Expert Review: Heart Failure

Effectiveness and Safety of Digoxin Among Contemporary Adults With Incident Systolic Heart Failure

Background
In the current European Society of Cardiology guidelines on heart failure (HF)1, digoxin for HF falls into the group of less-certain benefits where it is classified as class IIb, level B: digoxin could be considered to reduce risk of hospitalization in patients with sinus rhythm and ejection fraction ≤45% or in patients who cannot tolerate BB or ivabradine when the latter is used as an alternative if the heart rate is ≥70 bpm. The guidelines advised that patients should also receive an angiotensin-converting enzyme/angiotensin receptor blocker and a mineralocorticoid receptor antagonist. An additional recommendation was that digoxin could also be considered to reduce risk of hospitalization if the ejection fraction were ≤45% plus persisting symptoms, despite therapy by a BB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and a mineralocorticoid receptor antagonist.
Those indications are based on interpretations as well as post hoc analyses of the Digitalis Investigation Group (DIG) randomized trial2, which dates from the early 1990s when ACE inhibitors were the latest thing and BB still aroused suspicion in HF. In that trial, digoxin didn’t cut mortality but did lower the risk of hospitalization for worsening heart failure2.

Knowledge Gap
There is not enough data to judge the supposed benefits of digoxin given to patients with HF in the modern era, one taking into account not only the evolving epidemiology of HF but also treatment improvements (including beta-blockers and aldosterone agonists).

Aim of the Study
The aim of this study was to evaluate the effectiveness and safety of digoxin in a contemporary cohort of patients with incident systolic HF

Methods
The authors identified adults with incident systolic HF between 2006 and 2008 and applied multivariable-extended Cox regression to examine the association between new digoxin use and risks of death and HF hospitalization, controlling for medical history, laboratory results, medications, HF disease severity, and the propensity for digoxin use.

Results
They found that among 2891 newly diagnosed patients with systolic HF, 529 (18%) received digoxin. During a median 2.5 years of follow up, the crude rate of death was significantly higher on digoxin therapy (14.2 per 100 person-years) than off digoxin therapy (11.3 per 100 person-years; P=0.04). After adjustment for potential confounders, current digoxin use was associated with a 72% higher relative rate of death
(adjusted hazard ratio, 1.72; 95% CI, 1.25–2.36) but no difference in the risk of HF hospitalization (hazard ratio, 1.05; 95% CI, 0.82–1.34). This significant increase in all-cause mortality was seen in both women and men and regardless of whether patients were also taking BB.

Conclusion
Incident digoxin use was associated with a higher risk of death but no significant difference in hospitalization for HF in a large, diverse, community-based cohort of adults with newly diagnosed systolic HF. These results were consistent in men and women and in concurrent BB users and nonusers.

Clinical Impact:
Current use of digoxin is now declining for several reasons. First, there are major doubts on the ideal dose and blood levels. Second, even in the large DIG trial at a time when HF therapy was relatively primitive by current standards2 and did not have the benefit of BB and angiotensin-converting enzyme inhibitors2,3 there were only limited benefits without decreased mortality. Third, the narrow therapeutic-toxic window and numerous drug interactions have cast further doubt. Fourth, and based on several retrospective analyses of the DIG trial4,5, digoxin came to be accepted as an add-on in otherwise optimally treated chronic HF.
In the light of these reasons and the results of the present study, it must be considered that, in addition to BB and digoxin, there is another treatment for heart failure that reduces heart rate: ivabradine. This agent has been tested in the SHIFT trial, a randomized, double blind, placebo controlled, parallel-group study of 6,558 patients with symptomatic HF and a history of hospital admission for HF within previous year, treated with stable doses of HF drugs including BB in about 90 % of participants, and LVEF of <35 %, who were in sinus rhythm with HR C 70 bpm6. Ivabradine demonstrated a reduction in the composite of cardiovascular death or hospital admission for HF, fewer hospital admissions for worsening HF and fewer deaths due to HF. There was a small but significant improvement in NYHA class on Ivabradine arm. The effect of Ivabradine was still significant in the subset of patients already on BB. Side effects of Ivabradine were mild, with about 5 % having symptomatic bradycardia and 3 % having visual symptoms. Therefore, the current HF guidelines recommend Ivabradine as an option for treating chronic heart failure for people: with NYHA class II to IV stable chronic heart failure with systolic dysfunction (LVEF ≤35%) and who are in sinus rhythm with a heart rate of ≥70 bpm or more and who are given ivabradine in combination with standard therapy including BB therapy, angiotensin-converting enzyme inhibitors and aldosterone antagonists, or when BB therapy is contraindicated or not tolerated.
Digoxine should probably be only regarded as a second-line drug added to BB to control the ventricular rate in patients with atrial fibrillation or when HF patients have persisting symptoms, despite therapy by a BB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and a mineralocorticoid receptor antagonist, and Ivabradine cannot be administered because of atrial fibrillation is present.

Corresponding author from original paper
Alan S. Go, MD, Division of Research, Kaiser Permanente Northern California, 2000 Broadway St, Oakland, CA 94612-2304.
E-mail Alan.S.Go@kp.org

References:
1. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Rønnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A; Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 201 of the European Society of Cardiology, Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S, McDonagh T, Sechtem U, Bonet LA, Avraamides P, Ben Lamin HA, Brignole M, Coca A, Cowburn P, Dargie H, Elliott P, Flachskampf FA, Guida GF, Hardman S, Iung B, Merkely B, Mueller C, Nanas JN, Nielsen OW, Orn S, Parissis JT, Ponikowski P. ESC Committee for Practice Guidelines; ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012;14:803–869.

2. 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.

3. Georgiopoulou VV, Kalogeropoulos AP, Giamouzis G, Agha SA, Rashad MA, Waheed S, Laskar S, Smith AL, Butler J. Digoxin therapy does not improve outcomes in patients with advanced heart failure on contemporary medical therapy. Circ Heart Fail. 2009;2:90–97.

4. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA. 2003;289:871–878.

5. Ahmed A, Pitt B, Rahimtoola SH, Waagstein F, White M, Love TE, Braunwald E. Effects of digoxin at low serum concentrations on mortality and hospitalization in heart failure: a propensity-matched study of the DIG trial. Int J Cardiol. 2008;123:138–146.

6. Böhm M, Swedberg K, Komajda M, Borer J, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L; on behalf of the SHIFT investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet 2010;376:886–894.

Citation: Circ Cardiovasc Qual Outcomes. 2013;6:525-533

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