WHO FC Research Articles

Pulmonary Hypertension in Patients With COPD: Results From the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA)

Pulmonary hypertension (PH) in COPD is a poorly investigated clinical condition. Which factors determine the outcome of PH in COPD? We analyzed the characteristics and outcome of patients enrolled in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) with moderate or severe PH in COPD as defined during the 6th PH World Symposium who received medical therapy for PH and compared them with patients with idiopathic pulmonary arterial hypertension (IPAH). The population included incident patients with moderate PH in COPD (n= 68), with severe PH in COPD (n= 307), and with IPAH (n= 489). Patients with PH in COPD were older, predominantly male, and treated mainly with phosphodiesterase-5 inhibitors. Despite similar hemodynamic impairment, patients with PH in COPD achieved a worse 6-min walking distance (6MWD) and showed a more advanced World Health Organization functional class (WHO FC). Transplant-free survival rates at 1, 3, and 5 years were higher in the IPAH group than in the PH in COPD group (IPAH: 94%, 75%, and 55%vsPH in COPD: 86%, 55%, and 38%; P= .004). Risk factors for poor outcomes in PH in COPD were male sex, low 6MWD, and high pulmonary vascular resistance (PVR). In patients with severe PH in COPD, improvements in 6MWD by≥ 30m or improvements in WHO FC after initiation of medical therapy were associated with better outcomes. Patients with PH in COPD were functionally more impaired and had a poorer outcome than patients with IPAH. Predictors of death in the PH in COPD group were sex, 6MWD, and PVR. Our data raise the hypothesis that some patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further. ClinicalTrials.gov; No.: NCT01347216; URL: www.clinicaltrials.gov.

Clinical evaluation of pulmonary hypertension using patient-reported outcomes: a cross-sectional study

BackgroundPatients with pulmonary hypertension (PH) have progressive and disabling symptoms, as well as a burden of treatments and a difficult clinical evaluation that make health-related quality of life a particularly relevant endpoint in this disease. The objective of the study was to evaluate patient-reported outcomes of patients receiving specific treatment for PH in a tertiary hospital using a specific questionnaire (Cambridge Pulmonary Hypertension Outcome Review-CAMPHOR) in the pharmacy consultation.MethodsA cross-sectional, observational, descriptive study was conducted. It included all patients receiving specific treatment for PH in a tertiary hospital in Madrid, Spain. The inclusion period comprised between August to December 2019. CAMPHOR questionnaires containing three domains: symptoms, activities and quality of life were completed by the patients at the pharmacy consultation. Demographic and clinical variables, including WHO Functional Class (WHO FC), PH-specific tests and hemodynamic parameters, were recorded. Non-parametric analyses to assess relations between variables and CAMPHOR domains were performed.ResultsThirty-six patients consented to participate in the study and completed the questionnaire. Median scores for symptoms, activities, and quality of life domains were 5.5 (2.5–10), 8.0 (4.5–10.5) and 3.5 (1–7.5), respectively. Statistically significant differences were found in the three domains when comparing by WHO FC, in the activities domain for 6-m walking test and in the quality of life domain for patients who had emergency visits or hospitalizations in the last year.ConclusionsThe CAMPHOR questionnaire could be useful as a complementary test to achieve an integrated evaluation of PH patients, who could complete it easily during their routine pharmacy visits.

Efficacy and safety of novel-targeted drugs in the treatment of pulmonary arterial hypertension: a Bayesian network meta-analysis

Background: Pulmonary arterial hypertension (PAH) is a severe and fatal clinical syndrome characterized by high blood pressure and vascular remodeling in the pulmonary arterioles, which is also a rapidly progressing disease of the lung vasculature with a poor prognosis. Although PAH medication made great advances in recent years, the efficacy and safety of the medication are unsatisfactory. Therefore, we aimed to update and expand previous studies to explore the efficacy and safety of PAH-targeted medications. Methods: Relevant articles were searched and selected from published or publicly available data in PubMed, Cochrane Library, CNKI, PsycInfo, and MEDLINE (from inception until October 1st, 2020). To assess the efficacy and safety of PAH therapies, five efficacy outcomes [6-minute walking distance (6MWD), mean pulmonary arterial pressure (mPAP), WHO functional class (WHO FC) improvement, clinical worsening, death] and two safety outcomes [adverse events (AEs), serious adverse events (SAEs)] were selected. And 6MWD was regarded as the primary efficacy outcome. Results: 50 trials included with 10 996participants were selected. In terms of efficacy, all targeted drugs were more effective than placebo. For 6MWD, Bosentan + Sildenafil, Sildenafil, Bosentan + Iloprost were better than others. Bosentan + Iloprost and Bosentan + Sildenafil were better for mPAP. Bosentan + Iloprost and Ambrisentan + Tadalafil were more effective in improving WHO FC. Bosentan + Tadalafil and Bosentan + Iloprost had the Ambrisentan probability to reduce the incidence of clinical worsening. It is demonstrated that Ambrisentan had clear benefits in reducing all-cause mortality. In terms of safety, no therapies had been shown to reduce the incidence of SAEs significantly, and Ambrisentan + Tadalafil significantly increased the incidence of AEs. Conclusions: Phosphodiesterase 5 inhibitor (PDE5i) + Endothelin Receptor Antagonists (ERA) seems to be better therapy for PAH. Prostacyclin analogs (ProsA) + ERA appear promising, though additional data is warranted. Registration PROSPERO CRD42020218818.

