical reluctance. Among patients who had recurrent hemorrhagic complications, the total score on the Charleson comorbidity scale was significantly higher (4.232.01vs3.521.43;p=0.0425). Patients with recurrent bleeding were significantly more likely to suffer from CKD with a decrease in GFR less than 60 ml/min/1.73 sq. m, and also had a history of erosive and ulcerative lesions of the gastrointestinal tract. There was also a significant Association of recurrent bleeding with the use of proton pump inhibitors. Subgroups of patients who switched from warfarin to taking direct oral anticoagulants after the first bleeding and subsequent recurrent bleeding did not differ in basic clinical characteristics from patients without bleeding after changing the anticoagulant. According to multiple regression analysis, NSAIDs showed a tendency to develop a relapse of B/C bleeding on the background of direct oral anticoagulants in patients who underwent GO on the background of warfarin therapy (b=0.4524,p=0.0530). CONCLUSION: During the 20-year follow-up, the frequency of all major and clinically significant bleeding was 2.6/100 patients-years, the frequency of first bleeding was 5.86/100 patients-years, while the frequency of repeated hemorrhagic complications was 7.06/100 patients-years. Patients with a high thromboembolic risk should receive anticoagulants, provided that the modifiable risk factors for bleeding are carefully corrected.

Prediction-Determining Outcomes and Their Predictors in Atrial Fibrillation Patients Receiving Multicomponent Antithrombotic Therapy in Real Clinical Practice.

Aim      Searching for clinical, angiographic, and biochemical predictors of cardiovascular complications (CVC) and hemorrhagic complications in patients with atrial fibrillation (AF) receiving a multicomponent antithrombotic therapy (MAT) for an elective percutaneous coronary intervention (PCI). Patients with ischemic heart disease (IHD) and AF who require MAT for PCI are at a high risk of thrombotic complications (stroke, systemic embolism, coronary events) and hemorrhage. This warrants searching for new risk factors determining prediction of the outcome.Materials and methods This study included 207 patients (146 males aged 70.1±8.3 years) with IHD and AF who received direct oral anticoagulants (DOAC) as a part of their MAT therapy. Median duration of the follow-up was 12 [8.0; 12.0] months. The efficacy endpoint was a sum of CVCs combining cardiovascular death, ischemic stroke, venous thromboembolic complications, acute coronary syndrome (ACS), and requirement for an unscheduled PCI. "Coronary events", including ACS and requirement for an unscheduled PCI were analyzed separately. The safety endpoint was BARC type 2-5 bleeding. Upon admission, biomarkers (growth-differentiation factor 15 (GDF-15), D-dimer, thrombin-activated fibrinolysis inhibitor (TAFI), and plasminogen activator inhibitor-1 (PAI-1)) were measured for all patients. Searching for prognostically significant indexes was performed with the Cox proportional hazards regression.Results Incidence of all CVCs was 16.4 %. Independent predictors of CVC included the DOAC treatment at a reduced dose (odds ratio (OR) 2.5 at 95 % confidence interval (CI) 1.02-6.15; p=0.0454), GDF-15 >1191 pg /ml (OR 3.76 at 95 % CI, 1.26-11.18; p=0.0172), PAI-1 >13.2 U/ml (OR 2.67 at 95 % CI, 1.13-6,26; p=0.0245). Incidence of coronary complications was 9.2 %. Independent predictors of coronary complications included a SYNTAX index >26.5 (OR 4.5 at 95 % CI, 1.45-13.60; p=0.0090), PCI for chronic coronary occlusion (OR 3.21 at 95 % CI, 1.10-9.33; p=0.0326), a GDF-15 >1191 pg/ml (ОR 4.70 at 95 % CI, 1.32-16.81; p=0.0172). Incidence of BARC type 2-5 bleeding was 26.1 %. The only independent predictor for hemorrhage complications was the total PRECISE-DAPT score >30 (ОR 3.22; 95 % CI, 1.89-5.51; р<0.0001).Conclusion      Three independent predictors of CVC were identified for patients with IHD and AF treated with MAT following an elective PCI: treatment with a reduced dose of DOAC, GDF-15 >1191 pg /ml, and PAI-1>13.2 U/ml. Independent predictors of coronary complications included a SYNTAX index >26.5, PCI for chronic coronary occlusion, and GDF-15 >1191 pg/ml. The factor associated with a risk of bleeding was the total PRECISE-DAPT score >30.

