The Place of Digoxin/Digitalis Cardiac Agent/ Today in the Treatment of Elderly Population: the Challenges of Undefined Dose Effect Relationship and State of the Art

Proceedings of the World Medical Conference

The Place of Digoxin/Digitalis Cardiac Agent/ Today in the Treatment of Elderly Population: The Challenges of Undefined Dose Effect Relationship and State of the Art

H. Tesfaye

oedema of cardiac origin. Reportedly an old woman in Abstract—Digoxin remains one of the most commonly Shropshire cured some people with dropsy; Withering, who prescribed of all cardiac medications. The main indications for heard about the herbal user assumed that the component of digoxin usage include atrial fibrillation and heart failure; both these foxglove may be the cause of that effect. Withering thought conditions are more prevalent in older patients. Given the aging that it acts on kidney due to its diuretic effect observed. population and the increasing incidence of heart failure we would expect prescribing of digoxin to remain as frequent or to even However, he later reported its power on the heart function. increase in older patients. Older patients are also more likely to While earlier empirical use of digitalis is well documented, develop toxicity and diagnosis of digoxin toxicity can be difficult in William Withering is credited with formally introducing this group. Numerous components contribute to the development of digitalis into clinical medicine over two centuries ago toxicity in older patients, ranging from aging-related changes in renal publishing a book titled “An account of digitalis (dried leaves function or body mass to polypharmacy and possible interactions of the purple foxglove) and some of its medical uses, where he with digoxin. It is therefore important to understand how the pharmacokinetics of digoxin may be altered in the older population. included practical remarks on dropsy and other diseases. [1] Application of basic pharmacological principles may be helpful in Withering also emphasized the significant toxicity behind the anticipating these problems. This review describes the cardiac glycosides extracted from Foxgloves in collection of pharmacokinetics of digoxin, the changes in pharmacokinetics with cases he published today used as historical document. [2]. increasing age and how concomitant disease states or drug With the development of chemical techniques, digitoxin was interactions may affect the pharmacokinetics of digoxin. The main isolated and identified from Digitalis purpurea and digoxin objectives of this paper is to draw attention to pro and contra challenging opinions on digoxin use for elderly population, where, from Digitalis lanata. Since then, digitalis glycosides have significantly high number of patients on long term digoxin therapy is been the subject of considerable discussion and exposed to levels beyond recommended and evidently within experimentation. Introduced for the treatment of the dropsy, potentially toxic levels. Emphasizing and discussing the burdens of digitalis was soon promoted as a treatment for a wide variety poly pharmacy and possible drug–drug interactions and benefits of of conditions, including mania and pneumonia, with therapeutic drug monitoring (TDM) is relevant in these regards. considerable ill-effects. After more than two centuries in use

the secret of this medicine is only gradually discovered thanks Keywords— Digitalis toxicity, digoxin dosage, elderly patients. to development of science and technology as well as outcome I. INTRODUCTION research approach of modern medicine. Although clinical experience, experimental data and haemodynamic studies n ancient times plant extracts containing cardioactive supported the use of digitalis for the treatment of heart failure, steroids we know today as cardiac glycosides (digitalis) I repeated controversies surrounded its efficacy and appropriate were used either for curing or poisoning purposes. Native indications. At the end of the last century, the issue was not people of old Egypt and ancient Romans had also used whether digoxin is effective, but whether it has a role in digitalis as medicine against several disorders including state patients with sinus rhythm treated with ACE-inhibitors and in of oedema. Certain steroids and their glycosides found in heart failure with preserved systolic function. [3] Although nature (Digitalis purpurea, Digitalis lanata, and Strophantus digitalis continued to be an important part of heart failure gratus) were known to have characteristic actions on management, the role of digoxin in patients with heart failure contractility and electrophysiology of the heart. Developments and sinus rhythm has been increasingly challenged. of digitalis from the folk remedy to the cardiac specific In this paper we go through development, state of the arts medicine is considered the merit of William Withering, who and place of digoxin in treatment of heart failure today. described digitalis in particular as medicine most likely for As mentioned above digoxin (digitalis) as remedy has long been used to treat heart failure; however, complete analysis of H. Tesfaye, Charles University, Czech Republic. E-mail: its overall effectiveness was not available until recently. [email protected]

