Transcript New European Guidelines and The Role of Low-dose Combinations Bernard Waeber

New European Guidelines and
The Role of Low-dose Combinations
Bernard Waeber
Lausanne, Switzerland
Goals of treatment
-BP < 140/90 mmHg in all hypertensive patients
< 130/80 mmHg in hypertensive patients
with diabetes or renal disease
-Control of all cardiovascular risk factors
ESH - ESC Guidelines, J Hypertens 2003
Patient 1
Patient 2
Sympathetic nervous system
Renin-angiotensin system
Total body sodium
Patient 3
Dose titration
Therapeutic effect
Percent
maximum effect
100
80
Toxic effect
Critical dose
60
40
Optimal dose
20
0
0
1
10
100
Dose arbitrary units
1000
10000
Percentage of patients with AE
N° of trials :
20
15
59
96
10
62
5
96
44
0
-5
-blockers
ACE inhibitors
Thiazides
Half
standard
dose
Standard
dose
Twice
standard
dose
Calcium antagonists
AT1-receptor blockers
Law et al, BMJ 2003
Sequential monotherapy
Percentage of patients with
normal blood pressure
Drug A
Drug B
Drugs C
0
20
40
60
80
100
%
BP control rate during antihypertensive
monotherapy
Achieved BP:
80
60
<140/90 mmHg
39
% 40
20
0
During monotherapy
(diuretic, -blocker, ACE inhibitor or Ca antagonist)
Dickerson et al, Lancet, 1999
Sequential monotherapy and dose ranging
strategy:yes,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
-time consuming approach
possible
discouragement of the patient and … of the doctor!
Combination therapy
Percentage of patients with
normal blood pressure
Drug A
Drug B
Drugs A + B
0
20
40
60
80
100
%
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 
Effects of two different drugs on BP
separately and in combination
Placebo-subtracted
BP response. mmHg
(119 randomized placebo controlled trials)
0
"First" drug
alone
"Second"
drug alone
Combination
-5
-10
-5
Systolic
Diastolic
Law et al, BMJ 2003
Percent of ALLHAT participants who achieved their
goal blood pressure (SBP/DBP < 140/90 mmHg)
100
Percent
80
% Controlled (<140/90 mmHg)
60
On 1 drug
40
On 2 drugs
20
On 3 drugs
On >4 drugs
0
0
6
12
24
36
48
60
Cushman et al, J Clin Hypertens, 2002
A multifactorial trial design to assess combination
therapy in hypertension
512 patients with esential hypertension
0
6.25
25
Frishman et al, Arch Intern Med, 1994
Bisoprolol
mg/d
0
2.5
10
40
0
2.5
10
40
0
2.5
10
40
4 weeks
HCTZ
mg/d
3 x 4 factorial trial
double-blind treatment
Responses rate (%)
Response rate in sitting diastolic blood pressure
(<90 mmHg)
90
80
70
60
50
40
30
20
10
0
HCTZ 0 mg
HCTZ 6.25 mg
HCTZ 25 mg
Bisoprolol
0 mg
Bisoprolol
2.5 mg
Bisoprolol
10 mg
Bisoprolol
40 mg
Frishman et al, Arch Intern Med, 1994
Mean change from baseline in serum potassium
HCTZ
mg/d
Bisoprolol
mg/d
∆ Potassium concentration
mmol/l
0
0
2.5
10
40
0
2.5
10
40
0
2.5
10
40
-0.04
+0.17
+0.07
+0.12
-0.5
+0.03
-0.01
-0.12
-0.36
-0.28
-0.07
-0.23
6.25
25
Frishman et al, Arch Intern Med, 1994
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
Control rate at the end of the trial
(DBP ≤ 90 mmHg)
p<0.001
p<0.01
77
56
%
44
21
Bisoprolol/HCTZ Amlodipine
(n=77)
(n=82)
Enalapril
(n=84)
Placebo
(n=78)
Neutel et al, CVR and R, 1996
Bisoprolol/HCTZ
Enalapril
Amlodipine
Placebo
Overall
discontinuations
(%)
17
33
38
58
Patients with
at least 1 AE (%)
29
34
27
27
Neutel et al, CVR and R, 1996
Biological parameters at baseline and 12 weeks
of treatment
Baseline
12-week Biso/HCTZ
7
6
mmol/l
5
4
3
2
1
0
Cholesterol
LDL
HDL
Triglycerides
Cholesterol Cholesterol
Glucose
Potassium
Benetos et al, J Hypertens, 2002
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
ABPM
Bisoprolol/HCTZ
2.5 mg/6.25 mg
*
5 mg/6.25 mg
*
10 mg/6.25 mg
Losartan
50 mg
*
100 mg
*
50 mg/12.5 mg
Placebo
*
2 weeks
Placebo
*
2 weeks
Placebo
2 weeks
ABPM
* if DBP > 90 mmHg
Maintenance
phase 6 weeks
Papademetriou et al, CVR and R, 1998
Mean change from baseline in sitting DBP and SBP
Treatment Groups
5
Bis/HCTZ
Los:Los/HCTZ
Placebo
mmHg
0
-5
*
-10
-15
*
#*
#*
-20
# p < 0.05 vs Los/HCTZ
* p < 0.05 vs Placebo
Diastolic
Systolic
Papademetriou et al, CVR and R, 1998
Mean change from baseline in 24 hr
average diastolic and systolic ABPM
mmHg
Treatment Groups
2
0
-2
-4
-6
-8
-10
-12
-14
-16
-18
Bis/HCTZ
Los:Los/HCTZ
Placebo
*
*
#*
# p < 0.05 vs Los/HCTZ
* p < 0.05 vs Placebo
*
Diastolic
Systolic
Papademetriou et al, CVR and R, 1998
Self-reported erectile dysfunction in prospective,
randomized trials
Enalapril (n=102)
Bisoprolol/HCTZ (n=333)
Amlodipine (n=103)
Placebo (n=190)
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
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 
Advantages of fixed versus liberal combinations of
two antihypertensive drugs
Fixed
Liberal
Simplicity of treatment
+
-
Compliance
+
-
Efficacy
+
+
Tolerability
+*
-
Price
+
-
Flexibility
-
+
Risk of administering
contraindicated drug
+
-
* lower doses generally used in fixed-dose combinations
Pharmacological treatment of hypertension
Consider :
Blood pressure level before treatment
Absence or presence of TOD and risk factors
Choose between :
Single agent at low dose
Two-drug combination 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
Algorithm for treatment of hypertension
Lifestyle modifications
Not at goal BP (<140/90 mmHg or <130/80 mmHg for those with diabetes or chronic kidney disease)
Initial drug choices
Hypertension without compelling indications
Hypertension with compelling indications
Stage 1 hypertension
(SBP 140-159 or DBP 90-99 mmHg)
Stage 2 hypertension
(SBP ≥160 mmHg or DBP ≥100 mmHg)
Drug(s) for the compelling
indications
Thiazide-type diuretics for most
2-drug combination for most (usually
thiazide-type diuretic and ACE inhibitor
or ARB or -blocker or CCB)
Other antihypertensive drugs
(diuretics, ACE inhibitor, ARB,
-blocker, CCB) as needed
May consider ACE inhibitor, ARB, blocker, CCB, or combination
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
Normalization
of BP
Good
tolerability
Simple drug
regimen
Satisfaction
Day-to-day compliance 
Long-term compliance 