Increased Mortality Among Patients Taking Digoxin
Increased Mortality Among Patients Taking Digoxin
Our findings suggest that, in patients with AF, digoxin is associated with increased all-cause mortality after controlling for comorbidities and propensity scores, regardless of gender and the presence or absence of underlying HF. All-cause mortality was 41% higher in patients on digoxin. This effect was consistent across all HF strata.
Digoxin has survived as a mainstay of therapy for AF and CHF for decades despite controversies about its safety and continues to be utilized in the United States and worldwide. Digoxin use has ranged from 35 to 70% in recent AF studies despite limited data addressing its safety for this indication. The AFFIRM study provided a unique opportunity to assess the safety of digoxin in a large AF cohort.
In patients with AF and no HF, digoxin was associated with a 37% increase in mortality in an analysis that controlled for a host of comorbidities and propensity scores. This group represented more than half of all patients enrolled in AFFIRM. These findings are consistent with previously published results from the Registry of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS-HIA) study. The RIKS-HIA study examined 1-year outcomes of patients with AF, CHF, or both on digoxin by comparing them to a matched group of patients not receiving digoxin. The 4426 patients with AF and no history of CHF taking digoxin had a significant increase in overall mortality (estimated relative risk 1.42, 95% CI 1.29–1.56) compared with 16 587 controls at discharge.
Patients without CHF or low EF lack the neurohormonal and inotropic derangements that may improve with digoxin, while remaining exposed to its potential deleterious effects such as proarrhythmia and bradycardia. In the AFFIRM trial, digoxin was utilized to meet the stringent rate control strategy requirement (resting heart rate <80 b.p.m. and exercise heart rate <110 b.p.m.), usually in combination with other atrioventricular (AV) nodal blockers such as beta-blockers or calcium-channel blockers. Indeed, digoxin was used as monotherapy for rate control in only 17% of patients. In those patients, higher doses of digoxin with an increased risk for toxicity may have been used to achieve the stringent rate control goal, as high serum levels of digoxin were encouraged in the AFFIRM protocol (>1.0 ng/mL). It is currently thought that strict rate control at baseline is not superior to a more lenient strategy (resting heart rate <110 b.p.m.). The major objectives of a rate control strategy are to minimize symptoms and avoid sustained rapid ventricular rates that can lead to rhythm-induced cardiomyopathies. Digoxin is known to slow heart rates and potentiate bradyarrhythmias through its parasympathetic effect on the AV node, but has little effect on fast ventricular rates in the setting of enhanced sympathetic tone. Therefore, digoxin is not the ideal choice to control rapid ventricular rates in most patients.
Digoxin may seem appealing for patients with AF and HF, in whom positive inotropic effects and improved neurohormonal responses are desired. Digoxin may also be beneficial during SR by reducing the heart rate as suggested in an analysis of the Dig trial. However, in our analysis, digoxin was associated with a 41% increase in mortality for patients with HF. It may be hypothesized that potential benefits are offset by deleterious effects. For example, patients with CHF who experience AF may incur more frequent CHF exacerbations, frequent electrolyte fluctuations, and varying levels of acute kidney injury that increase susceptibility to digoxin toxicity. Furthermore, a number of medications frequently prescribed to this patient population may directly interact with digoxin or impact digoxin levels indirectly via volume status changes, electrolyte imbalance, or drug elimination, all of which can potentiate the risk of lethal tachy- and bradyarrhythmias (e.g. amiodarone, diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and calcium-channel blockers).
