Evaluation of compliance of pulmonary hypertension patients to the treatment with inhaled iloprost (Ventavis): results of prospective, multicenter, non-interventional IVENT study

Aim. To evaluate patients’ (pts.) compliance with Ventavis inhaled treatment. Secondary aim: to study pts. characteristics; reason for low compliance; changes in 6-minute walking distance (6MWD) test and dyspnea score; changes in the parameters of pulmonary hemodynamics; pulmonary function changes; quality of life (QOL) according to compliance with Ventavis use; to assess frequency, severity and other characteristics of AE. Materials and methods. Prospective, multicenter, single cohort non-interventional IV phase study IVENT (NCT01971450). The study lasted 12 month. Pts. evaluation was scheduled as follows: initial visit done at baseline (pts. inclusion) - iV, 6 (follow-up visit 1) - V1, and 12 (follow-up visit 2, final) month - V2 thereafter. Evaluation of basic demographic and functional characteristics using needed armamentarium was planned at these time points. Treatment compliance was analyzed at 1 (6 month) and 2 (12 month) follow-up visits (ITT population). Results. As many as 82 pts. averages (mean±SD) 47.6±14.2 years with mean PH syndrome duration 3.2±5.7 years were included. Substantial number of pts. presented with severe disorders in anamnesis, i.e. pulmonary embolism, heart defect, arterial hypertension, heart failure in 35.4; 14.6; 36.6 and 70.7% of pts., respectively. PH syndrome verification methods varied with right heart catheterization (RHC) being the most prevalent one in 45.1% of pts., following by echocardiography (EchoCG) in 30.5%. At the iV EchoCG was performed in all the pts; and at the final visit in 82.9%; RHC - in 62.2% and 7.3%, respectively. Study population mean 6MWD estimated to be 257.7±109.6 m at the time of inclusion with Borg index score 6.4±4.2. All 82 pts. were being treated with iloprost inhaled [average daily dose 8.0±7.9 (95% CI 6.2-9.7) mcg] at the iV. 53 and 29 pts. of ITT population formed ‘sufficient-compliant’ (SC) and ‘low-compliant’ (LC) subgroups (sbgr.), respectively. Patients’ compliance of inhaled treatment with Ventavis in the overall population was shown to be 82.3±27.7% at the V1 and 81.8±28.4% at the V2; in SC sbgr. - 96.9±5.4 and 96.6±5.8%, respectively; in LC sbgr. - 49.1±29.1 and 46.4±29.9%, respectively. AE, lack of the drug or drug ineffectiveness, patient preferences not to receive the drug were demonstrated to be the main reasons for treatment discontinuation in both sbgr. At 6 month mean daily dose of iloprost was 7.7±5.5 mcg; at 12 month 7.2±4.9 mcg. At the iV 63.4% of pts. was receiving inhalations 6 times in a days at month 6 and 12 - 58.5% and 48.8%, respectively. Mean number of inhalations per day was estimated to be 5.9±1.3 at the iV and 6.1±1.3 at V1 and V2. Ventavis treatment interruptions were registered in 37.8% of pts. at the end of observation period (22.6% SC sbgr.; 65.5% LC sbgr.). Premature discontinuation of the drug treatment was noted in 8.5% of pts. at V1 and 20.7% at the V2. Dose correction took place in 4.9% and 1.2% of pts. at V1 and final visit, accordingly. SC sbgr. of pts. at baseline was characterized by 6MWD of 266.9±114.23 vs. 240.5±100.2 m in LC one. At 12 month 6MWD had increased up to 307.1±115.4 vs. 263.5±107.4 m in SC and LC sbgr., respectively. Baseline Borg dyspnea score in SC sbgr. was 6.1±3.8 vs. 6.9±4.9 in LC pts. At the end of the study, Borg dyspnea score for SC and LC pts. estimated to be 6.3±3.6 and 7.7±5.7, respectively. Thus, in SC sbgr. was achieved positive changes in 6MWD with persistent dyspnea, but in LC sbgr. dyspnea severity had increased. In ITT population systolic PAP (SPAP) measured by EchoCG was slightly decreased from 83.2±27.9 to 76.6±29.7 mmHg at the final visit; in SC sbgr. - from 82.5±24.1 to 76.5±26.7 mmHg; in LC sbgr. - from 84.5±34.5 to 76.8±35.7 mmHg. Due to the fact RHC data is available only for several pts., it is impossible to analyze changes in hemodynamic variables. Patients’ QoL according to SF-12 questioner showed positive changes from mean score 30.8±7.7 to 35.1±9.3 in SC pts. at the end of observation. QoL in LC sbgr. did not change substantially. Same trend could be revealed when evaluating psychological component: 41.7±10.6 and 46.3±10.9 in SC sbgr.; 40.6±11.4 and 40.2±11.7 in LC sbgr. During the study 64 AE in 24.4% of pts. were registered, 37 AE in 17.1% of pts. judged to be drug-related. Iloprost dose was remaining unchanged in 13.4% of pts., whereas in 2.4% of pts. dose decreased; in 8.5% of pts. drug intake was discontinued. At the end of the study, 35 AE in 15.9% of pts. successfully resolved. The most frequent AE became cough (9.8%), dysphonia (3.7%), headache (6.1%), dizziness (4.9%), syncope (3.7%), asthenia (2.4%), edema (2.4%). Overall 24 serious AE (SAE) had occurred in 20.7 of pts. 17 (out of 24) SAE in 11 (37.9%) pts. emerged in LC sbgr. None of the SAE were considered to be drug-related. Iloprost dose remained unchanged in 6.1% of pts. (8 SAE cases), treatment paused in 1.2% of pts., and treatment was discontinued in a single case. 13 SAE in 11 (13.4%) pts. were fatal, 4 SAE in 4 (4.9%) pts. had resolved, 3 SAE in 2 (2.4%) pts. was resolving, 4 SAE in 2 (2.4%) pts. were continuing at the end of observation. In 8 cases in 6 (7.3%) pts. dose correction measures were not undertaken; in 6 SAE cases in 5 (6.1%) pts. there is no information available. Conclusion. In general population studied, it’s been demonstrated sufficient PH patients’ compliance of Ventavis inhaled treatment.

