The Effects of Discontinuation of Vitamin K Antagonists on the Rate of Elastin Degradation

• Conditions: Aneurysm; Alpha 1-Antitrypsin Deficiency; Emphysema or COPD; Cystic Fibrosis

• Registration Number: NCT03285100
• Lead Sponsor: Canisius-Wilhelmina Hospital

Brief Summary

Background: Elastin is a unique protein providing elasticity, resilience and deformability to dynamic tissues, such as lungs and vasculature. Elastin fibers are characterized by their high affinity for calcium. However, calcified elastin is more prone to the degrading effects of proteases and, in turn, partially degraded elastin has an even higher affinity for calcium. A disturbed balance between proteases and anti-proteases is a major underlying mechanism in the development of chronic obstructive pulmonary disease (COPD). Virtually the only protein that can protect elastin from calcification is matrix Gla-protein (MGP), which needs vitamin K for its activation. In COPD patients, a lower vitamin K status is found when compared to control subjects and an inverse association exists between vitamin K status and elastin degradation. In addition, vitamin K status is lower and elastin degradation is accelerated in Vitamin K antagonist (VKA) users.

VKAs are widely used. Nowadays, an increasing number of patients uses direct oral anticoagulants (DOACs), which do not influence vitamin K status. The hypothesis of this study is that discontinuation of VKAs results in an improved vitamin K status and deceleration of elastin degradation. In order to test this hypothesis, an observational pilot study will be conducted in which the change in elastin degradation- quantified by plasma desmosine concentrations - in patients who discontinue use of VKAs will be used as primary endpoint.

Study design: Observational study. Study population: A total of 30 VKA users who will discontinue the use of VKAs. Elastin degradation rate (quantified by plasma desmosine levels) and vitamin K status (quantified by measuring plasma levels of dephosphorylated uncarboxylated (dp-uc)MGP) will be measured during the use of VKAs and approximately 6 months after discontinuation of VKAs. Furthermore, the VKORC1 polymorphisms will be determined.

Main study parameters: The primary endpoint is the change in the rate of elastin degradation quantified by the plasma desmosine assay. Secondary endpoints are the change in vitamin K status quantified by measuring plasma levels of dp-ucMGP, the relation between desmosine and dp-ucMGP and differences of desmosine and dp-ucMGP levels among subjects with different polymorphisms of the vitamin K 2,3-epoxide reductase complex 1 (VKORC1) gene.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2017-09-13
• Study First Submitted QC: 2017-09-14
• Study First Posted: 2017-09-15
• Study Start: 2017-10-31
• Status Verified: 2018-01
• Last Update Submitted: 2018-01-23
• Last Update Posted: 2018-01-25
• Primary Completion: 2018-10-01
• Study Completion: 2018-10-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• Use of VKAs for at least 3 months
• Stop VKAs at short time
• Written informed consent
• Age ≥18 years
• Ability to comply with all study requirements

Exclusion Criteria

• Active malignancy or cured malignancy <12 months prior to enrollment
• Use of maintenance dose oral corticosteroids
• Serious mental impairment
• Life expectation of less than 6 months on the basis of concurrent disease

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Difference in elastin degradation rate	Plasma desmosine is measured at baseline and 6 months after discontinuation of VKAs	Difference in elastin degradation rate before and after discontinuation of VKAs, quantified by the change in plasma desmosine levels

Secondary Outcome Measures

Name	Time	Method
Association between desmosine and dp-ucMGP	Desmosine and dp-ucMGP are determined before discontinuation of VKAs and 6 months after discontinuation of VKAs	Association between desmosine and dp-ucMGP both in patients who use VKAs and do not use VKAs.
Difference in vitamin K status	Plasma dp-ucMGP is measured at baseline and 6 months after discontinuation of VKAs	Difference in vitamin K status before and after discontinuation of VKAs, quantified by the change in dp-ucMGP, discontinuation of VKAs.
Differences in desmosine and dp-ucMGP levels between different VKORC1 polymorphisms	Desmosine and dp-ucMGP are determined, both before discontinuation of VKAs and 6 months after discontinuation of VKAs. VKORC1 polymorphisms are determined before discontinuation of VKAs.	Levels of dp-ucMGP and desmosine levels of subjects with different VKORC1 polymorphisms are compared, both during the use of VKAs and after discontinuation.

Trial Locations

Locations (1)

Canisius Wilhelmina Hospital; 🇳🇱 Nijmegen, Netherlands