Clinical pharmacy services in heart failure: an opinion paper from the Heart Failure Society of America and American College of Clinical Pharmacy Cardiology Practice and Research Network.

BACKGROUND: Heart failure (HF) care takes place in multiple settings, with a variety of providers, and generally involves patients who have multiple comorbidities. This situation is a "perfect storm" of factors that predispose patients to medication errors. METHODS AND RESULTS: The goals of this paper are to outline potential roles for clinical pharmacists in a multidisciplinary HF team, to document outcomes associated with interventions by clinical pharmacists, to recommend minimum training for clinical pharmacists engaged in HF care, and to suggest financial strategies to support clinical pharmacy services within a multidisciplinary team. As patients transition from inpatient to outpatient settings and between multiple caregivers, pharmacists can positively affect medication reconciliation and education, assure consistency in management that results in improvements in patient satisfaction and medication adherence, and reduce medication errors. For mechanical circulatory support and heart transplant teams, the Centers for Medicare and Medicaid Services considers the participation of a transplant pharmacology expert (e.g., clinical pharmacist) to be a requirement for accreditation, given the highly specialized and complex drug regimens used. Although reports of outcomes from pharmacist interventions have been mixed owing to differences in study design, benefits such as increased use of evidence-based therapies, decreases in HF hospitalizations and emergency department visits, and decreases in all-cause readmissions have been demonstrated. Clinical pharmacists participating in HF or heart transplant teams should have completed specialized postdoctoral training in the form of residencies and/or fellowships in cardiovascular and/or transplant pharmacotherapy, and board certification is recommended. Financial mechanisms to support pharmacist participation in the HF teams are variable. CONCLUSIONS: Positive outcomes associated with clinical pharmacist activities support the value of making this resource available to HF teams.

Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice.

Mineralocorticoid receptor antagonists (MRAs) improve survival and reduce morbidity in patients with heart failure, reduced ejection fraction (HF-REF), and mild-to-severe symptoms, and in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. These clinical benefits are observed in addition to those of angiotensin converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers. The morbidity and mortality benefits of MRAs may be mediated by several proposed actions, including antifibrotic mechanisms that slow heart failure progression, prevent or reverse cardiac remodelling, or reduce arrhythmogenesis. Both eplerenone and spironolactone have demonstrated survival benefits in individual clinical trials. Pharmacologic differences exist between the drugs, which may be relevant for therapeutic decision making in individual patients. Although serious hyperkalaemia events were reported in the major MRA clinical trials, these risks can be mitigated through appropriate patient selection, dose selection, patient education, monitoring, and follow-up. When used appropriately, MRAs significantly improve outcomes across the spectrum of patients with HF-REF.

Predictors of mortality after discharge in patients hospitalized with heart failure: an analysis from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF).

BACKGROUND: Patients with heart failure (HF) are at high risk for mortality and rehospitalization in the early period after hospital discharge. We developed clinical models predictive of short-term clinical outcomes in a broad patient population discharged after hospitalization for HF. METHODS: The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry is a comprehensive hospital-based registry and performance-improvement program for patients hospitalized with HF. Follow-up data were scheduled to be prospectively collected at 60 to 90 days postdischarge in a prespecified 10% sample. For the 4,402 patients included in this analysis, 19 prespecified potential predictor variables were used in a stepwise Cox proportional hazards model for all-cause mortality. Logistic regression including 45 potential variables was used to model mortality or rehospitalization. RESULTS: The 60- to 90-day postdischarge mortality rate was 8.6% (n = 481), and 29.6% (n = 1,715) were rehospitalized. Factors predicting early postdischarge mortality include age, serum creatinine, reactive airway disease, liver disease, lower systolic blood pressure, lower serum sodium, lower admission weight, and depression. Use of statins and beta-blockers at discharge was associated with significantly decreased mortality. The C-index of the model was 0.74. The most important predictors for the combined end point of death or rehospitalization were admission serum creatinine, systolic blood pressure, admission hemoglobin, discharge use of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and pulmonary disease. From this analysis, 8 factors identified to carry significant risk were selected for use in a point scoring system to predict the risk of mortality within 60 days after discharge, with a C-index of 0.72. CONCLUSIONS: A substantial risk of mortality and mortality or rehospitalization is present in the first 60 to 90 days after discharge from a hospitalization for HF. Several factors were identified that signal high-risk patients. Application of these findings with a simple algorithm can distinguish patients who are low risk from those at high risk who may benefit from closer monitoring and aggressive evidence-based treatment.

