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Digoxin Toxicity and Its Avoidance in Elderly Persons

Dr. TK KongConsultant Geriatrician

Department of Medicine and GeriatricsPrincess Margaret Hospital

Digoxin Toxicity• Why a concern?• Why are elderly people so prone to digoxin toxicity?• The many faces of digoxin toxicity in old age

Its Avoidance• When indicated and when inappropriate?• What digoxin dose and what digoxin level?• How to monitor digoxin therapy in elderly patients?

Digoxin Toxicity and Its Avoidance in Elderly PersonsOutline

HAHO Pharmacy Data on Use of At-risk Medication in Elders (9/2008 – 8/2009) Average daily discharge episodes for 65+ elders = 1176

178

1429

929

63

12 17

13

4

0

20

40

60

80

100

120

140

160

180

200As

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War

farin

Dig

oxin

Thia

zide

s

Insu

lin

Sulp

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Num

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fou

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as antiplatelet

as analgesics

typicalatypical

2.5%

Dig

oxin

• Older people are the most frequent users of digoxin because the 2 primary indications for its use, CHF & AF are highly prevalent in old age

Digoxin Toxicity in Elderly PersonsWhy a Concern?


• In both in-patients and out-patients increased age is associated with enhanced susceptibility to digoxin toxicity.


Dall JLC. Digitalis intoxication in elderly patients. Lancet 1965;1:194-5.

Age-stratified Prevalence of Definite Digoxin Toxicity in Elderly Patients (n = 297)

1/8/2008-31/10/2008 and 1/8/2009-31/10/2009

5 4

11

26

0

5

10

15

20

25

30

≥60-


• In both in-patients and out-patients increased age is associated with enhanced susceptibility to digoxin toxicity.

• Adverse drug reactions (ADR) with digoxin are responsible for many older people attending emergency departments (EDs) and being admitted to hospital.

• Older adults who have been hospitalised are at significantly increased risk of further hospitalisation (4.5 x) due to digoxin toxicity for up to 2 months after discharge


Budnitz DS, Shehab N, Kegler SR, et al. Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med 2007; 147: 755–65.

Caamano F, Pedone C, Zuccala G, Carbonin P. Sociodemographic factors related to the prevalence of adverse drug reaction at hospital admission in an elderly population. Arch GerontolGeriat 2005; 40: 45–52.

Haynes K, Hennessy S, Localio AR, et al. Increased risk of digoxin toxicity following hospitalization. Pharmacoepid Drug Safety 2009; 18: 28–35.

Digoxin Toxicity in Elderly PersonsWhy are elderly people so prone to digoxin toxicity?

Furosemide (hypokalaemia, dehydration)Amiodarone, Verapamil, Diltiazem (increase intestinal absorption & reduced clearance, inhib p-glycoprotein)Oral macrolideantibacterials (eliminate digoxin-inactivating gut bacteria)Spironolactone, steroids (falsely low digoxin level)Non-steroidal anti-inflammatory drugs

heart failureearly phase post-myocardial infarctionrenal failurelow lean body masshypothyroidismhypokalaemiahypomagnaesaemiaacid-base imbalancehypoxiaacute and chronic lung diseasedementiadehydrationmalnutrition

Age-related reduction in volume of distribution of hydrophilic drugsAge-related decline in glomerular filtration rate

DrugsDiseases/ConditionsAgeing

Table. Factors that increase the risk of digoxin toxicity in old age.

105

143136

113

92 88 87 84 7665

5341

3122 14 10 6 4 3 1 1 1 0 0 0 0 0 0 00

20

40

60

80

100

120

140

160

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Num

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ay w

ith

the

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num

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No. with >= 5 items: 588 (50%)

No. with >= 10 items: 187 (16%)

HAHO Pharmacy Data on Polypharmacy in Elders (9/2008-8/2009) Average daily discharge episodes for 65+ elders = 1176

Number of Drug Items

Digoxin Toxicity in Elderly PersonsWhy are elderly people so prone to digoxin toxicity?

