The Role of Positive Inotropic Drugs in the Treatment of Older Adults with Heart Failure and Reduced Ejection Fraction.

Positive inotropic drugs have long been studied for their potential benefits in patients with heart failure and reduced ejection fraction (HFrEF). Although there has been an extensive amount of research about the clinical effects of these drugs in general, few studies examined their effect in older patients. Therefore, there is little or no evidence to guide the use of positive inotropes in older patients with HFrEF. However, recommendations from national heart failure guidelines may be generalized to older HFrEF patients on an individual basis, taking into consideration the basic geriatric principles of pharmacotherapy: start low and go slow.

Length of stay and readmission in older adults hospitalized for heart failure.

INTRODUCTION: Hospital length of stay (LoS) and hospital readmissions are metrics of healthcare performance. We examined the association between these two metrics in older patients hospitalized with decompensated heart failure (HF). MATERIAL AND METHODS: Eight thousand and forty-nine patients hospitalized for HF in 106 U.S. hospitals had a median LoS of 5 days; among them, 3777 had a LoS > 5 days. Using propensity scores for LoS > 5 days, we assembled 2723 pairs of patients with LoS 1-5 vs. > 5 days. The matched cohort of 5446 patients was balanced on 40 baseline characteristics. We repeated the above process in 7045 patients after excluding those with LoS > 10 days, thus assembling a second matched cohort of 2399 pairs of patients with LoS 1-5 vs. 6-10 days. Hazard ratios (HR) and 95% confidence intervals (CI) for outcomes associated with longer LoS were estimated in matched cohorts. RESULTS: In the primary matched cohort (n = 5446), LoS > 5 days was associated with a higher risk of all-cause readmission at 30 days (HR = 1.16; 95% CI: 1.04-1.31; p = 0.010), but not during longer follow-up. A longer LoS was also associated with a higher risk of mortality during 8.8 years of follow-up (HR = 1.13; 95% CI: 1.06-1.21; p < 0.001). LoS had no association with HF readmission. Similar associations were observed among the matched sensitivity cohort (n = 4798) that excluded patients with LoS > 10 days. CONCLUSIONS: In propensity score-matched balanced cohorts of patients with HF, a longer LoS was independently associated with poor outcomes, which persisted when LoS > 10 days were excluded.

One- to 10-Day Versus 11- to 30-Day All-Cause Readmission and Mortality in Older Patients With Heart Failure.

Heart failure (HF) is the leading cause for 30-day all-cause readmission in older Medicare beneficiaries and 30-day all-cause readmission is associated with a higher risk of mortality. In the current analysis, we examined if that association varied by timing of 30-day all-cause readmission. Of the 8,049 Medicare beneficiaries hospitalized for HF, 1,688 had 30-day all-cause readmissions, of whom 1,519 were alive at 30 days. Of these, 626 (41%) had early (first 10 days) 30-day readmission. Propensity scores for early 30-day readmission, estimated for all 1,519 patients, were used to assemble a matched cohort of 596 pairs of patients with early versus late (11 to 30 days) all-cause readmission balanced on 34 baseline characteristics. Two-year all-cause mortality occurred in 51% and 57% of matched patients with early versus late 30-day all-cause readmissions, respectively (hazard ratio [HR] associated with late 30-day readmission, 1.22; 95% confidence interval [CI], 1.04 to 1.42; p = 0.014). This association was not observed in the subset of 436 patients whose 30-day all-cause readmission was due to HF (HR, 1.01; 95% CI, 0.79 to 1.28; p = 0.963), but was observed in the subset of 756 patients whose 30-day all-cause readmission was not due to HF (HR, 1.37; 95% CI, 1.12 to 1.67; p = 0.002; p for interaction, 0.057). In conclusion, in a high-risk subset of older hospitalized HF patients readmitted within 30 days, readmission during 11 to 30 (vs 1 to 10) days was associated with a higher risk of death and this association appeared to be more pronounced in those readmitted for non-HF-related reasons.

Spironolactone and Outcomes in Older Patients with Heart Failure and Reduced Ejection Fraction.

