May 20, 2008 A team lead by Dr. Binay K De from Medical College and Hospital, Calcutta, India, used a hemodynamic study to document for the first time that the combination of spironolactone with propranolol is not only better than propranolol alone in reducing portal pressure, but the reduction is significant enough to virtually abolish the risk of re-bleeding in a significant majority of the patients.
Bleeding from ruptured esophageal varices is the main complication of portal hypertension and a major cause of death. About one-third of variceal bleeding episodes are fatal while 70% of survivors re-bleed within a year. Propranolol, the drug of choice for primary prevention of variceal bleeding, has been found to be effective in 45% of patients who have never bled, and in only 40% of patients who have had a bleeding episode before.
Thus, this drug does not protect a significant number of patients and combination therapy has been advocated as a result. Various drug combinations have been tried, most commonly propranolol with isosorbide mononitrate. However, the problem with combination therapy is an increased incidence of side effects, poor tolerability and lack of compliance. The search for an ideal drug combination that is effective, relatively free from side effects and easy to administer, has been elusive.
Spironolactone, a drug commonly used in cirrhotics with ascites to reduce fluid overload, has been found to have an independent portal hypotensive effect. This drug has been in use for a long period of time and has been found to be safe and free of side effects, except for occasional gynaecomastia.
In the authors' view, the combination of spironolactone with propranolol scores over other combinations for variceal re-bleed, because of the different mechanisms of action of the two drugs and some of the unique properties of spironolactone.
Spironolactone has a direct portal hypotensive effect in addition to its ability to reduce plasma volume by diuresis. Spironolactone has a direct effect on the vasculature and suppressive effect on immunoactive and inflammatory cytokines, independent of its anti-aldosterone effect. An antifibrotic property has also been evidenced experimentally in rats. Because it is a long acting drug, a single daily dosage will suffice.
Using a rational study design, portal pressure was measured after hemodynamic stabilization of the patients. The drugs were administered and the effects were re-assessed on day eight. This allowed time for stabilization of drug levels in the plasma and also provided us information on the early portal hemodynamic changes following drug administration, because the maximal risk of re-bleeding is during the first two weeks.
However, further research using a larger number of patients with a long term follow up is warranted before declaring this combination to be the choice of treatment in preventing variceal re-bleeding.
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- De BK, Dutta D, Som R, Biswas PK, Pal SK, Biswas A. Hemodynamic effects of propranolol with spironolactone in patients with variceal bleed: A randomized controlled trial. World J Gastroenterol 2008; 14(12): 1908-1913 [link]
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