Clinical trial NCT04615624: Furosemide vs. Placebo for Severe Antepartum Hypertension
Official title: A Randomized Control Trial of Furosemide or Placebo With Usual Antihypertensives in the Antepartum Management of Severe Hypertension With Wide Pulse Pressure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pre-Eclampsia
Hypertension in Pregnancy
Pregnancy Complications
Hypertension, Pregnancy-Induced
Keywords: Severe range blood pressure
Pre-eclampsia
Gestational hypertension
Wide pulse pressure
High-risk pregnancy
Pregnancy complications
Lead sponsor: Hawaii Pacific Health
Sponsor class: OTHER
First posted: 2020-11-04
Enrollment: 65
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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)

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

Primary outcomes:
measure: Mean Systolic Blood Pressure During Hour After Study Drug
timeFrame: 0 minutes to 60 minutes post-dose
Secondary outcomes:
measure: Mean Diastolic Blood Pressure During Hour After Study Drug
timeFrame: 0 minutes to 60 minutes post-dose
measure: Change From Qualifying Systolic Blood Pressure
timeFrame: 0 minutes to 1 hour post-dose
measure: Change From Qualifying Diastolic Blood Pressure
timeFrame: 0 minutes to 1 hour post-dose
measure: Pulse Pressure at 2 Hours After Study Drug.
timeFrame: 2 hours post-dose
measure: Systolic Blood Pressure at 2 Hours After Study Drug
timeFrame: 2 hours post-dose
measure: Diastolic Blood Pressure at 2 Hours After Study Drug
timeFrame: 2 hours post-dose
Other outcomes:
measure: Gestational Age at Delivery
timeFrame: at the time of birth
measure: Time From Admission to Delivery
timeFrame: at the time of delivery
measure: Time From Treatment to Delivery
timeFrame: at the time of delivery
measure: Induction of Labor
timeFrame: at the time of induction of labor
measure: Mode of Delivery
timeFrame: at time of delivery
measure: Eclampsia
timeFrame: at time of hospital discharge
measure: Low Apgar Scores of Neonate (Apgar Score <7 at 5 Min)
timeFrame: at 5 minutes after delivery
measure: Newborns Admitted to Intensive Care Nursery
timeFrame: assessed from time of delivery until discharge since neonates can be admitted to the NICU at any time during this interval if issues arise.
measure: Time to Achieve First Non-severe BP (m)
timeFrame: Assessed from time of severe range blood pressure to time at resolution of severe range blood pressure. Reported at time of resolution of severe range blood pressure.
measure: Number of Participants Who Required Additional Antihypertensive Agents in an Hour After Allocation
timeFrame: Assessed from 0 minutes to 1 hour post-dose, 1-hour post-dose reported
measure: Latency Until Next First-line Antepartum Antihypertensive Agents
timeFrame: 0 minutes to delivery of baby (72 hours post-dose)
measure: Discharged Without Delivery
timeFrame: at time of hospital discharge
measure: Length of Stay
timeFrame: at time of hospital discharge
measure: Birthweight
timeFrame: at time of birth
Locations:
city: Honolulu
country: United States
facility: Kapiolani Medical Center for Women and Children
state: Hawaii
Study officials:
affiliation: Maternal-Fetal Medicine Faculty
name: Stacy Tsai, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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
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citation: 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.
citation: 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.