By Dr. Geoffrey Modest
A recent review looked at the varying efficacies of different nonselective b-blockers in patients with portal hypertension in cirrhosis (see Li T. BMJ Open 2016; 6: e010902), finding that carvedilol may be more effective than propranolol or nebivolol and as effective as the combo of nadalol plus isosorbide mononitrate.
Details:
- 12 RCTs were evaluated, though mostly not-so-great quality
Results:
- 7 trials (379 patients, about 2/3 male, mean age around 50, most with alcoholic cirrhosis but some hepatitis B or C) compared carvedilol vs propranolol for hemodynamic outcomes: hepatic venous pressure(HVPG) reduction, hemodynamic response rate, post-treatment arterial pressure (mean arterial pressure, MAP). Most follow-up of only up to 6 weeks. Finding:
- Carvedilol was associated with a greater (%) HVPG reduction within 6 months (mean difference -8.49 (-12.36 to -4.63) and improvement in hemodynamic response rate, both being consistently found in each of the trials. There was a nonsignificant decrease in MAP in almost all of the trials
- 3 trials compared carvedilol vs endoscopic variceal band ligation (EVL) for clinical outcomes: all-cause mortality, bleeding-related mortality, upper GI bleeding.
- 1 trial was secondary prevention, 64 patients, 26 months follow-up, Child-Pugh class B. No significant difference in clinical outcomes, though very wide confidence intervals
- 2 trials of primary prevention, 341 patients, 13-26 month median follow-up, mostly Child-Pugh class A. Also no significant difference in clinical outcomes
- 1 trial compared carvedilol vs nadalol plus isosorbide mononitrate, 121 patients, 30 month follow-up:
- No significant difference in mortality or bleeding. carvedilol group had fewer adverse events (5/61 vs 23/61)
- 1 trial compared carvedilol vs nebivolol, 20 patients, 14 day follow-up:
- Carvedilol had greater reduction in HVPG, mean difference of -10.9 percentage of HVPG reduction
Commentary:
- Acute variceal bleeding has 6 week mortality of 10-20%, depending on Child-Pugh class; and a 60% 1-year rate of recurrent variceal bleeds
- HVPG is the strongest predictor of bleeds: if >10 mmHg, it predicts varices; if >12 mmHg, it is associated with high rate of bleeds; if >20 mmHg, there is a high mortality.
- Risk of bleeding decreases if HVPG decreases to <12 mmHg or by 20% from baseline
- Nonselective b-blockers work by both decreasing cardiac output (b1) and constricting splanchnic vessels (b2); but only 40% of patients reach therapeutic levels
- Carvedilol (blocking both a1 and b1/b2) also decreases intrahepatic resistance. Prior reports have found that >50% of propranolol non-responders do respond to carvedilol, though there are concerns about systemic hypotension and renal failure (and perhaps increased mortality) especially in people with refractory ascites.
- The above trials were pretty short-term. It is somewhat reassuring that in the carvedilol studies looking at hemodynamic outcomes, there was not much difference acutely and at 6 months, suggesting that the benefit was, and might continue to be, sustained
- Studies suggest that there is not much additional effect of higher doses of carvedilol in terms of HVPG (i.e., it may be reasonable to start with 3.125 mg bid, then increase as tolerated to 6.25 mg bid)
- There is not a lot of data comparing carvedilol to EVL, but the limited data above suggest relative equivalence, and the quality of evidence is low. Other studies have found that EVL is superior to nonselective b-blockers.
What does this all mean?
- Interestingly (and anecdotally), I happened to see a patient today who was not tolerant of nadolol (made her feel weak, trouble exercising/walking). And, having seen this review, I started her on carvedilol 3.25mg bid. We’ll see….
- There are concerns about EVL, since it requires endoscopy and a procedure, and about 50% need retreatment within one year. The data comparing EVL and nonselective b-blockers is a bit unclear: a review (Cheung J. Alimentary Pharmacology and Therapeutics 2009; 30: 577), which included only propranolol and nadolol as meds, found pretty poor quality of evidence (significantly, no documentation of the number of patients actually achieving target heart rate). Their comparison noted that EVL was better than b-blockers if the mean dose was <80mg. But given other studies finding lots of people not achieving optimal b-blocker dose, it is hard to be sure that EVL really is better than even the old b-blockers.
- So, I am a bit concerned about the reports of more hypotension with carvedilol, since many of my patients with cirrhosis have pretty low blood pressures to begin with, and the reported concerns of possible increased acute kidney injury/mortality in patients with advanced decompensated liver disease/refractory ascites is a tad worrisome. Since the above data are mostly based on not-so-great quality studies with small numbers of patients, I think it is important to have bigger, better, and longer comparative studies before using carvedilol as first-line. so, my approach will be to continue using nadolol or propranolol initially, but as in the case I saw today, to try carvedilol gingerly if the other b-blockers are not tolerated/target heart rate not achieved (reduction of 25% or down to <55-60 bpm)
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