Original Article. Noradrenaline is as Effective as Terlipressin in Hepatorenal Syndrome Type 1: A Prospective, Randomized Trial

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1 30 Journal of The Association of Physicians of India Vol. 64 September 2016 Original Article Noradrenaline is as Effective as Terlipressin in Hepatorenal Syndrome Type 1: A Prospective, Randomized Trial Omesh Goyal 1, Sandeep Singh Sidhu 2, Natasha Sehgal 3, Sandeep Puri 4 Abstract Objectives: Hepatorenal syndrome (HRS) is a functional renal failure occurring in end stage liver disease, which is associated with poor prognosis. Terlipressin has been shown to be effective in treatment of HRS. More recently, it was suggested that noradrenaline, an alpha-adrenergic drug may be also effective in HRS. We aimed to compare the efficacy of noradrenaline versus terlipressin in treatment of HRS type 1. Methods: Consecutive patients with cirrhosis and HRS type 1 were enrolled and randomised into 2 groups- Group A received intravenous noradrenaline infusion (0.5-3 mg/h) and group B received intravenous terlipressin (0.5-2 mg/6h) for 2 weeks. Intravenous albumin (20 g/day) was given to both groups. Results: Out of 55 cirrhotics screened, 41 were randomised into group A (n=21) or group B (n=20). Baseline characteristics of the two groups were similar. HRS reversal was seen in 47.6%(10/21) patients in group A, and 45% (9/20) patients in group B (p=1.00). In both groups, there was a significant decrease in serum creatinine from baseline (group A- 3.1±1.4 mg/dl to 2.2±1.3 mg/dl, p=0.028; group B- 3.4±1.6 mg/dl to 2.3±1.3 mg/dl, p=0.035). Both the groups showed a significant increase in mean arterial pressure (group A- 77.3±8.6 mmhg to 103.4±8.3 mmhg, p=0.0001; group B- 76.8±11.6 mmhg to 100±9.4 mmhg, p=0.0001). Noradrenaline was associated with fewer adverse events and was significantly cheaper than terlipressin. Lower baseline MELD score was an independent predictor of response to treatment. Conclusion: Noradrenaline is as effective and safe as terlipressin in the treatment of HRS type 1. Introduction Renal dysfunction is a common complication of decompensated cirrhosis, occurring in about 20% of hospitalised patients with cirrhosis and ascites. 1,2 Most cases of renal dysfunction in patients with cirrhosis are functional resulting from hemodynamic changes primarily systemic arterial vasodilatation, that leads to extreme under filling of the arterial circulation resulting in intense vasoconstriction of the renal circulation and functional renal failure. 3 Most of these cases respond to intravascular volume replacement. 2 Hepatorenal Editorial Viewpoint Hepatorenal syndrome is a functional renal failure associated with poor prognosis. The study finds lower model for end-stage liver disease (MELD) score as an independent predictor of response to treatment. Noradrenaline was found to be as effective and safe as terlipressin. syndrome (HRS) is the most severe form of functional renal dysfunction in cirrhotics which is not responsive to intravascular volume challenge. 4 HRS is present in approximately 17% of patients admitted to hospital with ascites and develops in more than 50% of cirrhotics who do not survive. 2 HRS is sub-classified into types 1 and 2. 4 Type 1 HRS is characterized by rapid progressive renal failure, usually accompanied by multiorgan failure. Type 2 HRS manifests itself as a slowly progressive functional renal failure associated with refractory ascites. The development of type 1 HRS carries an ominous prognosis, with 80% mortality at 2 weeks and only 10% of patients surviving more than 3 months if left untreated. 1-2,4 Liver transplantation is the 1 Assistant Professor, 2 Professor, Department of Gastroenterology, 3 Former Resident, Department of Medicine, 4 Professor of Medicine and Principal, Dayanand Medical College & Hospital, Ludhiana, Punjab Received: ; Revised: ; Accepted:

