Carvedilol as Best β-Blocker for Secondary Prophylaxis of Variceal Bleeding: Are We There, or Not Yet?

Carvedilol has emerged as the nonselective β-blocker (NSBB) of choice for treating portal hypertension in compensated cirrhosis.1de Franchis R. Bosch J. Garcia-Tsao G. et al.Baveno VII: renewing consensus in portal hypertension.J Hepatol. 2022; 76: 959-974Abstract Full Text Full Text PDF PubMed Scopus (522) Google Scholar, 2Bosch J. Carvedilol: the beta-blocker of choice for portal hypertension?.Gut. 2013; 62: 1529-1530Crossref PubMed Scopus (23) Google Scholar, 3Villanueva C. Torres F. Sarin S.K. et al.Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis.J Hepatol. 2022 May 31; (S0168-8278(22)00336-1)Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 4Bosch J. Carvedilol for portal hypertension in patients with cirrhosis.Hepatology. 2010; 51: 2214-2218Crossref PubMed Scopus (63) Google Scholar, 5Sinagra E. Perricone G. D'Amico M. et al.Systematic review with meta-analysis: the haemodynamic effects of carvedilol compared with propranolol for portal hypertension in cirrhosis.Aliment Pharmacol Ther. 2014; 39: 557-568Crossref PubMed Scopus (105) Google Scholar This is because of strong evidence demonstrating that it has a more pronounced effect than propranolol to reduce the hepatic vein pressure gradient (HVPG; equivalent to portal pressure gradient in cirrhosis),5Sinagra E. Perricone G. D'Amico M. et al.Systematic review with meta-analysis: the haemodynamic effects of carvedilol compared with propranolol for portal hypertension in cirrhosis.Aliment Pharmacol Ther. 2014; 39: 557-568Crossref PubMed Scopus (105) Google Scholar, 6Banares R. Moitinho E. Piqueras B. et al.Carvedilol, a new nonselective beta-blocker with intrinsic anti-Alpha1-adrenergic activity, has a greater portal hypotensive effect than propranolol in patients with cirrhosis.Hepatology. 1999; 30: 79-83Crossref PubMed Scopus (143) Google Scholar, 7Banares R. Moitinho E. Matilla A. et al.Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis.Hepatology. 2002; 36: 1367-1373Crossref PubMed Scopus (0) Google Scholar, 8Tripathi D. Therapondos G. Lui H.F. et al.Haemodynamic effects of acute and chronic administration of low-dose carvedilol, a vasodilating beta-blocker, in patients with cirrhosis and portal hypertension.Aliment Pharmacol Ther. 2002; 16: 373-380Crossref PubMed Scopus (61) Google Scholar together with good patient acceptability and safety profile.1de Franchis R. Bosch J. Garcia-Tsao G. et al.Baveno VII: renewing consensus in portal hypertension.J Hepatol. 2022; 76: 959-974Abstract Full Text Full Text PDF PubMed Scopus (522) Google Scholar,3Villanueva C. Torres F. Sarin S.K. et al.Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis.J Hepatol. 2022 May 31; (S0168-8278(22)00336-1)Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar More importantly, high-quality evidence from phase II and phase III prospective randomized clinical trials (RCT) and meta-analyses has shown that this hemodynamic advantage translates into a better clinical efficacy in terms of preventing decompensation, ascites, and bleeding, and in improving survival compared with other treatments (placebo, propranolol, endoscopic variceal ligation, or no therapy).3Villanueva C. Torres F. Sarin S.K. et al.Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis.J Hepatol. 2022 May 31; (S0168-8278(22)00336-1)Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar,9McDowell H.R. Chuah C.S. Tripathi D. et al.Carvedilol is associated with improved survival in patients with cirrhosis: a long-term follow-up study.Aliment Pharmacol Ther. 2021; 53: 531-539PubMed Google Scholar Because of this, the very recent Baveno VII recommendations declare carvedilol as the preferred NSBB, and support its use in all compensated patients with direct (HVPG ≥10 mm Hg) or indirect signs of clinically significant portal hypertension (presence of varices on endoscopy or of collaterals in imaging, presence of clinical or subclinical ascites or hydrothorax, fulfillment of Baveno VI criteria for need of endoscopy because of suspicion of varices needing treatment).1de Franchis R. Bosch J. Garcia-Tsao G. et al.Baveno VII: renewing consensus in portal hypertension.J Hepatol. 2022; 76: 959-974Abstract Full Text Full Text PDF PubMed Scopus (522) Google Scholar The only recommended precaution is to use low doses (6.25–12.5 mg/day) to avoid hypotension (systolic blood pressure <90 mm Hg). A special case is the patient with high blood pressure (present in up to two-thirds of patients with compensated cirrhosis nowadays9McDowell H.R. Chuah C.S. Tripathi D. et al.Carvedilol is associated with improved survival in patients with cirrhosis: a long-term follow-up study.Aliment Pharmacol Ther. 2021; 53: 531-539PubMed Google Scholar) in which carvedilol can be used as primary antihypertensive agent at doses of up to 25–50 mg/day to control arterial hypertension and portal hypertension (rather than associating with other antihypertensive drugs with uncertain effects on HVPG). Why is carvedilol then not yet recommended in secondary prophylaxis, which is the scenario where propranolol was first used? The main reason is that a previous study (at a time when carvedilol was titrated up to 50 mg/day) showed that it might worsen sodium retention in one-third of patients with ascites, as suggested by a mild increase in body weight, plasma volume, and in the dose of diuretics, which was ascribed to a significant decline in arterial blood pressure.7Banares R. Moitinho E. Matilla A. et al.Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis.Hepatology. 2002; 36: 1367-1373Crossref PubMed Scopus (0) Google Scholar Of note, there was no drop in glomerular filtration rate, no increase in plasma creatinine, and plasma renin activity decreased significantly after carvedilol. In any case, to be on the safe side, it was suggested at that time that initial RCTs testing clinically the use of carvedilol should be restricted to compensated patients. Although this advice was followed in the PREDESCI trial (aimed at testing whether NSBBs might prevent decompensation and ascites, which was indeed demonstrated),10Villanueva C. Albillos A. Genesca J. et al.Beta blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.Lancet. 