*Jae Hyun Kim and Jung Min Kim contributed equally to this study.
Angiotensin receptor blockers (ARBs) inhibit activated hepatic stellate cell contraction and are thought to reduce the dynamic portion of intrahepatic resistance. This study compared the effects of combined treatment using the ARB candesartan and propranolol versus propranolol monotherapy on portal pressure in patients with cirrhosis in a prospective, randomized controlled trial.
Between January 2008 and July 2009, 53 cirrhotic patients with clinically significant portal hypertension were randomized to receive either candesartan and propranolol combination therapy (26 patients) or propranolol monotherapy (27 patients). Before and 3 months after the administration of the planned medication, the hepatic venous pressure gradient (HVPG) was assessed in both groups. The dose of propranolol was subsequently increased from 20 mg bid until the target heart rate was reached, and the candesartan dose was fixed at 8 mg qd. The primary endpoint was the HVPG response rate; patients with an HVPG reduction of >20% of the baseline value or to <12 mmHg were defined as responders.
The mean portal pressure declined significantly in both groups, from 16 mmHg (range, 12-28 mmHg) to 13.5 mmHg (range, 6-20 mmHg) in the combination group (
The addition of candesartan (an ARB) to propranolol confers no benefit relative to classical propranolol monotherapy for the treatment of portal hypertension, and is thus not recommended.
Portal hypertension (PH) is a critical prognostic factor for patients with cirrhosis.
The renin-angiotensin-aldosterone (RAA) system plays multiple key roles in the pathogenesis of chronic liver disease and portal hypertension. Angiotensin II which act on angiotensin II type 1 receptor (AT1-R) is a main actor in RAA system and elevated in liver cirrhosis.
Patients between 19 and 75 years of age with liver cirrhosis who visited the Wonju College of Medicine Wonju Severance Christian Hospital from January 2009 to July 2012 were considered eligible for the study. All cirrhotic patients who admitted hospital to get an intensive examination for PHT or to manage the already developed PHT related complications such as variceal hemorrhage or ascites were consider for this study. The target inclusion criteria were any etiology originated cirrhotic patients who needed anti-portal hypertension therapy with severe portal hypertension more than 12 mmHg in HVPG. The diagnosis of liver cirrhosis was confirmed in 231 patients by liver biopsy and the presence of varices in the esophagogastroduodenoscopy, laboratory data, or image studies, including ultrasonography and computer tomography (CT) scans, in the others. Patients who did not provide informed consent or had hepatocellular carcinoma, other malignancies within the past 3 years, severe hepatic failure (serum bilirubin level >5 mg/dL or hepatic encephalopathy), thrombosis in the inferior vena cava or hepatic or portal vein, uncontrolled infectious conditions (such as spontaneous bacterial peritonitis or sepsis), heart failure greater than NYHA class III, acute renal failure or severe chronic renal failure (eGFR <30 mL/min/1.73 m2), uncontrolled hypertension, pregnancy or lactation, or any other medical or psychiatric problems deemed to be unsuitable for clinical study were excluded. After all exclusions, 61 patients were ultimately enrolled in this study (
The presented study was approved by the institutional review board (IRB) for human research at the Yonsei University Wonju Severance Christian Hospital and written informed consent for the treatment and examination was obtained in all patients.
This study was done prospectively as a randomized open-labeled controlled trial involving one center in Republic of Korea. The primary endpoint was to compare response rate (%) between two groups based on follow-up HVPG after a 3-month of treatment. The response was defined when HVPG was reduced more than 20% from baseline or to an absolute value of less than 12 mmHg. The study groups were composed of two depends on the anti-PH medication. One was combination group of candesartan and propranolol and the other was propranolol monotherapy group. Baseline and follow up HVPG after 3 months medication were measured in all enrolled patients. After measurement of baseline HVPG, patients were randomized into two groups by the pharmacy at Wonju Severance Christian Hospital using serially numbered sealed envelopes in batches that designated a patient to one of two treatments. Combination therapy of oral candesartan and propranolol was given to 26 patients, and monotherapy of propranolol was given to 27. In combination group, 8 mg of candesartan was given daily to all patients with propranolol. The initial dose of propranolol was 40 mg a day and it was elevated by additional 40mg every other day to a maximum dose of 360mg to reach 25% reduction from baseline heart rate or minimal heart rate of 55 beats per minute to both combination and monotherapy groups. If a patient was intolerable or had less than 55 beats of heart rate per minute or systolic blood pressure of less than 90mmHg, the dose of propranolol was gradually reduced to the level which was tolerable to the patient. If the abnormal response persisted despite of dose reduction, the drug was temporarily discontinued. When the symptoms and signs improved, the drug was reintroduced in a dose less than the dose that caused the abnormal response. If the response occurred again during dose modification, the patient was dropped from the study. After 3 months later 2 patients (1 for ingestion of alcohol, 1 for lost to follow up) in combination therapy group and 2 patients (1 for ingestion of alcohol, 1 for intolerance) in monotherapy group were withdrawn. Then 25 patients of combination therapy group and 24 patients of monotherapy group were completed study with follow up HVPG measurement and entered data analysis (
All enrolled patients underwent measurement of HVPG between the 7th-10thdays of admission. HVPG was measured after an overnight fast. The right HV was catheterized per cutaneously through the femoral vein, and pressure was recorded in both the wedged position and the free position with a 7-F balloon-tipped catheter (Arrow International, Erding, Germany). All measurements were performed at least in triplicate, and permanent tracings were obtained on a multichannel recorder. HVPG was determined by subtracting the free HV pressure from the wedged HV pressure.
