[Characteristics of patients with chronic thromboembolic pulmonary hypertension according to the Russian National Registry].

AIM: To assess demographic and clinical characteristics, to describe of the functional and hemodynamic status, profile of concomitant pathology, data of instrumental examination in chronic thromboembolic pulmonary hypertension (CTEPH) patients; to study the features of specific and supportive therapy according to the data of the Russian national registry. MATERIALS AND METHODS: From 2012 till 2020 a multicenter, prospective study in 15 regional expert centers of the Russian Federation (www.medibase.pro) included 404 newly diagnosed CTEPH patients over the age of 18 years in the Russian registry of patients with pulmonary arterial hypertension and CTEPH (NCT03707561). The diagnosis was established by European and Russian clinical guidelines for the diagnosis and management of pulmonary hypertension. 154 inoperable CTEPH patients an additional analysis of specific and supportive therapy was performed. RESULTS: The study included 404 patients (55.6% women and 44.3% men) at the age of 58.6 [48.6; 69.3] years. Median time from symptom onset to the diagnosis verification waswas 2.4 years (from 0.1 to 2.9 years). 79.1% of patients were in the III and IV functional class (World Health Organization) at the time of diagnosis and in 44.1% with RHF (right heart failure). In assessing the profile of concomitant pathology, it was noted that CTEPH patients were more often with arterial hypertension (39.1%), erosive-ulcerative lesions of the stomach/duodenum (16.1%), atrial fibrillation (13.8%), obesity (13.1%). Distance in 6MWD (6-min walk distance) was 337.2 [250; 422] m, Borg dyspnea index scale 4.1 [3.0; 5.0] points. Hemodynamic parameters according to right heart catheterization were: Mean PAP (pulmonary arterial pressure) (51.114.04) mmHg, CO (cardiac output) (3.50.98) l/min, CI (cardiac index) (2.00.48) l/min/m2, PVR (2008528) dyns/cm5. CONCLUSION: According to the Russian registry, inoperable CTEPH patients had precapillary PH (pulmonary hypertension) with severe functional status, in combination with frequent concomitant pathology (arterial hypertension, erosive-ulcerative lesions of the stomach/duodenum, atrial fibrillation, obesity, right heart failure). 66% of inoperable CTEPH patients received specific drug therapy.

[Features of clinical, functional and hemodynamics profile, medical treatment and prognosis evaluation in patients with inoperable chronic thromboembolic pulmonary hypertension and idiopathic pulmonary arterial hypertension according to the Russian registry].

AIM: to perform the complex analysis of clinical, functional, hemodynamics profile in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) compared to the idiopathic pulmonary arterial hypertension (IPAH) group at the time of diagnosis verification according to the Russian registry, and to evaluate the features of medical therapy and it's influence on prognosis in these patients. MATERIALS AND METHODS: In the retrospective study 193 patients with IPAH and 130 patients with inoperable CTEPH older than 18 years were included. All included patients were the participants of Russian registry (www.medibase.pro) in 15 Russian expert centers during the period from 01.01.2012 to 31.12.2018 year. The diagnosis was verified according to the algorithm, reflected in the Russian guidelines on diagnosis and treatment of PH and CTEPH (2016 year). The comparison analysis of clinical, functional, hemodynamics parameters in patients with IPAH and inoperable CTEPH was made. RESULTS: The status of 193 patients with IPAH (32 male and 162 female) and 130 patients with inoperable CTEPH - (40 male and 90 female) was analyzed during the study. The CTEPH patients were older compared to the IPAH patients: 52.2 [41.1; 60.6] and 36.5 [26.8; 36.5] years, respectively. The median period since symptom occurrence till CTEPH verification was 1.08 [0.2; 3.1] years, in IPAH patients - 2.01 [0.6; 4.2] years. More than 80% of inoperable CTEPH patients had III and IV functional class (FC) according to the World Health Organization classification at the time of diagnosis verification versus 61% of IPAH patients. According to echocardiography the level of mean pulmonary arterial pressure was comparable in two groups of PH patients. However in inoperable CTEPH patients the right atrial area was larger. The significantly higher value of mean pulmonary arterial pressure and lower value oxygen saturation of arterial blood according to the right heart catheterization were revealed. The 5-year survival in CTEPH patients, receiving initial dual combination therapy in 75% cases (in 40% - combination of riociguat and iloprost ) was 93% versus 86.5% in patients with IPAH. CONCLUSION: It was revealed, that inoperable CTEPH patients were significantly older with severe functional and hemodynamics status at the time of diagnosis verification, although with higher level of 5-year survival compared to the IPAH patients according to the Russian registry.

