Imaging modality for left ventricular ejection fraction estimation and effect of implantable cardioverter-defibrillator on mortality in patients with heart failure.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) improve outcomes in patients with heart failure (HF) with left ventricular ejection fraction (LVEF) ≤35%. Less is known about whether outcomes varied between the 2 noninvasive imaging modalities used to estimate LVEF-2-dimensional echocardiography (2DE) and multigated acquisition radionuclide ventriculography (MUGA)-which use different principles (geometric vs count-based, respectively). OBJECTIVE: The purpose of this study was to examine whether the effect of ICD on mortality in patients with HF and LVEF ≤35% varied on the basis of LVEF measured by 2DE or MUGA. METHODS: Of the 2521 patients with HF with LVEF ≤35% in the Sudden Cardiac Death in Heart Failure Trial, 1676 (66%) were randomized to either placebo or ICD, of whom 1386 (83%) had LVEF measured by 2DE (n = 971) or MUGA (n = 415). Hazard ratios (HRs) and 97.5% confidence intervals (CIs) for mortality associated with ICD were estimated overall, checking for interaction, and within the 2 imaging subgroups. RESULTS: Of the 1386 patients in the present analysis, all-cause mortality occurred in 23.1% (160 of 692) and 29.7% (206 of 694) of patients randomized to ICD or placebo, respectively (HR 0.77; 97.5% CI 0.61-0.97), which is consistent with that in 1676 patients in the original report. HRs (97.5% CIs) for all-cause mortality in the 2DE and MUGA subgroups were 0.79 (0.60-1.04) and 0.72 (0.46-1.11), respectively (P = .693 for interaction). Similar associations were observed for cardiac and arrhythmic mortalities. CONCLUSION: We found no evidence that in patients with HF and LVEF ≤35%, the effect of ICD on mortality varied by the noninvasive imaging method used to measure LVEF.

TRAIL-receptor 2-a novel negative regulator of p53.

TNF-related apoptosis-inducing ligand (TRAIL) receptor 2 (TRAIL-R2) can induce apoptosis in cancer cells upon crosslinking by TRAIL. However, TRAIL-R2 is highly expressed by many cancers suggesting pro-tumor functions. Indeed, TRAIL/TRAIL-R2 also activate pro-inflammatory pathways enhancing tumor cell invasion, migration, and proliferation. In addition, nuclear TRAIL-R2 (nTRAIL-R2) promotes malignancy by inhibiting miRNA let-7-maturation. Here, we show that TRAIL-R2 interacts with the tumor suppressor protein p53 in the nucleus, assigning a novel pro-tumor function to TRAIL-R2. Knockdown of TRAIL-R2 in p53 wild-type cells increases the half-life of p53 and the expression of its target genes, whereas its re-expression decreases p53 protein levels. Interestingly, TRAIL-R2 also interacts with promyelocytic leukemia protein (PML), a major regulator of p53 stability. PML-nuclear bodies are also the main sites of TRAIL-R2/p53 co-localization. Notably, knockdown or destruction of PML abolishes the TRAIL-R2-mediated regulation of p53 levels. In summary, our finding that nTRAIL-R2 facilitates p53 degradation and thereby negatively regulates p53 target gene expression provides insight into an oncogenic role of TRAIL-R2 in tumorigenesis that particularly manifests in p53 wild-type tumors.

Outcomes of Premature Ventricular Contraction-Cardiomyopathy in the Veteran Population: A Secondary Analysis of the CHF-STAT Study.