Pulmonary Hypertension and Pregnancy

Pregnancy in patients with any type of pulmonary hypertension (PH) is associated with significant morbidity and mortality. That is why pulmonary artery hypertension (PAH) is a contraindication to pregnancy and belongs to class IV maternal cardiovascular risks. Maternal mortality rates for pulmonary (especially arterial) hypertension remain high even in the era of specific therapy, in particular, it reaches 12-30% in patients with PAH, 36% in Eisenmenger syndrome and up to 56% in secondary PH. Perinatal effects in such patients are also unfavorable, with high rates of fetal loss, premature birth and miscarriage.
 Multidisciplinary team of specialists of the National Amosov Institute of Cardiovascular Surgery and Institute of Pediatrics, Obstetrics and Gynecology named after acad. O. M. Lukianova has been providing medical support to such women for 7 years, using modern recommendations and wide experience. Overall, 39 pregnant and parturient women with PH were admitted to the clinic of the National Amosov Institute of Cardiovascular Surgery in the period from December 2013 to October 2020. Patients with PH were assigned to group II (n=24), and those with PAH (8 women) and acute PH (7 women) were assigned to group I. A total of 20 cardiac surgeries were performed. Patients with acute PH (n=6) underwent operations with cardiopulmonary bypass, those with critical mitral valve stenosis had “closed” off-pump surgery, and also there was one case of ECMO system implantation in patient with dilated cardiomyopathy (CMP). Endovascular operations (n=4) involved occluder implantation to patent ductus arteriosus (PDA), implantation of a cardioverter-defibrillator, cardiac resynchronization therapy with pacemaker (CRT-P) and cava-filter insertion. Early (n=1) and late (n=1) maternal mortality rates were 2.6% each. Perinatal loss (n=5) was 12.8%.
 The main goal at the preconception stage in patients with PH is to eliminate causative factors, and, if it is impossible (idiopathic, familial PAH, Eisenmenger syndrome, etc.), to avoid pregnancy. Patients who become pregnant should be informed of the high risk of pregnancy and discuss abortion, regardless of the WHO FC or other predictive markers. At prolongation of pregnancy careful clinical monitoring, by pregnancy heart team members is strongly recommended. Multidisciplinary support of pregnant women with PH is the cornerstone of a successful treatment strategy for such patients. The professional association of obstetric risk specialists, cardiologists, interventionists, neonatologists, and cardiac surgeons significantly increases the chances of a PH patient for safe delivery and giving birth to a healthy baby.

Abstract 15029: Atrial Arrhythmias and Pulmonary Hypertension Across Wsph Groups

Introduction: Previous reports have shown that atrial and ventricular arrhythmias (VA) are common in all forms of pulmonary hypertension (PH) with prevalence of supraventricular arrhythmias ranging from 13-25% and VA 27%. Arrhythmias are also associated with clinical worsening events. Reports have limited numbers of patients with a variety of forms of PH and limited data comparing the prevalence of atrial arrhythmias across WSPH groups and whether advancing age, WHO FC, echocardiographic, exercise capacity and hemodynamic patterns are associated with a higher prevalence of atrial arrhythmias. Methods: As part of the PVDOMICS program, we enrolled 1195 PH participants, controls and PH comparators and prospectively collected electrocardiograms (ECGs) at enrollment for 1147 of them. Comparisons across participants with and without atrial fibrillation/atrial flutter (afib/flutter) used analysis of variance (ANOVA) or Kruskal-Wallis test in continuous variables based on distribution with statistics presented as mean + SD or median [P25, P75] respectively. Pearson’s chi-square test was used for categorical variables. Results: Of 732 PH participants (467F) who had ECGs available at baseline, 527 (72.0%) were in normal sinus rhythm and 62 had afib/flutter (8.5%). Afib/flutter participants were older (75 + 8 vs 57 + 14 years; p<0.001), most commonly in WSPH group 2 (28.1%) vs. WSPH 1 (3.3%), WSPH 3(6.5%) and WSPH group 4 (3.7%), had predominantly WHO FC II/III symptoms (89.5%), higher RAP (12.6 + 5 vs.7.8 + 5mmHg; p<0.001) and PCWPm (17.8 + 5.8 vs. 12.3 + 6.2mmHg; p<0.001) and lower CO (4.3+ 1.5 vs. 5.2 +1.8L/min;p<0.001). Participants with afib/flutter had lower 6MWD 277 + 117 vs.356 + 134meters (p<0.001) than PH participants without. Echocardiography demonstrated increase in LA volume index (mL/m2), RA volume (mL) and tricuspid regurgitation severity with reduced TAPSE and LVEF (54 + 10 vs. 61 + 10%;p<0.001). ProBNP was higher in afib/flutter participants 2029 [1073, 2964] vs.268 [100, 1074]pg/ml; P<0.001) Conclusions: In this analysis of atrial arrhythmias in a large cohort of PH participants across all WSPH groups, afib/flutter was present most often in older WSPH group 2 patients who demonstrated clinical and hemodynamic features of worse heart failure.

Management of Pulmonary Arterial Hypertension Patients with World Health Organization Functional Class II.

