Beneficial effects of pimobendan on exercise tolerance and quality of life in patients with heart failure. Results of a multicenter trial. The Pimobendan Multicenter Research Group.

BACKGROUND. This multicenter trial was conducted to determine the efficacy and safety of pimobendan, an inotropic agent with calcium-sensitizing properties and activity as a phosphodiesterase inhibitor, in patients with heart failure. METHODS AND RESULTS. One hundred ninety-eight ambulatory patients with symptoms of moderate to severe heart failure despite therapy with digitalis and diuretics with or without a single vasodilator were randomly assigned to receive either placebo (n = 49) or pimobendan (n = 149) in a double-blind fashion for 12 weeks. A dose range of pimobendan was used including 2.5 (n = 49), 5 (n = 51), or 10 mg/day (n = 49). One hundred fifty-eight (80%) patients were taking a converting enzyme inhibitor (CEI) and 28 (14%) patients were taking a non-CEI vasodilator. At end point, the 5-mg dose of pimobendan significantly increase exercise duration compared with placebo (121.6 +/- 19.1 seconds, p less than 0.001), whereas the 10-mg dose produced an increase of borderline significance (81.1 +/- 19.5 seconds, p = 0.05). Peak VO2 was significantly increased by 2.23 +/- 0.58 ml/kg/min in the 5-mg group (p less than 0.01 versus placebo). Furthermore, quality of life measured with the Minnesota Living With Heart Failure Questionnaire improved by 8.5 +/- 2.3 units in the 5-mg group compared with 1.3 +/- 2.2 units in the placebo group (p less than 0.01). There were a total of 23 all-cause hospitalizations in the placebo group, which was significantly greater compared with 33 in the three groups treated with pimobendan (p less than 0.01). There were no significant differences between the placebo and pimobendan groups with respect to changes in ejection fraction and plasma norepinephrine measured at baseline and at the completion of the 12-week study, proarrhythmic effect, or the number of patients with a significant adjustment in background therapy. Eleven patients died, including three (6%) on placebo and eight (5%) on pimobendan (p = NS). Among all adverse events, headache tended to be more common in the pimobendan groups compared with placebo, with the incidence increasing with dose (p less than 0.05). CONCLUSIONS. These data demonstrate that pimobendan significantly increases exercise duration, peak VO2, and quality of life in patients with heart failure. Pimobendan appears to be useful adjunctive therapy when added to digitalis, diuretics, and vasodilators.     

Effect of isosorbide-5-mononitrate on exercise performance and clinical status in patients with congestive heart failure. Results of the Nitrates in Congestive Heart Failure (NICE) Study.

BACKGROUND AND AIMS: Nitrate therapy improves hemodynamics in patients with heart failure, but the chronic effects of oral nitrates on exercise performance and clinical status have not been well studied. METHODS: Oral isosorbide-5-mononitrate (ISMN) (50 mg once daily) or placebo was administered to 136 patients (NYHA Class 2-3) treated for heart failure, all receiving captopril and most also furosemide. Endpoints were treadmill exercise time at 12 weeks by modified Naughton protocol (primary), with an additional 12-week follow-up period. Secondary endpoints included left ventricular dimensions, ejection fraction, cardiothoracic ratio, functional class, quality of life, hospitalizations and plasma norepinephrine and atrial natriuretic peptide in a four-center substudy. RESULTS: Intention-to-treat analysis showed that mean change in treadmill exercise duration tended to be greater in patients receiving ISMN than placebo (treatment difference +42 s, 95% CI -5, +90 s at 12 weeks and +21 s, 95% CI -25, +74 s after 24 weeks) (NS). Treatment difference was greater in the prespecified subgroup with ejection fraction 31-40% (+55 s, 95% CI -11, +136 s at 12 weeks and +65 s, 95% CI +3, +147 s) (p = 0.035) at 24 weeks. No deleterious effects (i.e. hypotension) were observed with ISMN, although headache was reported in 19% of the active treatment group (p = 0.0001). CONCLUSIONS: ISMN added to captopril increased treadmill exercise time in patients with heart failure and a lesser reduction in baseline ejection fraction, although for the group as a whole, the increase in treadmill time was not significant.     

Effect of pimobendan in patients with chronic heart failure

OBJECTIVE:

To assess the effects of a calcium sensitizer, pimobendan, in patients with mild to moderate chronic heart failure.

PATIENTS AND METHODS:

Pimobendan was administered at a dose of 2.5 mg/day for 12 months to 34 patients with chronic heart failure (New York Heart Association functional class IIm to III) after treatment with diuretics and angiotensin-converting enzyme inhibitors. The etiologies of heart failure were dilated cardiomyopathy (DCM), old myocardial infarction (OMI) and other heart disease (Others). The effects of pimobendan were assessed by echocardiography, blood pool scintigraphy, Holter monitoring, ¹²³I-meta-iodobenzylguanidine (MIBG) imaging and ¹²³I-β-methyl-p-iodophenyl-pentadecanoic acid (BMIPP) imaging.

