Evidence-based medicine is an evolutionary process, intended to foster and disseminate the best practice guidelines from an ongoing critical analysis of available data. An underaddressed challenge relates to detecting and correcting delays where the evidence supports, but fails to effect, a timely change in practice. An example pertains to serum digoxin concentrations (SDCs) in the treatment of chronic heart failure (HF) because (1) the widely disseminated and used “therapeutic” SDCs for treating HF are not consistently aligned with considerably lower evidence-based values and (2) this discrepancy—a variant of the “clinical inertia” syndrome—may lead to unnecessary exposure of patients to potentially life-threatening toxicities.
Given its historic place in medical therapeutics, digoxin and related cardiac glycosides bypassed formal rigorous multiphase clinical trials designed to determine tolerability, toxicity, and efficacy. For more than two centuries, digitalis preparations have had a long-standing history in controlling the ventricular response in atrial fibrillation and treating HF. Furthermore, several randomized trials performed beginning 30 years ago have demonstrated that digoxin confers benefits in patients with chronic HF related to improved exercise tolerance and quality of life. However, these studies were small, with important limitations. More convincing evidence was unavailable until publication of the Digitalis Investigation Group (DIG) trial in 1997. This large-scale prospective randomized trial demonstrated that long-term treatment with digoxin had no effect on mortality alone but modestly decreased the combined risk of death and hospitalization in patients meeting entry criteria.
The American College of Cardiology/American Heart Association and the European Society of Cardiology currently recommend digoxin for the treatment of HF under specific clinical circumstances. Despite these recommendations, overall use of digoxin has decreased over the previous 10 years. One report of a concomitant decrease in digitalis-related morbidity and mortality may reflect its decreased use. Other reasons may be related to concerns about digitalis toxicity and the availability of multiple other approaches to treat HF, which are accompanied by a strong evidence base supporting mortality benefits—namely angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and β-adrenergic antagonists. However, as a cautionary note, a recently published article has reported that, in elderly patients, digoxin is responsible for the third highest hospitalization rate for adverse drug events in the United States. Therefore, at an estimated annual incidence of 4% to 5% per user and a cost of >$6,500 per episode, with associated morbidity and potential mortality, digoxin toxicity remains an important issue in contemporary clinical practice.
The development of a radioimmunoassay about 40 years ago was a breakthrough in relating SDC to risk of toxicity. As reported by Smith et al, serum digoxin levels in 10 nontoxic patients (without atrial fibrillation) on oral doses of 0.25 mg/day were 1.1 ± 0.3 ng/ml (range 0.8 to 1.6) and 1.4 ± 0.4 ng/ml (range 0.9 to 2.4) for 11 clinically nontoxic patients on 0.50 mg/day (a dose rarely used in contemporary practice). Toxicity determined solely by electrocardiographic manifestations (e.g., atrial tachycardia with block, ventricular tachycardia, frequent or multifocal premature atrial or ventricular beats, second- or third-degree block, atrial fibrillation with slow ventricular response) was seen in 18 patients at a level of 3.3 ± 1.5 ng/ml (range 2.1 to 8.7). The findings from this small but seminal study became the basis for the unofficial but widely accepted guideline that the risk of toxicity is most likely to occur with serum concentrations >2.0 ng/ml and is almost certain at >3.0 ng/ml. Based on data derived from these 39 patients, a therapeutic range of 0.8 to 2.0 ng/ml was established.
However, retaining the upper serum concentration limit ∼2.0 ng/ml is no longer defensible. First, it may provide clinicians a false sense of reassurance that patients with lower levels are not at risk from digitalis excess. Some patients are more sensitive to digitalis (especially elderly individuals) and may show signs of toxicity with therapeutic SDCs. Second, additional agents used in conjunction with digoxin in treating HF may further predispose a patient to toxicity (e.g., potassium-wasting diuretics). In addition, patients with chronic HF and paroxysmal or persistent atrial fibrillation may be placed on amiodarone or dronedarone, which increases the steady-state concentration of digoxin, necessitating a dose decrease by ≥50%.
