Prospective crossover comparison of carvedilol and metoprolol in patients with chronic heart failure

OBJECTIVES: This study investigates the effects of a change of beta-adrenergic blocking agent treatment from metoprolol to carvedilol and vice versa in patients with heart failure (HF).BACKGROUND: Beta-blockers improve ventricular function and prolong survival in patients with HF. It has recently been suggested that carvedilol has more pronounced effects on left ventricular ejection fraction (LVEF) compared with metoprolol. It is uncertain whether a change from one beta-blocker to the other is safe and leads to any change of left ventricular function.METHODS: Forty-four patients with HF due to ischemic (n = 17) or idiopathic cardiomyopathy (n = 27) that had responded well to long-term treatment with either metoprolol (n = 20) or carvedilol (n = 24) were switched to an equivalent dose of the respective other beta-blocker. Before and six months after crossover of treatment, echocardiography, radionuclide ventriculography and dobutamine stress echocardiography were performed.RESULTS: Six months after crossover of beta-blocker treatment, LVEF had further improved with both carvedilol and metoprolol (carvedilol: 32 +/- 3% to 36 +/- 4%; metoprolol: 27 +/- 4% to 30 +/- 5%; both p < 0.05 vs. baseline), without interindividual differences. There were no changes in either New York Heart Association functional class or any other hemodynamic parameters at rest. Dobutamine stress echocardiography revealed a more pronounced increase of heart rate after dobutamine infusion in metoprolol- compared with carvedilol-treated patients. After dobutamine infusion, LVEF increased in the carvedilol- but not in the metoprolol-treated group.CONCLUSIONS: When switching treatment from one beta-blocker to the other, improvement of LVEF in patients with HF is maintained. Despite similar long-term effects on hemodynamics at rest, beta-adrenergic responsiveness is different in both treatments.     

Double-blind placebo-controlled comparison of enoximone and dobutamine infusions in patients with moderate to severe chronic heart failure

Few data exist on the safety of transferring patients to standard oral therapy for chronic heart failure (CHF) after acute management with inotropic agents. This study compares hemodynamic responses and cardiac dysrhythmic effects of continuous infusion of enoximone, dobutamine, or placebo in patients with moderate to severe CHF. The authors enrolled 136 patients who were randomly assigned to either open-label dobutamine or double-blind enoximone vs placebo. After 24 hours of treatment, the study was unblinded. Patients receiving placebo completed the study. Patients receiving enoximone or dobutamine received the infusion for an additional 24 hours and were then switched to standard oral therapy for 72 hours. Compared with placebo, both enoximone and dobutamine increased cardiac index and decreased pulmonary capillary wedge pressure (PCWP). Compared with dobutamine, enoximone significantly increased cardiac index after the first 24 hours of infusion and significantly decreased PCWP throughout the infusion period. There was no difference in the incidence of arrhythmias between enoximone and dobutamine. More patients (65%) tolerated the switch to oral therapy in the enoximone group compared with dobutamine (49%; P =.12). Enoximone is effective in improving the hemodynamics in patients with moderate to severe CHF and is tolerated at least as well as dobutamine.     

Milrinone versus dobutamine in heart failure subjects treated chronically with carvedilol.

OBJECTIVE: To compare the efficacy of milrinone and dobutamine in patients chronically treated with carvedilol. BACKGROUND: Milrinone and dobutamine are used to manage decompensated heart failure, but their efficacy in patients on beta-blocker therapy was unknown. METHODS: Twenty patients with decompensated heart failure were prospectively enrolled. Inotropic responses to milrinone (12.5, 25 or 50 microg/kg bolus infusions) or dobutamine (5, 10, 15 or 20 microg/kg/min infusions) were evaluated by right-heart catheterization. RESULTS: Milrinone increased cardiac index (2.0-2.6 l/min/m2, P=0.0001) without significantly altering heart rate (70-75 bpm, P=0.19). Milrinone decreased mean pulmonary artery pressure (36-29 mm Hg, P=0.0001), pulmonary capillary wedge pressure (24-18 mm Hg, P=0.0001) and mean arterial blood pressure (78-75 mm Hg, P=0.0002). Left ventricular stroke volume index increased in the milrinone group (31-35 ml/beat/m2, P=0.0001). Dobutamine produced an increase in cardiac index (2.4-3.3 l/min/m2, P=0.0001) only at doses that are not typically used to treat heart failure (15-20 microg/kg/min). At these doses, dobutamine increased heart rate (68-82 bpm, P=0.008), mean systemic pressure (90-117 mm Hg, P=0.0001) and mean pulmonary artery pressure (21-30 mm Hg, P=0.001). Dobutamine did not alter left ventricular stroke volume index or pulmonary capillary wedge pressure. Conclusions: Dobutamine and milrinone have different hemodynamic effects in patients treated chronically with carvedilol. These differences should be considered when selecting inotropic therapy for decompensated heart failure.     

