Rationale, design, and methods for a Coreg (carvedilol) Heart Failure Registry (COHERE). COHERE Participant Physicians.

BACKGROUND: The success of beta-blocking agents in clinical trials of heart failure (HF) has led to a widespread call for their increased use, which assumes these agents will perform as well in the usual care setting. Given the traditional contraindication of the use of beta-blocking agents in HF, and their perception as difficult to use in HF, observing how they perform in the usual care setting could be critical in accelerating their widespread application. Carvedilol is the only beta-blocking agent currently approved in the United States for use in HF. METHODS: The Coreg (brand of carvedilol; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) Heart Failure Registry (COHERE) is intended to collect data on outcomes and other clinical variables in a typical HF population and to observe experience with carvedilol in the hands of community practitioners. COHERE does not include any specific patient selection or exclusion criteria. The decision to use carvedilol is entirely at the discretion of the participant physician, based on evidence of HF as judged by assessments the practitioner usually uses. All patients will be followed for 1 year, with information on outcomes and other clinical variables collected and analyzed at baseline, the end of titration, and at 6 and 12 months after reaching the maximum tolerated dose. About 600 participant physicians selected to be as representative as possible of the community practice setting will enroll approximately 6,000 patients. CONCLUSIONS: COHERE will be the first and largest prospective observational experience with a new treatment, ie, carvedilol, in patients with HF managed in the usual care setting and should provide valuable information about this new treatment in this environment compared with the more rigid clinical trials setting.

Beta-adrenergic blocking agents: past, present, and future perspectives.

The 'proof of concept' of beta-blockade for heart failure (i.e. that the pharmacologic actions of beta-blockers are beneficial) is now firmly established, as the treatment of heart failure has progressed from using positive inotropic stimulation, via drugs with no direct effect on cardiac function, to beta-blockers with negative intropic effects. This review addresses some remaining issues regarding beta-blockade in heart failure. The mechanism of action of beta-blockers in heart failure is more likely to be improved intrinsic cardiac myocyte function and prevention or reversal of remodeling, than restoration of beta-adrenergic signal transduction. The role of the differentiating characteristics of beta-blockers is not clear at this time, and there is no compelling evidence to select one agent over another on the basis of individual drug properties. Recent reports suggest that beta-blockers reduce the combined risk of all-cause mortality and hospitalizations by about 30-35%. These results are heavily influenced by experience with carvedilol, but other agents tested include metoprolol, bucindolol, bisoprolol, and nebivolol. Responsiveness to beta-blockers is not related to patients' age, sex, or race, or to the etiology or severity of heart failure. Beta-blockers are currently recommended as adjunctive treatment in patients who remain mildly to moderately symptomatic while receiving added digitalis, diuretics, and angiotensin-converting enzyme inhibitors. Existing gaps in our knowledge must be filled in order to achieve optimal clinical application of beta-blockers. Ongoing studies will provide much of the information required. The role of beta-blockers will probably expand as we improve our understanding of the pathophysiology of heart failure, and especially of the remodeling process.

Commentary on the use of run-in periods in clinical trials.

Concerns have been raised about the applicability of clinicals trials to the so-called "real world" setting of clinical practice when such trials employ run-in periods. In fact, run-in periods are an essential part of good medical practice, and the limited practical applicability of clinical trial results relates more to their rigid artificial protocol setting.

Acute hemodynamic effects of norepinephrine inhibition in patients with severe chronic congestive heart failure.

The pathophysiologic role of high levels of circulating catecholamines in patients with congestive heart failure remains unclear. To assess the hemodynamic contribution of circulating catecholamines, metyrosine (alpha-methyl-p-tyrosine), an inhibitor of catecholamine synthesis, was administered to nine patients with acutely decompensated chronic congestive heart failure. Baseline left ventricular ejection fraction averaged 23.3 +/- 9.9%, whereas cardiac output averaged 3.69 +/- 1.03 liters/min, with a pulmonary wedge pressure of 27.4 +/- 8.5 mm Hg. After 48 h of metyrosine administration, plasma norepinephrine concentration decreased from 919.4 +/- 810.6 to 335.4 +/- 143.1 pg/ml (p less than 0.05). Plasma epinephrine concentration averaged 176.4 +/- 166.0 pg/ml at baseline, and was unchanged during metyrosine administration. Despite the significant decrease in circulating norepinephrine, no significant hemodynamic changes were observed during metyrosine administration. These results suggest that high levels of circulating norepinephrine may be more a marker of severe congestive heart failure than an important contributor to the underlying pathophysiology at this advanced stage of the disease process.

