Platelet Reactivity and Treatment With Prostacyclin Analogues in Pulmonary Arterial Hypertension (PAPAYA)

Background: Prostacyclin analogues (epoprostenol, treprostinil and iloprost) induce vasodilation in advanced pulmonary arterial hypertension (PAH) but also inhibit platelets, increasing patients' bleeding risk. The antiplatelet effects of different prostacyclin analogues have never been compared head-to-head. The goal of the PAPAYA (Platelet Reactivity and Treatment With Prostacyclin Analogues in Pulmonary Arterial Hypertension) trial is(i) to compare platelet function (platelet reactivity, extracellular vesicles concentration and thrombus formation) in patients with PAH treated with prostacyclin analogues on top of endothelin receptor antagonists (ERA) and/or phosphodiesterase type 5 inhibitors (PDE5i) and patients treated only with ERA and PDE5i, and (ii) to compare the antiplatelet effect of different prostacyclin analogues.

Venous blood will be collected from patients treated with prostacyclin analogues (study group; n=40) and patients treated with ERA or PDE5i (control group; n=40). Platelet reactivity will be analysed in whole blood by impedance aggregometry using arachidonic acid, adenosine diphosphate and thrombin receptor-activating peptide as agonists. Concentrations of extracellular vesicles from all platelets (CD61+), activated platelets (CD62P+), leukocytes (CD45+) and endothelial cells (CD146+) will be analysed in platelet-depleted plasma using flow cytometry (A-60 Micro). Platelet-rich thrombus formation will be measured using whole blood perfusion system. The study will determine the antiplatelet effect of prostacyclin analogues and compare different prostacyclin analogues head-to-head to identify the best drugs to use in case of thrombosis or bleeding.

Study Overview

• Status: Completed
• Conditions: Pulmonary Hypertension

• Study Type: Observational
• Enrollment (Actual): 80

Contacts and Locations

Study Locations

• Poland
  • Warsaw, Poland
    • Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Education Medical, European Health Centre Otwock

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients were eligible for enrolment if they (i) had PAH diagnosed according to the criteria of European Society of Cardiology and European Respiratory Society, confirmed during right heart catheterization, (ii) were treated with prostacyclin analogues on top of other drugs (study group) or only other drugs (ERA and PDE-5i; control group) for at least 1 month.

Description

Inclusion Criteria:

• Informed consent to participate in the study
• Pulmonary arterial hypertension confirmed with right heart catheterization
• Treatment with prostacyclin analogues (epoprostenol, treprostinil, iloprost) - study group
• Treatment with endothelin receptor antagonists and phosphodiesterase type 5 inhibitors - control group

Exclusion Criteria:

• Known coagulopathy
• Active pathological bleeding
• Known history of bleeding disorder
• Severe thrombocytopenia (platelet count < 50,000/μL )
• Need for antiplatelet therapy with acetylsalicylic acid or P2Y12 antagonists
• Severe chronic renal failure (estimated glomerular filtration rate < 30 mL/min)
• Severe liver insufficiency (Child-Pugh class C)
• Known pregnancy, breast-feeding, or intention to become pregnant during the study period
• Study drug intolerance
• Participation in any previous study with prostacyclin analogues

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Study group; Patients with pulmonary arterial hypertension treated with prostacyclin analogues on top of ERA or PDE-5i.
Control group; Patients with pulmonary arterial hypertension treated with ERA or PDE-5i only.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet reactivity	Difference in platelet reactivity between patients treated with prostacyclin analogues and treated with ERA and/ or PDE5-i, assessed using impedance aggregometry	July 5, 2017 - November 30, 2019

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of extracellular vesicles from platelets, leukocytes and endothelial cells	Differences in concentration of extracellular vesicles from platelets, leukocytes and endothelial cells between patients treated with prostacyclin analogues and treated with ERA and/ or PDE5i, assessed using flow cytometry	July 5, 2017 - November 30, 2019
Platelet-rich thrombus formation parameters	Differences in platelet-rich thrombus formation parameters between patients treated with prostacyclin analogues and treated with ERA and/ or PDE5i, assessed using whole-blood flow-chamber perfusion system	July 5, 2017 - November 30, 2019

Collaborators and Investigators

• Sponsor: Medical University of Warsaw
• Collaborators: European Health Centre Otwock

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2017
• Primary Completion (Actual): November 30, 2019
• Study Completion (Actual): September 23, 2020

Study Registration Dates

• First Submitted: September 30, 2020
• First Submitted That Met QC Criteria: September 30, 2020
• First Posted (Actual): October 8, 2020

Study Record Updates

• Last Update Posted (Actual): October 9, 2020
• Last Update Submitted That Met QC Criteria: October 8, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: platelet reactivity; pulmonary arterial hypertension; extracellular vesicles; prostacyclin analogues; thrombus formation
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Pulmonary Arterial Hypertension; Hypertension, Pulmonary
• Other Study ID Numbers: KB/138/217

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No