Incidence of pulmonary hypertension and determining factors in patients with systemic sclerosis

Objective: The objective of this study was to evaluate the incidence of pulmonary hypertension (PH) and determining factors in patients with systemic sclerosis (SSc) and a DLCO < 60% predicted.Methods:In this bicentric, prospective cohort study, patients with SSc were assessed at baseline and after 3 years clinically including right heart catheterization (RHC). Analysis of determining factors for development of PH was performed using univariate and multivariate analysis.Results:Ninety-six patients with mean pulmonary artery pressure (mPAP) <25 mmHg at baseline were followed 2.95±0.7 (median 3) years. Seventy-one had a second RHC; 18 of the 71 patients (25.3%) developed PH, 5 (7%) a SSc-associated pulmonary arterial hypertension. For patients with mPAP between 21 and 24 mmHg at baseline, the likelihood of presenting with PH as opposed to normal pressures on follow-up was significantly higher (p=0.026). Pulmonary vascular resistance, tricuspid regurgitation velocity, diffusion capacity and size of inferior vena cava at baseline were independent predictors for development of PH during follow-up.Conclusion:In a selected cohort of SSc patients with a DLCO < 60%, pulmonary pressures appear to rise progressively during follow up. In this population using prospective RHC during follow-up it was possible to identify manifest PH in almost 25% of 44 patients. Therefore, regular clinical assessment including RHC might be useful in SSc-patients.Most important findings:In a selected cohort of SSc patients pulmonary pressures appear to rise progressively, leading to a development of manifest PH in 25% within 3 years

Factors associated with disease progression in early-diagnosed pulmonary arterial hypertension associated with systemic sclerosis: longitudinal data from the DETECT cohort

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc). In this longitudinal study, we aimed to identify factors associated with an unfavourable outcome in patients with SSc with early PAH (SSc-PAH) from the DETECT cohort. METHODS: Patients with SSc-PAH enrolled in DETECT were observed for up to 3 years. Associations between cross-sectional variables and disease progression (defined as the occurrence of any of the following events: WHO Functional Class worsening, combination therapy for PAH, hospitalisation or death) were analysed by univariable logistic regression. RESULTS: Of 57 patients with PAH (median observation time 12.6 months), 25 (43.9%) had disease progression. The following factors (OR (95% CI)) were associated with disease progression: male gender (4.1 (1.2 to 14.1)), high forced vital capacity % predicted/carbon monoxide lung diffusion capacity (DLCO)% predicted ratio (3.6 (1.2 to 10.7)), high Borg Dyspnoea Index (1.7 (1.1 to 2.6)) and low DLCO% predicted (non-linear relationship). CONCLUSION: More than 40% of early-diagnosed patients with SSc-PAH had disease progression during a short follow-up time, with male gender, functional capacity and pulmonary function tests at PAH diagnosis being associated with progression. This suggests that even mild PAH should be considered a high-risk complication of SSc

Three- Versus Two-Drug Therapy for Patients With Newly Diagnosed Pulmonary Arterial Hypertension

BACKGROUND: In pulmonary arterial hypertension (PAH), there are no data comparing initial triple oral therapy with initial double oral therapy. OBJECTIVES: TRITON (The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension; NCT02558231), a multicenter, double-blind, randomized phase 3b study, evaluated initial triple (macitentan, tadalafil, and selexipag) versus initial double (macitentan, tadalafil, and placebo) oral therapy in newly diagnosed, treatment-naive patients with PAH. METHODS: Efficacy was assessed until the last patient randomized completed week 26 (end of main observation period). The primary endpoint was change in pulmonary vascular resistance (PVR) at week&nbsp;26. RESULTS: Patients were assigned to initial triple (n&nbsp;=&nbsp;123) or initial double therapy (n&nbsp;=&nbsp;124). At week 26, both treatment strategies reduced PVR compared with baseline (by 54% and 52%), with no significant difference between groups (ratio of geometric means: 0.96; 95% confidence interval: 0.86-1.07; P&nbsp;=&nbsp;0.42). Six-minute walk distance and N-terminal pro-brain natriuretic peptide improved by week 26, with no difference between groups. Risk for disease progression (to end of main observation period) was reduced with initial triple versus initial double therapy (hazard ratio: 0.59; 95% confidence interval: 0.32-1.09). Most common adverse events with initial triple therapy included headache, diarrhea, and nausea. By the end of the main observation period, 2 patients in the initial triple and 9 in the initial double therapy groups had died. CONCLUSIONS: In patients with newly diagnosed PAH, both treatment strategies markedly reduced PVR by week 26, with no significant difference between groups (primary endpoint not met). Exploratory analyses suggested a possible signal for improved long-term outcomes with initial triple versus initial double oral therapy

Reply: Reduction in Risk of Disease Progression With Triple Therapy: Is it True for All?

