Prospective Trial Of Intravenous Milrinone Research Articles

Directions for Research in the Post-Myocardial Infarction Patient with Left Ventricular Dysfunction

Left ventricular dysfunction (LVD) in post-myocardial infarction (MI) patients is an important predictor of a poor prognosis. LVD may be asymptomatic in the post-MI patient, but it can also manifest as heart failure (HF) or sudden cardiac death. Early revascularization and pharmacologic therapy targeting coronary artery disease (CAD) and LVD reduce post-MI mortality as well as rates of HF and recurrent MI. However, despite dramatic gains in the treatment of post-MI LVD, there remains considerable room for improvement. The following is a brief summary of important areas of investigation addressing this goal. Improved Utilization of Proven Therapies Current acute HF syndrome registries highlight the importance of CAD as a therapeutic target. In the Acute Decompensated Heart Failure National Registry (ADHERE) database, CAD was documented in approximately 60% of patients, with a large proportion of patients classified as post MI. 1 Data from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry show that patients with CAD and LVD had an early postdischarge (60-90 days) combined mortality and rehospitalization rate of 36.2%. 2 Similar results were seen in the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study, in which HF patients with CAD had a higher 60-day mortality rate than patients with a nonischemic etiology. 3 As discussed elsewhere in this supplement, the current available data suggest that this patient population is not fully evaluated during hospitalization and is often managed by noncardiologists. Therefore, all the available therapeutic options are not uniformly implemented. These options include medical therapy (with -blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, aldosterone antagonists, antiplatelet agents, and statins), revascularization procedures (percutaneous coronary intervention and coronary artery bypass graft surgery), cardiac surgery (mitral valve repair or replacement, and left ventricular aneurysmectomy), and device therapy (cardiac resynchronization therapy [CRT] and implantable cardioverter defibrillators [ICDs]). Studies investigating the complete assessment of therapeutic targets and implementation of proven therapies may improve outcomes in the post-MI patient with LVD. Systems for optimal use of proven therapies for post-MI patients with LVD must incorporate all locations of care and providers, including the emergency department, inpatient wards, specialty clinics, and primary care offices. Disease management programs for ambulatory HF patients have produced a statistically significant risk reduction in total mortality and significant reductions in the rates of all-cause and HF-related rehospitalization as well as improved cost savings. 4 Study of the utility of such programs in the post-MI patient with LVD may yield similar benefits. In addition to studies about early and complete implementation of potentially lifesaving therapies, investigations addressing the optimal titration of these therapies may improve outcomes. For instance, ambulatory HF patients monitored to achieve lower levels of serum brain natriuretic peptide through -blocker and angiotensin-converting enzyme inhibitor dose adjust

Admission or Changes in Renal Function During Hospitalization for Worsening Heart Failure Predict Postdischarge Survival

Background— Admission measures of renal function (blood urea nitrogen [BUN], estimated glomerular filtration rate [eGFR]) in patients hospitalized for worsening heart failure are predictors of in-hospital outcomes. Less is known about the changes and relationships among these variables and the postdischarge survival rate. Methods and Results— In a retrospective analysis of 949 patients from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure, we investigated the relation between admission values and changes in BUN and eGFR and rate of death by 60 days after discharge. On admission, median eGFR was 51 mL � min −1 � 1.73 m −2 (interquartile range, 37 to 70 mL � min −1 � 1.73 m −2 ), and BUN was 25 mg/dL (interquartile range, 17 to 41 mg/dL). On average, there was a 1.1–mL � min −1 � 1.73 m −2 decrease in eGFR and a 4.7-mg/dL increase in BUN from admission to discharge. By discharge, 12% of patients had a >25% decrease in eGFR, and 39% had a >25% increase in BUN. Although both lower admission eGFR and higher admission BUN were associated with higher risk of death by 60 days after discharge, multivariable-adjusted Cox proportional-hazards analysis showed that BUN was a stronger predictor of death by 60 days than was eGFR (χ 2 , 11.6 and 0.6 for BUN and eGFR, respectively). Independently of admission values, an increase of ≥10 mg/dL in BUN during hospitalization was associated with worse 60-day survival rate: BUN (per 5-mg/dL increase) had a hazard ratio of 1.08 (95% CI, 1.01 to 1.16). Although milrinone treatment led to a minor improvement in renal function by discharge, the 60-day death and readmission rates were similar between the milrinone and placebo groups. Conclusions— A substantial number of patients admitted with heart failure have worsening renal function during hospitalization. Higher admission BUN and increasing BUN during hospitalization, independently of admission values, are associated with a worse survival rate. Use of milrinone in these high-risk patients does not improve outcomes despite minor improvements in the renal function.

