Gastroenterology
Volume 134, Issue 5 , Pages 1608-1611, May 2008

Vasoconstrictor Therapy for the Hepatorenal Syndrome

  • Joseph K. Lim

      Affiliations

    • Yale Liver Center, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut
    • ,
  • Roberto J. Groszmann

      Affiliations

    • Yale Liver Center, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut
    • Hepatic Hemodynamic Laboratory, Digestive Diseases Section, Veterans Administration Medical Center, West Haven, Connecticut
    • Corresponding Author InformationAddress requests for reprints to: Address correspondence to: Roberto J. Groszmann, MD, FRCP, Professor of Medicine, Hepatic Hemodynamic Laboratory, Digestive Diseases Section/111J, Veterans Administration Medical Center, 950 Campbell Avenue, West Haven, CT 06516.

Article Outline

 

See “A randomized prospective double-blind placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome” by Sanyal A, Boyer T, Garcia-Tsao G, et al, on page 1360 and “Terlipressin and albumin versus albumin in patients with cirrhosis and hepatorenal syndrome” by Martin-Llahi M, Pepin MN, Guevara M, et al, on page 1352.

Hepatorenal syndrome (HRS) represents one of the most serious and life-threatening complications of end-stage liver disease, occurring in patients with ascites and profound circulatory dysfunction. Among individuals with ascites, HRS develops in 20% and 40% of individuals within 1 and 5 years, respectively, with the highest risk among individuals with severe sodium and water retention, and activation of sympathetic and renin–angiotensin vasoconstrictive responses.1 HRS is defined by a rapidly progressive decline in renal function in the absence of other triggers (eg, obstructive or parenchymal renal disease, bacterial infection, circulatory shock, severe volume losses, or nephrotoxic drugs) that does not respond to 2 days of diuretic withdrawal and adequate plasma volume expansion with albumin.2, 3, 4 HRS type 1 is characterized by a rapid decline in renal function to serum creatinine levels >2.5 mg/dl (220 μmol/l) or a 50% decrease in initial 24-hour creatinine clearance to <20 ml/min within 2 weeks, and is associated with a very poor prognosis. The median survival is <2 weeks, and 1- and 3-month survivals are only 25% and 10%, respectively. By contrast, HRS type 2 represents a more gradual decline in renal function to serum creatinine >1.5 mg/dl (132 μmol/l) or 24-hour creatinine clearance <40 ml/min, and is associated with a more favorable prognosis (70% 3-month survival).1

HRS is best characterized as an extreme expression of the profound circulatory dysfunction in cirrhosis, with marked splanchnic arterial and systemic vasodilatation, insufficient cardiac output, severe reduction of effective blood volume, homeostatic activation of vasoactive systems, and intense renal vasoconstriction, thereby ultimately resulting in a critical decrease in renal blood flow.5 Whereas HRS type 2 is a chronic functional renal failure occurring spontaneously in the setting of refractory ascites, HRS type 1 represents an acute functional renal failure often triggered by a precipitating insult, leading to profound renal, cardiac, and cerebrovascular dysfunction, and multiorgan failure (Figure 1A, B). Liver transplantation remains the gold standard of therapy for HRS and end-stage liver disease, although HRS at the time of transplant is associated with more frequent postoperative complications, and slightly poorer posttransplant survival.11, 12 Although including serum creatinine in the MELD score has helped to prioritize patients with HRS for transplantation, most patients will die from complications of liver disease before transplantation owing to the ongoing organ shortage. Accordingly, additional measures to bridge patients to liver transplantation are sorely needed.

  • View full-size image.
  • Figure 1. 

