INTRODUCTION

Cardiac glycosides, including digitalis and digoxin, have long-standing use in clinical practice [1]. Digoxin is indicated in patients with heart failure (HF) and impaired systolic function who are in sinus rhythm and continue to have signs and symptoms despite standard therapy that includes angiotensin-converting enzyme inhibitors and beta-blockers. Digoxin may also be particularly useful in patients with severe symptoms, left ventricular ejection fraction (LVEF) less than 25%, or cardiomegaly on chest x-ray. Digoxin is also indicated in patients with atrial fibrillation, with or without HF, and a rapid ventricular response [2].

 

Digoxin is a cardiac glycoside with positive inotropic characteristics. It works by inhibiting the sodium-potassium adenosine triphosphatase (ATPase) pump at the cellular level and prevents the transport of sodium from the intracellular to the extracellular space [3]. In addition, digoxin also has effects on the autonomic nervous system. It has parasympathomimetic actions that clinically manifest by increasing vagal tone to the sinus and atrioventricular (AV) nodes, thus decreasing heart rate and slowing conduction through the AV node. In patients with heart failure, digoxin has anti-sympathetic effects, including restoration of baroreceptor sensitivity (which is decreased in low-output heart failure). The exact underlying mechanism for these effects remains unclear but the sympatholytic actions first appear at relatively low digoxin concentrations – below those needed to cause a measurable increase in the force of contraction [4]. Although considered generally safe, several recent studies have reported digoxin to have potential proarrhythmic properties, long-term effects on cardiac remodeling, and even link to adverse prognosis in atrial fibrillation (AF) [5].

 

Digoxin has a narrow therapeutic window so it can easily reach toxic levels in the body. As a result, digoxin users should be closely monitored for adverse effects and the serum level need to be kept within therapeutic range to prevent the increased risk of digoxin-associated mortality [6]. The common symptoms may be mild and include nausea, vomiting, and anorexia. It can also cause visual side effects that include color changes, also known as xanthopsia. However, yellow or green-tinted vision is usually associated with digoxin toxicity. Besides, patients may also highlight blurry vision or photopsia. At toxic levels, digoxin is proarrhythmic. An impaired ventricle is more prone to ventricular tachyarrhythmias and ectopy. Abnormally high levels of digoxin will stimulate atrial activation, thus atrial tachycardias, which, in a patient on digoxin, is highly suggestive of toxicity. These atrial tachycardias are persistent and resolve with a decrease in serum digoxin levels. Other common side effects include rash, headache, gynecomastia, and weakness [1].

 

This systematic review aims to provide a detailed analysis of the currently available case reports related to digoxin toxicity. It also aims to investigate the clinical and lab manifestations including potential risk factors presented leading to digoxin toxicity (e.g.: renal impairment or drug-drug interaction (DDIs)).

 

MATERIALS AND METHODS

Data Sources and Searches

Articles published in PubMed and Ovid were systematically searched using the keywords “digoxin” and “toxicity”. The search covered all case studies published until 2020.

 

Study Selection

The titles and the abstracts were screened based on the following inclusion criteria:

1. Case reports (the presenting symptoms and risk factors observed were based on real settings);
2. Involved human;
3. Published in English or translated study in English;
4. Described the dose of digoxin used, possible interacting drugs with digoxin, risk factors, and presenting symptoms of digoxin toxicity

 

Studies related to digoxin-herbal medicine interaction were excluded. The selected articles were later screened based on the full-text content and any redundancy was removed.

 

Data Extraction and Data Synthesis

A detailed review of full-text articles was conducted and relevant information in each of the articles was identified. The articles were categorized according to their topic relevance and the extraction of data includes:

1. Reference information: author, year of publication, and source of the journal;
2. Patient information: age, gender;
3. Characteristics of digoxin therapy: the dose of digoxin use, the purpose of the use, duration of digoxin therapy;
4. Possible cause of digoxin toxicity: exposure to digoxin monotherapy, potential interacting drugs with digoxin;
5. Case presentation: medical history, the clinical manifestation of digoxin toxicity, heart profile (ECG diagram), and digoxin concentration level; and
6. Risk factors of the occurrence of digoxin toxicity: advanced age, female gender, drug-drug interactions, renal impairment or insufficiency condition, loose communication between health practitioners, lack of knowledge on plants recognition

 

All data analyzed were presented as a descriptive summary of the studies and results. No additional statistical analysis was performed.

