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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. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to determine quality of life (QOL) and exercise performance (EP) in patients with persistent atrial fibrillation (AF) converted to sinus rhythm (SR) compared with those remaining in or reverting to AF. Background: Restoration of SR in patients with AF improving QOL and EP remains controversial. Methods: Patients with persistent AF were randomized double-blind to amiodarone, sotalol, or placebo. Those not achieving SR at day 28 were cardioverted and classified into SR or AF groups at 8 weeks (n = 624) and 1 year (n = 556). The QOL (SF-36), symptom checklist (SCL), specific activity scale (SAS), AF severity scale (AFSS), and EP were assessed. Results: Favorable changes were seen in SR patients at 8 weeks in physical functioning (p < 0.001), physical role limitations (p = 0.03), general health (p = 0.002), and vitality (p < 0.001), and at 1 year in general health (p = 0.007) and social functioning (p = 0.02). Changes in the scores for SCL severity (p = 0.01), functional capacity (p = 0.003), and AFSS symptom burden (p < 0.001) at 8 weeks and in SCL severity (p < 0.01) and AF symptom burden (p < 0.001) at 1 year showed significant improvements in SR versus AF. Symptomatic patients were more likely to have improvement. The EP in SR versus AF was greater from baseline to 8 weeks (p = 0.01) and to 1 year (p = 0.02). The EP correlated with physical functioning and functional capacity except in the AF group at 1 year. Conclusions: In patients with persistent AF, restoration and maintenance of SR was associated with improvements in QOL measures and EP. There was a strong correlation between QOL measures and EP. [Copyright &y& Elsevier]

: ObjectivesThe purpose of this study was to assess the effect of oral azimilide dihydrochloride (AZ) 100 mg versus placebo on the onset, termination, and prevalence of atrial fibrillation (AF) in a subpopulation of patients in the Azimilide Postinfarct Survival Evaluation (ALIVE) trial.: BackgroundPrevious clinical trials have demonstrated the antiarrhythmic effects of AZ in patients with AF. Azimilide was investigated for its effects on mortality in patients with depressed left ventricular (LV) function after recent myocardial infarction (MI) and in a subpopulation of patients with AF.: MethodsA total of 3,381 post-MI patients with depressed LV function were enrolled in this randomized, placebo-controlled, double-blind study of AZ 100 mg on all-cause mortality. A total of 93 patients had AF on the baseline 12-lead electrocardiogram (ECG). An additional 27 patients developed AF after initially being in sinus rhythm at randomization. These patients were identified through 12-lead ECGs obtained during routine visits at week 2, months 1, 4, 8, and 12.: ResultsPatients with AF at baseline had a higher mortality than those without AF (p = 0.0006). Among AF patients, there was no difference in mortality between AZ patients and placebo patients (p = 0.82). Fewer AZ patients developed AF than placebo patients (p = 0.04). More AZ patients than placebo patients converted to sinus rhythm, but this difference did not achieve statistical significance (p = 0.076). Over one-year follow-up, more AZ patients were in sinus rhythm than placebo patients (p = 0.04).: ConclusionsAzimilide was safe and effective AF therapy in patients with depressed LV function after an MI. [Copyright &y& Elsevier]

The Sotalol-Amiodarone Fibrillation Efficacy Trial (SAFE-T) is a randomized, double-blind, multicenter, placebo-controlled trial in which the effects of sotalol and amiodarone in maintaining stability of sinus rhythm are being examined in patients with persistent atrial fibrillation at 20 Veterans Affairs medical centers. The time to the occurrence of atrial fibrillation or flutter in patients with atrial fibrillation converted to sinus rhythm is the primary outcome measure, with a number of parameters as secondary end points. SAFE-T had randomized 665 patients when enrollment terminated on October 31, 2001. Follow-up of patients continued until October 31, 2002, for a maximum period of 54 months and a minimum period of 12 months for all patients. [Copyright &y& Elsevier]

Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce sudden cardiac death and all-cause mortality. They also may have direct antiarrhythmic properties. We retrospectively analyzed the data from the Multicenter UnSustained Tachycardia Trial (MUSTT), to determine the effects of ACE inhibitors on inducibility of sustained ventricular tachycardia and on sudden cardiac death and overall mortality in 2,087 patients with prior myocardial infarction, nonsustained ventricular tachycardia, and depressed left ventricular function. Results of electrophysiologic testing were compared by use of ACE inhibitors at baseline, and outcomes were compared between the 564 patients prescribed ACE inhibitors at discharge and the 1,523 patients who did not receive treatment. The inducibility of sustained ventricular tachycardia during electrophysiologic testing did not differ by baseline ACE inhibitor use (unadjusted p = 0.75). Patients discharged from hospital on ACE inhibitors had a lower ejection fraction, more extensive coronary artery disease, and fewer previous revascularizations at baseline. After adjustments for differences in baseline factors and initial hospitalization variables, there were no significant differences in total mortality (p = 0.47) or arrhythmic death or cardiac arrest (p = 0.51) with ACE inhibitor use at discharge over a median 43 months of follow-up. [ABSTRACT FROM AUTHOR]

Patients with congestive heart failure frequently have ventricular arrhythmias on ambulatory electrocardiographic recordings and sudden cardiac death is seen in almost 50% of such patients. Many antiarrhythmic agents have been approved to suppress the arrhythmia in an effort to improve survival. Some sodium-channel blockers not only failed to improve survival but have been shown to be harmful. This led to the development of potassium-channel blockers, such as d-sotalol, amiodarone, dofetilide, and azimilide. d-Sotalol was associated with excess mortality in patients with left ventricular dysfunction; amiodarone seems to be potentially beneficial; and dofetilide has a neutral effect on mortality. The Sudden Cardiac Death Heart Failure Trial (SCD HEFT) is testing the implantable cardioverter defibrillator (ICD) against amiodarone and placebo. The ICDs appear to be superior to antiarrhythmic drugs in certain high-risk patients, although not proved in unstratified patients with heart failure. [ABSTRACT FROM AUTHOR]

Analyzes the effects of the antiarrhythmic drug d-sotalol in patients with congestive heart failure. Mechanism of action; Assessment of hemodynamic variables; Absence in changes in blood pressure and right atrial pressure; Decrease in cardiac index; Inadequate hemodynamic actions.

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. [ABSTRACT FROM AUTHOR]

A response by Bramah N. Singh and colleagues to several letters to the editor about their article concerning impact of amiodarone and sotalol on the quality of life, which appeared in the May 5, 2005 issue, is presented.

Background: The optimal pharmacologic means to restore and maintain sinus rhythm in patients with atrial fibrillation remains controversial. Methods: In this double-blind, placebo-controlled trial, we randomly assigned 665 patients who were receiving anticoagulants and had persistent atrial fibrillation to receive amiodarone (267 patients), sotalol (261 patients), or placebo (137 patients) and monitored them for 1 to 4.5 years. The primary end point was the time to recurrence of atrial fibrillation beginning on day 28, determined by means of weekly transtelephonic monitoring. Results: Spontaneous conversion occurred in 27.1 percent of the amiodarone group, 24.2 percent of the sotalol group, and 0.8 percent of the placebo group, and direct-current cardioversion failed in 27.7 percent, 26.5 percent, and 32.1 percent, respectively. The median times to a recurrence of atrial f ibrillation were 487 days in the amiodarone group, 74 days in the sotalol group, and 6 days in the placebo group according to intention to treat and 809, 209, and 13 days, respectively, according to treatment received. Amiodarone was superior to sotalol (P<0.001) and to placebo (P<0.001), and sotalol was superior to placebo (P<0.001). In patients with ischemic heart disease, the median time to a recurrence of atrial fibrillation was 569 days with amiodarone therapy and 428 days with sotalol therapy (P=0.53). Restoration and maintenance of sinus rhythm significantly improved the quality of life and exercise capacity. There were no significant differences in major adverse events among the three groups. Conclusions: Amiodarone and sotalol are equally efficacious in converting atrial fibrillation to sinus rhythm. Amiodarone is superior for maintaining sinus rhythm, but both drugs have similar efficacy in patients with ischemic heart disease. Sustained sinus rhythm is associated with an improved quality of life and improved exercise performance. N Engl J Med 2005;352:1861-72. [ABSTRACT FROM AUTHOR]

