International Journal of Cardiology 178 (2015) 162–164

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Letter to the Editor

Oral nifedipine versus intravenous labetalol for the treatment of severe hypertension in pregnancy Qingquan Shi a,1, Wenying Leng b,1, Qiang Yao a, Chen Mi a, Aiyun Xing a,⁎ a

Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China Department of Emergency, Chengdu First People’s Hospital, Chengdu, People's Republic of China

b

a r t i c l e

i n f o

Article history: Received 25 September 2014 Accepted 21 October 2014 Available online 22 October 2014 Keywords: Labetalol Nifedipine Pregnancy Meta-analysis

Hypertensive disorders of pregnancy (HDP) are one of the most common medical disorders during pregnancy and play an important role in maternal and perinatal mortality and morbidity [1]. According to reported data, hypertension complicates about 7%–10% of pregnancies worldwide [2]. Definitions of severe pregnancy hypertension according to guidelines are systolic blood pressure (sBP) ≥ 160–170 mm Hg and/or diastolic blood pressure (dBP) ≥ 110 mm Hg [3]. Women with severe hypertension should receive antihypertensive therapy to smoothly and safely lower their pressure. Hydralazine has been used as the standard drug of choice for a long time; in addition, recent guidance [4] also lists hydralazine, nifedipine and labetalol as first-line alternatives for lowering BP during hypertensive emergency in pregnancy. However, a metaanalysis [5] did not support hydralazine use as a first-line drug as it causes severe hypotension and other worrisome maternal and fetal complications. A later Cochrane review [6] concluded that there was no clear evidence that labetalol or nifedipine was more effective than hydralazine. Presently, the decision of drug selection depends on an individual clinician's experience and familiarity with the drug. Moreover, the decision of health care providers is also influenced by convenience, the cost of the drug and what is known about adverse effects. Due to a lack of data, there is still no

⁎ Corresponding author at: Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, 20# Renminnan Road, Chengdu, Sichuan 610041, People's Republic of China. E-mail address: [email protected] (A. Xing). 1 Qingquan Shi and Wenying Leng contributed equally to this work and should be considered as co-first author.

http://dx.doi.org/10.1016/j.ijcard.2014.10.111 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

reliable evidence that one drug is preferable over the others. Currently, there are few trials that have compared nifedipine and labetalol in term of control of severe hypertension during pregnancy. Therefore, their comparative benefits and side effects remain uncertain. Here we performed a meta-analysis to assess the efficacy and safety of oral nifedipine compared with those of intravenous labetalol in pregnant women with severe hypertension. A comprehensive and systematic literature search was carried out for all randomized controlled trials (RCTs) related to oral nifedipine versus intravenous labetalol for severe hypertension in pregnancy/postpartum. The PubMed (from 1974 to September 2014), EMBASE (from 1974 to September 2014), and Cochrane database (up to September 2014) were searched and MeSH terms were used as follows: ‘antihypertensive agents’, ‘labetalol’, ‘nifedipine’, ‘hypertension’ and ‘pregnancy’. We use the following criteria as study selection: (i) the trial was a randomized controlled trial (RCT); (ii) the patients were pregnant or postpartum women who had severe hypertension (defined as sBP ≥ 160 mm Hg and/or dBP ≥ 110 mm Hg) and (iii) the treatment intervention was oral nifedipine versus intravenous labetalol. Exclusion criteria were as follows: (i) the studies were not RCTs; (ii) the patients were nonpregnant women and (iii) the patients were not diagnosed as severe hypertension. Two investigators evaluated all identified trials and assessed the methodological quality separately, and relevant data were also extracted. Any discrepancies were solved by discussions. The primary outcome measures were time interval required to achieve the target blood pressure and number of doses needed for BP control. The secondary outcomes were maternal and neonate adverse events. Statistical analyses were conducted by Review Manager 5.1.0. The Mantel–Haenszel chi-squared (χ2) test and I2 test were used to assess statistical heterogeneity. Risk ratios (RRs) were used to evaluate dichotomous variables and mean differences (MDs) for continuous variables, accompanied by 95% confidence intervals (CIs). A p value b 0.05 was considered statistically significant. Four randomized controlled trials (RCTs) [7–10] including 226 pregnant women and 34 postpartum women within 48 h of delivery were identified. Table 1 shows the characteristics of the included trials. Compared with the intravenous labetalol group, the oral nifedipine group showed significantly lower number of doses (MD = 0.54 dose (95% CI = 0.33–0.75, P b 0.00001)) (Fig. 1A) and less time (MD = 17.08 mins (95% CI = 8.56–25.59, P b 0.0001)) (Fig. 1B) for BP control. Maternal adverse events (AEs) were reported in both groups, but severe AEs such as severe hypotension and placental abruption were not seen.

