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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 1  |  Issue : 3  |  Page : 69-74

Efficacy and predictors to response of octreotide and midodrine combination in patients with hepatorenal syndrome


1 King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
2 King Faisal Specialist Hospital and Research Center; Therapeutic Affairs Deputyship, Ministry of Health, Riyadh, Saudi Arabia

Date of Submission22-Feb-2022
Date of Acceptance10-Aug-2022
Date of Web Publication30-Sep-2022

Correspondence Address:
Dr. Ahmed Al-Jedai
Pharmaceutical Care Division, King Faisal Specialist Hospital and Research Centre, Riyadh 11211
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjcp.sjcp_4_22

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  Abstract 

Background: Hepatorenal syndrome (HRS) is a functional form of acute kidney injury (AKI) that develops in patients with advanced liver disease. The use of octreotide (OCT) and midodrine (MID) along with albumin is commonly used in practice despite lack of strong evidence. Objective: The purpose of the study is to evaluate the efficacy of combining octreotide and midodrine in HRS patients. Materials and Methods: This is a retrospective, single center study. All patients who received both OCT/MID from January 2005 to April 2013 were identified from the electronic pharmacy system at a major tertiary care center in Riyadh, Saudi Arabia. The aim of the study is to evaluate the safety and efficacy and predictors to response of the combination of OCT/MID in patients with decompensated liver cirrhosis with type I HRS receiving standard of care therapy. The primary endpoint was the change in estimated glomerular filtration rate (eGFR) within 30 days of starting therapy compared to baseline. Results: There was no significant improvement in eGFR using Cockcroft-Gault (CG) from baseline until the end of treatment (P = 0.311). Conclusion: Combination therapy of octreotide and midodrine along with albumin did not improve the eGFR in patients with type 1 HRS.

Keywords: Hepatorenal syndrome, midodrine, octreotide


How to cite this article:
Alabdulkarim Z, Alkortas D, Alsebayel MI, Alkhail FA, Elsiesy H, Al-Jedai A. Efficacy and predictors to response of octreotide and midodrine combination in patients with hepatorenal syndrome. Saudi J Clin Pharm 2022;1:69-74

How to cite this URL:
Alabdulkarim Z, Alkortas D, Alsebayel MI, Alkhail FA, Elsiesy H, Al-Jedai A. Efficacy and predictors to response of octreotide and midodrine combination in patients with hepatorenal syndrome. Saudi J Clin Pharm [serial online] 2022 [cited 2022 Dec 2];1:69-74. Available from: http://www.sjcp.org/text.asp?2022/1/3/69/357709


  Introduction Top


Liver cirrhosis is one of the leading causes of death among adults which results in 1.03 million deaths per year worldwide. The main causes of end-stage liver disease (ESLD) are viral hepatitis, non-alcoholic fatty liver disease (hepatic steatosis), autoimmune hepatitis, primary biliary cirrhosis, and cryptogenic causes.[1] Portal hypertension is the most common serious complication of cirrhosis which can cause other complications including ascites, gastroesophageal varices, acute variceal hemorrhage, bacterial peritonitis, and hepatorenal syndrome (HRS).[2]

HRS is a functional form of acute kidney injury (AKI), which occurs in patients with advanced liver disease or cirrhosis as a result of intense renal vasoconstriction due to the reduction in the effective blood volume and splanchnic vasodilatation.[3],[4] HRS is characterized by a marked reduction in estimated glomerular filtration rate (eGFR), urinary excretion of sodium and free water, and renal plasma flow (RPF). However, tubular function is preserved with normal renal histology despite a significant reduction in renal function.[5],[6] There are two subtypes of HRS that have been identified. Type 1 HRS is a rapidly progressive renal failure that is defined by doubling of initial serum creatinine to a level greater than 221 μmol/L (2.5 mg/dL) or by 50% reduction in creatinine clearance to a level less than 20 mL/min in 2 weeks. Type 2 HRS is a moderate, slowly progressing decline in renal function with a serum creatinine of more than 133 μmol/L (1.5 mg/dL).[3]

In the last two decades, knowledge of the pathogenesis and management of HRS have improved greatly.