• The narrow therapeutic window of digoxin becomes more relevant in older individuals with multiple comorbidities and polypharmacy, which greatly increase the risk of drug-drug and drug-disease interactions

Digoxin-Herb Interactions: Pharmacokinetic

open-label randomisedcrossover study in healthy volunteers

increase AUC of digoxin; no significant difference in Cmax, half-life, plasma clearance;therapeutic drug monitoring required

Ginkgo biloba (銀杏)

controlled clinical trial in healthy subjects;no case reports so far

increase digoxin clearance; reduced AUC and Cmax of digoxin;reduce therapeutic effect of digoxin

St. John’s wort (金絲桃)(Hypericum perforatum貫葉連翹)

Level of evidenceClinical significanceHerb

Dasgupta A. Herbal supplements and therapeutic drug monitoring: focus on digoxin immunoassays and interactions with St. John's wort. Therapeutic Drug Monitoring 2008; 30(2): 212-7.

Digoxin-Herb Interactions: Inactive digoxin analogues

animal studiesmodest interference with polyclonal-based digoxin immunoassays

Asian ginseng(亞洲人參)Panax ginseng

animal studiesmodest interference with polyclonal-based digoxin immunoassays

Dan Shen(丹參) Salvia miltiorrhiza

animal studies;

case report

modest interference with polyclonal-based digoxin immunoassays;elevate synthetic digoxindrug levels without clinical toxicity)

Siberian ginseng(西伯利亞人參)EleutherococcusSenticosis

Level of evidenceClinical significanceHerb

McRae S. Elevated serum digoxin levels in a patient taking digoxin and Siberian ginseng. CMAJ 1996; 155:293-5.

Dasgupta A, Wu S, et al. Effect of Asian and Siberian Ginseng on Serum Digoxin Measurement by Five Digoxin Immunoassays. American Journal of Clinical Pathology 2003; 119(2): 298-303.

Dasgupta A. Herbal supplements and therapeutic drug monitoring: focus on digoxin immunoassays and interactions with St. John's wort. Therapeutic Drug Monitoring 2008; 30(2): 212-7.

Digoxin-Herb Interactions: Active digoxin analoguesPlant origin: Apocynaceae (夾竹桃科)

Thevetia peruvianaYellow oleander 黃花夾竹桃

Nerium oleanderCommon oleander 夾竹桃

Strophanthus divaricatusGoat Horns羊角拗

Cerbera manghasSea mango 海芒果

強心

利尿

消腫

喘咳

癲癎

傷口

跌打腫痛

血瘀經閉

Mashour NH, et al. Herbal medicine for the treatment of cardiovascular disease: clinical considerations." Arch Intern Med 1998; 158(20): 2225-2234.

Digoxin-Herb Interactions: Active digoxin analoguesPlant origin: Apocynaceae (夾竹桃科)

Digoxin-Herb Interactions: Active digoxin analoguesAnimal origin: Bufonidae (蟾蜍科) Toad Venom(蟾酥)

Bufo bankorensisCantor 中華大蟾蜍、癩蛤蟆

Bufo melanostictusSchneider 黑眶蟾蜍

癌, 止痛, 瘡毒, 心弱蟾酥藥粉/丸, 乾蟾皮炭

暑濕痧藥

牙齦腫痛牙痛一粒丸

清熱解毒, 消腫止痛梅花點舌丸

清熱解毒, 消腫止痛金蒲膠囊

中風, 胸痹血栓心脈寧膠囊

胸痹靈寶護心丹, 麝香保心丸

胸痹救心 (Kyushin)

咽喉腫痛, 口苦咽幹六神丸 (Lu-Shen-Wan) , 六應丸

咽喉腫痛牛黃消炎片

中華人民共和國藥典2005年版第一部

Panesar NS. Bufalin and unidentified substance(s) in traditional Chinese medicine cross-react in commercial digoxin assay [letter]. Clin Chem. 1992;38:2155-2156

Fushimi RT, et al. Digoxin-like immunoreactivity in Chinese medicine. Therapeutic Drug Monitoring 1990; 12(3): 242-245.

