New European Guidelines and The Role of Lowdose Combinations

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New European Guidelines and The Role of Low-dose
Combinations

• Bernard Waeber
• Lausanne, Switzerland

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Goals of treatment
-BP lt 140/90 mmHg in all hypertensive
patients lt 130/80 mmHg in hypertensive patients
with diabetes or renal
disease -Control of all cardiovascular risk
factors
ESH - ESC Guidelines, J Hypertens 2003
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Patient 1 Patient 2 Patient 3
Sympathetic nervous system Renin-angiotensin
system Total body sodium
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Dose titration
5
Therapeutic effect
100
80
Toxic effect
Critical dose
60
Percent maximum effect
40
Optimal dose
20
0
0
1
10
100
1000
10000
Dose arbitrary units
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N of trials
20
59
15
96
10
62
Percentage of patients with AE
5
96
44
0
-5
Standard dose
Twice standard dose
Half standard dose
?-blockers ACE inhibitors Thiazides
Calcium antagonists AT1-receptor blockers
Law et al, BMJ 2003
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Sequential monotherapy
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Percentage of patients with normal blood pressure
Drug A
Drug B
Drugs C

0 20 40 60 80 100
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BP control rate during antihypertensive
monotherapy
Achieved BP lt140/90
mmHg
80
60
39

40
20
0
During monotherapy (diuretic, b-blocker, ACE
inhibitor or Ca antagonist)
Dickerson et al, Lancet, 1999
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Sequential monotherapy and dose ranging
strategyyes,but !
-blood pressure normalization in only a fraction
of hypertensive patients -each drug class cannot
be given to each patient -dose-dependent
side-effects for most antihypertensive agents -tim
e consuming approach
possible discouragement of the patient and of
the doctor!
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Combination therapy
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Percentage of patients with normal blood pressure
Drug A
Drug B
Drugs A B

0 20 40 60 80 100
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Combination therapy rationale
-Combination of drugs lowering blood pressure by
different mechanisms ? antihypertensive efficacy
? -Complementary actions of drugs from different
classes? prevention of counter-balancing
mechanisms? antihypertensive efficacy ? -Lower
doses generally needed when two drugs are
combined? incidence of side-effects ?
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Effects of two different drugs on BP separately
and in combination (119 randomized placebo
controlled trials)
"First" drug alone
"Second" drug alone
Combination
0 -5 -10 -5
Placebo-subtracted BP response. mmHg
Systolic Diastolic
Law et al, BMJ 2003
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Percent of ALLHAT participants who achieved their
goal blood pressure (SBP/DBP lt 140/90 mmHg)
100 80 60 40 20 0
Controlled (lt140/90 mmHg)
Percent
On 1 drug
On 2 drugs
On 3 drugs
On gt4 drugs
0
6
12
24
36
48
60
Cushman et al, J Clin Hypertens, 2002
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A multifactorial trial design to assess
combination therapy in hypertension
512 patients with esential hypertension 3 x 4
factorial trialdouble-blind treatment
HCTZ mg/d
Bisoprolol mg/d
0 6.25 25
0 2.5 10 40 0 2.5 10 40 0 2.5 10 40
4 weeks
Frishman et al, Arch Intern Med, 1994
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Response rate in sitting diastolic blood pressure
(lt90 mmHg)
HCTZ 0 mg HCTZ 6.25 mg HCTZ 25 mg
90 80 70 60 50 40 30 20 10 0
Responses rate ()
Bisoprolol 0 mg
Bisoprolol 2.5 mg
Bisoprolol 10 mg
Bisoprolol 40 mg
Frishman et al, Arch Intern Med, 1994
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Mean change from baseline in serum potassium
Bisoprolol mg/d
HCTZ mg/d
? Potassium concentrationmmol/l
0 2.5 10 40 0 2.5 10 40 0 2.5 10 40
0 6.25 25
-0.04 0.17 0.07 0.12 -0.5 0.03 -0.01 -0.12 -0.
36 -0.28 -0.07 -0.23
Frishman et al, Arch Intern Med, 1994
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Low-dose combination therapy as first line
treatment of mild-to-moderate hypertension the
efficacy and safety of bisoprolol/HCTZ (LODOZ)
versus amlodipine, enalapril, and placebo
323 hypertensive patients
bisoprolol/HCTZ (2.5/6.25 ? 10/6.25 mg
q.d.) amlodipine (2.5 ? 10 mg q.d.) enalapril (5
mg q.d. ? 20 mg b.i.d.) placebo
Treatment 18 weeks
Neutel et al, CVR and R, 1996
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Control rate at the end of the trial (DBP 90
mmHg)
plt0.001
plt0.01
77
56
44

