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

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. CONCLUSIONS: Noradrenaline is as effective and safe as terlipressin in the treatment of HRS type 1.

TERLIPRESSIN VERSUS NORADRENALINE FOR HEPATORENAL SYNDROME. Economic evaluation under the perspective of the Brazilian Public Health System.

BACKGROUND: - Terlipressin and noradrenaline are the best studied treatments for hepatorenal syndrome, and there is no evidence of superiority of one over the other regarding to efficacy. While the former drug is more costly, the latter requires admission into an intensive care unit. OBJECTIVE: - The aim of this study was to perform an economic evaluation, comparing treatments for hepatorenal syndrome with terlipressin and noradrenaline. METHODS: - For the economic evaluation, a cost-minimization analysis was performed. Direct medical costs of the two treatment strategies were compared under the perspective of the Brazilian Public Health System as the third-party payer. A probabilistic sensitivity analysis was performed. RESULTS: - The costs of treatments with terlipressin or noradrenaline were 287.77 and 2,960.45 International Dollars (Int$) respectively. Treatment using terlipressin would save Int$2,672.68 for the Public Health System for each hospital admission related to hepatorenal syndrome. In the probabilistic sensitivity analysis, it was verified that the cost of the treatment with noradrenaline could vary between Int$2,326.53 and Int$3,644.16, while costs related to the treatment using terlipressin are not variable. CONCLUSION: - The treatment strategy using terlipressin was more economical than that using noradrenaline under the perspective of the Brazilian Public Health System as the third-party payer.

Terlipressin versus noradrenaline in the treatment of hepatorenal syndrome: systematic review with meta-analysis and full economic evaluation.

OBJECTIVE: The aim of this study was to compare the efficacy and costs of terlipressin and noradrenaline for the treatment of hepatorenal syndrome from the perspective of the Brazilian public health system and that of a major private health insurance. METHODS: Comparison of efficacy was performed through a systematic review with a meta-analysis of randomized-controlled trials using a random-effects model. Economic evaluation was carried out through cost minimization. RESULTS: Four studies (154 patients) were included in the meta-analysis. There was no evidence of a difference between treatments with terlipressin or noradrenaline in terms of 30-day survival (risk ratio=1.04, 95% confidence interval=0.84-1.30, P=0.70). From the perspective of the public health system, costs of the treatments with terlipressin or noradrenaline were Int$7437.04 and Int$8406.41, respectively. From the perspective of the private health insurance, costs of treatments with terlipressin and noradrenaline were Int$13,484.57 and Int$15,061.01, respectively. CONCLUSION: There was no evidence of superiority between treatment strategies using terlipressin or noradrenaline in terms of the survival of patients with hepatorenal syndrome, but the strategy using terlipressin was more economical under two different perspectives.

Noradrenaline or terlipressin for hepatorenal syndrome?

Hepatorenal syndrome is a condition associated with very high mortality that may be reverted in some cases with vasoconstrictors. Terlipressin has generally been considered standard treatment, but noradrenaline has been postulated as alternative. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including four pertinent randomized controlled trials. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded noradrenaline and terlipressin probably have similar effects on reverting hepatorrenal syndrome and decreasing mortality, but noradrenaline is associated with less adverse effects, and has lower costs.

El síndrome hepatorrenal es una condición asociada a altísima mortalidad, que puede ser recuperada en ciertos casos con el uso de vasoconstrictores. Generalmente se considera que terlipresina es el tratamiento estándar, pero noradrenalina se ha planteado como una alternativa. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 30 bases de datos, identificamos seis revisiones sistemáticas que en conjunto incluyen cuatro estudios aleatorizados. Realizamos un metanálisis y tablas de resumen de los resultados utilizando el método GRADE. Concluimos que noradrenalina y terlipresina son probablemente igual de efectivas en lograr mejoría del síndrome hepatorrenal y disminuir la mortalidad, pero que noradrenalina se asocia a menos efectos adversos, y tiene un menor costo.

Effects of terlipressin on pulmonary artery pressure in a septic cooled infant: an echocardiographic assessment.