Pulmonary arterial hypertension (PAH) is an incurable chronic and progressive debilitating disease associated with significant morbidity and mortality. The World Health Organization functional class (WHO FC) at diagnosis and at follow-up remains one of the strongest predictors of survival in PAH. Studies have shown improved long-term outcomes in PAH patients who received PAH-specific treatment, as monotherapy or as combination therapy, early in their disease course. Studies have also shown that without treatment, PAH rapidly deteriorates even in patients with less advanced (low risk) disease state. In this article, we review evidence from randomized controlled clinical trials to support our position on the importance of early PAH management in WHO FC II patients. The growing importance of combination therapy in the early treatment of PAH and recommendations by the most recent guidelines for the diagnosis and treatment of pulmonary hypertension are also discussed in this article.

Arrhythmias assessed with long-term continuous cardiac monitoring in pulmonary hypertension

Abstract Background Arrhythmias are considered a prominent phenomenon in pulmonary hypertension (PH) as the disease progresses. In short-term retrospective studies with up to 24 hours of monitoring, supraventricular tachycardia (SVT) has been found in 8–35% of patients, with significant impact on survival. The incidence of arrhythmias and their clinical role is based on a small number of retrospective studies. Purpose Assessment of arrhythmias in PH by continuous long-term cardiac monitoring Methods Patients diagnosed with PH were included in this prospective single-centre study where the diagnosis of PAH was established according to international guidelines. Patients received a Reveal LINQ (Medtronic) insertable cardiac monitor (ICM). ICM's continuously monitor the heart rhythm for arrhythmias according to algorithms; and an ECG of the episode will automatically be transmitted whenever an arrhythmia is detected. Results Twenty-eight patients were included, of whom 24 patients had pulmonary arterial hypertension (PAH) and four had chronic thromboembolic pulmonary hypertension (table 1) treated according to Table 1. During 168 patient-months of continuous monitoring (median: 206 days per patient) no long-lasting arrhythmias were observed, but only transient SVTs in one patient lasting a total of 2.5 days. Two had SVTs lasting 4.5 hours, and two hours. Five patients had isolated episodes of SVTs lasting 0–10 minutes and two patients had an episode of bradycardia for 10 seconds. The total arrhythmic burden was a period prevalence of less than 0.001%, despite a RVEF of 20.3% and 35.7% in WHO FC IV and III, respectively. Conclusion This is the first study with long-term continuous rhythm monitoring in patients with PH. In contrast to earlier observations no long-lasting arrhythmias occurred during 168 patient-months with a period prevalence of arrhythmias as low as less than 0.001% in this cohort of PH patients with WHO FC I-IV and the majority on modern specific PAH therapy. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Actelion

Safety and efficacy of transitioning from the combination of bosentan and sildenafil to alternative therapy in patients with pulmonary arterial hypertension.

The combination of bosentan and sildenafil is commonly used to treat patients with pulmonary arterial hypertension (PAH); however, there is evidence of a significant drug interaction between these two medications. We sought to evaluate the safety and efficacy of transitioning patients with PAH from the combination of bosentan and sildenafil to alternative therapy. A retrospective database review was performed on 16 patients with PAH who were treated with the combination of bosentan and sildenafil and transitioned to alternative treatment at our center. Invasive and non-invasive patient parameters were collected at baseline and after transition. 56.3% of patients were in World Health Organization functional class (WHO FC) III and a majority of patients (68.7%) were on background prostacyclin therapy. The most common reason for transition was concern for a drug interaction in seven patients (43.8%). The most common transition was bosentan to macitentan in eight patients (50%). Fifteen patients (93.8%) tolerated the transition after a median follow-up of 6.5 months with minor adverse events occurring in four patients (25%). In 11 patients, 6-min walk distance (6MWD) was unchanged comparing baseline to post transition measurements with a median change of +8 m (range: −50 to + 70; P = 0.39). Nine patients (81.8%) had stable (within 15% margin) or significant improvement (increase by ≥15%) in 6MWD after transition. All patients demonstrated stable or improved WHO FC after transition. There were no significant changes after transition in hemodynamics, N-terminal pro-brain natriuretic peptide (NT-proBNP) values, or Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk scores. In our study, transitioning patients from bosentan and sildenafil to alternative therapy was safe and resulted in clinical stability.

SWITCHING TO RIOCIGUAT IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION NOT AT TREATMENT GOAL WITH PHOSPHODIESTERASE TYPE-5 INHIBITORS: SUBGROUP ANALYSIS RESULTS OF THE REPLACE STUDY

SWITCHING TO RIOCIGUAT IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION NOT AT TREATMENT GOAL WITH PHOSPHODIESTERASE TYPE-5 INHIBITORS: SUBGROUP ANALYSIS RESULTS OF THE REPLACE STUDY

Clinical and Instrumental Characteristics of Newly Diagnosed Patients with Various Forms of Pulmonary Hypertension according to the Russian National Registry.

