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Multicentre randomised controlled study comparing carvedilol with variceal band ligation in the prevention of variceal rebleeding
Research Article
Multicentre randomised controlled study comparing carvedilol with variceal band ligation in the prevention of variceal rebleeding Adrian J. Stanley1,⇑, Sheila Dickson1, Peter C. Hayes2, Ewan H. Forrest1, Peter R. Mills3, Dhiraj Tripathi2, , Joanna A. Leithead2, , Kim MacBeth2, Lyn Smith1, Daniel R. Gaya1, Harry Suzuki4, David Young5 3
1 Gastroenterology Unit, Glasgow Royal Infirmary, Glasgow, UK; 2Liver Unit, Royal Infirmary of Edinburgh, Edinburgh, UK; Gastroenterology Unit, Gartnavel General Hospital, Glasgow, UK; 4Gastroenterology Unit, Southern General Hospital, Glasgow, UK; 5 Department of Statistics, Strathclyde University, Glasgow, UK
Background & Aims: Rebleeding after an initial oesophageal variceal haemorrhage remains a significant problem despite therapy with band ligation, non-selective b-blockers or a combination of these. Carvedilol is a vasodilating non-selective b-blocker with alpha-1 receptor and calcium channel antagonism. A recent study has suggested it is effective in the prevention of a first variceal bleed. Our aim was to compare oral carvedilol with variceal band ligation (VBL) in the prevention of rebleeding following a first variceal bleed. Methods: Patients who were stable 5 days after presentation with a first oesophageal variceal haemorrhage and had not been taking b-blockers were randomised to oral carvedilol or VBL. Patients were followed-up after one week, monthly, then every 3 months. The primary end point was variceal rebleeding on intention-to-treat analysis. Results: 64 patients were randomised, 33 to carvedilol and 31 to VBL. 58 (90.6%) patients had alcohol related liver disease. Age and Child-Pugh score were similar in both groups at baseline. Median follow-up was 26.3 (interquartile range [IQR] 10.2–46.6) months. Compliance was 68% and 65% for carvedilol and VBL respectively (p = 0.993) and serious adverse events between the two groups were similar (p = 0.968). Variceal rebleeding occurred during follow-up in 12 (36.4%) and 11 (35.5%) patients in the carvedilol and VBL groups, respectively (p = 0.857), with 9 (27.3%) and 16 (51.6%) deaths in each group, respectively (p = 0.110). Conclusions: Carvedilol is not superior to VBL in the prevention of variceal rebleeding. The trend to a survival benefit for patients
Keywords: Variceal haemorrhage; Portal hypertension; Carvedilol; Band ligation. Received 2 April 2014; received in revised form 25 May 2014; accepted 9 June 2014; available online 19 June 2014 ⇑ Corresponding author. Address: Gastroenterology Unit, Glasgow Royal Infirmary, Castle St, Glasgow G4 0SF, UK. Tel.: +44 141 211 4073; fax: +44 141 211 5131. E-mail address: [email protected] (A.J. Stanley). Present address: Liver Unit, University Hospitals Birmingham, UK. Abbreviations: b-blockers, beta-blockers; VBL, variceal band ligation; NAFLD, non-alcoholic fatty liver disease; TIPSS, transjugular intrahepatic portosystemic stent-shunt; MELD, model for end stage liver disease; CPs, Child-Pugh score; IQR, interquartile range; GRI, Glasgow Royal Infirmary; ERI, Royal Infirmary of Edinburgh; GGH, Gartnavel General Hospital Glasgow; SGH, Southern General Hospital Glasgow.
taking this drug compared with those undergoing banding requires further exploration. Ó 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Introduction Variceal bleeding continues to be a major clinical challenge with high mortality [1]. Recent evidence suggests the incidence of variceal bleeding in the UK is increasing, probably due to the increased prevalence of cirrhosis as a consequence of alcohol, viral hepatitis, and non-alcoholic fatty liver disease (NAFLD) [2]. Following control of an acute variceal bleed, rebleeding occurs in up to 70% patients with associated high mortality [1,3,4]. Recent studies have suggested reduction in the rebleeding rate with variceal band ligation (VBL), drug therapy with b-blockers ± isosorbide mononitrate, or a combination of VBL and drug therapy [5–11]. Interestingly, some studies have reported a mortality benefit from drug therapy compared with VBL in the prevention of variceal rebleeding [12,13]. Evidence from meta-analyses suggests that although combined VBL and drug therapy may reduce variceal rebleeding, this does not generally affect mortality and is associated with more serious adverse effects [10,11]. Carvedilol is a vasodilating non-selective b-blocker with alpha-1 antagonism and calcium blocking effects. Haemodynamic studies have shown it to be superior to propranolol in reducing portal hypertension [14–19]. Initial clinical studies have also shown superiority of carvedilol over VBL in the prevention of a first variceal bleed [20] and equal efficacy to combined nadolol and isosorbide mononitrate in the prevention of variceal rebleeding [21]. The aim of this multicentre study was to compare oral carvedilol with VBL in the prevention of variceal rebleeding.
Materials and methods Patients who were clinically stable after an endoscopically proven first oesophageal variceal bleed in four centres were recruited. The centres were: Glasgow
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JOURNAL OF HEPATOLOGY Royal Infirmary (GRI), Royal Infirmary of Edinburgh (ERI), Gartnavel General Hospital, Glasgow (GGH), and Southern General Hospital, Glasgow (SGH). Ethical approval was obtained for each site. The study was registered under the trial number ISRCTN 69643049. All patients had had their acute bleed managed by VBL, terlipressin and antibiotics as is standard practice. Patients who were clinically stable five days after their variceal bleed were given a patient information sheet and recruited after signing informed witnessed consent. Randomisation to oral carvedilol or VBL in a 1:1 ratio was undertaken by computer generated random numbers. Exclusion criteria were: age <18 or >75 years; advanced malignancy or comorbidity, resulting in life expectancy <6 months; obstructive airways disease; baseline pulse rate <50 bpm or systolic blood pressure <90 mmHg; severe peripheral vascular disease; heart block or severe heart failure; pregnancy; type-I diabetes; portal vein thrombosis; previous transjugular intra-hepatic portosystemic stent shut (TIPSS) or porto-caval shunt surgery; a gastric variceal bleed; or treatment with b-blockers, or alpha-blockers within 4 weeks of the index bleed. Patients randomised to carvedilol (Roche, Herts, UK) were given it orally 6.25 mg daily for one week, then increased to 12.5 mg long-term if tolerated. The dose chosen was based on previous data [18,20]. Drug compliance was assessed by the patient’s history, collateral history and tablet count where possi-
Enrollment
ble. Patients randomised to VBL underwent VBL at one week, then at 2 weekly intervals until eradication, with subsequent surveillance endoscopies undertaken at 6-month intervals. Patients unable to tolerate carvedilol due to symptoms, pulse rate <50 bpm or systolic blood pressure <85 mmHg were converted to VBL. All patients were reviewed at one week, one month, then every 3 months unless clinically indicated earlier. The primary end point was variceal rebleeding, defined by haematemesis or melaena, confirmed by endoscopy with drop in Hb of 3 g if no transfusion given [22]. The secondary end points were mortality, any gastrointestinal rebleeding and serious adverse events. Serious adverse events were defined as events, which were life-threatening, required hospitalisation (or prolonged hospitalisation), or resulted in significant disability. Statistics To achieve a power of 80% at the 5% significance level, 54 patients were required in each group to prove superiority of carvedilol, assuming recurrent bleeding rates of 45% with VBL and 20% with carvedilol. Therefore assuming a 10% drop out rate, 60 patients were required in each group to complete the study. All analyses were undertaken using the intention to treat basis unless stated otherwise.