2 Journal of The Association of Physicians of India Vol. 64 September best option in patients without contraindications to the procedure, but it is not always possible. Treatment of HRS consists of drugs which have vasoconstrictor activity in the splanchnic circulation. Vasoconstrictor agents such as midodrine (alphaadrenergic agent), and vasopressin agonists such as ornipressin and terlipressin improve renal perfusion and glomerular filtration in patients with HRS by inducing vasoconstriction of the splanchnic circulation. 5-7 More recently, it has been suggested that noradrenaline, a catecholamine with predominantly alpha-adrenergic activity, may be also effective in HRS. 8-9 However, randomised trials comparing the efficacy of noradrenaline with terlipressin in the treatment of HRS type 1 are scarce. Therefore, we planned this study to compare the efficacy and safety of noradrenaline with terlipressin in the treatment of HRS-type 1. Methods This open label, prospective, randomised trial was carried out in the department of Gastroenterology, D.M.C. and Hospital, Ludhiana, India over a period of 3 years. Hospitalised patients with decompensated cirrhosis and HRS type 1 were included. Cirrhosis was diagnosed based on clinical, biochemical, radiological and/or histological criteria (if available). HRS was diagnosed according to the standard criteria. 4 Inclusion criteria were- decompensated cirrhosis with HRS type 1 and age between years. Exclusion criteria were: (a) improvement in renal function after central blood volume expansion; (b) presence of severe sepsis, pancreatitis, or shock (c) use of nephrotoxic drugs, (d) history of coronary artery disease, obstructive cardiomyopathy, ventricular arrhythmia, or obliterative arterial disease of the limbs. Written informed consent was taken from patients/ relatives. The study protocol was approved by the institutional ethics committee and the study was performed according to the ethical guidelines of the 1975 Declaration of Helsinki. HRS was defined using the criteria proposed by the International Ascites Club (a) presence of cirrhosis with ascites, (b) serum creatinine > 133 µmol/l (1.5 mg/dl), (c) no improvement of serum creatinine (decrease to a level of < 133 µmol/l) after at least 2 days with diuretic withdrawal or volume expansion with albumin at a dose of 1 g/kg of body weight per day (up to a maximum of 100 g/day), (d) absence of shock, (e) no current or recent treatment with nephrotoxic drugs and (f) absence of parenchymal kidney disease as indicated by proteinuria > 500 mg/day, microhematuria (> 50 red blood cells per high power field) and / or abnormal renal ultrasonography. HRS type 1 (acute HRS) was defined as the doubling of the initial serum creatinine to >220 mmol/l (2.5 mg/dl) in <2 weeks. Type 2 (chronic HRS) was defined as moderate renal failure that progressed gradually over weeks to months with a serum creatinine of mmol/l ( mg/dl). Patients with suspected HRS type 1 were shifted to the intensive care unit. A central venous pressure (CVP) line was inserted and CVP was measured every 4 hourly. Pulse rate and blood pressure was checked every 4 hours, urine output were measured every 1 hour. Pulse pressure (PP) was calculated by systolic blood pressure (SBP) minus diastolic blood pressure (DBP), and mean arterial pressure (MAP) was calculated by DBP + 1/3 PP. 10 Each patient was given a standard medical treatment for 48 h, which consisted of IV albumin infusion (20 g/100 ml) to increase the central venous pressure to the upper normal range (10 12 cm of saline). Repeat evaluation of patients was done after 48 hrs. Patients who did not show improvement (creatinine <1.5 mg/dl and/or urine output more than 600 ml/day), were included in the study. Patients were randomized into two groups (A and B) using a computer-generated randomization table to receive treatment for 2 weeks. Group A received a continuous infusion of noradrenaline (Adrenor, Samarth Life Sciences, Mumbai, India) at an initial dose of 0.5 mg/h administered by an automatic syringe pump, aimed to achieve an increase in MAP of at least 10 mm Hg or an increase in 1-h urine output to >40 ml. If either of these goals was not achieved, the noradrenaline dose was stepped up by 0.5 mg/h every 4 h, up to the maximum dose of 3 mg/h. Furosemide was added as intravenous infusion at a dose of mg/kg/min if adequate urine output was not achieved despite an increase in MAP. Furosemide dose was adjusted to maintain a urine output of at least 40 ml/1hr. (10) Group B received Terlipressin (Remestyp, Ferring Pharmaceuticals, Saint Prex, Switzerland) at an initial dose of 0.5 mg every 6 hour (IV bolus). If a significant (> 25%) reduction in serum creatinine level was not observed at 3 days, the dose of terlipressin was stepped up to 1 mg every 6 hour, up to a maximum of 2 mg every 6 hours. Patients in both the groups received daily IV albumin (Buminate, Baxter private limited, Gurgaon, India) 20 g/day until the end of the study period. Albumin administration was stopped temporarily if central venous pressure increased above 12cm of saline or if serum albumin was >4g/L. All patients received intravenous third-generation cephalosporins prophylactically during the study period. All patients had an indwelling urinary catheter for accurate measurement of urine output, which was removed when the patient recovered. Blood samples including hemogram, liver function tests