The economic burden of chronic thromboembolic pulmonary hypertension in Russian Federation.

AIM: The aim of current study was to estimate the economic burden of the chronic thromboembolic pulmonary hypertension (CTEPH) in Russia based on patient registry. MATERIALS AND METHODS: Cost of illness study was based on data derived from CTEPH patient registry that was developed at the Division of hypertension of FSBI "National Medical Research Center of Cardiology". Demographic and clinical patient characteristics were analyzed with descriptive statistic methods. Cost of illness study was performed from the state perspective and with bottom-up approach. Bootstrapping was used for calculation of average costs per patient/year. Within the study direct costs (medical costs: outpatient, inpatient, emergency, PAH-specific therapy, concomitant therapy; non-medical costs: pension due to disability status, payments for patients on sick-leave) and indirect costs (loss in GDP) were estimated. RESULTS: Overall, 113 CTEPH patients (67 women and 46 men) from 33 Russian regions were included, mean age of patients with CTEPH was 54.6±13.95 years. Most of the patients (55%) were in able-bodied age. It was found that about half of patients with diagnosed CTEPH had a disability. Average duration of disease at the time of analysis was 6.88±11.41 years. Period from the first occurrence of symptoms to the confirmation of diagnosis of CTEPH was 2.58±5.21 years on average. More than 70% of patients had III and IV FC (WHO) at the time of diagnosis. Mean number of outpatient visits was 1.97±1.65 per patient/year, and inpatient visits were reported for 59% of patients. About 54% of patients used PAH-specific therapy, moreover 46% patients had interruptions of PAH-specific therapy (58.4±66.3 days). The total costs of CTEPH per patient/year were calculated as 805,901 RUB. The overall burden of CTEPH in Russia for total CTEPH population (470 patients) was 379 million RUB per year. CONCLUSION: CTEPH is the rare disease that is characterized with later diagnosis due to absence of disease-specific symptoms. Therefore economic burden of the CTEPH is significantly low in comparison to widespread cardiovascular diseases. Development of network of expert PH-centers and increase of the access for PAH-specific therapy will help to increase the quality of health care for patients with CTEPH.

New horizons for the use of the second generation of endothelin receptor antagonist macitentan in patients with pulmonary hypertension.

Since 2015, macitentan, the new oral dual endothelin receptors antagonist (ERA), has been successfully introduced into clinical practice in the Russian Federation for the treatment of pulmonary arterial hypertension (PAH) patients. It has improved physicochemical properties, which provides tissue specificity. Among ERA and other drugs of specific therapy, macitentan is the only one with indication-prevention of PAH progression. In the randomized, placebo-controlled study SERAPHIN in 742 PAH patients aged >12 years, macitentan 10 mg compared with placebo reduced the risk of morbidity and mortality by 45%. By month 6, macitentan with favorable tolerability profile provided a significant increase in the 6-minute walk test distance, the improvement of the functional class (FC) and hemodynamic parameters - pulmonary vascular resistance (PVR) and cardiac index. Macitentan significantly reduced the need for hospitalization for all reasons, including associated with PAH worsening. This review presents a modern view on the possibility of using macitentan in the clinical practice. It is shown that the drug is an important choice among ERA for the treatment of PAH patients. In the study MERIT-1 macitentan significantly improved PVR (geometric mean ratio 0.84, 95% CI 0.70-0,99, p=0.041) in inoperable CTEPH patients. The evidence base for the macitantan use in various PAH subgroups, including portopulmonary hypertension, in children as well as beyond group 1 - CTEPH, left heart diseases - is supplementing with the new data, which will expand the possibilities of its clinical use.