Assessed for eligibility (n = 84)
Excluded (n = 20) Not meeting inclusion criteria (n = 16.) 7 of these due to recent β-blocker use Declined to participate (n = 3) Other reasons (n = 1)
Randomized (n = 64)
Allocation Allocated to carvedilol (n = 33) Received allocated intervention (n = 31) Did not receive allocated intervention (n = 2; patients on reflection preferred to have band ligation)
Allocated to VBL (n = 31) all 31 received allocated intervention
Follow-up Lost to follow-up (n = 1; patient had already discontinued drug due to side effects) Discontinued intervention (n = 12; 5 due to side effects, 2 ongoing alcohol excess, 5 with reasons uncertain)
Lost to follow-up (n = 4) No other patient discontinued VBL, but 7 had interruptions to attendance for VBL surveillance
Analysis Analysed per protocol (n = 19) Excluded from analysis (n = 0)
Analysed per protocol (n = 20) Excluded from analysis (n = 0 )
Fig. 1. CONSORT flow diagram for the study.
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Research Article Free from variceal rebleeding
Time to rebleeding was assessed using survival analysis. Univariate analyses were done to estimate hazard ratios associated with each possible predictor of survival and Cox regression analysis was used to determine independent predictors of rebleeding. All analyses were done using SPSS (version 20) at a 5% significance level. One interim analysis was planned after recruitment of over 60 patients (30 in each group), at which point the number of further patients required to be recruited to achieve a significant difference in the primary end point would be calculated.
Results
1.0
0.8 Carvedilol 0.6 p = 0.857
Band ligation 0.4 0.0
In total, 64 patients were recruited (37 at GRI, 21 at RIE, 5 at GGH and one at SGH) with 33 patients randomised to carvedilol and 31 to VBL. Patients were recruited from June 2006 until December 2011, with follow-up until June 2012. The consort flow diagram is shown in Fig. 1. Median follow-up for all patients was 26.3 (IQR 10.2–46.6) months. There were no differences in baseline characteristics between both groups (Table 1), with ChildPugh class A, B, and C disease in 11 (17%), 28 (44%), and 25 (39%) patients, respectively. 58 (91%) patients had alcohol related liver disease. Other aetiologies included three (5%) with non-alcoholic fatty liver disease, two (3%) with primary biliary cirrhosis, and one (2%) with drug induced chronic liver disease.
0
20
40
60
Follow-up (mo) Carvedilol VBL
33 31
16 9
12 6
3 1
Fig. 2. Variceal rebleeding (intention to treat analysis).
ysis (p = 0.715). Three (10%) patients in the VBL group rebled from banding induced ulceration, although none died from this. Univariate analysis of prognostic variables are shown in Table 4, with only MELD, serum bilirubin and albumin predicting variceal rebleeding, and with only serum albumin being significant on multivariate analysis.
Rebleeding Mortality Variceal rebleeding was similar in both groups, occurring in 12 (36.4%) of the carvedilol group and in 11 (35.5%) of the VBL group (p = 0.857; Fig. 2). All patients bled from oesophageal varices. The results were similar using the per protocol analysis (p = 0.755). There was no difference in variceal rebleeding between the two largest recruiting centres (p = 0.955). Only two of the patients in the VBL arm had their varices eradicated prior to their rebleeding. The percentage of patients with variceal rebleeding in the carvedilol and VBL groups at 12 months was 29.9% and 25.3% respectively, and at 24 months it was 29.3% and 42.2% respectively. Eight (35%) patients had their rebleeding managed by TIPSS insertion (three in the carvedilol and five in the VBL arm). Rebleeding from any upper gastrointestinal site was 13 (39%) and 14 (45%) in the carvedilol and VBL groups respectively (p = 0.393). This was also non-significant using per protocol anal-
Table 1. Patient characteristics.
Characteristic Age, years; mean ± SD Male:Female Child-Pugh Score MELD Bilirubin, μmol/L Albumin, g/L Prothrombin, time (s) Ascites, n (%) Follow-up, months
Carvedilol (n = 33) 51.4 ± 10.8 22:11 9 (7.0-10.5) 13 (8.25-18.5) 39 (19.5-63.0) 27 (22.5-31.5) 15 (13.0-19.0) 12 (36.3%) 30.7 (7.9-47.1)
VBL (n = 31) 49.6 ± 12.87 21:10 9 (8.0-11.0) 14 (11.0-16.0) 35 (23.0-82.0) 27 (24.0-33.0) 16 (14.0-17.0) 12 (38.7%) 23.5 (10.3-44.8)
All values are expressed as median (IQR) unless otherwise stated. There were no significant differences between groups for any variable. SD, standard deviation; VBL, variceal band ligation; MELD, model for end stage liver disease.
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Mortality during follow-up was 9 (27.3%) in the carvedilol group and 16 (51.6%) the VBL group (p = 0.110; Fig. 3). Mortality in the per protocol analysis was non-significant at p = 0.125. Only three (5%) patients died within 6 weeks, two in the carvedilol group and one treated with VBL. The percentage mortality in the carvedilol and VBL groups at 12 months was 19.5% and 23.0% respectively, and at 24 months it was 23.0% and 38.3% respectively. Mortality was lower for Child-Pugh class B patients treated with carvedilol compared with VBL (16.7% vs. 56.2%; p = 0.033), while mortality for Child-Pugh class A and Child-Pugh class C patients was similar in both groups (p = 0.731 and p = 0.722 respectively). Causes of death are shown in Table 2. Most of the deaths in the carvedilol group were bleeding related, compared with only one in the VBL group. However none of the carvedilol patients died of (non-bleeding) liver related causes, but this accounted for the deaths of 6 patients in the VBL group. Overall mortality due to non-bleeding causes in the carvedilol and VBL groups was 4 (12.1%) and 15 (48.4%) respectively.
Table 2. Causes of death.
All causes Bleeding related Sepsis Decompensated liver disease or HCC *Other ⁄
Carvedilol (n = 33) 9 5 4 0
VBL (n = 31) 16 1 1 6
0
8
Other causes of death (one of each): lung cancer, pulmonary hypertension, cerebrovascular accident, subarachnoid haemorrhage, intra-cranial haemorrhage, ischaemic bowel, ischaemic heart disease, heroin overdose. VBL, variceal band ligation; HCC, hepatocellular carcinoma.
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JOURNAL OF HEPATOLOGY Table 3. Adverse events, compliance and ongoing alcohol consumption.
1.0
VBL 18 (58%) 20 (65%) 15 (48%)
p value 0.968 0.993 0.994
⁄
The number of serious adverse events not related to rebleeding or ongoing progression of chronic liver disease were 7 in the carvedilol group (shortness of breath [n = 2], dizziness, diarrhoea, hallucinations, hyperglycaemia and overdose of carbamazepine) and 6 in the VBL group (ischemic bowel, cerebellar haematoma, septicaemia, lung cancer, renal impairment and diarrhoea). # 5 patients had been intolerant of the medication, therefore were not included in this analysis.
Age Gender Child-Pugh score MELD Aetiology Ongoing alcohol Bilirubin Creatinine Sodium Albumin Prothrombin time Ascites
Relative hazard (95% confidence intervals) 0.997 (0.963-1.032) 0.489 (0.181-1.323) 0.881 (0.732-1.061) 1.107 (1.025-1.195) 2.852 (0.383-21.229) 0.567 (0.219-1.465) 1.008 (1.002-1.014) 0.999 (0.999-1.008) 0.999 (0.963-1.036) 0.891 (0.817-0.971) 1.043 (0.994-1.095) 0.899 (0.380-2.124)
p value 0.869 0.181 0.183 0.010 0.306 0.242 0.010 0.865 0.951 0.009 0.088 0.808
On multivariate analysis, only serum albumin was significant
Mortality Variable Age Gender Child-Pugh score MELD Aetiology Ongoing alcohol Bilirubin Creatinine Sodium Albumin Prothrombin time Ascites
Relative hazard (95% confidence intervals) 1.006 (0.973-1.041) 0.687 (0.433-1.089) 1.248 (1.011-1.540) 1.071 (1.003-1.143) 3.387 (0.457-25.119) 1.889 (0.809-4.413) 1.010 (1.004-1.016) 0.996 (0.983-1.009) 0.998 (0.958-1.040) 0.897 (0.835-0.964) 0.995 (0.935-1.058) 1.431 (0.641-3.192)
Carvedilol 0.6 p = 0.110
0.4 Band ligation
0.2
0.0
Table 4. Cox regression analysis of variables for outcome.
