Drug therapy in chronic heart failure.

Chronic heart failure is widely recognised as a common and escalating problem that causes major disability and often shortens life. Diuretics and digoxin have formed the mainstay of treatment for many years. Clinical trials have demonstrated that angiotensin converting enzymes and beta-blockers, in selected patients, improve symptoms and reduce mortality. Angiotensin-II antagonists and spironolactone may also have a role in certain individuals. Newer pharmacological approaches to the management of this complex disease are being developed, but await full evaluation.

Beneficial haemodynamic effects of insulin in chronic heart failure.

OBJECTIVE: To characterise the central and regional haemodynamic effects of insulin in patients with chronic heart failure. DESIGN: Single blind, placebo controlled study. SETTING: University teaching hospital. PATIENTS: Ten patients with stable chronic heart failure. INTERVENTIONS: Hyperinsulinaemic euglycaemic clamp and non-invasive haemodynamic measurements. MAIN OUTCOME MEASURES: Change in resting heart rate, blood pressure, cardiac output, and regional splanchnic and skeletal muscle blood flow. RESULTS: Insulin infusion led to a dose dependent increase in skeletal muscle blood flow of 0.36 (0.13) and 0.73 (0.14) ml/dl/min during low and high dose insulin infusions (p < 0.05 and p < 0.005 v placebo, respectively). Low and high dose insulin infusions led to a fall in heart rate of 4.6 (1.4) and 5.1 (1.3) beats/min (p < 0.05 and p < 0.005 v placebo, respectively) and a modest increase in cardiac output. There was no significant change in superior mesenteric artery blood flow. CONCLUSION: In patients with chronic heart failure insulin is a selective skeletal muscle vasodilator that leads to increased muscle perfusion primarily through redistribution of regional blood flow rather than by increased cardiac output. These results provide a rational haemodynamic explanation for the apparent beneficial effects of insulin infusion in the setting of heart failure.

Cognitive impairment in heart failure with Cheyne-Stokes respiration.

OBJECTIVES: To document the degree of cognitive impairment in stable heart failure, and to determine its relation to the presence of Cheyne-Stokes respiration during sleep. SUBJECTS: 104 heart failure patients and 21 healthy normal volunteers. METHODS: Overnight oximetry was used (previously validated as a screening tool for Cheyne-Stokes respiration in heart failure). Cognitive function was assessed using a battery of neuropsychological tests. Left ventricular function was assessed by echocardiography. RESULTS: Heart failure patients performed worse than the healthy volunteers in tests that measured vigilance. Reaction times were 48% slower (0.89 (0.03) s v 0.60 (0.05) s p < 0.005) and they hit twice as many obstacles on the Steer Clear simulator (75 (6.4) v 33 (4.6); p < 0.005). Cognitive impairment within the heart failure group was unrelated to either the presence of Cheyne-Stokes respiration, the degree of left ventricular dysfunction, or indices of nocturnal oxygenation. CONCLUSIONS: Vigilance was impaired in heart failure but this did not appear to be related to the presence of Cheyne-Stokes respiration during sleep. Impaired vigilance as measured on the Steer Clear test has been associated with an increased risk of motor vehicle accidents. The issue of fitness to drive in heart failure requires further attention.

Randomised comparison of losartan vs. captopril on quality of life in elderly patients with symptomatic heart failure: the losartan heart failure ELITE quality of life substudy.

OBJECTIVE: To measure health-related quality-of-life (HRQoL) in elderly symptomatic heart failure patients following treatment with an angiotensin II receptor antagonist (losartan) vs. an angiotensin-converting-enzyme (ACE) inhibitor (captopril). METHODS: Patients (age > or = 65 years) were randomised to losartan, titrated to 50 mg once daily, or captopril, titrated to 50 mg three times daily, as tolerated. Sickness Impact Profile (SIP) and Minnesota Living with Heart Failure (LIhFE) questionnaires were administered at baseline, weeks 12 and 48. Composite hypothesis testing of change in HRQoL from baseline for completers, and withdrawal for unfavourable events (death, clinical/laboratory adverse experience) was used to account for differential dropout rates. RESULTS: In 203 patients completing the substudy (week 48), significant and comparable improvements in HRQoL from baseline were observed for both treatment groups (p < or = 0.001). Although there was a trend favouring losartan vs. captopril for the composite HRQoL endpoint (unadjusted p = 0.018, one-sided), this was not considered significant after adjusting for multiple testing. Significantly more captopril patients in the substudy subset withdrew for unfavourable reasons (19.6 vs. 10.9%, p = 0.038). CONCLUSIONS: Significant improvements in HRQoL were observed in elderly patients with symptomatic heart failure treated with losartan and captopril long-term. A trend favouring losartan in the composite measure of drug tolerability/quality of life was not significant, but losartan was generally better tolerated than captopril in that significantly fewer losartan patients discontinued therapy.

