Expert Review: Heart Failure

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

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 in the result of several large randomized trials showing clear benefits, which include an increase in survival.

Knowledge Gap

However it is also true that in some cases the results were neutral or even negative – this was the case in the ELITE II randomized trial, which compared the survival benefits of losartan 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 heart failure patients as compared with candesartan.

Methods

The present study is a nationwide Danish registry-based cohort study. All patients were aged 45 years and older, were hospitalized for heart failure 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 included4397 users of losartan and 2082 users of candesartan. Among the patients prescribed losartan 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 heart failure 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

Among patients with heart failure, 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

This study was of sound design, with an accurate statistical methodology and an adequate patient sample size – these were considered among the strengths of the manuscript. However, a major limitation of the present study is that the findings apply only to the Danish population therefore rendering the generalability of the conclusions problematic.

The majority of outcomes trials assessing ARBs have been performed in 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 findings to a world-wide scale.

Nevertheless, the results agree with the solid bibliography in this field. For example, 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 article adds information that confirms previous findings and supports the use of losartan and candesartan in the optimal dosing , in patients chronic heart failure.

Corresponding author from original paper: Department of Epidemiology Research, Statens Serum Institut, Ørestads Boulevard 5, 206/305, 2300 København S Denmark. htr@ssi.dk

Citation: JAMA 2012 Apr 11; 307(14):1506-12

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