Cost-effectiveness of beta-blocker therapy with metoprolol or with carvedilol for treatment of heart failure in Canada

OBJECTIVE: The purpose of this study was to estimate the cost-effectiveness of beta-blocker therapy with either metoprolol or carvedilol in addition to conventional therapy for patients with heart failure (HF) in Canada. DESIGN: A Markov simulation was used to estimate the costs and life expectancy for treating patients with conventional therapy alone and with the addition of metoprolol or carvedilol. Although carvedilol has been marketed in Canada since 1999, metoprolol succinate has yet to be marketed there, so the price is unknown. Therefore we input a Canadian price based on the price ratio of the 2 drugs in the United States. RESULTS: For subjects aged 60 years at HF onset, the expected years of life are 4.53 years for those treated with conventional therapy alone, 5.70 years for those who receive conventional therapy plus metoprolol, and 6.21 years for those who receive conventional therapy plus carvedilol. The expected costs (in 1999 Canadian dollars) are $8,989, $13,833, and $18,114, respectively. This yields incremental cost-effectiveness ratios (ICERs) for metoprolol relative to conventional therapy alone of $4,140 per life-year gained, and for carvedilol relative to metoprolol, the ICER is $8,394 per life-year gained. CONCLUSIONS: In addition to conventional therapy with furosemide and angiotensin converting enzyme inhibitors, treatment with either metoprolol or carvedilol confers a survival benefit that is attractive from a cost-effectiveness point of view. Until better information becomes available, it is not possible to distinguish between the two beta-blockers on the basis of cost-effectiveness. This means that the choice of beta-blockers for HF should be based largely on clinical considerations because both beta-blockers prolong life at relatively low cost.     

Left ventricular inotropic reserve and right ventricular function predict increase of left ventricular ejection fraction after beta-blocker therapy in nonischemic cardiomyopathy.

OBJECTIVES: The purpose of this study was to determine whether higher left ventricular inotropic reserve, defined as the increase in left ventricular ejection fraction (LVEF) in response to intravenous dobutamine infusion, or other ventriculographic variables predict the increase in LVEF after beta-blocker therapy in patients with nonischemic cardiomyopathy (NICM). BACKGROUND: Long-term beta-blocker therapy increases LVEF in some patients with NICM. Other than dose, there are no definite predictors of LVEF increase. METHODS: Thirty patients with LVEF < or = 0.35 and NICM underwent assessment of LVEF at rest and after a 10-min intravenous infusion of dobutamine at 10 microg/kg/min, using equilibrium radionuclide ventriculography. Age was 49 +/- 11 years, 33% women, functional class 2.6 +/- 0.5, duration of chronic heart failure 3.2 +/- 2.9 years, LVEF 0.21 +/- 0.07, left ventricular end-diastolic volume index 180 +/- 64 ml/m2. Right ventricular ejection fraction (RVEF) was abnormal in 37%. Mean dobutamine-induced augmentation of LVEF (DoALVEF) was 0.12 +/- 0.08. Patients were started on one of three beta-blockers (carvedilol, bucindolol or metoprolol) and the dose was advanced to the maximum tolerated. RESULTS: Left ventricular ejection fraction, reassessed 7.4 +/- 5.9 months after maximum beta-blocker dose was reached, increased to 0.34 +/- 0.13 (p = 0.0006). The following baseline variables correlated with improvement of LVEF: DoALVEF (p = 0.001), RVEF (p = 0.005), systolic blood pressure at end of dobutamine infusion (p = 0.02) and dose of beta-blocker (p = 0.07). In a multivariate analysis, only DoALVEF (p = 0.0003) and RVEF (p = 0.002) were predictive of the increase in LVEF. CONCLUSIONS: Patients with nonischemic cardiomyopathy who have higher left ventricular inotropic reserve and normal RVEF derive higher increase in LVEF from beta-blocker therapy.     

