Combination Therapy for Hypertension

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1 Combination Therapy for Hypertension Se-Joong Rim, MD Cardiology Division, Yonsei University College of Medicine, Seoul, Korea

2 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

3 Classification of BP JNC VI (1997) Category SBP DBP Optimal <120 <80 Normal <130 <85 High-normal Hypertension Stage Stage Stage JNC 7 (2003) Category SBP DBP Normal <120 <80 Prehypertension Treat >130/80 : DM, CRD Hypertension Stage Stage

4 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 or Yes No antihypertensive drug indicated. Drug(s) for compelling indications. Stage 1 Hypertension Stage 2 Hypertension >160 or 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.

5 Algorithm for Treatment of Hypertension Initial Drug Choices* Without Compelling indication Thiazide-Type Diuretics (or ACEI, ARB, BB, CCB) *Based on randomized controlled trials

6 JAMA 2002;288:; 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.

7 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

8 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

9 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 or DBP 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.

10 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

11 Why combination therapy?

12 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: Colhoun et al, J Hyperten. 1998;16: Joffres et al, Am J Hypertens 1997;10: Marques-Vidal et al, J Hum Hypertens 1997;11:213

13 Hypertension Awareness, Treatment, and Control Prevalence Awareness Treatment Control Percent Mulrow. Hypertension Primer ; 2 Primatesta et al. Hypertension ;38:

14 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)

15 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

16 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

17 Increasing Dose of Monotherapy BP Lowering Effect or Side Effect

18 Combination Therapy 48-51% of patients for control of BP Materson BJ et al NEJM 1993:328: % of patients to achieve normotension STOP-Hypertension Lancet 1991:338:1281 SHEP JAMA 1991:265: % of patients assigned to thiazide-type type diuretics, for control of BP ALLHAT JAMA 2002:288: :288:2981

19 Combination Therapy with Benefit Lower Dose Complementary/Synergistic mechanisms of action Lower side effect Better compliance

20 Combination Therapy from Caution Beginning Orthostatic hypotension Risk in Diabetes Autonomic dysfunction Older patients

21 What is Ideal Combination Therapy?

22 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

23 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

24 Diuretics + ACEI / ARB RAA system Metabolic complication Less effect in low renin-volume overload state

25 Diuretics + β-blocker RAA system Sodium retention

26 DHP CCB + β-blocker Reflex tachycardia Adrenergic vasoconstriction

27 ACEI + DHP CCB Reflex tachycardia Ankle edema

28 ACEI + Non-DHP CCB Proteinuria Proteinuria Reduce proteinuria more than either drug alone Epstein M, et al, Arch Intern Med,1996

29 Diuretics Beta blockers ACE inhibitors Alpha blockers Calcium antagonist Angiotensin II antagonist 2003 ESH-ESC guideline

30 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) Number of BP Medications

31 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

32 Fixed-Dose Combination Lower Cost Better Compliance ACE inhibitors + HCTZ(12.5mg) β- blockers + HCTZ(12.5mg) AR II blockers + HCTZ(12.5mg)

33 Combination Therapy Strategy for improving efficacy and reducing side effects Thank you for attention!

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