Purpose: Patients with heterotaxy syndrome have a high rate of congenital heart disease, often requiring surgical interventions, including palliative procedures to augment or restrict pulmonary blood flow.Pulmonary hypertension in this setting complicates surgical interventions and overall management.Pulmonary vasodilators may be used to treat pulmonary hypertension and facilitate surgical interventions.We describe the use of pulmonary vasodilators in patients with heterotaxy syndrome.Methods: Single-center retrospective chart review of patients with heterotaxy syndrome who underwent at least one cardiac operation from Jan 1 2008 to Oct 31 2019.The diagnosis of heterotaxy syndrome was established from imaging studies performed prior to intervention.Surgical interventions were reviewed from operative reports.Pulmonary vasodilator use was assessed from progress notes and medication reconciliation at all inpatient and outpatient encounters.Results: Thirty-four patients with heterotaxy syndrome were treated at our center during the study period, with follow up ranging from 18 to 3385 days.Palliative surgical interventions included restriction of pulmonary blood flow in 8 patients and augmentation of pulmonary blood flow in 11 patients.Pulmonary vasodilators were used in 16 patients (47%): 7 (20%) received inhaled nitric oxide while admitted, 3 (9%) received supplemental oxygen as outpatients, 12 (35%) received sildenafil as outpatients, 5 (14%) received multiple agents.Treatment was initiated in the inpatient setting in all patients.All patients on supplemental oxygen and the majority of patients on sildenafil continued on treatment at most recent follow up (10 patients, 83% of patients ever prescribed).There was no difference in pulmonary vasodilator use when stratified by surgical palliation strategy, and no differences in survival between patients with and without pulmonary vasodilator use.Conclusion: Pulmonary vasodilator use is common in patients with heterotaxy syndrome undergoing surgical interventions for congenital heart disease.It is typically initiated in the inpatient setting but well-tolerated on a long-term basis, and may facilitate treatment in this challenging population.

Most pulmonary arterial hypertension (PAH) in Indonesia is associated with uncorrected congenital heart disease (CHD). Other type of PAH has not been reported from Indonesia, despite current availability of PAH-specific medication. The aim of this study is to describe the characteristics of nonCHD-associated PAH and its mortality. We had established the COHARD-PH registry which is a prospective singlecenter study enrolling adult patients with CHD-associated PAH. We also enrolled and followed subjects with nonCHD-PAH into separate cohort. Layers of diagnostic procedures were performed from echocardiography, HRCT thorax, MSCT pulmonary angiography and right heart catheterization (RHC). The baseline data were collected during the index of diagnosis of PH probability by echocardiography. The RHC was performed to diagnose PAH. Subjects were followed up during their visit to our PH clinic. Sixty-three patients were enrolled, 57 (90.5%) were idiopathic/hereditary PAH (I/H-PAH), five (7.9%) connective tissue disease-associated PAH (CTD-PAH) and one portopulmonary PAH (po-PAH). Most subjects were young females (I/H-PAH 82.5%, 39.0 14.0 years and CTDPAH 80.0%, 41.2 6.3 years). Most subjects had WHO functional class II. The RHC was performed in 26 I/H-PAH subjects, with mean mPAP 62.3 18.7mmHg and PVRi 29.2 14.0 WU. m. Most treatment was sildenafil monotherapy (71%) and sildenafilþberaprost combination (12.7%). During follow-up, 12 (19.1%) subjects died. Those who died were younger (32.6 10.8 years vs. 41.1 13.7 years, p< 0.05). Subjects with CTD-PAH had the highest mortality rate (two subjects (40%) and I/H-PAH had 15.8% mortality rate (nine subjects)). The only poPAH subject died during follow-up. Among I/H-PAH and CTD-PAH, higher right atrial diameter by echocardiography significantly associated with mortality. In I/H-PAH, mortality had tendency toward higher mPAP and PVRi. In conclusion, among non CHD-associated PAH, CTD-PAH had worse outcome as compared with I/H-PAH. Younger age and higher right atrial diameter by echocardiography were significantly associated with mortality in I/H-PAH and CTD-PAH.