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Results of the Digitalis Investigation Group trial showed that treatment group did not seem to develop increased toxicity, all adding digoxin to standard heart failure therapy had no effect animals developed asystole secondary to digoxin toxicity. No on mortality.[4] However, adding digoxin decreased clear benefit or detriment related to the administration of hospitalizations related to heart failure and improved Calciumchloride was shown. An earlier study, using a guinea- symptoms in patients treated for heart failure. In a prospective, pig model of digoxin-induced hyperkalemia, reported a trend randomized, double-blind, placebo-controlled multicenter trial toward decreased rates of dysrhythmia and death following of patients with chronic, stable mild to moderate heart failure treatment with intravenous calcium chloride. [12] Until secondary to left ventricular systolic dysfunction who had definitive data demonstrating the safety and efficacy of normal sinus rhythm and were receiving long-term treatment calcium administration in the setting of digoxin-induced with diuretic drugs and digoxin, authors demonstrated that hyperkalemia are available, its use should be avoided. withdrawal of digoxin (placebo group) or its continuation The goal of digoxin therapy in patients with congestive (digoxin group) had significantly different outcomes. Patients heart failure is to improve quality of life by reducing withdrawn from digoxin therapy showed worsened maximal symptoms and preventing hospitalizations. [13] Fundamental exercise capacity compared with those patients who continued cellular effects of dioxin is Inhibition of Na+, K+ -ATPase to receive digoxin. Patients withdrawn from digoxin therapy leading to increase of intracellular sodium and extracellular showed also an increased incidence of treatment failures in calcium. [14] Positive inotropic effect (used for congestive digoxin withdrawal group compared to digoxin maintenance heart failure) Electrophysiologic action (used as group). [5]. antiarrhythmic) includes influences on conductivity, refractory period, and automaticity. In the DIG trial digoxin therapy was II. DIGOXIN VERSUS OTHER TREATMENT OPTIONS IN HEART most beneficial in patients with ejection fractions of 25 percent FAILURE or lower, patients with enlarged hearts (cardiothoracic ratio of ACE inhibitors, beta blockers and spironolactone have been greater than 0.55) and patients in NYHA functional class III or shown to improve survival in patients with heart failure. IV. [4] The findings of the DIG trial also indicated that Consequently, the role of digoxin in the treatment of heart digoxin was clinically beneficial in subgroups of patients with failure remains secondary, despite renewed interest in its use. less severe forms of heart failure. Digoxin has been shown to reduce the morbidity associated Using direct clinical measures of heart failure, the PROVED . with congestive heart failure but to have no demonstrable and the RADIANCE trials showed definite clinical effect on survival. In the absence of a survival benefit, the goal improvement in patients who were treated with digoxin, even of digoxin therapy is to improve quality of life by reducing patients with mild heart failure. [5], [15] At present, patients symptoms and preventing hospitalizations. with preserved left ventricular systolic function probably Some authorities declare that digoxin should be used should not be treated with digoxin. Based on the study routinely, in conjunction with diuretics, ACE inhibitors, beta findings, digoxin therapy may be effective in patients with blockers and spironolactone, in all patients with severe mild or moderate heart failure, although the magnitude of the congestive heart failure and reduced systolic function. It is also effect may be quite modest. [16] Reanalyses of the trial’s advised to be added to the therapy of patients with mild to findings have raised new questions about the role of digoxin in moderate congestive heart failure if they have not responded heart failure treatment. These new analyses showed that low adequately to an ACE inhibitor or a beta blocker. [6], [7] If serum digoxin concentrations used in patients with more digoxin acts primarily by reducing neurohormonal activation, severe disease offered the most benefit. Another controversy its value is in question in patients with heart failure who are regarding digoxin therapy is its role in the treatment of already being treated with beta blockers. Patients with acute symptomatic diastolic dysfunction. The DIG ancillary trial digoxin toxicity often present with hyperkalemia. The demonstrated a trend toward decreased hospitalization and administration of calcium, which is often used in the treatment improved exercise performance in patients who received of hyperkalemia, has long been presumably contraindicated in digoxin; however, these benefits were not statistically the setting of digoxin toxicity. This is based on a proposed significant. . [17] Diastolic heart failure treatment has been synergistic relationship between cardiac glycosides, which directed at modifying physiologic factors (e.g., decreasing cause a physiologic rise in intracellular and extracellular heart rate, controlling blood pressure) because of the paucity calcium, to explain the enhanced toxicity seen with concurrent of outcome data. . [18] Pump function is relatively preserved calcium administration.( [8] Studies also demonstrate that high in patients with diastolic heart failure, and inotropic therapy is extracellular calcium increased the toxicity of cardiac usually not appropriate in this population. Clinical trials are glycosides at lower doses. [8], [9] Individual case reports have underway to provide better guidelines for the treatment of not demonstrated adverse effects from the administration of diastolic heart failure; however, digoxin will not likely emerge calcium to treat hyperkalemia in the setting of digoxin toxicity. as a standard therapy. . [18], [19] Digoxin generally does not [10] ,[11] A recent study examined the effects of the have a role in the treatment of diastolic heart failure and is not administration of intravenous calcium chloride in a porcine a first-line therapy for managing atrial fibrillation in patients model of digoxin toxicity.126 Although the animals in the with heart failure. . [20] In ambulatory patients with chronic