Aim To study demographic and clinical characteristics and to give a comparative description of the functional and hemodynamic status, profile of concomitant pathology in patients with various forms of pulmonary arterial hypertension (PAH), and chronic thromboembolic pulmonary hypertension (CTEPH) according to the Russian National Registry. Methods During the period from January 01, 2012, till January 01, 2019, 1105 patients aged >18 years with verified diagnosis of PAH and CTEPH, who were subsequently observed at 15 PH expert centers of the Russian Federation in the 52 provinces, are included in the Russian registry on the basis of the Federal State Budgetary Institution of Cardiology of the Ministry of Healthcare of Russia. All newly diagnosed patients (n = 727) were entered into the registry database (NCT03707561). A comparative analysis of demographic and clinical characteristics, profile of concomitant pathology, and parameters of a comprehensive examination of patients was performed. Results Among newly diagnosed patients, 67% had PAH and 28.3% had CTEPH. In the PAH group, 40.9% of patients had idiopathic arterial PAH (IPAH), 36.6% had PAH associated with simple congenital heart disease (PAH-CHD), 19.3% had PAH associated with systemic connective tissue disease (PAH-CTD), 1.8% had portal pulmonary hypertension (PoPH), 0.6% had PAH associated with HIV infection (PAH-HIV), 0.4% had heritable PAH (HPAH), and 0.4% had drug/toxin-induced PAH. At the time of diagnosis, PAH patients were younger than patients with CTEPH (45.2 ± 14.9; 52.6 ± 15.3 years, respectively) (p < 0.05). At the time of diagnosis, 71% PAH and 77% CTEPH patients had WHO FC III/IV. Mean (±SD) 6MWD was significantly less in CTEPH vs. the PAH group 331.3 ± 110.3 vs. 361.8 ± 135.7 m (p = 0.0006). Echo data showed a comparable sPAP between groups; CTEPH population had a more pronounced increase in the area of the right atrium (SRA) (24 [20; 32] cm2 and 19 [15; 26] cm2, respectively), and a significant decrease in FAC (24.7 [22, 4; 29.0] and 29.0 [23.0; 31.0] %, respectively) as compared to the PAH group. RHC showed a comparable increase of sPAP and mPAP in PAH and CTEPH groups. 15.2% of patients with IPAH and HPAH demonstrated positive results in the acute vasoreactivity testing. CTEPH patients were more often obese and suffered from arterial hypertension and right heart failure. Deep venous thrombosis was significantly more often observed in patients with CTEPH (53%). The most common concomitant pathology was erosive-ulcerative lesion of the stomach/duodenum, less often of the esophagus (23.5% and 44.5%, respectively). Conclusion According to the Russian registry in patients with PAH and IPAH, the diagnosis is established at a younger age in comparison with the European registries. CTEPH patients are characterized by more severe functional status, pronounced signs of right heart failure taking into account the older age and the spectrum of comorbid pathology, which limits the possibility of surgical treatment. An increase in the number of expert centers participating in the registry is the key to improving early diagnosis of PH and optimal follow-up according to common standards in order to timely optimize therapy and reduce mortality of patients.

Does combination therapy work in chronic thromboembolic pulmonary hypertension?

The current experience with combination therapy in chronic thromboembolic pulmonary hypertension (CTEPH) is limited. We present the first survival results up to 5years for dual combination therapy versus monotherapy in CTEPH. All consecutive, non-operated CTEPH or residual PH after pulmonary endarterectomy patients treated with PH-specific medical therapy between January 2002 and November 2019 were included. We report and compare survival between monotherapy and (upfront or sequential) dual combination therapy until five years after medication initiation. In total, 183 patients (mean age 65±14years, 60% female, 66% WHO FC III/IV, 86% non-operated) were included, of which 83 patients received monotherapy and 100 patients received dual combination therapy. At baseline, patients receiving combination therapy had a higher NT-proBNP (p=0.02) mean pulmonary artery pressure (p=0.0001) and pulmonary vascular resistance (p=0.02), while cardiac index was lower (p=0.03). Total follow-up duration was 3.3±1.8years, during which 31 (17%) patients died. Estimated 1-, 3- and 5-year survival for monotherapy were 99%, 92% and 79%, respectively. For combination therapy percentages were 98%, 89% and 70%, respectively. Survival did not significantly differ between both groups (p=0.22). Survival up to 5years for patients treated with combination therapy, regardless of the combination strategy, was similar as patients with monotherapy, despite worse clinical and haemodynamic baseline characteristics.

MicroRNA-17 as a potential diagnostic biomarker in pulmonary arterial hypertension.

ObjectiveThis study aimed to detect circulating microRNA (miR)-17 and miR-20a levels in patients with pulmonary arterial hypertension (PAH), and to investigate whether circulating miR-17 levels are associated with PAH.MethodsThirty-five PAH patients and 20 healthy controls were enrolled in the study. Circulating miR-17 and miR-20a levels were measured using real-time PCR analysis.ResultsmiR-17 levels were significantly increased in PAH patients compared with healthy controls. They were also higher in PAH patients at World Health Organization functional class (WHO FC) III–IV than WHO FC I–II PAH patients. There was no significant difference in miR-20a levels between PAH patients and controls. miR-17 had a high area under the corresponding receiver operating characteristic curve. Further, we found that circulating miR-17 levels correlated with the 6-minute walk distance, mean pulmonary artery pressure, and mean right atrial pressure in PAH patients.ConclusionCirculating miR-17 levels may be associated with human PAH. Therefore, miR-17 could be used as a diagnostic index and prognostic factor for PAH patients.

