Incident Pulmonary Arterial Hypertension Research Articles

Right ventricular phenotyping in incident patients with idiopathic pulmonary arterial hypertension

BackgroundRight ventricular (RV) imaging has not a definite role in risk stratification of pulmonary arterial hypertension (PAH) patients. We tested the hypothesis that echocardiography-derived phenotypes, depicting different degrees of RV remodeling and dysfunction, may provide additional prognostic information to current risk stratification tools. MethodsConsecutive incident PAH patients aged ≥ 18 years, diagnosed between January 2005 and December 2021, underwent clinical assessment, right heart catheterization, standard echocardiography. Simple echocardiographic variables were combined in order to define a priori four phenotypes representing different degrees of RV dilatation and RV-pulmonary arterial (PA) coupling: Phenotype 1 with mildy dilated right ventricle and preserved RV-PA coupling (n=152 patients); phenotype 2 with mildly dilated right ventricle and poor RV-PA coupling (n=143 patients); phenotype 3 with severely dilated right ventricle and preserved RV-PA coupling (n=201 patients); phenotype 4 with severely dilated right ventricle and poor RV-PA coupling, with or without severe tricuspid regurgitation (n=519 patients). Risk stratification was based on on the ESC/ERS 3-strata model and REVEAL 2.0 score. ResultsThese phenotypes were present in all risk groups. Notably, regardless of the ESC/ERS risk stratum assigned to the patient, phenotype 4 was associated with a 2-fold increase of the odds of death (HR 2.1, 95% C.I. 1.6-2.8, p<0.001), while phenotype 1 was associated with a 71% reduction in the odds of dying (HR 0.29, 95% C.I. 0.18-0.47, p<0.001). ConclusionsEchocardiography-derived phenotypes describing RV remodeling and dysfunction may provide prognostic information which is independent of and additional to the clinically defined risk in incident PAH patients.

Characteristics and outcomes of patients developing pulmonary hypertension associated with proteasome inhibitors.

Pulmonary arterial hypertension (PAH) has been described in patients treated with proteasome inhibitors (PIs). Our objective was to evaluate the association between PIs and PAH. Characteristics of incident PAH cases previously treated with carfilzomib or bortezomib were analysed from the French pulmonary hypertension registry and the VIGIAPATH programme from 2004 to 2023, concurrently with a pharmacovigilance disproportionality analysis using the World Health Organization (WHO) global database (VigiBase) and a meta-analysis of randomised controlled trials. 11 incident cases of PI-associated PAH were identified (six with carfilzomib and five with bortezomib) with a female:male ratio of 2.7:1, a median age of 61 years, and a median delay between PI first exposure and PAH of 6 months. Four patients died (two from right heart failure, one from respiratory distress and one from an unknown cause). At diagnosis, six were in New York Heart Association Functional Class III/IV with severe haemodynamic impairment (median mean pulmonary arterial pressure 39 mmHg, cardiac index 2.45 L·min-1·m-2 and pulmonary vascular resistance 7.2 WU). In the WHO pharmacovigilance database, 169 cases of PH associated with PI were reported since 2013 with significant signals of disproportionate reporting (SDR) for carfilzomib, regardless of the definition of cases or control group. However, SDR for bortezomib were inconsistent. The systematic review identified 17 clinical trials, and carfilzomib was associated with a significantly higher risk of dyspnoea, severe dyspnoea and PH compared with bortezomib. PIs may induce PAH in patients undergoing treatment, with carfilzomib emitting a stronger signal than bortezomib, and these patients should be monitored closely.

Frequency, characteristics and risk assessment of pulmonary arterial hypertension with a left heart disease phenotype.

To obtain real-world evidence about the features and risk stratification of pulmonary arterial hypertension (PAH) with a left heart disease (LHD) phenotype (PAH-LHD). By reviewing the records of consecutive incident PAH patients at 7 tertiary centers from 2001 to 2021, we selected 286 subjects with all parameters needed to determine risk of death at baseline and at first follow-up with COMPERA and COMPERA 2.0 scores. Fifty seven (20%) had PAH-LHD according to the AMBITION definition. Compared with no-LHD ones, they were older, had higher BMI, more cardiovascular comorbidities, higher E/e' ratio and left atrial area, but lower BNP concentrations and better right ventricular function and pulmonary hemodynamics. Survival was comparable between PAH-LHD and no-LHD patients, although the former were less commonly treated with dual PAH therapy. Both COMPERA and COMPERA 2.0 discriminated all-cause mortality risk of PAH-LHD at follow-up, but not at baseline. Risk profile significantly improved during follow-up only when assessed by COMPERA 2.0. At multivariable analysis with low-risk status as reference, intermediate-high and high-risk, but not LHD phenotype, were associated with higher hazard of all-cause mortality. Results were comparable in secondary analyses including patients in the last 10years and atrial fibrillation and echocardiographic abnormalities as additional criteria for PAH-LHD. In real life, PAH-LHD patients are frequent, have less severe disease and are less likely treated with PAH drug combinations than no-LHD. TheCOMPERA 2.0 model may be more appropriate to evaluate their mortality risk during follow-up and how it is modulated by therapy.

