Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04435210 |
| Other study ID # |
FETHA/REC/VOL1/2017/590 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
August 13, 2018 |
| Est. completion date |
February 20, 2019 |
Study information
| Verified date |
June 2020 |
| Source |
Alex Ekwueme Federal University Teaching Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Introduction - Hypertension is the commonest medical complication of pregnancy. When severe,
it puts the lives of both the mother and the unborn baby at risk. Therefore, immediate
lowering of blood pressure is indicated whenever this is detected. Different
anti-hypertensive drugs are being used to that effect, but more commonly these include:
hydralazine, labetalol and nifedipine. Nifedipine, despite being cheap, readily available,
safe in pregnancy and easy to administer, is hardly utilized for this purpose in our setting.
Hydralazine is usually used instead.
Objectives - This will be: to determine the efficacy of nifedipine and compare it with that
of hydralazine, which is more commonly used, and to compare their maternal and fetal side
effect profile.
Materials and methods - This will be a prospective randomized controlled open label study of
nifedipine versus hydralazine. Patients will be assigned to different arms of the study using
computer-generated random numbers. Efficacy and adverse effects of the drugs will be noted on
each arm of the study. Data will be collated, tabulated and then statistically analysed using
the statistical package for social sciences (SPSS).
Conclusion - The outcome of the study will enable recommendation to be made on the use of
nifedipine for severe hypertension if found to be effective.
Description:
Introduction Hypertension is the commonest medical complication of pregnancy. It is
associated with high maternal and perinatal mortality, especially when severe. Hypertensive
disorders of pregnancy constitute one of the five major causes of maternal morbidity and
mortality in obstetric practice, accounting for approximately 63,000 maternal deaths
worldwide annually. It has been noted to complicate about 6-12% of pregnancies; with
preeclampsia accounting for about half of these cases, while the relatively benign chronic
hypertension and gestational hypertension constitute the rest. Hypertension is defined as
systolic blood pressure equal to or above 140 mmHg and diastolic blood pressure equal to or
above 90 mmHg, measured on two or more occasions, at least four to six hours apart. It is
said to be severe when the systolic blood pressure is equal to or greater than 160 mmHg
and/or the diastolic blood pressure is equal to or greater than 110 mmHg.
Hypertension in pregnancy is most worrisome when it is severe because of the associated
maternal end organ damage, with associated maternal morbidity and mortality, as well as fetal
complications. The end organ damage associated with severe hypertension includes renal
impairment, heart failure, liver damage, pulmonary edema and cerebral injury. Though any of
these complications may eventually lead to patient's demise, the most common cause of death
in patients with severe hypertension is cerebro-vascular accident, resulting from disruption
of cerebral auto-regulatory mechanism and increased perfusion pressure. There is also
increased vascular permeability, leading to hemo-concentration, which predisposes the patient
to cerebral thrombosis as well as the vasospasm associated with convulsion. Other
complications include placenta abruption, preterm delivery and increased risk of cesarean
delivery. In order to reduce the maternal complications associated with severe hypertension
in pregnancy, there is the need for immediate treatment to lower the severely elevated blood
pressure. However, due to the fact that the placenta functions as a low resistance shunt
without auto-regulation, lowering the blood pressure too fast or too far may lead to reduced
utero-placental perfusion, which is detrimental to the fetus. Therefore the reduction in
blood pressure, though prompt, should be controlled, with a target of 140-150 mmHg systolic
and 90-100 mmHg diastolic. The primary purpose of this treatment is not to change the course
of the disease but to prevent cerebral hemorrhage and hypertensive encephalopathy associated
with such severely elevated blood pressure. Thus the initial focus of the treatment is
directed towards the safety of the mother, which is necessary to ensure that of the fetus.
The most commonly used anti-hypertensive drugs for the control of severe hypertension in
pregnancy are nifedipine, labetalol and hydralazine. Nifedipine is a calcium channel blocker
which blocks the L-type calcium channels in both the cardiac and vascular smooth muscle
cells, thereby exerting negative inotropic effects on the heart and causing vascular
dilatation which results in decreased systemic vascular resistance. It is available in tablet
and capsule forms. Labetalol is a non-selective α1, β1, and β2 adrenergic receptors
antagonist. It acts by dilating arterioles, thereby decreasing vascular resistance without
significantly lowering the cardiac output. It may be administered orally (tablet) or
intravenously. Hydralazine also lowers blood pressure by decreasing systemic vascular
resistance through direct dilatation of arterioles. It is administered both intravenously and
orally. These drugs have been compared with each other in different randomized controlled
trials. While it is generally accepted that the three drugs are effective in controlling
severe hypertension, different trials have recommended labetalol, hydralazine or nifedipine
as the first line agent; and the others (as the case may be), as alternatives, depending on
the prevailing circumstances and considerations of the trials.