Digoxin-Herb Interactions: Active digoxin analoguesAnimal origin: Bufonidae (蟾蜍科) Toad Venom(蟾酥)

Digoxin Toxicity in Elderly PersonsRecognizing the many faces of digoxin toxicity in old age

Manifestations of Digitalis IntoxicationWithering W. Account of the Foxglove, 1785.

http://manybooks.net/support/w/witheringw/witheringw2488624886-8.exp.html

Digitalis lanata (Woolly Foxglove) 毛花洋地黃

digoxin

Digitalis purpurea (Common Foxglove) 洋地黃 digitoxin

Presentations of Digitalis IntoxicationLelyAH, et al. Large-scale Digitoxin Intoxication.BMJ 1970; 3(5725): 737-740.

0% 20% 40% 60% 80% 100%

n (poisoned) = 179• Sickness• Vomiting• Purging• Giddiness• Confused vision -

objects appearing green or yellow

• Increased secretion of urine

• Frequent motions• Slow pulse• Cold sweats• Convulsions• Syncope• Death

Withering W. Account of the Foxglove, 1785.

n (treated) = 163Fatigue 95%

Visual symptoms 95%

Muscular weakness 82%

Nausea 81%

Anorexia 80%

Psychic symptoms 65%

Abdominal pain 65%

Dizziness 59%

Dreams 54%

Headache 45%

Diarrhoea 41%

Vomiting 40%

The Starry Night (Van Gogh, June 1889)a typical example of digitalis toxicity with haloes and yellow vision

Lee TC. Van Gogh’s vision. Digitalis intoxication? JAMA 1981; 245: 727–9.

Portrait of Dr Gachet (1890) by Vincent van GoghNote the foxglove (digitalis) which was used to treat Van Gogh’s epilepsy.

Lee TC. Van Gogh’s vision. Digitalis intoxication? JAMA 1981; 245: 727–9.

Bronzetti G, et al. Van Gogh, Doctor Gachet, and Digitalis: A Self-Diagnostic Portrait? Cardiovascular Drug Reviews 2002; 20(3): 233-6.

• Mechanism– Reversible rod and cone dysfunction occur during exposure

to toxic levels of digoxin (blockade of Na+, K+-ATPasepumps)

• Clinical message– Important to consider the possibility of digitalis intoxication

in patients (especially elderly patients) who have new visual symptoms while receiving digoxin, even if serum digoxinlevels are within the normal therapeutic range

– Such patients often report new visual symptoms to a physician (usually an ophthalmologist) other than the one who prescribed digoxin, and the association may be overlooked.

Non-cardiac Manifestations of Digoxin Intoxication:Visual Dysfunction

Madreperla SA, et al. Electrophysiologic and Electroretinographic Evidence for Photoreceptor Dysfunction as a Toxic Effect of Digoxin. Arch Ophthalmol 1994; 112:807-812Butler, V. P. et. al. Digitalis-Induced Visual Disturbances with Therapeutic Serum Digitalis Concentrations. Ann Intern Med 1995;123:676-680

Called to see a 90-year-old man c/o anorexia, failing memory (noted by his family), dizziness since discharge

• Just discharged 3 days ago with discharge Dx: CHF, AF, Community acquired pneumonia

CLOX1 = 5/15

• Just discharged 3 days ago with discharge Dx: CHF, AF, Community acquired pneumonia


Electrocardiogram lead aVf. Atrioventricular junctional escapes with aberrancy inthe presence of atria! fibrillation. Frequent impulses from the fibrillating atria (A) enter theatrioventricular junction (A -V) but are prevented from penetrating to the ventricles (V) bythe high degree of entrance block produced by digitalis. (The fibrillating impulses are presentthroughout the tracing but are diagrammed in one area only.) The junctional pacemaker thenescapes at an interval of 1.32 to 1.36 Sec (rate of 44 beats/ min) and is conducted in an aberrantfashion (jagged lines) to the ventricles (marked X in the tracing). The entrance block. however,is not sufficient to block all atrial impulses. A few are transmitted (marked QRS) withnormal intraventricular conduction. Note that the escape intervals are the longest on the record. Retrograde conduction to the atria (dotted lines on the ladder diagram) does not occur

AV Junctional Escape Beats in Digioxin Intoxiation

KastorJA. Recognition of digitalis intoxication in the presence of AF. Ann Intern Med 1967;67(5): 1045-1054.

