A.J. Cowley

Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE)

BACKGROUND To determine whether specific angiotensin II receptor blockade with losartan offers safety and efficacy advantages in the treatment of heart failure over angiotensin-converting-enzyme (ACE) inhibition with captopril, the ELITE study compared losartan with captopril in older heart-failure patients. METHODS We randomly assigned 722 ACE inhibitor naive patients (aged 65 years or more) with New York Heart Association (NYHA) class II-IV heart failure and ejection fractions of 40% or less to double-blind losartan (n = 352) titrated to 50 mg once daily or captopril (n = 370) titrated to 50 mg three times daily, for 48 weeks. The primary endpoint was the tolerability measure of a persisting increase in serum creatinine of 26.5 mumol/L or more (> or = 0.3 mg/dL) on therapy; the secondary endpoint was the composite of death and/or hospital admission for heart failure; and other efficacy measures were total mortality, admission for heart failure, NYHA class, and admission for myocardial infarction or unstable angina. FINDINGS The frequency of persisting increases in serum creatinine was the same in both groups (10.5%). Fewer losartan patients discontinued therapy for adverse experiences (12.2% vs 20.8% for captopril, p = 0.002). No losartan-treated patients discontinued due to cough compared with 14 in the captopril group. Death and/or hospital admission for heart failure was recorded in 9.4% of the losartan and 13.2% of the captopril patients (risk reduction 32% [95% CI -4% to + 55%], p = 0.075). This risk reduction was primarily due to a decrease in all-cause mortality (4.8% vs 8.7%; risk reduction 46% [95% CI 5-69%], p = 0.035). Admissions with heart failure were the same in both groups (5.7%), as was improvement in NYHA functional class from baseline. Admission to hospital for any reason was less frequent with losartan than with captopril treatment (22.2% vs 29.7%). INTERPRETATION In this study of elderly heart-failure patients, treatment with losartan was associated with an unexpected lower mortality than that found with captopril. Although there was no difference in renal dysfunction, losartan was generally better tolerated than captopril and fewer patients discontinued losartan therapy. A further trial, evaluating the effects of losartan and captopril on mortality and morbidity in a larger number of patients with heart failure, is in progress.

Prospective Study of Heart Rate Variability and Mortality in Chronic Heart Failure Results of the United Kingdom Heart Failure Evaluation and Assessment of Risk Trial (UK-Heart)

BACKGROUND Patients with chronic heart failure (CHF) have a continuing high mortality. Autonomic dysfunction may play an important role in the pathophysiology of cardiac death in CHF. UK-HEART examined the value of heart rate variability (HRV) measures as independent predictors of death in CHF. METHODS AND RESULTS In a prospective study powered for mortality, we recruited 433 outpatients 62+/-9.6 years old with CHF (NYHA functional class I to III; mean ejection fraction, 0.41+/-0.17). Time-domain HRV indices and conventional prognostic indicators were related to death by multivariate analysis. During 482+/-161 days of follow-up, cardiothoracic ratio, SDNN, left ventricular end-systolic diameter, and serum sodium were significant predictors of all-cause mortality. The risk ratio for a 41.2-ms decrease in SDNN was 1.62 (95% CI, 1.16 to 2.44). The annual mortality rate for the study population in SDNN subgroups was 5.5% for >100 ms, 12.7% for 50 to 100 ms, and 51.4% for <50 ms. SDNN, creatinine, and serum sodium were related to progressive heart failure death. Cardiothoracic ratio, left ventricular end-diastolic diameter, the presence of nonsustained ventricular tachycardia, and serum potassium were related to sudden cardiac death. A reduction in SDNN was the most powerful predictor of the risk of death due to progressive heart failure. CONCLUSIONS CHF is associated with autonomic dysfunction, which can be quantified by measuring HRV. A reduction in SDNN identifies patients at high risk of death and is a better predictor of death due to progressive heart failure than other conventional clinical measurements. High-risk subgroups identified by this measurement are candidates for additional therapy after prescription of an ACE inhibitor.

Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure

BACKGROUND Drugs that improve symptoms in patients with heart failure must also be assessed for their effects on survival. Ibopamine stimulates DA-1 and DA-2 receptors and causes peripheral and renal vasodilatation; the drug improves symptoms of heart failure. We assessed the effect of ibopamine on survival in patients with advanced heart failure in a multicentre, randomised placebo-controlled study. METHODS Patients with advanced severe heart failure (New York Heart Association classes III and IV) and evidence of severe left-ventricular disease, who were already receiving optimum treatment for heart failure, were randomly allocated oral ibopamine 100 mg three times daily or placebo. The primary endpoint was all-cause mortality. The study was designed to recruit 2200 patients, and the minimum duration of treatment would be 6 months. We did intention-to-treat and on-treatment analyses; a post-hoc subgroup analysis was also done. FINDINGS After we had recruited 1906 patients the trial was stopped early, because of an excess of deaths among patients in the ibopamine group. 232 (25%) of 953 patients in the ibopamine group died, compared with 193 (20%) of 953 patients in the placebo group (relative risk 1.26 [95% CI 1.04-1.53], p = 0.017). The average length of follow-up was 347 days in the ibopamine group and 363 days in the placebo group. In multivariate analysis, only the use of antiarrhythmic drugs at baseline was a significant independent predictor of increased fatality in ibopamine-treated patients. INTERPRETATION Ibopamine seems to increase the risk of death among patients with advanced heart failure who are already receiving optimum therapy, but the reasons for this increase are not clear. Our finding that antiarrhythmic treatment was a significant predictor of increased mortality in ibopamine-treated patients may be important, but exploratory analyses must be interpreted with caution.

