An Update on the Role of Digoxin in Older Adults with Chronic Heart Failure

Ali Ahmed, MD, MPH, FACC, FAHA, FESC

Geriatrics and Aging. 2008;11(1):37-41. 

Abstract and Heart Failure: A Geriatric Syndrome

Heart failure (HF) is the leading cause of hospitalization among older adults. Digoxin has been shown to reduce hospitalization due to worsening HF. However, at the commonly prescribed dose of 0.25 mg/day, digoxin does not reduce mortality. New data suggest that at low doses (0.125 mg/day or lower) digoxin not only reduces hospitalization due to HF, but may also reduce mortality. Further, at lower doses, it also reduces the risk of digoxin toxicity and obviates the need for routine serum digoxin level testing. Digoxin in low doses should be prescribed to older adults with symptomatic HF.

Heart failure (HF) is common, and with the aging of the population, its incidence and prevalence are projected to rise.^[1,2] Heart failure is a geriatric syndrome as most people with HF are older adults, and HF is the leading cause for hospitalization for the population 65 years and older. Heart failure among older adults is different in many ways than it is among younger individuals. The assessment of HF in older adults is often complicated by underreporting of symptoms, functional impairment, other morbidities with symptoms similar to those of HF, and the presence of a normal left ventricular ejection fraction.^[3,4]

Assessment of Heart Failure in Older Adults

Assessment of HF in older adults can be summarized and simplified by the mnemonic DEFEAT-HF.^[5] D stands for diagnosis: HF is a clinical diagnosis; a clinical diagnosis of HF must be made before echocardiography is ordered as about half of all older adults with HF have normal left ventricular ejection fraction. E represents etiology: HF is a syndrome and not a disease, so an underlying etiology must be determined. This is important as there may be an ongoing ischemia causing further myocardial damage. F indicates fluid volume: the assessment of fluid volume is essential to achieving and maintaining euvolemia, which is needed to reduce hospitalization and improve patients’ quality of life. Further, life-saving therapies such as beta-blockers are ideally initiated when patients are stable and euvolemic. Fluid volume status can be most reliably assessed by estimating jugular venous pressure at the neck. EA stands for ejection fraction: an estimation of ejection fraction, most commonly via echocardiography, is the single most important test after a clinical diagnosis of HF has been made. This is important for both prognostic and therapeutic reasons. Persons with systolic HF generally have a poorer prognosis than do those with diastolic HF or clinical HF with a normal or near-normal ejection fraction. However, the poor prognosis of systolic HF can be favourably modified by the appropriate use of life-saving drugs such as angiotensin-converting enzyme inhibitors (ACEIs) or beta-blockers. T represents treatment: treatment of HF is rapidly evolving, and clinicians should follow the recommendations of a national HF guideline.^[2,6]

Treatment of Systolic Heart Failure: Neurohormonal Blockade

The evidence-based recommendation for pharmacotherapy for chronic HF using neurohormonal antagonists is generally reserved for individuals with systolic HF or clinical HF with a low left ventricular ejection fraction.^[2,6] These recommendations can be summarized as the use of an ACEI for those with systolic HF in the absence of a true contraindication such as angioedema or a past history of allergy or intolerance. Some degree of rise in serum creatinine is expected and should not be considered a contraindication or a past history of intolerance.^[7,8] Individuals who cannot tolerate an ACEI should be prescribed an angiotensin receptor blocker. Patients with systolic HF should also be prescribed a beta-adrenergic receptor blocker that has been shown to reduce the risk of death in these patients, namely, metoprolol succinate extended release, carvedilol, and bisoprolol. There is no need to maximize the dose of an ACEI or an angiotensin receptor blocker before initiating a beta-blocker. Persons with advanced HF may also be treated with an aldosterone antagonist such as spironolactone, or eplerenone for those who cannot tolerate spironolactone. These drugs should be avoided in persons with advanced kidney disease and those with high serum potassium.

Treatment of Heart Failure: Diuretics

Diuretics are commonly used in the treatment of HF, regardless of ejection fraction, and most persons with HF require diuretics to achieve and maintain euvolemia. However, the use of diuretics for HF is the only class I recommendation for drug therapy that is based on level C evidence (generally due to a lack of data from randomized clinical trials or nonrandomized studies).^[2,6] There is growing evidence that the use of diuretics may activate neurohormones and be associated with a poor prognosis.^[9-11] Therefore, once euvolemia is achieved, the dose of diuretic should be reduced to the lowest dose that will maintain euvolemia. Torsemide may be superior to furosemide as it is less likely to cause neurohormonal activation and hypokalemia.^[12,13] Low serum potassium is common in HF and is worsened by the use of diuretics. Serum potassium <4 mEq/L may be associated with increased mortality in HF.^[14] Serum potassium should be kept at approximately 4.5 mEq/L for persons with chronic HF.^[15] While potassium supplements may be used to correct hypokalemia, aldosterone antagonists may be superior to potassium supplements in maintaining normokalemia.^[16]