Experience with terlipressin (TP) in the neonatal field is scarce. We describe the effects of TP on pulmonary circulation, studied with echocardiography, in an asphyxiated septic cooled infant with pulmonary hypertension (PH) who developed catecholamine-resistant hypotension and exacerbation of PH shortly after the beginning of the rewarming. TP was added to norephinephine and adrenaline infusions at the dose of 0.02 mg kg(-1) every 6 h, because of refractory hypotension and oliguria. After 10 min, blood pressure dramatically and definitely increased, and urinary output was re-established after 60 min. Echocardiographic evaluation 30 min after the second bolus of TP showed unchanged velocity of the tricuspidal valve regurgitation and improved biventricular functional indexes respect to the pre-treatment assessment. TP was continued for 12 h (three doses) without significant adverse effect except for a transient increase in troponin levels. Addition of TP boluses to catecholamine infusion in our newborn was effective in increasing systemic vascular resistance without increasing pulmonary vascular resistance, successfully reversing the hemodynamics of severe PH, and suggesting a potential primary vasodilator effect on pulmonary circulation. Transient increase of troponin levels during TP treatment confirms the risk of excessive coronary vasoconstriction when TP boluses are added to high dose catecholamines.

Perioperative assessment of terlipressin infusion during living donor liver transplantation.

OBJECTIVE: To investigate the safety and efficacy of infusion of terlipressin during living donor liver transplantation (LDLT). METHODS: Patients undergoing LDLT with low systemic vascular resistance index (SVRI) and pulmonary vascular resistance index (PVRI) (n=41) were randomly allocated into control (n=20) and terlipressin groups (n=21). Terlipressin was infused at 1.0-4.0 µg/kg per h in the terlipressin group during surgery. Controls received generally accepted inotropic and vasopressor agents. RESULTS: Terlipressin infusion induced significantly higher SVRI and PVRI at 60 min after drug infusion, produced significantly greater hourly urine output during the anhepatic phase, and was related to significantly shorter stays in the postoperative intensive care unit (ICU) compared with control treatment (mean±SD ICU stay 5.7±1.5 versus 6.9±1.5 days, respectively). Patients given a terlipressin infusion>2.0 µg/kg per h during the preanhepatic phase had a median ICU stay of <6 days (sensitivity 90.0%; specificity 89.0%). CONCLUSIONS: Terlipressin infusion improved low SVRI and PVRI during LDLT and may have contributed to better renal function and shorter ICU stays.

Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study.

BACKGROUND/AIMS: Treatment of hepatorenal syndrome (HRS) is based on vasoconstrictors. Terlipressin is the one with the soundest evidence. Noradrenalin has been suggested as an effective alternative. The current study was aimed at assessing the efficacy and safety of noradrenalin vs terlipressin in patients with HRS. METHODS: Twenty-two consecutive cirrhotic patients with HRS (9 with HRS type 1; 13 with HRS type 2) were included. Patients were randomly assigned to be treated with noradrenalin (0.1-0.7 microg/kg/min) and albumin (10 patients) or with terlipressin (1-2 mg/4h) and albumin (12 patients). Treatment was administered until HRS reversal or for a maximum of two weeks. Patients were followed-up until liver transplantation or death. RESULTS: Reversal of HRS was observed in 7 of the 10 patients (70%) treated with noradrenalin and in 10 of the 12 patients (83%) treated with terlipressin, p=ns. Treatment led in both groups to a significant improvement in renal and circulatory function. No patient developed signs of myocardial ischemia. CONCLUSIONS: Data from this unblinded, pilot study suggest that noradrenalin is as effective and safe as terlipressin in patients with HRS. These results would support the use of noradrenalin, a cheap and widely available drug, in the management of these patients.

An economic evaluation of vasoactive agents used in the United Kingdom for acute bleeding oesophageal varices in patients with liver cirrhosis.