3 32 Journal of The Association of Physicians of India Vol. 64 September 2016 Allocated to receive Noradrenaline (n=21) Lost to follow up (n=0) Discontinued intervention due to side effects (n=0) Died (n=11) Fig. 1: Flow of participants in the study Table 1: Baseline characteristics in the two study groups Characteristic Analyzed (n=21) Assessed for eligibility (n=55) Randomized (n=41) Noradrenaline group (n=21) Terlipressin group (n=20) p value Age (years) 54.7 ± ± Male (%) 95.2% 85% Etiology of Cirrhosis Alcohol 61.9% 75% Hepatitis C Virus 19.1% 15% Others 19.1% 15% 1.0 Child Pugh score 10.8 ± ± MELD score 29.2 ± ± Serum bilirubin (mg/dl) 1.7 ± ± Serum albumin (g/dl) 2.7 ± ± Serum sodium (meq/l) ± ± Serum creatinine (mg/dl) 3.14 ± ± Urine sodium (meq/l) 20.1 ± ± Mean arterial pressure (mmhg) 77.3 ± ± Data are expressed as mean ± SD or proportions; MELD: model for end stage liver disease and prothrombin time were done before the initiation of therapy, at 6 days, at the end of treatment and in between if required. Ascitic fluid analysis was done at baseline. In addition, renal function tests were done after every 3 days. Blood, urine and ascitic fluid cultures were taken at baseline Response to treatment was defined as: (i) Complete response: Decrease in serum creatinine to a value of 1.5 mg/dl or lower during the treatment, (ii) Partial response: Excluded (n=14) Improvement by volume expansion (n=7) Evidence of severe sepsis (n=3) Presence of shock (n=3) History of CAD (n=1) Allocated to receive Terlipressin (n=20) Lost to follow up (n=0) Discontinued intervention due to side effects (n=1) Died (n=11) Analyzed (n=20) Decrease of 50% or greater in the serum creatinine level compared with the baseline value to a final value higher than 1.5 mg/dl, or (iii) No response: Decrease in serum creatinine level of less than 50% compared with the baseline value to a final value higher than 1.5 mg/dl or an increase in serum creatinine compared with the baseline value. The primary end point of the study was -complete response (i.e., reversal of HRS), and the secondary end points were- completion of 2 weeks of therapy or liver transplantation or death. Data are expressed as mean with standard deviation (SD) for quantitative variables and as proportions with 95 % CI for qualitative variables. The results were analyzed at baseline and at the end of therapy. Comparisons between groups were performed using Student s t-test for quantitative variables and the Fisher s exact test for qualitative variables. The baseline characteristics of responders and non-responders to therapy were compared irrespective of the treatment arm. Univariate and multivariate analyses were performed to determine baseline predictors of response. A value of p < 0.05 was taken as significant. Results A total of 55 patients with decompensated cirrhosis and renal dysfunction were enrolled. Out of these, seven patients showed improvement in renal function by volume expansion and were excluded. In addition, 3 patients were excluded due to severe sepsis, 3 due to the presence of shock and one due to history of coronary artery disease. The remaining 41 patients were randomized into 2 treatment groups Group A (noradrenaline group) and Group B (terlipressin group). In group A, 11 (52.4%) patients died during the study period (due to sepsis-7, liver failure-3, gastro-intestinal bleed-1). In group B, 11 (55%) patients died during the study period (due to sepsis-8, liver failure-2, acute tubular necrosis-1). The flow of patients in the study is shown in figure 1. Baseline characteristics of the 2 groups were similar (Table 1). The mean age was 55.5 ± 6.2 years and male: female ratio was 9.1:1. HRS reversal was seen in 47.6% (10/21) patients in group A, and 45% (9/20) patients in group B (p=1.00). The change in biochemical