Treatment of Heart Failure: Digitalis

Digitalis glycosides, discovered first by 18th-century English physician Dr. William Withering and derived from the leaves of the foxglove plant, are among the oldest cardiovascular drugs.^[17,18] Long known as a positive inotrope, digoxin (obtained from Digitalis lanata) acts by improving the contractile function of both the failing and normal heart.^[19] At the cellular level, digitalis inhibits the sodium-potassium adenosine triphosphatase enzyme, thus increasing the intracellular concentration of calcium. However, digoxin also acts as neurohormonal modulator, and much of the beneficial effects of digoxin may be due to its neurohormonal suppressing properties.^[6] Digoxin is approved by the U.S. Food and Drug Administration for use in chronic HF and is recommended for use by the Canadian Cardiovascular Society guideline for diagnosis and management of HF.^[20,21,22] Digoxin is the most commonly used digitalis and was the digitalis used in the Digitalis Investigation Group trial, the only randomized clinical trial of digitalis in chronic HF.^[23]

The Digitalis Investigation Group Trial

In the Digitalis Investigation Group trial, 7,788 individuals with chronic HF were randomly assigned to receive digoxin or placebo.^[23] Most of these persons were already receiving an ACEI and a diuretic. Of the 7,788 participants, 6,800 had systolic HF and were enrolled in the main trial and followed up for a median of 37 months. Digoxin had no effect on mortality among those with systolic HF (relative risk [RR] 0.99, 95% confidence interval [CI] 0.91-1.07) but reduced hospitalization resulting from worsening HF (RR 0.72, 95% CI 0.66-0.79).^[23] Among individuals with diastolic HF enrolled in the ancillary trial, digoxin had similar effects: no influence on mortality (RR 0.99, 95% CI 0.76-1.28) but a reduction in hospitalization due to worsening HF (RR 0.79, 95% CI 0.59-1.04).^[24] This latter association was not statistically significant, likely due to the small sample size in the DIG ancillary trial.

Low Serum Digoxin Concentration and Reduction in Mortality in Heart Failure

A comprehensive post hoc analysis of the Digitalis Investigation Group trial that included men and women with systolic and diastolic HF demonstrated that at low serum digoxin concentrations (0.5-0.9 ng/mL), the use of digoxin was associated with reductions in mortality and hospitalization.^[25] Compared with individuals receiving placebo, those with serum digoxin concentrations 0.5-0.9 ng/mL had lower risks of death due to all causes (adjusted hazard ratio [AHR] 0.77, 95% CI 0.67-0.89) and hospitalization due to all causes (AHR 0.85, 95% CI 0.78-0.92). A repeat of these analyses using propensity score matching yielded similar results: the use of digoxin at low serum digoxin concentrations (0.5-0.9 ng/mL) was associated with reductions in all-cause mortality (hazard ratio [HR] 0.81, 95% CI 0.68-0.98) and cardiovascular hospitalization (HR 0.82, 95% CI 0.70-0.95)^[26] Digoxin reduced hospitalizations due to worsening HF regardless of serum digoxin concentrations.

Effects of Digoxin in Older Adults with Chronic HF

A subgroup analysis of the Digitalis Investigation Group trial participants 65 years and older demonstrated that use of digoxin at low serum digoxin concentrations (0.5-0.9 ng/mL) was associated with reductions in all-cause mortality (AHR 0.81, 95% CI 0.680-0.96) (Figure 1) and all-cause hospitalization (AHR 0.86, 95% CI 0.76-0.98)^[27]

Findings from that study also suggest that the dose of digoxin was the strongest predictor of serum digoxin concentration among older adults, while use of diuretics was the strongest predictor of serum digoxin concentration among persons <65 years. Patient characteristics independently associated with low serum digoxin concentrations are presented in Figure 2.

Practical Tips for the Use of Digoxin in Older Adults with Chronic Heart Failure

Older adults with symptomatic HF should be prescribed digoxin in low doses starting at 0.125 mg/d. For persons with HF who are 75 years and older, are women, have renal insufficiency, are receiving large doses of diuretics, or have pulmonary edema, digoxin should be prescribed as 0.125 mg every other day. There is no need for routine laboratory testing of serum digoxin concentrations. However, if patients remain symptomatic at these low doses of digoxin, serum digoxin concentration should be checked before increasing the dose to 0.25 mg/d. Serum digoxin concentration should be checked at least 6 hours after the last dose of digoxin. If used in low doses, digoxin is unlikely to cause digoxin toxicity for older adults with HF.

Generally, for clinically stable new systolic HF patients, it may be preferable to initiate therapy with digoxin after initiation of therapy with an ACEI or an angiotensin receptor blocker, a beta-blocker, and an aldosterone antagonist, as appropriate. However, if a patient is symptomatic despite receiving above medications in appropriate dosages, and especially for patients with recurrent hospital admission due to worsening HF, digoxin should be prescribed on an initial visit. Digoxin should also be prescribed to any patients who cannot afford or tolerate an ACEI or an angiotensin receptor blocker, a beta-blocker, and an aldosterone antagonist. Digoxin should not be discontinued in those with known HF who are already receiving that drug.^[28] Symptomatic patients with diastolic HF may also benefit from therapy with digoxin; it should be prescribed using a similar protocol to that described above.^[23,28]

Conclusions

Heart failure is a common disorder associated with significant morbidity and mortality. It is the leading cause of hospital admission for adults 65 years and older, and worsening HF is the most common cause for hospitalization for persons with HF. Digoxin has been proven to reduce hospitalization due to HF and, if used in low doses, may also reduce mortality. Digoxin should be considered in the treatment of older adults with chronic HF.

Geriatrics and Aging. 2008;11(1):37-41. © 2008  1453987 Ontario, Ltd.

Cite this: An Update on the Role of Digoxin in Older Adults with Chronic Heart Failure - Medscape - Jan 01, 2008.