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Cardiac glycosides in the next millennium
Progress in
Cardiovascular Diseases
Vol. 41, No. 4 January/February 1999
Cardiac Glycosides in the Next Millennium Paul J. Hauptman, Rekha Garg, and Ralph A. Kelly
Despite the documented efficacy of cardiac glycosides in improving symptoms in patients with heart failure caused by systolic ventricular dysfunction, considerable debate continues as to whether the use of this class of drugs should continue into the next millennium. In this review, the authors briefly examine the basic pharmacology of these drugs relevant to the treatment of heart failure, emphasizing their role in reducing sympathetic nervous system activity in patients with advanced heart failure. Next, withdrawal trials and the Digoxin Investigation Group dataset are reviewed in some detail. Despite these important additional data on the safety and efficacy of digitalis use in heart failure that became available in the 1990s, considerable controversy remains. Perhaps most importantly, if the mechanism by which these drugs improve symptoms in patients with heart failure is principally mediated by sympatholytic activity, do they remain relevant as -adrenergic antagonists become standard therapy for this disease? Copyright 娀 1999 by W.B. Saunders Company
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n an era in which neurohormonal antagonists have been shown to prolong survival in patients with heart failure and the long-term administration of orally bioavailable inotropic agents has fallen into disfavor, the debate over the mechanism(s) by which cardiac glycosides deliver a salutary clinical effect persists. Although there is no doubt that these agents (exclusively digoxin in recent clinical trials) act to improve the inotropic state of cardiac muscle (see1,2 for reviews of these mechanisms), it is unlikely that
this mechanism is primarily responsible for the beneficial effects seen in patients, particularly at serum digoxin levels in the range of 0.5 to 1.5 ng/mL. Alternative mechanisms for the beneficial effect of cardiac glycosides have been debated for some time. More than 30 years ago, Mason and Braunwald3 noted that intravenous infusions of ouabain, a water-soluble, rapidly acting glycoside, would increase vascular resistance and blood pressure in healthy subjects but had an opposite effect in patients with advanced heart failure, decreasing both mean arterial pressure and heart rate. Those changes were attributed to improved baroreflex responsiveness. Subsequent work in human and experimental animal preparations support this analysis.2 In this review, the authors briefly examine basic research evidence of how cardiac glycosides exert a beneficial effect in heart failure. Next, they review in some detail recent data from clinical trials, focusing on the Digoxin Investigation Group (DIG) trial. From the Cardiology Division, Saint Louis University Hospital and Saint Louis University School of Medicine, St Louis, MO; Eli Lilly and Company, Indianapolis, IN; and the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. Supported in part by grants No. HL52320 and HL36141 from the National Institutes of Health, Bethesda, MD. Address reprint requests to Ralph A. Kelly, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. Copyright 娀 1999 by W.B. Saunders Company 0033-0620/99/4104-0001$10.00/0
Progress in Cardiovascular Diseases, Vol. 41, No. 4 (January/February), 1999: pp 247-254
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Inotropic Mechanism By the late 1920s, it became clear that digitalis preparations caused a positive inotropic effect on the intact ventricle, resulting in a greater rate of increase of intracavitary pressure during isovolumic systole at constant heart rate and aortic pressure that could be shown in healthy, as well as failing, cardiac muscle. Cardiac glycoside administration caused the ventricular function (FrankStarling) curve of the intact heart to shift upward and to the left; thus, more stroke work is generated at a given filling pressure. These effects appear to be sustained during in vivo administration of digitalis for periods of weeks to months without any evidence of desensitization or tachyphylaxis. It is now generally believed that digitalis compounds bring about an increase in the availability of activator Ca⫹⫹ in heart cells, and that this increase in intracellular Ca⫹⫹ activity is sufficient to explain both the inotropic and arrhythmogenic effects of these drugs. Importantly, it is also now accepted that the increase in intracellular Ca⫹⫹ is a consequence of the direct effect of cardiac glycosides on transmembrane Na⫹ transport by inhibiting sodium, potassium adenosine triphosphatase (NaK-ATPase) activity (for a review, see Kelly RA, Smith TW2). Interestingly, recent evidence suggests that the immediate positive inotropic effect of cardiac glycosides, measured either in the intact heart in a conscious dog model or in isometrically contracting papillary muscle strips, is achieved with remarkable energy-transfer efficiency and little oxygen wasting.4 When compared with -adrenergic agonists or phosphodiesterase inhibitors, ouabain caused no significant change for the same degree of tension development in the tension-time integral per unit initial heat, an index of the economy of isometric contraction in an isolated muscle preparation. With long-term administration of cardiac glycosides, it has been argued that the increase in cardiac output that accompanies the positive inotropic effect would eventually lead to reduced oxygen consumption as ventricular chamber size and pressures decline and wall stress diminishes. These new data indicate that, even in the short term, cardiac glycosides could provide a moderate but metabolically efficient inotropic effect, an important consideration in patients with ischemic cardiomyopathies.
Neurally Mediated Actions of Cardiac Glycosides It is important to understand the pathophysiological course of heart failure and the role of digitalis glycosides in modifying the abnormal autonomic nervous system activity that is characteristic of advanced heart failure, including altered baroreflex activity. Heart failure is well known to be accompanied by an increase in sympathetic nervous system activity caused, in part, by a reduction in the sensitivity of the arterial baroreflex response to blood pressure. This results in a decline in tonic baroreflex suppression of central nervous system–directed sympathetic activity. This loss of sensitivity of the normal baroreflex arc also appears to contribute to the sustained elevation in plasma norepinephrine, renin, and vasopressin levels characteristic of heart failure. This sustained activation of sympathetic nervous system activity, which initially serves to maintain blood pressure and cardiac output by increasing heart rate, contractility, and systemic vascular resistance, also contributes to decreased excretion of salt and water by the kidneys. Despite the obvious evolutionary utility of this adaptive response to such stresses as hypovolemia, the longer-term consequences in chronic heart failure are often maladaptive. Mason and Braunwald3 observed that intravenous ouabain increased mean arterial pressure, forearm vascular resistance, and venous tone in healthy human subjects, probably because of direct but transient effects on vascular smooth muscle. In contrast, patients with heart failure responded with a decline in heart rate and other effects that were consistent with enhanced baroreflex responsiveness. More recently, Ferguson et al5 showed in patients with moderate to severe heart failure that an infusion of deslanoside (a rapidly acting cardiac glycoside) increased forearm blood flow and cardiac index and decreased heart rate, concomitant with a marked decrease in skeletal muscle sympathetic nerve activity measured as an indicator of centrally mediated sympathetic nervous system activity. In contrast, dobutamine, a sympathomimetic drug that increased cardiac output to a similar degree, did not affect muscle sympathetic nerve activity in these patients. Although Gheorghiade et al6-8 and others9 showed short-term hemodynamic effects with intravenous cardiac glycosides in patients with
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ventricular systolic dysfunction, abnormal hemodynamics, and advanced symptoms of heart failure in sinus rhythm, these rapid beneficial hemodynamic effects often do not predict long-term outcomes. Subsequent investigations have established a possible role for cardiac glycosides in diminishing the overactivity of the sympathetic nervous system, as suggested by direct nerve recordings, cardiac norepinephrine spillover and heart rate variability studies, and a decline in plasma norepinephrine, aldosterone, and plasma renin levels.10-17 Based on these observations, reduced sympathetic nervous system activation may be an important mechanism contributing to the efficacy of cardiac glycosides in the treatment of patients with heart failure (and may occur at blood levels of these drugs that are less than those necessary to achieve a direct inotropic effect).