OBJECTIVE: To conduct an economic evaluation of terlipressin, octreotide and placebo in the treatment of bleeding oesophageal varices (BOV) where endotherapy could be used concomitantly. METHODS: A discrete event simulation model was created with transition states: bleeding, no bleeding, no bleeding post transjugular intrahepatic portosystemic shunt, post-salvage surgery, and death. Efficacy data on survival, re-bleeding and control of bleeding were obtained from high quality studies reported in Cochrane meta-analyses. Baseline outcomes related to the course of disease and health-state utilities were derived from published sources. Vasoactive treatment costs and all related BOV costs were obtained from published UK sources. RESULTS: The average aggregated treatment cost per person for all medical interventions at 1 year was lower for terlipressin-treated patients (2623 pounds sterling) compared with those treated using octreotide (2758 pounds sterling) or placebo (2890 pounds sterling). The incremental analysis comparing terlipressin with octreotide and placebo using a cost per quality adjusted life year (QALY) and cost per life year gained (LYG) approach indicated that terlipressin was the dominant BOV treatment option (i.e. it cost less and it was more effective). Based on a maximum willingness to pay of 20,000 pounds sterling/QALY terlipressin was more effective and cost-saving compared to octreotide and placebo for simulations ranging from 42 days to 2 years. In point estimation analyses octreotide was dominant compared to placebo; however, probabilistic sensitivity analysis indicated that octreotide was unlikely to be cost-effective compared to placebo. CONCLUSIONS: The findings indicated that vasoactive treatment in BOV was cost-saving compared to no vasoactive treatment. Furthermore, terlipressin was the more cost-effective vasoactive treatment for BOV in cirrhotic patients.

Treating bleeding oesophageal varices with vasoactive agents: good value for money?

This article provides an editorial commentary to accompany the publication of an article on the economic evaluation of vasoactive agents used in the United Kingdom for acute bleeding oesophageal varices in patients with cirrhosis by Wechowski et al. From a clinical standpoint, the successful management of bleeding oesophageal varices should be based on definitive treatments such as therapeutic endoscopy or transjugular intrahepatic portosystemic stent shunt (TIPSS). Vasoactive agents such as terlipressin can be useful and potentially cost-effective additional therapy, however, particularly in patients where endoscopic treatment is likely to be delayed or is contraindicated.

Science to practice: Noninvasive assessment of portal hypertension--can US aid in the prediction of portal pressure and monitoring of therapy?

A method that could be used to accurately assess portal venous pressure would be valuable when diagnosing portal hypertension, evaluating patient prognosis, and monitoring the progress of therapy. Baik et al have suggested that a qualitative noninvasive Doppler US parameter can be used to monitor therapy of portal hypertension. Further clinical investigation is needed to confirm these results and to determine whether hepatic venous Doppler waveform tracings can be used to monitor patient response to therapy. Ongoing research suggests that microbubble contrast agents may enable a more quantitative noninvasive estimate of intravascular pressures with US.

Recent variceal bleeding: Doppler US hepatic vein waveform in assessment of severity of portal hypertension and vasoactive drug response.

PURPOSE: To prospectively evaluate both the correlation between abnormal Doppler ultrasonography (US) hepatic vein waveforms and the hepatic venous pressure gradient (HVPG) and the response to drug treatment in patients with cirrhosis. MATERIALS AND METHODS: Ethics committee approval and informed consent of patients and control subjects were obtained. In 78 patients with cirrhosis (70 men, eight women; mean age, 49.4 years +/- 9.7 [standard deviation]) and a history of variceal bleeding, both the hepatic vein waveform--as measured with Doppler US--and the HVPG were measured, and the relationship between them was analyzed. Hepatic vein Doppler waveforms were classified as triphasic, biphasic, or monophasic. Severe portal hypertension was defined as an HVPG of more than 15 mm Hg. In a subgroup of 21 patients, changes in hepatic vein waveform and HVPG were evaluated after intravenous administration of 2 mg of terlipressin. Statistical analyses were performed with Spearman rank correlation, logistic regression analysis, and cross tabulation. RESULTS: Abnormal hepatic vein waveforms were seen in 72 patients (92%). Forty-four patients (56%) had biphasic waveforms, 28 (36%) had monophasic waveforms, and six (8%) had triphasic waveforms. A positive correlation was found between the extent of abnormalities in hepatic vein waveforms and the increase in HVPG (P < .05). Monophasic waveforms were associated with severe portal hypertension, with a sensitivity of 74% and a specificity of 95%. Twenty patients in the terlipressin subgroup had abnormal baseline waveforms; the baseline waveform improved in 18 patients in association with the HVPG reduction after injection of terlipressin. CONCLUSION: Doppler US hepatic vein waveform assessment is useful in the noninvasive evaluation of the severity of portal hypertension and the response to vasoactive drugs in patients with portal hypertension and variceal bleeding.

Switch therapy with ciprofloxacin vs. intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis: similar efficacy at lower cost.

