Digoxin Holiday

INTRODUCTION

DIGOXIN HOLIDAY

MECHANISM OF ACTION

Digoxin has two principal mechanisms of action – it increases the force of myocardial contractions and reduces conduction velocity at the atrioventricular (AV) node. It thus has a positive inotropic and electrophysiological effect on the heart.^[6]

PHARMACOKINETICS

Absorption of digoxin is 70% on oral administration and about 25% is serum albumin bound.^[7] Digoxin has a high volume of distribution due to extensive binding to the muscle, and hence, lean body weight should be considered while dosing.^[4,7] The renal excretion of digoxin is mostly unchanged and is directly proportional to the glomerular filtration rate (GFR).^[6] Digoxin cannot be cleared by dialysis.^[7]

DETERMINANTS OF METABOLISM

IMPLICATIONS OF DETERMINANTS

Due to the narrow therapeutic range of digoxin, toxicity is a major concern.^[11] This is particularly important in the elderly, renal insufficiency, electrolyte abnormalities, multiple drugs, lean body mass, and female sex. There is an increased risk of all-cause mortality with digoxin levels of more than 1.6– 2 ng/ml.^[10] Thus, monitoring of the serum levels is essential and blood samples should be taken optimally every 12 h.^[11]

DIGOXIN TOXICITY

The most common symptoms of digoxin toxicity are gastrointestinal and include nausea, vomiting, abdominal pain, and diarrhoea. The cardiac manifestations are the most concerning and can be fatal. The classic arrhythmias due to digoxin include atrial tachycardia with a 2:1 conduction, bidirectional ventricular tachycardia, and atrial fibrillation with a slow ventricular response. In a literal sense, its toxicity can induce every arrhythmia except for rapidly conducted atrial arrhythmias (atrial fibrillation and atrial flutter). In AF, an increase in the dose can result in AV block and regular junctional rhythm. Arrhythmias can occur at both therapeutic and subtherapeutic concentrations.^[11] Neurological symptoms include lethargy, confusion, and vertigo altered mental status/delirium in the absence of hypoperfusion of the brain. Ocular manifestations include xanthopsia or seeing a yellow, blurred vision, and diplopia.^[4]

CURRENT INDICATIONS FOR THE USE OF DIGOXIN

RATIONALE BEHIND DIGOXIN HOLIDAY

Digitalis should always be prescribed under specialist supervision. Given its distribution and clearance, caution should be exerted in females, the elderly, and patients with reduced renal function.^[15] The patients who would benefit most from the addition of digoxin are also those at greatest risk of exhibiting the toxic effect of the drug.^[4] Based on clinical trial data, the therapeutic range of digoxin would be about 0.5–1.5 ng/ml.^[4,16] For heart failure patients, the targeted steady state serum digoxin level is between 0.5 and 0.9 ng/ml.^[17,18] Ventricular rate control in atrial fibrillation patients will usually require higher digoxin steady state serum concentrations. The toxicity increases as the serum drug levels increase above 2.0 ng/ml. The narrow therapeutic range of digoxin makes it a difficult drug to administer. In patients with comorbidities or other factors affecting digoxin metabolism (including other drugs) and/ or the elderly, the maintenance dose may also be difficult to estimate theoretically, and in this situation, it should be established empirically, based on the measurements of digoxin concentration in peripheral blood.^[15] When measuring a digoxin serum level, it is essential to draw blood at least 6–8 h after the last dose. Considering the narrow therapeutic range and limited availability of serum digoxin measurements, a digoxin ‘holiday’ is given where the patient is given the dose 5–6 days a week to minimise digoxin toxicity due to the lack of therapeutic drug monitoring.^[19] It is not clear whether this ‘holiday’ is justified in all cases since digoxin plasma levels might decrease to below therapeutic levels.^[20,21] Despite this fact, ‘digoxin holiday’ is frequently used in many countries.^[22-24] The practice of prescribing digoxin with ‘breaks’ on weekends or even a weekday is based on traditional treatments or ancient preparations and does not have a proven scientific basis.^[25] There is still no consensus statement recommending interrupted digoxin therapy. It is excreted exponentially, with an elimination half-life of 36–48 h in patients with normal renal function, resulting in the loss of about one-third of body stores daily.^[4] After 2 days of rest, the levels of digoxin, from a pharmacokinetic point of view, can decrease by half. It is not clear if these interrupted digoxin regimens really offer a safer alternative over the continuous dosing regimens without compromising the effectiveness and patient QoL. It is anticipated that plasma digoxin levels may fall below the therapeutic range during the holiday which may affect patient clinical status.