Variceal bleeding Variable
0.8
Survival
Serious adverse events* Compliance Ongoing alcohol
Carvedilol 19 (56%) 19 (68%)# 16 (48%)
p value 0.718 0.110 0.040 0.039 0.233 0.142 0.001 0.571 0.942 0.003 0.866 0.382
On multivariate analysis, only Childs-Pugh score and MELD were significant
On univariate analysis of prognostic variables for mortality, Child-Pugh score (CPS), MELD, serum bilirubin and albumin were significant (see Table 4). On multivariate analysis, only CPS and MELD were significant. Of the patients randomised to carvedilol or VBL, 12 in each group had ascites at recruitment to the study. Seven patients
Carvedilol VBL
0
20 40 Follow-up (mo)
60
33 31
19 17
4 2
14 9
80
Fig. 3. Mortality (intention to treat analysis).
had worsening ascites during the study, two who had been randomized to carvedilol, and five had been randomised to VBL. One patient (who had been randomised to VBL) had documented spontaneous bacterial peritonitis during follow-up. Five (41.7%) of the 12 patients in each group who had ascites at randomisation died during follow-up. Haemodynamics Patients randomised to carvedilol had a drop in pulse rate from 84.9 ± 15.0 to 71.5 ± 10.8 bpm (p = 0.008) during the study, with the mean arterial pressure (MAP) falling from 86.0 ± 12.4 to 82.8 ± 10.3 mmHg (p = 0.053). For patients randomised to VBL, there was no difference in the pulse rate (85.4 ± 19.7 vs. 81.6 ± 16.9 bpm; p = 0.919) or MAP (88.7 ± 14.4 vs. 87.1 ± 12.1; p = 0.783) during the study. Compliance and adverse events Compliance with therapy was similar in both groups (see Table 3 and Fig. 1). In the carvedilol group, five patients were unable to tolerate the medication, but of the remaining 28 patients, nineteen (68%) were compliant with therapy. Two patients discontinued carvedilol due to problems with alcohol excess, two patients subsequently chose to stop taking carvedilol and asked to change to VBL and 5 patients discontinued for reasons not documented or uncertain. In the VBL group, 20 (65%) were compliant with VBL during follow-up. Of those who were non-compliant, three were known to have ongoing issues with alcohol excess and the others failed to attend for VBL procedures at various stages for reasons which were unclear. Serious adverse events were observed in 19 (56%) patients randomised to carvedilol and 18 (58%) randomised to VBL (see Table 3). When those relating to progression of underlying liver disease were excluded, there were 7 serious adverse events in the carvedilol group and 6 in the VBL group. These are described in Table 3. Ongoing alcohol intake was reported in 16 (48%) carvedilol patients and 15 (48%) VBL patients during follow-up.
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Research Article Discussion This study shows that carvedilol is not superior to VBL in the prevention of variceal rebleeding. The study was stopped at the planned interim analysis due to very similar rates of the primary end point of variceal rebleeding, indicating that more than 1000 patients would be required to show a significant difference. The strong trend we observed towards improved survival with carvedilol is consistent with other studies assessing b-blockers in cirrhosis and requires further study. Rebleeding after a first variceal bleed is common but can be reduced by treatment with drug therapy, VBL or a combination if these [1,22]. While recent consensus guidelines have more recently recommended the combination of b-blockade and VBL in this situation [3,23], these were published after recruitment commenced for this study. Although meta-analyses suggest that combined VBL and drug therapy can reduce rebleeding, it does not appear to reduce mortality and is associated with more serious adverse effects [10–12]. Indeed in one meta-analysis, mortality was lower in the drug treatment group [12]. In addition, a recent large study from India reported no reduction in rebleeding or mortality and increased adverse events with combined bblocker, nitrates and VBL compared with VBL alone [24]. Key researchers in this field have also suggested ‘‘the jury is still out’’ over the use of drug therapy, VBL, or both for the prevention of variceal rebleeding [25]. Therefore we felt it was justifiable to continue the study until the planned interim analysis. This has shown very similar variceal rebleeding rates with a trend towards a survival advantage for those given carvedilol. We found virtually identical variceal rebleeding rates of 36.4% and 35.5% during follow-up in the carvedilol and VBL groups respectively, with a similar result using per protocol analysis. The rebleeding rates from any gastrointestinal source (including oesophageal ulceration) were also very similar, as were serious adverse events and compliance. Several studies have suggested that drug therapy to reduce portal hypertension, particularly b-blockade, may improve survival in cirrhosis, possibly due to effects on sepsis including spontaneous bacterial peritonitis, and effects on intestinal transit [26–28]. However, other recent publications have suggested a deleterious effect on outcome by the use of b-blockers, especially in patients with ascites, possibly due to limitation of the compensatory increase in cardiac output or paracentesisinduced circulatory dysfunction [29,30]. Interestingly, among the patients in our study who had ascites at randomisation, more patients in the VBL group had deterioration in their ascites during follow-up, although mortality among ascitic patients in each group was equal. No patient had refractory ascites at entry to our study. Therefore we have found no major deleterious effect from carvedilol use in ascitic patients in this clinical situation. In our study, overall mortality in the carvedilol group was 27% vs. 52% in the VBL group, although this did not reach statistical significance. Interestingly, most deaths in the carvedilol group were bleeding related, whereas in the VBL group the vast majority was due to non-bleeding causes, which may suggest a pleiotropic protective effect of this drug in cirrhotic patients. It is interesting that survival for Child-Pugh class B patients (the grade with the highest number of patients in our study) was significantly higher for patients given carvedilol compared with VBL, while there was no mortality difference for Child-Pugh class A or
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C patients. This might suggest Child-Pugh class B patients benefit most from carvedilol in this situation. This is interesting given the recently described ‘‘window hypothesis’’ suggesting b-blockers offer survival benefit for cirrhotic patients in the mid (early decompensated) phase of the disease, but not for those with either well compensated or end-stage cirrhosis [31,32]. However, this was a post-hoc analysis of a relatively small number of patients and requires further confirmation. A UK multicentre study comparing carvedilol with VBL in the primary prevention of variceal bleeding reported reduced bleeding with carvedilol [20], although another trial comparing these therapies as primary prophylaxis from Pakistan reported similar bleeding rates [33]. In addition, a study from Taiwan reported carvedilol to be as effective as combined b-blocker and nitrates for variceal rebleeding, but with fewer side-effects [21]. All three studies reported similar survival in both treatment groups. A recent study has also reported improved outcome when using carvedilol in non-haemodynamic responders to propranolol in the primary prophylaxis of variceal haemorrhage [34]. Although further clinical studies are required, the complex mechanisms of action of carvedilol make it an attractive drug for use in patients with cirrhosis. This study had several limitations. First, our control group was given VBL alone. However, for the reasons expressed above, we believe it was ethical to continue the study until the interim analysis. Secondly, recruitment was slow, with many patients not even considered for the study due to prior b-blocker use, or known contraindications. The former is a particular problem in areas such as ours where there is a widespread use of b-blockers as primary prophylaxis for variceal haemorrhage. Thirdly, we did not undertake hepatic venous pressure gradient measurements to assess response or guide therapy. However access to this measurement is not readily available to many clinicians and we had designed this as a pragmatic study to compare simple, readily available treatment strategies. In addition, almost 80% cirrhotic patients have a haemodynamic response to this dose of carvedilol [18]. In conclusion, our results suggest that carvedilol is not superior to VBL in the prevention of variceal rebleeding. However the trend to a survival benefit with this drug requires further study. Larger multicentre studies assessing the role of carvedilol in the prevention of variceal haemorrhage, either alone or in combination with VBL are needed. Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Acknowledgements We would like to thank A.J. Morris, M. Neilson, R. Gillespie, N. Kochar, J. Winter, D. Craig, S. Barclay, M. Priest, J.W. Ferguson. References [1] Garcia-Tsao G, Bosch J. Management of varices and variceal haemorrhage in cirrhosis. N Engl J Med 2010;362:823–832. [2] Hearnshaw SA, Logan RFA, Lowe D, Travis CPL, Murphy MF, Palmer KR. Acute upper gastrointestinal bleeding in the UK: patient characteristics, diagnoses and outcomes in the 2007 audit. Gut 2011;60:1327–1335.
