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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.