Chronic liver disease and cirrhosis are the 12th leading cause of death in the United States leading to nearly 28,000 deaths per year.1 Portal hypertension in patients with cirrhosis accounts for a great deal of morbidity and mortality. It is associated with gastroesophageal varices, ascites, and variceal hemorrhage and increased risk of bacterial infection. Treatment of portal hypertension can reduce the incidence of these sequelae. The mainstay of treatment in portal hypertension is non-selective beta-blockers such as propranolol or nadolol. However, many patients are unable to tolerate the titration of these drugs to appropriate therapeutic doses or have relative contraindications to beta blocker therapy such as asthma or insulin dependent diabetes with risk of hypoglycemia.1,2 Additional treatment options either in addition to or instead of beta blockers, that act selectively on the hepatic circulation are needed. HMG-CoA reductase inhibitors have been proposed as a class of drugs that may prove beneficial in portal hypertension.
A recent proof-of-concept, randomized, double-blind, controlled trial evaluated the effect of simvastatin in patients with portal hypertension and cirrhosis.3 It was performed at 3 different sites in Spain and evaluated 27 patients in the placebo arm and 28 in the simvastatin arm. Distribution of patients concurrently on beta-blocker therapy was allocated evenly to each arm of the trial.
Simvastatin was administered at a starting dose of 20 mg/day and then increased to 40 mg/day at day 15 if no safety or clinical contraindications existed. Final evaluation occurred on day 30 of treatment.
Wedged and free hepatic venous pressures were measured using balloon catheterization and the difference was calculated as the hepatic venous pressure gradient (HVPG). The primary endpoint was to determine whether 1 month of treatment with simvastatin reduced the HVPG. Secondary endpoints included evaluation of the safety of simvastatin in cirrhosis, comparative effects with and without beta-blockers, and others.
Placebo resulted in no significant change of HVPG (p=0.473) while simvastatin caused a decrease of HVPG from 18.5 ± 7.2 to 17.1 ± 4.6 mm Hg (p=0.003). A greater percentage of patients who received simvastatin (32% vs. 11%) achieved the target reduction in portal pressure defined as HVPG decrease 20% or greater from baseline or HVPG <12 mm Hg. The implication of these results is that simvastatin has effects as a hepatic vasodilator. This is in contrast to the non-specific beta-blockers that decrease portocollaterol blood flow.
Liver function was measured using indocyanine green clearance, which was increased in those receiving simvastatin. This puts forward the possibility that statins improve hepatic perfusion and liver function. The authors postulate, that it is possible that increased nitric oxide due to simvastatin acts on the hepatic stellate cells allowing for greater perfusion of hepatocytes.
The liver selectivity of simvastatin’s vasodilatory effects was demonstrated by no change in mean arterial pressure, cardiac index, or systemic vascular resistance. No significant adverse effects were noted with only 3 patients in the simvastatin arm developing any symptoms. The limitations of this study include patients with severe liver failure were not included and treatment was for only 30 days, and these findings should be viewed with caution.
Simvastatin significantly decreased portal pressure, and ...