Association of treatment with losartan vs candesartan and mortality among patients with heart failure

In the present study the authors asked whether losartan use is associated with increased all-cause mortality in heart failure (HF) patients compared with candesartan. Among patients with HF, the overall use of losartan compared with candesartan was not associated with an increased mortality risk. Although low doses of losartan were associated with increased mortality, there was no increased mortality comparing high-dose losartan against the highest doses of candesartan, highlighting the need for optimal dosing in this clinical setting.

Background

Angiotensin receptor blockers (ARBs) are considered first line drugs for the treatment of chronic heart failure in most international committee guidelines. This recommendation is based on the result of several large randomized trials showing clear benefits, which include an increase in survival.
Knowledge Gap

Despite the clear benefits of ARBs, it is also true that in some cases the results were neutral or even negative. That was the case in ELITE II randomized trial which compared the survival benefits of losartan as compared to those of captopril in chronic heart failure patients.
Aim of the Study

The aim of the present study was to clarify whether losartan use is associated with increased all-cause mortality in HF patients as compared with candesartan.
Methods: The present study is a nationwide Danish registry-based cohort study, including all patients aged >45 years, hospitalized for HF from 1998 to 2008 and were prescribed losartan or candesartan for the first time. All cause mortality was considered as the primary outcome measure.
Results

The study included 4397 patients recieving losartan and 2082 recieving candesartan. Among the losartan-prescribed patients, 1212 deaths were recorded during 11,347 person-years of follow-up (unadjusted incidence rate [IR]/100 person-years, 10.7; 95% CI, 10.1-11.3) compared with 330 deaths during 3675 person-years among candesartan prescribed HF patients (unadjusted IR/100 person-years, 9.0; 95% CI, 8.1-10.0). Compared with candesartan, losartan was not associated with increased all-cause mortality (adjusted hazard ratio [HR], 1.10; 95% CI, 0.96-1.25) or cardiovascular mortality (adjusted HR, 1.14; 95% CI, 0.96-1.36). Compared with high doses of candesartan (16-32 mg), low-dose (12.5 mg) and medium-dose losartan (50 mg) were associated with increased mortality (HR, 2.79; 95% CI, 2.19-3.55 and HR, 1.39; 95% CI, 1.11-1.73, respectively); use of high-dose losartan (100 mg) was similar in risk (HR, 0.71; 95% CI, 0.50-1.00).
Conclusion

In patients with HF, overall use of losartan compared with candesartan was not associated with an increased mortality risk. Although low doses of losartan were associated with increased mortality, there was no increased mortality comparing high-dose losartan against the highest doses of candesartan.
Perspective-Clinical Impact

Sound study design, accurate statistical methodology and adequate patients sample size are considered among the strengths of this manuscript. However, a major limitation of the present study was that the findings apply only to the Danish population, therefore rendering the generalization of the conclusions problematic. The majority of outcomes trials assessing ARBs have been performed in the context of multi-centre mega-trials that incorporate populations from many different countries, including patients from different races, on variable diets and subject to diverse climates. Therefore, caution is warranted when applying these new findings to a worldwide scale.

Nevertheless, the results agree with solid bibliography in this field. The outlined ‘dose-related effect’ has been also observed in the HEAAL study (which compared losartan low -50mg- vs high -150 mg- dose), where findings clearly favoured the higher dose, showing lower mortality in the arm receiving high-dose losartan 150 mg.
In summary, the study adds information to confirm previous findings and support the use of losartan and candesartan in the optimal dosing in patients chronic HF.

Corresponding author from original paper

Svanström H, Pasternak B, Hviid A. Department of Epidemiology Research, Statens Serum Institut, Ørestads Boulevard 5, 206/305, 2300 København S Denmark.  htr@ssi.dk 

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