Declaration of conflict of interest Claudio Borghi Lectures fees: Menarini International, Servier International, Recordati International, Ely-Lilly USA, BMS, Boheringer Ingelheim, Novartis Pharma Research grant: Menarini International, Novartis Pharma Membership Scientific Commitees: Ely-Lilly, Menarini International, Institute de Reseach Servier, Novartis Pharma, Takeda Pharmaceuticals
Pharmacotherapy for CV disease in pregnancy. Antihypertensive therapy Claudio Borghi, F.A.H.A, F.E.S.C. Department of Medical and Surgical Sciences University of Bologna Bologna, Italy
ESH Guidelines, Eur Heart J 2011
HYPERTENSION IN PREGNANCY Epidemiology Most common medical disorder in pregnancy* Overall complicates 6-8% of all pregnancies* Its prevalence is progressively increasing (age, other RF s)* Responsible for an increase in maternal/perinatal mortality and morbidity* Responsible for the 12.3% of all pregnancy-related maternal deaths ** From N.H.B.P.E.P. Working Group on HBP in Pregnancy, Am J Obstet Gynecol, 2000, (mod) ** From Berg Cj et al, Obstet Gunecol 2010
The treatment of hypertension in pregnancy 1. Should we reduce blood pressure?
Effects of less vs. more tight BP control in patients with mild-to-moderate hypertension in pregnancy. The Control of Hypertension In Pregnancy Study-Pilot Less Tight BP control (n.66) Tight BP control (n.66) Average DBP difference (mmhg) -3.5 (-6.4 / - 0.6) Post-randomization antihypertensive treatment 69.7% 89.2% Proteinuria 24.2 % 30.8% Severe hypertension 57.6% 40.0% Serious maternal complication 4.6% 3.1% Preterm birth 36.4% 40.0% Birthweight (kg) 2675 ± 858 2501 ± 855 Magee LA el al, BJOG 2007
The treatment of hypertension in pregnancy 1. Should we reduce blood pressure? 2. Which one is the goal of treatment?
The stated goals of treating HBP during pregnancy are the same among the different guidelines : - prevention of maternal stroke - prevention of maternal target organ damage - prevention of other CV complications - fetal protection
The treatment of hypertension in pregnancy 1. Should we reduce blood pressure? 2. Which one is the goal of treatment? 3. Who should be treated?
CWG Redman BMJ 2011
Reasons not supporting the antihypertensive treatment in mild-moderate HBP in pregnancy. Non significant maternal benefit - young age of most patients - brief duration of hypertension Increased fetal risk - impaired utero-placental perfusion - exposure to medication with potential AE s
UTERO-PLACENTAL DOPPLER VELOCIMETRY AND BLOOD PRESSURE IN PATIENTS WITH PRE-ECLAMPSIA TREATED WITH NIFEDIPINE-GITS OR METHYLDOPA Blood Pressure Uterine Artery Resistance Index *,** p<0.005 vs Baseline * ** p<0.05 vs Baseline p<0.05 vs N * * ** * Borghi C et al J Hypertension 2003
Kaplan-Meier plots of cumulative probability of being free of HTN, CHD, and stroke among nulliparous women, those with history of normotensive pregnancy, and women with a history of either hypertensive or preeclamptic pregnancy p = 0.045 vs normo p< 0.001 vs normo p = 0.049 vs normo p < 0.001 vs normo p< 0.001 vs normo p= 0.009 vs normo HTN, hypertension CHD, coronary heart disease Garovic VD et Al., J Hypertens 2010;28(4):826-833
Proposal for a more extensive approach to the treatment of HBP in pregnancy Condition Treatment strategy Management Chronic Hypertension (pre-pregnancy) De-novo hypertension >20 weeks, BP 140/90 mmhg Continue medications other than ACEI/ARB s Specific anti-hbp therapy (Methyldopa, CCB s, β- blockers, diuretics, hydralazine) Monitor drug dosage during first and second trimester and adapt to manage BP < 140/90 mmhg Close follow-up for the development of pre-eclampsia and fetal monitoring Moser M et al J Hypertension 2012
The treatment of hypertension in pregnancy 1. Should we reduce blood pressure? 2. Which one is the goal of treatment? 3. Who should be treated? 4. Which antihypertensive drugs?