Comparison between the positive inotropic effects of enoximone, a cardiac phosphodiesterase III inhibitor, and dobutamine in patients with moderate to severe congestive heart failure. A study using the end-systolic pressure-volume relationship method.

This study was designed to compare the positive inotropic properties of enoximone, a cardiac phosphodiesterase III inhibitor, with those of dobutamine in a population of moderate to severe congestive heart failure patients. The end-systolic pressure-volume relationship method was used. In addition, the haemodynamic effects of both drugs were compared. In seven of the 11 patients studied, enoximone induced a significant shift upwards and to the left of the end-ejection pressure/end-systolic volume (EEP/ESV) relation, giving evidence of a true positive inotropic effect. In the remaining patients, improvement in cardiac pump function was observed together with a shift of the EEP/ESV relation along the line of iso-inotropism and appeared to be the result of the vasodilatory effect of the drug alone. Data from nine patients were available for comparison with dobutamine which induced a shift upward and to the left of the EEP/ESV relation in seven patients. At the therapeutic doses chosen, the difference between the inotropic effects of the two drugs was not significant (P = 0.07). Of the three patients available for comparison who did not manifest inotropic response with enoximone, two were also dobutamine 'non-responders': they differed from the 'responder' patients in two respects: they had undergone surgery for correction of valvular disease and had significantly higher pulmonary artery pressures. The haemodynamic measurements confirmed the vasodilatory properties of enoximone; in particular, the fall in ventricular filling pressures was much greater with enoximone than with dobutamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Should beta‐blocker therapy be reduced or withdrawn after an episode of decompensated heart failure? Results from COMET

BACKGROUND: It is unclear whether beta-blocker therapy should be reduced or withdrawn in patients who develop acute decompensated heart failure (HF). We studied the relationship between changes in beta-blocker dose and outcome in patients surviving a HF hospitalisation in COMET. METHODS: Patients hospitalised for HF were subdivided on the basis of the beta-blocker dose administered at the visit following hospitalisation, compared to that administered before. RESULTS: In COMET, 752/3029 patients (25%, 361 carvedilol and 391 metoprolol) had a non-fatal HF hospitalisation while on study treatment. Of these, 61 patients (8%) had beta-blocker treatment withdrawn, 162 (22%) had a dose reduction and 529 (70%) were maintained on the same dose. One-and two-year cumulative mortality rates were 28.7% and 44.6% for patients withdrawn from study medication, 37.4% and 51.4% for those with a reduced dosage (n.s.) and 19.1% and 32.5% for those maintained on the same dose (HR,1.59; 95%CI, 1.28-1.98; p<0.001, compared to the others). The result remained significant in a multivariable model: (HR, 1.30; 95%CI, 1.02-1.66; p=0.0318). No interaction with the beneficial effects of carvedilol, compared to metoprolol, on outcome was observed (p=0.8436). CONCLUSIONS: HF hospitalisations are associated with a high subsequent mortality. The risk of death is higher in patients who discontinue beta-blocker therapy or have their dose reduced. The increase in mortality is only partially explained by the worse prognostic profile of these patients.     

Levosimendan versus dobutamine in heart failure patients treated chronically with carvedilol

