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Digoxin/ Sotalol

Type Recommendation
When to deprescribe
CBR

Digoxin

We suggest deprescribing decisions be made in consultation with the individual and their GP and/or specialist providers to ensure it aligns with their preferences, goals and overall treatment plans. Given the risks of digitalis toxicity and drug-drug interactions potentially outweigh the benefits in older people, especially in those with declining renal function or polypharmacy, we suggest offering deprescribing digoxin:

  • For individuals with heart failure with reduced ejection fraction (HFrEF) who are in sinus rhythm and have been stabilised on one or more of the “four pillars” of the guideline-directed medical therapy (GDMT)
  • For individuals with atrial fibrillation treated with digoxin in combination with other agents (such as beta-blockers, diltiazem or verapamil) and have achieved the target heart rate [i.e. resting heart rate of < 110 beats per minute (bpm), or stricter control of < 80 bpm for those with persistent symptoms of atrial fibrillation especially breathlessness]
  • For individuals experiencing potential adverse effects (e.g. cardiac disturbances, gastrointestinal symptoms)
CBR

Sotalol

Given the risk of adverse effects (e.g. arrhythmia) potentially outweighing the benefits, we suggest deprescribing be offered to older people taking sotalol who:

  • Have permanent atrial fibrillation without an intention to restore or maintain sinus rhythm; or
  • Have been stabilised and in normal sinus rhythm for at least two to three months
Ongoing treatment
CBR

We suggest continuing GDMT for heart failure or beta-blockers for atrial fibrillation.

How to deprescribe
CBR

Digoxin

We suggest individualising the tapering schedule based on the individual's clinical context. When digoxin is identified as being suitable for deprescribing, we suggest abrupt cessation if the serum level is subtherapeutic.

We suggest abrupt cessation when clinically indicated, such as in cases of digitalis toxicity (e.g. bradycardia), and introducing an alternative agent for rate control if indicated. If tapering is preferred and the individual is experiencing symptoms of tachycardia, we suggest reducing the dose by 50% every two weeks until the dose reaches ≤ 62.5 microgram, then cease completely.

CBR

Sotalol

We suggest gradual tapering of the dose by 25% every one to two weeks, ensuring individuals remain symptom-free before initiating each tapering. Once half the lowest standard dose formulation is reached, we suggest ceasing completely. If clinically indicated, consider an alternative for rate control, preferably a beta-blocker.

Note: This suggestion does not apply to cases of sotalol poisoning, where urgent procedures are required to monitor and treat QT-interval prolongation and torsades de pointes. Refer to relevant clinician resources, such as the Therapeutic Guidelines toxicology section (https://www.tg.org.au/content-updates/toxicologyandtoxinology/).

Monitoring
CBR

Digoxin and sotalol

We suggest closely monitoring for changes in heart rate and/or signs of cardiac decompensation (e.g. shortness of breath) including addressing electrolyte disturbances, every one to two weeks until at least four weeks after the medicine is fully ceased if practical. After this initial period, we suggest monitoring at three and six months, followed by monitoring every six months thereafter. However, this should be tailored based on individual factors such as their other medications, preferences, responses, and tolerance to deprescribing.

If in-person visits are impractical, we suggest advising people to self-monitor symptoms using pulse monitors and report to their healthcare providers as needed.

CBR, consensus-based recommendation

Atrial fibrillation (AF)

AF is the most common arrhythmia affecting older people [279]. Beta-blockers are the preferred rate control agents in this population due to their favourable safety profile compared to digoxin, which has a narrow therapeutic index.

Digoxin, a cardiac glycoside, is used as a rate control agent for atrial fibrillation with rapid ventricular response and heart failure. However, its clinical role has declined over time due to safety concerns. If prescribed, serum digoxin concentration should be monitored to maintain a concentration below 1.2 ng/mL, particularly in older people with renal impairment [280]. However, in practice, routine monitoring of serum digoxin concentration in the community is rarely undertaken.

Sotalol, a class III anti-arrhythmic with beta-blocking properties, is predominantly used for rhythm control in AF [280]. Its use in older people requires caution due to its significant risk of QTc prolongation, which can lead to polymorphic ventricular tachycardia, including Torsades de Pointes. The incidence of Torsades de Pointes, a potentially life-threatening arrhythmia, ranges from 0.4% to 2.3% globally, with a higher risk during therapy initiation [280]. A study of people aged over 80 years who were newly prescribed sotalol found that 40% required dose reduction or discontinuation due to safety concerns [281].

