Early and late effects of high- versus low-dose angiotensin receptor blockade on renal function and outcomes in patients with chronic heart failure.
OBJECTIVE
This study investigated the dose-related effect of losartan on changes in renal function using data from the HEAAL (Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan) trial.


BACKGROUND
Angiotensin receptor blockers adversely affect renal function in patients with heart failure (HF). The time course and dose dependency of this time course, as well as the clinical implications of these changes in renal function, are not well described.


METHODS
Subjects in the HEAAL dataset (n = 3,843) were studied. Changes in estimated glomerular filtration rate (eGFR) over time were compared between dose groups. The association between the timing of incident increases in serum creatinine (SCr) >0.3 mg/dl and clinical outcomes was explored.


RESULTS
Compared with 50 mg, 150 mg losartan led to a greater reduction in eGFR across time (mean difference:-3.76 ml/min/1.73 m(2); p < 0.0001). This difference was driven by early changes, and differences in eGFRafter 4 months were not significant (mean difference: 0.42 ml/min/1.73 m(2); p = 0.15) [corrected]. Although an increase in SCr >0.3 mg/dl from baseline was associated with increased risk of death or hospitalization for HF (hazard ratio [HR]: 1.36; p < 0.0001), the relationship was not significant if the change occurred before 4 months (HR: 1.09; p = 0.20). Despite increased risk of worsening renal function, 150 mg losartan was associated with reduced risk of death or hospitalization for HF compared with 50 mg (HR: 0.85; p < 0.0001).


CONCLUSIONS
Compared with 50 mg, 150 mg losartan is associated with an increased risk of acute rise in SCr, as well as with greater long-term reductions in eGFR. Despite these effects, high-dose losartan retains its net clinical benefit and is associated with reduced risk of death or hospitalization for HF. (Study to Evaluate Potential Decrease in Hospitalization Events, Time Between Events, and Increasing Longevity in Patients With Symptomatic Heart Failure; NCT00090259).
Division of Cardiology, Tufts Medical Center, Boston, Massachusetts. Electronic address: mkiernan@tuftsmedicalcenter.org.
Michael S
MS
Kiernan
Cardiovascular Clinical Science Foundation, Boston, Massachusetts.
Douglas
D
Gregory
Division of Nephrology, Tufts Medical Center, Boston, Massachusetts.
Mark J
MJ
Sarnak
Inserm 1433 Clinical Investigation Centre, Nancy University Hospital & University of Lorraine, Nancy and INI-CRCT F-CRIN, Nancy, France.
Patrick
P
Rossignol
Boston University School of Public Health, Boston, Massachusetts.
Joseph
J
Massaro
Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Robb
R
Kociol
Inserm 1433 Clinical Investigation Centre, Nancy University Hospital & University of Lorraine, Nancy and INI-CRCT F-CRIN, Nancy, France.
Faiez
F
Zannad
Division of Cardiology, Tufts Medical Center, Boston, Massachusetts.
Marvin A
MA
Konstam
D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D019808:Losartan / Q000008:administration & dosage*; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome
D057911:Angiotensin Receptor Antagonists; D019808:Losartan
angiotensin receptor blocker; heart failure; renal failure