JAMA: HF patients given high-dose losartan not at increased risk of death

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Counter to some findings, a large prospective study of two angiotensin II receptor blockers (ARBs) found no increased risk of death in heart failure (HF) patients taking a high dose of losartan (Cozaar, Merck) compared with higher doses of candesartan (Atacand, AstraZeneca). Low doses of losartan, though, were associated with increased mortality. The study was published in the April 11 issue of the Journal of the American Medical Association.

Henrik Svanström, MSc, of the epidemiology department at Statens Serum Institut in Copenhagen, Denmark, and colleagues wrote that no randomized controlled clinical trials have been conducted to compare losartan with candesartan in HF patients. Observational studies comparing losartan with other ARBs and with candesartan showed that losartan may be associated with increased mortality in the patient population, though.

To test whether losartan use was associated with increased all-cause mortality in HF patients compared with candesartan, they turned to a number of Danish databases: the Danish Civil Registration System, which includes a unique civil registration number for people living in Denmark; the Danish National Patient Registry for patients with incident HF hospitalizations between 1998 and 2008; the National Prescription Registry for individual-level data on the use of ARBs; and the Danish Cause of Death Register for cause of death.

They identified 6,479 patients who were 45 years old or older with a first time hospitalization for HF who were new users of either losartan (4,397 patients) or candesartan (2,082 patients).  They used Cox proportional hazard regression models to compare the risks of all-cause mortality and cardiovascular mortality between the two groups.

They found that losartan users on average were older and had higher prevalence of cardiovascular comorbidities. Within 19,491 person-years of follow-up, 330 patients in the candesartan group died and 1,212 in the losartan group died. The candesartan group had a shorter median treatment duration, 1.1 years, compared with 1.8 years for the losartan group.

The results showed that a 12.5 mg dose of losartan was associated with a more than two-fold increased risk of death compared with doses of 16 mg to 32 mg of candesartan and a 50 mg dose of losartan also had a higher mortality risk. But a 100 mg dose of losartan did not have an increased risk of mortality.

“Overall, use of losartan was not associated with increased all-cause mortality or cardiovascular mortality,” Svanström and colleagues wrote. “Compared with high doses of candesartan, use of low- and medium-dose losartan was associated with increased mortality, as was low-dose candesartan, but use of high-dose losartan was not.”

Their study included a wide range of comorbidities, they wrote, which distinguishes their work from previous studies and may be a factor in the conflicting results. They suggested that not accounting for differences in comorbidities may have exaggerated the benefit of candesartan. “Compared with previous observational studies, our data provide a more detailed insight into the complexity of the association between losartan use and mortality risk in heart failure,” they wrote.

They observed that patients given lower doses of candesartan also were at an increased risk of death compared with those using high doses. “Given these findings, it cannot simply be concluded that any single drug of losartan and candesartan is superior to the other in patients with heart failure, but rather that differential effects may be expected according to the dose achieved,” they continued.

They acknowledged that unmeasured confounding also may be a factor in the results, and noted that the data lacked clinical measures of HF severity and could only show ARBs were prescribed, not prove they were taken. While the nationwide data represented patients experiencing a first-time HF hospitalization, the results may not be generalizable to different types of HF patients.