This document provides guidelines for combination therapy for hypertension. It begins by classifying blood pressure and outlining initial drug therapy options for different BP levels, with or without compelling indications. It recommends thiazide-type diuretics, ACE inhibitors, ARBs, beta-blockers, or calcium channel blockers. The document then discusses reasons for treatment unresponsiveness and inadequate control, and provides support for combination therapy to control BP for 48-51% of patients. It outlines recommended two-drug combination therapies and cautions about their initial use.
2. 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
140–159 or 90–99 Yes Thiazide-type diuretics for most.
May consider ACEI, ARB, BB,
CCB, or combination.
Drug(s) for the compelling
indications.‡
Other antihypertensive
drugs (diuretics, ACEI,
ARB, BB, CCB) as
needed.
Stage 2
Hypertension
>160 or >100 Yes Two-drug combination for most†
(usually thiazide-type diuretic and
ACEI or ARB or BB or CCB).
*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.
Classification of BP and Drug TherapyClassification of BP and Drug Therapy
3. Initial Drug Choices*
Without Compelling
indication
Thiazide-Type Diuretics
(or ACEI, ARB, BB, CCB)
*Based on randomized controlled trials
Algorithm for Treatment of
Hypertension
6. Not at Goal Blood Pressure (<140/90 mmHg)
(<130/80 mmHg for those with diabetes or chronic kidney disease)
Initial Drug Choices
Drug(s) for the compelling
indications
Other antihypertensive drugs
(diuretics, ACEI, ARB, BB, CCB)
as needed.
With Compelling
Indications
Lifestyle Modifications
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)
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
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 HypertensionAlgorithm for Treatment of Hypertension
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)
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)
7. Not at Goal Blood Pressure (< 140/90 mm Hg)
Initial Drug Choices
Algorithm for Treatment of
Hypertension
Optimize Dosages or Add additional drugs
Consultation with hypertension specialists
? Titrate to full dose
? Substitute another drug
9. Poor Control ofPoor Control of
Hypertension WorldwideHypertension Worldwide
Percent of patients with BP controlledPercent of patients with BP controlled
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 997;11:213
USA1
Canada3
Finland4
Spain4
Australia4
England2
Germany4
Scotland4
India4
Zaire4
28% 16% 20.5% 20% 19%
6%
22.5% 17.5% 9%
2.5%
>65 yr only
10. Hypertension Awareness, Treatment,Hypertension Awareness, Treatment,
and Controland Control
0
20
40
60
80
United
States
Canada Egypt China England
11
Mulrow.Mulrow. Hypertension PrimerHypertension Primer. 1999;. 1999; 22
Primatesta et al.Primatesta et al. HypertensionHypertension. 2001;38:827-832.. 2001;38:827-832.
AwarenessAwareness TreatmentTreatment ControlControlPrevalencePrevalence
PercentPercent
1 1 1 1 2
11. Causes of InadequateCauses of Inadequate
Responsiveness to Therapy …Responsiveness to Therapy …
• PseudoresistancePseudoresistance
““White-coat HTN” or office elevationsWhite-coat HTN” or office elevations
Pseudohypertension in older patientsPseudohypertension in older patients
Use of regular cuff on very obese armUse of regular cuff on very obese arm
• Associated conditionsAssociated conditions
SmokingSmoking
Increasing obesityIncreasing obesity
Sleep apneaSleep apnea
Insulin resistanceInsulin resistance
AlcoholAlcohol
Anxiety or PainAnxiety or Pain
Intense vasoconstriction (arteritis)Intense vasoconstriction (arteritis)
12. ……Causes of InadequateCauses of Inadequate
Responsiveness to TherapyResponsiveness to Therapy
• Non-adherence to therapyNon-adherence to therapy
• Volume overloadVolume overload
Excess salt intakeExcess salt intake
Progressive renal damageProgressive renal damage
Fluid retention from reduction of BPFluid retention from reduction of BP