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mild to moderate diastolic heart failure and normal sinus findings from a meta-analysis of seven randomized trials rhythm receiving angiotensin-converting enzyme inhibitor and published before the PROVED, RADIANCE, and DIG trials. diuretics, digoxin had no effect on natural history end points [27] such as mortality and all-cause or cardiovascular The meta-analysis showed that the NNT to prevent the hospitalizations. [21]. clinical deterioration of one patient was nine. The presence of a third heart sound, the severity and duration of heart failure, III. DIGOXIN IN ACUTE MYOCARDIAL INFARCTION and cardiomegaly on a chest radiograph predicted the Digoxin has been reported to have detrimental effects in effectiveness of digoxin. Digoxin is not recommended for myocardial infarction. [22] The drug may increase myocardial patients with significant sinoatrial or atrioventricular block. oxygen consumption by augmenting contractility and inducing The DIG investigators concluded that adding digoxin to peripheral or coronary vasoconstriction. It may also provoke standard heart failure therapy (i.e., ACE inhibitors plus ventricular arrhythmias and increase infarct size. [23] Because diuretics) significantly decreased hospitalizations for myocardial stunning may be present for weeks or longer after worsening heart failure and improved exercise performance, an infarction, digoxin therapy should be avoided in the acute whereas adding digoxin to standard therapy did not improve phase after myocardial infarction, unless its use is strongly cardiovascular or all-cause mortality during the trial. [4] indicated as for conditions like atrial fibrillation ,where Reanalyses of the DIG trial have brought into question the ventricular rate control cannot be achieved with beta blockers safety of digoxin, including the optimal serum digoxin or calcium channel blockers, or when the use of these concentration for treating heart failure and the role of the medications is contraindicated for any reason. patient’s sex in digoxin therapy. Two studies in 1993 examined the effects of withdrawing digoxin therapy in patients with heart failure; The Randomized IV. QUESTIONS AROUND SERUM DIGOXIN CONCENTRATIONS Assessment of Digoxin on Inhibitors of Angiotensin- Digoxin serum levels monitoring is aimed to optimise Converting Enzyme (RADIANCE) trial and the Prospective therapy, whereas the concentration required for optimal Randomized Study of Ventricular Failure and the Efficacy of efficacy without risking toxicity remains not clearly defined Digoxin (PROVED) trial studied patients with mild to even post DIG conclusion. The very challenging matter is that moderate heart failure in normal sinus rhythm and showed that concentration/dose effect relation ship of digoxin, especially in withdrawing digoxin in these patients significantly worsened elderly population, to whom digoxin is frequently prescribed. heart failure symptoms and lowered exercise tolerance. [15], In our previous study ten year ago, only 29% of the subjects on [5] Digoxin has electrophysiologic effects that decrease long-term digoxin maintenance doses showed serum digoxin atrioventricular node conduction, making it potentially useful levels within published therapeutic ranges, whereas digoxin for controlling ventricular rates in patients with heart failure withdraw was warranted in 13% of cases due to levels showing and concomitant atrial fibrillation. However, digoxin appears probability to toxicity, despite absence of typical symptoms. to be most effective in controlling heart rate at rest in this Surprisingly 58% of the subjects had levels below 0.8 ng/mL population. Large doses of digoxin often are required when and some undetectable. [28] Farther more, elderly people are digoxin is used alone, usually resulting in higher serum prone to toxicity due to natural changes conditioned by aging. digoxin concentrations. Evidence suggests that using digoxin Besides knowing underlying pathophysiology in the elderly as a first-line agent for heart rate control may potentiate the patient population and the drug itself better, therapeutic drug shortening of the effective atrial refractory period, possibly monitoring with very qualified interpretation my help to better facilitating short-term atrial fibrillation recurrence and control the toxicity risk at the same time avoiding sub increasing a patient’s risk of future episodes. [24], [25]. therapeutic levels. A widely used reference range for serum American Academy of Family Physicians (AAFP) and digoxin concentration is 0.8 ng per mL (1.0 nmol per L) to 2 American College of Physicians (ACP) joint guidelines on ng per mL (2.6 nmol per L). This range was established to managing newly detected atrial fibrillation do not apply to assess digoxin toxicity, not effectiveness [29] patients with NYHA class IV heart failure, but may be applied Retrospective subgroup analysis of the DIG trial showed to patients with less severe symptoms [26]. For patients with increased mortality in men who received serum digoxin atrial fibrillation, the AAFP/ACP guidelines recommend the concentrations