Atorvastatin in Pulmonary Arterial Hypertension (APATH) study

Abstract

Statins have been shown to both prevent and attenuate pulmonary hypertension in animal models. This study investigates the potential therapeutic benefits of atorvastatin as an affordable treatment for pulmonary hypertension patients. 220 patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) were randomised, double-blind, to receive atrovastatin 10 mg daily or matching placebo in addition to supportive care.At 6 months, 6-min walk distance decreased by 16.6 m in the atorvastatin group and 14.1 m in the placebo group. The mean placebo-corrected treatment effect was -2.5 m (95% CI: -38-33; p50.96), based on intention to treat. A small nonsignificant increase in pulmonary vascular resistance and fall in cardiac output was seen in both treatment groups. There was no significant difference in the proportion of patients who improved, remained stable or showed a deterioration in World Health Organization functional class between atorvastatin and placebo treatments. Nine patients died in the atorvastatin group and 11 in the placebo group. Serum cholesterol levels fell significantly on atorvastatin treatment. Discontinuation rates were 23.2% and 26.9% on atorvastatin and placebo, respectively.Atorvastatin 10 mg daily has no beneficial effect on the natural history of PAH or CTEPH over 6 months.

Proinflammatory High‐Density Lipoprotein Results from Oxidized Lipid Mediators in the Pathogenesis of Both Idiopathic and Associated Types of Pulmonary Arterial Hypertension

“…[24][25][26][27][28] Further, in studies of pleiotropic HMG CoA (3-hydroxy-3-methyl-glutaryl coenzyme A) reductase inhibitor medications ("statins") which, despite effectuating a reduction in "oxidant stress," a reduction in Rho/Rho-kinase (ROCK) signaling, enhanced endothelial nitric oxide production, and increased expression of bone morphogenetic protein receptor type 2, have been disappointing in both the treatment of PAH and experimental models of vascular PGI 2 production. [29][30][31][32][33][34] "Oxidant stress" has been reported in PAH by Cracowski et al, 35 who described increased isoprostane urinary levels that correlated with worsened patient survival. Further, using oligonucleotide microarray gene expression, Geraci et al 36 have described an increase in pulmonary expression of oxidative genes in PAH patients.…”

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

“…Among the most investigated and consistent has been simvastatin, which in doses of 2 to 20mg/kg daily not only prevented but also consistently reversed pulmonary hypertension in animal models. Studies on human cells in culture demonstrated inhibition of vascular smooth muscle and fibroblast proliferation, providing further confidence of a direct anti-vascular remodeling effect but subsequent studies in PAH patients have failed to demonstrate a clear benefit (Kawut, Bagiella, Lederer, & Shimbo, 2011;Wilkins, Ali, Bradlow, & Wharton, 2010;Zeng et al, 2012). Simvastatin 40 to 80mg daily, the higher end of the dose range used for cholesterol reduction, reduced right ventricular mass transiently over 6 months but had no significant effect on 6 minute walk distance (Kawut et al, 2011;Wilkins et al, 2010).…”

Rosuvastatin, Sildenafil and Their Combination in Monocrotaline-Induced Pulmonary Hypertension in Rat

“…Nevertheless, recent clinical trials demonstrate only transient efficacy when phosphodiesterase type 5 inhibitor and/or endothelin receptor antagonist were supplemented by statins in PH (18). Such disappointing results have raised i.e., the question of whether particular statins at particular doses or regimens will be effective rather than all statins (18,20). The time when statin is added to PH conventional therapy might also influence its efficacy.…”