BW = 46 kg, serum creatinine = 85 umol/L, Na 128 mmol/L, K 4.3 mmol/L, eCrCl=33/min


CLOX1 = 5/15 (6 days later)

CLOX1 = 12/15

(14 days later)

CLOX1 = 12/15


On digoxin Digoxin stopped

Non-cardiac Manifestations of Digoxin Intoxication:Neuropsychiatric Dysfunction

• Mechanism– Drug-induced delirium & cognitive decline

from cumulative anti-cholingeric burdenTune LE. Delirium. In: Hazzard WR et al. Principles and Practice of Geriatric Medicine and Gerontology. 4th edition 1998, p 1233Han L, McCusker J, Cole M, et al. Use of medications with anticholinergic effect predicts clinical severity of delirium symptoms in older medical inpatients. Arch Intern Med 2001; 161:1099-1105.C.-j. L.u, Tune LE. Chronic exposure to anticholinergic medications adversely affects the course of Alzheimer disease. Am J GeriatrPsychiatry 2003; 11:458-461.

“Women the poorer class in Derbyshire drink large draughts of Foxglove tea, as a cheap means of obtaining the pleasures, or the forgetfulness, of intoxication.”

Withering’s son

King JT. Digitalis delirium. Ann Int Med 1950; 33: 1360.

• Clinical message– Neuropsychiatric symptoms and delirium may be the

first and only manifestation of digoxin toxicity without accompanying electrocardiographic abnormalities in elderly patients, and can occur at serum concentrations within or above the therapeutic range.

– When delirium complicates an already complex syndrome, the drug is often not suspected

– It may form part of the picture of Wernicke'sencephalopathy from thiamin deficiency secondary to prolonged anorexia from digitalis intoxication.

Cooke DM. The use of central nervous system manifestations in the early detection of digitalis toxicity. Heart Lung 1993; 22: 477–81.

Eisendrath SJ and Sweeney MA. Toxic neuropsychiatric effects of digoxin at therapeutic serum concentrations. Am J Psychiatry 1987; 144: 506–7.Portnoi VA. Digitalis delirium in elderly patients. J Clin Pharm 1979; 19: 747.Richmond J. Wernicke's encephalopathy associated with digitalis poisoning. Lancet 1959; 1: 344.

Non-cardiac Manifestations of Digoxin Intoxication:Neuropyschiatric Dysfunction

0

5

10

15

20

25

01/11/98 11/11/98 21/11/98 01/12/98 11/12/98 21/12/98 31/12/98

Albumin/2

Na/10

CrClHb

100 x U/C

K

Creat/100

Hosp 1 Hosp 2 Hosp 3 Hosp 2

Lasix

Digoxin

Fluid restriction

An 89-year-old Woman With “Poor Feeding”

Hyp

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oxin

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)

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Restraint

Fore

head

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Con

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Dep

ress

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NS146

• Mechanism– due to stimulation of a chemoreceptor zone in the

medulla (area postrema)– (local emetic action: gastric irritation)

• Clinical message– Nausea, anorexia and vomiting are the earliest &

commonest manifestations of digoxin toxicity– May lead to dehydration, reduced renal clearance,

hypokalaemia; completing the vicious cycle of digoxinintoxication

– Forced (tube) feeding without diagnosing “poor feeding” will add further distress

Williamson KM, Thrasher KA, Fulton KB, et al. Digoxin toxicity: an evaluation in current clinical practice. Arch Intern Med 1998; 158: 2444–9.

Abad-Santos F, Carcas AJ, Ibanez C, et al. Digoxin level and clinical manifestations as determinants in the diagnosis of digoxin toxicity. Ther Drug Monit 2000; 22: 163–8.

