Efficacy of felodipine in chronic congestive heart failure: a placebo controlled haemodynamic study at rest and during exercise and orthostatic stress.

A vascular selective calcium antagonist, felodipine, was evaluated in a randomised, double blind, crossover trial in 18 patients with chronic congestive heart failure of ischaemic cause. Felodipine (10 mg twice daily) or a corresponding placebo was added to conventional treatment. After three weeks haemodynamic function was assessed at rest, during a standard supine leg exercise, and during 45 degrees passive upright tilt. In patients in the supine resting position, felodipine reduced the mean arterial pressure (9%) and systemic vascular resistance (24%) and increased the stroke volume (25%) and cardiac index (23%). The heart rate and right and left ventricular filling pressures were unchanged. During felodipine treatment the standard exercise was accomplished at a similar cardiac index but at a substantially lower heart rate (7%), arterial pressure (10%), systemic vascular resistance (17%), and left ventricular filling pressure (19%), and a higher stroke volume (13%). During both placebo and felodipine administration there were substantial reductions in cardiac filling pressure during upright tilting. Upright tilting during the placebo phase did not increase the heart rate. It also caused a greater fall in systemic vascular resistance while the arterial pulse pressure but not the mean pressure was maintained and the cardiac index and stroke volume increased. The reduced cardiac filling pressures during the felodipine upright tilt were accompanied by reductions in arterial pulse pressure and stroke volume and the patients were able to maintain the mean arterial pressure by an increase in both the heart rate and systemic vascular resistance. Thus three weeks treatment with felodipine improved haemodynamic function at rest and during standard exercise and normalised the baroreflex mediated haemodynamic response in patients with congestive heart failure. The haemodynamic efficacy of the drug in such patients may be associated with a baroreceptor mediated effect as well as direct vasodilatation.     

Restoration of normal reflex responses to orthostatic stress during felodipine therapy in congestive heart failure

The mechanisms underlying the abnormal responses to orthostatic stress in congestive heart failure are ill defined and little is known about the effects of specific therapy. In the present study intravascular pressures and plasma noradrenaline levels were measured in nine patients with heart failure subjected to 45 degrees and 90 degrees upright tilt. Studies were repeated during 4 weeks of vasodilator therapy with felodipine and again after felodipine withdrawal. Before the introduction of vasodilator therapy, tilt did not activate orthostatic reflexes despite significant reductions in left ventricular filling pressure and cardiac output. Thus, plasma noradrenaline, heart rate and systemic vascular resistance were unaffected and blood pressure fell. Felodipine resulted in a rapid and sustained improvement in left ventricular function but restoration of orthostatic reflexes was delayed and could be detected only after 48 h therapy. At this time, and during the subsequent 4 weeks, tilt-induced reductions in ventricular filling and cardiac output produced a normal rise in plasma noradrenaline and heart rate. A postural drop in blood pressure, however, was not averted because the direct action of felodipine on vascular smooth muscle prevented adrenergically-mediated increments in systemic vascular resistance. Felodipine withdrawal led to a prompt deterioration in left ventricular function. Orthostatic reflexes, however, were still intact 48 h later when tilt elicited a completely normal pattern of responses. These observations confirm that the abnormal responses to orthostatic stress in congestive heart failure are due principally to impairment of autonomic control mechanisms and are not related to the absence of venous pooling. Importantly the autonomic dysfunction is reversible with felodipine therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy of felodipine in congestive heart failure

The efficacy of felodipine, a vasodilating calcium antagonist, was analysed in 23 patients with congestive heart failure, New York Heart Association class III, during an 8-week, double-blind, randomized, placebo-controlled, parallel study. After felodipine, exercise duration increased significantly without changes in oxygen consumption. Heart rate, arterial pressures and rate pressure product decreased at similar submaximal exercise levels. Invasive haemodynamics before and after 8 weeks of therapy revealed arterial vasodilation without reflex tachycardia and no significant reduction in right atrial, pulmonary and capillary wedge pressures. Subjective symptom scores improved and side-effects were minor. Fluid retention, as assessed by body weight and ankle circumference did not occur. Felodipine has a beneficial effect in patients with moderately severe heart failure. Further research is necessary to demonstrate its long-term efficacy and safety.     

Acute haemodynamic and metabolic effects of felodipine in congestive heart failure.

