Survival in pulmonary hypertension associated with the scleroderma spectrum of diseases: Impact of interstitial lung disease

119

Objective. Endothelin is implicated as a participatory pathway in systemic sclerosis (SSc). We tested this hypothesis in a 12-month trial of bosentan, a nonselective endothelin receptor antagonist, as a therapy for SSc-related interstitial lung disease (ILD).Method. Patients with SSc and significant ILD were recruited to this prospective, double-blind, randomized, placebo-controlled, parallel group study. The inclusion criteria were designed to select a cohort enriched for patients with active and progressive disease. Exclusion factors included significant pulmonary hypertension. Patients with a diffusing capacity for carbon monoxide of <80% predicted and a 6-minute walk distance of 150-500 meters or a 6-minute walk distance of >500 meters with a decrease in oxygen saturation received bosentan or placebo. The primary efficacy end point was a change in the 6-minute walk distance from baseline up to month 12. Secondary end points included time to death or worsening results of pulmonary function tests (PFTs). The safety and tolerability of bosentan were also assessed.Results. Among the 163 patients, 77 were randomized to receive bosentan, and 86 were randomized to receive placebo. No significant difference between treatment groups was observed for change in the 6-minute walk distance up to month 12. No deaths occurred in this study group. Forced vital capacity and diffusing capacity for carbon monoxide remained stable in the majority of patients in both groups. Significant worsenClinicalTrials.gov identifier: NCT00070590.

Section: Discussionmentioning

confidence: 99%

Randomized, prospective, placebo‐controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis

Seibold

Denton

Fürst

et al. 2010

119

“…Patients in whom PAH therapy had been initiated prior to diagnostic RHC and patients who were referred after starting PAH therapy were excluded. Some of the patients from the Johns Hopkins site have been described in a previous report (6).…”

Section: Methodsmentioning

confidence: 99%

“…Several recent clinical reports have highlighted the prognostic impact of pulmonary hypertension (PH) combined with ILD (5-7). While SSc patients with ILD alone have a median survival of 5-8 years (8), survival is significantly shortened with the development of PH (PH-ILD), as we and other investigators have recently suggested (6,9). In multivariate analyses, PH-ILD in SSc patients was associated with a 5-fold increased risk of death as compared to SSc-related PAH (6).…”

mentioning

confidence: 88%

“…While SSc patients with ILD alone have a median survival of 5-8 years (8), survival is significantly shortened with the development of PH (PH-ILD), as we and other investigators have recently suggested (6,9). In multivariate analyses, PH-ILD in SSc patients was associated with a 5-fold increased risk of death as compared to SSc-related PAH (6). Similarly, in a recent large study by Condliffe et al (7), the 3-year survival was significantly worse (28%) in SSc patients with PH-ILD as compared to those with isolated SSc-related PAH (47%).…”

mentioning

confidence: 88%

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Systemic sclerosis–related pulmonary hypertension associated with interstitial lung disease: Impact of pulmonary arterial hypertension therapies

Pavec¹,

Girgis²,

Lechtzin³

et al. 2011

Self Cite

119

Objective. Precapillary pulmonary hypertension (PH) is an important cause of death in patients with systemic sclerosis (SSc). It can occur in isolation (pulmonary arterial hypertension [PAH]) or in associationwith interstitial lung disease (ILD). Importantly, the outcomes and efficacy of PAH therapies in patients with SSc-related PH complicating ILD (PH-ILD) remain unknown. This study was undertaken to evaluate our experience with PH-ILD with regard to the efficacy and safety of PAH therapies in this patient cohort.Methods. We conducted a retrospective analysis of consecutive SSc patients from 2 large referral centers who had PH-ILD confirmed by right-sided heart catheterization and who received targeted PAH therapies. World Health Organization (WHO) functional class, 6-minute walk distance, and hemodynamic parameters were assessed at baseline and after a mean ؎ SD of 7.7 ؎ 6.2 months of treatment for PAH. Kaplan-Meier and Cox proportional hazards models were used to analyze survival and to identify prognostic factors.Results. Seventy patients were included in the study. No significant changes were observed in WHO functional class, 6-minute walk distance, or hemodynamic parameters after therapy. The 1-, 2-, and 3-year survival estimates were 71%, 39%, and 21%, respectively. In the multivariate model, worsening oxygenation during followup and reduced renal function were the only significant risk factors for death.Conclusion. This study represents the largest series to date in which the impact of PAH therapies in SSc-related PH-ILD was examined. In this cohort, PAH therapies were associated with no clear benefits. Deterioration in oxygenation was an important determinant of long-term survival. Prospective clinical trials focusing on this group of patients are warranted.Systemic sclerosis (SSc) is a heterogeneous disorder characterized by dysfunction of the endothelium,

“…Isolated survival of SSc patients with PAH while receiving pulmonary vasodilator therapy was recently reported to be 78% (1-year rate), 68% (2-year rate), and 47% (3-year rate) (7,19,20). Importantly, Tolle and coworkers have suggested that exercise-induced pulmonary hypertension (PH) may represent an intermediate phenotype "between" normal and resting PH (21).…”

Section: Methodsmentioning

confidence: 99%

Exercise‐induced pulmonary hypertension associated with systemic sclerosis: Four distinct entities

Saggar

Khanna

Fürst

et al. 2010

Objective. Exercise-induced pulmonary hypertension (PH) may represent an early but clinically relevant phase in the spectrum of pulmonary vascular disease. There are limited data on the prevalence of exerciseinduced PH determined by right heart catheterization in scleroderma spectrum disorders. We undertook this study to describe the hemodynamic response to exercise in a homogeneous population of patients with scleroderma spectrum disorders at risk of developing pulmonary vascular disease. Methods.Patients with normal resting hemodynamics underwent supine lower extremity exercise testing. A classification and regression tree (CART) analysis was used to assess combinations of variables collected during resting right heart catheterization that best predicted abnormal exercise physiology, applicable to each individual subject.Results. Fifty-seven patients who had normal resting hemodynamics underwent subsequent exercise right heart catheterization. Four distinct hemodynamic groups were identified during exercise: a normal group, an exercise-induced pulmonary venous hypertension (ePVH) group, an exercise out of proportion PH (eoPH) group, and an exercise-induced PH (ePH) group. The eoPH and ePVH groups had higher pulmonary capillary wedge pressure (PCWP) than the ePH group (P < 0.05). The normal and ePH groups had exercise PCWP <18 mm Hg, which was lower than that in the ePVH and eoPH groups (P < 0.05). During submaximal exercise, the transpulmonary gradient and pulmonary vascular resistance (PVR) were elevated in the ePH and eoPH groups as compared with the normal and ePVH groups (P < 0.05). CART analysis suggested that resting mean pulmonary artery pressure (mPAP) >14 mm Hg and PVR >160 dynes/seconds/cm ؊5 were associated with eoPH and ePH (positive predictive value 89% for mPAP 14-20 mm Hg and 100% for mPAP >20 mm Hg).Conclusion. We characterized the exercise hemodynamic response in at-risk patients with scleroderma spectrum disorders who did not have resting PH. Four distinct hemodynamic groups were identified during exercise. These groups may have potentially different prognoses and treatment options.