Heart failure

A 2015 study highlighted that inappropriate prescribing of digoxin (defined as prescribing digoxin for HFrEF patients who are not receiving an ACE inhibitor or beta-blocker) remains prevalent [282]. In this study, 99 consecutive patients hospitalised for digoxin toxicity were assessed, and 67% of them were prescribed digoxin without appropriate indications.

The management of heart failure has advanced over the past decade. The 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America guideline for the management of heart failure recommends guideline-directed medical therapy (GDMT) for people with heart failure and reduced ejection fraction (HFrEF) [283]. The GDMT, also known as the “four pillars”, includes a renin-angiotensin system inhibitor, a heart-failure specific beta-blocker, a mineralocorticoid receptor antagonist and a sodium-glucose cotransporter 2 inhibitor, as the four main recommended drug treatment regimens for HFrEF. This quadruple therapy is recommended as the regimen for HFrEF due to its demonstrated benefits in reducing morbidity and mortality [284].

Comorbid atrial fibrillation and heart failure

AF and heart failure often coexist, with a complex interplay between the two conditions that complicate management [285]. AF can worsen heart failure by reducing cardiac output due to the loss of atrial contraction, promoting tachycardia, neurohormonal activation, and irregular ventricular contractions. Conversely, heart failure increases the risk of AF through structural atrial remodelling, mitral regurgitation, and neurohormonal changes [286].

Pharmacological treatment for comorbid AF and heart failure, whether for rhythm or rate control, requires an individualised approach, especially in older people. Treatment decisions should be based on symptom burden, the success of reversion strategies, ejection fraction, and comorbidities [287]. Rhythm control strategies, such as cardioversion or catheter ablation, may benefit certain people with HFrEF and have shown superiority over pharmacological therapy in reducing mortality and hospitalisations related to worsening heart failure [288]. This further diminishes the role of digoxin in the management of coexisting AF and heart failure. From a deprescribing perspective, managing these conditions requires careful evaluation and regular review of treatment regimens to ensure therapies align with evolving clinical goals and priorities.

Refer to the narrative evidence summary, the GRADE Summary of Findings table in the guidelines, and the Technical Report for a complete presentation of the deprescribing evidence based on the GRADE framework (including other factors considered in developing the recommendations).

In the era of GDMT, the role of digoxin in heart failure management is very limited as it has not been shown to improve mortality in this context [289]. Current guidelines offer a class IIb recommendation (weak recommendation) for the use of digoxin in patients with symptomatic HFrEF despite GDMT or in those who cannot tolerate GDMT, to reduce hospitalisations related to heart failure [290]. The risk of digoxin toxicity increases significantly with age, particularly in the presence of renal impairment, hypokalaemia, or acute illness, and can lead to severe arrhythmias or death. Notably, digoxin toxicity accounts for 3% of all emergency department visits for adverse drug effects in older people [291]. For acute rate control during critical illness in hospitalised patients, digoxin or amiodarone may be added if beta-blockers alone are insufficient. However, for long-term rate control in older people in the community, digoxin should be limited to specific situations, such as in cases of poor tolerance to beta-blockers or non-dihydropyridine calcium channel blockers, or for persistent tachycardia (>110 bpm). Given the significant risk of toxicity, digoxin should be used with extreme caution when combined with amiodarone, as drug-drug interactions can markedly increase digoxin levels. For people without heart failure, digoxin is an independent predictor of mortality [292].

Sotalol should not be used in permanent AF where rhythm control is deemed futile. For long-term rate control in people with AF, an alternative beta-blocker is recommended as the choice of agent [280]. As with all treatment choices, long-term use of pharmacological rhythm control should balance the possible adverse effects, along with the individual comorbid conditions, symptoms, as well as values and preferences. Considerations to deprescribe sotalol may be reasonable in people who have been stabilised and in normal sinus rhythm for at least two to three months if the risk of adverse effects (e.g. QT prolongation, arrhythmia, hypokalaemia, hypomagnesemia) outweighs the potential benefits. In older people, impaired kidney function can further prolong the half-life of sotalol, increasing the risk of adverse effects. If sotalol is considered suitable to deprescribe, gradual tapering is necessary, such as reducing the dose by 25% every one to two weeks to avoid beta-blocker withdrawal syndrome [293]. If sotalol is considered suitable to deprescribe, gradual tapering may be appropriate to avoid beta-blocker withdrawal syndrome, such as reducing the dose by 25% every one to two weeks [293].