[Use of Statins, Anticoagulants, Antiaggregants and Antiarrhythmic Drugs in Patients With COVID-19. The Agreed Experts' Position of Russian Society of Cardiology, Eurasian Association of Therapists, National Society on Atherothrombosis, Societies of Experts in Urgent Cardiology, Eurasian Arrhythmology Association].

This article discusses relevant aspects in the treatment of patients with COVID-19. Up-to-date information about principles for administration of statins, antithrombotics, and antiarrhythmics is presented. The authors addressed in detail specific features of reversing heart rhythm disorders in patients with coronavirus infection and the interaction of antiarrhythmic and antiviral drugs. Recommendations are provided for outpatient and inpatient antithrombotic therapy for patients with COVID-19. Issues of antithrombotic and antiviral drug interaction are discussed.

[Comparative efficacy and safety of enoxaparin followed by warfarin and rivaroxaban monotherapy in the treatment of venous thrombosis in patients after intracardiac catheter interventions].

AIM: to compare two anticoagulant therapy (ACT) regimens in the treatment of venous thrombosis (VT) in patients after catheter interventions - electrophysiological studies (EFIs) and ablations: enoxaparin followed by warfarin, and rivaroxaban monotherapy. MATERIALS AND METHODS: The study included patients from 18 years and older with heart rhythm disorders and planned catheter ablation. When parietal venous thrombosis (VT) were detected at the femoral vein puncture site, all patients were randomly assigned to two treatment groups. In group I enoxaparin 1 mg/kg was prescribed every 12 hours with switching to warfarin after 7 days with maintenance of the target INR values (2.0-3.0). In group II rivaroxaban therapy was started at a dose of 15 mg twise/day for 21 days with a further transition to a dose of 20 mg/day. The total period of observation and treatment of patients was at least 3 months. RESULTS: 408 patients were observed, 42 (10.3%) patients with parietal VT were divided into two treatment groups. In group I (n=16) complete lysis of VT was noted by the 7th day of treatment in 7 (58.3%) patients, however this scheme was associated with a greater risk of complications (р=0.003) at the puncture site in the form of arteriovenous fistulae (n=1; 8.3%) and intermuscular hematomas (n=4; 25%). In group II (n=26), no complications were noted, the lysis time of VT was on average 21 days (n=18; 69.2%). Complete lysis of VT was noted in both groups at the time of the control observation point (3rd month). CONCLUSION: The efficiency of the two VT treatment regimens was comparable. Enoxaparin therapy is associated with a high risk of local complications, namely intermuscular hematomas (n=4; 25%) and arteriovenous fistulas (n=1; 8.3%). Rivaroxaban monotherapy is safer (p=0.003); in Group II none of the patients had any complications.

[Thrombotic and hemorrhagic complications in atrial fibrillation patients, undergoing elective percutaneous coronary intervention].

AIM: To evaluate efficacy and safety of reduced dose of direct oral anticoagulants (DOACs) as part of triple antithrombotic therapy in AF patients, undergoing elective percutaneous coronary intervention (PCI), and to identify factors, associated with this strategy. MATERIALS AND METHODS: The study is a cohort analysis of AF patients with AF, who successfully underwent elective PCI and assigned DOACs as part of triple antithrombotic therapy (TAT).Influence of a reduced DOACs dose as a part of TAT on the frequency of thecomposite efficacy endpoint (acute coronary syndrome, ischemic stroke, venous thromboembolic events, cardiovascular death and angina pectoris aggravation/need for unplanned PCI) and safety endpoint (hemorrhagic complications BARC types 2-5) were assessed using the Log-Rank criterion. RESULTS: The study included 124 pts (69.4% women, mean aged 69±8.2 years). Themedian total score CHA2DS2-VASc was 5, the median of the Charlson index composed 7. Half (52%) of AF patients with high risk of thrombotic events after elective PCI received reduced-DOACs dose. Median follow up period was 11.0 month. 17 adverse thrombotic events were recorded during this period, BARC 2-5 bleedings occurred in 27 patients. Reduced DOACs doses in AF patients undergoing PCI were associated with significant increase of thrombotic events during follow up period compared to patients received full DOACs doses (0.79 vs 0.93, Log-Rank p=0.0292). Patients, who received full and reduced DOAC doses, were comparable in the frequency of BARC 2-5 bleedings (0.78 vs 0.75, Log-Rank p=0.06742). CONCLUSIONS: The administration of a reduced DOACs dose as a part of TAT in patients with AF, who underwent PCI, was associated with significant increase in the incidence of all thrombotic events, compared to patients, who received full dose of anticoagulants. The number of hemorrhagic complications was comparable.