OBJECTIVES: This study sought to assess the rate and outcomes of premature ventricular contractions (PVC)-cardiomyopathy from the CHF-STAT (Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure) trial, a population with cardiomyopathy (left ventricular [LV] ejection fraction of <40%) and frequent PVCs (>10 PVCs per hour). BACKGROUND: PVCs are associated with heart failure and PVC-cardiomyopathy. The prevalence of PVC-cardiomyopathy and outcome benefits of PVC suppression are not clear. METHODS: A secondary analysis of the CHF-STAT study was performed to compare the rate of successful PVC suppression (≥80% PVC reduction), LV recovery (defined as improvement in LV ejection fraction of ≥10% points), and PVC-cardiomyopathy between amiodarone and placebo groups at 6 months. PVC-cardiomyopathy was defined if both PVC reduction of ≥80% and LV ejection fraction improvement of ≥10% were present at 6 months. Cardiac events (death or resuscitated cardiac arrest) were compared between PVC-cardiomyopathy versus non-PVC-cardiomyopathy during a 5-year follow-up. RESULTS: The rates of successful PVC suppression and LV recovery were significantly higher in the amiodarone (72% and 39%, respectively) when compared to the placebo group (12% and 16%, respectively; p < 0.001), regardless of cardiomyopathy etiology. PVC-cardiomyopathy was present in 29% and 1.8% of patients in the amiodarone and placebo groups, respectively (p < 0.001). Similar PVC-cardiomyopathy rates were found in ischemic (24% amiodarone vs. 2% placebo; p < 0.001) and nonischemic populations (41% amiodarone vs. 1.5% placebo; p < 0.001). Death and resuscitated cardiac arrest were significantly lower in patients with PVC-cardiomyopathy and those treated with amiodarone. CONCLUSIONS: The overall prevalence of PVC-cardiomyopathy in the CHF-STAT study was significant regardless of ischemic substrate (29%, overall population; 41%, nonischemic cardiomyopathy). Treatment of PVC-cardiomyopathy with amiodarone is likely to improve survival in this high-risk population.

Digoxin Initiation and Outcomes in Patients with Heart Failure (HFrEF and HFpEF) and Atrial Fibrillation.

BACKGROUND: Digoxin reduces the risk of heart failure hospitalization but has no effect on mortality in patients with heart failure without atrial fibrillation in the randomized controlled trial setting. Observational studies of digoxin use in patients with atrial fibrillation have suggested a higher risk for poor outcomes. Less is known about this association in patients with heart failure and atrial fibrillation, the examination of which was the objective of the current study. METHODS: We conducted an observational propensity score-matched study of predischarge digoxin initiation in 1768 hospitalized patients with heart failure and atrial fibrillation in the Medicare-linked Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry, balanced on 56 baseline characteristics (mean age, 79 years; 55% women; 7% African American). Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes were estimated for the 884 patients initiated on digoxin compared with 884 not initiated on digoxin. RESULTS: HRs (95% CIs) for 30-day, 2-year, and 4-year all-cause mortality were 0.80 (0.55-1.18; P = .261), 0.94 (0.87-1.16; P = .936), and 1.01 (0.90-1.14; P = .729), respectively. Respective HRs (95% CIs) for heart failure readmission were 0.67 (0.49-0.92; P = .014), 0.81 (0.69-0.94; P = .005), and 0.85 (0.74-0.97; P = .022), and those for all-cause readmission were 0.78 (0.64-0.96; P = .016), 0.90 (0.81-1.00; P = .057), and 0.91 (0.83-1.01; P = .603). These associations were homogeneous between patients with left ventricular ejection fraction ≤45% vs >45%. CONCLUSIONS: Among hospitalized older patients with heart failure (HFrEF and HFpEF) and atrial fibrillation, initiation of digoxin was associated with a lower risk of heart failure readmission but had no association with mortality.

Digoxin Initiation and Outcomes in Patients with Heart Failure with Preserved Ejection Fraction.

