Shekhar, Shashank MD; Sharma, Chanderdeep MD, DNB; Thakur, Sita MD; Verma, Suresh MD
OBJECTIVE: To compare the effectiveness of orally administered nifedipine and intravenously administered labetalol for acute blood pressure control in hypertensive emergency of pregnancy.
METHODS: In this double-blind, randomized, controlled trial, pregnant women with sustained increase in systolic blood pressure of 160 mm Hg or higher or diastolic blood pressure of 110 mm Hg or higher were randomized to receive nifedipine (10 mg tablet orally up to five doses) and intravenous placebo saline injection or intravenous labetalol injection in escalating doses of 20, 40, 80, 80, and 80 mg and a placebo tablet every 20 minutes until the target blood pressure of 150 mm Hg systolic and 100 mm Hg diastolic, or lower, was achieved. Crossover treatment was administered if the initial treatment failed. The primary endpoint of the study was time necessary to achieve target blood pressure. Secondary endpoints were number of dosages required, adverse maternal and neonatal effects, side effect profile, and perinatal outcome.
RESULTS: From October 2012 to April 2013, we enrolled 60 patients. The median time taken to achieve target blood pressure was 40 minutes (interquartile range, 20–60 minutes) compared with 60 minutes (interquartile range 40–85 minutes) for nifedipine and labetalol, respectively (P=.008). The median dose required was two (interquartile range 1–3) compared with three (interquartile range 2–4.25) for nifedipine and labetalol, respectively (P=.008). No serious adverse maternal or perinatal side effects were witnessed in either group.
CONCLUSION: As administered in this trial, oral nifedipine lowered blood pressure more quickly than did intravenous labetalol during hypertensive emergency in pregnancy.
CLINICAL TRIAL REGISTRATION: Clinical Trials Registry—India, www.ctri.nic.in, CTRI/2013/02/003350.
LEVEL OF EVIDENCE: I
Hypertension is one of the most common medical disorders during pregnancy. Various drugs have been used for acute blood pressure (BP) control during hypertensive emergencies in pregnancy. Hydralazine had been the drug of choice for a long time; however, a meta-analysis of clinical trials reported worrisome maternal and fetal side effects with its use.1 Despite the listing of hydralazine as a first-line alternative with two other drugs for acute lowering of BP during hypertensive emergency in pregnancy by a Cochrane review,2 the confidence in hydralazine has dwindled. Moreover, because of manufacturing shortages, hydralazine is unavailable in many parts of the world.3 This decline of hydralazine has led to the emergence of labetalol and nifedipine for control of BP in hypertensive emergency during pregnancy. Currently, all three drugs have been proposed as first-line alternatives to one another.2 The decision to select one drug rests with health care providers, and their choice reflects experience and convenience of using the drug, local availability, and cost. This lack of proof of the superiority of one drug over the others reflects insufficient evidence because of lack of data.1 There are a number of trials comparing hydralazine with either nifedipine or labetalol, but there are few trials comparing nifedipine and labetalol for control of severe hypertension during pregnancy. The American College of Obstetricians and Gynecologists Committee Opinion on emergency therapy of hypertensive emergency during pregnancy does not list nifedipine as an alternative, citing lack of literature for its use with this clinical condition.4 We performed a PubMed database search for trials comparing labetalol and nifedipine for lowering BP during hypertensive emergencies in pregnancy published in the English literature between 1990 and 2013, using key words “severe hypertension,” “pregnancy,” “nifedipine,” and “labetalol.” We found only two randomized controlled trials that compared oral nifedipine and intravenous labetalol for lowering of BP during hypertensive emergency in pregnancy.
Our search results make a strong case for research on this topic. After all, hypertensive disorders of pregnancy are common, affecting 7–10% of pregnancies worldwide.5 Thus, every year, thousands of pregnant women all over the world require antihypertensive drugs for lowering the acute increase in BP. Even if the advantages of one drug over the other are quite modest, a large number of women and neonates might benefit if the drug found to be superior is used more extensively.