[Renal function in patients receiving long-term warfarin therapy: A five-year prospective follow-up]. / Funktsiia pochek u bol'nykh, dlitel'no prinimaiushchikh varfarin (5-letnee prospektivnoe nabliudenie).

AIM: To investigate the prognostic value of renal function and to estimate glomerular filtration rate (GFR) changes during a 5-year follow-up of patients receiving warfarin therapy. SUBJECTS AND METHODS: 200 patients (124 men, 76 women) mainly from a group at high risk for thromboembolic events (mean CHA2DS2-VASc scores, 3.25±1.89) were examined. The patients' mean age was 62.3±9.4 years; the follow-up period was 5 years. 74% of the patients received warfarin monotherapy (international normalized ratio (INR) 2.0 to 3.0); 36% took vitamin K antagonists in combination with one or two antiplatelet agents. The CKD-EPI formula was used to estimate GFR in all the patients at baseline and throughout the investigation once a year. RESULTS: GFR less than 70.9 ml/min/1.73 m2 was found to be a predictor of fatal and nonfatal thrombotic events. The decreased GFR was unassociated with the development of major and clinically relevant hemorrhagic complications within 5 years of warfarin therapy. The initial decline in renal function (GFR <70.9 ml/min/1.73 m2) was associated only with an increased rate of recurrent minor hemorrhagic complications. During 5-year warfarin therapy, there was a significant decrease in GFR from 97.1±24.85 to 91.9±28.9 ml/min/1.73 m2; at the same time, a rapidly progressive loss of renal function (GFR ≥3 ml/min/1.73 m2/year) was recorded in 25.9% of the patients. Discriminant analysis showed that a baseline left ventricular ejection fraction of <40% was a predictor for the rapidly progressive loss of kidney function. CONCLUSION: Long-term warfarin therapy achieved the therapeutic range for INR is safe in the environment of the created patronage system. The initial decrease in GFR is a predictor of thrombotic events and is unassociated with an increased risk of bleeding.

[Risk Factors of Recurrent Bleedings at Therapeutic International Normalized Ratio in Patients on Long-Term Warfarin Therapy].

AIM: to investigate parameters of fibrinolysis in patients on long-term warfarin (W) therapy, and assess their relation to the risk of recurrent bleeding occurring at therapeutic international normalized ratio (INR). MATERIALS AND METHODS: Our prospective study involved 78 W-naive patients (40 men, age 64.3+/-12.2 years). Follow up period was 5.6+/-3.4 months. INR was measured monthly; determination of coagulation parameters (D-dimer, fibrinogen, complex plasmin-2-antiplasmin [PAP] and thrombin-activatable fibrinolysis inhibitor [TAFI] was performed before and after at least 3 months of W therapy. RESULTS: During follow-up bleedings occurred in 47 (60.3%) patients, 26 patients (33.3%) had recurrent bleedings at therapeutic INR and 21 patients (26.9%) had single bleeding. Mean time in therapeutic range (TTR) was >70.

[HAS-BLED and HEMORR2HAGES Scales in Assessment of Bleeding Risk in Patients on Long-Term Warfarin Therapy].

