Editorial: Carvedilol Remains the First-Line Treatment of Portal Hypertension After the CALIBRE Trial

Abstract

Portal hypertension (PH) is a major consequence of cirrhosis, driving severe complications such as variceal bleeding or ascites. For the prevention of variceal haemorrhage in cirrhosis patients, primary prophylaxis can be performed by non-selective beta-blockers (NSBB) or endoscopic variceal ligation (EVL); however, the Baveno-VII consensus strongly recommends the Carvedilol as the first-line approach [1]. Recent results of the prematurely terminated and thus, underpowered CALIBRE trial [2] showed no significant difference of bleeding rates in the carvedilol versus EVL arm. Next to being cost-sparing, no major safety concerns about Carvedilol emerged, while numerically more bleedings in the EVL arm occurred [2]. Already more than 20 years ago, Tripathi et al. demonstrated that carvedilol ameliorates PH by its additional α1-adrenergic activity on top of combined beta-1/2-adrenergic blockade [3]. Later their randomised controlled trial established that carvedilol was more effective than EVL for primary prophylaxis: bleeding rates were 10% versus 23% after a median of 20 months (relative hazard 0.41) [4]. Long-term follow-up of this trial confirmed that patients treated with carvedilol had improved survival compared to EVL [5].

In other studies, carvedilol consistently exerted superior efficacy as compared to propranolol in reducing hepatic venous pressure gradient (HVPG) and preventing variceal (re)-bleeding in primary and secondary prophylaxis [6, 7]. Moreover, a dose–response study identified 12.5 mg/day as an optimal dose, balancing portal pressure reduction with acceptable systemic side effects on arterial blood pressure [8].

The superior ability of Carvedilol to improve PH-related outcomes over traditional NSBB via more potent HVPG reduction was underscored by recent multicenter studies: Carvedilol significantly reduced the risk of any type of decompensation (39% risk reduction) in patients with compensated cirrhosis and prevented further decompensation and mortality (43% risk reduction) in patients with decompensated cirrhosis [9]. An individual patient data meta-analysis of randomised controlled trials (comparing Carvedilol vs. no treatment or EVL) confirmed a significantly lowered risk of both first decompensation (by 49%) and deaths (by 58%) with carvedilol—indicating an overall survival benefit of Carvedilol-treated cirrhosis patients that goes beyond prevention of variceal haemorrhage [10].

Considering the previous evidence, the surprising ‘negative’ CALIBRE trial results [2] of similar first bleeding rates with Carvedilol (5 patients, 3.8%) versus EVL (10 patients, 7.6%) should be critically reviewed, even if the early trial termination and lack of power (only 265 patients were recruited representing 10% of the initially planned sample size) prevent meaningful conclusions. For example, the interpretation of the similar rate of cirrhosis-related complications seems problematic as both compensated and decompensated patients were included.

Despite the lack of difference in the efficacy of Carvedilol to prevent first variceal bleeding versus EVL in the CALIBRE trial [2], the full body of evidence still supports Carvedilol as a mainstay of PH management (Table 1). Thus, Baveno-VII recommendations [1] to use carvedilol as the first-line treatment in compensated patients with PH to prevent variceal bleeding and non-bleeding decompensation remain valid. The paradigm shift of administering effective medical treatment of PH as the underlying cause rather than just ligation of varices will result in improved patient outcomes while saving healthcare resources and costs related to cirrhosis and PH.

Thomas Reiberger: conceptualization, writing – original draft, writing – review and editing. Benedikt Simbrunner: writing – review and editing.

T.R. received grant support from Abbvie, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, Siemens and W. L. Gore & Associates; speaking/writing honoraria from Abbvie, Echosens, Gilead, GSK, Intercept/Advanz Pharma, Pfizer, Roche, MSD, Siemens, and W. L. Gore & Associates; consulting/advisory board fees from Abbvie, Astra Zeneca, Bayer, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Resolution Therapeutics and Siemens; and travel support from Abbvie, Boehringer Ingelheim, Dr. Falk Pharma, Gilead and Roche. B.S. has received travel support from AbbVie, Gilead and Falk.

This article is linked to Tripathi et al paper. To view this article, visit https://doi.org/10.1111/apt.70080.