Amlodipine Versus Nifedipine ER for the Management of Postpartum Hypertension: A Randomized Controlled Noninferiority Trial
Phase: PHASE4
Conditions: Hypertension in Pregnancy
Sponsor: Prisma Health-Upstate

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PROTOCOL TITLE: Amlodipine versus nifedipine ER for the management of postpartum 
hypertension: A randomized controlled noninferiority trial  
 
Lead Investigator: 
Katelyn Pratt, MD 
Prisma Health/University of South Carolina Greenville 
Version Date: August 8, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
Table of contents……………...………………………………….………………………………2 
Protocol Synopsis……………………………………………………………………………..….3 
1 
BACKGROUND AND RATIONALE…………………………….………………….5  
2 
STUDY OBJECTIVES………………………………………………………………..7 
3 
INVESTIGATIONAL PLAN…………………………………………………………8 
4 
STUDY PROCEDURES……………………………………………………………...9 
5 
STUDY EVALUATIONS AND MEASUREMENTS………………………………12 
6 
STATISTICAL CONSIDERATIONS……………………………………………….13 
7 
DATA COLLECTION AND MANAGEMENT…………………………………….13 
8 
REFERENECES……………………………………………………………………..13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
Study Title 
Amlodipine versus nifedipine ER for the management of postpartum 
hypertension: A randomized controlled noninferiority trial  
Funder 
 Prisma Health OBGYN Departmental Research Fund 
Study Rationale 
-A significant number of pregnancies are complicated by hypertensive 
disorders (chronic hypertension, gestational hypertension, preeclampsia)  
-Hypertension is often exacerbated in the postpartum period 
 
-Many of these patients require initiation of antihypertensives after 
delivery 
 
-There are a limited number of well-studied treatment options routinely 
used (labetalol and nifedipine ER) 
 
-Prior studies have shown that both labetalol and nifedipine ER are 
effective 
 
-Nifedipine ER has few contraindications, but has significantly more side 
effects than labetalol 
 
-Headache is one of the most commonly reported side effects with 
nifedipine ER 
 
-Headache is also a commonly reported symptom of preeclampsia 
 
-Amlodipine is in the same drug class as nifedipine ER, but does not cause 
headaches 
 
-Amlodipine is a first-line antihypertensive in the non-obstetric population 
 
-Amlodipine has not been studied in the obstetric population 
Study Objectives 
Primary 
 
-To evaluate whether amlodipine is noninferior to nifedipine ER in the 
management of postpartum hypertension 
 
Secondary 
 
-To evaluate whether patients tolerate amlodipine better than nifedipine 
ER  
Study Design 
Unmasked, pragmatic randomized controlled trial  
 
 
 

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Subject Population Inclusion criteria 
 
-English and Spanish-speaking postpartum women with a diagnosis of 
chronic hypertension, gestational hypertension, or preeclampsia 
 
-Delivery at or beyond 20 weeks’ gestation 
 
-Need for antihypertensive therapy, defined as blood pressure >/= 150 
mmHg systolic and/or 100 mmHg diastolic on two occasions four hours 
apart, or one severe blood pressure >160 mmHg systolic and/or 110 
mmHg diastolic. 
 
-Age 18 years or older 
 
Exclusion criteria 
 
-Use of antihypertensives prior to delivery (either for hypertension or 
other indications, i.e. tachycardia) 
 
-Allergy to nifedipine ER or amlodipine 
 
-Persistent tachycardia (as defined by the treatment team) 
Number of Subjects 160 
Study Duration  
Each subject’s participation is expected to last less than 8 weeks 
 
The entire study is expected to last 24 months  
Study phases 
-Screening: Women admitted to Greenville Memorial Hospital Family 
Birthplace will be screened on admission to determine if they have a 
hypertension diagnosis. Additionally, postpartum women on the Women’s 
Specialty unit who do not meet criteria prior to delivery will be rescreened 
once daily. Women with hypertensive diagnoses will be approached about 
their willingness to participate in the study, either at the time of admission 
or at time of diagnosis. 
 
-Randomization: Participants will be randomized to either nifedipine ER 
or amlodipine at the time of enrollment. In order to maximize participant 
capture, all screened patients who have a hypertensive diagnosis and agree 
to study participation will be consented and randomized. Only those who 
progress to needing antihypertensives will meet full inclusion criteria and 
ultimately be enrolled in the study.  
 
