Abstract:
Potential conflict of interest: Nothing to report. Reply: We appreciate the interest of de Mattos and de Mattos in our article recently published in hepatology1 comparing the administration of terlipressin in continuous intravenous infusion (TERLI‐INF) versus intravenous boluses (TERLI‐BOL) in the treatment of hepatorenal syndrome (HRS). In our study the primary endpoint was the onset of drug‐related adverse events, and the sample size was calculated accordingly. Regarding the efficacy of treatment, we think 90‐day survival is not the optimal indicator of efficacy in HRS. Indeed, several variables, other than response to treatment, affect survival in patients with HRS, such as age, failure of organs other than the kidney, and degree of liver failure.1 Anyway, when we adjusted our analysis for all these variables, the randomization had no effect on survival. Moving to a more adequate parameter of efficacy, response to treatment, a higher rate of response was observed in the TERLI‐INF group than the TERLI‐BOL group, although the difference was not significant. Concerning the initial dose of terlipressin, we want to highlight that studies on pharmacokinetics and pharmacodynamics of terlipressin are lacking in patients with HRS; thus, the optimal initial dose is still to be determined. de Mattos and de Mattos, while citing our article comparing terlipressin versus midodrine/octreotide in the treatment of HRS,2 forgot to cite our first study on the use of terlipressin in HRS,3 in which we used terlipressin by continuous intravenous infusion starting from 2 mg/24 hours. Therefore, when we planned the study, we selected a 2 mg/24 hours initial dose in the TERLI‐INF group. We accept the speculation that a lower starting dose may justify a lower incidence of side effects in the TERLI‐INF versus the TERLI‐BOL group, but a lower dose could have caused the risk to be less effective. Nevertheless, most of the patients in the TERLI‐INF group responded to 2 mg/24 hours (Fig. 1).Figure 1: Dose of terlipressin needed to achieve response to treatment in patients assigned to TERLI‐BOL (A) and those assigned to TERLI‐INF (B).Finally, concerning economic issues, our study was not planned to identify differences in costs between the two groups. We agree that a comprehensive economic evaluation should take into account the whole treatment administered, invasive procedures, days of hospitalization, and so on. Thus, although in the whole population the mean dose of terlipressin was significantly lower in the TERLI‐INF group than in the TERLI‐BOL group (2.6 ± 1.4 versus 3.5 ± 1.7 mg/day, P < 0.025), no speculation can be made about the global cost of treatment. In conclusion, although there are still open questions, our study provided an answer to what is the most tolerated way of administration of terlipressin in patients with HRS.Keywords:
Terlipressin
Midodrine
Pharmacodynamics
Clinical endpoint
Potential conflict of interest: Nothing to report. Reply: We appreciate the interest of de Mattos and de Mattos in our article recently published in hepatology1 comparing the administration of terlipressin in continuous intravenous infusion (TERLI‐INF) versus intravenous boluses (TERLI‐BOL) in the treatment of hepatorenal syndrome (HRS). In our study the primary endpoint was the onset of drug‐related adverse events, and the sample size was calculated accordingly. Regarding the efficacy of treatment, we think 90‐day survival is not the optimal indicator of efficacy in HRS. Indeed, several variables, other than response to treatment, affect survival in patients with HRS, such as age, failure of organs other than the kidney, and degree of liver failure.1 Anyway, when we adjusted our analysis for all these variables, the randomization had no effect on survival. Moving to a more adequate parameter of efficacy, response to treatment, a higher rate of response was observed in the TERLI‐INF group than the TERLI‐BOL group, although the difference was not significant. Concerning the initial dose of terlipressin, we want to highlight that studies on pharmacokinetics and pharmacodynamics of terlipressin are lacking in patients with HRS; thus, the optimal initial dose is still to be determined. de Mattos and de Mattos, while citing our article comparing terlipressin versus midodrine/octreotide in the treatment of HRS,2 forgot to cite our first study on the use of terlipressin in HRS,3 in which we used terlipressin by continuous intravenous infusion starting from 2 mg/24 hours. Therefore, when we planned the study, we selected a 2 mg/24 hours initial dose in the TERLI‐INF group. We accept the speculation that a lower starting dose may justify a lower incidence of side effects in the TERLI‐INF versus the TERLI‐BOL group, but a lower dose could have caused the risk to be less effective. Nevertheless, most of the patients in the TERLI‐INF group responded to 2 mg/24 hours (Fig. 1).Figure 1: Dose of terlipressin needed to achieve response to treatment in patients assigned to TERLI‐BOL (A) and those assigned to TERLI‐INF (B).Finally, concerning economic issues, our study was not planned to identify differences in costs between the two groups. We agree that a comprehensive economic evaluation should take into account the whole treatment administered, invasive procedures, days of hospitalization, and so on. Thus, although in the whole population the mean dose of terlipressin was significantly lower in the TERLI‐INF group than in the TERLI‐BOL group (2.6 ± 1.4 versus 3.5 ± 1.7 mg/day, P < 0.025), no speculation can be made about the global cost of treatment. In conclusion, although there are still open questions, our study provided an answer to what is the most tolerated way of administration of terlipressin in patients with HRS.