Non-cardiac Manifestations of Digoxin Intoxication:Gastrointestinal (nausea, anorexia, vomiting)

A 89-yr-old woman cared by her younger sister (aged 86, with multiple myeloma)

2006• recurrent stroke (5/2006, 3/2005)• hypertension• recurrent falls with # hips, vertebral collapse• THR: Rt 5/2006, Lt 1998• osteoporosis• rehab to walk with frame

2009 (then aged 92)• on wheelchair, accompanied by 2 daughters and a relative• just discharged 2 wk ago after a 2-wk hospitalization with Dx: - recurrent stroke (ischaemic),- complicated by UTI;- also AF detected and started on digoxin 125mcg daily

• now bed- and chair-bound• poor feeding.• can tolerate enacal feeding• doubly incontinent, on napkins• BP 133/63 mmHg, P 91/min AF• heel sores+ superficial perineal sore• poor sitting posture, lean to her left

• refer CNS for pressure sore care;• check digoxin level (watch out for digoxin overdose),• reduce digoxin

Admitted to another hospital the same night, died 8 hours later, referred coroner for unknown cause of death and sudden arrest

Discharge diagnoses:- Atrial fibrillation - CVA - Decreased general condition - Hypertension

GC with passage of loose stoolvomited out sputumno fever recordedSOB+/-no cough/ sputum

• Physical functional decline:

– on wheelchair, require 3 to escort to OPD, bed sores

– decreased general condition

• Poor feeding• Loose stool• Vomiting out sputum• At risk:

– Extreme old age– Recent hospital

discharge– Digoxin newly added– Poor feeding leading to

dehydration• No warning ECG signs

Lesson to Learn: Geriatric Presentations of Digoxin Intoxication

LelyAH, et al. Large-scale Digitoxin Intoxication.BMJ 1970; 3(5725): 737-740.

0% 20% 40% 60% 80% 100%

n (poisoned) = 17992-year old woman

Fatigue 95%

Visual symptoms 95%

Muscular weakness 82%

Nausea 81%

Anorexia 80%

Psychic symptoms 65%

Abdominal pain 65%

Dizziness 59%

Dreams 54%

Headache 45%

Diarrhoea 41%

Vomiting 40%

• In a meta-analysis of 29 observational studies on medication use and falls risk, use of digoxinwas found to be significantly associated with falls (OR = 1.2)

• Clinical implication: increases operative risk of injurious falls

Geriatric Presentations of Digoxin Intoxication:Falls

Leipzig RM, Cumming RG, Tinetti ME. Drugs and falls in older people: a systemic review and meta-anlaysis: II. Cardiac and analgesic drugs. J Am Geriatrc Soc 1999; 47(1): 40–50.

Increases the investigations/ procedure burden (can be risky)

Digoxintoxicity

Clinical implications of not recognizing the manifestations of Digoxin Intoxication:

nausea, anorexia, vomiting

poor feeding

confusion, delirium

falls, syncope

death

OGD

tube feeding, aspiration risk

CT brain, LP, EEG, restraint

Holter, carotid sinus massage

post-mortem

may be ascribed to the underlying condition of heart failurePrescribing Cascade Completing the Vicious Cycle

Digoxin overdose

Fatigue Nausea

Tachycardia

Symptoms attributed as due to heart failure (esp.

with “normal” digoxin level)

Digoxin

Diuretics

Fluid intake

Fluid output

Pre-renal failure from dehydration

Clinical implications of not recognizing the manifestations of Digoxin Intoxication:

The Digitalis Investigation Group (DIG)NEJM 1997;336:525-534.

Mor

talit

y

from

Any

Cau

se (%

)

Dea

th o

r Hos

pita

lizat

ion

Due

to

Wor

seni

ng H

eart

Fai

lure

(%)

Months

Months

Placebo

Digoxi

n

Placebo

Digoxi

nP < 0.001

P = 0.80

N = 3403Age: 63.5yr ± 10.8

>70yr: 27.4%EF: 28.4 ± 8.9

N = 3397Age: 63.4yr ± 11.0

>70yr: 26.7%EF: 28.6 ± 8.9

Avoiding Digoxin Toxicity in Elderly PersonsWhen indicated?

