Digoxin for the Control of Congestive Heart Failure Symptoms in Palliative Care

Abstract: End-stage congestive heart failure has several symptoms, such as debilitating shortness of breath. Different classes of medications, including diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, beta blockers, and calcium channel blockers, are used to treat symptoms associated with congestive heart failure. In palliative care, patients with heart failure who remain symptomatic are often additionally prescribed non-cardiac classes of medications, such as opioids or benzodiazepines, to manage symptoms. Digoxin is an old medication for the treatment of heart failure that has since been supplanted by better alternative treatments. However, there is evidence to suggest that digoxin may be useful for managing symptoms of congestive heart failure in the palliative care setting. The authors describe two cases to illustrate the use of digoxin in end-stage heart failure with the goal of achieving better symptom control while managing the potential for digoxin toxicity.

Key words: End-stage heart failure, palliative care, symptom control, digoxin, shortness of breath, congestive heart failure.

Citation: Annals of Long-Term Care: Clinical Care and Aging. 2015;23(8):29-32.

Older medications that were once the treatment of choice for a particular indication often are prescribed less frequently as newer treatment options come on the market. This is especially the case when more clinical data is gathered and the accumulated real-world evidence shows less promising results than clinical trials originally indicated. Digoxin is a medication that has followed this pattern.

Digoxin was first harvested as digitalis from the leaf of the beautiful flowering plant, Digitalis purpurea (the foxglove), and was used for medicinal purposes centuries before the advent of what we currently call modern medicine. Sir William Withering (1741–1799), a physician and botanist from England, used it to treat dropsy, which at the time merely described the accumulation of edematous fluid that was often—but not always—due to heart failure. A 1965 article in Scientific American asserted that, “One could learn to use digitalis effectively and safely if one had no other text than Withering’s Account of the Foxglove.”^1,2 For physicians who trained during the 20th century, particularly prior to the veritable pharmacotherapy explosion during the period after World War II, the armamentarium for heart disease treatments were limited. Without treatment, many individuals—including those who developed rapid atrial fibrillation secondary to rheumatic mitral stenosis as a result of rheumatic fever, prior to the introduction of penicillin—would drown in their own pulmonary edema fluids. Administered intravenously during an acute episode, digoxin was used to slow the patient’s rapid heart rate while other supportive measures such as morphine, oxygen, and phlebotomy were used to treat shortness of breath.

Clinicians who prescribed digoxin from the 1950s through the 1970s were aware of the drug’s narrow therapeutic index and the potential for toxicity, which, although usually not serious, can be fatal.³ A patient’s ventricular response rate was used as a guide to good therapeutic effect when digoxin was prescribed for the treatment of atrial fibrillation. Further, ECGs could often discern rhythms that could be associated with toxic doses. The treatment of difficult cases was further simplified when in the 1970s, the ability to measure and interpret serum levels of digoxin became more readily available.^4,5 Current digoxin dosing aims at achieving a target serum digoxin level in the range of 0.5 to 0.8 ng/mL as an increase in mortality is associated with serum digoxin levels above 1ng/mL.⁶

Yet, the benefits of digoxin seemed less profound in patients with heart failure who were in normal sinus rhythm.⁷ Contemporary studies have demonstrated other potential risks of digoxin use for heart disease treatment.^8,9 Digoxin failed to show an effect on overall mortality in patients with CHF in the 1997 DIG (Digitalis Investigation Group) trial.⁸ In a 2014 study that examined data from the TREAT-AF (The Retrospective Evaluation and Assessment of Therapies in AF) trial, Turakhia and colleagues9 found an association between digoxin use and increased risk of death in individuals with newly diagnosed atrial fibrillation. This link was independent of drug adherence, kidney function, cardiovascular comorbidities, and concomitant therapies.
In addition, other cardiac-effective drugs became available for the treatment of heart failure, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and rate-controlling medications such as beta blockers and calcium channel blockers.8 Unlike digoxin, these medications have been shown to decrease mortality in patients with congestive heart failure (CHF).^10–13 As a result, digoxin fell out of favor.^8,14
However, there is evidence that digoxin decreases morbidity associated with CHF^8,15 and can thus be considered beneficial for the treatment of end-stage heart failure, when the focus is on comfort and symptom management as part of the palliative philosophy of care. We present two cases in which digoxin therapy led to improved symptoms in older adult patients with end-stage heart failure.