As a result of the differences in the outcomes of randomized controlled trials on efficacy
and safety of anti-hypertensive use in pregnancy, there is no consensus on which agent is the
safest and most effective. A recent Cochrane review on 'drugs for treatment of very high
blood pressure during pregnancy' concluded that, until better evidence was available, the
choice of anti-hypertensive drugs should depend on the clinician's experience with the
particular drug, on what was known about the side effects, as well as the women's
preferences. Other factors that determine anti-hypertensive choice are availability, cost,
fetal and maternal condition at admission. This leaves the choice of drugs to the physician's
discretion which is very subjective. In Nigeria, there has been no clinical data specifying
the preferred anti-hypertensive agent (among the three earlier stated) in the management of
severe hypertension in pregnancy. Drug use in such circumstances has generally been based on
studies done in America and Europe.
Intravenous hydralazine is the most commonly used anti-hypertensive drug in severe
hypertension because of its long term established safety, efficacy, availability and
cost-effectiveness. However, its administration requires more resources in terms of equipment
(i.e. syringes and needles as well as intravenous cannula) and personnel (administered
usually by doctors or occasionally, nurses) than that of oral agents. Its common side
effects, such as headache, nausea, and vomiting may mimic symptoms of deteriorating
preeclampsia and thereby create confusion during management. Also, maternal hypotension is
common with parenteral hydralazine, which has been shown to be associated with an excess of
caesarean sections, placental abruptions, and low Apgar scores (< 7) at five minutes compared
to labetalol and nifedipine. In view of these limitations of hydralazine, there is a need to
find alternative drugs with equal efficacy in controlling severe hypertension but with fewer
side effects. Nifedipine is cheap, easy to administer, widely available and has less tendency
to cause maternal hypotension resulting in fetal compromise. As a result of these qualities
and the peculiarity of our society in terms of availability of skilled man-power, it is
necessary to know if it is comparable with hydralazine in terms of efficacy and safety, with
the hope of recommending its use in treatment of severe hypertension in pregnancy in Nigeria.
Justification The use of parenteral agents, such as hydralazine for severe hypertension in
pregnancy requires more resources, monitoring and supervision because they are fast-acting;
and as a result they have the potential to lower BP within minutes and cause maternal
hypotension and fetal compromise. Due to the limited manpower and resources in Nigeria, any
agent that is cheap, effective, easy to administer without much expertise and causes the
fewest side effects will be beneficial to patients in such setting. Nifedipine is an
effective rapidly acting anti-hypertensive. It does not crash BP but controls it gradually
over a period of time. Its simplicity stems from the fact that it comes in tablet and capsule
forms, which can be easily administered without elaborate training. These qualities make it
easy to administer in many rural settings which are prevalent in developing countries such as
Nigeria.
The need for this study stems from the fact that further studies have been recommended by the
studies done on this subject which are mainly in Europe and America. Its use for control of
severe hypertension may be important in Nigeria setting, if found effective as hydralazine,
due to the aforementioned challenges.
Research questions
1. Is nifedipine as effective as hydralazine in controlling severe hypertension in
pregnancy?
2. Is nifedipine comparable to hydralazine in sustaining blood pressure control?
3. Is nifedipine comparable to hydralazine in fetal and maternal side effects? Aim of the
study The aim of the study is to compare the efficacy of oral nifedipine with
intravenous (I.V.) hydralazine in controlling severe hypertension in pregnancy.
Objectives of the study
The objectives of this study are as follows:
1. To determine the efficacy of oral nifedipine in the management of severe hypertension in
pregnancy in terms of reduction in BP below 160 mmHg systolic and 110 mmHg diastolic
2. To determine the efficacy of I.V. hydralazine in the management of severe hypertension
in pregnancy in terms of reduction in BP below 160 mmHg systolic and 110 mmHg diastolic
3. To compare the efficacy of oral nifedipine with that of intravenous hydralazine in terms
of reduction of blood pressure below 160 mmHg systolic and 110 mmHg diastolic and
maintaining blood pressure control
4. To compare the risk of maternal hypotension using nifedipine compared with hydralazine
5. To compare neonatal side effects following administration of nifedipine to that of
hydralazine using APGAR scores at 1st and 5th minutes after delivery Materials and
method Study design This will be an open label randomized controlled trial of nifedipine
versus hydralazine in control of severe hypertension in pregnancy at the Federal
Teaching Hospital, Abakaliki, Ebonyi State. Nifedipine 20 mg tablet will be used and
compared with 10 mg intravenous hydralazine. Equivalence study design will be used.