RESULTS:

Pimobendan produced improvement of symptoms in the majority of patients. Improvement was more common in the DCM group than in the OMI group. Left ventricular internal diameter measured by echocardiography was significantly decreased. Left ventricular ejection fraction was significantly increased in the DCM and Others groups. The heart to mediastinum ratio on MIBG imaging was significantly increased in the DCM and Others groups, and the heart to mediastinum ratio on BMIPP imaging was significantly increased in the DCM group.

CONCLUSIONS:

Pimobendan is effective in patients with chronic heart failure but is less effective in patients with OMI than in patients with DCM or other heart diseases.     

Ultrafiltration versus usual care for hospitalized patients with heart failure: the Relief for Acutely Fluid-Overloaded Patients With Decompensated Congestive Heart Failure (RAPID-CHF) trial.

OBJECTIVES: The purpose of this research was to assess the safety and efficacy of ultrafiltration (UF) in patients admitted with decompensated congestive heart failure (CHF). BACKGROUND: Ultrafiltration for CHF is usually reserved for patients with renal failure or those unresponsive to pharmacologic management. We performed a randomized trial of UF versus usual medical care using a simple UF device that does not require special monitoring or central intravenous access. METHODS: Patients admitted for CHF with evidence of volume overload were randomized to a single, 8 h UF session in addition to usual care or usual care alone. The primary end point was weight loss 24 h after the time of enrollment. RESULTS: Forty patients were enrolled (20 UF, 20 usual care). Ultrafiltration was successful in 18 of the 20 patients in the UF group. Fluid removal after 24 h was 4,650 ml and 2,838 ml in the UF and usual care groups, respectively (p = 0.001). Weight loss after 24 h, the primary end point, was 2.5 kg and 1.86 kg in the UF and usual care groups, respectively (p = 0.240). Patients tolerated UF well. CONCLUSIONS: The early application of UF for patients with CHF was feasible, well-tolerated, and resulted in significant weight loss and fluid removal. A larger trial is underway to determine the relative efficacy of UF versus standard care in acute decompensated heart failure.     

Spectrum of heart failure in older patients: results from the National Heart Failure project

Background The elderly make up the majority of patients with heart failure (HF), but information on this segment of the HF population is lacking because clinical trials typically enroll younger patients and population-based studies lack clinical detail. We sought to describe a contemporary national sample of elderly patients with HF and to examine the sample for age-related trends in clinical characteristics. Methods We studied the charts of 800 Medicare patients per state who were hospitalized with a principal diagnosis of HF between April 1998 and March 1999. There were 34,587 patients in the sample after exclusion of patients who were <65 years old, repeat discharges, discharges to another acute care facility or against medical advice, or receiving long-term hemodialysis. Results Comorbidity was common. About one third of patients had chronic obstructive pulmonary disease, about 40% had diabetes, more than half had coronary heart disease, and more than half had a history of hypertension, but comorbidity rates declined with age. Left ventricular ejection fraction was <40% in only 50.4% of patients in whom it was assessed. Associated laboratory abnormalities were relatively constant across the age spectrum, but renal insufficiency was more common with advancing age. The likelihood that patients were in long-term care facilities before admission rose quite steeply with age. Conclusions Elderly patients with HF are a heterogeneous group and appear to differ substantially from patients enrolled in clinical trials. Evidence-based guidance for treatment in the context of multiple comorbid conditions, poor renal function, HF with preserved left ventricular systolic function, and residence in long-term care facilities is urgently needed. (Am Heart J 2002;143:412-7.)     

Confirmation of a heart failure epidemic: findings from the Resource Utilization Among Congestive Heart Failure (REACH) study.

OBJECTIVES: The purpose of this study was to create an automated surveillance tool for reporting the incidence, prevalence and processes of care for patients with heart failure. BACKGROUND: Previous epidemiologic studies suggest that the increasing prevalence of heart failure is a consequence of improved survival coupled with minimal changes in disease prevention. Developing new, efficient methods of assessing the incidence and prevalence of heart failure could allow continued surveillance of these rates during an era of rapidly changing treatments and health care delivery patterns. METHODS: Using administrative data sets, we created a definition of heart failure using diagnosis codes. After adjustment for patients leaving our health system or death, we derived the incidence, prevalence and mortality of the population with heart failure from 1989 to 1999. RESULTS: A total of 29,686 patients of all ages, 52.6% women and 47.4% men, met the definition of heart failure. Mean ages were 71.1 +/- 14.5 for women and 67.7 +/- 14.4 for men, p < 0.0001. Race proportions were 50.5% white, 44.6% African American and 4.9% other race. Incidence rates were higher in men and African Americans across all age groups. There was an annual increase in prevalence of 1/1,000 for women and 0.9/1,000 for men, p = 0.001 for both trends. CONCLUSIONS: Through the feasible and valid use of automated data, we have confirmed a chronic disease epidemic of heart failure manifested primarily by an increase in prevalence over the past decade. Our surveillance system mirrors the results of epidemiologic studies and may be a valid method for monitoring the impact of prevention and treatment programs.     