UNLABELLED: Aim of the study was to elucidate value of HAS-BLED and HEMORR2HAGES scales for prediction bleedings in patients receiving long-term warfarin (W) therapy. MATERIAL AND METHODS: The study involved 119 patients (72 men) aged 60.9 ± 9.6 years with atrial fibrillation or venous thromboembolic complications. Follow up period was 5.6 ± 3.4 years. All bleedings were categorized as 1) single bleeding with INR > 4.0 during the 1st month of W therapy; 2) any single bleeding after 1st month of W therapy; 3) recurrent bleedings. CYP2C9 and VKORC1 (G3673A) genotypic variants were determined by PCR. Patients were divided into low (< 3 points of HAS-BLED scale, n = 58; < 4 points of HEMORR2HAGES scale, n = 109) and high (3 points of HAS-BLED scale, n = 61, ≥ 4 points of HEMORR2HAGES scale, n = 10) bleeding risk groups. RESULTS: There was no relationship between total HAS-BLED, HEMORR2HAGES scores and numbers of all as well as category 1 and 2 bleedings. The difference in bleeding frequency between high and low risk groups was significant only for recurrent bleedings. There were 22 (36.1%) and 5 (8.6%) recurrent bleedings among 61 and 58 patients with high and low-risk HAS-BLED score, respectively (p = 0.0048). Recurrent bleedings also occurred more frequently among patients with high risk (7/10, 70%) compared with low risk (20/109, 18.35%) HEMORR2HAGES score (p = 0.018). Subgroups of high and low bleeding risk according to HAS-BLED and HEMORR2HAGES scores differed only by proportion of patients with recurrent bleedings. High W sensitivity represented by 2*/2*, 2*/3*, 3*/3* CYP2C9 and/or AA VKORC1 homozygosis was detected in 25 of 119 patients. Six of 8 patients (75%) with category 1 bleedings were carriers of any polymorpism. CONCLUSION: HAS-BLED and HEMORR2HAGES scales performed best in predicting recurrent bleedings in patients on long term W therapy. Single bleedings with INR > 4.0 during 1st month of W therapy were associated with reduced W metabolism (AA VKORC1 or/and CYP2C9 allelic variants 2*/2*, 2*/3*, 3*/3*).

[HAS-BLED and HEMORR2HAGES Scales in Assessment of Bleeding Risk in Patients on Long-Term Warfarin Therapy].

Aim of the study was to elucidate value of HAS-BLED and HEMORR2HAGES scales for prediction bleedings in patients receiving long-term warfarin (W) therapy. MATERIAL AND METHODS: The study involved 119 patients (72 men) aged 60.9+/-9.6 years with atrial fibrillation or venous thromboembolic complications. Follow up period was 5.6 +/-3.4 years. All bleedings were categorized as 1) single bleeding with INR>4.0 during the 1st month of W therapy; 2) any single bleeding after 1st month of W therapy; 3) recurrent bleedings. CYP29 and VKORC1 (G3673A) genotypic variants were determined by PCR. Patients were divided into low (<3 points of HAS-BLED scale, n=58; <4 points.

[Practical aspects of therapy with new oral anticoagulants in patients with impaired renal function].

The article deals with renal dysfunction, methods of assessment and monitoring in patients receiving anticoagulant therapy. Due to the negative impact of renal impairment on the incidence of thromboembolic and hemorrhagic complications in patients with atrial fibrillation problem identifying renal failure and its degree is an actual problem. Set forth in Article current recommendations and practical aspects of the evaluation of renal function and selecting dosing regimen can improve the safety of anticoagulants therapy.

[CYP2C9 and VKORC1 gene polymorphism and acenocoumarol anticoagulant activity in Russian patients at high risk of thromboembolic complications].

The study included 25 patients at high risk of thromboembolic complications. All of them were treated with acenocoumarol for 6 months under control of the frequency of hemorrhage and episodes of severe hypocoagulation (a more than 3-fold rise in INR). All the patients underwent CYP2C9 and VKORC1 genotyping. It was shown that the presence of CYP2C9*2 and CYP2C9*3 alleles in the CYP2C9 locus and the AA genotype of the polymorphous G-1639(3673)A marker of the VKORC1 gene was not associated with the development of severe hypocoagulation episodes (p = 0.261--for CYP2C9, p = 0.616 and 0.361 for VKORC1 in the total group and a subgroup of patients having the CYP2C9*1/*1 genotype respectively and treated with acenocoumarol. The search for other genetic markers of efficacy and safety of this drug should be continued.

[Anticoagulant action and safety of warfarin dosing based on pharmacogenetic testing: results of the first Russian prospective pilot study].