Felodipine is a new calcium antagonist with a high degree of vascular selectivity. To examine its potential value as an afterload reducing agent in congestive heart failure 11 patients were studied. Substantial increments in cardiac index were associated with a fall in systemic vascular resistance. Left ventricular end diastolic pressure was also significantly reduced. Although left ventricular maximum dP/dt remained unchanged, maximum dP/dt/P increased. Left ventricular unloading was reflected by a reduction in cavity dimensions and a shift in the relation between end systolic pressure and dimension downwards and to the left. The myocardial oxygen supply to demand ratio was also improved: coronary sinus flow increased significantly despite a decline in myocardial oxygen consumption. These beneficial haemodynamic and metabolic effects suggest that felodipine may extend the clinical application of calcium antagonists to include the treatment of congestive heart failure.     

Characterization of lymphocyte beta-adrenergic receptors at rest and during exercise in ambulatory patients with chronic congestive heart failure

To investigate beta-adrenergic receptor dysfunction in congestive heart failure (CHF), the density of lymphocyte beta receptors and adenylate cyclase activity was measured at rest and at peak exercise in 30 patients with CHF and 7 age-matched control subjects. At rest, patients with CHF had reduced beta-receptor density (normals 33 +/- 2; CHF 21 +/- 2 fmol/mg protein; p less than 0.01) and isoproterenol-stimulated adenylate cyclase activity (normals 50 +/- 9; CHF 28 +/- 4 pmol/mg protein/min; p less than 0.05). Sodium fluoride-stimulated adenylate cyclase activity was also reduced (normals 98 +/- 17; CHF 48 +/- 12 pmol/mg protein/min; p less than 0.01). In the patients with CHF, there was no significant correlation between receptor density and peak exercise VO2, ejection fraction or resting plasma catecholamines. In the normal subjects, maximal exercise increased beta-receptor density by 100% (rest 33 +/- 2; exercise 67 +/- 7 fmol/mg protein) and isoproterenol-stimulated adenylate cyclase activity by 66% (rest 50 +/- 9; exercise 83 +/- 18 pmol/mg protein/min (both p less than 0.01]. In contrast, patients with CHF exhibited only a 58% increase in beta-receptor density (rest 20 +/- 3; exercise 32 +/- 6 fmol/mg protein; p less than 0.01) and no significant change in isoproterenol-stimulated adenylate cyclase activity (rest 27 +/- 5; exercise 24 +/- 5 pmol/mg protein/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of vasodilator treatment with felodipine on haemodynamic responses to treadmill exercise in congestive heart failure

Treatment with vasodilators in heart failure has not always produced a useful improvement in the haemodynamic responses to exercise, and in many cases early drug tolerance has further limited the potential of this type of treatment. In a study to evaluate the efficacy of felodipine, a new calcium antagonist with selective vasodilator properties, in the management of congestive heart failure 10 patients with congestive heart failure underwent treadmill exercise testing before and during oral treatment with felodipine 30 mg daily. At every level of exercise felodipine lowered the pulmonary capillary wedge pressure, whereas cardiac index and stroke index increased considerably. The haemodynamic improvement was associated with an increase in the duration of exercise to exhaustion. Importantly, these beneficial effects were sustained throughout four weeks of treatment without evidence of drug tolerance. These observations suggest a useful role for felodipine in the long term management of congestive heart failure.     

Effects of vasodilator treatment with felodipine on haemodynamic responses to treadmill exercise in congestive heart failure.

Treatment with vasodilators in heart failure has not always produced a useful improvement in the haemodynamic responses to exercise, and in many cases early drug tolerance has further limited the potential of this type of treatment. In a study to evaluate the efficacy of felodipine, a new calcium antagonist with selective vasodilator properties, in the management of congestive heart failure 10 patients with congestive heart failure underwent treadmill exercise testing before and during oral treatment with felodipine 30 mg daily. At every level of exercise felodipine lowered the pulmonary capillary wedge pressure, whereas cardiac index and stroke index increased considerably. The haemodynamic improvement was associated with an increase in the duration of exercise to exhaustion. Importantly, these beneficial effects were sustained throughout four weeks of treatment without evidence of drug tolerance. These observations suggest a useful role for felodipine in the long term management of congestive heart failure.     