Background: Asymptomatic ventricular arrhythmias in patients with congestive heart failure are associated with increased rates of overall mortality and sudden death. Amiodarone is now used widely to prevent ventricular tachycardia and fibrillation. We conducted a trial to determine whether amiodarone can reduce overall mortality in patients with congestive heart failure and asymptomatic ventricular arrhythmias. Methods: We used a double-blind, placebo-controlled protocol in which 674 patients with symptoms of congestive heart failure, cardiac enlargement, 10 or more premature ventricular contractions per hour, and a left ventricular ejection fraction of 40 percent or less were randomly assigned to receive amiodarone (336 patients) or placebo (338 patients). The primary end point was overall mortality, and the median follow-up was 45 months (range, 0 to 54). Results: There was no significant difference in overall mortality between the two treatment groups (P = 0.6). The two-year actuarial survival rate was 69.4 percent (95 percent confidence interval, 64.2 to 74.6) for the patients in the amiodarone group and 70.8 percent (95 percent confidence interval, 65.7 to 75.9) for those in the placebo group. At two years, the rate of sudden death was 15 percent in the amiodarone group and 19 percent in the placebo group (P = 0.43). There was a trend toward a reduction in overall mortality among the patients with nonischemic cardiomyopathy who received amiodarone (P = 0.07). Amiodarone was significantly more effective in suppressing ventricular arrhythmias and increased the left ventricular ejection fraction by 42 percent at two years. Conclusions: Although amiodarone was effective in suppressing ventricular arrhythmias and improving ventricular function, it did not reduce the incidence of sudden death or prolong survival among patients with heart failure, except for a trend toward reduced mortality among those with nonischemic cardiomyopathy. (N Engl J Med 1995;333:77-82.) [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background--Hypertension treatment and control remain low worldwide. Strategies to improve blood pressure control have been implemented in the United States and around the world for several years. This study was designed to assess improvement in blood pressure control over a 10-year period in a large cohort of patients in the Department of Veterans Affairs. Methods and Results--A cohort of 582 881 hypertensive patients and 260 924 normotensive individuals treated in 15 Department of Veterans Affairs medical centers between 2000 and 2010 were examined. Strategies used system-wide included blood pressure control as a performance measure, automatic notification to healthcare providers, electronic reminders, and a systematic revisit schedule. The main outcome measure was the percentage of hypertensive patients whose hypertension was controlled and the level of blood pressure each month. In the hypertensive cohort (mean age 62.9± 13.4 years, 96.0% male), 52.3% of patients were white, 25.1% were black, and 21.1% were Hispanic. Blood pressure control rates improved from 45.7% in September 2000 to 76.3% in August 2010. Improvements were similar across ethnic, racial, age, and sex groups. Average systolic/diastolic blood pressure decreased from 142.6/77.1 mm Hg in 2000 to 131.2/74.8 mm Hg in 2010, a decrease of 11.3/2.3 mm Hg (P<0.0001 for both). Systolic and diastolic blood pressures were lower in summer than in winter, and this trend continued through 2010. On average, control rates increased by 3.0% per year and were 6.8% higher in summer than in winter. Conclusions--High rates of blood pressure control can be achieved in all age and ethnic groups and in both sexes. INSET: CLINICAL PERSPECTIVE. [ABSTRACT FROM AUTHOR]