We identified six non-controlled studies related to digoxin deprescribing from the systematic review and meta-analysis; however, no studies related to sotalol deprescribing [294-299].

Overall, the current evidence for deprescribing digoxin is derived from studies conducted in the 90s. These are single-arm studies with very small sample sizes and are of very low certainty due to significant methodological limitations. Most participants without evidence of heart failure or AF in these studies were able to safely discontinue digoxin, particularly in people who had been in sinus rhythm before withdrawal. However, the evidence is insufficient to support the development of evidence-based recommendations. Close monitoring of pulse rate and/or signs of cardiac decompensation (e.g. shortness of breath) including addressing electrolyte disturbances may be appropriate.

Key study characteristics and results

A narrative summary of each study is provided below, highlighting key characteristics and main findings.

Daly and Edwards 1983 [294] recruited people on maintenance digoxin with a mean daily dosage between 62.5mcg to 375mcg. Deprescribing was attempted in 15 participants with subtherapeutic digoxin concentrations without heart failure. Among the 15 participants, 11 (73%) remained asymptomatic while three participants developed tachycardia during the one-month follow-up and one participant withdrew from the study.

Fair 1990 [295] reported deprescribing digoxin in 32 participants receiving long-term digoxin while only two participants received beta-blockers. 18 (56%) participants restarted their digoxin due to tachycardia, but digoxin was successfully discontinued in the remaining 14 participants (44%). Successful withdrawal was more likely in participants who had been in sinus rhythm before withdrawal.

Fonrose 1974 [296] reported deprescribing digoxin in 31 participants of whom 15 had an original indication for congestive heart failure, two for AF, and the reason was not known in 14 participants. Of the 31 participants, 15 (48%) successfully discontinued digoxin at the end of four months. Digoxin was restarted in the remaining 16 participants due to signs and symptoms indicative of cardiac decompensation. These signs and symptoms were chest pain, gallop rhythm, dyspnoea, pulmonary congestion, venous dilatation, and recurrence of oedema.

Macarthur 1990 [297] reported deprescribing maintenance digoxin in 14 nursing home residents in sinus rhythm without evidence of atrial dysrhythmia or AF during examinations before trial inclusion. Of the 14 residents, 12 (86%) successfully discontinued digoxin without deleterious effects or a change in exercise tolerance over the 18-month follow-up. Digoxin was restarted in one resident who had a history of supraventricular tachycardia (SVT) following an episode of SVT, whereas one other resident developed heart failure requiring a diuretic.

Sommers 1981 [298] reported deprescribing digoxin in 20 participants with a history of left ventricular failure but had been in sinus rhythm for at least four months without a record of previous AF. Of the 20 participants, 18 (90%) successfully discontinued digoxin without detrimental effects, one developed tachyarrhythmia and signs indicative of heart failure due to hyperthyroidism whereas one other participant also showed signs indicative of heart failure.

Wilkins and Khurana 1985 [299] reported deprescribing digoxin in 19 nursing home residents with sinus rhythm, and no evidence of congestive heart failure or AF during examinations before trial inclusion. Of the 19 residents, 16 (84%) discontinued digoxin without a change in clinical status, one resident with a history of fibrillation restarted digoxin due to AF, one resident developed shortness of breath and was subsequently started on diuretic, and another resident with pancreatic carcinoma restarted digoxin due to tachycardia and poor general condition. During the first week of withdrawal, nine residents (47%) had an increase in pulse rate, nine (47%) had no change, and one (5%) had a decrease in pulse rate. Ten (52%) residents showed weight gain and five (26%) showed weight loss.

The method of deprescribing was not described in all identified studies, except one where digoxin was ceased abruptly on the first day of the trial and participants were seen weekly for five consecutive weeks [298].

The half-life of digoxin is between 36 to 48 hours but may be prolonged in certain individuals such as those with renal impairment [300]. If digoxin is identified as being suitable for deprescribing, abrupt cessation may be considered, particularly if the serum level is subtherapeutic. If tapering is preferred, it may be reasonable to reduce the dose by 50% every two weeks until the dose reaches ≤ 62.5 microgram, then cease completely.

Note that in cases of digitalis toxicity, abrupt cessation is necessary and introduce an alternative agent for rate control if indicated. The management of digoxin toxicity is out of the scope of the current guidelines.