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JOURNAL OF HEPATOLOGY [3] Garcia-Tsao G, Bosch J, Groszmann RJ. Portal hypertension and variceal bleeding – Unresolved issues. Summary of an American Association for the study of liver diseases and European Association for the study of the liver single-topic conference. Hepatology 2008;47:1764–1772. [4] Bari K, Garcia-Tsao G. Treatment of portal hypertension. World J Gastroenterol 2012;11:1166–1175. [5] Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for treatment of oesophageal variceal bleeding: a meta-analysis. Ann Intern Med 1995;123:280–287. [6] Lebrec D, Poynard T, Hilton P, Benhamou J-P. Propranolol for the prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study. N Engl J Med 1981;305:1371–1374. [7] Gournay J, Masliah C, Martin T, Perrin D, Galmiche JP. Isosorbide mononitrate and propranolol compared with propranolol alone for the prevention of variceal rebleeding. Hepatology 2000;31:1239–1245. [8] Patch D, Sabin CA, Goulis J, et al. A randomised, controlled trial of medical therapy vs. endoscopic ligation for the prevention of variceal rebleeding in patients with cirrhosis. Gastroenterology 2002;123:1013–1019. [9] Villaneuva C, Minana J, Ortiz J, et al. Endoscopic ligation compared with combined treatment nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding. N Engl J Med 2001;345:647–655. [10] Gonzalez R, Zamora J, Gomez-Camarero J, Molinero LM, Banares R, Albillos A. Meta-analysis: combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis. Ann Intern Med 2008;149:109–122. [11] Thiele M, Kraq A, Rohde U, Gluud LL. Meta-analysis: banding ligation and medical interventions for the prevention of rebleeding from oesophageal varices. Aliment Pharmacol Ther 2012;35:1155–1165. [12] Li L, Yu C, Li Y. Endoscopic band ligation vs. pharmacological therapy for variceal bleeding in cirrhosis: a meta-analysis. Can J Gastroenterol 2011;25:147–155. [13] Lo GH, Chen WC, Lin CK, Tsai WL, Chan HH, Chen TA, et al. Improved survival in patients receiving medical therapy as compared with banding ligation for the prevention of esophageal variceal rebleeding. Hepatology 2008;48:580–587. [14] Forrest EH, Bouchier IAD, Hayes PC. Acute haemodynamic changes after oral carvedilol, a vasodilating beta-blocker, in patients with cirrhosis. J Hepatol 1996;25:909–915. [15] Stanley AJ, Therapondos G, Helmy A, Hayes PC. Acute and chronic haemodynamic and renal effects of carvedilol in patients with cirrhosis. J Hepatol 1999;30:479–484. [16] Banares R, Moitinho E, Piqueras B, et al. Carvedilol, a new nonselective betablocker with intrinsic anti-alpha-1-adrenergic activity, has a greater portal hypotensive effect than propanol in patients with cirrhosis. Hepatology 1999;30:79–83. [17] Banaras R, Moitinho E, Matilla A, et al. Randomised comparison of long term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis. Hepatology 2002;36:1367–1373. [18] Tripathi D, Therapondos G, Lui HF, Stanley AJ, Hayes PC. Haemodynamic effects of acute and chronic administration of low dose carvedilol, a vasodilating B-Blocker in patients with cirrhosis and portal hypertension. Aliment Pharmacol Ther 2002;16:373–380. [19] Sinagra E, Perricone G, D’Amico M, Tine F, D’Amico G. Systemic review with meta-analysis: the haemodynamic effects of carvedilol compared with
[20]
[21]
[22]
[23]
[24]
[25] [26]
[27]
[28]
[29]
[30]
[31]
[32] [33]
[34]
propranolol for portal hypertension in cirrhosis. Aliment Pharmacol Ther 2014;39:557–568. Tripathi D, Ferguson JW, Kochar N, Leithead JA, Therapondos G, McAvoy NC, et al. Randomized controlled trial of carvedilol vs. band ligation for the prevention of the first variceal bleed. Hepatology 2009;50:674–677. Lo GH, Chen WC, Wang HM, Yu HC. Randomized, controlled trial of carvedilol vs. nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding. J Gastroenterol Hepatol 2012;27:1681–1687. http:// dx.doi.org/10.1111/j.1440-1746.2012.07244.x. Portal hypertension IV. In: De Franchis R, editor. Proceedings of the IVth Baveno international consensus workshop on methodology of diagnosis and treatment. Oxford, UK: Blackwell Publishing; 2005. De Franchis R. Revising consensus on portal hypertension; Report of the Baveno V consensus workshop on methodology of diagnosis and therapy of portal hypertension. J Hepatol 2010;53:762–768. http://dx.doi.org/10.1016/ j.jhep.2010.06.004. Kumar A, Jhn SK, Dubey S, Tvagi P, Sharma BC, Sarin SK. Addition of propranolol and isosorbide mononitrate to endoscopic variceal ligation does not reduce variceal rebleeding incidence. Gastroenterology 2009;137:892–901. Mehta G, Abraldes JG, Bosch J. Developments and controversies in the management of oesophageal and gastric varices. Gut 2010;59:701–705. Senzolo M, Cholongitas E, Burra P, Leandro G, Thalheimer U, Patch D, et al. Beta-blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. Liver Int 2009;29:1189–1193. Turnes J, Garcia-Pagan JC, Abraldes JG, Hernandez-Guetta M, Dell-Era A, Bosch J. Pharmacological reduction of portal pressure and long-term use of first variceal bleeding in patients with cirrhosis. Am J Gastroenterol 2006;101:506–512. Perez-Paramo M, Munoz J, Albillos A, Freile I, Portero F, Santos M, et al. Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites. Hepatology 2000;1:43–48. Ruiz-del-Arbol L, Monescillo A, Aroncena C, Valer P, Gines P, Moreira V, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005;42:439–447. Sertse T, Melot C, Francoz C, Durand F, Rautou PE, Valla D, et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2010;52:1017–1022. Krag A, Wiest R, Albillos A, Gluud LL. The window hypothesis: haemodynamic and non-haemodynamic effects of Beta-blockers improve survival of patients with cirrhosis during a window in the disease. Gut 2012;61:967–969. Ge PS, Runyon BA. The changing role of beta-blocker therapy in patients with cirrhosis. J Hepatol 2014;60:643–653. Shah HA, Azam Z, Rauf J, et al. Carvedilol vs. esophageal variceal band ligation in the primary prophylaxis of variceal haemorrhage: a multicentre randomized controlled trial. J Hepatol 2014. http://dx.doi.org/10.1016/ j.jhep.2013.11.019, Epub ahead of publication. Reiberger T, Ulbrich G, Ferlitsch A, Payer BA, Schwabl P, Pinter M, et al. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol. Gut 2013;62: 1634–1641.