Study background Alex Ekwueme Federal University Teaching Hospital, Abakaliki (AEFUTHA),
where this study will be carried out, is the only tertiary hospital in Ebonyi state, Nigeria.
It is located at the center of Abakaliki, the capital city of Ebonyi state. The state,
located in the South-Eastern part of Nigeria, was created on October 1, 1996 and has 13 local
government areas; with Abakaliki, the state capital as the only urban settlement in the
state. The state has a population of about 2.1 million people, based on the 2006 national
population census.
The department of Obstetrics and Gynecology, AEFUTHA, is one of the clinical departments in
the hospital. It serves as a major referral center for other hospitals in Ebonyi and the
neighboring states of Enugu, Benue and Cross River. There are 52 obstetric bed spaces
including antenatal and postnatal wards. The department has five teams which are sub-divided
into two units each. Each unit is manned by at least two consultants. Resident doctors are
distributed to cover all the units. The department runs antenatal clinics managed by the
consultants and resident doctors, assisted by midwives and other health workers. Antenatal
clients are booked daily on every week day and are assigned consultants according to the
units/teams running antenatal clinic each day. The average antenatal booking is about 4,200
clients per year, while the total antenatal clinic attendance averages 21,000 per year, with
an average annual delivery rate of 2,900. The department has established protocols for
management of specific cases which are in accordance with international best practices, and
are displayed in the labor ward, antenatal ward and the accident and emergency unit of the
hospital. These protocols serve as guides, as patient management is still individualized.
Pregnant women with severe hypertension in pregnancy are usually admitted into any of the
aforementioned wards, depending on the clinical condition at presentation. For patients with
severe preeclampsia, the departmental protocol is to stabilize the patient and deliver
through the most expeditious route following stabilization, while those with chronic
hypertension and gestational hypertension may be allowed for prolongation of gestation so far
the blood pressure is under control; and other clinical and laboratory parameters are
satisfactory. Blood pressure control in severe hypertension is one of the cardinal points in
stabilization; and this is usually done with intravenous hydralazine, or occasionally with
intravenous labetalol. Hydralazine is usually given intravenously as 5-10 mg, diluted in 10
ml of normal saline and given over 10 minutes. Blood pressure is checked every 5 minutes,
with target blood pressure of 140-150 mmHg systolic and 90-100 mmHg diastolic. Excessive
lowering of BP is avoided to prevent fetal compromise. Following this, blood pressure control
is usually maintained with oral medications which include nifedipine and α-methyl dopa, used
singly or in combination, in majority of cases. Labetalol tablets may be added in cases where
blood pressure control becomes difficult. Patients are usually managed in conjunction with
the cardiologists, who may modify the drugs as the need arises.
From the preliminary report of unpublished yearly departmental audit, 175 pregnant women were
admitted and managed for severe hypertension in pregnancy in 2016 out of 2,910 deliveries.
Study population Participants to be included in this study will be patients with severe
hypertension in pregnancy admitted and managed at the Federal Teaching Hospital, Abakaliki
who meet the inclusion criteria and consent to participate in the study.
Sample size determination The minimum sample size will be determined using statistical
formula for equivalence study design N = 2 x {Z1-α/2 + Z1-β}2 x P x (1-P) { δo }
N = number of patients per group Z = the standard normal deviate for a one or two sided
study, usually set at 1.96.
δo = clinically acceptable difference in attainment of target blood pressure will be set at
30% P = treatment response of nifedipine relative to hydralazine in a systematic review = 84%
α = type I error = ≤5% β = type II error =≤ 10% (90% power) N = 2 {1.96 + 1.28}2 x 0.84 x
(1-0.84) { 0.3 } N = 2 (3.24)2 x 0.84 x 0.16 ( 0.3) N = 2 x 10.82 x 0.1344 N = 2 x 116.64 x
0.1344 N = 31.35 ≈ 31 patients per group This will represent the number of patients per
group. Twenty percent of this minimum sample size will be added to correct for any attrition
that may occur in the course of the study. The final sample size on each arm of the study
will now be 37 while the total will be 74.
Patients' selection, drug administration and study procedure Patients' Selection Patients to
be included in the study are those who present with severe hypertension in pregnancy; meet
the inclusion criteria and consent to participate in the study. Detailed history will be
obtained and thorough examination will be carried out on all patients. Relevant
investigations, which include blood group and Rhesus type, complete blood count, liver
function tests, renal function tests, coagulation profile and urine analysis for proteinuria,
will be carried out. The participants will be randomized by means of computer generated
random numbers, by a statistician, using the software Research Randomizer®. Using this
software, thirty-four numbers will be randomly generated from a pool of sixty-eight numbers
(1-74) and these numbers will be assigned to group A (nifedipine) while the remaining
thirty-four numbers will automatically be assigned to group B (hydralazine).
