Dofetilide-induced anorexia in an older adult

Abstract

An 84-year-old woman presented to her primary care physician with an unexplained 4-month history of weight and appetite loss after initiation of dofetilide 125 mcg orally twice daily for atrial fibrillation. She was noted to have lost 2.5 kg, which was a 3.6% decrease from her initial body weight of 69.4 kg. After excluding other etiologies for her anorexia, such as medication changes or changes in other diseases or conditions, her primary care physician and cardiologists elected to continue dofetilide but monitor the patient’s appetite and body weight. After 7 months of dofetilide use with persistent appetite loss, the cardiology team discontinued dofetilide. Continued weight loss was observed until approximately 1 month after stopping dofetilide, with a maximum weight loss of 2.9 kg or a 4.2% decrease. Improvements in appetite were reported 2 months after discontinuing dofetilide, with minor increases in weight that eventually stabilized. In this case, while taking dofetilide, the patient experienced anorexia leading to weight loss that subsided after discontinuation of the drug. Based on the temporal association between the patient’s changes in appetite and body weight and treatment with dofetilide, the drug was most likely the cause of the patient’s anorexia. We are unaware of other reports of anorexia associated with dofetilide, but clinicians may want to consider the drug as a potential cause for otherwise unexplained changes in appetite or body weight.

Introduction

Dofetilide is a class III antiarrhythmic agent indicated for the maintenance of normal sinus rhythm in patients with atrial fibrillation/flutter.¹ The drug’s mechanism of action is selective inhibition of the rapid component of the cardiac delayed-rectifier potassium current, I_Kr, resulting in an increased action potential duration and effective refractory period.^1,2 The drug is primarily renally excreted and has a terminal half-life of approximately 10 h, with a longer half-life observed in patients with renal impairment.¹ Additionally, women have been shown to have a 12–18% lower clearance of dofetilide than men.¹ Common adverse effects of dofetilide include chest pain (10%), headache (11%), dizziness (8%), increased QTc interval (5–7%), and ventricular arrhythmias (14.5%) including torsade de pointes (1.6%).^1,2

The US Food and Drug Administration (FDA) approved dofetilide for use in the United States, with a required medication guide to inform patients of the risks of dofetilide use. The guide instructs patients to call their healthcare provider immediately if experiencing loss of appetite when taking dofetilide.¹ This recommendation is based on appetite loss being a symptom resulting from electrolyte imbalances such as hypokalemia and hypomagnesemia, which may independently occur in patients taking dofetilide and increase the risk for QTc interval prolongation and ventricular arrhythmias during dofetilide use (Figure 1).¹ No clinically relevant direct effects of dofetilide on serum electrolytes were observed in clinical studies and there have been no published reports of anorexia or weight loss directly related to dofetilide use.^1,3–5

Figure 1.

Association of dofetilide use and concurrent electrolyte imbalances with increased risk of cardiac adverse events.

Unintended weight loss in older adults is considered clinically significant if there is more than a 5% reduction in body weight within 6–12 months.⁶ The leading cause of unintended weight loss in older adults is malignancy.⁶ However, etiologies such as gastrointestinal disease, psychiatric disorders, other chronic illnesses, and medications also need to be evaluated. Examples of common medications known to cause weight loss in older adults include antidepressants, acetylcholinesterase inhibitors, anticonvulsants, and oral decongestants.⁶ Unintended weight loss in older adults has been associated with functional decline and increased overall mortality, and should be considered a serious medical problem.⁶

The purpose of this report is to describe the case of an older adult who developed anorexia and subsequent weight loss after initiating dofetilide for the treatment of atrial fibrillation. Verbal consent of the patient was obtained during a scheduled phone follow-up visit and the consent was documented in the electronic medical record. However, approval by the Colorado Multiple Institutional Review Board was not obtained, as ethics approval is not required at our institution for case reports.

Case report

An 84-year-old Caucasian woman presented to her primary care physician with concerns of unintended weight loss secondary to decreased appetite (anorexia). The patient had a past medical history significant for gastroesophageal reflux disease, hypertension, coronary artery disease with a proximal left anterior descending stent, primary open-angle glaucoma, heart failure with preserved ejection fraction, hypothyroidism following thyroidectomy, untreated asymptomatic chronic lymphocytic leukemia (CLL), left breast cancer in full remission, sacroiliac joint and right knee arthritis, osteopenia, and atrial fibrillation. She denied smoking tobacco, drinking alcohol, or using recreational drugs. Her family history included heart disease in both parents.

During her visit, the patient reported she had a general appetite loss beginning around the time she started taking dofetilide 125 mcg orally twice daily for atrial fibrillation 4 months prior to the visit. Her body weight at the visit was 67.2 kg, which was a 2.5 kg or 3.59% decrease in weight over 4 months (Table 1).

Table 1.

Body weight, medication changes, and documented symptoms through the course of dofetilide therapy.