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Bisoprolol/HCTZ Amlodipine Enalapril Placebo (n
77) (n82) (n84) (n78)
Neutel et al, CVR and R, 1996
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Bisoprolol/HCTZ Enalapril
Amlodipine Placebo
Overall 17 33 38 58 discontinuations () Patients
with 29 34 27 27 at least 1 AE ()
Neutel et al, CVR and R, 1996
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Biological parameters at baseline and 12 weeks
of treatment
Baseline 12-week Biso/HCTZ
7 6 5 4 3 2 1 0
mmol/l
Cholesterol
LDL Cholesterol
HDL Cholesterol
Triglycerides
Glucose
Potassium
Benetos et al, J Hypertens, 2002
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Comparison of bisoprolol and low dose
hydrochlorothiazide combination with losartan,
alone or in combination with hydrochlorothiazide,
in the treatment of hypertension A double
blind, randomized, placebo controlled trial
75 hypertensive patients
Bisoprolol/HCTZ Losartan Placebo 2.5 mg/6.25
mg 50 mg 5 mg/6.25 mg 100 mg Placebo 10
mg/6.25 mg 50 mg/12.5 mg Placebo
ABPM
2 weeks






2 weeks
2 weeks
ABPM if DBP gt 90 mmHg
Maintenance phase 6 weeks
Papademetriou et al, CVR and R, 1998
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Mean change from baseline in sitting DBP and SBP
Treatment Groups
Bis/HCTZ
LosLos/HCTZ
Placebo
5 0 -5 -10 -15 -20
mmHg



Diastolic

Systolic
p lt 0.05 vs Los/HCTZ p lt 0.05 vs Placebo
Papademetriou et al, CVR and R, 1998
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Mean change from baseline in 24 hr average
diastolic and systolic ABPM
Treatment Groups
2 0 -2 -4 -6 -8 -10 -12 -14 -16 -18
Bis/HCTZ
LosLos/HCTZ
Placebo
mmHg



Diastolic

Systolic
p lt 0.05 vs Los/HCTZ p lt 0.05 vs Placebo
Papademetriou et al, CVR and R, 1998
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Self-reported erectile dysfunction in
prospective, randomized trials
Enalapril (n102)
Bisoprolol/HCTZ (n333)
Amlodipine (n103)
Placebo (n190)
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5

Prisant et al, J Clin Hypertens, 1999
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Advantages of fixed low-dose combinations
Fixed low-dose combination Early normalization
of blood pressure Turbulences associated with
adjustments in antihypertensive therapy
? Motivation of patients to adhere to lifelong
treatment ?
Costs ?
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Advantages of fixed versus liberal combinations
of two antihypertensive drugs
Fixed Liberal Simplicity of treatment - Complia
nce - Efficacy Tolerability - Price - F
lexibility - Risk of administering
-contraindicated drug
lower doses generally used in fixed-dose
combinations
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Pharmacological treatment of hypertension
Consider Blood pressure level before
treatment Absence or presence of TOD and risk
factors
Choose between
Two-drug combination at low dose
Single agent at low dose
If goal BP not achieved
Previous agent at full dose
Switch to different agent at low dose
Previous combination at full dose
Add a third drug at low dose
If goal BP not achieved
Two-three drug combination
Two-three drug combination
2003 European Society of Hypertension - European
Society of Cardiology Guidelines for the
Management of Arterial Hypertension, J Hypertens,
2003
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Algorithm for treatment of hypertension
Lifestyle modifications
Not at goal BP (lt140/90 mmHg or lt130/80 mmHg for
those with diabetes or chronic kidney disease)
Initial drug choices
Hypertension with compelling indications
Hypertension without compelling indications
Stage 1 hypertension (SBP 140-159 or DBP 90-99
mmHg) Thiazide-type diuretics for most May
consider ACE inhibitor, ARB, ?-blocker, CCB, or
combination
Stage 2 hypertension (SBP 160 mmHg or DBP 100
mmHg) 2-drug combination for most (usually
thiazide-type diuretic and ACE inhibitor or ARB
or ?-blocker or CCB)
Drug(s) for the compelling indications Other
antihypertensive drugs (diuretics, ACE inhibitor,
ARB, ?-blocker, CCB) as needed
Not at goal BP
Optimize dosages or add additional drugs until
goal BP is achieved Consider consultation with
hypertension specialist
The JNC VII Report, 2003
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Normalization of BP
Good tolerability
Simple drug regimen
Satisfaction
Day-to-day compliance ?
Long-term compliance ?