BACKGROUND: The efficacy of mineralocorticoid receptor antagonists or aldosterone antagonists in heart failure with reduced ejection fraction (HFrEF) is well known. Less is known about their effectiveness in real-world older patients with HFrEF. METHODS: Of the 8206 patients with heart failure and ejection fraction ≤35% without prior spironolactone use in the Medicare-linked OPTIMIZE-HF registry, 6986 were eligible for spironolactone therapy based on serum creatinine criteria (men ≤2.5 mg/dL, women ≤2.0 mg/dL) and 865 received a discharge prescription for spironolactone. Using propensity scores for spironolactone use, we assembled a matched cohort of 1724 (862 pairs) patients receiving and not receiving spironolactone, balanced on 58 baseline characteristics (Creatinine Cohort: mean age, 75 years, 42% women, 17% African American). We repeated the above process to assemble a secondary matched cohort of 1638 (819 pairs) patients with estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 (eGFR Cohort: mean age, 75 years, 42% women, 17% African American). RESULTS: In the matched Creatinine Cohort, spironolactone-associated hazard ratios (95% confidence intervals) for all-cause mortality, heart failure readmission, and combined endpoint of heart failure readmission or all-cause mortality were 0.92 (0.81-1.03), 0.87 (0.77-0.99), and 0.87 (0.79-0.97), respectively. Respective hazard ratios (95% confidence intervals) in the matched eGFR Cohort were 0.87 (0.77-0.98), 0.92 (0.80-1.05), and 0.91 (0.82-1.02). CONCLUSIONS: These findings provide evidence of consistent, albeit modest, clinical effectiveness of spironolactone in older patients with HFrEF regardless of renal eligibility criteria used. Additional strategies are needed to improve the effectiveness of aldosterone antagonists in clinical practice.

Role of High-Dose Beta-Blockers in Patients with Heart Failure with Preserved Ejection Fraction and Elevated Heart Rate.

BACKGROUND: Beta-blockers in high target doses are recommended for heart failure with reduced ejection fraction (HFrEF) but not for preserved ejection fraction (HFpEF). Treatment benefits are often more pronounced in high-risk subgroups, and patients with HFpEF with heart rate ≥70 beats per minute have emerged as such a high-risk subgroup. We examined the associations of high-dose beta-blocker use with outcomes in these patients. METHODS: Of the 8462 hospitalized patients with heart failure with ejection fraction ≥50% in the Medicare-linked Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry, 5422 had a discharge heart rate ≥70 beats per minute. Of these, 4537 had no contraindications to beta-blocker use, of which 2797 (2592 with dose data) received prescriptions for beta-blockers. Of the 2592, 730 received high-dose beta-blockers, defined as atenolol ≥100 mg/day, carvedilol ≥50 mg/day, metoprolol tartrate or succinate ≥200 mg/day, or bisoprolol ≥10 mg/day, and 1740 received no beta-blockers. Using propensity scores for the receipt of high-dose beta-blockers, we assembled a matched cohort of 1280 patients, balanced on 58 characteristics. RESULTS: All-cause mortality occurred in 63% and 68% of matched patients receiving high-dose beta-blocker vs no beta-blocker, respectively, during 6 years (median, 2.8) of follow-up (hazard ratio, 0.86; 95% confidence interval, 0.75-0.98; P = .027). The hazard ratios (95% confidence intervals) for all-cause readmission and the combined endpoint of all-cause readmission or all-cause mortality associated with high-dose beta-blocker use were 0.90 (0.81-1.02) and 0.89 (0.80-1.00), respectively. CONCLUSIONS: In patients with HFpEF and heart rate ≥70 beats per minute, high-dose beta-blocker use was associated with a significantly lower risk of death. Future randomized controlled trials are needed to examine this association.

Digoxin use and lower risk of 30-day all-cause readmission in older patients with heart failure and reduced ejection fraction receiving ß-blockers.

