Ascites Clinical Trial
Official title:
Losartan in the Prevention of Sodium Retention and Ascites in Liver Cirrhosis – a Prospective Randomized Long-Term Study
The purpose of this study is to determine whether losartan, an angiotensin II blocker prevents the sodium retention in patients with liver cirrhosis and by that reduces the fluid retention. Moreover is the purpose to asses whether losartan is antifibrotic.
Patients with cirrhosis tend to retain sodium and water leading to the development of
ascites, which in the terminal stage of decompensation cannot be eliminated despite the use
of massive diuretic treatment. These decompensated patients have a very high mortality of 50
% within 3 years and morbidity, and until now no symptomatic treatment has been able to
improve the prognosis.
It has been hypothesized that ascites and edema develop first due to renal sodium retention
secondary to increased activity of hormones like angiotensin II and aldosterone, which may
be stimulated by reduced arterial filling caused by systemic vasodilatation, and secondly
due to liver fibrosis which may cause lymphatic overflow and formation of ascites.
Decreased central volume filling is believed to stimulate baroreceptors with activation of
the renin-angiotensin-aldosterone system, the sympathetic nervous system and arginine
vasopressin .
In cirrhotic patients systemic vasodilatation with hypotension, tachycardia, increased
cardiac output and increased plasma volume has been thought to be caused by increased levels
of vasodilating substances like nitric oxide (NO), but blocking NO synthesis using
N(G)-monomethyl-L-arginine-acetate (L-NMMA) did not favorably influence renal sodium
excretion, probably due to an important role of NOS in renal sodium handling .
It is evident that the pathophysiology of the development of excessive sodium and water
retention in cirrhotic patients is insufficiently elucidated, and that an increased
knowledge in this field may improve the therapeutic possibilities. Patients with cirrhosis
without ascites have normal or increased glomerular filtration rate (GFR) and normal or
suppressed plasma levels of renin, angiotensin II and aldosterone. Later renal blood flow
and GFR may be decreased and patients have avid tubular sodium reabsorption as they can
produce a virtually sodium-free urine. These functional renal changes regress after
transplantation with a normal liver. Suggestions have been made that overfilling rather than
central underfilling precede ascites formation. In any case blocking the mineralocorticoid
receptor with spironolactone is an effective diuretic treatment in many cirrhotic patients,
and this points to the importance of the distal part of the nephron in the mediation of
excess sodium reabsorption.
Angiotensin II (ANG II) binds to the AT1 receptor localized to renal glomeruli and tubules,
the adrenals and arterioles, not only efferent arterioles in the kidneys, but also
resistance vessels of the systemic vasculature. In the adrenals ANG II stimulates
aldosterone secretion. In addition it has been shown in rats that the expression of the
vasopressin receptor V2 is upregulated by ang II, an effect expected to increase water
reabsorption (10). Most likely ANG II aggravates the portal hypertension due to stimulation
of stellate myofibroblasts, and this may be part of the circulus vitiosus which should be
broken in cirrrhosis. In another volume retaining disorder - heart failure - blockade of the
renin angiotensin aldosterone system has been shown to be extremely effective in retarding
progression of the disease.
Treatment of cirrhotic patients with ACE-inhibitors has been tried but was poorly tolerated
since blood pressure and GFR decreased. In one study, however, the addition of a low dose of
Captopril to furosemide and spironolactone increased natriuresis in half the patients . It
could be expected that an ANG II blocker would be better tolerated in cirrhotic patients,
because bradykinin metabolism, and the production of NO and prostaglandins are not affected.
Accordingly three recent studies have shown that low dose ANG II receptor type I blocking
increased sodium excretion in cirrhotic patients without affecting systemic or renal
hemodynamics, also in patients with normal systemic levels of renin-angiotensin-aldosterone.
Losartan at a dose of 7.5 mg was able to counteract the sodium retention otherwise
demonstrated in preascitic patients going from supine to standing position . Low dose
Losartan could inhibit sodium retention when preascitic patients were given a high sodium
diet . Losartan given at a higher dose -25 mg daily - to both preascitic and ascitic
patients increased GFR and natriuresis without affection of blood pressure . In contrast to
some previous results Schneider et al found that Losartan was able to reduce the portal
pressure of cirrhotic patients at a dose at which the systemic circulation was not adversely
affected, and even a natriuretic effect could be demonstrated . Accordingly a reducing
effect of the ANG II antagonist Irbesartan has been demonstrated . Unfortunately an
ameliorating effect of ANG II antagonists on portal pressure without adverse effects on
blood pressure could not be demonstrated in two recent studies. A long-term (years)
longitudinal study of cirrhotic patients with registration of consecutive changes in sodium
handling, systemic and renal hemodynamics and neurohumoral regulations has never been done
but is likely to elucidate the pathophysiology in these patients. In addition it is
hypothesized that early intervention with the ANG II receptor antagonist Losartan could
delay or even prevent development of the decompensated stage and thus improve survival and
quality of life in these patients.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Prevention
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