Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Quality of life and psychological status of patients with implantable cardioverter defibrillators.

INTRODUCTION: Implantable cardioverter defibrillators (ICDs) are effective at reducing mortality in patients at high risk for sudden cardiac death (SCD) but can cause psychological distress and reduce quality of life (QOL). The full benefits of ICDs can only be achieved when the patient's QOL and psychological status are maintained. We examined psychological status and QOL post ICD implantation; the relationship of psychological status to QOL; the relationship of time since implantation to psychological status and QOL; and the relationship of time since ICD implantation and age of patient to these variables. METHODS AND RESULTS: A cross-sectional self-administered assessment of QOL, depression, anxiety, demographic characteristics and cardiovascular health history of patients (n = 48) who had received ICDs within the past 10 years at an urban hospital. Patients who had ICDs for longer experienced worse depression and QOL. Patients who were younger had worse depression, anxiety, and QOL. The combination of anxiety, depression, age, and time since ICD implant significantly predicted overall QOL and the psychosocial and physical dimensions of QOL explaining 55.5, 54, and 34.9% of the variance, respectively. CONCLUSION: Younger ICD patients are at highest risk for psychological distress and poor QOL. Longitudinal research would facilitate determination of the trajectory of changes in psychological status and QOL over the duration of the ICD experience.

Renal effects of adenosine A1-receptor antagonists in congestive heart failure.

Renal function is a very important prognostic indicator in patients with congestive heart failure. While some of the prognostic importance of poor renal function is related to the worse physiology associated with it, there are suggestions that the dysfunction itself is detrimental. Recently, it has been shown that adenosine may mediate much kidney activity. In addition to vasoconstrictive and vasodilatory effects, adenosine is intrinsic to the tubuloglomerular feedback which occurs when an acute increase in sodium levels in the proximal tubule feeds back to decrease glomerular filtration. Adenosine works via both adenosine A1 and A2 receptors. A1-receptor antagonists decrease afferent arteriolar pressure, and increase urine flow and sodium excretion. Studies suggest that A1-receptor antagonists cause a diuretic effect not by a change in the renal haemodynamics, but by the inhibition of water and sodium reabsorption in tubular sites secondary to direct tubuloglomerular feedback. Less consistent has been the occasional finding of increased glomerular filtration rate despite the lack of improved renal plasma flow. Clinically important questions are: what role adenosine plays in causing the poor renal function associated with heart failure and what A1-receptor antagonists do in such situations? If an A1-receptor antagonist could cause diuresis while maintaining or improving glomerular filtration, it would be a useful adjunct in the treatment of severe heart failure. We evaluated the effects of the A1-receptor antagonist CVT-124 (BG-9719) in heart failure patients. CVT-124 increased sodium excretion without decreasing glomerular filtration rate. These data suggest that adenosine might be an important determinant of renal function in patients with heart failure.

Exercise in the geriatric patient with congestive heart failure.

The benefits of exercise in the elderly patient with heart failure have been well documented, but the studies have been limited by restrictive inclusion criteria. Most studies have involved patients who are younger and healthier than those normally seen in clinical practice. Improvements in neurohormonal, metabolic, and vascular status have been well documented in the relatively young patients who have been evaluated. Consequently, peak exercise time, oxygen consumption, submaximal exercise, and quality of life have also improved. Studies suggest that older, more severely limited patients may also benefit from exercise. However, they are less likely to tolerate an exercise program and may not improve their quality of life if the exercise is excessive. Caution is warranted when exercise is prescribed to elderly patients with heart failure.

Comparative effects of three beta blockers (atenolol, metoprolol, and propranolol) on survival after acute myocardial infarction.

The beneficial impact of beta blockade after an acute myocardial infarction (AMI) is clear, but beta-adrenergic blockers differ in multiple characteristics, including lipophilicity and selectivity. The impact of these factors on the effects of beta blockade is unknown. We therefore compared the effects of different beta blockers on mortality after AMI. Charts of 201,752 patients with AMI were abstracted by the Cooperative Cardiovascular Project, a quality assurance program sponsored by the Health Care Financing Administration. Of the 69,338 patients prescribed beta blockers, we compared mortality of patients receiving different beta-adrenergic blockers using the Cox proportional-hazards model accounting for multiple factors that might influence survival. The mortality rates of the 2 selective agents, metoprolol and atenolol, were virtually identical (13.5% and 13.4% 2-year mortality, respectively). Compared with metoprolol, patients discharged on propranolol had a slightly increased mortality (15.9% 2-year mortality), which may be related to undetected differences at baseline. Survival with all of the drugs was superior to the 23.9% 2-year mortality seen in patients not receiving beta blockers. Beta blockade overall was associated with a 40% improvement in survival. Although the use of beta blockade after AMI has major prognostic importance, the present study suggests that the specific beta blocker chosen will have little influence on mortality.