BACKGROUND: Digoxin use has been associated with a lower risk of 30-day all-cause admission and readmission in patients with heart failure and reduced ejection fraction (HFrEF). HYPOTHESIS: Digoxin use will be associated with improved outcomes in patients with HFrEF receiving ß-blockers. METHODS: Of the 3076 hospitalized Medicare beneficiaries with HFrEF (EF <45%), 1046 received a discharge prescription for ß-blockers, of which 634 were not on digoxin. Of the 634, 204 received a new discharge prescription for digoxin. Propensity scores for digoxin use, estimated for each of the 634 patients, were used to assemble a matched cohort of 167 pairs of patients receiving and not receiving digoxin, balanced on 30 baseline characteristics. Matched patients (n = 334) had a mean age of 74 years and were 46% female and 30% African American. RESULTS: 30-day all-cause readmission occurred in 15% and 27% of those receiving and not receiving digoxin, respectively (hazard ratio [HR]: 0.51, 95% confidence interval [CI]: 0.31-0.83, P = 0.007). This beneficial association persisted during 4 years of follow-up (HR: 0.72, 95% CI: 0.57-0.92, P = 0.008). Digoxin use was also associated with a lower risk of the combined endpoint of all-cause readmission or all-cause mortality at 30 days (HR: 0.54, 95% CI: 0.34-0.86, P = 0.009) and at 4 years (HR: 0.76, 95% CI: 0.61-0.96, P = 0.020). CONCLUSIONS: In hospitalized patients with HFrEF receiving ß-blockers, digoxin use was associated with a lower risk of 30-day all-cause readmission but not mortality, which persisted during longer follow-up.

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.

Systolic-diastolic hypertension versus isolated systolic hypertension and incident heart failure in older adults: Insights from the Cardiovascular Health Study.

BACKGROUND: Isolated systolic hypertension (ISH) is common in older adults and is a risk factor for incident heart failure (HF). We examined the association of systolic-diastolic hypertension (SDH) with incident HF and other outcomes in older adults. METHODS: In the Cardiovascular Health Study (CHS), 5776 community-dwelling adults≥65years had data on baseline systolic and diastolic blood pressure (SBP and DBP). We excluded those with DBP<60mmHg (n=821), DBP≥90 and SBP<140mmHg (n=28), normal BP, taking anti-hypertensive drugs (n=1138), normal BP, not taking anti-hypertensive drugs, history of hypertension (n=193), and baseline HF (n=101). Of the remaining 3495, 1838 had ISH (SBP≥140 and DBP<90mmHg) and 240 had SDH (SBP≥140 and DBP≥90mmHg). The main outcome was centrally-adjudicated incident HF over 13years of follow-up. RESULTS: Participants had a mean (±SD) age of 73 (±6)years, 57% were women, and 16% African American. Incident HF occurred in 25%, 22% and 11% of participants with ISH, SDH and no hypertension, respectively. Compared to no hypertension, multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for incident HF associated with ISH and SDH were 1.86 (1.51-2.30) and 1.73 (1.23-2.42), respectively. Cardiovascular mortality occurred in 22%, 24% and 9% of those with ISH, SDH and no hypertension, respectively with respective multivariable-adjusted HRs (95% CIs) of 1.88 (1.49-2.37) and 2.30 (1.64-3.24). CONCLUSION: Among older adults with hypertension, both SDH and ISH have similar associations with incident HF and cardiovascular mortality.

Lack of evidence of lower 30-day all-cause readmission in Medicare beneficiaries with heart failure and reduced ejection fraction discharged on spironolactone.

BACKGROUND: Therapy with evidence-based heart failure (HF) medications has been shown to be associated with lower risk of 30-day all-cause readmission in patients with HF and reduced ejection fraction (HFrEF). METHODS: We examined the association of aldosterone antagonist use with 30-day all-cause readmission in this population. Of the 2443 Medicare beneficiaries with HF and left ventricular EF ≤35% discharged home from 106 Alabama hospitals during 1998-2001, 2060 were eligible for spironolactone therapy (serum creatinine ≤2.5 for men and ≤2mg/dl for women, and serum potassium <5mEq/L). After excluding 186 patients already receiving spironolactone on admission, the inception cohort consisted of 1874 patients eligible for a new discharge prescription for spironolactone, of which 329 received one. Using propensity scores for initiation of spironolactone therapy, we assembled a matched cohort of 324 pairs of patients receiving and not receiving spironolactone balanced on 34 baseline characteristics (mean age 72years, 42% women, 33% African American). RESULTS: Thirty-day all-cause readmission occurred in 17% and 19% of matched patients receiving and not receiving spironolactone, respectively (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.64-1.32; p=0.650). Spironolactone had no association with 30-day all-cause mortality (HR, 0.84; 95% CI, 0.38-1.88; p=0.678) or HF readmission (HR, 0.74; 95% CI, 0.41 1.31; p=0.301). These associations remained unchanged during 12months of post-discharge follow-up. CONCLUSION: A discharge prescription for spironolactone had no association with 30-day all-cause readmission among older, hospitalized Medicare beneficiaries with HFrEF eligible for spironolactone therapy.