Inadequate diuretic therapyInadequate diuretic therapy
• Drug-related causesDrug-related causes
13. Increasing Dose of MonotherapyIncreasing Dose of Monotherapy
BP Lowering EffectBP Lowering Effect ↑↑
oror ↔↔
Side EffectSide Effect ↑↑
Effect
Dose
Therapuetic
Toxic
0.1 1 10 102
103
104
14. Combination TherapyCombination Therapy
• 48-51% of patients for control of BP48-51% of patients for control of BP
Materson BJ et al NEJM 1993:328:914Materson BJ et al NEJM 1993:328:914
• 54-70% of patients to be normotensives54-70% of patients to be normotensives
STOP-HypertensionSTOP-Hypertension Lancet 1991:338:1281Lancet 1991:338:1281
SHEPSHEP JAMA 1991:265:3255JAMA 1991:265:3255
• 70% of patients assigned to thiazide-type70% of patients assigned to thiazide-type
diuretics, for control of BPdiuretics, for control of BP
ALLHAT JAMA 2002:288:2981
15. Combination Therapy with Lower DoseCombination Therapy with Lower Dose
BenefitsBenefits
• ComplementaryComplementary / Synergistic/ Synergistic mechanisms ofmechanisms of
actionaction
• Lower side effectLower side effect
• Better complianceBetter compliance
16. Combination Therapy from BeginningCombination Therapy from Beginning
CautionCaution
• Orthostatic hypotensionOrthostatic hypotension
• Risk in DiabetesRisk in Diabetes
• Autonomic dysfunctionAutonomic dysfunction
• Older patientsOlder patients
17. Diuretics and Counter-RegulatoryDiuretics and Counter-Regulatory
MechanismMechanism
Volume Renin Ang II TPR
CO
Thiazide type
Diuretics
Na+
excretion
+
+
Activation of SNSActivation of SNS
+
β-blockers
AT1-receptor blockers
ACE inhibitors
18. Recommended Combination
Therapies
• Diuretics and ACEI
• Diuretics and β-blockers
• ACE I and Calcium antagonists
∀ β-blockers and Calcium antagonists
• Calcium antagonists and diuretics
∀ β-blockers and α-blockers
• Thiazides and potassium-sparing diuretics
19. Diuretics +
• RAA system ↑↑
• Metabolic
complication
ACEI
• Less effect in low
renin-volume overload
state
25. Number of Agents Required toNumber of Agents Required to
Achieve BP GoalAchieve BP Goal
Number of BP Medications
UKPDS (<85 mm Hg,
diastolic)
4321
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)
26. Combination TherapyCombination Therapy
Selecting DrugSelecting Drug
• Consider thiazide typeConsider thiazide type diureticsdiuretics when you facewhen you face
inadequate BP controlinadequate BP control
• Consider underlying risk factor or disease whenConsider underlying risk factor or disease when
you add medicine one by oneyou add medicine one by one
• Consider fixed-dose productsConsider fixed-dose products
National health surveys in several countries worldwide have documented the patterns of awareness, treatment, and control of hypertension. The surveys shown here for the United States, Canada, Egypt, and China (Mulrow), and England (Primatesta) used the 140/90 mm Hg cutoff for hypertension control. The studies were performed following standardized protocols with trained personnel and included nationwide cross-sectional studies of randomly selected subjects.
As shown here, treatment rates were 25% to 50% lower than awareness rates. Rates of hypertension control were less than half of the treatment rates; in all of these countries more than 50% of treated hypertensive patients were not controlled.
Polypharmacy may be necessary to reach BP goals in hypertension management. A review of clinical trials in which patients with either diabetes or renal impairment were randomized to 2 different BP reduction targets demonstrated that patients assigned to the lower BP target required an average of 3.2 daily antihypertensive medications to achieve the goal. Patients in the lower-pressure groups had much lower rates of CV events and slower declines in renal function than those in the higher-pressure groups, even when the average blood pressure was &lt;140/90 mm Hg.
