Digoxin Toxicity and Trials

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Extensive Discussion on Digoxin Farmacology, Toxicity and recent clinical Trials on why we should not use it anymore

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Digoxin Toxicity and Trials

  1. 1. Digoxin - Time to take the gloves off ? Diego Bellavia
  2. 2. Cardiac Glycosides: Molecular Structure  All Cardiac glycosides  ag lyco ne (genin) part (active pharmacologically)  Glyco ne : sug ar (g luco se o r dig ito xo se ) attache d at Carbo n 3 o f nucle us  Aglycone – Steroid ring (cyclopentanoperhydrophenanthrene ring) and lactone ring attached at 17th position
  3. 3. Pharmacokinetics  IV peaks within 10 to 30 minutes, PO peaks within 1 to 2 hours  About 70 to 80% of an oral dose of digoxin is absorbed. The degree of binding to serum albumin is 20 to 30%.  Half Life: 1.5 day  Level increased by several medications  Verapamil, Diltiazem, Am io daro ne , itraconazole - decreased clearance  Erythromycin, clarithromycin, tetracycline - decreased gut flora metabolism  Toxicity can be increased by any medication decreasing serum K or potentially affecting renal function
  4. 4. Drug-Drug Interactions
  5. 5. Digoxin - Pharmacological actions  Myocardial contractility  Electrophysiological properties  Parasympatho-mimetic effect
  6. 6. Myocardial Contractility StrokeVolume Preload (LV Filling Pressure) Normal Digitalis CHF
  7. 7. Digitalis – Electrophysiological actions
  8. 8. Digitalis – Electrophysiological actions  Autonomic actions:  Involves both Parasympathetic and sympathetic systems  At therapeutic doses – cardio selective parasympathomimetic action  Rate and Conduction:  Bradycardia  Slowing of impulse generation (SAN)  Delay of conductivity of AVN  However sympathetic action is increased in toxic doses
  9. 9. Simplified diagram of apparent digitalis-induced changes in ANS activity CNS output of autonomic tone Dose of digitalis sympathetic parasympathetic slowing VT VF - death partial AV block PVCs
  10. 10. Digitalis – EKG Changes
  11. 11. Afterpolarization actions Weir & Hess, 1984
  12. 12. Afterpolarization actions Cont’d  DADs may elicit premature depolarizations or “ectopic beats” that are coupled to the preceding normal action potentials.  If DADs in the Purkinje system regularly reach threshold, bigeminy will be recorded on the ECG.  With further intoxication, each DAD-evoked action potential will itself elicit an afterpotential, and a self-sustaining tachycardia will be established.  Such a tachycardia may deteriorate into fibrillation;
  13. 13. Digitalis-induced bigeminy: NSR: normal sinus rhythm PVB: premature ventricular beats
  14. 14. Digitalis - Clearance  Digoxin is primarily (i.e. 70%) excreted unchanged in urine and rate of excretion parallels creatinine (So, renal impairment and elderly Accumulation)  25 to 28%: eliminated by non-renal routes.  Biliary excretion up to 30% of a given dose, but the enterohepatic cycle seems to be of minor importance.
  15. 15. Interactions With K+ , Ca2+ , Mg2+  Potassium and digitalis inhibit each other's binding to Na+/K+ ATPase  Hyperkalemia reduces the enzyme-inhibiting actions of cardiac glycosides, whereas hypokalemia facilitates these actions.  Abnormal automaticity is inhibited by hyperkalemia. Moderately increased extracellular K+ therefore reduces the (toxic) effects of digitalis.
  16. 16. Interactions With K+ , Ca2+ , Mg2+ Cont’d  Ca2+ facilitates the toxic actions of cardiac glycosides by accelerating the overloading of intracellular calcium stores.  Hypercalcemia increases the risk of a digitalis induced arrhythmia.  The effects of Mg2+ is opposite to those of calcium.  These interactions mandate evaluation of serum electrolytes in digitalis-induced arrhythmias.