BACKGROUND: Intravenous administration of a third-generation cephalosporin is optimal antibiotic treatment for spontaneous bacterial peritonitis. AIMS: To compare an intravenous-oral step-down schedule with ciprofloxacin (switch therapy) to intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis, and to evaluate the impact of terlipressin and albumin in the treatment of type 1 hepatorenal syndrome on mortality. METHODS: A total of 116 cirrhotic patients with spontaneous bacterial peritonitis, were randomly given switch therapy with ciprofloxacin (61 patients) or intravenous ceftazidime (55 patients). All patients who developed type 1 hepatorenal syndrome were treated with terlipressin (2-12 mg/day) and albumin (20-40 g/day). RESULTS: Resolution of infection was achieved in 46/55 patients treated with ceftazidime (84%) and in 49/61 patients treated with ciprofloxacin (80%, P = N.S.). An intravenous-oral step-down schedule was possible in 50/61 patients (82%) who received ciprofloxacin; 45/61 patients (74%) were discharged before the end of antibiotic treatment and completed it at home. The mean saving per patient due to the reduction of hospital stay in the ciprofloxacin group was 1150 . Type 1 hepatorenal syndrome was treated successfully in 12/19 patients (63%). As a consequence, the in-hospital mortality rate due to infection was 10%. CONCLUSIONS: Switch therapy with cephalosporin is more cost-effective than intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in cirrhotic patients who are not on prophylaxis with quinolones.

Effects of terlipressin on systolic pulmonary artery pressure of patients with liver cirrhosis: an echocardiographic assessment.

AIM: Portopulmonary hypertension is a serious complication of chronic liver disease. Our aim was to search into the effect of terlipressin on systolic pulmonary artery pressure among cirrhotic patients. METHODS: Twelve patients (6 males and 6 females) with liver cirrhosis were recruited in the study. Arterial blood gas samples were obtained in sitting position at rest. Contrast enhanced echocardiography and measurements of systolic pulmonary artery pressure were performed before and after the intravenous injection of 2 mg terlipressin. RESULTS: Of 12 patients studied, the contrast enhanced echocardiography was positive in 5, and the positive findings in contrast enhanced echocardiography were reversed to normal in two after terlipressin injection. The mean systolic pulmonary artery pressure was 25.5+/-3.6 mmHg before terlipressin injection, and was 22.5+/-2.5 mmHg after terlipressin (P=0.003). The systolic pulmonary artery pressure was above 25 mmHg in seven of these 12 patients. After the terlipressin injection, systolic pulmonary artery pressure was <25 mmHg in four of these cases (58.3% vs 25%, P=0.04). CONCLUSION: Terlipressin can decrease the systolic pulmonary artery pressure in patients with liver cirrhosis.

Endoscopic Doppler ultrasound for measurement of azygos blood flow. Validation against thermodilution and assessment of pharmacological effects of terlipressin in portal hypertension.

BACKGROUND: Endoscopic ultrasound (EUS) is a new modality allowing real-time flow measurements by means of the Doppler technique. The aim of the study was to evaluate azygos blood flow measurements by endoscopic ultrasound. METHODS: Measurements of azygos blood flow by EUS and by the thermodilution technique were compared in 20 patients with portal hypertension. The ability of EUS flowmetry to detect changes in the azygos and portal venous flow after an intravenous dose of 2 mg of terlipressin was evaluated in 13 of the patients in a double-blind, randomized, placebo-controlled, cross-over design. RESULTS: The EUS Doppler and thermodilution measurements correlated significantly (R=0.81, P < 0.001). The azygos blood flow was found to be 14% higher by the EUS method than by thermodilution. The coefficient of variation of the EUS Doppler measurements of the azygos blood flow was 14.8%. After administration of terlipressin, the azygos blood flow, as measured by EUS Doppler, decreased significantly by 23% from 915 to 704 ml/min (P = 0.014) and the portal venous flow decreased by 28% from 1170 to 789 ml/min (P = 0.03). No effects of placebo were detected. CONCLUSIONS: These results show that EUS measurement of the azygos blood flow correlate strongly to the measurements by the thermodilution technique, and EUS is moreover well tolerated by the patients. The method is applicable for monitoring pharmacological effects on the superior porto-systemic collateral circulation and portal venous flow in patients with portal hypertension.