Combined treatment with losartan and an ACE inhibitor in mild to moderate heart failure: results of a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Although the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in patients with heart failure are well recognized, there are theoretical advantages in combining ACE inhibition with angiotensin (AT)1 receptor antagonism. METHODS: Twenty patients with mild to moderate heart failure and maximally treated with an ACE inhibitor were randomly assigned to losartan or placebo. Patients underwent repeated assessment of exercise tolerance, quality of life, central and regional hemodynamics, and neurohumoral and biochemical parameters over a period of 12 weeks. RESULTS: Losartan treatment was well tolerated in terms of adverse events, heart rate, and blood pressure response, and there were no significant changes in serum creatinine or potassium. After 12 weeks of treatment, no significant differences were observed between the losartan and placebo groups in exercise tolerance, quality of life, central and regional hemodynamics, or neurohumoral parameters. CONCLUSIONS: In patients with mild to moderate heart failure already maximally treated with an ACE inhibitor, additional treatment with losartan is well tolerated, but we have not observed any significant improvement in exercise capacity, quality of life, central and regional hemodynamics, or neurohormones. Our data suggest that the combination of losartan with an ACE inhibitor does not offer any substantial advantages over treatment with an ACE inhibitor alone in these patients.

The relationship between QT intervals and mortality in ambulant patients with chronic heart failure. The united kingdom heart failure evaluation and assessment of risk trial (UK-HEART)

AIMS: Mortality in patients with heart failure remains high and is difficult to predict. QT interval parameters on a 12-lead ECG have been shown to predict arrhythmic events in patients with a variety of myocardial diseases. There is some, but not consistent, evidence that QT interval parameters may act as predictors of mortality, in particular sudden death, in patients with heart failure. In an adequately powered prospective study we have studied QT interval parameters in patients with stable chronic heart failure in order to determine whether they are predictive of all-cause mortality or mode of death. METHODS AND RESULTS: Five hundred and fifty-four ambulant outpatients with chronic heart failure were recruited. A 12-lead ECG, chest radiograph, echocardiogram, 24 h ambulatory electrocardiogram and serum for biochemical analysis were obtained at baseline. Patients were followed for 471+/-168 days. QT intervals were measured in all leads blinded to patient's characteristics and outcome, were corrected for heart rate, and the maximum QT intervals, and QT dispersion (range of QT intervals) were determined. The same parameters were determined for JT intervals. The primary end-point was all-cause mortality, secondary end-points were sudden cardiac death and death due to progressive heart failure. Multivariate analysis with the Cox's proportional hazards model was used to determine which variables were independently related to outcome. Four hundred and ninety-five patients had analysable ECGs at study entry and of these 71 died during follow-up. The heart rate corrected QT dispersion and maximum QT interval were significant univariate predictors of all-cause mortality (P=0.026 and <0.0001 respectively), and also of sudden death and progressive heart failure death, but were not related to outcome in the multivariate analysis. The independent predictors of all-cause mortality were cardiothoracic ratio (P=0.0003), creatinine (P=0.0009), heart rate (P=0.007), echocardiographically derived left ventricular end-diastolic dimension (P=0.007) and ventricular couplets on 24 h electrocardiographic monitoring (P=0.015). CONCLUSION: In an adequately powered prospective study none of the QT or JT parameters were shown to be independent predictors of outcome in patients with mild to moderate congestive heart failure. These variables do not therefore add to the prognostic information which can be gained from simple radiographic, biochemical, echocardiographic and Holter data in this group of patients.

Effects of losartan and captopril on QT dispersion in elderly patients with heart failure. ELITE study group.