in a trial designed to study the effect of milrinone on survival in heart failure patients, an effect that was independent of ejection fraction.20 The issue of appropriate dosing appears to be as relevant for digoxin as with angiotensin-converting enzyme (ACE) inhibitors21 and -adrenergic antagonists22 in heart failure. In the case of digoxin, the relatively narrow therapeutic window and the difficulty of predicting individual patient responsiveness complicate the debate over dose or serum levels. Regardless, the judicious use of digitalis in appropriate patient subgroups and the recognition of concomitant medications or disease states that could affect digoxin pharmacokinetics, as well as the early recognition of potential toxicity, remain essential for safe and effective dosing of this class of agents.23
Relevance of Digoxin Levels
The results of randomized controlled trials over the past decade have supported the use of digoxin when administered either alone or with vasodilators to patients with heart failure caused by predominant systolic dysfunction. The Prospective Randomized Study of Ventricular Failure and Efficacy of Digoxin (PROVED)24 and Randomized Assessment of Digoxin on Inhibition of ANgiotensin-Converting Enzyme (RADIANCE)25 trials were two prospective, multicenter, placebocontrolled trials that examined the effects of the withdrawal of digoxin on patients with stable mild-to-moderate heart failure (ie, NYHA classes II and III) and systolic ventricular dysfunction (ie, a left ventricular ejection fraction ⱕ0.35). All patients studied were in sinus rhythm. The target serum digoxin concentration in both studies during the baseline run-in phase was 0.9 to 2.0 ng/mL, achieved with an average digoxin dose of 0.38 mg/d. Patients in the RADIANCE trial also received concurrent therapy with an ACE inhibitor. When patients were randomly assigned to either continue active digoxin therapy or withdraw from active therapy and receive a matching placebo, 40% of the patients in PROVED and 28% of the patients in RADIANCE who received the placebo noted a significant worsening of heart failure symptoms compared with 20% and 6%, respectively, in patients who continued to receive the active drug. This absolute risk reduction of 20% in digoxin-treated patients constituted a substantial treatment effect. Maximal treadmill
Recent data from some clinical trials, reviewed next, suggest that digoxin’s sympatholytic effects may occur at serum drug concentrations less than those necessary to achieve a classic positive inotropic effect. The issue of what concentrations of digoxin are relevant has been examined in several small clinical studies. Gheorghiade et al18 showed that increasing the dose from a mean of 0.2 to 0.39 mg/d (corresponding to an increase in serum levels from 0.67 to 1.22 ng/mL) resulted in an increase in ejection fraction but no change in exercise tolerance or decline in venous norepinephrine levels. Slatton et al19 enrolled 19 men in sinus rhythm with New York Heart Association (NYHA) class II or III failure and studied them at baseline, 2 weeks after digoxin therapy at 0.125 mg/d, and again 2 weeks after another dose escalation to 0.25 mg/d. Although average heart rate and heart rate variability changed at the low dose compared with baseline, no additional improvement was observed at the higher dose. Krum et al11 showed that after 4 to 8 weeks of digoxin therapy in patients with classes I to III failure, plasma norepinephrine levels declined and abnormalities in heart rate variability improved, but only the latter correlated with serum digoxin levels. The possibility that a gradient of effect may exist could explain why patients with high digoxin levels (⬎1.1 ng/mL) had a greater mortality
The Digoxin Withdrawal Trials
250 exercise tolerance also declined significantly in patients withdrawn from digoxin in both trials, despite continuation of other medical therapies for heart failure, notably ACE inhibitors in RADIANCE.25 However, neither of these trials had the statistical power to detect an effect of digoxin therapy on the survival of patients with heart failure. Many short- and long-term, controlled and uncontrolled clinical trials, reviewed recently in detail by Rahimtoola and Tak26 and Jaeschke et al,27 suggested that digoxin results in an impressive array of benefits, including increases in left ventricular function, prolongation of exercise time, and improvement in clinical status. Nevertheless, there are once again conflicting results for some therapeutic end points, and the conclusions that can be drawn from these and other relatively recent trials are quite limited. For example, in a trial of ibopamine, an orally bioavailable dopamine analogue, control patients treated with digoxin and diuretics alone (most with moderate NYHA class II failure) showed an increase in exercise time and a decrease in blood norepinephrine levels at 6 months, but there was no change in a heart failure score.28 In the Secondary Prevention Reinfarction Israeli Nifedipine Trial trial, a secondary prevention study of the efficacy of nifedipine in patients after a myocardial infarct, digoxin use was associated with a significant increase in mortality. This finding held even after accounting for an increased prevalence of comorbidities in the digoxin-treated patients, although patients with advanced heart failure symptoms who might have been expected to receive the most benefit from digoxin were excluded by design.29 In the contemporary era of large multicenter trials, small numbers of patient subjects and the use of surrogate end points limit many of the conclusions that can be drawn from smaller clinical studies. There are differences in trial design (eg, cross-over and drug withdrawal), patient inclusion criteria (eg, symptomatic or asymptomatic heart failure, use and type of concomitant heart failure therapies permitted), and methodology (eg, use of target digoxin dosing or serum levels and duration of follow-up) that confound their interpretation. Most of these trials share one important feature, however, in that patients with atrial fibrillation or isolated diastolic dysfunction were generally excluded.
