Skip Navigation

European Journal of Heart Failure 2001 3(5):593-599; doi:10.1016/S1388-9842(01)00141-6
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Hassapoyannes, C. A.
Right arrow Articles by Welch, G. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hassapoyannes, C. A.
Right arrow Articles by Welch, G. W.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2001 European Society of Cardiology

The effect of chronic digitalization on pump function in systolic heart failure

Constantine A. Hassapoyannes*, Bruce M. Easterling, Kiran Chavda, Krina K. Chavda, M. Reza Movahed and Gary W. Welch

The Divisions of Cardiology, Departments of Medicine, William Jennings Bryan Dorn Veterans Affairs Medical Center and the University of South Carolina School of Medicine Columbia, SC, USA

* Corresponding author. Division of Cardiology (111C), WJB Dorn VAMC, 6439 Garners Ferry Road, Columbia, SC 29209-1639, USA; Tel.: +1-803-776-4000, ext. 7142; fax: +1-803-695-7913. E-mail address: cahass{at}aol.com or hassapoyannes.c_a{at}columbia-sc.va.gov (C.A. Hassapoyannes)


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Short- and intermediate-term use of cardiac glycosides promotes inotropy and improves the ejection fraction in systolic heart failure.

Aim: To determine whether chronic digitalization alters left ventricular function and performance.

Methods: Eighty patients with mild-to-moderate systolic heart failure (baseline ejection fraction ≤ 45%) participated from our institution in a multi-center, chronic, randomized, double-blind study of digitalis vs. placebo. Of the 40 survivors, 38 (20 allocated to the digitalis arm and 18 to the placebo arm) were evaluated at the end of follow-up (mean, 48.4 months). Left ventricular systolic function was assessed by both nuclear ventriculography and echocardiography. The ejection fraction was measured scintigraphically, while the ventricular volumes were computed echocardiographically.

Results: The groups did not differ, at baseline or end-of-study, with respect to the ejection fraction and the loading conditions (arterial pressure, ventricular volumes and heart rate) by either intention-to-treat or actual-treatment-received analysis. Over the course of the trial, the digitalis arm exhibited no significant increase in the use of diuretics (18%, P = 0.33), in distinction from the placebo group (78%, P = 0.004), and a longer stay on study drug among those patients who withdrew from double-blind treatment (28.6 vs. 11.4 months, P = 0.01).

Conclusion: Following chronic use of digitalis for mild-to-moderate heart failure, cross-sectional comparison with a control group from the same inception cohort showed no appreciable difference in systolic function or performance. Thus, the suggested clinical benefit cannot be explained by an inotropic effect.

Key Words: Digitalis • Heart failure • Congestive • Ventricular dysfunction, left • Systole

Received November 13, 2000; Revised December 28, 2000; Accepted February 12, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Cardiac glycosides are the most frequently used inotropic agents. Previous studies on diverse inotropes have shown an increase in mortality despite an early positive effect on ventricular performance (ejection fraction) [1–4]. In distinction, long-term digitalization does not affect cardiac or all-cause mortality while it benefits morbidity, with respect to the rate of hospitalization from worsening heart failure [5].

Digitalis improves indices of cardiac function following intravenous administration [6–9] or short and intermediate-term oral use for up to 6 months [10–13]. However, it is not known whether this effect, usually modulated by the concurrent use of afterload reducing agents [14] and the degree of the underlying contractile impairment [6,10] is chronically (in excess of 1 year) sustained. Moreover, it is not clear whether a direct effect on contractility or altered neurohormonal milieu [15–18] is causally related to the long-term benefit.