Comparison of Balloon Pulmonary Angioplasty and Pulmonary Vasodilators for Inoperable Chronic Thromboembolic Pulmonary Hypertension: A Systematic Review and Meta-Analysis

Treatment options for chronic thromboembolic pulmonary hypertension (CTEPH) that is not amenable to thromboendarterectomy or is recurrent/persistent after thromboendarterectomy (inoperable CTEPH) include pulmonary vasodilators or balloon pulmonary angioplasty (BPA). We compared efficacy and safety outcomes of BPA with or without pulmonary vasodilators to pulmonary vasodilator therapy alone in patients with inoperable CTEPH. Observational and randomized trial data reporting outcomes for >5 patients with inoperable CTEPH were sought. Single-arm random effects meta-analyses were performed. The primary outcome was change in six-minute walk distance (6MWD). Secondary outcomes included safety; World Health Organization functional class (WHO FC); and change in mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and cardiac index. Thirty-four studies with 1604 patients were eligible for analyses. Both treatments resulted in significant improvement in 6MWD (71.0 meters, 95% CI: 47.4–94.5 meters with BPA versus 47.8 meters, 95% CI: 34.5–61.2 meters with pulmonary vasodilators), PVR [−3.1 Wood Units (WU), 95% CI: −4.9 to −1.4 WU versus −1.6 WU, 95% CI: −2.4 to −0.8 WU] and mPAP (−14.8 mmHg, 95% CI: −18.2 to −11.5 mmHg versus −4.9 mmHg, 95% CI: −6.9 to −2.8 mmHg). Cardiac index was similar and most patients were WHO FC II and III after their respective interventions. More complications occurred in the BPA arm. In conclusion, BPA and pulmonary vasodilators both improve 6MWD and hemodynamics in patients with inoperable CTEPH. While BPA may offer greater functional and hemodynamic improvements, this technique carries the accompanying risks of an invasive procedure.

Treatment of Drug- and Toxin-Induced Pulmonary Arterial Hypertension (PAH): Real-World Experience with Macitentan

To describe real-world experience with macitentan in drug- and toxin-induced PAH (D&T-APAH) patients in the OPsumit® USers (OPUS) Registry and the OPsumit® Historical USers cohort study (OrPHeUS). OPUS is a prospective, US, multicentre, observational drug registry, ongoing since April 2014 (NCT02126943). OrPHeUS was a retrospective, US, multicentre medical chart review (NCT03197688); data collected Oct 2013-Mar 2017. The analysis describes characteristics, safety and outcomes in D&T-APAH patients newly treated with macitentan in the combined OPUS/OrPHeUS data set. Data are descriptively compared with idiopathic/heritable PAH (I/HPAH) patients from the same data set. As of April 2019, OPUS/OrPHeUS PAH patients with follow-up data (N=4286) included 207 D&T-APAH patients (72.0% female) and 2311 I/HPAH patients (72.8% female). At macitentan initiation, median age (Q1, Q3) was 51 (45, 59) years for D&T-APAH and 64 (53, 73) years for I/HPAH patients. At baseline, WHO functional class (FC) was recorded for 108 (52.2%) D&T-APAH and 1244 (53.8%) I/HPAH patients; 63.0% and 61.3% were WHO FC III/IV. At baseline median (Q1, Q3) 6-minute walk distance, recorded in 70 (33.8%) D&T-APAH and 790 (34.2%) I/HPAH patients, was 363 (288, 423) and 288 (195, 375) m. Median (Q1, Q3) time from diagnosis was 11.3 (1.1, 46.2) and 7.6 (1.4, 38.7) months in D&T-APAH and I/HPAH patients. The table shows PAH treatment and discontinuations. Alanine/aspartate aminotransferase ≥3x upper limit of normal occurred in 2.4% D&T-APAH and 2.8% I/HPAH patients. There were 28.0% D&T-APAH and 36.2% I/HPAH patients who had ≥1 hospitalisation; 8.2% D&T-APAH and 10.2% I/HPAH patients died. The 12-month Kaplan-Meier survival estimate (95% CI) was 93.2% (87.7, 96.3) and 92.9% (91.6, 94.1) for D&T-APAH and I/HPAH patients. In OPUS/OrPHeUS, while a higher proportion of D&T-APAH patients were on double and triple therapy, their outcomes were similar to I/HPAH patients.

P805 Clinical and echocardiographic characteristics of Polish patients with Eisenmenger Syndrome - results of a snapshot registry

Abstract The first national registry of patients (pts) with PAH-CHD, predominantly with Eisenmenger Syndrome (ES), treated within national program was conducted. We studied clinical and echocardiographic characteristics of a group of adult patients including current therapy profile and mortality. A multicenter observational study (snapshot registry) was conducted under auspices of Polish Cardiac Society, including pts with PAH-CHD, identified in centers, that treated &amp;gt; 5 pts in the first 10 years of therapeutic program (2008-2018). This analysis included 322 pts (70 deceased), mean age 42 ± 2 years, 65% females. The registry included patients meeting the criteria of the Eisenmenger syndrome in echocardiography (right-left or aligned leak). The living patients were divided into 2 groups: Gr.1 (n = 227) – uncorrected and Gr.2 (n = 25) - after correction of the heart disease. The average age in Gr.1 was 40 ± 2 years, in Gr.2 40 ± 6 years. The majority were women (68% and 62%). There was no significant differences for mean duration of treatment in groups: 60 ± 12 months vs. 66 ± 6 months (p = 0.42). Both groups didn’t differ in terms of clinical data, i.e. 6MWT 417 ± 50 m vs. 384 ± 15 m;p = 0.15, NT-proBNP level 869 ± 470 pg/ml vs. 901 ± 212 pg/ml;p = 0.57. There was no significant differences for mean LVd in groups: 41,24 mm [12-82] vs. 44,25 mm [30-55]. Mean LVEF was good (60% in gr.1 vs. 57% in gr.2). Mean TAPSE was slightly better in Gr.1: 19,36 mm vs. 17,09 mm. Pericardial effusion were present in almost 15% pts from Gr.1 and less than 1% pts from Gr.2. Pts after correction were mostly in the II WHO FC, and those uncorrected in the II/III WHO FC. Pts from Gr.2 were more likely to receive polytherapy (60% vs. 47%). ERA were the most commonly used (near 90%). The most common heart defect was VSD (46% in Gr.1 vs. 32% in Gr.2). Mortality was 22% in entire period, i.e. annual mortality rate of 2.2%. In the group of dead pts women accounted for 74%, the average age was 49 ± 4 years and mean length of treatment was 42 ± 13 months. About 9% of pts from this group had heart defect correction in the past. Monotherapy (66%) predominated among the deceased, mainly using ERA (77%). Pts receiving combination therapy had a longer survival (p = 0.04). It isn’t known whether this result confirms the greater effectiveness of such treatment, as some patients couldn’t wait until the polytherapy became possible within the framework of the Drug Program. Among the deceased, the most common heart disease was ASD (30%), slightly less VSD (29%). In this first national snapshot registry we documented improving prognosis in PAH-CHD under specific therapies. No differences were present in the length of therapy, clinical data and quality of life depending on whether or not correction surgery was performed. Post-correction pts more often received a polytherapy. The annual mortality in this population is small estimated just over 2%. Targeted combination therapy may contribute to better survival.