Case Report 1
Mr. D was a 72-year-old man admitted to the palliative care unit (PCU) from home with end-stage CHF, New York Heart Association class IV. He was living in the community and was cared for by a palliative care home care team. He had severe grade IV left ventricular systolic dysfunction secondary to coronary artery disease and chronic hypertension, known atrial fibrillation, cardiac cirrhosis, and chronic renal failure. The focus of this patient’s care in the PCU was comfort.

At home, Mr. D was experiencing progressively worsening shortness of breath while at rest. Although he spent most of his days sitting in a chair, he also felt dizzy when standing, which limited his ability to ambulate. Mr. D also found speaking and eating to require a great deal of effort. He had anasarca, with significant bilateral upper- and lower-extremity edema. Mr. D could not tolerate any further increases in cardiac medications and diuretics secondary to worsening of his baseline renal failure and hypotension-related symptoms. His medications, which he was compliant in taking, included carvedilol 3.25 mg twice daily, spironolactone 12.5 mg daily, ramipril 2.5 mg daily, furosemide 20 mg orally twice daily, and metolazone 2.5 mg twice weekly. Mr. D was unable to cope at home and was admitted to the PCU for symptom control.

On admission, Mr. D was in atrial fibrillation with a baseline heart rate of 68 beats per minute, a blood pressure of 103/80 mm Hg, an oxygen saturation of 90% on room air, and a respiratory rate of 24 breaths per minute. There was no ischemia noted on electrocardiogram (ECG), and cardiac enzymes were within normal range. Chest x-ray was consistent with heart failure. Pertinent metabolic investigations revealed a potassium level of 6.1 mEq/L (reference range, 3.5–5.0 mEq/L); sodium level of 126 mEq/L (reference range, 136–142 mEq/L); blood urea nitrogen (BUN) level of 23 mg/dL (reference range, 8–23 mg/dL); and creatinine level of 276 mg/dL (reference range, 0.6–1.2 mg/dL), worsening from a baseline level of 183 mg/dL, with an estimated creatinine clearance of 0.19 mL/min/1.73m2 (reference range, 75–125 mL/min/1.73m2). Spironolactone, ramipril, and metolazone were subsequently withheld. Over the next few days, intravenous hydration and diuresis improved Mr. D’s renal function and electrolyte balance; however, he remained uncomfortably short of breath.

Low-dose oral hydromorphone at 0.3 mg every 4 hours was then initiated to help manage Mr. D’s dyspnea, but he became reluctant to continue taking them when he started experiencing somnolence after only a few dosages. The patient accepted his poor prognosis and did not want to compromise his ability to communicate with his family in order to achieve better control of his dyspnea with opioids.

The question of whether Mr. D would benefit from digoxin for symptom control was raised during team rounds. In light of Mr. D’s renal failure, the team was initially reluctant to consider digoxin because of the drug’s potential for serious toxicity. After weighing all of his options, Mr. D decided that the potential for better symptom control was worth the close monitoring and risk of toxicity. The attending physicians recommended that the patient have regular laboratory investigations to monitor electrolyte levels, renal function, and digoxin levels. Before the initial loading dose of digoxin, Mr. D’s carvedilol dosage frequency was decreased from twice daily to once daily to account for the possibility of bradycardia and hypotension. The targeted serum digoxin level was between 0.5 ng/mL and 0.8 ng/mL, and the drug was initiated in a dose-appropriate manner due to Mr. D’s lowered creatinine clearance.^16,17 Mr. D was administered digoxin at a dose of 0.0625 mg twice per week, appreciating that, with this slow rate of administration, a steady state of digoxin would take longer to achieve with possible delayed symptom control. Mr. D’s dyspnea symptoms at rest improved after one week of starting 0.0625 mg twice per week, and he was later able to take steps again with no orthostatic problems. Over the course of a few weeks with close monitoring of renal and electrolyte function, Mr. D had no symptoms of digoxin toxicity. After 2 months in the PCU, and with improved symptom control, Mr. D was able to return home with supportive home-based palliative care and continued close monitoring.

Case Report 2
Mr. R was a 78-year-old man who transferred to the PCU from a local acute care hospital, where he had been admitted for urosepsis. He had a diagnosis of metastatic prostate cancer and a history of coronary artery disease, for which he took bisoprolol 5 mg every 12 hours and candesartan 4 mg daily; sick sinus syndrome; chronic renal failure; severe eczema, for which he took high-dose prednisone; and steroid-induced diabetes. He also had a pacemaker, which was inserted years before his admission. He had developed a tachyarrhythmia while in the hospital, and diltiazem 120 mg daily had been added to his cardiac regimen.