Pharmacologically, digitalis promotes inotropy by inhibiting the cellular Na+–K+ pump, which results in higher cytosolic calcium concentration and increased calcium binding by the contractile proteins. However, there are suggestions that chronically high intracellular calcium can have a detrimental effect on the function of human cardiomyocytes [19–21]. Against this background, we tested the hypothesis that following chronic use of digitalis in patients with mild-to-moderate systolic heart failure, left ventricular pump function and performance differ between the treatment and control groups.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
From the total of 80 patients with mild-to-moderate systolic heart failure who were enrolled at the WJB Dorn Veterans Affairs Medical Center in a multi-center, chronic, randomized, double-blind study of digitalis vs. placebo, 38 of the 40 survivors underwent assessment of left ventricular systolic function at the end of follow-up (mean, 48.4 months) with the evaluators being blinded to treatment used. The two survivors not included in the assessment were censored, one due to chronic atrial fibrillation, the other because of relocation. Patient enrollment was conducted between February 1991 and September 1992, and follow-up was concluded in December 1995. Enrollment criteria included: stable systolic heart failure of at least 3-months duration; ejection fraction≤45% [measured within 3 months before randomization by blood-pool scintigraphy in 48 patients (60.0%), echocardiography in 30 patients (37.5%) or contrast ventriculography in two patients (2.5%), in accordance with the protocol of the multi-center trial]; NYHA functional classes I–IV; and normal sinus rhythm. Though not a requisite, treatment with angiotensin converting enzyme inhibitors (or other vasodilators) and diuretics was strongly encouraged, while prior digitalization was permitted. Exclusion criteria included: age less than 21 years; complex congenital heart disease; unstable or refractory angina pectoris; atrial fibrillation or flutter; cor pulmonale; constrictive pericarditis; hypertrophic cardiomyopathy; recent myocardial infarction; and uncorrected severe valvular heart disease. Heart failure was etiologically stratified into six categories: ischemic; hypertensive; alcohol-related; idiopathic dilated cardiomyopathy; valvular; and ‘other’. The dose of digoxin was derived using creatinine clearance calculated by age, body weight, serum creatinine and sex. The protocol provided that patients who withdrew from double-blind treatment, at their own decision or that of their primary physicians, remained in the cohort. For these participants, unblinding was not permitted at the time of withdrawal, but their primary physicians were allowed to pursue treatment with open-label, or off of, digitalis.

The procedures used were in accordance with institutional guidelines. The trial was approved by the Human Studies Subcommittee and conforms to the principles outlined in the Declaration of Helsinki. Signed, informed consent was obtained from all subjects before screening. Both nuclear scintigraphy and echocardiography were performed in all survivors between February 15 and March 15, 1996, while they were still randomly assigned to digitalis vs. placebo. Analysis of data was completed before unblinding, which took place in April 1996.

2.1. Nuclear ventriculography
Gated blood-pool scintigraphy was performed at high temporal resolution (64 frames/cycle) using a DSX rectangular camera with a parallel-hole collimator (Sopha Medical) and approximately 25 mCi of technetium-99m pertechnetate-labeled albumin injectate. Data acquisition was gated to the first peak of the QRS complex, which was recorded with an IBS 101 patient monitor (Ivy Biomedical Systems, Inc.). Only those cycles that were within 5% of the predominant R–R interval were incorporated into the data set. Following background correction using a manually determined region-of-interest, a left ventricular time-activity curve was generated by compiling a total of 600 s of accepted cycles. Correction of the time–activity curve for end-cycle drop-off [22] was accomplished by removing all data points beyond the final local maximum. The raw time–activity curve was smoothed in the time domain with a modified Kaiser–Bessel low-pass finite impulse response filter (normalized cutoff frequency: 0.125; stopband attenuation: –60 dB; filter length: 8 points). The ejection fraction was calculated from the raw time–activity curve.

2.2. Echocardiography
Echocardiograms were obtained immediately before or following scintigraphy in order to ensure identical hemodynamic state. Targeted M-mode images were recorded with a Sonos 1000 ultrasound system (Hewlett–Packard) with a 2.5-MHz phased-array transducer from the long axis view in the left parasternal position. Left ventricular dimensions and volumes were recorded at both end-diastole and end-systole.

2.3. Statistics
The data were processed by both intention-to-treat (digitalis vs. placebo arm) and actual-treatment-received (on digoxin vs. off of digoxin patients at end-of-study) analyses to prevent bias from a ‘carryover’ effect due to crossing over treatment lines over the course of the trial (Fig. 1). For crossover patients, that is, those randomized to digitalis who withdrew from double-blind drug and were not started on open-label digoxin (dropouts) and the patients assigned to the placebo arm who switched to open-label digitalis (drop-ins), follow-up with respect to actual-treatment-received analysis was taken to begin when the double-blind medication was discontinued. Statistical significance of differences between group means, and of mean differences within groups was computed with Student's t-test for unpaired and paired variates, respectively. The null hypothesis was rejected at P<0.05 (two-tail). Unless otherwise noted, all data presented in tabular form reflect intention-to-treat analysis and values are mean±S.E.