[Carriage of A Allele of Polymorphic Marker G(-238)A of TNF Gene Is Associated With Unfavorable Prognosis in Patients With Chronic Systolic Heart Failure].

AIM: to elucidate association between polymorphic markers of interleukin-6 (Il-6) and tumor necrosis factor (TNF) genes and unfavorable outcomes in patients with chronic heart failure (CHF). MATERIAL AND METHODS: We determined levels of TNF and Il-6 and genotypes of polymorphic markers G(-238)A of TNF gene (rs361525) and G(--174)C of IL-6 gene (rs1800795) in 151 patients (mean age 64.5 years) hospitalized because of decompensation of systolic CHF (left ventricular ejection fraction ≤ 40%) after stabilization of their state. Unfavorable outcomes were registered during follow-up for 2 years. RESULTS: Mean levels of NT-proBNP, Il-6, and TNF were 2481.1 ± 199.86 fmol/ml, 21.8 7.46 rg/ml, and 10.07 ± 0.65 rg/ml, respectively. 138 (94.4%), 13 (8.6%) and 0 patients were carriers of genotypes GG, AG, and AA of polymorphic marker G(-238)A of TNF gene, respectively; 54 (35.8%), 69 (45.7%), and 28 (18.5%) patients carried genotypes GG, GC, and CC of polymorphic marker G(-174)C gene IL-6, respectively. There was no association between Il-6, TNF levels and carriage of either of genotypes as well as unfavorable clinical course of CHF. Mean survival time before repetitive episode of CHF decompensation (including lethal one) was significantly shorter among carriers of A allele compared with carriers of G allele of polymorphic marker G(-238)A of TNF gene (243 ± 97.7 and 947 ± 78 days, respectively, p = 0.018). Mean time before all cause death was also shorter in carriers of A compared with carriers of G allele (289 ± 122.9 and 1039 ± 73.3 days, respectively, p = 0.03). The studied polymorphism of IL-6 gene had no prognostic value. CONCLUSION: We obtained data on association between carriage of A allele of polymorphic marker G(-238)A of TNF gene and unfavorable prognosis in patients with CHF and inpraired left ventricular systolic function.

[Carriage of A Allele of Polymorphic Marker G(-238)A of TNF-alfa Gene Is Associated With Unfavorable Prognosis in Patients With Chronic Systolic Heart Failure].

AIM: to elucidate association between polymorphic markers of interleukin- 6 (Il-6) and tumor necrosis factor (TNF) genes and unfavorable outcomes in patients with chronic heart failure (CHF). MATERIAL AND METHODS: We determined levels of TNF and Il-6 and genotypes of polymorphic markers G(-238)A of TNF gene (rs361525) and G(-174)C of IL-6 gene (rs1800795) in 151 patients (mean age 64.5 years) hospitalized because of decompensation of systolic CHF (left ventricular ejection fraction less or equal 40%) after stabilization of their state. Unfavorable outcomes were registered during follow-up for 2 years. RESULTS: Mean levels of NT-proBNP, Il-6, and TNF were 2481.1+/-199.86 fmol/ml, 21.8+/-7.46 rg/ml, and 10.07+/-0.65 rg/ml, respectively. 138 (94.4%), 13 (8.6%) and 0 patients were carriers of genotypes GG, AG, and AA of polymorphic marker G(-238)A of TNF gene, respectively; 54 (35.8%), 69 (45.7%), and 28 (18.5%) patients carried genotypes GG, GC, and of polymorphic marker G(-174)C gene IL-6, respectively. There was no association between Il-6, TNF levels and carriage of either of genotypes as well as unfavorable clinical course of CHF. Mean survival time before repetitive episode of CHF decompensation (including lethal one) was significantly shorter among carriers of A allele compared with carriers of G allele of polymorphic marker G(-238)A of TNF gene (243+/-97.7 and 947+/-78 days, respectively, =0.018). Mean time before all cause death was also shorter in carriers of A compared with carriers of G allele (289+/-122.9 and 1039+/-73.3 days, respectively, p=0.03). The studied polymorphism of IL-6 gene had no prognostic value. CONCLUSION: We obtained data on association between carriage of A allele of polymorphic marker G(-238)A of TNF gene and unfavorable prognosis in patients with CHF and inpraired left ventricular systolic function.