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Multicentre randomised controlled study comparing carvedilol with variceal band ligation in the prevention of variceal rebleeding Adrian J. Stanley1,⇑, Sheila Dickson1, Peter C. Hayes2, Ewan H. Forrest1, Peter R. Mills3, Dhiraj Tripathi2, , Joanna A. Leithead2, , Kim MacBeth2, Lyn Smith1, Daniel R. Gaya1, Harry Suzuki4, David Young5 3
1 Gastroenterology Unit, Glasgow Royal Infirmary, Glasgow, UK; 2Liver Unit, Royal Infirmary of Edinburgh, Edinburgh, UK; Gastroenterology Unit, Gartnavel General Hospital, Glasgow, UK; 4Gastroenterology Unit, Southern General Hospital, Glasgow, UK; 5 Department of Statistics, Strathclyde University, Glasgow, UK
Background & Aims: Rebleeding after an initial oesophageal variceal haemorrhage remains a significant problem despite therapy with band ligation, non-selective b-blockers or a combination of these. Carvedilol is a vasodilating non-selective b-blocker with alpha-1 receptor and calcium channel antagonism. A recent study has suggested it is effective in the prevention of a first variceal bleed. Our aim was to compare oral carvedilol with variceal band ligation (VBL) in the prevention of rebleeding following a first variceal bleed. Methods: Patients who were stable 5 days after presentation with a first oesophageal variceal haemorrhage and had not been taking b-blockers were randomised to oral carvedilol or VBL. Patients were followed-up after one week, monthly, then every 3 months. The primary end point was variceal rebleeding on intention-to-treat analysis. Results: 64 patients were randomised, 33 to carvedilol and 31 to VBL. 58 (90.6%) patients had alcohol related liver disease. Age and Child-Pugh score were similar in both groups at baseline. Median follow-up was 26.3 (interquartile range [IQR] 10.2–46.6) months. Compliance was 68% and 65% for carvedilol and VBL respectively (p = 0.993) and serious adverse events between the two groups were similar (p = 0.968). Variceal rebleeding occurred during follow-up in 12 (36.4%) and 11 (35.5%) patients in the carvedilol and VBL groups, respectively (p = 0.857), with 9 (27.3%) and 16 (51.6%) deaths in each group, respectively (p = 0.110). Conclusions: Carvedilol is not superior to VBL in the prevention of variceal rebleeding. The trend to a survival benefit for patients
Keywords: Variceal haemorrhage; Portal hypertension; Carvedilol; Band ligation. Received 2 April 2014; received in revised form 25 May 2014; accepted 9 June 2014; available online 19 June 2014 ⇑ Corresponding author. Address: Gastroenterology Unit, Glasgow Royal Infirmary, Castle St, Glasgow G4 0SF, UK. Tel.: +44 141 211 4073; fax: +44 141 211 5131. E-mail address: [email protected] (A.J. Stanley). Present address: Liver Unit, University Hospitals Birmingham, UK. Abbreviations: b-blockers, beta-blockers; VBL, variceal band ligation; NAFLD, non-alcoholic fatty liver disease; TIPSS, transjugular intrahepatic portosystemic stent-shunt; MELD, model for end stage liver disease; CPs, Child-Pugh score; IQR, interquartile range; GRI, Glasgow Royal Infirmary; ERI, Royal Infirmary of Edinburgh; GGH, Gartnavel General Hospital Glasgow; SGH, Southern General Hospital Glasgow.
taking this drug compared with those undergoing banding requires further exploration. Ó 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Introduction Variceal bleeding continues to be a major clinical challenge with high mortality [1]. Recent evidence suggests the incidence of variceal bleeding in the UK is increasing, probably due to the increased prevalence of cirrhosis as a consequence of alcohol, viral hepatitis, and non-alcoholic fatty liver disease (NAFLD) [2]. Following control of an acute variceal bleed, rebleeding occurs in up to 70% patients with associated high mortality [1,3,4]. Recent studies have suggested reduction in the rebleeding rate with variceal band ligation (VBL), drug therapy with b-blockers ± isosorbide mononitrate, or a combination of VBL and drug therapy [5–11]. Interestingly, some studies have reported a mortality benefit from drug therapy compared with VBL in the prevention of variceal rebleeding [12,13]. Evidence from meta-analyses suggests that although combined VBL and drug therapy may reduce variceal rebleeding, this does not generally affect mortality and is associated with more serious adverse effects [10,11]. Carvedilol is a vasodilating non-selective b-blocker with alpha-1 antagonism and calcium blocking effects. Haemodynamic studies have shown it to be superior to propranolol in reducing portal hypertension [14–19]. Initial clinical studies have also shown superiority of carvedilol over VBL in the prevention of a first variceal bleed [20] and equal efficacy to combined nadolol and isosorbide mononitrate in the prevention of variceal rebleeding [21]. The aim of this multicentre study was to compare oral carvedilol with VBL in the prevention of variceal rebleeding.
Materials and methods Patients who were clinically stable after an endoscopically proven first oesophageal variceal bleed in four centres were recruited. The centres were: Glasgow
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JOURNAL OF HEPATOLOGY Royal Infirmary (GRI), Royal Infirmary of Edinburgh (ERI), Gartnavel General Hospital, Glasgow (GGH), and Southern General Hospital, Glasgow (SGH). Ethical approval was obtained for each site. The study was registered under the trial number ISRCTN 69643049. All patients had had their acute bleed managed by VBL, terlipressin and antibiotics as is standard practice. Patients who were clinically stable five days after their variceal bleed were given a patient information sheet and recruited after signing informed witnessed consent. Randomisation to oral carvedilol or VBL in a 1:1 ratio was undertaken by computer generated random numbers. Exclusion criteria were: age <18 or >75 years; advanced malignancy or comorbidity, resulting in life expectancy <6 months; obstructive airways disease; baseline pulse rate <50 bpm or systolic blood pressure <90 mmHg; severe peripheral vascular disease; heart block or severe heart failure; pregnancy; type-I diabetes; portal vein thrombosis; previous transjugular intra-hepatic portosystemic stent shut (TIPSS) or porto-caval shunt surgery; a gastric variceal bleed; or treatment with b-blockers, or alpha-blockers within 4 weeks of the index bleed. Patients randomised to carvedilol (Roche, Herts, UK) were given it orally 6.25 mg daily for one week, then increased to 12.5 mg long-term if tolerated. The dose chosen was based on previous data [18,20]. Drug compliance was assessed by the patient’s history, collateral history and tablet count where possi-
Enrollment
ble. Patients randomised to VBL underwent VBL at one week, then at 2 weekly intervals until eradication, with subsequent surveillance endoscopies undertaken at 6-month intervals. Patients unable to tolerate carvedilol due to symptoms, pulse rate <50 bpm or systolic blood pressure <85 mmHg were converted to VBL. All patients were reviewed at one week, one month, then every 3 months unless clinically indicated earlier. The primary end point was variceal rebleeding, defined by haematemesis or melaena, confirmed by endoscopy with drop in Hb of 3 g if no transfusion given [22]. The secondary end points were mortality, any gastrointestinal rebleeding and serious adverse events. Serious adverse events were defined as events, which were life-threatening, required hospitalisation (or prolonged hospitalisation), or resulted in significant disability. Statistics To achieve a power of 80% at the 5% significance level, 54 patients were required in each group to prove superiority of carvedilol, assuming recurrent bleeding rates of 45% with VBL and 20% with carvedilol. Therefore assuming a 10% drop out rate, 60 patients were required in each group to complete the study. All analyses were undertaken using the intention to treat basis unless stated otherwise.
