Early Vascular Adjustments During Hypertensive Pregnancy (EVA)

March 23, 2021 updated by: Maastricht University Medical Center

Personalized Hemodynamically Guided Antihypertensive Treatment in Pregnant Women With Mild to Moderate Hypertension: a Randomized Controlled Trial

Paradoxical fetal and maternal results of studies have led to inconsistent use of antihypertensive drugs or no treatment at all in mild to moderate gestational hypertension in the Netherlands. However, none of the studies have taken the individual maternal circulatory state or the contemplated blood pressure response into account. Hypertension may be accompanied by high (hyperdynamic vasodilated profile), normal (normodynamic profile) of low (hypodynamic vasoconstrictive profile) cardiac output, and preeclampsia is not restricted to one circulatory profile. Therefore antihypertensive drugs should be viewed upon as correctors of the hemodynamic state rather than solely reducers of blood pressure. Without taking the maternal hemodynamic profile and condition into account, generic antihypertensive treatment can be expected to result in disappointing, inadequate and paradoxical results. The investigators hypothesize that in mild to moderate hypertension, personalized hemodynamically guided antihypertensive therapy (with target systolic and diastolic blood pressure <130/80mmHg), prevents the progression to severe hypertension and/or preeclampsia compared to no treatment, without the alleged side-effects.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Anticipated)

368

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 48 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Patients ages 18years or older
  • Before 37 weeks of gestational age;
  • Diagnosed with mild to moderate gestational hypertension

Exclusion Criteria:

  • Women with severe hypertension: systolic blood pressure ≥ 160mmHg and/or diastolic blood pressure ≥ 110mmHg.
  • Women with chronic hypertension who are already on antihypertensive drugs. If no antihypertensive drugs are used yet, women with pre-existent hypertension are eligible to participate.
  • Women diagnosed with preeclampsia or eclampsia in the current pregnancy.
  • Women who are not able to comprehend the study outline.
  • Women who have already participated in this study cannot be included a second time.
  • Women who have a (relative) contra-indication for one of the possible prescribed medications (for example women who have tested positive for antinuclear antibodies, which is a contraindication for Methyldopa).
  • Women who intend to terminate the pregnancy
  • Women who have a fetus with a major anomaly or chromosomal abnormality

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: randomized, interventiongroup
Women with a hyperdynamic vasodilated profile, characterized by a mean arterial pressure (MAP)/ Heart rate (Hr) ratio ≤ 1.1 are prescribed a beta-blocker. Women with a hypodynamic vasoconstrictive profile (MAP/Hr ratio ≥ 1.4) are prescribed nifedipine. Women with normodynamic profile (MAP/Hr ratio in between 1.1 and 1.4) are prescribed Methyldopa.
Drug: Nifedipine
Other Names:
  • Adalat
Drug: Labetalol
Other Names:
  • Trandate
Drug: Methyldopa
Other Names:
  • Aldomet
No Intervention: randomized, control-group
Women who give informed consent for randomization, and are randomized to the control group will not be medicinally treated for mild to moderate gestational hypertension.
No Intervention: not-randomized, control-group
Women who do not want to be randomized, but who give informed consent for follow-up on their data until discharge after delivery. They will receive standard care, i.e. no medication is prescribed for mild to moderate gestational hypertension.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
number of patients with severe gestational hypertension
Time Frame: from date of randomization until the date of this study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
Systolic blood pressure ≥ 160mmHg and/or diastolic blood pressure ≥ 110mmHg, measured at every visit
from date of randomization until the date of this study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
number of patients with preeclampsia
Time Frame: from date of randomization until the date of this study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)

Preeclampsia is defined as the coexistence of de novo hypertension after 20 weeks of gestation and one or more of the following new-onset conditions:

