Furosemide vs. Placebo for Severe Antepartum Hypertension

NCT ID: NCT04615624

Last Updated: 2024-04-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 65 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-01-04
• Study Completion Date: 2022-04-29

Brief Summary

Primary objective: To determine whether the addition of intravenous furosemide with usual antihypertensives is associated with a reduction in mean systolic blood pressure from baseline compared to treatment with placebo plus usual antihypertensives (intravenous labetalol, intravenous hydralazine, or oral immediate release nifedipine) for the management of severe antepartum hypertension.

Secondary objectives:

To determine whether the addition of intravenous furosemide with usual antihypertensives is associated with a reduction in mean diastolic blood pressure compared to treatment with placebo plus usual antihypertensives listed above.

Detailed Description

Blood pressure is a measure of blood flow and resistance in blood vessels. In normal pregnancy, total blood volume increases while systemic vascular resistance decreases, thereby leading to an overall reduction in blood pressure with return to baseline at term. Hypertensive disorders in pregnancy, including preeclampsia, are a polymorphic syndrome characterized by elevated blood pressures which can affect multiple organ systems. Although the exact mechanism of preeclampsia has yet to be determined, previous studies have shown that there may be two distinct phenotypes - one characterized by vasoconstriction and diminished micro-circulation and the other involving a hyperdynamic high cardiac output state.

Given its potential for both significant maternal and fetal morbidity, hypertensive disorders in pregnancy comprise a substantial proportion of antepartum admissions. Management of acute severe hypertension (systolic blood pressure greater than or equal to 160 or diastolic blood pressure greater than or equal to 110) is important to reduce the risk of stroke, hypertensive encephalopathy, placental abruption, and heart failure or myocardial infarction. In the antepartum and intrapartum period, the use of antihypertensives including labetalol, nifedipine, and hydralazine have been well-described. Despite these options for blood pressure control, preeclampsia can be a progressive disorder that may not respond to the aforementioned agents.

In preeclampsia manifested by high blood volume due to salt and water retention rather than vasoconstriction, standard antihypertensives may be less effective. Furosemide is a commonly used diuretic that can lower blood pressure by inhibiting the absorption of sodium, chloride, and water, thereby decreasing the volume of blood that the heart pumps. The onset of action of action of IV furosemide is 5 minutes, with peak effect at 30 minutes, and duration of action of 2 hours.

Previous studies have demonstrated the safety and efficacy of furosemide to treat preeclampsia in the antepartum and postpartum period as well as its utility in treating heart failure in pregnant women. To our knowledge, no randomized studies exist that investigate the use of furosemide in treating hypertension in the antepartum period. We aim to determine the utility of the addition of furosemide to usual antihypertensives in this clinical setting.

This will be a prospective double-blinded randomized placebo control trial of women with a diagnosis of preeclampsia with severe features at ≥20 weeks of gestation with persistent antepartum hypertension (sustained systolic blood pressure ≥160 or diastolic blood pressure ≥110 mmHg) and a wide pulse pressure (>60 mmHg) who meet all inclusion criteria and have no exclusion criteria. It is routine that laboratory studies are performed on admission for all women with hypertensive disorders. If electrolyte disturbances exist, therapy will not be initiated unless the electrolyte is normalized or repleted.

After informed consent and upon meeting inclusion criteria with severe range hypertension with wide pulse pressure, the study personnel will inform pharmacy personnel who will then randomly assigned the patient to groups by opening the next previously prepared sequential and numbered opaque study envelope. Participants will be randomized to furosemide plus an antihypertensive versus placebo containing normal saline and an antihypertensive. The pharmacy staff will send the assigned treatment, which will be administered by the bedside nurse. The vials containing the treatment will be indistinguishable as both furosemide and normal saline placebo are clear, colorless solutions. Thus, the provider, nurse, and patient will be blinded to the treatment. The choice of antihypertensive will be determined by the primary obstetric provider. At our institution, this will be one or more of the recommended medications for urgent blood pressure control as outlined by the American College of Obstetricians and Gynecologists Practice Bulletin on gestational hypertension and preeclampsia. These include IV labetalol, IV hydralazine, or immediate-release oral nifedipine. As meta-analyses have not shown that one of the aforementioned antihypertensives is superior than another, and all are reasonable options, the choice of antihypertensive will be left up to the obstetric provider. This will also improve the generalizability of the study as it does not interfere with what is typically done in clinical practice.

As a procedure of the study, patients will have their blood pressure recorded at least every 15 minutes up to one hour after administration of the study drug. Thereafter, as part of routine care, patients in both groups will receive similar antepartum surveillance, including blood pressure and pulse assessment every four hours or more frequently if vital signs are abnormal, daily weight measurement, and daily urinary output measurements.

Study Procedures

1. Antepartum patient diagnosed with a hypertensive disorder in pregnancy.

2. Patient approached for study participation and informed consent obtained if interested.

3. Patient develops severe range BP (systolic blood pressure > or = 160 and/or diastolic blood pressure> or =10) with increased pulse pressure (>60mmHg). This will be considered baseline BP.

4. When ordering provider's choice of antihypertensive, pharmacy notified that patient is study participant and randomizes patient by choosing from sequential opaque envelope.

5. a. Patient randomized to treatment arm and receives 40mg /4 milliliters IV furosemide in addition to usual antihypertensive.

b. Patient randomized to placebo and receives 4 milliliters normal saline in addition to usual antihypertensive.

