Selective or nonselective beta-adrenergic blockade in patients with congestive heart failure.

Controlled clinical trials, performed in more than 13,000 patients, have consistently shown the beneficial effects of long-term beta-blocker therapy in patients with chronic heart failure. However, it is not clear whether this is a class effect or if it is specific only for some agents. Beneficial effects on the prognosis of the patients with mild to moderate heart failure have been obtained with metoprolol, bisoprolol, and carvedilol. Metoprolol and bisoprolol are selective for beta(1)-receptors and without ancillary properties, carvedilol, at doses of 25 mg twice daily, blocks beta(1)-, beta(2)-, and a(1)-adrenergic receptors, and has associated antiproliferative and antioxidant activities. These differences are important for the acute hemodynamic effects, but it is still controversial whether they may also influence the long-term effects of therapy. Differently from selective b-blockers, carvedilol blocks all adrenergic receptors, does not upregulate beta1-receptors, decreases cardiac norepinephrine release, and has associated antioxidant effects. These differences may cause a larger increase in left ventricular function, which was significant in some, but not all of the direct comparisons of the two agents. The long-term effects of different beta-blockers on prognosis are currently compared in the Carvedilol or Metoprolol European Trial, in which more than 3000 patients with chronic heart failure have been 1:1 randomized to metoprolol or carvedilol and are going to be followed for more than 2 years.

Differential effects of beta-blockers in patients with heart failure: A prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol.

BACKGROUND: Both metoprolol and carvedilol produce hemodynamic and clinical benefits in patients with chronic heart failure; carvedilol exerts greater antiadrenergic effects than metoprolol, but it is unknown whether this pharmacological difference results in hemodynamic and clinical differences between the 2 drugs. METHODS AND RESULTS: We randomized 150 patients with heart failure (left ventricular ejection fraction

A rationale for the use of beta-blockers as standard treatment for heart failure.

BACKGROUND: Cardiac sympathetic activation is one of the major and earlier changes observed in patients with heart failure. Its relation to the severity of the disease and its independent prognostic value show that it may directly contribute to the progression of heart failure. beta-Blockers are the most effective tool to counteract the untoward effects of sympathetic activation on the cardiovascular system. METHODS AND RESULTS: We reviewed the results of the placebo-controlled, double-blind studies about the effects of beta-blockers in patients with heart failure. These studies have involved almost 10,000 patients to date and have consistently shown that the long-term administration of beta-blockers is associated with a highly significant improvement in both left ventricular function and prognosis of the patients with heart failure. The evidence supporting the use of beta-blockers now equals or even surpasses that of angiotensin-converting enzyme inhibitors; therefore beta-blockers should be considered part of standard therapy. Issues that remain unclarified include the mechanisms through which beta-blockers may improve cardiac function and their tolerability and efficacy in specific groups of patients (such as those with asymptomatic left ventricular dysfunction, severe heart failure, the elderly, or those with left ventricular diastolic dysfunction). It is not currently clear whether the pharmacologic differences between individual beta-blockers are clinically relevant. If they are, the potential for even greater benefit with certain agents exists. It is hoped that these issues will be clarified by the results of ongoing multicenter trials.

[Etiopathogenesis of acute myocardial infarction: role of early leukocytosis]. / Eziopatogenesi dell'infarto miocardico acuto. Ruolo della leucocitosi precoce.

It has recently been suggested that inflammation may play an important role in the pathogenesis of acute ischemic syndromes. It may therefore be important to relate their clinical features with plasma indexes of inflammation. We have studied leukocyte, platelet and fibrinogen blood levels in 57 consecutive patients with acute myocardial infarction admitted to our Intensive Care Unit within 90 min after the onset of chest pain and treated with primary coronary angioplasty. Patients were divided into two groups on the basis of blood leukocyte levels: Group A, 24 patients, 17 males, mean age 54.2 +/- 13.7 years, with high blood leukocytes and Group B, 33 patients, 28 males, mean age 60.9 +/- 10.3 years, with normal blood leukocytes. Group A patients also had higher serum fibrinogen (p = 0.05) and blood platelet levels (p < 0.05). The stenosis observed after guidewire advancement was significant (> 75%) in 33% of the patients with leukocytosis vs 94% of the others (p < 0.01). No difference between the two groups was observed in the success rate of coronary angioplasty and prevalence of stent placement (100 vs 97%, and 43 vs 42% of the patients of Group A and B, respectively). In contrast, a tendency to rethrombosis requiring Rheopro administration was observed in 62% Group A patients vs 21% Group B patients (p < 0.01). In conclusion, the finding of leukocytosis in the acute phase of myocardial infarction suggests that coronary occlusion is mainly caused by a coronary thrombus occurring at the site of a non significant stenosis. In contrast, when blood leukocytes are normal, the underlying coronary stenosis is more often critical and the thrombotic process is less important. The high blood leukocytes, platelet and fibrinogen levels of Group A patients are consistent with a significant role of inflammation in the pathogenesis of the thrombotic process while hemodynamic and local mechanical factors are probably more important in patients with normal blood leukocytes.

