UMIN-CTR Clinical Trial

Public title

The acquired von Willebrand syndrome coexisting with cardiovascular diseases Study

Acronym

The AVeC Study

Scientific Title

The acquired von Willebrand syndrome coexisting with cardiovascular diseases Study

Scientific Title:Acronym

The AVeC Study

Region

Japan

Condition

Various circulatory diseases including aortic stenosis, mitral regurgitation, hypertrophic cardiomyopathy, pulmonary hypertension, acute pulmonary embolism, mechanical circulatory support, congenital heart diseases, and small-intestinal bleeding

Classification by specialty

Medicine in general	Gastroenterology	Cardiology
Hematology and clinical oncology	Cardiovascular surgery

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

von Willebrand factors (VWF), produced as huge multimers, are shear stress-dependently cleaved and present as large molecules with molecular weight no more than 20 million dalton. Since larger multimer of VWF has stronger potency for the induction of platelet thrombus, loss of VWF large multimer causes hemorrhagic tendency classified as VWD type II. Recently, bleeding of gastrointestinal tract associated with severe aortic stenosis, called Heydes syndrome, has been found to be caused by the acquired von Willebrand syndreome (aVWS) due to excess cleavage of VWF by high shear stress at the stenotic aortic valve (NEJM, 367, 1954-6, 2012). The clinical feature of the aVWS is similar to that of VWD type II. We evaluated approximately 30 patients with severe aortic stenosis and found that most of patients had aVWS and that 40% of patients exhibited severe or moderate anemia. However, the association between aortic stenosis and gastrointestinal bleeding is not widely known in many clinical settings in Japan. Furthermore, we have found that some of patients with other circulatory diseases possibly associated with high shear stress, such as pulmonary hypertension, (obstructive) hypertrophic cardiomyopathy and acute pulmonary embolism also exhibited aVWS. Then, we have found that patients with severe heart failure treated with mechanical circulatory support such as PCPS and VAD also exhibited aVWS. However, so far, systematic analysis for these pathological/clinical conditions has not been performed, and therefore, the incidence of aVWS and bleeding events in each disease. In this study, we will further expand small studies so far performed and evaluate various circulatory diseases possibly associated with aVWS systematically. Then, we aim to elucidate the clinical features of those diseases associated with aVWS and establish the ways of treatment for each cardiac disease.

Basic objectives2

Safety,Efficacy

Basic objectives -Others

Trial characteristics_1

Exploratory

Trial characteristics_2

Explanatory

Developmental phase

Not applicable

Primary outcomes

This study is a prospective observational study to evaluate and elucidate incidence and clinical condition such as values obtained by laboratory examinations of aVWS and related bleeding events in each target circulatory disease by transverse and longitudinal analyses. Further, patients with small intestinal bleeding will be also enrolled and the contribution of cardiovascular disease-related aVWS would be also evaluated in the same way.

Key secondary outcomes

Elucidation of relationship between aVWS or bleeding events and values of blood examination such as ADAMTS13 activity and multiuser analysis of VWF, in each circulatory disease.
aVWS-related bleeding sites such as gastrointestinal tract in each circulatory disease.
Elucidation of set-up that possibly inducing aVWS under treatment of mechanical circulatory support device

Study type

Observational

Basic design

Randomization

Randomization unit

Blinding

Control

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

Purpose of intervention

Type of intervention

Interventions/Control_1

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

Not applicable

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

This research is consisted following A and B lines.

