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"Benjamin, Nicola"
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Long-term oxygen therapy in precapillary pulmonary hypertension – SOPHA study
Current guidelines recommend oxygen (O
2
) supplementation in patients with pulmonary hypertension (PH), despite scarce data on long-term O
2
therapy (LTOT). The aim of this prospective, randomized, controlled trial was to investigate the effect of LTOT in patients with precapillary PH on exercise capacity, clinical parameters and hemodynamics. Patients with precapillary PH under stable therapy and O
2
desaturations at rest and/or during exercise were randomized to receive LTOT (≥ 16 h/day) or no O
2
(control group) for 12 weeks. The control group was offered LTOT after 12 weeks. The primary endpoint changes of 6-minute walking distance (6MWD) from baseline to 12 weeks was hierarchically tested: (1) pre-post primary and secondary intervention (2) intervention vs. control group. Secondary endpoints included changes in clinical parameters. Twenty patients were randomized (women n = 14, age 67 ± 11.4 years, mean pulmonary arterial pressure 39.7 ± 12.5 mmHg, 70% functional class III). 6MWD significantly improved by 42.2 ± 34.20 m (
p
= 0.003) within 12 weeks LTOT. The intervention group significantly improved in 6MWD (38.9 ± 33.87 m) compared to the control group (− 12.3 ± 21.83 m,
p
= 0.015). No consistent between-group differences in other parameters were found. LTOT was well tolerated and led to significant improvement of 6MWD. The effect of LTOT should be investigated in larger controlled-trials.
Journal Article
Reduced gastrointestinal iron uptake in pulmonary arterial hypertension: a prospective cross-sectional study
Background
Iron deficiency (ID) is common in patients with pulmonary arterial hypertension (PAH) and is associated with worse clinical outcomes. The etiology of ID in PAH is poorly understood. The aim of this study was to systematically determine whether differences in oral iron absorption exist between PAH patients with and without chronic ID compared with healthy controls.
Methods
This single-center prospective, cross-sectional cohort study enrolled 45 subjects: 15 PAH patients with chronic ID, 15 PAH patients without ID and 15 healthy age and sex matched controls. Chronic ID was defined by either recorded ID anemia or clinical indication for i.v. iron supplementation in the past 3 years. Plasma iron levels and transferrin saturation (TSAT) were measured before and after a standardized oral iron absorption test with 200 mg ferrous iron. Additional iron and inflammation laboratory parameters were determined. Hepcidin and erythroferrone levels were measured using enzyme-linked immunosorbent assay, and tumor necrosis factor alpha and ferroportin expression were determined by quantitative polymerase chain reaction.
Results
Both PAH groups showed a similar increase of plasma iron and TSAT after 3 h. The increase in plasma iron and TSAT was significantly lower in both PAH groups (with chronic ID: 71.5 (IQR 44.1–188.8) µg/dl; 22 (IQR 14–49) %; without ID: 86.0 (IQR 27.9–105.6) µg/dl; 26 (IQR 11–42) %) compared to healthy controls (154.1 (IQR 129.0–181.5) µg/dl; 45 (IQR 34–54) %,
p
= 0.015 and
p
= 0.031, respectively).
Conclusions
This study is the first to demonstrate a significantly reduced gastrointestinal iron uptake in PAH patients compared to healthy age and sex matched controls. Interestingly, PAH patients with chronic ID showed similar iron uptake levels as those without, suggesting that factors other than iron stores, such as chronic inflammation, may impair iron absorption in this patient population.
Journal Article
Effect of ambrisentan in patients with systemic sclerosis and mild pulmonary arterial hypertension: long-term follow-up data from EDITA study
Background
In the EDITA trial, patients with systemic sclerosis (SSc) and mild pulmonary vascular disease (PVD) treated with ambrisentan had a significant decline of pulmonary vascular resistance (PVR) but not of mean pulmonary arterial pressure (mPAP) vs. placebo after six months. The EDITA-ON study aimed to assess long-term effects of open label therapy with ambrisentan vs. no pulmonary arterial hypertension (PAH) therapy.
