943 eligible patients; 14
100 (56.5%) were included in the study (). The number of discontinued patients was significantly higher in the losartan group compared to the candesartan group, 31.4% (n
=2123) vs 27.5% (n
<0.0001). Patients who were initially treated with losartan were also more frequently converted to another RAS inhibitor compared with candesartan-treated patients 13.9% (n
=939) vs 10.8% (n
<0.0001) during the study. Other reasons for discontinuations were death (2.3% (n
=155) vs 2.1% (n
=0.1588), in the losartan group and the candesartan group, respectively) or cessation of study drug prescription (15.2% (n
=1029] vs 14.6% (n
=0.3768), in the losartan group and the candesartan group, respectively).
To assess the effects of the difference in discontinuation, 265 discontinued subjects from the losartan group were omitted to obtain the proportion of discontinued subjects equal to the candesartan group, and the survival models were re-run. The 265 discontinued subjects were selected in three different ways: subjects with shortest exposure time, subjects with longest exposure time, and randomly in 1000 repeated analyses. None of these analyses changed the conclusions as compared with the primary survival model (data on file).
The proportion of included patients per year, from 1999 to 2007, was similar when comparing the losartan and candesartan group (data on file). All 72 primary care centres prescribed both losartan and candesartan, although in various ratios. The prescription ratio for losartan/candesartan had a linear range from 7 to 85% among the centres.
The losartan group were older (+0.7 years), had lower systolic and diastolic blood pressures (−1/−1
Hg), had higher blood glucose (+0.1
), had higher HbA1c (+0.1%), and had a higher prevalence of diabetes (+2.8%), were less frequently treated with thiazides (−2.3%) and β-blockers (−2.0%) and more frequently treated with glucose lowering drugs (+1.7%), statins (+1.3%), and antithrombotics (+0.8%) compared with the candesartan group ().
Table 1 Baseline data from 14100 hypertensive patients without previous cardiovascular disease
Some blood pressure recordings were absent at all time points. shows the similar blood pressure levels that were recorded during the follow-up, and also the number of missing values. The frequency of blood pressure recordings was equal in both groups. When calculating 95% CIs for the blood pressures values at each time point, no significant differences between the losartan and candesartan group were observed (data on file).
Blood pressure during follow-up. *No, number of patients with blood pressure readings; †, per cent blood pressure readings among patients at risk; Los, losartan; Can, candesartan.
During the study (median follow-up 2.0 years, maximal follow-up 9.0 years, and 36
339 patient years), 676 CVD events occurred in the losartan group, and 575 in the candesartan group (). The cumulative incidence of the primary composite end point was lower in the candesartan group compared to the losartan group () and the adjusted HR was 0.86 (95% CI 0.77–0.96, P
Clinical outcomes obtained from primary care journals and Swedish national discharge and death registers
Kaplan–Meier curves of primary composite end point.
illustrates the risk development among six separate end points. The cumulative incidence of heart failure, cardiac arrhythmias, and peripheral artery disease was lower with candesartan than losartan (, panels a, b, and c). Compared to losartan, the adjusted HR was lower for heart failure 0.64 (95% CI 0.50–0.82, P=0.0004), cardiac arrhythmias 0.80 (95% CI 0.65–0.98, P=0.0330), and peripheral artery disease 0.61 (95% CI 0.41–0.91, P=0.0140) in the candesartan group (). Cardiac arrhythmias were mainly because of atrial fibrillation (n=193, 91.9%), which had a separate adjusted HR of 0.77 (95% CI 0.62–0.95, P=0.0170).
Kaplan–Meier curves for separate end points. Los, losartan; Can, candesartan.
Chronic ischemic heart disease, myocardial infarction, and stroke showed similar cumulative incidence in both groups (, panels d, e, and f, respectively). The losartan group showed a small non-significant, increased incidence of the following events: chronic ischemic heart disease, myocardial infarction, stroke, hospitalization for unstable angina, elective coronary revascularization, cardiovascular mortality, total mortality, and new onset diabetes compared with the candesartan group (). No differences in risk for these events were found in proportional hazards regression models. Chronic ischemic heart disease was the exception and had an unadjusted lower risk in the candesartan group (0.80 (95% CI 0.66–0.99, P=0.0350)) compared with the losartan group.
shows that the use of both losartan and candesartan was according to prescribing recommendations for hypertension. The losartan group generally started with 50
mg and up-titrated to fixed combination 50/12.5
mg. The candesartan group, on the other side, mainly started with 4 and 8
mg in patients with higher blood pressure at baseline, +1/+1
Hg. Within the first 6 months these patients were up-titrated to 16 and 16/12.5
mg. Within the first 6 months losartan was up-titrated by 6.1% and candesartan by 13.2%.
Figure 5 Changes of losartan and candesartan doses during follow-up. Losartan 12.5mg and losartan/hydrochlorothiazide 100/12.5mg were used in very small numbers (<2% respectively) and were therefore excluded in the figure.
The frequency of fixed combination tablets (ARB+hydrochlorothiazide) in the losartan group rose from 24.7 to 60.5% (+35.9%) compared with an increase from 13.4 to 33.4% (+20.0%) in the candesartan group.
shows the use of other antihypertensive medications (thiazides, calcium channel blockers, and β-blockers) increased in both groups during follow-up. The use of thiazides (both separate and in fixed combination tablets) was more frequent in the losartan group compared to the candesartan group. Slightly more prescriptions of oral glucose lowering drugs at baseline and during follow-up were observed in the losartan group compared to the candesartan group.
Concomitant medications during 8 years of follow up. *Thiazides (ATC C03A A, C03A B, C09D A01, C09D A06), †dihydropyridine derivates (ATC C08 CA).
When additionally adjusting for lipid lowering drugs, thiazides, β-blockers, and antithrombotics the risk of CVD in the candesartan group remained significantly lower (HR 0.84, 95% CI 0.75–0.94, P=0.0030). When adding systolic blood pressure to the adjustments (age, gender, diabetes, index year, lipid lowering drugs, thiazides, β-blockers, and antithrombotics), the number of patients available for a survival analysis was reduced by 20% (n=11230) because of absent blood pressure values. However, despite this loss of patients in the survival model, the risk remained similar (HR 0.87, 95% CI 0.77–0.98, P=0.0250) compared with the primary survival model.
To further evaluate potential effects of differences at baseline, patients without a history of diabetes or treated with any glucose lowering drug (n=11 596) were analysed separately. When adjusting for age, gender, and index year, the risk of CVD remained similar (HR 0.86, 95% CI 0.76–0.98, P=0.0210) in patients without diabetes.