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en Journal of Human Hypertension (2010) 24, 263273
& 2010 Macmillan Publishers Limited All rights reserved 0950-9240/10 $32.00
www.nature.com/jhh
ORIGINAL ARTICLE
Effects of losartan vs candesartan in
reducing cardiovascular events in the
primary treatment of hypertension
SE Kjeldsen1, J Stalhammar2, P Hasvold3, J Bodegard3, U Olsson4 and D Russell5
1
l, Oslo, Norway; 2Department of Public Health
Department of Cardiology, Oslo University Hospital, Ulleva
and Caring Sciences, Uppsala University, Uppsala, Sweden; 3Medical Department, AstraZeneca AS, Oslo,
Norway; 4Statisticon AB, Uppsala, Sweden and 5Department of Neurology, Oslo University Hospital,
Rikshospitalet, Oslo, Norway
Although angiotensin receptor blockers have different cause register. There was no difference in blood pressure
receptor binding properties no comparative studies with reduction when comparing the losartan and candesartan
cardiovascular disease (CVD) end points have been groups during follow-up. Compared with the losartan
performed within this class of drugs. The aim of this study group, the candesartan group had a lower adjusted hazard
was to test the hypothesis that there are blood pressure ratio for total CVD (0.86, 95% confidence interval (CI) 0.77
independent CVD-risk differences between losartan and 0.96, P 0.0062), heart failure (0.64, 95% CI 0.500.82,
candesartan treatment in patients with hypertension with- P 0.0004), cardiac arrhythmias (0.80, 95% CI 0.650.92,
out known CVD. Seventy-two primary care centres in P 0.0330), and peripheral artery disease (0.61, 95% CI
Sweden were screened for patients who had been 0.410.91, P 0.0140). No difference in blood pressure
prescribed losartan or candesartan between the years reduction was observed suggesting that other mechan-
1999 and 2007. Among the 24 943 eligible patients, 14 100 isms related to different pharmacological properties of the
patients were diagnosed with hypertension and prescribed drugs may explain the divergent clinical outcomes.
losartan (n 6771) or candesartan (n 7329). Patients Journal of Human Hypertension (2010) 24, 263273;
were linked to Swedish national hospitalizations and death doi:10.1038/jhh.2009.77; published online 5 November 2009
mmHg
(mm Hg) 110
Diastolic blood pressure 89 (10) 90 (10) o0.0001 Mean arterial
100
(mm Hg)
Total cholesterol (mmol l1) 5.7 (1.0) 5.7 (1.1) 0.2243 90
LDL cholesterol (mmol l1) 3.34 (0.81) 3.39 (0.81) 0.0647
HDL cholesterol (mmol l1) 1.38 (0.32) 1.37 (0.31) 0.4826 80 Diastolic
Triglycerides (mmol l1) 1.64 (0.81) 1.62 (0.78) 0.2965
Glucose (mmol l1) 6.3 (2.4) 6.2 (2.3) 0.0024 70
HbA1c (%) 5.9 (1.4) 5.8 (1.4) 0.0342
60
Diabetes, n (%) 1215 (17.9) 1112 (15.2) o0.0001
Serum creatinine (mmol l1) 84 (21) 84 (19) 0.6895
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Potassium (mmol l1) 4.0 (0.4) 4.0 (0.4) 0.7452
Time (months)
Thiazides, n (%) 848 (12.5) 1087 (14.8) 0.0001
Calcium channel blockersa, 968 (14.3) 1104 (15.1) 0.2071 No.*
n (%) Can. 5860 4011 3908 2558 1703 1228 837 481 224
b-blockers, n (%) 1605 (23.7) 1883 (25.7) 0.0066 % 80.0 62.6 70.2 71.9 71.1 71.5 73.6 70.2 72.3
Oral glucose lowering 628 (9.3) 559 (7.6) 0.0005 Los. 5370 3662 3740 2510 1663 1172 792 453 236
drugs, n (%) % 79.3 61.7 70.8 73.9 72.4 71.5 67.1 71.6 72.2
Statins, n (%) 727 (10.7) 688 (9.4) 0.0084
Antithrombotics, n (%) 421 (6.2) 395 (5.4) 0.0386 Figure 2 Blood pressure during follow-up. *No, number of
Angiotensin receptor 101 (1.5) 120 (1.6) 0.5301 patients with blood pressure readings; w, per cent blood pressure
blockersb, n (%) readings among patients at risk; Los, losartan; Can, candesartan.
