Choice of antihypertensive Peter von Dadelszen BMedSc, MBChB, DipObst, DPhil, FRANZCOG, FRCSC, FRCOG Associate Professor of Obstetrics & Gynaecology, UBC.

Choice of antihypertensive

Peter von DadelszenBMedSc, MBChB, DipObst, DPhil, FRANZCOG, FRCSC, FRCOG

Associate Professor of Obstetrics & Gynaecology, UBCConsultant in Maternal-Fetal Medicine, BC Women’s

Co-Director, CFRI Reproduction & Healthy Pregnancy Cluster

Dr Peter von DadelszenBMedSc, MBChB, DipObst, DPhil, FRANZCOG, FRCSC, FRCOG

Principal Investigator

Department of Obstetrics & Gynaecology, UBCReproduction & Healthy Pregnancy Cluster, CFRI Consultant in Maternal-Fetal Medicine, BC Women’s

2H30-4500 Oak Street, Vancouver, BC V6H 3N1, Canada

PRE-eclampsiaEclampsiaMonitoring,Prevention &Treatment

Phone: +1-604-875-3054 | Fax: +1-604-875-2725 | e-mail: pvd@cw.bc.ca

Christchurch

PRE-EMPT(PRE-eclampsia-Eclampsia Monitoring, Prevention &

Treatment)

• Five objective, LMIC community intervention-focussed, pre-eclampsia project

• Funding:– Bill & Melinda Gates Foundation

Why use antihypertensives?

• Maternal stroke risk associated with both severe systolic and/or diastolic hypertension– sBP >160mmHg– dBP >110mmHg CEMACH 2007

• Severe hypertension associated with placental abruption and attendant maternal and perinatal risks

• Severe hypertension is included in most definitions of ‘severe’ pre-eclampsia, although such classification systems are flawed

Menzies et al. Hypertens Pregnancy 2007

Why use antihypertensives?

• In non-severe pregnancy hypertension – No clear evidence of benefit other than to reduce

the frequency of episodes of severe hypertension– May adversely effect fetal growth velocity

von Dadelszen et al. Lancet 2000

• Therefore, my focus will be on the pharmacological management of severe hypertension

The ‘ideal’ agent in rural & remote settings

• Oral administration• Reliable reduction in BP• Smooth reduction in BP• Rapid onset of action• Minimal overshoot

– BP in target range• sBP 130-160mmHg• dBP 80-110mmHg

From what can we choose?

• Hydralazine• Beta-blockers (& alpha-/beta-blockers)

– Atenolol– Labetalol

• Calcium channel blockers– Nifedipine

• Alpha-methyldopa• Angiotensin converting enzyme inhibitors• Angiotensin-II receptor blockers

From what can we choose?

• Hydralazine• Beta-blockers (& alpha-/beta-blockers)

– Atenolol– Labetalol

• Calcium channel blockers– Nifedipine

• Alpha-methyldopa• Angiotensin converting enzyme inhibitors• Angiotensin-II receptor blockers

– Risks of fetal renal toxicity and IUFD

From what can we choose?

•MgSO4 is NOT an antihypertensive

The ‘ideal’ agent in rural & remote settings

• Oral administration• Reliable reduction in BP• Smooth reduction in BP• Rapid onset of action• Minimal overshoot

– BP in target range• sBP 130-160mmHg• dBP 80-110mmHg

Oral administration

• Atenolol– No adverse effects on fetal growth when used acutely

• Labetalol• Methyldopa• Nifedipine capsules• Nifedipine intermediate acting

– PA/Retard• Hydralazine

Modified from: Magee & Abdullah. Expert Opin Drug Saf 2004

The ‘ideal’ agent in rural & remote settings

• Oral administration• Reliable reduction in BP• Smooth reduction in BP• Rapid onset of action• Minimal overshoot

– BP in target range• sBP 130-160mmHg• dBP 80-110mmHg

Reliable reduction in BPsevere hypertension

• CCBs are more reliable than hydralazine in lowering BP in pregnant women with severe hypertension

Magee et al. BMJ 2004Duley et al. CDSR 2006

• Hydralazine appears more reliable than labetalolMagee et al. BMJ 2004

• Methyldopa may be an agent of choice for severe hypertension

Duley et al. CDSR 2006

Reliable reduction in BPsevere hypertension

• CCBs are more reliable than hydralazine in lowering BP in pregnant women with severe hypertension

