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.     

Milrinone in heart failure. Effects on exercise haemodynamics during short term treatment.

The effects of milrinone, a new bipyridine inotropic agent, on the haemodynamic responses to treadmill exercise were studied in 12 patients with congestive heart failure. Four weeks' treatment with milrinone 20 mg daily produced an improvement in left ventricular function during exercise as reflected by significant increments in cardiac index and stroke volume index without change in pulmonary capillary wedge pressure. Systemic oxygen consumption, measured at submaximal exercise, also increased suggesting that the drug induced rise in stroke output was associated with improved skeletal muscle perfusion. Maximum exercise capacity increased. Importantly, the beneficial effects of milrinone on exercise haemodynamics and exercise tolerance were sustained throughout the four week treatment period. No drug related side effects occurred. After treatment with milrinone was stopped left ventricular function deteriorated to a level slightly, but significantly, worse than that before treatment. These observations indicate a potentially useful role for milrinone in treating heart failure.     

Milrinone in heart failure. Effects on exercise haemodynamics during short term treatment

The effects of milrinone, a new bipyridine inotropic agent, on the haemodynamic responses to treadmill exercise were studied in 12 patients with congestive heart failure. Four weeks' treatment with milrinone 20 mg daily produced an improvement in left ventricular function during exercise as reflected by significant increments in cardiac index and stroke volume index without change in pulmonary capillary wedge pressure. Systemic oxygen consumption, measured at submaximal exercise, also increased suggesting that the drug induced rise in stroke output was associated with improved skeletal muscle perfusion. Maximum exercise capacity increased. Importantly, the beneficial effects of milrinone on exercise haemodynamics and exercise tolerance were sustained throughout the four week treatment period. No drug related side effects occurred. After treatment with milrinone was stopped left ventricular function deteriorated to a level slightly, but significantly, worse than that before treatment. These observations indicate a potentially useful role for milrinone in treating heart failure.     

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.     

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.     

Treatment of hypertension with felodipine in patients with concomitant diseases

Coexisting medical conditions often complicate the selection of antihypertensive drugs. Felodipine, a new vascular-selective calcium antagonist with demonstrated antihypertensive efficacy, has not been found to alter lipid profiles in hypertensive patients. Studies in additional patient populations have yielded insights into the effects of the drug on other diseases that may coexist with hypertension. In individuals with stable angina pectoris or congestive heart failure, acute administration of felodipine reduces systemic vascular resistance and increases cardicac output and total coronary blood flow; myocardial contractility is not depressed at doses that produce a clinically significant reduction in vascular resistance. In patients with coronary stenoses, the drug increases vessel diameter in the vicinity of obstructive lesions. Single-dose and long-term studies in patients with exertional angian have found that felodipine reduces anginal frequency and improves exercise tolerance. In patients with congestive heart failure, chronic dosing with felodipine produces a persistent reduction in vascular resistance and an increase in cardiac output, both at rest and during exercise. Symptomatic improvement and increased exercise tolerance have been noted in some studies. In patients with Raynaud's phenomenon, felodipine has been assoicated with a dose-dependent improvement in symptomatology. Among individuals with exercise-induced bronchospasm, the drug has no effect on resting bronchial tone and may exert some positive effects during exercise. In hypertensive patients with Type II diabetes, felodipine has not been found to raise glucose levels significantly. The data obtained thus far suggest that felodipine is safe for use in hypertensive patients with a variety of concomitant diseases.     

Felodipine in patients with chronic heart failure: discrepant haemodynamic and clinical effects.

Previous open studies have suggested that felodipine, a selective calcium antagonist and vasodilator, may be useful in the treatment of heart failure. A double blind placebo controlled crossover trial was therefore conducted to investigate the clinical and haemodynamic effects of felodipine in 15 patients with chronic ischaemic heart failure in New York Heart Association symptom class III. Felodipine significantly increased resting and exercise (25W bicycle ergometry) cardiac output without producing concomitant changes in resting or exercise heart rate or right and left ventricular filling pressures. Felodipine did not significantly improve symptom scores or exercise capacity in the group as a whole. It also resulted in significant fluid retention as shown by a rise in ankle circumference, body weight, and a fall in haematocrit. Further research is required to elucidate the mechanism that is responsible for the discrepancy between the haemodynamic and clinical effects of felodipine in patients with moderately severe heart failure.     