Impact of Left Heart Disease Risk Factors on Outcomes in Pulmonary Arterial Hypertension Therapy

BackgroundCurrent guidelines recommend initial monotherapy for pulmonary arterial hypertension (PAH) with ‘cardiopulmonary comorbidities’, despite limited available evidence to guide management. Research QuestionDo left heart disease (LHD) risk factors have an impact on treatment response and influence applicability of risk assessment in a real-world cohort of PAH patients? Study Design and MethodsThe AMBITION trial criteria was used to define the phenotype of PAH patients with risk factors for LHD. Treatment strategy, functional outcome, long term survival and risk discrimination were compared with a reference PAH cohort using the PHSANZ registry. Results487 incident PAH patients diagnosed between 2011-2020 were included. Of these, 103 (21.1%) fulfilled the definition of PAH with LHD risk factors with 384 (78.9%) remaining as reference group. PAH with LHD risk factors were older (66±13 vs. 58±19years, p<0.001), had lower pulmonary vascular resistance (393±266 vs 708±391dynes/sec/cm-5, p=0.031) and worse 6-minute walk distance (286±130 vs. 327±136m, p=0.005) at diagnosis. PAH with LHD risk factors were less likely to receive less initial combination therapy (27% vs. 44%, p=0.02). Changes in 6-minute walk distance at 12-months were similar in both groups, 43±77 in PAH with LHD risk factors and 50±90m in reference group (p=0.5), including when stratified by initial treatment strategy (monotherapy: 40±81 vs. 38±95m p=0.87 and combination therapy: 53±78 vs. 64±106m, p=0.511; PAH with LHD risk factors vs. reference PAH). Functional class improvements were also similar in both groups. REVEAL 2.0 risk score effectively discriminated risk in both populations (C-statistic=0.756 for PAH with LHD risk factors and C-statistic=0.750 for reference PAH). There was no difference in survival between the two groups (log-rank test p=0.29). InterpretationIn a real-word cohort, PAH patients with LHD risk factors were less likely to be exposed to initial combination therapy. Nevertheless, selected PAH patients with LHD risk factors who were treated with initial combination therapy derived similar functional response compared to reference group. Further studies are needed to phenotype PAH patients with cardiopulmonary comorbidities who may benefit from initial combination therapy.

Triple therapy for incident pulmonary arterial hypertension in Finland between 2008 and 2020. A descriptive real-world FINPAH cohort study

Abstract Background Treatment of pulmonary arterial hypertension (PAH) with triple therapy (TriT) including phosphodiesterase type-5 inhibitors (PDE5), endothelin receptor antagonists (ERA), and prostacyclin receptor agonists (PRA) or analogues (PCA) is indicated in severe PAH. There is evidence of benefit also in intermediate-risk patients. Purpose To describe the real-world use of TriT in a contemporary cohort of Finnish PAH patients. Methods Data was collected via chart review by treating clinicians. Pulmonary hypertension (PH) patients were diagnosed between 2008–19 at the five Finnish university hospitals. Patient characteristics and clinical information were combined with mortality data from Statistics Finland. Persistence and survival were estimated using Kaplan-Meier. Results Out of 493 incident PH patients with medication history available, TriT was recorded for 41 (8%), with a median follow-up of 5.86 years (IQR: 4.12-8.72). TriT patients were predominantly women (73%), mean age 55 years (IQR 46–69) at diagnosis. 35 patients (85%) had PAH (37% iPAH, 27% PAH associated with connective tissue disease and 22% other PAH subclasses), and 6 patients (15%) had other PH types, mostly CTEPH. TriT was started at a median of 2.15 years (IQR: 0.65-3.64) after diagnosis. At the initiation of TriT, 7 patients (17%) had NYHA functional class (FC) IV, 21 (51%) had FC III, 8 (20%) had FC II. Median six-minute walking distance (6MWD) was 360 m (IQR 245-435 m, N=33). Median BNP was 328 pg/mL (IQR 190-723, N=10), and median NT-proBNP was 1082 pg/mL (IQR 745-3420, N=31). Fewer than 3 patients (&amp;lt;7%) were at ESC/ERS 2015 high risk. Initial PRA or PCA in TriT was iloprost (n=21, 51%), selexipag (n=12, 29%), or treprostinil (n=8, 20%). Initial ERA in TriT was macitentan (n=20, 49%), bosentan (n=11, 27%), or ambrisentan (n=10, 24%). Initial PDE5 was sildenafil (n=36, 88%) or tadalafil (n=5, 12%). Estimated persistence with TriT was 88% at 1 year and 84% at 5 years. Selexipag and iloprost were discontinued in &amp;lt;3 (&amp;lt;25% of users) and in 12 (57% of users), respectively, and 10 patients (24%) were switched to treprostinil. 6 TriT patients were listed for lung transplant after start of TriT, and 4 received a lung transplant. Six months after start of TriT, 4 patients (10%) had died and 5 (12%) had discontinued TriT. For the patients with 6 months of recorded TriT use (N=31), NT-proBNP changed by median -184 pg/mL (IQR -689 to +165, N=24), and 6MWD changed by median +20 m (IQR -3 to +35, N=22). In 8 patients (30%) FC improved within 6 months of TriT, was stable in 15 patients (56%) and worsened in 4 patients (15%). After 6 months of TriT, no patient was at high risk. Estimated overall survival was 90% (95%-CI 82-100%) at 6 months and 1 year after start of TriT. Estimated 5-year survival was 52% (95%-CI 38-72%). Conclusion(s) The study shows infrequent use but high persistence of TriT in Finnish PAH patients. TriT patients remained generally stable while on TriT.