Research A: When patients undergo bleeding events and surgical therapy during follow-up period, they are evaluated for laboratory examination including VWF multimer analysis several times after the evemts.
1. Aortic stenosis with peak pressure gradients more than 30 mmHg evaluated with Doppler ultrasound cardiography (UCG), 500cases.
2. Mitral regargitation more than II degree at B-mode UCG, 500 cases.
3. Hypertrophic obstractive cardiomyopathy with intraventricular pressure gradient more than 20 mmHg, 200 caases.
4. Pulmonary hypertension (PH) more than 40 mmHg maximal trans-tricuspid valve pressure gradient estimated by Doppler UCG including primary pulmonary hypertension, collagen-disease-related PH, CTEPH, PH caused by congenital heart diseases, 500 cases.
5. Acute pulmonary embolism, 100 cases.
6. Patients with mechanical circulatory support 195 cases (percutaneous cardiopulmonary support 150 cases, extracorponeal left ventricular assist device (VAD) 15 cases, implantable left ventricular VAD)
7. Patients congenital heart diseases with possible high shear stress within bodies including grown-ups and those after surgical repair, 200 cases.

Research B: patients with intestinal bleeding in following (a) and (b ) categories are enrolled, 200 cases:
a: definite small-intestinal bleeding from angiodysplasia evaluated with capsule endoscopy or baloon-type small-intestinal endoscopy
b: suspected small-intestinal bleeding compatible with following categories.
(i) apparent gastrointestinal bleeding. No causative origin observed by upper and lower endoscopic examination. clinically considered small-intestinal bleeding.
(ii) tumor lesion, inflammatory bowel diseases, infectious colitis, and drug-induced colitis are excluded by capsule endoscopy or baloon-type small-intestinal endoscopy

Key exclusion criteria

none

Target sample size

2300

Name of lead principal investigator

1st name	Hisanor
Middle name
Last name	i Horiuchi

Organization

Tohoku University

Division name

Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer

Zip code

980-8575

Address

4-1 Seiryomachi, Sendai, 980-8575, Japan

TEL

+81-22-717-8463

Email

hisanori.horiuchi.e8@tohoku.ac.jp

Name of contact person

1st name	Hisanori
Middle name
Last name	Horiuchi

Organization

Tohoku University

Division name

Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer

Zip code

980-8575

Address

4-1 Seiryomachi, Sendai, 980-8575, Japan

TEL

+81-22-717-8463

Homepage URL

http://www2.idac.tohoku.ac.jp/avec2/

Email

hisanori.horiuchi.e8@tohoku.ac.jp

Institute

The Research Group for the AVec Study
(Main Offiece at IDAC,Tohoku University)

Institute

Department

Personal name

Organization

AMED

Organization

Division

Category of Funding Organization

Japanese Governmental office

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Tohoku University

Address

2-1 Seiryomachi, Sendai, 980-8575, Japan

Tel

022-717-8007

Email

rinri-esct@proj.med.tohoku.ac.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2015

Year

07

Month

01

Day

URL releasing protocol

Publication of results

Unpublished

URL related to results and publications

Number of participants that the trial has enrolled

Results

Results date posted

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Participant flow

Adverse events

Outcome measures

Plan to share IPD

IPD sharing Plan description

Recruitment status

Open public recruiting

Date of protocol fixation

2015

Year

06

Month

20

Day

Date of IRB

2014

Year

10

Month

29

Day

Anticipated trial start date

2015

Year

07

Month

15

Day

Last follow-up date

2023

Year

03

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

It is known that various cardiovascular diseases with high shear stress sometimes cause acquired von Willebrand factor syndrome (aVWS) and bleedings. However, many things such as incidences of aVWS and bleeding events, and risk factors for aVWS and bleedings in each disease remain unclear. In this study, patients with various cardiovascular diseases possibly causing high shear stress are enrolled and the incidence of aVWS and bleedings and their relationship in each disease are evaluated by transverse and longitudinal analyses. The aVWS-associated gastrointestinal bleeding often occurs in small-intestine. In the study, patients with bleeding in the small intestine are also enrolled and evaluated for aVWS and cardovascular diseases. It would uncover the contribution of aVWS in the small-intestinal bleeding.

Registered date

2015

Year

06

Month

30

Day

Last modified on

2021

Year

07

Month

05

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000019166