BACKGROUND: Digoxin reduces the risk of heart failure hospitalization in patients with heart failure with reduced ejection fraction. Less is known about this association in patients with heart failure with preserved ejection fraction (HFpEF), the examination of which was the objective of the current study. METHODS: In the Medicare-linked OPTIMIZE-HF registry, 7374 patients hospitalized for HF had ejection fraction ≥50% and were not receiving digoxin prior to admission. Of these, 5675 had a heart rate ≥50 beats per minute, an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 or did not receive inpatient dialysis, and digoxin was initiated in 524 of these patients. Using propensity scores for digoxin initiation, calculated for each of the 5675 patients, we assembled a matched cohort of 513 pairs of patients initiated and not initiated on digoxin, balanced on 58 baseline characteristics (mean age, 80 years; 66% women; 8% African American). Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes associated with digoxin initiation were estimated in the matched cohort. RESULTS: Among the 1026 matched patients with HFpEF, 30-day heart failure readmission occurred in 6% and 9% of patients initiated and not initiated on digoxin, respectively (HR 0.70; 95% CI, 0.45-1.10; P = .124). HRs (95% CIs) for 30-day all-cause readmission and all-cause mortality associated with digoxin initiation were 0.95 (0.73-1.23; P = .689) and 0.93 (0.55-1.56; P = .773), respectively. Digoxin initiation had no association with 6-year outcomes. CONCLUSION: Digoxin initiation prior to hospital discharge was not associated with 30-day or 6-year outcomes in older hospitalized patients with HFpEF.

Prior Heart Failure Hospitalization and Outcomes in Patients with Heart Failure with Preserved and Reduced Ejection Fraction.

BACKGROUND: A prior hospitalization resulting from heart failure is associated with poor outcomes in ambulatory patients with heart failure. Less is known about this association in hospitalized patients with heart failure and whether it varies by ejection fraction. METHODS: Of the 25,345 hospitalized patients in the Medicare-linked OPTIMIZE-HF registry, 22,491 had known heart failure, of whom 7648 and 9558 had heart failure with preserved (≥50%) and reduced (≤40%) ejection fraction (HFpEF and HFrEF), respectively. Overall, 927 and 1862 patients with HFpEF and HFrEF had hospitalizations for heart failure during the 6 months before the index hospitalization, respectively. Using propensity scores for prior heart failure hospitalization, we assembled two matched cohorts of 924 pairs and 1844 pairs of patients with HFpEF and HFrEF, respectively, each balanced for 58 baseline characteristics. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes during 6 years of follow-up. RESULTS: Among 1848 matched patients with HFpEF, HRs (95% CIs) for all-cause mortality, all-cause readmission, and heart failure readmission were 1.35 (1.21-1.50; P <0.001), 1.34 (1.21-1.47; P <0.001), and 1.90 (1.67-2.16; P <0.001), respectively. Respective HRs (95% CIs) in 3688 matched patients with HFrEF were 1.17 (1.09-1.26; P <0.001), 1.32 (1.23-1.41; P <0.001), and 1.48 (1.37-1.61; P <0.001). CONCLUSIONS: Among hospitalized patients with heart failure, a previous hospitalization for heart failure is associated with higher risks of mortality and readmission in both HFpEF and HFrEF. The relative risks of death and heart failure readmission appear to be higher in HFpEF than in HFrEF.

Opioid Use and Outcomes in Hospitalized Older Patients With Heart Failure Receiving and Not Receiving Hospice Referrals.

BACKGROUND: The use of opioids is associated with poor outcomes. Less is known about this association in patients with heart failure (HF) and whether it varies by the receipt of hospice care. METHODS: Of the 7467 patients hospitalized for HF without previous opioid use, 124 received discharge opioids. We matched 123 of these patients with 123 not receiving opioids based on their propensity scores for opioid use, thus assembling a matched cohort of 246 patients balanced on 30 baseline characteristics (mean age, 76 years, 60% women, and 11% African American). We repeated the process in hospice (n = 155; 20 received opioids) and nonhospice (n = 7298; 104 received opioids) subgroups, thus assembling 2 matched cohorts of 22 and 208 patients, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) associated with opioid use were estimated from matched cohorts. RESULTS: During 8.6 (median, 1.4) years of follow-up, all-cause mortality occurred in 80% and 68% of matched patients in the opioid and nonopioid groups, respectively (HR, 1.49; 95% CI, 1.11-1.99; P = 0.008). There was evidence of heterogeneity in this association between hospice and nonhospice patients (P for interaction, 0.027). Among matched hospice and nonhospice patients, HRs (95% CIs) for mortality were 6.37 (2.06-19.69; P = 0.001) and 1.42 (1.03-1.96; P = 0.035), respectively. HRs (95% CIs) for 30-day and 1-year mortality were 1.98 (1.06-3.70; P = 0.033) and 1.72 (1.18-2.49; P = 0.004), respectively. HRs (95% CIs) for all-cause, HF, and non-HF readmissions were 1.31 (0.97-1.76; P = 0.079), 1.03 (0.71-1.49; P = 0.866), and 1.75 (1.05-2.91; P = 0.031), respectively. Readmission associations were similar among matched nonhospice patients. There was no readmission among matched hospice patients receiving opioids. CONCLUSIONS: In older patients with HF, opioid use is associated with a higher risk of mortality, which is greater in the hospice subgroup, and a higher risk of non-HF readmission in the nonhospice subgroup.