Angiotensin converting 1361 (20.1) 1459 (19.9) 0.7906
enzyme inhibitorsb, n (%)
end point was lower in the candesartan group
Numbers in brackets represent standard deviation, where no other compared to the losartan group (Figure 3) and the
description is given. adjusted HR was 0.86 (95% CI 0.770.96, P 0.0062)
a
Dihydropyridine substances. (Table 2).
b
Discontinued treatment before index prescription.
Figure 4 illustrates the risk development among
six separate end points. The cumulative incidence
of heart failure, cardiac arrhythmias, and peripheral
prescription ratio for losartan/candesartan had a artery disease was lower with candesartan than
linear range from 7 to 85% among the centres. losartan (Figure 4, panels a, b, and c). Compared to
The losartan group were older ( 0.7 years), losartan, the adjusted HR was lower for heart failure
had lower systolic and diastolic blood pressu- 0.64 (95% CI 0.500.82, P 0.0004), cardiac ar-
res (1/1 mm Hg), had higher blood glucose rhythmias 0.80 (95% CI 0.650.98, P 0.0330), and
( 0.1 mmol l1), had higher HbA1c ( 0.1%), and peripheral artery disease 0.61 (95% CI 0.410.91,
had a higher prevalence of diabetes ( 2.8%), were P 0.0140) in the candesartan group (Table 2).
less frequently treated with thiazides (2.3%) and Cardiac arrhythmias were mainly because of atrial
b-blockers (2.0%) and more frequently treated with fibrillation (n 193, 91.9%), which had a separate
glucose lowering drugs ( 1.7%), statins ( 1.3%), adjusted HR of 0.77 (95% CI 0.620.95, P 0.0170).
and antithrombotics ( 0.8%) compared with the Chronic ischemic heart disease, myocardial in-
candesartan group (Table 1). farction, and stroke showed similar cumulative
Some blood pressure recordings were absent at all incidence in both groups (Figure 4, panels d, e,
time points. Figure 2 shows the similar blood and f, respectively). The losartan group showed a
pressure levels that were recorded during the small non-significant, increased incidence of the
follow-up, and also the number of missing values. following events: chronic ischemic heart disease,
The frequency of blood pressure recordings was myocardial infarction, stroke, hospitalization for
equal in both groups. When calculating 95% CIs for unstable angina, elective coronary revascularization,
the blood pressures values at each time point, no cardiovascular mortality, total mortality, and new
significant differences between the losartan and onset diabetes compared with the candesartan group
candesartan group were observed (data on file). (Table 2). No differences in risk for these events
During the study (median follow-up 2.0 years, were found in proportional hazards regression
maximal follow-up 9.0 years, and 36 339 patient models. Chronic ischemic heart disease was the
years), 676 CVD events occurred in the losartan exception and had an unadjusted lower risk in
group, and 575 in the candesartan group (Table 2). the candesartan group (0.80 (95% CI 0.660.99,
The cumulative incidence of the primary composite P 0.0350)) compared with the losartan group.
Primary composite end pointb,c 676 (10.0) 575 (7.8) 0.79 (0.710.89) o0.0001 0.86 (0.770.96) 0.0062
Heart failurec 164 (2.4) 101 (1.4) 0.58 (0.450.74) o0.0001 0.64 (0.500.82) 0.0004
Cardiac arrhythmiasc 210 (3.1) 163 (2.2) 0.73 (0.600.90) 0.0029 0.80 (0.650.98) 0.0330
Peripheral artery diseasec,d 68 (1.0) 40 (0.5) 0.61 (0.380.83) 0.0035 0.61 (0.410.91) 0.0140
Chronic ischemic heart disease 202 (3.0) 172 (2.3) 0.80 (0.660.99) 0.0350 0.86 (0.701.05) 0.1400
Myocardial infarctionc 138 (2.0) 123 (1.7) 0.85 (0.661.08) 0.1800 0.93 (0.731.19) 0.5600
Strokec,e 157 (2.3) 146 (2.0) 0.88 (0.701.10) 0.2600 0.95 (0.761.19) 0.6400
Hospitalization for unstable angina 26 (0.4) 21 (0.3) 0.77 (0.431.36) 0.3600 0.80 (0.451.42) 0.4500
Elective coronary revascularization 18 (0.3) 14 (0.2) 0.74 (0.371.48) 0.3900 0.78 (0.391.58) 0.4900
Cardiovascular mortality 75 (1.1) 66 (0.9) 0.83 (0.601.16) 0.2800 0.93 (0.661.29) 0.6500
Total mortality 155 (2.3) 156 (2.1) 0.96 (0.771.20) 0.7100 1.06 (0.851.32) 0.6200
New onset diabetes 318 (4.7) 309 (4.2) 0.92 (0.791.08) 0.3000 0.90 (0.771.05) 0.1900
a
Adjusted for age, gender, diabetes, and index-year.
b
Primary composite end point consists of heart failure, cardiac arrhythmias, peripheral artery disease, chronic ischemic heart disease, myocardial
infarction, stroke, elective coronary revascularization, hospitalization for unstable angina, or cardiovascular mortality.
c
Includes fatal events.
d
Includes aortic aneurysms.
e
Ischemic, haemorrhagic stroke, and transient ischemic attacks.