MATERIALS AND METHODS
We conducted a randomized, double-blind, controlled trial for acute lowering of BP during hypertensive emergencies of pregnancy. The trial was conducted in the labor ward of the Department of Obstetrics and Gynecology of Dr. Rajendra Prasad Government Medical College and Hospital, Tanda Kangra, India, which is a tertiary care teaching and referral hospital. The recruitment took place from October 2012 to April 2013 after obtaining approval from the Dr. Rajendra Prasad Government Medical College and Hospital institutional ethics committee. The trial was also registered on the trial registry of India (vide number CTRI/2013/02/003350).
All pregnant women with sustained severe hypertension (defined as systolic BP 160 mm Hg or higher or diastolic BP 110 mm Hg or higher on two separate occasions, at least 30 minutes apart) were approached for enrollment. Women were eligible for inclusion if they were between 18 years and 45 years of age, were at 24 weeks of gestation or more, their heart rate was between 60 beats or more and fewer than 120 beats per minute, and they had a reassuring fetal heart rate. Exclusion criteria were a known atrial-ventricular heart block or history of heart failure, moderate-to-severe bronchial asthma allergy to either study drug, exposure to any antihypertensive medication within the past 24 hours, and nonpregnancy-related hypertension (diagnosed cases of chronic or secondary hypertension).
Written informed consent was obtained from participating women. The randomization sequence was computer-generated in blocks of four or eight. The study medications were placed in sequentially numbered sealed envelopes. Each envelope contained two packages, one labeled A and one labeled B. Package A contained either intravenous labetalol vials (total 60 mL as labetalol 5 mg/mL) and five placebo tablets or intravenous saline placebo (60 mL as 0.9%) and five 10-mg nifedipine tablets. Package B contained the opposite regimen if treatment crossover was required. These envelopes were opened by an investigator, and package A was administered to the participant first.
Oral nifedipine and placebo tablets were identical in appearance. Each tablet contained 10 mg nifedipine or inactive placebo. Colorless intravenous study solution (labetalol or placebo) was placed into three 20 mL syringes (total 60 mL) by the investigator and labeled as A, and was then given to the care provider for intravenous administration, along with five tablets (nifedipine or placebo) from package A. Intravenous study solution was administered through an intravenous line that was secured as soon as the women were enrolled in the trial.
In case of crossover to regimen B, the contents of the package B were then prepared in a similar manner as described for regimen A, and the syringes were labeled as B. Thus, the provider and the participant were blinded regarding the treatment administered.
Women rested in bed in the semi-recumbent position. The providers were instructed to administer one tablet to be swallowed from package A and to administer 4 mL intravenously from syringe A as the initial treatment. After 20 minutes, if the systolic BP was higher than 150 mm Hg or if the diastolic BP was higher than 100 mm Hg, then the second tablet was administered and 8 mL intravenous solution from syringe A was administered. If the target BP was not achieved even after another 20 minutes, the third tablet was administered, along with intravenous administration of 16 mL solution from syringe A. This was repeated for another two cycles of treatment if required to lower BP to the target range. Crossover to regimen B occurred if target BP was not achieved after five cycles of regimen A. Regimen B was administered in a fashion identical to that of regimen A. If the target BP was still not achieved, open-label treatment was performed according to the preference of the provider.
The BP was measured with mercury sphygmomanometer as per standard recommendations, using Korotkoff sound five for diastolic BP. The BP was measured every 20 minutes for at least 100 minutes or more until the target BP of 150 mm Hg systolic and 100 mm Hg diastolic or lower was achieved. Once the target BP was achieved, no further trial medication was administered.
During the course of treatment, continuous electronic fetal heart monitoring was performed. In the event of nonreassuring fetal or maternal status, the trial protocol was abandoned and appropriate measures like open antihypertensive treatment or expedited delivery were instituted. If clinically significant maternal hypotension occurred, the trial was suspended and appropriate measures were suggested for the provider's consideration. After completion of the trial protocol, women were requested to complete a questionnaire regarding occurrence of side effects during the trial period.
After successfully lowering the BP to target range, further antihypertensive therapy was started 2 hours after the last trial medication as per discretion of the provider. Delivery of the newborn as definite treatment for severe pregnancy-induced hypertension was performed as per the standard practice. The primary outcome measured was the time needed to achieve target systolic BP of 150 mm of Hg or lower and diastolic BP of 100 mm of Hg or lower (both targets had to be fulfilled). Secondary outcome included total number of antihypertensive dosages required to achieve the target systolic BP of 150 mm of Hg or lower and diastolic BP of 100 mm of Hg or lower, maternal heart rate profile during the first 100 minutes, maternal hypotension (BP less than 90/60 mm Hg), side effects profile, and perinatal outcome.