Although amiodarone may increase serum digoxin levels, in our analysis, digoxin's deleterious effect on mortality persisted after adjustment for amiodarone use. More recently, dronedarone has been associated with an increased mortality in the PALLAS study. The increase in mortality is thought to be related to the interaction between dronedarone and digoxin. The largest trial to examine the safety of digoxin in patients with HF, the DIG study, excluded patients with AF. In that trial, patients were randomized to digoxin vs. placebo. Digoxin was found to have a neutral effect on the all-cause mortality (EHR 0.99; 95% CI 0.91–1.07; P = 0.80). However, it is important to note that real-world patients, including those in AFFIRM, are not routinely subject to the close follow-up and frequent monitoring of serum digoxin concentrations mandated in the DIG study. It is possible that such strict monitoring is required to ensure safety. Further analysis of the DIG trial data demonstrated that digoxin's beneficial effect applied only to patients in SR with low serum digoxin drug levels (<0.9 ng/mL). Indeed, positive inotropic and neurohormonal effects are attained with low plasma drug concentrations. Patients with higher digoxin levels had worse outcomes, including 60% higher all-cause mortality (P = 0.006), an increase in hospitalizations for suspected digoxin toxicity (P < 0.001), and an increase in arrhythmic mortality (15 vs. 13% in placebo, P = 0.04). More recently, a positive association between serum digoxin concentrations and mortality was again demonstrated in patients with end-stage renal failure (EHR 1.28; 95% CI 1.25–1.31; P < 0.001). Also, a higher proportion of patients in the AFFIRM trial were on beta-blockers (58.3%) compared with patients in the DIG and other trials. While digoxin's positive neurohormonal effects in HF patients may be attenuated or lost when beta-blockers are concomitantly prescribed, the association between digoxin and mortality observed in our study was independent of beta-blocker use.
The mechanism by which digoxin increases total mortality in patients without HF remains speculative. Classic cardiac digoxin toxicity (i.e. lethal tachy- or bradyarrhythmias, drug interactions, narrow therapeutic window) may be implicated to a lesser degree in patients without HF, since cardiovascular mortality was not significantly increased in patients without HF. It is worthwhile noting that the accuracy of clinical classifications of death (in particular, of cardiovascular or arrhythmic death) is limited. Moreover, subgroup analyses are inherently limited by smaller sample sizes. Although it is theoretically possible for digoxin to increase non-cardiac deaths, similar to the association between amiodarone and cancer deaths reported in a prior AFFIRM substudy, our analysis of causes of death did not link digoxin to non-cardiovascular causes. However, digoxin was associated with non-ischaemic cardiac causes.
The greater increase in mortality with digoxin among women compared with men described in a post hoc analysis of the DIG study is regarded as controversial. It was unclear whether this increase was due to higher serum drug concentrations or an unidentified gender-specific toxicity. In our study, we did not find a gender interaction with digoxin therapy. Both men and women experienced significantly increased overall mortality with digoxin use. Our findings are consistent with other recent analyses involving patients with AF.
Our study is subject to the limitations inherent to post hoc analyses. The AFFIRM trial was designed to compare rhythm control to rate control and did not, therefore, randomize patients to digoxin therapy. The mortality excess with digoxin decreased from 66% without any covariates present to 41% with adjustments for covariates (including propensity scores). The association between digoxin and mortality may still be overestimated due to unknown and/or unmeasured potential confounders. However, given the large observed magnitude of effect and directionally consistent main and sensitivity analyses, invalidation of these results by residual confounding appears implausible.
While our results strongly suggest that mortality was increased by digoxin in the AFFIRM study, the pathophysiological mechanism remains to be elucidated. In keeping with standard clinical care, routine monitoring of digoxin levels, although encouraged, was not mandated nor recorded in the AFFIRM trial. We cannot, therefore, assess whether serum digoxin levels are predictive of mortality outcomes. No specific digoxin dosing recommendations were provided by the AFFIRM protocol and individual doses were not available. Measures of renal function (creatinine level, creatinine clearance) were not collected and, therefore, not available for analyses. Similarly, the exact duration of and compliance with digoxin therapy were not confirmed. However, our Cox proportional hazards models did account for the approximate duration of digoxin therapy by defining digoxin use as a time-dependent covariate based on whether the patient was on digoxin at each follow-up visit.
Finally, the threshold of <40% for defining a low EF was based on common clinical practice; whether a lower threshold (e.g. 30 or 35%) may yield similar mortality trends has not been explored.