Methods
Patients who participated in the EDITA study and received regular follow-up were included in EDITA-ON. Clinical, echocardiographic, laboratory, exercise and hemodynamic parameters during follow-up were analysed. The primary endpoint was to assess whether continued treatment with ambrisentan vs. no treatment prevented the development of PAH according to the new definition.
Results
Of 38 SSc patients included in the EDITA study four were lost to follow-up. Of the 34 remaining patients (age 55 ± 11 years, 82.1% female subjects), 19 received ambrisentan after termination of the blinded phase, 15 received no PAH medication. The mean follow-up time was 2.59 ± 1.47 years, during which 29 patients underwent right heart catheterization. There was a significant improvement of mPAP in catheterised patients receiving ambrisentan vs. no PAH treatment (-1.53 ± 2.53 vs. 1.91 ± 2.98 mmHg,
p
= 0.003). In patients without PAH treatment 6/12 patients had PAH vs. 1/17 of patients receiving ambrisentan (
p
< 0.0001).
Conclusion
In SSc patients with early PVD, the development of PAH and/or deterioration was less frequent among patients receiving ambrisentan, indicating that early treatment and close follow-up could be beneficial in this high-risk group. Future trials in this field are needed to confirm these results.
Journal Article
Early treatment with ambrisentan of mildly elevated mean pulmonary arterial pressure associated with systemic sclerosis: a randomized, controlled, double-blind, parallel group study (EDITA study)
Objective
The objective of this randomized, placebo-controlled, double-blind, parallel group, trial was to assess the effect of ambrisentan on mean pulmonary arterial pressure (mPAP) in patients with systemic sclerosis (SSc) and mildly elevated pulmonary hypertension (PH).
Methods
Thirty-eight SSc patients with mildly elevated mPAP at rest between 21 and 24 mmHg and/or > 30 mmHg during low-dose exercise were randomly assigned to treatment with either ambrisentan 5–10 mg/day or placebo. Right heart catheterization and further clinical parameters were assessed at baseline and after 6 months. The primary endpoint was the difference of mPAP change at rest between groups.
Results
After 6 months, the two groups did not differ in the primary endpoint (ambrisentan mPAP − 1 ± 6.4 mmHg vs. placebo − 0.73 ± 3.59 mmHg at rest,
p
= 0.884). However, three patients from the placebo group but none of the ambrisentan group progressed to SSc-associated pulmonary arterial hypertension. Furthermore, ambrisentan treatment showed significant improvements in the secondary endpoints cardiac index (CI) and pulmonary vascular resistance (PVR) at rest (CI 0.36 ± 0.66 l/min/m
2
vs. − 0.31 ± 0.71 l/min/m
2
,
p
= 0.010; PVR − 0.70 ± 0.78 WU vs. 0.01 ± 0.71 WU,
p
= 0.012) and during exercise (CI 0.7 ± 0.81 l/min/m
2
vs. − 0.45 ± 1.36 l/min/m
2
,
p
= 0.015; PVR − 0.84 ± 0.48 WU vs. − 0.0032 ± 0.34 WU,
p
< 0.0001).
Conclusion
This is the first randomized, double-blind, placebo-controlled study testing the effect of ambrisentan in patients with mildly elevated mPAP and/or exercise PH. The primary endpoint change in mPAP did only tendentially improve in the ambrisentan group, but the significant improvement of other hemodynamic parameters points to a possible benefit of ambrisentan and will be helpful to design future trials.
Trial registration
www.ClinicalTrials.gov, unique identifier NCT:
NCT02290613
, registered 14
th
of November 2014.
Journal Article
Prognostic meaning of right ventricular function and output reserve in patients with systemic sclerosis
Background
The objective of this study was to investigate the prognostic impact of right ventricular (RV) function at rest and during exercise in patients with systemic sclerosis (SSc) presenting for a screening for pulmonary hypertension (PH).
Methods
In this study, data from SSc patients who underwent routinely performed examinations for PH screening including echocardiography and right heart catheterization at rest and during exercise were analysed. Uni- and multivariable analyses were performed to identify prognostic parameters.
