Is digoxin still useful in the treatment of heart failure?

As most patients with heart failure remain symptomatic despite optimal medical treatment, there is a continuing need for drugs that improve symptoms, functional capacity, exercise tolerance, and quality of life.

Digitalis glycosides owe their effects in heart failure to their ability to inhibit the Na+/K+ adenosine triphosphatase pump, thereby increasing Ca2+ availability to contractile proteins and the contractile function of the heart. Thus, for many decades positive inotropism was considered mainly responsible for the benefits of digitalis in heart failure. However, digitalis may also inhibit enzymes in noncardiac tissues, eg, the central nervous system and kidney, or even exert its principal effect in heart failure by attenuating neurohumoral system activation.

Several digoxin trials have shown that its main benefit is to alleviate symptoms and improve clinical status in mild-to-moderate heart failure, regardless of etiology (ischemic or nonischemic), concomitant atrial fibrillation, or concomitant therapy (P-block-ade and/or angiotensin-converting enzyme [ACE] inhibition). In the Randomized Assessment of’the effect of Digoxin on Inhibitors of the ANgiotensin Converting Enzyme (RADIANCE) and the Prospective Randomized study Of Ventricular failure and Efficacy of Digoxin (PROVED), digoxin withdrawal was associated with clinical deterioration, mostly in patients with idiopathic dilated cardiomyopathy. The Digitalis Investigation Group (DIG) trial, in 6800 patients with chronic heart failure, is the only randomized placebo-controlled trial to have evaluated the long-term effects of digoxin therapy (follow-up: >37 months). Although there was little or no effect on either all-cause mortality (34.8% on digoxin vs 35.1% on placebo) or cardiovascular mortality (29.9% on digoxin vs 29.5% on placebo), positive effects were observed in terms of symptom relief and a decreased hospitalization rate, with a trend towards a decreased risk of death from worsening heart failure (11.6% on digoxin vs 13.2% on placebo group, P<0.06). However, this was offset by an apparent increase in deaths presumed due to arrhythmias and in deaths from atherosclerotic coronary artery disease. Several sources indicate that medium to high doses of digoxin carry a higher risk of adverse effects. Doses should therefore be low enough to maintain the blood level below 1 nmol/L. The finding that digoxin has little effect on survival has restricted its indications to patients whose symptoms persist after receiving drugs that decrease the risk of death and hospitalization (P-blockers and ACE inhibitors). Since digoxin acts mainly on the symptoms of the disease and not its progression, it can be used whenever symptom relief is required or reserved for patients whose symptoms persist despite other treatments. Digoxin is considered most appropriate in patients with heart failure and atrial fibrillation with a high ventricular rate, although a P-blocker may be more effective in controlling the ventricular response to exercise. In patients receiving other drugs that can depress sinus or atrioventricular node function, digoxin should be used with caution. Digoxin is not indicated either to stabilize acutely decompensated heart failure (unless rapid atrial fibrillation is present) or in asymptomatic left ventricular dysfunction (New York Heart Association class I). Since it has no demonstrable effect on progression in symptomatic patients, it is unlikely to benefit those with no symptoms. A recent post-hoc analysis of the DIG trial showed gender differences in the effect of digoxin in heart failure. The 755 women randomized to digoxin had a worse prognosis than those randomized to placebo, with a 1.92 adjusted hazard ratio of cardiovascular death. In summary, digoxin may be recommended at a low dose in men whose heart failure symptoms persist despite adequate diuretic therapy, ACE inhibition, and p-blockade. Gheorghiade M. Neurohumoral effects of digoxin: a target for further investigation. Cardiologia. 1996;41.967-972. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2001;38:2101-2113. Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med. 1993;329:1 -7. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med. 2002;347:1403-1411. Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Task Force for the Diagnosis and Treatment of Chronic Heart Failure, European Society of Cardiology. Eur Heart J. 2001 ;22:1527-1560. Rich MW, McSherry F, Williford WO, Yusuf S. Effect of oge on mortality, hospitalizations and response to digoxin in patients with heart failure: ihe DIG study. Digitalis Investigation Group. J Am Coll Cardiol. 2001 ;38:806-813. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med. 1997;336:525-533. Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, Jolty MK. Randomized study assessing the effect of digoxin withdrawal ;n Dartents with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol. 1993,22:955-962. Keywords drug; digoxin; functional capacity; survival; symptomatic treatment [gallery ids=""]

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