Sample size calculations were based on a previous study by Vermillion et al,6 whose results revealed that women administered oral nifedipine achieved the target BP in 25.0±13.6 minutes (mean±standard deviation [SD]) as compared with 43.6±25.4 minutes (mean±SD) in women receiving labetalol. Using these results as guidance data, with an alpha value of 0.05 and 90% power, we required 21 participants in each group. Allowing for attrition and possible skewed distributions that might require nonparametric testing, we planned to randomize a total of 60 women (30 in each group).
Data were entered into SPSS 17. Analysis was based on intention-to-treat. One-sample Kolmogorov–Smirnov test was used to check normal distribution of continuous data. Student t test was used to analyze normally distributed data and ordinal data were analyzed by Mann–Whitney U test. Categorical 2×2 data sets were analyzed with Fisher exact test. Repeated measure analysis of the variants was applied to the repeated measurements of BP and heart rate. All tests were two-sided and P<.05 was considered significant. Participants were analyzed on an intention-to-treat basis.
Figure 1 shows the Consolidated Standards of Reporting Trials flow chart of the participants after enrollment. Sixty women were enrolled into the study, and 30 each were randomized to receive either intravenous labetalol or oral nifedipine. As shown in the Table 1, two groups were similar with respect to maternal age, gravidity, period of gestation, incidence of preeclampsia, use of antenatal steroids, and the use of prophylactic magnesium sulfate. The initial mean systolic BP and diastolic BP were lower in the nifedipine group, although the difference was not statistically significant. A high systolic BP or diastolic BP alone or both high systolic and diastolic BP were also comparable among two groups.
All women were started on their allocated treatment. However, one woman in the nifedipine group had development of tachycardia after receiving a single dose of nifedipine. The trial protocol was abandoned and the target BP was achieved with 20 mg intravenous labetalol. The median time needed to achieve the target BP in women receiving nifedipine was 40 minutes (interquartile range 20–60 minutes) as compared with the median time of 60 minutes (interquartile range 40–85 minutes) for those receiving intravenous labetalol, as shown in Table 2. Importantly, the rapidity with which nifedipine achieved the target BP as compared with labetalol was also statistically significantly quicker (P=.008). The nifedipine group required significantly fewer doses to achieve the target BP (median dose, 2; interquartile range 1–3) as compared with the labetalol group (median dose, 3; interquartile range 2–4.25; P=.008). Failure to achieve target BP occurred in five women (16.6%) randomized to labetalol compared with one woman in the nifedipine group (3.3%). After crossover to nifedipine, target BP was achieved with a maximum of two doses of nifedipine in all five women. The group-wise (nifedipine and labetalol) systolic BP and diastolic BP profiles for the first 100 minutes at 20-minute interval are shown in Figure 2. Repeated measures analysis of variance of BP for the first 100 minutes indicated that both systolic BP and diastolic BP decreased significantly over time in both groups (Fig. 2). However, the between-patient comparison of the nifedipine and labetalol groups showed that both systolic BP and diastolic BP decreased significantly more rapidly in the nifedipine group (P=.03 and P=.001, respectively). Figure 3 is the graphical depiction of the cumulative percentage of patients in both groups over time who achieved target BP.
The mean maternal heart rate at the beginning of treatment was 88±9.3 (SD) in the labetalol group and was 87±4.9 in the nifedipine group. Corresponding values at the end of treatment were 86±6.1 (SD) and 97±10.3 (SD) in the labetalol group and nifedipine group, respectively. Repeated measure analysis of variance of maternal heart rate for the first 100 minutes revealed a significant increase over time in the nifedipine group (P<.001). However, the decline in maternal heart rate was not significant in the labetalol group during the first 100 minutes (P=.12).
Maternal and neonatal outcomes in both groups were similar, as shown in Table 2. There was no maternal hypotension during the trial period in either group.