Association Between the Pulmonary Artery Pulsatility Index and Prognosis in Pulmonary Arterial Hypertension: A Multicentre Study

BackgroundRisk stratification is fundamental in the management of pulmonary arterial hypertension (PAH). Pulmonary artery pulsatility index (PAPi), defined as pulmonary arterial pulse pressure divided by right atrial pressure (RAP), is a hemodynamic index shown to predict acute right ventricular (RV) dysfunction in several settings. Our objective was to test the prognostic utility of PAPi in a diverse multicentre cohort of patients with PAH. MethodsA multicentre retrospective cohort study of consecutive adult patients with a new diagnosis of PAH on right heart catheterization between January 2016 and December 2020 was undertaken across 4 major centres in Canada. Hemodynamic data, clinical data, and outcomes were collected. The association of PAPi and other hemodynamic variables with mortality was assessed by receiver-operating characteristic curves and Cox proportional hazards modeling. ResultsWe identified 590 patients with a mean age of 61.4 ± 15.5 years, with 66.3% being female. A low PAPi (defined as < 5.3) was associated with higher mortality at 1 year: 10.2% vs 5.2% (P = 0.02). In a multivariable model including age, sex, body mass index, and functional class, a low PAPi was associated with mortality at 1 year (area under the curveof 0.64 (95% confidence interval 0.55-0.74). However, high RAP (> 8 mm Hg) was similarly predictive of mortality, with an area under the curve of 0.65. ConclusionPAPi was associated with mortality in a large incident PAH cohort. However, the discriminative value of PAPi was not higher than that of RAP alone.

Residual risk identified in routine noninvasive follow-up assessments in pulmonary arterial hypertension.

The 2022 ESC/ERS guidelines on pulmonary hypertension recommend noninvasive risk assessments based on three clinical variables during follow-up in patients with pulmonary arterial hypertension (PAH). We set out to test whether residual risk can be captured from routinely measured noninvasive clinical variables during follow-up in PAH. We retrospectively studied 298 incident PAH patients from a German pulmonary hypertension centre who underwent routine noninvasive follow-up assessments including exercise testing, echocardiography, electrocardiography, pulmonary function testing and biochemistry. To select variables, we used least absolute shrinkage and selection operator (LASSO)-regularised Cox regression models. Outcome was defined as mortality or lung transplant after first follow-up assessment. 12 noninvasive variables that were associated with outcomes in a training sub-cohort (n=208) after correction for multiple testing entered LASSO modelling. A model combining seven variables discriminated 1-year (area under the curve (AUC) 0.83, 95% confidence interval (CI) 0.68-0.99, p=8.4×10-6) and 3-year (AUC 0.81, 95% CI 0.70-0.92, p=2.9×10-8) outcome status in a replication sub-cohort (n=90). The model's discriminatory ability was comparable to that of the guideline approach in the replication sub-cohort. From the individual model components, World Health Organization functional class, 6-min walking distance and the tricuspid annular plane systolic excursion to systolic pulmonary arterial pressure (TAPSE/sPAP) ratio were sensitive to treatment initiation. Addition of TAPSE/sPAP ratio to the guideline approach numerically increased its ability to discriminate outcome status. Our real-world data suggest that residual risk can be captured by noninvasive clinical procedures during routine follow-up assessments in patients with PAH and highlights the potential use of echocardiographic imaging to refine risk assessment.

Evaluation of the European Society of Cardiology/European Respiratory Society derived three- and four-strata risk stratification models in pulmonary arterial hypertension: introducing an internet-based risk stratification calculator.