of more than 1.0 ng per mL (1.3 nmol per L) following drugs as first-line therapy for controlling heart rate and showed decreased mortality in men with serum digoxin during exercise and while at rest: atenolol, metoprolol , concentrations of 0.5 ng per L (0.6 nmol per L) to 0.8 ng per diltiazem, and verapamil. Digoxin has only been shown to mL. However, because less than one third of patients had a effectively control heart rate at rest and, therefore, should only concentration measurement at one month, there was be used as a second-line therapy for heart rate control in insufficient statistical power to determine whether digoxin use patients with atrial fibrillation. was associated with benefit or harm or had a neutral effect for Digoxin therapy may be delayed until the patient is women in this or any serum digoxin concentration range. [25] stabilized using these agents and initiated only if the patient Reanalysis of the PROVED and RADIANCE trials indicated remains symptomatic. This recommendation is supported by that patients with low serum digoxin concentrations (0.5 to 0.9

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ng per mL ) experienced similar benefits regarding symptoms states and medications that could change digoxin of heart failure, improvement in LVEFs, and increased pharmacokinetics, along with a recognition of digoxin toxicity treadmill time compared with patients with moderate (1.0 to symptoms. [32] New data questioning the effectiveness of 1.2 ng per mL) to high (more than 1.2 ng per mL) serum digoxin for heart failure create a dilemma for physicians. digoxin concentrations. [30] Before these new data were published, digoxin was the only The cardiac toxicity from a digoxin overdose is related to positive inotropic agent that had not been shown to increase digoxin’s effects on both the sympathetic and parasympathetic mortality in patients with heart failure. This observation now innervation of the heart. Consequently, digoxin poisoning may must be reevaluated. result in almost any type of cardiac dysrhythmia, including Although good evidence suggests that digoxin improves sinus bradycardia, atrial tachycardia, fibrillation or flutter with symptoms and reduces hospitalization in select patients with slow ventricular response, all degrees of AV block, junctional heart failure, recent data suggest that the use of higher serum tachycardia, and ventricular tachycardia or fibrillation. digoxin concentrations in men and the use of digoxin at any However, rapidly conducted supraventricular concentration in women are associated with increased tachydysrhythmias cannot occur, due to inhibition of AV nodal mortality. conduction. Bidirectional ventricular tachycardia is considered to be pathognomonic for digoxin toxicity and is caused by V. DILEMMA ABOUT PATIENT’S SEX AND DIGOXIN TREATMENT alterations of intraventricular conduction, junctional OUTCOMES RELATIONSHIP tachycardia with aberrant intraventricular conduction, or Controversy continues concerning the clinical utility of alternating ventricular pacemakers. However, the most digoxin in women with heart failure. Investigation of the commonly seen cardiac conduction abnormalities are relationship of serum digoxin concentration and outcomes in premature ventricular contractions often the first signs of women with heart failure through retrospective analysis of data digoxin poisoning. Electrocardiographic manifestations of from the DIG trial indicated a beneficial effect of digoxin on digoxin toxicity are due to decreased conduction accompanied morbidity and no excess mortality in women at serum by increased automaticity and a shortened repolarization concentrations from 0.5 to 0.9 ng/ml, whereas serum interval. Electrocardiogram (ECG) findings include an concentrations > or =1.2 ng/ml seem harmful. [33] increased PR interval, AV nodal block, and QT segment Digoxin use in women was apparently associated with shortening. Scooping of the ST segment, commonly referred to increased mortality risk. This finding should be interpreted as “Salvador Dali’s mustache,” may be found in patients with with caution, however, because it was based on retrospective therapeutic digoxin levels and is due to ST segment and T- data, and the cause of this phenomenon has not been fully wave forces in an opposing direction to the major QRS forces. elucidated. Prospective clinical trials are needed to determine [31] Although some investigators advocate the use of serum the serum digoxin concentration that is associated with the levels to guide digoxin dosing, little evidence supports this most clinical benefit and to determine the role of digoxin approach.30 The serum level of digoxin may be used to assist therapy for women. Another retrospective analysis of the DIG in evaluating a patient for toxicity, but not to determine the trial that included participants with only systolic heart failure, efficacy of the drug. When digoxin was considered to be examined the effects of digoxin on mortality based on the sex mainly an inotrope, higher dosages (greater than 0.25 mg per of patients. Overall, women in the DIG trial had a lower day) were generally used, and the incidence of toxicity was mortality rate than men. However, women randomized to much higher. In the PROVED and RADIANCE trials, the receive digoxin had a higher mortality rate than women who mean digoxin dosage was 0.375 mg per day. However, a study received placebo. [34] The reason for this finding is unclear. of a subset of patients in the RADIANCE trial showed that Although female participants in the DIG trial were slightly increasing the digoxin dosage from