HAUPTMAN, GARG, AND KELLY
The DIG Trial A number of lingering controversies over the role of digoxin were to be resolved by the large multicenter DIG trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and Department of Veteran’s Affairs in 302 centers in the United States and Canada.30,31 The main trial required patients be in sinus rhythm with a documented left ventricular ejection fraction of 0.45 or less and have a diagnosis of heart failure based on signs, symptoms, and/or radiographic criteria. Patients receiving digoxin were eligible because of concern that limiting the trial to patients not currently receiving digoxin therapy would select patients who would likely be less ill and thus have a lower event rate. Thus, the DIG trial also included patients previously receiving digoxin, and 50% of them would be randomized to receive placebo, thus incorporating a digoxin withdrawal trial into the DIG study. The use of ACE inhibitors was not mandated, but was strongly encouraged; additional drugs could be added at the discretion of the investigator, and follow-up was established at 4 weeks, 4 months, and then every subsequent 4 months. The primary end point was all-cause mortality, and secondary end points were mortality from cardiovascular causes, mortality from worsening heart failure, and hospitalization from worsening heart failure or other causes. Among the 6,800 patients enrolled onto this main trial, there were no differences in baseline characteristics between activedrug and placebo group, including demographics; cause of heart failure; ejection fraction; prior use of digoxin, ACE inhibitors, nitrates, or diuretics; or daily dose of study medication prescribed. After a mean follow-up of 37 months (range, 28 to 58 months), there were no differences in all-cause or cardiovascular mortality. There was a trend toward a reduction in death from worsening heart failure with a relative risk of 0.88 (95% confidence interval, 0.77 to 1.01). Importantly, there was a statistically significant decreased risk for hospitalization for worsening heart failure in the digoxin group compared with the placebo group, with a relative risk of 0.72 (95% confidence interval, 0.66 to 0.79). This effect was sufficiently large so that, when combined with the mortality end points, it remained statistically significant. A higher percentage of deaths or hospitalizations caused by worsening heart fail-
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ure (45.3%) occurred in patients previously receiving digoxin and randomized to receive the placebo (a digoxin withdrawal group) compared with patients who were not previously receiving and did not receive the drug (32.0%). The effect of digoxin was similar (risk ratios of 0.74 and 0.77, respectively) regardless of prior digoxin use. However, the reduction in relative risk was also greater for patients with ejection fractions less than 25%, more advanced symptoms as measured by the NYHA classification, and enlarged hearts. The heart failure survival and hospitalization curves appeared to separate early after randomization, especially in the patient subgroup in which digoxin was withdrawn, supporting the conclusions reached in the PROVED24 and RADIANCE25 trials. Although there were more hospitalizations for suspected digoxin toxicity in the digoxin group (2%) compared with the placebo group (0.9%), the total number was minimal. Hospitalizations for other reasons (including myocardial infarction, unstable angina, need for revascularization, or cerebrovascular accident) were not different between the digoxin and placebo groups. Overall, there were nearly 10% fewer total cardiovascular hospitalizations (1,694 [49.9%] v 1,850 [54.4%]), as well as fewer hospitalizations, for the digoxin group. Nevertheless, fewer deaths from other cardiac causes, which included deaths presumed to be caused by arrhythmias without worsening heart failure, atherosclerotic coronary disease, low-output states, and in cardiac surgery, were noted in the placebo group. Out-of-hospital death presumed to be caused by an arrhythmia was not a prespecified end point, and no data have been published from the trial for this outcome. Open-label digoxin was administered to more patients receiving placebo than digoxin (22.0% v 14.2%). In the subgroup of patients with recorded digoxin levels, more than 88% were within the prescribed therapeutic range of 0.5 to 2.0 ng/mL at 1 month. The impact of serum digoxin level on clinical outcome is currently being evaluated. Despite the comprehensive data set that emerges from the DIG trial, potential confounders and changing trends in the management of patients with heart failure between the time the trial was conceived and final patient enrollment limit the authors’ ability to resolve all outstanding controversies with digoxin. The question of an ideal (ie, most efficacious and least toxic) serum digoxin level remains unresolved (discussed later).
What are the procedural lessons learned from the DIG study, the first large clinical trial conducted by the NHLBI and the first designed to test the safety and efficacy of cardiac glycosides? First, the data coordinating center should conduct site visits to the participating centers early in the study and at random times throughout the trial. Because the study was national in scope with over 300 participating sites, it would have been important to identify regions and have regional coordinators who could mediate between individual sites and the data coordinating center. Second, the substudies in the DIG trial were not fully developed before the initiation of the main trial, reducing overall enrollment and limiting their power to detect potentially significant differences. Scientifically, the two major design issues were whether this should be a simple large trial and whether patients with an ejection fraction greater than 0.45 should be included. Previously, the NHLBI had not performed a trial on this scale raising some concern about its feasibility and the integrity of the plans for data collection. Most of the key decision makers in the design of the trial were uncomfortable with a traditional format with a smaller number of selected clinical centers who had contracts with the institute. The large simple model was carried out with a reimbursement policy that relied on payment on a perpatient enrolled basis as opposed to direct contracting with the investigators. The second issue was the proposed inclusion of patients with heart failure and an ejection fraction greater than 0.45. This was opposed by some because these patients were considered to have predominant diastolic failure, and, as such, would have a lower event rate. There was also concern that digoxin might be harmful in this patient population. However, the large number of patients with diastolic failure and ongoing questions about the role of digoxin in this clinical setting led to a compromise. The primary study would enroll patients with heart failure and ejection fractions of 0.45 or less, whereas an ancillary study with separate analyses would enroll patients with heart failure but an ejection fraction greater than 0.45.
Digoxin Prescribing Patterns The ultimate impact of the DIG trial on practice is difficult to predict. Physician surveys previously have suggested that cardiologists relied on di-
252 goxin as part of the management of congestive heart failure to a greater degree than internists or family practitioners, independent of the severity of the illness.32 These attitudes parallel what is known about the use of ACE inhibitors. However, skepticism about the ability of digoxin to save lives is long standing. Hlatky et al33 reported that only approximately one third of the physicians surveyed in 1986 believed there was a survival benefit with digoxin. This may explain, in part, current practice patterns that suggest that despite an overall trend toward increasing pharmacotherapy for heart failure, the use of digoxin has remained largely unchanged. According to data from the Studies of Left Ventricular Dysfunction Registry,34 only 45% of the patients in that study were receiving digoxin at enrollment. Use of digoxin correlated with the severity of left ventricular dysfunction (65% of the patients with an ejection fraction ⬍0.20 v 30% of the patients with an ejection fraction of 0.36 to 0.45). Moreover, a recent study of practice at an academic medical center showed that the use of digoxin in patients with left ventricular systolic dysfunction did not change significantly between 1990 and 1995, despite the publication of the PROVED and RADIANCE trials during this period of time, whereas important increases were seen in the overall use of ACE inhibitors, other vasodilator therapy, and -adrenergic blockers.35 Reis et al36 also showed that the use of digoxin differs among internal medicine specialties. Conversely, little is known about whether certain subgroups of patients, such as the aging patient population, are treated differently with digoxin. It has been shown that older patients with acute myocardial infarction tend to receive less aggressive pharmacotherapy,37,38 but whether these findings apply to congestive heart failure therapy in general and to digoxin in particular is not known. At the very least, a study of physician self-reported prescribing practices suggests heightened concern about the risk for digoxin toxicity in the elderly cohort.33 There also appear to be important geographic differences in digoxin dosing. Saunders et al39 reported on their screening of prescription databases from the United States, France, and the United Kingdom and found that digoxin dosing in the United Kingdom was significantly less than in either the United States or France. The economic impact of treating heart failure with di-
HAUPTMAN, GARG, AND KELLY
goxin has not been as rigorously analyzed as it has been with ACE inhibitors.40,41 Nevertheless, Ward et al,42 using data from the digoxin withdrawal studies, showed significant cost savings would be realized if digoxin therapy were continued in otherwise stable patients with heart failure. Other investigators examined the potential costs of care associated with digoxin toxicity,43,44 although it has been pointed out that judicious monitoring and the targeted use of widely available antidigoxin immunotherapy should lower the costs of this complication.44 Although no data are yet published directly from the DIG trial on the potential savings from decreased hospitalizations caused by heart failure, estimates have been generated by Mark.40 Before any formal pharmacoeconomic analysis is performed, however, the debate about the magnitude of this beneficial effect needs to be resolved.