Categorical variables were expressed as proportions. Continuous variables were expressed as the median, range. Because of small numbers included patients in both, we used non-parametric analysis. To compare differences between two groups, continuous data were analyzed using Mann-Whitney U test, while categorical data were analyzed using the chi-square and Fisher exact tests. The Wilcoxon test was conducted to compare paired continuous variables within a group.
There was no difference in general characteristics between the combination and propranolol monotherapy group (
Response rates were 61.5 % (16 out of 26) in combined therapy group, and 55.6 %(15 out of 27) in propranolol monotherapy group (
In propranolol monotherapy group, there were two cases of orthostatic dizziness, two cases of generalized weakness, and a case of acute bradycardia. Incombined group, there were two cases of acute bradycardia, and two cases of orthostatic dizziness. The related symptoms were managed. In both groups there was no hepatic failure or AV block.
Prevention of variceal growing and bleeding is very crucial in managing and treating patients with cirrhosis. NSBB is the only generally recommended medication to reduce increased portal pressure, and lowers portal pressure mainly through attenuation of portal blood flow.
For this reason, a number of studies have been undertaken to develop a new medical therapy for portal hypertension. In this regard, the potential improvement in resistance to blood flow within the liver has increasingly drawn attention. IHR is composed of two components. One is static component by extracellular matrix deposition and structural changes of hepatic sinusoids. The other is relatively dynamic and reversible portion which is caused by sinusoidal twist and contraction by activated HSCs which play the key role in hepatic fibrosis.
ARBs like irbesartan and losartan have been tested with the aim to reduce portal pressure in many clinical trials. Almost studies studied about the HVPG response rate with ARB monotherapy, however the results were controversial. Some studies showed benefit effect
As a result, the rates and features of side effects were similar between two groups. The biochemical examination, liver and renal functions, electrolyte balance as well as blood cell contents did not change in either group. In addition, no serious side effects, including renal failure or hepatic decompensation, were noted. Mean blood pressure changed mildly but significantly between the initiation and completion of the study. However, no patient had a hypotensive reaction that required cessation of medication during treatment, which is indicative of good tolerance. Candesartan administration was deemed to be safe in terms of circulatory hemodynamics as well as liver function in patients with liver cirrhosis with PH.
However, the addition of candesartan to propranolol did not show additional effect in the lowering of PH. The result could be explained by several reasons. First of all, we need to think about the dose of candesartan. Unlike propranolol, as mentioned above, to avoid renal complication ARB dose was fixed as same dose in all enrolled patients. We previously reported the beneficial effects of ARB on hepatic fibrosis in a rat model and clinical trial.
In the line of above reason, per oral administration of ARB to the level that reduces the intrahepatic resistance probably needs very high dose however it is impossible in clinical practice because of risk of too severe hypotension and serious renal problem. It suggests the limitation of ARB in the application of PH treatment.
In addition, ARB absorbed through gastrointestinal tract can act with so many AT1-R in splanchnic organ before it arrives at portal blood flow into liver and it can also induce to unexpected direction in hemodynamics and aggravation of hyperdynamic circulation. Therefore, when we put together all above thing, special delivery system to carry ARBs into the liver at an optimum level needs to be developed in order to ensure desirable effect of ARB by applying clinically desirable dose without other organs side effects.
This study has several limitations. First of all, this study was performed without statistical design for proper sample size and we cannot deny the possibility that this point attenuated the statistical results and power. In addition, the fixation of ARB dose can be another limitation of this study to investigate the effect of combination therapy.
In conclusion, in the present study, the combined therapy of candesartan, an ARB and propranolol, showed significant decrease in HVPG after 3 months therapy; however the response rate was not better than propranolol monotherapy. ARB additional therapy to NSBB seems less effective within the traditional clinical dose and administration method and further well designed study for variable ARB's dose and clinical situation need to be followed.