Background: Heart failure is associated with ventricular tachyarrhythmias (VT/VF). Fluid accumulation during worsened heart failure may trigger VT/VF. Increased intrathoracic impedance has been correlated with fluid accumulation during heart failure. Implanted defibrillators capable of daily measures of intrathoracic impedance allow correlation of impedance with occurrence of VT/VF. We hypothesized that VT/VF episodes are preceded by decreases in intrathoracic impedance. The goal was to identify the relationship of intrathoracic impedance measured by implanted cardioverter defibrillators to the occurrence of VT/VF. Method: Implanted defibrillator follow-up data were obtained retrospectively. Those with Medtronic OptiVol (Medtronic Inc., Minneapolis, MN, USA), storing averaged daily and reference impedance values, were reviewed for VT/VF episodes. Impedance changes in the week leading up to VT/VF were analyzed. Results: A total of 317 VT/VF episodes in a cohort of 121 patients’ follow-up data were evaluated. Averaged daily intrathoracic impedance declined preceding 64% of VT/VF episodes, with an average decline of 0.46 ± 0.35 Ohms from the day before the VT/VF episodes. However, the mean values of the averaged daily and reference impedance did not change significantly. A novel measure, ΔTI, the sum of the daily differences between the averaged daily and reference impedance, was negative preceding 66% of VT/VF episodes (P < 0.001). The mean ΔTI was −4.0 ± 1.3 Ohms, which was significantly lower than the theoretically expected value of zero Ohms (P < 0.01). Conclusion: (1) Averaged daily impedance declined preceding 64% of VT/VF episodes, but the overall decline was of small magnitude; (2) a novel measure, ΔTI, was negative preceding 66% of VT/VF episodes, and significantly below zero. (PACE 2010; 33:960–966) [ABSTRACT FROM AUTHOR]

Background. Right ventricular pacing (RVP) has been associated with adverse outcomes, including heart failure and death. Minimizing RVP has been proposed as a therapeutic goal for a variety of pacing devices and indications. Objective. Quantify survival according to frequency of RVP in veterans with pacemakers. Methods. We analyzed electrograms from transtelephonic monitoring of veterans implanted with pacemakers between 1995 and 2005 followed by the Eastern Pacemaker Surveillance Center. We compared all cause mortality and time to death between patients with less than 20% and more than 80% RVP. Results. Analysis was limited to the 7198 patients with at least six trans-telephonic monitoring records (mean = 21). Average follow-up was 5.3 years. Average age at pacemaker implant was significantly lower among veterans with <20% RVP (67 years versus 72 years;P < .0001). An equal proportion of deaths during follow-up were noted for each group: 126/565 patients (22%) with <20% RVP and 1113/4968 patients (22%) with >80% RVP. However, average post-implant survival was 4.3 years with <20% RVP versus 4.7 years with >80% RVP (P < .0001). Conclusions. Greater frequency (>80%) of RVP was not associated with higher mortality in this population of veterans. Those veterans utilizing <20% RVP had a shortened adjusted survival rate (P = .0016). [ABSTRACT FROM AUTHOR]

Introduction. Information regarding the effect of exercise capacity on mortality risk in individuals with high-normal blood pressure is severely limited. Thus, we evaluated the association of exercise capacity and all-cause mortality in individuals with high-normal blood pressure. Methods. Exercise test was performed in 1727 males with high-normal blood pressure at two Veteran sites (Washington, DC, and Palo Alto, CA). Fitness status was assessed in metabolic equivalents (METs) at exercise peak. All-cause mortality was recorded for a mean follow-up period of 9.8±6.0 years. Results. Exercise capacity was inversely associated with all-cause mortality, and the association was independent of traditional cardiovascular risk factors. For each 1 MET increase in exercise capacity, the adjusted mortality risk was reduced by 13%, underscoring the strong predictive value of exercise capacity that was confirmed by ROC analysis. Data analysis according to fitness levels revealed a threshold level of 4 METs, over which the mortality risk was progressively reduced by 30% (hazard ratio=0.70; CI 0.51-0.95) for those who achieved 4.1-6.0 METs and 61% (hazard ratio=0.39; CI 0.26-0.57) for those who achieved 8.1-10 METs. No additional reductions in risk were noted until the MET level achieved exceeded 12 METs. Conclusions. We observed a strong, inverse, graded and independent association between exercise capacity and all-cause mortality in individuals with high-normal blood pressure. Our findings indicate that a shift of the fitness curve to the right is associated with significant survival benefits, and even slight differences in fitness levels are associated with substantial reductions in mortality risk. [ABSTRACT FROM AUTHOR]

