Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure.

BACKGROUND: With beta-blocker use becoming more prevalent in treating chronic heart failure (CHF), the choice of drugs raises important theoretical and practical questions. Although the second-generation compound metoprolol is beta1-selective, the third-generation compound carvedilol is beta-nonselective, with ancillary pharmacological properties including alpha-blockade and antioxidant effects. A prospective comparison of these 2 agents can address the issue of optimal adrenergic blockade in selecting agents for therapy in CHF. METHODS AND RESULTS: Sixty-seven patients with symptomatic stable heart failure were randomly assigned to receive either carvedilol or metoprolol in addition to standard therapy for CHF. Measured variables included symptoms, exercise, ejection fraction, and thiobarbituric acid-reactive substances (TBARS) as an indirect marker of free radical activity. Metoprolol and carvedilol were well tolerated, and both patient groups showed beneficial effects of beta-blocker therapy in each of the measured parameters, with no between-group differences. Ejection fraction increased over 6 months from 18+/-6.3% to 23+/-8.7% (P<0.005) with metoprolol and from 19+/-8.5% to 25+/-9.9% (P<0.0005) with carvedilol (P=NS between groups). With metoprolol, TBARS values decreased from 4.7+/-0.9 nmol/mL at baseline to 4.2+/-1.5 nmol/mL at month 4 to 3.9+/-1.0 nmol/mL at month 6 (P<0.0001). With carvedilol, there was a parallel decline from 4.7+/-1.4 to 4.2+/-1.3 to 4.1+/-1.2 nmol/mL over the same time frame (P<0.025), with no between-group difference in these changes. CONCLUSIONS: Carvedilol and metoprolol showed parallel beneficial effects in the measured parameters over 6 months, with no relevant between-group differences in this heart failure population.

Prognostic importance of atrial natriuretic peptide in patients with chronic heart failure.

Several circulating neurohormones have been shown to have prognostic significance in patients with chronic heart failure, but the relation between plasma levels of atrial natriuretic peptide and mortality in this disorder remains unknown. Plasma levels of immunoreactive atrial natriuretic peptide were measured in 102 patients in whom left ventricular ejection fraction, ventricular arrhythmias on ambulatory electrocardiographic recording and plasma levels of norepinephrine, renin activity, aldosterone and arginine vasopressin were also measured. Compared with patients with atrial natriuretic peptide concentrations below the median value of 125 pg/ml, patients with higher levels of the peptide had a higher plasma renin activity (8.9 +/- 1.8 versus 2.6 +/- 0.4 ng/ml per h) and plasma norepinephrine (858 +/- 116 versus 538 +/- 45 pg/ml), more frequent premature ventricular depolarizations (4,485 +/- 715 versus 2,004 +/- 495/day) and more advanced hemodynamic abnormalities (all p less than 0.05). During the subsequent 13 to 25 months of follow-up, patients with high levels of atrial natriuretic peptide had a significantly lower rate of survival than did those whose initial circulating peptide concentrations were normal or mildly increased (p = 0.01). These data indicate that, in patients with chronic heart failure, plasma atrial natriuretic peptide provides important prognostic information. This may relate to the ability of the hormone to reflect the interplay of several pathophysiologic factors that contribute to mortality in this disease.

Prognostic importance of the serum magnesium concentration in patients with congestive heart failure.