Figure 1
View larger version (29K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Flow of participants through the trial.

 
For our total population, mortality and morbidity (number of hospitalizations) were assessed by intention-to-treat analysis in order to capture all events from inception. Survival data among groups were compared using Pearson's chi-square method.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Of the 38 survivors, 20 had been randomized to the digitalis group (0.25 mg/day except for one subject who received 0.125 mg/day) and 18 to placebo. The mean trough digoxin level at 1 month and 12 months into the trial was 1.03 ng/ml with a mean range within the sample of 0.31 ng/ml. Over the course of trial, 14 participants, seven from each group, withdrew from double-blind medication. Of these seven in each group, six were placed on open-label digoxin while one opted to stay off of digitalis (Fig. 1). Thus, only seven patients (18.4%) crossed over treatment lines, six randomized to placebo that switched to open-label digitalis (drop-ins), and one assigned to digitalis who stopped taking the drug (dropout). In all but one case, in each arm (where double-blind medication was stopped due to atrial fibrillation/flutter), discontinuation of study medication reflected the participants’ or their primary physicians’ blinded decision, and the difference between the groups was not significant. However, the interval from enrollment to discontinuation of double-blind medication differed between the digitalis and placebo groups (28.6±4.23 months vs. 11.4±3.55 months, respectively, P=0.01), consistent with a clinical benefit from digoxin.

With respect to demographics and clinical characteristics at enrollment, the groups did not differ by either intention-to-treat or actual-treatment-received analysis (Table 1). Twenty-three (92.0%) of the treated and 11 (84.6%) of the untreated patients were in NYHA functional class II or III.


View this table:
[in this window]
[in a new window]

  		Table 1 Demographics and clinical characteristics at enrollment for survivorsa

 
The three techniques to measure the ejection fraction at enrollment were evenly distributed among the digitalis and placebo arms. The ejection fraction at baseline was similar between the groups by both methods of analysis and did not change during the trial within either arm. Moreover, despite comparable loading conditions (arterial pressure, ventricular volumes and heart rate) at the trial's end, the lack of difference in ejection fraction persisted (Tables 2 and 3). This applied even when the patients who crossed over treatment lines were excluded from analysis. It is also noteworthy that the six drop-ins and the one dropout did not differ at enrollment from their respective group means with respect to all measured parameters. The 95% confidence intervals for the mean changes in ejection fraction within the groups (from baseline to end-of-study) were very narrow by both methods of analysis (Table 3).


View this table:
[in this window]
[in a new window]

  		Table 2 Hemodynamic characteristics among survivorsa

 


View this table:
[in this window]
[in a new window]

  		Table 3 Ejection fraction among survivors

 
Table 4 shows that there was no difference between the groups vis-à-vis the use of cardiac medications at baseline and end-of-study. However, over the course of the trial, the use of potassium-wasting diuretics increased significantly in the placebo arm (78%, P=0.004 and 83%, P=0.02 by intention-to-treat and actual-treatment-received analyses, respectively) consistent with disease progression, but not in the digitalis group (29%, P=0.10 and 18%, P=0.33).


View this table:
[in this window]
[in a new window]

  		Table 4 Medication use among survivorsa

 
With respect to our total population (80 participants), there were no group differences in demographics and clinical characteristics at enrollment, and the total cardiac mortality and the all-cause mortality were similar between the two arms. However, in the digitalis group there was a lower mortality (7.3% vs. 23.1%, P=0.05) and a trend toward reduced early (30-month) morbidity (17.1% vs. 30.8%, P=0.15) from worsening heart failure.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This is the first study since the introduction of the foxglove by Sir William Withering to assess the effect of chronic digitalization (in excess of 1 year) on left ventricular performance. Cross-sectional comparison with a control group from the same inception cohort showed that digitalis conferred no appreciable increase in ejection fraction, the afterload- and preload-dependent index of ventricular performance. However, the fact that both the ejection fraction and the loading conditions (arterial pressure, ventricular volumes and heart rate) were similar among the groups strongly suggests that the intrinsic contractility also remained unaltered. Lack of significance applied whether the data analysis was based on the intention-to-treat or actual-treatment-received principle and persisted when the crossover patients were censored to eliminate bias from a ‘carryover’ effect.