Heart Rate and Outcomes in Hospitalized Patients With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: A lower heart rate is associated with better outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). Less is known about this association in patients with HF with preserved ejection fraction (HFpEF). OBJECTIVES: The aims of this study were to examine associations of discharge heart rate with outcomes in hospitalized patients with HFpEF. METHODS: Of the 8,873 hospitalized patients with HFpEF (EF ≥50%) in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 6,286 had a stable heart rate, defined as ≤20 beats/min variation between admission and discharge. Of these, 2,369 (38%) had a discharge heart rate of <70 beats/min. Propensity scores for discharge heart rate <70 beats/min, estimated for each of the 6,286 patients, were used to assemble a cohort of 2,031 pairs of patients with heart rate <70 versus ≥70 beats/min, balanced on 58 baseline characteristics. RESULTS: The 4,062 matched patients had a mean age of 79 ± 10 years, 66% were women, and 10% were African American. During 6 years (median 2.8 years) of follow-up, all-cause mortality was 65% versus 70% for matched patients with a discharge heart rate <70 versus ≥70 beats/min, respectively (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.80 to 0.93; p < 0.001). A heart rate <70 beats/min was also associated with a lower risk for the combined endpoint of HF readmission or all-cause mortality (HR: 0.90; 95% CI: 0.84 to 0.96; p = 0.002), but not with HF readmission (HR: 0.93; 95% CI: 0.85 to 1.01) or all-cause readmission (HR: 1.01; 95% CI: 0.95 to 1.08). Similar associations were observed regardless of heart rhythm or receipt of beta-blockers. CONCLUSIONS: Among hospitalized patients with HFpEF, a lower discharge heart rate was independently associated with a lower risk of all-cause mortality, but not readmission.

A randomized pilot study on the effect of niacin on pulmonary arterial pressure.

BACKGROUND: Niacin induces the release of vasodilating prostaglandins, for which receptors are present within the pulmonary arterial circulation. We hypothesized that immediate-release niacin would reduce right ventricular systolic pressure in patients with pulmonary hypertension in a randomized, double-blinded, single-dose provocation study. METHODS: We recruited inpatient subjects with a Doppler echocardiogram showing a peak tricuspid regurgitation (TR) jet velocity of 2.7 m/s or greater, and who were free of known pulmonary vascular disease. Subjects were randomized in a 1:2:2 ratio to receive a single dose of either placebo, niacin 100 mg or niacin 500 mg, respectively. TR jet velocities were measured immediately before, and 1 hour post dose, corresponding to peak niacin absorption and prostaglandin release. The primary endpoint was the change in mean TR jet velocity measured over ten successive cardiac cycles. RESULTS: The baseline mean estimated right ventricular systolic pressure (RVSP) for all 49 subjects (25 male) was 51.9 ± 12.1 mm Hg. The primary endpoint of mean change in TR jet velocity was 0.016 ± 0.065 m/s in the placebo group, compared to -0.017 ± 0.065 m/s with niacin 100 mg, and -0.063 ± 0.038 m/s with niacin 500 mg (P = 0.63). The change in maximum estimated RVSP across the three drug groups was 0.2 ± 1.6 mm Hg, -1.3 ± 1.8 mm Hg and -2.2 ± 1.2 mm Hg (P = 0.62). In exploratory pairwise analysis in the high-dose niacin group (500 mg), the reduction in mean RVSP was from 50.9 ± 9.4 mm Hg to 48.7 ± 10.0 mm Hg (P = 0.09). CONCLUSIONS: A single dose of immediate-release niacin (100 mg or 500 mg) had no significant effect on RVSP 1 hour post administration. A nonsignificant dose-dependent trend for a modest reduction in RVSP, most notable in the 500 mg group, was noted. (ISRCTN number 12353191, registered April 23, 2015).