Estimation of prognosis in pulmonary arterial hypertension (PAH) has been influenced by that various risk stratification models use different numbers of prognostic parameters, as well as the lack of a comprehensive and time-saving risk assessment calculator. We therefore evaluated the various European Society of Cardiology (ESC)-/European Respiratory Society (ERS)-based three- and four-strata risk stratification models and established a comprehensive internet-based calculator to facilitate risk assessment. Between 1 January 2000 and 26 July 2021, 773 clinical assessments on 169 incident PAH patients were evaluated at diagnosis and follow-ups. Risk scores were calculated using the original Swedish Pulmonary Arterial Hypertension Registry (SPAHR)/Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) three-strata model, the updated SPAHR three-strata model with divided intermediate risk, and the simplified three-parameter COMPERA 2.0 four-strata model. The original SPAHR/COMPERA and the updated SPAHR models were tested for both 3-6 and 7-11 available parameters, respectively. Prognostic accuracy [area under the receiver operating characteristic (ROC) curve (AUC)] and Uno's cumulative/time-dependent C-statistics (uAUC) were calculated for 1-, 3-, and 5-year mortality. At baseline, both the original SPAHR/COMPERA and the updated SPAHR models, using up to six parameters, provided the highest accuracy (uAUC = 0.73 for both models) in predicting 1-, 3-, and 5-year mortality. At follow-ups, the updated SPAHR model with divided intermediate risk (7-11 parameters) provided the highest accuracy for 1-, 3-, and 5-year mortality (uAUC = 0.90), followed by the original SPAHR/COMPERA model (7-11 parameters) (uAUC = 0.88) and the COMPERA 2.0 model (uAUC = 0.85). The present study facilitates risk assessment in PAH by introducing a comprehensive internet-based risk score calculator (https://www.svefph.se/risk-stratification). At baseline, utilizing the original or the updated SPAHR models using up to six parameters was favourable, the latter model additionally offering sub-characterization of the intermediate risk group. Our findings support the 2022 ESC/ERS pulmonary hypertension guidelines' strategy for risk stratification suggesting the utilization of a three-strata model at baseline and a simplified four-strata model at follow-ups. Our findings furthermore support the utility of the updated SPAHR model with divided intermediate risk, when a more comprehensive assessment is needed at follow-ups, complementing the three-parameter COMPERA 2.0 model. Larger multi-centre studies are encouraged to validate the utility of the updated SPAHR model. By introducing an internet-based risk score calculator (https://www.svefph.se/risk-stratification), risk assessment is facilitated. Our results support the 2022 ESC/ERS pulmonary hypertension guidelines' risk stratification strategy, additionally suggesting the updated SPAHR three-strata model with divided intermediate risk, as a promising complement to the new simplified three-parameter COMPERA 2.0 four-strata strategy, when a more comprehensive overview is needed.

Interest of TAPSE/sPAP ratio for noninvasive pulmonary arterial hypertension risk assessment.

Although ventriculoarterial coupling is associated with better survival in pulmonary arterial hypertension (PAH), existing PAH risk assessment method has not considered echocardiographic criteria of right ventricular to pulmonary artery coupling. We aimed to test the prognostic value of the echocardiographic tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (TAPSE/sPAP) ratio for noninvasive PAH risk assessment. We retrospectively studied a cohort of 659 incident PAH patients from 4 independent French PH centers (training cohort: n=306, validation cohort n=353) who underwent follow-up TAPSE/sPAP measurement in addition to previously validated noninvasive risk stratification variables. The primary composite outcome was 3-year all-cause mortality or lung transplantation from re-evaluation. Mean age was 55 ± 17 years-old with a majority of female (66%). The three main PAH causes were connective tissue disease (26%), idiopathic (24%) and porto-pulmonary (19%). The primary composite outcome occurred in 71 (23%) patients. Multivariable Cox regression analysis retained 3 noninvasive low-risk criteria as associated with the primary composite outcome: NYHA I-II (p=0.001), NTproBNP <300 ng/L or BNP <50 ng/L (p=0.004), and TAPSE/sPAP >0.33 mm/mmHg (p=0.004). The more the low-risk criteria achieved at follow-up, the better the event-free survival both in the training and validation cohort (log-rank p < 0.001). In the training cohort, the c-index for these 3 criteria, for COMPERA 2.0 and for the noninvasive French Pulmonary Hypertension Network method were 0.75, 95%CI(0.70-0.82), 0.72 95%CI(0.66-0.75), 0.71 95%CI(0.62-0.73), respectively. The 3 following dichotomized low-risk criteria: TAPSE/sPAP >0.33 mm/mmHg, NYHA I-II and NTproBNP <300 ng/L or BNP <50 ng/L allow to identify low-risk PAH patients at follow-up.

Socioeconomically disadvantaged veterans experience treatment delays for pulmonary arterial hypertension.

