Why do we use the combination of furosemide and spironolactone in the treatment of cirrhotic ascites?

How many times have you prescribed diuretic therapy for a cirrhotic patient with ascites?

It's muscle memory at this point: furosemide 40mg, spironolactone 100mg. Done.

Today, we break things down and ask: why do we use these diuretics/doses? Should I always use them together?

Let's start by looking at the current recommendations...

AASLD:

• Diuretics begin with 100 spiro and 40 furosemide
• “Starting with both drugs appears to be the preferred approach in achieving rapid natriuresis and maintaining normokalemia.”

EASL:

• “Patients with the first episode of grade 2 ascites should receive an aldosterone antagonist...alone, increasing stepwise...if there is no response. In patients who do not respond to aldosterone antagonists...,or in patients who develop hyperkalemia, furosemide should be added….”
• “Patients with recurrent ascites should be treated with a combination of an aldosterone antagonist plus furosemide…”
• “Aldosterone antagonists are more effective than loop diuretics in the management of ascites and are the diuretics of choice.”

Ok, surprise! The recommendations are actually slightly different. It's not always combination therapy. 

Why does ascites even form?

I’ll leave it to the experts to wax poetic about the pathophysiologic mechanisms of ascites, but I do want to highlight some key components that will help us understand some of the mechanisms of diuretic responsiveness (or lack thereof).

The most commonly-posited therapy of ascites formation is the forward theory.

[Note that other, contributing mechanisms exist (including chronic systemic inflammation) but will not be expounded upon here.]

Initially, portal hypertension results in pooling of blood in the splanchnic circulation, which is sensed as a decrease in effective arterial blood volume (EABV). As a result, cardiac and renal compensatory mechanisms (namely increased free water retention and cardiac output) kick in. The patient remains “compensated” and there is no ascites. As the liver disease and portal hypertension progress, the compensatory mechanisms become maladaptive. Ongoing free water retention and an inability to excrete sodium contribute to an increased trans-capillary gradient in the splanchnic circulation, leading to ascites formation.

A few renal mechanisms are particularly important here.

1. In early, compensated phases, the renin-angiotensin-aldosterone system (RAAS) is not overactive and renal perfusion and glomerular filtration rate (GFR) are also largely unaffected.
2. With disease progression, an initial inciting event is activation of the RAAS and a state of hyper-aldosteronism.
   • Aldosterone leads to increased sodium reabsorption in the distal/collecting tubules
3. With even further disease progression, renal perfusion and GFR also decrease
   • Further activation of the sympathetic nervous system (SNS) leads to more proximal increases in sodium reabsorption (in the proximal tubule and loop of Henle)
   • Now you have two mechanisms to battle against -- proximal and distal reabsorption

Ok, so why choose one type of diuretic over another?

Well, let’s start by discussing how each works.

Furosemide = loop diuretic

• Inhibits Na+ reabsorption in the loop of Henle

Spironolactone = aldosterone antagonist

• Inhibits Na+ reabsorption that occurs more distally in the nephron

For decades, spironolactone was favored over loop diuretics. Why?

1. Known hyperaldosteronism in cirrhosis
2. Observed efficacy of spironolactone as a single agent

In 1981, Fogel et al. published a randomized controlled trial comparing 3 regimens:

• Furosemide alone
• “Sequential spironolactone” (starting with spironolactone and increasing dose, and only adding lasix if no response to max spironolactone)
• Combination therapy (both diuretics given from the start).

You can see in the above graph that the mean weight loss in the sequential spironolactone and combination therapy groups was greater than in the furosemide alone group.

Other important findings from this study included:

• Combination group = sequential spironolactone in terms of mobilization of ascites and weight loss and requirement to reduce dosage to avoid excessive diuresis
• Onset of diuresis significantly slower in sequential spironolactone group (13 vs 9 days)
• Combination group = higher likelihood of significant increase in BUN and hyponatremia
• Furosemide only group = required continually increasing doses to maintain diuresis, required large amounts of potassium supplementation

The takeaways were that:

1. Furosemide only is a bad choice
2. Combination therapy is faster but more likely to have lab abnormalities that need to be monitored (azotemia, hyponatremia)
3. Spironolactone first is slightly slower, but gentler in terms of side effects and works just as well as combination therapy

Another important study in 1983 by Perez-Ayuso pitted furosemide and spironolactone against one another in a randomized population of cirrhotic inpatients. No combination therapy was used here.