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Incidence of pulmonary hypertension and determining factors in patients with systemic sclerosis

The objective of this study was to evaluate the incidence of pulmonary hypertension (PH) and determining factors in patients with systemic sclerosis (SSc) and a DLCO < 60% predicted.In this bicentric, prospective cohort study, patients with SSc were assessed at baseline and after 3 years clinically including right heart catheterization (RHC). Analysis of determining factors for development of PH was performed using univariate and multivariate analysis.Ninety-six patients with mean pulmonary artery pressure (mPAP) <25 mmHg at baseline were followed 2.95±0.7 (median 3) years. Seventy-one had a second RHC; 18 of the 71 patients (25.3%) developed PH, 5 (7%) a SSc-associated pulmonary arterial hypertension. For patients with mPAP between 21 and 24 mmHg at baseline, the likelihood of presenting with PH as opposed to normal pressures on follow-up was significantly higher (p=0.026). Pulmonary vascular resistance, tricuspid regurgitation velocity, diffusion capacity and size of inferior vena cava at baseline were independent predictors for development of PH during follow-up.In a selected cohort of SSc patients with a DLCO < 60%, pulmonary pressures appear to rise progressively during follow up. In this population using prospective RHC during follow-up it was possible to identify manifest PH in almost 25% of 44 patients. Therefore, regular clinical assessment including RHC might be useful in SSc-patients.In a selected cohort of SSc patients pulmonary pressures appear to rise progressively, leading to a development of manifest PH in 25% within 3 years

Acute hemodynamic effects of single-dose sildenafil when added to established bosentan therapy in patients with pulmonary arterial hypertension: Results of the COMPASS-1 study

This study investigated the acute pharmacodynamic effects of sildenafil in patients with pulmonary arterial hypertension (PAH) and concomitant bosentan treatment, in view of a mutual pharmacokinetic interaction between the 2 drugs. This prospective, open-label, noncomparative, multicenter, phase II study enrolled 45 patients (ĝ‰¥18 years) with stable PAH (idiopathic, familial, or related to corrected congenital systemic-to-pulmonary shunts, drugs, or toxins) and on bosentan treatment for at least 3 months. Patients underwent right heart catheterization to evaluate the acute hemodynamic effects of (a) inhaled nitric oxide (iNO) and (b) a single oral dose of sildenafil (25 mg). Mean pulmonary vascular resistance (PVR) decreased from baseline following iNO (ĝ€"15%; 95% confidence limits: ĝ€"21%, ĝ€"8%; P =.0001). A statistically significant decrease from baseline in mean PVR was also observed 60 minutes following sildenafil administration (ĝ€"15%; 95% confidence limits: ĝ€"21%, ĝ€"10%; P <.0001). The reduction in PVR following sildenafil was comparable to that resulting from iNO. There were no unexpected safety findings. The pharmacodynamic effect suggests that addition of sildenafil to bosentan treatment can elicit additional hemodynamic benefits. These data represent a rationale for long-term combination studies with the 2 compounds. © 2009 the American College of Clinical Pharmacology

Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study

Contains fulltext : 137979.pdf (publisher's version ) (Open Access)OBJECTIVE: Earlier detection of pulmonary arterial hypertension (PAH), a leading cause of death in systemic sclerosis (SSc), facilitates earlier treatment. The objective of this study was to develop the first evidence-based detection algorithm for PAH in SSc. METHODS: In this cross-sectional, international study conducted in 62 experienced centres from North America, Europe and Asia, adults with SSc at increased risk of PAH (SSc for >3 years and predicted pulmonary diffusing capacity for carbon monoxide <60%) underwent a broad panel of non-invasive assessments followed by diagnostic right heart catheterisation (RHC). Univariable and multivariable analyses selected the best discriminatory variables for identifying PAH. After assessment for clinical plausibility and feasibility, these were incorporated into a two-step, internally validated detection algorithm. Nomograms for clinical practice use were developed. RESULTS: Of 466 SSc patients at increased risk of PAH, 87 (19%) had RHC-confirmed PAH. PAH was mild (64% in WHO functional class I/II). Six simple assessments in Step 1 of the algorithm determined referral to echocardiography. In Step 2, the Step 1 prediction score and two echocardiographic variables determined referral to RHC. The DETECT algorithm recommended RHC in 62% of patients (referral rate) and missed 4% of PAH patients (false negatives). By comparison, applying European Society of Cardiology/European Respiratory Society guidelines to these patients, 29% of diagnoses were missed while requiring an RHC referral rate of 40%. CONCLUSIONS: The novel, evidence-based DETECT algorithm for PAH detection in SSc is a sensitive, non-invasive tool which minimises missed diagnoses, identifies milder disease and addresses resource usage