Terlipressin
Midodrine
Pharmacodynamics
Clinical endpoint
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Hepatorenal syndrome (HRS), a serious complication of cirrhosis, is associated with high mortality without treatment. Terlipressin with albumin is effective in the reversal of HRS. Where terlipressin is not available, as in the United States, midodrine and octreotide with albumin are used as an alternative treatment of HRS. The aim was to compare the effectiveness of terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of HRS in a randomized controlled trial. Twenty‐seven patients were randomized to receive terlipressin with albumin (TERLI group) and 22 to receive midodrine and octreotide plus albumin (MID/OCT group). The TERLI group received terlipressin by intravenous infusion, initially 3 mg/24 hours, progressively increased to 12 mg/24 hours if there was no response. The MID/OCT group received midodrine orally at an initial dose of 7.5 mg thrice daily, with the dose increased to a maximum of 12.5 mg thrice daily, together with octreotide subcutaneously: initial dose 100 μg thrice daily and up to 200 μg thrice daily. Both groups received albumin intravenously 1 g/kg of body weight on day 1 and 20‐40 g/day thereafter. There was a significantly higher rate of recovery of renal function in the TERLI group (19/27, 70.4%) compared to the MID/OCT group (6/21, 28.6%), P = 0.01. Improvement in renal function and lower baseline Model for End‐Stage Liver Disease score were associated with better survival. Conclusion : Terlipressin plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with HRS (H epatology 2015;62:567–574
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Terlipressin
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Midodrine
Terlipressin
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Kalambokis, Georgios N.a; Baltayiannis, Gerasimosb; Christodoulou, Dimitriosb; Christou, Leonidasa Author Information
Midodrine
Terlipressin
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Purpose: Hepatorenal syndrome (HRS) is a grave complication of end-stage liver disease and is associated with a very high mortality. This case report describes a 42-year-old female with advanced alcoholinduced cirrhosis who developed HRS that was initially treated with midodrine and octreotide but renal function continued to deteriorate. Vasopressin therapy was added and HRS was successfully reversed. There is limited data available on the use of vasopressin for HRS and this case supports its use in treatment of HRS, particularly in countries where the more widely studied terlipressin is unavailable. This case also demonstrates that a patient failing one medical therapy for HRS may respond to an alternative or adjunctive therapy; therefore this should be attempted to increase the patient's chance of survival.
Terlipressin
Midodrine
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Midodrine
Terlipressin
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Terlipressin
Midodrine
Hepatic Encephalopathy
Liver disease
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Background: Terlipressin is the first-line pharmacological treatment for hepatorenal syndrome. When terlipressin is unavailable, midodrine/octreotide or norepinephrine, with albumin, represent the alternative treatments. The comparative efficacy of these alternative regimens remains unclear. Objective: To compare the efficacy of midodrine/octreotide to that of norepinephrine for the treatment of patients with hepatorenal syndrome. Methods: In the intensive care setting, sixty patients with hepatorenal syndrome were randomized to initially receive either 0.5 mg/h of norepinephrine (maximum 3 mg/h) or 5 mg of oral midodrine three times/day (maximum 12.5 mg three times/day) plus octreotide (100 μg/6 h) as subcutaneous injection (maximum 200 μg/6 h), together with albumin (20–40 g/day). Treatment was allowed for a maximum of 10 days. Survival was analyzed for up to 30 days. The primary efficacy outcome was the proportion of patients who achieved full response, defined as the return of serum creatinine to a value within 0.3 mg/dl of the baseline at the end of treatment. Results: There was a significantly higher rate of full response in the norepinephrine group (15/26, 57.60%) than the midodrine/octreotide group (5/25, 20%) ( p = 0.006). Eleven (42.30%) patients in the norepinephrine group and 6 (24%) in the midodrine/octreotide group survived ( p = 0.166). Conclusion: Norepinephrine plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with hepatorenal syndrome. (ClinicalTrials.gov, identifier: NCT03455322). https://clinicaltrials.gov/ct2/show/NCT03455322?cond = Hepatorenal+Syndrome&cntry = EG&draw = 2&rank = 1.
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Terlipressin
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Hepatorenal syndrome (HRS) is a type of renal failur e occurring in patients with cirrhosis, ascites and liver failure . Among the pharmacological treatment available, terlipressin has been found to be most efficacious vasoconstrictor agent in improving renal function. Though terlipressin has significant HRS reversal benefits, it lacks long term mortality benefits. Evidences on mortality benefits and renal failure reversal efficacy of midodrine plus octreotide in HRS are insufficient and controversial. The primary and secondary objectives of the study were t o analyze mortality benefits and HRS reversal efficacy of midodrine plus octreotide in HRS respectively. Electronic databases were searched for the relevant articles in PUBMED, The Cochrane Register for Controlled trials, SCIRUS and Google scholar with MeSH search terms‘midodrine’ ‘octreotide’ and ‘hepatorenal syndrome’. Studies comparing mortality benefits of midodrine plus octreotide with control group were eligible to be included under analysis. Of the total 26 studies found relevant and deemed further scr eening only three studies met the eligibility criteria and were included in analysis. With total 309 patients included in analysis there was significant decrease in odds of occurrence of death at three months (Odds Ratio, OR = 0.17; 95% CI= 0.03 to 0.96) i n midodrine plus octreotide treated group. Results of the study suggest that mortality benefits of midodrine plus octreotide appear to be significant even at three months. Though HRS reversal efficacy of this combination remains inconclusi ve, this combinat ion may have HRS reversal benefits in terms of retarding the progression of the HRS rather than reversing it.
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Terlipressin
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Midodrine
Terlipressin
Intravascular volume status
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