654 Fragility of functional/symptomatic endpoints to assess the efficacy of drugs for pulmonary arterial hypertension

Abstract Aims Drugs for pulmonary arterial hypertension (PAH) have historically been evaluated for their efficacy in improving functional capacity and decreasing symptoms. However, these measures of treatment effect are approximate and subject to substantial variability, and therapeutic choices based on them may be aleatory. Methods and results We reviewed the articles reporting the results of phase 3 PAH randomized controlled trials (RCTs) and calculated the fragility index (FI) for the outcomes exploring functional capacity and symptoms. The FI corresponds to the number of events that need to be added to the arm with the smallest number of events to make a significant result non-significant: the lower the FI, the fragile the trial with respect to the endpoint examined. For RCTs with non-significant results, we calculated the FI as the number of events that need to be removed from the investigational drug (ID) group to reach a P-value <0.05. When possible, we also computed the FI for PAH hospitalization. Data about the rate of functional/symptomatic improvement were available for 22 (63%) of 35 RCTs (Table). The ID was superior to placebo or comparator with P < 0.05 in 10 (45%) of these 22 studies. The median FI was 2 [interquartile range (IQR): 6.5], with 4 RCTs having a FI = 1 and only 2 > 10 (Table). For the 12 RCTs in which the effect of the ID was neutral (P > 0.05), the median FI was 6 (IQR 4.25) (Table). The hospitalization FI was determined for 17 (77%) of the 22 RCTs and was overall higher than the one for the functional/symptomatic outcome (median 6, IQR 8). Conclusions Accessible information about the effects of PAH drugs on functional capacity and/or symptoms is published for 6 in 10 RCTs, in which very few events in one arm could have flipped the results from non-significant to significant or, more remarkably, from significant to non-significant. The evidence supporting the reduction of PAH hospitalizations as a treatment goal appears to be more robust.

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EXPRESS: Association of daily physical activity with psychosocial aspects and functional capacity in patients with Pulmonary Arterial Hypertension: a cross-sectional study

Pulmonary Circulation ◽

10.1177/2045894021999955 ◽

2021 ◽

pp. 204589402199995

Author(s):

Layse Nakazato Lima ◽

Felipe Mendes ◽

Ilma Paschoal ◽

Daniela Oliveira ◽

Marcos Mello Moreira ◽

...

Keyword(s):

Quality Of Life ◽

Physical Activity ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Functional Capacity ◽

Daily Physical Activity ◽

Cross Sectional ◽

Pulmonary Arterial ◽

The Mean

Pulmonary arterial hypertension (PAH) impairs exercise tolerance and daily physical activity (PA). Aside from the hemodynamic limitations, physical, cognitive and emotional factors may play a relevant and as yet unexplored role. We investigated whether there is an association between the PA level and psychological disorders, health-related quality of life, and daily activities. We also searched for an association of the PA level with clinical factors and functional capacity. This was an analytical, cross-sectional, observational study conducted in a Brazilian University Hospital. Twenty stable PAH subjects wore an accelerometer for a week and completed an activity diary. They answered the quality of life questionnaire (SF-36), as well as the anxiety and depression scale (HADS), and the Manchester Respiratory Activities of Daily Living questionnaire (MRADL). Transthoracic echocardiography, the 6-Minute walk test (6MWT), the 1-minute sit-to-stand test (STST), and spirometry were performed. For statistical analysis we used Chi-square tests or Fisher's test as appropriate and the Mann-Whitney test to compare numerical values between two groups. The relationship between the parameters was assessed using the Spearman correlation test. The mean age was 44.3 years, 80% were women, 80% had idiopathic PAH, and 20% had connective tissue disease . The mean daily step count was 4,280 Â± 2,351, and the mean activity time was 41.6 Â± 19.3 minutes. The distance covered (6MWT) was 451.5 m, and the number of movements (1-STST) was 23.8. Thirty percent scored positive for anxiety, and 15% for depression (HADS). There was a significant correlation between accelerometer data and walking distance (6MWT), number of movements (1-STST), level of daily physical activity (MRADL), and depression symptoms. Our findings support the hypothesis that other aspects beyond physical and hemodynamic ones might impact the daily physical activity of patients with PAH.