Reduction in HF-related hospital admissions (ARR 7.9%)

CHF, SR, LVSD• digoxin should be considered

as an add-on therapy for CHF with abnormal LV EF (< 45%) & SR patients who are still symptomatic after optimum therapy (ACEI, β-blocker, diuretics)

• benefit weighed vs toxicity• for a patient with CHF who is

taking digoxin but not an ACEI or a �β- blocker, treatment with digoxin should not be withdrawn, but appropriate therapy with the neurohormonal antagonists should be instituted

How applicable is DIG Trial to CHF in Elders?

primarily womenmuch older, with multiple comorbidities, on multiplemedications, functionally impairedoften with systolic function preserved

less often female (22.4 % female) younger (mean age 64 years)

more likely to have reducedejection fraction

Majority of elderly patients with CHF in the community/ long-term care facilities

Patients recruited in DIG trail

ParmleyWW. Do we practice geriatric cardiology? J Am Coll Cardiol 1997; 29: 217–8.

Gambassi G, Lapane KL, Sgadari A, et al. Effects of angiotensin-converting enzyme inhibitors and digoxin on health outcomes of very old patients with heart failure. SAGE Study Group. Systematic Assessment of Geriatric drug use via Epidemiology. Arch Intern Med 2000; 160(1): 53–60.

Misiaszek B, Heckman GA, Merali F, et al. Digoxin prescribing for heart failure in elderly residents of long-term care facilities. Can J Card 2005; 21(3): 281–6.

Heckman GA and McKelvie RS. Necessary cautions when considering digoxin in heart failure. CMAJ 2007; 176(5): 644–5.

• has been considered contraindicated in HFPEF, being thought to aggravate HF by increasing LV stiffness and thus filling pressure through increasing contractility

• However, recent evidence has suggested that digoxin, at low concentration, can improve early myocardial relaxation through neurohormonal modulation in HFPEF

• In a parallel sub-study of the DIG trial that enrolled 988 patients (mean age 67 years, 64% aged >=65 years) with HFPEF in sinus rhythm (ejection fraction > 45%, mean 55%), the addition of digoxin to ACEI and diuretics resulted in an insignificant 18% reduction (p = 0.136) in the combined outcome of heart failure mortality or heart failure hospitalization

• The American College of Cardiology 2009 updated guideline and the Canadian Cardiovascular Society guideline state that the use of digitalis to minimize symptoms of heart failure in patients with HFPEF might be considered(recommendation class: IIb; level of evidence: C).

Is Digoxin Useful in HFPEF (“diastolic heart failure”)?

• Digoxin monotherapy may only be adequate for control of ventricular rate in the older, sedentary patient with permanent AF

• Combining digoxin with either a β-blocker or non-dihydropyridine calcium channel blocker may be done to achieve optimal heart rate during activity

• not recommended for acute treatment of rapid ventricular response to AF in settings associated with high sympathetic tone or a haemodynamically compromised state due to its slow onset of action, possible adrenergic activity and lack of efficacy in these conditions:– exercise, fever, thyrotoxicosis, acute volume loss,

postoperative state, paroxymal AF

Use of digoxin in AF

• Though digoxin is prescribed routinely in patients with HF and chronic AF, �β-blockers are usually more effective when added to digoxin in controlling the ventricular rate, especially during exercise

• digoxin may be used initially while the �β-blocker is being introduced

• alternatively, digoxin may be used as adjunct therapy to�β-blockers in patients with AF and HF because of its synergistic effect with β-blockers on the AV node in rate control

• enhanced survival with the digoxin-carvedilol combinationhas been demonstrated in a retrospective analysis of the US Carvedilol Heart Failure Trials program

• Though non-dihydropyridine calcium channel blockers (including verapamil and diltiazem) also are effective rate-controlling agents, they may not be tolerated at doses required for optimal ventricular rate control because of their negative inotropic effect, especially in patients with low EF.

Use of digoxin in CHF + AF

Avoiding Digoxin Toxicity in Elderly Persons What digoxin dose and what digoxin level?

Rising Mortality Rates with Increasing Serum Digoxin (SDC) Concentrations (Post hoc analysis of DIG trial)

Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of Serum DigoxinConcentration and Outcomes in Patients With Heart Failure. JAMA; 2003: 289: 871-878.