Magnesium abnormalities are common in patients with congestive heart failure but the clinical and prognostic significance of an abnormal serum magnesium concentration in this disorder has not been investigated. Therefore, the relation between serum magnesium concentration and the clinical characteristics and long-term outcome of 199 patients with chronic heart failure was evaluated. The serum magnesium concentration was less than 1.6 mEq/liter in 38 patients (19%), within the normal range in 134 patients (67%) and greater than 2.1 mEq/liter in 27 patients (14%). Patients with hypomagnesemia had more frequent ventricular premature complexes and episodes of ventricular tachycardia than did patients with a normal serum magnesium concentration (p less than 0.05). Even though the two groups were similar with respect to severity of heart failure and neurohormonal variables, patients with a low serum magnesium concentration had a significantly worse prognosis during long-term follow-up (45% versus 71% 1 year survival, p less than 0.05). Patients with hypermagnesemia had more severe symptoms, greater neurohormonal activation and worse renal function than did patients with a normal serum magnesium concentration but tended to have fewer ventricular arrhythmias. Hypermagnesemic patients had a worse prognosis than did those with a normal magnesium concentration (37% versus 71% 1 year survival, p less than 0.05). In conclusion, the measurement of serum magnesium concentration provides important clinical and prognostic information in patients with chronic heart failure.

Hemodynamic comparison of twice daily metoprolol tartrate with once daily metoprolol succinate in congestive heart failure.

OBJECTIVES: To compare the hemodynamic effects of twice daily metoprolol tartrate (MT) and once daily metoprolol succinate (MS) in congestive heart failure patients. BACKGROUND: Adverse hemodynamic effects with MT demonstrated during initiation persist with drug readministration during chronic therapy. METHODS: Patients were randomly assigned to 6.25 mg MT or 25 mg MS orally and the dose was gradually increased to a target of 50 mg twice a day or 100 mg once a day, respectively. Hemodynamic measurements were obtained at baseline and after three months of therapy--both before and after drug readministration. RESULTS: Long term metoprolol therapy produced significant functional, exercise and hemodynamic benefits with no difference in response between either metoprolol preparation in the 27 patients (MT [14], MS [13]). When full dose metoprolol was readministered during chronic therapy, there were parallel adverse hemodynamic effects in both drug groups. Cardiac index decreased by 0.6 liters/min/m2 (p < 0.0001) with MT and by 0.5 liters/min/m2 (p < 0.0001) with MS. Systematic vascular resistance increased by 253 dyne-sec-cm(-5) (p < 0.001) with MT and by 267 dyne-sec-cm(-5) (p < 0.0005) with MS. Stroke volume index decreased by 7.0 ml/m2 (p < 0.0005) with MT and by 6.5 ml/m2 (p < 0.0001) with MS, while SWI decreased by 6.2 g-m/m2 (p < 0.0005) with MT and by 6.0 g-m/m2 (p < 0.001) with MS. CONCLUSION: Metoprolol tartrate and MS produce similar hemodynamic and clinical effects acutely and chronically despite the fourfold greater starting dose of MS used in this study. A more rapid initiation with readily available starting doses of MS may offer distinct advantages compared with MT in treating chronic heart failure patients with beta-adrenergic blocking agents.

Relation between exercise-induced changes in ejection fraction and systolic loading conditions at rest in aortic regurgitation.

To examine the role of systolic wall stress at rest in determining left ventricular performance during exercise in aortic regurgitation (AR), systolic wall stress (measured by M-mode echocardiography) was related to changes in left ventricular function during maximal exercise (evaluated by radionuclide ventriculography) in 30 patients with chronic aortic regurgitation. Of these 30 patients, 7 had a normal exercise response, defined as an absolute increase in ejection fraction of 5% or greater (Group I) and 23 had abnormal exercise response, defined as no change (less than 5% change) or a decline (less than or equal to 5%) in ejection fraction (Group II). Patients in Group I had a significantly lower radius/wall thickness ratio (2.5 +/- 0.2 versus 3.1 +/- 0.1, p less than 0.01) and lower peak systolic wall stress (123 +/- 11 versus 211 +/- 12 X 10(3) dynes/cm2, p less than 0.01) than patients in Group II. An increase in ejection fraction during exercise was seen in 6 of the 9 patients with normal systolic wall stress at rest (less than 150 X 10(3) dynes/cm2), but in only 1 of 21 patients with elevated systolic wall stress (p less than 0.001). Peak systolic wall stress at rest varied linearly, and inversely with changes in left ventricular ejection fraction during exercise (r = 0.60, p less than 0.001). Groups I and II did not differ in ejection fraction at rest, clinical symptoms or maximal work load achieved.(ABSTRACT TRUNCATED AT 250 WORDS)

Sustained hemodynamic response to flosequinan in patients with heart failure receiving angiotensin-converting enzyme inhibitors.

