Increased mortality among patients taking digoxin—analysis from the AFFIRM study or Lack of evidence of increased mortality among patients with atrial fibrillation taking digoxin Kyung Hee University Jornal Conference Sang Jin Ha Division of Cardiology, Cardiovascular Center Kyung Hee University Hospital

WHEN ‘DIGOXIN USE’ IS NOT THE SAME AS ‘DIGOXIN USE’: LESSONS FROM THE AFFIRM TRIAL -Statistical viewpoint -European Heart Journal (2013) 34, 1465–1467

Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Tria The AFFIRM trial randomized 4060 patients with AF and a high risk of stroke or death to rate control vs. rhythm control. In the rate control arm, different therapies were allowed including digoxin, betablockers, calcium channel blockers (verapamil and diltiazem), and combinations of these drugs. In the rhythm control arm, antiarrhythmic drugs included amiodarone, disopyramide, flecainide, moricizine, procainamide, propafenone, quinidine, sotalol, and combinations of these drugs.  mean follow-up =3.5 years  356 deaths (23.8%) in rhythm control group  vs 310 deaths (21.3%) among rate control groupa   directionally but not significantly lower mortality with rate control (P = 0.08). N Engl J Med 2002;347:1825–1833.

Increased mortality among patients taking digoxin ? European Heart Journal (2013) 34, 1481–1488 The association of digoxin use withmortality was evaluated treating digoxin as a time-dependent covariate in a Cox proportional hazard model.  patients changed from being in the ‘on-digoxin’ group to the ‘not on-digoxin’ group if their medication use changed over time in the study, and their associated time at risk for death contributed to each respective group. 1.Using digoxin as a time-dependent covariate, the Whitbeck analysis found a significant increase in all-cause mortality associated with digoxin [hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.19– 1.67, P< 0.001] after controlling for clinical and demographic variables, aswell as propensity score. 2.Additional sensitivity analysis found similar observations when restricted to patients randomized to the rate control only cohort (HR 1.46, 95% CI 1.13– 1.90, P = 0.004).

Lack of evidence of increased mortality among patients with atrial fibrillation taking digoxin European Heart Journal (2013) 34, 1489–1497 digoxin use was assessed at a fixed time point only, at the time of randomization.  Patients were excluded from the analysis if they were on digoxin in the previous 6 months but discontinued digoxin as initial therapy at randomization (n = 465) or had missing information on digoxin use at randomization(n = 887). Using digoxin at randomization, the Gheorghiade analysis found no increase in all-cause mortality associated with digoxin (HR 1.06; 95% CI, 0.83–1.37; P = 0.640) in a propensity-matched analysis (n ¼ 1756)

Several issues contributed to the different conclusions European Heart Journal (2013) 34, 1465–1467

Several issues contributed to the different conclusions I How digoxin use was defined  time-dependent covariate definition (Whitbeck et al. definition) seems the prefered method 1) but not always appropriate, such as when the change in treatment is related to worsening of the patients’ health. 2) indication bias: can be reduced by adjusting forthe factors that may prompt the change in treatment.  Cohort difference : Gheorghiade manuscript : missing data from AFFIRM coholrt  selection bias possible (mortality was higher among subjects with missing data on digoxin use at randomization as compared with subjects with digoxin data available). -Gheorghiade M. Communication with author

Several issues contributed to the different conclusions II Propensity method difference 1.Whitbeck et al.  propensity adjustment ( the propensity score is added to the treatment effect model as a covariate). 주의 : incorrect assumptions about the functional relationship of the propensity scores and outcome, e.g. non-linear relationships and mis-specification of the propensity model, both of which can result in biased treatment effect estimates. 2.Gheorghiade et al. used propensity matching ( selects one patient from the treated group (i.e. the ‘on-digoxin group’) and matches them to one patient from the control group (i.e. the ‘not on-digoxin group’) with a similar propensity score). 단점 : allows for baseline covariate balance but faces the limitation of a reduced sample size since matches between experimental and control therapy cannot be found for all patients Eur Heart J 2011;32:1704–1708 / Biometrika 1983;70:41–55..