Why are angiotensin converting enzyme inhibitors underutilised in the treatment of heart failure by general practitioners

Treatment with angiotensin converting enzyme inhibitors confers significant morbidity and mortality benefits in patients with heart failure, yet previous studies have repeatedly shown that these drugs are underutilised in general practice. To investigate why this is the case, we conducted an anonymous questionnaire survey of 515 general practitioners in the Nottingham Health District. The response rate was 60.2%. We found that although 39.3% of respondents underestimated the poor prognosis associated with heart failure, 98% were aware of the prognostic benefits conferred by angiotensin converting enzyme inhibitors. However, 46.3% of respondents expressed concern about the potential adverse effects associated with angiotensin converting enzyme inhibitors, the main fears being hypotension and renal impairment. General practitioners who were concerned about adverse effects were significantly less likely to have initiated an angiotensin converting enzyme inhibitor for heart failure than those who were not (P<0.01). Further research is needed to identify which patients can safely be commenced on angiotensin converting enzyme inhibitors in general practice. In the meantime, general practitioners should be encouraged to refer patients whenever they are concerned about initiating angiotensin converting enzyme inhibitors in the community.

CAPTOPRIL THERAPY FOR HEART FAILURE: A Placebo Controlled Study

Abstract In a placebo controlled study, the angiotensin-converting enzyme inhibitor captopril significantly improved exercise tolerance in ten patients with severe heart failure whose symptoms were not controlled with digoxin and diuretics. Serial measurements of forearm vascular resistance (an indirect index of arteriolar tone) and of venous tone were made. Improvement in exercise performance was correlated significantly with reduction in forearm vascular resistance caused by captopril.

Flosequinan in heart failure: acute haemodynamic and longer term symptomatic effects.

There is no single, simple test with which to evaluate new treatments for heart failure. Various methods need to be used, and a study of both the acute haemodynamic and longer term symptomatic effects of flosequinan, a new direct acting arteriolar and venous vasodilator, was therefore carried out in patients with heart failure. In one group of patients flosequinan increased cardiac output and caused a fall in pulmonary capillary wedge pressure, both effects lasting for 24 hours. In a double blind, placebo controlled study in another group flosequinan improved mean exercise tolerance from 9.9 to 12.7 minutes after four weeks of treatment. The drug also reduced perceived exertion during submaximal exercise and increased calf and therefore skeletal muscle blood flow. It reduced plasma renin activity and noradrenaline concentrations. Flosequinan possesses all the important properties of a drug likely to be of value in the treatment of heart failure.

Clinical and economic factors in the treatment of congestive heart failure.

SummaryCongestive heart failure (CHF) is a disease of massive clinical and economic importance throughout the developed world. Approximately 1 % of the population are affected, with incidence and prevalence of CHF increasing with age. The major aetiological factor is ischaemic heart disease and, despite advances in treatment, mortality from CHF remains appallingly high, and comparable to that of many mal ignancies. The majority of patients with CHF require treatment with a diuretic, though there is now clear evidence that the addition of an angiotensin converting enzyme (ACE) inhibitor will not only improve symptoms but also reduce mortality and delay the progression of the disease. The vast economic impact of CHF is now becoming fully appreciated, with the majority of expenditure on hospital admissions. The earlier and more widespread use of ACE inhibitors in the treatment ofCHF would be highly cost effective, with substantial savings in hospitalisation costs, though new and effective treatments are still urgently required.

Assessing exercise capacity, quality of life and haemodynamics in heart failure: do the tests tell us the same thing?

The objective measurement of exercise tolerance is an important component of heart failure trials. The use of laboratory‐based treadmill exercise testing has attracted criticism, however, as being unrepresentative of patients’ true capabilities.

The diagnosis of heart failure in general practice: Implications for the UK National Service Framework

The UK National Service Framework recommends patients with suspected heart failure undergo echocardiography. Selection of patients for this investigation in primary care is difficult. It is not clear which clinical features best identify patients with left ventricular systolic dysfunction.

Is dialysis hypotension caused by an abnormality of venous tone

The role of peripheral vascular tone in the development of hypotension induced by dialysis was investigated in eight patients undergoing haemodialysis with acetate or bicarbonate buffered fluid. Each patient had two sessions of dialysis with acetate fluid and two with bicarbonate fluid in the order acetate, bicarbonate, bicarbonate, acetate or bicarbonate, acetate, acetate, bicarbonate. Mean arterial blood pressure fell at a mean rate of 3·9 mm Hg/hour during dialysis with acetate fluid and 1·4 mm Hg/hour during dialysis with bicarbonate fluid. The rate of fall was significantly greater during dialysis with acetate fluid compared with bicarbonate fluid. Heart rate increased by a mean rate of 2·6 beats/min/hour during dialysis with both acetate and bicarbonate fluid. Vascular resistance in the forearm increased at a rate of 3·6 units/hour during dialysis with acetate fluid and 4·5 units/hour during dialysis with bicarbonate fluid, but the venous bed of the forearm dilated. The index of venous tone rose at a mean rate of 0·23 ml/100 dl over 40 mm Hg/hour during dialysis with acetate fluid and 0·20 ml/dl over 40 mm Hg/hour during dialysis with bicarbonate fluid. Inappropriate peripheral venodilatation may be important in the development of hypotension induced by dialysis.