Combination Therapy for Hypertension Se-Joong Rim, MD Cardiology Division, Yonsei University College of Medicine, Seoul, Korea
Goals of Therapy Reduce CVD and renal morbidity and mortality. Treat to BP <140/90 mmhg or BP <130/80 mmhg in patients with diabetes or chronic kidney disease. Achieve SBP goal especially in persons >50 years of age. JNC-VII, 2003
Classification of BP JNC VI (1997) Category SBP DBP Optimal <120 <80 Normal <130 <85 High-normal 130-139 85-89 Hypertension Stage 1 140-159 90-99 Stage 2 160-179 100-109 Stage 3 180 110 JNC 7 (2003) Category SBP DBP Normal <120 <80 Prehypertension 120-139 80-89 Treat >130/80 : DM, CRD Hypertension Stage 1 140-159 90-99 Stage 2 160 100
Classification of BP and Drug Therapy BP classification SBP* mmhg DBP* mmhg Lifestyle modification Initial drug therapy Without compelling indication With compelling indications Normal <120 and <80 Encourage Prehypertension 120 139 or 80 89 Yes No antihypertensive drug indicated. Drug(s) for compelling indications. Stage 1 Hypertension Stage 2 Hypertension 140 159 >160 or 90 99 or >100 Yes Yes Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Two-drug combination for most (usually thiazide-type diuretic and ACEI or ARB or BB or CCB). Drug(s) for the compelling indications. Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. *Treatment determined by highest BP category. Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmhg.
Algorithm for Treatment of Hypertension Initial Drug Choices* Without Compelling indication Thiazide-Type Diuretics (or ACEI, ARB, BB, CCB) *Based on randomized controlled trials
JAMA 2002;288:;2981-97. Chlorthalidone, Lisinopril, Amlodipine, Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.
Compelling Indications for Individual Drug Classes Compelling Indication Heart failure Postmyocardial infarction Initial Therapy Options THIAZ, BB, ACEI, ARB, ALDO ANT BB, ACEI, ALDO ANT Clinical Trial Basis ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS High CAD risk THIAZ, BB, ACE, CCB ALLHAT, HOPE, ANBP2, LIFE, CONVINCE
Compelling Indications for Individual Drug Classes Compelling Indication Diabetes Chronic kidney disease Initial Therapy Options THIAZ, BB, ACE, ARB, CCB ACEI, ARB Clinical Trial Basis NKF-ADA Guideline, UKPDS, ALLHAT NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK Recurrent stroke prevention THIAZ, ACEI PROGRESS
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) Stage 1 Hypertension (SBP 140 159 or DBP 90 99 mmhg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Without Compelling Indications Initial Drug Choices Stage 2 Hypertension (SBP >160 Stage or 2 DBP Hypertension >100 mmhg) (SBP >160 or DBP >100 mmhg) Stage 2 Hypertension 2-drug combination 2-drug (SBP >160 or DBP for >100 for most mmhg) (usually most (usually 2-drug combination for most and (usually thiazide-type ACEI, or ARB, or diuretic BB, or and and CCB) ACEI, or ARB, or BB, or CCB) 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. With Compelling Indications Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.
Algorithm for Treatment of Hypertension Initial Drug Choices Not at Goal Blood Pressure (< 140/90 mm Hg) Optimize Dosages or Add additional drugs Consultation with hypertension specialists
Why combination therapy?
Poor Control of Hypertension Worldwide Percent of patients with BP controlled USA 1 Canada 3 Finland 4 Spain 4 Australia 4 28% 16% 20.5% 20% 19% England 2 Germany 4 Scotland 4 India 4 Zaire 4 6% 22.5% 17.5% 9% 2.5% >65 yr only 1. JNC VI, Arch Intern Med 1997;157:2413 2. Colhoun et al, J Hyperten. 1998;16:747 3. Joffres et al, Am J Hypertens 1997;10:1097 4. Marques-Vidal et al, J Hum Hypertens 1997;11:213
Hypertension Awareness, Treatment, and Control Prevalence Awareness Treatment Control Percent 1 1 1 1 2 1 Mulrow. Hypertension Primer.. 1999; 2 Primatesta et al. Hypertension.. 2001;38:827-832. 832.
