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.

TABLE 1. Key facts on carvedilol in portal hypertension.

Mechanism of action	Non-selective beta-1/beta-2 adrenergic blocker with additional anti-alpha-1-adrenergic blockade, that results in a reduction in cardiac output, splanchnic blood inflow, and intrahepatic vascular resistance and thus, in a potent reduction of portal pressure
Efficacy	More effective than propranolol (and other conventional NSBBs) in reducing HVPG, thus achieving higher hemodynamic response rates, and higher efficacy in preventing variceal bleeding and rebleeding
Comparison to EVL	Carvedilol seems superior in primary bleeding prophylaxis. EVL does not prevent non-bleeding decompensation. Carvedilol improves overall survival as compared to EVL
Additional benefits	Carvedilol reduces the risk of decompensation beyond variceal haemorrhage. Carvedilol improves overall survival in patients with cirrhosis and portal hypertension
Optimal carvedilol dose	A Carvedilol dose of 12.5 balances portal pressure reduction with systemic safety (e.g., no pronounced arterial hypotensive effects at this dose, at least in compensated patients). Patient with arterial hypertension may be treated with higher doses of Carvedilol
Baveno VII guideline recommendation	Carvedilol represent the first-line treatment in patients with compensated cirrhosis (cACLD) and clinically significant portal hypertension (CSPH) with the target of preventing variceal haemorrhage and non-bleeding decompensation

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.