  17. 17. Toxicity: Extracardiac Symptoms  The GI tract is the most common extra cardiac site of digitalis toxicity. It causes anorexia, nausea, vomiting, and diarrhea.  Central nervous system effects include vagal and CTZ stimulation.  In the elderly disorientation, hallucinations and visual disturbances (as color misperception) may occur.
  18. 18. Digoxin Toxicity: The Heart  Arrythmias  Atrial Tachycardia with AV block  Advanced (III) AV Block  Ectopic Rhythms  AFlutter, Afib, VT  Junctional Tachicardias  Sustained Ventricular Tachycardia  Ventricular Fibrillation  ANY Arrythmia is possible
  19. 19. Treatment  If early after intentional overdose, can give activated charcoal  Bradycardia  If asymptomatic keep serum K+ at least 4.0 (or higher)  Symptomatic- Atropine, prompt pacing  Tachicardia  Excessive ventricular automaticity: Lidocaine IV  DC Shock ONLY if VFib (NEVER for PSVT)  DigiBindDigiFAB (Humanized sheep Mab)  Symptomatic bradycardia – advanced AVB (unresponsive to Atropine)  Malignant arrhythmia (particularly in the se tting o f hype rkale m ia)  Hyperkalemia (K+ > 5 mEqL)  Digoxin > 10 ngL (or > 4 ngL in chronic toxicity)  Plasmapheresis will prevent rebound effect  Monitor K, Free Digoxin Levels and ECG
  20. 20. Treatment of acute digoxin intoxication by digoxin immune Fab (Digibind® )
  21. 21. Absolute Contraindications  Hypersensitivity  Uncontrolled Ventricular Arrhythmias  AV block  Constrictive Pericarditis  Idiopathic Hypertrophic Subaortic Stenosis  WPW syndrome: VF may occur  Severe Mitral Stenosis
  22. 22. Relative ContraIndications  Renal & Hepatic impairment  Electrolyte imbalance (+++ Hypokalemia)  Acute Myocardial Infarction (inside 24hr, pro- arrythmic)  Thyroid Disoder (Mixoedema  Slow Clearance)  Obesity  Elderly Patient (more sensitive)  Pregnancy  Breastfeeding infant
  23. 23. Digitalization  Digoxin has low therapeutic window and margin of safety is very low  Therapeutic SDC: 0.5 – 1.5 ng/mL (BUT 0.5 – 0.9 in HF)  Rapid digitalization (12hr):  Digoxin 0.5 mg EV + 0.25 mg (6hr) + 0.25 mg after (6hr)  Slow digitalization:  Digoxin 0.25 mg (or even 0.125mg) daily in the evening – full response in 5-7 days  If no improvement administer 0.375 for 1 week  Monitor patient for blood levels,  If bradycardia, stop the drug  HF : No Loading dose, maintainance 0.125 mg/day (0.0625 if Dyalisis)
  24. 24. Digitalis Indications Today – CHF AHA/ACC Update (2012) and HFSA Update (2010)
  25. 25. Digoxin Indications – AFib (EHRA)  “…digoxin is an acceptable choice for ventricular rate control in AF, and is recommended if the heart rate cannot be adequately controlled by a beta blocker or calcium channel blocker…” Camm A et al. Eur Heart J 2010;31(19):2369–429.