Relation of low hemoglobin and anemia to morbidity and mortality in patients hospitalized with heart failure (insight from the OPTIMIZE-HF registry).

Anemia in heart failure (HF) is increasingly recognized and treated, but little is known about the prevalence and its relation to outcomes in patients hospitalized for decompensated HF in a situation of both reduced and preserved systolic function. We hypothesized that lower hemoglobin is correlated with death during hospitalization and 60 to 90 days postdischarge in patients with HF. The Organized Program to Initiate Lifesaving Treatment in Patients with Heart Failure is a registry and performance improvement program for hospitalized patients with HF. Study cohorts were defined by admission hemoglobin quartile. Data from 48,612 patients at 259 hospitals showed that half of the total cohort had low hemoglobin (<12.1 g/dl) and that 25% were moderately to severely anemic (lowest hemoglobin quartile, 5 to 10.7 g/dl). Patients with low hemoglobin were older, were more often women and Caucasian, and had preserved systolic function and elevated creatinine. They were also less likely to receive angiotensin-converting enzyme inhibitors and beta blockers at discharge. Anemic patients had higher in-hospital mortality (4.8% vs 3.0%, lowest vs highest quartile), longer hospital length of stay (6.5 vs 5.3 days), and more readmissions by 90 days (33.1% vs 24.2%) (all p <0.0001). In conclusion, these data reveal a higher prevalence of low hemoglobin in hospitalized patients than noted in randomized HF trials and outpatient registries. Lower hemoglobin is associated with higher morbidity and mortality in hospitalized patients with HF.

Influence of coronary artery disease and coronary revascularization status on outcomes in patients with acute heart failure syndromes: a report from OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure).

BACKGROUND: Coronary artery disease (CAD) is frequent among patients hospitalized with acute heart failure syndromes (AHFS). AIMS: To describe the influence of coronary revascularization status on survival in patients with AHFS. METHODS AND RESULTS: OPTIMIZE-HF enrolled 48,612 patients with AHFS from 259 U.S. hospitals. In-hospital data were obtained for all patients and post-discharge 60-90 day follow-up in a pre-specified 10% sample. CAD was associated with higher in-hospital (3.7% vs. 2.9%, OR 1.14, 95% CI 1.00-1.31) and post-discharge mortality (9.2% vs. 6.9%, HR 1.37, 95% CI 1.03-1.81) compared to no CAD. Post-discharge, patients with CAD who were not revascularized had higher mortality compared to patients without CAD (10.6% vs. 6.9%, HR 1.56, 95% CI 1.15-2.11). This association was similar in patients with left ventricular systolic dysfunction (EF <40%, adjusted HR 1.52, 95% CI 0.98-2.35) and preserved systolic function (EF > or =40%, adjusted HR1.58, 95% CI 1.05-2.39). Patients with CAD who were revascularized had similar mortality to patients without CAD (HR 1.06, 95% CI 0.62-1.80 for PSF, HR 1.13, 95% CI 0.71-1.80 for LVSD). CONCLUSIONS: In AHFS, patients with CAD have a higher 60-90 day post-discharge mortality compared to no-CAD patients. However, patients with CAD who are revascularized appear to have similar post-discharge mortality when compared to the no-CAD group. This suggests that revascularization status may confer a survival advantage in this high risk population.

Influence of a performance-improvement initiative on quality of care for patients hospitalized with heart failure: results of the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF).

BACKGROUND: Despite evidence-based national guidelines for optimal treatment of heart failure (HF), the quality of care remains inadequate. We sought to evaluate the effect of a national hospital-based initiative on quality of care in patients hospitalized with HF. METHODS: Two hundred fifty-nine US hospitals participating in the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) submitted data on 48 612 patients with HF from March 1, 2003, through December 31, 2004. Admission, hospital, discharge care, and outcomes data were collected using a Web-based registry that provided real-time feedback on performance measures benchmarked to other hospitals. Process-of-care improvement tools, including evidence-based best-practice algorithms and customizable admission and discharge sets, were provided. RESULTS: Provision of complete discharge instructions and smoking-cessation counseling increased significantly (from 46.8%-66.5% and 48.2%-75.6%, respectively; P < .001 for both). Left ventricular function assessment started at a high rate (89.3%) and improved to 92.1% (P < .001). Angiotensin-converting enzyme inhibitors were prescribed at discharge to 75.8% of eligible patients, which did not improve during the 2-year study. There were trends for reduction of in-hospital mortality, postdischarge death, and combined postdischarge death and rehospitalization and a significant reduction in mean length of stay. Use of preprinted admission order sets and/or discharge checklists increased from 35.6% to 54.1% and was associated with an increase in the use of evidence-based therapies and lower risk-adjusted in-hospital mortality. CONCLUSIONS: Participation in OPTIMIZE-HF was associated with an increase in use of evidence-based therapy, adherence to performance measures, and shorter lengths of stay in patients hospitalized with HF. Increased use of process-of-care improvement tools was associated with further improvements in quality of care. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00344513.