Prompt initiation of therapy after pulmonary arterial hypertension (PAH) diagnosis is critical to improve outcomes; yet delays in PAH treatment are common. Prior research demonstrates that individuals with PAH belonging to socially disadvantaged groups experience worse clinical outcomes. Whether these poor outcomes are mediated by delays in care or other factors is incompletely understood. We sought to examine the association between race/ethnicity and socioeconomic status and time-to-PAH treatment. We conducted a retrospective cohort study of Veterans diagnosed with incident PAH between 2006 and 2019 and treated with PAH therapy. Our outcome was time-to-PAH treatment. Our primary exposures were race/ethnicity, annual household income, health insurance status, education, and housing insecurity. We calculated time-to-treatment using multivariable mixed-effects Cox proportional hazard models. Of 1827 Veterans with PAH, 27% were Black, 4% were Hispanic, 22.1% had an income < $20,000, 53.3% lacked non-VA insurance, 25.5% had <high school education, and 3.9% had housing insecurity. Median time-to-treatment was 114 days (interquartile range [IQR] 21-336). Our multivariable models demonstrated increased time-to-treatment among patients with lower household income (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.60-0.91 for < $20,000 vs. ≥ $100,000) and those without non-VA insurance (HR 0.90, 95% CI 0.82-1.00). Race/ethnicity, education, and housing insecurity were not associated with time-to-treatment. Veterans with PAH experienced substantial and potentially harmful treatment delays, with median time-to-treatment of 16 weeks after diagnosis. Those with lower income and those without non-VA health insurance experienced even greater treatment delays. Additional research is urgently needed to develop interventions to improve timely PAH treatment and mitigate economic disparities in treatment.

The direct and indirect health care costs associated with pulmonary arterial hypertension among commercially insured patients in the United States.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare, progressive, and fatal disease associated with considerable overall clinical and economic burden. Although the direct health care costs of PAH have been well described, there are few data regarding indirect costs and productivity loss associated with PAH. Patient data were assessed until the earliest of death, end of full-time employment, end of continuous enrollment, or end of study period. OBJECTIVES: To update data on the direct burden and address the knowledge gap regarding the indirect burden associated with PAH. METHODS: This is a retrospective case-control study with prevalent and incident patients with PAH aged 18-64 years identified from the MarketScan Commercial and Health and Productivity management datasets during the identification period (January 1, 2016, to November 30, 2018). Patients were required to have continuous enrollment for 12 months or longer from the baseline period and 1 month or longer from the follow-up (post-index) period. Among patients with PAH (cases), the first observed PAH diagnosis claim date during the identification period was the index date. Patients without PAH (controls) were selected and assigned a random index date during the same period. Controls were matched 1:1 by age, sex, and region to prevalent and incident PAH cases. Per patient per month (PPPM), all-cause health care resource utilization, costs, and short-term disability (STD) were examined for cases and controls during the follow-up period. Multivariable analysis was performed using the generalized linear model to determine the adjusted direct and indirect health care utilization and costs. RESULTS: A total of 1,293 prevalent and 455 incident patients with PAH were identified. During the follow-up period, prevalent patients with PAH had significantly higher total mean all-cause health care costs ($9,915 vs $359, P < 0.0001) and inpatient length of stay (0.63 vs 0.02 days, P < 0.0001) PPPM as compared with controls. Prevalent patients with PAH had significantly longer STD (6.0 vs 1.5 days, P < 0.0001) and higher STD-related costs ($1,226 vs $277, P < 0.0001) PPPM as compared with controls. Incident patients with PAH had significantly higher total mean all-cause health care costs ($9,353 vs $336, P < 0.0001) and inpatient length of stay (0.92 vs 0.01 days, P < 0.0001) PPPM as compared with controls. Incident patients with PAH also had longer STD (8.1 vs 1.5 days, P < 0.0001) and higher STD-related costs ($1,706 vs $263, P < 0.0001), as compared with controls. CONCLUSIONS: This study showed that incident and prevalent patients with PAH had significantly higher direct and indirect health care resource utilization and costs as well as productivity loss compared with patients without PAH. DISCLOSURES: Ms Ogbomo and Mr Mallampati were paid employees of STATinMED Research at the time of study completion; STATinMED Research is a paid consultant to Janssen Scientific Affairs, LLC. Drs Tsang and Panjabi are employees of Janssen Scientific Affairs LLC, a subsidiary of Johnson and Johnson, the study sponsor.

Time-Velocity Integral of Left Ventricular Outflow Tract Predicts Worse Long-Term Survival in Pulmonary Arterial Hypertension

BackgroundThe time-velocity integral of the left ventricular outflow tract (TVILVOT) has been demonstrated to correlate with heart failure hospitalization and mortality, but the association of TVILVOT with the severity and prognosis of pulmonary arterial hypertension (PAH) has not been evaluated. ObjectivesThe aim of this study was to investigate the predictive value of baseline TVILVOT in PAH. MethodsA total of 225 consecutive patients with a diagnosis of incident PAH were prospectively studied and echocardiology-derived TVILVOT was measured at enrollment followed by right heart catheterization examination within 48 hours. Cox proportional hazards analysis was performed to assess the association between baseline variables and mortality. ResultsDuring a median follow-up period of 33.8 months, 44 patients died of cardiovascular events. Baseline TVILVOT was significantly lower in the nonsurvivors compared with the survivors (P < 0.001). Baseline TVILVOT was positively correlated with stroke volume obtained by right heart catheterization (r = 0.709; P < 0.001), and inversely correlated with N-terminal pro–B-type natriuretic peptide (r = −0.533; P < 0.001), pulmonary vascular resistance (r = −0.423; P < 0.001). Multivariate analysis showed that baseline TVILVOT (hazard ratio: 0.856; 95% CI: 0.780-0.941; P = 0.001) was an independent predictor of cardiovascular mortality in PAH. Patients with a baseline TVILVOT <17.1 cm (median value) had a significantly worse survival than those with a baseline TVILVOT ≥17.1 cm (P < 0.001). ConclusionsThe findings of this study suggest that noninvasive TVILVOT provides a practical method to assess the severity and predict long-term outcome of PAH.

