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Drug Info Question #1 Internal Medicine Rotation Question: I just read something about digoxin causing an increased risk of death in women who use it for heart failure. Is this true? Is there any literature available on this subject? Should I D/C digoxin in all my female patients? Please clarify this issue. Background Information: Currently, digoxin is indicated for the treatment of congestive heart failure (CHF), tachyarrhythmias, and cardiogenic shock.1 Digoxin exerts a positive inotropic effect and a negative chronotropic effect. Although used for over 200 years for a variety of cardiac conditions, the safety, efficacy, and beneficial serum levels of digoxin are often questioned.2 In 1997, the results of the Digitalis Investigational Group (DIG) trial were published in the New England Journal of Medicine. This randomized, double-blind, placebo controlled clinical trial evaluated the role of digoxin in 6,800 CHF patients in terms of mortality and hospitalizations.2 These results indicated when digoxin is used concomitantly with an ACE Inhibitor and a diuretic in patients with an ejection fraction 45% or less, the only statistically significant conclusion was a reduction in the rate of overall hospitalizations and hospitalizations due to worsening CHF (26.8% in patients receiving digoxin vs. 34.7% in patients receiving placebo; risk ratio, 0.72; 95% confidence interval, 0.66 to 0.79; P<0.001).2 No statistically significant difference was found between the two groups in terms of mortality.2 However, the DIG trial had nearly four times the number of men than women. Sex-based differences in terms of mortality would have been skewed by this disproportionate ratio. In October 2002, a post hoc subgroup analysis was published in the NEJM that evaluated sex-based outcomes, like mortality, in patients receiving digoxin.3 The result of this study were surprising: “Digoxin therapy is associated with an increased risk of death from any cause among women, but not in men, with heart failure and depressed left ventricular systolic function.”3 This conclusion should be analyzed further by reviewing patient characteristics, the actual data collected, and methods used to collect the data before the safety and efficacy of digoxin use in women can truly be established. Information Obtained: Although there were no statistically significant differences between baseline characteristics of men receiving digoxin therapy compared to men receiving the placebo, and women receiving digoxin compared to women receiving the placebo, there were statistically significant differences between the men and women.3 When compared, women were older, had higher ejection fractions, heart rates, cardiothoracic ratios, and more significant histories of diabetes, hypertension, angina, prior digoxin use, and had a higher percentage classified as NYHA class III or IV. Women did however have a lower serum creatinine, and a less significant history in terms of rales or ischemia when compared to men. The primary outcome of the post hoc analysis was mortality.3 In terms of this outcome, women were associated with an increased risk of death with digoxin use (33.1% in the digoxin group vs. 28.9% in the placebo group; absolute difference, 4.2%; 95% confidence interval, -0.5 to 8.8; P=0.034), but the men did not exhibit this associated risk (35.2% in the digoxin group vs. 36.9% in the placebo group; absolute difference, -1.6%; 95% confidence interval, -4.2 to 1.0). A subsequent multivariable analysis adjustment revealed women had a statistically significant increased risk of death using digoxin (hazard ratio, 1.23; 95% confidence interval, 1.02 to 1.47; P=0.014), while men had a non-significant reduction in terms of mortality (hazard ratio, 0.93; 95% confidence interval, 0.85 to 1.02). The absolute difference in terms of mortality between women and men using digoxin was 5.8% (95% confidence interval, 0.5 to 11.1). These results do not necessarily support the discontinuation of digoxin in women.3 A subgroup analysis does not provide answers that are as definitive as those obtained from a prospective study. In a retrospective study, the baseline patient characteristics cannot be adjusted at the start and no additional possible pertinent medical data may be collected. For example, the Heart and Estrogen/Progestin Replacement Study found an increase rate of cardiovascular events in patients receiving digoxin and hormone replacement therapy (HRT).3 In the DIG trial and this subsequent subgroup analysis, we do not know the percentage of women who where receiving HRT during the investigation, and how this interaction might have increased the mortality of women. The accompanying editorial to the article evaluating sex-based differences stressed the fact that digoxin serum levels may have played a significant role in the findings.4 The women in the study had a significantly higher digoxin level at one month of use than the men (0.9 ng per ml vs. 0.8 ng per ml, P=0.007).4 Since digoxin has a narrow therapeutic index and recent data supports maintaining a lower serum digoxin level, the increased mortality in women may have been due to a digoxin dose that was simply too high.4,5 Based on this retrospective study, it is not necessary to discontinue digoxin in women. In fact the PROVED (Prospective Randomized study of Ventricular failure and Efficacy of Digoxin) and RADIANCE (Randomized Assessment of Digoxin on Inhibitors of Angiotensin-Converting Enzyme) studies revealed withdrawing the drug worsens heart failure.6 Proper initiation and appropriate therapeutic monitoring is necessary for digoxin use in women and men. The HFSA (Heart Failure Society of America) guidelines state: “Digoxin should be considered for patients who have symptoms of heart failure (NYHA class II-III, Strength of Evidence A and NYHA class IV, Strength of Evidence C) caused by left ventricular systolic dysfunction while receiving started therapy” (i.e. diuretics, ACEIs).7 Careful monitoring of digoxin levels throughout therapy is required. Most patients should maintained in the 0.5 to 1 ng/ml range, since higher ranges may be deleterious to the patient’s health.6 In fact, higher levels have been associated with adrenergic stimulation and arrhythmias, which can lead to an increased mortality rate.4 Summary: Based on the DIG trial, a statistically significant association between digoxin use and increased mortality was not established. A retrospective analysis of this study focused on sex-based differences in terms of mortality revealed a statistically significant higher mortality rate for women using digoxin, but not for men. However, this study does have noteworthy drawbacks that weaken the conclusion. Several questions may be answered from this study though. 1. Should all women be discontinued from digoxin based on these findings? Certainly not. There are several considerable studies, such as PROVED and RADIANCE, that emphasize the benefits of continued digoxin therapy. 2. Should digoxin be initiated in all women? The current guidelines should be followed when initiating digoxin therapy. However, careful monitoring of serum levels, clinical effects, and drug interactions should be undertaken in both men and women. 3. Should more research concerning women and digoxin use be conducted? Absolutely. This perhaps was the most important conclusion drawn from the study. References 1. Lacy CF, Armstrong LL, Goldman MP, et al. Drug information handbook. 9th ed. Hudson:Lexi-Comp Inc.; 2001. 2. Garg R, Gorlin R, Smith T, et al. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997; 336(8):525-33. 3. 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(18):140311. 4. Eichorn EJ, Gheorghiade M. Increased mortality among women with heart failure treated with digoxin N Engl J Med. 2002; 347(18):1395-5. Perspective 5. Adams KF Jr, Gheorghiade M, Uretsky BF, et al. Clinical benefits of low serum digoxin concentrations in heart failure. J Am Coll Cardio. 2002; 39(6):954-6. 6. McGuinness ME and Talbert RL. Cardiovascular testing. In: Pharmacotherapy: A pathophysiologic approach. 5th ed. Dipiro JT, Talbert RL, Yee GC, et al., eds. New York:McGraw-Hill: 2002:123-43. 7. Adams KF, Baughman KL, Dec WG, et al. HFSA Practice Guidelines. Pharmacotherapy. 2000; 20(5):455-521.