    A, Beneficial effects of vasoconstriction. In liver cirrhosis, progressive splanchnic vasodilatation leads to renal vasoconstriction. Splanchnic and systemic vasoconstrictors increases renal perfusion pressure and flow with the consequent increase in the excretion of sodium and water and improvement of renal function.6, 7. B, On the contrary reversal of systemic vasodilatation induces detrimental effects on cardiac function6, 7 and may aggravate brain edema in patients with liver failure, although results are mixed.8, 9 The reports in the pulmonary circulation are also mixed.10

Vasoconstrictors demonstrate the greatest promise to reverse HRS because of their unique properties of counteracting the effects of intense splanchnic vasodilatation and augmenting effective arterial blood volume, thereby suppressing endogenous renal vasoconstrictors and improving renal function. Several classes have been employed, including vasopressin analogs (terlipressin and ornipressin), somatostatin analogs (octreotide), and alpha-1 adrenergic receptor agonists (midodrine and norepinephrine). Increasing data show that in combination with plasma expanders such as intravenous albumin, vasoconstrictors may reverse HRS13 and improve posttransplant outcomes and survival.14, 15 Unfortunately, most of these studies have been limited by poor methodology, including mostly small, single-center, unblinded, uncontrolled, retrospective, or nonrandomized prospective studies.

Terlipressin is the most common vasoconstrictor and portal hypotensive agent used in Europe and Asia for the treatment of HRS type 1, based on several pilot studies and uncontrolled trials which demonstrated that initial doses of 0.5–1.0 mg every 4–6 hours, followed by doses of 1.5–12 mg daily over a course of 7–15 days, results in HRS reversal in 25–80% of patients, and may improve short-term survival.13

Only 2 prospective controlled studies have previously evaluated the role of terlipressin for the treatment of HRS type 1. Hadengue et al16 reported findings from a small, double-blind, randomized, cross-over study in which 6 of 9 patients with HRS treated with terlipressin at a rate of 2 mg/day over 2 days experienced HRS reversal. Solanski et al17 reported findings from a small, single-blind, randomized, placebo-controlled trial in which 5 of 12 patients treated with terlipressin at a dose of 2 mg/day over 14 days experienced HRS reversal compared with 0 of 12 patients treated with placebo.17 Two recent meta-analyses of primarily uncontrolled studies concluded that terlipressin reversed hepatorenal syndrome type 1 in 52% of patients and reduced mortality by 34%.18, 19

In this issue of Gastroenterology, Sanyal et al6 and Martin-Llahi et al7 report the results of the first large randomized, controlled, multicenter trials comparing terlipressin plus albumin versus albumin alone for the treatment of HRS. In the first, Sanyal and the Terlipressin Study Group6 evaluated the safety and efficacy of terlipressin in a multinational cohort of 112 patients with HRS type 1 from 35 centers across the United States, Germany, and Russia. The authors randomized 56 patients to terlipressin and 56 patients to placebo (1:1), initially dosed at 1 mg IV every 6 hours, then 2 mg IV every 6 hours if the serum creatinine failed to decrease by 30% by day 4 of the study, up to 14 days total. All patients were recommended to receive 100 g of IV albumin on day 1, followed by 25 g daily until the end of treatment. The primary outcome was a stricter version of HRS reversal “treatment success,” defined as a decrease in serum creatinine to <1.5 mg/dl on 2 occasions 48 hours apart, in the absence of dialysis, death or HRS recurrence within the 14-day treatment course. Whereas significantly more patients in the terlipressin group achieved HRS reversal than the placebo group (33.9% vs 12.5%; P = .008), only a trend toward increased treatment success rates were observed in the terlipressin group (25.0% vs 12.5%; P = .093). Overall 6-month survival between the terlipressin and placebo groups was not significantly different (42.9% vs 37.5%; P = .839). Five patients (9%) in the terlipressin group and 1 patient (2%) in the placebo group experienced serious adverse events, including nonfatal myocardial infarction, nonsustained supraventricular tachycardia, and arrhythmia.