Early Effects of Starting Doses of Enalapril in Patients with Chronic Heart Failure in the SOLVD Treatment Trial.

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.

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

BACKGROUND: The deleterious effects of discontinuation of digoxin on outcomes in ambulatory patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) receiving angiotensin-converting enzyme inhibitors are well-documented. OBJECTIVES: The authors sought to determine the relationship between digoxin discontinuation and outcomes in hospitalized patients with HFrEF receiving more contemporary guideline-directed medical therapies including beta-blockers and mineralocorticoid receptor antagonists. METHODS: Of the 11,900 hospitalized patients with HFrEF (EF ≤45%) in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 3,499 received pre-admission digoxin, which was discontinued in 721 patients. Using propensity scores for digoxin discontinuation, estimated for each of the 3,499 patients, a matched cohort of 698 pairs of patients, balanced on 50 baseline characteristics (mean age 76 years; mean EF 28%; 41% women; 13% African American; 65% on beta-blockers) was assembled. RESULTS: Four-year post-discharge, digoxin discontinuation was associated with significantly higher risks of HF readmission (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.05 to 1.39; p = 0.007), all-cause readmission (HR: 1.16; 95% CI: 1.04 to 1.31; p = 0.010), and the combined endpoint of HF readmission or all-cause mortality (HR: 1.20; 95% CI: 1.07 to 1.34; p = 0.002), but not all-cause mortality (HR: 1.09; 95% CI: 0.97 to 1.24; p = 0.163). Discontinuation of digoxin was associated with a significantly higher risk of all 4 outcomes at 6 months and 1 year post-discharge. At 30 days, digoxin discontinuation was associated with higher risks of all-cause mortality (HR: 1.80; 95% CI: 1.26 to 2.57; p = 0.001) and the combined endpoint (HR: 1.36; 95% CI: 1.09 to 1.71; p = 0.007), but not of HF readmission (HR: 1.19; 95% CI: 0.90 to 1.59; p = 0.226) or all-cause readmission (HR: 1.03; 95% CI: 0.84 to 1.26; p = 0.778). CONCLUSIONS: Among hospitalized older patients with HFrEF on more contemporary guideline-directed medical therapies, discontinuation of pre-admission digoxin therapy was associated with poor outcomes.

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.

Systolic Blood Pressure and Outcomes in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: National guidelines recommend that systolic blood pressure (SBP) in patients with heart failure with reduced ejection fraction (HFrEF) and hypertension be maintained below 130 mm Hg. OBJECTIVES: This study sought to determine associations of SBP <130 mm Hg with outcomes in patients with HFrEF. METHODS: Of the 25,345 patients in the Medicare-linked OPTIMIZE-HF registry, 10,535 had an ejection fraction (EF) ≤40%. Of these, 5,615 had stable SBP (≤20 mm Hg admission to discharge variation), and 3,805 (68%) had a discharge SBP <130 mm Hg. Propensity scores for SBP <130 mm Hg, estimated for each of the 5,615 patients, were used to assemble a matched cohort of 1,189 pairs of patients with SBP <130 versus ≥130 mm Hg, balanced on 58 baseline characteristics (mean age 76 years; mean EF 28%, 45% women, 13% African American). This process was repeated in 3,946 patients, after excluding 1,669 patients (30% of 5,615) with a discharge SBP <110 mm Hg and assembled a second matched balanced cohort of 1,099 pairs of patients with SBP 110 to 129 mm Hg versus ≥130 mm Hg. RESULTS: Thirty-day all-cause mortality occurred in 7% and 4% of matched patients with SBP <130 mm Hg versus ≥130 mm Hg, respectively (hazard ratio [HR]: 1.76; 95% confidence interval [CI]: 1.24 to 2.48; p = 0.001). HRs (95% CIs) for all-cause mortality, all-cause readmission, and HF readmission at 1 year, associated with SBP <130 mm Hg, were 1.32 (1.15 to 1.53; p < 0.001), 1.11 (1.01 to 1.23; p = 0.030), and 1.24 (1.09 to 1.42; p = 0.001), respectively. HRs (95% CIs) for 30-day and 1-year all-cause mortality associated with SBP 110 to 129 mm Hg (vs. ≥130 mm Hg) were 1.50 (1.03 to 2.19; p = 0.035), and 1.19 (1.02 to 1.39; p = 0.029), respectively. CONCLUSIONS: Among hospitalized older patients with HFrEF, SBP <130 mm Hg is associated with poor outcomes. This association persisted when the analyses were repeated after excluding patients with SBP <110 mm Hg. There is an urgent need for randomized controlled trials to evaluate optimal SBP reduction goals in patients with HFrEF.

