High- versus low-dose losartan and uric acid: An analysis from HEAAL.

BACKGROUND: Serum uric acid (SUA) is activated in catabolic, hypoxic, and inflammatory conditions characteristic of heart failure (HF) and is a source of reactive oxygen species. Losartan is unique among other angiotensin receptor blockers in reducing SUA. OBJECTIVES: To study the patient characteristics and outcome associations by SUA levels, as well as the effect of high- vs. low-dose losartan on SUA levels in HF. METHODS: HEAAL was a double-blind trial, comparing the effect of two doses of losartan 150 (high dose) vs. 50 (low dose) mg/day among 3834 patients with symptomatic HF, a left ventricular ejection fraction≤40 %, and known intolerance to angiotensin-converting enzyme inhibitors. In the present study, we studied the associations of SUA with outcomes and the effect of high- vs. low-dose losartan on SUA levels, incident hyperuricemia, and gout. RESULTS: Patients with higher SUA had more comorbidities, worse renal function, were more symptomatic, used diuretics more frequently, and were 1.5- to 2-fold more likely to experience HF hospitalizations and cardiovascular death. The benefit of high-dose losartan to improve HF outcomes was not influenced by baseline SUA levels (interaction p > 0.1). Compared with low-dose, high-dose losartan reduced SUA by -0.27 (-0.34 to -0.21) mg/dL, p < 0.001. The incidence of hyperuricemia was reduced with high-dose losartan, but the incidence of gout was not. CONCLUSIONS: In HEAAL, hyperuricemia was associated with worse outcomes. High-dose losartan reduced SUA and hyperuricemia more than low-dose and the cardiovascular benefits of high-dose losartan were not modified by SUA levels.

High- Versus Low-dose Losartan and Serum Potassium: An Analysis From HEAAL.

BACKGROUND: Patients with heart failure (HF) experience frequent alterations of serum potassium. Despite the high risk of events associated with hypokalemia, hyperkalemia is feared by clinicians and often leads to interruption or discontinuation of renin-angiotensin-aldosterone system inhibitors. Data on serum potassium of patients treated with different doses of renin-angiotensin-aldosterone system inhibitors are scarce. METHODS AND RESULTS: The effects of high-dose vs low-dose losartan on clinical outcomes in patients with heart failure (HEAAL) trial randomized 3834 patients with HFrEF intolerant to angiotensin-converting enzyme inhibitors to losartan 150 mg/d (high dose) vs 50 mg/d (low dose). We studied the associations of serum potassium (baseline and time updated) with study outcomes and the effect of the randomized treatment on serum potassium. Patients with higher baseline potassium were older, had diabetes, poorer renal function, and used mineralocorticoid receptor antagonists more frequently. In time-updated models, hyperkalemia (>5.0 or ≥5.5 mmol/L) was not associated with cardiovascular death or the composite of cardiovascular death or HF hospitalization. Hypokalemia (serum potassium of ≤3.5 mmol/L, in particular) was associated with a higher risk of the composite of cardiovascular death or HF hospitalization (hazard ratio [HR] 1.58, 95% confidence interval [CI] 1.19-2.08), all-cause death (HR 1.68, 95% CI 1.26-2.24), and sudden cardiac death or resuscitated cardiac arrest (HR 1.74, 95% CI 1.11-2.73). High-dose losartan decreased the risk of hypokalemia (HR 0.77, 95% CI 0.63-0.92) and increased the risk of hyperkalemia (HR 1.21, 95% CI 1.05-1.39). High-dose losartan decreased the composite of cardiovascular death or HF hospitalizations consistently across the full spectrum of serum potassium at baseline (interaction P = .85). CONCLUSIONS: In patients with HF with reduced ejection fraction intolerant to angiotensin-converting enzyme inhibitors and treated with either high- or low-dose losartan, incident hypokalemia had a stronger association with poor outcomes than incident hyperkalemia. High-dose losartan reduced the incidence of hypokalemia, and its benefits were maintained across the full spectrum of serum potassium.

Determinants of Diuretic Responsiveness and Associated Outcomes During Acute Heart Failure Hospitalization: An Analysis From the NHLBI Heart Failure Network Clinical Trials.

