Χριστίνα Χρυσοχόου Καρδιολόγος Επι,Α Καρδιολογική Κλινική Πανεπιστηίου Αθηνών, ΙΓΝΑ

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1 Χριστίνα Χρυσοχόου Καρδιολόγος Επι,Α Καρδιολογική Κλινική Πανεπιστηίου Αθηνών, ΙΓΝΑ

2 Digitalisis a genus of about 20 species of herbaceousperennials, shrubs, and biennialsthat are commonly called foxgloves. The use of Digitalis purpurea extract containing cardiac glycosidesfor the treatment of heartconditions was first described in the English speaking medical literature by William Withering, in 1785

3 Combined inotropic bradycardic actions decreases the activity of the renal sodium pump less renin release controversial use In a ValHeFT substudy, there was a significantly greater lowering of Btype natriuretic peptide at 12 months among patients not on digoxin. DIG study 3782 patients followed up for 3 yrs. Low levels digoxin (0.61 ng/ml), mortality decreased by 6%. Higher levels digoxin (>1.2 ng/ml) mortality increased by 12%. N Eng J Med 1997;336:52533

4 DigoxinIndications Today, the most common indications for digoxin are probably atrial fibrillationand atrial flutterwith rapid ventricular response, but betablockers or calcium channelblockers should be the first choice The use of digoxin in heart problems during sinus rhythmwas once standard, but is now controversial. In theory, the increased force of contraction should lead to improved pumping function of the heart, but its effect on prognosis is disputable and other effective treatments are now available

5 Severe hypokalemia, hypercalcemia, hypomagnesemia Concurrent cardiac drugs (quinidine, verapamil, amiodarone, propafenone) Depressed renal blood flow (congestive heart failure, bblockers) Depressed GFR (elderly patients, renal disease) In some patients, antibiotics (erythromycin, tetracycline) can inhibit bacteria converting digoxin to inactive reduction products. Diuretics Thyrotoxic heart disease Low lean body mass Acute myocardial infarction Acute rheumatic carditis Opie L. Drugs for the heart, 7 th ed

6 Risk of digoxin intoxication in heart failure patients exposed to digoxin diuretic interactions: a population based study British Journal of Clinical Pharmacology 2010; 70;

7 455 advanced HF patients referred for transplant evaluation (age, 52years; ejection fraction, 18.38%); 227 (49.9%) were on digoxin at baseline. Patients were on optimal therapy: angiotensin+ii modulation, 92.5%; b+ blockers, 91.2%; aldosterone antagonists, 45.6%; and devices, 71.0%. Median daily digoxin dose was 0.13 mg/day (25% to 75%: 0.13 to 0.19). After a median of 27 months, the composite of primary outcome plus HF hospitalization was met in 63.0% of patients on digoxin versus 40.4% in those not on digoxin (HR, 1.71; 95% CI, 1.32 to 2.23; P=0.001) Digoxin was associated with higher risk among patients in sinus rhythm compared with atrial fibrillation. Digoxin was not associated with improvement in either all+ cause or HF hospitalization rates. Circ Heart Fail. 2009;2:90+97

8 Clusters of patients, within the DIG population, who had increased mortality with digoxin treatment, were more likely to be females; with a higher prevalence of hypertension; and higher left ventricular EF and higher SBP. Clusters of patients who had a significant reduction in admissions due to HF but no effect on mortality with digoxin treatment, had lower EF and SBP, higher prevalence of males, third heart sound and peripheral edema. International Journal of Cardiology 150 (2011)

9 Meyer et al., reported that digoxin was equally effective in reducing the combined end point of HF hospitalizations, or HF mortality in patients with diastolic HF similar to patients with systolic HF. These findings contradict the results of the main DIG trial It should be noted that the study by Meyer et al, did not report independent all#cause mortality, but rather the combined end point of HF hospitalizations and HF mortality. Second, Meyer et al. reported that the reduction in HF admissions was significant only in the first 2 years and not beyond. The investigators attributed this to loss of benefit due to potential cross over or higher cumulative digoxin serum concentrations in later years. Am J Cardiol 2008;102:

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11 A retrospective analysis of two digoxin withdrawal studies, the Prospective randomized Study of Ventricular Failure and Efficacy of Digoxin (PROVED) and the Randomized Assessment of Digoxin on Inhibitors of the Angiotensin&Converting Enzyme (RADIANCE), found a lower risk of worsening CHF in patients taking digoxin (independent of the dosage) and, in particular, patients with low SDC ( ng/ml) were less likely to experience worsening of CHF Q J Med 2011; 104: J Am Coll Cardiol 2002; 39:946 53

12 Allcause death in patients with atrial fibrillation and heart failure according to treatment with a blocker alone, both a blocker and digoxin, digoxin alone, or with conventional therapy without blocker or digoxin. Am J Cardiol 2009;103:

13 Allcause death in patients with atrialfibrillation and heart failure according to Allcause death in patients with atrialfibrillation and heart failure according to treatment with a blocker (upper panels) or with digoxin(lower panels) in nonpermanent atrial fibrillation (left) and permanent atrial fibrillation (right).

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15 Allcause death in patients with atrialfibrillation and heart failure according to treatment Allcause death in patients with atrialfibrillation and heart failure according to treatment with a blocker (upper panels) or with digoxin(lower panels) in HF of ischemic etiology (left) and HF of nonischemic etiology (right).

16 In unselected patients with AF and HF, treatments with blocker alone or with blocker plus digoxinare associated with a similar decrease in the risk of death. Digoxinalone is associated with a worse survival chance, similar to that of patients without any rate control treatment. Am J Cardiol 2009;103:248 54

17 I IIa IIbIII III The Benefits of Digitalis In patients with symptomatic HF and AF, digoxin may be used to slow a rapid ventricular rate. In patients with AF and an LVEF 40% it should be used to control heart rate in addition to, or prior to a b#blocker. I IIa IIbIII III In patients in sinus rhythm with symptomatic HF and an LVEF 40%, treatment with digoxin (in addition to an ACEI) improves ventricular function and patient well# being, reduces hospital admission for worsening HF, but has no effect on survival. European Journal of Heart Failure (2008),

18 The patients in the DIG trial may no longer reflect the heart failure population today. When should digoxin be added to the treatment of patients with decompensated systolic heart failure? A low digoxin dose (0.125 mg/day) was the strongest predictor of a low serum concentration of the drug, which is thought to be the most important predictor of beneficial clinical outcome Should dosing beguided by digoxin serum concentrations? Clinical studieshave suggested increased hospitalizations and all"cause mortalitywhen discontinuing chronic digoxin therapy in stablepatients. Once started, when should digoxin be discontinuedin patients with improved left ventricular function and stable symptoms? Circ Heart Fail 2008;1;206"207

19 In practice, most HF patientsare elderly, have impaired renal function, and take concomitantmedications that may either alter renal function or havedrug to drug interaction with digoxin. DIG study revealed that the serum digoxin concentration associatedwith improved outcomes ranged between 0.5 and 0.8 ng/ml. This represents a narrow therapeutic range and raises practical real'life management issues. Digoxin has modest inotropic properties, and multiple inotropes in the past have been shown to worsen outcomes inhf, especially the risk of sudden death. Therefore, the routine useof digoxin therapy should be cautiously re'evaluated, at least in patients with advanced HF.