Discussion
Our findings suggest that, in patients with AF, digoxin is associated with increased all-cause mortality after controlling for comorbidities and propensity scores, regardless of gender and the presence or absence of underlying HF. All-cause mortality was 41% higher in patients on digoxin. This effect was consistent across all HF strata.
Digoxin has survived as a mainstay of therapy for AF and CHF for decades despite controversies about its safety and continues to be utilized in the United States and worldwide. Digoxin use has ranged from 35 to 70% in recent AF studies despite limited data addressing its safety for this indication. The AFFIRM study provided a unique opportunity to assess the safety of digoxin in a large AF cohort.
Patients With no Congestive Heart Failure and Ejection Fraction ≥40%
In patients with AF and no HF, digoxin was associated with a 37% increase in mortality in an analysis that controlled for a host of comorbidities and propensity scores. This group represented more than half of all patients enrolled in AFFIRM. These findings are consistent with previously published results from the Registry of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS-HIA) study. The RIKS-HIA study examined 1-year outcomes of patients with AF, CHF, or both on digoxin by comparing them to a matched group of patients not receiving digoxin. The 4426 patients with AF and no history of CHF taking digoxin had a significant increase in overall mortality (estimated relative risk 1.42, 95% CI 1.29–1.56) compared with 16 587 controls at discharge.
Patients without CHF or low EF lack the neurohormonal and inotropic derangements that may improve with digoxin, while remaining exposed to its potential deleterious effects such as proarrhythmia and bradycardia. In the AFFIRM trial, digoxin was utilized to meet the stringent rate control strategy requirement (resting heart rate <80 b.p.m. and exercise heart rate <110 b.p.m.), usually in combination with other atrioventricular (AV) nodal blockers such as beta-blockers or calcium-channel blockers. Indeed, digoxin was used as monotherapy for rate control in only 17% of patients. In those patients, higher doses of digoxin with an increased risk for toxicity may have been used to achieve the stringent rate control goal, as high serum levels of digoxin were encouraged in the AFFIRM protocol (>1.0 ng/mL). It is currently thought that strict rate control at baseline is not superior to a more lenient strategy (resting heart rate <110 b.p.m.). The major objectives of a rate control strategy are to minimize symptoms and avoid sustained rapid ventricular rates that can lead to rhythm-induced cardiomyopathies. Digoxin is known to slow heart rates and potentiate bradyarrhythmias through its parasympathetic effect on the AV node, but has little effect on fast ventricular rates in the setting of enhanced sympathetic tone. Therefore, digoxin is not the ideal choice to control rapid ventricular rates in most patients.
Patients With Congestive Heart Failure and/or Ejection Fraction <40%
Digoxin may seem appealing for patients with AF and HF, in whom positive inotropic effects and improved neurohormonal responses are desired. Digoxin may also be beneficial during SR by reducing the heart rate as suggested in an analysis of the Dig trial. However, in our analysis, digoxin was associated with a 41% increase in mortality for patients with HF. It may be hypothesized that potential benefits are offset by deleterious effects. For example, patients with CHF who experience AF may incur more frequent CHF exacerbations, frequent electrolyte fluctuations, and varying levels of acute kidney injury that increase susceptibility to digoxin toxicity. Furthermore, a number of medications frequently prescribed to this patient population may directly interact with digoxin or impact digoxin levels indirectly via volume status changes, electrolyte imbalance, or drug elimination, all of which can potentiate the risk of lethal tachy- and bradyarrhythmias (e.g. amiodarone, diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and calcium-channel blockers).
