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Background: Renin-angiotensin system inhibitors improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, less is known about their effectiveness in patients with HFrEF and advanced kidney disease., Methods: In the Medicare-linked Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF), 1582 patients with HFrEF (ejection fraction ≤40%) had advanced kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m 2 ). Of these, 829 were not receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) prior to admission, of whom 214 were initiated on these drugs prior to discharge. We calculated propensity scores for receipt of these drugs for each of the 829 patients and assembled a matched cohort of 388 patients, balanced on 47 baseline characteristics (mean age 78 years; 52% women; 10% African American; 73% receiving beta-blockers). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated comparing 2-year outcomes in 194 patients initiated on ACE inhibitors or ARBs to 194 patients not initiated on those drugs., Results: The combined endpoint of heart failure readmission or all-cause mortality occurred in 79% and 84% of patients initiated and not initiated on ACE inhibitors or ARBs, respectively (HR associated with initiation, 0.79; 95% CI, 0.63-0.98). Respective HRs (95% CI) for the individual endpoints of - Respective HRs (95% CI) for the individual endpoints of all-cause mortality and heart failure readmission were 0.81 (0.63-1.03) and 0.63 (0.47-0.85)., Conclusions: The findings from our study add new information to the body of cumulative evidence that suggest that renin-angiotensin system inhibitors may improve clinical outcomes in patients with HFrEF and advanced kidney disease. These hypothesis-generating findings need to be replicated in contemporary patients., (Published by Elsevier Inc.)

Background: Recent evidence suggests that the mineralocorticoid receptor antagonist spironolactone should be the preferred fourth-line antihypertensive treatment in resistant hypertension (RHTN). Whether spironolactone improves blood pressure (BP) control in heart failure with preserved ejection fraction (HFpEF) and RHTN is unknown., Methods: We identified patients with RHTN, defined as baseline systolic blood pressure (SBP) between 140 and 160 mm Hg on 3 or more medications, in the Americas cohort of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial, in which patients with HFpEF were randomized to spironolactone vs. placebo. We evaluated the effects of spironolactone vs. placebo on BP reduction in this group and related this to the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure., Results: We identified 403 participants in the Americas with RHTN. Compared to people without RHTN, those with RHTN were more frequently women, non-White, diabetics, with a higher left ventricular ejection fraction and body mass index, and a lower hemoglobin concentration. In the RHTN group, spironolactone resulted in a decrease of SBP: -6.1 (-8.9, -3.3); P < 0.001 and diastolic BP: -2.9 (-4.6, -1.2); P = 0.001 mm Hg during the first 8 months. BP became controlled after 4 weeks in 63% of patients receiving spironolactone vs. 46% receiving placebo (P = 0.003), with similar responses at 8 weeks, 4 and 8 months. Patients with RHTN derived similar overall benefit from spironolactone on the primary outcomes as those without., Conclusions: In HFpEF patients with RHTN, spironolactone lowered BP substantially and was associated with similar benefit as those without RHTN., Clinical Trials Registration: Trial Number NCT00094302 (ClinicalTrials.gov identifier).

Background: The incidence of hyperkalemia caused by mineralocorticoid receptor antagonists may vary by race, but whether race influences efficacy of mineralocorticoid receptor antagonists in heart failure (HF) is unknown., Methods and Results: We assessed hyperkalemia and outcomes in African Americans (AAs; n=120) and non-AAs (n=1543; white 93%) with New York Heart Association (NYHA) class III or IV HF and left ventricular dysfunction who were randomized to spironolactone, titrated to 25 or 50 mg daily or placebo, in the Randomized Aldactone Evaluation Study (RALES). AA participants were significantly younger, less likely to have an ischemic HF pathogenesis, more likely to be NYHA functional class IV, and more likely to have a higher estimated glomerular filtration rate and heart rate, less hypertension, diabetes mellitus, or history of myocardial infarction compared with non-AA participants. Potassium increased with spironolactone in non-AAs (4.29±0.5-4.55±0.49 mmol/L) but not in AAs (4.32±0.54-4.31±0.49 mmol/L; race by treatment interaction, P=0.03) during the first month and remained higher throughout the trial. Compared with AAs, non-AAs were more likely to attain maximal spironolactone dose (13.9% versus 5.8%; P=0.04) and had higher rates of hyperkalemia (potassium>5.5 mmol/L; 9.7% versus 4.2%; P<0.046), as well as lower rates of hypokalemia (potassium<3.5 mmol/L; 5.6% versus 17.9%; P<0.001). After adjustment for differences in baseline characteristics and achieved study drug dose, spironolactone reduced the combined end point of death or hospitalization for HF in non-AAs (hazard ratio, 0.63; 95% confidence interval, 0.55-0.73) but not in AAs (hazard ratio, 1.07; 95% confidence interval, 0.67-1.71; P value for interaction=0.032)., Conclusions: AAs with HF exhibited less hyperkalemia and more hypokalemia with spironolactone compared with non-AAs and seemed to derive less clinical benefit. These hypothesis-generating findings suggest that safety and efficacy of mineralocorticoid receptor antagonists may differ by race.