MANAGEMENT OF HYPERTENSION IN WOMEN AND PREGNANCY Suzanne Oparil, M.D. Professor of Medicine, and Physiology & Biophysics Director, Vascular Biology and Hypertension Program Division of Cardiovascular Disease Department of Medicine University of Alabama at Birmingham Birmingham, AL Atlanta, GA March 30, 2005
Systolic BP (mmHg) 1 year 3 years 5 years 16 years 17 years AGE Systolic Blood Pressure levels for the 90th and 95th percentiles of blood pressure for boys and girls age 1 to 17 years at 95th percentile of height http://hin.nhlbi.nih.gov/nhbpep_slds/ped/pedp1_1.htm
THE WOMEN’S HEALTH INITIATIVE- PREVALENCE AND TREATMENT STATUS BY RACE/ ETHNICITY WHITE 76 80 BLACK 63 63 HISPANIC 59 60 60 OTHER 44 41 36 36 40 PERCENT OF COHORT 33 32 30 20 0 HYPERTENSIVE TREATED CONTROLLED Wassertheil-Smoller et al. Hypertension 2000;36:780-789
THE WOMEN’S HEALTH INITIATIVE- PREVALENCE AND TREATMENT STATUS BY AGE 80 AGE 50-59 70 65 AGE 60-69 64 63 AGE 70-79 60 53 50 41 41 PERCENT OF COHORT 37 40 29 27 30 20 10 0 HYPERTENSIVE TREATED CONTROLLED Wassertheil-Smoller et al. Hypertension 2000;36:780-789
THE WOMEN’S HEALTH INITIATIVE-ANSWERS TO QUESTIONS ABOUT BP • Hypertension is most prevalent in the oldest women and in blacks. • Hypertension is undertreated in postmenopausal women~ 65% treatment rates- despite documented physicians visits. • BP control is inadequate in postmenopausal women- worst (~29%) in the oldest women- independent of drug class. Wassertheil-Smoller et al. Hypertension 2000;36:780-789
ALLHAT U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute Major Outcomes in High Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) The ALLHAT Collaborative Research Group Sponsored by the National Heart, Lung, and Blood Institute (NHLBI) JAMA. 2002;288:2981-2997
ALLHAT AntihypertensiveTrial Design • Randomized, double-blind, multi-center clinical trial • Determine whether occurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (CCB, ACEI, alpha-blocker) compared with a diuretic • 42,418 high-risk hypertensive patients ≥ 55 years
ALLHAT Total 0.98 (0.90, 1.07) Total 0.99 (0.91, 1.08) Age <65 0.99 (0.85, 1.16) Age < 65 0.95 (0.81, 1.12) Age>=65 0.97 (0.88, 1.08) Age >= 65 1.01 (0.91, 1.12) Men 0.98 (0.87, 1.09) Men 0.94 (0.85, 1.05) Women 0.99 (0.85, 1.15) Women 1.06 (0.92, 1.23) Black 1.01 (0.86, 1.18) Black 1.10 (0.94, 1.28) Non-Black 0.97 (0.87, 1.08) Non-Black 0.94 (0.85, 1.05) Diabetic 0.99 (0.87, 1.13) Diabetic 1.00 (0.87, 1.14) Non-Diabetic 0.97 (0.86, 1.09) Non-Diabetic 0.99 (0.88, 1.11) 0.50 1 2 0.50 1 2 Amlodipine Better Chlorthalidone Better Lisinopril Better Chlorthalidone Better Nonfatal MI + CHD Death – Subgroup Comparisons – RR (95% CI)
An investigator initiated community-based study in945 sites in 7 countries enrolling 9193 patients Steering Committee Chair/Vice-Chair B. Dahlöf, D. Devereux European/US Coordinators S.E. Kjeldsen, S. Julius Data and Safety Monitoring Committee Chair J. Kjekshus Clinical Endpoint Classification Committee D. Levy, K. Thygesen The Losartan Intervention For Endpoint Reductionin Hypertension Study
* * * * * * * Odds ratio Total mortality CV-related death Fatal Strokes All Strokes Fatal coronary events All major coronary events Main CV events * p<0.05 TREATMENT EFFECT BY GENDER Gueyffier et al. Ann Intern Med 1997;126:761-67
ALLHAT Antihypertensive Trial:Implications • Diuretics should be the drug of choice for first step therapy of hypertension • For the patient who cannot take a diuretic (which should be an unusual circumstance), CCB’s and ACEI’s may be considered. • Most hypertensive patients require more than one drug. Diuretics should generally be part of the antihypertensive regimen. Lifestyle advice should also be provided.