4 Journal of The Association of Physicians of India Vol. 64 September Table 2: Change in parameters with therapy in both the groups Parameter Noradrenaline group (n=21) Terlipressin group (n=20) Baseline At end of therapy p value Baseline At end of therapy p Value Serum creatinine 3.14 ± ± ± ± (mg/dl) Serum sodium ± ± ± ± (meq/l) Urine sodium (meq/l) 20.1 ± ± ± ± Urine output (ml/24 hours) ± ± ± ± Mean arterial pressure (mmhg) 77.3 ± ± ± ± Data are expressed as mean ± SD Table 3: Univariate analysis of baseline factors predicting response to treatment Characteristic Responders (n=19) Non-responders (n=22) p value Age (years) ± ± Male (%) 84.2 % 95.5% Alcoholic cirrhosis (%) 47.4% 86.4% Child Pugh score ± ± MELD score 27.9 ± ± S. sodium (meq/l) ± ± Creatinine (mg/dl) 2.57 ± ± Urine sodium (meq/l) 19.1 ± ± Mean arterial pressure (mmhg) 71.4 ± ± Data are expressed as mean ± SD or proportions; MELD: model for end stage liver disease parameters with treatment in both the groups is shown in Table 2. In both the groups, there was a significant decrease in serum creatinine from baseline (group A- from 3.1±1.4 mg/dl to 2.2±1.3 mg/dl, p=0.0248; group B- from 3.4±1.6 mg/ dl to 2.3±1.3 mg/dl, p=0.0311). Both the groups showed a significant increase in mean arterial pressure (group A- from 77.3±8.6 mg/dl to 103.4±8.3 mg/dl, p=0.0001; group B- from 76.8±11.6 mg/dl to 100±9.4 mg/ dl, p=0.0001). The serum sodium, urine output and urine sodium excretion increased significantly in both the groups. The mean duration of therapy in group A was 9.1 ± 2.8 days (range 5 14 days) and 8.3 ± 2.4 days (range 5 14 days) in group B. The per day cost of treatment with terlipressin with a median dose of 3 mg/day 4500 INR, while that of noradrenaline with a median dose of 13.1 mg/day was approximately 1000 INR (p=0.0001). However, costs of hospital admission, albumin and other medications were not taken into account while calculating this cost in either group. Non serious adverse events were noted in both the groups. In group A, mild chest pain occurred in three patients, which improved with decrease in the dose of noradrenaline. In group B, two patients had loose stools, two patients had mild chest pain and one had abdominal pain. All of these adverse events improved with a decrease in dose of terlipressin, except one patient who had persistent loose stools and terlipressin had to be stopped on day 8. Responders (N =19) and nonresponders (N =22) to treatment, regardless of the treatment group were compared with regard to baseline parameters to determine the predictors of response. On univariate analysis, lower MELD score, lower serum creatinine and non-alcoholic cirrhosis were associated with response to treatment (noradrenaline/ terlipressin) (Table 3). However, on multivariate analysis only MELD score emerged as independent predictor of response to treatment. Discussion The present study is one of the few studies which directly compare the efficacy and safety of noradrenaline with terlipressin in the treatment of HRS type 1. The results of our study suggest that noradrenaline is as effective as terlipressin in the treatment of HRS type 1. Noradrenaline was also safe and much cheaper than terlipressin. The ideal treatment for HRS would consist of a drug which has a selective vasodilatory action on the renal vessels but does not cause vasodilatation in other vascular beds, especially the splanchnic circulation. Such an ideal drug does not exist at present. 11 Therefore, as an alternative, drugs with vasoconstrictor activity in the splanchnic circulation have been used for the treatment of HRS. Vasoconstrictor agents such as vasopressin agonists and midodrine (alpha-adrenergic agent) have been shown to improve renal function and reverse HRS. 4 Ornipressin, a vasopressin analogue, is not preferred because it causes severe ischemic complications. Terlipressin is a newer vasopressin analogue with fewer side-effects. Terlipressin promotes vasoconstriction in both systemic and splanchnic circulation through activation of V1 receptors of the vascular smooth muscle cells and is reported to reduce portal inflow, portal systemic shunting, and to dilate intrahepatic vessels, consequently reducing intrahepatic resistance to portal inflow. 4,12 Multiple clinical trials and three meta-analyses have confirmed the efficacy of terlipressin in the treatment of HRS by improving renal functions and an increasing the median survival time. 6,7,12-14 However, terlipressin is not readily available in several countries and