Felodipine in patients with chronic heart failure: discrepant haemodynamic and clinical effects

Previous open studies have suggested that felodipine, a selective calcium antagonist and vasodilator, may be useful in the treatment of heart failure. A double blind placebo controlled crossover trial was therefore conducted to investigate the clinical and haemodynamic effects of felodipine in 15 patients with chronic ischaemic heart failure in New York Heart Association symptom class III. Felodipine significantly increased resting and exercise (25W bicycle ergometry) cardiac output without producing concomitant changes in resting or exercise heart rate or right and left ventricular filling pressures. Felodipine did not significantly improve symptom scores or exercise capacity in the group as a whole. It also resulted in significant fluid retention as shown by a rise in ankle circumference, body weight, and a fall in haematocrit. Further research is required to elucidate the mechanism that is responsible for the discrepancy between the haemodynamic and clinical effects of felodipine in patients with moderately severe heart failure.     

Different results in cardiopulmonary exercise tests after long-term treatment with felodipine and enalapril in patients with congestive heart failure due to ischaemic heart disease

We evaluated the cardiopulmonary exercise test results before and after long-term (16 weeks) treatment with the dihydropyridine calcium antagonist, felodipine (10 mg b.i.d., n = 9), and the ACE inhibitor, enalapril (10 mg b.i.d., n = 11), in 20 patients with New York Heart Association class III congestive heart failure. There were no significant differences at baseline. After 16 weeks patients in the enalapril group showed a significant increase in exercise duration and VO2max, without changes in arterial pressures and heart rate. In the felodipine group, exercise duration and VO2max did not change significantly, but arterial pressures and heart rate were significantly reduced at all exercise levels. Between group analysis showed a significant reduction in arterial pressures and heart rate in the felodipine group compared with enalapril, but no differences in aerobic capacity and exercise duration. These results demonstrate that felodipine and enalapril have essentially different effects on cardiopulmonary exercise results in patients with congestive heart failure.     

Acute and chronic effects of sustained action buccal nitroglycerin in severe congestive heart failure

Vasodilators, such as nitroglycerin, have been widely used in the treatment of acute and chronic heart failure for therapeutic manipulation of the venous and arterial circulations to improve left ventricular function. We have tested the efficacy of a new formulation for sustained release buccal delivery of nitroglycerin (biological life 5-6 hr) in 21 patients with severe congestive heart failure due to ischaemic cardiomyopathy using maximal treadmill exercise testing and radionuclide angiography. A single-blind placebo-controlled acute and an open chronic phase (4 weeks) of treatment were employed. The mean dose was 23.4 mg daily, and clinical assessment suggested significant improvement in 15 patients. The mean ejection fraction (placebo) of 14.1% +/- 1.6 SEM increased to 19.1% +/- 1.7 (acute) and to 21.6% +/- 1.7 (chronic treatment) (P less than 0.001; n = 16). The mean exercise time increased from 3.02 +/- 0.4 min (basal) to 5.95 +/- 0.6 min (chronic) (P less than 0.001). Segmental wall motion abnormality was shown to improve after treatment for 4 weeks. There were no major side effects. Nine patients were reassessed after 24 weeks on the same regimen; exercise time and left ventricular ejection fraction were similar to the 4-week period, thus demonstrating a sustained improvement in cardiac function and functional capacity. A worthwhile functional and objective haemodynamic improvement was demonstrated in these patients with severe chronic congestive heart failure. This mode of treatment may have useful therapeutic value in the management of patients with a wide range of ischaemic heart failure.     

Symptoms,haemodynamics, and exercise capacity during long term treatment of chronic heart failure. Experience with pirbuterol.

An open study of long term treatment with an oral beta 2 agonist (pirbuterol 20 mg three times daily) was undertaken in 63 patients with severe chronic heart failure. During three months of treatment 20 (32%) patients died, of whom 16 were taking the drug at the time of death. Mortality was related to initial functional class (New York Heart Association classification: 23% in grade III and 75% in grade IV). Concomitant treatment with digoxin did not affect mortality. The drug was well tolerated by most patients but unwanted side effects necessitated withdrawal of the drug in six (10%). Thirty-five patients were continuing to take the drug after three months, of whom 22 reported symptomatic improvement and only four deterioration. There was a relation between symptomatic improvement and increase in exercise capacity. At initial haemodynamic assessment a single dose of pirbuterol increased the cardiac index by 34% and the stroke index by 21%. Left ventricular filling pressure fell by 23% and systemic vascular resistance by 22%. Haemodynamic reassessment after three months of continuous treatment in 29 patients showed maintained improvement in the group as a whole, although individual variation was considerable. There was no apparent relation between haemodynamic improvement and improvement in exercise duration and symptoms. Severe heart failure has a poor prognosis. Identification of those patients who may derive benefit from treatment with a particular drug is not yet possible.     