Q. Shi et al. / International Journal of Cardiology 178 (2015) 162–164

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Table 1 Characteristics of included trials Trial

Design Jadad Participants Populations score Total Oral Intravenous nifedipine labetalol

Outcome measures

Raheem (2012)

RCT

5

50

25

25

Antepartum patients

Shekhar (2013)

RCT

5

60

30

30

Antepartum patients

Vermillion RCT (1999)

5

50

25

25

Lakshmi (2012)

3

100

50

50

Intrapartum and postpartum (within 24 h) patients Intrapartum and postpartum (within 48 h) patients

Time taken to achieve target SBP/DBP; total number of antihypertension doses to achieve target BP; SBP/DBP; maternal heart rate; CTG abnormality; maternal hypotension; AEs; perinatal outcomes Time taken to achieve target SBP/DBP; total number of antihypertension doses to achieve target BP; maternal heart rate; maternal hypotension; AEs; perinatal outcomes Time taken to achieve target SBP/DBP; agent failure; urinary output; AEs

RCT

Total number of antihypertension doses to achieve target BP; time required to reduce the MAP by 25%; additional drugs required, resurgence of hypertensive crisis; AEs

SBP, systolic blood pressure; DBP, diastolic blood pressure; BP, blood pressure; RCT, randomized controlled trial; CTG, cardiotocography; AEs, adverse events; MAP, mean arterial blood pressure.

Fig. 1. (A): Fixed effect model of mean difference (MD) with 95% confidence intervals (CIs) of number of doses to achieve the target BP: oral nifedipine vs. intravenous labetalol; (B) fixed effect model of MD with 95% CIs of time required to achieve the target BP: oral nifedipine vs. intravenous labetalol.

Fig. 2. (A) Fixed effect model of the risk ratios (RRs) with 95% confidence intervals (CIs) of maternal adverse events at the end of treatment: oral nifedipine vs. intravenous labetalol; (B) fixed effect model of the RRs with 95% CIs of the neonate 5-min Apgar score b7: oral nifedipine vs. intravenous labetalol; (C) Fixed effect model of the RRs with 95% CIs of the NICU admission: oral nifedipine vs. intravenous labetalol.

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In the nifedipine group, the most common AEs were headaches, dizziness and palpitations. While in the labetalol group, AEs such as nausea, vomiting, headaches and dizziness were observed. Pooled analysis showed that there were no significant AEs (RR = 1.47 (95% CI = 0.9– 2.41, P = 0.12)) (Fig. 2A) between the nifedipine group and the labetalol group. Also, no statistically significant difference was found for the neonate 5-min Apgar score b7 (RR = 2.07 (95% CI = 0.4– 10.65, P = 0.38)) (Fig. 2B) and neonate intensive care unit (NICU) admission (RR = 1.01 (95% CI = 0.63–1.62, P = 0.97)) (Fig. 2C) between the two groups. Thus, for those pregnant women with severe hypertension who needed acute control of their BP, our pooled analysis showed that oral nifedipine was more effective for safely reducing BP to target levels and with lower number of doses compared with intravenous labetalol. Therefore, oral nifedipine can be an alternative to intravenous labetalol for lowering BP during hypertensive emergencies in pregnancy. Oral nifedipine may also be preferable because of its ease of oral administration, low cost and a flat dosing regimen. Conflict of interest No author declares any conflict of interest. Acknowledgments The authors thank the patients and clinical investigators involved in the trials included in this paper.

References [1] G. Lewis, The confidential enquiry into maternal and child health (CEMACH), Saving mother's lives: reviewing maternal deaths to make motherhood safer — 2003–2005, The Seventh Report on Confidential Enquiries into Maternal Deaths in the United KingdomCEMACH, London, 2007. [2] AR Samadi, RM Mayberry, AA Zaidi, et al., Maternal hypertension and associated pregnancy complications among African-American and other women in the United States, Obstet. Gynecol. 87 (1996) 557–563. [3] Committee on Obstetric Practice, Committee Opinion no. 514: emergent therapy for acute-onset, severe hypertension with severe preeclampsia or eclampsia, Obstet. Gynecol. 118 (2011) 1465–1468. [4] National Collaborating Centre for Women's and Children's Health, Hypertension in pregnancy: the management of hypertensive disorders during pregnancy, RCOG Press, London, 2010. [5] LA Magee, C Cham, EJ Waterman, et al., Hydralazine for treatment of severe hypertension in pregnancy: meta-analysis, BMJ 327 (2003) 955–960. [6] L Duley, S Meher, L Jones, Drugs for treatment of very high blood pressure during pregnancy, Cochrane Database Syst. Rev. 7 (2013) CD001449. [7] ST Vermillion, JA Scardo, RB Newman, et al., A randomized, double-blind trial of oral nifedipine and intravenous labetalol in hypertensive emergencies of pregnancy, Am. J. Obstet. Gynecol. 181 (1999) 858–861. [8] IA Raheem, R Saaid, SZ Omar, et al., Oral nifedipine versus intravenous labetalol for acute blood pressure control in hypertensive emergencies of pregnancy: a randomized trial, BJOG 119 (2012) 78–85. [9] S Shekhar, C Sharma, S Thakur, et al., Oral nifedipine or intravenous labetalol for hypertensive emergency in pregnancy: a randomized controlled trial, Obstet. Gynecol. 122 (2013) 1057–1063. [10] BS Lakshmi, P Dasari, Oral nifedipine versus intravenous labetalol in hypertensive urgencies and emergencies of pregnancy: a randomized clinical trial, Obstet. Med. 5 (2012) 171–175.

Oral nifedipine versus intravenous labetalol for the treatment of severe hypertension in pregnancy.

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