Prevention of Variceal Rebleeding
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Reference
Villanueva C, Balanzó J, Novella M, etal. Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding. N Engl J Med 1996; 334: 1624-9.
Reviewed by
James J. Stevermer, M.D. and M. Lee Chambliss, M.D., M.S.P.H.
Clinical question
Is medical therapy with beta-blockers and nitrates better than endoscopic sclerotherapy in preventing recurrent bleeding from esophageal varices?
Background
Even after successful treatment for an acute episode, patients with a history of bleeding from esophageal varices have a poor prognosis, with high rates of rebleeding and death. Recent data support the use of endoscopic sclerotherapy or propranolol to reduce the risk of rebleeding. Nonetheless, that risk remains around 50%, with significant morbidity and mortality. Beta-blockers have been shown to lower the hepatic venous pressure gradient, and there is evidence that lowering this gradient may be protective from recurrent bleeding. Preliminary reports also suggest that the addition of a nitrate to a beta-blocker can further lower the gradient. This study compared the safety and efficacy of this combination of medications compared to standard endoscopic therapy.
Population studied
This study took place in Barcelona, Spain. All of the patients had cirrhosis with acute variceal bleeding documented by emergent endoscopy. The subjects were enrolled immediately after the acute bleeding was controlled. Sixty percent of the patients had cirrhosis as a result of alcohol abuse. The study excluded patients that were under 18 years, had advanced hepatocellular cancer, a history of previous sclerotherapy, inability to control the initial bleed, or very severe cirrhosis (Child-Pugh score greater than 12).
Study design and validity
The study was a randomized clinical trial comparing the safety and efficacy of routine endoscopic sclerotherapy to that of nadolol and isosorbide mononitrate. Forty-three patients were randomized to each arm, stratified by severity of liver failure and previous history of variceal bleeding. The investigators were not blinded, and there were no placebo tablets given to the endoscopic group and no sham procedure done in the medication group. Endoscopic sclerotherapy involved injecting sclerosant into varices on days 0, 4, 10 and 30, and then monthly until varices were eradicated. Patients in the medication group were started immediately on oral nadolol 80 mg per day. The dose of the beta-blocker was titrated up until the heart rate dropped by 25% or a resting pulse of 55 was attained. At that point, oral isosorbide mononitrate was added and increased to 40 mg twice daily, or until side effects developed. Follow-up ranged from 7-24 months. Randomization was effective and follow-up was excellent. Placebo controls and blinding would have strengthened the study, although the reported end-points rely little on judgment decisions.
Outcomes measured
The primary outcomes were the development of rebleeding, complications or death. All episodes of possible rebleeding were evaluated by endoscopy. In addition, the authors measured hemodynamic parameters, including hepatic venous pressure gradient and cardiac output, at baseline and approximately 3 to 4 months later.
Results
Follow-up and compliance were excellent. An intention to treat analysis showed that the risk of rebleeding was lower in the medication group (0.3 episodes of rebleeding per patient) than in the sclerotherapy group (1.1 episodes per patient). The medication group had improved hemodynamic indices, and the hepatic venous pressure gradient was more likely to be normal. Survival analysis showed a non-significant trend towards survival in the medication group (p = 0.07). There were fewer iatrogenic complications in the medication group.
Recommendations for clinical practice
Although this study has some limitations, it provides good evidence that the use of nadolol and isosorbide mononitrate is at least as safe and more effective than endoscopic sclerotherapy for prevention of recurrent esophageal bleeding. There was a strong trend towards increased survival in the medication group. Although no cost-effectiveness analysis was done, we suspect the cost of the endoscopic regime would be much higher than medical management, at least in the United States. Clinicians should strongly consider medical management of esophageal varices with beta-blockers and isosorbide mononitrate instead of endoscopic sclerotherapy.
copyright 1997, Appleton and Lange
