Zeenat Safdar

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis. Eligible subjects were adults with idiopathic pulmonary fibrosis of <3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo. Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n=119) or placebo (n=59). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients. In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group. Long-term exposure to macitentan was well tolerated in IPF in a trial that did not meet its primary end-point http://ow.ly/p0RDL

Portopulmonary hypertension: An update

Portopulmonary hypertension (POPH) is a serious complication of cirrhosis that is associated with mortality beyond that predicted by the Model for End‐Stage Liver Disease (MELD) score. Increased pulmonary vascular resistance (PVR) may be initiated by pulmonary vasoconstriction, altered levels of circulating mediators, or shear stress, and can eventually lead to the classic vascular remodeling (plexiform lesion) that characterizes POPH. Portal hypertension is a prerequisite for the diagnosis of POPH, although the severity of pulmonary hypertension is unrelated to the severity of portal hypertension or the nature or severity of liver disease. POPH precludes liver transplantation (LT) unless the mean pulmonary artery pressure (MPAP) can be reduced to a safe level. The concept of an acceptable pressure has changed: we now consider both MPAP and PVR in the diagnosis, and we include the transpulmonary pressure gradient so that we can factor in fluid overload and left ventricular failure. Pulmonary vasodilator therapy includes oral, inhaled, and parenteral agents, and one or more of these agents may significantly lower pulmonary artery pressures to the point that LT becomes possible. The United Network for Organ Sharing recommends MELD exception points for patients with medically controlled POPH, but this varies by region. Patients who undergo LT need specialized intraoperative and postoperative management, which includes the availability of intraoperative transesophageal echocardiography for assessing right ventricular function, and rapidly acting vasodilators (eg, inhaled nitric oxide and/or epoprostenol). Published case series suggest excellent outcomes after LT for patients who respond to medical therapy. Liver Transpl , 2012.

Management of pulmonary arterial hypertension during pregnancy: a retrospective, multicenter experience.

BACKGROUND Pulmonary arterial hypertension (PAH) is a rare disease with a predilection for young women that is associated with right ventricular failure and premature death. PAH can complicate pregnancy with hemodynamic instability or sudden death during parturition and postpartum. Our aim was to examine the impact of PAH on pregnancy outcomes in the modern era. METHODS We conducted a retrospective evaluation of pregnant patients with PAH managed between 1999 and 2009 at five US medical centers. Patient demographics, medical therapies, hemodynamic measurements, manner of delivery, anesthetic administration, and outcomes were assessed. RESULTS Among 18 patients with PAH, 12 continued pregnancy and six underwent pregnancy termination. Right ventricular systolic pressure in patients managed to parturition was 82 ± 5 mm Hg and in patients with pregnancy termination was 90 ± 16 mm Hg. Six patients underwent pregnancy termination at mean gestational age of 13 ± 1.0 weeks with no maternal deaths or complications. Twelve patients elected to continue their pregnancy and were hospitalized at 29 ± 1.4 weeks. PAH-specific therapy was administered to nine (75%) at time of delivery consisting of sildenafil, IV prostanoids, or combination therapy. All parturients underwent Cesarean section at 34 weeks with one in-hospital death and one additional death 2 months postpartum for maternal mortality of 16.7%. CONCLUSIONS Compared with earlier reports, maternal morbidity and mortality among pregnant women with PAH was reduced, yet maternal complications remain significant and patients should continue to be counseled to avoid pregnancy.

Original ResearchPulmonary Vascular DiseasesManagement of Pulmonary Arterial Hypertension During Pregnancy: A Retrospective, Multicenter Experience

BACKGROUND Pulmonary arterial hypertension (PAH) is a rare disease with a predilection for young women that is associated with right ventricular failure and premature death. PAH can complicate pregnancy with hemodynamic instability or sudden death during parturition and postpartum. Our aim was to examine the impact of PAH on pregnancy outcomes in the modern era. METHODS We conducted a retrospective evaluation of pregnant patients with PAH managed between 1999 and 2009 at five US medical centers. Patient demographics, medical therapies, hemodynamic measurements, manner of delivery, anesthetic administration, and outcomes were assessed. RESULTS Among 18 patients with PAH, 12 continued pregnancy and six underwent pregnancy termination. Right ventricular systolic pressure in patients managed to parturition was 82 ± 5 mm Hg and in patients with pregnancy termination was 90 ± 16 mm Hg. Six patients underwent pregnancy termination at mean gestational age of 13 ± 1.0 weeks with no maternal deaths or complications. Twelve patients elected to continue their pregnancy and were hospitalized at 29 ± 1.4 weeks. PAH-specific therapy was administered to nine (75%) at time of delivery consisting of sildenafil, IV prostanoids, or combination therapy. All parturients underwent Cesarean section at 34 weeks with one in-hospital death and one additional death 2 months postpartum for maternal mortality of 16.7%. CONCLUSIONS Compared with earlier reports, maternal morbidity and mortality among pregnant women with PAH was reduced, yet maternal complications remain significant and patients should continue to be counseled to avoid pregnancy.

