The results of our study demonstrate that digoxin reduces HF hospitalization in a wide spectrum of ambulatory chronic HF patients in normal sinus rhythm receiving diuretics and ACE inhibitors. In addition, digoxin reduces all-cause mortality and all-cause hospitalization at low SDC. Our data suggest that digoxin can play an important role in HF care, regardless of ejection fraction or gender. In the developed nations, where diuretics and ACE inhibitors are the most commonly used regimen for HF therapy, digoxin can play an important role in reducing morbidity and mortality, and decreasing health care costs. In the developing nations, where most HF patients do not have a left ventricular function evaluation and cannot afford ACE inhibitors and beta-blockers, digoxin is the only available drug that can play a critical role in reducing mortality and morbidity.
The beneficial effects of digoxin observed by us are likely due to hemodynamic and neurohormonal properties of digoxin. Digitalis is the only inotropic agent that does not increase mortality and improves neurohormonal profile in HF.28, 29
The effects of digoxin have long been known to be dependent on SDC.1, 5, 30, 31
However, ours is the first study to demonstrate a beneficial effect of low SDC in all HF patients, including those with diastolic HF. As risk of hospitalization is relatively high in diastolic HF patients, digoxin can play an important role in reducing morbidity and health care costs. Furthermore, digoxin reduces mortality and all-cause hospitalization if care is taken to achieve a SDC between 0.5 and 0.9 ng/ml.
Digitalis is the oldest and probably the least expensive drug for the management of HF. Yet, despite FDA approval and guideline recommendations, there has been a recent decline in the use of digoxin in HF patients.9-11, 32
The recent ACC/AHA HF guidelines have also downgraded the role of digoxin in HF care, while promoting expensive device-based therapies with selective indications.12
This change in policy and practice regarding digoxin use appears to be due in part to lack of mortality benefit,31, 33
in particular in those with diastolic HF.4
Despite recent evidence to the contrary,14, 34
a widely publicized earlier study questioning the safety of digoxin in women35
also likely played a role. Finally, availability of newer neurohormonal antagonists such as beta-blockers and aldosterone antagonists,4
lack of industry sponsorship for digoxin, and aggressive promotion of expensive devices with selective indications10, 11
have further slighted the role of digoxin in HF care. However, our data demonstrate that in ambulatory men and women with chronic stable systolic or diastolic HF, use of digoxin was associated with over 30% reduction in HF hospitalization regardless of SDC, and significant reduction in mortality and hospitalizations from all causes at low SDC. This is important as HF is one of the major causes of hospitalization, especially among older adults, and HF hospitalizations are expensive and associated with poor patient outcomes.
Our findings support a more expanded role of digoxin in HF. Digoxin should be used in systolic HF patients with or without atrial fibrillation who continue to remain symptomatic despite therapy with ACE inhibitors or angiotensin receptor blockers (ARB), and beta-blockers, or for those who cannot afford or tolerate these drugs. Specifically, digoxin should be used for relief of HF symptoms before considering aggressive therapy with high-dose non-potassium-sparing diuretics, as these drugs may increase mortality and hospitalizations.36, 37
Second, digoxin should be considered before initiating an aldosterone antagonist as these drugs often cause hyperkalemia.38
Third, digoxin should be prescribed before adding an ARB to an ACE inhibitor. In the Val-HeFT and CHARM-added trials, addition of ARB’s, which are expensive, did not result in reduction in mortality and was associated with increased adverse effects.32, 39
Finally, digoxin should be tried before considering cardiac resynchronization therapy (CRT), which is invasive and costly.10, 11, 40
In addition, CRT is reserved for systolic HF patients with wide QRS complex and response to CRT is often unpredictable.
The role of digoxin in the management of HF in developing nations deserves special consideration. Digoxin, along with diuretics, forms the basis of HF therapy in most developing countries. However, clinicians in those countries often follow guidelines and practice patterns in the U.S. and Europe. As the use of digitalis glycosides is being discouraged in developed nations,41
clinicians in the developing countries are also likely to decrease use of digitalis. This could have the untoward consequence of increasing mortality and morbidity in millions of HF patients worldwide. This is important as most HF patients in developing countries cannot afford expensive therapy with ACE inhibitors and beta-blockers. In addition, our data suggest that digoxin is beneficial regardless of EF. Thus, digoxin can play a very special role in HF care in developing nations as most HF patients there cannot afford an echocardiographic evaluation of left ventricular function.