Assessed for eligibility (n = 84)
Excluded (n = 20) Not meeting inclusion criteria (n = 16.) 7 of these due to recent β-blocker use Declined to participate (n = 3) Other reasons (n = 1)
Randomized (n = 64)
Allocation Allocated to carvedilol (n = 33) Received allocated intervention (n = 31) Did not receive allocated intervention (n = 2; patients on reflection preferred to have band ligation)
Allocated to VBL (n = 31) all 31 received allocated intervention
Follow-up Lost to follow-up (n = 1; patient had already discontinued drug due to side effects) Discontinued intervention (n = 12; 5 due to side effects, 2 ongoing alcohol excess, 5 with reasons uncertain)
Lost to follow-up (n = 4) No other patient discontinued VBL, but 7 had interruptions to attendance for VBL surveillance
Analysis Analysed per protocol (n = 19) Excluded from analysis (n = 0)
Analysed per protocol (n = 20) Excluded from analysis (n = 0 )
Fig. 1. CONSORT flow diagram for the study.
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Research Article Free from variceal rebleeding
Time to rebleeding was assessed using survival analysis. Univariate analyses were done to estimate hazard ratios associated with each possible predictor of survival and Cox regression analysis was used to determine independent predictors of rebleeding. All analyses were done using SPSS (version 20) at a 5% significance level. One interim analysis was planned after recruitment of over 60 patients (30 in each group), at which point the number of further patients required to be recruited to achieve a significant difference in the primary end point would be calculated.
Results
1.0
0.8 Carvedilol 0.6 p = 0.857
Band ligation 0.4 0.0
In total, 64 patients were recruited (37 at GRI, 21 at RIE, 5 at GGH and one at SGH) with 33 patients randomised to carvedilol and 31 to VBL. Patients were recruited from June 2006 until December 2011, with follow-up until June 2012. The consort flow diagram is shown in Fig. 1. Median follow-up for all patients was 26.3 (IQR 10.2–46.6) months. There were no differences in baseline characteristics between both groups (Table 1), with ChildPugh class A, B, and C disease in 11 (17%), 28 (44%), and 25 (39%) patients, respectively. 58 (91%) patients had alcohol related liver disease. Other aetiologies included three (5%) with non-alcoholic fatty liver disease, two (3%) with primary biliary cirrhosis, and one (2%) with drug induced chronic liver disease.
0
20
40
60
Follow-up (mo) Carvedilol VBL
33 31
16 9
12 6
3 1
Fig. 2. Variceal rebleeding (intention to treat analysis).
ysis (p = 0.715). Three (10%) patients in the VBL group rebled from banding induced ulceration, although none died from this. Univariate analysis of prognostic variables are shown in Table 4, with only MELD, serum bilirubin and albumin predicting variceal rebleeding, and with only serum albumin being significant on multivariate analysis.
Rebleeding Mortality Variceal rebleeding was similar in both groups, occurring in 12 (36.4%) of the carvedilol group and in 11 (35.5%) of the VBL group (p = 0.857; Fig. 2). All patients bled from oesophageal varices. The results were similar using the per protocol analysis (p = 0.755). There was no difference in variceal rebleeding between the two largest recruiting centres (p = 0.955). Only two of the patients in the VBL arm had their varices eradicated prior to their rebleeding. The percentage of patients with variceal rebleeding in the carvedilol and VBL groups at 12 months was 29.9% and 25.3% respectively, and at 24 months it was 29.3% and 42.2% respectively. Eight (35%) patients had their rebleeding managed by TIPSS insertion (three in the carvedilol and five in the VBL arm). Rebleeding from any upper gastrointestinal site was 13 (39%) and 14 (45%) in the carvedilol and VBL groups respectively (p = 0.393). This was also non-significant using per protocol anal-
Table 1. Patient characteristics.
Characteristic Age, years; mean ± SD Male:Female Child-Pugh Score MELD Bilirubin, μmol/L Albumin, g/L Prothrombin, time (s) Ascites, n (%) Follow-up, months
Carvedilol (n = 33) 51.4 ± 10.8 22:11 9 (7.0-10.5) 13 (8.25-18.5) 39 (19.5-63.0) 27 (22.5-31.5) 15 (13.0-19.0) 12 (36.3%) 30.7 (7.9-47.1)
VBL (n = 31) 49.6 ± 12.87 21:10 9 (8.0-11.0) 14 (11.0-16.0) 35 (23.0-82.0) 27 (24.0-33.0) 16 (14.0-17.0) 12 (38.7%) 23.5 (10.3-44.8)
All values are expressed as median (IQR) unless otherwise stated. There were no significant differences between groups for any variable. SD, standard deviation; VBL, variceal band ligation; MELD, model for end stage liver disease.
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Mortality during follow-up was 9 (27.3%) in the carvedilol group and 16 (51.6%) the VBL group (p = 0.110; Fig. 3). Mortality in the per protocol analysis was non-significant at p = 0.125. Only three (5%) patients died within 6 weeks, two in the carvedilol group and one treated with VBL. The percentage mortality in the carvedilol and VBL groups at 12 months was 19.5% and 23.0% respectively, and at 24 months it was 23.0% and 38.3% respectively. Mortality was lower for Child-Pugh class B patients treated with carvedilol compared with VBL (16.7% vs. 56.2%; p = 0.033), while mortality for Child-Pugh class A and Child-Pugh class C patients was similar in both groups (p = 0.731 and p = 0.722 respectively). Causes of death are shown in Table 2. Most of the deaths in the carvedilol group were bleeding related, compared with only one in the VBL group. However none of the carvedilol patients died of (non-bleeding) liver related causes, but this accounted for the deaths of 6 patients in the VBL group. Overall mortality due to non-bleeding causes in the carvedilol and VBL groups was 4 (12.1%) and 15 (48.4%) respectively.
Table 2. Causes of death.
All causes Bleeding related Sepsis Decompensated liver disease or HCC *Other ⁄
Carvedilol (n = 33) 9 5 4 0
VBL (n = 31) 16 1 1 6
0
8
Other causes of death (one of each): lung cancer, pulmonary hypertension, cerebrovascular accident, subarachnoid haemorrhage, intra-cranial haemorrhage, ischaemic bowel, ischaemic heart disease, heroin overdose. VBL, variceal band ligation; HCC, hepatocellular carcinoma.
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JOURNAL OF HEPATOLOGY Table 3. Adverse events, compliance and ongoing alcohol consumption.
1.0
VBL 18 (58%) 20 (65%) 15 (48%)
p value 0.968 0.993 0.994
⁄
The number of serious adverse events not related to rebleeding or ongoing progression of chronic liver disease were 7 in the carvedilol group (shortness of breath [n = 2], dizziness, diarrhoea, hallucinations, hyperglycaemia and overdose of carbamazepine) and 6 in the VBL group (ischemic bowel, cerebellar haematoma, septicaemia, lung cancer, renal impairment and diarrhoea). # 5 patients had been intolerant of the medication, therefore were not included in this analysis.
Age Gender Child-Pugh score MELD Aetiology Ongoing alcohol Bilirubin Creatinine Sodium Albumin Prothrombin time Ascites
Relative hazard (95% confidence intervals) 0.997 (0.963-1.032) 0.489 (0.181-1.323) 0.881 (0.732-1.061) 1.107 (1.025-1.195) 2.852 (0.383-21.229) 0.567 (0.219-1.465) 1.008 (1.002-1.014) 0.999 (0.999-1.008) 0.999 (0.963-1.036) 0.891 (0.817-0.971) 1.043 (0.994-1.095) 0.899 (0.380-2.124)
p value 0.869 0.181 0.183 0.010 0.306 0.242 0.010 0.865 0.951 0.009 0.088 0.808
On multivariate analysis, only serum albumin was significant
Mortality Variable Age Gender Child-Pugh score MELD Aetiology Ongoing alcohol Bilirubin Creatinine Sodium Albumin Prothrombin time Ascites
Relative hazard (95% confidence intervals) 1.006 (0.973-1.041) 0.687 (0.433-1.089) 1.248 (1.011-1.540) 1.071 (1.003-1.143) 3.387 (0.457-25.119) 1.889 (0.809-4.413) 1.010 (1.004-1.016) 0.996 (0.983-1.009) 0.998 (0.958-1.040) 0.897 (0.835-0.964) 0.995 (0.935-1.058) 1.431 (0.641-3.192)
Carvedilol 0.6 p = 0.110
0.4 Band ligation
0.2
0.0
Table 4. Cox regression analysis of variables for outcome.