Critical Role for IL-18 in Spontaneous Lung Inflammation Caused by Autophagy Deficiency

Autophagy is an important component of the immune response. However, the functions of autophagy in human diseases are much less understood. We studied biological consequences of autophagy deficiency in mice lacking the essential autophagy gene Atg7 or Atg5 in myeloid cells. Surprisingly, these mice presented with spontaneous sterile lung inflammation, characterized by marked recruitment of inflammatory cells, submucosal thickening, goblet cell metaplasia, and increased collagen content. Lung inflammation was associated with increase in several proinflammatory cytokines in the bronchoalveolar lavage and in serum. This inflammation was largely driven by IL-18 as a result of constitutive inflammasome activation. Following i.p. LPS injection, autophagy-deficient mice had higher levels of proinflammatory cytokines in lungs and in serum, as well as increased mortality, than control mice. Intranasal bleomycin challenge exacerbated lung inflammation in autophagy-deficient mice and produced more severe fibrotic changes than in control mice. These results uncover a new and important role for autophagy as negative regulator of lung inflammation.

Circulating Collagen Biomarkers as Indicators of Disease Severity in Pulmonary Arterial Hypertension

OBJECTIVES The goal of this study was to determine if biomarkers of collagen metabolism in PAH identify patients with worse disease and higher risk of death. BACKGROUND The relationship between circulating markers of collagen metabolism, degree of disease severity, and outcome in pulmonary arterial hypertension (PAH) is unknown. METHODS Patients with stable idiopathic, anorexigen-associated, and hereditary PAH were prospectively enrolled. Levels of the following collagen biomarkers were measured: N-terminal pro-peptide of type III procollagen (PIIINP), C-terminal telopeptide of collagen type I (CITP), matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1. Patients were divided into mild, moderate, and severe PAH groups. Data were compared between tertiles of each biomarker. Pearson correlation and Spearman rank coefficient analyses were performed. Data on time to death or transplantation were examined by Kaplan-Meier survival curves. RESULTS Circulating levels of PIIINP, CITP, MMP-9, and TIMP-1 were higher in the PAH group (n = 68) as compared with age- and sex-matched healthy controls (n = 37) (p < 0.001 for each). PIIINP levels increased with the severity of disease (p = 0.002). PIIINP tertile data indicated that with increasing levels, 6-min walk distance and cardiac index decreased, World Health Organization functional classification worsened, and resting heart rate increased. A significant correlation existed between PIIINP levels and worsening World Health Organization functional classification (rs = 0.320; p < 0.01), and there was a negative correlation between cardiac index and 6-min walk distance (r = -0.304 and r = -0.362, respectively; p < 0.05). PIIINP tertiles showed a trend toward worse outcome in patients with higher tertiles (lung transplant or death) (p = 0.07; log-rank test). CONCLUSIONS Markers of collagen metabolism were associated with worse disease in patients with PAH.

Risk assessment in pulmonary hypertension associated with heart failure and preserved ejection fraction

BACKGROUND Pulmonary hypertension (PH) is common in patients with left heart failure (HF), especially those with HF and preserved ejection fraction (HFpEF). However, there is limited data on risk stratification in these patients. METHODS Baseline clinical and hemodynamic variables of 339 patients with World Health Organization (WHO) Group 2 PH, 90% of whom had HFpEF, were studied to derive a multivariate Cox proportional hazards model. A simplified prognostic risk score was created based on the outcome of all-cause mortality. Nine predictors, significant after stepwise multivariable regression (p < 0.05), were used to create the risk score. Components of the risk score were functional class, diastolic blood pressure, pulmonary artery saturation, interstitial lung disease, hypotension on initial presentation, right ventricular hypertrophy, diffusion capacity of the lung for carbon monoxide, and 2 serum creatinine variables (≤ 0.9 mg/dl and ≥ 1.4 mg/dl). RESULTS Overall 2-year survival was 73.8% ± 2.4% in the derivation cohort, and 87.5% ± 2.3%, 66.4% ± 4.9%, and 24.4% ± 6.7% for risk scores of 0 to 2, 3 to 4, and 5+, respectively (p < 0.0001 for the trend), with a C-index of 0.76 (95% confidence interval [CI], 0.71-0.81). The risk score was validated in 2 independent PH-HFpEF cohorts: 179 patients with a C-index of 0.68 (95% CI, 0.55-0.80) and 117 patients with a C-index of 0.68 (95% CI, 0.53-0.83). For the 3 cohorts combined (N = 635), the overall C-index was 0.72 (95% CI 0.68-0.76). In all 3 cohorts individually and in the 3 cohorts combined, the risk score predicted death (hazard ratio, 1.4-1.6; p < 0.01). CONCLUSIONS Several clinical factors independently predict death in PH-HFpEF confirmed by validation. A novel risk score composed of these factors can be used to determine prognosis and may be useful in making therapeutic decisions.