Without Compelling Indications With Compelling Indications Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Stage 1 Hypertension(SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Stage 2 Hypertension(SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved.Consider consultation with hypertension specialist. Algorithm for Treatment of Hypertension Lifestyle Modifications Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease) Initial Drug Choices
SELECTIVE ANTIHYPERTENSIVE THERAPY FOR WOMEN • No evidence to suggest that women respond differently to antihypertensive therapy than men • Diuretics may be particularly useful • Adverse effects are more troublesome • ACE inhibitor cough 3 times more common • Dihydropyridine CCB edema more common • Hirsutism with minoxidil intolerable • Treatment outcomes are probably similar
Classification • Preeclampsia-eclampsia • Chronic hypertension • Preeclampsia superimposed upon chronic hypertension • Gestational hypertension (only during pregnancy) • Transient hypertension (only after pregnancy)
Chronic hypertension BP CLASSIFICATION OF HYPERTENSION IN PREGNANCY
Chronic hypertension BP CLASSIFICATION OF HYPERTENSION IN PREGNANCY
Clinical Implications of Preeclampsia • Preeclampsia ranges from mild to severe. • Progression may be slow or rapid – hours to days to weeks. For clinical management, preeclampsia should be overdiagnosed to prevent maternal and perinatal morbidity and mortality – primarily through timing of delivery.
Classification of Preeclampsia-Eclampsia (cont.) The following are more ominous signs and increase certainty of diagnosis: • SBP > 160 mm Hg or DBP > 110 mm Hg • Proteinuria > 2.0 g in 24 hours (2+ or 3+ dipstick) • Increased serum creatinine • Platelet count < 100,000 cells/mm3 and/or evidence of microangiopathic hemolytic anemia with increased LDH • Elevated ALT or AST • Persistent headache or other cerebral or visual disturbances • Persistent epigastric pain
MATERNAL RISK FACTORS FOR PREECLAMPSIA Primigravida Positive family history (maternal or paternal) Multiple gestations Diabetes mellitus Insulin resistance/obesity Chronic hypertension Preexisting renal disease Extremes of reproductive age Hydatidiform disease History of severe early preeclampsia in a prior pregnancy Collagen vascular disease Black race Increased circulating testosterone Thrombophilias
Hypothetical cause and pathogenesis of pre-eclampsia. TGF=transforming growth factor. IFN=interferon. VEGF=vascular endothelial growth factor. PIGF=placental growth factor. ANGIO=angiopoietin 2. Sibai et al. Lancet 365:785-99, 2005.
Levels of evidence (I–IV) as outlined by the US Preventive Task Force Sibai et al. Lancet 365:785-99, 2005.
Preeclampsia • Maternal Evaluation • Early recognition of preeclampsia • Observe progression, both to prevent maternal complications and protect well-being of fetus. Early signs: • BP rises in late second and early third trimesters. • Initial appearance of proteinuria is important.
Preeclampsia (cont.) • Maternal Evaluation (cont.) • Often, hospitalization recommended with new-onset preeclampsia to assess maternal and fetal conditions. • Hospitalization for duration of pregnancy indicated for preterm onset of severe gestational hypertension or preeclampsia. • Ambulatory management at home or at day-care unit may be considered with mild gestational hypertension or preeclampsia remote from term.
Preeclampsia (cont.) • Antepartum Management of Preeclampsia • Little to suggest therapy alters the underlying pathophysiology of preeclampsia. • Restricted activity may be reasonable. • Sodium restriction and diuretic therapy appear to have no positive effect.
Preeclampsia (cont.) • Indications for Delivery in Preeclampsia* - Maternal • Gestational age 38 weeks • Platelet count < 100,000 cells/mm3 • Progressive deterioration in liver and renal function • Suspected abruptio placentae • Persistent severe headaches, visual changes, nausea, epigastric pain, or vomiting • *Delivery should be based on maternal and fetal conditions as well as gestational age.
Preeclampsia (cont.) • Indications for Delivery in Preeclampsia* - Fetal • Severe fetal growth restriction • Nonreassuring fetal testing results • Oligohydramnios • *Delivery should be based on maternal and fetal conditions • as well as gestational age.
