Original Article
Sex-Based Differences in the Effect of Digoxin for the Treatment of Heart Failure
N Engl J Med 2002; 347:1403-1411October 31, 2002
- Abstract
Background
The Digitalis Investigation Group trial reported that treatment with digoxin did not decrease overall mortality among patients with heart failure and depressed left ventricular systolic function, although it did reduce hospitalizations slightly. Even though the epidemiologic features, causes, and prognosis of heart failure vary between men and women, sex-based differences in the effect of digoxin were not evaluated.
Methods
We conducted a post hoc subgroup analysis to assess whether there were sex-based differences in the effect of digoxin therapy among the 6800 patients in the Digitalis Investigation Group study. The presence of an interaction between sex and digoxin therapy with respect to the primary end point of death from any cause was evaluated with the use of Mantel–Haenszel tests of heterogeneity and a multivariable Cox proportional-hazards model, adjusted for demographic and clinical variables.
Results
There was an absolute difference of 5.8 percent (95 percent confidence interval, 0.5 to 11.1) between men and women in the effect of digoxin on the rate of death from any cause (P=0.034 for the interaction). Specifically, women who were randomly assigned to digoxin had a higher rate of death than women who were randomly assigned to placebo (33.1 percent vs. 28.9 percent; absolute difference, 4.2 percent, 95 percent confidence interval, –0.5 to 8.8). In contrast, the rate of death was similar among men randomly assigned to digoxin and men randomly assigned to placebo (35.2 percent vs. 36.9 percent; absolute difference, –1.6 percent; 95 percent confidence interval, –4.2 to 1.0). In the multivariable analysis, digoxin was associated with a significantly higher risk of death among women (adjusted hazard ratio for the comparison with placebo, 1.23; 95 percent confidence interval, 1.02 to 1.47), but it had no significant effect among men (adjusted hazard ratio, 0.93; 95 percent confidence interval, 0.85 to 1.02; P=0.014 for the interaction).
Conclusions
The effect of digoxin therapy differs between men and women. Digoxin therapy is associated with an increased risk of death from any cause among women, but not men, with heart failure and depressed left ventricular systolic function.
Media in This Article
Figure 1
Kaplan–Meier Estimates of Survival among Men and Women, According to Whether They Were Randomly Assigned to Receive Digoxin or Placebo.Table 1
Characteristics of the Patients.Article Activity
- Article
In 1997, the Digitalis Investigation Group reported the results of a randomized, double-blind, placebo-controlled trial evaluating the efficacy of digoxin therapy for patients with heart failure.1 The investigators found that digoxin did not reduce overall mortality or three of the five secondary outcomes (death due to cardiovascular causes, death due to worsening heart failure, and the combined end point of death or hospitalization due to worsening heart failure in an ancillary trial). However, digoxin did decrease the risk of hospitalization for worsening heart failure and the overall risk of hospitalization during three years of follow-up. Since these results were published, the American College of Cardiology and American Heart Association,2 the European Society of Cardiology,3 and the Heart Failure Society of America4 have issued clinical guidelines that strongly endorse the use of digoxin for patients with heart failure.
Although men and women differ with respect to the risk, causes, and prognosis of heart failure,5 the Digitalis Investigation Group trial did not prespecify or report sex-specific subgroup analyses, and current clinical guidelines do not differentiate between the use of digoxin in men and the use of this agent in women. The majority of deaths attributable to heart failure occur in women,6 even though women with heart failure have a lower risk of death than men.7-10 Women with heart failure have more symptoms than men with similar ejection fractions,11 are older,8 and are more likely to have hypertension,12 diabetes mellitus,13 and preserved systolic function.13 Sex-based or sex hormone–associated differences have also been documented in myocardial-cell function,14-16 signal transduction and ion-channel activity,15,17-20 autonomic nervous system function,14 muscle metabolism,21 and cardiac-cell growth.16,22,23 Because the Digitalis Investigation Group trial enrolled nearly four men for every woman,24 any differences in the effect of digoxin among women would have been subsumed by the effect of digoxin therapy among men. Accordingly, we assessed whether the effect of digoxin therapy varied according to the sex of the patients in the Digitalis Investigation Group trial.
Methods
Trial Data Base
We obtained a public-use copy of the data base of the Digitalis Investigation Group trial by submitting a written request to the National Heart, Lung, and Blood Institute. None of the authors were members of the Digitalis Investigation Group Investigators, and thus none were involved in the conduct or initial analysis of the trial.
Study Design
Details of the design and results of the Digitalis Investigation Group trial have been reported previously.1,24 Patients who had stable heart failure were enrolled between February 1991 and August 1993 at 302 clinical centers in the United States and Canada. Patients were eligible for randomization if they had clinically confirmed heart failure, had an ejection fraction of 45 percent or less, and were in normal sinus rhythm. The diagnosis of heart failure was based on current or past clinical symptoms or signs or radiographic evidence of pulmonary congestion. A simultaneously conducted ancillary study enrolled patients who had symptomatic heart failure and an ejection fraction of more than 45 percent.
Treatment
The 6800 patients in the main trial and the 988 patients in the ancillary trial were assigned to receive digoxin or placebo therapy within each center according to a block-randomization approach. The initial recommended dose of the study drug was based on a nomogram that accounted for the patient's age, sex, weight, and renal function.25 Modifications in dosage were permitted to account for the dose of digoxin a patient had been taking before enrollment and the use of concomitant drugs that might affect the pharmacokinetics of digoxin. To avoid the loss of blinding, investigators were discouraged from having patients' serum digoxin levels determined locally.
Outcomes
The primary study outcome was death from any cause within 37 months (range, 24 to 48) after randomization in the main trial. The five prespecified secondary outcomes in the Digitalis Investigation Group trial were death from cardiovascular causes, death from worsening heart failure, hospitalization for worsening heart failure, hospitalization for causes other than worsening heart failure, and the composite end point of death or hospitalization for worsening heart failure in the ancillary trial.24 Causes of deaths and hospitalizations were prospectively recorded by local investigators who were blinded to the patients' treatment assignments.
Statistical Analysis
Analyses were conducted according to the intention-to-treat principle. Base-line characteristics were compared between men and women overall and stratified according to treatment-group assignment with the use of chi-square and Wilcoxon rank-sum tests. Rates of hospitalization for suspected digoxin-related toxicity and median serum digoxin levels, assessed 1 month and 12 months after randomization in a randomly selected subgroup of patients from the main trial cohort, were also compared.
Our analysis focused solely on the possible interaction between sex and digoxin therapy; no other subgroup analyses were conducted. Kaplan–Meier curves for death from any cause were plotted for the four groups represented by the combination of sex and treatment assignment — men randomly assigned to receive digoxin, men randomly assigned to receive placebo, women randomly assigned to receive digoxin, and women randomly assigned to receive placebo — and compared with use of a log-rank test.
To minimize concern about multiple testing, we based our statistical evaluation of the possible interaction between sex and digoxin therapy on the trial's primary outcome of death from any cause among patients enrolled in the main trial.1 The existence of an interaction between sex and digoxin therapy was formally evaluated with use of the Mantel–Haenszel test of the heterogeneity of the effects of digoxin therapy according to sex and a Cox proportional-hazards model incorporating terms for the main effect of sex, the main effect of digoxin therapy, and the interaction between sex and digoxin therapy. To quantify the magnitude of the interaction, we determined the difference in the effects of digoxin therapy between men and women.26,27
A multivariable Cox proportional-hazards analysis was conducted to determine whether the interaction between sex and digoxin therapy was independent of other clinical factors. Patients' characteristics assessed at base line, including demographic characteristics, medical history, history of digoxin use, and current medications, were entered in a backward, stepwise Cox proportional-hazards model to identify predictors of mortality. Variables with a P value of less than 0.50 were entered into the model, and those with a P value of less than 0.10 were retained. The characteristics incorporated into the final Cox proportional-hazards model for death from any cause were age, race, body-mass index, left ventricular ejection fraction, cardiothoracic ratio, New York Heart Association (NYHA) functional class, the number of signs and symptoms of heart failure, the serum creatinine level, systolic blood pressure, and the presence or absence of diabetes, prior digoxin use, and concomitant use of diuretics, nitrates, and other vasodilators. This model was also repeated separately for men and women to estimate the sex-specific effect of digoxin therapy. The trial's secondary outcomes were also analyzed in order to identify additional interactions between sex and digoxin therapy.