Although amiodarone may increase serum digoxin levels, in our analysis, digoxin's deleterious effect on mortality persisted after adjustment for amiodarone use. More recently, dronedarone has been associated with an increased mortality in the PALLAS study. The increase in mortality is thought to be related to the interaction between dronedarone and digoxin. The largest trial to examine the safety of digoxin in patients with HF, the DIG study, excluded patients with AF. In that trial, patients were randomized to digoxin vs. placebo. Digoxin was found to have a neutral effect on the all-cause mortality (EHR 0.99; 95% CI 0.91–1.07; P = 0.80). However, it is important to note that real-world patients, including those in AFFIRM, are not routinely subject to the close follow-up and frequent monitoring of serum digoxin concentrations mandated in the DIG study. It is possible that such strict monitoring is required to ensure safety. Further analysis of the DIG trial data demonstrated that digoxin's beneficial effect applied only to patients in SR with low serum digoxin drug levels (<0.9 ng/mL). Indeed, positive inotropic and neurohormonal effects are attained with low plasma drug concentrations. Patients with higher digoxin levels had worse outcomes, including 60% higher all-cause mortality (P = 0.006), an increase in hospitalizations for suspected digoxin toxicity (P < 0.001), and an increase in arrhythmic mortality (15 vs. 13% in placebo, P = 0.04). More recently, a positive association between serum digoxin concentrations and mortality was again demonstrated in patients with end-stage renal failure (EHR 1.28; 95% CI 1.25–1.31; P < 0.001). Also, a higher proportion of patients in the AFFIRM trial were on beta-blockers (58.3%) compared with patients in the DIG and other trials. While digoxin's positive neurohormonal effects in HF patients may be attenuated or lost when beta-blockers are concomitantly prescribed, the association between digoxin and mortality observed in our study was independent of beta-blocker use.
Death Mechanism With Digoxin
The mechanism by which digoxin increases total mortality in patients without HF remains speculative. Classic cardiac digoxin toxicity (i.e. lethal tachy- or bradyarrhythmias, drug interactions, narrow therapeutic window) may be implicated to a lesser degree in patients without HF, since cardiovascular mortality was not significantly increased in patients without HF. It is worthwhile noting that the accuracy of clinical classifications of death (in particular, of cardiovascular or arrhythmic death) is limited. Moreover, subgroup analyses are inherently limited by smaller sample sizes. Although it is theoretically possible for digoxin to increase non-cardiac deaths, similar to the association between amiodarone and cancer deaths reported in a prior AFFIRM substudy, our analysis of causes of death did not link digoxin to non-cardiovascular causes. However, digoxin was associated with non-ischaemic cardiac causes.
Digoxin and Gender
The greater increase in mortality with digoxin among women compared with men described in a post hoc analysis of the DIG study is regarded as controversial. It was unclear whether this increase was due to higher serum drug concentrations or an unidentified gender-specific toxicity. In our study, we did not find a gender interaction with digoxin therapy. Both men and women experienced significantly increased overall mortality with digoxin use. Our findings are consistent with other recent analyses involving patients with AF.
Study Limitations
Our study is subject to the limitations inherent to post hoc analyses. The AFFIRM trial was designed to compare rhythm control to rate control and did not, therefore, randomize patients to digoxin therapy. The mortality excess with digoxin decreased from 66% without any covariates present to 41% with adjustments for covariates (including propensity scores). The association between digoxin and mortality may still be overestimated due to unknown and/or unmeasured potential confounders. However, given the large observed magnitude of effect and directionally consistent main and sensitivity analyses, invalidation of these results by residual confounding appears implausible.
While our results strongly suggest that mortality was increased by digoxin in the AFFIRM study, the pathophysiological mechanism remains to be elucidated. In keeping with standard clinical care, routine monitoring of digoxin levels, although encouraged, was not mandated nor recorded in the AFFIRM trial. We cannot, therefore, assess whether serum digoxin levels are predictive of mortality outcomes. No specific digoxin dosing recommendations were provided by the AFFIRM protocol and individual doses were not available. Measures of renal function (creatinine level, creatinine clearance) were not collected and, therefore, not available for analyses. Similarly, the exact duration of and compliance with digoxin therapy were not confirmed. However, our Cox proportional hazards models did account for the approximate duration of digoxin therapy by defining digoxin use as a time-dependent covariate based on whether the patient was on digoxin at each follow-up visit.
Finally, the threshold of <40% for defining a low EF was based on common clinical practice; whether a lower threshold (e.g. 30 or 35%) may yield similar mortality trends has not been explored.