5 34 Journal of The Association of Physicians of India Vol. 64 September 2016 Table 4: Comparison of reversal rates of type 1 HRS with noradrenaline and terlipressin in various studies Allesandria et al 16 (n=22) has relatively high cost, which makes it less practical to use especially for prolonged durations. Noradrenaline, an alphaadrenergic receptor agonist, causes intense vasoconstriction especially of the splanchnic bed, which leads to increase in the effective arterial blood volume. 8-9 This improves renal perfusion and glomerular filtration leading to reversal of HRS. In addition, noradrenaline has renal vasodilatory effect as documented by Anderson et al in healthy dogs at doses similar to those used in clinical practice ( μg/kg/min). 16 This leads to further improvement in renal perfusion and helps in HRS reversal. In a pilot study with 12 patients, Duvoux et al reported reversal of HRS-1 in 10 (83%) patients with noradrenaline. 9 Since then, few randomized trials including both type 1 and type 2 HRS patients have been carried out to compare the efficacy of noradrenaline and terlipressin (Table 3) The overall HRS reversal rate of type 1 HRS in these trials was about 55%, which was similar in the noradrenaline and terlipressin groups. The results of the present study are in concordance with these studies. Patients with type 2 HRS have been reported to have better response rates- 74% in the study by Ghosh et al 19 and 77% in the study Alessandria et al. 16 The overall thirty day-mortality rates in the previous studies was about 50%, while it was 65% in the two studies that included only type 1 HRS patients (Table 4). 17,18 Our study had lower mortality rates in both the groups. A recent Systematic Review and Meta-Analysis including all the studies comparing noradrenaline and terlipressin in HRS concluded Sharma et al 17 (n=40) Singh et al 18 (n=46) Present study (n=41) Type of HRS Type 1 and 2 Type 1 Type 1 Type 1 Noradrenaline 70% 55% 43.4% 47.6% group Terlipressin group 83% 55% 39.1% 45% that noradrenaline seems to be an attractive alternative to terlipressin in the treatment of HRS. 20 Noradrenaline and terlipressin both have a safe adverse event profile. 20 Cardiovascular events noted with both of these (mostly episodes of segment ST depression) are non-serious and usually resolve with a titration of dose. Diarrhoea and abdominal pain are common with terlipressin which are self-limiting and decrease with titration of dose. Therapy had to be withdrawn in one patient in our study due to persistent diarrhoea with terlipressin. Noradrenaline has a significantly lower cost of treatment compared to terlipressin, so may be preferable especially in developing countries. However, terlipressin has some advantage over noradrenaline as it is given as an intravenous bolus in a peripheral vein, while noradrenaline is given intravenously as a continuous infusion in a central venous catheter, usually in the setting of intensive care unit. Our study has few limitations. First is the small sample size. This problem has been faced by most of the previous investigators also, as it is difficult to get a large number of patients with this condition at a single centre. Most of the previously published studies could enrol about 40 patients only. Secondly, plasma renin and aldosterone levels were not measured in our study. To conclude, noradrenaline and terlipressin had similar response rates for the treatment of type 1 HRS. However, noradrenaline was associated with fewer adverse events and was much cheaper than terlipressin. Therefore, noradrenaline can be used as an alternative to terlipressin in treatment of HRS, especially in developing countries, and at places where terlipressin is not available. Larger multi-centric clinical trials comparing noradrenaline with terlipressin in the treatment of HRS are required to draw firm conclusions on this subject. References 1. Wong F. Recent advances in our understanding of hepatorenal syndrome. Nat Rev Gastroenterol Hepatol 2012; 9: Garcia-Tsao G, Parikh C R, Viola A. Acute kidney injury in cirrhosis. Hepatology 2008; 48: Arroyo V, Guevara M, Gines P. Hepatorenal syndrome: Pathogenesis and treatment. Gastroenterology 2002; 122: Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007; 56: Angeli P, Volpin R, Gerunda G, Craighero R, Roner P, Merenda R, et al. Reversal of type I hepatorenal syndrome with the administration of midodrine and octreotide. 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