Results
Patients
In the main Digitalis Investigation Group trial, women as a whole were older than men and had a higher average left ventricular ejection fraction, heart rate, systolic blood pressure, and cardiothoracic ratio. A greater proportion of women had a history of diabetes, hypertension, angina, and prior use of digoxin than men or were in NYHA functional class III or IV, whereas fewer women presented with rales, a history of myocardial infarction, and ischemia as their primary cause of heart failure. Serum creatinine values and the initial dose of study medication prescribed were also lower in women (Table 1Table 1
Characteristics of the Patients.). There were no significant differences between the 2642 men who were randomly assigned to receive digoxin and the 2639 men who were randomly assigned to receive placebo or between the 755 women who were randomly assigned to receive digoxin and the 764 women who were randomly assigned to receive placebo.Primary Outcome
As reported in the original study,1 digoxin was not associated with a significant reduction in the rate of death from any cause (34.8 percent in the digoxin group, as compared with 35.1 percent in the placebo group; P=0.79; crude relative risk, 0.99; 95 percent confidence interval, 0.93 to 1.06). Women had a lower overall rate of death than men (31.0 percent vs. 36.1 percent, P<0.001). The rate of death was also lower among women in the placebo group than among men in this group (28.9 percent vs. 36.9 percent, P<0.001) and among women in the digoxin group than among men in the digoxin group (33.1 percent vs. 35.2 percent, P=0.034). Survival curves, however, differed significantly among the four subgroups (P=0.002) (Figure 1Figure 1
Kaplan–Meier Estimates of Survival among Men and Women, According to Whether They Were Randomly Assigned to Receive Digoxin or Placebo.).The Mantel–Haenszel test of crude rates and a Cox proportional-hazards analysis identified a significant interaction between sex and digoxin therapy with respect to death from any cause. There was a 5.8 percent (95 percent confidence interval, 0.5 to 11.1) absolute difference in the effect of digoxin on the rate of death from all causes between men and women (Table 2Table 2
Rates of Death and Hospitalization among Men and Women, According to Treatment Assignment.). Digoxin therapy was not associated with a significantly increased rate of death among men (35.2 percent in the digoxin group, as compared with 36.9 percent in the placebo group; absolute difference, –1.6 percent; 95 percent confidence interval, –4.2 to 1.0), but it was associated with an increased rate of death among women that was of borderline significance (33.1 percent in the digoxin group, as compared with 28.9 percent in the placebo group; absolute difference, 4.2 percent; 95 percent confidence interval, –0.5 to 8.8; P=0.034 for the interaction between sex and digoxin). After multivariable adjustment, digoxin therapy was associated with a small, nonsignificant reduction in the risk of death from any cause among men (hazard ratio, 0.93; 95 percent confidence interval, 0.85 to 1.02) and a significantly increased risk of death from any cause among women (hazard ratio, 1.23; 95 percent confidence interval, 1.02 to 1.47; P=0.014 for the interaction between sex and digoxin) (Table 3Table 3
Digoxin-Associated Risk of Death and Hospitalization among Men and Women.).Secondary Outcomes
Digoxin therapy was associated with a 4.7 percent (95 percent confidence interval, –0.6 to 10.0) smaller absolute reduction in the rate of hospitalization for worsening heart failure among women as compared with men (absolute difference between the digoxin and placebo groups, –4.2 percent [95 percent confidence interval, –8.9 to 0.5] for women and –8.9 percent [95 percent confidence interval, –11.4 to –6.5] for men; P=0.053 for the interaction between sex and digoxin). The effect of digoxin on the rate of death from cardiovascular causes differed by 4.3 percent (95 percent confidence interval, –0.8 to 9.4) between women and men (absolute difference between the digoxin and placebo groups, 3.7 percent [95 percent confidence interval, –0.7 to 8.1] for women and –0.6 percent [95 percent confidence interval, –3.1 to 1.9] for men; P=0.092 for the interaction between sex and digoxin). Digoxin was associated with a small, nonsignificant increase in the rate of death due to worsening heart failure among women but not among men (absolute difference between the digoxin and placebo groups, 0.5 percent [95 percent confidence interval, –2.8 to 3.8] for women and –2.2 percent [95 percent confidence interval, –4.0 to –0.4] for men; P=0.16 for the interaction between sex and digoxin). There was no interaction between sex and digoxin therapy with respect to the end point of hospitalization for causes other than worsening heart failure (P=0.78 for the interaction) or for the composite end point of death or hospitalization for worsening heart failure among patients enrolled in the ancillary trial (P=0.16 for the interaction) (Table 2).
Multivariable modeling confirmed the interaction between sex and digoxin therapy that was observed in unadjusted analyses. Digoxin was associated with an increased risk of death from cardiovascular causes among women (hazard ratio, 1.24; 95 percent confidence interval, 1.02 to 1.52) but not among men (hazard ratio, 0.96; 95 percent confidence interval, 0.87 to 1.06; P=0.035 for the interaction between sex and digoxin). Digoxin was associated with a decreased risk of death from worsening heart failure among men (hazard ratio, 0.79; 95 percent confidence interval, 0.68 to 0.92) but not among women (hazard ratio, 1.17; 95 percent confidence interval, 0.87 to 1.56; P=0.026 for the interaction between sex and digoxin). Although men who were randomly assigned to receive digoxin had a lower risk of hospitalization for worsening heart failure than men who were assigned to receive placebo (hazard ratio, 0.66; 95 percent confidence interval, 0.60 to 0.73), the benefit was smaller for women (hazard ratio, 0.87; 95 percent confidence interval, 0.72 to 1.04; P=0.011 for the interaction between sex and digoxin). Digoxin had a similar effect in men and women with respect to the end point of hospitalization for causes other than worsening heart failure (hazard ratio for men, 1.17 [95 percent confidence interval, 1.07 to 1.28]; hazard ratio for women, 1.15 [95 percent confidence interval, 0.97 to 1.37]; P=0.91 for the interaction between sex and digoxin) and the end point of death or hospitalization due to worsening heart failure among patients enrolled in the ancillary trial (hazard ratio for men, 0.72 [95 percent confidence interval, 0.48 to 1.07]; hazard ratio for women, 0.92 [95 percent confidence interval, 0.64 to 1.31]; P=0.32 for the interaction between sex and digoxin) (Table 3).
Medication Doses, Serum Digoxin Levels, and Suspected Digoxin Toxicity
The mean daily dose of medication prescribed at randomization was 0.25 mg in men and 0.22 mg in women (P=0.28). When the dose was standardized according to the body-mass index, men received a higher dose of digoxin than women (0.0093 mg per unit of body-mass index vs. 0.0084 mg per unit of body-mass index, P<0.001). However, the median serum digoxin level was slightly higher in a group of 475 randomly selected women than in a group of 1653 randomly selected men one month after study entry (0.9 ng per milliliter vs. 0.8 ng per milliliter, P=0.007). The median serum digoxin level was the same 12 months after randomization among 581 randomly selected women and 2063 randomly selected men (0.6 ng per milliliter and 0.6 ng per milliliter, P=0.46). The proportion of patients who had serum digoxin levels of more than 2.0 ng per milliliter was similar among men and women 1 month after randomization (2.3 percent and 3.4 percent, respectively; P=0.20) and 12 months after randomization (2.1 percent and 1.4 percent, P=0.30). Although random assignment to digoxin therapy was associated with higher rates of hospitalization for suspected digoxin-related toxic effects in the main trial (2.0 percent, as compared with 0.9 percent in the placebo group; P<0.001), the magnitude of this effect was similar among men (1.8 percent and 0.8 percent, respectively; P=0.002) and women (2.5 percent and 1.2 percent, respectively; P=0.053; P=0.97 for the interaction between sex and digoxin).