Introduction : Although beta‐blockers are highly effective in the treatment of heart failure (HF), many patients with HF receiving a beta‐blocker continue to become decompensated and require hospitalization for worsening HF. Levosimendan and dobutamine are used to manage decompensated HF, but their comparative effects on left ventricular (LV) function in patients prescribed beta‐blockers are unknown. Aims : The aim of this study was to compare the effects of dobutamine and levosimendan on LV systolic and diastolic functions in chronic HF patients treated chronically with carvedilol. Forty patients with chronic HF who had NYHA class III to IV symptoms, a LV ejection fraction (LVEF) <40%, and ongoing treatment with carvedilol were enrolled in this randomized (1:1), dobutamine controlled, open‐label study. Before and 24 h after treatment, LVEF, mitral inflow peak E and A wave velocity, E/A ratio, the deceleration time of the E wave (DT), isovolumic relaxation time (IVRT), peak systolic (Sm) and early diastolic (Em) mitral annular velocity, and systolic pulmonary artery pressure (SPAP) were measured by echocardiography. Results : Levosimendan produced a statistically significant increase in LVEF (28 ± 5% vs. 33 ± 3%), Sm (6.5 ± 1.2 cm/s vs. 7.4 ± 0.9 cm/s), DT (120 ± 10 ms vs. 140 ± 15 ms), and Em (7.5 ± 0.4 cm/s vs. 8.1 ± 0.5 cm/s) and significant decrease in E/A ratio (2.1 ± 0.3 vs. 1.7 ± 0.4) and SPAP (55 ± 5 mmHg vs. 40 ± 7 mmHg). No significant change occurred in LV systolic and diastolic function parameters, or SPAP with dobutamine treatment. Levosimendan did not significantly alter the heart rate (72 ± 4 bpm vs. 70 ± 3 bpm), systolic (105 ± 5 mmHg vs. 102 ± 4 mmHg), or diastolic blood pressure (85 ± 5 mmHg vs. 83 ± 5 mmHg) whereas with dobutamine treatment, all these parameters significantly increased. Conclusions : Dobutamine and levosimendan have different effects on LV functions in patients treated chronically with carvedilol. These differences should be considered when selecting inotropic therapy for decompensated HF receiving long‐term carvedilol.     

Myocardial beta-1 adrenoceptor down-regulation in aging and heart failure: implications for beta-blocker use in older adults with heart failure

Heart failure is associated with increased sympathetic nervous stimulation that results in down-regulation of myocardial beta-1 receptors. The failing heart might depend more on beta-2 receptors for positive inotropic support than the normal heart. Suppression of both beta-1 and beta-2 adrenoceptors by a non-selective beta-blocker, such as carvedilol, is likely to eliminate the failing heart's much needed inotropic support, resulting in an exacerbation of symptoms. Use of a beta-1 selective blocker, such as metoprolol, on the other hand, is likely to be well tolerated. Unlike carvedilol, the use of metoprolol is associated with up-regulation of beta-1 receptors. The clinical significance of the pharmacodynamic differences between these two beta-blockers in terms of their short-term hemodynamic and long-term beneficial effects is not clearly understood. However, in clinical trials, both carvedilol and metoprolol improved left ventricular function, heart failure symptoms and survival. Both drugs are well tolerated as well. Aging itself is associated with elevated myocardial and serum norepinephrine levels, which is associated with down-regulation of beta-1 receptors. In this article, we reviewed the literature to examine the clinical implications of this dual (age- and heart failure-related) sympathetic stimulation and beta-1 receptor down-regulation on selection of beta-blockers in older adults with heart failure.     

Enoximone, a new phosphodiesterase inhibitor: the spectrum of applications during heart surgery--a comparison with dobutamine

During cardiac surgery treatment of deterioration of myocardial function is usually based on catecholamines. Development of selective phosphodiesterase-(PDE-)III-inhibitors seems to be a new aspect in treating myocardial dysfunction. Therefore the hemodynamic effects of the new PDE-inhibitor enoximone were investigated in 20 coronary surgery patients unable to be weaned from extracorporeal circulation (ECC) without pharmacological intervention (MAP less than 60 mmHg, CI less than 2.00 l/min.m2, PCP greater than 15 mmHg). After controlled reperfusion with 2.4 1/min.m2 two groups were separated in a random sequence receiving either 0.5 mg/kg enoximone as a bolus (n = 10), or dobutamine (n = 10, 5 micrograms/kg.min) as perfusion. In the dobutamine-group MAP and CI (-14%) were decreased, while HR was increased significantly (+30%). Application of enoximone was followed by a slight increase in CI (+5%), a significant decrease in TSR while HR remained almost unchanged. PCP, too, differed significantly between the groups (enoximone: -38%; dobutamine: -10%). Ten minutes after weaning from ECC additional pharmacologic therapy (calcium, vasodilators, epinephrine) was necessary in eight dobutamine treated patients in contrast to four patients in the enoximone group (calcium, epinephrine). In patients with impaired myocardial performance during weaning from ECC enoximone seems to be an alternative therapy and is judged to be of some advantage compared to dobutamine application in this situation. The mechanism for improvement appears to be enhanced contractility owing to its positive inotropic effects, as well as a decrease in left ventricular outflow resistance resulting from peripheral vasodilation.     