Symptoms, haemodynamics, and exercise capacity during long term treatment of chronic heart failure. Experience with pirbuterol

An open study of long term treatment with an oral beta 2 agonist (pirbuterol 20 mg three times daily) was undertaken in 63 patients with severe chronic heart failure. During three months of treatment 20 (32%) patients died, of whom 16 were taking the drug at the time of death. Mortality was related to initial functional class (New York Heart Association classification: 23% in grade III and 75% in grade IV). Concomitant treatment with digoxin did not affect mortality. The drug was well tolerated by most patients but unwanted side effects necessitated withdrawal of the drug in six (10%). Thirty-five patients were continuing to take the drug after three months, of whom 22 reported symptomatic improvement and only four deterioration. There was a relation between symptomatic improvement and increase in exercise capacity. At initial haemodynamic assessment a single dose of pirbuterol increased the cardiac index by 34% and the stroke index by 21%. Left ventricular filling pressure fell by 23% and systemic vascular resistance by 22%. Haemodynamic reassessment after three months of continuous treatment in 29 patients showed maintained improvement in the group as a whole, although individual variation was considerable. There was no apparent relation between haemodynamic improvement and improvement in exercise duration and symptoms. Severe heart failure has a poor prognosis. Identification of those patients who may derive benefit from treatment with a particular drug is not yet possible.     

Placebo controlled trial of felodipine in patients with mild to moderate heart failure. UK Study Group.

OBJECTIVE--To compare the effects of felodipine and placebo in patients with New York Heart Association functional class II or III and stable congestive heart failure despite treatment with an angiotensin converting enzyme inhibitor, diuretic, or digoxin, or any combination of these three drugs. PATIENTS AND DESIGN--252 patients were randomised in a double blind, parallel group study after a 2-4 week placebo run-in to oral treatment with either felodipine extended release formulation or placebo 2.5-10 mg twice daily given in addition to existing background medication for a further 12 weeks. METHODS--Patients aged 18-75 years of either sex with chronic congestive heart failure due to ischaemic heart disease, hypertensive heart disease, or dilated cardiomyopathy with or without secondary mitral insufficiency that was stable during the preceding two months were included in the study. Treadmill exercise tests according to the modified Naughton protocol were performed at baseline, and after six, 11, and 12 weeks of treatment. Signs and symptoms of heart failure were assessed at every visit. Physical examination was performed and left ventricular ejection fraction measured at baseline and after 12 weeks. RESULTS--Mean (SD) baseline exercise test times increased from 434 (162) s and 480 (157) s for felodipine and placebo groups respectively to 541 (217) s and 591 (218) s at 12 weeks or the last visit. The change in exercise from baseline to last visit was 107 (141) s for patients given felodipine and 112 (128) s for those given placebo (P > 0.20). There was also no difference between treatments with respect to the other efficacy variables. There were few deaths in the study (felodipine n = 3, placebo n = 2). More patients who received felodipine were withdrawn from treatment (n = 29) than those who received placebo (n = 17). The most common adverse events of the 54 and 28 cited as reasons for withdrawal in the felodipine and placebo groups respectively were increased need for non-study heart failure treatment (n = 10; 8%)--that is, starting new medication or changes in the dosage of existing treatment for patients given felodipine, and nausea (n = 4; 3%) for those given placebo. Patients withdrawn from the study due to increased need for non-study heart failure treatment rapidly stabilised and recovered. CONCLUSION--Felodipine has not been shown to be of benefit in patients with mild to moderate heart failure.     

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.     

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.     

Effect of captopril on the exercise performance in patients with congestive heart failure]

We studied the effect of captopril on exercise performance in 30 patients with congestive heart failure using a randomized, double-blind and placebo-controlled method. 4-week captopril treatment can significantly increase the exercise tolerance time and work load, heart function, blood flow in exercising lower limbs as well as oxygen metabolic capacity. However, 3-day captopril treatment had no effect on exercise performance. A significant correlation was found between improvement in exercise performance and the pretreatment level of plasma angiotensin II. The increased levels of plasma prostaglandins E 2 and I 2 after captopril treatment were also correlated with improvement of exercise performance. The results indicated that long-term captopril treatment can increase exercise performance in congestive heart failure by improving both central and peripheral hemodynamics and metabolism. Certain vasomotor or endocrine factor may play a mediate role in the above changes.     