Discussion
Our post hoc subgroup analysis of data from the Digitalis Investigation Group trial indicates that the effect of digoxin in the treatment of outpatients with stable heart failure differs between men and women. There was an absolute difference of 5.8 percent in the effect of digoxin on the rate of death from any cause between men and women. Digoxin was associated with an increased risk of death among women but not among men. Among women, digoxin therapy was also associated with an increased risk of the secondary outcomes of death from cardiovascular causes and death from worsening heart failure. Furthermore, women had a smaller digoxin-associated reduction in the rate of hospitalization for worsening heart failure than men. In the absence of other data concerning sex-based differences in the efficacy of digoxin, our findings raise strong concern about the appropriate role of digoxin therapy in women.
Subgroup analyses are generally not considered to provide definitive evidence for several reasons, including the manner in which post hoc analyses are planned and reported, the statistical methods used to identify interactions, and the spurious associations that may arise as a result of multiple testing.28-34 Our analysis addressed each of these issues. There are sufficient clinical data concerning sex-based differences in the pathophysiology and outcomes of heart failure to justify a post hoc investigation of the effect of these differences on the efficacy of digoxin therapy. We identified the interaction between sex and digoxin therapy using formal tests of treatment interaction rather than comparing the results of significance tests within the separate strata of men and women.30,35 We addressed concern about multiple testing31,36 by basing our evaluation of the interaction between sex and digoxin therapy principally on the trial's prespecified primary outcome of death from any cause. The magnitude of the interaction between sex and digoxin therapy and the precision in its estimation afforded by the size of the Digitalis Investigation Group trial lead us to believe that the interaction we identified is clinically significant and probably not a statistical artifact.
To our knowledge, there are no published data concerning interactions between sex and digoxin therapy with which to compare our results, and previous randomized, controlled trials of digoxin therapy in patients with heart failure did not report sex-stratified results.5,11,37 Although we cannot identify the mechanism of the interaction between sex and digoxin therapy, our data suggest that some hypotheses can be discounted. Instances of suspected digoxin toxicity and hospitalization for complications of digoxin therapy were infrequent, and there were no sex-based differences in digoxin-associated complications. The interaction between sex and digoxin therapy is not attributable to age, because age does not modify the efficacy of digoxin.38 The interaction does not reflect a dosing effect, since men received higher drug doses (standardized according to the body-mass index) than women. The slightly higher serum digoxin levels in women than in men one month after randomization raises the possibility of sex-associated differences in the pharmacokinetics of digoxin. Because serum digoxin levels were measured in less than one third of patients at one month, the trial had insufficient statistical power to test whether the interaction between sex and digoxin therapy was independent of sex-based differences in serum digoxin levels.
A possible mechanism for the increased risk of death among women may involve an interaction between hormone-replacement therapy and digoxin. Progestin may increase serum digoxin levels by inhibiting P-glycoprotein and thereby reducing the excretion of digoxin through the renal tubules.39 Furthermore, the Heart and Estrogen/Progestin Replacement Study reported an interaction between digoxin and hormone-replacement therapy that was associated with a higher rate of cardiovascular events.40 This hypothesis could not be tested because the Digitalis Investigation Group trial did not collect information about the use of hormone-replacement therapy. Other endogenous factors, which are either due to or associated with sex, may also be possible, although sex-based differences in pharmacodynamics are rare.
Although based on a post hoc analysis of the Digitalis Investigation Group trial, our study provides robust evidence of an interaction between sex and digoxin therapy and suggests an increased risk of death among women with heart failure treated with digoxin. This finding is particularly important for practice, given that the sole benefit of digoxin therapy is a small reduction in the secondary end point of hospitalization. There is no accepted method by which to balance a possible therapy-associated increased risk of death with a demonstrated therapy-associated benefit of a decreased risk of complications. However, women may not consider the potential increased risk of death associated with digoxin therapy worth the small reduction in the risk of hospitalization.
Our study underscores the importance of investigations of sex-based variations in treatment efficacy.5,41 However, few randomized, controlled trials are designed to test for sex-specific effects, and relatively few women have been enrolled in trials of heart-failure therapies.5,11,42 The interaction between sex and digoxin therapy can be confirmed only by a sex-stratified, randomized, controlled trial of digoxin therapy. However, such a study may not be considered ethical, since it would be designed to confirm risk and not benefit. In the absence of definitive evidence from trials and despite the lack of clear knowledge of the mechanism of the interaction of sex with digoxin, we believe that our data provide sufficient grounds for a reexamination of the use of digoxin therapy for women with heart failure.
The Digitalis Investigation Group study was conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the Digitalis Investigation Group Investigators. This manuscript was not prepared in collaboration with investigators of the Digitalis Investigation Group and does not necessarily reflect the opinions or the views of the Digitalis Investigation Group or the NHLBI.
We are indebted to Maria Johnson, B.A., for her editorial assistance; to Kevin Weinfurt, Ph.D., and Kerry Lee, Ph.D., for their statistical advice; and to Jared Selter, M.D., for his support of the project.
Source Information
From the Section of Cardiovascular Medicine, Department of Internal Medicine (S.S.R., Y.W., H.M.K.), and the Section of Health Policy and Administration, Department of Epidemiology and Public Health (H.M.K.), Yale University School of Medicine; and the Center for Outcomes Research and Evaluation, Yale–New Haven Hospital (H.M.K.) — both in New Haven, Conn.
- References
References
1
The Digitalis Investigation Group
Full Text | Web of Science | Medline2
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). Circulation 2001;104:2996-3007
CrossRef | Web of Science | Medline3
Remme WJ ,Swedberg K . Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527-1560
CrossRef | Web of Science | Medline4
Heart Failure Society of America (HFSA) practice guidelines: HFSA guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction -- pharmacological approaches. J Card Fail 1999;5:357-382
CrossRef | Web of Science | Medline5
Wenger NK . Women, heart failure, and heart failure therapies. Circulation 2002;105:1526-1528