 

Assessment of Study Quality

Joanna Briggs Institute (JBI) Critical Appraisal Checklist was used for case reports to assess the quality of studies. The tool consists of eight domains including:

1. The patient’s demographic characteristics;
2. The patient’s history timeline;
3. The current clinical condition of the patient on presentation;
4. Description of diagnostics tests or assessment methods and the results;
5. Description of intervention or treatment procedure;
6. Description of post-intervention clinical condition;
7. Identification and description of adverse events (harms) and/or unanticipated events;
8. Provide takeaway lessons.

 

Each domain was considered for each of the studies included and overall appraisal determined whether the study would be included or excluded from the systematic review.

 

Data Analysis

All data gathered were summarized in tables according to the topic of relevance. The summarized data were analyzed and discussed qualitatively.

 

RESULTS AND DISCUSSION

A total of 2399 articles were generated from both PubMed and Ovid searches (1827 and 572, respectively). “Case report” was included in the search filter. Further searches were performed using the inclusion criteria such as human studies in English languages. All articles related to drug toxicity induced by factors other than digoxin treatment were excluded. Based on these features, 80 potentially relevant articles were obtained in this study.

 

Upon further screening, 63 articles were removed due to duplication and accessibility issues. The remaining articles were appraised for eligibility. Nine articles were excluded since detailed information from the full-text screening indicated that the case involved false-elevation of digoxin levels induced by plants and other cases of drug toxicity that were unrelated to the ingestion of digoxin. In total, 8 articles on digoxin-induced toxicity were included in this systematic review.

Study Eligibility

All case reports presented in this study were reported in complete detail as recommended by the eight domains listed in the (JBI) Critical Appraisal Checklist. A total of 10 eligible case reports were included in this study.

 

Use and Dosage of Digoxin

Digoxin is a type of medicine known as a cardiac glycoside that was commonly used to manage arrhythmias including atrial fibrillation. It is also indicated in the management of symptoms associated with congestive heart failure, usually in combination with other medications.

 

There were four cases (50%) reported the use of digoxin to treat atrial fibrillation [7-10], one case for the treatment of congestive heart failure (CHF) only [11], and one case for the treatment of both clinical conditions [12]. Digoxin had also been used for the treatment of dilated cardiomyopathy with Left Ventricular Ejection Fraction (LVEF) [13] and paroxysmal supraventricular tachycardia [14].

 

The dosage prescribed in four of the cases (50%) was 0.25 mg daily [7, 8, 10, 12] while 0.125 mg dosage was reported in 2 cases [9, 11].

 

Drug-Drug Interaction with Digoxin

There were 2 cases of digoxin toxicity that were not related to any possible drug-drug interaction [8, 9]. The remaining six cases had several possible interacting drugs which were likely to interfere with the mechanisms of digoxin and eventually lead to the occurrence of digoxin toxicity.

 

Diuretics were the most reported possible interacting drug in four cases. One of them had caused drug-drug interaction [12] and another three cases were classified as potential to cause digoxin-diuretic interaction [11, 13, 14]. The possible interacting diuretics reported in three cases involved Furosemide, which is a loop diuretic, and Spironolactone, which belongs to potassium-sparing diuretics [11-13]. One case reported the digoxin-diuretic interaction without indicating the specific agent [14].

 

Another frequently reported possible interacting drug was Diltiazem, which was reported in 2 cases of digoxin toxicity [7, 11].  Renard et al. 2015, stated that the digoxin-diltiazem interaction was most probably caused by the increased exposure to digoxin through uncertain mechanisms, possibly by inhibiting P-glycoprotein, while in the case of Yang et al. 2012 diltiazem was discontinued due to high clinical suspicion for digoxin toxicity. Besides Diltiazem, other atrioventricular nodal blocking agents such as Carvedilol may also cause possible drug-drug interaction with digoxin [11].