Are all beta-blockers the same for chronic heart failure?

beta-Adrenergic receptor blockade has been conclusively proven to increase survival and morbidity in patients with heart failure. Hospitalization rate decreases and patients feel better after receiving beta-blockers. Furthermore, this benefit is observed in a wide range of patients. The beta-blockers bisoprolol, metoprolol, and carvedilol have been extensively evaluated in heart failure patients. These drugs all show marked benefit. Bucindolol, an investigational beta-blocker, showed only mild improvement in survival in patients with heart failure. The beta-blockers differ regarding beta-selectivity, vasodilation properties, and perhaps other ancillary properties. At present, the importance and consequences of these differences are unknown.

Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Study Investigators.

BACKGROUND: We determined the short-term hemodynamic and clinical effects of levosimendan, a novel calcium-sensitizing agent, in patients with decompensated heart failure. METHODS AND RESULTS: One hundred forty-six patients with New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21+/-1%) who had a pulmonary capillary wedge pressure >/=15 mm Hg and a cardiac index

The impact of beta-blockade on mortality rates in patients with congestive heart failure.

The beneficial effects of beta-adrenergic blockade on mortality rates in patients after a myocardial infarction have been clear for decades. The efficacy data are now just as apparent for patients with heart failure. Although there are many subgroups of patients in whom the mortality effects of beta-blockers are not proven, knowledge about these specific populations continues to increase. Nevertheless, more information is needed so that we can properly tailor our therapy for individual patients.

Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure.

BACKGROUND: Elevated plasma endothelin-1 (ET-1) levels in patients with chronic heart failure correlate with pulmonary artery pressures and pulmonary vascular resistance. ET(A) receptors on vascular smooth muscle cells mediate pulmonary vascular contraction and hypertrophy. We determined the acute hemodynamic effects of sitaxsentan, a selective ET(A) receptor antagonist, in patients with chronic stable heart failure receiving conventional therapy. METHODS AND RESULTS: This multicenter, double-blind, placebo-controlled trial enrolled 48 patients with chronic New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21+/-1%) treated with ACE inhibitors and diuretics. Patients with a baseline pulmonary capillary wedge pressure >/=15 mm Hg and a cardiac index

The effect of coenzyme Q10 in patients with congestive heart failure.

BACKGROUND: Coenzyme Q10 is commonly used to treat congestive heart failure on the basis of data from several unblinded, subjective studies. Few randomized, blinded, controlled studies have evaluated objective measures of cardiac performance. OBJECTIVE: To determine the effect of coenzyme Q10 on peak oxygen consumption, exercise duration, and ejection fraction. DESIGN: Randomized, double-blind, controlled trial. SETTING: University and Veterans Affairs hospitals. PATIENTS: 55 patients who had congestive heart failure with New York Heart Association class III and IV symptoms, ejection fraction less than 40%, and peak oxygen consumption less than 17.0 mL/kg per minute (or <50% of predicted) during standard therapy were randomly assigned. Forty-six patients completed the study. INTERVENTION: Coenzyme Q10, 200 mg/d, or placebo. MEASUREMENTS: Left ventricular ejection fraction (measured by radionuclide ventriculography) and peak oxygen consumption and exercise duration (measured by a graded exercise evaluation using the Naughton protocol) with continuous metabolic monitoring. RESULTS: Although the mean (+/-SD) serum concentration of coenzyme Q10 increased from 0.95+/-0.62 microg/mL to 2.2+/-1.2 microg/mL in patients who received active treatment, ejection fraction, peak oxygen consumption, and exercise duration remained unchanged in both the coenzyme Q10 and placebo groups. CONCLUSION: Coenzyme Q10 does not affect ejection fraction, peak oxygen consumption, or exercise duration in patients with congestive heart failure receiving standard medical therapy.

Effects of BG9719 (CVT-124), an A1-adenosine receptor antagonist, and furosemide on glomerular filtration rate and natriuresis in patients with congestive heart failure.

