Preeclampsia And Nonsteroidal Drugs for Analgesia: a Randomized Non Inferiority Trial (PANDA)

Preeclampsia And Nonsteroidal Drugs for Analgesia (PANDA): a Randomized Non Inferiority Trial

A randomized non-inferiority trial of women with preeclampsia with severe features to determine if the addition of nonsteroidal anti-inflammatory drugs is inferior or non-inferior to standard analgesic bundles in their impact on postpartum hypertension.

Study Overview

• Status: Recruiting
• Conditions: Preeclampsia Postpartum; Preeclampsia Severe
• Intervention / Treatment: Drug: Ibuprofen 600 mg; Drug: Ketorolac; Drug: Acetaminophen; Drug: Oxycodone

Detailed Description

Recently published clinical guidelines for the care of women with hypertensive disorders recommended that nonsteroidal anti-inflammatory drugs (NSAIDs) should be withheld from patients with hypertension that persists for more than one day postpartum (1). This recommendation is based in data from the general medicine literature, which suggests a role of NSAIDs in precipitating hypertension in non-pregnant adults (2,3). It may also draw from previously published case reports of post-partum hypertension that were thought to be NSAID induced (4). There has been a paucity of data from the obstetric literature to support or rebuff this recommendation. As the opioid crisis worsens in the United States, additional attention and resources have focused on limiting the use of narcotic medications. The effective employment of non-opioid analgesics has been shown to reduce narcotic use (5). Ibuprofen and other NSAIDs are the most effective and most commonly prescribed analgesics for postpartum pain, but clinicians now find themselves stuck between these recommendations and their efforts to limit unnecessary opioid prescriptions.

The investigators propose a randomized controlled non-inferiority trial of women with preeclampsia comparing a postpartum analgesic protocol that includes NSAIDs, to one that excludes them. The central hypothesis is that NSAID use does not worsen hypertensive diseases of pregnancy.

• Study Type: Interventional
• Enrollment (Estimated): 286
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jonathan S Hirshberg, MD; Phone Number: 314-362-5000; Email: jhirshberg@wustl.edu
• Study Contact Backup: Name: Tracy Burger; Phone Number: 3147471390; Email: tburger@wustl.edu

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Barnes Jewish Hospital
      • Contact: Jonathan Hirshberg, MD; Phone Number: 314-362-5000; Email: jhirshberg@wustl.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Women at > 23 weeks gestational age undergoing vaginal or cesarean delivery at Barnes-Jewish Hospital with:
• An antepartum diagnosis of preeclampsia with severe features
• Pre-eclampsia with severe features will be defined as:
• Elevated blood pressure ≥ 160/110, or
• Pre-eclampsia in the setting of thrombocytopenia (platelet count < 100,000), or
• Impaired liver function (AST elevated to twice upper limit of normal), or
• Persistent epigastric pain, or
• Renal insufficiency (serum creatinine of 1.1 mg/dl or doubling of prior value), or
• Pulmonary edema, or
• New onset visual disturbance or headache unresponsive to therapy.

Exclusion Criteria:

• NSAID allergy
• Allergy to acetaminophen
• Antihypertensive use in this pregnancy prior to 20 weeks gestation
• Chronic kidney disease or Acute kidney injury with Creatine clearance less than 60 mL/min
• Inability to obtain consent
• Opioid abuse disorder
• Peptic ulcer disease.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NSAID Analgesic bundle; Ibuprofen 600mg PO q 6 hrs as needed for pain, Acetaminophen 1000mg q 8 hrs as needed for pain, and Oxycodone 5 to 10 mg q 4 hrs as needed for pain. In patients undergoing cesarean section, ketorolac 30mg IV q 6 hrs may be substituted as an IV alternative to ibuprofen for the first 24 hours after surgery	Drug: Ibuprofen 600 mg; NSAID pain medication to be used in the experimental bundle for postpartum analgesia; Drug: Ketorolac; NSAID analgesic to be used in the experimental bundle for postpartum analgesia in patients who underwent cesarean section; Drug: Acetaminophen; Analgesic medication to be used in both treatment arms; Drug: Oxycodone; Analgesic medication to be used in both treatment arms
Active Comparator: NSAID free analgesic bundle; Acetaminophen 1000mg q 8 hrs as needed for pain, and Oxycodone 5 to 10 mg q 4 hrs as needed for pain.	Drug: Acetaminophen; Analgesic medication to be used in both treatment arms; Drug: Oxycodone; Analgesic medication to be used in both treatment arms

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
postpartum antihypertensive requirements	measurement of anti-hypertensive requirements at time of discharge	at the end of hospitalization, up to 7 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postpartum pain scores	Evaluate the effect of NSAIDs on patient perception of pain	From randomization to 6 weeks after randomization
Postpartum opioid use	Compare the opioid requirements in each arm	From randomization to 6 weeks after randomization
Mean arterial blood pressure	Compare peak, average and median MAPs postpartum	From randomization to 6 weeks after randomization
End organ damage	Evaluate for evidence of renal, hepatic or neurological injury in the poatpartum period	during hospitalization, an average of 4 days
Hospital readmission	Evaluate the incidence of hospital readmission rate postpartum	From randomization to 6 weeks after randomization
Continued anti-hypertensive requirement	evaluate the need for antihypertensive medications at 6 weeks postpartum	up to 6 weeks

Collaborators and Investigators

• Sponsor: Washington University School of Medicine

Publications and helpful links

General Publications

• Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013 Nov;122(5):1122-1131. doi: 10.1097/01.AOG.0000437382.03963.88. No abstract available.
• Viteri OA, England JA, Alrais MA, Lash KA, Villegas MI, Ashimi Balogun OA, Chauhan SP, Sibai BM. Association of Nonsteroidal Antiinflammatory Drugs and Postpartum Hypertension in Women With Preeclampsia With Severe Features. Obstet Gynecol. 2017 Oct;130(4):830-835. doi: 10.1097/AOG.0000000000002247.
• Lo JO, Mission JF, Caughey AB. Hypertensive disease of pregnancy and maternal mortality. Curr Opin Obstet Gynecol. 2013 Apr;25(2):124-32. doi: 10.1097/GCO.0b013e32835e0ef5.
• Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005 Feb 26-Mar 4;365(9461):785-99. doi: 10.1016/S0140-6736(05)17987-2.
• Mogos MF, Salemi JL, Spooner KK, McFarlin BL, Salihu HH. Hypertensive disorders of pregnancy and postpartum readmission in the United States: national surveillance of the revolving door. J Hypertens. 2018 Mar;36(3):608-618. doi: 10.1097/HJH.0000000000001594.

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2019
• Primary Completion (Estimated): January 31, 2025
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: May 18, 2019
• First Submitted That Met QC Criteria: June 5, 2019
• First Posted (Actual): June 7, 2019

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Ibuprofen; NSAIDs
• Additional Relevant MeSH Terms: Pregnancy Complications; Hypertension, Pregnancy-Induced; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Pre-Eclampsia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antipyretics; Analgesics, Opioid; Narcotics; Ketorolac; Acetaminophen; Ibuprofen; Oxycodone
• Other Study ID Numbers: 201901202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes