Placebo-controlled comparison of candoxatril, an orally active neutral endopeptidase inhibitor, and captopril in patients with chronic heart failure

AIMS: To compare the effects on exercise capacity of the neutral endopeptidase inhibitor candoxatril, and the angiotensin converting enzyme inhibitor captopril, in patients with mild to moderate heart failure. METHODS: In this multi-centre double-blind placebo controlled study, 60 patients with NYHA Class I-III heart failure were randomised to candoxatril 200 mg b.d. (n = 22), captopril 25-50 mg b.d. (n = 23) or placebo (n = 15). Treadmill exercise tests were carried out weekly during a 5-week single-blind placebo run-in phase until a stable baseline was achieved, and repeated at 4 weekly intervals during the 12-week double-blind treatment phase. RESULTS: Nine patients withdrew from the study--four candoxatril and five captopril. The placebo-adjusted increase in exercise duration after 12 weeks was 56 s (95% CI, -26 to +137 s; P = 0.12) with candoxatril and 37 s (-43 to + 117 s; P = 0.29) with captopril. CONCLUSIONS: Both candoxatril and captopril were well tolerated and treadmill exercise duration appeared to increase during 12 weeks of therapy but this did not achieve statistical significance. This study tentatively suggests that in patients with heart failure, neutral endopeptidase inhibition may provide similar symptomatic benefits to angiotensin converting enzyme inhibition.     

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.     

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.     

Neurohormonal activation in patients with mild or moderately severe congestive heart failure and effects of ramipril. The Ramipril Trial Study Group.

OBJECTIVES--To describe neurohormonal activation in patients with mild or moderate heart failure and how it may be modified by treatment with ramipril. SETTING--Cardiology departments at 24 hospitals in Denmark, Finland, Norway, and Sweden. PATIENTS--223 patients with mild or moderately severe congestive heart failure who were taking diuretics with or without digitalis. DESIGN--Randomised, double bind, multicentre, placebo controlled comparison of ramipril and placebo. Venous blood samples were drawn at rest, before blind treatment, and after 12 weeks of treatment with the study drug. A probability prediction score for mortality derived by stepwise linear discriminant from neurohormone data in the first cooperative north Scandinavian enalapril survival study (CONSENSUS I) was used to assess combined activity of the different neurohormonal systems. RESULTS--Plasma concentrations of atrial natriuretic peptide were raised at baseline but angiotensin II, aldosterone, and noradrenaline concentrations were within normal limits. There was, however, a wide interindividual variation. Plasma noradrenaline concentration and prediction score were higher among patients with class III congestive heart failure according to the New York Heart Association's classification than among patients with class II congestive heart failure (P < 0.05). There was a modest but significant inverse correlation between exercise duration at baseline and plasma noradrenaline concentration (r = -0.21, P = 0.0023), aldosterone concentration (r = -0.14, P = 0.04), and prediction score (r = -0.24, P = 0.0004). Prediction score at baseline was significantly higher among those who died (n = 10) than among survivors (P = 0.03). Angiotensin converting enzyme activity was suppressed and plasma concentrations of aldosterone and atrial natriuretic peptide were reduced after 12 weeks of treatment with ramipril compared with placebo. In patients with the most pronounced neurohormonal activation at baseline (highest third of noradrenaline concentration or prediction score), noradrenaline concentration and prediction score were significantly lower after 12 weeks of taking ramipril compared with placebo. Patients with a prediction score in the highest third at baseline had a higher heart rate than to those in the lowest third (P = 0.003). CONCLUSIONS--Neurohormonal activation is associated with the degree of symptoms and the severity of disease in mild or moderately severe congestive heart failure. Treatment with ramipril attenuates neurohormonal activation. This effect is most pronounced among patients with the highest circulating concentrations of neurohormones before the start of treatment.     

Oral enoximone therapy in chronic heart failure: a placebo-controlled randomized trial. The Western Enoximone Study Group.

In a parallel study design, 164 patients with New York Heart Association Functional class II or III heart failure were randomized to receive either enoximone given as 50 mg three times a day, or 100 mg three times a day, or a matching placebo. All patients were receiving digitalis and/or diuretics and had left ventricular ejection fractions less than or equal to 45. Exercise tests were performed after 1, 4, 8, and 12 weeks of treatment. Enoximone produced significantly greater increases in exercise time than placebo treatment at weeks 4 and 8 (p = 0.012, p = 0.029, respectively) but not after 12 weeks. Left ventricular ejection fraction increased significantly after the first dose of enoximone but not after 12 weeks of long-term therapy. Heart failure symptoms and the physicians' evaluations of cardiac status were significantly improved in both enoximone therapy groups during the first 4 weeks of evaluation when compared with evaluations of cardiac status in the placebo group. Diuretic doses were increased more frequently for patients who were receiving a placebo. Adverse events were reported with similar frequency in the placebo and 50 mg enoximone treatment groups; 100 mg enoximone resulted in a significantly greater incidence of adverse events. Mean heart rate and ventricular ectopic activity were not significantly different among the three treatment limbs. Enoximone appears to improve exercise tolerance, ventricular function, and symptoms of heart failure for 4 to 8 weeks. Heart rate, ventricular ectopic activity, and mortality rate were not increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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 chronic stable angina: a randomized, double-blind, placebo-controlled, crossover study

To investigate the antianginal efficacy and tolerability of felodipine, a new dihydropyridine calcium antagonist, 20 patients with stable exertional angina, not completely controlled by beta-blocker monotherapy, entered a randomized, double-blind, placebo-controlled, crossover study. Patients on standard beta-blocker therapy, who had at least 3 weekly anginal episodes and a reproducible exercise test (stopped for angina and ECG signs of ischaemia) at the end of 2 weeks placebo treatment, were eligible for the study. They were randomized to one sequence of treatment: felodipine 5 mg twice daily for 2 weeks followed by placebo for a further 2 weeks, or vice versa. Beta-blocker treatment was unchanged throughout the study. A treadmill test was carried out at the end of each crossover period, 2-4 h after drug administration. The number of anginal attacks and nitroglycerin consumption was recorded on a diary card. At rest, felodipine significantly (P less than 0.05) reduced standing systolic but not diastolic blood pressure. Heart rate was not modified by the active treatment. At ischaemic threshold and at peak exercise, heart rate, systolic blood pressure and rate-pressure product remained unchanged. Exercise duration was increased by felodipine (P less than 0.01) and maximal ST change was reduced (P less than 0.01). Time to 1 mm ST depression was prolonged non-significantly by felodipine (basal 5.7 +/- 1.5, felodipine 7.4 +/- 2.0, placebo 6.6 +/- 1.5 min). The number of patients who stopped exercise due to angina and ST change was 20/20 at baseline, 16/20 with placebo and 10/20 with felodipine. Felodipine significantly reduced weekly anginal episodes (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of isosorbide-5-mononitrate on exercise performance and clinical status in patients with congestive heart failure. Results of the Nitrates in Congestive Heart Failure (NICE) Study.

BACKGROUND AND AIMS: Nitrate therapy improves hemodynamics in patients with heart failure, but the chronic effects of oral nitrates on exercise performance and clinical status have not been well studied. METHODS: Oral isosorbide-5-mononitrate (ISMN) (50 mg once daily) or placebo was administered to 136 patients (NYHA Class 2-3) treated for heart failure, all receiving captopril and most also furosemide. Endpoints were treadmill exercise time at 12 weeks by modified Naughton protocol (primary), with an additional 12-week follow-up period. Secondary endpoints included left ventricular dimensions, ejection fraction, cardiothoracic ratio, functional class, quality of life, hospitalizations and plasma norepinephrine and atrial natriuretic peptide in a four-center substudy. RESULTS: Intention-to-treat analysis showed that mean change in treadmill exercise duration tended to be greater in patients receiving ISMN than placebo (treatment difference +42 s, 95% CI -5, +90 s at 12 weeks and +21 s, 95% CI -25, +74 s after 24 weeks) (NS). Treatment difference was greater in the prespecified subgroup with ejection fraction 31-40% (+55 s, 95% CI -11, +136 s at 12 weeks and +65 s, 95% CI +3, +147 s) (p = 0.035) at 24 weeks. No deleterious effects (i.e. hypotension) were observed with ISMN, although headache was reported in 19% of the active treatment group (p = 0.0001). CONCLUSIONS: ISMN added to captopril increased treadmill exercise time in patients with heart failure and a lesser reduction in baseline ejection fraction, although for the group as a whole, the increase in treadmill time was not significant.     

Lack of effect of nitrates on exercise tolerance in patients with mild to moderate heart failure caused by coronary disease already treated with captopril.

OBJECTIVE--To test the hypothesis that the addition of nitrates improves exercise tolerance in patients with heart failure caused by coronary artery disease already treated with an angiotensin converting enzyme inhibitor and diuretics. DESIGN--Randomised, double blind, placebo controlled, 16 week treatment periods. SETTING--Outpatient clinic at a university hospital. PATIENTS--54 patients with previous myocardial infarction, symptoms of mild to moderate heart failure, left ventricular ejection fraction below 40%, no exercise-induced angina or electrocardiographic signs of ischaemia. Four patients in the nitrate group (n = 24) and one patient of the placebo group (n = 25) were withdrawn from the study. INTERVENTION--After the patients had been on constant doses of captopril and diuretics for at least 2 weeks, they were randomised to receive a target dose of 40 mg isosorbide dinitrate twice daily or placebo in addition to the continuation of captopril and diuretics. MEASUREMENTS--Bicycle exercise tests with measurement of gas exchange were carried out before randomisation and after 1, 6, 12, and 16 weeks of the double blind treatment. The change in peak oxygen uptake from control to week 16 was prospectively defined as the main outcome measure. RESULTS--The increase in peak oxygen uptake from before randomisation tended to be greater in the placebo group (before randomisation 17.4 (3.4) ml/min/kg) than in the nitrate group (before randomisation 17.1 (3.5) ml/min/kg) after 12 weeks (mean increase 1.1 (2.7) v 0.0 (2.7) ml/min/kg, p < 0.12) and 16 weeks (1.7 (3.0) v 0.3 (2.6) ml/min/kg, p < 0.14) of treatment. CONCLUSION--The addition of nitrates to a baseline treatment consisting of captopril and diuretics did not improve exercise tolerance.     

Felodipine in addition to beta-adrenergic blockade for angina pectoris.A multicentre, randomized, placebo-controlled trial

The additional efficacy, duration of action and tolerabilityof felodipine were evaluated in patients with stable anginapectoris and a positive stress test who were already receivingtherapy with a beta-adrenergic blocker. One hundred and twenty-eightpatients were randomized to double-blind treatment with 5–10mg felodipine once daily or matching placebo, and were evaluatedby serial exercise testing during 12 weeks of treatment. Felodipine at 4 h significantly increased exercise durationassessed after 4 weeks of treatment (increase 34 ±65s vs 18±71 s in placebo-treated patients; 95% confidenceinterval 1.01–1.11; P=0.01), and after 12 weeks of treatment(increase 39 ± 103 s vs 3 ± 72 s; 95% confidenceinterval 1.01–1.16; P=0.02). The time until onset of exercise-inducedanginal pain and time until 1 mm ST depression assessed after4 weeks of treatment also increased significantly with felodipinecompared to placebo. No statistically significant changes inexercise test parameters evaluated 24 h after medication wereobserved. The addition of felodipine once daily demonstrated a sustainedimprovement in exercise duration in patients symptomatic despitetreatment with a beta-blocker evaluated 4 h after drug intake.At 24 h post dose, no statistically significant effect was observed.Felodipine is well tolerated with a low incidence of side-effectsand no adverse effect on quality of life.     

Acute effects on exercise tolerance of felodipine and diltiazem, alone and in combination, in stable effort angina

The acute effects on exercise tolerance and electrocardiographic ischaemia of felodipine and diltiazem, alone or in combination, were investigated in 12 patients with documented stable effort-induced angina pectoris. After being withdrawn from their previous antianginal treatments, patients received a single oral dose of felodipine 10 mg, diltiazem 60 mg, their combination or placebo on four different days, according to a double-blind, 4 x 4 latin-square design. Exercise time to ischaemic threshold (ST-segment depression = 1 mm) and to peak exercise was significantly prolonged by the felodipine-diltiazem combination (492 and 504 s, respectively) against placebo (301 and 370 s, both P less than 0.01), felodipine alone (381 and 428 s, both P less than 0.01) and diltiazem alone (367 and 422 s, both P less than 0.01). The effects on total work followed a similar pattern. In comparison with placebo, the administration of felodipine and diltiazem alone significantly increased exercise duration as well as total work to ischaemic threshold and to peak exercise, with no differences between the two drugs. Systolic blood pressure during exercise was not affected by any of the treatments. However, in comparison with both placebo and diltiazem, the combination induced an increase (P less than 0.01) in heart rate during exercise. One patient suffered from symptomatic hypotension with the combination, and another had sinus tachycardia after felodipine. In conclusion, the acute concomitant administration of felodipine and diltiazem in patients with stable effort angina induces a marked improvement in exercise tolerance in comparison with placebo, felodipine alone and diltiazem alone. However, the benefit/risk profile of such a combination requires further, long-term investigation.     