Introduction. Information regarding the effect of exercise capacity on mortality risk in individuals with high-normal blood pressure is severely limited. Thus, we evaluated the association of exercise capacity and all-cause mortality in individuals with high-normal blood pressure. Methods. Exercise test was performed in 1727 males with high-normal blood pressure at two Veteran sites (Washington, DC, and Palo Alto, CA). Fitness status was assessed in metabolic equivalents (METs) at exercise peak. All-cause mortality was recorded for a mean follow-up period of 9.8±6.0 years. Results. Exercise capacity was inversely associated with all-cause mortality, and the association was independent of traditional cardiovascular risk factors. For each 1 MET increase in exercise capacity, the adjusted mortality risk was reduced by 13%, underscoring the strong predictive value of exercise capacity that was confirmed by ROC analysis. Data analysis according to fitness levels revealed a threshold level of 4 METs, over which the mortality risk was progressively reduced by 30% (hazard ratio=0.70; CI 0.51–0.95) for those who achieved 4.1–6.0 METs and 61% (hazard ratio=0.39; CI 0.26–0.57) for those who achieved 8.1–10 METs. No additional reductions in risk were noted until the MET level achieved exceeded 12 METs. Conclusions. We observed a strong, inverse, graded and independent association between exercise capacity and all-cause mortality in individuals with high-normal blood pressure. Our findings indicate that a shift of the fitness curve to the right is associated with significant survival benefits, and even slight differences in fitness levels are associated with substantial reductions in mortality risk. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- The purpose of this study was to assess the association between exercise capacity and mortality in African Americans and Caucasians with type 2 diabetes and to explore racial differences regarding this relationship. RESEARCH DESIGN AND METHODS -- African American (n = 1,703; aged 60 ± 10 years) and Caucasian (n = 1,445; aged 62 ± 10 years) men with type 2 diabetes completed a maximal exercise test between 1986 and 2007 at the Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, California. Three fitness categories were established (low-, moderate-, and high-fit) based on peak METs achieved. Subjects were followed for all-cause mortality for 7.3 ± 4.7 years. RESULTS -- The adjusted mortality risk was 23% higher in African Americans than in Caucasians (hazard ratio 1.23 [95% CI 1.1-1.4]). A graded reduction in mortality risk was noted with increased exercise capacity for both races. There was a significant interaction between race and METs (P < 0.001) and among race and fitness categories (P < 0.001). The association was stronger for Caucasians. Each 1-MET increase in exercise capacity yielded a 19% lower risk for Caucasians and 14% for African Americans (P < 0.001). Similarly, the risk was 43% lower (0.57 [0.44-0.73]) for moderate-fit and 67% lower (0.33 [0.22-0.48]) for high-fit Caucasians. The comparable reductions in African Americans were 34% (0.66 [0.55-0.80]) and 46% (0.54 [0.39-0.73]), respectively. CONCLUSIONS-- Exercise capacity is a strong predictor of all-cause mortality in African American and Caucasian men with type 2 diabetes. The exercise capacity-related reduction in mortality appears to be stronger and more graded for Caucasians than for African Americans. [ABSTRACT FROM AUTHOR]

Abstract: Background: Many patients receiving amiodarone therapy are male. The long-term risk for amiodarone-induced thyroid dysfunction in these patients has not been systematically and prospectively investigated. The purpose of this study was to determine the extent of amiodarone-induced thyroid dysfunction in a large male cohort. Methods: This is a substudy of a prospective randomized controlled trial (SAFE-Trial) in which amiodarone, sotalol, and placebo for persistent atrial fibrillation were evaluated. For the purpose of this substudy, sotalol and placebo groups were combined into a control group. Serial thyroid function tests were performed over 1-4.5 years. Of the 665 patients enrolled in the SAFE-Trial, 612 patients were included in this sub-study. Results: Subclinical hypothyroidism, thyroid-stimulating hormone (TSH) level 4.5-10 mU/L, was seen among 25.8% of the amiodarone-treated patients and only 6.6% of controls (P <.0001). Overt hypothyroidism, TSH level >10 mU/L, was seen among 5.0% of the amiodarone-treated patients, and only 0.3% of controls (P <.001). By 6 months, 93.8% of the patients who developed TSH elevations above 10 mU/L on amiodarone had been detected. There was a trend toward a greater proportion of hyperthyroidism, defined as a TSH <0.35 mU/L, in the amiodarone group compared with the control group (5.3% vs 2.4%, P =.07). Conclusions: Hypothyroidism developed in 30.8% of older males treated with amiodarone and in only 6.9% of the controls. Hypothyroidism presented at an early stage of therapy. Hyperthyroidism occurred in 5.3% of amiodarone treated patients, and was a subclinical entity in all but 1 case. [Copyright &y& Elsevier]