TRANSITIONING FROM INHALED ILOPROST TO ORAL SELEXIPAG: A CASE REPORT

SESSION TITLE: Monday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: The TRANSIT-1 study looked into transition from inhaled Treprostinil to oral Selexipag (SXP) over the course of 16 weeks[1]. To our knowledge, similar published studies or case series regarding transition from inhaled Iloprost (ILO) to SXP are not yet available. We report the safe transition of a patient with connective tissue disease associated pulmonary arterial hypertension (CTD-PAH) from ILO over to SXP. CASE PRESENTATION: 52 y/o woman with SLE-SSc overlap, Raynauds syndrome, CTD-PAH, & resolved past APLA-related PEs on indefinite warfarin, had been on Bosentan 125mg BID & ILO 5mcg 6 inhalations a day for many years. Patient’s CTD-PAH had been stable at WHO FC 2. She had minimal adverse effects from her current medication regimen. Recently, patient expressed a preference for SXP over ILO. Transition was planned based on GRIPHON study[2] . Parallel up-titration of SXP with down-titration of ILO was performed, while patient continued to take Bosentan. For the 1st week, SXP was started at 200mcg BID in addition to usual 6 inhalations daily ILO. SXP was increased by 200mcg BID per week, while ILO was decreased by 3 inhalations per week. By 3rd week, patient took 600 mcg BID of SXP only, her highest tolerable dose. Throughout the transition, patient was in regular communication with the provider & a visiting specialty pharmacy nurse. Adverse reactions reported were nausea and episodic vomiting, which resolved with time & supportive care. Patient maintained her WHO FC & oxygenation, & had no clinical signs of right heart failure. DISCUSSION: The efficacy adverse profile for SXP against placebo is similar to ILO[2-4]. No head to head comparison is available for both drugs. TRANSIT-1 reported side-effect of muscle bleeding for a patient on warfarin. Our patient didn’t report any such event. TRANSIT-1 study continued their parallel titration for 8 weeks, followed by close monitoring for 4 weeks. In contrast, our patient safely stopped her ILO by the 2nd week, while continued the up-titration of SXP to tolerance. CONCLUSIONS: Our case report suggests that a relatively rapid & safe transition from ILO over to SXP is possible in clinically stable patients with CTD-PAH & relatively better preserved functional status. Reference #1: Frost, A., et al., Safety and tolerability of transition from inhaled treprostinil to oral selexipag in pulmonary arterial hypertension: Results from the TRANSIT-1 study. J Heart Lung Transplant, 2019. 38(1): p. 43-50. Reference #2: Sitbon, O., et al., Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med, 2015. 373(26): p. 2522-33. Reference #3: Olschewski, H., et al., Inhaled Iloprost for Severe Pulmonary Hypertension. New Engl J Med, 2002. 347(5): p. 322-329. DISCLOSURES: No relevant relationships by Sajeer Bhura, source=Web Response No relevant relationships by William Gibbons, source=Web Response

4283Exercise right heart catheterization before and after balloon pulmonary angioplasty in inoperable patients with chronic thromboembolic pulmonary hypertension

Abstract Background Balloon pulmonary angioplasty (BPA) is an evolving treatment option for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). The main indicator for success is improvement in pulmonary hemodynamics, but outcome data are heterogeneous. Purpose The aim of the present study was to evaluate pulmonary hemodynamics not only at rest, but also during exercise before and 6 months after BPA. Methods We report a prospective series of 64 consecutive patients with inoperable CTEPH who were treated interventionally with BPA. All patients underwent standardized assessment prior to the first BPA and 6 months after the last intervention. Assessment included WHO FC, Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR), 6-minute walking distance (6MWD), serum levels of the N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP), and exercise RHC. Results The mean number of sessions per patient was 5.6 (± 1.3) and the mean number of pulmonary segments targeted in all interventions was 11 (± 3). BPA treatment led to improvements in pulmonary hemodynamics and exercise capacity (6MWD: 416±94 m vs. 463±96 m; p&lt;0.0001) except for CO and CI during RHC at rest; these parameters showed improvements only during exercise RHC. MPAP at rest showed a reduction from 41±9 to 31±9 mmHg (p&lt;0.0001) and PVR at rest decreased from 6.8±2.3 WU to 4.3±1.9 WU (p&lt;0.0001). Further decreases were observed for systolic pulmonary arterial pressure, TPG, PVR, and TPR. Cardiac output (7.0±2.0 L/min vs. 8.3±2.0 L/min; p&lt;0.0001) and cardiac index during exercise RHC (3.8±1.1 L/min/m2 vs. 4.4±1.1 L/min/m2; p&lt;0.0001) improved significantly. Median NT-proBNP concentrations decreased from 741 ng/L (IQR 192–1425 ng/L) to 139 ng/L (IQR 60–266 ng/L) during BPA treatment (p&lt;0.0001). Results from the CAMPHOR questionnaire showed significant improvements in symptoms (11±5.8 vs. 5.5±4.9, p&lt;0.0001), activity limitations (9.2±5.6 vs. 5.2±4.5, p&lt;0.0001), and quality of life (6.4±5.7 vs. 3.5±3.7, p&lt;0.0001). Conclusion Significant improvements in pulmonary hemodynamics at rest and during exercise were observed 6 months after BPA. Exercise right heart catheterization offers a more discriminating evaluation of the changes in pulmonary hemodynamics after BPA.