BACKGROUND: Poor response to loop diuretic therapy is a marker of risk during heart failure hospitalization. We sought to describe baseline determinants of diuretic response and to further explore the relationship between this response and clinical outcomes. METHODS AND RESULTS: Patient data from the National Heart, Lung, and Blood Institute Heart Failure Network ROSE-AHF and CARRESS-HF clinical trials were analyzed to determine baseline determinants of diuretic response. Diuretic efficiency (DE) was defined as total 72-hour fluid output per total equivalent loop diuretic dose. Data from DOSE-AHF was then used to determine if these predictors of DE correlated with response to a high- versus low-dose diuretic strategy. At 72 hours, the high-DE group had median fluid output of 9071 ml (interquartile range: 7240-11775) with median furosemide dose of 320 mg (220-480) compared with 8030 ml (6300-9915) and 840 mg (600-1215) respectively for the low DE group. Cystatin C was independently associated with DE (odds ratio 0.36 per 1mg/L increase; 95% confidence interval: 0.24-0.56; P < 0.001). Independently from baseline characteristics, reduced fluid output, weight loss and DE were each associated with increased 60 day mortality. Among patients with estimated glomerular filtration rate below the median, those randomized to a high-dose strategy had improved symptoms compared with those randomized to a low-dose strategy. CONCLUSIONS: Elevated baseline cystatin C, as a biomarker of renal dysfunction, is associated with reduced diuretic response during heart failure hospitalization. Higher loop diuretic doses are required for therapeutic decongestion in patients with renal insufficiency. Poor response identifies a high-risk population.

Early and late effects of high- versus low-dose angiotensin receptor blockade on renal function and outcomes in patients with chronic heart failure.

OBJECTIVES: 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).

Cardiovascular function and treatment in ß-thalassemia major: a consensus statement from the American Heart Association.

This aim of this statement is to report an expert consensus on the diagnosis and treatment of cardiac dysfunction in ß-thalassemia major (TM). This consensus statement does not cover other hemoglobinopathies, including thalassemia intermedia and sickle cell anemia, in which a different spectrum of cardiovascular complications is typical. There are considerable uncertainties in this field, with a few randomized controlled trials relating to treatment of chronic myocardial siderosis but none relating to treatment of acute heart failure. The principles of diagnosis and treatment of cardiac iron loading in TM are directly relevant to other iron-overload conditions, including in particular Diamond-Blackfan anemia, sideroblastic anemia, and hereditary hemochromatosis. Heart failure is the most common cause of death in TM and primarily results from cardiac iron accumulation. The diagnosis of ventricular dysfunction in TM patients differs from that in nonanemic patients because of the cardiovascular adaptation to chronic anemia in non-cardiac-loaded TM patients, which includes resting tachycardia, low blood pressure, enlarged end-diastolic volume, high ejection fraction, and high cardiac output. Chronic anemia also leads to background symptomatology such as dyspnea, which can mask the clinical diagnosis of cardiac dysfunction. Central to early identification of cardiac iron overload in TM is the estimation of cardiac iron by cardiac T2* magnetic resonance. Cardiac T2* <10 ms is the most important predictor of development of heart failure. Serum ferritin and liver iron concentration are not adequate surrogates for cardiac iron measurement. Assessment of cardiac function by noninvasive techniques can also be valuable clinically, but serial measurements to establish trends are usually required because interpretation of single absolute values is complicated by the abnormal cardiovascular hemodynamics in TM and measurement imprecision. Acute decompensated heart failure is a medical emergency and requires urgent consultation with a center with expertise in its management. The first principle of management of acute heart failure is control of cardiac toxicity related to free iron by urgent commencement of a continuous, uninterrupted infusion of high-dose intravenous deferoxamine, augmented by oral deferiprone. Considerable care is required to not exacerbate cardiovascular problems from overuse of diuretics or inotropes because of the unusual loading conditions in TM. The current knowledge on the efficacy of removal of cardiac iron by the 3 commercially available iron chelators is summarized for cardiac iron overload without overt cardiac dysfunction. Evidence from well-conducted randomized controlled trials shows superior efficacy of deferiprone versus deferoxamine, the superiority of combined deferiprone with deferoxamine versus deferoxamine alone, and the equivalence of deferasirox versus deferoxamine.