Digoxin and mortality in chronic heart failure S J Lindsay, M T Kearney, R J Prescott, K A A Fox, J Nolan, for the UK Heart Investigation Data from recent clinical trials suggest digoxin is now widely used in patients with chronic heart failure in sinus rhythm. We present data from a heart failure registry that reiterates concerns about the safety of digoxin in this population.
Digoxin has been used in the treatment of chronic heart failure for over 200 years. During this time controversy has continued as to whether its clearly established acute haemodynamic effects are translated into long-term benefit. The first large-scale randomised placebo-controlled clinical trial of digoxin in patients with heart failure in sinus rhythm (The DIG study)1 showed an overall neutral effect on mortality. However, close examination of the results revealed a significant reduction in death due to progressive heart failure but a concomitant increase in other cardiovascular deaths (presumed arrhythmic in origin), which offset the beneficial effect. Digoxin is now widely used in patients with chronic heart failure with persistent symptomatic limitation after optimal diuretic and ACEinhibitors (52% of patients in CIBIS II and 63% in MERITHF when only 20% and 16% respectively were in atrial fibrillation.)2,3 Because of continuing concerns about safety, we evaluated the prognostic significance of digoxin in patients recruited to the UK HEART study.4 This was a prospective study of prognostic markers in ambulant outpatients in sinus rhythm with stable chronic heart failure undergoing usual care in several UK centres. Recent myocardial infarction was an exclusion criteria. UK HEART demonstrated that the SD of the normal to normal of 24-h RR intervals (SDNN) was an independent predictor of mortality along with cardiothoracic ratio (CTR), left ventricular end systolic dimension (LVESD), and serum sodium. The demographic characteristics of our population were broadly similar to those of the DIG study. We followed 484 patients of New York Heart Association (NYHA) class 2·4 (SD 0·6) for 1014 (360) days. There were 90 patients taking digoxin (mean dose 200 [71] g, median 250 g), of whom 44 were NYHA class II. All cause mortality was 24·5% (119 deaths). For patients treated with digoxin, mortality was 38·9% vs 21·3% for those not taking digoxin (p⭐0·001). Renal functional and serum potassium did not differ in patients on digoxin. To determine whether digoxin usage was independently associated with mortality, we did a multivariate analysis using the Cox proportional-hazards model. When digoxin use was adjusted for, several predictive variables (age, diuretic dose, NYHA
Adjusted survival curves for patients taking and not taking digoxin
THE LANCET • Vol 354 • September 18, 1999
class, CTR, SDNN, LVESD, serum sodium, presence of non-sustained ventricular tachycardia and anti-arrhythmic therapy) it remained an independent predictor of mortality (see figure). This result was consistent across several other multivariate models. These data should be interpreted with care, because the analysis is retrospective and digoxin use was not randomised. Nonetheless, in a variety of multivariate models digoxin was independently associated with an adverse prognosis. Spargias and colleagues reported similar findings in post-infarct patients with left ventricular dysfunction enrolled in the AIRE study.5 Taken in combination these concordant results from UK-HEART and AIRE suggest that, in routine clinical practice, there may be a deleterious shift in the risk benefit ratio associated with digoxin therapy, resulting in an overall adverse effect on mortality. For patients with heart failure that is not adequately controlled by a diuretic and ACE inhibitor alone, spironolactone and beta blockers may be superior to digoxin, irrespective of the timing of previous myocardial infarction. 1
The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336: 525–33. 2 CIBIS-II Investigators. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999; 353: 9–13. 3 MERIT-HF Study Group. Effect of metroprolol CR/XL in chronic heart failure: metoprolol CR/LX randomised intervention trial in congestive heart failure (MERIT-HF). Lancet 1999; 353: 2001–07. 4 Nolan J, Batin PD, Andrews R, et al. 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). Circulation 1998; 98: 1510–16. 5 Spargias KS, Hall AS, Ball SH. Safety concerns about digoxin after acute myocardial infarction. Lancet 1999; 354: 391–92.
Institute for Cardiovascular Research, Leeds General Infirmary, Great George Street, Leeds, LS1 3EX (S J Lindsay MD, M T Kearney DM), Departments of Medical Statistics (R J Prescott PhD) and Cardiology (K A A Fox FRCP), University of Edinburgh and North Staffordshire Hospital Cardiac Services Directorate, City General, Newcastle Road, Stoke on Trent, Staffordshire, ST4 6QG (J Nolan MD) Correspondence to: Dr J Nolan
Prophylaxis against respiratory syncytial virus in premature infants L Bont, A J van Vught, J L L Kimpen Postconceptional age was studied in 33 mechanically ventilated preterm infants with respiratory syncytial virus (RSV) bronchiolitis. Preterm infants without chronic lung disease had an increased risk of severe RSV infection until a postconceptional age of 44 weeks.
Prematurity, with or without the presence of chronic lung disease, is regarded as a risk factor for severe respiratory syncytial virus (RSV) infection, commonly resulting in the need for mechanical ventilation.1 New strategies to prevent severe RSV infection in preterm infants will soon become available; these strategies include administration of palivizumab, a humanised RSV monoclonal antibody.2 However, the necessary duration of RSV prophylaxis in preterm infants is not known. We hypothesised that the length of time premature infants remain at risk of severe RSV infection is determined by postconceptional age. We studied postconceptional age (in weeks) on admission in all preterm infants without congenital heart disease admitted to a paediatric intensivecare unit for mechanical ventilation during a period of 5 years. Prematurity was defined as a gestational age at birth of 36 weeks or less.
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