Effect of nicardipine on rest and exercise hemodynamics in chronic congestive heart failure

The hemodynamic response to vasodilation induced by the new calcium channel antagonist nicardipine was studied in 10 patients with severe, chronic congestive heart failure. Rest and exercise hemodynamics were evaluated in the baseline state and after 1 week of oral nicardipine therapy (30 mg 3 times daily). In addition, respiratory gas exchange and arteriovenous oxygen difference were measured to assess changes in oxygen utilization. The responses of the sympathetic nervous system were evaluated by measuring plasma norepinephrine concentrations at rest and during maximal exercise. At rest, nicardipine administration was associated with significant reductions in mean systemic arterial pressure, systemic vascular resistance, pulmonary artery wedge pressure and pulmonary arterial pressure, and significant increases in cardiac index and stroke volume index. These effects were maintained during exercise. In contrast to findings with other calcium channel antagonists, no negative inotropic effect of nicardipine was identified. Nicardipine administration was associated with reduction of arteriovenous oxygen difference. Nicardipine had no effect on plasma norepinephrine concentrations, suggesting absence of reflex sympathetic nervous activation. Thus, nicardipine-mediated vasodilation leads to significant improvements in both rest and exercise cardiac performance.     

Acute and chronic efficacy of felodipine in congestive heart failure

In 13 patients with congestive heart failure we tested the acute hemodynamic effects of 5 vs. 10 mg felodipine tablets, in a double-blind, cross-over study. One hour after felodipine 5 mg, echocardiographic ejection fraction (%), cardiac index (thermodilution-ml/min/m2), and pulmonary wedge pressure (mm Hg) significantly changed (from 21 +/- 2 to 26 +/- 2, 2350 +/- 150 to 2790 +/- 160, 24 +/- 4 to 17 +/- 4) while they remained steady after felodipine 10 mg. The greatest stroke index increases were associated with felodipine 5 mg in 12 patients and 10 mg in 1 patient. Therefore we evaluated (open study) the long-term (2 months- 1 year) clinical and hemodynamic efficacy following the treatment with the acutely most effective dose (twice daily). After 2 months ejection fraction, cardiac index and pulmonary wedge pressure were respectively 24 +/- 2, 2550 +/- 150, and 18 +/- 4 (12 hours after the last drug administration, n = 11, P less than 0.02 from baseline). These parameters further increased one to two hours after the following administration of felodipine. Clinical improvement (reduction of 1 functional class, according to the New York Heart Association) was observed in 8/13 patients. These 8 patients participated to the one year follow-up. In 5 patients follow-up was interrupted because of acute cardiovascular events. However, before study interruption (5 patients) or ending (3 patients) clinical status did not worsen and ejection fraction remained higher than in the pretreatment period. Therefore, low dose felodipine might be used in the treatment of congestive heart failure.     

Hemodynamic effects of alinidine (ST 567) at rest and during exercise in patients with chronic congestive heart failure

Selective inhibition of sinus node function offers the possibility to decrease heart rate and reduce myocardial oxygen consumption in patients with impaired cardiac function, if myocardial contractility is not further attenuated. To study the influence of a specific sinus node inhibitor on myocardial function, alinidine was given to 10 patients with chronic congestive heart failure and stable sinus rhythm. Radionuclide ventriculography was used to monitor left ventricular function at rest and during a standardized exercise protocol. After a bolus injection of 45 mg of alinidine followed by infusion of 10 mg/hr, radionuclide studies were repeated 1.5 and 3 hours later. The results show that left ventricular ejection fraction, stroke volume, and end-diastolic volume index were essentially unchanged, whereas cardiac index decreased by 10% at rest and during exercise. Heart rate decreased markedly by 14% at rest and by 13% during exercise. Systolic blood pressure was reduced by 6% at rest and by 14% during exercise. As a result of the marked decrease of these two parameters, a pronounced effect was seen on rate-pressure product with a 19% decrease at rest and a 24% decrease during exercise. No significant side effects were observed. Alinidine might be given to patients with chronic congestive heart failure and sinus rhythm in doses up to 45 mg without exerting a clinically relevant negative inotropic effect. Therefore it may represent an alternative to other drugs when a decrease in heart rate is desired to reduce myocardial oxygen consumption.     

非洛地平缓释片治疗慢性心功能不全的临床观察

目的：评价非洛地平治疗慢性心功能不全的疗效与安全性。方法：采用随机对照的方法,将80例慢性心功能不全患者随机分为对照组与治疗组,对照组以洋地黄、利尿剂及血管紧张素转换酶抑制剂等类药物治疗,治疗组在对照组治疗基础上加用非洛地平缓释片2．5～5．0mg/d。比较两组左室射血分数(LVEF)、左室舒张末期内径(LVDd)、尿常规、电解质、肝肾功能、血压、心率等指标。结果：治疗4周后两组心功能均有显著改善,血压、心率、LVDd降低,LVEF升高,治疗前后比较,有显著性差异(P＜0．05)；与对照组相比治疗组收缩压下降,LVEF升高的幅度更显著(P＜0．01)。两组患者在治疗期间尿常规、电解质及肝肾功能均无明显改变。结论：治疗剂量的非洛地平是治疗慢性心功能不全较为理想的药物。     