Treatment of pulmonary arterial hypertension: the role of prostacyclin and prostaglandin analogs.

Pulmonary arterial hypertension is a progressive, fatal disease characterized by elevated pulmonary arterial pressure ≥25 mm Hg and normal pulmonary capillary wedge pressure ≤ 5 mm Hg. Physiological features of pulmonary arterial hypertension are characterized clinically by the presence of pre-capillary pulmonary hypertension not caused by other conditions such as lung diseases or chronic thromboembolic pulmonary hypertension. There are several therapies currently available that have been shown to improve hemodynamics and improve outcomes in patients with pulmonary arterial hypertension. These therapies include synthetic prostacyclin and prostaglandin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Multiple prostacyclin and prostaglandin analog formulations are currently in use (both branded and generic), available for parenteral, inhaled, or oral administration. This review discusses the pharmacology, clinical effects, and routes of administration of prostacyclin and prostaglandin analogs, emphasizing the advantages and disadvantages of each from the clinical perspective.

Outcome of pulmonary hypertension subjects transitioned from intravenous prostacyclin to oral bosentan

INTRODUCTION Prostacyclin (PG) remains the gold standard therapy for severe pulmonary arterial hypertension (PAH). Previously, we reported the successful transitioning of PAH subjects from intravenous prostacyclin to oral bosentan (Suleman et al. Chest 2004;126:808-15). We report here the 5-year follow-up data. METHODS In the transition study, 11 PAH subjects were successfully transitioned to oral bosentan in 12 weeks. Two subjects who subsequently developed liver function test (LFT) abnormalities were taken off bosentan and switched to another endothelin receptor antagonist. Demographics, six-minute walk distance (6MWD), WHO functional class (FC), and survival data was collected. RESULTS 10 Females and 1 male ranging in age from 35 to 79 were successfully transitioned. Mean duration of illness prior to transition was 50.55+/-26 months. Mean duration that these subjects remained on oral therapy was 34+/-24 months. Mean duration that patients remained off PG was 28+/-21 months. In 7 of the 11 subjects (64%), PG was resumed due to clinical deterioration. One patient remained on bosentan as monotherapy, five had phosphodiesterase 5-inhibitor added. 9 Of the 11 subjects were WHO FC II post-transition and 5 of the 7 subjects at follow-up were WHO FC II (82% vs 67%). Post-transition 6MWD was 386+/-85 in 10 subjects and at follow-up 6MWD was 396+/-99 in 9 subjects (p=0.81). CONCLUSIONS In this study, patients frequently required prostanoid resumption after transition from intravenous prostanoid to oral therapy. However, in these carefully selected patients, transition to oral therapy offered prolonged stable FC and 6MWD, cost savings and substantial quality of life benefits.

Circulating Aldosterone Levels and Disease Severity in Pulmonary Arterial Hypertension.

Objectives: It is not known whether aldosterone levels are associated with increased mortality in patients with pulmonary arterial hypertension (PAH). The primary goal of this study was to determine whether circulating aldosterone levels predict severity of PAH in terms of hemodynamic characteristics and mortality. Methods: Patients with stable PAH were enrolled at the Baylor PH program. The plasma levels of aldosterone and BNP were measured. Clinical, hemodynamic, and outcome data was collected by chart review. Mean follow up time from study enrollment was 39 ± 102 months. Cox proportional hazards model was used to assess time to death. Results: There were 125 PAH patients with plasma aldosterone levels. Median aldosterone level was 9.9 pg/ml (25th-75th percentile: 4.1 pg/ml, 27.1 pg/ml) and median brain natriuretic peptide (BNP) level was 67.5 pg/ml (25th- 75th percentile: 31 pg/ml, 225 pg/ml). Aldosterone levels were not significantly associated with BNP levels, six-minute walk distance, Borg dyspnea score, right ventricular systolic pressure, cardiac output and cardiac index. However, the association between aldosterone and right atrial pressure was dependent on mineralocorticoid receptor blocker treatment (Coef.=2.88, 95CI: 1.19, 4.56, p=0.001). By log-rank statistic there was no statistical difference between the survival of patients divided by median aldosterone level (p=0.914). However, there was a significant difference in patient survival between the BNP categories (p 180 pg/mL) had a shorter survival time. conclusions: The aldosterone level was not associated with increased mortality in PAH but was a marker of disease severity.