Upfront riociguat and ambrisentan combination therapy for newly diagnosed pulmonary arterial hypertension: A prospective open-label trial

Initial combination therapy with an endothelin receptor antagonist (ERA) and riociguat in pulmonary arterial hypertension (PAH) has limited supporting data. We performed a prospective, single-arm, open-label trial of riociguat, and ambrisentan for incident PAH patients in functional class III. The primary endpoint was pulmonary vascular resistance (PVR) at 4-months. Twenty patients (59 ± 13 years old, 85% female) enrolled and 1 died before their 4-month follow-up. Fifteen patients completed a 4-month and 13 completed the 12-month follow-up. At 4-months PVR decreased 54% with an absolute change of -5.8 Wood units (95% CI -4.0; -7.5, p < 0.001). Other hemodynamic variables and risk scores also improved. Six patients discontinued riociguat and 8 discontinued ambrisentan, with 5 (25%) discontinuing both. These results do not support the routine use of riociguat plus ambrisentan in initial regimens. Future studies are needed to compare this strategy with phosphodiesterase-5 inhibitors and an ERA with respect to tolerability and long-term outcomes.

Risk Stratification in Patients with Pulmonary Arterial Hypertension under Treatment - Results of Four German Centers

Risk stratification plays an essential role in the management of patients with pulmonary arterial hypertension (PAH). According to the current European guidelines the expected 1-year risk of mortality for PAH patients can be categorized as low, intermediate, or high, based on clinical, non-invasive and hemodynamic data.Data from 131 patients with incident PAH (age 64 ± 14) and frequent comorbidities (in 66.4 %) treated between 2016 and 2018 at 4 German PH centers were analyzed. At baseline, most patients were classified as intermediate risk (76 %), 13.8 % as high risk and only 9.9 % as low risk.During follow-up while on treatment after 12 ± 3 months (range 9-16 months) 64.9 % were still classified as intermediate risk (76 %), 14.4 % as high risk and 20.7 % as low risk.Survival at 12 and 24 months was 96 % and 82 % in the intermediate risk group, while only 89 % and 51 % of the high risk patients were alive at these time points. In contrast, all patients in the low risk category were alive at 24 months.Despite the availability of various treatment options for patients with PAH even in specialized centers only a minority of patients can be stabilized in the low risk group associated with a good outcome.

Ventricular mass discriminates pulmonary arterial hypertension as redefined at the SixthWorld Symposium on Pulmonary Hypertension.

Cardiac magnetic resonance (CMR) measures of right ventricular (RV) mass, volumes, and function have diagnostic and prognostic value in pulmonary arterial hypertension (PAH). We hypothesized that RV mass‐based metrics would discriminate incident PAH as redefined by the lower mean pulmonary arterial pressure (mPAP) threshold of >20 mmHg at the Sixth World Symposium on Pulmonary Hypertension (6th WSPH). Eighty‐nine subjects with suspected PAH underwent CMR imaging, including 64 subjects with systemic sclerosis (SSc). CMR metrics, including RV and left ventricular (LV) mass, were measured. All subjects underwent right heart catheterization (RHC) for assessment of hemodynamics within 48 h of CMR. Using generalized linear models, associations between CMR metrics and PAH were assessed, the best subset of CMR variables for predicting PAH were identified, and relationships between mass‐based metrics, hemodynamics, and other predictive CMR metrics were examined. Fifty‐nine subjects met 6th WSPH criteria for PAH. RV mass metrics, including ventricular mass index (VMI), demonstrated the greatest magnitude difference between subjects with versus without PAH. Overall and in SSc, VMI and RV mass measured by CMR were among the most predictive variables discriminating PAH at RHC, with areas under the receiver operating characteristic curve 0.86 and 0.83. respectively. VMI increased linearly with pulmonary vascular resistance and with mPAP in PAH, including in lower ranges of mPAP associated with mild PAH. VMI ≥ 0.37 yielded a positive predictive value of 90% for discriminating PAH. RV mass metrics measured by CMR, including VMI, discriminate incident, treatment‐naïve PAH as defined by 6th WSPH criteria.

