Which trial established the dose of terlipressin (vasopressin analogue) for variceal bleeding?

Terlipressin Dosing for Variceal Bleeding

The recommended dose of terlipressin for variceal bleeding was established as 2 mg IV every 4 hours for the initial 48 hours until bleeding is controlled, followed by a maintenance dose of 1 mg IV every 4 hours for 2-5 days to prevent rebleeding. 1

Dosing Regimen Details

The standard dosing regimen for terlipressin in acute variceal hemorrhage consists of:

• Initial phase (first 48 hours): 2 mg IV every 4 hours until bleeding is controlled
• Maintenance phase: 1 mg IV every 4 hours for a total duration of 2-5 days 1

This dosing protocol is recommended by the American Association for the Study of Liver Diseases (AASLD) in their 2017 practice guidance on portal hypertensive bleeding in cirrhosis 1.

Recent Developments in Terlipressin Administration

Recent evidence suggests that continuous infusion of terlipressin may be more effective than bolus administration:

• A 2023 randomized controlled trial found that continuous terlipressin infusion at 4 mg/24 hours was more effective than bolus administration (2 mg every 4 hours) in reducing hepatic venous pressure gradient (HVPG) 2
• Continuous infusion achieved:
  • Higher HVPG response at 24 hours (85.4% vs. 58.2%, p=0.002)
  • Lower total daily dose (4.25 mg vs. 7.42 mg, p<0.001)
  • Fewer adverse events (36.3% vs. 56.4%, p=0.03)
  • Lower incidence of very early rebleed (1.8% vs. 14.5%, p=0.03) 2

Comparative Efficacy

• A Cochrane meta-analysis showed that terlipressin is associated with a 34% relative risk reduction in mortality compared to placebo in acute variceal hemorrhage 3
• Terlipressin has similar efficacy to somatostatin and octreotide in controlling variceal bleeding 1
• A 2012 randomized trial found that a shorter 24-hour course of terlipressin was as effective as the standard 72-hour course when used as adjunctive therapy to successful endoscopic variceal band ligation 4

Safety Considerations

• Terlipressin has more adverse events compared to octreotide or somatostatin, including abdominal pain, chest pain, diarrhea, and hyponatremia 1
• Terlipressin is contraindicated in patients with hypoxia, worsening respiratory symptoms, and those with ongoing coronary, peripheral, or mesenteric ischemia 1
• Vasopressin is no longer advised for variceal hemorrhage due to high risk of cardiovascular adverse events 1

Clinical Application

1. Start terlipressin as soon as variceal bleeding is suspected, along with antibiotics and before diagnostic endoscopy 1
2. Administer the initial dose of 2 mg IV every 4 hours for the first 48 hours 1
3. After bleeding is controlled, reduce to maintenance dose of 1 mg IV every 4 hours 1
4. Continue for a total duration of 2-5 days depending on control of bleeding and severity of liver disease 1
5. Consider continuous infusion at 4 mg/24 hours as an alternative administration method with potentially better efficacy and fewer side effects 2

Important Caveats

• Octreotide is the only vasoactive drug available in the United States for variceal bleeding; terlipressin is used primarily outside the US 1
• The FDA label for terlipressin in the US does not include acute variceal hemorrhage as an indication 1
• Only one of the vasoactive agents (terlipressin, octreotide, somatostatin, or vasopressin) should be used at a time 1