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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Preeclampsia Severe, Preeclampsia Postpartum

Intervention / Treatment
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* Drug: Ibuprofen 600 mg
* Drug: Ketorolac
* Drug: Acetaminophen
* Drug: Oxycodone


Participation Criteria
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Eligibility Criteria
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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.
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized non-inferiority clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NSAID Analgesic bundle<br>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<br>* NSAID pain medication to be used in the experimental bundle for postpartum analgesia<br>Drug: Ketorolac<br>* NSAID analgesic to be used in the experimental bundle for postpartum analgesia in patients who underwent cesarean section<br>Drug: Acetaminophen<br>* Analgesic medication to be used in both treatment arms<br>Drug: Oxycodone<br>* Analgesic medication to be used in both treatment arms<br>|
| Active Comparator: NSAID free analgesic bundle<br>Acetaminophen 1000mg q 8 hrs as needed for pain, and Oxycodone 5 to 10 mg q 4 hrs as needed for pain. | Drug: Acetaminophen<br>* Analgesic medication to be used in both treatment arms<br>Drug: Oxycodone<br>* Analgesic medication to be used in both treatment arms<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSAIDs, Ibuprofen