Causes of Inadequate Responsiveness to Therapy (1) Pseudoresistance White-coat HTN or office elevations Pseudohypertension in older patients Use of regular cuff on very obese arm Associated conditions Smoking Increasing obesity Sleep apnea Insulin resistance Alcohol Anxiety or Pain Intense vasoconstriction (arteritis( arteritis)
Causes of Inadequate Responsiveness to Therapy (2) Non-adherence to therapy Volume overload Excess salt intake Progressive renal damage Fluid retention from reduction of BP Inadequate diuretic therapy Drug-related related causes
Failure of Single-Drug Regimen Most drugs only reduce SBP 7~13 mmhg DBP 4~8 mmhg Due to Multifactorial mechanism of HiBP tiating therapy with 2 drugs Counter-regulatory regulatory mechanism If BP>20/10 mmhg above Goal BP, initiating therapy with 2 drugs JNC-VII, 2003
Increasing Dose of Monotherapy BP Lowering Effect or Side Effect
Combination Therapy 48-51% of patients for control of BP Materson BJ et al NEJM 1993:328:914 54-70% of patients to achieve normotension STOP-Hypertension Lancet 1991:338:1281 SHEP JAMA 1991:265:3255 70% of patients assigned to thiazide-type type diuretics, for control of BP ALLHAT JAMA 2002:288:2981 02:288:2981
Combination Therapy with Benefit Lower Dose Complementary/Synergistic mechanisms of action Lower side effect Better compliance
Combination Therapy from Caution Beginning Orthostatic hypotension Risk in Diabetes Autonomic dysfunction Older patients
What is Ideal Combination Therapy?
Diuretics and Counter-Regulatory Na + excretion Diuretics Mechanism + AT 1 -receptor blockers Volume Renin Ang II TPR + CO + Activation of SNS ACE inhibitors β-blockers
Recommended Combination Therapies ACEI / ARB and diuretics β-blockers and diuretics Calcium antagonists and ACEI β-blockers and Calcium antagonists Calcium antagonists and diuretics β-blockers and α-blockers Thiazides and potassium-sparing diuretics 2003 ESH-ESC guideline
Diuretics + ACEI / ARB RAA system Metabolic complication Less effect in low renin-volume overload state
Diuretics + β-blocker RAA system Sodium retention
DHP CCB + β-blocker Reflex tachycardia Adrenergic vasoconstriction
ACEI + DHP CCB Reflex tachycardia Ankle edema
ACEI + Non-DHP CCB Proteinuria Proteinuria Reduce proteinuria more than either drug alone Epstein M, et al, Arch Intern Med,1996
Diuretics Beta blockers ACE inhibitors Alpha blockers Calcium antagonist Angiotensin II antagonist 2003 ESH-ESC guideline
Number of Agents Required to Achieve BP Goal UKPDS (<85 mm Hg, diastolic) MDRD (92 mm Hg, MAP) HOT (<80 mm Hg, diastolic) AASK (<92 mm Hg, MAP) RENAAL (<140/90 mm Hg) IDNT ( 135/85 mm Hg) 1 2 3 4 Number of BP Medications
Combination Therapy Selecting Drug Consider diuretics when you face inadequate BP control Consider underlying risk factor or disease when you add medicine one by one Consider fixed-dose dose products
Fixed-Dose Combination Lower Cost Better Compliance ACE inhibitors + HCTZ(12.5mg) β- blockers + HCTZ(12.5mg) AR II blockers + HCTZ(12.5mg)
Combination Therapy Strategy for improving efficacy and reducing side effects Thank you for attention!