Preeclampsia (cont.) • Route of Delivery • Vaginal delivery is preferable. • Aggressive labor induction (within 24 hours). • Neuraxial (epidural, spinal, and combined spinal-epidural) techniques offer advantages. • Hydralazine, nitroglycerin, or labetalol may be used as pretreatment to reduce significant hypertension during delivery.
Preeclampsia (cont.) • Anticonvulsive Therapy • Indicated to prevent recurrent convulsions in women with eclampsia or to prevent convulsions in women with preeclampsia. • Parenteral magnesium sulfate reduces the frequency of eclampsia. (Caution in renal failure.)
Treatment of Acute Severe Hypertension in Pregnancy • SBP > 160 mm Hg and/or DBP > 105 mm Hg • Parenteral hydralazine is most commonly used. • Parenteral labetalol is second-line drug (avoid in women with asthma and CHF.) • Oral nifedipine used with caution. (Short-acting nifedipine is not approved by FDA for managing hypertension.) • Sodium nitroprusside may be used in rare cases.
CLINICAL CHARACTERISTICS AND LABORATORY TESTS USED TO DISCRIMINATE PREECLAMPSIA FROM CHRONIC HYPERTENSION
Chronic hypertension BP MANAGEMENT OF CHRONIC HYPERTENSION IN PREGNANCY BEFORE CONCEPTION
Chronic Hypertension in Pregnancy Prepregnancy counseling: • Evaluate using JNC7 criteria • Discontinue use of ACE inhibitors and ARBs • Evaluate for target organ damage in women with longstanding hypertension • Discontinue use of tobacco and/or alcohol, even if not hypertensive • Discuss lifestyle changes, if applicable
Chronic hypertension BP MANAGEMENT OF CHRONIC HYPERTENSION IN PREGNANCY DURING PREGNANCY
Treatment of Chronic Hypertension in Pregnancy • Most women with stage 1 to 2 chronic hypertension are candidates for nondrug therapy, absent evidence of target organ damage. • Most of the increased risk associated with chronic hypertension occurs with superimposed preeclampsia. • End points for reinstituting treatment include SBP > 150-160 or DBP > 100-110 or evidence of target organ damage.
Antihypertensive Drug Selection • ACEI and ARB are contraindicated in pregnancy. • Methyldopa preferred first-line therapy; labetalol if methyldopa not tolerated. • Alternatives to methyldopa can be substituted based on rational mechanisms of action. • Long-term studies of most other agents are lacking in pregnant women. • Diuretics not used as first-line agents but are not contraindicated except in cases of reduced uteroplacental perfusion.
Fetal Assessment in Chronic Hypertension • Efforts directed at early detection of superimposed preeclampsia and possible fetal growth restriction. • Initial sonogram at 18 to 20 weeks gestation. • Fetal growth carefully assessed thereafter. • If growth restriction, assess by nonstress tests or biophysical profiles.
Chronic hypertension BP MANAGEMENT OF CHRONIC HYPERTENSION IN PREGNANCY DELIVERY
Chronic hypertension BP MANAGEMENT OF CHRONIC HYPERTENSION IN PREGNANCY POSTPARTUM LATE ISSUES AFTER HYPERTENSIVE PREGNANCY
Treating Hypertension During Lactation • Breastfeeding encouraged (with limits). • Little information on excretion of agents in breast milk or long-term effects on exposed infants. • No short-term adverse effects reported with methyldopa or hydralazine. • Beta-blockers: propanolol & labetalol recommended. • No data on calcium antagonists. • Diuretics may reduce milk volume/suppress lactation. • ACEI and ARB should be avoided.
Postpartum Counseling and Followup • Counseling for Future Pregnancies • Risk of recurrent preeclampsia increases with • Preeclampsia before 30 weeks (40%) • Multiparas as compared with nulliparas or new father • Risk of recurrent preeclampsia may be substantially greater in African Americans.
RISK FACTORS FOR RECURRENT HYPERTENSION IN PREGNANCY Early onset of hypertension in a prior pregnancy Chronic hypertension Persistent hypertension beyond 5 weeks postpartum High baseline blood pressure early in pregnancy
Pregnancy, Hypertension, and Renal Disease • Renal insufficiency may progress and jeopardize fetal survival. • As renal failure progresses, consider sodium restriction, use of loop diuretics, or dialysis. • Magnesium sulfate is hazardous in women with severe renal failure; doses should be reduced and guided by plasma magnesium determinations. Phenytoin may be an alternative. • Significant maternal morbidity associated with chronic dialysis during pregnancy: conception should be discouraged.