非洛地平缓释片治疗慢性心功能不全的临床观察

目的:评价非洛地平治疗慢性心功能不全的疗效与安全性.方法:采用随机对照的方法,将80例慢性心功能不全患者随机分为对照组与治疗组,对照组以洋地黄、利尿剂及血管紧张素转换酶抑制剂等类药物治疗,治疗组在对照组治疗基础上加用非洛地平缓释片2.5～5.0mg/d.比较两组左室射血分数(LVEF)、左室舒张末期内径(LVDd)、尿常规、电解质、肝肾功能、血压、心率等指标.结果:治疗4周后两组心功能均有显著改善,血压、心率、LVDd降低,LVEF升高,治疗前后比较,有显著性差异(P＜0.05);与对照组相比治疗组收缩压下降,LVEF升高的幅度更显著(P＜0.01).两组患者在治疗期间尿常规、电解质及肝肾功能均无明显改变.结论:治疗剂量的非洛地平是治疗慢性心功能不全较为理想的药物.     

Efficacy of oral propafenone in chronic ventricular arrhythmias: a placebo controlled cross-over exercise study

The efficacy of propafenone, a new class I C antiarrhythmic drug, on ventricular premature contractions (VPCs) during rest and exercise was assessed during a two-phase protocol: phase 1, an initial two week placebo controlled double blind cross-over assessment; phase 2, an open 3 month follow-up. Twelve consecutive patients with symptomatic chronic ventricular arrhythmias and fulfilling other inclusion criteria underwent an exercise test and were allocated to either propafenone or placebo. During the double blind phase, oral propafenone significantly reduced the number of VPCs at rest with the patient supine or sitting, during the bicycle ergometer test, and after the exercise test. After 3 months of treatment a 90 to 100% reduction of VPCs was achieved in 11 patients continuing on 600 to 900 mg of propafenone daily. Treatment was stopped in one patient during the double blind phase because of drug induced LBBB. A prolongation of the PR interval and QRS duration occurred in all patients with propafenone doses exceeding 450 mg day-1. Subjective side effects were slight and consisted of abnormal taste sensations and minor central nervous symptoms. The results suggest that propafenone is an effective drug for the treatment of ventricular arrhythmias in selected patients. A-V or intraventricular conduction disturbances contraindicate its use.     

Chrome congestive heart failure: Non-invasive measurement of cardiac output by a carbon dioxide rebreathing method at rest and during exercise

Cardiac output was measured in 11 patients undergoing routinecardiac catheterization using a carbon dioxide rebreathing techniqueand compared with cardiac output measured by direct Fick andthermodilution. The carbon dioxide rebreathing technique gaveconsistently lower values for cardiac output than the othertwo methods (mean difference –0·73, 95% CI –0·95to–0·511. min^–1 with the direct Fick and–0·72. 95% CI –1·19 to –0·261.min^–1 with thermodilution). The direct Fick and thermodilutionmethods gave similar results (mean dtfference –0·08,95% CI –0·32 to 0·16a. min^–1). Cardiacoutput was also measured in 10 healthy subjects at rest andduring two steady-state levels of exercise using the carbondioxide rebreathing technique. Measurements were made in triplicateon 3 separate days. The technique gave reproducible resultsbetween replicates at rest (coefficient of variation 91%) andbecame more reproducible on exercise (coefficients of variation56% and 54% respectively at each exercise level). There wasa good correlation between cardiac output and oxygen consumption(r=0·98 The carbon dioxide rebreathing technique is afeasible non-invasive way of measuring cardiac output. It tendsto underestimate cardiac output at rest but is reproducibleand becomes more so on exercise which is where it should beof most value.     

Haemodynamic effects of hydralazine at rest and during exercise in patients with chronic heart failure.

The administration of vasodilator drugs has been shown to have beneficial effects at rest in patients with acute or chronic heart failure. To determine the efficacy of hydralazine during exercise, 10 severely symptomatic patients with chronic left ventricular failure from diffuse coronary disease or cardiomyopathy were studied at rest and during upright exercise on a bicycle ergometer. All patients were already receiving optimal treatment with digitalis and diuretics. At rest treatment with hydralazine resulted in a fall in both mean arterial and pulmonary wedge pressure. There was a 50 per cent reduction in systemic vascular resistance compared with pretreatment measurements and there was an equally impressive increase in stroke volume index. During exertion the changes noted at rest were sustained though occurred to a lesser degree; thus there was a 20 per cent fall in arterial resistance and a 20 per cent rise in stroke volume index compared with control. These findings show that hydralazine administration not only results in a beneficial effect on cardiac function at rest but that this effect is maintained during upright exercise in patients with impaired left ventricular function, thus providing further support for its use in the long-term management of such patients.     