a mean of 0.2 mg per day older and had more comorbidities than their male counterparts, to 0.39 mg per day did not significantly improve heart failure these factors are not thought to influence the effectiveness of symptoms, exercise time or serum norepinephrine levels. digoxin therapy. [35] Hwever, the instances of suspected When lower dosages are used, the side effects of digoxin, digoxin toxicity and hospitalization were similar in men and especially ventricular arrhythmias, decrease. Use of lower women. [34] Although there was an inadequate number of dosages is particularly important in the elderly, because women in the DIG trial to determine whether a specific serum digitalis toxicity may be difficult to recognize in this patient digoxin concentration range was beneficial, or at least did not population.32 It is generally agreed that digoxin should be increase mortality, it is premature to conclude that digoxin given in a dosage of 0.125 to 0.25 mg per day. Dosages higher should never be used in women. It seems reasonable to initiate than 0.25 mg per day are probably unwarranted. digoxin therapy in women only when they are clearly Renal function plays a major role in the pharmacokinetics of symptomatic despite receiving maximal treatment with more- digoxin and is an important factor in determining the dosage. proven agents such as diuretics like furosemide, ACE Medications such as quinidine, amiodarone and verapamil inhibitors or angiotensin-II receptor blockers and beta may increase the serum digoxin concentration. Thus, safe and blockers. Although good evidence suggests that digoxin effective dosing requires recognition of concomitant disease improves symptoms and reduces hospitalization in select

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patients with heart failure, recent data suggest that the use of despite having serum dioxin concentrations within the higher serum digoxin concentrations in men and the use of recommended therapeutic range. [39] It is likely that there may digoxin at any concentration in women may be associated with be excessive use of digoxin in elderly populations perhaps increased mortality, but this should be examined carefully based on the prevalence of diastolic heart failure in the elderly Appropriate patient population and existing guedelines to as well as other co-morbid conditions that may mimic heart prescribe digoxin failure signs and symptoms. Cardiovascular disease is common The ACC/AHA staging system for heart failure can be a within the elderly population and requires treatment with useful tool when determining whether to initiate digoxin multiple types of medications. As with any cardiovascular therapy. This staging system and corresponding NYHA pharmaceutical regimen, the risk versus the benefit of each functional classifications for heart failure are included the medication must be strongly considered. This is particularly American College of Cardiology/American Heart Association true where, for various reasons, adverse effects are more often Task Force on Practice Guidelines and 2009 Focused update prevalent and pronounced. Over the years, it has been incorporated into the ACC/AHA 2005 Guidelines for the documented that digoxin is a frequently prescribed medication Diagnosis and Management of Heart Failure in Adults A in elderly populations. Although this drug can be beneficial Report of the American College of Cardiology when used in the appropriate setting, recent data would suggest Foundation/American Heart Association Task Force on that inappropriate administration of digoxin is common and Practice Guidelines Developed in Collaboration With the not without potentially serious consequences. Currently, the International Society for Heart and Lung Transplantation. [36] use of digoxin can be advocated to control heart failure in Whatever, digoxin therapy is used to treat heart failure atrial fibrillation and when added to ACE inhibitors and patients since more than 200 years todate. However, absence diuretics in those patients with symptomatic heart failure of effect on overall mortality found in the DIG study related to systolic left ventricular dysfunction. It is likely that associated with frequent adverse effects due to overdosing in the excessive use of digoxin in elderly populations as elderly patients with impaired renal function finally persuaded discussed in this review is perhaps based on the prevalence of medical opinion to the weak interest of digoxin in chronic diastolic heart failure in the elderly as well as other co-morbid heart failure. Yet, regarding strict data from the literature, it conditions that may mimic heart failure signs and symptoms. remains a lot of positive factors in favor of the interest for Since the elderly appear to be at high risk for digoxin toxicity, digoxin: reduction of morbidity, reduction of mortality at low the inappropriate use of this medication to treat these serum concentration <1.0 ng/ml, very low cost with favorable conditions could result in significant and unnecessary cost-effectiveness ratio. [37] morbidity. [40] Since the elderly appear to be at high risk for Due age related polymorbidity, the elderly population digoxin toxicity, the inappropriate use of this medication to requires treatment with multiple types of medications treat these conditions could result in significant and including cardiovascular pharmacotherapeutic regimen, where unnecessary morbidity.To add to the challenge, older patients the risk versus the benefit of each medication must be strongly are also more likely to develop toxicity and diagnosis of considered particularly