Ginès et al.[7] estimated the probability of developing HRS at 1 year in patients with cirrhosis complicated by ascites to be around 18% and 39% at 1 and 5 years, respectively. However, one recent study showed that the 5-year probability of HRS development was only 11.4%.[8] The prognosis of type 1 of HRS is still poor; mortality in untreated patients with type 1 HRS is as high as 80% in 2 weeks; and 10% of the patients survive for more than 3 months. In contrast, patients with type 2 HRS have a much better median survival with approximately 6 months.[9] The criteria to diagnose HRS were initially developed in 1996 and were updated by the International Ascites Club (IAC) in 2007.[10]

The European Association for the Study of the Liver practice guidelines[11] recommend the combination of terlipressin with albumin to be considered as first line of therapy. If terlipressin is unavailable, alternative vasoconstrictors such as norepinephrine, vasopressin, or a combination of octreotide and midodrine (OCT/MID), together with albumin, should be considered in patients with HRS type 1.[12] The American Association for the Study of Liver Diseases recommends albumin infusion plus administration of vasoactive drugs such as octreotide and midodrine in the treatment of type I HRS but with weaker recommendation (Class IIa, Level B) due to limited data.[13] The combination use of intravenous or subcutaneous octreotide and oral midodrine in addition to intravenous albumin is commonly used in practice in Saudi Arabia, whereas terlipressin was historically not approved by the Saudi Food and Drug Authority until 2014.

The data supporting the effectiveness of combining OCT/MID in terms of eGFR improvement in HRS patients are limited, despite the widespread adoption of this practice.[14],[15],[16],[17],[18]

The purpose of the study was to evaluate the safety and efficacy of combining octreotide and midodrine in type 1 HRS cirrhosis Saudi patients and to evaluate predictors to response as judged by improvement in eGFR.


  Materials and Methods Top


Study design

This is a retrospective, single-center study. All patients who received OCT/MID from January 2005 to April 2013 were identified via the electronic pharmacy system at King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, Saudi Arabia.

Study endpoints

The primary endpoint of this study was the change in eGFR using the Cockcroft–Gault (CG) method within 30 days of starting therapy compared with baseline. CG was used instead of Modification of Diet in Renal Disease (MDRD) method because MDRD has been validated in patients with sable kidney function but not in patients with rapidly changing GFR. Moreover, the secondary endpoints are predictors to response, 30-day mortality rate, and adverse events of medications.

Patients

Patients were included in the study if they met the HRS criteria as defined by the IAC in 2007, were ≥ 16 years, had documented liver disease with evidence of portal hypertension according to ultrasonographic results or clinical parameters such as varices, ascites, and splenomegaly, in addition to serum creatinine >1.5 mg/dL (133 μmol/L).

Patients were excluded if the duration of their hospital stay was less than 48 h, serum creatinine improved by greater than 50% within 48 h after hydration with 1.5 L colloid or crystalloid fluids, had proteinuria >500 mg/day, died within 7 days, had previous liver or renal transplantation, transplanted within 2 weeks, had ultrasonographic evidence of renal disease or urinary tract obstruction, did not receive albumin and/or continued on furosemide for more than 2 days after study therapy.

Data collection

The pharmacy electronic records were reviewed for all patients who received OCT/MID for HRS from October 2012 to June 2013. Clinical data for all patients were reviewed using patients’ charts and electronic medical records.

Data collected included baseline characteristics such as age, weight, gender, model for end-stage liver disease (MELD) score and Child–Pugh classification, systolic blood pressure, serum sodium, serum bilirubin, serum albumin, and international normalized ratio (INR). Etiology of liver disease includes hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic hepatitis, non-alcoholic steatohepatitis (NASH) cirrhosis, cryptogenic cirrhosis, autoimmune hepatitis, hepatocellular carcinoma (HCC), primary sclerosing cholangitis, primary biliary cirrhosis, Wilson’s disease, and schistosomiasis (bilharziasis).

Other co-morbid medical conditions were collected and included hypertension, diabetes mellitus, ascites, hepatic encephalopathy, variceal bleeding, other gastrointestinal bleeding, and bacterial infections. Nephrotoxic agents taken within a week before initiation of therapy and up to 30 days of therapy were also documented.

These included furosemide, aminoglycosides, amphotericin B, vancomycin, contrast media, non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme inhibitors (ACEI), and angiotensin receptor blockers (ARBs), in addition to drug levels whenever available. Medication doses, duration of therapy, number of courses, and adverse events of both study drugs were reported.

Moreover, serum creatinine and eGFR using the CG method were documented at baseline, 7, 14, and 30 (±5 days), and death at day 30. In addition, intensive care unit (ICU) length of stay, hemodialysis, and/or liver transplantation were reported.

Statistical analysis

The effect size selected was a 20% difference between baseline eGFR and end of treatment. Descriptive statistics for all the continuous variables were reported as mean ± standard deviation, whereas categorical variables were reported as frequencies and percentages.