CrossRef | Web of Science | Medline6
2002 Heart and stroke statistical update. Dallas: American Heart Association, 2001.
7
Croft JB ,Giles WH ,Pollard RA ,Keenan NL ,Casper ML ,Anda RF . Heart failure survival among older adults in the United States: a poor prognosis for an emerging epidemic in the Medicare population. Arch Intern Med 1999;159:505-510
CrossRef | Web of Science | Medline8
Ho KK ,Anderson KM ,Kannel WB ,Grossman W ,Levy D . Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation 1993;88:107-115
Web of Science | Medline9
Schocken DD ,Arrieta MI ,Leaverton PE ,Ross EA . Prevalence and mortality rate of congestive heart failure in the United States. J Am Coll Cardiol 1992;20:301-306
CrossRef | Web of Science | Medline10
Adams KF Jr ,Dunlap SH ,Sueta CA , et al. Relation between gender, etiology and survival in patients with symptomatic heart failure. J Am Coll Cardiol 1996;28:1781-1788
CrossRef | Web of Science | Medline11
Lindenfeld J ,Krause-Steinrauf H ,Salerno J . Where are all the women with heart failure? J Am Coll Cardiol 1997;30:1417-1419
CrossRef | Web of Science | Medline12
Levy D ,Larson MG ,Vasan RS ,Kannel WB ,Ho KK . The progression from hypertension to congestive heart failure. JAMA 1996;275:1557-1562
CrossRef | Web of Science | Medline13
Ho KK ,Pinsky JL ,Kannel WB ,Levy D . The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol 1993;22:Suppl 4:6A-13A
CrossRef | Web of Science | Medline14
Aronson D ,Burger AJ . Gender-related differences in modulation of heart rate in patients with congestive heart failure. J Cardiovasc Electrophysiol 2000;11:1071-1077
CrossRef | Web of Science | Medline15
Dash R ,Frank KF ,Carr AN ,Moravec CS ,Kranias EG . Gender influences on sarcoplasmic reticulum Ca2+-handling in failing human myocardium. J Mol Cell Cardiol 2001;33:1345-1353
CrossRef | Web of Science | Medline16
Griffin M ,Lee HW ,Zhao L ,Eghbali-Webb M . Gender-related differences in proliferative response of cardiac fibroblasts to hypoxia: effects of estrogen. Mol Cell Biochem 2000;215:21-30
CrossRef | Web of Science | Medline17
Kadokami T ,McTiernan CF ,Kubota T ,Frye CS ,Feldman AM . Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression. J Clin Invest 2000;106:589-597
CrossRef | Web of Science | Medline18
Riemer RK ,Wu YY ,Bottari SP ,Jacobs MM ,Goldfien A ,Roberts JM . Estrogen reduces beta-adrenoceptor-mediated cAMP production and the concentration of the guanyl nucleotide-regulatory protein, Gs, in rabbit myometrium. Mol Pharmacol 1988;33:389-395
Web of Science | Medline19
Song M ,Helguera G ,Eghbali M , et al. Remodeling of Kv4.3 potassium channel gene expression under the control of sex hormones. J Biol Chem 2001;276:31883-31890
CrossRef | Web of Science | Medline20
Schaible TF ,Malhotra A ,Ciambrone G ,Scheuer J . The effects of gonadectomy on left ventricular function and cardiac contractile proteins in male and female rats. Circ Res 1984;54:38-49
Web of Science | Medline21
Duscha BD ,Annex BH ,Keteyian SJ , et al. Differences in skeletal muscle between men and women with chronic heart failure. J Appl Physiol 2001;90:280-286
Web of Science | Medline22
Tamura T ,Said S ,Gerdes AM . Gender-related differences in myocyte remodeling in progression to heart failure. Hypertension 1999;33:676-680
Web of Science | Medline23
Carroll JD ,Carroll EP ,Feldman T , et al. Sex-associated differences in left ventricular function in aortic stenosis of the elderly. Circulation 1992;86:1099-1107
Web of Science | Medline24
Rationale, design, implementation, and baseline characteristics of patients in the DIG trial: a large, simple, long-term trial to evaluate the effect of digitalis on mortality in heart failure. Control Clin Trials 1996;17:77-97
CrossRef | Medline25
Jelliffe RW ,Brooker G . A nomogram for digoxin therapy. Am J Med 1974;57:63-68
CrossRef | Web of Science | Medline26
Pocock SJ ,Hughes MD . Estimation issues in clinical trials and overviews. Stat Med 1990;9:657-671
CrossRef | Web of Science | Medline27
Matthews JNS ,Altman DG . Interaction 3: how to examine heterogeneity. BMJ 1996;313:862-862
CrossRef | Web of Science | Medline28
Brookes ST ,Whitley E ,Peters TJ ,Mulheran PA ,Egger M ,Davey Smith G . Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives. Health Technol Assess 2001;5:1-56
Medline29
Oxman AD ,Guyatt GH . A consumer's guide to subgroup analyses. Ann Intern Med 1992;116:78-84
Web of Science | Medline30
Pocock SJ ,Hughes MD ,Lee RJ . Statistical problems in the reporting of clinical trials: a survey of three medical journals. N Engl J Med 1987;317:426-432
Full Text | Web of Science | Medline31
Assmann SF ,Pocock SJ ,Enos LE ,Kasten LE . Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet 2000;355:1064-1069
CrossRef | Web of Science | Medline32
Yusuf S ,Wittes J ,Probstfield J ,Tyroler HA . Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991;266:93-98
CrossRef | Web of Science | Medline33
Freemantle N . Interpreting the results of secondary end points and subgroup analyses in clinical trials: should we lock the crazy aunt in the attic? BMJ 2001;322:989-991
CrossRef | Web of Science | Medline34
Buyse ME . Analysis of clinical trial outcomes: some comments on subgroup analyses. Control Clin Trials 1989;10:Suppl:187S-194S
CrossRef | Medline35
Simon R . Patient subsets and variation in therapeutic efficacy. Br J Clin Pharmacol 1982;14:473-482
Web of Science | Medline36
Moye LA . Random research. Circulation 2001;103:3150-3153
CrossRef | Web of Science | Medline37
Petrie MC ,Dawson NF ,Murdoch DR ,Davie AP ,McMurray JJ . Failure of women's hearts. Circulation 1999;99:2334-2341
Web of Science | Medline38
Rich MW ,McSherry F ,Williford WO ,Yusuf S . Effect of age on mortality, hospitalizations and response to digoxin in patients with heart failure: the DIG study. J Am Coll Cardiol 2001;38:806-813
CrossRef | Web of Science | Medline39
Aebi S ,Schnider TW ,Los G , et al. A phase II/pharmacokinetic trial of high-dose progesterone in combination with paclitaxel. Cancer Chemother Pharmacol 1999;44:259-265
CrossRef | Web of Science | Medline40
Furberg CD ,Vittinghoff E ,Davidson M , et al. Subgroup interactions in the Heart and Estrogen/Progestin Replacement Study: lessons learned. Circulation 2002;105:917-922
CrossRef | Web of Science | Medline41
Wizemann TM, Pardue M-L, eds. Exploring the biological contributions to human health: does sex matter? Washington, D.C.: National Academy Press, 2001.
