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Combination of Carvedilol With Variceal Band Ligation for Prevention of First Variceal Bleed in Child–Turcotte–Pugh B and C Cirrhosis With High-Risk Oesophageal Varices
TAKE-HOME MESSAGE
- In this randomised controlled trial, patients with Child–Turcotte–Pugh B and C cirrhosis with high-risk varices and no prior history of a variceal bleed were randomised to carvedilol (n = 110), variceal band ligation (VBL; n = 110), or a combination of carvedilol and VBL (n = 110). Combination therapy significantly reduced the incidence of initial variceal bleed by 69.3% and 62.9% compared with carvedilol (P < .001) and VBL (P < .003), respectively. Furthermore, 1-year mortality was significantly lower in the combination arm (6.4%) than in the carvedilol (20.0%) and VBL (14.5%) arms (P < .005 for both).
- VBL or non-selective beta blockers are recommended for primary prophylaxis of variceal bleeding. These findings suggest a role for combination therapy with VBL and carvedilol in patients with Child–Turcotte–Pugh B and C cirrhosis and high-risk varices.
abstract
This abstract is available on the publisher's site.
Access this abstract nowOBJECTIVES
Beta-blockers and endoscopic variceal band ligation (VBL) have been preferred therapies for primary prophylaxis of variceal bleeding. However, the choice of therapy in patients with advanced liver disease with high-risk varices is not clear. A comparison of these therapies alone or in combination to prevent the first variceal bleed in advanced cirrhosis patients was carried out.
DESIGN
330 Child-Turcotte-Pugh (CTP) B and C cirrhosis patients, with 'high-risk' varices were prospectively enrolled (n=110 per group) to receive carvedilol (group A), VBL (group B) or combination (group C). Primary endpoint was reduction in the incidence of first variceal bleed at 12 months. The secondary endpoints included overall mortality, bleed-related mortality, new-onset decompensation, change in hepatic vein pressure gradient (HVPG) and treatment-related adverse events.
RESULTS
The patients were predominantly males (85.2%), aged 51.4±10.5 years with CTP score of 8.87±1.24, MELD score 15.17±3.35 and HVPG-16.96±3.57 mm Hg. The overall incidence of variceal bleed was 23.8% (n=78) at 1 year. Intention-to-treat analysis showed that the combination arm (group C) significantly reduced the incidence of first variceal bleed by 62.9% as compared with group B (HR 0.37, 95% CI 0.192 to 0.716, p<0.003) and by 69.3% as compared with group A (HR 0.31, 95% CI 0.163 to 0.578, <0.001). The overall mortality was 13.6% (45/330). The 1-year mortality in group C was lowest among the three groups (A, B, C=20%, 14.5%, 6.3%, p=0.012). Reduction in HVPG (20.8% vs 25.1%, p=0.54) and the rate of non-response to carvedilol (53.4% vs 41.25%, p=0.154) were not different between group A and C patients. The incidence of new-onset ascites, spontaneous bacterial peritonitis, shock, and acute kidney injury and postbleed organ failure was also comparable between the groups.
CONCLUSION
In CTP B and C cirrhosis patients with high-risk varices, combination of carvedilol and VBL is more effective than either therapy alone, for primary prevention of variceal bleeding.
Additional Info
Disclosure statements are available on the authors' profiles:
Combination of carvedilol with variceal band ligation in prevention of first variceal bleed in Child-Turcotte-Pugh B and C cirrhosis with high-risk oesophageal varices: the 'CAVARLY TRIAL'
Gut 2024 Jul 27;[EPub Ahead of Print], HV Tevethia, A Pande, R Vijayaraghavan, G Kumar, SK SarinFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Endoscopic variceal band ligation (EVL) and beta-blockers are commonly recommended therapies to prevent first oesophageal variceal haemorrhage in good-risk patients with cirrhosis with medium-sized or large oesophageal varices. Patients with advanced cirrhosis have a higher risk of developing first oesophageal variceal haemorrhage and higher mortality rates than those without advanced cirrhosis. However, there is a controversy regarding the best strategy for primary prophylaxis to prevent first oesophageal variceal haemorrhage and its associated mortality in such patients. Although a combination of beta-blockers and EVL is recommended for secondary prevention of recurrent oesophageal variceal haemorrhage, combination therapy for primary prophylaxis needs further study.
Sarin and his colleagues in New Delhi performed a randomised controlled trial to compare the clinical outcomes of patients with Child–Turcotte–Pugh B and C cirrhosis in three different groups of 110 patients each treated with either EVL, carvedilol, or a combination of the two. In well-matched patients at baseline, the primary outcome of first oesophageal variceal bleeding rate was significantly lower in the combination group than the carvedilol group by 69.3% (HR, 0.31; 95% CI, 0.163–0.578; P < .001) and the EVL group by 62.9% (HR, 0.37; 95% CI, 0.192–0.716; P < .003). The 1-year mortality rate was also significantly lower for the combination therapy (6.3%) than the EVL (14.5%) and carvedilol (20.0%) groups. The rates of new-onset ascites, spontaneous bacterial peritonitis, acute kidney failure, and other complications of cirrhosis were comparable between the groups. For the beta-blocker and combination groups, respectively, the reductions in hepatic venous pressure gradient (HVPG; 20.8% vs 25.1%) and nonresponse rates of HVPG to carvedilol (53.4% vs 41.25%) were not significantly different.
The results of this study are clinically important and potentially will help improve the primary prophylactic treatment to prevent first variceal haemorrhage and reduce associated mortality in patients with Child–Turcotte–Pugh B and C cirrhosis. There appears to be a synergistic effect with the combination treatment, which is not attributable to the rate of HVPG reduction alone. Close monitoring of peripheral haemodynamic effects of carvedilol and titration of dosage are required to prevent complications. Validation of the study results in more diverse patient populations with different ethnicities, more females, and those with higher BMI is recommended to confirm and expand the potential generalisability of the randomised controlled trial, including for patients listed for orthotopic liver transplantation.