25
20
15
10
5
Adjusted risk reduction 14.4% p=0.0062
0 Unadjusted risk reduction 20.6% p<0.0001
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time (months)
Number at risk
29 771
12
48
88
91
38
58
69
90
Los.
3
3
1
95
92
71
52
38
25
18
58
45
39
31
25
17
14
11
20
6
Can.
1
60
91
85
42
42
75
80
02
21
2
9
78
79
59
43
25
15
73
62
48
40
33
27
22
18
15
13
10
Figure 5 shows that the use of both losartan and were up-titrated to 16 and 16/12.5 mg. Within the
candesartan was according to prescribing recom- first 6 months losartan was up-titrated by 6.1% and
mendations for hypertension. The losartan group candesartan by 13.2%.
generally started with 50 mg and up-titrated to fixed The frequency of fixed combination tablets
combination 50/12.5 mg. The candesartan group, on (ARB hydrochlorothiazide) in the losartan group
the other side, mainly started with 4 and 8 mg in rose from 24.7 to 60.5% ( 35.9%) compared with
patients with higher blood pressure at baseline, 1/ an increase from 13.4 to 33.4% ( 20.0%) in the
1 mm Hg. Within the first 6 months these patients candesartan group.
Figure 6 shows the use of other antihypertensive treated with any glucose lowering drug (n 11 596)
medications (thiazides, calcium channel blockers, and were analysed separately. When adjusting for age,
b-blockers) increased in both groups during follow-up. gender, and index year, the risk of CVD remained
The use of thiazides (both separate and in fixed similar (HR 0.86, 95% CI 0.760.98, P 0.0210) in
combination tablets) was more frequent in the losartan patients without diabetes.
group compared to the candesartan group. Slightly
more prescriptions of oral glucose lowering drugs at
baseline and during follow-up were observed in the Discussion
losartan group compared to the candesartan group.
In this study, 14 100 patients in a primary preven-
tion setting were treated with either losartan
(n 6771) or candesartan (n 7329). They fulfilled
Sensitivity analyses the inclusion criteria of being hypertensive and
When additionally adjusting for lipid lowering without previously known CVD. Patients were
drugs, thiazides, b-blockers, and antithrombotics followed for a median of 2 years with a total of
the risk of CVD in the candesartan group remained 36 339 patient years, using the combination of
significantly lower (HR 0.84, 95% CI 0.750.94, patient journal data in 72 primary care centres and
P 0.0030). When adding systolic blood pressure to the mandatory Swedish national hospital discharge
the adjustments (age, gender, diabetes, index year, and cause of death registers. There was a substantial
lipid lowering drugs, thiazides, b-blockers, and blood pressure reduction after treatment with both
antithrombotics), the number of patients available drugs, with no difference in blood pressure between
for a survival analysis was reduced by 20% the two treatment groups during the follow-up
(n 11230) because of absent blood pressure values. period. Our results showed that candesartan was
However, despite this loss of patients in the survival more effective than losartan in reducing the risk of
model, the risk remained similar (HR 0.87, 95% CI primary composite end point, HR 0.86 (95% CI
0.770.98, P 0.0250) compared with the primary 0.7796, P 0.0062).
survival model. We used a method that uses the strengths of
To further evaluate potential effects of differences electronic patient registers, which cover large
at baseline, patients without a history of diabetes or patient groups, making them increasingly accessible
60
50
40
30
20
10
0
50 mg 100 mg 50 mg/12.5 mg 100 mg/25 mg
Index 12 24 36 48 60 72 84 96 months
60
50
40
30
20
10
0
4 mg 8 mg 16 mg 16 mg/12.5 mg
Index 12 24 36 48 60 72 84 96 months
Figure 5 Changes of losartan and candesartan doses during follow-up. Losartan 12.5 mg and losartan/hydrochlorothiazide 100/12.5 mg
were used in very small numbers (o2% respectively) and were therefore excluded in the figure.
Figure 6 Concomitant medications during 8 years of follow up. *Thiazides (ATC C03A A, C03A B, C09D A01, C09D A06),
wdihydropyridine derivates (ATC C08 CA).