42
Heiat A ,Gross CP ,Krumholz HM . Representation of the elderly, women, and minorities in heart failure clinical trials. Arch Intern Med 2002;162:1682-1688
CrossRef | Web of Science | Medline
- Citing Articles (131)
Citing Articles
1
Vera Regitz-Zagrosek, Carina Blomstrom Lundqvist, Claudio Borghi, Renata Cifkova, Rafael Ferreira, Jean-Michel Foidart, J. Simon R. Gibbs, Christa Gohlke-Baerwolf, Bulent Gorenek, Bernard Iung, Mike Kirby, Angela H.E.M de Maas, Joao Morais, Petros Nihoyannopoulos, Petronella G. Pieper, Patrizia Presbitero, Jolien W. Roos-Hesselink, Maria Schaufelberger, Ute Seeland, Lucia Torracca. (2012) Guía de práctica clínica de la ESC para el tratamiento de las enfermedades cardiovasculares durante el embarazo. Revista Española de Cardiología 65:2, 171.e1-171.e44
CrossRef2
J. L. Andrey, S. Romero, A. García-Egido, M. A. Escobar, R. Corzo, G. Garcia-Dominguez, V. Lechuga, F. Gómez. (2011) Mortality and morbidity of heart failure treated with digoxin. A propensity-matched study. International Journal of Clinical Practice 65:12, 1250-1258
CrossRef3
David R. Holmes, Jeffrey A. Becker, Christopher B. Granger, Marian C. Limacher, Robert Lee Page, Cathy Sila, Joseph P. Drozda, Joseph G. Cacchione, Blair D. Erb, Robert A. Harrington, Jerry D. Kennett, Harlan M. Krumholz, Frederick A. Masoudi, Eric D. Peterson, Athena Poppas, David J. Sahn, Mark L. Sanz, David M. Shahian, John R. Windle, Janet F. Wyman. (2011) ACCF/AHA 2011 Health Policy Statement on Therapeutic Interchange and Substitution. Journal of the American College of Cardiology 58:12, 1287-1307
CrossRef4
YI-ZHOU XU, PAUL A. FRIEDMAN, TRACY WEBSTER, KELLY BROOKE, DAVID O. HODGE, HEATHER J. WISTE, WEI HUA, SHU ZHANG, DAVID L. HAYES, YONG-MEI CHA. (2011) Cardiac Resynchronization Therapy: Do Women Benefit More Than Men?. Journal of Cardiovascular Electrophysiologyno-no
CrossRef5
, , V. Regitz-Zagrosek, C. Blomstrom Lundqvist, C. Borghi, R. Cifkova, R. Ferreira, J.-M. Foidart, J. S. R. Gibbs, C. Gohlke-Baerwolf, B. Gorenek, B. Iung, M. Kirby, A. H. E. M. Maas, J. Morais, P. Nihoyannopoulos, P. G. Pieper, P. Presbitero, J. W. Roos-Hesselink, M. Schaufelberger, U. Seeland, L. Torracca, , J. Bax, A. Auricchio, H. Baumgartner, C. Ceconi, V. Dean, C. Deaton, R. Fagard, C. Funck-Brentano, D. Hasdai, A. Hoes, J. Knuuti, P. Kolh, T. McDonagh, C. Moulin, D. Poldermans, B. A. Popescu, Z. Reiner, U. Sechtem, P. A. Sirnes, A. Torbicki, A. Vahanian, S. Windecker, , H. Baumgartner, C. Deaton, C. Aguiar, N. Al-Attar, A. A. Garcia, A. Antoniou, I. Coman, U. Elkayam, M. A. Gomez-Sanchez, N. Gotcheva, D. Hilfiker-Kleiner, R. G. Kiss, A. Kitsiou, K. T. S. Konings, G. Y. H. Lip, A. Manolis, A. Mebaaza, I. Mintale, M.-C. Morice, B. J. Mulder, A. Pasquet, S. Price, S. G. Priori, M. J. Salvador, A. Shotan, C. K. Silversides, S. O. Skouby, J.-I. Stein, P. Tornos, N. Vejlstrup, F. Walker, C. Warnes. (2011) ESC Guidelines on the management of cardiovascular diseases during pregnancy: The Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). European Heart Journal
CrossRef6
Martin Stockburger, Alice Krebs, Oezlem Celebi, Aischa Nitardy, Dirk Habedank, Thomas Knaus, Mathias Rauchhaus, Rainer Dietz. (2011) Long-Term Survival of Routine Implantable Cardioverter/Defibrillator Recipients Appears to be Significantly Impaired with Concomitant Diuretics and Improved with Aldosterone Antagonists. Cardiovascular Therapeutics 29:4, 243-250
CrossRef7
Ana C. Freire, Abdul W. Basit, Rahul Choudhary, Chee W. Piong, Hamid A. Merchant. (2011) Does sex matter? The influence of gender on gastrointestinal physiology and drug delivery. International Journal of Pharmaceutics 415:1-2, 15-28
CrossRef8
Sameer Ather, Leif E. Peterson, Vijay G. Divakaran, Anita Deswal, Kumudha Ramasubbu, Irakli Giorgberidze, Alvin Blaustein, Xander H.T. Wehrens, Douglas L. Mann, Biykem Bozkurt. (2011) Digoxin treatment in heart failure — Unveiling risk by cluster analysis of DIG data. International Journal of Cardiology 150:3, 264-269
CrossRef9
Emma Eade, Rebecca Cooper, Andrew R.J. Mitchell. (2011) Digoxin — Time to take the gloves off?. International Journal of Cardiology
CrossRef10
Mayank K Mittal, Priya Chockalingam, Anand Chockalingam. (2011) Contemporary Indications and Therapeutic Implications for Digoxin Use. American Journal of Therapeutics 18:4, 280-287
CrossRef11
A. H. E. M. Maas, Y. T. van der Schouw, V. Regitz-Zagrosek, E. Swahn, Y. E. Appelman, G. Pasterkamp, H. ten Cate, P. M. Nilsson, M. V. Huisman, H. C. G. Stam, K. Eizema, M. Stramba-Badiale. (2011) Red alert for women's heart: the urgent need for more research and knowledge on cardiovascular disease in women: Proceedings of the Workshop held in Brussels on Gender Differences in Cardiovascular disease, 29 September 2010. European Heart Journal 32:11, 1362-1368
CrossRef12
Ryan P. Morrissey, Lawrence Czer, Prediman K. Shah. (2011) Chronic Heart Failure. American Journal Cardiovascular Drugs 11:3, 153-171
CrossRef13
Nicholas B Norgard, Gina M Prescott. (2011) Future of personalized pharmacotherapy in chronic heart failure patients. Future Cardiology 7:3, 357-379
CrossRef14
Longjian Liu. (2011) Changes in Cardiovascular Hospitalization and Comorbidity of Heart Failure in the United States: Findings from the National Hospital Discharge Surveys 1980–2006. International Journal of Cardiology 149:1, 39-45
CrossRef15
Anu M. Neuvonen, Jukka U. Palo, Antti Sajantila. (2011) Post-mortem ABCB1 genotyping reveals an elevated toxicity for female digoxin users. International Journal of Legal Medicine 125:2, 265-269
CrossRef16
Erin Y. Tjam, George A. Heckman, Stuart Smith, Bruce Arai, John Hirdes, Jeff Poss, Robert S. McKelvie. (2011) Predicting heart failure mortality in frail seniors: Comparing the NYHA functional classification with the Resident Assessment Instrument (RAI) 2.0
. International Journal of Cardiology
CrossRef17
Sabine Oertelt-Prigione. (2011) Gender differences and clinical trial design. Clinical Investigation 1:2, 187-190
CrossRef18
Offie P. Soldin, Sarah H. Chung, Donald R. Mattison. (2011) Sex Differences in Drug Disposition. Journal of Biomedicine and Biotechnology 2011, 1-14
CrossRef19
Lutz Frankenstein, Andrew L. Clark, Jorge P. Ribeiro. (2011) Influence of Sex on Treatment and Outcome in Chronic Heart Failure. Cardiovascular Therapeuticsno-no
CrossRef20
Dawn Lombardo. 2010. Digoxin, Diuretics, and Vasodilators in Heart Failure. , 117-135.
CrossRef21
Andrew J Carlin, Zarko Alfirevic, Gillian ML Gyte, Andrew J Carlin. 2010. Interventions for treating peripartum cardiomyopathy to improve outcomes for women and babies. .
