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.
TIPS PROCEDURE: NO ROLE AT PRESENT
The transjugular intrahepatic portosystemic shunt (TIPS) procedure is used to treat the main consequences of portal hypertension, including ascites and variceal hemorrhage. The procedure entails accessing the hepatic vein via the right jugular vein and placing a stent to the portal vein, forming a low-resistance channel and allowing blood to return to the systemic circulation.
TIPS placement increases the risk of encephalopathy; liver failure is a rare complication, and procedural complications (ie, shunt dysfunction) also occur. Trials comparing the TIPS procedure with other forms of therapy to prevent first variceal hemorrhages have not been performed.40 Research to improve the outcome of the TIPS procedure is ongoing, but currently this procedure has no role in primary prevention of variceal bleeding.
ENDOSCOPIC SCLEROTHERAPY MAY INCREASE THE RISK OF DEATH
Numerous clinical trials evaluated sclerotherapy as prophylaxis against a first esophageal variceal hemorrhage. The procedure involves injecting a sclerosant in and around varices.
In a large Veterans Administration study,41 sclerotherapy was compared with sham treatment in 281 men with alcoholic liver disease who had documented varices but no history of bleeding. The trial was terminated after 22.5 months because the rate of all-cause mortality was significantly higher in the sclerotherapy group (32.5%) than in the sham therapy group (17.4%). The higher death rate did not persist after the treatment was discontinued, and it was speculated that, although sclerotherapy had reduced new episodes of variceal hemorrhage, the procedure might have caused bleeding from esophageal ulcers, leading to an increased mortality rate in that group.
The PROVA Study Group from Norway and Denmark found similar results when 286 cirrhotic patients were randomized to receive sclerotherapy, propranolol, combination sclerotherapy and propranolol, or no treatment to prevent a first variceal hemorrhage.42 The incidence of variceal bleeding was almost identical in the four groups, but the mortality rate with variceal bleeding was 2.75 times higher in the sclerotherapy groups than in the other groups (P = .002). It was speculated that repeated sclerotherapy sessions might be poorly tolerated by patients in Child-Pugh classes B and C and might have contributed to the precipitation of liver failure and other common complications of cirrhosis.
A meta-analysis by D’Amico et al11 evaluated 19 trials (1,630 patients) comparing sclerotherapy with nonactive treatment. Sclerotherapy tended to be favorable in trials with a high bleeding rate in the control patients and unfavorable in trials with a low bleeding rate. The benefit seen in patients at high risk is consistent with the efficacy of sclerotherapy for preventing rebleeding, whereas the harmful effect in the low-risk patients points towards side effects and complications exceeding the potential benefits.
In general, currently available evidence suggests that the benefits of prophylactic sclerotherapy are marginal, and therefore sclerotherapy is not recommended as primary prophylaxis for variceal hemorrhage.
NITRATES: NO LONGER USED AS MONOTHERAPY
Unlike vasoconstrictors, which decrease portal pressure by decreasing blood flow, vasodilators reduce hepatic pressure by decreasing intrahepatic and portocollateral vascular resistance.43 In addition, larger doses directly affect the arterial circulation, lowering systemic and therefore splanchnic perfusion pressure.44 Unfortunately, the systemic vasodilatory effects of nitrates exacerbate the hyperdynamic state that is characteristic of cirrhosis, thereby limiting their use and tolerability in many patients.
A trial comparing propranolol vs isosorbide mononitrate initially found that the groups did not differ significantly with regard to bleeding rates and 2-year survival rates,45 but a 6-year follow-up found the likelihood of death greater in patients older than 50 years in the nitrate group.46 In an additional study comparing isosorbide mononitrate vs placebo in patients with contraindications to or intolerance of beta-blockers, no difference in the relative risk of first variceal hemorrhage was found between the two groups.47 Therefore, nitrates are no longer used as monotherapy to prevent variceal bleeding.
Combination therapy with beta-blockers plus nitrates is controversial. In a trial in 1996, Merkel et al48 found the cumulative risk of variceal bleeding was 18% at 40 months with nadolol alone vs 7.5% with nadolol plus isosorbide mononitrate. However, in a later trial, Garcia-Pagán et al49 found no significant advantage to combination therapy. The incidence of variceal bleeding at 1 year was 8.3% in the group receiving propranolol plus placebo and 5% in the group receiving propranolol plus isosorbide mononitrate; at 2 years, the rates were 10.6% vs 12.5%.