Magee et al. BMJ 2004Duley et al. CDSR 2006

• Hydralazine appears more reliable than labetalolMagee et al. BMJ 2004

• Methyldopa may be an agent of choice for severe hypertension

Magee et al. BMJ 2004

Reliable reduction in BPsevere hypertension

• CCBs are more reliable than hydralazine in lowering BP in pregnant women with severe hypertension

Magee et al. BMJ 2004Duley et al. CDSR 2006

• Hydralazine appears more reliable than labetalolMagee et al. BMJ 2004

• Methyldopa may be an agent of choice for severe hypertension– Widely used – routinely on EMLs

The ‘ideal’ agent in rural & remote settings

• Oral administration• Reliable reduction in BP• Smooth reduction in BP• Rapid onset of action• Minimal overshoot

– BP in target range• sBP 130-160mmHg• dBP 80-110mmHg

Smooth reduction in BP

• The ideal agent will reduce BP effectively and over a relatively short period of time– <60min– Stabilise and reduce MAP by 10% per hour

• BP fall will not be precipitous– Adverse maternal CNS effects– Adverse fetal effects

Normal Pregnancy

Early-onsetpre-eclampsia

The ‘ideal’ agent in rural & remote settings

• Oral administration• Reliable reduction in BP• Smooth reduction in BP• Rapid onset of action• Minimal overshoot

– BP in target range• sBP 130-160mmHg• dBP 80-110mmHg

‘Rapid’ onset of action

Modified from: Magee & Abdullah. Expert Opin Drug Saf 2004

Drug Dosage Onset Peak Duration

Atenolol 25 – 50 mg 1hr 2-4hr 24hr

(dose dependent)

Labetalol 200 mg 20min – 2hr 1-4 hr 8-12hr

(dose dependent)

Methyldopa 500 mg – 2 g 40 min 3-6hr 12-24hr

Nifedipine PA (or retard) 10 mg 30min 4hr 12hr

Nifedipine capsule 5 – 10 mg 5-10min 30min 6.5hr

The ‘ideal’ agent in rural & remote settings

• Oral administration• Reliable reduction in BP• Smooth reduction in BP• Rapid onset of action• Minimal overshoot

– BP in target range• sBP 130-160mmHg• dBP 80-110mmHg

Minimal overshoot

• CCBs less likely to cause overshoot than hydralazine Magee et al. BMJ 2004

• Beta-blockers less likely to cause overshoot than hydralazine Magee et al. BMJ 2004

• Nifedipine PA/Retard less likely to cause overshoot than capsules? Brown et al. AJOG 2002

– Small RCT– End-point (‘in range BP’) measured at time PA

approaching maximal effect

On balance• An intervention package should include 1 - 3 oral

antihypertensive agent(s)• The choice for a single antihypertensive lies between

methyldopa, nifedipine, and another beta-blocker, probably atenolol – labetalol is not on EMLs

• Theoretical and practical reasons to have all available– Combined CNS control, beta-blockade and vasodilatation– Second effective agent for women whose BP is resistant to

another agent • Reserve i.v. hydralazine for obtunded/comatose

women

PRE-EMPTObjective 3

• CLIP (Community-Level Interventions for Pre-eclampsia)

– Cluster randomised controlled trial of community level interventions for women with pre-eclampsia

– Aims• Can

– identification, – early risk stratification, and – initiation of life-saving treatment at the community level

• decrease pre-eclampsia-related maternal and perinatal mortality in LMIC?

CLIP• Intervention

– CLIP package of care• Case recognition & triage• Treatment of severe hypertension (sBP ≥160mmHg)

– Oral antihypertensive ? Atenolol; ? Nifedipine, ? Methyldopa– Intramuscular MgSO4 (5g each buttock)

• Treatment of eclampsia– Intramuscular MgSO4 (5g each buttock)

• Transfer into facilities offering evidence-based care – Setting

• Community – community health workers• Primary health units (not repeated)

The ‘ideal’ agent in rural & remote settings

• Oral administration• Reliable reduction in BP• Smooth reduction in BP• Rapid onset of action• Minimal overshoot

– BP in target range• sBP 130-160mmHg• dBP 80-110mmHg