There were two neonatal deaths in the labetalol group (P=.34) attributable to complications of extreme prematurity. They were born to two young primigravid women with severe preeclampsia at 27 weeks of gestation and 28 weeks of gestation. Both participants received antepartum corticosteroids after initial stabilization of severely high BP. Labor induction was performed after 48 hours of a course of corticosteroids. Both neonates were born by normal vaginal delivery and weighed 850 g and 920 g. The neonates had development of respiratory distress syndrome and died on day 2 and day 3 of life.
In this placebo-controlled, double-blinded, randomized, clinical trial, pregnant women allocated to oral nifedipine achieved target BP significantly more rapidly and with fewer doses as compared with those receiving intravenous labetalol. Our findings of nifedipine being more efficacious than labetalol are in keeping with the findings of Vermillion et al.6 However, Raheem et al7 found both nifedipine and labetalol to be equally efficacious. In the study by Vermillion et al,6 mean times needed to achieve target BP were 25 minutes and 43.6 minutes for the nifedipine group and the labetalol group, respectively, compared with median times of 40 minutes and 60 minutes, respectively, in our study. The longer time needed to achieve target BP in the present study might be attributable to a flat dose of nifedipine (10 mg) used in our trial. Moreover, we had a lower BP (systolic) target in our trial. In the study by Raheem et al,7 median times needed to achieve target BP were 30 minutes and 45 minutes in the nifedipine group and the labetalol group, respectively (P=not significant). The shorter time needed to achieve target BP in comparison with that of the present study may be explained by the frequent dosing interval of 15 minutes used in their study compared with 20 minutes in the present study.
Vermillion et al6 reported 100% success rate in achieving the target BP with both drugs, whereas Raheem et al7 reported 20% failure rate with both drugs and requiring crossover treatment. In the present study, nifedipine was more successful (one failure) in achieving the target BP in comparison with the labetalol group (five failures), requiring crossover treatment with nifedipine. Concerns have been raised about the safety of nifedipine in obstetric patients, such as possibility of overshoot hypotension with short-acting nifedipine with its maternal and fetal consequences and synergistic action with magnesium sulfate (often used simultaneously in severe preeclampsia) leading to profound neuromuscular blockade. All these concerns about the safety of nifedipine during pregnancy have been disproven by a number of trials evaluating nifedipine as an antihypertensive agent8–10 or as a tocolytic agent.11–15 There was no symptomatic hypotension or recordable overshoot hypotension in the present study. Reassuring evidence regarding the safety of contemporaneous use of nifedipine and magnesium sulfate is echoed in a retrospective review by Magee et al.16 The authors compared 162 women who received both nifedipine and magnesium sulfate with 215 women who received magnesium sulfate without calcium channel antagonists. Their findings suggest that contemporaneous use of magnesium sulfate and nifedipine does not increase the risk of neuromuscular blockade and maternal hypotension. Doubts have also been raised regarding the possible prolongation of labor or uterine atonia after delivery because of the tocolytic properties of nifedipine. These doubts remain theoretical only, because there are no data in the literature to suggest this.17 In our study, a majority of the participants required only two to three doses (30 mg) of nifedipine to achieve target BP; therefore, they were exposed to only smaller concentrations of the drug than when used for tocolysis.
The study may be questioned for using labetalol at 20-minute intervals instead of 15-minute intervals, as recommended by a few studies.18–20 We chose a 20-minute interval to keep the dosing interval the same for both drugs. Further, many other authors recommend 20-minute dosing frequency for oral nifedipine.17,21 In our study, the side effect profiles of both the drugs were similar, and this is consistent with the observations of Vermillion et al6 and Raheem et al.7 We did not witness any serious adverse maternal or neonatal effects attributable to either of the study medications per se. Minor side effects were infrequent and comparable among both the groups. However, none of these studies (including ours) is sufficiently powered to evaluate the safety profile of these drugs conclusively.
Our finding that nifedipine is more efficacious is at variance with the results of a previously conducted trial (with similar design) that found both drugs to be equally efficacious.7 Although we have tried to analyze almost all the possible factors, it would be prudent to say that more analyses and a larger sample are required to derive the definite conclusion regarding difference in the effectiveness of nifedipine as compared with labetalol and to assess whether this difference is clinically significant. Nevertheless, these results do establish nifedipine as an alternative to labetalol for lowering BP during hypertensive emergencies in pregnancy. In summary, nifedipine may be preferred because of a flat dosing regimen, ease of oral administration, wide availability, and low cost.
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© 2013 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.