[Clinical guidelines for the diagnosis and treatment of pulmonary hypertension].

Pulmonary hypertension (PH) is a group of diseases characterized by progressive increases in pulmonary vascular resistance and pulmonary artery pressure, which results in right ventricular heart failure and sudden death. Based on the current version of the guidelines for PH diagnosis and treatment, adopted by the experts of the European Society of Cardiology and the European Respiratory Society in 2009, and on the data of Russian and foreign clinical trials, the Russian experts elaborated clinical guidelines for PH in 2013. The latter consider the current classifications of PH, the specific features of its pathogenesis, and its diagnostic algorithm. The section dealing with drugs for maintenance therapy discusses data on the use of oral anticoagulants, diuretics, cardiac glycosides, and oxygen therapy. PH-specific therapy includes calcium antagonists, prostanoids, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. Surgical procedures for PH involve atrial septostomy, thromboendartectomy, and lung or heart-lung transplantation. A treatment algorithm is proposed for PH patients. The current medicinal approaches using specific therapy agents and their combinations offer new promises for the effective treatment of patients with PH and improve its prognosis.

[Pulmonary hypertension in Russia: the first results of the national register].

AIM: To investigate the demographic and clinical characteristics of patients with pulmonary hypertension (PH) and chronic thromboembolic pulmonary hypertension (CTEPH), regions of their residence, the specific features of diagnosis and drug therapy, and the patients' survival within the framework of a multicenter open-label prospective study. SUBJECTS AND METHODS: The study enrolled patients over 18 years of age with PH classified as Group 1 (PH) and Group 4 (CTEPH). The follow-up was made in 9 expert centers of Russia on January 1 to February 28, 2014. The data of patients with PH and CTEPH were electronically entered at the register website: www.pul-hyp.medibase.ru. RESULTS: The study included 242 patients (183 women and 59 men) from 44 regions of the Russian Federation. PH of different etiologies was present in 79.3%, including 43.8% with idiopathic PH, 28.5% with congenital heart disease-associated PH, 6.2% with diffuse connective tissue-associated PH, 0.8% with hereditary PH; 20.7% were diagnosed with CTEPH. The patients' mean age at the inclusion in the register was 43.2 ± 15.8 years; the median PH duration was 4.4 years (1.4 to 10.6%). The distance covered during a 6-minute walk test was 395.2?111.1 m; the Borg dyspnea index was 3.4 ± 1.4 scores and the functional class was 2.5 ± 0.8. After right cardiac catheterization, the mean pulmonary artery pressure was 53.1 ± 19.5 mm Hg; cardiac output, 3.8 ± 1.2 l/ min; cardiac index, 2.1 ± 0.6 l/min/m2; pulmonary vascular resistance, 1105 ± 677.6 dyn·sec/cm5. A positive acute pharmacological test was seen in 16.3% of the patients. The most common comorbidity was erosive ulcerative lesion of the gastrointestinal tract (23.5%), hypertension (16.9%), and obesity (16.5%). 66% of the patients received PH-specific therapy: sildenafil (51.6%), bosentan (20.9%), or iloprost (7%); 7.4% of the patients were observed within the framework of clinical trials, 17.7% received combined therapy for PH: 16.3 and 1.4% had dual- or triple-component therapy, respectively; 55.8% of the patients took calcium antagonists, 61.4% had diuretics, 85.6% had antithrombotic drugs. The survival rates were 98% in the first year of the follow-up and 90.1% by the end of 2013. CONCLUSION: The formation of a national register of patients with PH and CTEPH makes it possible to introduce current approaches to diagnosing and treating the patients of this category and to evaluate the efficiency and quality of rendered medical care and will contribute to the estimation of required health care volumes and the expenditure of public health resources.