-Intervention: Those participants meeting inclusion criteria for 
antihypertensives will be administered the study medication. Participants 
will be administered either amlodipine or nifedipine ER, depending on 
their treatment arm allocation. 

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-Follow-up: Data regarding the patient’s need for additional medications, 
side effects, and length of stay will be collected throughout the 
hospitalization. Patients will attend a blood pressure check visit ideally 3 
to 7 days after hospital discharge (virtual (for patients with home blood 
pressure cuff only) or in-person) and a postpartum visit ideally 4-6 weeks 
after delivery (in person), per standard of care. Additional data will be 
collected at these visits.  
Safety Evaluations While hospitalized, patients will be monitored daily by the clinical team to 
assess for side effects and ensure adequate blood pressure control. 
Adjustments will be made by the clinical team as indicated based on 
patient status. After hospital discharge, patients will be able to call the 
office with any concerns and additional appointments for evaluation can 
be made as necessary.  
Statistical and  
Noninferiority of amlodipine will be assessed with Wilcoxon Rank-Sum                            
Analytic Plan  
 
 
Data and Safety  
Participants will be provided with contact information for the PI should      
Monitoring Plan       they have any concerns.  
 
1     BACKGROUND AND RATIONALE 
Hypertensive disorders of pregnancy are a major cause of maternal morbidity and mortality, and 
it is felt that at least a portion of these adverse outcomes are preventable1. Worldwide, between 2 
and 8 percent of pregnancies are complicated by preeclampsia2. Additionally, 0.9 to 1.5 percent 
of pregnant women have pre-existing chronic hypertension3. Postpartum hypertension can either 
be due to an exacerbation of existing chronic hypertension or preeclampsia, or it can be new 
onset2,4. Blood pressures tend to increase in the postpartum period, peaking at three to six days 
postpartum. It is not uncommon for women who did not require medications during the 
pregnancy to be started on an antihypertensive in the postpartum period3,5. If blood pressures are 
greater than or equal to 150 mmHg systolic and/or 100 mmHg diastolic on two occasions four to 
six hours apart, antihypertensive therapy is recommended4,6,7.  

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The most commonly used antihypertensive medications in the postpartum period are 
labetalol and nifedipine ER. Studies have shown that nifedipine ER is at least as effective, and 
potentially even more effective, than labetalol in achieving blood pressure control4,7. However, 
significantly more patients have side effects when taking nifedipine ER (48% versus 20%), and 
24% of women using nifedipine ER report headache as a side effect7. Headache is a known 
symptom of preeclampsia, and its presence as a symptom can change patient management. When 
patients are using nifedipine ER, it can be difficult to determine if the headache is due to the 
medication or the disease, making management decisions difficult.  
 
Like nifedipine ER, amlodipine is a dihydropyridine calcium channel blocker8. Headache 
is not a commonly reported side effect of amlodipine. Amlodipine is not commonly used in the 
postpartum setting, but a prior study in the non-obstetrical population demonstrated that 
amlodipine and nifedipine ER resulted in comparable reductions in blood pressure and can be 
considered equivalent. Amlodipine was also found to have a significantly lower rate of side 
effects than nifedipine ER (27% versus 41%)9.   
 
Nifedipine ER is considered safe in breastfeeding women. Typically, a relative infant 
dose (RID) less than 10% is considered safe, and nifedipine ER has a RID of 2.3%. There is 
limited data on amlodipine use in breastfeeding women, and therefore the LactMed Database 
currently recommends an alternative to amlodipine if possible. However, one study has shown 
that the median RID for amlodipine is 4.18%, suggesting it is safe to use in breastfeeding 
women. In addition, multiple case reports of breastfeeding mothers using amlodipine did not 
demonstrate any adverse effects in the infant10. Although further data should continue to be 
collected, these prior studies and case reports are reassuring.   