Digoxin Use in the Next Millennium Any assessment of the likelihood that digoxin will remain a mainstay of standard heart failure therapy is also made more difficult by the emergence of agents that act directly to suppress neurohormonal activation in heart failure, particularly the -adrenergic antagonists. The US Carvedilol, Metoprolol in Dilated Cardiomyopathy, and Cardiac Insufficiency Bisoprolol Study trials45-49 permitted, but did not require, digoxin use in patients randomized to receive either -blocker or placebo. In these studies, digoxin use ranged from 38% to 91% at entry. In no trial did the baseline use of digoxin differ between treatment and placebo groups, and no changes in digoxin dosing were allowed in the period just before randomization. To date, no analyses have been performed using data from these trials50,51 that would establish whether digoxin is associated with incremental beneficial effects on heart rate response, rates of hospitalization, or sudden death in the subset of patients treated with a -adrenergic blocker. Nevertheless, Massie and Abdalla52 recently argued that there is a trend toward reduced mortality and morbidity in patients with heart failure symptoms and preserved systolic function based on a subgroup analysis of the DIG trial dataset, presumably because of digoxin’s ability to reduce neurohumoral activities. However, if digoxin works primarily by indirectly reducing
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neurohormonal activation, we are left with an unanswered question: Should heart failure patients treated with a -blocker continue to receive digoxin? It is unlikely that another study will be performed to resolve the outstanding clinical issues in the post–DIG trial era. The effort and costs required to enroll patients onto a nonindustry sponsored trial of a generically available drug with sufficient power are prohibitive. Also, as standard drug therapy for heart failure improves, a larger number of patients will be required to show an effect on survival. Other end points would need to be developed and validated that would more accurately reflect the underlying pathophysiological factors of ventricular remodeling. In the setting of the maturation of newer therapies that focus on survival as the important outcome, the likelihood is that the debate over the cardiac glycosides, as well as the use of this venerable class of drugs, will inevitably decline. As recently noted by Packer,53 ‘‘As the list of therapeutic agents that prolong life grows, the use of digitalis will inevitable wane. . . . This is not a prediction of doom and gloom; it is merely a reflection of the natural evolution of medical practice.’’
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nous captopril and digoxin and their combinations in patients with severe heart failure. J Am Coll Cardiol 13:134-142, 1989 Gheorghiade M, Benatar D, Konstam MA, et al: Pharmacotherapy for systolic dysfunction: A review of randomized clinical trials. Am J Cardiol 80:14H-27H, 1997 Ribner HS, Plucinski DA, Hsieh AM, et al: Acute effects of digoxin on total systemic vascular resistance in congestive heart failure due to dilated cardiomyopathy: A hemodynamic hormonal study. Am J Cardiol 56:896-904, 1985 Newton GE, Tong JH, Schofield AM, et al: Digoxin reduces cardiac sympathetic activity in severe congestive heart failure. J Am Coll Cardiol 28:155-161, 1996 Krum H, Bigger JT Jr, Goldsmith RL, et al: Effect of long-term digoxin therapy on autonomic function in patients with chronic heart failure. J Am Coll Cardiol 2:289-294, 1995 van Veldhuisen DJ, Man In’T Veld AJ, Dunselman PHJM, et al: Double-blind placebo-controlled study of ibopamine and digoxin in patients with mild to moderate heart failure: Results of the Dutch Ibopamine Multicenter Trial (DIMT). J Am Coll Cardiol 22:15641573, 1993 Leier CV: Positive inotropic therapy: An update and new agents. Curr Probl Cardiol 21:527-581, 1996 Sackner-Bernstein JD, Mancini DM: Rationale for treatment of patients with chronic heart failure with adrenergic blockade. JAMA 274:1462-1467, 1995 Tsutamoto T, Wada A, Maeda K, et al: Digitalis increases brain natriuretic peptide in patients with severe congestive heart failure. Am Heart J 134:910916, 1997 Khoury AM, Davila DF, Bellabarba G, et al: Acute effects of digitalis and enalapril on the neurohormonal profile of chagasic patients with severe congestive heart failure. Int J Cardiol 57:21-29, 1996 Flapan AD, Goodfield NE, Wright RA, et al: Effects of digoxin on time domain measures of heart rate variability in patients with stable chronic cardiac failure— Withdrawal and comparison group studies. Int J Cardiol 59:29-36, 1997 Gheorghiade M, Hall VB, Jacobsen G, et al: Effects of increasing maintenance dose of digoxin on left ventricular function and neurohormones in patients with chronic heart failure treated with diuretics and angiotensin-converting enzyme inhibitors. Circulation 92: 1801-1807, 1995 Slatton ML, Irani WN, Hall SA, et al: Does digoxin provide additional hemodynamic and autonomic benefit at higher doses in patients with mild to moderate heart failure and normal sinus rhythm? J Am Coll Cardiol 29:1206-1213, 1997 Yusuf S, Garg R, Held P, et al: Need for a large randomized trial to evaluate the effect of digitalis on morbidity and mortality in congestive heart failure. Am J Cardiol 69:64G-70G, 1992 Packer M: Do ACE inhibitors prolong life in patients with heart failure treated in clinical practice? J Am Coll Cardiol 28:1323-1327, 1996
254 22. Bristow MR, O’Connell JB, Gilbert EM, et al: Doseresponse of chronic -blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy. Circulation 89:1632-1642, 1994 23. Borron SW, Bismuth C, Muszynski J: Advances in the management of digoxin toxicity in the older patient. Drugs Aging 10:18-33, 1997 24. Uretsky BF, Young JB, Shahidi E, et al: Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: Results of the PROVED trial. J Am Coll Cardiol 22:955-962, 1993 25. Packer M, Gheorghiade M, Young JB, et al: Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors. N Engl J Med 329:1-7, 1993 26. Rahimtoola SH, Tak T: The use of digitalis in heart failure. Curr Probl Cardiol 21:787-853, 1996 27. Jaeschke R, Oxman A, Guyatt G: To what extent do congestive heart failure patients in sinus rhythm benefit from digoxin therapy? A systematic overview and meta-analysis. Am J Med 88:279-286, 1990 28. Brouwer J, Van Veldhuisen DJ, Manintveld AJ, et al: Heart rate variability in patients with mild to moderate heart failure—Effects on neurohormonal modulation by digoxin and ibopamine. J Am Coll