Differences in QT dispersion (a predictor for sudden death) were observed in a subgroup of patients in the ELITE heart failure study of losartan compared with captopril, and may explain improved survival with losartan.

Ventricular dilatation in the absence of ACE inhibitors: influence of haemodynamic and neurohormonal variables following myocardial infarction.

OBJECTIVE: To examine the relation between patterns of ventricular remodelling and haemodynamic and neurohormonal variables, at rest and during symptom limited exercise, in the year following acute myocardial infarction in patients not receiving angiotensin converting enzyme (ACE) inhibitors. DESIGN: A prospective observational study. PATIENTS: 65 patients recruited following hospital admission with a transmural anterior myocardial infarction. METHODS: Central haemodynamics and neurohormonal activation at rest and during symptom limited treadmill exercise were measured at baseline before hospital discharge, one month later, and at three monthly intervals thereafter. PATIENTS were classified according to individual patterns of change in left ventricular end diastolic volumes at rest, assessed at each visit using transthoracic echocardiography. RESULTS: In most patients (n = 43, 66%) ventricular volumes were unchanged or reduced. Mean (SEM) treadmill exercise capacity and peak exercise cardiac index increased at month 12 by 200 (24) seconds (p < 0.001 v baseline) and by 0.8 (0.4) l/min/m2 (p<0.05 v baseline), respectively, in this group. In patients with limited ventricular dilatation (n = 11, 17%) exercise capacity increased by 259 (52) seconds (p < 0.001 v baseline) and peak exercise cardiac index improved by 0.8 (0.7) l/min/m2 (NS). In the remaining 11 patients with progressive left ventricular dilatation, exercise capacity increased by 308 (53) seconds (p< 0. 001 v baseline) and peak exercise cardiac index similarly improved by 1.3 (0.7) l/min/m2 (NS). There were trends towards increased atrial natriuretic factor (ANF) secretion at rest and at peak exercise in this group. CONCLUSIONS: Ventricular dilatation after acute myocardial infarction is a heterogeneous process that is progressive in only a minority of patients. Compensatory mechanisms, including ANF release, appear capable of maintaining and improving exercise capacity in most patients for at least 12 months, even in those with a progressive increase in ventricular size.

Haemodynamic, neurohumoral and exercise effects of losartan vs. captopril in chronic heart failure: results of an ELITE trial substudy. Evaluation of Losartan in the Elderly.

BACKGROUND: The AT1 receptor antagonists differ from the angiotensin converting enzyme inhibitors by achieving a more complete blockade of angiotensin II's actions and by not affecting bradykinin metabolism. There is little information on whether this causes clinically significant differences in haemodynamics, neurohormones and exercise tolerance in heart failure. AIMS: To compare the effects of losartan and captopril upon central and regional haemodynamics, neurohormones and exercise capacity in heart failure. METHODS: In a double-blind, randomised trial 18 patients aged > or =65 years with symptomatic heart failure were allocated to treatment with losartan (10 patients) or captopril (eight patients). Patients underwent assessment at baseline, after the first dose, at 12 weeks and at 24 weeks. RESULTS: Systolic blood pressure fell by - 10.7% 1 h after captopril 6.25 mg (P = 0.007) and by - 4.8% 3 h after losartan 12.5 mg (P = 0.02). The blood pressure reduction was sustained with losartan at 12 and 24 weeks. Systemic vascular resistance fell acutely after captopril (-16.4%, P = 0.01). Captopril caused an acute and sustained rise in superior mesenteric artery blood flow (+ 22.9%, P = 0.04), and a slower rise in renal artery blood flow (+31.7%, P = 0.01). Losartan had no acute effects on regional haemodynamics but had increased superior mesenteric artery blood flow by 38.1% at 12 weeks (P = 0.02). There were no substantial differences between losartan and captopril, and no changes occurred in neurohormones or exercise capacity. CONCLUSION: No substantial differences were observed between losartan and captopril on central or regional haemodynamics, neurohormones or exercise capacity in elderly patients with stable symptomatic heart failure.

Achieving appropriate endpoints in heart failure trials: the PRIME-II protocol. The Second Perspective Randomised study of Ibopamine on Mortality and Efficacy.

Many clinical trials unintentionally include patients with a low risk of the trial endpoints. PRIME II (The Second Perspective Randomised study of Ibopamine on Mortality and Efficacy) was a large international randomised double blind trial comparing the addition of ibopamine or placebo to the therapy of patients with advanced heart failure. The trial was stopped prematurely because ibopamine was associated with an increased fatality rate, but the protocol achieved its objective of including high-risk patients. Here we describe the protocol details that enabled patients with the desired degree of risk to be included. We also amplify our definition of mode of death. The PRIME II protocol was designed with the intention that patients in the placebo group would have an annual fatality rate of 20%. Since the study was to be conducted in some 200 centres in 13 European countries, the inclusion criteria had to be simple and flexible, allowing for different clinical practice. The inclusion criteria, together with the use of simple investigations (which did not have to include angiographic or radionuclide ventriculography) are described. The annual fatality rate in the placebo group was just over 20%. Six categories of mode of death were used, but while they were reasonably easy to apply they did not reveal the reason for the unexpected adverse effect of ibopamine. The inclusion and exclusion criteria used for PRIME II, and the definitions of mode of death, were effective. The PRIME II protocol can be used as a model for future heart failure studies.

A randomized controlled trial of inspiratory muscle training in stable chronic heart failure.

AIMS: To assess whether a domiciliary programme of specific inspiratory muscle training in stable chronic heart failure results in improvements in exercise tolerance or quality of life. METHODS AND RESULTS: We conducted a randomized controlled trial of 8 weeks of inspiratory muscle training in 18 patients with stable chronic heart failure, using the Threshold trainer. Patients were randomized either to a training group inspiring for 30 min daily at 30% of maximum inspiratory mouth pressure, or to a control group of 'sham' training at 15% of maximum inspiratory mouth pressure. Sixteen of the 18 patients completed the study. Maximum inspiratory mouth pressure improved significantly in the training group compared with controls, by a mean (SD) of 25.4 (11.2) cmH2O (P=0.04). There were, however, no significant improvements in treadmill exercise time, corridor walk test time or quality of life scores in the trained group compared with controls. CONCLUSION: Despite achieving a significant increase in inspiratory muscle strength, this trial of simple domiciliary inspiratory muscle training using threshold loading at 30% of maximum inspiratory mouth pressure did not result in significant improvements in exercise tolerance or quality of life in patients with chronic heart failure.

Effect of oxygen on sleep quality, cognitive function and sympathetic activity in patients with chronic heart failure and Cheyne-Stokes respiration.

BACKGROUND: Cheyne-Stokes respiration disrupts sleep, leading to daytime somnolence and cognitive impairment. It is also an independent marker of increased mortality in heart failure. This study evaluated the effectiveness of oxygen therapy for Cheyne-Stokes respiration in heart failure. METHODS: Eleven patients with stable heart failure and Cheyne-Stokes breathing were studies. Oxygen and air were administered for 4 weeks in a double-blind, cross-over study. Sleep and disordered breathing was assessed by polysomnography. Symptoms were assessed using the Epworth Sleepiness Scale, visual analogue and quality of lift scores. Cognitive function was assessed by neuropsychometric testing. Overnight urinary catecholamine excretion was used as a measure of sympathetic nerve activity. RESULTS: Ninety-seven percent of apnoeas were central in origin. Oxygen therapy reduced the central apnoea rate (18.4 +/- 4.1 vs 3.8 +/- 2.1 per hour; p = 0.05) and periodic breathing time (33.6 +/- 7.4 vs 10.7 +/- 3.9% of actual sleep time; p = 0.003). Oxygen did not improve sleep quality, patient symptoms or cognitive failure. Oxygen reduced urinary noradrenaline excretion (8.3 +/- 1.5 vs 4.1 +/- 0.6 nmol.mmol-1 urinary creatinine; p = 0.03). CONCLUSION: Oxygen stabilized sleep disordered breathing and reduced sympathetic activity in patients with heart failure and Cheyne-Stokes respiration. We were unable to demonstrate an effect on either patient symptoms or cognitive function.

Nocturnal desaturation in patients with stable heart failure.