This study was supported by a grant of the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (No. 100054).
The authors have no conflicts to disclose.
angiotensin receptor blocker
angiotensin II type 1 receptor
hepatic venous pressure gradient
hepatic stellated cells
intrahepatic résistance
non-selective beta blocker
portal hypertension
renin-angiotensin-aldosterone
Flow chart of study. EF, ejection fraction; SBP, spontaneous bacterial peritonitis; EGD, esophagogastroduodenoscopy; HVPG, hepatic venous pressure gradient; NSBB, non-selective beta blocker.
Comparison of the HVPG (mmHg) between baseline and 3 months after treatment in each group. The HVPG reduced significantly in both groups after 3 months of treatment (
Comparison of the change in HVPG (mmHg) and in the change ratio of HVPG after 3 months of therapy to reduce portal hypertension. A Both treatment groups exhibited significant changes in the mean HVPG: by 3.5 mmHg (range, -3-11 mmHg) in the combination therapy group, and by 3 mmHg (range, -8-10 mmHg) in the monotherapy group, with no significant difference between the two groups (
General characteristics of the patients
Monotherapy group (N=27) | Combination group (N=26) | ||
---|---|---|---|
Age, years | 52 (43−66) | 56 (43−67) | 0.173 |
Sex ratio (%) | 21 (77.8) : 6 (22.2) | 25 (96.2) : 1 (3.8) | 0.048 |
Propranolol dose (mg) | 160 (80−280) | 140 (80−240) | 0.344 |
Mean BP (mmHg) | |||
Baseline | 86.7 (63.3−96.7) | 88.3 (63.3−113.3) | 0.183 |
Follow up | 83.3 (66.7−110) | 83.3 (60−123.3) | 0.795 |
Heart rate | |||
Baseline | 75 (65−90) | 80 (64−88) | 0.097 |
Follow up | 70 (50−84) | 69 (50−97) | 0.536 |
Child-Pugh class (A/B/C) | 13/14/0 | 7/15/4 | |
Child-Pugh score | |||
Baseline | 7 (5−12) | 7 (5−15) | 0.25 |
Follow up | 5 (5−9) | 6 (5−9) | 0.693 |
MELD score | |||
Baseline | 9 (6−18) | 10 (2−16) | 0.157 |
Follow up | 8 (6−16) | 9 (5−16) | 0.06 |
Etiology (%) | |||
Alcohol | 19 (70.4) | 24 (92.3) | |
HBV | 6 (22.2) | 2 (7.7) | |
Alcohol + HBV | 2 (7.4) | 0 (0) | |
Albumin (g/dl) | 3.3 (2.5−4.3) | 3.2 (2.3−3.7) | 0.48 |
Prothrombin time (INR) | 1.13 (0.92−1.51) | 1.24 (1.05−1.50) | 0.094 |
Creatinine | |||
Baseline | 0.7 (0.4−3.1) | 0.7 (0.4−1.1) | 0.391 |
Follow up | 0.7 (0.5−2.7) | 0.9 (0.5−2.2) | 0.002 |
Platelet count (/mm³) | 91000 (52000−262000) | 90500 (31000−368000) | 0.403 |
AST (U/L) | 53 (25−168) | 55.5 (25−188) | 0.769 |
ALT (U/L) | 20 (5−172) | 27 (10−205) | 0.533 |
Na (mmol/L) | |||
Baseline | 139 (134−144) | 138 (130−144) | 0.246 |
Follow up | 139 (133−144) | 141 (131−145) | 0.053 |
HVPG, hepatic venous pressure gradient; INR, international normalized ratio; AST, aspartate transaminase; ALT, alanine transaminase; Na, sodium.
Comparison of the change in the hepatic venous pressure gradient between the propranolol monotherapy group and the propranolol and candesartan combination therapy group
Monotherapy group | Combination group | ||
---|---|---|---|
No. of patients | 27 | 26 | |
HVPG (mmHg) | |||
Baseline | 17 (12−27) | 16 (12−28) | 0.694 |
Follow up | 14 (7−25) | 13.5 (6−20) | 0.914 |
The change of HVPG (mmHg) | 3 (-8−10) | 3.5 (-3−11) | 0.674 |
The change of HVPG (%) | 22.2 (-66.6−58.8) | 21.8 (-18.7−60) | 0.783 |
The change of mean blood pressure (mmHg) | 0 (-30−23) | 6.6 (-26.6−33.4) | 0.079 |
The change of heart rate | 4 (-10−30) | 10 (-17−30) | 0.090 |
HVPG, hepatic venous pressure gradient.