OBJECTIVES: To determine the effects of furosemide and the selective A1 adenosine receptor BG9719 on renal function in patients with congestive heart failure (CHF). BACKGROUND: Studies suggest that adenosine may affect renal function by various mechanisms, but the effects of blockade of this system in humans is unknown. In addition, the effects of a therapeutic dose of furosemide on glomerular filtration rate (GFR) and renal plasma flow (RPF) in heart failure patients are controversial. METHODS: On different days, 12 patients received placebo, BG9719 and furosemide. Glomerular filtration rate, RPF and sodium and water excretion were assessed immediately following drug administration. RESULTS: Glomerular filtration rate was 84 +/- 23 ml/min/1.73m2 after receiving placebo, 82 +/- 24 following BG9719 administration and a decreased (p < 0.005) 63 +/- 18 following furosemide. Renal plasma flow was unchanged at 293 +/- 124 ml/min/1.73m2 on placebo, 334 +/- 155 after receiving BG9719 and 374 +/- 231 after receiving furosemide. Sodium excretion increased from 8 +/- 8 mEq following placebo administration to 37 +/- 26 mEq following BG9719 administration. In the six patients in whom it was measured, sodium excretion was 104 +/- 78 mEq following furosemide administration. CONCLUSIONS: Natriuresis is effectively induced by both furosemide and the adenosine A1 antagonist BG9719 in patients with CHF. Doses of the two drugs used in this study did not cause equivalent sodium and water excretion but only furosemide decreased GFR. These data suggest that adenosine is an important determinant of renal function in patients with heart failure.

Depression is common and precludes accurate assessment of functional status in elderly patients with congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) and depression are independently known to result in physical decline and diminished functional capacity in the general population. The prevalence and relationship of depressive symptoms in CHF to physical limitations has not been objectively examined. METHODS AND RESULTS: The Center for Epidemiological Studies Depression Scale (CES-D) was used to ascertain depressive symptoms in 33 elderly ambulatory individuals with CHF. Self-report assessment of functional status, cardiopulmonary exercise testing (CPX), and measurement of energy expenditure by doubly labeled water and Caltrac Accelerometer (Muscle Dynamics, Torrance, CA) were performed. Depressed and nondepressed groups were compared. Forty-two percent of the patients scored in the depressed range (CES-D score of 16 or greater). There were no differences in demographic variables or severity of illness between the depressed and nondepressed patients. Energy expenditure was comparable across groups. Although obtaining similar maximal heart rate and maximal oxygen consumption (VO2max) on CPX, the depressed group showed less exertion on exercise testing with a significantly lower respiratory quotient (P = .017). CONCLUSION: Depressive symptoms were common and unrelated to the severity of CHF. Although depressed individuals tended to report worse physical functioning than nondepressed individuals, objective assessment of energy expenditure was comparable. Depressed patients appear to underestimate their functional ability. Subsequently, inaccurate assessment of functional status may occur.

Effects of exercise training on peak performance and quality of life in congestive heart failure patients.

BACKGROUND: Exercise programs for patients with heart failure have often enrolled and evaluated relatively healthy, young patients. They also have not measured the impact of exercise performance on daily activities and quality of life. METHODS AND RESULTS: We investigated the impact of a 6-month supervised and graded exercise program in 33 elderly patients with moderate to severe heart failure randomized to usual care or an exercise program. Six of 17 patients did not tolerate the exercise program. Of those who did, peak oxygen consumption increased by 2.4 +/- 2.8 mL/kg/min (P < .05) and 6-minute walk increased by 194 ft (P < .05). However, outpatient energy expenditure did not increase, as measured by either the doubly labeled water technique or Caltrac accelerometer. Perceived quality of life also did not improve, as measured by the Medical Outcomes Study, Functional Status Assessment, or Minnesota Living With Heart Failure questionnaires. CONCLUSION: Elderly patients with severe heart failure can safely exercise, with an improvement in peak exercise tolerance. However, not all patients will benefit, and daily energy expenditure and quality of life do not improve to the same extent as peak exercise.

A four-part regimen for clinical heart failure.

Combination therapy with a diuretic, digoxin, ACE inhibitor, and beta-blocker can help patients with heart failure caused by severe systolic dysfunction feel better and live longer. Especially with ACE inhibitors and beta-blockers, the key to success is starting at low doses and titrating carefully to proven target doses. The demanding complexity of the four-drug regimen is well worth the results.

Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction.