All-

Cau

se M

orta

lity

Rat

es (%

) by

Seru

m

Dig

oxin

Con

cent

ratio

n G

roup

s• SDC of 0.8 – 1.3 nmol/L (0.6 – 1.0 ng/mL) is the likely optimal therapeutic range for digoxin therapy• may represent the most clinically efficacious balance of digoxin’s competing neurohormonal & inotropic effects

Serum Digoxin Concentration (ng/mL)

Irrespective of LVEF, low SDC reduced mortality & hospitalizations

Ahmed A, Rich M, Love T, et al. Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial. Eur Heart J 2006; 27:178-186.

Kaplan-Meier plots for cumulative risk of death due to all causes by serum digoxin concentration (SDC) in the Digoxin Investigation Group (DIG) trial

>=1.3nmol/L

0.6–1.2nmol/L

Avoiding Digoxin Toxicity in Elderly PersonsWhat digoxin dose and what digoxin level?

• Evidence of clinical efficacy of digoxin at the lower SDC and higher risk of toxicity and mortality at higher SDC, resulted in a revised lower therapeutic range for SDC in heart failure (0.6 - 1.2 nmol/L )

• Although there is some overlap in ‘therapeutic’ and toxic levels in the original study by Smith (1970’s), none have digoxin toxicity with the newly adopted therapeutic SDC of less than 1.3 nmol/L

• Quoting the lower therapeutic digoxin range on computerized and printed laboratory report forms is therefore important to guide clinicians to avoid unnecessarily high SDC without compromising the benefit for heart failure

Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults. J Am Coll Cardiol 2009; 53: e1-e90. Available at: http://www.acc.org/clinical/guidelines/failure//index.pdf.

Rich MW. Heart failure in the elderly. In: Pathy MSJ, Sinclair AJ, Morley JE. Principles and Practice of Geriatric Medicine 4th edn, 2006. p. 575.

Rich MW. Heart failure: Halter J, Ouslander J, Tinetti M, et al, editors. Hazzard's Geriatric Medicine & Gerontology, ed. 6, New York 2009, McGraw-Hill, Chapter 78, p 944.

Howard M. Fillit, Kenneth Rockwood, Kenneth Woodhouse.Brocklehurst’s Textbook of Geriatric Medicine and Gerontology, Online and Print, 7th Ed 2010. Ch42

Harrison’s Principles of Internal Medicine, 17th edition, 2008. Vol 2, Ch. 227, p 1451

• No geriatric dose• For most older patients with preserved renal function (est.

creatinine clearance > 50 ml/minute), digoxin 125 mcg dailyprovides a therapeutic effect.

• Lower dosages ( < 125 mcg daily) should be used in patients with renal insufficiency (titrate according to CrCl for CrCl < 50 ml/min).

• “It is much better to give a smaller dose every day than to rely on the failing memory of the elderly to take the tablets just on certain days of the week (5 days a week).”


Rich MW. Heart failure in the elderly. In: Pathy MSJ, Sinclair AJ, Morley JE. Principles and Practice of Geriatric Medicine 4th edn, 2006. p. 575.


Howard M. Fillit, Kenneth Rockwood, Kenneth Woodhouse. Brocklehurst’s Textbook of Geriatric Medicine and Gerontology, Online and Print, 7th Ed 2010. Ch42

• Most dosing guidelines use the Cockcroft-Gault formula • Cockcroft-Gault eGFR (ml/min) in SI units [(140—age (years))

bodyweight (kg)1.23]/(serum creatinine (umol/L)) 0.85 (if the subject is female)

• The modification of diet in renal disease (MDRD) equation does not use body weight to estimate the GFR.

• The MDRD derived eGFR has not been validated for extremes of age or dose adjustment. Unadjusted for body surface area, in the presence of the reduced height and weight observed in normal aging, the MDRD is likely to overestimate renal clearance in older adults.


How to titrate with eGFR?

• Digoxin dosing based on eGFRmust be supplemented by clinical acumen as these formulae tend to underestimate at higher ranges of creatinine clearance and overestimate in the lower ranges, and are unreliable in sick hospitalized patients

• Serum digoxin concentrations rapidly rise as creatinineclearance/eGFR falls.