Rationale and design of the enoximone clinical trials program

BACKGROUND: Chronic heart failure is a disease syndrome characterized in its advanced stages by a poor quality of life, frequent hospitalizations, and a high risk of mortality. In advanced and ultra-advanced chronic heart failure, many treatment options, such as cardiac transplantation and mechanical devices, are severely limited by availability and cost. Short-term Phase II clinical trials suggest that low-dose oral inotropic therapy with enoximone may improve hemodynamics and exercise capacity, without adversely affecting mortality, in selected subjects with advanced chronic heart failure. Based on these data, the ability of enoximone to deliver safe and efficacious palliative treatment of advanced/ultra-advanced chronic heart failure is being evaluated in Phase III clinical trials. METHODS AND RESULTS: The Enoximone Clinical Trials Program is a series of 4 clinical trials designed to evaluate the safety and efficacy of oral enoximone in advanced chronic heart failure. ESSENTIAL I and II (The Studies of Oral Enoximone Therapy in Advanced Heart Failure) will investigate the effects of oral enoximone on all-cause mortality and cardiovascular hospitalization, submaximal exercise capacity, and quality of life in subjects with New York Heart Association Class III/IV chronic heart failure. EMOTE (Oral Enoximone in Intravenous Inotrope-Dependent Subjects) will evaluate the potential of oral enoximone to wean subjects with ultra-advanced chronic heart failure from chronic intravenous inotropic therapy to which they have been shown to be dependent. EMPOWER (Enoximone Plus Extended-Release Metoprolol Succinate in Subjects with Advanced Chronic Heart Failure) will explore the potential of enoximone to increase the tolerability of continuous release metoprolol in subjects shown previously to be hemodynamically intolerant to beta-blocker treatment. CONCLUSION: These studies are Phase III, multicenter, randomized, double-blinded, placebo-controlled trials designed to test the general hypothesis that chronic oral administration of low doses of enoximone can produce beneficial effects in subjects with advanced or ultra-advanced chronic heart failure.     

Comparative hemodynamic and hormonal response of enoximone and dobutamine in severe congestive heart failure

The peak hemodynamic effect and hormonal response of the phosphodiesterase inhibitor enoximone (MDL 17,043) were compared with those of dobutamine in 10 patients with severe congestive heart failure. Both agents significantly (p less than 0.05) increased cardiac index, stroke volume index and heart rate. Enoximone tended to decrease mean systemic arterial and pulmonary artery wedge pressures (0.05 less than p less than 0.1), whereas dobutamine did not. Both agents decreased systemic vascular resistance (p less than 0.05). The increase in heart rate was greater with dobutamine than with enoximone (p less than 0.05). Plasma renin activity increased significantly with dobutamine (from 11.3 +/- 13.5 to 17.8 +/- 15.0 ng/ml/hour, p less than 0.01) and with enoximone (from 13.6 +/- 18.3 to 16.6 +/- 18.8 ng/ml/hour, 0.05 less than p less than 0.1). Dobutamine suppressed plasma norepinephrine level (p less than 0.05) and enoximone did not. Neither agent affected the plasma vasopressin level. These data demonstrate a similar acute hemodynamic and hormonal profile for both enoximone and dobutamine. Further, dobutamine, like other beta agonists, provokes renin secretion and may do so to a greater extent than enoximone.     

Combined Oral Positive Inotropic and Beta-Blocker Therapy for Treatment of Refractory Class IV Heart Failure