6. Blood pressure check every 15 minutes after administration of furosemide/placebo for four recordings (15, 30, 45, 60 minutes)

Conditions

Pre-Eclampsia; Hypertension in Pregnancy; Pregnancy Complications; Hypertension, Pregnancy-Induced

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Furosemide

When patient meets inclusion criteria and is randomized to treatment drug, she receives 40mg /4 milliliters (mL) IV furosemide in addition to usual antihypertensive.

Group Type: EXPERIMENTAL

Furosemide

Intervention Type: DRUG

Furosemide, a loop diuretic

Placebo

When patient meets inclusion criteria and is randomized to placebo, she receives one dose of 4mL normal saline in addition to usual antihypertensive.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Normal saline

Interventions

Furosemide

Furosemide, a loop diuretic

Intervention Type: DRUG

Placebo

Normal saline

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Subjects 18 years of age or older
• Subjects with intrauterine pregnancy at or beyond 20 weeks of gestation
• Subjects with a diagnosis of hypertensive disorder in pregnancy
• Subjects with persistent (on repeat BP check 15 min apart) severe range blood pressure recordings (systolic BP greater than or equal to 160 or diastolic greater than or equal to BP 110) with wide pulse pressure (>60 mmHg)
• Subject able to provide informed consent

Exclusion Criteria

• Subjects less than 18 years of age
• Subjects with intrauterine pregnancy less than 20 weeks of gestation
• Subjects with known fetal anomaly
• Subjects with hypokalemia (K <3.0 milliequivalent per liter) on admission
• Subjects with anuria (<50 milliliters urine in 24 hours) or renal failure
• Subjects previously taking diuretics or potassium supplements for any reason
• Subjects with a known allergy/adverse reaction to furosemide
• Subjects who are unable to understand and/or sign the informed consent
• Subjects who are in active labor defined as 6 centimeters of cervical dilation or more
• Subjects who have an epidural (neuraxial anesthesia) in place

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Melanie Maykin, MD

OTHER

Sponsor Role: lead

Responsible Party

Melanie Maykin, MD

Sponsor-Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Stacy Tsai, MD

Role: PRINCIPAL_INVESTIGATOR

Maternal-Fetal Medicine Faculty

Locations

Kapiolani Medical Center for Women and Children

Honolulu, Hawaii, United States

Countries

United States

References

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Reference Type: BACKGROUND

PMID: 22179091 (View on PubMed)

Phillips JK, Janowiak M, Badger GJ, Bernstein IM. Evidence for distinct preterm and term phenotypes of preeclampsia. J Matern Fetal Neonatal Med. 2010 Jul;23(7):622-6. doi: 10.3109/14767050903258746.

Reference Type: BACKGROUND

PMID: 20482241 (View on PubMed)

Easterling TR, Benedetti TJ, Schmucker BC, Millard SP. Maternal hemodynamics in normal and preeclamptic pregnancies: a longitudinal study. Obstet Gynecol. 1990 Dec;76(6):1061-9.

Reference Type: BACKGROUND

PMID: 2234714 (View on PubMed)

ACOG Practice Bulletin No. 202: Gestational Hypertension and Preeclampsia. Obstet Gynecol. 2019 Jan;133(1):1. doi: 10.1097/AOG.0000000000003018.

Reference Type: BACKGROUND

PMID: 30575675 (View on PubMed)

https://www.uptodate.com/contents/furosemide-drug information?search=furosemide&source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1

Reference Type: BACKGROUND

Tamas P, Hantosi E, Farkas B, Ifi Z, Betlehem J, Bodis J. Preliminary study of the effects of furosemide on blood pressure during late-onset pre-eclampsia in patients with high cardiac output. Int J Gynaecol Obstet. 2017 Jan;136(1):87-90. doi: 10.1002/ijgo.12019. Epub 2016 Nov 3.

Reference Type: BACKGROUND

PMID: 28099709 (View on PubMed)

Ascarelli MH, Johnson V, McCreary H, Cushman J, May WL, Martin JN Jr. Postpartum preeclampsia management with furosemide: a randomized clinical trial. Obstet Gynecol. 2005 Jan;105(1):29-33. doi: 10.1097/01.AOG.0000148270.53433.66.

Reference Type: BACKGROUND

PMID: 15625138 (View on PubMed)

Duley L, Meher S, Jones L. Drugs for treatment of very high blood pressure during pregnancy. Cochrane Database Syst Rev. 2013 Jul 31;2013(7):CD001449. doi: 10.1002/14651858.CD001449.pub3.

Reference Type: BACKGROUND

PMID: 23900968 (View on PubMed)

Committee on Obstetric Practice. Committee Opinion No. 692: Emergent Therapy for Acute-Onset, Severe Hypertension During Pregnancy and the Postpartum Period. Obstet Gynecol. 2017 Apr;129(4):e90-e95. doi: 10.1097/AOG.0000000000002019.

Reference Type: BACKGROUND

PMID: 28333820 (View on PubMed)

Maykin MM, Mercer E, Saiki KM, Kaneshiro B, Miller CB, Tsai PS. Furosemide to lower antenatal severe hypertension: a randomized placebo-controlled trial. Am J Obstet Gynecol MFM. 2024 Apr;6(4):101348. doi: 10.1016/j.ajogmf.2024.101348. Epub 2024 Mar 12.

Reference Type: DERIVED

PMID: 38485054 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

2020-003

Identifier Type: -

Identifier Source: org_study_id