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Reduction in Serum Uric Acid Levels in Response to Tadalafil Predicts Improved Outcome in PAH

Michael Risbano

Hunter Champion


Michael Mathier


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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 06.22.2012

Presentation Type: Abstracts

Risbano MG, Champion HC, Mathier MM.

Comprehensive Pulmonary Hypertension Program, University of Pittsburgh, Pittsburgh PA,

BACKGROUNDAdvanced pulmonary arterial hypertension (PAH) is a devastating disease characterized by increased pulmonary vascular resistance and low cardiac output. Uric acid (UA) is the end product of purine degradation and may be released into the circulation due to peripheral tissue hypoxia and ischemia. UA levels have been shown to be elevated in idiopathic PAH (iPAH) and PAH associated with connective tissue disease (APAH). UA levels inversely correlate with cardiac output and decrease with vasodilator therapy. We sought to evaluate the predictive value of uric acid levels, pre and post oral vasodilator therapy, on clinical outcomes in subjects with advanced PAH.

METHODSA retrospective analysis of the PHIRST trial, a multicenter, 16-week, double blind, placebo-controlled trial of the phosphodiesterase type 5 inhibitor tadalafil in patients with iPAH and APAH. Patients were either treatment-naive or on background therapy with the endothelin receptor antagonist bosentan. Serum UA levels were measured and evaluated at baseline and week 16 in subjects receiving tadalafil (n=302) versus placebo (n=76). A sub-study of patients undergoing invasive hemodynamic evaluation (tadalafil (n=77); placebo (n=18)) was also analyzed. Time to clinical worsening (TTCW) was defined as death, lung or heart-lung transplantation, hospitalization due to worsening PAH, initiation of new PAH-approved therapy or worsening WHO functional class.

RESULTSTreatment with tadalafil resulted in a statistically significant increase in cardiac index at week 16 (p=0.026) and a decrease in UA levels when compared to placebo (p=0.002). Elevated UA levels at baseline for subjects treated with tadalafil were associated with a significantly increased risk of death (n=302; HR=1.722; p=0.023). Elevated UA levels at baseline for all subjects (tadalafil and placebo) were associated with a statistically significant increase in TTCW (n=378; HR=1.294; p=0.003). A decrease in UA level after treatment with tadalafil resulted in a 27% improvement in the TTCW (n=237; HR=0.631; p=0.024).

CONCLUSIONElevated baseline UA levels are associated with increased risk of long-term morbidity and mortality in patients with PAH. A reduction of UA levels following treatment with tadalafil is associated with improved morbidity and mortality. Whether the reduction in UA contributes to the clinical benefit of tadalafil in PAH is unclear.