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Serum Markers of Vascular Angiogenesis and Inflammation Are Predictive of Functional Capacity and Invasive Hemodynamics in Patients with Pulmonary Arterial Hypertension

The Journal of Heart and Lung Transplantation ◽

10.1016/j.healun.2014.01.839 ◽

2014 ◽

Vol 33 (4) ◽

pp. S311

Author(s):

A. Raina ◽

L. Zhang ◽

R.L. Benza

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Functional Capacity ◽

Serum Markers ◽

Pulmonary Arterial ◽

Invasive Hemodynamics

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P4688Additional role of unmodifiable risk factors in pulmonary arterial hypertension risk stratification according to current ESC/ERS guidelines

European Heart Journal ◽

10.1093/eurheartj/ehz745.1069 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

E Zuffa ◽

F Dardi ◽

M Palazzini ◽

E Gotti ◽

A Rinaldi ◽

...

Keyword(s):

Risk Factors ◽

Pulmonary Arterial Hypertension ◽

High Risk ◽

Risk Stratification ◽

Arterial Hypertension ◽

Specific Treatment ◽

Low Risk ◽

P Value ◽

Pulmonary Arterial

Abstract Background Current pulmonary hypertension (PH) guidelines stratify the risk of patients with pulmonary arterial hypertension (PAH) using a multiparametric approach. Anyway, the role of unmodifiable risk factors is not taken into account. Purpose The aim of this study was to evaluate the role of unmodifiable risk factors (age, gender, PAH aetiology) in PAH risk stratification using the recently proposed simplified risk table and to test if these factors influence the response to PAH-specific treatment. Methods All patients with PAH referred to a single centre were included from 2003 to 2017. We applied a simplified risk assessment strategy using the following criteria: WHO functional class, 6-min walking distance, right atrial pressure or brain natriuretic peptide plasma levels and cardiac index (CI) or mixed venous oxygen saturation (SvO2). The last 2 criteria were based on which parameter was available; if both were available the worst was chosen. Risk strata were defined as: Low risk= at least 3 low risk and no high-risk criteria; High risk= at least 2 high risk criteria including CI or SvO2; Intermediate risk= definitions of low or high risk not fulfilled. Then we performed multivariate Cox analysis to evaluate what are the independent predictors of survival (age, gender, PAH aetiology together with the recently proposed simplified PAH risk table) and we tested if these factors influence the response to PAH specific therapy comparing the % improvement of hemodynamic parameters from baseline to 3–4 months after starting treatment. Wilcoxon-Mann-Whitney test was used for comparisons. Results Six hundreds and twenty-one treatment-naïve patients were enrolled. Age [HR (95% CI) = 1.022 (1.014–1.030); p-value <0.001], male gender [HR (95% CI) = 1.881 (1.479–2.392); p-value <0.001] and connective tissue disease (CTD)-PAH aetiology [HR (95% CI)= 2.278 (1.733–2.995); p-value <0.001] were all independent predictors of prognosis in patients with PAH together with the recently validated simplified PAH risk table [HR (95% CI) = 2.161 (1.783–2.618); p-value <0.001] but they didn't significantly influence the response to PAH specific treatment as shown in the Figure. Figure 1 Conclusions Age, gender and CTD-PAH aetiology significantly influence prognosis together with the recently validated simplified PAH risk table but don't significantly influence the response to PAH-specific treatment. Acknowledgement/Funding None

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Pulmonary vasculature

10.1093/med/9780199657742.003.0017 ◽

2017 ◽

Author(s):

Sophie Vergnaud ◽

David Dobarro ◽

John Wort

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Treatment Strategies ◽

Symptomatic Improvement ◽

Pulmonary Vasculature ◽

History Of ◽

Diffuse Cutaneous Systemic Sclerosis ◽

Pulmonary Arterial ◽

Phosphodiesterase 5 ◽

Haemodynamic Improvement

A 16-year-old girl with a diagnosis of diffuse cutaneous systemic sclerosis is referred to a specialist pulmonary hypertension centre with a history of progressive breathlessness, reduced exercise tolerance, and raised pulmonary pressures on transthoracic echocardiogram. She is found to have pulmonary arterial hypertension on right cardiac catheterization and is started on sildenafil, a phosphodiesterase-5 inhibitor, which stabilizes her condition. An endothelin receptor antagonist is added, which provides some initial symptomatic improvement. She continues to deteriorate over a period of 5 years, ultimately requiring intravenous prostanoids, the only treatment to provide a real symptomatic and haemodynamic improvement. This chapter explores the physiology and pathophysiology of pulmonary arterial hypertension, its classification, the means of investigation and diagnosis, who to refer to specialist centres, and the concepts behind current and future treatment strategies.