CrossRef22
Javed Butler, Inder S. Anand, Michael A. Kuskowski, Thomas Rector, Peter Carson, Jay N. Cohn, . (2010) Digoxin Use and Heart Failure Outcomes: Results from the Valsartan Heart Failure Trial (Val-HeFT). Congestive Heart Failure 16:5, 191-195
CrossRef23
(2010) Section 15: Management of Heart Failure in Special Populations. Journal of Cardiac Failure 16:6, e169-e175
CrossRef24
Alba Riesgo, Pablo Herrero, Pere Llorens, Javier Jacob, Francisco Javier Martín-Sánchez, Ernest Bragulat, Òscar Miró. (2010) Influencia del sexo del paciente en la forma de presentación y en el tratamiento de la insuficiencia cardíaca aguda en los servicios de Urgencias españoles. Medicina Clínica 134:15, 671-677
CrossRef25
Antonella dʼArminio Monforte, Lorena González, Annette Haberl, Lorraine Sherr, Winnie Ssanyu-Sseruma, Sharon L Walmsley. (2010) Better mind the gap: addressing the shortage of HIV-positive women in clinical trials. AIDS 24:8, 1091-1094
CrossRef26
Kumanan Wilson. (2010) Evidence-based medicine. The good the bad and the ugly. A clinician's perspective. Journal of Evaluation in Clinical Practice 16:2, 398-400
CrossRef27
Jens Seiler, William G. Stevenson. (2010) Atrial Fibrillation in Congestive Heart Failure. Cardiology in Review 18:1, 38-50
CrossRef28
Poornima Bhupathy, Christopher Dean Haines, Leslie Anne Leinwand. (2010) Influence of sex hormones and phytoestrogens on heart disease in men and women. Women's Health 6:1, 77-95
CrossRef29
Sara Haack, Angela Seeringer, Petra A Thürmann, Thomas Becker, Julia Kirchheiner. (2009) Sex-specific differences in side effects of psychotropic drugs: genes or gender?. Pharmacogenomics 10:9, 1511-1526
CrossRef30
Rashmee U Shah, Liviu Klein, Donald M Lloyd-Jones. (2009) Heart failure in women: epidemiology, biology and treatment. Women's Health 5:5, 517-527
CrossRef31
C Catananti, R Liperoti, S Settanni, F Lattanzio, R Bernabei, D Fialova, F Landi, G Onder. (2009) Heart Failure and Adverse Drug Reactions Among Hospitalized Older Adults. Clinical Pharmacology & Therapeutics 86:3, 307-310
CrossRef32
Sabine Oertelt-Prigione, Vera Regitz-Zagrosek. (2009) Gender Aspects in Cardiovascular Pharmacology. Journal of Cardiovascular Translational Research 2:3, 258-266
CrossRef33
Eileen M. Hsich, Ileana L. Piña. (2009) Heart Failure in Women. Journal of the American College of Cardiology 54:6, 491-498
CrossRef34
Sharon Ann Hunt, William T. Abraham, Marshall H. Chin, Arthur M. Feldman, Gary S. Francis, Theodore G. Ganiats, Mariell Jessup, Marvin A. Konstam, Donna M. Mancini, Keith Michl, John A. Oates, Peter S. Rahko, Marc A. Silver, Lynne Warner Stevenson, Clyde W. Yancy. (2009) 2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. Journal of the American College of Cardiology 53:15, e1-e90
CrossRef35
Offie P. Soldin, Donald R. Mattison. (2009) Sex Differences in Pharmacokinetics and Pharmacodynamics. Clinical Pharmacokinetics 48:3, 143-157
CrossRef36
Laurent Fauchier, Caroline Grimard, Bertrand Pierre, Emilie Nonin, Laurent Gorin, Bruno Rauzy, Pierre Cosnay, Dominique Babuty, Bernard Charbonnier. (2009) Comparison of Beta Blocker and Digoxin Alone and in Combination for Management of Patients With Atrial Fibrillation and Heart Failure. The American Journal of Cardiology 103:2, 248-254
CrossRef37
Karen Sliwa, Kemi Tibazarwa, Denise Hilfiker-Kleiner. (2008) Management of peripartum cardiomyopathy. Current Heart Failure Reports 5:4, 238-244
CrossRef38
Heidi N. Schmaltz, Danielle A. Southern, Colleen J. Maxwell, Merril L. Knudtson, William A. Ghali, . (2008) Patient Sex Does Not Modify Ejection Fraction as a Predictor of Death in Heart Failure: Insights from the APPROACH Cohort. Journal of General Internal Medicine 23:12, 1940-1946
CrossRef39
George V. Moukarbel, Scott D. Solomon. (2008) Treatment of asymptomatic left ventricular dysfunction. Current Treatment Options in Cardiovascular Medicine 10:6, 476-485
CrossRef40
V. Regitz-Zagrosek, C. Schubert. (2008) Geschlechterunterschiede in der kardiovaskulären Pharmakotherapie. Der Internist 49:11, 1383-1390
CrossRef41
Vera Regitz-Zagrosek, Christa Gohlke-Bärwolf, Annette Geibel-Zehender, Markus Haass, Harald Kaemmerer, Irmtraut Kruck, Christoph Nienaber. (2008) Herzerkrankungen in der Schwangerschaft. Clinical Research in Cardiology 97:9, 630-665
CrossRef42
Robina Matyal. (2008) Newly Appreciated Pathophysiology of Ischemic Heart Disease in Women Mandates Changes in Perioperative Management: A Core Review. Anesthesia & Analgesia 107:1, 37-50
CrossRef43
Robina Matyal, Feroze Mahmood, Peter Panzica, Frank Pomposelli, Kyung W. Park, Allen Hamden, Mark Schermerhorn, Philip Hess. (2008) Sex-Related Differences in Outcome After High-Risk Vascular Surgery After the Administration of β-Adrenergic–Blocking Drugs. Journal of Cardiothoracic and Vascular Anesthesia 22:3, 354-360
CrossRef44
Gerin R. Stevens, Jill Kalman. (2008) Heart failure in women: An equal opportunity player in the expanding epidemic of heart failure. Current Cardiovascular Risk Reports 2:3, 210-216
CrossRef45
Albert-Jan L.H.J. Aarnoudse, Jeanne P. Dieleman, Loes E. Visser, Pascal P. Arp, Ilse P. van der Heiden, Ron H.N. van Schaik, Mariam Molokhia, Albert Hofman, André G. Uitterlinden, Bruno H.Ch. Stricker. (2008) Common ATP-binding cassette B1 variants are associated with increased digoxin serum concentration. Pharmacogenetics and Genomics 18:4, 299-305
CrossRef46
Jalal K Ghali, JoAnn Lindenfeld. (2008) Sex differences in response to chronic heart failure therapies. Expert Review of Cardiovascular Therapy 6:4, 555-565
CrossRef47
V. Regitz-Zagrosek, E. Lehmkuhl, H.B. Lehmkuhl. (2008) Herzinsuffizienz – geschlechtsspezifische Aspekte?. Der Internist 49:4, 422-428
CrossRef48
William H Frishman, Wilbert S Aronow, Angela Cheng-Lai. 2008. Cardiovascular Drug Therapy in the Elderly. , 99-136.
CrossRef49
John A. McClung, Michele Nanna, Wilbert S. Aronow. 2008. Cardiomyopathies in the Elderly. , 493-516.
