Hemodynamic effects of carvedilol plus simvastatin in cirrhosis with severe portal hypertension and suboptimal response to β-blockers: A double-blind, placebo-controlled, randomized trial

Abstract

Background and aims: Carvedilol is a nonselective β-blocker (NSBB) with anti-α1-adrenergic activity, more effective than traditional NSBBs in reducing portal pressure hepatic venous pressure gradient (HVPG). However, 35%-45% of patients still have insufficient HVPG decrease. Statins ameliorate endothelial dysfunction, reduce hepatic vascular resistance, and have pleiotropic effects. We investigated whether the addition of simvastatin improves the efficacy of carvedilol on HVPG in cirrhosis with severe portal hypertension and suboptimal response to traditional NSBBs.

Methods: Patients with cirrhosis and high-risk varices referred for primary prophylaxis were consecutively included. HVPG was measured at baseline and again after i.v. propranolol. Suboptimal responders (HVPG decrease <20%) were treated with carvedilol and were randomized to double-blind administration of placebo or simvastatin. Chronic HVPG response was assessed after 4-6 weeks, repeating HVPG measurements after a standard liquid meal to estimate endothelial dysfunction. Plasma samples were obtained before each study to investigate inflammatory parameters.

Results: Of 184 eligible patients, 82 were randomized to carvedilol + simvastatin (N = 41) or carvedilol + placebo (N = 41). Baseline characteristics were similar. HVPG significantly decreased with both, carvedilol + simvastatin (18.6 ± 4 to 15.7 ± 4 mm Hg, p < 0.001) and carvedilol + placebo (18.9 ± 3 to 16.9 ± 3 mm Hg, p < 0.001). The decrease was greater with carvedilol + simvastatin (2.97 ± 2.5 vs. 2.05 ± 1.6 mm Hg, p = 0.031). An HVPG decrease ≥20% occurred in 37% versus 15% of patients, respectively (OR: 3.37, 95% CI = 1.15-9.85; p = 0.021). With test meal, HVPG increased in both groups ( p < 0.01), although carvedilol + simvastatin attenuated such increment (12 ± 8% vs. 23 ± 16%, p < 0.001). Cytokine levels (Interleukine-6, monocyte-chemoattractant protein-1, and malondialdehyde) decreased significantly more with carvedilol + simvastatin ( p < 0.01). The incidence of adverse events was similar.

Conclusions: In patients with severe portal hypertension (all with high-risk varices) and suboptimal hemodynamic response to traditional NSBBs, combined therapy with carvedilol plus simvastatin significantly enhances the portal pressure reduction achieved with carvedilol monotherapy, improves endothelial dysfunction, and reduces proinflammatory cytokines.

Keywords: HVPG; carvedilol; inflammation; nonselective beta-blockers; simvastatin.