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We hypothesize that amlodipine will be as effective as nifedipine ER in controlling blood 
pressures in patients with postpartum hypertension, as reflected by equivalent times from 
delivery to hospital discharge. In addition, we hypothesize that women taking amlodipine will 
report fewer side effects than those taking nifedipine ER. No effects on breastfeeding outcomes 
are expected.  
1.1 
Description of Intervention 
Amlodipine and nifedipine ER are both dihydropyridine calcium channel blockers. In women 
with hypertensive disorders who meet criteria for initiation of treatment as outlined above, the 
allocated treatment will be initiated by the inpatient clinical team. The recommended starting 
dose for nifedipine ER will be 30 mg daily and the recommended starting dose for amlodipine 
will be 2.5 mg daily. Doses will be adjusted as needed by the clinical team. Patients will be 
treated with additional short-acting antihypertensives, additional long-acting 
antihypertensives or intravenous magnesium for seizure prophylaxis as would otherwise be 
clinically indicated.  
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STUDY OBJECTIVE 
2.1 
Primary Objective 
The primary hypothesis of this study is that amlodipine is noninferior to nifedipine ER in the 
management of postpartum hypertension, as evidenced by length of stay from delivery until 
hospital discharge. A noninferiority limit of 24 hours was selected as a clinically relevant 
difference.  
2.2.     Secondary Objective 
Secondary outcomes include the need for additional antihypertensive medications (either 
increased dose, additional long-acting agents, or additional short-acting agents), patient-

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reported side effects, medication discontinuation due to side effects, hospital readmissions, 
duration of breastfeeding, and breastfeeding continuation and satisfaction.  
3 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
This is an unmasked, pragmatic randomized controlled trial.  
Women randomized to arm 1 will be started on amlodipine 2.5 mg daily. Women randomized 
to arm 2 will be started on nifedipine ER 30 mg daily. Dose adjustments will be made as 
deemed appropriate by the clinical team. Intravenous magnesium, additional long-acting 
antihypertensives, and short-acting antihypertensives will be administered as deemed 
appropriate by the clinical team. Women will be discharged from the hospital when the team 
feels that all discharge criteria have been met. While each provider may use slightly different 
discharge criteria based on their practice patterns, it is agreed upon that no patient will be 
discharged until her blood pressure is < 160/110 mmHg. They will be scheduled for a blood 
pressure check (virtual or in-person) ideally 3 to 7 days after discharge and an in-person visit 
ideally at 4 to 6 weeks postpartum. Participation in the study will not affect usual 
management aside from medication assignment.  
3.2 
Allocation to Treatment Groups and Blinding (if applicable) 
A computer-generated randomization schedule with 1:1 allocation will be utilized. 
Randomization will occur at time of study enrollment utilizing REDCap. Randomization will 
be stratified by chronic hypertension diagnosis status. The research staff will be responsible 
for accessing the centralized randomization system, obtaining patient allocation, and notifying 
the treatment team of patient assignment. 
3.3 
Study Duration, Enrollment, and Number of Subjects 

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Study duration for each participant will last less than 8 weeks (enrollment during initial 
hospitalization through postpartum visit). 160 patients will be enrolled. This is anticipated to 
take approximately 18 months.  
3.4 
Study Population 
English and Spanish-speaking postpartum women, who delivered at or beyond 20 weeks’ 
gestation, with a diagnosis of chronic hypertension, gestational hypertension, or preeclampsia 
requiring initiation of antihypertensives.  
Exclusion criteria: Use of antihypertensives antepartum, allergy to nifedipine or amlodipine, 
persistent tachycardia (as defined by treatment team). 
4 
STUDY PROCEDURES 
4.1 
Screening procedure 
Women will initially be screened for study participation at the time of admission to Greenville 
Memorial Hospital’s Family Birthplace unit. Additionally, women who do not initially meet 
criteria will be rescreened daily for the development of a new hypertension diagnosis. Women 
will be consented for enrollment and randomized at the time of admission or at time of diagnosis 
to ensure maximum trial participation. Not all women who are initially consented will meet 
criteria for final inclusion in the study and initiation of the study drug. Based on review of 
historical data, approximately 50% of patients who meet diagnostic criteria will eventually meet 
criteria for medication administration.  
4.2 
Intervention 
Once a woman meets inclusion criteria for antihypertensives, she will be administered the 
appropriate study drug. Randomization will have already occurred at the time of enrollment so 
that there will not be a delay in patient treatment while awaiting randomization. Randomization 