Placebo treatment in congestive heart failure.

In order to evaluate the effect of placebo treatment in congestive heart failure, we retrospectively studied 24 patients with moderately severe congestive heart failure who participated in heart failure treatment trials performed over the past 10 years in the Ohio State University Heart Failure Research Laboratory. Placebo-treated patients from 4 placebo-controlled trials comprised the placebo treatment group (n = 15), while one natural course-controlled trial provided patients for the non-placebo control group (n = 9). Changes in symptoms, left ventricular function and exercise duration were assessed following an 8-week course of therapy. Chronic placebo therapy resulted in an 81-second improvement in exercise duration which was statistically significant when compared to pretreatment baseline and to the duration achieved by the nonplacebo control group. Clinically, functional class improved significantly by 27% above baseline only for the placebo treatment group. Indices of left ventricular function did not change for either group. The salient feature of this study is that the placebo treatment effect, while believed to exist in congestive heart failure, has never been demonstrated in a manner which controlled for the natural course and variability of the disease process. The operative components of the placebo effect remain unknown, and further investigation will be necessary to elucidate the underlying mechanisms involved. However, the importance of this phenomenon lies not only with the response to and effects of placebo therapy but also in the role that the placebo effect plays in what is generally presumed to be the predominant responses, effects and benefits of active drug therapy.     

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.     

非洛地平与拜新同和硝苯地平治疗稳定型心绞痛的平行对照临床研究

目的 观察非洛地平治疗冠心病心绞痛的临床疗效和副作用.方法 采用随机分组平行对照的方法研究钙拮抗剂对心绞痛疗效的影响.结果 表明非洛地平缓解临床症状总有效率为96.7%,与硝苯地平86.7%、拜新同90.0%比较无统计学意义.运动试验的结果提示非洛地平与拜新同和硝苯地平一样,可以明显的延长总的运动时间和运动到ST降低1mm的时间,显著的提高最大运动负荷量(Mets).非洛地平的治疗对心率无明显的影响.对血压均有降低作用.因此,认为非洛地平是一种长效、安全以及不良反应少的抗心绞痛药物,尤其是适用于冠心病合并高血压患者.     

Controlled trial of enalapril in congestive cardiac failure.

Twenty five patients with chronic congestive cardiac failure had enalapril (n = 13) or placebo (n = 12) added to their existing regimen of digoxin and frusemide in a randomised double blind trial. Four hours after the first 5 mg dose, the enalapril group showed significant falls in blood pressure, heart rate, and concentrations of plasma angiotensin II, angiotensin converting enzyme, and noradrenaline. During the 12 week trial heart failure became worse in one enalapril treated patient (8%) and in seven placebo treated patients (58%). There were no significant changes in cardiac ejection fraction or exercise duration in either group. Plasma noradrenaline response to graded exercise and maximum exercise rate-pressure product were significantly reduced after four and 12 weeks of active treatment but unchanged with placebo treatment. There was a sustained increase in plasma potassium and a slight rise in plasma creatinine in the enalapril group. Plasma concentrations of the active drug, enalaprilate, were dose related and log enalaprilate correlated significantly with percentage of plasma angiotensin converting enzyme activity (r = -0.66). Enalapril was well tolerated and produced no adverse effects. The drug appears to be superior to placebo and offers considerable promise for the treatment of this condition.     

Low-dose enoximone improves exercise capacity in chronic heart failure. Enoximone Study Group