Correlates of high SDC identified in our study can be used to reduce the risk of high SDC in situations where SDC cannot be measured. Based on our observations, we suggest that for young men with clinically stable HF (no pulmonary congestion by chest x-ray and not receiving diuretics) and normal renal function, a daily digoxin dose of 0.25 mg or lower would be therapeutic. In contrast, for HF patients who are elderly, women, have pulmonary congestion or receiving diuretics, or have renal impairment, a daily dose of 0.125 mg would probably be more appropriate. For patients with multiple risk factors for high SDC, such as elderly women with CKD, or elderly women with pulmonary congestion or receiving diuretics, digoxin should be started at a daily dose of 0.0625 mg. When possible, SDC should be monitored to guide therapy for these patients.
To the best of our knowledge, this is the most comprehensive and in-depth analysis of the DIG dataset based on pre-defined outcomes. DIG was the largest multicenter randomized controlled trial of digoxin in patients with HF with the longest follow up. Because most of the studies in the literature either were based on subgroups of DIG patients,14, 35, 42
did not account for SDC,35
were of shorter duration or used intermediate outcomes,6, 43-46
our findings provide the strongest evidence of a significant benefit of digoxin in a wide spectrum of HF patients.
HF patients in the DIG trial were not receiving beta-blockers or aldosterone antagonists. A post-hoc analysis of the U.S. Carvedilol Trials data demonstrated that digoxin use was associated with a reduction in the combined endpoint of death or hospitalization from all causes in patients both receiving (relative risk, 0.64; 95% CI, 0.52 to 0.79) and not receiving (relative risk, 0.82; 95% CI, 0.71 to 0.99) carvedilol.47
In the RALES trial, the survival benefit of spironolactone, an aldosterone antagonist, was only significant in patients receiving digoxin.48
Therefore, there is no reason to withhold digoxin from systolic HF patients receiving beta-blockers or aldosterone antagonists. As there is currently no evidence of survival benefit from beta-blockers or aldosterone antagonists in patients with diastolic HF, digoxin could be considered in preference to those drugs in this population.
Several limitations of our study must be acknowledged. The results of this study are based on post-hoc analysis and patients were not randomized to a certain SDC. Despite our efforts to balance baseline covariate distribution by propensity score matching, bias due to unmeasured covariates cannot be ruled out as a possible explanation of our results. Although we can never know if such a hidden bias exists, careful sensitivity analysis permits us to quantify the size of hidden bias that would be required to invalidate our conclusions. Our sensitivity analysis demonstrates that for an unmeasured binary covariate (unrelated to covariates in our propensity model) to explain away our results, that unmeasured covariate would need to increase the odds of a patient receiving digoxin by at least 48% and would also need to be a near-perfect predictor of all-cause mortality, suggesting that these results are at least somewhat resistant to hidden bias.
About 22% of DIG participants randomized to placebo were receiving open labeled digoxin, and about 20% of those randomized to digoxin were not receiving the drug.2
In our study, all patients in the treatment group were receiving digoxin at 1 month follow-up, as indicated by the presence of a detectable serum digoxin level. However, digoxin may have been subsequently discontinued in some patients, and some of the placebo patients may have been started on digoxin during follow-up. However, as our analysis starts at 30 days after randomization, we were not able to estimate an early effect of digoxin.
Results of our study are based on predominantly white, male, and relatively younger patients with mild to moderate HF and normal sinus rhythm. Our finding of a significant interaction between low SDC and race might be due to chance and lacks biological basis. Subgroup analyses without biological basis can be misleading. For example, in the MERIT-HF trial, survival benefit of extended release metoprolol was only observed in HF patients in Europe, and not in the U.S.49
In summary, our comprehensive post-hoc analysis of data from the DIG trial indicates that at low doses, which is likely to achieve low SDC (<0.9 ng/ml), digoxin reduces mortality and hospitalization in a broad spectrum of ambulatory men and women with chronic systolic or diastolic HF. In systolic HF, digoxin should be used in patients who are symptomatic despite ACE inhibitors or ARB and beta-blocker therapy. Use of digoxin should be considered before CRT, high-dose diuretics, aldosterone antagonists, or adding an ARB to an ACE inhibitor.