Cardiol 26:983990, 1995 29. Leor J, Goldbourt U, Behar S, et al: Digoxin and mortality in survivors of acute myocardial infarction: Observations in patients at low and intermediate risk. The SPRINT Study Group. Secondary Prevention Reinfarction Israeli Nifedipine Trial. Cardiovasc Drugs Ther 9:609-617, 1995 30. The Digitalis Investigation Group: The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 336:525-533, 1997 31. The Digitalis Investigation Group: Rationale, design, implementation, and baseline characteristics of patients in the DIG trial: A large, simple, long-term trial to evaluate the effect of digitalis on mortality in heart failure. Controlled Clin Trials 17:77-97, 1996 32. Chin MH, Friedmann PD, Cassel CK, et al: Differences in generalist and specialist physicians’ knowledge and use of angiotensin-converting enzyme inhibitors for congestive heart failure. J Gen Intern Med 12:523530, 1997 33. Hlatky MA, Fleg JL, Hinton PC, et al: Physician practice in the management of congestive heart failure. J Am Coll Cardiol 4:966-970, 1986 34. Bourassa MG, Gurne´ O, Bangdiwala SI, et al: Natural history and patterns of current practice in heart failure. J Am Coll Cardiol 32:14A-19A, 1993 35. Rich MW, Brooks K, Luther P: Temporal trends in the pharmacotherapy of congestive heart failure at an academic medical center: 1990-1995. J Am Coll Cardiol 29:323A, 1997 (abstr) 36. Reis SE, Holubkov R, Edmundowicz D, et al: Treatment of patients admitted to the hospital with congestive heart failure: Specialty-related disparities in practice patterns and outcomes. J Am Coll Cardiol 30:733-738, 1997
HAUPTMAN, GARG, AND KELLY 37. Gurwitz JH, Goldberg RJ, Chen Z, et al: -Blocker therapy in acute myocardial infarction: Evidence for underutilization in the elderly. Am J Med 93:605-610, 1992 38. McLaughlin TJ, Soumerai SB, Willison DJ, et al: Adherence to national guidelines for drug treatment of suspected acute myocardial infarction: Evidence for undertreatment in women and the elderly. Arch Intern Med 156:799-805, 1996 39. Saunders KB, Amerasinghe AKCP, Saunders KL: Dose of digoxin prescribed in the UK compared with France and the USA. Lancet 349:833-836, 1997 40. Mark DB: Economics of treating heart failure. Am J Cardiol 80:33H-38H, 1997 41. McMurray J, Davie A: The pharmacoeconomics of ACE inhibitors in chronic heart failure. Pharmacoeconomics 9:188-197, 1996 42. Ward RE, Gheorghiade M, Young JB, et al: Economic outcomes of withdrawal of digoxin therapy in adult patients with stable congestive heart failure. J Am Coll Cardiol 26:93-101, 1995 43. Gandhi AJ, Vlasses PH, Morton DJ, et al: Economic impact of digoxin toxicity. Pharmacoeconomics 12:175181, 1997 44. Mauskopf JA, Wenger TL: Cost-effectiveness analysis of the use of digoxin immune Fab (ovine) for treatment of digoxin toxicity. Am J Cardiol 68:1709-1714, 1991 45. Waagstein F, Bristow MR, Swedberg K, et al: Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 342:1441-1446, 1993 46. Packer M, Bristow MR, Cohn JN, et al: The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 334:1349-1355, 1996 47. Bristow MR, Gilbert EM, Abraham WT, et al: Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation 94:2807-2816, 1996 48. Australia/New Zealand Heart Failure Research Collaborative Group: Randomized, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischemic heart disease. Lancet 349:375-380, 1997 49. CIBIS Investigators and Committees: A randomized trial of -blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation 90:17651773, 1994 50. Heidenreich PA, Lee TT, Massie BM: Effect of -blockade on mortality in patients with heart failure: A meta-analysis of randomized clinical trials. J Am Coll Cardiol 30:27-34, 1997 51. Lechat P, Packer M, Chalon S, et al: Clinical effects of -adrenergic blockade in chronic heart failure: A metaanalysis of double-blind, placebo-controlled, randomized trials. Circulation 98:1184-1191, 1998 52. Massie BM, Abdalla I: Heart failure in patients with preserved left ventricular systolic function: Do digitalis glycosides have a role? Prog Cardiovasc Dis 40:357369, 1998 53. Packer M: Digoxin in patients with heart failure. N Engl J Med 337:131, 1997
Cardiovascular Diseases
Vol. 41, No. 4 January/February 1999
Cardiac Glycosides in the Next Millennium Paul J. Hauptman, Rekha Garg, and Ralph A. Kelly
Despite the documented efficacy of cardiac glycosides in improving symptoms in patients with heart failure caused by systolic ventricular dysfunction, considerable debate continues as to whether the use of this class of drugs should continue into the next millennium. In this review, the authors briefly examine the basic pharmacology of these drugs relevant to the treatment of heart failure, emphasizing their role in reducing sympathetic nervous system activity in patients with advanced heart failure. Next, withdrawal trials and the Digoxin Investigation Group dataset are reviewed in some detail. Despite these important additional data on the safety and efficacy of digitalis use in heart failure that became available in the 1990s, considerable controversy remains. Perhaps most importantly, if the mechanism by which these drugs improve symptoms in patients with heart failure is principally mediated by sympatholytic activity, do they remain relevant as -adrenergic antagonists become standard therapy for this disease? Copyright 娀 1999 by W.B. Saunders Company
I
n an era in which neurohormonal antagonists have been shown to prolong survival in patients with heart failure and the long-term administration of orally bioavailable inotropic agents has fallen into disfavor, the debate over the mechanism(s) by which cardiac glycosides deliver a salutary clinical effect persists. Although there is no doubt that these agents (exclusively digoxin in recent clinical trials) act to improve the inotropic state of cardiac muscle (see1,2 for reviews of these mechanisms), it is unlikely that