clinical study IVENT, iloprost, inhalation, nebulizer, pulmonary hypertension

1. Чазова И.Е., Авдеев С.Н., Царева Н.А. и др. Клинические рекомендации по диагностике и лечению легочной гипертензии. Терапевтический архив. 2014; 9: 4-23.

2. Galie N, Humbert M, Vachiery J et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016; 37: 67-119.

3. Валиева З.С., Валеева Э.Г., Глухова С.И. и др. Разработка скринингового опросника для улучшения ранней диагностики легочной артериальной гипертензии. Системные гипертензии. 2014; 4: 62-7.

4. Чазова И.Е., Мартынюк Т.В. Проблемы диагностики и лечения хронической тромбоэмболической легочной гипертензии. Тихоокеанский мед. журн. 2017; 4 (70): 6-16.

5. Мартынюк Т.В., Чазова И.Е. Стратегия медикаментозного лечения легочной артериальной гипертензии в свете современных зарубежных рекомендаций. Системные гипертензии. 2016; 13 (2): 46-65.

6. Мартынюк Т.В., Чазова И.Е. Илопрост - ингаляционный аналог простациклина для лечения больных легочной гипертензией. Системные гипертензии. 2011; 8 (4): 57-63.

7. Чазова И.Е., Мартынюк Т.В. Легочная гипертензия. М: Практика, 2015.

8. Olschewski H, Simonneau G, Galie N et al. for the AIR Study Group. Inhaled iloprost in severe pulmonary hypertension. N Engl J Med 2002; 347: 322-9.

9. Olschewski H, Hoeper M.M, Behr J et al. Long-term therapy with inhaled iloprost in patients with pulmonary hypertension. Respir Med 2010; 104: 731-40.

10. McLaughlin V.V, Oudiz R.J, Frost A et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006; 174: 1257-63.

11. Чазова И.Е., Мартынюк Т.В. от имени рабочей группы по разработке и подготовке текста Российских рекомендаций по диагностике и лечению ХТЭЛГ. Клинические рекомендации по диагностике и лечению хронической тромбоэмболической легочной гипертензии (II часть). Терапевтический архив. 2016; 88 (10): 63-74.

12. Вентавис. Инструкция по медицинскому применению лекарственного препарата Вентавис. Регистрационный номер: ЛСР-005775/10 (от 15.03.2018). https://grls.rosminzdrav.ru/ Grls_View_v2.aspx?routingGuid=511c65f9-2b5f-447b-b6c7-276cdf19c6d8&t=

13. Мартынюк Т.В. Легочная гипертензия: диагностика и лечение. М.: Медицинское информационное агентство, 2018.

14. Отчет по наблюдательному исследованию IVENT (NCT01971450) от 6 декабря 2018 года.