CrossRef50
Ali Ahmed, Bertram Pitt, Shahbudin H. Rahimtoola, Finn Waagstein, Michel White, Thomas E. Love, Eugene Braunwald. (2008) Effects of digoxin at low serum concentrations on mortality and hospitalization in heart failure: A propensity-matched study of the DIG trial. International Journal of Cardiology 123:2, 138-146
CrossRef51
G. Bolte. (2008) Gender in der Epidemiologie. Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 51:1, 3-12
CrossRef52
Lori A. Blauwet, Rita F. Redberg. (2007) The Role of Sex-Specific Results Reporting in Cardiovascular Disease. Cardiology in Review 15:6, 275-278
CrossRef53
OMEED ZARDKOOHI, VEENA NANDIGAM, LORNE MURRAY, E. KEVIN HEIST, THEOFANIE MELA, MARY ORENCOLE, JEREMY N. RUSKIN, JAGMEET P. SINGH. (2007) The Impact of Age and Gender on Cardiac Resynchronization Therapy Outcome. Pacing and Clinical Electrophysiology 30:11, 1344-1348
CrossRef54
Wilbert S. Aronow. (2007) Treatment of Heart Failure with Abnormal Left Ventricular Systolic Function in the Elderly. Heart Failure Clinics 3:4, 423-436
CrossRef55
David Rosen, Matthew V. Decaro, Mark G. Graham. (2007) Evidence-based Treatment of Chronic Heart Failure. Comprehensive Therapy 33:1, 2-17
CrossRef56
Pär Hallberg, Johan Lindbäck, Bertil Lindahl, Ulf Stenestrand, Håkan Melhus, . (2007) Digoxin and mortality in atrial fibrillation: a prospective cohort study. European Journal of Clinical Pharmacology 63:10, 959-971
CrossRef57
Wilbert S. Aronow, William H. Frishman, Angela Cheng-Lai. (2007) Cardiovascular Drug Therapy in the Elderly. Cardiology in Review 15:4, 195-215
CrossRef58
G. William Dec. (2007) Management of Acute Decompensated Heart Failure. Current Problems in Cardiology 32:6, 321-366
CrossRef59
Annette Geibel, Christoph Bode, Manfred Zehender. (2007) Herzrhythmusstörungen bei Schwangeren. Intensivmedizin und Notfallmedizin 44:4, 219-226
CrossRef60
Austin Chin Chwan Ng, Helen Siu Ping Wong, Andy Sze Chiang Yong, Andrew Paul Sindone. (2007) Impact of gender on outcomes in chronic systolic heart failure. International Journal of Cardiology 117:2, 214-221
CrossRef61
Yohannes Gebreegziabher, Amgad N Makaryus, John N Makaryus, Samy I McFarlane. (2007) Heart failure: metabolic derangements and therapeutic rationale. Expert Review of Cardiovascular Therapy 5:2, 331-343
CrossRef62
Wilbert S. Aronow. (2007) Treatment of Heart Failure with Abnormal Left Ventricular Systolic Function in the Elderly. Clinics in Geriatric Medicine 23:1, 61-81
CrossRef63
Lori A. Blauwet, Sharonne N. Hayes, David McManus, Rita F. Redberg, Mary Norine Walsh. (2007) Low Rate of Sex-Specific Result Reporting in Cardiovascular Trials. Mayo Clinic Proceedings 82:2, 166-170
CrossRef64
L. A. Blauwet, S. N. Hayes, D. McManus, R. F. Redberg, M. N. Walsh. (2007) Low Rate of Sex-Specific Result Reporting in Cardiovascular Trials. Mayo Clinic Proceedings 82:2, 166-170
CrossRef65
Wilbert S. Aronow. (2006) Treatment of heart failure with decreased left ventricular ejection fraction. Comprehensive Therapy 32:4, 218-225
CrossRef66
Stacie E. Geller, Marci Goldstein Adams, Molly Carnes. (2006) Adherence to Federal Guidelines for Reporting of Sex and Race/Ethnicity in Clinical Trials. Journal of Women's Health 15:10, 1123-1131
CrossRef67
Jill M. Gelow, James C. Fang. (2006) Update in the Approach to and Management of Heart Failure. Southern Medical Journal 99:12, 1346-1355
CrossRef68
Francesc Formiga, David Chivite, Nicolás Manito, Ramon Pujol. (2006) Perfil de uso de la digoxina en pacientes ingresados por insuficiencia cardíaca. Medicina Clínica 127:10, 397
CrossRef69
Ali Ahmed, Wilbert S. Aronow, Jerome L. Fleg. (2006) Predictors of Mortality and Hospitalization in Women with Heart Failure in the Digitalis Investigation Group Trial. American Journal of Therapeutics 13:4, 325-331
CrossRef70
María G. Crespo Leiro, María J. Paniagua Martín. (2006) Insuficiencia cardiaca. ¿Son diferentes las mujeres?. Revista Española de Cardiología 59:7, 725-735
CrossRef71
Olaf Forster, Aftab A Ansari, Karen Sliwa. (2006) Current issues in the diagnosis and management of peripartum cardiomyopathy. Women's Health 2:4, 587-596
CrossRef72
Douglas N. Carroll, Timothy M. Murray. (2006) Prevalence of Nonoptimal Serum Digoxin Concentrations in a Cohort of Patients with Heart Failure. Hospital Pharmacy 41:6, 538-541
CrossRef73
Beatrice Wong, Maureen P. Flattery. (2006) Use of Digoxin in the Treatment of Chronic Heart Failure. Progress in Cardiovascular Nursing 21:3, 158-161
CrossRef74
Zainal Hussain, Jason Swindle, Paul J. Hauptman. (2006) Digoxin Use and Digoxin Toxicity in the Post-DIG Trial Era. Journal of Cardiac Failure 12:5, 343-346
CrossRef75
Markus Flesch, Erland Erdmann. (2006) The problem of polypharmacy in heart failure. Current Cardiology Reports 8:3, 217-225
CrossRef76
Wilbert S. Aronow. (2006) Epidemiology, Pathophysiology, Prognosis, and Treatment of Systolic and Diastolic Heart Failure. Cardiology in Review 14:3, 108-124
CrossRef77
Vera Regitz-Zagrosek. (2006) Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nature Reviews Drug Discovery 5:5, 425-239
CrossRef78
Juan Tamargo, Eva Delpón, Ricardo Caballero. (2006) The safety of digoxin as a pharmacological treatment of atrial fibrillation. Expert Opinion on Drug Safety 5:3, 453-467
CrossRef79
Gastone Sabbadini, Marco Metra, Andrea Di Lenarda, Savina Nodari, Gianfranco Sinagra, Livio Dei Cas. (2006) Managing heart failure in the very old. Aging Health 2:2, 253-275
CrossRef80
M. Böhm, N. Werner, M. Kindermann. (2006) Stand der medikamentösen Therapie bei chronischer Herzinsuffizienz. Clinical Research in Cardiology 95:S4, 36-56
CrossRef81
Lisa M. Mielniczuk, Anju Nohria. 2006. Inotropic Therapy in Heart Failure Management. , 137-154.
CrossRef82
Wilbert S. Aronow. (2006) Treatment of Systolic and Diastolic Heart Failure in the Elderly. Journal of the American Medical Directors Association 7:1, 29-36