Studies entailing addition [11] or withdrawal [12,13] of digoxin in the treatment of patients with systolic heart failure, with or without concomitant treatment with angiotensin-converting-enzyme inhibitors, have shown that the incremental effect of short-term digitalization on ejection fraction is statistically significant but modest (approx. 3–5 percentage points). Hence, with consideration to the fact that the mean digoxin dose employed in our cohort was at least 33% lower than that used in the RADIANCE and PROVED trials, the findings of unaltered ventricular performance are not in discord with those from earlier studies. Our data are further supported by the work of Gheorghiade et al. [6], which indicates that even in patients with severe congestive heart failure (NYHA class IV), the pump function responsiveness to the acute administration of digitalis varies (responders vs. non-responders) depending on the degree of existing contractile impairment.

It has been postulated that an effect on pump function alone, even if it were to be sustained, may not explain the efficacy of digitalis [23]. In accordance, we showed that even though digitalis did not enhance pump function, it conferred a clinical benefit, as judged by a lack of an increase in the requirement of diuretics and by a longer stay on study drug among patients who withdrew from double-blind treatment. A plausible explanation for these findings could be a positive neurohormonal effect which is in evidence even with low-dose digitalization [24].

4.1. Limitations
These data should be viewed cautiously. The sample size is small and, therefore, the lack of statistical significance of differences in ejection fraction could be due to a beta error. Nevertheless, there is 95% confidence that, even in an infinitely large population, the ‘true’ change in ejection fraction would have been no larger than approximately±5% (absolute points), which is clinically unimportant considering that the error due to technique alone in estimating the ejection fraction is within±5% (absolute points) [25].

Certain characteristics of this population such as: locality; veteran status; mostly male sex; and enrollment of patients taking digitalis before randomization, could lend themselves to statistical bias. Importantly though, the similarity of our data to those from a large cohort with respect to morbidity and mortality [5] suggests that our population is not aberrant.

Furthermore, this study, by design, cannot answer how the non-survivors in the digitalis group responded with respect to pump function. Likewise, these data which stem from patients with mild-to-moderate heart failure under optimal preload and afterload control, may not be extrapolated to patients with severe or decompensated systolic heart failure.

4.2. Conclusions
Following chronic use of digitalis for mild-to-moderate heart failure, comparison with a control group from the same inception cohort showed no appreciable difference in systolic ventricular function or performance among survivors. Therefore, the suggested long-term clinical benefit from digitalis cannot be explained by an inotropic effect.