The continuous variables were compared using Student’s paired t-test. Categorical variables were compared using the χ2 test and Fisher’s exact test with low counts. A P-value of less than 0.05 was used to define statistical significance. No sample size was calculated since all patients were included in the study for the pre-specified time period. All statistical analysis was conducted using the software package SAS version 9.3 (Statistical Analysis System, SAS Institute Inc., Cary, NC, USA).

Study oversight

The study protocol was approved by the local Institutional Review Board (RAC# 2121 133). The study was conducted according to the latest version of the Declaration of Helsinki and Good Clinical Practice[19] and International Conference on Harmonization,[20] the policies and procedures of Research Advisory Council at KFSHRC, and the national laws.

All decisions regarding the patient medical management were made by the treating physician according to his/her clinical judgment. Only investigators had access to the study data and assumed responsibility for the integrity and completeness of the reported data. No informed consent was required since this was a retrospective study.


  Results Top


Of the 367 patients screened, 30 patients met the inclusion criteria and were enrolled in the study [Diagram 1]. The baseline clinical and laboratory characteristics of patients are summarized in [Table 1]. The percentage of patients who had HCV were 50% followed by cryptogenic cirrhosis (20%), HBV (13.33%), and NASH (10%); 10 patients (33.33%) had HCC. More than half of the patients were on furosemide but withdrawn later after the initiation of study therapy. Of which, five patients continued on furosemide with no improvement of the eGFR for 2 days and then it was stopped. The majority received vancomycin during study therapy and two patients (6.67%) had critical high trough levels [Table 2].
Diagram 1: Patients’ enrollment and follow-up

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Table 1: Baseline clinical and laboratory characteristics

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Table 2: Exposure to nephrotoxic agents

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The doses of OCT/MID were variable. Approximately 43.33% of the patients received 150 mcg per day of octreotide and 40% received 30 mg per day of midodrine, and the mean dose of albumin was 0.67 g/kg/day.

Most of the patients received the study therapy for less than 7 days and only one course of therapy [Table 3]. Sixteen patients (53.33%) were treated with OCT/MID as a combination therapy, whereas 14 patients (46.67%) received OCT/MID as a sequential therapy.
Table 3: Study drugs

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There was no statistically significant improvement in eGFR using the CG method (P = 0.311) from baseline until the end of treatment [Figure 1]. Logistic regression analysis revealed that patients with prior HCV infection responded to OCT/MID in terms of eGFR improvement [P = 0.03, odds ratio (OR)=7.43] [Table 4]. In terms of mortality, 16 patients (53.33%) died within 30 days of diagnosis. Hyperglycemia was the most common side effect related to the study therapy, which occurred in 63.33% of the patients followed by hypertension (50%), dysuria (36.67%), diarrhea (36.67%), sinus bradycardia (13.33%), and nausea (6.67%). Twenty-two patients required dialysis (36.67%) and only four patients (13.33%) underwent liver transplantation after 2 weeks of therapy. In addition, 10 patients (33.33%) required ICU due to hemodynamic instability.
Figure 1: Efficacy of combination therapy on eGFR, comparing baseline eGFR to the eGFR at the end of treatment (P = 0.311)

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Table 4: Association of different pre-existing conditions and response

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  Discussion Top


HRS is a functional form of AKI that develops in patients with advanced liver disease. The prognosis of HRS type 1 is poor; mortality in untreated patients with type 1 HRS is as high as 80% in 2 weeks, and 10% of the patients survive for more than 3 months. In contrast, patients with type 2 HRS have a much better median survival with approximately 6 months.[9]

The recommended available management option for HRS is to use vasoactive drugs such as octreotide and midodrine. Octreotide is a splanchnic arterial vasoconstrictor; it decreases portal pressure, splanchnic blood flow, and glucagon secretion and ultimately improves eGFR. In contrast, midodrine is an alpha-1-adrenergic agonist (arteriolar and venous constrictor), resulting in increased renal perfusion and blood pressure.[21]

Few studies are published that evaluated the effect of combination of OCT/MID in HRS patients. In a small non-randomized study of 13 patients with type 1 HRS, 8 patients were treated with intravenous dopamine (2–4 mcg/kg/min) and the remaining 5 patients were treated with oral midodrine (7.5–12.5 mg three times daily) plus octreotide (100–200 mcg subcutaneously three times daily). Despite the small study size, the study suggested that patients who received midodrine and octreotide along with albumin had better reduction in eGFR compared with dopamine and albumin, whereas more patients died after dopamine and albumin during the first 12 days.[13]

Another retrospective study enrolled 81 patients, 60 of whom treated with OCT/MID found that the sustained improvement in serum creatinine was defined as a serum creatinine ≤ 1.5 mg/dL occurred more with the OCT/MID group (40%) when compared with the control group (10%) (P = 0.01). Thirty-day mortality was 43% in the treatment group, compared with 71% in the control group (P = 0.03).[14]

However, that study did not identify predictors for response in terms of dosing, combination, severity of HRS, or underline disease of ESLD.