  26. 26. Evidence for Digoxin in CHF  Digoxin–withdrawal studies (1993)  Digitalis Investigation Group (DIG) 7788 pts radomized to digoxin (N=3397) vs placebo (N=3403)  6800 EF < 45% (80% on ACE-I, 90% on Diuretics)  988 EF > 45%  Median F/Up: 37 months,  No difference in overall mortality but 6% reduction in hospital admissions  Trend toward lower mortality from worsening heart failure(11.6% vs 13.2% for placebo, P=.06)
  27. 27. DIG Trial Flaws  Generalizability Issues:  study population ~5-10 years younger than an unselected population of ambulatory HF patients  20% of Women  Pts with AFibAFlutter excluded  Biases  20% of placebo group received open label digoxin  SDC measured several times at follow-up (no standard of care)  Applicability Issues:  Beta-Blockers, MRA or CRT-D not available at the time of trial
  28. 28. DIG Post-hoc: Digoxin SDC Rathore SS et al. JAMA 2003
  29. 29. DIG Post-hoc: Sex Differences  adjusted HR for death of  1.23 for women vs pbo  0.93 for men vs pbo Rathore S et al., New Engl J Med 2002
  30. 30. Digoxin Use Today - Epidemiology IMS National Disease and Therapeutic Index, January 1997 to December 2012 Digoxin Prescript. Overall Digoxin Prescription For Heart Failure Goldberger Z. et al. JAMA Int. Med 2014
  31. 31. Digoxin Toxicity Today - Epidemiology  DIG Trial: 11.9% (treated) vs 7.9% (controls)  In 2008, US poison control centers were called for 2632 cases involving digoxin toxicity, and 17 cases resulted in digoxin-related deaths Bronstein AC et al. Clin Toxicol (Phila) 2009  Estimated 5156 annual visits for digoxin toxicity ; more than three fourths (78.8% resulted in hospitalization.  The rate of ED visits among patients ≥85 years was twice that of patients 40 to 84 years; among women, the rate was twice that of men  ED visits and hospitalizations remained constant from 2005 to 2010. See I et al. Circ Heart Fail. 2014 Digoxin toxicity is not declining !
  32. 32. Digoxin Toxicity - Etiology  Medical Error  Excessive dosing  Inappropriate prescription  Significant kidney disease (CrCl < 50 mLhr)  Patient non compliance Chan K. et al. J Am Soc Nephrol 2010 Kongkaew C. et al. Arch. of Card. Dis. (2012)
  33. 33. Beyond DIG: the UK-HEART Study  prospective study of prognostic markers in outpatients with stable CHF (NYHA II-IV)  N = 484 followed up for a median of 1000 days  Crude Mortality Rate: 38.9% (dig) vs 24.5% (pbo)  No difference in CrCl or K levels  Still significant in the multivariate analysis  Digoxin was NOT randomised Lindsay SJ et al. Lancet 1999
  34. 34. Beyond DIG: The SPORTIF III-V  7329 pts with AFib randomized to ximelagatran or warfarin, 53.4% were using digoxin at baseline  Multivariate COX: HR = 1.53, (95% CI 1.22 to 1.92)  NO Randomization (to Digoxin)  No data on LV performance  No Sex difference K Gjesdal et al. Heart 2008
  35. 35. Beyond DIG: The SCAF Study  2824 patients with AF f/up for a mean of 4.6 years.  802 pts on digoxin  2022 pts not on digoxin  1342 pts enrolled in the PS matched survival analysis Friberg L. et al. Heart 2010
  36. 36. Beyond DIG: The Val-HeFT Study
  37. 37. Beyond DIG: Val-HeFT Study Cont’d  Cohort On Beta-Blockers (n = 1177):  HR 1.45 for all causes mortality (Dig vs No Dig)  HR 2.49 for HF Hospitalizations (Dig vs No Dig)
  38. 38. Beyond DIG: the AFFIRM Trial  4060 patients with AF randomized to rate vs. rhythm control with a mean fup of 3.5 years.  PSs and Multivariate Cox applied  Pts stratified by EF  58% on B-Blockers  HR 1.46 for digoxin useWhitbeck et al. European Heart Journal (2013)
  39. 39.  Confounding by Indication Bias  Difference in Cohort used  Possible Selection Bias  mortality was higher among subjects with missing data on digoxin use as compared with subjects with digoxin data available.  Different Propensity Score approaches were used Beyond DIG: the AFFIRM Trial, Cont’d Gheorghiade et al. European Heart Journal (2013)
