Renin-Angiotensin Inhibition and Outcomes in HFrEF and Advanced Kidney Disease.

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 m2). 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.

Initiation of Anti-Hypertensive Drugs and Outcomes in Patients with Heart Failure with Reduced Ejection Fraction.

BACKGROUND: In patients with heart failure with reduced ejection fraction (HFrEF) and hypertension, systolic blood pressure is recommended to be maintained below 130 mmHg, although this has not been shown to be associated with improved outcomes. We examined the association between anti-hypertensive drug initiation and outcomes in patients with HFrEF. METHODS: In the Medicare-linked OPTIMIZE-HF, 7966 patients with HFrEF (ejection fraction ≤40%) without renal failure were not receiving anti-hypertensive drugs before hospitalization, of whom 692 received discharge prescriptions for those drugs (thiazides and calcium channel blockers). We assembled a propensity score-matched cohort of 687 pairs of patients initiated and not initiated on anti-hypertensive drugs, balanced on 38 baseline characteristics. Hazard ratios (HR) and 95% confidence intervals (CIs) for outcomes associated with anti-hypertensive drug initiation were estimated in the matched cohort. RESULTS: Matched patients (n = 1374) had a mean age of 74 years, 41% were female, 17% were African-American, 66% were discharged on renin-angiotensin system inhibitors and beta blockers, and 10% on aldosterone antagonists. During 6 (median 2.5) years of follow-up, 70% of the patients died and 53% had heart failure readmission. Anti-hypertensive drug initiation was not significantly associated with all-cause mortality (HR, 0.95; 95% CI, 0.83-1.07) or heart failure readmission (HR, 0.93; 95% CI, 0.80-1.07). Similar associations were observed during 30 days and 12 months of follow-up. CONCLUSIONS: Among hospitalized older patients with HFrEF receiving contemporary treatments for heart failure, initiation of an anti-hypertensive drug was not associated with a lower risk of all-cause mortality or hospital readmission.

Digoxin Use and Outcomes in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Heart failure is a leading cause for hospital readmission. Digoxin use may lower this risk in patients with heart failure with reduced ejection fraction (HFrEF), but data on contemporary patients receiving other evidence-based therapies are lacking. METHODS: Of the 11,900 patients with HFrEF (ejection fraction ≤45%) in Medicare-linked OPTIMIZE-HF, 8401 were not on digoxin, of whom 1571 received discharge prescriptions for digoxin. We matched 1531 of these patients with 1531 not receiving digoxin by propensity scores for digoxin use. The matched cohort (n = 3062; mean age, 76 years; 44% women; 14% African American) was balanced on 52 baseline characteristics. We assembled a second matched cohort of 2850 patients after excluding those with estimated glomerular filtration rate <15 mL/min/1.73 m2 and heart rate <60 beats/min. Hazard ratios (HRs) and 95% confidence intervals (CIs) for digoxin-associated outcomes were estimated in the matched cohorts. RESULTS: Among the 3062 matched patients, digoxin use was associated with a significantly lower risk of heart failure readmission at 30 days (HR, 0.74; 95% CI, 0.59-0.93), 1 year (HR, 0.81; 95% CI, 0.72-0.92), and 6 years (HR, 0.90; 95% CI 0.81-0.99). The association with all-cause readmission was significant at 1 and 6 years but not 30 days. There was no association with mortality. Similar associations were observed among the 2850 matched patients without bradycardia or renal insufficiency. CONCLUSIONS: Among hospitalized older patients with HFrEF receiving contemporary treatments for heart failure, digoxin use is associated with a lower risk of hospital readmission but not all-cause mortality.

Similar clinical benefits from below-target and target dose enalapril in patients with heart failure in the SOLVD Treatment trial.

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.