Another small prospective study found that octreotide alone (300 mcg subcutaneously two times daily) did not improve systemic hemodynamics nor eGFR in non-azotemic cirrhotic patients with ascites, whereas the addition of oral midodrine (7.5 mg three times daily) to octreotide improved systemic hemodynamic circulation and eGFR to 91 mL/min at day 10 compared with octreotide alone (79.5 mL/min; P = 0.04).[15]

Furthermore, a retrospective cohort study included 75 patients in the treatment arm, which showed that the combination therapy of midodrine, octreotide, and albumin (treatment group) had a higher transplant-free survival rate compared with the control group of patients who met criteria for HRS prior to 2001 before initiation of this specific therapy (control group) (P = 0.0001). After 1 month of treatment, there was a significant improvement in the eGFR in the treatment cohort (47.67 ± 33.98 mL/min) compared with control cohort (34.39 ± 18.79 mL/min) (P = 0.03).[16]

A meta-analysis of only three small studies[13],[14],[17] found a significant mortality benefit with midodrine plus octreotide at 1 month [OR=0.33; 95% confidence interval (CI) 0.18–0.60] and 3 months (OR=0.17; 95% CI 0.03–0.96).[18]

However, in our study, we found no statistically significant improvement of the eGFR in cirrhotic patients with type 1 HRS with the use of octreotide and midodrine along with albumin; this could be due to the fact that our study was not powered enough to show difference. Therefore, the probability of type II error is expected. Other limitations of our study include inherent weaknesses of the retrospective design; namely, lack of randomization and control and lack of a standardized dosing regimen. Therefore, this warranted a large randomized prospective controlled trial to validate these findings and to identify the optimal drug regimen.

In conclusion, combination therapy of octreotide and midodrine along with albumin did not improve the eGFR in patients with type 1 HRS.

Financial support and sponsorship

The authors have no financial support to declare.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Acknowledgement

The authors thank Maher Mominah, Manager, Pharmacy Informatics and Automation, Pharmacy Automation and Support Services, King Faisal Specialist Hospital and Research Center, Riyadh and Tarek Alhallaq, Specialist, Pharmacy Automation and Support Services, King Faisal Specialist Hospital and Research Center, Riyadh.

Authors’ contribution

  1. ZA: proposal writing, data collection, data validation, data analysis, manuscript writing, and manuscript reviewing;
  2. DA: idea generation, proposal writing, data validation, data analysis, manuscript writing, and manuscript reviewing;
  3. MA: manuscript reviewing;
  4. FAA: manuscript writing and manuscript reviewing;
  5. HE: manuscript writing and manuscript reviewing;
  6. AA: idea generation, proposal writing, data validation, data analysis, manuscript writing, and manuscript reviewing.


 
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Wadei HM. Hepatorenal syndrome: A critical update. Semin Respir Crit Care Med 2012;33:55-69.  Back to cited text no. 4
    
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Nadim MK, Kellum JA, Davenport A, Wong F, Davis C, Pannu N, et al; ADQI Workgroup. Hepatorenal syndrome: The 8th International Consensus Conference of the acute dialysis quality initiative (ADQI) group. Crit Care 2012;16:R23.  Back to cited text no. 12
    
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Angeli P, Volpin R, Gerunda G, Craighero R, Roner P, Merenda R, et al. Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology 1999;29:1690-7.  Back to cited text no. 14
    
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Esrailian E, Pantangco ER, Kyulo NL, Hu KQ, Runyon BA. Octreotide/midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome. Dig Dis Sci 2007;52:742-8.  Back to cited text no. 15
    
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Kalambokis G, Economou M, Fotopoulos A, Al Bokharhii J, Pappas C, Katsaraki A, et al. The effects of chronic treatment with octreotide versus octreotide plus midodrine on systemic hemodynamics and renal hemodynamics and function in nonazotemic cirrhotic patients with ascites. Am J Gastroenterol 2005;100:879-85.  Back to cited text no. 16
    
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Hiremath SB, Lokikere SD, Madalageri NK. Efficacy of midodrine plus octreotide in hepatorenal syndrome: A meta-analysis. Int J Res Ayur Pharm 2012;3:576-81.  Back to cited text no. 18
    
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Leung W, Wong F. Hepatorenal syndrome: Do the vasoconstrictors work? Gastroenterol Clin N Am 2011;40:581-98.  Back to cited text no. 21
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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