Download Review: labetalol for the treatment of hypertension

Review:
labetalol for the treatment of hypertension in pregnancy
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Objectives:
The objective of this evidence summary is to inform and advise a discussion on the
inclusion of labetalol in the Essential Medicines List as an additional option for
hypertension in pregnancy, and determine if atenolol is a suitable replacement for
labetalol.
Background:
Pregnancy induced hypertension complicates about 10% of pregnancies; preeclampsia affects 2-8% of pregnancies; the incidence of eclampsia greatly varies
between settings, being higher in developing countries where it affects between
1/100 and 1/1700 deliveries, whilst in industrialized countries it affects about 1/2000
deliveries. Pre-eclampsia and eclampsia increase maternal and perinatal morbidity
and mortality. Perinatal mortality is also higher in women with severe essential
hypertension (1).
Antihypertensive drug groups represented in the WHO Model Formulary 2004
include beta-blocker (atenolol), ACE inhibitors (enalapril), vasodilators (hydralazine
and nitroprusside), thiazide diuretics (hydrochlorothiazide), centrally acting
antihypertensive drugs (methyldopa) and calcium channel blockers (nifedipine);
some of these drugs are contraindicated in pregnancy. The WHO Model Formulary
2004 recommends magnesium sulfate for eclampsia and severe pre-eclampsia and
highlights methyldopa as the safest antihypertensive in pregnancy (p 238). It
discourages the use of ACE inhibitors and cautions against prescribing beta
blockers in early pregnancy because of potential adverse effects to the baby, but
stays short of making specific recommendations. WHO has issued guidelines
recommending the use of hydralazine, nifedipine and labetalol (2) –the later not
included in WHO Model Formulary 2004.
Evidence summary:
A regularly updated overview of the evidence on treatments for pre-eclampsia and
hypertension in pregnancy (most recent update search December 2003) found a
paucity of evidence on clinical effects of antihypertensive treatments in pregnancy;
most studies focused on blood pressure reduction. Throughout, adverse effects of
antihypertensive treatments in pregnancy remain poorly reported and studied in
babies and women alike. (1)
The overview assessed the effects of antihypertensive drugs in women with: severe
pre-eclampsia and very high blood pressure; mild-moderate hypertension developed
in pregnancy; high risk for pre-eclampsia and being offered prophylaxis with
antihypertensives. (1)
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In women with severe pre-eclampsia or very high blood pressure: the overview
found one Cochrane review (search date 2002, 20 RCTs, 1637 women)(3) and one
subsequent RCT (126 women). The overview found that all antihypertensives
reduced blood pressure but studies were small and it was impossible to establish if a
particular drug was overall better than others. Hydralazine was better than
ketanserin at reducing persistent hypertension. Labetalol produced significantly less
hypotension requiring treatment -a harmful effect that may compromise fetoplacental
blood flow, than diazoxide (1 RCT, 0/45 with labetalol v 8/45 [18%] with diazoxide;
RR 0.06, 95% CI 0 to 0.99).(3) Adverse effects were poorly reported and the
indication to treat women with severe hypertension is based on experts’ consensus.
(1)
In women who develop mild-moderate hypertension during pregnancy: The
overview found two Cochrane reviews(4; 5) and two small subsequent RCTs which
didn’t assess the effects of beta blockers. (6; 7) The first systematic review found that
overall, antihypertensive drugs halved the risk of developing severe hypertension,
compared with no antihypertensive drugs (17 RCTs; 103/1113 v 196/1042; RR 0.52,
95% CI 0.41 to 0. 64).(4) The review included a subgroup analysis for beta blockers,
which has been eclipsed by the second Cochrane Review that focuses on the
effects of beta blockers and is more up-to-date.(5) The second Cochrane review
found that beta blockers significantly reduced severe maternal hypertension and
neonatal respiratory distress syndrome. Overall, it found no significant differences
between beta blockers and placebo or no treatment in the incidence of preeclampsia, perinatal mortality, or the need to change drug treatment due to adverse
maternal effects. Compared with placebo or no treatment, beta blockers increased
the risk of newborns being small-for-gestational-age, but no significant differences
were found in the incidence of caesarean sections, perinatal mortality, preterm
delivery or admission of infants to special care (Table 1).(5)
Table 1. Meta-analysis data comparing beta blockers versus placebo or no treatment in
women who develop mild-moderate hypertension in pregnancy(5)
Outcome
RCTs
AR [%]
Beta blocker
Severe hypertension
11
36/565 [6%]
Proteinuria/Pre-eclampsia
11
102/666 [15%]
Respiratory
syndrome
4
6/283 [2%]
Small for gestational age
12
99/676 [15%]
Drugs stopped/changed
due to maternal side
effect
9
14/534 [3%]
distress
AR [%]
Control
99/563
[18%]
123/674
[18%]
22/284
[8%]
68/670
[10%]
7/525 [1%]
10/710
[1%]
88/477
Preterm birth
8
91/485 [19%]
[18%]
Admission to special care
90/309
4
82/291 [28%]
baby unit
[29%]
(NS) non significant statistical differences at 95% confidence interval
Perinatal mortality
13
10/719 [1%]
RR
95% CI
0.37
0.26 to 0.53
0.86
0.68 to 1.08
0.29
0.12 to 0.67
1.36
1.02 to 1.82
1.72
0.79
(NS)
to
3.72
0.46
(NS)
0.76
(NS)
0.76
(NS)
to
2.22
to
1.30
to
1.24
1.01
1.00
0.97
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No significant differences were found between beta blockers and methyldopa in the
incidence of perinatal mortality, small-for-gestational-age infants, admission to
special newborn care units and few other clinically important outcomes (Table 2
presents outcomes with narrower confidence intervals).