this mechanism is primarily responsible for the beneficial effects seen in patients, particularly at serum digoxin levels in the range of 0.5 to 1.5 ng/mL. Alternative mechanisms for the beneficial effect of cardiac glycosides have been debated for some time. More than 30 years ago, Mason and Braunwald3 noted that intravenous infusions of ouabain, a water-soluble, rapidly acting glycoside, would increase vascular resistance and blood pressure in healthy subjects but had an opposite effect in patients with advanced heart failure, decreasing both mean arterial pressure and heart rate. Those changes were attributed to improved baroreflex responsiveness. Subsequent work in human and experimental animal preparations support this analysis.2 In this review, the authors briefly examine basic research evidence of how cardiac glycosides exert a beneficial effect in heart failure. Next, they review in some detail recent data from clinical trials, focusing on the Digoxin Investigation Group (DIG) trial. From the Cardiology Division, Saint Louis University Hospital and Saint Louis University School of Medicine, St Louis, MO; Eli Lilly and Company, Indianapolis, IN; and the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. Supported in part by grants No. HL52320 and HL36141 from the National Institutes of Health, Bethesda, MD. Address reprint requests to Ralph A. Kelly, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. Copyright 娀 1999 by W.B. Saunders Company 0033-0620/99/4104-0001$10.00/0
Progress in Cardiovascular Diseases, Vol. 41, No. 4 (January/February), 1999: pp 247-254
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Inotropic Mechanism By the late 1920s, it became clear that digitalis preparations caused a positive inotropic effect on the intact ventricle, resulting in a greater rate of increase of intracavitary pressure during isovolumic systole at constant heart rate and aortic pressure that could be shown in healthy, as well as failing, cardiac muscle. Cardiac glycoside administration caused the ventricular function (FrankStarling) curve of the intact heart to shift upward and to the left; thus, more stroke work is generated at a given filling pressure. These effects appear to be sustained during in vivo administration of digitalis for periods of weeks to months without any evidence of desensitization or tachyphylaxis. It is now generally believed that digitalis compounds bring about an increase in the availability of activator Ca⫹⫹ in heart cells, and that this increase in intracellular Ca⫹⫹ activity is sufficient to explain both the inotropic and arrhythmogenic effects of these drugs. Importantly, it is also now accepted that the increase in intracellular Ca⫹⫹ is a consequence of the direct effect of cardiac glycosides on transmembrane Na⫹ transport by inhibiting sodium, potassium adenosine triphosphatase (NaK-ATPase) activity (for a review, see Kelly RA, Smith TW2). Interestingly, recent evidence suggests that the immediate positive inotropic effect of cardiac glycosides, measured either in the intact heart in a conscious dog model or in isometrically contracting papillary muscle strips, is achieved with remarkable energy-transfer efficiency and little oxygen wasting.4 When compared with -adrenergic agonists or phosphodiesterase inhibitors, ouabain caused no significant change for the same degree of tension development in the tension-time integral per unit initial heat, an index of the economy of isometric contraction in an isolated muscle preparation. With long-term administration of cardiac glycosides, it has been argued that the increase in cardiac output that accompanies the positive inotropic effect would eventually lead to reduced oxygen consumption as ventricular chamber size and pressures decline and wall stress diminishes. These new data indicate that, even in the short term, cardiac glycosides could provide a moderate but metabolically efficient inotropic effect, an important consideration in patients with ischemic cardiomyopathies.
Neurally Mediated Actions of Cardiac Glycosides It is important to understand the pathophysiological course of heart failure and the role of digitalis glycosides in modifying the abnormal autonomic nervous system activity that is characteristic of advanced heart failure, including altered baroreflex activity. Heart failure is well known to be accompanied by an increase in sympathetic nervous system activity caused, in part, by a reduction in the sensitivity of the arterial baroreflex response to blood pressure. This results in a decline in tonic baroreflex suppression of central nervous system–directed sympathetic activity. This loss of sensitivity of the normal baroreflex arc also appears to contribute to the sustained elevation in plasma norepinephrine, renin, and vasopressin levels characteristic of heart failure. This sustained activation of sympathetic nervous system activity, which initially serves to maintain blood pressure and cardiac output by increasing heart rate, contractility, and systemic vascular resistance, also contributes to decreased excretion of salt and water by the kidneys. Despite the obvious evolutionary utility of this adaptive response to such stresses as hypovolemia, the longer-term consequences in chronic heart failure are often maladaptive. Mason and Braunwald3 observed that intravenous ouabain increased mean arterial pressure, forearm vascular resistance, and venous tone in healthy human subjects, probably because of direct but transient effects on vascular smooth muscle. In contrast, patients with heart failure responded with a decline in heart rate and other effects that were consistent with enhanced baroreflex responsiveness. More recently, Ferguson et al5 showed in patients with moderate to severe heart failure that an infusion of deslanoside (a rapidly acting cardiac glycoside) increased forearm blood flow and cardiac index and decreased heart rate, concomitant with a marked decrease in skeletal muscle sympathetic nerve activity measured as an indicator of centrally mediated sympathetic nervous system activity. In contrast, dobutamine, a sympathomimetic drug that increased cardiac output to a similar degree, did not affect muscle sympathetic nerve activity in these patients. Although Gheorghiade et al6-8 and others9 showed short-term hemodynamic effects with intravenous cardiac glycosides in patients with
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ventricular systolic dysfunction, abnormal hemodynamics, and advanced symptoms of heart failure in sinus rhythm, these rapid beneficial hemodynamic effects often do not predict long-term outcomes. Subsequent investigations have established a possible role for cardiac glycosides in diminishing the overactivity of the sympathetic nervous system, as suggested by direct nerve recordings, cardiac norepinephrine spillover and heart rate variability studies, and a decline in plasma norepinephrine, aldosterone, and plasma renin levels.10-17 Based on these observations, reduced sympathetic nervous system activation may be an important mechanism contributing to the efficacy of cardiac glycosides in the treatment of patients with heart failure (and may occur at blood levels of these drugs that are less than those necessary to achieve a direct inotropic effect).