Relation between dose of loop diuretics and outcomes in a heart failure population: results of the ESCAPE trial.

BACKGROUND: We examined the relation of maximal in-hospital diuretic dose to weight loss, changes in renal function, and mortality in hospitalised heart failure (HF) patients. METHODS: In ESCAPE, 395 patients received diuretics in-hospital. Weight was measured at baseline, discharge, and every other day before discharge. Weight loss was defined as the difference between baseline and last in-hospital weight. Mortality was assessed using a log-logistic model with non-zero background. RESULTS: Median weight loss: 2.8 kg (0.7, 6.1); mean: 3.7 kg (22% of values <0). Weight loss and maximum in-hospital dose were correlated (p=0.0007). Baseline weight, length of stay, and baseline brain natriuretic peptide were significant predictors of weight loss. After adjusting for these, dose was not a significant predictor of weight loss. A strong relation between dose and mortality was seen (p=0.003), especially at >300 mg/day. Dose remained a significant predictor of mortality after adjusting for baseline variables that significantly predicted mortality. Correlation between maximal dose and creatinine level change was not significant (r=0.043; p=0.412) CONCLUSIONS: High diuretic doses during HF hospitalisation are associated with increased mortality and poor 6-month outcome.

Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study.

BACKGROUND: The prognostic value of serum sodium in patients hospitalized for worsening heart failure has not been well defined. METHODS AND RESULTS: The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study randomized 949 patients with systolic dysfunction hospitalized for worsening heart failure to receive 48 to 72 hours of intravenous milrinone or placebo in addition to standard therapy. In a retrospective analysis, we investigated the relationship between admission serum sodium and the primary end point of days hospitalized for cardiovascular causes within 60 days of randomization, as well as the secondary end points of in-hospital mortality, 60-day mortality, and 60-day mortality/rehospitalization. The number of days hospitalized for cardiovascular causes was higher in the lowest sodium quartile: 8.0 (4.5, 18.5) versus 6 (4, 13) versus 6 (4, 11.5) versus 6 (4, 12) days (P<0.015 for comparison with the lowest quartile). Lower serum sodium was associated with higher in-hospital and 60-day mortality: 5.9% versus 1% versus 2.3% versus 2.3% (P<0.015) and 15.9% versus 6.4% versus 7.8% versus 7% (P=0.002), respectively. There was a trend toward higher mortality/rehospitalization for patients who were in the lowest sodium quartile. Multivariable-adjusted Cox proportional hazards analysis showed that serum sodium on admission, when modeled linearly, predicted increased 60-day mortality: sodium (per 3-mEq/L decrease) had a hazard ratio of 1.18 with a 95% CI of 1.03 to 1.36 (P=0.018). CONCLUSIONS: In patients hospitalized for worsening heart failure, admission serum sodium is an independent predictor of increased number of days hospitalized for cardiovascular causes and increased mortality within 60 days of discharge.

Dose response characterization of the association of serum digoxin concentration with mortality outcomes in the Digitalis Investigation Group trial.

AIMS: Many patients with heart failure and reduced EF remain at high risk for hospitalization despite evidence-based therapy. Digoxin may decrease hospitalization; however, uncertainty persists concerning its proper administration and effect on mortality. This study investigated whether using dose response concepts to re-evaluate the relationship between serum digoxin concentration and key mortality outcomes in patients with reduced EF in the Digitalis Investigation Group trial would help clarify efficacy and safety. METHODS AND RESULTS: Multivariable Cox proportional hazards modelling and propensity score adjustment assessed the relationship between serum digoxin concentration (≥0.5 ng/mL) as a continuous variable and mortality outcomes. In patients treated with digoxin, a significant linear association was found between serum concentration and all-cause mortality [adjusted hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.14-1.38, P < 0.001 per 0.5 ng/mL increase in serum concentration]. Based on this relationship, a bidirectional association was found between digoxin therapy and all-cause mortality when compared with placebo. The lowest serum concentrations (0.5-0.7 ng/mL) were associated with the lowest risk of all-cause mortality (adjusted HR 0.77, 95% CI 0.67-0.89, P < 0.001) while high serum concentrations (1.6-2.0 ng/mL) were associated with increased mortality (adjusted HR 1.33, 95% CI 1.12-1.58, P = 0.001). Consistent with this finding, lower serum concentrations (0.5-0.7 ng/mL) were associated with reduced death from worsening heart failure and a neutral effect on cardiovascular death not due to worsening heart failure. CONCLUSION: These findings favour targeting serum concentrations from 0.5 to 0.7 ng/mL when dosing digoxin in patients with heart failure and reduced EF.