Inclusion of echocardiographic measure of right ventricular function in the non-invasive French pulmonary arterial hypertension risk stratification method

Although preserved right ventricular (RV) function is consistently associated with better survival in pulmonary arterial hypertension (PAH), the French risk assessment method has not yet considered echocardiographic criteria of RV function. In the present study, we tested the value of tricuspid annular plane systolic excursion (TAPSE) measured by echocardiography for non-invasive PAH risk assessment. We retrospectively studied a cohort of 306 incident PAH patients treated in two French expert centers who underwent follow-up TAPSE measurement from echocardiographic apical 4-chamber view in addition to previously validated invasive and non-invasive risk stratification variables. The primary composite outcome was 3-year lung transplantation free survival after follow-up assessment. At re-evaluation, 66% of patients were in NYHA functional class I-II and mean pulmonary arterial pressure, cardiac index, N-Terminal pro brain natriuretic peptide (NTproBNP), and 6-minute walk distance (6MWD) were 40 ± 16 mmHg, 3.5 ± 1.1 L/min/m 2 , 270 [interquartile range (IQR) 896] ng/L and 401 (IQR 213) meters, respectively. The primary outcome occurred in 58 (19%) patients. In multivariable Cox regression analysis, NYHA functional class I-II ( P = 0.02), NTproBNP < 300 ng/L or BNP < 50 ng/L ( P = 0.02), 6MWD > 440 m ( P = 0.049) and TAPSE≥17 mm ( P = 0.02) were associated with lung transplantation free survival. TAPSE provided similar information over 6MWD when both were used alternatively to stratify PAH patients at low risk (log-rank < 0.001); Harrell's c-index 0.73 ( Fig. 1 ). Three dichotomized low-risk criteria (TAPSE, 6MWD and NTproBNP or BNP plasma levels) allow non-invasive risk assessment in PAH.

Clinical Relevance of Right Atrial Functional Response to Treatment in Pulmonary Arterial Hypertension

Background: Right atrial (RA) function has emerged as an important determinant of outcome in pulmonary arterial hypertension (PAH). However, studies exploring RA function after initiation of specific pulmonary vascular treatment and its association with outcome in patients with incident PAH are lacking.Methods: RA peak longitudinal strain (PLS), passive strain (PS), and peak active contraction strain (PACS) were retrospectively assessed in 56 treatment-naïve patients with PAH at baseline and during follow-up after initiation of specific monotherapy or combination therapy. Patients were grouped according to their individual RA functional response to treatment, based on change from baseline (Δ): worsened (first Δ-tertile), stable (second Δ-tertile), and improved (third Δ-tertile). The Spearman's rho correlation and linear regression analysis were used to determine associations. Time to clinical worsening (defined as deterioration of functional class or 6-min walking distance, disease-related hospital admission, or death) was measured from the follow-up assessment. The association of RA functional treatment response with time to clinical worsening was assessed using the Kaplan–Meier and the Cox regression analyses.Results: Median (interquartile range) time to echocardiographic follow-up was 11 (9–12) months. Of the 56 patients, 37 patients (66%) received specific dual or triple combination therapy. Δ RA PLS during follow-up was significantly associated with changes in key hemodynamic and echocardiographic parameters. The change of pulmonary vascular resistance, right ventricular (RV) end-systolic area, and global longitudinal strain were independently associated with Δ RA PLS. The median time to clinical worsening after echocardiographic follow-up was 6 (2–14) months [17 events (30%)]. In the multivariate Cox regression analysis, worsening of RA PLS was significantly associated with clinical deterioration (hazard ratio: 4.87; 95% CI: 1.26–18.76; p = 0.022). Patients with worsened RA PLS had a significantly poorer prognosis than those with stable or improved RA PLS (log-rank p = 0.012). By contrast, PS and PACS did not yield significant prognostic information.Conclusion: Treatment-naïve patients with PAH may show different RA functional response patterns to PAH therapy. These functional patterns are significantly associated with clinically relevant outcome measures. Improvements of RA function are driven by reductions of afterload, RV remodeling, and RV dysfunction.

Mortality trends in pulmonary arterial hypertension in Canada: a temporal analysis of survival per ESC/ERS guideline era.

BackgroundThe evolution in pulmonary arterial hypertension (PAH) management has been summarised in three iterations of the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. No study has assessed whether changes in management, as reflected in the changing guidelines, has translated to improved long-term survival in PAH.MethodsWe performed a mixed retrospective/prospective analysis of treatment-naïve, incident PAH patients (n=392) diagnosed at three major centres in Canada from 2009 to 2021. Patients were divided into two groups based on their diagnosis date and in accordance with the 2009 and 2015 ESC/ERS guideline iterations. Overall survival was assessed based on date of diagnosis and initial treatment strategy (i.e. monotherapy versus combination therapy).ResultsThere was a shift towards more aggressive upfront management with combination therapy in Canada after the publication of the 2015 ESC/ERS guidelines (10.4% and 30.8% in patients from 2009 to 2015 and 36.0% and 57.4% in patients diagnosed after 2015 for baseline and 2-year follow-up, respectively). A key factor associated with combination therapy after 2015 was higher pulmonary vascular resistance (p=0.009). The 1-, 3- and 5-year survival rates in Canada were 89.2%, 75.6% and 56.0%, respectively. Despite changes in management, there was no improvement in long-term survival before and after publication of the 2015 ESC/ERS guidelines (p=0.53).ConclusionsThere was an increase in the use of initial and sequential combination therapy in Canada after publication of the 2015 ESC/ERS guidelines, which was not associated with improved long-term survival. These data highlight the continued difficulties of managing this aggressive pulmonary disease in an era without a cure.