Objective: We aimed to evaluate myocardial diastolic function in patients with beta-thalassemia major (β-TM) using pulsed-tissue Doppler imaging (TDI) and flow propagation (VP), in relation to BNP levels. Methods: We enrolled 192 consecutive patients with β-TM (88 men (25 ± 6 years) and 104 women (26 ± 6 years), with normal left ventricular (LV) systolic function. By TDI, diastolic myocardial velocities were sampled at the lateral section of the mitral annulus (Smv, Emv, Amv). From the apical four-chamber view diastolic transmitral flow velocities, including measures of E- and A-waves were performed. The propagation velocity of early flow into the LV cavity was measured by color M-mode Doppler. Plasma BNP levels were measured in all patients. Results: A nonlinear relationship was found between BNP levels and E/A ratio (beta coefficient for the second-order term = 1.4 ± 0.4, P = 0.001). We also found a positive association of BNP levels with Amv (r = 0.28, P = 0.023), and a reverse with Smv (r =−0.59, P = 0.01) and Emv/Amv (r =−0.36, P = 0.019). Moreover, an inverse relationship was observed between BNP and Vp (r =−0.43, P = 0.012) levels. Finally, a strong positive linear relationship was found between E/Vp ratio and BNP levels (r = 0.76, P < 0.001). Conclusion: A U-curved association of E/A ratio of transmitral Doppler velocity was revealed with BNP levels, while the tissue Doppler of the Emv/Amv of the mitral annulus movement showed a negative linear association with BNP levels. [ABSTRACT FROM AUTHOR]

Objectives: The analysis goal was to estimate incremental cost-effectiveness ratios (ICERs) for the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial patients who received cardiac resynchronization therapy (CRT) via pacemaker (CRT-P) or pacemaker-defibrillator (CRT-D) in combination with optimal pharmacological therapy (OPT) relative to patients with OPT alone. Background: In the COMPANION trial, CRT-P and CRT-D reduced the combined risk of all-cause mortality or first hospitalization among patients with advanced heart failure and intraventricular conduction delays, but the cost effectiveness of the therapy remains unknown. Methods: In this analysis, intent-to-treat trial data were modeled to estimate the cost effectiveness of CRT-D and CRT-P relative to OPT over a base-case seven-year treatment episode. Exponential survival curves were derived from trial data and adjusted by quality-of-life trial results to yield quality-adjusted life-years (QALYs). For the first two years, follow-up hospitalizations were based on trial data. The model assumed equalized hospitalization rates beyond two years. Initial implantation and follow-up hospitalization costs were estimated using Medicare data. Results: Over two years, follow-up hospitalization costs were reduced by 29% for CRT-D and 37% for CRT-P. Extending the cost-effectiveness analysis to a seven-year base-case time period, the ICER for CRT-P was $19,600 per QALY and the ICER for CRT-D was $43,000 per QALY relative to OPT. Conclusions: For the COMPANION trial patients, the use of CRT-P and CRT-D was associated with a cost-effectiveness ratio below generally accepted benchmarks for therapeutic interventions of $50,000 per QALY to $100,000 per QALY. This suggests that the clinical benefits of CRT-P and CRT-D can be achieved at a reasonable cost. [Copyright &y& Elsevier]