OBJECTIVE: To determine the prevalence of sleep disordered breathing within a United Kingdom heart failure population. SUBJECTS: 104 patients and 21 matched normal volunteers. METHODS: Overnight home pulse oximetry with simultaneous ECG recording in the patient group; daytime sleepiness was assessed using the Epworth sleepiness scale (ESS); 41 patients underwent polysomnography to assess the validity of oximetry as a screening test for Cheyne-Stokes respiration. RESULTS: Home oximetry was a good screening test for Cheyne-Stokes respiration (specificity 81%, sensitivity 87%). Patients with poorer New York Heart Association (NYHA) classes had higher sleepiness scores (p < 0.005). Twenty three patients had "abnormal" patterns of nocturnal desaturation suggestive of Cheyne-Stokes respiration. The mean (SEM) frequency of dips in Sao2 exceeding 4% was 10.3 (0.9) per hour in the patients and 4.8 (0.6) in normal controls (p < 0.005). Ejection fraction correlated negatively with dip frequency (r = -0.5, p < 0.005). The patient subgroup with > or = 15 dips/hour had a higher mean (SEM) NYHA class (3.0 (0.2) v 2.3 (0.1), p < 0.05), and experienced more ventricular ectopy (220 (76) v 78 (21) beats/hour, p < 0.05). There was no excess of serious arrhythmia. CONCLUSIONS: Nocturnal desaturation is common in patients with treated heart failure. Low ejection fraction was related to dip frequency. Lack of correlation between dips and ESS suggests that arousal from sleep is more important than hypoxia in the aetiology of daytime sleepiness in heart failure. Overnight oximetry is a useful screening test for Cheyne-Stokes respiration in patients with known heart failure.

The effect of dietary creatine supplementation on skeletal muscle metabolism in congestive heart failure.

AIMS: To assess the effects of dietary creatine supplementation on skeletal muscle metabolism and endurance in patients with chronic heart failure. METHODS: A forearm model of muscle metabolism was used, with a cannula inserted retrogradely into an antecubital vein of the dominant forearm. Maximum voluntary contraction was measured using handgrip dynanometry. Subjects performed handgrip exercise, 5 s contraction followed by 5 s rest for 5 min at 25%, 50%, and 75% of maximum voluntary contraction or until exhaustion. Blood was taken at rest and 0 and 2 min after exercise for measurement of lactate and ammonia. After 30 min the procedure was repeated with fixed workloads of 7 kg, 14 kg and 21 kg. Patients were assigned to creatine 20 g daily or matching placebo for 5 days and returned after 6 days for repeat study. RESULTS: Contractions (median (25th, 75th interquartiles)) until exhaustion at 75% of maximum voluntary contraction increased after creatine treatment (8 (6, 14) vs 14 (8, 17), P = 0.025) with no significant placebo effect. Ammonia per contraction at 75% maximum voluntary contraction (11.6 mumol/l/contraction (8.3, 15.7) vs 8.9 mumol/l/contraction (5.9, 10.8), P = 0.037) and lactate per contraction at 75% maximum voluntary contraction (0.32 mmol/l/contraction (0.28, 0.61) vs 0.27 mmol/l/contraction (0.19, 0.49), P = 0.07) fell after creatine but not after placebo. CONCLUSIONS: Creatine supplementation in chronic heart failure augments skeletal muscle endurance and attenuates the abnormal skeletal muscle metabolic response to exercise.

Endogenous insulin and insulin sensitivity. An important determinant of skeletal muscle blood flow in chronic heart failure?

AIM: Patients with heart failure have a reduced sensitivity to insulin's actions on glucose metabolism and a compensatory increase in endogenous plasma insulin levels. As insulin has a selective vasodilatory action in skeletal muscle, we have studied the association between insulin sensitivity and central and regional haemodynamics in patients with heart failure. METHODS: Ten patients with stable symptomatic heart failure were studied. We used non-invasive techniques to measure cardiac output, forearm blood flow, superior mesenteric artery blood flow and right renal artery blood flow. Blood samples were assayed for noradrenaline, renin and atrial natriuretic peptide levels. Insulin sensitivity was assessed using the low dose short insulin tolerance test. RESULTS: There was a significant inverse correlation between forearm blood flow and insulin sensitivity (r = -0.67, P = 0.03), patients with lesser degrees of insulin sensitivity having the greater forearm blood flows. There was no correlation with the other haemodynamic or neurohumoral parameters. Patients with greater insulin resistance tended to have higher circulating endogenous insulin levels, although this relationship did not reach statistical significance (r = -0.53, P = 0.12). CONCLUSIONS: Insulin sensitivity appears to be an important determinant of skeletal muscle blood flow in heart failure. We speculate that this is secondary to the increased circulating endogenous insulin levels, and suggest that the therapeutic potential of exogenous insulin merits further investigation.