because adverse effects are more often digoxin toxicity can be difficult in this group. Despite all prevalent and pronounced in this population. Over the years, it digoxin continues to be an important drug in long-term heart has been documented that digoxin is a frequently prescribed failure patient management in elderly patients. Thus, greater medication in elderly populations . Although this drug can be knowledge about the causes and prevention of digoxin toxicity beneficial when used in the appropriate setting, recent data should further reduce the morbidity and mortality arising from would suggest that inappropriate administration of digoxin is digoxin toxicity, especially in the elderly population. [41] common and not without potentially serious consequences. Digitalis glycosides have been used for more than 200 years in Increasing age is associated with progressively worse clinical the treatment of heart failure, but the serum dioxin outcomes in patients with heart failure. However, the concentration required for optimal clinical efficacy and beneficial effects of digoxin in reducing all-cause admissions, acceptable toxicity remains controversial. The study sought to heart failure admissions, and heart failure death or determine whether there was a relationship between serum hospitalization are independent of age, indicating that digoxin digoxin concentration, including concentrations typically remains a useful agent for the adjunctive treatment of heart regarded as low, and clinical efficacy related to digoxin in failure due to impaired left ventricular systolic function in patients with symptomatic left ventricular dysfunction utlized patients of all ages. [35] Older patients who undergo heart data from two randomized, double-blinded, placebo- failure are at increased risk for side effects from digoxin, controlled, digoxin-withdrawal trials concluded that patients in which are often nonspecific and can occur at serum digoxin the low serum dioxin category were significantly less likely concentrations generally considered therapeutic. [38] than placebo patients to experience worsening heart failure Increased age is most likely associated with enhanced during follow-up, but the beneficial effects of digoxin on susceptibility to digoxin toxicity, possibly due to unknown common clinical end points in patients with heart failure were pharmacodynamic changes. This raises the possibility that similar, regardless of serum digoxin concentration. [42] patients >71 years show clinical evidence of digoxin toxicity Among cardiovascular agents, digoxin is one of the most

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commonly involved in fatalities causing 17% of the reported Failure Society of America and the American College of fatalities. [43] Assessment of variations in serum digoxin Cardiology/American Heart Association recommends that the concentration and their association with mortality and lower dose should be used in patients over 70 years of age, hospitalization in patients with heart failure demonstrated that those with impaired renal function, or those with a low lean higher serum digoxin concentrations were associated with body mass, whereas digoxin toxicity is commonly associated increased mortality suggesting that the effectiveness of digoxin with serum levels >2 ng/mL but may occur with lower digoxin therapy in men with heart failure and a left ventricular ejection levels if hypokalemia, hypomagnesemia, or hypothyroidism fraction of 45% or less may be optimized in the range of 0.5 to coexist. Likewise, the concomitant use of agents such as 0.8 ng/mL. [25] Digoxin at low serum concentration quinidine, verapamil, spironolactone, flecainide, and significantly reduced mortality and hospitalizations in amiodarone can increase serum digoxin levels and increase the ambulatory chronic systolic and diastolic HF patients. [44] likelihood of digoxin toxicity. Digoxin concentrations Digoxin-associated risk in mortality may be due to an increased during concomitant administration of clarithromycin, increases in myocardial oxygen consumption and where the percentage increase in digoxin concentrations after arrhythmogenesis at higher serum concentrations. We the usual oral dose of clarithromycin was approximately 70% hypothesized that the serum concentration of digoxin is a was also reported .[50] For patients with heart failure and major determinant factor of its efficacy on mortality rates in atrial fibrillation with a rapid ventricular response, the patients with congestive heart failure. The maintenance of administration of high doses of digoxin (>0.25 mg daily) for digoxin's serum concentration at the lower end of the reference the purpose of rate control is not recommended. When range, i.e., between 0.5 and 0.8 ng/ml, may reduce mortality necessary, additional rate control should be achieved by the rates as well as improve clinical symptoms. [45] Clinical addition of beta-blocker therapy or amiodarone (strength of studies have solidified the utility of digoxin in patients with evidence = C). If amiodarone is added, the dose of digoxin left ventricular dysfunction and normal sinus rhythm. No should be reduced. Digitalis preparations are now entering definitive data have been published to clarify the range of their fourth century of clinical use for the treatment of chronic serum digoxin concentrations associated with clinical benefit. heart failure symptoms. Its clinical efficacy can no longer be The traditional therapeutic range of 0.8-2.0 ng/ml was doubted and its safety has been verified by the multicenter developed originally to classify