Right ventricular reverse remodeling assessed by echocardiography as a new goal-oriented treatment strategy in PAH patients

Abstract Background While in heart failure with reduced ejection fraction, left ventricular reverse remodeling assessed by transthoracic echocardiography (TTE) is associated with better prognosis, right ventricular reverse remodeling (RVRR) was less investigated in pulmonary arterial hypertension (PAH) Purpose We aimed to investigate whether RVVR assessed by echocardiography could help to stratify PAH patient's prognosis. Methods Between 2002 and 2019, all consecutive PAH patients were included, treated and followed in a single PAH center in accordance with the current ESC/ERS guidelines. In addition to regular risk stratification parameters, we measured several echocardiographic RV systolic function and size parameters, including tricuspid annular plane systolic excursion (TAPSE, mm) or RV-end diastolic area (cm2) from apical-4 chamber view both at baseline, 1-year of follow-up as well as their change. Primary composite outcome was three-year transplant-free survival and death from all cause from the 1-year evaluation. Conditional inference trees were used to determine which TTE parameters and cutoffs values were associated with primary outcome from hierarchy of multiple covariates in multivariable Cox regression analysis. Kaplan-Meier curves were then drawn and compared with log-rank test. Results 126 incident PAH patients were included (63% female, mean age 59±18 yo), mainly due to connectivite-tissue disease and idiopathic PAH (26% and 22% respectively). At baseline, mean pulmonary arterial pressure was 42 (33, 52) mmHg. At 1-y follow-up under pulmonary vasodilation therapy, NYHA (p&amp;lt;0.01), NTproBNP (p&amp;lt;0.01), mean pulmonary arterial pressure (p&amp;lt;0.01) and cardiac index (p&amp;lt;0.01) were significantly improved compared to baseline. Conditional inference trees showed that 1-year TAPSE gain &amp;gt;1 mm and 1-year RV end-diastolic area decreased &amp;gt;2 cm2 were associated with 3-year transplant-free survival in multivariable Cox regression analysis (HR=0.23, 95% CI [0.08–0.61] p=0,0035, HR=0.34, 95% CI [0.12–0.94], p=0.038). Simple score from 0 (absence of RVRR), 1 (partial RVRR) and 2 (complete RVRR), describing the number of TTE parameters reach at 1-year was then investigated. Patients with complete RVRR depicted better transplant-free survival than partial or absence of RVRR, log-rank p&amp;lt;0.001 (figure). Conclusion Complete reverse remodeling from right ventricular size and function could represent a new goal-oriented treatment strategy in PAH patients. Funding Acknowledgement Type of funding sources: None. RVRR survival curves

Right ventricular improvement is associated with left ventricular diastolic function and size enhancement in PAH patients: an echocardiographic study

Abstract Background While pulmonary vasodilation therapy improves right ventricular (RV) function in pulmonary arterial hypertension (PAH), data regarding left ventricular (LV) function remain sparse. Purpose We aimed to investigate whether PAH therapy improve LV function in PAH patients. Methods Between 2002 and 2020, all incident PAH patients from one PH referral centers were included, treated and followed-up according to current ESC/ERS guidelines. All patients had comprehensive echocardiography both investigating right and left ventricular function before and after 1-year of vasodilation therapy. In addition to RV echocardiographic evaluation, we focused on LV ejection fraction from Modified Simpson method, LV diameters by M-mode, transmitral pulsed-wave E/A ratio, Flow to tissue Doppler imaging E/e' ratio, and left atrial size. Results 126 patients were included (63% female, 57±17 yo), mainly from connectivite tissue associated and idiopathic PAH (24% and 28% respectively) causes. Compared to baseline, 1-year NYHA functional class (p&amp;lt;0.01), NTproBNP plasma level (p&amp;lt;0.001), invasive mean pulmonary arterial pressure (p&amp;lt;0.01) and cardiac index (p&amp;lt;0.01) significantly improved. While LV ejection fraction (p=0.68), LV end-diastolic diameter (p=0.11) as well as LA area and volume (p=0.09) were not significantly enhanced under vasodilation therapy, LV diastolic function, assessed by mitral E wave (p&amp;lt;0.01), tissue doppler imaging mitral e' wave (p=0.04), and E/A ratio (p=0.045) were significantly improved at 1-year. There was a significant correlation between LV end-diastolic diameter (p&amp;lt;0.001) and RV end-diastolic area (p&amp;lt;0.001) owing to the normalization of right- to left ventricular interdependence, as well as between mitral E wave and TAPSE (p=0.045). Conclusion By improving RV function, PAH vasodilation therapy enhances LV size and diastolic function and normalizes the biventricular interdependence. Funding Acknowledgement Type of funding sources: None.