Abstract Background The REPLACE study investigated the effect of switching to riociguat (RIO) in patients with pulmonary arterial hypertension receiving PDE5i but still at intermediate risk. The centrally adjudicated composite primary endpoint was clinical improvement in the absence of clinical worsening, where clinical improvement was defined as meeting at least two of the following criteria: 6-minute walk distance (6MWD), increase by ≥10% or ≥30 m from baseline (BL) to Wk 24; World Health Organization functional class (WHO FC) I or II at Wk 24; or N-terminal prohormone of brain natriuretic peptide reduction of ≥30% from BL to Wk 24. Twice as many patients switching to RIO (45/111, 41%) met the primary endpoint compared with those remaining on PDE5i (23/113, 20%); odds ratio (OR): 2.78 (95% confidence interval [CI] 1.53–5.06); p=0.0007. Purpose Assess changes in right and left ventricular (RV; LV) function using cardiac magnetic resonance imaging (cMRI) in a subgroup of patients participating in REPLACE. Methods REPLACE was a randomised, open-label, 24-week, Phase 4 study (NCT02891850). Patients in WHO FC III, with 6MWD 165–440 m, were randomised to switch to RIO 2.5 mg–max tid or remain on PDE5i. Background endothelin receptor antagonist therapy was permitted in both arms. cMRI was performed on a subset of patients from the full analysis set as an exploratory substudy. The following parameters were measured at BL and Wk 24: RV and LV end-diastolic and end-systolic volumes (RVEDV; RVESV; LVEDV; LVESV), RV stroke volume and stroke volume index (RVSV; RVSVI), LV stroke volume (LVSV), RV ejection fraction (RVEF), and pericardial effusion. Results Twenty-seven patients participated in the cMRI substudy. This comprised 11/111 (10%) patients in the RIO arm (mean [standard deviation {SD}] 40.0 [12.4] years), and 16/113 (14%) patients (mean 44.5 [17.6] years) in the PDE5i arm. Like the main population, the treatment response in the cMRI subpopulation favoured RIO versus PDE5i (OR: 6.11 [95% CI 0.90–41.60]). From BL to Wk 24, RVEDV and RVESV decreased in the RIO treatment arm but increased in the PDE5i treatment arm (Table 1). Similar, but less pronounced, changes were observed for the left ventricle (LVESV, LVEDV). RVSV and RVEF levels were close to normal at BL and did not increase in either arm at Wk 24 (Table 1). Pericardial effusion, which was present in 5 patients in each group at BL, decreased in 1 patient in the RIO arm and no patients in the PDE5i arm. Conclusions Decreases in RVEDV and RVESV suggest improvements in cardiac function in the RIO arm compared with the PDE5i arm. Values for RVEF and RVSVI were close to normal at BL and did not change at Wk 24. Improvements in cMRI parameters were in line with the clinical improvement observed in patients switching to RIO in the overall population. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): The REPLACE study was co-funded by Bayer AG (Berlin, Germany) and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Kenilworth, NJ, USA)

A proportion of patients with PAH have an insufficient response to phosphodiesterase-5 inhibitors (PDE5i) and do not reach treatment goals. Efficacy of PAH therapies has been assessed by functional measures such as 6MWD and WHO FC. However, mortality in PAH is usually related to RV failure. In the open-label RESPITE study, patients who switched from PDE5i to the soluble guanylate cyclase stimulator riociguat experienced improvements in 6MWD, WHO FC and NT-proBNP, and also hemodynamic parameters such as PVR and cardiac index. We performed a post hoc analysis of hemodynamic parameters to determine if switch to riociguat improved parameters of right ventricular function in patients with an insufficient response to PDE5i.

BACKGROUND:Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, debilitating, and life-threatening disease. We investigated associations between markers of disease severity and long-term outcomes in patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy (PEA) who were receiving the soluble guanylate cyclase stimulator riociguat. We also present safety and efficacy from the final data cutoff of CHEST-2, where most patients had received riociguat for at least 2 years.METHODS:Eligible patients from the CHEST-1 study entered the CHEST-2 open-label extension study, in which all patients received riociguat individually adjusted to a maximum dose of 2·5 mg three times per day. The primary endpoint was safety and tolerability. We did exploratory assessments of associations between markers of disease severity (6-min walking distance [6MWD], N-terminal prohormone of brain natriuretic peptide [NT-proBNP] concentration, and WHO functional class) at baseline and follow-up with overall survival and clinical worsening-free survival. We used Kaplan-Meier and Cox proportional hazards analyses. CHEST-2 is registered at ClinicalTrials.gov, number NCT00910429.FINDINGS:237 patients entered CHEST-2. At 2 years, overall survival was 93% (95% CI 89-96) and clinical worsening-free survival was 82% (77-87). A significant association with overall survival was seen for 6MWD and NT-proBNP concentration at baseline (p=0·0199 and p=0·0183, respectively) and at follow-up (p=0·0385 and p=0·0068, respectively). Change from baseline in 6MWD was also significantly associated with survival (p=0·0047). WHO functional class at baseline and follow-up showed no significant association with overall survival but was associated with clinical worsening-free survival. Riociguat was well tolerated by most patients and no new safety signals were identified. Serious adverse events were seen in 129 (54%) of 237 patients, and 14 (6%) discontinued riociguat therapy because of adverse events.INTERPRETATION:Riociguat may be used long term in patients with CTEPH. 6MWD and NT-proBNP concentration are good prognostic markers.FUNDING:Bayer Pharma AG.