Table 2. Meta-analysis data comparing beta blockers versus methyldopa in women who
develop mild-moderate hypertension in pregnancy(5)
RCTs AR [%]
AR [%]
RR
95% CI
Outcome
Beta blocker
Methyldopa
Perinatal mortality
12
10/441 [2%]
15/397 [4%]
0.61 0.28 to 1.31 (NS)
Severe hypertension
4
12/154 [8%]
14/143 [10%]
0.80 0.39 to 1.61 (NS)
Proteinuria/Pre-eclampsia 9
71/392 [18%]
64/350 [18%]
0.99 0.74 to 1.32 (NS)
Caesarean section
9
121/338 [36%] 118/316 [37%] 0.96 0.78 to 1.17 (NS)
Preterm birth
4
28/136 [21%]
33/128 [26%]
0.81 0.52 to 1.24 (NS)
Small for gestational age 5
30/193 [16%]
36/178 [20%]
0.76 0.50 to 1.16 (NS)
baby
Admission to special care 3
68/225 [30%]
64/203 [32%]
0.95 0.72 to 1.26 (NS)
neonatal unit
(NS) non significant statistical differences at 95% confidence interval
The assessment and reporting of adverse effects was poor in most studies.(1) Beta
blockers used in RCTs included labetalol, oxprenolol, pindolol, atenolol and
metoprolol. Labetalol was the most frequently used beta-blocker (5 RCTs, 792
women, usually at doses of 200-300 mg/day administered by mouth). Atenolol was
evaluated in 2 RCTs (153 women, usual doses of 50-100 mg/d by mouth).
Prophylactic antihypertensives in women at high risk of pre-eclampsia: The
overview found one small RCT (68 women without hypertension and with cardiac
output >7.4 L/min) providing insufficient evidence to draw conclusions on the
benefits of prophylactic antihypertensives. However it found a higher incidence of
low-birth-weight in babies from primiparous women receiving atenolol (beta-blocker),
compared with placebo (mean difference 440 g, P = 0.02).(1)
Note: Atenolol and labetalol are distinctively different beta blockers. Their
pharmacokinetics differ; atenolol has minimal hepatic metabolism, labetalol is
metabolised predominantly in the liver. Atenolol is a cardioselective beta blocker
reported to lack intrinsic sympathomimetic activity and membrane-stabilizing
properties. Labetalol is a non cardio-selective beta blocker reported to have some
sympathomimetic activity and membrane stabilizing activity, and alpha blocking
properties.(8; 9) Given these differences, the effects of atenolol and labetalol are
expected to be different.
Recommendation:
The Department of Reproductive Health and Research (WHO) is initiating a
multicentre RCT to compare labetalol with placebo in the treatment of mild to
moderate hypertension in pregnancy. However, the Department is still looking for
alternatives to evaluate because of the relatively high cost of labetalol. We therefore
think that while labetalol is different from other beta-blockers pharmacologically and
is the most tested beta-blocker to date the evidence base is not robust enough to
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add labetalol to the Essential Medicines List (EML) as a therapeutic option for
pregnant women with high blood pressure in pregnancy.
As new evidence on the safety and effectiveness of antihypertensive treatments in
pregnancy emerges this recommendation and the status of antihypertensives for
pregnancy may need to be revisited.
References:
(1) Duley L. Pre-eclampsia and hypertension. Clin Evid 2004; [search date
December 2003](12):2013-2081.
http://www.clinicalevidence.com/ceweb/ conditionpdf/1402.pdf
(2) WHO Department of Reproductive Health and Research. Management of
pregnancy-induced hypertension. WHO, UNFPA, UNICEF, World Bank,
editors. Managing complications in pregnancy and childbirth: a guide for
midwives and doctors. [WHO/RHR/00.7], S41-S50. 2000. World Health
Organization. Integrated Management of Pregnancy and Childbirth.
(3) Duley L, Henderson-Smart DJ. Drugs for treatment of very high blood
pressure during pregnancy. Cochrane Database Syst Rev 2002;(4):
CD001449.PM:12519557
(4) Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihypertensive drug
therapy for mild to moderate hypertension during pregnancy. Cochrane
Database Syst Rev 2001;(2):CD002252.PM:11406040
(5) Magee LA, Duley L. Oral beta-blockers for mild to moderate hypertension
during pregnancy. Cochrane Database Syst Rev 2003;(3): CD002863.
PM:12917933
(6) Elhassan EM, Mirghani OA, Habour AB, Adam I. Methyldopa versus no drug
treatment in the management of mild pre-eclampsia. East Afr Med J 2002;
79(4):172-175.PM:12625668
(7) Rudnicki M, Frolich A, Pilsgaard K, Nyrnberg L, Moller M, Sanchez M et al.
Comparison of magnesium and methyldopa for the control of blood pressure
in pregnancies complicated with hypertension. Gynecol Obstet Invest 2000;
49(4):231-235.PM:10828704
(8) Cardiovascular drugs. In: Parfitt K, editor. Martindale: the complete drug
reference. Taunton, MA: Pharmaceutical Press, 1999.
(9) Lim PO, McDonald TM. Antianginal drugs and -adrenoreceptor antagonists.
In: Dukes MNG, Aronson JK, editors. Meyler's Side Effects of Drugs. Elsevier,
2000: 575-628.
_________________________
15 December 2004
Department of Reproductive Health and Research
World Health Organization
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