OBJECTIVES: We evaluated the short- and long-term effects of flosequinan in 47 patients with severe heart failure despite ongoing captopril treatment. BACKGROUND: There have been no previous evaluations of the long-term hemodynamic effects of any direct-acting vasodilator in patients with heart failure receiving an angiotensin-converting enzyme inhibitor. Flosequinan is an arterial and venous vasodilator with actions similar to those of the hydralazine-isosorbide dinitrate combination. METHODS: After baseline hemodynamic measurements using balloon-tipped pulmonary artery and radial arterial catheters, patients were randomized to receive 50, 100 or 150 mg of flosequinan daily. Hemodynamic variables were measured immediately before and after short-term flosequinan administration and after 8 weeks of therapy. RESULTS: With short-term flosequinan administration, mean arterial, right atrial and left ventricular filling pressures decreased by 6.4 +/- 1.1, 3.8 +/- 0.5 and 7.3 +/- 0.7 mm Hg, respectively (all p < 0.001). Cardiac index increased by 0.5 +/- 0.1 liters/min per m2, systemic vascular resistance decreased by 616 +/- 105 dynes.s.cm-5 and heart rate increased by 4 +/- 1 beats/min (all p < 0.001). After 8 weeks of long-term flosequinan administration, the vasodilator effect of a dose of flosequinan persisted. Compared with pretreatment baseline values, mean arterial, right atrial and left ventricular filling pressures at the peak effect of flosequinan were decreased by 3.5 +/- 1.3, 2.8 +/- 0.7 and 5.1 +/- 1.3 mm Hg, respectively (all p < 0.01). Systemic vascular resistance had decreased by 585 +/- 95 dynes.s.cm-5, cardiac index had increased by 0.5 +/- 0.1 liters/min per m2 and heart rate had increased by 10 +/- 2 beats/min (all p < 0.001). CONCLUSIONS: The arterial and venous vasodilator flosequinan exerts both short- and long-term sustained hemodynamic effects in patients with heart failure receiving angiotensin-converting enzyme inhibitors.

Effect of race in the response to metoprolol in patients with congestive heart failure secondary to idiopathic dilated or ischemic cardiomyopathy.

We sought to determine the effect of race in response to metoprolol in patients with dilated cardiomyopathy. We found no difference in exercise, hemodynamic, and neurohormonal responses to metoprolol based on race in patients with cardiomyopathy.

Hemodynamic effects of renin inhibition by enalkiren in chronic congestive heart failure.

Previous efforts to block the renin-angiotensin system in patients with chronic congestive heart failure (CHF) have focused on 2 distal sites in the system, the angiotensin-converting enzyme and the angiotensin II receptor. Recent work, however, has led to the development of agents that directly inhibit renin, the proximal step in the cascade. In this study, we investigated the hemodynamic effects of renin inhibition in 9 patients with chronic CHF by using enalkiren, a primate-selective, dipeptide renin inhibitor, which has been previously shown to suppress plasma renin activity and to lower blood pressure in hypertensive patients. The acute intravenous administration of enalkiren (1.0 mg/kg) produced increases in cardiac index (2.0 +/- 0.3 to 2.3 +/- 0.1 liter/min/m2) and stroke volume index (26 +/- 3 to 34 +/- 4 ml/m2) and decreases in left ventricular filling pressure (31 +/- 3 to 25 +/- 3 mm Hg), mean right atrial pressure (15 +/- 1 to 13 +/- 2 mm Hg), heart rate (78 +/- 5 to 72 +/- 6 beats/min) and systemic vascular resistance (2,199 +/- 594 to 1,339 +/- 230 dynes.s.cm-5) (all p less than 0.01 to 0.05). These observations indicate that renin inhibition produces hemodynamic benefits in patients with chronic CHF and could potentially provide a novel approach to interfering with the renin-angiotensin system in patients with this disorder.

