Preventing a first episode of esophageal variceal hemorrhage

ENDOSCOPIC VARICEAL LIGATION

Endoscopic variceal ligation has been investigated extensively for use as prophylaxis against first variceal hemorrhage. The procedure involves placing a rubber band around a varix aspirated into a cylinder on the tip of an endoscope.

Effectiveness of ligation

Lay et al,²⁷ in a prospective, randomized trial in 126 cirrhotic patients endoscopically judged to be at high risk of hemorrhage, found that ligation significantly reduced the 2-year cumulative bleeding rate (19% with ligation vs 60% in an untreated control group) and the overall mortality rate (28% vs 58%). The lower risk of bleeding in the ligation group was attributed to a rapid reduction of variceal size; 60% of those in the ligation group had complete eradication of varices and 38% had varices reduced in size.

Imperiale and Chalasani²⁸ performed a meta-analysis in 2001 that included 601 patients in five trials comparing prophylactic ligation with untreated controls and 283 patients in four trials comparing ligation with beta-blocker therapy. Compared with no treatment, ligation reduced the risk of first variceal hemorrhage, bleeding-related death, and death from any cause. Compared with propranolol, ligation reduced the risk of first-time bleeding but had no effect on the death rate.

Schepke et al,²⁹ in a randomized controlled multicenter trial in 152 cirrhotic patients with two or more esophageal varices, found that neither bleeding incidence nor death rate differed significantly between ligation and propranolol.

Lui et al³⁰ followed 172 cirrhotic patients with grade II or III esophageal varices for 6 years and found that ligation was equivalent to propranolol. However, many patients reported side effects with propranolol, and 30% of patients withdrew from propranolol treatment, making ligation a more attractive option.

Khuroo et al³¹ performed a meta-analysis of eight randomized controlled trials including 596 patients and found that ligation significantly reduced the rates of first gastrointestinal hemorrhage by 31% and of first variceal hemorrhage by 43%. In subgroup analysis, ligation had a significant advantage compared with beta-blockers in trials with patients with a high bleeding risk, ie, trials in which more than 30% of patients were in Child-Pugh class C and more than 50% of the patients had large varices.

Jutabha et al³² performed a multicenter, prospective trial (published in 2005) in 62 patients with high-risk esophageal varices randomized to propranolol or banding. The trial was ended early after an interim analysis showed that the failure rate of propranolol was significantly higher than that of banding (6/31 vs 0/31, P = .0098). Esophageal variceal hemorrhage occurred in 4 (12.9%) of the patients in the propranolol group compared with 0 in the ligation group. Similarly, 4 patients in the propranolol group died, compared with 0 in the ligation group. All the patients in this trial were liver transplant candidates and therefore all had severe liver disease.

In another trial favoring variceal banding over beta-blockers, Psilopoulos et al³³ in 2005 followed 60 patients with cirrhosis and esophageal varices with no history of bleeding. Thirty percent of the patients in the propranolol group developed variceal bleeding compared with 6.7% in the ligation group (P = .043).

Lay et al³⁴ followed 100 cirrhotic patients for 2 years and found comparable cumulative bleeding rates with ligation vs propranolol (18% vs 16%, respectively) and also comparable rates of death (28% vs 24%, respectively).

Sarin et al³⁵ investigated the role of propranolol in addition to ligation in the prevention of first hemorrhage in 144 patients. Adding propranolol did not further decrease the incidence of initial bleeding (7% in the combination group vs 11% in the ligation-only group). Survival rates were similar at 20 months: 92% in the combination group vs 85% in the ligation-only group. However, the rate of variceal recurrence was lower with combination therapy: 6% in the combination group vs 15% with ligation alone.

Does esophageal variceal ligation increase gastric varices?

A less researched topic is whether variceal ligation results in gastric hemodynamic changes that increase the size of fundal varices and worsen portal hypertensive gastropathy.

Yuksel et al³⁶ found that 37 of 85 patients had fundal varices before they underwent ligation of esophageal varices, increasing to 46 after the procedure, a statistically significant increment. The severity of portal hypertensive gastropathy also increased.

Further research is required regarding the long-term consequences of these findings.

ANGIOTENSIN II RECEPTOR ANTAGONISTS: ROLE UNKNOWN

Angiotensin II increases portal pressure, and angiotensin II levels are elevated in patients with cirrhosis, suggesting that this hormone plays a role in the pathogenesis of portal hypertension.

Losartan (Cozaar), an angiotensin II receptor antagonist, was found to decrease the HVPG significantly in patients with severe and moderate portal hypertension in a pilot study³⁷ in 1999. However, in two subsequent studies,^38,39 losartan only moderately reduced the HVPG and caused hypotension and a reduction in the glomerular filtration rate. The role of angiotensin II receptor blockers in primary prevention of variceal bleeding is still unknown.

SURGICAL PORTAL DECOMPRESSION HAS BEEN ABANDONED

The first method investigated to prevent variceal bleeding was surgical portal decompression.

A meta-analysis of four randomized controlled trials in 302 patients with varices of all sizes compared portocaval shunt surgery and medical therapy.¹¹ Although shunt surgery was very effective in preventing variceal bleeding, the risk of chronic or recurrent encephalopathy was significantly increased (odds ratio 2.0), as was the risk of death (odds ratio 1.6).

These poor results, combined with advances in endoscopic procedures, led to the abandonment of surgical shunting for primary prophylaxis.