Multinational economic evaluation of valsartan in patients with chronic heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT)

Background

The Valsartan Heart Failure Trial (Val-HeFT) compared valsartan versus placebo in 5010 patients taking prescribed background therapy for New York Heart Association class II to IV heart failure. Valsartan reduced the risk of heart failure hospitalization and improved clinical signs and symptoms of heart failure. We sought to compare resource use, costs, and health outcomes among patients taking prescribed therapy for heart failure and randomly assigned to receive valsartan or placebo.

Methods

Measures of resource use were based on data collected during the trial. Unit cost estimates were collected from individual countries and converted to 1999 US dollars. Total costs were estimated for hospitalizations, inpatient and outpatient physician services, ambulance transportation, deaths outside the hospital, and outpatient cardiovascular medications.

Results

Mean follow-up was 23 months. Mean costs for heart failure hospitalizations were $423 lower among patients receiving valsartan (95% CI, −706 to −146). Mean total costs were $9008 for patients receiving valsartan and $8464 for patients receiving placebo, a net incremental cost of $545 (95% CI, −149 to 1148), including the cost of valsartan. There was an overall reduction in total costs of $929 (95% CI, −3243 to 1533) among patients not receiving an ACE inhibitor at baseline but a slight increase in costs of $334 (95% CI, −497 to 1199) among those receiving an ACE inhibitor without a β-blocker and a $1246 increase (95% CI, 54 to 2230) in patients receiving both an ACE inhibitor and a β-blocker at baseline.

Conclusions

Valsartan provided clinical benefits at a mean incremental cost of $285 per year during the trial. In patients not taking ACE inhibitors, valsartan was economically attractive, increasing survival while reducing or marginally increasing overall costs.     

Digoxin use and heart failure outcomes: results from the Valsartan Heart Failure Trial (Val-HeFT)

Several retrospective studies have raised concerns regarding digoxin therapy in select subgroups of heart failure patients. To assess the impact of digoxin therapy on outcomes in the current era of heart failure therapy, the authors analyzed data representing 5010 patients enrolled in the Valsartan Heart Failure Trial (Val-HeFT) to examine the relationship of baseline digoxin use and all-cause mortality, first morbid event, and heart failure hospitalizations. At baseline, 3374 patients (67%) were receiving digoxin therapy and 1636 (33%) were not. Patients receiving digoxin had features of worse heart failure with higher New York Heart Association class and lower blood pressure, ejection fraction, and β-blocker use (32.1% vs 40.8%). Digoxin use was associated with worse mortality (21.1 vs 15.0%, P<.001), first morbid event (34.6 vs 21.7, P<.001), and HF hospitalization rate (19.1 vs 10.1%, P<.001). After adjustment for baseline group differences including medical therapy and baseline rhythm, patients receiving digoxin remained at a higher risk for all-cause mortality (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.05-1.57), first morbid event (HR, 1.35; 95% CI, 1.15-1.59), and heart failure hospitalization (HR, 1.41; 95% CI, 1.12-1.78). These results remained materially unchanged with propensity matched analysis. No benefit with digoxin use was observed in this study, underscoring the need to reassess the role of digoxin in the contemporary management of heart failure.     

Rationale and design of a study assessing treatment strategies of atrial fibrillation in patients with heart failure: the Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial

Background Nonrandomized studies suggest that atrial fibrillation is independently associated with increased mortality in patients with heart failure. Whether restoring and maintaining sinus rhythm will have a beneficial impact on cardiovascular mortality in patients with heart failure has never been tested in an adequately powered randomized trial. Objective The primary objective of the Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial is to determine whether restoring and maintaining sinus rhythm significantly reduces cardiovascular mortality compared with a rate-control strategy in patients with atrial fibrillation and CHF. Methods AF-CHF is a prospective multicenter trial (109 centers in Canada, United States, South America, Europe, and Israel), that will randomize 1450 patients with CHF with left ventricular ejection fraction ≤35% and atrial fibrillation to 1 of 2 treatment strategies: (1) rhythm control with the use of electrical cardioversion combined with antiarrhythmic drugs (amiodarone or other class III agents), (2) rate control with the use of β-blockers, digoxin, or pacemaker and AV nodal ablation. Cardiovascular mortality is the primary end point and the intention-to-treat approach the primary method of analysis. We anticipate an 18.75% 2-year cardiovascular mortality in the rate control arm with a 25% mortality reduction in the rhythm control group. Results As of August 13, 2002, 334 patients have been enrolled from 68 participating centers. Enrollment is expected to be concluded in May 2003 with a minimum follow-up of 2 years. Conclusion The results of this trial should provide definitive information concerning 2 widely applicable treatment strategies of atrial fibrillation in a large cohort of patients with CHF. (Am Heart J 2002;144:597-607.)