Digoxin (Lanoxin) is an antiarrhythmic drug, which means that it is also a proarrhythmic drug. Any drug that affects the heart’s conduction system can produced changes that are bad, good, or a combination of the two. Digoxin has been associated with a higher death rate, but is that because it is prescribed to sicker patients?
Digoxin has been used worldwide for decades to achieve rate control in patients with AF. Its use in heart failure (HF) dates back centuries but remains controversial,5 due to its narrow therapeutic index and a potential to contribute to life-threatening ventricular tachyarrhythmias and severe bradyarrhythmias.6,7 
Digoxin is an antiarrhythmic, but a Class V antiarrhythmic. It doesn’t fit in anywhere, so it is in the none of the above class. Digoxin also is a rare inotrope (causes more forceful contraction of the heart), while generally not raising the heart rate. If the heart is already in failure, increasing heart rate to increase cardiac output may not be a good idea, which makes digoxin appealing and possibly beneficial in HF.
Digoxin is known to slow heart rates and potentiate bradyarrhythmias25 through its parasympathetic effect on the AV node, but has little effect on fast ventricular rates in the setting of enhanced sympathetic tone.26 Therefore, digoxin is not the ideal choice to control rapid ventricular rates in most patients.
AFFIRM was looking at whether rate control or rhythm control produced a better outcome for patients, not whether digoxin is beneficial, or harmful. The data are relevant for evaluating the possible risks from digoxin.
The AFFIRM trial design, baseline characteristics, and results have been published previously.4 In brief, the study enrolled 4060 patients with AF considered at high risk for stroke. These patients were randomized to rate control vs. rhythm control over a 4-year period with a mean follow-up of 3.5 years.
This study looks at the data from AFFIRM and EHRs (Estimated Hazard Ratios) for many risk factors with and without digoxin.
Digoxin was associated with increased all-cause (EHR 1.41, 95% CI 1.19–1.67, P < 0.001) and cardiovascular mortality (EHR 1.35, 95% CI 1.06–1.71, P = 0.016) after controlling for clinical and demographic variables, as well as propensity scores. Similarly, digoxin was associated with an increase in arrhythmic deaths (EHR 1.61, 95% CI 1.12–2.30, P = 0.009);
This graph shows the progressive divergence of the mortality rates which should be expected if digoxin increases the death rate.
Click on images to make them larger.
The one thing I did not like about this paper is the way they organized the data. If you look at the original tables, they are not organized in a way that helps to understand the relationships among different risk factors by organizing them according to their association with mortality. I rearranged the tables by p values to try to make those associations easier to see.
These all met statistical significance of a p value of less than 0.05, arranged from the weakest association to the strongest association within 6 months of adding digoxin. For example, patients with a history of cardiomyopathy did not do well on digoxin.
These are from the same the risk factors, but these are the ones that did not meet statistical significance. Prior interventional procedure actually trends toward a benefit with digoxin, while a Permanent pacemaker seems to be the least likely to be affected by digoxin.
These are Cardiovascular mortality and All-cause mortality, based on whether they were taking digoxin on their last recorded visit, rather than just within 6 months of entering the study.
I should have arranged these by All-cause mortality with digoxin, but some people would claim that digoxin only has cardiovascular effects. The first table is of the variables that are not statistically significant.
These are the variables that reached statistical significance with digoxin. A p value of <0.05 is a result considered to have a less than 5% chance of being due to chance. If the original study were redone 20 times, there is the possibility that the results would come out this way purely due to chance one time. A p value of <0.0001 is a result considered to have a less than 0.01% chance of being due to chance. If the original study were redone 10,000 times, there is the possibility that the results would come out this way purely due to chance one time. Not as far fetched as the Powerball odds, but the lottery far fewer variables. Each has roughly a 0.000000005714 chance of winning.
Comparing the EHR with all covariates present to that with none present, 62.6% of digoxin over-mortality cannot be attributed to confounding from the covariates.
That is nice and simple.
There are plenty of excuses, such as being prescribed to sicker patients, but they do not appear to have any validity.
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.21 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).
They were not able to adjust for the large doses of digoxin used in AFFIRM, so that may be a significant contributor to the elevated death rate.
The largest trial to examine the safety of digoxin in patients with HF, the DIG study, excluded patients with AF.10 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).7,32 
If the benefits of digoxin are limited to patients with a SR (Sinus Rhythm) and only at low doses of digoxin, maybe digoxin should have very limited indications.
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.
Even beta-blockers do not seem to protect against digoxin.
Is the best way to avoid killing patients to use less digoxin and to only use digoxin for very specific indications?
Go read the full paper. I don’t know how long it will be free as Advanced Access.
 Increased mortality among patients taking digoxin-analysis from the AFFIRM study.
Whitbeck MG, Charnigo RJ, Khairy P, Ziada K, Bailey AL, Zegarra MM, Shah J, Morales G, Macaulay T, Sorrell VL, Campbell CL, Gurley J, Anaya P, Nasr H, Bai R, Di Biase L, Booth DC, Jondeau G, Natale A, Roy D, Smyth S, Moliterno DJ, Elayi CS.
Eur Heart J. 2012 Nov 27. [Epub ahead of print]
PMID: 23186806 [PubMed - as supplied by publisher]
The difference in the odds of winning if you buy a ticket, or a hundred tickets, is essentially indistinguishable from the odds if you don’t buy any ticket at all.
Whitbeck, M., Charnigo, R., Khairy, P., Ziada, K., Bailey, A., Zegarra, M., Shah, J., Morales, G., Macaulay, T., Sorrell, V., Campbell, C., Gurley, J., Anaya, P., Nasr, H., Bai, R., Di Biase, L., Booth, D., Jondeau, G., Natale, A., Roy, D., Smyth, S., Moliterno, D., & Elayi, C. (2012). Increased mortality among patients taking digoxin-analysis from the AFFIRM study European Heart Journal DOI: 10.1093/eurheartj/ehs348