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Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension.

ABSTRACT: Our aim is to assess the safety and potential clinical benefit of intravenous iron (Ferinject) infusion in iron deficient patients with idiopathic pulmonary arterial hypertension (IPAH). Iron deficiency in the absence of anemia (1) is common in patients with IPAH; (2) is associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis; and (3) correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by reduced absorption due to elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown. Supplementation of Iron in Pulmonary Hypertension (SIPHON) is a Phase II, multicenter, double-blind, randomized, placebo-controlled, crossover clinical trial of iron in IPAH. At least 60 patients will be randomized to intravenous ferric carboxymaltose (Ferinject) or saline placebo with a crossover point after 12 weeks of treatment. The primary outcome will be the change in resting pulmonary vascular resistance from baseline at 12 weeks, measured by cardiac catheterization. Secondary measures include resting and exercise hemodynamics and exercise performance from serial bicycle incremental and endurance cardiopulmonary exercise tests. Other secondary measurements include serum iron indices, 6-Minute Walk Distance, WHO functional class, quality of life score, N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac anatomy and function from cardiac magnetic resonance. We propose that intravenous iron replacement will improve hemodynamics and clinical outcomes in IPAH. If the data supports a potentially useful therapeutic effect and suggest this drug is safe, the study will be used to power a Phase III study to address efficacy.

SUBMITTER: Howard LS

PROVIDER: S-EPMC3641712 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension.

Howard Luke S G E LS Watson Geoffrey M J GM Wharton John J Rhodes Christopher J CJ Chan Kakit K Khengar Rajeshree R Robbins Peter A PA Kiely David G DG Condliffe Robin R Elliott Charlie A CA Pepke-Zaba Joanna J Sheares Karen K Morrell Nicholas W NW Davies Rachel R Ashby Deborah D Gibbs J Simon R JS Wilkins Martin R MR

Pulmonary circulation 20130101 1

Our aim is to assess the safety and potential clinical benefit of intravenous iron (Ferinject) infusion in iron deficient patients with idiopathic pulmonary arterial hypertension (IPAH). Iron deficiency in the absence of anemia (1) is common in patients with IPAH; (2) is associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis; and (3) correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by reduced absorption du ...[more]

PMID: 23662181

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Project description:Pulmonary vascular arterial remodeling is an integral and well-understood component of pulmonary hypertension (PH). In contrast, morphological alterations of pulmonary veins in PH are scarcely described. Explanted lungs (n = 101) from transplant recipients with advanced chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary arterial hypertension (IPAH) were analyzed for venous vascular involvement according to a pre-specified, semi-quantitative grading scheme, which categorizes the intensity of venous remodeling in three groups of incremental severity: venous hypertensive (VH) grade 0 = characterized by an absence of venous vascular remodeling; VH grade 1 = defined by a dominance of either arterialization or intimal fibrosis; and VH grade 2 = a substantial composite of arterialization and intimal fibrosis. Patients were grouped according to clinical and hemodynamic characteristics in three groups: COPD non-PH, COPD-PH, and IPAH, respectively. Histological specimens were examined by a cardiovascular pathologist blinded to clinical and hemodynamic data. Pathological alterations of pulmonary veins were present in all hemodynamic groups, with the following incidences of VH grade 0/1/2: 34/66/0% in COPD non-PH; 19/71/10% in COPD-PH; and 11/61/28% in IPAH. In COPD, explorative correlation analysis of venous remodeling suggested a modest positive correlation with systolic and mean pulmonary artery pressure ( P = 0.032, respectively) and an inverse modest correlation with diffusion capacity for carbon monoxide ( P = 0.027). In addition, venous remodeling correlated positively with the degree of arterial remodeling ( P = 0.014). In COPD-PH and IPAH, advanced forms of pulmonary venous remodeling are present, emphasizing that the disease is not exclusively restricted to arterial lesions. In addition, venous remodeling may be related to the hemodynamic severity, but more rigorous analysis is required to clearly define potential relationships.

Project description:Background Metabolic dysfunction is highly prevalent in pulmonary arterial hypertension (PAH) and likely contributes to both pulmonary vascular disease and right ventricular (RV) failure in part because of increased oxidant stress. Currently, there is no cure for PAH and human studies of metabolic interventions, generally well tolerated in other diseases, are limited in PAH. Metformin is a commonly used oral antidiabetic that decreases gluconeogenesis, increases fatty acid oxidation, and reduces oxidant stress and thus may be relevant to PAH. Methods and Results We performed a single-center, open-label 8-week phase II trial of up to 2 g/day of metformin in patients with idiopathic or heritable PAH with the co-primary end points of safety, including development of lactic acidosis and study withdrawal, and plasma oxidant stress markers. Exploratory end points included RV function via echocardiography, plasma metabolomic analysis performed before and after metformin therapy, and RV triglyceride content by magnetic resonance spectroscopy in a subset of 9 patients. We enrolled 20 patients; 19/20 reached the target dose and all completed the study protocol. There was no clinically significant lactic acidosis or change in oxidant stress markers. Metformin did not change 6-minute walk distance but did significantly improve RV fractional area change (23±8% to 26±6%, P=0.02), though other echocardiographic parameters were unchanged. RV triglyceride content decreased in 8/9 patients (3.2±1.8% to 1.6±1.4%, P=0.015). In an exploratory metabolomic analysis, plasma metabolomic correlates of ?50% reduction in RV lipid included dihydroxybutyrate, acetylputrescine, hydroxystearate, and glucuronate (P<0.05 for all). In the entire cohort, lipid metabolites were among the most changed by metformin. Conclusions Metformin therapy was safe and well tolerated in patients with PAH in this single-arm, open-label phase II study. Exploratory analyses suggest that metformin may be associated with improved RV fractional area change and, in a subset of patients, reduced RV triglyceride content that correlated with altered lipid and glucose metabolism markers. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT01884051.

Dataset Information

Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension.

Publications

Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension.

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