Background PAH associated with CTD (PAH-CTD) has a worse prognosis than idiopathic/familial PAH (IPAH). Objectives Here we report a prospective subgroup analysis of patients (pts) with PAH-CTD from the PATENT studies of the soluble guanylate cyclase stimulator, riociguat. Methods PATENT-1 was a 12-wk, randomized Phase III trial in which pts with PAH received either riociguat individually dose-adjusted up to 2.5 mg tid (2.5 mg–maximum group), riociguat up to 1.5 mg tid (1.5 mg–maximum group; exploratory), or placebo (pbo). The primary endpoint was change from baseline in 6-minute walking distance (6MWD). Long-term safety and survival were assessed during the PATENT-2 open-label extension. Results In PATENT-1, 111 pts had PAH-CTD (systemic sclerosis [SSc; n=66, including diffuse SSc and limited SSc] non-SSc CTD [n=39], and unspecified CTD [n=6], derived from the medical history using MedDRA preferred terms). Of the overall group of PAH-CTD pts, 71, 15, and 25 were randomized to riociguat 2.5 mg–maximum, riociguat 1.5 mg–maximum, and pbo, respectively. At baseline, mean ± SD 6MWD was 348±70 m in the riociguat 2.5 mg–maximum group and 361±88 m in the pbo group versus 363±69 m in the overall PAH population. At Wk 12, there was an improvement in 6MWD in the 2.5 mg–maximum riociguat group (+18 m) and a deterioration in the pbo group (–8 m) (Figure 1a; PAH-CTD population; intention-to-treat [ITT], imputed values). Consistent with other studies, the least-squares mean treatment difference between riociguat and pbo (+28 m) was lower than that observed in the overall study population (+36 m). No pts in the riociguat 2.5 mg–maximum group required additional PAH therapy during PATENT-1, compared with 2 pts in the pbo group. At the March 2014 cut-off for PATENT-2, 70 pts with PAH-CTD had been receiving treatment for ≥2 yrs. Figure 1b shows change in 6MWD during PATENT-2 in pts with PAH-CTD. At 2 yrs, mean ± SD 6MWD had increased from PATENT-1 baseline by 25±82 m in pts with PAH-CTD versus 47±85 m in the overall population (ITT; observed values). Survival rates at 1 yr in pts with PAH-CTD, IPAH, and the overall population were 97% (95% CI: 90–99%), 98% (95% CI: 95–99%), and 97% (95% CI: 95–98%), respectively. Survival rates at 2 yrs were 93% in all cohorts (95% CI: 85–97%, 89–96%, and 90–95%, respectively). Riociguat had a similar safety profile in pts with PAH-CTD as observed in the overall population. Conclusions In pts with PAH-CTD, riociguat was associated with long-term improvements in exercise capacity. The 1- and 2-yr survival rates in riociguat-treated pts with PAH-CTD were high and similar to pts with IPAH. Disclosure of Interest C. Denton Consultant for: Bayer, Speakers bureau: Novertis, Pfizer, J. Coghlan: None declared, H.-A. Ghofrani Consultant for: Novertis, Pfizer, Speakers bureau: Novertis, Pfizer, F. Grimminger: None declared, J. He: None declared, G. Riemekasten Consultant for: Bayer, Speakers bureau: Bayer, C. Vizza Grant/research support from: Bayer, Actelion, GSK, Novartis, Gilead, Consultant for: Bayer, Actelion, GSK, Utel, A. Boeckenhoff Employee of: Bayer Pharma AG, C. Meier Employee of: Bayer Pharma AG, S. Nikkho Employee of: Bayer Pharma AG, J. Pena Employee of: Bayer Pharma AG, M. Humbert Consultant for: Novartis, Pfizer, GSK, Actelion, Bayer, Speakers bureau: Novartis, Pfizer, GSK, Actelion, Bayer