Polypharmacy and Adverse Drug Reactions (ADR) in the Elderly

Professor Graham Davies

Professor of Clinical Pharmacy & Therapeutics King’s College London

Content

Statistics and definitions

The risk of ADRs in the elderly

The ADR problem – the evidence• Causing hospital admission• Occurring in hospital

Challenges • Preventability• Managing the problem

Summary & questions

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Lloyd (1968)

“One of the greatest hazards is the use of potent drugs is their inherent toxicity……

…..the dangers of the drug appear to be greater now then ever before.”

David Barr MD; Hazards of modern diagnosis and therapy – the price we pay. Frank Billings Memorial Lecture.

J Am Med Assoc 1955;159 (15): 1452-1456

In US:

ADR estimated to be between 4th and 6th leading cause of death.

Lazarou JAMA 1998

For example…………NSAIDs Blower et al 1997 Aliment Pharmacol Therap

12,000 admissions/yr 20 to GI bleed

2000 deaths/yr cf 3500 RTA

400 bed hospital working at capacity

Impact greater for >65 yrs:– GI bleed, – CHF– Renal impairment

The statistics

In England:

Approx 20% population >60 years of age

Consume 56% of dispensed medicines

Costs around 40% of NHS drug budget

Growing ageing population

DefinitionsAdverse Drug Events (ADEs)

‘any injury resulting from the use of drugs’

5 categories of ADEs:1. Adverse drug reactions2. Medication errors3. Therapeutic failures4. Adverse drug withdrawal events5. Overdoses

Nebeker JR, Ann Intern Med. 2004;140(10):795-801

Adverse drug events

Medication errors

Risks from drug treatment

Adverse drug reactions

DEFINITION

WHO. International drug monitoring: The role of the hospital. WHO Tech Rep. 1969; 425: 5-24

“ADR is a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function”

Classification

Type A

Predictable from P’cology

Dose related

Influenced by kientic and dynamic changes

Account for 75% of ADR

Preventable

Type B

Unrelated to P’cology

Poor relationship with dose

Uncommon and difficult to detect during development

Patient idiosyncrasy major factor

Unavoidable

DEFINITION OF ADR

Edwards & Aronson. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000; 356: 1255-59

“An appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product ”

DEFINITION

Edwards & Aronson. Lancet. 2000;356: 1255-59

Why are the elderly at risk of ADRs?

Patient Medicine

Adverse DrugReaction

Poly-Pharmacy

Cognitiveimpairment &

adherence

Environment

Pharmaco-genetics

AlteredDrug

Handling

Altered Drug

Response

PhysiologicalDecline

Co-morbidities

Recovery, HospitalisationDisabilityDeath

Pharmacokinetic changes in the elderlyDrug distribution

• changes in body fat/lean ratio & protein binding• increase free drug concentrations (warfarin;

phenytoin)

Metabolism• changes to liver mass and blood flow• decrease first pass metabolism - increase

bioavailability (opiates, nitrates)

Elimination• Decrease clearance of renally excreted drugs (digoxin,

lithium, antibiotics)• active metabolites – morphine-6-glucuronide

Patient Medicine

Adverse DrugReaction

Poly-Pharmacy

Cognitiveimpairment &

adherence

Environment

Pharmaco-genetics

AlteredDrug

Handling

Altered Drug

Response

PhysiologicalDecline

Co-morbidities

Recovery, HospitalisationDisabilityDeath

Three recent reports:

Estimated that between 30 -50% medicines prescribed for long term illnesses are not taken as directed

If prescription was appropriate then this represents a loss for patients, healthcare providers and pharma industries

Effective interventions are elusive (Haynes, et al. 1996, 2003 - series of Cochrane reviews of efficacy of adherence interventions)

Non-adherence to medicines

1World Health Organization Report 2003.

2Horne et al. Concordance, adherence and compliance in medicine taking. NIHR SDO 2006.

3NICE. Medicines concordance & adherence:involving adults and carers in decisions about prescribed medicines 2008/9

Patient Medicine

Adverse DrugReaction

Poly-Pharmacy

Cognitiveimpairment &

adherence

Environment

Pharmaco-genetics

AlteredDrug

Handling

Altered Drug

Response

PhysiologicalDecline

Co-morbidities

Recovery, HospitalisationDisabilityDeath

ADRs and Age

Incidence of ADR increases with age

Elderly receive more medicines

Incidence of ADR increases the more

prescribed medicines taken (exponentially?)