in a trial designed to study the effect of milrinone on survival in heart failure patients, an effect that was independent of ejection fraction.20 The issue of appropriate dosing appears to be as relevant for digoxin as with angiotensin-converting enzyme (ACE) inhibitors21 and -adrenergic antagonists22 in heart failure. In the case of digoxin, the relatively narrow therapeutic window and the difficulty of predicting individual patient responsiveness complicate the debate over dose or serum levels. Regardless, the judicious use of digitalis in appropriate patient subgroups and the recognition of concomitant medications or disease states that could affect digoxin pharmacokinetics, as well as the early recognition of potential toxicity, remain essential for safe and effective dosing of this class of agents.23
Relevance of Digoxin Levels
The results of randomized controlled trials over the past decade have supported the use of digoxin when administered either alone or with vasodilators to patients with heart failure caused by predominant systolic dysfunction. The Prospective Randomized Study of Ventricular Failure and Efficacy of Digoxin (PROVED)24 and Randomized Assessment of Digoxin on Inhibition of ANgiotensin-Converting Enzyme (RADIANCE)25 trials were two prospective, multicenter, placebocontrolled trials that examined the effects of the withdrawal of digoxin on patients with stable mild-to-moderate heart failure (ie, NYHA classes II and III) and systolic ventricular dysfunction (ie, a left ventricular ejection fraction ⱕ0.35). All patients studied were in sinus rhythm. The target serum digoxin concentration in both studies during the baseline run-in phase was 0.9 to 2.0 ng/mL, achieved with an average digoxin dose of 0.38 mg/d. Patients in the RADIANCE trial also received concurrent therapy with an ACE inhibitor. When patients were randomly assigned to either continue active digoxin therapy or withdraw from active therapy and receive a matching placebo, 40% of the patients in PROVED and 28% of the patients in RADIANCE who received the placebo noted a significant worsening of heart failure symptoms compared with 20% and 6%, respectively, in patients who continued to receive the active drug. This absolute risk reduction of 20% in digoxin-treated patients constituted a substantial treatment effect. Maximal treadmill
Recent data from some clinical trials, reviewed next, suggest that digoxin’s sympatholytic effects may occur at serum drug concentrations less than those necessary to achieve a classic positive inotropic effect. The issue of what concentrations of digoxin are relevant has been examined in several small clinical studies. Gheorghiade et al18 showed that increasing the dose from a mean of 0.2 to 0.39 mg/d (corresponding to an increase in serum levels from 0.67 to 1.22 ng/mL) resulted in an increase in ejection fraction but no change in exercise tolerance or decline in venous norepinephrine levels. Slatton et al19 enrolled 19 men in sinus rhythm with New York Heart Association (NYHA) class II or III failure and studied them at baseline, 2 weeks after digoxin therapy at 0.125 mg/d, and again 2 weeks after another dose escalation to 0.25 mg/d. Although average heart rate and heart rate variability changed at the low dose compared with baseline, no additional improvement was observed at the higher dose. Krum et al11 showed that after 4 to 8 weeks of digoxin therapy in patients with classes I to III failure, plasma norepinephrine levels declined and abnormalities in heart rate variability improved, but only the latter correlated with serum digoxin levels. The possibility that a gradient of effect may exist could explain why patients with high digoxin levels (⬎1.1 ng/mL) had a greater mortality
The Digoxin Withdrawal Trials
250 exercise tolerance also declined significantly in patients withdrawn from digoxin in both trials, despite continuation of other medical therapies for heart failure, notably ACE inhibitors in RADIANCE.25 However, neither of these trials had the statistical power to detect an effect of digoxin therapy on the survival of patients with heart failure. Many short- and long-term, controlled and uncontrolled clinical trials, reviewed recently in detail by Rahimtoola and Tak26 and Jaeschke et al,27 suggested that digoxin results in an impressive array of benefits, including increases in left ventricular function, prolongation of exercise time, and improvement in clinical status. Nevertheless, there are once again conflicting results for some therapeutic end points, and the conclusions that can be drawn from these and other relatively recent trials are quite limited. For example, in a trial of ibopamine, an orally bioavailable dopamine analogue, control patients treated with digoxin and diuretics alone (most with moderate NYHA class II failure) showed an increase in exercise time and a decrease in blood norepinephrine levels at 6 months, but there was no change in a heart failure score.28 In the Secondary Prevention Reinfarction Israeli Nifedipine Trial trial, a secondary prevention study of the efficacy of nifedipine in patients after a myocardial infarct, digoxin use was associated with a significant increase in mortality. This finding held even after accounting for an increased prevalence of comorbidities in the digoxin-treated patients, although patients with advanced heart failure symptoms who might have been expected to receive the most benefit from digoxin were excluded by design.29 In the contemporary era of large multicenter trials, small numbers of patient subjects and the use of surrogate end points limit many of the conclusions that can be drawn from smaller clinical studies. There are differences in trial design (eg, cross-over and drug withdrawal), patient inclusion criteria (eg, symptomatic or asymptomatic heart failure, use and type of concomitant heart failure therapies permitted), and methodology (eg, use of target digoxin dosing or serum levels and duration of follow-up) that confound their interpretation. Most of these trials share one important feature, however, in that patients with atrial fibrillation or isolated diastolic dysfunction were generally excluded.
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The DIG Trial A number of lingering controversies over the role of digoxin were to be resolved by the large multicenter DIG trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and Department of Veteran’s Affairs in 302 centers in the United States and Canada.30,31 The main trial required patients be in sinus rhythm with a documented left ventricular ejection fraction of 0.45 or less and have a diagnosis of heart failure based on signs, symptoms, and/or radiographic criteria. Patients receiving digoxin were eligible because of concern that limiting the trial to patients not currently receiving digoxin therapy would select patients who would likely be less ill and thus have a lower event rate. Thus, the DIG trial also included patients previously receiving digoxin, and 50% of them would be randomized to receive placebo, thus incorporating a digoxin withdrawal trial into the DIG study. The use of ACE inhibitors was not mandated, but was strongly encouraged; additional drugs could be added at the discretion of the investigator, and follow-up was established at 4 weeks, 4 months, and then every subsequent 4 months. The primary end point was all-cause mortality, and secondary end points were mortality from cardiovascular causes, mortality from worsening heart failure, and hospitalization from worsening heart failure or other causes. Among the 6,800 patients enrolled onto this main trial, there were no differences in baseline characteristics between activedrug and placebo group, including demographics; cause of heart failure; ejection fraction; prior use of digoxin, ACE inhibitors, nitrates, or diuretics; or daily dose of study medication prescribed. After a mean follow-up of 37 months (range, 28 to 58 months), there were no differences in all-cause or cardiovascular mortality. There was a trend toward a reduction in death from worsening heart failure with a relative risk of 0.88 (95% confidence interval, 0.77 to 1.01). Importantly, there was a statistically significant decreased risk for hospitalization for worsening heart failure in the digoxin group compared with the placebo group, with a relative risk of 0.72 (95% confidence interval, 0.66 to 0.79). This effect was sufficiently large so that, when combined with the mortality end points, it remained statistically significant. A higher percentage of deaths or hospitalizations caused by worsening heart fail-
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ure (45.3%) occurred in patients previously receiving digoxin and randomized to receive the placebo (a digoxin withdrawal group) compared with patients who were not previously receiving and did not receive the drug (32.0%). The effect of digoxin was similar (risk ratios of 0.74 and 0.77, respectively) regardless of prior digoxin use. However, the reduction in relative risk was also greater for patients with ejection fractions less than 25%, more advanced symptoms as measured by the NYHA classification, and enlarged hearts. The heart failure survival and hospitalization curves appeared to separate early after randomization, especially in the patient subgroup in which digoxin was withdrawn, supporting the conclusions reached in the PROVED24 and RADIANCE25 trials. Although there were more hospitalizations for suspected digoxin toxicity in the digoxin group (2%) compared with the placebo group (0.9%), the total number was minimal. Hospitalizations for other reasons (including myocardial infarction, unstable angina, need for revascularization, or cerebrovascular accident) were not different between the digoxin and placebo groups. Overall, there were nearly 10% fewer total cardiovascular hospitalizations (1,694 [49.9%] v 1,850 [54.4%]), as well as fewer hospitalizations, for the digoxin group. Nevertheless, fewer deaths from other cardiac causes, which included deaths presumed to be caused by arrhythmias without worsening heart failure, atherosclerotic coronary disease, low-output states, and in cardiac surgery, were noted in the placebo group. Out-of-hospital death presumed to be caused by an arrhythmia was not a prespecified end point, and no data have been published from the trial for this outcome. Open-label digoxin was administered to more patients receiving placebo than digoxin (22.0% v 14.2%). In the subgroup of patients with recorded digoxin levels, more than 88% were within the prescribed therapeutic range of 0.5 to 2.0 ng/mL at 1 month. The impact of serum digoxin level on clinical outcome is currently being evaluated. Despite the comprehensive data set that emerges from the DIG trial, potential confounders and changing trends in the management of patients with heart failure between the time the trial was conceived and final patient enrollment limit the authors’ ability to resolve all outstanding controversies with digoxin. The question of an ideal (ie, most efficacious and least toxic) serum digoxin level remains unresolved (discussed later).
