Preventing a first episode of esophageal variceal hemorrhage
ABSTRACTIn patients with esophageal varices, hemorrhage is common and often lethal, so we need to take a proactive approach to preventing a first episode of bleeding. All patients with cirrhosis should undergo endoscopy to look for varices. Depending on the size and appearance of the varices and the patient’s Child-Pugh grade, prophylactic treatment may be indicated.
KEY POINTS
- The hepatic vein pressure gradient (HVPG) correlates well with the portal pressure and is easier to measure. However, whether it is cost-effective to measure the HVPG in clinical practice is controversial.
- Nonselective beta-blockers are the mainstay of treatment; selective beta-blockers do not reduce portal pressure to the same degree and are not recommended for preventing variceal bleeding.
- Endoscopic variceal ligation is an acceptable alternative to beta-blocker therapy for patients who cannot tolerate these drugs and for patients with varices at high risk of bleeding.
- Nitrates are no longer used as monotherapy for preventing variceal hemorrhage, and their use in combination with beta-blockers is controversial. Surgical portal decompression, transjugular intrahepatic portosystemic shunting, and endoscopic sclerotherapy are not recommended.
NONSELECTIVE BETA-BLOCKERS: THE MAINSTAY OF TREATMENT
Nonselective beta-blockers, the most commonly used drugs for preventing first esophageal variceal bleeding, decrease portal pressure by blocking both beta-1 and beta-2 adrenergic receptors.9 Beta-1 blockade decreases portal flow by decreasing the heart rate and cardiac output, while blockade of beta-2 receptors results in unopposed alpha-adrenergic-mediated vasoconstriction.
Selective beta-blockers do not appear to be as useful for primary prophylaxis. More than 2 decades ago, metoprolol (Toprol, Lopressor), a beta-1 selective antagonist, was compared with propranolol (Inderal), a nons-elective agent, in patients with cirrhosis and portal hypertension.10 Although both drugs significantly reduced the heart rate and cardiac output, only those taking propranolol showed a marked fall in portal pressure (mean decrease of 6.8 mm Hg vs 3.8 mm Hg with metoprolol) and a significant reduction in hepatic blood flow. The differences were thought to be related to beta-2 blockade of vasodilator receptors in the splanchnic circulation, which occurs only with nonselective beta-blockers such as propranolol.
The two nonselective beta-blockers most often used to prevent variceal bleeding are nadolol (Corgard) and propranolol. Both have been extensively studied in preventing a first variceal hemorrhage.
Effectiveness of beta-blockers
D’Amico et al11 performed a meta-analysis in 1995, examining nine trials (996 patients total) of the effectiveness of beta-blockers in preventing a first variceal hemorrhage. Seven trials found that bleeding risk was reduced with beta-blockers (significantly in four), one trial found that risk was unchanged, and one trial found that risk was increased—an outlier due to a small sample size. The meta-analysis showed a significant bleeding reduction with the use of a beta-blocker, either including the outlier trial (pooled odds ratio 0.54; 95% confidence interval 0.39–0.74) or excluding it (pooled odds ratio 0.48; 95% confidence interval 0.35–0.66).
Mortality rates were also reduced in seven trials, but the reduction was statistically significant in only one. However, in the pooled estimate, the mortality risk reduction approached statistical significance (pooled odds ratio 0.75; 95% confidence interval 0.57–1.06).
Ideo et al12 gave either nadolol or placebo to 79 patients with cirrhosis and large esophageal varices that had never bled. Nadolol was found to protect against a first variceal hemorrhage: at 2-year follow-up, only 1 of the 30 patients allocated to nadolol had had bleeding, vs 11 of the 49 patients in the placebo group.
Merkel et al13 found that the risk of variceal bleeding was lower in patients who started treatment with beta-blockers when their varices were small (12% at 5 years) than in those who started treatment after a diagnosis of large esophageal varices (22% at 5 years). They concluded that nadolol helps prevent small varices from growing into larger ones.
Response to beta-blockers is not uniform
Although beta-blockers decrease the portal pressure in many cirrhotic patients, the response is not uniform. In a study of 60 cirrhotic patients,14 40% showed no reduction or even a slight increase in HVPG with propranolol. Most patients showed a significant reduction in heart rate (17.5% ± 10%) after receiving 40 mg of propranolol. In the patients whose HVPG did not decrease by at least 10% with 40 mg of propranolol, increasing the dose caused a decrease in HVPG without a further decrease in heart rate. This suggests that 40 mg of propranolol successfully produced beta-1 blockade but that a higher dose was required for effective beta-2 blockade.
Failure to respond in certain patients may be due to a concurrent rise in collateral or hepatic sinusoidal resistance, or both. This was confirmed in a study in portal-hypertensive rats treated with propranolol.15 The reduction in portal blood flow expected was accompanied by a disproportionately small reduction in portal pressure, which was thought to be due to a rise in portal and collateral vascular resistance.