digoxin toxicity, not efficacy. DIG trial. Future advances in pharmacogenetics should In addition, this reference range was used before publication of facilitate identification of those patients most likely to benefit the Digitalis Investigators Group trial. Clinical and from its pharmacologic effects. [51] Digoxin at low SDC neurohormonal studies have attempted to characterize serum significantly reduced mortality and hospitalizations in concentrations that are associated with clinical efficacy. [46] ambulatory chronic systolic and diastolic HF patients. [52] Post hoc analyses of the Digitalis Investigation Group (DIG) Most heart failoure patients are > or = 65 years, yet the trial indicate that digoxin at low (0.5 to 0.9 ng/ml) serum effects of digoxin on outcomes in these patients have not been digoxin concentration reduces mortality, which is eliminated at well studied. Low-dose digoxin (< or = 0.125 mg/d) was the higher (>or=1 ng/ml), and that low-dose digoxin (

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fail to achieve control of the disease. [23]. Jugdutt BI, Khan MI, Jugdutt SJ, Blinston GE. Effect of prolonged inotropic stimulation on ventricular remodeling during healing after myocardial infarction in the dog: mechanistic insights. J Am Coll Cardiol. REFERENCES 1996 Jun;27(7):1787-95. [1]. Withering,W.: An account of the foxglove, and some of its medical [24]. Sticherling C, Oral H, Horrocks J, Chough SP, Baker RL, Kim MH, et uses:with practical remarks on dropsy, and other diseases. G. G. J. and al. Effects of digoxin on acute, atrial fibrillation-induced changes in atrial Robinson,Paternoster-Row, London (GB) a-Swiney, Birmingham, 1785 refractoriness. Circulation. 2000 Nov 14;102(20):2503-8. [2]. Somberg J, Greenfield B, Tepper D. Digitalis: historical development in [25]. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM (2003) clinical medicine. J Clin Pharmacol. 1985 Oct;25(7):484-9 Association of serum digoxin concentration and outcomes in patients with [3]. Jerie P. [Milestones of cardiovascular pharmacotherapy: II. Digitalis]. heart failure. JAMA. 2003 Feb 19;289(7):871-8. Cas Lek Cesk. 2007;146(4):314-20.) article in Czech(Milniky [26]. Snow V, Weiss KB, LeFevre M, McNamara R, Bass E, Green LA, et kardiovaskularni terapie al., Management of newly detected atrial fibrillation: a clinical practice [4]. The effect of digoxin on mortality and morbidity in patients with heart guideline from the American Academy of Family Physicians and the failure. The Digitalis Investigation Group.N Engl J Med. 1997 Feb American College of Physicians. Ann Intern Med. 2003 Dec 20;336(8):525-33 16;139(12):1009-17) [27]. Jaeschke R, Oxman AD, Guyatt GH. To what [5]. Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, Jolly MK. extent do congestive heart failure patients in sinus rhythm benefit from Randomized study assessing the effect of digoxin withdrawal in patients with digoxin therapy? A systematic overview and meta-analysis. Am J Med. 1990 mild to moderate chronic congestive heart failure: results of the PROVED Mar;88(3):279-86 trial. PROVED Investigative Group. J Am Coll Cardiol. 1993 Oct;22(4):955- [28]. Tesfaye H, Sechser T, Sedivy J, Moravek J. Therapeutic drug 62.) monitoring (TDM) and serum levels of digoxin: Is the so-called “therapeutic [6].(Levitzki A, Marbach I, Bar-Sinai A. The signal transduction range” indeed evidence based? Cor et Vasa 2002, 44(6):276-280. between beta receptors and adenyl cyclase.(Life Sci. 1993;52(26):2093-100. [29]. Beller GA, Smith TW, Abelmann WH, Haber E, Hood WB Jr. Digitalis [7]. Madan BR, Khanna NK, Soni RK. Effect of some arrhythmogenic intoxication. A prospective clinical study with serum level correlations. N agents upon the acetylcholine content of the rabbit atria. J Pharm Pharmacol. Engl J Med. 1971 May 6;284(18):989 -97. 1970 Aug;22(8):621-2. [25]. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz [8].Hack JB, Woody JH, Lewis DE, et al. The effect of calcium chloride in HMAssociation of serum digoxin concentration and outcomes in patients treating hyperkalemia due to acute digoxin toxicity in a porcine model. J with heart failure.JAMA. 2003 Feb 19;289(7):871-878. Toxicol Clin Toxicol. 2004;42(4):337-421. [30]. Adams KF Jr, Gheorghiade M, Uretsky BF, Patterson JH, Schwartz TA, [9].. Nola GT, Pope S, Harrison DC. Assessment of the syngerstic Young JB.Clinical benefits of low serum digoxin concentrations in heart relationship between serum calcium and digitalis. Am Heart J. 1970 failure.J Am Coll Cardiol. 2002 Mar 20;39(6):946-53.) Apr;79(4):499-507. [31]. Hack JB, Lewin NA. Cardiac glycosides. In: Goldfrank LR, [10]. Fenton F, Smally AJ, Laut J. Hyperkalemia and digoxin Flomenbaum NE, Lewin NA, et al, eds. Goldfrank’s Toxicologic toxicity in a patient with kidney failure. Ann Emerg Med. 1996 Emergencies. 7th ed. New York, NY: Mc- Graw-Hill; 2002:724-734. Oct;28(4):440-1. [32]. Cauffield JS, Gums JG, Grauer K. The serum digoxin concentration: ten [11]. Van Deusen SK, Birkhahn RH, Gaeta TJ. Treatment of hyperkalemia in questions to ask. Am Fam Physician. 1997 Aug;56(2):495-503, 509-510. a patient with unrecognized digitalis [33]. Adams KF Jr, Patterson JH, Gattis WA, O'Connor CM, Lee CR, toxicity. J Toxicol Clin Toxicol. 2003;41(4):373-376. Schwartz TA, Gheorghiade M. Relationship of serum digoxin concentration [12]. Ghaemmaghami CA, Harchelroad F. Dangers of intravenous to mortality and morbidity in women in the digitalis investigation group trial: calcium chloride in the treatment of digoxininduced a retrospective analysis. J Am Coll Cardiol. 