Variceal bleeding Variable
0.8
Survival
Serious adverse events* Compliance Ongoing alcohol
Carvedilol 19 (56%) 19 (68%)# 16 (48%)
p value 0.718 0.110 0.040 0.039 0.233 0.142 0.001 0.571 0.942 0.003 0.866 0.382
On multivariate analysis, only Childs-Pugh score and MELD were significant
On univariate analysis of prognostic variables for mortality, Child-Pugh score (CPS), MELD, serum bilirubin and albumin were significant (see Table 4). On multivariate analysis, only CPS and MELD were significant. Of the patients randomised to carvedilol or VBL, 12 in each group had ascites at recruitment to the study. Seven patients
Carvedilol VBL
0
20 40 Follow-up (mo)
60
33 31
19 17
4 2
14 9
80
Fig. 3. Mortality (intention to treat analysis).
had worsening ascites during the study, two who had been randomized to carvedilol, and five had been randomised to VBL. One patient (who had been randomised to VBL) had documented spontaneous bacterial peritonitis during follow-up. Five (41.7%) of the 12 patients in each group who had ascites at randomisation died during follow-up. Haemodynamics Patients randomised to carvedilol had a drop in pulse rate from 84.9 ± 15.0 to 71.5 ± 10.8 bpm (p = 0.008) during the study, with the mean arterial pressure (MAP) falling from 86.0 ± 12.4 to 82.8 ± 10.3 mmHg (p = 0.053). For patients randomised to VBL, there was no difference in the pulse rate (85.4 ± 19.7 vs. 81.6 ± 16.9 bpm; p = 0.919) or MAP (88.7 ± 14.4 vs. 87.1 ± 12.1; p = 0.783) during the study. Compliance and adverse events Compliance with therapy was similar in both groups (see Table 3 and Fig. 1). In the carvedilol group, five patients were unable to tolerate the medication, but of the remaining 28 patients, nineteen (68%) were compliant with therapy. Two patients discontinued carvedilol due to problems with alcohol excess, two patients subsequently chose to stop taking carvedilol and asked to change to VBL and 5 patients discontinued for reasons not documented or uncertain. In the VBL group, 20 (65%) were compliant with VBL during follow-up. Of those who were non-compliant, three were known to have ongoing issues with alcohol excess and the others failed to attend for VBL procedures at various stages for reasons which were unclear. Serious adverse events were observed in 19 (56%) patients randomised to carvedilol and 18 (58%) randomised to VBL (see Table 3). When those relating to progression of underlying liver disease were excluded, there were 7 serious adverse events in the carvedilol group and 6 in the VBL group. These are described in Table 3. Ongoing alcohol intake was reported in 16 (48%) carvedilol patients and 15 (48%) VBL patients during follow-up.
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Research Article Discussion This study shows that carvedilol is not superior to VBL in the prevention of variceal rebleeding. The study was stopped at the planned interim analysis due to very similar rates of the primary end point of variceal rebleeding, indicating that more than 1000 patients would be required to show a significant difference. The strong trend we observed towards improved survival with carvedilol is consistent with other studies assessing b-blockers in cirrhosis and requires further study. Rebleeding after a first variceal bleed is common but can be reduced by treatment with drug therapy, VBL or a combination if these [1,22]. While recent consensus guidelines have more recently recommended the combination of b-blockade and VBL in this situation [3,23], these were published after recruitment commenced for this study. Although meta-analyses suggest that combined VBL and drug therapy can reduce rebleeding, it does not appear to reduce mortality and is associated with more serious adverse effects [10–12]. Indeed in one meta-analysis, mortality was lower in the drug treatment group [12]. In addition, a recent large study from India reported no reduction in rebleeding or mortality and increased adverse events with combined bblocker, nitrates and VBL compared with VBL alone [24]. Key researchers in this field have also suggested ‘‘the jury is still out’’ over the use of drug therapy, VBL, or both for the prevention of variceal rebleeding [25]. Therefore we felt it was justifiable to continue the study until the planned interim analysis. This has shown very similar variceal rebleeding rates with a trend towards a survival advantage for those given carvedilol. We found virtually identical variceal rebleeding rates of 36.4% and 35.5% during follow-up in the carvedilol and VBL groups respectively, with a similar result using per protocol analysis. The rebleeding rates from any gastrointestinal source (including oesophageal ulceration) were also very similar, as were serious adverse events and compliance. Several studies have suggested that drug therapy to reduce portal hypertension, particularly b-blockade, may improve survival in cirrhosis, possibly due to effects on sepsis including spontaneous bacterial peritonitis, and effects on intestinal transit [26–28]. However, other recent publications have suggested a deleterious effect on outcome by the use of b-blockers, especially in patients with ascites, possibly due to limitation of the compensatory increase in cardiac output or paracentesisinduced circulatory dysfunction [29,30]. Interestingly, among the patients in our study who had ascites at randomisation, more patients in the VBL group had deterioration in their ascites during follow-up, although mortality among ascitic patients in each group was equal. No patient had refractory ascites at entry to our study. Therefore we have found no major deleterious effect from carvedilol use in ascitic patients in this clinical situation. In our study, overall mortality in the carvedilol group was 27% vs. 52% in the VBL group, although this did not reach statistical significance. Interestingly, most deaths in the carvedilol group were bleeding related, whereas in the VBL group the vast majority was due to non-bleeding causes, which may suggest a pleiotropic protective effect of this drug in cirrhotic patients. It is interesting that survival for Child-Pugh class B patients (the grade with the highest number of patients in our study) was significantly higher for patients given carvedilol compared with VBL, while there was no mortality difference for Child-Pugh class A or
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C patients. This might suggest Child-Pugh class B patients benefit most from carvedilol in this situation. This is interesting given the recently described ‘‘window hypothesis’’ suggesting b-blockers offer survival benefit for cirrhotic patients in the mid (early decompensated) phase of the disease, but not for those with either well compensated or end-stage cirrhosis [31,32]. However, this was a post-hoc analysis of a relatively small number of patients and requires further confirmation. A UK multicentre study comparing carvedilol with VBL in the primary prevention of variceal bleeding reported reduced bleeding with carvedilol [20], although another trial comparing these therapies as primary prophylaxis from Pakistan reported similar bleeding rates [33]. In addition, a study from Taiwan reported carvedilol to be as effective as combined b-blocker and nitrates for variceal rebleeding, but with fewer side-effects [21]. All three studies reported similar survival in both treatment groups. A recent study has also reported improved outcome when using carvedilol in non-haemodynamic responders to propranolol in the primary prophylaxis of variceal haemorrhage [34]. Although further clinical studies are required, the complex mechanisms of action of carvedilol make it an attractive drug for use in patients with cirrhosis. This study had several limitations. First, our control group was given VBL alone. However, for the reasons expressed above, we believe it was ethical to continue the study until the interim analysis. Secondly, recruitment was slow, with many patients not even considered for the study due to prior b-blocker use, or known contraindications. The former is a particular problem in areas such as ours where there is a widespread use of b-blockers as primary prophylaxis for variceal haemorrhage. Thirdly, we did not undertake hepatic venous pressure gradient measurements to assess response or guide therapy. However access to this measurement is not readily available to many clinicians and we had designed this as a pragmatic study to compare simple, readily available treatment strategies. In addition, almost 80% cirrhotic patients have a haemodynamic response to this dose of carvedilol [18]. In conclusion, our results suggest that carvedilol is not superior to VBL in the prevention of variceal rebleeding. However the trend to a survival benefit with this drug requires further study. Larger multicentre studies assessing the role of carvedilol in the prevention of variceal haemorrhage, either alone or in combination with VBL are needed. Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Acknowledgements We would like to thank A.J. Morris, M. Neilson, R. Gillespie, N. Kochar, J. Winter, D. Craig, S. Barclay, M. Priest, J.W. Ferguson. References [1] Garcia-Tsao G, Bosch J. Management of varices and variceal haemorrhage in cirrhosis. N Engl J Med 2010;362:823–832. [2] Hearnshaw SA, Logan RFA, Lowe D, Travis CPL, Murphy MF, Palmer KR. Acute upper gastrointestinal bleeding in the UK: patient characteristics, diagnoses and outcomes in the 2007 audit. Gut 2011;60:1327–1335.