In the second report, Martin-Llahi and the TAHRS (Terlipressin and Albumin for Hepatorenal Syndrome) investigators7 evaluated the safety and efficacy of terlipressin plus albumin in patients with HRS type 1 or type 2. The authors randomized 46 patients across 9 university centers in Spain to either terlipressin plus albumin versus albumin alone (1:1) for up to 15 days. HRS type 1 represented 74% and 78% of each treatment group, respectively. The terlipressin was initially dosed as 1 mg IV every 4 hours, then 2 mg IV every 4 hours if the serum creatinine failed to decrease by 25% after the first 3 days. All patients received albumin at a dose of 1 g/kg body weight during the initial 24 hours, followed by 40 g daily titrated to a central venous pressure of 10–15 cm H2O. The primary outcomes were 3-month survival and improvement in renal function (complete/partial). Complete response was defined as a decrease in serum creatinine to <133 μmol/l during treatment, and a partial response was defined as a decrease in serum creatinine of ≥50% from the baseline value but an end-of-treatment value >133 μmol/l. The terlipressin plus albumin group experienced a significantly higher rate of improvement in renal function than the albumin group (43.5% vs 8.7%; P = .017), and a trend toward improved 3-month survival (27% vs 19%; P = .7). Ten of 23 patients (43.5%) and 4 of 23 patients (19%) in the terlipressin plus albumin and albumin groups, respectively, experienced cardiovascular complications such as myocardial or intestinal ischemia, circulatory overload, and arrhythmias.

These 2 studies are the largest randomized controlled trials conducted to date in patients with HRS, and represent an important advance in our understanding of the safety and efficacy of terlipressin with or without albumin in reversing HRS in patients with cirrhosis and ascites. Both studies confirm previous reports that terlipressin improves renal function in a subset of patients, and provide important observations about treatment and patient factors that predict response. Although the studies were quite heterogeneous, the primary outcome findings on HRS reversal, survival, and cardiovascular complications were quite similar. Nevertheless, some important questions remain unanswered from these studies.

First, the optimal dose and timing of terlipressin remains unclear, although these studies suggest that goal-directed regimen adjusted by renal function recovery is superior to a fixed dose regimen. Second, baseline serum creatinine may represent an important factor influencing response to therapy, and further stratification of individuals by severe and moderate classifications of renal failure may provide new insight for patient selection. The Sanyal et al study identified a baseline serum creatinine of >7.0 mg/dl as an important predictor of nonresponse; none of these patients responded to terlipressin or survived, suggesting a threshold beyond which vasoconstrictor therapy is ineffective or an alternative etiology for renal failure. Third, albumin was used in both arms of the Martin-Llahi et al study, and in 88% of both arms of the Sanyal et al study, raising new questions about the role of albumin in the treatment of HRS. Although it is believed to augment renal response to terlipressin based on uncontrolled data, albumin alone has clearly been shown to be ineffective in improving renal function in HRS.20 These trials confirm this observation, although the 6-month survival in the placebo arm of the Sanyal et al study was much higher than expected, suggesting differences in patient selection or in the diagnosis of HRS. Alternatively, albumin may have important underrecognized antioxidant or vascular properties (such as nitric oxide trapping) that improve renal function. Fourth, the role of baseline circulatory failure or cardiomyopathy requires further investigation, and was not addressed adequately in these studies. Although individuals with known cardiovascular disease were excluded from participation, significant baseline abnormalities in cardiopulmonary function in these patients could not be excluded. Fifth, early administration of vasoconstrictor therapy is believed to represent an important bridge to liver transplantation, based upon previous data suggesting that individuals treated with terlipressin for HRS before transplantation had similar survival and complication rates as those undergoing transplantation without HRS.15 Although not studied as a primary outcome of the study, and the sample size was inadequate to detect a difference, Sanyal et al reported that overall survival was not different between terlipressin and placebo groups, but individuals experiencing HRS reversal had significantly improved posttransplant outcomes.

