A study of aspirin and clopidogrel in idiopathic pulmonary arterial hypertension

Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is characterised by in situ thrombosis and increased thromboxane (Tx) A 2 synthesis; however, there are no studies of antiplatelet therapy in IPAH. The aim of the current study was to determine the biochemical effects of aspirin (ASA) and clopidogrel on platelet function and eicosanoid metabolism in patients with IPAH.A randomised, double-blind, placebo-controlled crossover study of ASA 81 mg once daily and clopidogrel 75 mg once daily was performed. Plasma P-selectin levels and aggregometry were measured after exposure to adenosine diphosphate, arachidonic acid and collagen. Serum levels of TxB 2 and urinary metabolites of TxA 2 and prostaglandin I 2 (Tx-M and PGI-M, respectively) were assessed.A total of 19 IPAH patients were enrolled, of whom nine were being treated with continuous intravenous epoprostenol. ASA and clopidogrel significantly reduced platelet aggregation to arachidonic acid and adenosine diphosphate, respectively. ASA significantly decreased serum TxB 2 , urinary Tx-M levels and the Tx-M/PGI-M ratio, whereas clopidogrel had no effect on eicosanoid levels. Neither drug significantly lowered plasma P-selectin levels. Epoprostenol use did not affect the results.In conclusion, aspirin and clopidogrel inhibited platelet aggregation, and aspirin reduced thromboxane metabolite production without affecting prostaglandin I 2 metabolite synthesis. Further clinical trials of aspirin in patients with idiopathic pulmonary arterial hypertension should be performed.

Major bleeding with vitamin K antagonist anticoagulants in pulmonary hypertension

“…Preliminary studies evaluating the benefit of pure platelet function inhibitors have so far not led to prospective trials evaluating optimal anticoagulant treatment in PAH patients [32]. Nevertheless, the major bleeding rate in our cohort of IPAH patients, and in CTD-PAH patients especially, not only supersedes that of CTEPH patients, but more importantly, the rate is much higher than reported bleeding rates in larger, prospective studies [13,15,18].…”

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.…”

A Randomized Clinical Trial Of Aspirin And Simvastatin For Pulmonary Arterial Hypertension: ASA-STAT

“…2 Since Tx:PGI 2 ratio is elevated in PAH and platelet aggregation is thought to contribute to disease pathogenesis, it was hypothesized that platelet inhibition with aspirin would translate to clinical benefit in terms of exercise capacity. While aspirin suppressed production of TxB 2 by > 90%, there was no effect on 6MWD, NT-proBNP, or quality-oflife.…”

“…Patients with PAH have increased TxA 2 (and TxB 2 ) production and decreased PGI 2 production resulting in an increased Tx:PGI 2 ratio, even with treatment. [1][2][3][4][5] Clinical trials of intravenous epoprostenol 6 and other prostacyclin analogs which are efficacious in PAH [7][8][9] were predicated on the inference that low endogenous PGI 2 (and increased Tx:PGI 2 ratio) is detrimental in PAH. Investigators have visualized circulating platelet aggregates in the blood of patients with PAH, 10 and increased platelet aggregation is associated with more severe PAH.…”