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will not be blinded. Women in group 1 will be started on amlodipine 2.5 mg daily and women in 
group 2 will be started on nifedipine ER 30 mg daily. Aside from the study drug assignment, the 
remainder of the patient’s postpartum care will be performed according to the clinical team’s 
discretion. Study flow is described in the below figure.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Patient screened for hypertensive 
disorder on admission to Family 
Birthplace Unit
Patient has a hypertension diagnosis, 
approached about study enrollment 
Interested women consented and 
randomized 
Patient meets criteria for 
antihypertensive initiation 
Group 1:  
Amlodipine 
2.5 mg daily 
started 
Group 2:  
Nifedipine ER 
30 mg daily 
started 
Medications adjusted as needed by 
treatment team  
Patient eligible for hospital discharge. 
Side effect questionnaire completed. 
Data from hospital chart abstracted 
Postpartum blood pressure check 
ideally 3-7 days after discharge 
Postpartum visit ideally 4-6 weeks 
after delivery. Breastfeeding 
questionnaire completed 
Patient does not have a hypertension 
diagnosis 
Patient rescreened daily until hospital 
discharge 
Patient meets criteria for 
hypertensive diagnosis, approached 
about study enrollment 

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4.3 
Subject Completion/Withdrawal procedures  
Participants are instructed to inform their enrolling research personnel if they desire to withdraw 
from the study, at which point participation will be terminated.  
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STUDY EVALUATIONS AND MEASUREMENTS 
-Demographic characteristics and clinical data will be abstracted from the medical chart 
 
-Maternal age 
 
-Gestational age at delivery 
 
-Race 
 
-BMI 
 
-Parity 
 
-Mode of delivery 
 
-Hypertensive diagnosis 
 
-History of diabetes (gestational or pre-gestational) 
-Length of stay from delivery until discharge 
-Number of acute antihypertensive treatments 
-Number of dose increases of initial study drug 
-Number of additional long-acting antihypertensives started 
-Magnesium use 
-Side effects reported 
-Medication discontinuation 
-Discharging physician 
-Blood pressure at blood pressure check appointment 
-Blood pressure at postpartum visit 

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-Readmissions from time of discharge until postpartum visit 
-Breastfeeding status at time of postpartum visit 
-Patient-reported length of breastfeeding 
-Patient-reported breastfeeding satisfaction  
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STATISTICAL CONSIDERATION 
6.1 
Sample size calculation 
An initial power calculation was performed using a standard deviation of 55.2 hours and a non-
inferiority limit of 24 hours; to achieve 80% power with a 2-tailed alpha of 0.05, 66 women 
would be needed in each arm. 
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DATA COLLECTION AND MANAGEMENT  
Data will be entered directly from the medical record into the REDCap data management system 
for storage and access for statistical analysis by the primary investigator.  
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REFERENCES  
1. Hypertension in pregnancy: Executive summary. (2013). Obstetrics and 
Gynecology, 122(5), 1122-1131. 
2. ACOG practice bulletin no. 222: Gestational hypertension and preeclampsia. 
(2019). Obstetrics and Gynecology, 133(1), e1-e25. 
doi:10.1097/AOG.0000000000003018 [doi] 
3. American College of Obstetricians and Gynecologists' Committee on Practice 
Bulletins—Obstetrics. (2019). ACOG practice bulletin no. 203: Chronic hypertension in 
pregnancy. Obstetrics and Gynecology, 133(1), e26-e50. 
doi:10.1097/AOG.0000000000003020 [doi] 

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4. Ainuddin, J., Javed, F., & Kazi, S. (2019). Oral labetalol versus oral nifedipine for the 
management of postpartum hypertension a randomized control trial. Pakistan Journal of 
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5. Magee, L., & von Dadelszen, P. (2013). Prevention and treatment of postpartum 
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CD004351. doi:10.1002/14651858.CD004351.pub3 [doi] 
6. Cairns, A. E., Pealing, L., Duffy, J. M. N., Roberts, N., Tucker, K. L., Leeson, P., et al. 
(2017). Postpartum management of hypertensive disorders of pregnancy: A systematic 
review. BMJ Open, 7(11), e018696-2017-018696. doi:10.1136/bmjopen-2017-018696 
[doi] 
7. Sharma, K. J., Greene, N., & Kilpatrick, S. J. (2017). Oral labetalol compared to oral 
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Pregnancy, 36(1), 44-47. doi:10.1080/10641955.2016.1231317 [doi] 
8. Bloch, M. (2020). In Basile J. (Ed.), Major side effects and safety of calcium channel 
blockers. UpToDate. 
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Comparison of early side effects with amlodipine and nifedipine retard in 
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10. Naito, T., Kubono, N., Deguchi, S., Sugihara, M., Itoh, H., Kanayama, N., et al. (2015). 
Amlodipine passage into breast milk in lactating women with pregnancy-induced 
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