Aim of the study was to compare numbers of episodes of excess hypocoagulation and bleeding with warfarin dosing based on pharmacogenetic testing and traditional method in patients with high risk of thromboembolic complications. In 76 patients (43 men and 33 women aged 60.3 +/- 12.3 years) warfarin was administered starting with the dose calculated according to the gage algorithm with consideration of results of pharmacogenomic testing (genotyping of CYP2C9 and VKORC1). Control group comprised 78 patients aged 63.4 +/- 9.4 years who had participated in an earlier retrospective study in which they received warfarin according to traditional scheme with starting dose of 5 mg/day. In both groups we analyzed data obtained during 6 months after start of drug administration. Genotyping was carried out by polymerase chain reaction. Episodes of excess hypocoagulation (international normalized ratio above therapeutic range) and bleeding accurred more rarely with the use of pharmacogenetic approach to dosing of warfarin compared with standard method (17.1 vs 56.4%, p = 4.1 x10(-7), and 4 vs 18%, p = 0.009 respectively).

[Which of algorithms of warfarin dosing based on results of pharmacogenetic testing is suitable for patients in Russia].

Aim of the work was selection of optimal for patients in Russia algorithm of warfarin dosing based on results of pharmacogenomic testing. We analyzed data from 78 patients aged 63.4+/-9.4 years with known CYP29 and VKORC1 genotypes who had participated in an earlier retrospective study in which they received warfarin according to traditional scheme with starting dose of 5 mg/day. We used 5 known algorithms of determination of initial warfarin dose based on results of pharmacogenomic testing and correlated calculated doses with those which had been actually selected in our patients. Correlation was closest for doses obtained with algorithm of Gage et al (www.warfarindosing.org) (r=0.887, p<0.0001). Therefore we consider this algorithm most suitable for patients in Russia.

[Cytochrome P4502C9(CYP2C9) gene polymorphism and safety of therapy with warfarin].

Aim of the study was to investigate frequency and influence of alleles CYP2C9*2 and CYP2C9*3 on pharmacokinetics, pharmacodynamics and dosing regimen of warfarin and on development of hemorrhagic complications. We included 84 patients (mean age 62,8 +/- 10,5 years). Duration of follow-up varied between 1 month and 1 year. Carriage of allele variants was determined by polymerase chain reaction, measurement of plasma wafarin concentration was carried out with the help of high performance liquid chromatography. Wild type (CYP2C9*1/*1) was found in 68% of patients; overall frequency of 2C9*1/*1, *l/*3, *2/*2, *3/*3, *2/*3 genotypes was 32%. Average maintenance doses of warfarin for patients with allele variants CYP 2C9 *2 and 2C9 *3 were 3.6 and 3.1 mg/day, respectively, what was significantly lower than in wild type homozygotes (6.1 mg/day). Wild type homozygotes (1) had the highest warfarin clearance (3,51 ml/min). In carriers of 2C9 *2(2) and 2C9 *3(3) warfarin clearance was significantly lower (2.42 and 1.82 ml/min; p1 - 2 = 0,05; p1 - 3 = 0,0008). In carriers of allele variants CYP2C9*2, CYP2C9*3 values of international normalized ratio > 3,0 were met more often, especially in carriers of CYP2C9*3 (in 100% of cases) vs. 28% in wild type homozygotes (p=0,02). Carriers of CYP2C9*3 compared with wild type homozygotes had more hemorrhagic complications (67% and 16%, respectively, p=0,0008). Thus cytochrome P450 2C9 gene polymorphism influences frequency of development of hemorrhagic complications, metabolic clearance, and magnitude of warfarin maintenance dose.

[The influence of CYP2C9 genetic polymorphism on the pharmacokinetics and pharmacodynamics of warfarin in patients with constant atrial fibrillation].

CYP2C9 is the main enzyme participating in warfarin metabolism, of which genetic polymorphism is typical. The aim of the study was to investigate the influence of having allelic variants CYP2C9*2 and CYP2C9*3 on the pharmacokinetics, dosage regimen, and the rate of hemorrhage in patients with constant atrial fibrillation taking warfarin. Eighty-two patients with constant atrial fibrillation taking warfarin were included in the study. It was shown that in patients with CYP2C9*2 and CYP2C9*3 the clearance of warfarin and its dose were lower, while the episodes of excessive hypocoagulation and hemorrhage associated with warfarin were more frequent than in patients without these allelic variants. Basing on the results of the study, the authors propose an algorithm of choosing the initial warfarin dose depending on CYP2C9 genotype.