LONDON – Simvastatin improves short-term survival after variceal bleeding in patients with cirrhosis, results of a phase III, randomized, double blind study have shown.
At 2 years’ follow-up in the randomized, double-blind, Bleeding Prevention With Simvastatin (BLEPS) study, 17 of 78 placebo-treated (22%) and 6 of 69 simvastatin-treated (9%) patients died (P = .03). This represented a 61% reduction in the risk for death (hazard ratio, 0.387).
The benefit was almost exclusively seen in patients with Child-Pugh A/B cirrhosis (n = 124) in which mortality was just 5% in statin-treated patients vs. 21% in placebo-treated patients. Mortality was 25% vs. 27%, respectively, in patients with Child-Pugh C cirrhosis (n = 23).
"Our results indicate that the administration of simvastatin should be recommended in patients on secondary prophylaxis of variceal bleeding, especially in those with Child-Pugh A/B [cirrhosis]," study investigator Dr. Juan G. Abraldes of the University of Alberta (Canada) Hospital reported at the International Liver Congress sponsored by the European Association for the Study of the Liver (EASL).
Patients with cirrhosis are at risk for a number of complications, such as portal hypertension and the subsequent development of esophageal varices and variceal bleeding. Recommended treatment consists of beta-blockers and endoscopic banding ligation to prevent rebleeding (Am. J. Gastroenterol. 2007;102:2086-102).
"[Even] with this therapy the probability of rebleeding or death is still very high," Dr. Abraldes said at the meeting. Indeed, data suggest that variceal rebleeding carries a 1-year mortality of 36% (Gut 2009;58:1144-150).
Changes in portal hypertension and liver function are major determinants for rebleeding and death, the researcher added, noting that simvastatin has been shown to not only decrease portal pressure and improve liver function but also to potentially decrease fibrosis.
Dr. Abraldes and his colleagues at 14 Spanish centers therefore set out to see if simvastatin could have any beneficial effect in addition to standard treatments for secondary prophylaxis of variceal bleeding. They recruited a total of 158 patients who had confirmed esophageal variceal bleeding in the preceding 10 days and who were due to undergo endoscopic ligation and start preventative therapy with beta-blockers.
Patients were randomized to receive simvastatin at a daily dose of 15 mg for 15 days, which could be increased to 40 mg once daily or matching doses of a placebo. The primary endpoint was a composite of rebleeding from any cause or death. The average age of recruited patients was 68 years and the majority (71%) had cirrhosis from alcoholic liver disease. Nearly half were still active alcohol users, and around one-fifth had hepatitis C viral infection.
The primary endpoint was not reduced in the simvastatin arm relative to placebo, nor was the rate of rebleeding affected when the individual components of the composite endpoint were looked at, Dr. Abraldes reported. Yet there was a "marked survival benefit with simvastatin."
The addition of simvastatin to standard treatment was not associated with any significant adverse effects as compared with placebo.
"If we have a drug which is tolerated and can influence survival in patients with cirrhosis I think it should be used," EASL commentator Dr. Mauro Bernardi of the University of Bologna, Italy, said during a press briefing. While not involved in the study, Dr. Bernardi has a keen research interest in the management of cirrhosis and related complications.
The study was conducted in patients with advance cirrhosis, who already had portal hypertension, it was noted. The benefit on survival but not rebleeding was somewhat surprising but could have occurred because the simvastatin was having a beneficial effect on liver function and perhaps also liver injury, it was proposed.
"Overall, having an effect on mortality within 2 years in patients with Child-Pugh A/B cirrhosis is a very important result," Dr. Bernardi.
During discussions following the presentation it was noted that the use of a statin is contraindicated in patients with liver disease and also that the results might not extrapolate out to all patients with cirrhosis. Further studies are clearly needed, as "there are many, many questions," that remain said the session Chairman, Dr. Peter Ferenc of the Medical University of Vienna.
The Spanish government funded the study. Dr. Abraldes and Dr. Bernardi had no disclosures.