The Pilot Randomized Study of Nesiritide Versus Dobutamine in Heart Failure (PRESERVD-HF).

Acute heart failure syndromes (AHFS) are related to several diseases affecting not only the heart but also the kidneys and blood vessels. Emerging evidence indicates that myocardial injury may also play a role in the pathophysiology of AHFS, as suggested by increased levels of markers of injury, such as cardiac troponin (cTn). Although cTn is a known prognostic marker, the release of cTn during hospitalization has not been evaluated prospectively with serial measures. We prospectively evaluated patterns of cTn release by conducting serial measures of cTnI and cTnT in patients hospitalized for AHFS. This study enrolled 51 patients with AHFS who were admitted with worsening heart failure (HF) and a history of coronary artery disease (CAD) in whom an acute coronary event was not suspected. Levels of cTnI and cTnT were measured at 8, 32, 56, and 80 hours after study entry. At baseline, 73.9% of patients had detectable cTnI, and 43.5% had detectable cTnT levels. The median concentrations of cTnI and cTnT were unchanged from 0 to 32 hours, increased from 32 to 56 hours, then either plateaued (cTnT) or decreased to baseline (cTnI). Of the 26 patients who had no detectable cTn levels at baseline, 2 (7.7%) developed detectable cTnT and 5 (41.7%) developed detectable cTnI release during hospitalization. Detectable levels of cTn at baseline were related to short-term clinical events. In this study of patients with CAD in whom an acute coronary event was not suspected, most had detectable levels of cTn present at admission, and some patients developed cTn release during hospitalization. Because cTn release may be a marker for myocardial injury, this study raises the possibility that injury occurred in most patients admitted with AHFS. Therefore, the goal of therapy for AHFS should be not only to improve symptoms and hemodynamics but also to salvage myocardium. Accordingly, therapies for AHFS that are aimed at improving hemodynamics may affect long-term prognosis by either injuring or salvaging myocardium.

Agents with vasodilator properties in acute heart failure: how to design successful trials.

Agents with vasodilator properties (AVDs) are frequently used in the treatment of acute heart failure (AHF). AVDs rapidly reduce preload and afterload, improve left ventricle to aorta and right ventricle to pulmonary artery coupling, and may improve symptoms. Early biomarker changes after AVD administration have suggested potentially beneficial effects on cardiac stretch, vascular tone, and renal function. AVDs that reduce haemodynamic congestion without causing hypoperfusion might be effective in preventing worsening organ dysfunction. Existing AVDs have been associated with different results on outcomes in randomized clinical trials, and observational studies have suggested that AVDs may be associated with a clinical outcome benefit. Lessons have been learned from past AVD trials in AHF regarding preventing hypotension, selecting the optimal endpoint, refining dyspnoea measurements, and achieving early randomization and treatment initiation. These lessons have been applied to the design of ongoing pivotal clinical trials, which aim to ascertain if AVDs improve clinical outcomes. The developing body of evidence suggests that AVDs may be a clinically effective therapy to reduce symptoms, but more importantly to prevent end-organ damage and improve clinical outcomes for specific patients with AHF. The results of ongoing trials will provide more clarity on the role of AVDs in the treatment of AHF.

Clinical pharmacy services in heart failure: an opinion paper from the Heart Failure Society of America and American College of Clinical Pharmacy Cardiology Practice and Research Network.