Effect of oral sotalol on systemic hemodynamics and programmed electrical stimulation in patients with ventricular arrhythmias and structural heart disease.

We explored the central hemodynamic responses to oral sotalol during dose titration in patients with ventricular arrhythmias who underwent programmed ventricular stimulation. Twelve patients were included in the study, 9 with a history of sustained ventricular tachyarrhythmias (6 postmyocardial infarction and 3 with cardiomyopathy) and 3 with a history of nonsustained ventricular tachycardia postmyocardial infarction. Left ventricular ejection fractions were < 45% in 10 patients, and < 35% in 5; the mean ejection fraction was 37% (range 20-51%). Sotalol prevented the induction of ventricular tachycardia in each of 3 patients with nonsustained ventricular tachycardia and in 6 of 9 with sustained ventricular tachycardia at baseline study. At peak action (2 hours) after sotalol loading (mean dose, 167 mg orally twice daily), the hemodynamic effects included bradycardia, decreased cardiac index, increased left ventricular filling pressure and systemic vascular resistance, and no change in stroke volume or stroke work index. One patient was not continued on sotalol, owing to an excessive increase in the pulmonary capillary wedge pressure, despite the lack of symptomatic heart failure. Congestive heart failure in association with marked bradycardia developed in another patient, who had suppression of inducible ventricular tachycardia after sotalol loading; this patient was managed with a reduction in the dose of sotalol and a regimen of digoxin and furosemide, and has been well compensated and without a recurrence of sustained ventricular tachycardia for more than 4 years. Ventricular tachycardia has been controlled with sotalol, without hemodynamic deterioration, in 6 of these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Combined alpha-beta blockade (doxazosin plus metoprolol) compared with beta blockade alone in chronic congestive heart failure.

There has been growing evidence for the benefits of beta blockers, but alpha blockers have not shown sustained benefits in chronic congestive heart failure (CHF). Thirty patients with moderate to severe CHF (New York Heart Association class II to IV) were sequentially assigned to receive metoprolol 6.25 mg with the alpha-1 antagonist doxazosin 4 mg/day or metoprolol alone. The dose of metoprolol was gradually increased to a target dose of 50 mg orally twice daily. Hemodynamic measurements were obtained before drug therapy, 2 hours after the first dose of combined alpha-beta therapy or metoprolol alone, and after 3 months of continuous treatment. Nuclear ejection fraction, plasma norepinephrine, and submaximal and maximal exercise capacity were also measured before and after chronic therapy. With initial combined drug administration, mean arterial pressure, left ventricular filling pressure, and systemic vascular resistance decreased significantly compared with results after metoprolol alone. However, after 3 months of continuous therapy, both treatment groups showed similar and significant reductions in systemic vascular resistance and heart rate, with significant increases in cardiac index, stroke volume index, stroke work index, ejection fraction, and exercise capacity. Furthermore, the next dose of chronic combined medication no longer showed vasodilating effects. Chronic therapy with fixed-dose doxazosin and increasing doses of metoprolol produced identical effects as those seen in patients receiving metoprolol alone.

Noninvasive measurement of cardiac output by an acetylene uptake technique and simultaneous comparison with thermodilution in ICU patients.

