New European Guidelines and The Role of Low-dose Combinations
Bernard Waeber
Lausanne, Switzerland
ESH - ESC Guidelines, J Hypertens 2003
-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
Goals of treatment
Sympathetic nervous system
Renin-angiotensin system
Total body sodium
Patient 1 Patient 2 Patient 3
Dose titration
Percent
maximum effect
Dose arbitrary units
0
1
10
100
1000
10000
0
20
40
60
80
100
Therapeutic effect
Toxic effect
Critical dose
Optimal dose
Law et al, BMJ 2003
Percentage of patients with AE
Standard dose
Twice standard dose
Half standard dose
?-blockers
ACE inhibitors
Thiazides
Calcium antagonists
AT1-receptor blockers
20
15
10
5
0
-5
N° of trials :
59
96
62
96
44
Sequential monotherapy
Percentage of patients with
normal blood pressure
Drug A
0 20 40 60 80 100
%
Drugs C
Drug B
Achieved BP: <140/90 mmHg
Dickerson et al, Lancet, 1999
During monotherapy
(diuretic, b-blocker, ACE inhibitor or Ca antagonist)
%
39
0
20
40
60
80
BP control rate during antihypertensive monotherapy
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
0 20 40 60 80 100
%
Drugs A + B
Drug B
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 ?
Systolic
Diastolic
0 -5 -10 -5
Effects of two different drugs on BP separately and in combination (119 randomized placebo controlled trials)
Placebo-subtracted BP response. mmHg
Law et al, BMJ 2003
"First" drug alone
"Second" drug alone
Combination
On 1 drug
100
80
60
40
20
0
Percent
Percent of ALLHAT participants who achieved their goal blood pressure (SBP/DBP < 140/90 mmHg)
Cushman et al, J Clin Hypertens, 2002
0
6
12
24
36
48
60
On 2 drugs
On 3 drugs
On >4 drugs
% Controlled (<140/90 mmHg)
Frishman et al, Arch Intern Med, 1994
Bisoprolol
mg/d
A multifactorial trial design to assess combination therapy in hypertension
HCTZ
mg/d
512 patients with esential hypertension
3 x 4 factorial trial double-blind treatment
0
2.5
10
40
0
2.5
10
40
0
2.5
10
40
0
6.25
25
4 weeks
90
80
70
60
50
40
30
20
10
0
Response rate in sitting diastolic blood pressure (<90 mmHg)
Frishman et al, Arch Intern Med, 1994
Responses rate (%)
Bisoprolol 0 mg
Bisoprolol 2.5 mg
Bisoprolol 10 mg
Bisoprolol 40 mg
HCTZ 0 mg
HCTZ 6.25 mg
HCTZ 25 mg
Frishman et al, Arch Intern Med, 1994
Bisoprolol
mg/d
Mean change from baseline in serum potassium
HCTZ
mg/d
? Potassium concentration mmol/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
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)
%
Bisoprolol/HCTZ Amlodipine Enalapril Placebo
(n=77) (n=82) (n=84) (n=78)
77
56
44
21
p<0.001
p<0.01
Neutel et al, CVR and R, 1996
Neutel et al, CVR and R, 1996
Overall 17 33 38 58
discontinuations
(%)
Patients with 29 34 27 27
at least 1 AE (%)
Bisoprolol/HCTZ Enalapril
Amlodipine Placebo
7
6
5
4
3
2
1
0
Biological parameters at baseline and 12 weeks of treatment
Benetos et al, J Hypertens, 2002
mmol/l
Cholesterol
LDL
Cholesterol
HDL Cholesterol
Triglycerides
Baseline
12-week Biso/HCTZ
Glucose
Potassium
75 hypertensive patients
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
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
2 weeks
*
*
*
*
*
*
2 weeks
2 weeks
Papademetriou et al, CVR and R, 1998
ABPM
Maintenance phase 6 weeks
ABPM
* if DBP > 90 mmHg
5
0
-5
-10
-15
-20
Mean change from baseline in sitting DBP and SBP
Bis/HCTZ
Los:Los/HCTZ
Placebo
mmHg
# p < 0.05 vs Los/HCTZ
* p < 0.05 vs Placebo
#*
#*
*
*
Systolic
Diastolic
Treatment Groups
Papademetriou et al, CVR and R, 1998
2
0
-2
-4
-6
-8
-10
-12
-14
-16
-18
Mean change from baseline in 24 hr average diastolic and systolic ABPM
Bis/HCTZ
Los:Los/HCTZ
Placebo
mmHg
# p < 0.05 vs Los/HCTZ
* p < 0.05 vs Placebo
#*
*
*
*
Systolic
Diastolic
Treatment Groups
Papademetriou et al, CVR and R, 1998
Self-reported erectile dysfunction in prospective, randomized trials
Prisant et al, J Clin Hypertens, 1999
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
%
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 low-dose combinations
Advantages of fixed versus liberal combinations of two antihypertensive drugs
Fixed Liberal
Simplicity of treatment + -
Compliance + -
Efficacy + +
Tolerability +* -
Price + -
Flexibility - +
Risk of administering + - contraindicated