Heart failure (HF) care takes place in multiple settings, with a variety of providers, and generally involves patients who have multiple comorbidities. This situation is a "perfect storm" of factors that predispose patients to medication errors. The goals of this paper are to outline potential roles for clinical pharmacists in a multidisciplinary HF team, to document outcomes associated with interventions by clinical pharmacists, to recommend minimum training for clinical pharmacists engaged in HF care, and to suggest financial strategies to support clinical pharmacy services within a multidisciplinary team. As patients transition from inpatient to outpatient settings and between multiple caregivers, pharmacists can positively affect medication reconciliation and education, assure consistency in management that results in improvements in patient satisfaction and medication adherence, and reduce medication errors. For mechanical circulatory support and heart transplant teams, the Centers for Medicare and Medicaid Services considers the participation of a transplant pharmacology expert (e.g., clinical pharmacist) to be a requirement for accreditation, given the highly specialized and complex drug regimens used. Although reports of outcomes from pharmacist interventions have been mixed owing to differences in study design, benefits such as increased use of evidence-based therapies, decreases in HF hospitalizations and emergency department visits, and decreases in all-cause readmissions have been demonstrated. Clinical pharmacists participating in HF or heart transplant teams should have completed specialized postdoctoral training in the form of residencies and/or fellowships in cardiovascular and/or transplant pharmacotherapy, and board certification is recommended. Financial mechanisms to support pharmacist participation in the HF teams are variable. Positive outcomes associated with clinical pharmacist activities support the value of making this resource available to HF teams.

Influence of global region on outcomes in heart failure ß-blocker trials.

OBJECTIVES: We sought to describe the United States and the rest of the world (ROW) outcomes from the major ß-blocker heart failure (HF) trials. BACKGROUND: HF trials have demonstrated differences in outcomes by geographic region. METHODS: Randomized, double-blind, placebo-controlled studies that evaluated ß-blockers in HF patients, had a primary endpoint of mortality, and enrolled U.S. patients were included. Relative risk (RR) was calculated for patients enrolled in the United States and ROW. Meta-analysis of the combined mortality rates was performed using the Cochran-Mantel-Haenszel statistic, stratified by study. RESULTS: A total of 8,988 patients were enrolled in the MERIT-HF (Metoprolol Controlled-Release Randomized Intervention Trial in Heart Failure), COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival trial), and BEST (ß-Blocker Evaluation of Survival Trial) combined; 4,198 (46.7%) were from the United States. In the U.S. cohort, the RR reduction for each ß-blocker was of smaller magnitude than in the overall cohort and no longer significant, whereas in the ROW subgroup, the mortality benefit for ß-blockade persisted. In the pooled analysis (n = 11,635), the RR of death was reduced by 23% (p < 0.001) with ß-blockade compared with placebo. In contrast, the mortality reduction associated with ß-blockade in the U.S. cohort was small and not statistically significant (RR: 0.92, 95% confidence interval [CI]: 0.82 to 1.02, p = 0.11). The survival benefit persisted in the ROW cohort (RR: 0.64, 95% CI: 0.56 to 0.72, p < 0.001). CONCLUSIONS: Among patients enrolled in the United States, ß-blockade was associated with a lower magnitude of survival benefit, whereas the ROW response was similar to the total study population. This geographic difference in treatment response may be a reflection of population differences, genetics, cultural or social differences in disease management, or low power and statistical chance.

Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry.

AIMS: Hyponatraemia has been shown to be an independent predictor of mortality in selected patients with heart failure enrolled in clinical trials. The predictive value of hyponatraemia has not been evaluated in unselected patients hospitalized with heart failure. METHODS AND RESULTS: OPTIMIZE-HF is a registry and performance-improvement programme for patients hospitalized with heart failure and includes a subgroup with 60-90 day follow-up data. The relationship between admission serum sodium concentration and clinical outcomes was analysed in 48,612 patients from 259 hospitals. Admission serum sodium levels were analysed both as a continuous variable and by grouping patients with admission Na < 135 and Na > or = 135 mmol/L. Patients with hyponatraemia (Na <135 mmol/L) at the time of hospital admission had modest differences in baseline clinical characteristics and management during hospitalization compared with patients who had serum sodium > or =135 mmol/L. Patients with hyponatraemia were more likely to be Caucasian, have lower admission systolic blood pressure, and receive intravenous inotropes during hospitalization. Patients with hyponatraemia had significantly higher rates of in-hospital and follow-up mortality and longer hospital stays, although no difference in re-admission rates was observed. After adjusting for differences with multivariable analysis, the risk of in-hospital death increased by 19.5%, the risk of follow-up mortality by 10%, and the risk of death or rehospitalization by 8% for each 3 mmol/L decrease in admission serum sodium below 140 mmol/L. CONCLUSION: Hyponatraemia in hospitalized patients with heart failure is relatively common and is associated with longer hospital stays and higher in-hospital and early post-discharge mortality. Re-admission rates were equally high in patients with or without hyponatraemia.