Objectives. We sought to assess the effects of combined oral positive inotropic and beta-blocker therapy in patients with severe heart failure.Background. Patients with severe, class IV heart failure who receive standard medical therapy exhibit a 1-year mortality rate >50%. Moreover, such patients generally do not tolerate beta-blockade, a promising new therapy for chronic heart failure. Positive inotropes, including phosphodiesterase inhibitors, are associated with increased mortality when administered over the long term in these patients. The addition of a beta-blocker to positive inotropic therapy might attenuate this adverse effect, although long-term oral inotropic therapy might serve as a bridge to beta-blockade.Methods. Thirty patients with severe heart failure (left ventricular ejection fraction [LVEF] 17.2 ± 1.2%, cardiac index 1.6 ± 0.1 liter/min per m²) were treated with the combination of oral enoximone (a phosphodiesterase inhibitor) and oral metoprolol at two institutions. Enoximone was given at a dose of ≤1 mg/kg body weight three times a day. After clinical stabilization, metoprolol was initiated at 6.25 mg twice a day and slowly titrated up to a target dose of 100 to 200 mg/day.Results. Ninety-six percent of the patients tolerated enoximone, whereas 80% tolerated the addition of metoprolol. The mean duration of combination therapy was 9.4 ± 1.8 months. The mean length of follow-up was 20.9 ± 3.9 months. Of the 23 patients receiving the combination therapy, 48% were weaned off enoximone over the long term. The LVEF increased significantly, from 17.7 ± 1.6% to 27.6 ± 3.4% (p = 0.01), whereas the New York Heart Association functional class improved from 4 ± 0 to 2.8 ± 0.1 (p = 0.0001). The number of hospital admissions tended to decrease during therapy (p = 0.06). The estimated probability of survival at 1 year was 81 ± 9%. Heart transplantation was performed successfully in nine patients (30%).Conclusions. Combination therapy with a positive inotrope and a beta-blocker appears to be useful in the treatment of severe, class IV heart failure. It may be used as a palliative measure when transplantation is not an option or as a bridge to heart transplantation. Further study of this form of combined therapy is warranted.     

Effect of enoximone alone and in combination with metoprolol on myocardial function and energetics in severe congestive heart failure: Improvement in hemodynamic and metabolic profile

Summary The hemodynamic and myocardial metabolic effects of enoximone (phosphodiesterase III inhibitor), alone or in combination with metoprolol (beta-adrenergic blocker), were studied in patients with congestive heart failure. Ten patients (New York Heart Association Class III–IV) underwent right heart and coronary sinus catheterization, and parameters were assessed at basal condition, at peak enoximone response (mean intravenous loading dose=2.2 mg/kg), and after the combination with metoprolol (mean intravenous dose=8.5 mg). Heart rate tended to increase during enoximone administration (from 102±16 to 107±16 min^–1, ns) and was reduced during enoximone plus metoprolol (to 88±15 min^–1, p<0.05 vs. basal). Cardiac index was increased during enoximone (from 2.2±0.2 to 3.8±0.5 1/min/m², p<0.05) and decreased during enoximone plus metoprolol (to 2.8±0.5 1/min/m², p<0.05 vs. enoximone). Mean pulmonary wedge pressure fell during enoximone and remained reduced during enoximone plus metoprolol (from 27±9 to 9±3 and to 13±4 mmHg, respectively, both p<0.05). Myocardial oxygen consumption did not change during enoximone (from 27±8 to 25±13 ml/min, ns) and was reduced during enoximone plus metoprolol (to 19±8 ml/min, p<0.05 vs. basal). Myocardial lactate extraction tended to be lower during enoximone and during enoximone plus metoprolol conditions (from 38±17% to 26±20% and to 29±24%, respectively), but no statistical significance was found. Myocardial efficiency was increased during enoximone and during enoximone plus metoprolol (from 9±3% to 15±6% and to 14±6%, respectively, both p<0.05). Thus in patients with congestive heart failure enoximone improves hemodynamics and, in most cases, it does not influence energetics. The addition of metoprolol to enoximone reduces heart rate, cardiac index, and myocardial oxygen consumption without any other major changes, producing a more physiologic hemodynamic and metabolic profile.     

Carvedilol or Sustained-Release Metoprolol for Congestive Heart Failure: A Comparative Effectiveness Analysis

BackgroundRelative effectiveness of carvedilol and metoprolol succinate has never been compared in patients with heart failure (HF).Methods and ResultsFrom January 1998 to December 2008, 3,716 consecutive patients with ejection fraction (EF) ≤40%, initiated and maintained on carvedilol or metoprolol succinate, were enrolled and followed until June 2010. The primary end point was all-cause mortality, and the secondary end points were readmissions from HF and follow up EFs at 1, 3, and 5 years. HF etiology (ischemic or nonischemic) was a significant effect modifier, and separate analysis was performed for these subcohorts. Compared with those on carvedilol, patients on metoprolol succinate were less likely to experience mortality in the ischemic HF cohort (adjusted hazard ratio [aHR] 0.54, 95% confidence interval [CI] 0.43–0.66) but were more likely to die in the nonischemic HF cohort (aHR 1.18, 95% CI 1.10–1.28). Follow-up EF was similar by type of beta-blocker used in both ischemic and nonischemic HF cohorts. Furthermore, no significant difference was noted in the incidence of HF hospitalizations by beta-blocker type used in both ischemic and nonischemic HF cohorts.ConclusionsMetoprolol succinate was associated with an improved survival in patients with ischemic HF, and carvedilol was associated with an improved survival in patients with nonischemic HF.     