These numbers (1-74) will be inscribed on brown envelopes and a piece of paper with the
inscription 'nifedipine' or 'hydralazine' will be put, with the respective drug accordingly,
inside these envelopes and sealed. All the envelopes will be kept in a locker that will be
made accessible to all the members of the research team. During the counselling session,
patients will be made to know what the drug is meant to do for them and the possible side
effects.
Participants, who meet the inclusion criteria, having understood the study and signed the
informed consent form, will be given sequential study numbers and the corresponding numbered
opaque sealed envelope will then be allocated to the patient. The particular drug contained
in this numbered envelope, corresponding to the patient's study number, will be given to the
patient.
Drug Administration Patients on nifedipine arm (group A) of the study will receive oral
nifedipine 20 mg statim, then 20 mg after 30 minutes if blood pressure still remains equal to
or above 160/110 mmHg. The 20 mg dose will be repeated every 30 minutes until desired BP
(140-150 mmHg/90-100 mmHg) is reached or five doses have been given. The drug will be given
to the patient to swallow in the presence of a nurse. If a patient vomits within 10 minutes
of administration of the drug, the dose will be repeated. In cases where nifedipine fails to
control the B.P., other anti-hypertensive drugs (such as hydralazine or labetalol) will be
administered as may be required.
Those on hydralazine arm (group B) of the study will receive 10 mg of intravenous
hydralazine, diluted 10 ml of water for injection and given over 10 minutes. If B.P. remains
equal to or above 160/110 mmHg 30 minutes after administration of the drug, intravenous
hydralazine 10 mg, diluted with 10 ml of water for injection, will be administered over 10
minutes. This will be repeated every 30 minutes until the desired B.P. (140-150 mmHg/90-100
mmHg) is reached or five doses have been given. In cases where blood pressure remains
uncontrolled, other anti-hypertensive drugs (such as labetalol or nifedipine) will be
administered as may be required.
Blood pressure will be checked every 5 minutes during the period of administration of these
drugs. Intravenous Ringer's lactate or normal saline will be provided at the bedside of the
patients, which will be rapidly infused in case hypotension develops.
Monitoring of Patients Patients will be monitored by measuring the blood pressure with
mercury sphygmomanometers. These sphygmomanometers will be regularly calibrated to ensure
accuracy of blood pressure measurement. Blood pressure will be taken with the patients
sitting down to prevent the effect of the pregnant uterus on blood pressure and ensure
uniformity. Larger cuff will be provided for obese patients to minimize errors. The rate of
deflation of the cuff will be at 2-3 mmHg per second and the sphygmomanometer will be placed
at the level of the heart. The systolic blood pressure will be read at the point where the
first Korotkoff sound is heard with the eyes placed at the same level as the point of
systolic blood pressure; while the diastolic blood pressure will be the point of
disappearance of the Korotkoff sound or where it becomes muffled in cases where the sound
continues till or near the zero mark. The examiner's eyes will be placed at this level to
read the diastolic blood pressure. This is to avoid error due to parallax. Rounding off
figures will be discouraged.
Statistical analysis Data will be collated, tabulated and then statistically analysed using
the statistical package for social sciences (SPSS) (IBM) software (version 22, Chicago USA).
Continuous variables will be presented as mean and standard deviation (mean ±2SD), while
categorical variables will be presented as numbers and percentages. Chi-square test (X2) will
be used for comparison between groups of qualitative variables while normal z-test, odds
ratio and confidence interval at 95% will be used for comparison between groups of
quantitative variables. A difference with a p-value <0.05 will be considered statistically
significant.
Ethical considerations Ethical clearance has been obtained from the Health Research and
Ethics committee of the Hospital. In designing this study, the following ethical issues were
put into consideration.
Informed consent: A signed-written consent will be obtained from each participant before
recruitment into the study. The study objectives, procedure and full implications of
participation will be discussed with the participants before their consent is obtained. The
participants will be made to understand that declining participation in the study will have
no consequences in her obtaining adequate care.
Confidentiality of data: All information, including history, physical examination findings
and results obtained from the participants shall be kept strictly confidential. The
participants will be assured that their identity will be kept in confidence by the
investigator.
Dissemination of results from study The results from this proposed study will be submitted to
the Human Research and Ethics Committee (HREC) - AEFUTHA. A dissertation will be made from
the findings of this study and submitted to the West African College of Surgeons, Faculty of
Obstetrics & Gynecology. Finally it will be published in a reputable international medical
journal.