Background: Several clinical and observational studies have established that exercise capacity and activity status are strong predictors of cardiovascular and overall mortality. We aimed to evaluate the relationship between exercise tolerance test (ETT) indices and occurrence of coronary heart disease (CHD), in patients with heterozygous Familial Hypercholesterolemia (eFH). Methods: During 1987–1997, we enrolled 639 cardiovascular disease-free patients with heterozygous eFH; 58 (9%) patients were excluded since they had a positive ETT. A fatal or non-fatal CHD event was the end point. Cox proportional hazards models were applied to evaluate the association between the investigated outcome and ETT indices. Results: During the follow-up (1987–2002), 53 (18%) men and 34 (10%) women developed a CHD event (11 were fatal). The age-adjusted event rate was 87 events per 2915 person-years (3%). Statistical analysis revealed that exercise capacity (hazard ratio=0.82, P<0.001), heart rate recovery at 1 min (hazard ratio=0.91, P<0.05), and peak pulse pressure levels (hazard ratio=1.03, P<0.001), were predictors of CHD, after controlling for several potential confounders. Conclusion: Decreased exercise capacity, a delayed decrease in heart rate during the first minute of graded exercise, and increased peak pulse pressure are strong predictors of coronary events in patients with eFH. Physical activity should be strongly recommended in these patients. [Copyright &y& Elsevier]

Although the value of heart rate variability (HRV) for risk stratification after acute myocardial infarction has been demonstrated, the value of low HRV as a predictor of sudden cardiac death in patients with ischemic cardiomyopathy has not been shown convincingly to date. We retrospectively analyzed electrocardiographic data from 179 patients in the Veterans Affairs’ Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure to determine if HRV (expressed as the SD of the normal-to-normal RR intervals [SDNN]) would be useful as a predictor of overall mortality and sudden death. Because our goal was to identify high-risk patients, we compared patients in the lowest quartile of HRV with the remaining patients. Among the 127 patients meeting inclusion criteria, SDNN <65.3 ms (the lowest quartile) was the sole independent factor predictive of survival in a multivariate model (p = 0.0001). A Cox proportional-hazards model revealed that each increase of 10 ms in SDNN conferred a 20% decrease in risk of mortality (p = 0.0001). Furthermore, patients with SDNN <65.3 ms had a significantly increased risk of sudden death (p = 0.016). Thus, HRV was the sole independent predictor of overall mortality and was significantly associated with sudden death in this population. [Copyright &y& Elsevier]

: ObjectivesWe investigated the acute and long-term hemodynamic and neurohumoral effects of the vasopeptidase inhibitor omapatrilat in human heart failure.: BackgroundAngiotensin-converting enzyme (ACE) inhibition constitutes a major advance in the treatment of chronic heart failure (CHF). Simultaneous inhibition of both neutral endopeptidase and ACE with omapatrilat may represent a new treatment strategy in CHF.: MethodsThree hundred and sixty-nine patients with symptomatic heart failure were randomized to double-blind treatment with omapatrilat (first 190 patients: 2.5 mg, 5 mg or 10 mg; last 179 patients: 2.5 mg, 20 mg or 40 mg once daily) for 12 weeks.: ResultsAcutely, the 10 mg, 20 mg and 40 mg doses of omapatrilat produced greater reductions in pulmonary capillary wedge pressure (PCWP), systolic blood pressure (SBP) and systemic vascular resistance compared with 2.5 mg. Higher doses were associated with greater increases in vasodilator and natriuretic peptides, in addition to ACE inhibition. After 12 weeks, omapatrilat 20 mg and 40 mg showed greater falls from baseline in PCWP (40 mg: 0 h to 12 h average change −7.3 ± 0.8 mm Hg) and SBP (40 mg: −11.7 ± 1.7 mm Hg) than 2.5 mg (both p < 0.01 vs. 2.5 mg). The incidence of adverse experiences and patient withdrawal were similar in all groups.: ConclusionsIn CHF, the acute hemodynamic benefit seen with higher doses of omapatrilat was associated with increases in plasma vasodilator and natriuretic peptide levels in addition to ACE inhibition. After 12 weeks, the hemodynamic benefit was maintained. Omapatrilat may be a promising new agent in CHF. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]