Long-term outpatient vasodilator therapy of congestive heart failure. Consideration of agents at rest and during exercise.

Increased left ventricular filling pressure and reduced cardiac output are two major hemodynamic deficits in pump failure. In patients with chronic heart failure, consequences of these hemodynamic deficits and diminished cardiac reserve are manifested initially during stress and eventually at rest. The purpose of therapeutic interventions include reduction of ventricular filling pressure increase in cardiac output and improvement in cardiac reserve. To achieve these goals, the hemodynamic effects of predominantly venodilators (nitrates), predominantly arteriolar dilators (hydralazine) and the combination of nitrates and hydralazine were evaluated in patients with chronic heart failure at rest: left ventricular filling pressure (mm Hg) control 28, nitrates 17, hydralazine 25, nitrates plus hydralazine 18; cardiac output (liters/min/m2) control 2.1, nitrates 2.1, hydralazine 3.2, nitrates plus hydralazine 3.3; mean blood pressure (mm Hg) control 87, nitrates 85, hydralazine 83, nitrates plus hydralazine 85. These data suggest improved left ventricular performance with a combination of nitrates and hydralazine. Exercise hemodynamics improved in some patients, suggesting that such vasodilator therapy may be beneficial in chronic heart failure.     

Hemodynamic effects of felodipine in congestive heart failure

Summary The hemodynamic effects of increasing dosages of felodipine, a new calcium antagonist with selective vasodilator properties, were studied in 13 patients with chronic cardiac failure. A Swan-Ganz thermodilution catheter was positioned in the pulmonary artery and hemodynamic parameters were monitored from 9 am to 6 pm for five days. On the first and the fifth day patients received placebo (P) and on the second, third, and fourth day patients received felodipine 5, 10, and 20 mg, respectively. Symptom-limited exercise tests with a bicycle ergometer were performed on both days of P and on the fourth day. A marked reduction of systemic vascular resistance (SVR) and a significant increase of cardiac index without increments of heart rate (HR) were observed after felodipine at rest. A dose response effect could be demonstrated. During exercise a significant increment of cardiac index and decrease of pulmonary wedge pressure was observed after felodipine. Felodipine showed a potent vasodilator action on systemic circulation with significant changes on both stroke volume and filling pressures at rest and during exercise without side effects.Part of the data in this paper was presented at the Cardiovascular Pharmacotherapy International Symposium in Geneva, Switzerland, April 1985     

Vasodilatation with captopril and prazosin in chronic heart failure: double blind study at rest and on exercise

A double blind cross over study was performed to compare the long term hormonal, haemodynamic, and clinical responses to specific inhibition of the renin-angiotensin-aldosterone system (captopril) and of the alpha 1 adrenoceptors of the sympathetic system (prazosin) both at rest and during upright exercise in patients with chronic heart failure. Sixteen patients completed one month's treatment with each drug. During conventional diuretic treatment (control) plasma renin activity, aldosterone, and noradrenaline were increased at rest and on exercise. Control left ventricular filling pressures were raised, and correlated significantly with plasma renin activity both at rest and on exercise. Systemic vascular resistance was increased at rest, and its reduction during exercise correlated inversely with the increase in plasma renin activity and plasma noradrenaline. After one month's treatment with captopril there were reductions in plasma aldosterone, weight, left ventricular filling pressure, and systemic vascular resistance at rest and on exercise. Dyspnoea was relieved and exercise capacity increased. The greater fall in systemic vascular resistance on exercise no longer correlated with the increase in plasma renin activity. During treatment with prazosin there were increases in plasma noradrenaline and, transiently, in plasma aldosterone. Fluid retention occurred, and left ventricular filling pressure was unchanged. Compared with control values systemic vascular resistance was reduced at rest but not on exercise. Dyspnoea and exercise capacity did not improve. In chronic heart failure, vasodilatation by inhibition of the alpha adrenergic system with prazosin causes compensatory stimulation of the renin-angiotensin-aldosterone system and does not result in clinical benefit. Inhibition of the renin-angiotensin-aldosterone system with captopril causes secondary vasodilatation at rest and on exercise and results in improvement in symptoms and exercise capacity.