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Aims: We evaluated the effects of patiromer, a potassium (K(+))-binding polymer, in a pre-specified analysis of hyperkalaemic patients with heart failure (HF) in the OPAL-HK trial.Methods and Results: Chronic kidney disease (CKD) patients on renin-angiotensin-aldosterone system inhibitors (RAASi) with serum K(+) levels ≥5.1 mEq/L to <6.5 mEq/L (n = 243) received patiromer (4.2 g or 8.4 g BID initially) for 4 weeks (initial treatment phase); the primary efficacy endpoint was mean change in serum K(+) from baseline to week 4. Eligible patients (those with baseline K(+) ≥5.5 mEq/L to <6.5 mEq/L and levels ≥3.8 mEq/L to <5.1 mEq/L at the end of week 4) entered an 8-week randomized withdrawal phase and were randomly assigned to continue patiromer or switch to placebo; the primary efficacy endpoint was the between-group difference in median change in the serum K(+) over the first 4 weeks of that phase. One hundred and two patients (42%) had heart failure (HF). The mean [± standard error (SE)] change in serum K(+) from baseline to week 4 was -1.06 ± 0.05 mEq/L [95% confidence interval (CI), -1.16,-0.95; P < 0.001]; 76% (95% CI, 69,84) achieved serum K(+), 3.8 mEq/L to <5.1 mEq/L. In the randomized withdrawal phase, the median increase in serum K(+) from baseline of that phase was greater with placebo (n = 22) than patiromer (n = 27) (P < 0.001); recurrent hyperkalaemia (serum K(+), ≥5.5 mEq/L) occurred in 52% on placebo and 8% on patiromer (P < 0.001). Mild-to-moderate constipation was the most common adverse event (11%); hypokalaemia occurred in 3%.Conclusion: In patients with CKD and HF who were hyperkalaemic on RAASi, patiromer was well tolerated, decreased serum K(+), and, compared with placebo, reduced recurrent hyperkalaemia. [ABSTRACT FROM AUTHOR]

Background: The ELITE study showed an association between the angiotensin II antagonist losartan and an unexpected survival benefit in elderly heart-failure patients, compared with captopril, an angiotensin-converting-enzyme (ACE) inhibitor. We did the ELITE II Losartan Heart Failure Survival Study to confirm whether losartan is superior to captopril in improving survival and is better tolerated.Methods: We undertook a double-blind, randomised, controlled trial of 3,152 patients aged 60 years or older with New York Heart Association class II-IV heart failure and ejection fraction of 40% or less. Patients, stratified for beta-blocker use, were randomly assigned losartan (n=1,578) titrated to 50 mg once daily or captopril (n=1,574) titrated to 50 mg three times daily. The primary and secondary endpoints were all-cause mortality, and sudden death or resuscitated arrest. We assessed safety and tolerability. Analysis was by intention to treat.Findings: Median follow-up was 555 days. There were no significant differences in all-cause mortality (11.7 vs 10.4% average annual mortality rate) or sudden death or resuscitated arrests (9.0 vs 7.3%) between the two treatment groups (hazard ratios 1.13 [95.7% CI 0.95-1.35], p=0.16 and 1.25 [95% CI 0.98-1.60], p=0.08). Significantly fewer patients in the losartan group (excluding those who died) discontinued study treatment because of adverse effects (9.7 vs 14.7%, p<0.001), including cough (0.3 vs 2.7%). [ABSTRACT FROM AUTHOR]

During ATMOSPHERE, a trial comparing aliskiren, enalapril, or both for heart failure, two other trials suggested harm from aliskiren in patients with diabetes, and regulators stopped aliskiren in such patients in ATMOSPHERE. The data monitoring committee suggests that regulators should trust the DMC to ensure patient safety in a clinical trial. The trial sponsor (Novartis) and the regulatory agencies have responded in letters to the editor. [ABSTRACT FROM AUTHOR]

Background: and Methods Aldosterone is important in the pathophysiology of heart failure. In a double-blind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting–enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes. Results: The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P<0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confidence interval, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P<0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious hyperkalemia was minimal in both groups of patients. Conclusions: Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure. (N Engl J Med 1999:341:709-17.) [ABSTRACT FROM AUTHOR]

Aims: To examine associations of below-target and target dose of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, with outcomes in patients with heart failure and reduced ejection fraction (HFrEF) in the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial.Methods and Results: Two thousand five hundred and sixty-nine patients with HFrEF (ejection fraction ≤35%) were randomized to below-target (5-10 mg/day) dose placebo (n = 1284) or enalapril (n = 1285). One month post-randomization, blind up-titration to target (20 mg/day) dose was attempted for both study drugs in 2458 patients. Among the 1444 patients who achieved dose up-titration (placebo, n = 748; enalapril, n = 696; mean dose for both groups, 20.0 mg/day), target dose enalapril (vs. target dose placebo) was associated with a 9% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality [adjusted hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.60-0.81; P < 0.001] during 4 years of follow-up. Among the 1014 patients who could not achieve target dose (placebo, n = 486; enalapril, n = 528; mean dose for both groups, 8.8 mg/day), below-target dose enalapril (vs. below-target dose placebo) was associated with a 12% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 0.68; 95% CI 0.57-0.81; P < 0.001). Among the 1224 patients receiving enalapril, target (vs. below-target) dose had no association with the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 1.04; 95% CI 0.87-1.23; P = 0.695).Conclusion: In patients with HFrEF, the clinical benefits of ACE inhibitors appear to be similar at both below-target and target doses. [ABSTRACT FROM AUTHOR]

Aims To examine associations of below-target and target dose of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, with outcomes in patients with heart failure and reduced ejection fraction (HFrEF) in the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial. Methods and results Two thousand five hundred and sixty-nine patients with HFrEF (ejection fraction =35%) were randomized to below-target (5-10 mg/day) dose placebo (n = 1284) or enalapril (n = 1285). One month post-randomization, blind up-titration to target (20 mg/day) dose was attempted for both study drugs in 2458 patients. Among the 1444 patients who achieved dose up-titration (placebo, n=748; enalapril, n=696; mean dose for both groups, 20.0 mg/day), target dose enalapril (vs. target dose placebo) was associated with a 9% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality [adjusted hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.60-0.81; P < 0.001] during 4 years of follow-up. Among the 1014 patients who could not achieve target dose (placebo, n=486; enalapril, n=528; mean dose for both groups, 8.8 mg/day), below-target dose enalapril (vs. below-target dose placebo) was associated with a 12% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 0.68; 95% CI 0.57-0.81; P < 0.001). Among the 1224 patients receiving enalapril, target (vs. below-target) dose had no association with the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 1.04; 95% CI 0.87-1.23; P = 0.695). Conclusion In patients with HFrEF, the clinical benefits of ACE inhibitors appear to be similar at both below-target and target doses. [ABSTRACT FROM AUTHOR]

The article presents a randomized, double-blind trial which tests the efficacy of hypertension treatment with a combination angiotensin-converting-enzyme (ACE) inhibitor and a dihydropyridine calcium-channel blocker compared with treatment with an ACE inhibitor plus a thiazide diuretic in reducing the rate of cardiovascular events. 11,506 patients with hypertension at high risk for cardiovascular events received treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide. The time to the first event, a composite of cardiovascular event and death from cardiovascular causes, was the primary endpoint. Researchers found that the combination treatment benazepril with amlodipine was superior to benazepril with hydrochlorothiazide in reducing cardiovascular events.

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]