The most important concern regarding terlipressin remains the potential for uncommon, but potentially severe ischemic events. These studies further confirm that, despite the exclusion of individuals with known severe cardiovascular disease, these events occurred in 5 of 56 patients (9%) and 10 of 23 patients (43.5%) in the terlipressin arms, and in 1 of 56 (2%) and 4 of 23 (19%) in the placebo arms. The reasons for the significant disparity in adverse event rates between the 2 studies is unclear, although likely reflect differences in reporting, and possibly the higher doses of terlipressin used in the Martin-Llahi et al study (6–12 mg daily) versus the Sanyal et al study (4–8 mg daily), as reflected by the higher rates of circulatory overload and nonfatal arrhythmias observed in the former. Further clarification is required to determine optimal monitoring requirements and patients at greatest risk for adverse effects. It is clear that, although terlipressin is administered as intermittent intravenous infusions every 4–6 hours, it should be used only in an intensive care unit (ICU) or step-down unit where hemodynamic monitoring is performed.

Terlipressin is widely used in Europe and Asia for the treatment of HRS, but no vasopressin analogs are presently approved by the US Food and Drug Administration for this indication. In the United States, off-label use of intravenous albumin infusion plus the combination of midodrine plus octreotide, remains a commonly used regimen for HRS, and is supported by American Association for the Study of Liver Diseases treatment recommendations.2 The small number of primarily nonrandomized and retrospective studies evaluating this regimen suggest that a combination of oral midodrine, initiated at 5–10 mg then titrated up to 15 mg 3 times daily, plus subcutaneous octreotide, initiated at 100 μg then titrated up to 200 μg, may lead to recovery of renal function and improve 30-day survival.21, 22, 23 Both drug agents may be administered outside a monitored ICU setting and without requirement for intravenous infusion, and have not been associated with the cardiovascular complications observed with vasopressin analogs. It is important to emphasize that terlipressin is a powerful portal hypotensive drug. This effect is superior to what has been reported with octreotide alone. Whether this effect in portal pressure is necessary to improve renal perfusion merits further investigation.

In summary, the trials by Sanyal et al and Martin-Llahi et al provide important new data supporting prior evidence that terlipressin is a highly potent vasoconstrictor that reverses HRS in a significant proportion of patients, but fails to improve short-term mortality, and is associated with a significant risk of systemic ischemic complications, even in cohorts in which individuals with known cardiovascular disease were excluded. Future studies should clarify patient and disease-specific predictors for safe and effective telipressin therapy, its role as a bridge to liver transplantation, and compare terlipressin directly against other vasoconstrictors with fewer cardiovascular side effects. Industry support for these trials is unlikely in the face of its orphan status and ongoing routine use in Europe and Asia; institutional and foundation support for collaborative studies will be needed to address these important questions.

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References 

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PII: S0016-5085(08)00470-8

doi:10.1053/j.gastro.2008.03.034

Refers to article:

  • Editorial Accompanies Article A Randomized, Prospective, Double-Blind, Placebo-Controlled Trial of Terlipressin for Type 1 Hepatorenal Syndrome , 14 February 2008

    Arun J. Sanyal, Thomas Boyer, Guadalupe Garcia–Tsao, Frederick Regenstein, Lorenzo Rossaro, Beate Appenrodt, Andres Blei, Veit Gülberg, Samuel Sigal, Peter Teuber, The Terlipressin Study Group
    Gastroenterology May 2008 (Vol. 134, Issue 5, Pages 1360-1368)

  • Editorial Accompanies Article Terlipressin and Albumin vs Albumin in Patients With Cirrhosis and Hepatorenal Syndrome: A Randomized Study , 18 February 2008

    Marta Martín–Llahí, Marie–Noëlle Pépin, Mónica Guevara, Fernando Díaz, Aldo Torre, Alberto Monescillo, Germán Soriano, Carlos Terra, Emilio Fábrega, Vicente Arroyo, Juan Rodés, Pere Ginès, TAHRS Investigators
    Gastroenterology May 2008 (Vol. 134, Issue 5, Pages 1352-1359)

Gastroenterology
Volume 134, Issue 5 , Pages 1608-1611, May 2008

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