  40. 40. The Kaiser Permanente Story  2891 Pts with systolic HF, 529 (18%) on Dig. Median FUp 2.5 y (closed in 2010)  Digoxin use associated with higher mortality (HR = 1.72)  No significant difference in HF hospitalization (HR, 1.05)  No difference stratifying by Sex or β-Blocker (40%) Usage  Multivariate Analysis and Propensity Scores used, BUT no randomization Freeman J, Circ Cardiovasc Qual Outcomes. 2013
  41. 41. Digoxin and PLT Endothelial Activation  30 Pts with non-valvular AFib (16 on dig)  CD62P expression, PLT-Leucocytes conjugates were all higher in patients taking digoxin Chirinos J, Heart Rhythm 2005
  42. 42. Digoxin and Risk of Cancer  5,565 postmenopausal women with incident invasive breast carcinoma and and 55,650 matched population controls (1991-2007)  324 patients on Dig (5.9%)  Adjusted OR: 1.30; 95% CI: 1.14 to 1.48 Ahern T, Breast Cancer Res 2008
  43. 43. Conclusions: Proposing the DIG-IT Trial  Triple Blind, PBO controlled study  Stable HF Outpatients taking  BB, ACEI or ARB, and MRA  30-40% of HF patients with AFib  Adequate number of women and elderly  Initial dose: 0.125 mgd (Range: 0.0625 – 0.25)  Target SDC: 0.5 ng/mL  Validated patient-centered end-points  Surrogate ImagingBiochemical end-points to be collected
  44. 44. DigiFAB Protocol Fig. 1. Dosing recommendations for DSFab (Digibind or DigiFab). Infuse all doses over 30 minutes through a 0.22-mm filter. If cardiac arrest is imminent, give via slow intravenous push. [dig]SS, serum digoxin concentration (nanogram per milliliter) at steady state; F, esti- mated bioavailability (if intravenous digoxin or digitoxin use 1, if digoxin tablets use 0.8); TBW, total body weight. a Round number of vials upward. b If measurement in nanomole per liter, multiply by 0.781. c If measurement in nanomole per liter, multiply by 0.765. d Inges- tions of cardiac glycosides other than digoxin or digitoxin should be treated with empiric dosing recommendations.
  45. 45. 6 minutes walk test (6MWT) 6MWT<150 m Serious cardiac dysfunction 6MWT 150~425 m Moderate cardiac dysfunction 6MWT 426~550 m Mild cardiac dysfunction
  46. 46. Four stages of heart failure  Stage A: Asymptomatic with no heart damage but have risk factors for heart failure  Stage B: Asymptomatic but have signs of structural heart damage  Stage C: Have symptoms and heart damage  Stage D: Endstage disease ACC/AHA guidelines, 2001
  47. 47. Cardiac resynchronization therapy (CRT) CRT device: Patients with NYHA Class /Ⅲ Ⅳ Sympotomatic despite optimal medical therapy QRS ≥ 130 msec LVEF ≤ 35% CRT plus ICD: Same as above with ICD indication
  48. 48. The Donkey Analogy Ventricular dysfunction limits a patient’s ability to perform the routine activities of daily living…
  49. 49. Diuretics, ACE inhibitors Reduce the number of sacks on the wagon
  50. 50. Beta-blockers Limit donkey’s speed, thus saving energy
  51. 51. digitalis Like the carrot placed in front of the donkey
  52. 52. CRT/CRT-D Increase the donkey’s (heart) efficiency
  53. 53. Heart failure: More than just drugs. Dietary counseling Patient education Physical activity Medication compliance Aggressive follow-up Sudden death assessment
  54. 54. Take home message Heart failure is clinical diagnosis ACEI should be titrated to highest dose tolerable Beta-blockers should be used universally but must titrated slowly Spironolactone should be used in NYHA / patientsⅢ Ⅳ Digoxin can be used to reduce morbidity Role of ARB remains to be determined in patient intolerating ACEI Preventive therapy or patient education is the key to reduction of burden

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