OBJECTIVES: This study was designed to evaluate the effects of low-dose enoximone on exercise capacity. BACKGROUND: At higher doses the phosphodiesterase inhibitor, enoximone, has been shown to increase exercise capacity and decrease symptoms in heart failure patients but also to increase mortality. The effects of lower doses of enoximone on exercise capacity and adverse events have not been evaluated. METHODS: This is a prospective, double-blind, placebo-controlled, multicenter trial (nine U.S. centers) conducted in 105 patients with New York Heart Association class II to III, ischemic or nonischemic chronic heart failure (CHF). Patients were randomized to placebo or enoximone at 25 or 50 mg orally three times a day. Treadmill maximal exercise testing was done at baseline and after 4, 8 and 12 weeks of treatment, using a modified Naughton protocol. Patients were also evaluated for changes in quality of life and for increased arrhythmias by Holter monitoring. RESULTS: By the protocol-specified method of statistical analysis (the last observation carried-forward method), enoximone at 50 mg three times a day improved exercise capacity by 117 s at 12 weeks (p = 0.003). Enoximone at 25 mg three times a day also improved exercise capacity at 12 weeks by 115 s (p = 0.013). No increases in ventricular arrhythmias were noted. There were four deaths in the placebo group and 2 and 0 deaths in the enoximone 25 mg three times a day and enoximone 50 mg three times a day groups, respectively. Effects on degree of dyspnea and patient and physician assessments of clinical status favored the enoximone groups. CONCLUSIONS: Twelve weeks of treatment with low-dose enoximone improves exercise capacity in patients with CHF, without increasing adverse events.     

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.     

Felodipine, a new calcium antagonist, modifies exercise-induced asthma

Recently, calcium antagonists have been reported to have a clinically beneficial effect in patients with asthma. Felodipine is a new calcium antagonist of the dihydropyridine group with a high selectivity for arteriolar smooth muscle; it is under clinical investigation for the treatment of hypertension. In this double-blind, randomized crossover trial in 9 patients, the effect of 10 mg felodipine in oral solution on exercise-induced asthma was compared with a placebo on separate days. The FEV1 was at least 80% of the predicted normal value, with variation between study days of less than 10%. Heart rate, blood pressure, and FEV1 were measured before and at 15 and 30 min after each treatment. The exercise test consisted of steady state running at submaximal work loads for 6 to 8 min and started at 30 min after treatments. FEV1 was measured at 1, 2, 5, 10, 15, and 30 min after the end of exercise. The predrug baseline FEV1 values were comparable on the 2 days of the study, and felodipine had no effect on the resting lung function. The mean percentage fall in FEV1 (SEM) after exercise with placebo was 27.0 (4.5)%, and with felodipine it was 13.5 (3.7)%. The difference between felodipine and placebo was statistically significant. While receiving felodipine, the resting heart rate was increased by 15%, with a tendency to lower systolic and diastolic blood pressures. The heart rate after exercise was higher during felodipine treatment than during placebo treatment. One patient receiving placebo and 7 receiving felodipine noted a transient headache. Two patients receiving felodipine also noticed lightheadedness after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quality of life in chronic heart failure: cilazapril and captopril versus placebo. Cilazapril-Captopril Multicentre Group

OBJECTIVE: To measure quality of life (QOL) in patients with mild to moderate heart failure treated with angiotensin converting enzyme (ACE) inhibitors cilazapril or captopril. DESIGN: Randomised, double blind, placebo controlled, parallel groups trial. SUBJECTS: 367 patients with New York Heart Association (NYHA) heart failure class II (62%), III (36%) or IV (1%). METHODS: Patients were randomised to receive cilazapril 1 mg daily (n = 191) or captopril 25 mg three times daily (n = 90) for 24 weeks, or placebo for 12 weeks followed by cilazapril 1 mg daily for a further 12 weeks (n = 86). If patients had not responded after four weeks cilazapril was increased to 2.5 mg daily and captopril to 50 mg three times daily. QOL was assessed at baseline, 12, and 24 weeks using the sickness impact profile (SIP), the profile of mood states (POMS), the Mahler index of dyspnoea-fatigue, and a health status index (HSI). RESULTS: The physical dimension of the SIP averaged 7 units at baseline and improved after 12 weeks by 2.24 units in the cilazapril group, 2.38 units in the captopril group, and 1.51 units in the placebo group. The difference between drug and placebo was therefore 0.73 units (95% CI -0.86 to 2.32) for cilazapril, and 0.87 units (95% CI -0.96 to 2.70) for captopril, with small non-significant effect sizes (a statistical method for estimating the importance of a treatment related change) of 0.12 and 0.14. Similar results were observed for the total POMS and HSI scores. Although QOL improved more on the ACE inhibitors than on placebo, the effect sizes were not significant (< or = 0.26). CONCLUSIONS: Improvements in QOL in mild to moderate heart failure were small when treated with cilazapril or captopril compared with placebo.