INITIAL TREATMENT COMBINATION WITH MACITENTAN AND TADALAFIL IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION: RESULTS FROM THE OPTIMA STUDY

SESSION TITLE: Pulmonary Hypertension: Characteristics and Treatment SESSION TYPE: Original Investigations PRESENTED ON: 10/21/2019 1:30 PM - 2:30 PM PURPOSE: OPTIMA (NCT02968901) was a prospective, multicenter, single-arm, open-label, Phase IV trial evaluating the efficacy, safety and tolerability of initial oral combination therapy with macitentan and tadalafil in patients with newly diagnosed pulmonary arterial hypertension (PAH). METHODS: Newly diagnosed, treatment-naive adult PAH patients in WHO functional class (WHO FC) II-III were enrolled. Treatment with macitentan 10 mg once daily (o.d.) and tadalafil 20 mg o.d. was initiated on the same day; after 8±3 days, tadalafil dose was increased to 40 mg o.d. Efficacy was assessed at Week 16 and, thereafter, patients continued to be monitored for safety until study closure by the sponsor. Patients with missing data at Week 16 were imputed with baseline values. RESULTS: 46 patients were enrolled and treated (all 46 are included in the efficacy and safety analyses). At Week 16, mean pulmonary vascular resistance (primary endpoint) was reduced by 47% compared with baseline (geometric mean ratio 0.53; 95% CI 0.47, 0.59; p2.5 L/min/m2, mean right atrial pressure 440 m, NT-proBNP 65%. The number of patients meeting at least 3 low-risk criteria increased from 11/46 (23.9%) patients at baseline to 30/44 (68.2%) at Week 16. Median (Q1, Q3) duration of exposure to macitentan and tadalafil was 605.5 days (371.0, 806.0). At least one adverse event (AE) was reported in 43 patients (93.5%), 13 patients (28.3%) reported serious AEs, 3 patients (6.5%) discontinued treatment due to AEs, and 3 patients died. Causes of death were cardiac arrest, heart failure, and multiorgan failure with sepsis. The most frequent AEs were peripheral edema (13 patients), headache (11 patients), diarrhea (9 patients), dyspnea (7 patients), anemia (6 patients) and asthenia (6 patients). Four patients had a decrease in hemoglobin below 10 g/dL and one patient had aminotransferases ≥3 times the upper limit of normal. CONCLUSIONS: In OPTIMA, initial macitentan and tadalafil combination therapy was well tolerated in patients with PAH, and led to hemodynamic improvement, as well as improvements in functional parameters and risk profile. CLINICAL IMPLICATIONS: Initial combination therapy with macitentan and tadalafil offers hemodynamic and functional benefits for patients with PAH. DISCLOSURES: No relevant relationships by Fabrice BAUER, source=Web Response Board Member relationship with Actelion Please note: $1001 - $5000 Added 03/27/2019 by Emmanuel Bergot, source=Admin input, value=Honoraria Speaker/Speaker's Bureau relationship with Boeringer Ingelheim Please note: $1001 - $5000 Added 03/27/2019 by Emmanuel Bergot, source=Admin input, value=Honoraria Board Member relationship with Roche Please note: $1001 - $5000 Added 03/27/2019 by Emmanuel Bergot, source=Admin input, value=Honoraria Speaker/Speaker's Bureau relationship with Novartis Please note: $1001 - $5000 Added 03/27/2019 by Emmanuel Bergot, source=Admin input, value=Honoraria Board Member relationship with Chiesr Please note: $1001 - $5000 Added 03/27/2019 by Emmanuel Bergot, source=Admin input, value=Honoraria Speaker/Speaker's Bureau relationship with Astra Zeneca Please note: $1001 - $5000 Added 03/27/2019 by Emmanuel Bergot, source=Admin input, value=Honoraria Speaker/Speaker's Bureau relationship with Actelion Please note: $1-$1000 Added 03/15/2019 by Matthieu Canuet, source=Admin input, value=Honoraria No relevant relationships by Pierre Clerson, source=Web Response Consultant relationship with Actelion Please note: $1001 - $5000 Added 03/17/2019 by Vincent Cottin, source=Web Response, value=Honoraria No relevant relationships by Bruno Degano, source=Web Response No relevant relationships by prevot gregoire, source=Admin input Employee relationship with Actelion Pharmaceuticals Ltd Please note: >$100000 Added 03/14/2019 by Virginie Gressin, source=Web Response, value=Salary Shareholder relationship with Idorsia Pharmaceuticals Ltd Please note: >$100000 Added 03/20/2019 by Virginie Gressin, source=Web Response, value=Shares Employee relationship with Actelion Pharmaceuticals Ltd Please note: >$100000 Added 03/12/2019 by Loic Perchenet, source=Web Response, value=Salary No relevant relationships by Francois Picard, source=Web Response Consultant relationship with Actelion, Please note: $1001 - $5000 Added 03/13/2019 by Gerald Simonneau, source=Web Response, value=Honoraria Consultant relationship with Bayer Please note: $1001 - $5000 Added 03/13/2019 by Gerald Simonneau, source=Web Response, value=Consulting fee Consultant relationship with MSD Please note: $1001 - $5000 Added 03/13/2019 by Gerald Simonneau, source=Web Response, value=Consulting fee Advisory Committee Member relationship with ARENA Please note: $1001 - $5000 Added 03/13/2019 by Gerald Simonneau, source=Web Response, value=Honoraria Consultant relationship with Actelion Please note: $5001 - $20000 Added 03/12/2019 by Olivier Sitbon, source=Web Response, value=Honoraria Consultant <br Consultant relationship with Bayer Please note: $1001 - $5000 Added 03/12/2019 by Olivier Sitbon, source=Web Response, value=Honoraria Consultant relationship with United Therapeutics Please note: $1-$1000 Added 03/12/2019 by Olivier Sitbon, source=Web Response, value=Honoraria