2019; 393: 1597-1608Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar other RCTs on carvedilol focused on its use in primary prophylaxis of variceal bleeding in patients with high-risk varices, a situation in which about 40%–50% of the patients also have ascites.9McDowell H.R. Chuah C.S. Tripathi D. et al.Carvedilol is associated with improved survival in patients with cirrhosis: a long-term follow-up study.Aliment Pharmacol Ther. 2021; 53: 531-539PubMed Google Scholar,11Tripathi D. Ferguson J.W. Kochar N. et al.Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed.Hepatology. 2009; 50: 825-833Crossref PubMed Scopus (201) Google Scholar These studies also showed high efficacy in preventing bleeding and raised no alarms on adverse effects in patients with ascites. Based on the aforementioned data, there should be no concerns using carvedilol in secondary prophylaxis in patients without ascites (about 50% of the cases in this scenario), whereas in patients with ascites the concerns should probably be limited to those with refractory ascites where changes in blood pressure and renal function should be closely monitored. Why are there no large secondary prophylaxis RCTs that have been performed or are ongoing? The answer is probably related to the increasing cost of clinical trials and lack of interest from the pharmaceutical industry because carvedilol already has extensive label indications, such as arterial hypertension and heart failure. Despite several governments’ funding RCTs of no industrial interest, there are usually restrictions for international cooperation, diminishing the chances these will be ever conducted. In this context, one understands initiatives aimed at providing more information on the effects of carvedilol versus propranolol based on retrospective comparisons of series of patients treated with either drug associated with endoscopic variceal ligation. This is specifically what Jachs et al12Jachs M. Hartl L. Simbrunner B. et al.Carvedilol achieves higher hemodynamic response and lower rebleeding rates than propranolol in secondary prophylaxis.Clin Gastroenterol Hepatol. 2023; 21: 2318-2326Abstract Full Text Full Text PDF Scopus (8) Google Scholar have done in the carefully conducted study presented in this issue of Clinical Gastroenterology and Hepatology. The study confirms several important advantages of carvedilol in secondary prophylaxis, namely, its greater reduction of HVPG, which translates into a greater proportion of patients with good hemodynamic response (a fall in HVPG to values <12 mm Hg or at least of 20% of baseline),13Feu F. Garcia-Pagan J.C. Bosch J. et al.Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis.Lancet. 1995; 346: 1056-1059Abstract PubMed Scopus (499) Google Scholar, 14D'Amico G. Garcia-Pagan J.C. Luca A. et al.Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review.Gastroenterology. 2006; 131: 1611-1624Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar, 15Abraldes J.G. Tarantino I. Turnes J. et al.Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis.Hepatology. 2003; 37: 902-908Crossref PubMed Scopus (413) Google Scholar together with positive data confirming that such a good hemodynamic response is indeed associated with better clinical efficacy in terms of decreasing the risk of bleeding and enhancing survival. Unfortunately, the retrospective nature of the study and the fact that the pattern of choosing one drug or the other changed over time, that it encompassed a very prolonged period, and was not analyzed strictly on an intent-to-treat basis (among other limitations) precludes drawing definite conclusions on safety, and limits clinical efficacy comparisons. Nevertheless, the study is clinically valuable because it certainly does not point against the use of carvedilol for this indication. Moreover, even if carvedilol caused a mild decrease in arterial pressure, no instances of acute kidney injury-hepato-renal syndrome or signs of impending renal impairment were observed. Therefore, despite not being an RCT, the study still strongly suggests that carvedilol is at least as safe as propranolol. In addition, the study indicates that the more favorable hemodynamic effect contributes to a greater efficacy. As an expert in the field, I am in complete agreement with the authors in suggesting that carvedilol is likely to represent the best NSBB in the treatment of portal hypertension regardless of the clinical scenario, including prevention of decompensation, ascites, first bleeding, or recurrent bleeding. Admittedly, I am somewhat frustrated by experiencing increasing difficulties in performing high-quality investigator-initiated RCTs after being educated on the value of “evidence-based medicine” over “eminence” based opinions! I remember the advice I got in the past from Tom Chalmers, the father of RCTs in liver disease (“Randomize from the first patient!”), and another giant, Jean-Pierre Benhamou (“When I don’t know which treatment is best, I randomize”). It is hoped the time will come when new international initiatives, such as the Baveno Cooperation (an EASL consortium), and changes in priorities from funding agencies may facilitate progress in the treatment of portal hypertension. This is an area where most advances that have led to a dramatic reduction in the incidence and mortality from bleeding and from decompensation have been made possible by investigator-initiated studies and public funding. Carvedilol Achieves Higher Hemodynamic Response and Lower Rebleeding Rates Than Propranolol in Secondary ProphylaxisClinical Gastroenterology and HepatologyVol. 21Issue 9PreviewCarvedilol induces stronger decreases in hepatic venous pressure gradient (HVPG) than conventional nonselective β-blockers (ie, propranolol). Limited data exist on the efficacy of carvedilol in secondary prophylaxis of variceal bleeding. Full-Text PDF Open Access