Blood Urea Nitrogen and Serum Creatinine

Klein and colleagues1 have retrospectively analyzed results derived from the prospective, randomized Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study and contribute an interesting article to this inaugural issue of Circulation: Heart Failure . Their analysis provides further evidence that the level of renal function in patients with worsening heart failure and impaired systolic function is an important predictor of rehospitalization for cardiovascular events and death within 60 days of discharge. Renal function was assessed at admission. Change during hospitalization was recorded for blood urea nitrogen (BUN) and estimated glomerular filtration rate (GFR). Estimated GFR was calculated with the 4-variable equation of the Modification of Diet in Renal Disease study, which depends on serum creatinine, age, and sex.2 Of interest, the BUN on admission and change in BUN during the hospital stay (independent of the admission value) was a statistically better predictor of the 60-day death rate and days of rehospitalization than was estimated GFR. Because BUN is affected by protein intake, catabolism, and tubular reabsorption of urea, it is not as reliable an index of renal function as GFR. Thus, this observation by Klein et al1 is of particular interest and deserves explanation. Article p 25 Serum creatinine is freely filtered at the glomerulus, not reabsorbed, but undergoes tubular secretion. Thus, creatinine clearance exceeds inulin clearance, the gold standard for GFR. In contrast, urea is freely filtered, not secreted, but is reabsorbed by the renal tubules. This reabsorption of urea is flow dependent so that more urea is reabsorbed at lower urine flow rates (Figure 1).3 Most importantly, the reabsorption of urea in the collecting duct is mediated by the effect of arginine vasopressin (AVP) on the urea transporter in the collecting …

Racial Differences in the Characteristics of Patients Admitted for Acute Decompensated Heart Failure and Their Relation to Outcomes: Results From the OPTIME-CHF Trial

Recent data suggest that differences in response to therapy and survival exist between African Americans and Caucasians with heart failure. Whether these differences exist in acute decompensated heart failure (ADHF) is uncertain. We analyzed data from the OPTIME-CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) study, a randomized trial of intravenous milrinone versus placebo in 949 patients hospitalized with ADHF. We evaluated differences in clinical characteristics, outcomes, and response to milrinone therapy in African American patients compared with Caucasians. The primary end point of OPTIME-CHF was days hospitalized for cardiovascular causes or death within 60 days of randomization. Thirty-three percent (n = 310) of patients were African American. African American patients were younger (57 vs. 70 years, P < .0001) and more likely to have non-ischemic cardiomyopathy (74% vs. 36%, P < .0001). In unadjusted analysis, African American patients had a lower 60-day mortality (5% vs. 12%, P = .0004) and tended to have better overall clinical outcomes. After adjustment for baseline differences, however, these differences were no longer significant. We found no differential effect of milrinone therapy by race. African American patients with acute decompensated heart failure present with a different clinical profile than Caucasian patients. Although unadjusted clinical outcomes are better for African Americans presenting with ADHF, these differences diminished after adjustment for baseline characteristics.

Section 7: Heart Failure in Patients With Left Ventricular Systolic Dysfunction

Section 7: Heart Failure in Patients With Left Ventricular Systolic Dysfunction

Lower Serum Sodium Is Associated With Increased Short-Term Mortality in Hospitalized Patients With Worsening Heart Failure

The prognostic value of serum sodium in patients hospitalized for worsening heart failure has not been well defined. 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). 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.