Increased beta-receptor density and improved hemodynamic response to catecholamine stimulation during long-term metoprolol therapy in heart failure from dilated cardiomyopathy

Severe heart failure is associated with a reduction in myocardial beta-adrenergic receptor density and an impaired contractile response to catecholamine stimulation. Metoprolol was administered during a 6-month period to 14 patients with dilated cardiomyopathy to examine its effects on these abnormalities. The mean daily dose of metoprolol for the group was 105 mg (range, 75-150 mg). Myocardial beta-receptor density, resting hemodynamic output, and peak left ventricular dP/dt response to dobutamine infusions were compared in 9, 14, and 7 patients, respectively, before and after 6 months of metoprolol therapy while the patients were on therapy. The second hemodynamic study was performed 1-2 hours after the morning dose of metoprolol had been given. Myocardial beta-receptor density increased from 39 +/- 7 to 80 +/- 12 fmol/mg (p less than 0.05). Resting hemodynamic output showed a rise in stroke work index from 27 +/- 4 to 43 +/- 3 g/m/m2, p less than 0.05, and ejection fraction rose from 0.26 +/- 0.03 to 0.39 +/- 0.03 after 6 months of metoprolol therapy, p less than 0.05. Before metoprolol therapy, dobutamine caused a 21 +/- 4% increase in peak positive left ventricular dP/dt; during metoprolol therapy, the same dobutamine infusion rate increased peak positive dP/dt by 74 +/- 18% (p less than 0.05). Thus, long-term metoprolol therapy is associated with an increase in myocardial beta-receptor density, significant improvement in resting hemodynamic output, and improved contractile response to catecholamine stimulation. These changes indicate a restoration of beta-adrenergic sensitivity associated with metoprolol therapy, possibly related to the observed up-regulation of beta-adrenergic receptors.     

Enoximone treatment of impaired myocardial function during cardiac surgery: combined effects with epinephrine

Enoximone belongs to a new class of noncatecholamine-positive inotropes, which selectively inhibit phosphodiesterase type III and increase cyclic AMP (cAMP). This study was performed in 30 coronary artery surgery patients with impaired myocardial function (ejection fraction [EF] < 50%). The study's two purposes were to investigate the hemodynamic effects of enoximone, 0.5 mg/kg, administered following induction of anesthesia (phase I), and to assess whether enoximone can potentiate the actions of sympathomimetic agents during weaning from cardiopulmonary bypass (CPB) (phase II). Starting with already reduced hemodynamics, induction of anesthesia led to a further deterioration of blood pressure and cardiac output (CO). Administration of enoximone produced a significant increase in cardiac index (CI) (+47%), whereas pulmonary capillary wedge pressure (PCWP) (−37%), pulmonary artery pressure (PAP) (−17%). and systemic vascular resistance (SVR) (−17%) were significantly reduced. Heart rate (HR) was not increased, and no dysrhythmiss occurred during the investigation. The hemodynamic effects were maintained for 30 minutes until the start of the operation. In phase II, where weaning from CPB was not possible without pharmacological support, either enoximone (0.5 mg/kg) + epinephrine (0.1 gg/kg/min) or only epinephrine (same dosage) was randomly selected. Weaning was successful in both groups, but the combined therapy produced a larger increase in CI and a more pronounced decrease of the elevated filling pressure (PCWP). PAP was not changed in the combined therapy group, but increased in the patients receiving epinephrine alone. It is concluded that enoximone has beneficial hemodynamic effects in the perioperative period, and that potentiation of the effects of epinephrine in severe heart failure may be one of the drug's most useful features.     