DIGOXIN HOLIDAY AND THE EFFECTIVENESS OF THERAPY

Works done in Spain such as that of Gnocchi et al.^[23] or that of Pedre et al.^[22] demonstrated that in patients who tend to ‘rest,’ blood levels of digoxin were subtherapeutic, compared to patients who ‘do not rest.’ Although the number of patients in these studies was small, the results were statistically significant.^[25] In the single-blind randomised prospective study done in 36 patients with CHF and systolic dysfunction with AF or normal sinus rhythm by Gnocchi et al.,^[23] the results obtained also suggested that digitalis toxicity could be prevented by adjusting the dose according to the renal function rather than interrupting the treatment as is usual practice in their country. In the crossover prospective study conducted by Pedre et al.,^[22] the uninterrupted regimen proved better than the discontinuous one in controlling the heart rate. Similar results were obtained by Nematipour et al.,^[24] in their prospective crossover clinical trial done in Iranian patients. In their study, the two regimens used in patients with chronic atrial fibrillation showed that an interrupted regimen for digoxin prescriptions led to an insufficient serum concentration. Changing the holiday regimen to the continuous form led to better control of resting heart rate. In India, George and Thomas^[26] studied serum concentrations of digoxin on days 5^th, 6^th, and 7^th in patients taking digoxin on a 5/7 schedule. There was a significant fall in serum digoxin concentration when therapy was interrupted for 2 days. Although the sample size was small, the fall in digoxin concentration from day 5 to 7 was found to be uniform across their study population. A prospective cohort study was done by Sadray et al.,^[21] in 123 patients of CHF or AF, to evaluate the continuous and interrupted digoxin regimens. Based on the results, they concluded that a 1 tablet/day regimen is to be preferred.

Contrary to the above observations, a study conducted by Reinbach et al.,^[27] using four digoxin drug schedules – 0.25 mg/day, from Monday to Friday; 0.25 mg/day from Monday to Saturday; 0.25 mg/day, and 0.125 mg/day showed that the most patients using these different therapeutic schedules had plasma drug levels within the therapeutic range.

DIGOXIN HOLIDAY AND QoL

The first study to assess the QoL for atrial fibrillation patients taking different digoxin treatment regimens was done by Alshabasy et al.^[28] in the Egyptian population. It was a prospective randomised parallel study and the four digoxin regimens used were – 0.25 mg daily except Friday; 0.25 mg daily except Thursday and Friday; 0.125 mg/day or a tailored daily dose based on the patient’s renal function and ejection fraction. They concluded that calculating the proper dose based on kidney function was superior to all other regimens in maintaining the steady state of digoxin in the therapeutic range. The 2-day holiday led to a great fluctuation in the serum digoxin concentration with most patients falling below the therapeutic range post-holiday. Once daily tablet (0.25 mg) was suitable in maintaining digoxin serum concentration in the recommended therapeutic range. However, the fluctuation in digoxin serum concentration did not affect QoL for atrial fibrillation patients.

CONCLUSION

Serum concentration monitoring is a suitable guideline for the selection of a digoxin regimen.

Proper management of patients receiving digoxin also requires attention to renal function, electrolytes, and the associated drugs which the patient is receiving.

Although digoxin toxicity is a real concern, prescribing the drug in an uninterrupted regimen, without a ‘holiday’ is justified in patients with atrial fibrillation for achieving the therapeutic range and for better control of the heart rate.