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.

Systolic Blood Pressure and Outcomes in Patients With Heart Failure With Preserved Ejection Fraction.

Importance: Lower systolic blood pressure (SBP) levels are associated with poor outcomes in patients with heart failure. Less is known about this association in heart failure with preserved ejection fraction (HFpEF). Objective: To determine the associations of SBP levels with mortality and other outcomes in HFpEF. Design, Setting, and Participants: A propensity score-matched observational study of the Medicare-linked Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry included 25 354 patients who were discharged alive; 8873 (35.0%) had an ejection fraction of at least 50%, and of these, 3915 (44.1%) had stable SBP levels (≤20 mm Hg admission to discharge variation). Data were collected from 259 hospitals in 48 states between March 1, 2003, and December 31, 2004. Data were analyzed from March 1, 2003, to December 31, 2008. Exposure: Discharge SBP levels less than 120 mm Hg. A total of 1076 of 3915 (27.5%) had SBP levels less than 120 mm Hg, of whom 901 (83.7%) were matched by propensity scores with 901 patients with SBP levels of 120 mm Hg or greater who were balanced on 58 baseline characteristics. Main Outcomes and Measures: Thirty-day, 1-year, and overall all-cause mortality and heart failure readmission through December 31, 2008. Results: The 1802 matched patients had a mean (SD) age of 79 (10) years; 1147 (63.7%) were women, and 134 (7.4%) were African American. Thirty-day all-cause mortality occurred in 91 (10%) and 45 (5%) of matched patients with discharge SBP of less than 120 mm Hg vs 120 mm Hg or greater, respectively (hazard ratio [HR], 2.07; 95% CI, 1.45-2.95; P < .001). Systolic blood pressure level less than 120 mm Hg was also associated with a higher risk of mortality at 1 year (39% vs 31%; HR, 1.36; 95% CI, 1.16-1.59; P < .001) and during a median follow-up of 2.1 (overall 6) years (HR, 1.17; 95% CI, 1.05-1.30; P = .005). Systolic blood pressure level less than 120 mm Hg was associated with a higher risk of heart failure readmission at 30 days (HR, 1.47; 95% CI, 1.08-2.01; P = .02) but not at 1 or 6 years. Hazard ratios for the combined end point of heart failure readmission or all-cause mortality associated with SBP level less than 120 mm at 30 days, 1 year, and overall were 1.71 (95% CI, 1.34-2.18; P < .001), 1.21 (95% CI, 1.07-1.38; P = .004), and 1.12 (95% CI, 1.01-1.24; P = .03), respectively. Conclusions and Relevance: Among hospitalized patients with HFpEF, an SBP level less than 120 mm Hg is significantly associated with poor outcomes. Future studies need to prospectively evaluate optimal SBP treatment goals in patients with HFpEF.

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.

Outcomes of cardiac resynchronization therapy in patients with intermittent atrial fibrillation or atrial flutter in the COMPANION trial.