Acute and long-term hemodynamic response to low-dose enoximone in refractory heart failure

Summary Enoximone possesses both positive inotropic and vasodilatory properties. In heart failure, doses varying between 3 mg/kg and 6 mg/kg produce a beneficial acute hemodynamic response but have been associated with significant side effects. Little is known about the long-term hemodynamic efficacy of this agent. To assess whether a lower dose of enoximone could produce both acute and long-term hemodynamic benefits and be better tolerated, 15 patients with refractory heart failure were given enoximone 100 mg every 8 hours (mean dose, 1.7 mg/kg). The cardiac index, pulmonary capillary wedge pressure, pulmonary artery pressure, right atrial pressure, systemic vascular resistance, pulmonary vascular resistance, and stroke volume index all improved significantly during the first 24 hours. The systemic blood pressure and heart rate did not alter appreciably during this period. Five of six patients remaining on therapy at 6 months had a follow-up hemodynamic study. Sustained improvement was seen in the cardiac index, pulmonary capillary wedge pressure, and pulmonary artery pressure when compared to baseline (all p<0.05). A satisfactory trend, which did not reach statistical significance, was noted in the right atrial pressure (p=0.09) and stroke volume index (p=0.06). Diarrhea occurred in one patient. These findings indicate that enoximone has a beneficial acute and long-term hemodynamic effect at a low dose that is clinically well tolerated.     

Enoximone (MDL 17,043) for stable, chronic heart failure secondary to ischemic or idiopathic cardiomyopathy

To examine the efficacy and safety of enoximone for treatment of patients with chronic, clinically stable cardiac failure secondary to ischemic or myopathic heart disease, 31 patients were enrolled into an early phase II trial. The hemodynamic response to intravenous and oral enoximone was assessed and compared with the response to dobutamine therapy (5 to 10 micrograms/kg/min). Maximal O2 uptake, an objective measure of effort tolerance, was serially monitored. Intravenous (1 to 2 mg/kg) and oral (1 to 2 mg/kg) enoximone improved (p less than 0.05) cardiac index while reducing right atrial and wedge pressures to a greater extent than dobutamine. The salutary hemodynamic response to oral enoximone was sustained for 6 to 8 hours and was not associated with subacute drug tolerance. Maximal O2 uptake was increased (p less than 0.05) at 2, 4, 8, 12, 24 and 52 weeks of oral enoximone therapy (1.4 +/- 0.5 mg/kg every 8 hours) while radionuclide ejection fraction at 65 weeks increased (p less than 0.05) from baseline (39 +/- 16% vs 30 +/- 9%). Nine patients, 8 of whom were in functional class III or IV on enrollment, died after a mean of 18 weeks: 4 from cardiac failure and 5 suddenly. Two patients had adverse gastrointestinal effects. Oral enoximone (1 to 2 mg/kg every 8 hours) appears to be useful in the short- and long-term management of clinically stable, chronic cardiac failure. Controlled phase III trials are warranted.     

Beta-blockade in heart failure: a comparison of carvedilol with metoprolol.

OBJECTIVES: This study was performed to compare the long-term clinical efficacy of treatment with metoprolol versus carvedilol in patients with chronic heart failure. BACKGROUND: Beta-adrenergic blockade is of proven value in chronic heart failure. Metoprolol, a selective beta-blocker, is widely used, but recent trials suggest carvedilol, a nonselective beta-blocker with alpha-1-receptor antagonist activity and antioxidant activities, is also effective. It is uncertain, however, if these additional properties of carvedilol provide further clinical benefit compared with metoprolol. METHODS: In this randomized double-blind control trial, 51 patients with chronic heart failure and mean left ventricular (LV) ejection fraction of 26% +/- 1.8% were randomly assigned treatment with metoprolol 50 mg twice daily or carvedilol 25 mg twice daily in addition to standard therapy after a four-week dose titration period for a total of 12 weeks. Response was assessed by a quality of life questionnaire, New York Heart Association class, exercise capacity (6-min walk test), radionucleotide ventriculography for LV ejection fraction, two-dimensional echocardiography measurement of LV dimensions and diastolic filling and 24-h electrocardiograph monitoring to assess heart rate variability. RESULTS: Both carvedilol and metoprolol produced highly significant improvement in symptoms (p < 0.001), exercise capacity (p < 0.05) and LV ejection fraction (p < 0.001), and there were no significant differences between the two drugs. Carvedilol had a significantly greater effect on sitting and standing blood pressure, LV end-diastolic dimension and normalized the mitral E wave deceleration time. CONCLUSIONS: Both metoprolol and carvedilol were equally effective in improving symptoms, quality of life, exercise capacity and LV ejection fraction, although carvedilol lowers blood pressure more than metoprolol.