Day	Body weight (kg)	Change in weight (%)	Medication changes	Patient-reported symptoms
Index day I	69.7	Reference	Initiated dofetilide 125 mcg twice daily; metoprolol succinate 100 mg daily discontinued
+5	69.4	−0.4	Initiated metoprolol tartrate 25 mg twice daily
+12	70.4	+1.0	Losartan dose decreased to 25 mg daily
+15	70.8	+1.6
+98	68.4	−1.9	Losartan discontinued
+132	67.2	−3.6		Appetite loss reported over several months
+166	67.9	−2.6		Continued appetite loss; patient reported attempting to eat well
+196	67.1	−3.7		Continued appetite loss; patient reported she was forcing herself to eat and reported losing 5.9 kg on her scale
Index day II			Dofetilide discontinued
+24	66.8	−4.2
+52	67.1	−3.7	Metoprolol tartrate changed to metoprolol succinate 50 mg twice daily with metoprolol tartrate 25 mg as needed	Increased appetite
+89	67.1	−3.7	Initiated lorazepam 0.5 mg daily as needed
+207	68.0	−2.4

Weight on index day I (69.7 kg) is the reference weight used to calculate the change in weight for each day.

The dofetilide dose was reassessed and found to be appropriately dose adjusted for her creatinine clearance of 34.8 mL/min. Other medications at the time of the visit included apixaban 5 mg orally twice daily, aspirin 81 mg orally every morning, atorvastatin 20 mg orally at bedtime, cholecalciferol 1000 units orally daily, cyanocobalamin 1000 mcg orally daily, diclofenac sodium 1% gel 2–4 g topically four times a day as needed for knee pain, dorzolamide 2% ophthalmic solution one drop into both eyes twice daily, furosemide 20 mg orally twice daily, levothyroxine 100 mcg orally every morning, metoprolol tartrate 25 mg orally twice daily, omeprazole 20 mg orally daily, potassium chloride sustained-release 10 mEq orally every morning, and senna 17.2 mg orally daily as needed for constipation. Medication changes since starting dofetilide 4 months prior included decreasing her total daily dose of metoprolol from 100 mg to 50 mg and discontinuing losartan 1 month prior to the visit (Table 1).

Physical examination findings at the visit were unremarkable, with mood, affect, and behavior noted to be normal, including a negative depression screening (Patient Health Questionnaire 2), ruling out psychiatric illnesses as a potential cause of her appetite loss. The patient’s electrolytes, renal function, liver function tests, and vital signs were within normal limits and generally unchanged over the 4-month period, except for her serum potassium fluctuating slightly over that time, decreasing from 4.5 mmoL/L to 3.5 mmoL/L (reference range 3.5–5.1 mmoL/L) (Figure 2). Thyroid-stimulating hormone (TSH) decreased over the 4-month time period from 3.36 mIU/L to 0.56 mIU/L but was still within normal limits (reference range 0.34–5.60 mIU/L), and free T4 at the visit was also within normal limits at 1.71 ng/dL (reference range 0.89–1.76 ng/dL). Her glycated hemoglobin decreased over the 4-month time period from 6.9% to 6.1%, indicating better glycemic control and making diabetic-related cachexia an unlikely diagnosis. Her white blood cell count increased from 58.5 × 10⁹ cells/L to 72.8 × 10⁹ cells/L but was still within her baseline range of 48.8 × 10⁹ cells/L to 83.4 × 10⁹ cells/L over the past 2 years.

Figure 2.

Serum potassium concentrations prior to and after initiation of dofetilide.

Day 0 refers to start date of dofetilide use.

Reference range: 3.5–5.1 mmoL/L.

During this same time frame, the patient had routine follow up with hematology/oncology for her CLL every 6 months, with no significant changes noted. Her previous colonoscopy, 11 years ago, was normal, and an upper GI endoscopy was performed 3 years prior, showing chronic gastritis. However, she reported no symptom changes in her gastritis. Her last mammogram 4 years prior showed no evidence of malignancy. The patient’s echocardiogram (ECHO) was unchanged from 2 years prior, showing normal ventricular function and grade II diastolic dysfunction. Additionally, her electrocardiogram (ECG) was relatively unchanged, with a QTc interval of 514 ms 4 months prior and 515 ms 1 month prior to the visit. Both ECGs showed the patient was in sinus rhythm with premature atrial complexes and left bundle branch block. Regarding continuation of dofetilide, her primary care physician and cardiologist agreed to take a ‘wait and see’ approach to monitor for persistent weight loss versus weight stabilization or increase. At her next follow-up visit, approximately 6 months after starting dofetilide, the patient’s weight was stable at 67.1 kg, but she reported needing to force herself to eat. The cardiology team discontinued dofetilide after 7 months of therapy. About 1 month after stopping the drug, the patient’s weight was 66.8 kg, which was a 2.9 kg or 4.2% decrease in weight over 8 months (Table 1). At 2 months after stopping the drug, the patient endorsed having an increased appetite, and her weight improved slightly and stabilized at 67.1 kg.