Right atrial function for the prediction of prognosis in connective tissue disease-associated pulmonary arterial hypertension: a study with two-dimensional speckle tracking.

Pulmonary arterial hypertension (PAH) is a serious and often fatal complication of connective tissue disease (CTD). Right atrial (RA) function is essential to maintaining adequate total right heart function in PAH. However, little is known about prognostic utility of RA function in CTD-PAH. RA longitudinal strain (LS) and strain rate (LSR) were evaluated in 53 consecutive patients (51 female, mean age 42 ± 15years) with CTD-PAH, including systemic lupus erythematosus (SLE) (33.7%), mixed connective tissue disease (MCTD) (32.1%), primary Sjögren's syndrome (pSS) (26.4%), and systemic sclerosis (SSc) (3.8%). At a mean follow-up of 19.3 ± 10.9months, 20 patients (37.7%) were clinically worse. The group with clinical events had worse clinical conditions and poorer RA function at baseline compared with the group that had no clinical events. RA LS independently reflected World Health Organization functional class (WHO FC) after adjusting for RA area (RAA), tricuspid regurgitation (TR) grade, right ventricular (RV) global longitudinal strain (GLS), and pulmonary vascular resistance (PVR) (P = 0.006). Receiver operator characteristic (ROC) curve analysis indicated that RA LS < 22.9% was predictive of clinical worsening during follow-up (sensitivity = 80%; specificity = 87.9%; area under the curve (AUC) = 0.858), and the Kaplan-Meier curve confirmed that RA LS ≥ 22.9% was associated with more favorable long-term outcomes compared to RA LS < 22.9% (log-rank P < 0.01). On univariate Cox proportional hazards analysis, PVR, RVGLS, RAA, and RA LS were associated with long-term outcome, while RA LS was the only independent predictor in the multivariate analysis. Our findings suggest that RA LS measurements by speckle-tracking echocardiography (STE) can independently reflect the extent of right heart failure and predict clinical outcomes in patients with CTD-PAH. RA LS < 22.9% is associated with a higher risk of clinical worsening.

Meaningful and feasible composite clinical worsening definitions in paediatric pulmonary arterial hypertension: An analysis of the TOPP registry

BackgroundComposite clinical worsening (cCW) outcomes might allow measurement of disease progression in paediatric pulmonary arterial hypertension (PAH). This TOPP registry analysis investigated three cCW outcomes and their predictive strength for lung transplantation/death. MethodsPatients ≤17 years with idiopathic/familial PAH or PAH-associated congenital heart disease diagnosed ≤3 months before enrolment were included. cCW outcomes included the following variables at enrolment and/or follow-up: all-cause death, PAH-related hospitalisation, lung transplantation, atrial septostomy (cCW1, 2 and 3), WHO FC deterioration, intravenous/subcutaneous prostanoids initiation, syncope (cCW2,3) and occurrence/worsening of ≥2 PAH symptoms (cCW3). The predictive value of CW (excluding transplantation and death) to transplantation or death was assessed. Predictive values of each cCW for lung transplantation/death were analysed by Cox proportional hazards models. ResultsFrom 255 patients, first-event rate/100 person-years (95% CI) were cCW1: 23.1(19.3,27.6), cCW2: 43.6(37.6,50.6), and cCW3: 46.3(40.0,53.7) with PAH-related hospitalisation as the most frequent first event in each. The cCW definitions comprised from endpoints (excluding transplantation and death), were associated with higher risk [hazard ratio (95% CI)] for lung transplantation/death [4.23(2.27,7.91), 3.25(1.65,6.39), 2.74(1.41,5.34), respectively]; individual parameters with higher risks were WHO FC deterioration [3.49(1.47,8.29)], PAH-related hospitalisation [2.62(1.32,5.20)] and occurrence/worsening of ≥2 PAH symptoms [2.13(1.02,4.45)]. ConclusionsThese data support the use of cCW outcomes in paediatric PAH research. WHO FC deterioration, PAH-related hospitalisation, occurrence/worsening of ≥2 PAH symptoms may be important for risk assessment during clinical management.