Digoxin - Time to take the gloves off ?

Diego Bellavia

Cardiac Glycosides: Molecular Structure

All Cardiac glycosides aglycone (genin) part (active pharmacologically) Glycone: sugar (glucose or digitoxose) attached at Carbon 3 of

nucleus Aglycone – Steroid ring (cyclopentanoperhydrophenanthrene ring) and

lactone ring attached at 17th position

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, Amiodarone, 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

Drug-Drug Interactions

Digoxin - Pharmacological actions

Myocardial contractility

Electrophysiological properties

Parasympatho-mimetic effect

Myocardial Contractility

Str

oke

Vol

ume

Preload (LV Filling Pressure)

Normal

Digitalis

CHF

Digitalis – Electrophysiological actions

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

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

Digitalis – EKG Changes

Afterpolarization actions

Weir & Hess, 1984

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;

Digitalis-induced bigeminy:

NSR: normal sinus rhythm

PVB: premature ventricular beats

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.

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.

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.

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.

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

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 D\C Shock ONLY if VFib (NEVER for PSVT)

DigiBind\DigiFAB (Humanized sheep Mab) Symptomatic bradycardia – advanced AVB (unresponsive to

Atropine) Malignant arrhythmia (particularly in the setting of hyperkalemia) Hyperkalemia (K+ > 5 mEq\L) Digoxin > 10 ng\L (or > 4 ng\L in chronic toxicity)

Plasmapheresis will prevent rebound effect Monitor K, Free Digoxin Levels and ECG

Treatment of acute digoxin intoxication by digoxin immune Fab (Digibind®)

Absolute Contraindications

Hypersensitivity Uncontrolled Ventricular Arrhythmias AV block Constrictive Pericarditis Idiopathic Hypertrophic Subaortic

Stenosis WPW syndrome: VF may occur Severe Mitral Stenosis

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

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)

Digitalis Indications Today – CHF

AHA/ACC Update (2012) and HFSA Update (2010)

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.

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) No Improvement in Quality of Life

DIG Trial Flaws Generalizability Issues:

study population ~5-10 years younger than an unselected population of ambulatory HF patients

20% of Women Pts with AFib\AFlutter 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

DIG Post-hoc: Digoxin SDC

Rathore SS et al. JAMA 2003

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

Digoxin Use Today - Epidemiology

IMS National Disease andTherapeutic Index, January 1997 to December 2012

Digoxin Prescript. Overall

Digoxin Prescription For Heart Failure

Goldberger Z. et al. JAMA Int. Med 2014

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 !

Digoxin Toxicity - Etiology

Medical Error Excessive dosing Inappropriate prescription

Significant kidney disease (CrCl < 50 mL\hr)

Patient non compliance Chan K. et al. J Am Soc Nephrol 2010

Kongkaew C. et al. Arch. of Card. Dis. (2012)

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

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

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

Beyond DIG: The Val-HeFT Study

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)

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

use Post-hoc Analysis

Whitbeck et al. European Heart Journal (2013)

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)

The Kaiser Permanente Story

2891 Pts with systolic HF, 529 (18%) on Dig. Median F\Up 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

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

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

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 mg\d (Range: 0.0625 – 0.25) Target SDC: 0.5 ng/mL Validated patient-centered end-points Surrogate Imaging\Biochemical end-points to

be collected

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.

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

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

Cardiac resynchronization therapy (CRT)

CRT device:

Patients with NYHA Class /ⅢⅣ

Sympotomatic despite optimal medical therapy

QRS ≥ 130 msec

LVEF ≤ 35%

CRT plus ICD:

Same as above with ICD indication

The Donkey Analogy

Ventricular dysfunction limits a patient’s ability to perform the routine activities of daily living…

Diuretics, ACE inhibitors

Reduce the number of sacks on the wagon

Beta-blockers

Limit donkey’s speed, thus saving energy

digitalis

Like the carrot placed in front of the donkey

CRT/CRT-DIncrease the donkey’s (heart) efficiency

Heart failure: More than just drugs.

Dietary counseling

Patient education

Physical activity

Medication compliance

Aggressive follow-up

Sudden death assessment

Take home messageHeart 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 / patientsⅢⅣ

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