Depressor action of insulin on skeletal muscle vasculature: a novel mechanism for postprandial hypotension in the elderly.

OBJECTIVES: We sought to assess the role of insulin in postprandial blood pressure regulation in the elderly. BACKGROUND: Insulin is both a positive inotropic and chronotropic hormone that also vasodilates skeletal muscle vasculature. Insulin may thus mediate aspects of postprandial cardiovascular homeostasis. METHODS: Ten healthy elderly subjects were studied in the fasting state on three separate days. After baseline supine hemodynamic and neurohumoral measurements were taken (cardiac output and superior mesenteric artery blood flow were measured using Doppler ultrasound, and calf blood flow was measured using venous occlusion plethysmography), subjects ate on one occasion a 2.5-MJ high carbohydrate meal and on the other two occasions, an isoenergetic high fat meal. One high fat meal was accompanied by an insulin infusion reproducing the plasma insulin profile seen after a high carbohydrate meal while maintaining the glycemic profile seen after a high fat meal alone. After meal ingestion, measurements were repeated every 20 min for 2 h. RESULTS: After the three meals, there were similar increments in cardiac output and heart rate. After the high carbohydrate meal and high fat meal with insulin, mean arterial blood pressure fell by between 8 to 10 mm Hg, but did not change after the high fat meal. After the high carbohydrate meal and the high fat meal with insulin, calf vascular resistance did not change, whereas after the high fat meal, it increased by 15.5 +/- 4.4 U (mean +/- SEM). CONCLUSIONS: Insulin contributes to the failure of calf vasoconstriction seen after a high carbohydrate meal. By this vasodepressor action, insulin is at least in part responsible for the fall in blood pressure after a high carbohydrate meal.

"Value" of improved treadmill exercise capacity: lessons from a study of rate responsive pacing.

OBJECTIVES: To compare the value of a series of cardiovascular measurements in patients with symptomatic disease receiving an effective treatment (rate responsive pacing). PATIENTS: 12 pacemaker dependent patients with VVIR units. INTERVENTIONS: Single blind crossover between VVI and VVIR. OUTCOME MEASURES: Exercise capacity was assessed by treadmill tests (modified Bruce protocol and a fixed workload protocol) with respiratory gas analysis. Self paced corridor walk tests were also undertaken. Quality of life (QOL) was assessed by questionnaire. Daily activity was measured in the patients' homes using shoe and belt pedometers. RESULTS: Treadmill tests and QOL questionnaires correctly identified the clinical benefit associated with VVIR. The modified Bruce protocol was superior to the fixed workload protocol as it was better tailored to the fairly well preserved exercise capacity of the patients. Symptom scores, but not walking times, were improved with VVIR during corridor walk tests. VVIR did not improve daily activity measured using either the belt or shoe pedometers. CONCLUSIONS: VVIR pacing improved some but not all measures of exercise capacity. This finding illustrates the difficulty of selecting an instrument to measure symptomatic improvement in clinical research; and raises the question, what is the best way of measuring exercise capacity?

Failure of an ACE inhibitor to improve exercise tolerance. A randomized study of trandolapril. Trandolapril study group.

BACKGROUND: There has been conflicting evidence of the effect of angiotensin-converting enzyme (ACE) inhibitors on exercise tolerance. Meta-analysis of published results has suggested that a beneficial effect of ACE inhibitors is demonstrated if a trial design is adequate. SETTING: Multicentre International Trial. METHODS: In a double-blind, randomized, multicentre trial, 292 patients with moderate (New York Heart Association Grades II and III) heart failure were treated with trandolapril or placebo in addition to diuretics, and followed for 16 weeks. Exercise tolerance on a treadmill was assessed at baseline and after 4, 8, 12 and 16 weeks of treatment. Both a modified Bruce and a modified Naughton protocol were used. RESULTS: Exercise tolerance improved in both treatment groups, with no significant benefit from trandolapril treatment. CONCLUSION: Trandolapril does not improve exercise tolerance as measured by treadmill testing.