 

Other medications with the possibility to induce digoxin-drug interaction were Dronedarone (antiarrhythmic drug) [10], Celecoxib (NSAIDs), and Levothyroxine (antithyroid) [12]. Renard et al. 2015 also reported that Torsemide and Lisinopril could aggravate renal failure, risk of dehydration, and electrolyte imbalance which eventually lead to digoxin toxicity.

 

Presenting Symptoms of Digoxin Toxicity

The main presenting symptoms associated with toxicity that were mostly observed in these case reports were nausea and vomiting. The important laboratory result to determine the presence of digoxin toxicity was the serum digoxin level which the normal range is between 0.8 – 2.0 ng/ml.

 

Most of the cases reported the presence of nausea and vomiting associated with increased digoxin levels. Other symptoms of digoxin toxicity such as a visual change, visual disturbance (snowy and blurry vision), and visual hallucination were observed in four cases. Visual disturbances described as flashing lights and yellow or red halos around the object were observed in 1 case [14]. Snowy and blurry vision was reported by Renard et al. [7] while the change in vision with the disappearance of color vision was reported by Kolev [8]. Visual hallucinations were also reported by Naha et al. [14].

 

The occurrence of bradycardia was also observed in a total of three case reports [10, 11, 14]. In addition, one case reported the presence of weakness, fatigue [11], and lethargy [8], respectively. Other symptoms reported to be associated with digoxin toxicity were reduced level of consciousness [12], palpitation, chest discomfort, dysphagia [7], complete atrioventricular heart block [11], and loss of appetite [8].

 

The majority of the cases reported the value of serum digoxin level (SDL) higher than the cut-off point of 2.0 ng/ml [7, 9-11, 13, 14].

 

Table 1. Presenting symptoms of digoxin toxicity.
Author (Year)	Dose (mg/day)	Presenting symptoms				Serum Digoxin level Normal: 0.8-2.0 ng/mL
		Nausea & Vomiting	Change in vision	Bradycardia	Other symptoms
[7]	0.25	/	-Snowy and blurry vision		Dysphagia	5.7
[8]	0.25	/	The disappearance of color vision		-Lethargy -Loss of appetite -Slow AF:35-38 bpm	-
[9]	0.125				Ventricular fibrillation following bidirectional tachycardia	2.4
[10]	0.75			Junctional bradycardia	Dizziness	>5
[11]	0.125			/	-Recurrent episode of syncope associated with coughing - Increasing weakness -Dyspnoea -Become nonresponsive -Complete atrioventricular heart block showed by electrocardiogram (ECG)	4.3
[12]	0.25	/			-Increasing confusion -Reduced level of consciousness	3.0
[13]	Not stated	/				2.5
[14]	Not stated	Recurrent vomiting for 3 days	-Photophobia -Visual hallucination -Yellow vision		-Condition persisted although symptomatic treatment with antiemetics	3.63

 

Risk Factors of Digoxin Toxicity

They were four main possible risk factors that may be associated with digoxin toxicity: being female; elderly (60-91 years old); the presence of drug-drug interaction; and having a renal problem (renal disease/ renal impairment/ renal insufficiency). Most of the digoxin toxicity cases presented had at least one or more risk factors of digoxin toxicity. Other factors discussed in the case reports included hypomagnesemia, hypothyroidism, polypharmacy with questionable adherence, and loose communication between the cardiologist and general practitioner (GP). All the risk factors were summarized in the table below:

 

Table 2. Risk factors of digoxin toxicity
Author	Dose (mg)	Risk factors
		Female	Advanced age (years)	Drug-drug interaction	Renal problem	Others
[7]	0.25	/	91	Diltiazem, Torsemide, Lisinopril	Pre-existing advanced kidney disease	Polymedication with questionable
[8]	0.25	/	76		Impaired renal functions
[9]	0.125	/	79
[10]	0.75	/	82	Dronedarone		Hypomagnesemia
[11]	0.125		73	AV nodal blocking agents: carvedilol, diltiazem	Chronic renal insufficiency
[12]	0.25	/	69	Celecoxib, Furosemide, Levothyroxine, Spironolactone	An acute episode of renal impairment	Hypothyroidism
[13]		/	30	Furosemide
[14]		/	65	Diuretics