Comparison of the effects of captopril and enoximone in patients with severe heart failure: a placebo controlled double-blind study

The effects of enoximone, a new cyclic adenosine monophosphate phosphodiesterase inhibitor, were compared with those of captopril in a double-blind study in a group of 10 patients with severe heart failure. Four weeks treatment with enoximone improved symptom-limited exercise tolerance from a mean value of 11.33 to 13.36 minutes (P less than 0.05) and 4 weeks of captopril treatment from 11.01 to 13.92 minutes (P less than 0.05). Four of the patients had a greater exercise tolerance taking enoximone, the remaining 6 while taking captopril. Both drugs reduced perceived exertion during submaximal exercise. Minute ventilation measured at rest and during submaximal exercise was also reduced by both drugs. Resting and post exercise calf blood flow was increased to a similar extent with captopril (P less than 0.03) and enoximone (P less than 0.005). There was no difference in calf blood flow and calf vascular resistance between the drugs suggesting that the peripheral haemodynamic effects of enoximone are due to peripheral vasodilatation. Enoximone is a useful drug for the treatment of patients with severe heart failure.     

Haemodynamic effects of sodium nitroprusside in 21 subjects with congestive heart failure.

Twenty-one patients in severe congestive heart failure refractory to conventional medical management were treated with sodium nitroprusside on 22 occasions. On 14 occasions (responders) there was significant improvement in clinical and haemodynamic indices. On 8 occasions (non-responders) hypotension developed without haemodynamic improvement and nitroprusside treatment had to be abandoned. The initial mean arterial pressure and the capillary wedge pressure tended to be higher in the responders while the cardiac index tended to be higher in the non-responders. The systemic vascular resistance was higher in the responders than in the non-responders (2560 +/- 160 vs 1800 +/- 180 dynes s cm-5, P less than 0.001). All of the responders had systemic vascular resistance greater than 1900 dynes s cm-5, while only one of the non-responders had a systemic vascular resistance in this range. Thus, a variable response to vasodilator therapy for congestive cardiac failure is documented. The favourable response appears to be limited to patients with a high systemic vascular resistance.     

Haemodynamic effects of sodium nitroprusside in 21 subjects with congestive heart failure.

Twenty-one patients in severe congestive heart failure refractory to conventional medical management were treated with sodium nitroprusside on 22 occasions. On 14 occasions (responders) there was significant improvement in clinical and haemodynamic indices. On 8 occasions (non-responders) hypotension developed without haemodynamic improvement and nitroprusside treatment had to be abandoned. The initial mean arterial pressure and the capillary wedge pressure tended to be higher in the responders while the cardiac index tended to be higher in the non-responders. The systemic vascular resistance was higher in the responders than in the non-responders (2560 +/- 160 vs 1800 +/- 180 dynes s cm-5, P less than 0.001). All of the responders had systemic vascular resistance greater than 1900 dynes s cm-5, while only one of the non-responders had a systemic vascular resistance in this range. Thus, a variable response to vasodilator therapy for congestive cardiac failure is documented. The favourable response appears to be limited to patients with a high systemic vascular resistance.     

Ischaemic left ventricular failure: evidence of sustained benefit after 18 months' treatment with xamoterol

The long term effects of treatment with xamoterol in 14 patients aged 44-73 with mild to moderate heart failure as a result of ischaemic heart disease are reported. After 18 months' treatment with xamoterol, patients were assessed in a randomised double blind crossover comparison of xamoterol (200 mg twice a day) and placebo, each given for one month. Compared with placebo, xamoterol significantly increased exercise duration and work done on a bicycle ergometer and reduced the maximum exercise heart rate. Assessment of symptoms and activities at 12 months by visual analogue and Likert scales showed a trend towards the relief of symptoms of breathlessness and tiredness and an improvement in activity. There was an improvement in the clinical signs of heart failure and no haemodynamic deterioration over a 12 month period as assessed by ejection fraction. The improvement in exercise tolerance, symptoms, and activities was sustained for 18 months without side effects or development of tolerance.