Doses of each agent progressively increased if no response (based on weight changes), and non-responders were switched to the alternate diuretic.

Important findings:

• Lasix group: 50% response (all who responded did so within 1 day)
• Lasix non-responders: 90% responded when switched to spironolactone (response began within 2-3 days).
  • Significantly higher plasma renin and aldosterone levels than responders
• Spironolactone group: 95% responded to spironolactone initially (repsonse began to occur within 2-3 days)
• Spironolactone non-responder (1 patient): did not respond when switched to lasix

Takeaways:

1. If using one agent alone, spironolactone appears more likely to work
2. Much of the effect is likely due to hyperaldosteronism
3. Spironolactone response is slightly slower

On the basis of these and other similar studies in the 1980s, the takeaways appear to be:

1. Loop diuretics alone are ineffective
2. Spironolactone alone is effective, and may have slightly less lab derangements (although need to monitor for hyperkalemia)
3. Spironolactone alone may take slightly longer
4. Combination therapy is likely to have a more rapid effect 
5. Combination therapy may lead to mild azotemia and hyponatremia which respond to dose adjustment (and thus the clinical consequences of this are uncertain)

Why do we think loop diuretics alone are ineffective?

It comes down to hyperaldosteronism. As discussed above, the non-responders to furosemide appeared to have higher renin and aldosterone levels.

Remember how these diuretics work. The effect of a loop diuretic is at the loop of Henle, which is proximal to where aldosterone works. With high aldosterone levels, all of the Na+ that doesn’t get reabsorbed in the loop will get reabsorbed in the distal nephron unless you block the effect of aldosterone.

Ok, enter the new millennium. Why did we get to where we are now?

Two important studies came out in the decade of the oughts.

In 2003, Santos et al. published a randomized trial of 100 non-azotemic cirrhotics who were randomized to:

• Spironolactone alone
• Combination therapy
• FYI: The groups were stratified into degree of ascites at baseline (<4L or >4L). The <4L groups started at lower doses (100mg spironolactone only or 40/100 of combo therapy) and the >4L group started at double dose (200mg spiro or 80/200 of combo).
• Doses were increased every 4 days if no response

The important findings:

• No difference in mobilization of ascites (98 vs 94%)
• No difference in median response time (9.8 vs 10.3 days)
• No difference in rate of hypo/hyperkalemia, AKI, etc
• Combination therapy had a significantly higher need to reduce diuretic dosage (due to excessive diuresis)

In 2010, Angeli et al. published another similar randomized trial, comparing:

• Sequential therapy (starting with aldosterone antagonist potassium canrenoate, and if no response on max dose then adding furosemide)
• Combination therapy (lasix + potassium canrenoate)

Results:

• No difference in overall response rate (sequential 88% vs combination 96%)
• Combination therapy group with significantly shorter time to achieve effective response (5 vs 6.6 days) and time to resolution of ascites (15.5 vs 20.7 days)
• Sequential therapy group with significantly higher rates of “failure” (defined as adverse effects or excessive diuresis (sequential 44% vs combination 24%)
  • This was predominantly due to hyperkalemia in the sequential therapy group

The above two studies appear to conflict. What are the takeaways?

• Santos et al. showed essential equivalence, the only difference being a need to reduce dosage in the combination therapy group due to excessive diuresis (i.e. more monitoring needed)
• Angeli et al. seem to suggest combination therapy is better (faster, less hyperkalemia)

But we need to pay attention to the populations in each study:

• In the Santos study, 60% had “new” ascites and ~70% had previously been untreated
• In the Angeli study, 70% had “recurrent” ascites and nearly all had frank hyper-aldosteronism with a slightly higher baseline creatinine

The Angeli cohort might thus be in a later stage of RAAS activation and renal impairment…

• Going back to the pathophysiology discussed earlier, in earlier stages of disease, distal Na+ reabsorption predominates due to hyper-aldosteronism
• As disease progresses, there is more Na+ reabsorption proximally and in the loop
• If the Angeli cohort with more recurrent ascites was in a later stage of disease, it may explain why they responded faster to combination therapy and had higher rates of failure with spironolactone alone

We’ve now come full circle back to the current recommendations

The AASLD and EASL recommend slightly different approaches. As you can see from the above, both approaches (single-agent spironolactone first, or combination therapy) have their merits in different situations.