On admission to the PCU, Mr. R was quite confused, short of breath, and unable to complete full sentences. His blood pressure was 84/60 mm Hg, and his heart rate was 140 beats per minute and irregularly irregular. His jugular venous pressure was elevated, and there were significant inspiratory crackles in both lungs starting just below the scapula on auscultation. Candesartan and diltiazem were discontinued after it was determined that they were likely contributing to the patient’s low blood pressure.The management team determined that immediate control of Mr. R’s heart rate and aggressive diuresis were the best options for treatment, due to the severity of his symptoms. They thought that digoxin would offer heart rate control without compromising the patient’s blood pressure. Mr. R agreed to the proposed treatment plan after discussing it with the management team.

Blood work was initiated prior to starting digoxin therapy to ensure that the patient’s potassium level was normal and to determine renal function, as creatinine clearance would affect the dosing schedule of digoxin. Initial blood work revealed a potassium level of 5.7 mEq/L, a BUN level of 14 mg/dL, and a creatinine level of 178 mg/dL with an estimated creatinine clearance of 0.29 mL/min/1.73m2. The patient’s elevated potassium level was corrected with kayexalate. A modified digoxin loading dose was initiated to achieve the targeted serum digoxin level of 0.5–0.8 ng/mL, and to take into account the impaired creatinine clearance.16,17 Because of the patient’s symptom acuity, Mr. R was administered digoxin 0.25 mg every 12 hours for two doses followed by 0.125 mg for one dose. Within 24 hours, Mr. R’s heart rate was 88 beats per minute, his blood pressure stabilized at 117/60 mm Hg, and he was breathing more comfortably. He was maintained with digoxin 0.0625 mg on alternative days. Over the course of a few weeks, with close monitoring of renal and electrolyte function, Mr. D had no symptoms of digoxin toxicity. In a very comfortable manner, and without any disturbing symptoms of his heart failure, Mr. R died three weeks after he was administered his first dose of digoxin from the manifestations of his underlying malignancy.

Discussion
Collective trials have demonstrated that symptom control and quality of life can be improved with digoxin use in the setting of chronic end-stage heart failure.^8,18 There is, however, a dearth of high-quality clinical guidelines regarding initiation and maintenance of patients on digoxin therapy in the palliative care setting. The initiation of digoxin for symptom control should thus only be considered for patients with severe left ventricular systolic dysfunction and for whom symptoms are thought to be related to atrial fibrillation with a rapid ventricular response.

In patients who are not in an acutely decompensated state of heart failure, digoxin can be initiated slowly because of its prolonged half-life. Conversely, in patients who are symptomatic because of their rapid heart rates, more immediate ventricular rate control can be achieved by administering digoxin, which can be given via the oral or injectable route. Digoxin in dosages of higher than 0.125 mg per day is on the Beers Criteria for potentially inappropriate medications for use in older adults; dose adjustments are thus required for those with low body weight, renal dysfunction, and concomitant use of certain medications.^16,17,19 However, this should not preclude its use in the setting of end-of-life care. The Beers Criteria, although very informative of pharmacotherapy in elderly patients living in the community, in long-term care facilities, and in acute care hospitals, does not focus on the special needs of those requiring severe symptom amelioration as part of palliative and end-of-life care. In keeping with Beers’ recommendations, however, careful consideration of the appropriate dosage strategy is prudent in guiding management.

Laboratory investigations and ECGs can be used to guide management. For palliative care patients for whom such monitoring practices are not possible because of factors such as goals of care, prognosis, and location of care, the measurement of weight, amount of edema, and cardiac rate can be easily used to guide management of digoxin treatment as well.

Conclusion
Because the new generation of physicians may lack clinical experience with using digoxin in patients with heart failure with or without atrial fibrillation, it is not unusual to see patients with end-stage or even terminal heart failure who have never been offered digoxin therapy as part of their treatment regimen. The cases we describe are not uncommon and represent a sample of similar patients admitted to PCUs. Were the potential benefits of improving symptom control with digoxin use worth the risks of potential digoxin toxicity in the cases of Mr. D and Mr. R? No algorithm exists to answer this question, and detailed conversations were therefore initiated with both patients about quality of life, goals of care, risks associated with digoxin use for symptom control, alternative therapeutic options, trajectory of disease, and prognosis. For managing end of life care, physicians must sometimes seek alternatives to conventional treatment approaches, which may include medications like digoxin that have withstood the test of time and continue to have important roles in patient care.

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