Polypharmacy and Adverse Drug Reactions (ADR) in the Elderly

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Polypharmacy and Adverse Drug Reactions (ADR) in
the Elderly

• Professor Graham Davies
• Professor of Clinical Pharmacy Therapeutics
  Kings College London

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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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Lecturer
Level of performance
Audience
Time
Lloyd (1968)
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• 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 1955159 (15) 1452-1456

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In USADR estimated to be between 4th and 6th
leading cause of death.
Lazarou JAMA 1998
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For exampleNSAIDs 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 gt65 yrs
• GI bleed,
• CHF
• Renal impairment

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The statistics

• In England
• Approx 20 population gt60 years of age
• Consume 56 of dispensed medicines
• Costs around 40 of NHS drug budget
• Growing ageing population

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Definitions

• Adverse Drug Events (ADEs)
• any injury resulting from the use of drugs
• 5 categories of ADEs
• 1. Adverse drug reactions
• 2. Medication errors
• 3. Therapeutic failures
• 4. Adverse drug withdrawal events
• 5. Overdoses

Nebeker JR, Ann Intern Med. 2004140(10)795-801
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Risks from drug treatment
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DEFINITION
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
WHO. International drug monitoring The role of
the hospital. WHO Tech Rep. 1969 425 5-24
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Classification

• Type B
• Unrelated to Pcology
• Poor relationship with dose
• Uncommon and difficult to detect during
  development
• Patient idiosyncrasy major factor
• Unavoidable

• Type A
• Predictable from Pcology
• Dose related
• Influenced by kientic and dynamic changes
• Account for 75 of ADR
• Preventable

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DEFINITION OF ADR
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
Edwards Aronson. Adverse drug reactions
definitions, diagnosis, and management. Lancet
2000 356 1255-59
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DEFINITION
Edwards Aronson. Lancet. 2000356 1255-59
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Why are the elderly at risk of ADRs?
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Patient
Medicine
Poly- Pharmacy
Pharmaco- genetics
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Pharmacokinetic changes in the elderly

• Drug 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

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Patient
Medicine
Poly- Pharmacy
Pharmaco- genetics
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Non-adherence to medicines

• 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)

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Perceptions Practicalities Model of Adherence
INTENTIONAL Non-adherence
UNINTENTIONAL Non-adherence
Motivational Beliefs/preferences
Capacity resources
Perceptual barriers
Practical barriers
Horne R, Weinman et al Concordance, Adherence and
Compliance in Medicine Taking A conceptual map
and research priorities (2006). National
Institute for Health Research Service Delivery
and Organisation RD, London,
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Patient
Medicine
Poly- Pharmacy
Pharmaco- genetics
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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 gt50 yrs
• ADR rates 5 for 1 or 2 medicines
• Increased to 20 when gt5 medicines

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Table The Prescribing Cascade
Initial treatment Adverse effect Subsequent treatment Subsequent 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)
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The Evidence

• Elderly not extensively studied
• Usually part of general data-set
• Homogeneity of studies a problem

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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

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MAGNITUDE OF PROBLEM

• Published studies relating to ADR
• ?ADR causing hospital admission
• ?ADR during inpatient stay

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Systematic Review ADRs in hospital
patients (Wiffen et al 2002)
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ADR by Location (Wiffen et al 2002)
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Impact of inpatient ADR (Wiffen et al 2002)
Cost 380million/year to NHS England Consuming
4 available bed-days
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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 (gt65yr) compared to non-elderly
• 88 of the ADR considered preventable in elderly
  (vs 24 in non-elderly)

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More recently(Pirmohamed et al BMJ 2004)

• Landmark UK study
• 6 month Prospective study
• 2 hospital 1 teaching 1 district hospital
• Medical and surgical wards
• Patients gt16 years

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ADR causing hospital admission

• 6.5 of all admissions due to an ADR
• Older patients more likely to be admitted with
  ADR
• 76 yrs (65-83) vs 66 (46-79)
• 4 of hospital bed capacity
• 0.15 fatality
• Drug-interactions responsible for 1 in 6 ADRs
• 72 were (possibly or definitely) preventable
• Cost to NHS 466 million/year

Pirmohamed, M., et al. Adverse drug reactions as
cause of admission to hospital prospective
analysis of 18 820 patients. BMJ, 2004.
329(7456) 15-9.
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Older drugs continue to be the most commonly
implicated in causing admissions.
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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

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Drugs Causing ADR
Most frequent drug class causing ADR N
Cardiovascular active agents Analgesics (opioid mainly) Antibiotics Hypoglycemic agents Psychotropic agents Anticoagulants Others 28 15 12 8 6 4 10 34 18 15 10 7 5 12
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Lecturer
Level of performance
Audience
Time
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Preventability implies original decisions
incorrect?

• Rates vary
• 54 (1998,US gt70yr)
• 28 (2003,UK gt75 yr)
• 72 (2004,UK gt16 yr)
• 56 (2009,UK gt16 yr)
• 63 (2009,UK gt85 yr)

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Review Preventability
Decision Doctors Pcists
Remove label 5 2
Change decision 11 7
Closer monitoring 0 7
16 16

• 2 panels (Doctors Pharmacists)
• 16 preventable cases reviewed

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Summary

• ADR common admission and during in-patient stay
• Elderly more at risk
• Range of factors poly-pharmacy
• Established medicines common cause

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Drugs Commonly Implicated
Drug Common Issues
Antibiotics 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
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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?

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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)

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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 gt8 4

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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.

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Poly-pharmacy and Adverse Drug Reactions in the
Elderly

• Graham Davies,
• Professor of Clinical Pharmacy Therapeutics,
• Kings College, London