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Tadalafil: the evidence for its clinical potential in the treatment of pulmonary arterial hypertension.

ABSTRACT: INTRODUCTION:Pulmonary arterial hypertension (PAH), characterized by increased pulmonary artery pressures in the absence of elevated pulmonary venous pressures, is a progressive disease associated with reduced exercise capacity and increased mortality risk. Current treatments for PAH include nonspecific vasodilators, prostacyclin and related analogs, and endothelin receptor antagonists. Since phosphodiesterase type 5 is highly expressed in pulmonary vascular tissues, agents that selectively inhibit phosphodiesterase type 5 activity induce pulmonary arterial vasodilatation, and are being developed for the treatment of PAH. AIMS:The purpose of this review is to evaluate the existing evidence for the use of tadalafil, a selective phosphodiesterase type 5 inhibitor, in PAH. EVIDENCE REVIEW:Data from erectile dysfunction populations indicate that tadalafil is well tolerated with an elimination half-life of 17.5 hours. Small pilot studies in patients with PAH of mixed etiology demonstrate that tadalafil reduces pulmonary vascular resistance and is associated with improved clinical status. A multicenter, randomized, placebo-controlled clinical trial in patients with PAH is currently recruiting patients. CLINICAL POTENTIAL:Based on existing studies of sildenafil, a related selective phosphodiesterase type 5 inhibitor in PAH, and the findings of initial pilot studies, tadalafil appears to have excellent potential to provide therapeutic benefit in patients with pulmonary hypertension. The long elimination half-life of tadalafil makes it suitable for once-daily dosing.

SUBMITTER: Katz SD

PROVIDER: S-EPMC3012445 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Tadalafil: the evidence for its clinical potential in the treatment of pulmonary arterial hypertension.

Katz Stuart D SD

Core evidence 20080731 4

<h4>Introduction</h4>Pulmonary arterial hypertension (PAH), characterized by increased pulmonary artery pressures in the absence of elevated pulmonary venous pressures, is a progressive disease associated with reduced exercise capacity and increased mortality risk. Current treatments for PAH include nonspecific vasodilators, prostacyclin and related analogs, and endothelin receptor antagonists. Since phosphodiesterase type 5 is highly expressed in pulmonary vascular tissues, agents that selectiv ...[more]

PMID: 21221188

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Project description:BackgroundScleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH.MethodsIn this prospective, multicenter, open-label trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg daily for 36 weeks. Functional, hemodynamic, and imaging (cardiac magnetic resonance imaging and echocardiography) assessments at baseline and 36 weeks included changes in right ventricular (RV) mass and pulmonary vascular resistance as co-primary endpoints and stroke volume/pulmonary pulse pressure ratio, tricuspid annular plane systolic excursion, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide as secondary endpoints.ResultsAt 36 weeks, we found that treatment had resulted in significant reductions in median (interquartile range [IQR]) RV mass (28.0 g [IQR, 20.6-32.9] vs. 32.5 g [IQR, 23.2-41.4]; P < 0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P < 0.0001) and in improvements in median stroke volume/pulmonary pulse pressure ratio (2.6 ml/mm Hg [IQR, 1.8-3.5] vs. 1.4 ml/mm Hg [IQR 8.9-2.4]; P < 0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P < 0.0001), 6-minute walk distance (395 ± 99 m vs. 343 ± 131 m; P = 0.001), and serum N-terminal pro-brain natriuretic peptide (647 ± 1,127 pg/ml vs. 1,578 ± 2,647 pg/ml; P < 0.05).ConclusionsUp-front combination therapy with ambrisentan and tadalafil significantly improved hemodynamics, RV structure and function, and functional status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for this patient population. In addition, we identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT01042158).

Project description:Pulmonary hypertension is defined as a resting mean pulmonary artery pressure of 25 mm Hg or above. This review deals with pulmonary arterial hypertension (PAH), a type of pulmonary hypertension that primarily affects the pulmonary vasculature. In PAH, the pulmonary vasculature is dynamically obstructed by vasoconstriction, structurally obstructed by adverse vascular remodeling, and pathologically non-compliant as a result of vascular fibrosis and stiffening. Many cell types are abnormal in PAH, including vascular cells (endothelial cells, smooth muscle cells, and fibroblasts) and inflammatory cells. Progress has been made in identifying the causes of PAH and approving new drug therapies. A cancer-like increase in cell proliferation and resistance to apoptosis reflects acquired abnormalities of mitochondrial metabolism and dynamics. Mutations in the type II bone morphogenetic protein receptor (BMPR2) gene dramatically increase the risk of developing heritable PAH. Epigenetic dysregulation of DNA methylation, histone acetylation, and microRNAs also contributes to disease pathogenesis. Aberrant bone morphogenetic protein signaling and epigenetic dysregulation in PAH promote cell proliferation in part through induction of a Warburg mitochondrial-metabolic state of uncoupled glycolysis. Complex changes in cytokines (interleukins and tumor necrosis factor), cellular immunity (T lymphocytes, natural killer cells, macrophages), and autoantibodies suggest that PAH is, in part, an autoimmune, inflammatory disease. Obstructive pulmonary vascular remodeling in PAH increases right ventricular afterload causing right ventricular hypertrophy. In some patients, maladaptive changes in the right ventricle, including ischemia and fibrosis, reduce right ventricular function and cause right ventricular failure. Patients with PAH have dyspnea, reduced exercise capacity, exertional syncope, and premature death from right ventricular failure. PAH targeted therapies (prostaglandins, phosphodiesterase-5 inhibitors, endothelin receptor antagonists, and soluble guanylate cyclase stimulators), used alone or in combination, improve functional capacity and hemodynamics and reduce hospital admissions. However, these vasodilators do not target key features of PAH pathogenesis and have not been shown to reduce mortality, which remains about 50% at five years. This review summarizes the epidemiology, pathogenesis, diagnosis, and treatment of PAH.

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Tadalafil: the evidence for its clinical potential in the treatment of pulmonary arterial hypertension.

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Tadalafil: the evidence for its clinical potential in the treatment of pulmonary arterial hypertension.

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