Grymonpre et al (1988) – study >50 yrs• ADR rates – 5% for 1 or 2 medicines• Increased to 20% when >5 medicines

Table: The Prescribing Cascade Initial treatment Adverse effect Subsequent

treatmentSubsequent

adverse effect

NSAIDs Rise in blood pressure

Antihypertensive treatment

Orthostatic hypotension

Thiazide diuretics Hyperuricaemia Allopurinol Hypersensitivity reaction (Skin rashes)

Metoclopramide treatment

Parkinsonian symptoms

Treatment with levodopa

Visual and auditory hallucination

(Source: Adapted from Rochon and Gurwitz, 1997)

The Evidence

Elderly not extensively studied

Usually part of general data-set

Homogeneity of studies a problem

The problem of homogeneity

Primary end points – ADE vs ADR

Definitions used

Method of identifying ADR (chart review vs direct patient interview)

Assigning causality

Severity of harm

Preventability

Differ in:•Algorithms & agreement•Expert judgment

MAGNITUDE OF PROBLEM

Published studies relating to ADR

ADR causing hospital admission

ADR during inpatient stay

Systematic Review: ADRs in hospital patients(Wiffen et al 2002)

Table: ADR by Clinical Setting (Wiffen et al 2002)

Impact of inpatient ADR (Wiffen et al 2002)

Cost – £380million/year to NHS EnglandConsuming 4% available bed-days

ADR causing hospital admission Beijer & de Blaey. Pharm World Sci. 2002; 24(2):46-54

•Meta-analysis - 68 studies

•Hospitalisation of 6,071 pts ADR related (4.9%)

•ADR rate varied from 0.2% to 41.3%

•4 fold increase in ADR hospitalisation rate in elderly (>65yr) compared to non-elderly

•88% of the ADR considered preventable in elderly (vs 24% in non-elderly)

16.6%

4.1%4.9%

•Landmark UK study

•6 month Prospective study

•2 hospital: 1 teaching + 1 district hospital

•Medical and surgical wards

•Patients >16 years

More recently…(Pirmohamed et al BMJ 2004)

1. 6.5% of all admissions due to an ADR

2. Older patients more likely to be admitted with ADR

{76 yrs (65-83) vs 66 (46-79)}

3. 4% of hospital bed capacity

4. 0.15% fatality

5. Drug-interactions responsible for 1 in 6 ADRs

6. 72% were (possibly or definitely) preventable

7. Cost to NHS £466 million/yearPirmohamed, M., et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ, 2004. 329(7456): 15-9.

ADR causing hospital admission

“Older drugs continue to be the most commonly implicated in causing admissions.”

Low dose aspirin 18% cases

Inpatient Elderly (Tangiisuran et al; Journal of Nutrition Health and Ageing. 2009)

Prospective, observational design (6/12)• ADR in the very elderly (≥80 years old)• Preventability, severity and type of ADR

560 pts (mean 85 yrs; 63% female)• 1 in 8 experienced ADR• Majority serious (69%) some life-threatening(4%). No deaths.

• 63% preventable

Drugs Causing ADR

Most frequent drug class causing ADR

N %

Cardiovascular active agents

Analgesics (opioid mainly)AntibioticsHypoglycemic agentsPsychotropic agents AnticoagulantsOthers

28 15 12 8 6 4 10

3418 15107512

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Preventability – implies original decisions incorrect?

Rates vary:

54% (1998,US; >70yr)

28% (2003,UK; >75 yr)

72% (2004,UK; >16 yr)

56% (2009,UK; >16 yr)

63% (2009,UK >85 yr)

Review Preventability

2 panels (Doctors & Pharmacists)

16 preventable cases reviewed

Decision Doctors

P’cists

Remove label

5 2

Change decision

11 7

Closer monitoring

0 7

16 16

Summary

ADR common – admission and during in-patient stay

Elderly more at risk• Range of factors – poly-pharmacy• Established medicines common

cause

Drug Common IssuesAntibiotics Allergies & dosage adjustment in renal

dysfunction

Anticoagulants Bleeding; drug interactions, dynamic changes & environment

Cardiac glycosides 1 in 5 experience ADR, NTI & kinetic issues.

Diuretics Dehydration, electrolyte imbalance

Hypoglycaemic agents (oral & insulin)

Hypoglycaemia, changes to diet, poor monitoring

NSAIDs GI bleed, renal impairment

Opioid analgesia Sedation – dynamic and kinetic changes

Drug’s Commonly Implicated

Summary

ADR common – admission and during in-patient stay

Elderly more at risk• Range of factors – poly-pharmacy• Established medicines common cause• Many preventable

If preventable – strategies for reducing ADRs?

Strategies

Identify patients – triggers• Vitamin K, creatinine changes,

plasma concentrations

Improve process of care (NSF stds?)• e-prescribing systems• Clinical pharmacists on rounds• Better communication across

interface & with patients (carers)

Strategies (cont.)Predict at risk patients?

GerontoNet Study (NL,Belg,Italy,UK) (Arch Int Med)

483pts (mean 80yrs)

6 factors – score 8 or more = high risk• 4+ Co-morbidities = +1 • CCF = +1• Liver disease = +1• Renal impairment = +1• Previous ADR = +2• No of medicines = 5-7 = +1; >8 = +4

Prescribing to Reduce ADRs

Age, hepatic and renal disease may impair clearance of drugs so smaller doses may be needed.

Prescribe as few drugs as possible and give clear instructions to patients and carers

If serious ADRs are liable to occur warn the patient

Where possible use familiar drugs.

With new drugs be particularly alert for ADRs and unexpected event.

Poly-pharmacy and Adverse Drug Reactions in the Elderly

Graham Davies,Professor of Clinical Pharmacy & Therapeutics,King’s College, London