BACKGROUND: Controlled clinical trial data are lacking for cardiac resynchronization therapy (CRT) outcomes in patients with advanced heart failure (HF) from reduced left ventricular ejection fraction (HFrEF) and intermittent atrial fibrillation or flutter (IAF/AFL). OBJECTIVE: The purpose of this study was to describe CRT outcomes in patients with IAF/AFL and advanced HF. METHODS: HF outcomes in patients in the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial with New York Heart Association class III or IV HFrEF, left ventricular ejection fraction ≤0.35, sinus rhythm at randomization, and no history of baseline arrhythmia were compared with those with a history of IAF/AFL. RESULTS: In those with no history of baseline arrhythmia (n = 887), compared with optimal pharmacological therapy (OPT) with no CRT, the CRT + OPT arms exhibited a significant reduction in the end points of death or any hospitalization (hazard ratio [HR] 0.73 [95% Confidence Interval (CI): 0.60 to 0.89]; P = .002) and death or HF hospitalization (HR 0.53 [95% CI: 0.41 to 0.68]; P < .001). In contrast, in the IAF/AFL subgroup (n = 293), CRT did not result in improved outcomes compared with OPT (death or any hospitalization: HR 1.16 [95% CI: 0.83 to 1.63]; P = .38; death or HF hospitalization: HR 0.97 [95% CI: 0.64 to 1.46]; P = .88). The interaction between history of AF/AFL and CRT was statistically significant for both outcomes (P < .05). CONCLUSION: In the COMPANION trial, patients with moderate to severe HFrEF and a history of IAF/AFL had no benefit from CRT.

Data and Safety Monitoring Board evaluation and management of a renal adverse event signal in TOPCAT.

Clinical trial Data and Safety Monitoring Boards (DSMBs) have a primary obligation of ensuring study participant safety, while maintaining trial integrity. The role of DSMBs is expanding, and ideally should include post-hoc reporting of deliberative processes related to clinically important safety issues or factors that could impact on future trial designs. We describe how the TOPCAT DSMB detected, investigated, and adjudicated an unexpectedly large renal adverse event signal midway through the trial, and offer general guidelines for dealing with similar unanticipated occurrences in future trials. The detection of a greater than expected incidence of deterioration in renal function, occurring in 6.1% of patients in the spironolactone arm compared with 3.9% in the placebo arm (P = 0.009), led to an in-depth DSMB review of associated study medication withdrawals and adverse events. The trial continued uninterrupted throughout the review, which reached the conclusions that spironolactone-associated renal dysfunction did not compromise overall patient safety or interfere with a perceived efficacy signal. Although no discrete mechanism for the spironolactone-associated renal adverse event signal was identified, likely possibilities are discussed. In clinical trials, DSMBs and co-ordinating centres should have the resources to detect, investigate, and adjudicate unexpected safety issues, with goals of ensuring patient safety and preserving the potential for detection of therapeutic effectiveness. In TOPCAT, spironolactone-associated renal dysfunction emerged as a potentially trial-threatening adverse event and, although clinically important, did not lead to compromise of patient safety, trial interruption, termination, or apparent loss of treatment effectiveness.

Detection and Management of Geographic Disparities in the TOPCAT Trial: Lessons Learned and Derivative Recommendations.

TOPCAT was a multinational clinical trial of 3,445 heart failure with preserved ejection fraction (HFpEF) patients that enrolled in 233 sites in six countries in North America, Eastern Europe and South America. Patients with a heart failure hospitalization in the last 12 months or an elevated B-type natriuretic peptide (BNP) were randomized to the mineralocorticoid receptor antagonist spironolactone vs. placebo. Sites in Russia and the Republic of Georgia provided the majority of early enrollment, primarily based on the hospitalization criterion since BNP levels were initially unavailable there. With the emergence of country-specific aggregate event rate data indicating lower rates in Eastern Europe and differences in patient characteristics there, the DSMB recommended relatively increasing enrollment in North America plus other corrective measures. Although final enrollment reflected the increased contribution from North America, a plurality of the final cohort came from Russia and Georgia (49% vs. 43% in North America). BNP measurements from Russia and Georgia available later in the trial suggested no or a mild level of heart failure consistent with low event rates. The primary results showed no significant spironolactone treatment effect overall (primary endpoint hazard ratio 0.89 (0.77, 1.04)), with a significant hazard ratio in North and South America (0.82 (0.69, 0.98), p =0.026) but not in Russia and Georgia (1.10 (0.79, 1.51), interaction p = 0.12). This report describes the DSMB's detection and management recommendations for regional differences in patient characteristics in TOPCAT, and suggests methods of surveillance and corrective actions that may be useful for future trials.