Results
Out of 280 SSc patients screened for PH, 225 were included in the analysis (81.3% female, mean age 58.1±13.0 years, 68% limited cutaneous SSc, WHO-FC II–III 74%, 24 manifest PH). During the observation period of 3.2±2.7 (median 2.6) years 35 patients died. Tricuspid annular plane systolic excursion (TAPSE) at rest <18 mm (
p
=0.001), RV output reserve as increase of cardiac index (CI) during exercise <2 l/min (
p
<0.0001), RV pulmonary vascular reserve (Δ mean pulmonary artery pressure/Δ cardiac output) ≥3 mmHg/l/min (
p
<0.0001), peak CI <5.5 l/min/m
2
(
p
=0.001), pulmonary arterial compliance <2 ml/mmHg (
p
=0.002), TAPSE/systolic pulmonary arterial pressure (sPAP) ratio ≤0.6 ml/mmHg (
p
<0.0001) and echocardiographic qualitative RV function at rest (
p
<0.0001) significantly predicted worse survival. In the multivariable analysis TAPSE/sPAP ratio and diffusion capacity for carbon monoxide ≤65% were identified as independent prognostic predictors and had 75% sensitivity and 69% specificity to predict future development of pulmonary vascular disease (PVD) during follow-up.
Conclusions
This study demonstrates that assessment of RV function at rest and during exercise may provide crucial information to identify SSc patients who are at a high risk of poor outcome and for the development of PH and/or PVD.
Journal Article
Hypochromic red cells as a prognostic indicator of survival among patients with systemic sclerosis screened for pulmonary hypertension
Background
Patients with systemic sclerosis (SSc) are frequently affected by iron deficiency, particularly those with pulmonary hypertension (PH). The first data indicate the prognostic importance of hypochromic red cells (% HRC) > 2% among patients with PH. Hence, the objective of our study was to investigate the prognostic value of % HRC in SSc patients screened for PH.
Methods
In this retrospective, single-center cohort study, SSc patients with a screening for PH were enrolled. Clinical characteristics and laboratory and pulmonary functional parameters associated with the prognosis of SSc were analyzed using uni- and multivariable analysis.
Results
From 280 SSc patients screened, 171 could be included in the analysis having available data of iron metabolism (81% female, 60 ± 13 years of age, 77% limited cutaneous SSc, 65 manifest PH, and 73 pulmonary fibrosis). The patients were followed for 2.4 ± 1.8 (median 2.4) years. HRC > 2% at baseline was significantly associated with worse survival in the uni- (
p
= 0.018) and multivariable (
p
= 0.031) analysis independent from the presence of PH or pulmonary parenchymal manifestations. The combination of HRC > 2% and low diffusion capacity for carbon monoxide (DLCO) ≤ 65% predicted was significantly associated with survival (
p
< 0.0001).
Conclusion
This is the first study reporting that HRC > 2% is an independent prognostic predictor of mortality and can possibly be used as a biomarker among SSc patients. The combination of HRC > 2% and DLCO ≤ 65% predicted could serve in the risk stratification of SSc patients. Larger studies are required to confirm these findings.
Journal Article
Gene panel diagnostics reveals new pathogenic variants in pulmonary arterial hypertension
Background
A genetic predisposition can lead to the rare disease pulmonary arterial hypertension (PAH). Most mutations have been identified in the gene
BMPR2
in heritable PAH. However, as of today 15 further PAH genes have been described. The exact prevalence across these genes particularly in other PAH forms remains uncertain. We present the distribution of mutations across PAH genes identified at the largest German referral centre for genetic diagnostics in PAH over a course of > 3 years.
Methods
Our PAH-specific gene diagnostics panel was used to sequence 325 consecutive PAH patients from March 2017 to October 2020. For the first year the panel contained thirteen PAH genes:
ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9
and
TBX4.
T
hese were extended by the three genes
ATP13A3, AQP1
and
SOX17
from March 2018 onwards following the genes’ discovery.
Results
A total of 79 mutations were identified in 74 patients (23%). Of the variants 51 (65%) were located in the gene
BMPR2
while the other 28 variants were found in ten further PAH genes. We identified disease-causing variants in the genes
AQP1, KCNK3
and
SOX17
in families with at least two PAH patients
.
