Simvastatin as a treatment for pulmonary hypertension trial

Abstract

Rationale: In animal models of pulmonary hypertension, simvastatin has been shown to reduce pulmonary artery pressure and induce regression of associated right ventricular (RV) hypertrophy.

Objectives: To assess the therapeutic value of simvastatin in patients with pulmonary arterial hypertension (PAH).

Methods: Forty-two patients with PAH were randomized to receive either simvastatin (80 mg/d) or placebo in addition to current care for 6 months, and thereafter offered open-label simvastatin. The primary outcome was change in RV mass, assessed by cardiac magnetic resonance (CMR).

Measurements and main results: At 6 months, RV mass decreased by 5.2 +/- 11 g in the statin group (P = 0.045) and increased 3.9 +/- 14 g in the placebo group. The treatment effect was -9.1 g (P = 0.028). N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels decreased significantly in the statin group (-75 +/- 167 fmol/ml; P = 0.02) but not the placebo group (49 +/- 224 fmol/ml; P = 0.43; overall treatment effect -124 fmol/ml; P = 0.041). There were no significant changes in other outcome measures (including 6-minute walk test, cardiac index, and circulating cytokines). From 6 to 12 months, both RV mass and NT-proBNP increased toward baseline values in 16 patients on active treatment who continued with simvastatin but remained stable in 18 patients who switched from placebo to simvastatin. Two patients required a reduction in dose but not cessation of simvastatin.

Conclusions: Simvastatin added to conventional therapy produces a small and transient early reduction in RV mass and NT-proBNP levels in patients with PAH, but this is not sustained over 12 months.

Trial registration: ClinicalTrials.gov NCT00180713.

Figure 1.

Schematic overview of study. PAH = pulmonary arterial hypertension.

Figure 2.

Analysis of RV (right ventricular) mass changes over initial 6 months by intention to treat. (A) Change in fractional RV mass (g) after 6 months of treatment with placebo or simvastatin added to usual care. (B) Box and whisker plot of change in RV mass from baseline in placebo- (n = 23) and simvastatin- (n = 19) treated patients.

Figure 3.

Change in (A) fractional right ventricular mass, (B) fractional N-terminal pro–B-type natriuretic peptide levels, and (C) fractional total cholesterol levels over 12 months. From 0 to 6 months represents double-blind randomization to simvastatin or placebo. From 6 to 12 months patients were on open-label simvastatin (80 mg). Dotted lines indicate per-protocol analysis; solid lines indicate intention-to-treat analysis. Measurements were made at discrete time points as indicated by the ticks of the x axis. ITT = intention to treat; NT-proBNP = N-terminal pro–B-type natriuretic peptide; PP = per protocol; RV = right ventricular.

Figure 4.

Change in plasma nitric oxide metabolites (μmol/L) before and after 6 months of treatment with simvastatin or placebo. Statistics shown are paired t tests. Box plots indicate median and quartiles. NOx = nitric oxide metabolites.