Discharge Hospice Referral and Lower 30-Day All-Cause Readmission in Medicare Beneficiaries Hospitalized for Heart Failure.

BACKGROUND: Heart failure (HF) is the leading cause for hospital readmission. Hospice care may help palliate HF symptoms but its association with 30-day all-cause readmission remains unknown. METHODS AND RESULTS: Of the 8032 Medicare beneficiaries hospitalized for HF in 106 Alabama hospitals (1998-2001), 182 (2%) received discharge hospice referrals. Of the 7850 patients not receiving hospice referrals, 1608 (20%) died within 6 months post discharge (the hospice-eligible group). Propensity scores for hospice referral were estimated for each of the 1790 (182+1608) patients and were used to match 179 hospice-referral patients with 179 hospice-eligible patients who were balanced on 28 baseline characteristics (mean age, 79 years; 58% women; 18% non-white). Overall, 22% (1742/8032) died in 6 months, of whom 8% (134/1742) received hospice referrals. Among the 358 matched patients, 30-day all-cause readmission occurred in 5% and 41% of hospice-referral and hospice-eligible patients, respectively (hazard ratio associated with hospice referral, 0.12; 95% confidence interval, 0.06-0.24). Hazard ratios (95% confidence intervals) for 30-day all-cause readmission associated with hospice referral among the 126 patients who died and 232 patients who survived 30-day post discharge were 0.03 (0.04-0.21) and 0.17 (0.08-0.36), respectively. Although 30-day mortality was higher in the hospice referral group (43% versus 27%), it was similar at 90 days (64% versus 67% among hospice-eligible patients). CONCLUSIONS: A discharge hospice referral was associated with lower 30-day all-cause readmission among hospitalized patients with HF. However, most patients with HF who died within 6 months of hospital discharge did not receive a discharge hospice referral.

Drug-induced post-repolarization refractoriness as an antiarrhythmic principle and its underlying mechanism.

AIMS: We hypothesized that amiodarone (AM), unlike d-sotalol (DS) (a 'pure' Class III agent), not only prolongs the action potential duration (APD) but also causes post-repolarization refractoriness (PRR), thereby preventing premature excitation and providing superior antiarrhythmic efficacy. METHODS AND RESULTS: We tested this hypothesis in 31 patients with inducible ventricular tachycardia (VT) during programmed stimulation with the use of the 'Franz' monophasic action potential (MAP) catheter with simultaneous pacing capability. We determined the effective refractory period (ERP) for each of three extrastimuli (S2-S4) and the corresponding MAP duration at 90% repolarization (APD90), both during baseline and on randomized therapy with either DS (n = 15) or AM (n = 16). We defined ERP > APD90 as PRR and ERP < APD90 as 'encroachment' on repolarization. A revised computer action potential model was developed to help explain the mechanisms of these in-vivo human-heart phenomena. Encroachment but not PRR was present in all patients at baseline and during DS treatment (NS vs. baseline), and VT was non-inducible in only 2 of 15 DS patients. In contrast, in 12 of 16 AM patients PRR was present (P < 0.001 vs. baseline), and VT was no longer inducible. Our model (with revised sodium channel kinetics) reproduced encroachment and drug-induced PRR. CONCLUSION: Both, AM and DS, prolonged APD90 but only AM produced PRR and prevented encroachment of premature extrastimuli. Our computer simulations suggest that PRR is due to altered kinetics of the slow inactivation of the rapid sodium current. This may contribute to the high antiarrhythmic efficacy of AM.