2005 Aug 2;46(3):497-504.) hyperkalemia – fact or fiction. [34]. Rathore SS, Wang Y, Krumholz HM Acad Emerg Med 1999;6(5):378. Sex-based differences in the effect of digoxin for the treatment of heart failure [13]. Haji SA, Movahed A. N Engl J Med. 2002 Oct 31;347(18):1403-11.) [35]. Rich MW, McSherry F, Update on Digoxin Therapy in Congestive Heart Failure Am Fam Physician. Williford WO, Yusuf S; Digitalis Investigation Group. Effect of age on 2000 Jul 15;62(2):409-16. mortality, hospitalizations and response to digoxin in patients with heart [14]. Smith TW: Digitalis mechanism of action and Clinical Use N Engl J failure: the DIG study. J Am Coll Cardiol. 2001 Sep;38(3):806-13. Med. 1988 Feb 11;318(6):358-65. [36]. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats [15] Packer M, Gheorghiade M, Young JB, Costantini PJ, Adams KF, Cody TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, RJ, et al. Withdrawal of digoxin from patients with chronic heart failure Silver MA, Stevenson LW, Yancy CW; American College of Cardiology treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Foundation; American Heart Association. J Am Coll Cardiol. 2009 Apr Engl J Med. 1993 Jul 1;329(1):1-7 14;53(15):e1-e90.) [16] Soler-Soler J, Permanyer-Miralda G. Should we still prescribe digoxin in [37]. Juilliere Y, Selton-Suty C. Digoxin therapy: A persisting interest despite mild-to-moderate heart failure? Is quality of life the issue rather than contrary winds. Arch Cardiovasc Dis. 2010 May;103(5):281-4.) quantity? Eur Heart J. 1998 Dec;19 Suppl P:P26-31 [38]. George A. Heckman, Robert S. McKelvie Necessary cautions when [17]. The Digitalis Investigation Group. The effect of digoxin on mortality considering digoxin in heart failure CMAJ February 27, 2007 176(5) [ 644- and morbidity in patients with heart failure. N Engl J Med. 1997 Feb 45) 20;336(8):525-33 [39]. Miura T, Kojima R, Sugiura Y, Mizutani M, Takatsu F, Suzuki Y. [18]. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and Effect of aging on the incidence of digoxin toxicity. Ann Pharmacother. 2000 diastolic heart failure: part II: causal mechanisms and treatment. Circulation. Apr;34(4):427-32.) 2002 Mar 26;105(12):1503-8. [40]. Haas GJ, Young JB. Inappropriate use of digoxin in the elderly: how [19]. Aurigemma GP, Gaasch WH. Clinical practice. Diastolic heart failure. widespread is the problem and how can it be solved? Drug Saf. 1999 N Engl J Med. 2004 Sep 9;351(11):1097-105. [20]. Morris SA, Hatcher HF, Mar;20(3):223-30. Reddy DK Digoxin therapy for heart failure: an update. Am Fam Physician. [41]. Hanratty CG, McGlinchey P, Johnston GD, Passmore AP. Differential 2006;74(4):613-618. pharmacokinetics of digoxin in elderly patients. Drugs Aging. 2000 [21]. Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW, Love Nov;17(5):353-62. TE, Aronow WS, Adams KF Jr, Gheorghiade M. Effects of digoxin on [42]. Adams KF Jr, Gheorghiade M, Uretsky BF, Patterson JH, Schwartz TA, morbidity and mortality in diastolic heart failure: the ancillary digitalis Young JB. Clinical benefits of low serum digoxin concentrations in heart investigation group trial. Circulation. 2006 Aug 1;114(5):397-403. Epub failure. J Am Coll Cardiol. 2002 Mar 20;39(6):946-53. 2006 Jul 24. [43]. Watson WA, Litovitz TL, Klein-Schwartz, et al. 2003 Annual report of [22]. Casiglia E, Tikhonoff V, Pizziol A, Onesto C, Ginocchio G, Mazza A, the American Association of Poison Pessina ACJpn Heart J. Should digoxin be proscribed in elderly subjects in Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. sinus rhythm free from heart failure? A population-based study. Jpn Heart J. 2004 Sep;22(5):335-404.) 1998 Sep;39(5):639-51.

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[44]. Ahmed A, Pitt B, Rahimtoola SH, Waagstein F, White M, Love TE, Braunwald E Effects of digoxin at low serum concentrations on mortality and hospitalization in heart failure: a propensity-matched study of the DIG trial. Int J Cardiol. 2008 Jan 11;123(2):138-46. Epub 2007 Mar 23. [45]. Wang L, Song S. Digoxin may reduce the mortality rates in patients with congestive heart failure. Med Hypotheses. 2005;64(1):124-6. [46]. Terra SG, Washam JB, Dunham GD, Gattis WA.Therapeutic range of digoxin's efficacy in heart failure: what is the evidence? Pharmacotherapy. 1999 Oct;19(10):1123-6. [47]. Digitalis Investigation Group, Ahmed A, Waagstein F, Pitt B, White M, Zannad F, Young JB, Rahimtoola SH. Effectiveness of digoxin in reducing one-year mortality in chronic heart failure in the Digitalis Investigation Group trial. Am J Cardiol. 2009 Jan 1;103(1):82-7. Epub 2008 Oct 23. [48]. Ahmed A.Digoxin and reduction in mortality and hospitalization in geriatric heart failure: importance of low doses and low serum concentrations. J Gerontol A Biol Sci Med Sci. 2007 Mar;62(3):323-9. [49]. Ahmed A, Rich MW, Love TE, Lloyd-Jones DM, Aban IB, Colucci WS, Adams KF, Gheorghiade M.Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial. Eur Heart J. vol. 27(2):178-86. Jan 2006, Epub Dec 82005 Dec 8. [50]. Tanaka H, Matsumoto K, Ueno K, Kodama M, Yoneda K, Katayama Y, Miyatake K. Effect of clarithromycin on steady-state digoxin concentrations. Ann Pharmacother. Vol. 37(2):178-81 Feb 2003 [51]. Dec GW.Digoxin remains useful in the management of chronic heart failure. Med Clin North Am. Vol .87(2):317-37 Mar 2003 [52]. Ahmed A, Pitt B, Rahimtoola SH, Waagstein F, White M, Love TE, Braunwald E.Effects of digoxin at low serum concentrations on mortality and hospitalization in heart failure: a propensity-matched study of the DIG trial. Int J Cardiol. Vol. 123(2):138-46 Jan 2008 , Epub Mar 2007

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