Alternatives to Large Volume Paracentesis Study (LVP)
The overall objective of this proposal is to compare the effect of a combination of vasoconstrictors (midodrine + octreotide) to albumin on the time to recurrence of ascites in patients with refractory ascites treated with large volume paracentesis (LVP). This objective will be achieved through a prospective, randomized, double blind, placebo-controlled clinical trial.
Investigate the effect of LVP plus a combination of vasoconstrictors (octreotide + midodrine), compared to LVP + Albumin on time to recurrence of ascites in cirrhotic patients with refractory ascites.
- Investigate the rate of development of post-paracentesis circulatory dysfunction (PCD) in patients treated with LVP + vasoconstrictors and compare it to the rate obtained with LVP+ Albumin
- Correlate changes in forearm blood flow (FBF) and mean arterial pressure (MAP) with time to recurrence of ascites and development of PCD.
- Investigate the effect of LVP + vasoconstrictors compared to LVP+Albumin on time to development of hepatorenal syndrome (HRS) or death.
Drug: Albumin placebo
Drug: Midodrine placebo
Drug: Octreotide placeo
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Vasoconstrictors as Alternatives to Albumin After Large Volume Paracentesis Large Volume Paracentesis (LVP) in Cirrhosis|
- The Analysis of the Primary Endpoint, Time to Recurrence of Ascites, Will be According to the Principle of Intention-to-treat. The Primary Treatment Comparison Will be Patients Randomized to Vasoconstrictors vs Albumin. [ Time Frame: Participants were followed until time to recurrence of ascites, an average of 10 days ] [ Designated as safety issue: No ]The time to recurrence of ascites was defined as time from index large volume paracentesis to the requirement of repeat large volume paracentesis, as defined by the presence of moderate to severe ascites AND weight gain to 90-100% of baseline weight AND increase in abdominal girth to 90-100% of baseline abdominal girth.
|Study Start Date:||August 2003|
|Study Completion Date:||August 2012|
|Primary Completion Date:||August 2010 (Final data collection date for primary outcome measure)|
Subjects in this arm received an IV infusion of saline solution (albumin placebo) plus octreotide long-acting release 20 mg intramuscularly, to be repeated every month plus a tablet of 10 mg of midodrine to be administered at a dose of 10 mg orally 3 times a day.
Drug: Albumin placebo
Other Name: Normal salineDrug: Midodrine
Other Name: Midodrine oral tabletsDrug: Octreotide
Other Name: Intramuscular Octreotide long acting (LAR)
Active Comparator: Albumin
Subjects in this arm received intravenous (IV) albumin at a dose of 8 g/L of ascites removed plus intramuscular administration of 5 mL of saline solution (octreotide placebo) to be repeated every month plus a tablet (midodrine placebo) to be administered 3 times a day.
Other Name: Intravenous Albumin 25%Drug: Midodrine placebo
Other Name: Midodrine placebo pillsDrug: Octreotide placeo
Other Name: Octreotide placebo (normal saline) intramuscular injection
We hypothesize that vasoconstrictors can be used as an alternative to albumin after LVP in cirrhotic patients with refractory ascites (i.e. the use of vasoconstrictors will lead to an equal or lower rate of PCD). Unlike albumin, the advantage of vasoconstrictors is that they can be administered for a longer period of time and therefore their effect on effective arterial blood volume would be more sustained and result, not only in prevention of PCD, but also in the prevention of sodium retention and therefore in a delay in the reaccumulation of ascites. Additionally, peripheral vasodilatation and activation of renal vasoconstrictive systems have been shown to lead to renal dysfunction and to be of prognostic importance in cirrhosis, specifically, a low mean arterial blood pressure (a measure of peripheral vasodilatation) and increased PRA and angiotensin (a measure of activated renal vasoconstrictive systems) have been shown to be independent predictors of survival in cirrhosis . Therefore, a sustained amelioration in vasodilatation (with consequent reduction in renal vasoconstrictive systems) could potentially lead to a reduction in the rate of renal dysfunction and to an improvement in survival.
Patients randomized to LVP + vasoconstrictors will have a significantly longer time to recurrence of ascites compared to patients randomized to LVP+Albumin
- The development of post-paracentesis circulatory dysfunction or PCD (defined as an increase in PRA by >50% from baseline to a level > 4 ng/mL.h at post-paracentesis day 6) will be comparable in patients randomized to LVP + vasoconstrictors compared to patients randomized to LVP + ALB.
- Recurrence of ascites and development of PCD will be related to changes in the state of peripheral vasodilatation as assessed by measurements of mean arterial pressure (MAP) and forearm blood flow (FBF)
- Patients randomized to LVP + vasoconstrictors will have a significantly longer time to the development of hepatorenal syndrome (HRS) or death compared to those randomized to LVP + Albumin
|United States, Connecticut|
|VA Connecticut Healthcare System|
|West Haven, Connecticut, United States, 06516|
|Principal Investigator:||Guadalupe Garcia-Tsao, MD||Yale University|