Cost-effectiveness analysis of the terlipressin-glycerin trinitrate combination in the pre-hospital management of acute gastro-intestinal haemorrhage in cirrhotic patients.

OBJECTIVES: To assess the cost-effectiveness of an early treatment of upper gastro-intestinal haemorrages in cirrhotic patients. DESIGN: Utilization data linked to the results of a double-blind, placebo-controlled trial demonstrating the efficacy of the terlipressin-glycerin trinitrate combination (TER-GTN) in the reduction of mortality at day 42 for haemorragic patients due to rupture of oesophageal varices. SETTING: Hôpital Jean Verdier, Bondy, Assistance Publique-Hôpitaux de Paris, France. SUBJECTS: Eighty-four patients included over 2 years by emergency services and hospitalized in an intensive care unit (ICU) for haemorrage, 41 in the "treated" group and 43 in the "placebo" group. MAIN OUTCOME MEASURES: Mortality at day 42, cost per death avoided. RESULTS: The mortality rate in the placebo group was 46.5% versus 27.5% in the treated group. The mean length of stay was 5 days longer in the treatment group. The excess cost per death avoided was 25,849 FF. Of this extra cost 27% was due to treatment and 24% was due to increased length of stay. The excess cost per case treated was FF 5,097, 10% of the total cost per stay for rupture of oesophageal varices (ROV). CONCLUSIONS: Our results are of the same magnitude as those published by Mac Cormick et al. in the United Kingdom for similar treatment. The extra cost appears to be moderate, and much lower than monoclonal antibody therapy for sepsis. The impact on the study hospital budget did not exceed 1.7 10(-4).

Assessment of variceal pressure by continuous non-invasive endoscopic registration: a placebo controlled evaluation of the effect of terlipressin and octreotide.

Octreotide has been proposed for the treatment of variceal bleeding. The effects on portal pressure, however, have been variable in published studies. As bleeding is more directly related to pressure in the varices, this study investigated the effect on variceal pressure of octreotide and terlipressin, a vasoactive drug with a well established effect. Variceal pressure was measured during four to eight minutes by a continuous non-invasive endoscopic registration method. Thirty patients in whom a stable variceal pressure recording had been obtained during at least one minute, were randomised to receive either 2 mg terlipressin, 50 micrograms octreotide or an identical volume of saline, as a single intravenous injection given over 60 seconds. For the final analysis three patients had to be excluded because of lack of a satisfactory recording. There were no significant clinical differences between the three groups of patients. Placebo administration did not induce significant changes, but a mean decrease in variceal pressure of -27% was noted with terlipressin, starting from two minutes onwards. Variceal pressure changes after injection of octreotide were variable and the mean change in pressure did not reach statistical significance. Seven of 10 patients showed a temporary increase in variceal pressure. In conclusion, terlipressin induces a significant and progressive decrease in variceal pressure but inconsistent variations of variceal pressure changes were seen after octreotide administration. This is probably related to its effect on central venous pressure. This study also shows that continuous variceal pressure recording with the non-invasive endoscopic registration technique detects in an accurate way the effect of vasoactive drugs on variceal pressure, because placebo injection did not produce significant changes.

Octreotide versus terlypressin in acute variceal hemorrhage in liver cirrhosis. Emergency control and prevention of early rebleeding.

Sixty patients with endoscopically confirmed active variceal bleeding entered a randomized controlled clinical trial aimed at comparing the efficacy of octreotide vs. terlypressin in the control of acute variceal hemorrhage (period I, 24 h) and in the prevention of early rebleeding (period II, 6 days). Of the sixty 30 received octreotide (period I, 100 micrograms bolus followed by continuous intravenous infusion at 25 micrograms/h; period II, 100 micrograms t.i.d. subcutaneously), and 30 received terlypressin (period I, 2 mg intravenous bolus every 4 h; period II, 2nd day, 2 mg every 6 h; from 3th to 7th days, 1 mg every 6 h). Control of bleeding was achieved in 23 (76.6%) patients receiving octreotide and in 16 (53%) treated with terlypressin (NS); none of these patients suffered rebleeding during treatment. No significant difference in mortality was observed between the two groups during the hospitalization period. Complications due to therapy were lower with octreotide than with terlypressin (P < 0.01). Under the same effectiveness conditions the cost/benefit ratio must be taken into account.