Discussion

A PubMed and MEDLINE^® search was conducted to identify reports of anorexia and weight loss associated with dofetilide, but no reports were found. The mechanism and incidence of anorexia associated with dofetilide use is unknown. Within the Class III antiarrhythmics, amiodarone and sotalol have been reported to cause decreased appetite.^7–9 However, both agents are mechanistically different from dofetilide, and they have additional antiarrhythmic activities.⁸ While sotalol shares a methanesulfonanilide moiety with dofetilide and ibutilide, amiodarone is structurally different from dofetilide.⁸ Because loss of appetite is generally not observed with the other Class III antiarrhythmics, such as dronedarone and ibutilide, and the structures differ between the Class III antiarrhythmic agents, it is difficult to draw any conclusions about the mechanism of dofetilide leading to anorexia.

Of the patient’s concurrent medications at the time, anorexia has been reported only with furosemide.¹⁰ However, the patient had been taking furosemide for approximately 6 years prior to dofetilide initiation and the dose was unchanged for the entirety of dofetilide use, making furosemide an unlikely cause of the adverse reaction. Of note, the only major medication changes while the patient was taking dofetilide were the adjustments in losartan and metoprolol. The dose of losartan was decreased and it was eventually discontinued, which was the most likely cause of the 0.7 mmoL/L decrease in her serum potassium concentration. However, the patient’s electrolytes, including serum potassium, and vital signs were still within normal limits during the time she was prescribed dofetilide and were not likely attributing to her loss of appetite. In addition, metoprolol is not associated with weight loss or anorexia.^11,12

Given her history of CLL, the presence of malignancy was considered as a potential cause of the patient’s anorexia. However, based on an evaluation by her oncologist, her CLL had not progressed from the asymptomatic phase to the terminal phase. Additionally, her previous colorectal cancer screening was negative, and she had no complaints of gastrointestinal signs or symptoms. Furthermore, her previous mammogram showed no signs of breast cancer recurrence. One limitation to this case report is that further screenings for colon cancer and breast cancer were overdue, which does not allow malignancy to be fully ruled out as a cause for the patient’s lack of appetite. However, the patient’s anorexia did not persist after discontinuation of dofetilide, making it less likely that the patient had a new or worsening malignancy causing her appetite loss.

New, worsening, or uncontrolled diseases or conditions that are known to cause decreased appetite and unintentional weight loss, such as inflammatory bowel disease or malabsorption, depression or bipolar disorders, hyperthyroidism, congestive heart failure, or advanced kidney disease, were also excluded. The patient complained of no new or worsening gastrointestinal symptoms other than the anorexia. Furthermore, symptoms of depression were not apparent, and her TSH remained within normal limits. Her cardiac function evaluated on ECHO was stable. Lastly, her lower-extremity edema was stable, she had no pulmonary edema, and her renal function was stable.

The Naranjo adverse reaction probability score was calculated as 6 out of 13, indicating that the dofetilide was a ‘probable’ cause of the patient’s anorexia and weight loss.¹³ The score was calculated based on the following factors: the adverse event appeared after the suspected drug was administered, the adverse event improved when the drug was discontinued, there were no alternative explanations for the adverse event, and the event was confirmed by objective evidence.

The temporal relationship of decreased appetite and weight loss with the use of dofetilide and of increased appetite and weight gain, with stabilization, after discontinuation of dofetilide supports the probable causality of anorexia due to the drug. The patient reported having decreased appetite 132 days after starting dofetilide and a 3.6% decrease in weight was observed. The greatest decrease in weight of 4.2% was observed at a cardiology follow-up visit, 24 days after stopping dofetilide, but changes in appetite at that time were not explicitly stated. Based on the half-life of around 10 h, dofetilide is expected to be completely eliminated 50 h after stopping the drug. However, because clearance of the drug is decreased in female patients and those with renal impairment, complete elimination of dofetilide in this patient was likely prolonged and would explain the continued weight loss despite discontinuation of the drug. Increased appetite was first reported at a cardiology follow-up visit 52 days after stopping dofetilide, along with an increase in weight. These findings, together with the exclusion of other possible etiologies, demonstrate a positive temporal association between changes in appetite and weight and treatment with dofetilide.

Conclusion and implications for clinical care

Based on the findings of this case, dofetilide was the likely cause of anorexia and subsequent unintentional weight loss in our patient. The adverse reaction transpired after initiation of dofetilide and reversed with discontinuation. Common etiologies known to cause loss of appetite and possible drug-related causes were effectively ruled out, and objective evidence of changes in weight was apparent. Clinicians prescribing dofetilide are likely aware of the cardiac adverse effects that may occur with dofetilide use and likely monitor closely for these effects. However, this patient case underscores the relevance of regular monitoring for adverse events that may be less common but may have clinical implications and significance. More importantly, clinicians should consider all medications as a potential source for any change in condition in an older adult even in the absence of previous corroborative evidence.