PGE1 as Additive Anticoagulant in ECMO-Therapy (ECMO_PGE1)

A Prospective Randomized, Double Blind Study on Safety and Efficacy of Alprostadil as Additional Anticoagulant in Patients With Veno- Venous Extracorporeal Membrane Oxygenation (ECMO)

Bleeding complications and thromboembolic complications are frequent during extracorporeal membrane oxygenation (ECMO). Retrospective data suggest that platelet inhibition using prostaglandins, in this case PGE1, may reduce thromboembolic complications without increasing the bleeding risk. This randomized, double-blind trial aims to investigate the effects of PGE1 on bleeding risk, thromboembolic complications and the function of the ECMO.

Study Overview

• Status: Terminated
• Conditions: Extracorporeal Membrane Oxygenation; Respiratory Distress Syndrome, Adult
• Intervention / Treatment: Drug: Alprostadil; Drug: 0.9% sodium chloride solution

Detailed Description

Prostaglandins may inhibit platelet activation via the P2Y1 ADP receptor. Platelets may contribute to thromboembolic complications and coagulation activation during ECMO therapy. Retrospective data suggest that treatment with PGE1 may serve beneficial by reducing the amount of heparin needed for inhibition of coagulation activation, and by reducing the thromboembolic risk without increasing the risk of bleeding.

Inhibition of platelets via PGE1 (Alprostadil) may be interesting in this setting, because, in contrast to other platelet inhibitors, it has a very short half-life and platelets remain susceptible for activation by more potent agonists (i.e. thrombin, ADP). Thus, although reducing the contribution of platelets to coagulation activation, it may not affect safety of participating subjects.

This randomized, double-blind, placebo controlled trial will investigate whether treatment of patients with ECMO therapy proves beneficial.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna, Department of Medicine I, Intensive Care Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• minimum age 18 years

  • Veno-Venous- ECMO
  • Minimum of 24h planned ECMO- therapy

Exclusion Criteria:

• • Long- term therapy with other antiplatelet drugs including Acetyl Salicylic Acid

  • known Heparin induced thrombocytopenia
  • Bleeding diathesis = contraindication for heparin (e.g. GI-bleeding, Intracerebral bleeding)
  • Platelets < 50 G/L
  • Thromboplastin time < 50%
  • Pregnancy
  • Patient < 18 years
  • prothrombin time <50%

Drop out criteria:

• Major bleeding (from Type 3 bleeding; see "primary objective")
• Occurrence of HIT (4 T- Score: Number of platelets, development over time, manifestation of thrombosis, other reasons for thrombocytopenia [10])
• Plt < 50 G/l

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Alprostadil; heparin (dose adjusted to aptt 50-60s) + Alprostadil (=PGE1) 5ng/kg/min, continuously, start within 24h of initiation of ECMO therapy and end at the end of ECMO therapy	Drug: Alprostadil; 5ng/kg/min, continuously, start within 24h of initiation of ECMO therapy and end at the end of ECMO therapy
Placebo Comparator: Placebo; heparin (dose adjusted to aptt 50-60s) + 0.9% sodium chloride infusion, continuously, start within 24h of initiation of ECMO therapy and end at the end of ECMO therapy	Drug: 0.9% sodium chloride solution; continuously, start within 24h of initiation of ECMO therapy and end at the end of ECMO therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bleeding rate (quantified by the number of packed red blood cells transfused in relation to the duration of ECMO therapy)	The bleeding rate will be quantified by the number of packed red blood cells in relation to the duration of ECMO therapy. This duration may vary and cannot be predicted. Thus, we will calculate the required number of packed red blood cells i.e. per week.	up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
number of bleeding incidences and severity of bleeding (bleeding grades)	type 0: no bleeding type1: bleeding that is not actionable type 2: any overt actionable sign of hemorrhage type3: a) overt bleeding plut hb drop of 3-5g/dl b) >5g/dl, cardiac tamponade, requiring surgical intervention, bleeding requiring vasoactive agents c)intracranial bleeding, type 5: fatal bleeding number and severity of bleeding relative to the duration of ECMO therapy	up to six months
Number of Clotting Events	clinically noticeable thromboembolic events; cannulized veins (Duplex 24h after canula removal); need of Membrane- changes,, macroscopic thrombus, discoloration; Global clotting tests (prothrombin time, activated partial thromboplastin time, Fibrinogen, D-Dimer) number of Clotting events in relation to the duration of ECMO therapy.	up to six months
Function of the membrane oxygenator	The function of the membrane oxygenator will be assessed on a daily basis as part of clinical routine.This includes the capacity of oxygen transfer and carbon-dioxide (CO2) transfer.	up to six months
Number of changes of the membrane oxygenator relative to the duration of ECMO therapy	Membrane oxygenators need to be changed due to loss of function (cause by clotting etc.).	up to six months
Inflammation specific biomarkers (i.e. C-reactive protein, blood counts, reticulated platelets, etc.)	daily routine measurements and frozen plasma	Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months
Global Coagulation assays		Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months
Thromboelastometry		Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months
platelet function analyzer-100		Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months
Fibrinogen levels		Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months
whole blood aggregometry		Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months
D-Dimer levels		Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months
Catecholamines	need for and dose of catecholamines	Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months
cardiac output		Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months
blood pressure		Time points: Immediately prior to initiation of ECMO, 24, 48 and 72h after initiation of ECMO, then twice a week until end of ECMO therapy, up to 12 months
mortality	by chart review or telephone call	Day 28/90, ICU mortality assessed at the discharge from the Intensive Care unit, this will be up to 12 months after inclusion into the study
number of platelet transfusions, fresh frozen plamsa, coagulation interventions etc.	by chart review, number relative to the duration of ECMO therapy	up to six months
number of platelet transfusions	by chart review, number relative to the duration of ECMO therapy	up to six months
number of coagulation interventions	by chart review, number relative to the duration of ECMO therapy	up to six months

Collaborators and Investigators

• Sponsor: Thomas Staudinger
• Investigators: Principal Investigator: Thomas Staudinger, MD, Medical University of Vienna

Publications and helpful links

General Publications

• Buchtele N, Schorgenhofer C, Schwameis M, Jilma B, Schellongowski P, Herkner H, Riss K, Schmid M, Hermann A, Robak O, Nagler B, Traby L, Bojic A, Staudinger T. Add-On Prostaglandin E1 in Venovenous Extracorporeal Membrane Oxygenation: A Randomized, Double-Blind, Placebo-controlled Pilot Trial. Am J Respir Crit Care Med. 2022 Jul 15;206(2):170-177. doi: 10.1164/rccm.202110-2359OC.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2016
• Primary Completion (Actual): May 1, 2021
• Study Completion (Actual): July 1, 2021

Study Registration Dates

• First Submitted: June 30, 2016
• First Submitted That Met QC Criteria: September 5, 2016
• First Posted (Estimate): September 9, 2016

Study Record Updates

• Last Update Posted (Actual): February 9, 2022
• Last Update Submitted That Met QC Criteria: January 25, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: bleeding; extracorporeal membrane oxygenation; platelet inhibition; thromboembolic; alprostadil
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Vasodilator Agents; Urological Agents; Platelet Aggregation Inhibitors; Alprostadil
• Other Study ID Numbers: ECMO_PGE1_2.1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Data will be published in a peer-reviewed journal, individual data will not be made publicly available except by a direct request to the PI (in an anonymized fashion)