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Trans-right ventricle and transpulmonary metabolite gradients in human pulmonary arterial hypertension

Heart ◽

10.1136/heartjnl-2019-315900 ◽

2020 ◽

Vol 106 (17) ◽

pp. 1332-1341 ◽

Cited By ~ 2

Author(s):

Philippe Chouvarine ◽

Martin Giera ◽

Gabi Kastenmüller ◽

Anna Artati ◽

Jerzy Adamski ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Right Ventricle ◽

Arterial Hypertension ◽

Vena Cava ◽

Dicarboxylic Acids ◽

P Value ◽

Blood Collection ◽

Lipid Species ◽

Metabolite Concentrations ◽

Pulmonary Arterial

ObjectiveWhile metabolic dysfunction occurs in several pulmonary arterial hypertension (PAH) animal models, its role in the human hypertensive right ventricle (RV) and lung is not well characterised. We investigated whether circulating metabolite concentrations differ across the hypertensive RV and/or the pulmonary circulation, and correlate with invasive haemodynamic/echocardiographic variables in patients with PAH.MethodsProspective EDTA blood collection during cardiac catheterisation from the superior vena cava (SVC), pulmonary artery (PA) and ascending aorta (AAO) in children with PAH (no shunt) and non-PAH controls (Con), followed by unbiased screens of 427 metabolites and 836 lipid species and fatty acids (FAs) in blood plasma (Metabolon and Lipidyzer platforms). Metabolite concentrations were correlated with echocardiographic and invasive haemodynamic variables.ResultsMetabolomics/lipidomics analysis of differential concentrations (false discovery rate<0.15) revealed several metabolite gradients in the trans-RV (PA vs SVC) setting. Notably, dicarboxylic acids (eg, octadecanedioate: fold change (FC)_Control=0.77, FC_PAH=1.09, p value=0.044) and acylcarnitines (eg, stearoylcarnitine: FC_Control=0.74, FC_PAH=1.21, p value=0.058). Differentially regulated metabolites were also found in the transpulmonary (AAO vs PA) setting and between-group comparisons, that is, in the SVC (PAH-SVC vs Con-SVC), PA and AAO. Importantly, the differential PAH-metabolite concentrations correlated with numerous outcome-relevant variables (e.g., tricuspid annular plane systolic excursion, pulmonary vascular resistance).ConclusionsIn PAH, trans-RV and transpulmonary metabolite gradients exist and correlate with haemodynamic determinants of clinical outcome. The most pronounced differential trans-RV gradients are known to be involved in lipid metabolism/lipotoxicity, that is, accumulation of long chain FAs. The identified accumulation of dicarboxylic acids and acylcarnitines likely indicates impaired β-oxidation in the hypertensive RV and represents emerging biomarkers and therapeutic targets in PAH.

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Correlation between sympathovagal modulation and functional capacity in pulmonary arterial hypertension patients.

10.1183/13993003.congress-2018.pa3327 ◽

2018 ◽

Author(s):

Gabriela Roncato ◽

Fabricio Fontoura ◽

Fernanda Spilimbergo ◽

Gisela Meyer ◽

Guilherme Watte ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Functional Capacity ◽

Pulmonary Arterial

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A case of worsening pulmonary arterial hypertension and pleural effusions by bosutinib after prior treatment with dasatinib

Pulmonary Circulation ◽

10.1177/2045893217733444 ◽

2017 ◽

Vol 7 (4) ◽

pp. 808-812 ◽

Cited By ~ 10

Author(s):

Karan Seegobin ◽

Amit Babbar ◽

Jason Ferreira ◽

Brittany Lyons ◽

James Cury ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Kinase Inhibitors ◽

Symptomatic Improvement ◽

Cor Pulmonale ◽

Chemotherapeutic Agents ◽

Shortness Of Breath ◽

Pleural Effusions ◽

Pulmonary Arterial ◽

One Year

A 52-year-old man with a past medical history of chronic myeloid leukemia (CML) in remission developed progressive shortness of breath over a two-month period. He was initially treated with dasatinib for four years, until developing pulmonary arterial hypertension (PAH) with pleural effusions. His symptoms improved after stopping dasatinib. He was then switched to bosutinib for approximately one year, which was then stopped before admission due to worsening shortness of breath. His initial workup showed bilateral pleural effusions with severe PAH and cor pulmonale. He had symptomatic improvement with PAH-specific therapy following discontinuation of the bosutinib. The life expectancy of CML patients has increased in the era of the tyrosine kinase inhibitors (TKIs), and managing adverse events (AEs) of the TKIs and improving quality of life are becoming more important. Pulmonary hypertension (PH) and pleural effusions are rarely reported AEs of bosutinib. More reports with PH and pleural effusions arising after bosutinib use in patients previously treated with dasatinib is furthermore concerning. In this era with novel chemotherapeutic agents, physicians ought to be weary of the significant morbidity implicated by these agents in the lives of patients.

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