A simple, accurate, and noninvasive method of cardiac output measurement can be an extremely useful tool for the clinician and researcher. This study used the acetylene gas uptake technique to measure the absorption of acetylene into the pulmonary circulation during a constant exhalation, which is proportional to the pulmonary capillary blood flow and to the cardiac output, assuming no anatomic shunts. We compared cardiac output measured simultaneously by this and by the standard thermodilution (TD) technique in 21 patients in the ICU with a variety of medical and surgical conditions and a wide range of cardiac outputs. We also compared the two techniques in 19 ambulatory patients with a 2-h interval between the invasive and noninvasive test to assess variability over time. The two tests had an excellent correlation when done simultaneously with a correlation coefficient of 0.89 (p < 0.001). With a 2-h interval between the two tests, the correlation coefficient was 0.66 (p = 0.0018). Nine patients in the simultaneous group had cardiomyopathy. When they were excluded, the correlation coefficient increased to 0.96. Most of these patients had documented tricuspid regurgitation (TR), which may underlie the greater difference between acetylene uptake and TD values, with consistently higher TD values in these patients. This study confirms the correlation between the acetylene uptake and the standard invasive TD techniques in sick patients with various medical and surgical conditions and a wide range of cardiac outputs. Furthermore, we believe this would be a more accurate method for measuring cardiac output in patients with cardiomyopathy and TR because it is based only on pulmonary capillary blood flow.

Safety and efficacy of beta blockade in patients with chronic congestive heart failure awaiting transplantation.

BACKGROUND: Donor availability remains a limiting factor for heart transplantation while transplant waiting time entails significant morbidity and mortality. This study was designed to assess the efficacy and safety of long-term beta blockade as optimization of therapy in patients with severe congestive heart failure already receiving digoxin, diuretics, and converting enzyme inhibitors awaiting transplantation. METHODS: The beta-1 antagonist metoprolol was given to 19 patients with moderate to severe congestive heart failure. Hemodynamic, clinical, and neurohormonal measurements were obtained before drug therapy and after 3 months of treatment. Patients initially received 6.25 mg of metoprolol orally twice daily which was increased to a target dose of 50 mg twice daily over several weeks. RESULTS: Metoprolol produced significant clinical, exercise, and hemodynamic benefits. Long-term therapy was associated with improvements in New York Heart Association class, ejection fraction, 6-minute walk, and peak maximal oxygen consumption. There were significant decreases in heart rate, pulmonary arterial systolic pressure, and left ventricular filling pressure with significant increases in stroke volume index and stroke work index. Four patients were removed from the transplant list after improving to New York Heart Association I. Only one patient required hospitalization during the first 6 months of therapy. There were no deaths caused by progressive heart failure; however, one patient died suddenly. CONCLUSIONS: Beta blockade with metoprolol can be safely administered to patients awaiting heart transplantation producing clinical, exercise, and hemodynamic improvements. Thus, beta blockade may prove to be a safe and cost-effective bridge to transplantation.

Beta blockade in congestive heart failure: persistent adverse haemodynamic effects during chronic treatment with subsequent doses.

OBJECTIVE: To determine whether the acute adverse haemodynamic effects of beta blockade in patients with congestive heart failure persist during chronic treatment. DESIGN: Sequential haemodynamic evaluation of heart failure patients at baseline and after three months of continuous treatment with the beta 1 selective antagonist metoprolol. SETTING: Cardiac care unit in university hospital. PATIENTS: 26 patients with moderate to severe congestive heart failure (New York Heart Association grade II to IV) and background treatment with digoxin, diuretics, and angiotensin converting enzyme inhibitors, and with a left ventricular ejection fraction < 25%. METHODS: Baseline variables included a six minute walk, maximum oxygen consumption, and right heart catheterisation. All patients received metoprolol 6.25 mg orally twice daily initially and the dose was gradually increased to a target of 50 mg twice daily. Haemodynamic measurements were repeated after three months of treatment, both before (trough) and after drug readministration. RESULTS: Long term metoprolol had functional, exercise, and haemodynamic benefits. It produced decreases in heart rate, pulmonary capillary wedge pressure, and systemic vascular resistance, and increases in cardiac index, stroke volume index, and stroke work index. However, when full dose metoprolol was readministered during chronic treatment, there was a reduction in cardiac index (from 2.8 (SD 0.46) to 2.3 (0.38) l/min/m2, p << 0.001) and stroke work index (from 31.4 (11.1) to 26.6 (10.0) g.m/m2, p < 0.001) and an increase in systemic vascular resistance (from 943 (192) to 1160 (219) dyn.s.cm-5, p << 0.001). CONCLUSIONS: Adverse haemodynamic effects of beta blockers in heart failure persist during chronic treatment, as shown by worsening haemodynamic indices with subsequent doses.

New advances in the pharmacological management of chronic heart failure.

The management of heart failure has evolved in parallel with advances in the understanding of the disease process. Inotropes and diuretics are used to combat pump failure and fluid overload. While no convincing data has emerged regarding the long-term safety of inotropes, new exciting data concerning the role of diuretics, especially aldactone, has led to a renewed interest in this class of drug therapy. Angiotensin converting enzyme inhibitors (ACE inhibitors) were noted to not only affect symptomatology but also decrease mortality by interfering with the renin-angiotensin-aldosterone system. Recent research has focused on more complete blockade of the renin-angiotensin system than that achieved with ACE inhibitors alone with the addition of direct angiotensin II receptor blockers. This new class of drugs may become not only a reasonable alternative to ACE inhibitors in patients intolerant of the drug but also a possible addition to ACE inhibitors in the battle to prevent progression of remodelling and disease. beta-blockers are the most exciting new class of drugs used to combat heart failure. They appear not only to combat the remodelling process that occurs in the progression of disease but also other pathological events such as apoptosis and cellular oxidation. New medical therapies currently being investigated include novel agents such as endothelin antagonists, natriuretic peptides, vasopressin antagonists and anticytokine agents--all part of a new era in drug management of heart failure that has evolved with continued advances in the understanding of chronic heart failure (CHF).

The current status of angiotensin converting enzyme inhibitors in the management of patients with chronic heart failure.

Angiotensin converting enzyme (ACE) inhibitors are the only therapeutic agents used in the treatment of chronic heart failure that have been shown to both improve symptoms and prolong life. These agents produce long-term haemodynamic and clinical benefits in about 60-65% of patients. The only reliable means of determining which patients are most likely to respond favourably to treatment is by a therapeutic trial; the response cannot be predicted by demographic factors, pretreatment left ventricular function or plasma renin activity. In addition to their symptomatic benefits, ACE inhibitors reduce the mortality of patients with chronic heart failure, possibly by decreasing ventricular wall stress and decreasing the frequency and complexity of ventricular arrhythmias. The most serious adverse effects of treatment, hypotension, functional renal insufficiency and potassium retention, occur most commonly in patients with the most advanced disease [New York Heart Association (NYHA) class III and IV heart failure] and when efforts are made to block the formation of angiotensin (Ang) II continuously (as with the use of long-acting ACE inhibitors). The unique characteristics of the ACE inhibitors support their use as first-line agents in patients with chronic heart failure.

Are all beta blockers the same for heart failure?

Based on impressive morbidity and mortality data using beta blockers in heart failure, this therapy has now become part of the standard of care for patients with New York Heart Association II/III symptoms. The question remains whether there are clinically relevant differences between the beta blockers that have shown beneficial effects. This review summarizes the major mortality trials, and examines the smaller comparative trials of second and third generation beta blockers.

Beta-blockers and spironolactone in heart failure.

Neurohormonal antagonism is now recognized as an essential treatment modality for heart failure. As a prime example, the benefits of blocking the renin-angiotensin system with angiotensin converting enzyme inhibitors are clearly established for all four New York Heart Association classes. In this clinical trials review, we discuss two other therapies with neurohormonal targets: beta-blockers and the sympathetic nervous system, and the aldosterone antagonist spironolactone.