  1. Proteinuria (spot urine protein/creatinine ≥ 30g/mol or ≥ 300mg/day or at least 1 g/L [2+] on dipstick testing).

  2. Other maternal organ dysfunction:

    • Renal insufficiency (creatinine levels ≥ 90μmol/L);
    • Liver involvement (elevated transaminases: ASAT ≥31 U/L and/or ALAT ≥34U/L);
    • Neurological complications (hyperreflexia when accompanied by clonus and/or severe headaches, persistent visual scotomata, altered mental status, eclampsia);
    • Haematological complications (thrombocytopenia, platelet count below 150.000/dL, disseminated intravascular coagulation, haemolysis).
from date of randomization until the date of this study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
the pattern of change of the hemodynamic profile, measured by the ratio of mean arterial pressure and heart rate.
Time Frame: at baseline and each study visit/follow up measurement (at 1 week, 2 weeks, etc. up to 23 weeks after inclusion. The expected average is 8 weeks
hemodynamic profiles will be classified as hyperdynamic, hypodynamic vasocontricted or mixed profile.
at baseline and each study visit/follow up measurement (at 1 week, 2 weeks, etc. up to 23 weeks after inclusion. The expected average is 8 weeks
hemodynamic profile by mean arterial pressure/heart rate ratio
Time Frame: from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
hemodynamic profiles will be classified as hyperdynamic, hypodynamic vasocontricted or mixed profile.
from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
diameter aortic outflow tract and left ventricular outflow tract measured by transthoracic echocardiography
Time Frame: from baseline, and every 4 weeks (maximum 6 times, because in max. 23 weeks end of study is reached)
cardiac output can be derived from these values + heart rate
from baseline, and every 4 weeks (maximum 6 times, because in max. 23 weeks end of study is reached)
left ventricular volume after diastole and systole measured by transthoracic echocardiography
Time Frame: from baseline, and every 4 weeks (maximum 6 times, because in max. 23 weeks end of study is reached)
ejection fraction can be derived from these values
from baseline, and every 4 weeks (maximum 6 times, because in max. 23 weeks end of study is reached)
diameter aortic outflow tract and left ventricular outflow tract measured by transthoracic echocardiography
Time Frame: from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
cardiac output can be derived from these values + heart rate
from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
left ventricular volume after diastole and systole measured by transthoracic echocardiography
Time Frame: from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
ejection fraction can be derived from these values
from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
cardiac remodeling during pregnancy: number of patients with concentric left ventricular remodeling or concentric hypertrophy.
Time Frame: from baseline, and every 4 weeks (maximum 6 times, because in max. 23 weeks end of study is reached)
Echocardiographic concentric left ventricular (LV) remodelling and hypertrophy. Concentric remodeling is defined as a relative wall thickness (RWT) <=0.43 with a Left Ventricular Mass index (LVMi) of <95 gram/m2. Concentric hypertrophy is defined as a RWT <0.43 with a LVMi of ≥95 gram/m2.
from baseline, and every 4 weeks (maximum 6 times, because in max. 23 weeks end of study is reached)
cardiac remodeling during pregnancy: number of patients with concentric left ventricular remodeling or concentric hypertrophy.
Time Frame: from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
Echocardiographic concentric left ventricular (LV) remodelling and hypertrophy. Concentric remodeling is defined as a relative wall thickness (RWT) <=0.43 with a Left Ventricular Mass index (LVMi) of <95 gram/m2. Concentric hypertrophy is defined as a RWT <0.43 with a LVMi of ≥95 gram/m2.
from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
health status of the newborn by Apgar score
Time Frame: assessed immediately after delivery
scored by gynecologist or paediatrician on a scale of 1 to 10
assessed immediately after delivery
prevalence of small for gestational age infancy
Time Frame: assessed at delivery date
birth weight and percentile combined with gestational age at delivery
assessed at delivery date
prevalence of premature neonates
Time Frame: assessed at delivery date
gestational age at delivery
assessed at delivery date
number of a composite of adverse neonatal outcomes
Time Frame: from delivery up neonates will be followed for the duration of the hospital stay, an expected average of 6 weeks
Stillbirth, perinatal mortality, morbidity: chronic lung disease, neonatal sepsis, severe intra-ventricular haemorrhage (IVH) > grade II, periventricular leucomalacia > grade I, and necrotizing enterocolitis. Days on ventilation support, length of admission in neonatal intensive care, and total days in hospital until 3 months corrected age.
from delivery up neonates will be followed for the duration of the hospital stay, an expected average of 6 weeks
maternal well-being questionnaire,
Time Frame: at baseline and each study visit/follow up measurement (at 1 week, 2 weeks, etc. up to 23 weeks after inclusion. The expected average is 8 weeks
Reported medication side effects, and maternal well-being by signs and symptoms during pregnancy
at baseline and each study visit/follow up measurement (at 1 week, 2 weeks, etc. up to 23 weeks after inclusion. The expected average is 8 weeks
number of assessed maternal complications
Time Frame: from a study event participants will be followed for the duration of hospital stay, an expected average of 1 week
Composite of maternal complications including: mortality, stroke, eclampsia, blindness, uncontrolled hypertension, respiratory failure, birth related variables, needed level of care
from a study event participants will be followed for the duration of hospital stay, an expected average of 1 week
gestational age at the moment of progression to primary outcome.
Time Frame: from baseline/inclusion until a study event is reached (up to 18 weeks after inclusion), with an expected average of 4 weeks.
from baseline/inclusion until a study event is reached (up to 18 weeks after inclusion), with an expected average of 4 weeks.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Maastricht University Medical Center

Investigators

  • Principal Investigator: Marc Spaanderman, professor, Maastricht University Medical Centre

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2015

Primary Completion (Anticipated)

February 1, 2023

Study Completion (Anticipated)

April 1, 2023

Study Registration Dates

First Submitted

August 5, 2015

First Submitted That Met QC Criteria

August 21, 2015

First Posted (Estimate)

August 24, 2015

Study Record Updates

Last Update Posted (Actual)

March 24, 2021

Last Update Submitted That Met QC Criteria

March 23, 2021

Last Verified

March 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • METC152017

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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