[Risk of cardiovascular complications in patients with frequent hypertensive crises].

AIM: To investigate a relative risk of cardiovascular complications in uncomplicated hypertensive crises (UHC) in hypertensive patients. MATERIAL AND METHODS: A questionnaire retrospective case-control study covered one-third of patients registered in the data base of a hospital or outpatient clinic. The patients were matched by basic characteristics. By frequency of UHC the patients were divided into two groups. Group 1 (n = 305) comprised patients with frequent (weekly or more often) UHC, group 2 (n = 558) consisted of patients with rare UHC (monthly or less frequent). RESULTS: Patients of group 1 had a longer history of arterial hypertension (13 +/- 9 years vs 9 +/- 7.8 years, p < 0.05). The target blood pressure was achieved in group 1 in 42% vs 56% in group 2; p < 0.05). Group 1 patients had a higher risk of non-fatal stroke/transient ischemic attack (TIA)--18 and 10% (OR 1.94, 95% CI 1.28-2.93; p < 0.05), chronic cardiac failure (44 vs 30%; OR 1.64; 95% CI 1.22-2.21; p < 0.05), left ventricular hypertrophy (72 and 56%; OR 2.11; 95% CI 1.52-2.93; p < 0.05) and myocardial ischemia (56 and 38%; OR 2.05; 95%CI 1.53-2.74; p < 0.05). UHC frequency had no significant influence on the risk of non-fatal myocardial infarction (19 vs 15%; OR 1.34; 95% CI 0.92-1.94; p > 0.05). CONCLUSION: Frequent UHC raise the risk of non-fatal acute disorder of cerebral circulation, chronic cardiac failure, ischemia and left ventricular hypertrophy. Frequency of UHC is not related to the risk of myocardial infarction.

[The effect of long-term Fraxiparin treatment on hemostasis in patients with primary pulmonary hypertension]. / Vliianie dlitel'nogo lecheniia fraksiparinom na gemostaz u bol'nykh pervichnoi legochnoi gipertoniei.

The aim of the study was elucidation of hemostatic effects of low-molecular heparin Flaxiparin in patients with primary pulmonary hypertension (PPH). 10 PPH patients (mean age 39.0 (+)- 3.2 years, mean history of the disease 5.1 (+)- 0.9 years) were treated up to 6 months. For the first month Flaxiparin was injected in therapeutic doses 15,000 AXa ICU, twice a day. The next 5 months prophylactic doses were administered twice a day (7,500 AXa ICU). D-dimer, fragment 1 + 2, complex thrombin-antithrombin, beta-thromboglobulin, protein C, antithrombin III, antigen of tissue plasminogen activator and inhibitor of tissue plasminogen activator of type I, activity of the latter were measured before the treatment, after the therapeutic and prophylactic courses, 6 months after the treatment. Initially, the patients had procoagulative hemostatic disorders. i.e. activation of blood coagulation; fibrinolytic system was also affected. In the course of Flaxiparin therapy blood coagulation and fibrinolysis improved significantly. However, the effect was not persistent after the drug discontinuation. Flaxiparin can be recommended for treatment of PPH.

[The effect of Lomir (isradipine) on the tolerance for physical loading and on the gas exchange indices of patients with primary pulmonary hypertension]. / Vliianie lomira (isradipina) na tolerantnost' k fizicheskoi nagruzke i pokazateli gazoobmena u bol'nykh pervichnoi legochnoi gipertenziei.

Spirometry and bicycle ergometry were performed before and 3 weeks, 6 months after lomir treatment (mean dose 10.62 +/- 2.59 mg/day) of 8 patients with primary pulmonary hypertension. It was found that 3 weeks of the treatment produced a significant increase in the maximum power working capacity and performance, in 6 months of the treatment there were positive trends in gas exchange: anaerobic threshold became higher and maximum oxygen consumption rose. Thus, lomir is recommended for management of primary pulmonary hypertension as it improves exercise tolerance and gas exchange measured by means of spirometry and bicycle ergometry useful both for evaluating functional condition of the patients and the disease advance as well as its response to the therapy conducted.