Criteria for the choice of antihypertensive drugs in pregnancy The choice of antihypertensive drugs for the treatment of hypertension in pregnancy is limited to those drugs that: - Have long been in clinical use - Have been proven to be effective in BP control - Have been relatively well tolerated - Have side-effects profile considered tolerable by obstetricians
FIRST-LINE DRUGS FOR THE LONG-TERM, ORAL TREATMENT OF HYPERTENSION DURING PREGNANCY Drug Starting dose Maximum dose Safety profile Methyldopa 250 mg bid 4 g/day Good Labetalol 100 mg bid 2400 mg/day Good (fetal growth restriction) Nifedipine 30 mg oid 60 mg /day Good (no Mg ++ sulphate) Verapamil 120 mg bid 360 mg/day Good ß-blockers Variable Variable Low birth weight Neonatal bradicardia Diuretics 12.5 mg oid 50 mg/day Contraindicated in PE BP control in Chronic HBP ACEI, ARB s, DRI / / Absolutely contraindicated National High Blood Pressure Education Program Working Group, 2000 Sibai BM, Obstet Gynecol 2003, Podymow T, Hypertension 2008
The use of antihypertensive drugs in pregnancy: the ESH-ESC Guidelines In non-severe HBP and out-of-emergency situations, methyldopa, labetalol and CCB s are the preferred drugs. Atenolol should be given with caution because of reports of fetal growth retardation. Unless there is oliguria, diuretic therapy is inappropriate in pre-eclampsia. ACEI and ARB s (DRI) should never been used in hypertension ESH-ESC Guidelines, J Hypertens 2007
Antihypertensive drugs in patients with hypertension during pregnancy ESC Guidelines on the management of CV diseases in pregancy, Eur Heart J 2011
Drugs for the treatment of hypertension in pregnancy according to ASH and FDA Lindheimer MD et al, J Am Soc Hypertens 2008
Antihypertensive medication and pregnancy Centrally-acting agents Preferred Methyldopa Proven safety and efficacy Depression, liver problem, limited efficacy in BP control Alternative Clonidine As methyldopa Limited data on fetal safety Beta-blockers Preferred Labetalol Similar but more effective than methyldopa Contraindicated Atenolol N/A IUGR CCB s Preferred Nifedipine Similar but more effective than methyldopa Neonatal hypoglycemia with high doses Interaction with magnesium Alternative Verapamil Similar efficacy as other agents As nifedipine + bradycardia Direct vasodilators Hydralazine Efficacious i.v. (?) Poor safety profile Nitroprussid e Only for life-threatning severe HBP Poor safety profile Diuretics Thiazide Useful in chronic HBP Volume contraction, electrolyte disturbances (PE?) Moser M et al J Hypertension 2012 Podymov T et al, Hypertension 2008
Current international trials for HBP in pregnancy Trial Patients Drugs Control of Hypertension In Pregnancy Study (CHIPS) All More vs. less aggressive BP control Goal-directed Therapy in Pregnant Women at High Risk of Developing Pre-eclampsia Treatment Targets for Chronic Hypertension in Pregnancy Antihypertensive Treatment in Stable Pregnant Women with Severe Per-eclampsia Hydralazine Versus Labetalol for the Management of Hypertensive Disorders of Pregnancy High-risk pregnancy Chronic HBP Preeclampsia Hypertensive crisis Nifedipine vs. Labetalol Methyldopa vs. Labetalol vs. Nifedipine vs. Clonidine Labetalol vs. Hydralazine Labetalol vs. Hydralazine ClinicalTrial.gov, 2012 WHO ICTRP, 2012
2007 ESH-ESC Guidelines: Hypertension in pregnancy: Emergency situations Under emergency circumstances, intravenous labetalol and oral nifedipine are indicated. Intravenous hydralazine is no longer the drug of choice because of an excess of perinatal adverse effects. Intravenous infusion of sodium nitroprusside is useful in hypertensive crises, but prolonged administration should be avoided (fetal cyanide poisoning) ESH-ESC Guidelines, Journal of Hypertension 2007;25:1105-1187
Drugs for the urgen control of severe HBP in pregnancy according to ASH and ACOG Lindheimer MD et al, J Am Soc Hypertens 2008
The treatment of hypertension in pregnancy 1. Should we reduce blood pressure? 2. Which one is the goal of treatment? 3. Who should be treated? 4. Which antihypertensive drugs? 5. What else should be done?
Therapeutic approaches to treating HTN in pregnancy Potential new targets for the treatment of preeclampsia: Adenosine, L-arginine and NO (ALANO) pathway Heme oxygenase-1 pathway Endothelin-1 pathway Recombinant angiogenic factors AT1 receptor agonistic autoantibodies Drugs with anti-inflammatory actions Genetic approaches L-carnitine? Mod. from Mate A et Al, Drug Discovery Today 2012
LV diastolic dysfunction LV functional/geo metrical abnormalities LV global remodelling/hypertroph y Melchiorre K et al, Hypertension 2011
Effects of nifedipine GITS and methyldopa on LV structure and function in patients with preeclampsia LVESV LVEDV LVEF P<0.01 P<0.01 Borghi C et al J Hypertens 2004
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