What are the procedural lessons learned from the DIG study, the first large clinical trial conducted by the NHLBI and the first designed to test the safety and efficacy of cardiac glycosides? First, the data coordinating center should conduct site visits to the participating centers early in the study and at random times throughout the trial. Because the study was national in scope with over 300 participating sites, it would have been important to identify regions and have regional coordinators who could mediate between individual sites and the data coordinating center. Second, the substudies in the DIG trial were not fully developed before the initiation of the main trial, reducing overall enrollment and limiting their power to detect potentially significant differences. Scientifically, the two major design issues were whether this should be a simple large trial and whether patients with an ejection fraction greater than 0.45 should be included. Previously, the NHLBI had not performed a trial on this scale raising some concern about its feasibility and the integrity of the plans for data collection. Most of the key decision makers in the design of the trial were uncomfortable with a traditional format with a smaller number of selected clinical centers who had contracts with the institute. The large simple model was carried out with a reimbursement policy that relied on payment on a perpatient enrolled basis as opposed to direct contracting with the investigators. The second issue was the proposed inclusion of patients with heart failure and an ejection fraction greater than 0.45. This was opposed by some because these patients were considered to have predominant diastolic failure, and, as such, would have a lower event rate. There was also concern that digoxin might be harmful in this patient population. However, the large number of patients with diastolic failure and ongoing questions about the role of digoxin in this clinical setting led to a compromise. The primary study would enroll patients with heart failure and ejection fractions of 0.45 or less, whereas an ancillary study with separate analyses would enroll patients with heart failure but an ejection fraction greater than 0.45.
Digoxin Prescribing Patterns The ultimate impact of the DIG trial on practice is difficult to predict. Physician surveys previously have suggested that cardiologists relied on di-
252 goxin as part of the management of congestive heart failure to a greater degree than internists or family practitioners, independent of the severity of the illness.32 These attitudes parallel what is known about the use of ACE inhibitors. However, skepticism about the ability of digoxin to save lives is long standing. Hlatky et al33 reported that only approximately one third of the physicians surveyed in 1986 believed there was a survival benefit with digoxin. This may explain, in part, current practice patterns that suggest that despite an overall trend toward increasing pharmacotherapy for heart failure, the use of digoxin has remained largely unchanged. According to data from the Studies of Left Ventricular Dysfunction Registry,34 only 45% of the patients in that study were receiving digoxin at enrollment. Use of digoxin correlated with the severity of left ventricular dysfunction (65% of the patients with an ejection fraction ⬍0.20 v 30% of the patients with an ejection fraction of 0.36 to 0.45). Moreover, a recent study of practice at an academic medical center showed that the use of digoxin in patients with left ventricular systolic dysfunction did not change significantly between 1990 and 1995, despite the publication of the PROVED and RADIANCE trials during this period of time, whereas important increases were seen in the overall use of ACE inhibitors, other vasodilator therapy, and -adrenergic blockers.35 Reis et al36 also showed that the use of digoxin differs among internal medicine specialties. Conversely, little is known about whether certain subgroups of patients, such as the aging patient population, are treated differently with digoxin. It has been shown that older patients with acute myocardial infarction tend to receive less aggressive pharmacotherapy,37,38 but whether these findings apply to congestive heart failure therapy in general and to digoxin in particular is not known. At the very least, a study of physician self-reported prescribing practices suggests heightened concern about the risk for digoxin toxicity in the elderly cohort.33 There also appear to be important geographic differences in digoxin dosing. Saunders et al39 reported on their screening of prescription databases from the United States, France, and the United Kingdom and found that digoxin dosing in the United Kingdom was significantly less than in either the United States or France. The economic impact of treating heart failure with di-
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goxin has not been as rigorously analyzed as it has been with ACE inhibitors.40,41 Nevertheless, Ward et al,42 using data from the digoxin withdrawal studies, showed significant cost savings would be realized if digoxin therapy were continued in otherwise stable patients with heart failure. Other investigators examined the potential costs of care associated with digoxin toxicity,43,44 although it has been pointed out that judicious monitoring and the targeted use of widely available antidigoxin immunotherapy should lower the costs of this complication.44 Although no data are yet published directly from the DIG trial on the potential savings from decreased hospitalizations caused by heart failure, estimates have been generated by Mark.40 Before any formal pharmacoeconomic analysis is performed, however, the debate about the magnitude of this beneficial effect needs to be resolved.
Digoxin Use in the Next Millennium Any assessment of the likelihood that digoxin will remain a mainstay of standard heart failure therapy is also made more difficult by the emergence of agents that act directly to suppress neurohormonal activation in heart failure, particularly the -adrenergic antagonists. The US Carvedilol, Metoprolol in Dilated Cardiomyopathy, and Cardiac Insufficiency Bisoprolol Study trials45-49 permitted, but did not require, digoxin use in patients randomized to receive either -blocker or placebo. In these studies, digoxin use ranged from 38% to 91% at entry. In no trial did the baseline use of digoxin differ between treatment and placebo groups, and no changes in digoxin dosing were allowed in the period just before randomization. To date, no analyses have been performed using data from these trials50,51 that would establish whether digoxin is associated with incremental beneficial effects on heart rate response, rates of hospitalization, or sudden death in the subset of patients treated with a -adrenergic blocker. Nevertheless, Massie and Abdalla52 recently argued that there is a trend toward reduced mortality and morbidity in patients with heart failure symptoms and preserved systolic function based on a subgroup analysis of the DIG trial dataset, presumably because of digoxin’s ability to reduce neurohumoral activities. However, if digoxin works primarily by indirectly reducing
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neurohormonal activation, we are left with an unanswered question: Should heart failure patients treated with a -blocker continue to receive digoxin? It is unlikely that another study will be performed to resolve the outstanding clinical issues in the post–DIG trial era. The effort and costs required to enroll patients onto a nonindustry sponsored trial of a generically available drug with sufficient power are prohibitive. Also, as standard drug therapy for heart failure improves, a larger number of patients will be required to show an effect on survival. Other end points would need to be developed and validated that would more accurately reflect the underlying pathophysiological factors of ventricular remodeling. In the setting of the maturation of newer therapies that focus on survival as the important outcome, the likelihood is that the debate over the cardiac glycosides, as well as the use of this venerable class of drugs, will inevitably decline. As recently noted by Packer,53 ‘‘As the list of therapeutic agents that prolong life grows, the use of digitalis will inevitable wane. . . . This is not a prediction of doom and gloom; it is merely a reflection of the natural evolution of medical practice.’’
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13. 14.
15.
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