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JOURNAL OF HEPATOLOGY [3] Garcia-Tsao G, Bosch J, Groszmann RJ. Portal hypertension and variceal bleeding – Unresolved issues. Summary of an American Association for the study of liver diseases and European Association for the study of the liver single-topic conference. Hepatology 2008;47:1764–1772. [4] Bari K, Garcia-Tsao G. Treatment of portal hypertension. World J Gastroenterol 2012;11:1166–1175. [5] Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for treatment of oesophageal variceal bleeding: a meta-analysis. Ann Intern Med 1995;123:280–287. [6] Lebrec D, Poynard T, Hilton P, Benhamou J-P. Propranolol for the prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study. N Engl J Med 1981;305:1371–1374. [7] Gournay J, Masliah C, Martin T, Perrin D, Galmiche JP. Isosorbide mononitrate and propranolol compared with propranolol alone for the prevention of variceal rebleeding. Hepatology 2000;31:1239–1245. [8] Patch D, Sabin CA, Goulis J, et al. A randomised, controlled trial of medical therapy vs. endoscopic ligation for the prevention of variceal rebleeding in patients with cirrhosis. Gastroenterology 2002;123:1013–1019. [9] Villaneuva C, Minana J, Ortiz J, et al. Endoscopic ligation compared with combined treatment nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding. N Engl J Med 2001;345:647–655. [10] Gonzalez R, Zamora J, Gomez-Camarero J, Molinero LM, Banares R, Albillos A. Meta-analysis: combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis. Ann Intern Med 2008;149:109–122. [11] Thiele M, Kraq A, Rohde U, Gluud LL. Meta-analysis: banding ligation and medical interventions for the prevention of rebleeding from oesophageal varices. Aliment Pharmacol Ther 2012;35:1155–1165. [12] Li L, Yu C, Li Y. Endoscopic band ligation vs. pharmacological therapy for variceal bleeding in cirrhosis: a meta-analysis. Can J Gastroenterol 2011;25:147–155. [13] Lo GH, Chen WC, Lin CK, Tsai WL, Chan HH, Chen TA, et al. Improved survival in patients receiving medical therapy as compared with banding ligation for the prevention of esophageal variceal rebleeding. Hepatology 2008;48:580–587. [14] Forrest EH, Bouchier IAD, Hayes PC. Acute haemodynamic changes after oral carvedilol, a vasodilating beta-blocker, in patients with cirrhosis. J Hepatol 1996;25:909–915. [15] Stanley AJ, Therapondos G, Helmy A, Hayes PC. Acute and chronic haemodynamic and renal effects of carvedilol in patients with cirrhosis. J Hepatol 1999;30:479–484. [16] Banares R, Moitinho E, Piqueras B, et al. Carvedilol, a new nonselective betablocker with intrinsic anti-alpha-1-adrenergic activity, has a greater portal hypotensive effect than propanol in patients with cirrhosis. Hepatology 1999;30:79–83. [17] Banaras R, Moitinho E, Matilla A, et al. Randomised comparison of long term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis. Hepatology 2002;36:1367–1373. [18] Tripathi D, Therapondos G, Lui HF, Stanley AJ, Hayes PC. Haemodynamic effects of acute and chronic administration of low dose carvedilol, a vasodilating B-Blocker in patients with cirrhosis and portal hypertension. Aliment Pharmacol Ther 2002;16:373–380. [19] Sinagra E, Perricone G, D’Amico M, Tine F, D’Amico G. Systemic review with meta-analysis: the haemodynamic effects of carvedilol compared with
[20]
[21]
[22]
[23]
[24]
[25] [26]
[27]
[28]
[29]
[30]
[31]
[32] [33]
[34]
propranolol for portal hypertension in cirrhosis. Aliment Pharmacol Ther 2014;39:557–568. Tripathi D, Ferguson JW, Kochar N, Leithead JA, Therapondos G, McAvoy NC, et al. Randomized controlled trial of carvedilol vs. band ligation for the prevention of the first variceal bleed. Hepatology 2009;50:674–677. Lo GH, Chen WC, Wang HM, Yu HC. Randomized, controlled trial of carvedilol vs. nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding. J Gastroenterol Hepatol 2012;27:1681–1687. http:// dx.doi.org/10.1111/j.1440-1746.2012.07244.x. Portal hypertension IV. In: De Franchis R, editor. Proceedings of the IVth Baveno international consensus workshop on methodology of diagnosis and treatment. Oxford, UK: Blackwell Publishing; 2005. De Franchis R. Revising consensus on portal hypertension; Report of the Baveno V consensus workshop on methodology of diagnosis and therapy of portal hypertension. J Hepatol 2010;53:762–768. http://dx.doi.org/10.1016/ j.jhep.2010.06.004. Kumar A, Jhn SK, Dubey S, Tvagi P, Sharma BC, Sarin SK. Addition of propranolol and isosorbide mononitrate to endoscopic variceal ligation does not reduce variceal rebleeding incidence. Gastroenterology 2009;137:892–901. Mehta G, Abraldes JG, Bosch J. Developments and controversies in the management of oesophageal and gastric varices. Gut 2010;59:701–705. Senzolo M, Cholongitas E, Burra P, Leandro G, Thalheimer U, Patch D, et al. Beta-blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. Liver Int 2009;29:1189–1193. Turnes J, Garcia-Pagan JC, Abraldes JG, Hernandez-Guetta M, Dell-Era A, Bosch J. Pharmacological reduction of portal pressure and long-term use of first variceal bleeding in patients with cirrhosis. Am J Gastroenterol 2006;101:506–512. Perez-Paramo M, Munoz J, Albillos A, Freile I, Portero F, Santos M, et al. Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites. Hepatology 2000;1:43–48. Ruiz-del-Arbol L, Monescillo A, Aroncena C, Valer P, Gines P, Moreira V, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005;42:439–447. Sertse T, Melot C, Francoz C, Durand F, Rautou PE, Valla D, et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2010;52:1017–1022. Krag A, Wiest R, Albillos A, Gluud LL. The window hypothesis: haemodynamic and non-haemodynamic effects of Beta-blockers improve survival of patients with cirrhosis during a window in the disease. Gut 2012;61:967–969. Ge PS, Runyon BA. The changing role of beta-blocker therapy in patients with cirrhosis. J Hepatol 2014;60:643–653. Shah HA, Azam Z, Rauf J, et al. Carvedilol vs. esophageal variceal band ligation in the primary prophylaxis of variceal haemorrhage: a multicentre randomized controlled trial. J Hepatol 2014. http://dx.doi.org/10.1016/ j.jhep.2013.11.019, Epub ahead of publication. Reiberger T, Ulbrich G, Ferlitsch A, Payer BA, Schwabl P, Pinter M, et al. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol. Gut 2013;62: 1634–1641.
Journal of Hepatology 2014 vol. 61 j 1014–1019
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