Endothelin antagonism and uric acid levels in pulmonary arterial hypertension: Clinical associations

https://doi.org/10.1016/j.healun.2014.01.853Get rights and content

Background

Elevated serum uric acid is detected in pulmonary arterial hypertension (PAH) and is associated with poor patient outcomes. High serum uric acid is an independent risk factor for cardiovascular disease and renal impairment. We analyzed the effects of endothelin receptor antagonism on serum uric acid in PAH patients participating in the Sitaxentan to Relieve Impaired Exercise (STRIDE)-2/2X trial, and the impact of uric acid on 6-minute walk distance (6MWD), time to clinical worsening (TtCW) and survival.

Methods

In the 18-week, double-blind, placebo-controlled STRIDE-2 trial, 246 PAH patients were randomized and received matched placebo, sitaxentan 50 or 100 mg orally once daily, or open-label bosentan 125 mg twice daily. STRIDE-2X was a 1-year, open-label extension of STRIDE-2.

Results

Baseline serum uric acid was similar between groups. Increased serum uric acid was a significant risk factor for 1-year mortality and TtCW. Compared with placebo, sitaxentan 50 and 100 mg and bosentan all reduced serum uric acid (p < 0.05). Reduced serum uric acid correlated with increased 6MWD (p = 0.0037).

Conclusions

Endothelin receptor antagonism reduces serum uric acid in PAH patients, and this reduction is associated with improved survival and longer TtCW. Further prospective studies are needed to investigate the pathogenic role of serum uric acid in PAH and its prognostic potential.

Section snippets

Methods

The rationale and study design for the randomized, double-blind, placebo-controlled STRIDE-2 trial have been reported.17 Briefly, patients with PAH were randomized 1:1:1:1 to receive sitaxentan 50 or 100 mg or matched placebo orally once daily, or open-label bosentan 125 mg twice daily for 18 weeks. STRIDE-2X was an open-label extension of STRIDE-2.18 Patients were eligible if they completed the STRIDE-2 trial or had prematurely discontinued placebo or sitaxentan 50 mg in STRIDE-2 because of

Results

In this post hoc analysis, 246 patients from STRIDE-2/2X were assessed. Patients’ characteristics, primary and secondary study end-points and safety data have been reported previously.17 Briefly, STRIDE-2 demonstrated that sitaxentan 100 mg significantly improved exercise capacity and WHO FC compared with placebo; 50 mg was sub-therapeutic. Comparisons between sitaxentan and open-label bosentan were strictly observational because of the inability to blind the bosentan arm.

Baseline serum uric

Discussion

In this study, short-term increased serum uric acid was a risk factor for 1-year mortality and clinical worsening in PAH, whereas decreased (or maintained) serum uric acid was associated with an improvement in these outcomes. Both selective ETA (sitaxentan) and mixed ETA/B (bosentan) receptor antagonists effectively reduced serum uric acid in patients with PAH, and reduction was slightly affected by diuretic use.

The high levels of serum uric acid (baseline mean 6.4 mg/dl) in this study confirm

Disclosure statement

N.D. has received research grants and held academic fellowships from Pfizer Inc J.-L.V. has received consulting fees from Actelion, GlaxoSmithKline, Pfizer Inc, and United Therapeutics Europe, and has received speaker fees from Actelion, BayerSchering, Eli Lilly, GlaxoSmithKline, Pfizer Inc, and United Therapeutics Europe. R.L.B. has received research grants and honoraria for speaking from Pfizer Inc R.N. declares no conflicts of interest. L.-J.H. and S.T. are employees of Pfizer Inc, and hold

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