More concerning is that this therapeutic range is well above that indicated to be prudent based on published data. One small study of 20 patients with HF, published before the DIG trial, demonstrated that improved quality of life and functional exercise capacity could be derived from SDCs ranging from 1.2 to 1.8 ng/ml. The DIG trial sought to maintain trough SDCs at 0.5 to 1.5 ng/ml in enrolled patients, and the mean SDC was 0.8 ng/ml. Furthermore, 2 other large randomized trials published after the DIG trial, demonstrating that HF worsened with the withdrawal of digoxin, maintained SDCs of 1.2 ng/ml. Another study demonstrated that patients with end-stage renal disease on hemodialysis—a group predisposed to potassium and other electrolyte instabilities—were at increased risk of overall mortality from concomitant digoxin therapy; the safest SDCs were <0.9 ng/ml.
Post hoc analyses of the DIG trial further supported findings that higher SDCs were detrimental. One of these, although confirming that discontinuation of digoxin was associated with a worsening of HF in ambulatory patients, showed that continuation of digoxin at “low” SDCs (0.5 to 0.9 ng/ml) was associated with a significant decrease in all-cause mortality and hospitalizations compared to SDCs ≥1.0 ng/ml. Another analysis has indicated that SDCs >1.2 ng/ml may be harmful and that maintaining a trough concentration of 0.5 to 0.8 ng/mL seemed to provide the benefits of treatment with a lower risk of adverse effects.
In response to this evidence, the Heart Failure Society of America (HFSA), in its 2010 practice guidelines, stated the serum digoxin concentration should be <1.0 ng/ml and preferably 0.7 to 0.9 ng/ml. Of note, these HFSA recommendations were strengthened from those previously issued in 2000, in which no target range was specifically mentioned.
Thus, current data strongly support decreasing the widely used and recommended therapeutic trough SDC range from 0.8 to 2.0 ng/ml to much lower values (e.g., 0.5 to 0.8 ng/ml) in the treatment of chronic HF. Although some influential resources have adopted these narrower ranges, others have failed to do so. Even within some multiauthored texts, disparate recommendations are provided ( Table 1 ). Multiple factors may contribute to the failure in adopting evidence-based medicine into daily practice.
| Resource | Range (ng/ml) |
|---|---|
| Online/electronic references | |
| POISINDEX ® | 0.6–2.6 ⁎ |
| Lexi-Comp ® | 0.5–0.8 † |
| UpToDate ® | 0.5–0.8 † ; 0.8–2.0 §§ |
| DynaMed ™ | 0.5–2.0 |
| Epocrates | 0.5–0.8 † ; 0.8–2.0 ‡ § |
| DRUGDEX ® | 0.8–2.0 • |
| Specialty society heart failure guidelines | |
| American College of Cardiology/American Heart Association 2005 guideline update | 0.5–1.0 |
| European Society of Cardiology 2008 | 0.6–1.2 |
| Reference textbooks | |
| Braunwald’s Heart Disease, 9th Ed., 2012 | <1.0 † ; 0.5–1.0 † ; 0.8–2.0 ‡ ¶ |
| Goldman’s Cecil Medicine, 24th Ed., 2012 | 0.5–1.0 ¶¶ |
| Harrison’s Principles of Internal Medicine, 18th Ed., 2012 | <1.0 # |
| Tintinalli’s Emergency Medicine, 7th Ed., 2011 | 0.5–2.0 |
| Rosen’s Emergency Medicine, 7th Ed., 2010 | 0.7–1.1 † ## |
| Goldfrank’s Toxicologic Emergencies, 9th Ed., 2010 | 0.5–2.0 ⁎⁎ |
| Physicians’ Desk Reference, 2011 | 0.8–2.0 †† |
| Pharmacotherapy: A Pathophysiologic Approach, 8th Ed., 2011 | 0.5–1.0 |
| 2012 CURRENT Medical Diagnosis and Treatment | 0.5–0.9 † ; 0.5–2.0 † ∞ |
| Conn’s Current Therapy, 2012 | 0.6–2.0 |
| Oxford Textbook of Primary Medical Care, 2011 | 1.0–2.0 |
| Hurst’s The Heart, 13th Ed., 2011 | 0.5–1.1 |
| Commercial laboratory | |
| Quest Diagnostics | 0.8–2.0 |
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