• A reasonable rule of thumb is: use lower doses in small, old, females and even lower doses when the person is sick!


How to titrate with eGFR?

Howard M. Fillit, Kenneth Rockwood, Kenneth Woodhouse. Brocklehurst’s Textbook of Geriatric Medicine and Gerontology, Online and Print, 7th Ed 2010. Ch42


Vazquez-Hernandez M, et al. Glomerular filtration rate estimation using the Cockcroft-Gault and Modification of Diet in Renal Disease formulas for digoxin dose adjustment in patients with heart failure. Upsala Journal of Medical Sciences. 2009; 114: 154 159

great interindividual variability of the digoxin total CL/GFR ratio for GFR estimates < 60mL/min


Lack of an optimal “therapeutic” serum digoxinconcentration for the use of digoxin in atrial fibrillation

• Relatively few studies have systematically evaluated the efficacy and safety profile of digoxin in AF

• Further systematic study is required.• In 30 patients with acute AF and 30 patients with chronic AF,

digoxin was found to be relatively ineffective in controlling the ventricular rate at the traditional “therapeutic” SDC concentrations; and in some instances adequate rate control was only achieved at “toxic” SDC

• The poor correlation between SDC and resting heart rate in patients with AF may result in digoxin overdose if ventricular response is used as a yardstick for adjusting digoxin dose requirements.

• The American College of Cardiology guidelines caution that “Although digoxin continues to play a role in some patients with heart failure and AF, the traditional practice of arbitrarily increasing the dose and SDC of digoxin until ventricular response is controlled should be abandoned, because the risk of digoxin toxicity increases as well.”

• Therapeutic Drug Monitoring– to ensure that it is within the therapeutic range, serum digoxin concentration

(SDC) should be measured 2 - 4 weeks after starting digoxin:• in patients with deranged renal function• when used with agents that alter the disposition of digoxin• or whenever digoxin toxicity is suspected

– Digoxin dosage should be adjusted and the SDC monitored in patients with an acute illness which might cause a decline in renal function and also when medication changes.

– Ensuring that laboratory reports include the latest, lower and narrower therapeutic range of SDC (0.6 - 1.2 nmol/L) in heart failure, will help reduce the chance of the clinician overdosing the patient.

– limitation of therapeutic drug monitoring (TDM): wile digoxin TDM allows a clinician to compensate for factors that alter its pharmacokinetics (lean body mass, renal function, drug interactions), TDM cannot account for age-related changes in pharmacodynamic response to digoxin

– A SDC within the therapeutic range may not assure absence of digoxin toxicity, and clinical monitoring is just as important as TDM

Avoiding Digoxin Toxicity in Elderly PersonsHow to monitor digoxin therapy in elderly patients?

Kong TK. Safe and effective use of digoxin in old age. CME Geriatric Medicine 2010; 12(2): 86-97.

• Clinical monitor– Associated comorbidities, acute illnesses and medications that impact on

hydration and renal function, and potential drug interactions should also be taken into consideration in adjusting digoxin dosage

– The transition of care from the inpatient to the outpatient setting is an especially vulnerable period

– Close monitoring to ensure the correct dosage is prescribed and is being taken. The reasons given for nonadherence may indicate intolerance due to toxicity

– A heightened vigilance must be maintained not only for the cardiovascular (arrhythmia), but also for the gastrointestinal (commonly nausea, vomiting, anorexia), and neuropsychiatric symptoms and signs of digoxin overdose.

• Functional monitor (listen to patient/carers)– Any decline in functional level, such as recent confusion, instability and

falls, may also indicate digoxin toxicity.• ? ADR

– A useful rule of thumb in identifying any ADR is simply to ask oneself “could this patient’s condition be due to one or more of the drugs they have taken?”

– Disappearance of presumed toxic symptoms upon stopping digoxinmay support the clinical suspicion of digoxin toxicity.

Avoiding Digoxin Toxicity in Elderly PersonsHow to monitor digoxin therapy in elderly patients?

Kong TK. Safe and effective use of digoxin in old age. CME Geriatric Medicine 2010; 12(2): 86-97.

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