Risk stratification after hospitalization for decompensated heart failure

Background Decompensated heart failure (HF) is among the most common indications for hospitalization in the United States, but little is known about features on admission that predict adverse events. We used data from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study to develop a model that would predict outcomes in patients with decompensated HF. Methods and results OPTIME-CHF randomized 949 patients hospitalized with decompensated HF for 48 to 72 hours of infusion of either milrinone or placebo. We used multivariable modeling to evaluate variables on admission that would be predictive of 60-day mortality or the composite of death or rehospitalization at 60 days. Variables at presentation that predicted death at 60 days were increased age, lower systolic blood pressure, New York Heart Association class IV symptoms, elevated blood urea nitrogen (BUN), and decreased sodium. Predictors of the composite of death or rehospitalization within 60 days were the number of HF hospitalizations in the preceding 12 months, elevated BUN, lower systolic blood pressure, decreased hemoglobin, and a history of percutaneous coronary intervention (PCI). The discriminatory power of the model was substantial for the mortality model (c-index .77) but less for the composite endpoint (c-index .69). Conclusions Risk stratification of patients with decompensated HF may be accomplished using easily assessed clinical variables. Further research into the validity of this model in independent samples will potentially aid in the development of risk stratification strategies.

The impact of arrhythmias in acute heart failure

Background Arrhythmias are common in chronic heart failure and affect outcomes. The incidence and significance of new arrhythmias in acute heart failure, however, are largely unknown. Methods and results The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations study randomized 949 patients with decompensated heart failure to receive intravenous milrinone or placebo. In the study, patients were divided into 2 groups based on the occurrence of a new arrhythmic event during their index hospitalization and analyzed for outcome. There were 59 new arrhythmic events occurring in 6% of the population. Of these, 49% were atrial fibrillation/flutter. The primary endpoint of days hospitalized for cardiovascular causes within 60 days after randomization was 30.9±22.7 for those in the arrhythmia group and 11.3±12.7 days for those with no arrhythmias ( P = .0001). Mortality during index hospitalization was 26% in the arrhythmia group and 1.8% in the no arrhythmia group ( P = .001). Death or hospitalization at 60 days was also worse in the arrhythmia group (35 versus 8.2%, P = .0001; 57 versus 34%, P = .001, respectively). Cox proportional hazard analysis identified new arrhythmias as an independent risk factor for the primary endpoint and death at 60 days. Conclusion New arrhythmia during an exacerbation of heart failure identifies a high-risk group with higher intrahospital and 60-day morbidity and mortality.

Prognostic value of hyponatremia in hospitalized patients with worsening heart failure - insights from the outcomes of a prospective trial of intravenous milrinone for exacerbations of chronic heart failure (OPTIME - CHF)

Prognostic value of hyponatremia in hospitalized patients with worsening heart failure - insights from the outcomes of a prospective trial of intravenous milrinone for exacerbations of chronic heart failure (OPTIME - CHF)

Heart failure etiology and response tomilrinone in decompensated heart failure: Results from the OPTIME-CHF study

ObjectivesThe goal of this study was to assess the interaction between heart failure (HF) etiology and response to milrinone in decompensated HF. BackgroundEtiology has prognostic and therapeutic implications in HF, but its relationship to response to inotropic therapy is unknown. MethodsThe Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study randomized 949 patients with systolic dysfunction and decompensated HF to receive 48 to 72 h of intravenous milrinone or placebo. The primary end point was days hospitalized from cardiovascular causes within 60 days. In a post-hoc analysis, we evaluated the interaction between response to milrinone and etiology of HF. ResultsThe primary end point was 13.0 days for ischemic patients and 11.7 days for nonischemic patients (p = 0.2). Sixty-day mortality was 11.6% for the ischemic group and 7.5% for the nonischemic group (p = 0.03). After adjustment for baseline differences, there was a significant interaction between etiology and the effect of milrinone. Milrinone-treated patients with ischemic etiology tended to have worse outcomes than those treated with placebo in terms of the primary end point (13.6 days for milrinone vs. 12.4 days for placebo, p = 0.055 for interaction) and the composite of death or rehospitalization (42% vs. 36% for placebo, p = 0.01 for interaction). In contrast, outcomes in nonischemic patients treated with milrinone tended to be improved in terms of the primary end point (10.9 vs. 12.6 days placebo) and the composite of death or rehospitalization (28% vs. 35% placebo). ConclusionsMilrinone may have a bidirectional effect based on etiology in decompensated HF. Milrinone may be deleterious in ischemic HF, but neutral to beneficial in nonischemic cardiomyopathy.