Maximal and submaximal exercise testing in heart failure.

Although reduced exercise capacity is the main complaint of patients with congestive heart failure (CHF), the best method to measure it remains controversial. Peak VO2, obtained using maximal exercise testing, is the most accurate measure of maximal functional capacity. It is related to peak exercise cardiac output and is one of the most important independent variables for the prognostic assessment of patients with CHF. It has, however, a low sensitivity for measurement of changes induced by therapy and is poorly related to everyday physical activity, patient symptoms, and quality of life. The anerobic threshold may also be regarded as a parameter of maximal functional capacity. Its value is mainly indirect, because it shows that the patient is performing a maximal effort limited by the cardiovascular system. The VO2 kinetics at the start and at the end of exercise are probably more related to patient symptoms, but it is unresolved which protocols and parameters might best be used to study this aspect of exercise performance. Duration of a submaximal exercise at a constant work rate and the distance walked during a 6-min walking test are gaining wide popularity as parameters of submaximal performance. However, when these exams are carried out up to exhaustion in patients with severe functional limitation, they may involve attainment of the anerobic threshold and therefore their clinical meaning may be similar to the one of a maximal exercise test. Moreover, tests based on the assessment of submaximal exercise capacity have been useful for assessment of therapy in single-center trials but have been often inadequate in multicenter trials.

[The effects of mid- and long-term administration (3-4 years) of carvedilol in patients with idiopathic dilated cardiomyopathy]. / Effetti della somministrazione a medio e lungo termine (3-4 anni) di carvedilolo a pazienti affetti da cardiomiopatia dilatativa idiopatica.

Carvedilol has been shown to determine a significant improvement in left ventricular function, symptoms, clinical course and prognosis of patients with chronic heart failure. However, these results were obtained in medium-term studies of < 1 year duration. We report the results obtained with long-term (3-4 years) carvedilol administration to 40 patients with idiopathic dilated cardiomyopathy who were initially recruited in a 4-month double-blind placebo-controlled trial. In the initial 4-month double-blind trial, 20 patients were randomized to placebo and 20 to carvedilol treatment. All patients, except one who was not on ACE-inhibitors, were on digoxin, furosemide and ACE-inhibitors. Carvedilol or placebo doses were progressively titrated, at weekly intervals, up to the maximal doses of 25 mg bid. After the initial 4-month double-blind phase, all patients were followed long term. Mean follow-up duration was 52 +/- 12 months (range 48-61). Among the 20 patients initially randomized to carvedilol administration, 4 died (3 for cardiac and 1 for extracardiac causes) and 2 underwent heart transplant. Among the 20 patients initially randomized to placebo, 5 died for cardiac causes, 3 underwent heart transplant and 4 were started on carvedilol because of progressive heart failure during the initial 4 months of the study. The remaining 8 patients, who were kept on digoxin, furosemide and ACE-inhibitors, were used as control group. Each patient underwent an assessment of clinical conditions (NYHA functional classification and Minnesota Living with Heart Failure questionnaire), equilibrium radionuclide ventriculography, and maximal cardiopulmonary bicycle exercise testing. Exams were performed before treatment, after 4 and 12 months, and at the end of the follow-up period. No significant difference between the carvedilol and control group was present at baseline. Compared with baseline, patients in the control group presented a significant increase in left ventricular end-diastolic volume after long-term follow-up (from 126 +/- 62 to 138 +/- 43 and 158 +/- 52 ml/m2 after 12 and 48 months, respectively). No significant difference, compared to baseline values, was noted. Patients on carvedilol presented a persistent improvement in left ventricular function. This was shown by the progressive increment in left ventricular ejection fraction from 22 +/- 6 to 34 +/- 11, 37 +/- 11 and 37 +/- 13%, after 4, 12 and 48 months, respectively (p < 0.001) with a concomitant reduction in left ventricular end-diastolic volume from 147 +/- 54 to 101 +/- 44 ml/m2 at the end of the follow-up (p < 0.05). NYHA functional class remained significantly improved, in comparison with baseline (2.6 +/- 0.5 to 1.9 +/- 0.3, 1.9 +/- 0.8 and 2.0 +/- 1.0 after 4, 12 and 48 months, respectively; p < 0.01). Maximal functional capacity, assessed as peak VO2 was not significantly changed after 4 months (from 15.2 +/- 3.6 to 16.4 +/- 4.0 ml/kg/min) and showed a tendency towards a further improvement after 12 months and at the end of the follow-up (17.3 +/- 5.6 and 17.2 +/- 5.3 ml/kg/min, respectively). These results show that the favorable effects of carvedilol administration on left ventricular function and clinical symptoms are maintained also after long-term treatment.