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Post hoc analyses of the Digitalis Investigation Group (DIG) trial indicate that digoxin at low (0.5 to 0.9 ng/ml) serum digoxin concentration (SDC) reduces mortality, which is eliminated at higher (≥1 ng/ml) SDC, and that low-dose digoxin (≤0.125 mg/day) predicts low SDC. In the DIG trial, patients with ambulatory chronic systolic and diastolic heart failure (HF) (n = 7,788) in normal sinus rhythm receiving angiotensin-converting enzyme inhibitors and diuretics were randomized to receive placebo (n = 3,899) or digoxin (n = 3,889). The median dose of digoxin (0.25 mg/day) and the target SDC (0.8 to 2.5 ng/ml) were higher than what are currently recommended, which in part may explain the lack of long-term mortality benefit of digoxin in the DIG trial. To test this hypothesis, we examined the effect of digoxin on short-term outcomes; 1-year all-cause mortality occurred in 392 and 448 patients respectively in the digoxin and placebo groups (hazard ratio for digoxin 0.87, 95% confidence interval [CI] 0.76 to 0.995, p = 0.043). Respective hazard ratios for cardiovascular and HF deaths were 0.87 (95% CI 0.76 to 1.01, p = 0.072) and 0.66 (95% CI 0.52 to 0.85, p = 0.001). All-cause hospitalization occurred in 1,411 and 1,529 patients receiving digoxin and placebo respectively (hazard ratio 0.89, 95% CI 0.83 to 0.96, p = 0.002). Respective hazard ratios for cardiovascular and HF hospitalizations were 0.82 (95% CI 0.75 to 0.89, p <0.0001) and 0.59 (95% CI 0.52 to 0.66, p <0.0001). In conclusion, digoxin reduced 1-year mortality and hospitalization in patients with chronic HF receiving angiotensin-converting enzyme inhibitors and diuretics. Randomized clinical trials are needed to determine the effect of low-dose digoxin in contemporary patients with chronic HF. [Copyright &y& Elsevier]

Background: In the Studies of Left Ventricular Dysfunction (SOLVD) treatment trial, similar clinical benefits were observed between starting doses of enalapril and the target dose achieved by postrandomization up-titration. In our current analysis, protecting the randomization, we examined the early effects of starting doses of enalapril.Methods: There were 2569 patients with mild-to-moderate chronic heart failure with reduced ejection fraction (ejection fraction ≤35%) randomized to receive starting doses (5-10 mg/day) of placebo (n = 1284) or enalapril (n = 1285). At day 14, both study drugs were blindly up-titrated to the target dose (20 mg/day). Overall, 96% (2458/2569) of the patients returned for dose up-titration, which was achieved in 59% (1444/2458), 48% (696/1444) of whom were in the enalapril group. Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes in the enalapril group were estimated.Results: HRs (95% CIs) for all-cause mortality, heart failure hospitalization, and the combined endpoint of heart failure hospitalization or all-cause mortality at 14 days after randomization were 0.80 (0.32-2.03), 0.63 (0.35-1.12), and 0.65 (0.39-1.06), respectively. Corresponding HRs (95% CIs) at 30 days were 0.82 (0.41-1.67), 0.43 (0.27-0.68), and 0.43 (0.27-0.68), respectively. The magnitude of these early effects of starting doses of enalapril is similar to its previously reported long-term effects at the target dose.Conclusion: These data suggest that in stable ambulatory patients with heart failure with reduced ejection fraction, the magnitude of the early effect of starting doses of enalapril is similar to that observed during longer-term therapy with the target doses of the drug. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated the influence of baseline and worsening renal function (WRF) on the efficacy of spironolactone in patients with severe heart failure (HF). Background: Renal dysfunction or decline in renal function is a known predictor of adverse outcome in patients with HF, and treatment decisions are often on the basis of measures of renal function. Methods: We used data from the RALES (Randomized Aldactone Evaluation Study) in 1,658 patients with New York Heart Association functional class III or IV HF and an ejection fraction <35%. Participants were randomized to spironolactone 25 mg, which could be titrated to 50 mg, or placebo daily. Renal function (estimated glomerular filtration rate [eGFR]) was estimated by the Modification of Diet in Renal Disease equation. Worsening renal function was defined as a 30% reduction in eGFR from baseline to 12 weeks post-randomization. Results: Individuals with reduced baseline eGFR exhibited similar relative risk reductions in all-cause death and the combined endpoint of death or hospital stays for HF as those with a baseline eGFR >60 ml/min/1.73 m2 and greater absolute risk reduction compared with those with a higher baseline eGFR (10.3% vs. 6.4%). Moreover, WRF (17% vs. 7% for spironolactone and placebo groups, p < 0.001) was associated with an increased adjusted risk of death in the placebo group (hazard ratio: 1.9, 95% confidence interval: 1.3 to 2.6) but not in those randomized to spironolactone (hazard ratio: 1.1, 95% confidence interval: 0.79 to 1.5, p interaction = 0.009). The risk of hyperkalemia and renal failure was higher in those with worse baseline renal function and those with WRF, particularly in the spironolactone arm, but the substantial net benefit of spironolactone therapy remained. Conclusions: The absolute benefit of spironolactone was greatest in patients with reduced eGFR. Worsening renal function was associated with a negative prognosis, yet the mortality benefit of spironolactone was maintained. [Copyright &y& Elsevier]

Background: Older people are predisposed to hyperkalemia because of impaired renal function, comorbid conditions, and polypharmacy. Renin-angiotensin-aldosterone system inhibitors (RAASi), which are recommended to treat chronic kidney disease and heart failure augment the risk. Patiromer, a nonabsorbed potassium binder, was shown in the phase 3 OPAL-HK study to decrease serum potassium in patients with chronic kidney disease taking RAASi. We studied the efficacy and safety of patiromer in a prespecified subgroup of patients aged ≥65 years from OPAL-HK.Methods: Chronic kidney disease patients with mild or moderate-to-severe hyperkalemia received patiromer, initially 8.4 g/d or 16.8 g/d, respectively, for 4 weeks (treatment phase, part A). Eligible patients entered an 8-week randomized withdrawal phase (part B) and continued patiromer or switched to placebo.Results: Mean ± standard error change in serum potassium from baseline to week 4 of part A (primary endpoint) in patients aged ≥65 years was -1.01 ± 0.05 mEq/L (P < .001); 97% achieved serum potassium 3.8-<5.1 mEq/L. The serum potassium increase during the first 4 weeks of part B was greater in patients taking placebo than in those taking patiromer (P < .001). Fewer patients taking patiromer (30%) than placebo (92%) developed recurrent hyperkalemia (serum potassium ≥5.1 mEq/L). Mild-to-moderate constipation occurred in 15% (part A) and 7% (part B) of patients aged ≥65 years. Serum potassium <3.5 mEq/L and serum magnesium <1.4 mg/dL were infrequent (4% each in patients aged ≥65 years in part A).Conclusions: Patiromer reduced recurrent hyperkalemia and was well tolerated in older chronic kidney disease patients taking RAASi. [ABSTRACT FROM AUTHOR]