Beta-receptor-active agents: role of partial agonists in patients with heart failure.

Current heart failure therapy has included both stimulation and inhibition of beta-adrenergic receptors. Full beta-agonists have not been clinically effective because of side effects or loss of efficacy over the long term. Full beta-antagonists are effective in selected patients but are not tolerated in others because of cardiac depression. Partial beta-antagonists (beta-blockers with weak intrinsic sympathomimetic activity) do not possess sufficient agonist activity to counteract their own cardiac depressant action. Partial beta-agonists produce mild beta-antagonism, but not enough to offset their overall cardiac stimulating property. The partial beta-agonists have been clinically effective in some patients with heart failure and appear to be a potentially useful and unique class of agents because of their ability to modulate cardiac beta-receptors in such a way as to avoid an excessive response to endogenous or exogenous stimuli.

Application of noninvasive techniques for measuring cardiac output in hypertensive patients.

The hemodynamic hallmark of hypertension is increased systemic vascular resistance, although this variable is usually not determined in hypertensive patients because it has generally required invasive procedures to measure cardiac output. Reliable, totally noninvasive methods are now available that measure cardiac output accurately enough under a variety of conditions, including rest, exercise, and pharmacologic interventions. These methods include echocardiography, Doppler echocardiography, CO2 rebreathing, and impedance cardiography. Their serial application to large numbers of patients offers the opportunity to significantly broaden our understanding of the spectrum and course of hemodynamic alterations associated with hypertension. A more complete knowledge of underlying hemodynamics could improve our diagnostic and prognostic accuracy in hypertensive patients and enhance our understanding of the pathophysiology of hypertension and the mechanism of action of antihypertensive interventions.

Percutaneous transluminal coronary angioplasty of one vessel for refractory unstable angina pectoris: efficacy in single and multivessel disease.

Forty patients with unstable angina refractory to medical treatment had one vessel percutaneous transluminal angioplasty to the most stenotic lesion in a major coronary artery. The procedure was successful in 35 patients, and the remaining five patients underwent emergency coronary artery bypass graft surgery. The initial success rate (84%) for the 16 patients with single or the 19 patients with multivessel disease (90%) was similar. At early follow up (average nine days) all patients with successful angioplasty remained symptomatically improved; 10 patients (83%) with single and 10 patients (63%) with multivessel disease had negative treadmill stress tests. Five of six cardiac events occurred within the intermediate (average 11 months) follow up period; two patients had recurrent refractory unstable angina, two had angioplasty for progression of disease in a vessel not previously treated by angioplasty, and one had bypass graft surgery. During late (average 26 months) follow up one patient had a non-fatal myocardial infarction while seven patients (58%) with single vessel disease and nine patients (75%) with multivessel disease had negative stress tests; 29 of 40 patients showed long term improvement.

Vasodilators for heart failure--useful or useless?

Vasodilators have gained widespread acceptance in the management of congestive heart failure. They produce prompt hemodynamic and clinical improvement in acute left ventricular failure, and in chronic congestive heart failure they also improve symptoms, functional capacity, and survival. This efficacy, however, is limited to those vasodilators which have venodilating ability, such as nitrates and angiotensin-converting enzyme inhibitors, when they are added to digitalis and diuretics in patients with moderate to severe heart failure. The utility of vasodilators without digitalis or diuretics requires further evaluation. The potential for vasodilators to prevent the development or progression of heart failure from latent to clinically overt disease is also being evaluated.

Why patients with heart failure die: hemodynamic and functional determinants of survival.

The high mortality of heart failure is associated with hemodynamic abnormalities, depressed cardiac function, and reduced exercise capacity. That these factors can be modified by drug treatment is of potential prognostic significance. Hemodynamic variables are related to survival, and long-term prognosis is better in patients with only midly abnormal cardiac output or ventricular filling pressures. Indexes of left ventricular function such as ejection or shortening fraction tend to be higher in patients who survive for longer periods. The relation between exercise capacity and survival, however, is unclear. Those patients with severe exercise intolerance (maximal oxygen uptake below 10 ml/min/kg) or with severe symptoms are at great risk of dying. However, exercise capacity and functional class are not related to prognosis when all classes of patients are considered together, especially if class IV patients are excluded. Most of the available data derive from retrospective analyses of trials involving heterogeneous patient populations and aimed at improving left ventricular performance or functional capacity. Large prospective trials aimed primarily at affecting mortality in a broad spectrum of patients are needed to learn more about determinants of survival in heart failure.