CrossRef83
2006. Cardiac glycosides. , 648-674.
CrossRef84
Wolfgang Aichhorn, Alexandra B Whitworth, Elisabeth M Weiss, Josef Marksteiner. (2006) Second-Generation Antipsychotics. Drug Safety 29:7, 587-598
CrossRef85
Lois S. Lee, Lingtak-Neander Chan. (2006) Evaluation of a Sex-Based Difference in the Pharmacokinetics of Digoxin. Pharmacotherapy 26:1, 44-50
CrossRef86
W. S. Aronow. (2005) Drug Treatment of Systolic and of Diastolic Heart Failure in Elderly Persons. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 60:12, 1597-1605
CrossRef87
Claudio Pedone, Andrea Corsonello, Luciana Carosella, Raffaele Antonelli-Incalzi. (2005) Comparison of digitalis-related adverse events in hospitalized men and women in Italy: An observational study. Clinical Therapeutics 27:12, 1922-1929
CrossRef88
Ulf Landmesser, Helmut Drexler. (2005) Chronic heart failure: an overview of conventional treatment versus novel approaches. Nature Clinical Practice Cardiovascular Medicine 2:12, 628-638
CrossRef89
Johan Sundström, Ramachandran S. Vasan. (2005) Homocysteine and heart failure: a review of investigations from the Framingham Heart Study. Clinical Chemistry and Laboratory Medicine 43:10, 987-992
CrossRef90
Sharon Ann Hunt. (2005) ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult. Journal of the American College of Cardiology 46:6, e1-e82
CrossRef91
Michael A. Crouch. (2005) Chronic Heart Failure: Developments and Perspectives. The Consultant Pharmacist 20:9, 751-765
CrossRef92
John V Terrovitis, Maria I Anastasiou-Nana, John N Nanas. (2005) Out-patient management of chronic heart failure. Expert Opinion on Pharmacotherapy 6:11, 1857-1881
CrossRef93
Kirkwood F. Adams, J. Herbert Patterson, Wendy A. Gattis, Christopher M. O’Connor, Craig R. Lee, Todd A. Schwartz, Mihai Gheorghiade. (2005) Relationship of Serum Digoxin Concentration to Mortality and Morbidity in Women in the Digitalis Investigation Group Trial. Journal of the American College of Cardiology 46:3, 497-504
CrossRef94
U. C. Hoppe, M. Böhm, R. Dietz, P. Hanrath, H. K. Kroemer, A. Osterspey, A. A. Schmaltz, E. Erdmann. (2005) Leitlinien zur Therapie der chronischen Herzinsuffizienz. Zeitschrift für Kardiologie 94:8, 488-509
CrossRef95
James B. Young. (2005) Whither Withering’s Legacy?. Journal of the American College of Cardiology 46:3, 505-507
CrossRef96
G. Aldama López, M. Piñeiro Portela, R. Campo Pérez, P. Piñón Esteban. (2005) Insuficiencia cardíaca: concepto, epidemiología, clasificación, etiología y fisiopatología. Medicine - Programa de Formación Médica Continuada Acreditado 9:35, 2279-2290
CrossRef97
Denise D. Barnard. (2005) Heart failure in women. Current Cardiology Reports 7:3, 159-165
CrossRef98
Domenic A. Sica, Mark Wood, Michael Hess. (2005) Gender and Its Effect in Cardiovascular Pharmacotherapeutics: Recent Considerations. Congestive Heart Failure 11:3, 163-166
CrossRef99
U. C. Hoppe, E. Erdmann. (2005) Digitalis in heart failure! Still applicable?. Zeitschrift für Kardiologie 94:5, 307-311
CrossRef100
Mary Norine Walsh. (2005) Advanced heart failure and transplantation in women. Current Cardiology Reports 7:3, 184-189
CrossRef101
M. Domanski, J. Fleg, M. Bristow, S. Knox. (2005) The Effect of Gender on Outcome in Digitalis-Treated Heart Failure Patients. Journal of Cardiac Failure 11:2, 83-86
CrossRef102
Robert A. Ruelaz, Shahbudin H. Rahimtoola. (2005) Was it Digoxin Toxicity?…Very Likely. Journal of Cardiac Failure 11:2, 87-90
CrossRef103
Cary P. Gross, Pushkal P. Garg, Harlan M. Krumholz. (2005) The generalizability of observational data to elderly patients was dependent on the research question in a systematic review. Journal of Clinical Epidemiology 58:2, 130-137
CrossRef104
Jerry H. Gurwitz. (2005) The Age/Gender Interface in Geriatric Pharmacotherapy. Journal of Women's Health 14:1, 68-72
CrossRef105
Gail D. Anderson. (2005) Sex and Racial Differences in Pharmacological Response: Where Is the Evidence? Pharmacogenetics, Pharmacokinetics, and Pharmacodynamics. Journal of Women's Health 14:1, 19-29
CrossRef106
W. Schillinger, H. P. Hermann, G. Hasenfu
. (2004) Differenzialtherapie der Herzinsuffizienz. Der Internist 45:12, 1378-1387
CrossRef107
John C Somberg, Janos Molnar. (2004) The Pharmacologic Treatment of Heart Failure. American Journal of Therapeutics 11:6, 480-488
CrossRef108
Robert E Hobbs. (2004) Guidelines for the Diagnosis and Management of Heart Failure. American Journal of Therapeutics 11:6, 467-472
CrossRef109
Lars H. Lund, Donna Mancini. (2004) Heart failure in women. Medical Clinics of North America 88:5, 1321-1345
CrossRef110
Jennifer Elston Lafata, Manel Pladevall, George Divine, Melissa Ayoub, Edward F. Philbin. (2004) Are There Race/Ethnicity Differences in Outpatient Congestive Heart Failure Management, Hospital Use, and Mortality Among an Insured Population?. Medical Care 42:7, 680-689
CrossRef111
Helen M. Fernandez, Reena Karani, Jennifer Brand, Rosanne M. Leipzig, Rainier P. Soriano. (2004) That Was the Year That Was: An Evidence-Based Clinical Geriatrics Update 2002â03. Journal of the American Geriatrics Society 52:5, 828-837
CrossRef112
William B Hood, Jr., Antonio L Dans, Gordon H Guyatt, Roman Jaeschke, John JV McMurray, William B Hood, Jr.. 2004. Digitalis for treatment of heart failure in patients in sinus rhythm. .
CrossRef113
William B. Hood, Antonio L. Dans, Gordon H. Guyatt, Roman Jaeschke, John J.V. McMurray. (2004) Digitalis for treatment of congestive heart failure in patients in sinus rhythm: a systematic review and meta-analysis. Journal of Cardiac Failure 10:2, 155-164
CrossRef114
CJ Moerman, J van Mens-Verhulst. (2004) Gender-sensitive epidemiological research: suggestions for a gender-sensitive approach towards problem definition, data collection and analysis in epidemiological research. Psychology, Health & Medicine 9:1, 41-52
CrossRef115
Pär Hallberg, Håkan Melhus, Lars-Olof Hansson, Anders Larsson. (2004) Cystatin C vs creatinine as markers of renal function in patients on digoxin treatment. Upsala Journal of Medical Sciences 109:3, 247-254
CrossRef116
Arthur M Feldman. (2004) Clinical Characteristics of Vesnarinone. Drug Safety 27:Supplement 1, 1-9
CrossRef117
Ileana L Piña. (2003) A better survival for women with heart failure? it's not so simple…. Journal of the American College of Cardiology 42:12, 2135-2138
CrossRef118
Jane Chen, Michael W. Rich. (2003) Atrial fibrillation in the elderly. Current Treatment Options in Cardiovascular Medicine 5:5, 355-367
CrossRef119
Janice B. Schwartz. (2003) Gender-Specific Implications for Cardiovascular Medication Use in the Elderly. Cardiology in Review 11:5, 275-298
CrossRef120
Mandeep R. Mehra, Patricia A. Uber. (2003) Diverse Populations, New Techniques: Non-Surgical Advances in Heart Failure 2003. Congestive Heart Failure 9:4, 189-190
CrossRef121
Wilbert S. Aronow. (2003) Mortality in Nursing Home Patients with Congestive Heart Failure. Journal of the American Medical Directors Association 4:4, 220-221
CrossRef122
Wilbert S. Aronow. (2003) Epidemiology, Pathophysiology, Prognosis, and Treatment of Systolic and Diastolic Heart Failure in Elderly Patients. Heart Disease 5:4, 279-294
CrossRef123
(2003) Pharmacogenetics. New England Journal of Medicine 348:20, 2041-2043
Full Text124
Bobbi L. Hoppe, Denise D. Hermann. (2003) Sex differences in the causes and natural history of heart failure. Current Cardiology Reports 5:3, 193-199
CrossRef125
KELD KJELDSEN, HENNING BUNDGAARD. (2003) Myocardial Na,K-ATPase and Digoxin Therapy in Human Heart Failure. Annals of the New York Academy of Sciences 986:1, 702-707
CrossRef126
Sunil V. Rao, Robert M. Califf. (2003) Lessons Learned From Clinical Trials A Roundtable Discussion. Critical Pathways in Cardiology: A Journal of Evidence-Based Medicine 2:1, 55-59
CrossRef127
Sunil V. Rao, Robert M. Califf. (2003) Lessons Learned From Clinical Trials. Critical Pathways in Cardiology: A Journal of Evidence-Based Medicine 2:1, 55-59
CrossRef128
(2003) Digoxin for the Treatment of Heart Failure. New England Journal of Medicine 348:7, 661-663
Full Text129
&NA;. (2002) Digoxin increases mortality among women with heart failure. Inpharma Weekly &NA;:1363, 21
CrossRef130
&NA;. (2002) Digoxin increases mortality among women with heart failure. Reactions Weekly &NA;:927, 4
CrossRef131
Eichhorn, Eric J., , Gheorghiade, Mihai, . (2002) Digoxin — New Perspective on an Old Drug. New England Journal of Medicine 347:18, 1394-1395
Full Text
- Letters