What conclusions can be drawn from these two analyses? 1.Non-randomized, observational design  only Hypothesis generating. 2.Even sophisticated statistical methods such as propensity analysis cannot replace randomization. 3.Crucial for the reader to understand the cohorts and the how treatment groups are defined, because sometimes digoxin use is not the same as digoxin use.

DIGOXIN FOR PATIENTS WITH ATRIAL FIBRILLATION AND HEART FAILURE: PARADISE LOST OR NOT?† European Heart Journal (2013) 34, 1468–1470

Digoxin for patients with atrial fibrillation and heart failure : paradise lost or not? 2012 European Society of Cardiology (ESC) HF Guidelines Eur Heart J 2012;33:1787– For patients with HF and a left ventricular ejection fraction (LVEF) ≤40%, who are in sinus rhythm ‘digoxin may be used’. 2.For HF patients with AF, other drugs (in particular beta-blockers) should be preferred, since they provide better rate control : digoxin is effective for long-term rate control at rest, but not during exercise.

Digoxin in heart failure 1.Digoixin effect 1) positive inotropic properties-more pronounced at higher doses of the drug 2) favourable autonomic- or neurohormonal-inhibiting properties -lower serum digoxin concentrations (SDCs) Circulation 2006;113:2556–2564. J Am Coll Cardiol 1996; 28:813–819. Circulation 1991;84:2181–2186. J Am Coll Cardiol 1993;22:1564–1573.

Digoxin in atrial fibrillation 2012 European Society of Cardiology (ESC) HF Guidelines & 2010 Guidelines for the management of atrial fibrillation. Eur Heart J 2012;33:1787–1847. Eur Heart J 2010;31:2369– the primary effect of digoxin is slowing down atrioventricular (AV) conduction, leading to a reduction in ventricular response at rest, but much less so during exercise 2.beta-blockers are more effective than digoxin in slowing heart rate during exercise in patients with AF, and beta-blockers now have a prominent place in AF patients, both with and without HF  SCAF data : digoxin use is associated with an increased mortality in AF patients with or without HF, its effect becomes neutral when differences in baseline characteristics are taken into account Heart 2010;96:275–280.suggest

Digoxin in the AFFIRM study Whitbeck et al. data 1.of a large number of other variables (reported in their table 2), it is unclear whether these were different between patients on digoxin vs. those not on digoxin. 2.Digoxin was also associated with cardiovascular mortality and arrhythmic mortality.  In a stepwise examination of the multivariate Cox regression model for all-cause mortality, the HR for the association between digoxin and all-cause mortality ranged between 1.36 and 1.66, and the greatest effect was seen after adding NYHA functional class.  the authors also mention that high serum levels were encouraged in the AFFIRM protocol (≥1.0 ng/mL), but data on SDCs or on the dose of digoxin used in the study are not reported.

Discussion post hoc analysis - Patients in the present analysis were obviously not randomized for digoxin. patients in AFFIRM were receiving high doses of digoxin, since they were encouraged to have an SDC ≥1.0 ng/mL.  occurrence of digoxin toxicity  it is very likely that digoxin acted as an inotrope in most AFFIRM patients, and did not have a significant vagal effect, which is the most important (beneficial) effect of the drug in AF.

Lessons from Whitbeck et al. study In AF, rate control is now the treatment of choice for many patients, so, for that reason, digoxin could still be of value in patients.  1.Achieving an SDC ≥1.0 ng/mL should no longer be recommended a. if lower SDCs can be reached and maintained, digoxin could still be of use in HF. Eur Heart J 2006; 27:178–186. JAMA 2003; 289:871–878. J Am Coll Cardiol 2002;39:954–956 b. the effects of the sinus node inhibitor ivabradine in the Systolic Heart failure treatment with the If inhibitor Ivabradine Trial (SHIFT) were compared with the effect of digoxin in the DIG trial, and they showed a remarkable similarity  Eur Heart J 2012;33:1137–1141

TAKE HOME MESSAGE Digoxin in patients with HF may still have a place, not as an inotropic drug, because for these drugs paradise is ‘lost’, but as a neurohormonal modulator, when given in low doses.