Veterans Administration Cooperative Study on Vasodilator Therapy of Heart Failure: influence of prerandomization variables on the reduction of mortality by treatment with hydralazine and isosorbide dinitrate.

The Veterans Administration Cooperative Study on Vasodilator Therapy of Heart Failure was designed to determine whether vasodilator drugs could alter the survival of patients with chronic congestive heart failure treated with digoxin and diuretics. Among the 642 patients entered into the study, 273 were randomly assigned to placebo, 186 were randomly assigned to the combination of hydralazine and isosorbide dinitrate, and 183 patients were randomly assigned to prazosin; all patients were followed for periods ranging from 6 months to 5.7 years. Treatment with hydralazine-nitrate produced a 28% reduction in mortality compared with that in patients receiving placebo (95% confidence interval, 3% to 46%), whereas prazosin exerted no apparent beneficial effect. Data were further examined to determine if any baseline variables had an impact on the response to treatment. Mortality in the placebo group was higher in those with coronary artery disease, with a history of antiarrhythmic drug use, and with values lower than the median for ejection fraction and exercise tolerance. A reduction in mortality with hydralazine-isosorbide dinitrate was observed in all of the above pairs of subgroups as well as in those above and below 60 years of age and those with and without a history of hypertension or excess alcohol ingestion. The benefit of hydralazine and isosorbide dinitrate was particularly prominent in younger patients with a lower ejection fraction and those with a history of hypertension and without an alcoholic history.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of the left ventricle on the right ventricle.

The importance of the once-obscure right ventricle is becoming evident. Even in disorders that primarily affect the left ventricle, the once-considered-passive conduit has proved essential for maintenance of normal cardiac output. In coronary artery disease, the function of the right ventricle is affected by both its circulation and the after-load placed on it by dysfunction of the left ventricle. In congestive heart failure, right ventricular function relates to functional capacity, whereas left ventricular function does not, and right ventricular ejection fraction is a useful prognostic guide in these patients. In mitral and aortic valvular disease, the role of the right ventricle is only now becoming evident, and the precise interplay of all factors has yet to be explained. In systemic hypertension, it is likely that the pulmonary circulation is affected by the same humoral factors that elevate systemic pressures.

Intracoronary prostaglandin E1 plus streptokinase in acute myocardial infarction.

Fourteen patients with acute myocardial infarction (duration of chest pain 5 +/- 2 hours) received intracoronary infusion of prostaglandin E1 (PGE1) and streptokinase. Intracoronary PGE1 was followed by intracoronary streptokinase in 10 patients (group A), with successful recanalization in all patients. Of 4 patients in whom recanalization failed with intracoronary streptokinase given first (group B), 2 had successful recanalization after addition of intracoronary PGE1. Immediately after successful recanalization, left ventricular ejection fraction increased from 50 +/- 9% to 62 +/- 10% (p less than 0.0008), left ventricular end-diastolic pressure decreased from 20 +/- 10 to 16 +/- 10 mm Hg (p less than 0.05) and stroke volume index increased from 34 +/- 10 to 44 +/- 12 ml/m2 (p less than 0.02). Infarct segment shortening improved from 9 +/- 5 to 18 +/- 4% (p less than 0.0002). Transient hypotension in 1 patient was the only complication. Follow-up catheterization in recanalized patients at 2 to 10 days showed maintained improvement in left ventricular global and infarct segment function. Reocclusion occurred in 1 patient. Thus, intracoronary infusion of PGE1 was effective in establishing reperfusion in all patients when followed by streptokinase and was associated with immediately improved left ventricular global and regional function. PGE1 deserves further evaluation in acute myocardial infarction.

Indoramin in heart failure: possible adverse effects on hemodynamics and exercise capacity.

Indoramin is an alpha 1-adrenergic antagonist vasodilator of potential value in heart failure. We measured hemodynamics and exercise capacity in 12 patients with heart failure, before and after 1 week of indoramin dosing, 75 mg b.i.d. Maximal hemodynamic effects 2 hours after the first dose of indoramin consisted of reduced mean systemic arterial pressure from 96.0 +/- 15.3 to 87.9 +/- 15.3 mm Hg (P less than 0.05) and pulmonary wedge pressure from 23.6 +/- 7.8 to 16.9 +/- 6.6 mm Hg (P less than 0.001). Heart rate, cardiac index, and total systemic resistance did not change acutely after indoramin, but after 1 week mean systemic arterial pressure was still reduced whereas cardiac index fell from 2.69 +/- 0.38 to 2.32 +/- 0.44 L/min/m2 (P less than 0.05) and total systemic resistance rose from 20.4 +/- 2.8 to 21.9 +/- 4.0 U (P less than 0.1). After 1 week maximal exercise oxygen uptake fell from 16.8 +/- 5.6 to 12.5 +/- 3.5 ml/min/kg (P less than 0.02). This limited observation suggests that indoramin is a predominant venodilator acutely in patients with heart failure but that despite this effect it may worsen functional capacity and hemodynamics during continuous dosing in these patients.

Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study.

To evaluate the effects of vasodilator therapy on mortality among patients with chronic congestive heart failure, we randomly assigned 642 men with impaired cardiac function and reduced exercise tolerance who were taking digoxin and a diuretic to receive additional double-blind treatment with placebo, prazosin (20 mg per day), or the combination of hydralazine (300 mg per day) and isosorbide dinitrate (160 mg per day). Follow-up averaged 2.3 years (range, 6 months to 5.7 years). Mortality over the entire follow-up period was lower in the group that received hydralazine and isosorbide dinitrate than in the placebo group. This difference was of borderline statistical significance. For mortality by two years, a major end point specified in the protocol, the risk reduction among patients treated with both hydralazine and isosorbide dinitrate was 34 percent (P less than 0.028). The cumulative mortality rates at two years were 25.6 percent in the hydralazine--isosorbide dinitrate group and 34.3 percent in the placebo group; at three years, the mortality rate was 36.2 percent versus 46.9 percent. The mortality-risk reduction in the group treated with hydralazine and isosorbide dinitrate was 36 percent by three years. The mortality in the prazosin group was similar to that in the placebo group. Left ventricular ejection fraction (measured sequentially) rose significantly at eight weeks and at one year in the group treated with hydralazine and isosorbide dinitrate but not in the placebo or prazosin groups. Our data suggest that the addition of hydralazine and isosorbide dinitrate to the therapeutic regimen of digoxin and diuretics in patients with chronic congestive heart failure can have a favorable effect on left ventricular function and mortality.

Predictive value of M-mode echocardiography in patients with congestive heart failure.

The M-mode echocardiogram (ECHO) is widely used to follow patients with congestive heart failure (CHF), but the value of ECHO for this purpose is unclear. In 49 patients with symptomatic CHF, we obtained ECHO during baseline evaluation to determine the value of ECHO for predicting 1-year survival or maximal oxygen uptake during exercise (VOmax). The cause of CHF was coronary artery disease in 12 patients and idiopathic dilated cardiomyopathy in 37 patients. Overall mortality at 1 year was 10 of 49 (20%), but was higher in patients with coronary artery disease (42%) compared to those with idiopathic dilated cardiomyopathy (14%), p less than 0.001. ECHO indices of left ventricular contractility were greater in survivors (S) in whom shortening fraction averaged 16 +/- 8 (SD)% vs 10 +/- 4% in nonsurvivors (NOS), p less than 0.025. Velocity of circumferential fiber shortening averaged 0.53 +/- 0.25 Hz in S vs 0.35 +/- 0.15 Hz in NOS, p less than 0.05. No left ventricular dimensions, including systolic and diastolic diameters, volume, wall thickness, and mass differed significantly between S and NOS. No ECHO measure of left ventricular dimensions or contractility correlated significantly with VOmax. Thus, ECHO may be useful to predict survival but not functional capacity in patients with CHF.

Epidemiologic patterns, clinical evaluation, and long-term prognosis in chronic congestive heart failure.

Congestive heart failure affects more than 2,000,000 Americans and is likely to increase in prevalence as our population ages. Clinical congestive heart failure should not be equated with cardiac dysfunction, as indexes of cardiac performance do not correlate with clinical manifestations. The clinical signs and symptoms of heart failure often lack sufficient sensitivity and specificity to permit accurate diagnosis. Objective tests, such as echocardiography and radionuclide angiography, are usually needed to establish the presence of left ventricular dysfunction, and exercise testing may be needed to quantitate symptomatic severity. Indexes of cardiac function do not correlate well with symptomatic status, and clinical assessment of severity of symptoms is often inaccurate. Therefore, exercise testing may be very useful in assessing symptomatic severity and in following patient progress. Prognosis in heart failure is very poor, with fewer than 50 percent of patients surviving five years from the time of initial diagnosis. Survival appears to relate more to the degree of cardiac dysfunction and less to the degree of symptomatic severity. Early recognition of heart failure in a latent stage and development of strategies aimed at preventing or delaying the onset of overt heart failure appear to offer the best chance of reducing mortality from heart failure.