PLOS ONE | DOI:10.1371/journal.pone.0168124 January 26, 2017

Clonidine versus captopril for severe postpartum hypertension: a randomized controlled trial 

Carlos Noronha Neto; Sabina B. Maia; Leila Katz; Isabela C. Coutinho; Alex S.R. Souza and Melania M.R. Amorim

Post Graduate Program on Maternal and Child Health, Instituto de Medicina Integral Prof. Fernando Figueira, Recife, Pernambuco, Brazil

To whom correspondence should be addressed: Prof. Melania Maria Ramos Amorim, Rua Neuza Borborema de Souza, 300, 58406-120, Campina Grande, PB, Brazil. Telephone:  55 83 8822-1514. Fax: 55 83 33424525. Email: profmelania.amorim@gmail.com     

Clinical trial registration:  clinicaltrials.gov: www.clinicaltrial.gov, NCT01761916.

 

Abstract

Background 

Changes during the puerperium are still unclear, particularly in women with hypertension. The choice of antihypertensives, both to control very high blood pressure episodes and to keep blood pressure stable, also requires further elucidation. Currently, there are no clear data to guide the decision for the choice of post partum antihypertensives. Captopril plays an important role in the treatment of very high blood pressure episodes and may be used postpartum. Clonidine has been used as an alternative in pregnant or postpartum women with contraindications to captopril, with satisfactory effect. The objective of the present study was to evaluate the effectiveness and safety of clonidine compared to captopril for treating severe postpartum hypertension.

Methods and findings

A randomized, drug-controlled, triple-blind clinical trial evaluating postpartum women receiving captopril or clonidine.  Inclusion criteria consisted of: women with hypertensive disorders of pregnancy systolic blood pressure (SBP) ≥180 mmHg and/or diastolic blood pressure (DBP) ≥110 mmHg], requiring magnesium sulfate.  Exclusion criteria were: heart disease, smoking, illicit drug use, contraindications to captopril, clonidine or oral medication, and having used captopril/clonidine previously.  The primary outcome was the frequency of very high blood pressure episodes while in the obstetric ICU.

A total of 90 postpartum women met the study inclusion criteria, with 45 randomized to each group (Fig. 1).  There were fewer very high blood pressure episodesduring hospitalization (2.1 ± 2.1 vs. 3.5 ± 4.7, p=0.08), greater percentage reduction in SBP (14.0% ± 8.6% vs. 10.8% ± 8.8%, p=0.08) and fewer women requiring sodium nitroprusside (2.3% vs. 13.3%; RR: 0.17; 95%CI: 0.02-1.39; p=0.06) in the clonidine group compared to the captopril group; however, these differences were not significant.  The groups were similar regarding daily mean SBP or DBP (Figs. 2 and 3); however, on the third postpartum day, mean SBP was lower in the clonidine compared to the captopril group (151.9 ± 11.8 mmHg vs. 158.1 ± 13.6 mmHg, p=0.02) (Figs. 2). Although not statistically significant, adverse reactions were more common in the captopril group (28.8%) compared to the clonidine group (18.6%).

Conclusion 

Clonidine and captopril represent safe, effective treatments for severe postpartum hypertension.

Key words:  postpartum; hypertension; antihypertensive agents; clonidine; captopril; randomized controlled trials.

 

Supplement

Based on the present data, blood pressure control was similar in both groups, suggesting that both drugs are effective for the treatment of very high blood pressure episodes in postpartum women with hypertensive disorders of pregnancy. However, mean SBP was lower in the clonidine group on the third day (Fig.  2).  In these patients, the reduction in blood pressure levels could possibly be explained by the resolution of the endothelial lesion and vasospasm following delivery, and also by diuresis of the fluid extravasated to the third space, which would be potentiated by the pharmacokinetics of clonidine and its vascular effect [1].

The need for other antihypertensive drugs was high, and similar (around 80%) in both groups.  Nevertheless, it is debatable whether or not there is any need to maintain treatment in postpartum women with preeclampsia or eclampsia, and a Cochrane systematic review failed to find any evidence supporting the use of medication to control postpartum hypertension [2].

The frequencies of complications were similar in both groups, with the most common complication being the HELLP syndrome. Although the difference between the two groups regarding the need for other antihypertensive drugs was slight, the need for sodium nitroprusside was greater in the captopril group compared to the clonidine group. There were also fewer very high blood pressure episodes per day in this group, although this difference was not statistically significant. It is possible that with larger sample sizes differences may be identified.

In relation to the cost of the drugs, a 30-tablet package of captopril (25 mg) is sold in Brazil for US$50-80 [3], while a 30-tablet package of clonidine hydrochloride (0.1 mg) costs US$13-20 [4].  Taking the daily frequency of peaks and the mean number of hospitalization days in the obstetric ICU into account, the women used approximately 10 clonidine and 14 captopril tablets, resulting in a mean treatment cost of US$4.20 for the clonidine group and US$23.12 for the captopril group. Therefore, clonidine is more cost-effective than captopril.

           This study is important because it investigates another option for the treatment of hypertensive emergency during the postpartum period. It was a well-designed randomized clinical trial and to the best of our knowledge, there are no systematic reviews or clinical trials evaluating these aspects in which oral captopril (25 mg) is compared with oral clonidine (0.1mg) in this specific group of postpartum patients.

The sample size is still small, and maybe a grater sample would be necessary to show more differences in the effect of the two drugs. An analysis of the level of clonidine in breast milk of the patients was also not conducted. It would also have been interesting in conducting a longer observation of the women and evaluating blood pressure levels after discharge from ICU.

External validity is still limited since this was a very selected population of patients, and in a very specific setting and new studies is different hospitals with different populations are still necessary.

We consider that antihypertensive treatment with clonidine may constitute a safe, effective alternative for avoiding postpartum very high blood pressure episodes, with certain advantages such as a lower treatment costs. To define whether this antihypertensive should be adopted in different services and regions, each hospital should take into consideration the characteristics of the population, the frequency of very high blood pressure episodes in postpartum women and the confidence and ease of the medical team with the use of this drug.

Although no studies of this type have yet been conducted with this particular group of postpartum patients, a systematic review including a metaanalysis of future studies should also be carried out to evaluate outcomes such as the duration of postpartum hospital stay, the occurrence of other complications related to very high blood pressure episodes, the behavior and control of blood pressure postpartum and patient satisfaction.

 

 

Fig 1.  Procedures for the selection and follow-up of participants (CONSORT flow chart)

Fig 2. Mean systolic blood pressure according to hospitalization day.

Fig 3. Mean diastolic blood pressure according to hospitalization day.

 

References

  1. Stocche RM, Garcia LV, Klamt JG, Pachione A, Yu HH, Oliveira WA. Comparison between sublingual nifedipine and intravenous clonidine to control perioperative arterial hypertension in cataract procedures. Rev Bras Anestesiol 2002;52(4):426-33.
  2. Sibai BM. Etiology and management of postpartum hypertension-preeclampsia. Am J Obstet Gynecol 2012;206(6):470-5.
  3. http://www.medicamentos.med.br/?act=Search&_id_=182&_ev_=Submit&_formSearchSubmit=%3Adefault%3A&Description=captopril&Global=1&x=0&y=0. Accessed February 12, 2012.
  4. http://www.medicamentos.med.br/?act=Search&_id_=182&_ev_=Submit&_formSearchSubmit=%3Adefault%3A&Description=atensina&Global=1&x=0&y=0. Accessed February 12, 2012.