   Acknowledgements
 
We thank Carlton Hornung, PhD for his assistance with the statistical analysis and Felicitas K. Brown of the echocardiography laboratory for her commitment.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. The PROMISE Study Research GroupPacker M., Carver J.R., Rodeheffer R.J., et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med (1991) 325:1468–1475.[Abstract]
  2. The Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet (1990) 336:1–6.[CrossRef][Web of Science][Medline]
  3. Vesnarinone Study Group. Feldman A.M., Bristow M.R., Parmley W.W., et al. Effects of vesnarinone on morbidity and mortality in patients with heart failure. N Engl J Med (1993) 329:149–155.[Abstract/Free Full Text]
  4. Applefeld M.M., Newman K.A., Sutton F.J., et al. Outpatient dobutamine and dopamine infusions in the management of chronic heart failure: clinical experience in 21 patients. Am Heart J (1987) 114:589–595.[CrossRef][Web of Science][Medline]
  5. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med (1997) 336:525–533.[Abstract/Free Full Text]
  6. Gheorghiade M., St Clair J., St Clair C., Beller G.A. Hemodynamic effects of intravenous digoxin in patients with severe heart failure initially treated with diuretics and vasodilators. J Am Coll Cardiol (1987) 9:849–857.[Abstract]
  7. Tisdale J.E., Gheorghiade M. Acute hemodynamic effects of digoxin alone or in combination with other vasoactive agents in patients with congestive heart failure. Am J Cardiol (1992) 69:34G–47G.[CrossRef][Medline]
  8. Rackow E.C., Packman M.I., Weil M.H. Hemodynamic effects of digoxin during acute cardiac failure: a comparison in patients with and without acute myocardial infarction. Crit Care Med (1987) 15:1001–1005.[Web of Science][Medline]
  9. Kleiman J.H., Alderman E.L., Goldman R.H., Ingels N.B., Daughters 2nd G.T., Stinson E.B. Effects of digitalis on normal and abnormal left ventricular segmental dynamics. Am J Cardiol (1979) 43:1001–1008.[CrossRef][Web of Science][Medline]
  10. Lee D.C., Johnson R.A., Bingham J.B., et al. Heart failure in outpatients: a randomized trial of digoxin versus placebo. N Engl J Med (1982) 306:699–705.[Abstract]
  11. The Captopril Digoxin Multicenter Research Group. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JAMA (1988) 259:539–544.[Abstract/Free Full Text]
  12. PROVED Investigative Group. Uretsky B.F., Young J.B., Shahidi F.E., Yellen L.G., Harrison M.C., Jolly M.K. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. J Am Coll Cardiol (1993) 22:955–962.[Abstract]
  13. Packer M., Gheorghiade M., Young J.B., 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.[Abstract/Free Full Text]
  14. Gheorghiade M., Hall V., Lakier J.B., Goldstein S. Comparative hemodynamic and neurohormonal effects of intravenous captopril and digoxin, and their combinations in patients with severe heart failure. J Am Coll Cardiol (1989) 13:134–142.[Abstract]
  15. Covit A.B., Schaer G.L., Sealey J.E., Laragh J.H., Cody R.J. Suppression of the renin–angiotensin system by intravenous digoxin in chronic congestive heart failure. Am J Med (1983) 75:445–447.[CrossRef][Web of Science][Medline]
  16. Ribner H.S., Plucinski D.A., Hsieh A.M., et al. Acute effects of digoxin on total systemic vascular resistance in congestive heart failure due to dilated cardiomyopathy: a hemodynamic–hormonal study. Am J Cardiol (1985) 56:896–904.[CrossRef][Web of Science][Medline]
  17. Newton G.E., Tong J.H., Schofield A.M., Baines A.D., Floras J.S., Parker J.D. Digoxin reduces cardiac sympathetic activity in severe congestive heart failure. J Am Coll Cardiol (1996) 28:155–161.[Abstract]
  18. The Dutch Ibopamine Multicenter Trial (DIMT) Study Group. Brouwer J., van Veldhuisen D.J., Man in't Veld A.J., et al. Heart rate variability in patients with mild to moderate heart failure: effects of neurohormonal modulation by digoxin and ibopamine. J Am Coll Cardiol (1995) 26:983–990.[Abstract]
  19. Morgan J.P., Erny R.E., Allen P.D., Grossman W., Gwathmey J.K. Abnormal intracellular calcium handling, a major cause of systolic and diastolic dysfunction in ventricular myocardium from patients with heart failure. Circulation (1990) 81:III21–32.[Medline]
  20. Morgan J.P. Abnormal intracellular modulation of calcium as a major cause of cardiac contractile dysfunction. N Engl J Med (1991) 325:625–632.[Web of Science][Medline]
  21. Gwathmey J.K., Copelas L., MacKinnon R., et al. Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ Res (1987) 61:70–76.[Abstract/Free Full Text]
  22. Juni J.E., Chen C.C. Effects of gating modes on the analysis of left ventricular function in the presence of heart rate variation. J Nucl Med (1988) 29:1272–1278.[Abstract/Free Full Text]
  23. Smith T.W. Digoxin in heart failure (editorial; comment). N Engl J Med (1993) 329:51–53.[Free Full Text]
  24. Slatton M.L., Irani W.N., Hall S.A., et al. Does digoxin provide additional hemodynamic and autonomic benefit at higher doses in patients with mild to moderate heart failure and normal sinus rhythm? J Am Coll Cardiol (1997) 29:1206–1213.[Abstract]
  25. Wackers F.J., Berger H.J., Johnstone D.E., et al. Multiple gated cardiac blood pool imaging for left ventricular ejection fraction: validation of the technique and assessment of variability. Am J Cardiol (1979) 43:1159–1166.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Hassapoyannes, C. A.
Right arrow Articles by Welch, G. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hassapoyannes, C. A.
Right arrow Articles by Welch, G. W.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?