Mutations were not only detected in patients with heritable and idiopathic but also with associated PAH.
Conclusions
Genetic defects were identified in 23% of the patients in a total of 11 PAH genes. This illustrates the benefit of the specific gene panel containing all known PAH genes.
Journal Article
Right ventricular size and function under riociguat in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (the RIVER study)
Background
Riociguat is a soluble guanylate cyclase stimulator approved for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTPEH). The objective of this study was to evaluate right heart size and function assessed by echocardiography during long term treatment with riociguat.
Methods
Patients who started riociguat treatment (1.0–2.5 mg tid) within the trials phase II, PATENT, PATENTplus, EAS, CHEST and continued treatment for 3–12 months were included in this study. Echocardiography was analysed off-line at baseline, after 3, 6 and 12 months by investigators who were blinded to clinical data. Last and baseline observation carried forward method (LOCF, BOCF) were performed as sensitivity analysis.
Results
Seventy-one patients (45% PAH, 55% CTEPH; 53.5% female; 60 ± 13 years, mean pulmonary arterial pressure 46 ± 10 mmHg, mean PVR 700 ± 282dynes·sec·cm-5) were included. After 6 months, RA and RV area, RV thickness tricuspid regurgitation velocity showed a significant reduction. After 12 months, patients receiving riociguat therapy showed a significant reduction in right atrial (− 2.6 ± 4.4 cm2, 95% CI -3.84, − 1.33;
p
< 0.001,
n
= 49) and right ventricular (RV) area (− 3.5 ± 5.2 cm2, 95% CI -5.1, − 1.9;
p
< 0.001;
n
= 44), RV thickness (− 0.76 ± 2.2 mm, 95% CI -1.55, 0.03;
n
= 32), and a significant increase in TAPSE (2.95 ± 4.78 mm, 95% CI 1.52, 4.39;
n
= 45) and RV fractional area change (8.12 ± 8.87 mm, 95% CI 4.61, 11.62;
n
= 27).
Both LOCF and BOCF showed similar results but lower effect sizes.
Conclusion
Patients under long-term treatment with riociguat show significantly reduced right heart size and improved RV function in PAH and CTEPH. Further controlled prospective studies are needed to confirm these results.
Journal Article
Risk stratification and prognostic factors in patients with pulmonary arterial hypertension and comorbidities a cross-sectional cohort study with survival follow-up
Background
The objective of this study was to analyze prognostic factors and risk stratification in patients with pulmonary arterial hypertension (PAH) and comorbidities.
Methods
Patients with invasively diagnosed PAH were included in the analysis. Comorbidities were clinically diagnosed as proposed in the 6th World Symposium of pulmonary hypertension. Uni- and multivariate analysis were employed for identification of factors predicting survival and time to first clinical worsening (TTCW). Risk stratification was based on parameters from ESC/ERS-guidelines 2015.
Results
In total 142 patients were enrolled in the study, 90 of them were diagnosed as PAH without and 52 with comorbidities. All patients received targeted PAH therapy and were followed for 3.3 ± 2.4 years. In PAH patients without comorbidities survival and TTCW were significantly associated with reduced 6-min walking distance (6MWD), elevated N-terminal pro brain natriuretic peptide (NT-proBNP), WHO-functional class (WHO-FC) and right atrial (RA) area. In the multivariate analysis, 6MWD was an independent predictor for survival (
p
= 0.002) and WHO-FC for TTCW (
p
= 0.001). In patients with PAH and comorbidities these parameters had no significant association with survival and TTCW. Average risk score was significantly associated with survival (
p
= 0.001) and TTCW (
p
= 0.013) in PAH but not in PAH with comorbidities (both
p
> 0.05; figure 1).
Conclusion
Risk stratification based on ESC/ERS-guidelines could only be confirmed in patients without comorbidities, but not in patients with PAH and comorbidities. The data of this study suggest, that a different risk stratification needs to be applied to PAH patients with comorbidities. Further studies are needed to confirm these results.
Trial registration
Not applicable, retrospective registry.
Journal Article