BACKGROUND: Long-term administration of beta-adrenergic blockers to patients after myocardial infarction improves survival. However, physicians are reluctant to administer beta-blockers to many patients, such as older patients and those with chronic pulmonary disease, left ventricular dysfunction, or non-Q-wave myocardial infarction. METHODS: The medical records of 201,752 patients with myocardial infarction were abstracted by the Cooperative Cardiovascular Project, which was sponsored by the Health Care Financing Administration. Using a Cox proportional-hazards model that accounted for multiple factors that might influence survival, we compared mortality among patients treated with beta-blockers with mortality among untreated patients during the two years after myocardial infarction. RESULTS: A total of 34 percent of the patients received beta-blockers. The percentage was lower among the very elderly, blacks, and patients with the lowest ejection fractions, heart failure, chronic obstructive pulmonary disease, elevated serum creatinine concentrations, or type 1 diabetes mellitus. Nevertheless, mortality was lower in every subgroup of patients treated with beta-blockade than in untreated patients. In patients with myocardial infarction and no other complications, treatment with beta-blockers was associated with a 40 percent reduction in mortality. Mortality was also reduced by 40 percent in patients with non-Q-wave infarction and those with chronic obstructive pulmonary disease. Blacks, patients 80 years old or older, and those with a left ventricular ejection fraction below 20 percent, serum creatinine concentration greater than 1.4 mg per deciliter (124 micromol per liter), or diabetes mellitus had a lower percentage reduction in mortality. Given, however, the higher mortality rates in these subgroups, the absolute reduction in mortality was similar to or greater than that among patients with no specific risk factors. CONCLUSIONS: After myocardial infarction, patients with conditions that are often considered contraindications to beta-blockade (such as heart failure, pulmonary disease, and older age) and those with nontransmural infarction benefit from beta-blocker therapy.

The effects of diuresis on the pharmacokinetics of the loop diuretics furosemide and torsemide in patients with heart failure.

PURPOSE: To evaluate the pharmacokinetics of furosemide and torsemide before and after diuresis in patients presenting with marked fluid overload. SUBJECTS AND METHODS: We studied 44 patients with New York Heart Association class III or IV heart failure, ejection fraction < or =40%, and an estimated excess fluid body weight > or =6.8 kg. Oral furosemide or torsemide was administered before and after diuresis. Pharmacokinetic parameters were assessed before and after diuresis. RESULTS: Following diuresis, maximum plasma concentration increased from 11.0+/-5.0 microg/mL to 13.9+/-6.8 with torsemide (P <0.05) and from 3.1< or =1.5 to 3.9+/-1.9 with furosemide (P=0.16). Maximum concentration increased by more than 30% in only one third of the patients. Total absorption (by area under the curve method) increased 6% among patients on torsemide (P=0.38) and 7% among patients on furosemide (P=0.63) and increased >30% in only 1 torsemide and 2 furosemide patients. The time to maximum concentration decreased from 1.40+/-.82 h to 0.81+/-0.36 with torsemide (P <0.01). There were no differences between furosemide and torsemide in the effects of edema on absorption. CONCLUSION: Marked diuresis altered the pharmacokinetics of both furosemide and torsemide in only a small percentage of patients. The use of adequate doses of oral diuretics in edematous patients may be successful, thereby permitting home treatment with oral diuretics and avoiding the cost of hospitalizations or home intravenous administration services.

Daily energy requirements in heart failure patients.

Diminished body cell mass in heart failure patients contributes to poor prognosis and decreased quality of life. The level of daily energy intake needed to maintain body cell mass and optimal physiological function in heart failure patients is unknown. Thus, we examined daily energy expenditure in free-living heart failure patients to estimate daily energy requirements. Daily energy expenditure (doubly labeled water) and its components (resting and physical activity energy expenditures) were measured in 26 heart failure patients (25 men and one woman aged 69 +/- 7 years) and 50 healthy controls (48 men and two women aged 69 +/- 6 years). Resting energy expenditure was measured by indirect calorimetry; physical activity energy expenditure from the difference between daily and resting energy expenditure; body composition by dual-energy x-ray absorptiometry; leisure time physical activity from a questionnaire; and peak oxygen consumption ([peak VO2] n = 16 heart failure patients) from a treadmill test to exhaustion. Plasma markers of nutritional status were also considered. Daily energy expenditure was 17% lower (2,110 +/- 500 v 2,543 +/- 449 kcal/d) and physical activity energy expenditure 54% lower (333 +/- 345 v 728 +/- 374 kcal/d) in heart failure patients compared with healthy controls. Daily energy expenditure was related to physical activity energy expenditure (r = .79, P < .01), resting energy expenditure (r = .63, P < .01), leisure time physical activity (r = .63, P < .01), and peak VO2 (r = .58, P < .01) in heart failure patients. Stepwise regression analysis showed that daily energy requirements in heart failure patients were best estimated by a combination of resting energy expenditure and reported leisure time physical activity (total R2 = 61%; standard error of the estimate, +/- 333 kcal/d). Daily energy requirements predicted from equations derived in healthy elderly were inaccurate when applied to heart failure patients, deviating -10% to +30% from measured daily energy expenditure. We conclude that despite low levels of activity, markers of physical activity predicted daily energy needs in heart failure patients. We provide a new equation to estimate energy needs in free-living heart failure patients based on measurements of daily energy expenditure.