P432 Prognostic value of hyponatremia in hospitalized patients with heart failure ? insights from the outcomes of a prospective trial of intravenous milrinone for exacerbations of chronic heart failure

P432 Prognostic value of hyponatremia in hospitalized patients with heart failure ? insights from the outcomes of a prospective trial of intravenous milrinone for exacerbations of chronic heart failure

Clinical Outcomes in Patients on Beta‐Blocker Therapy Admitted With Worsening Chronic Heart Failure

Clinical Outcomes in Patients on Beta‐Blocker Therapy Admitted With Worsening Chronic Heart Failure

Clinical outcomes in patients on beta-blocker therapy admitted with worsening chronic heart failure

Beta blockers have been shown to reduce morbidity and mortality in patients with heart failure without evidence of overt congestion. No data are available describing outcomes of patients admitted with exacerbated chronic heart failure who are receiving β blockade at the time of admission. The purpose of this analysis was to evaluate clinical outcomes in patients from the Outcomes of the Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study who were prescribed β blockers on admission compared with patients who were not prescribed β blockers at admission. In all, 212 patients were treated with β blockers at admission and 737 patients were not. Baseline characteristics were similar between groups, except that patients prescribed β blockers on admission had slightly higher ejection fractions, fewer New York Heart Association class IV symptoms, and lower heart rates. There was no difference in clinical events between patients who were treated with β blockers at the time of admission and those who were not. Exploratory analyses suggested that patients whose β-blocker therapy was discontinued had a higher risk of adverse outcomes, particularly in the subset of patients randomized to milrinone. The data from this nonrandom comparison suggest that continuation of pre-existing β-blocker therapy is not associated with an increased risk of adverse clinical events in patients admitted with worsening heart failure. These results also suggest that caution should be taken when withdrawing β blockade in this population.

Rationale and design of the OPTIME CHF trial: Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure

Background The optimal management of an acute exacerbation of chronic heart failure (CHF) is uncertain. There is little randomized evidence available to support the various treatment strategies for patients hospitalized with an exacerbation of CHF. Inotropic agents may produce beneficial hemodynamic effects, and although they are currently used in these patients, their effect on clinical response and impact on clinical outcome is unclear. We present a unique and simple study designed to determine whether a treatment strategy for CHF exacerbations that includes an intravenous agent with inotropic properties can reduce hospital length of stay and lead to improved patient outcome. Methods The OPTIME CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) trial is an ongoing multicenter, randomized, placebo-controlled trial of a treatment strategy for patients with acute exacerbations of CHF. The design of this study provides a novel approach to the evaluation of treatment strategies in the care of this population. The OPTIME CHF design uses early initiation of intravenous milrinone as both an adjunct to the best the medical therapy and to facilitate optimal dosing of standard oral therapy for heart failure. Patients with known systolic heart failure requiring hospital admission for a CHF exacerbation are randomly assigned within 48 hours of admission to receive a 48-hour infusion of either intravenous milrinone or placebo. The primary end point of this design is a reduction in the total hospital days for cardiovascular events within 60 days after therapy. Enrollment of 1000 patients began July 7, 1997, at 80 US centers and is projected to conclude in late 1999. (Am Heart J 2000;139:15-22.)

Rationale and design of the OPTIME CHF trial: Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure

Rationale and design of the OPTIME CHF trial: Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure