1. Polypharmacy and Adverse Drug Reactions (ADR) in the Elderly
Professor Graham Davies
Professor of Clinical Pharmacy & Therapeutics King’s College London

2. 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

3. Level of performance Time Lecturer Audience Lloyd (1968)
Lecturers only slightly above students
Time
Lloyd (1968)

4. …..the dangers of the drug appear to be greater now then ever before.”
“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):

5. In US: ADR estimated to be between 4th and 6th leading cause of death
In US: ADR estimated to be between 4th and 6th leading cause of death Lazarou JAMA 1998

6. 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

7. 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

8. ‘any injury resulting from the use of drugs’
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. 2004;140(10): 8

9. Risks from drug treatment
Adverse drug events
Medication errors
Adverse drug reactions

10. 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 10

11. Classification Type B Type A Unrelated to P’cology
Poor relationship with dose
Uncommon and difficult to detect during development
Patient idiosyncrasy major factor
Unavoidable
Type A
Predictable from P’cology
Dose related
Influenced by kientic and dynamic changes
Account for 75% of ADR
Preventable

12. 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: 12

13. DEFINITION
Edwards & Aronson. Lancet. 2000;356: 13

14. Why are the elderly at risk of ADRs?

15. Patient Medicine Adverse Drug Reaction Cognitive impairment &
adherence
Environment
Physiological
Decline
Co-morbidities
Poly-
Pharmacy
Adverse Drug
Reaction
Altered
Drug
Handling
Response
Pharmaco-
genetics
Recovery,
Hospitalisation
Disability
Death

16. 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

17. Patient Medicine Adverse Drug Reaction Cognitive impairment &
adherence
Environment
Physiological
Decline
Co-morbidities
Poly-
Pharmacy
Adverse Drug
Reaction
Altered
Drug
Handling
Response
Pharmaco-
genetics
Recovery,
Hospitalisation
Disability
Death

18. Non-adherence to medicines
Three recent reports:
Estimated that between % 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, series of Cochrane reviews of efficacy of adherence interventions)
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
But, as a recent report by the WHO has identified between one third and a half of medicines prescribed for long-term illness are not taken as directed.
If we assume that the prescription was appropriate then this level of non-adherence is a concern for those, receiving, providing or funding care because it not only entails a waste of resources but also a missed opportunity for therapeutic benefit and health gain.

19. Perceptions & Practicalities
Model of Adherence
INTENTIONAL
Non-adherence
UNINTENTIONAL
Non-adherence
Motivational
Beliefs/preferences
Capacity & resources
Practical barriers
Perceptual 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 R&D, London, 19

20. Patient Medicine Adverse Drug Reaction Cognitive impairment &
adherence
Environment
Physiological
Decline
Co-morbidities
Poly-
Pharmacy
Adverse Drug
Reaction
Altered
Drug
Handling
Response
Pharmaco-
genetics
Recovery,
Hospitalisation
Disability
Death

21. 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

22. 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)

23. The Evidence Elderly not extensively studied
Usually part of general data-set
Homogeneity of studies a problem

24. 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

25. MAGNITUDE OF PROBLEM Published studies relating to ADR
ADR causing hospital admission
ADR during inpatient stay 25

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

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

28. ADR by Location (Wiffen et al 2002)

29. Impact of inpatient ADR (Wiffen et al 2002)
Cost – £380million/year to NHS England
Consuming 4% available bed-days

30. ADR causing hospital admission Beijer & de Blaey. Pharm World Sci
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) 30

31. 16.6%
4.1%
4.9%

32. 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 >16 years 32

33. 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 patients. BMJ, (7456): 15-9. 33

34. “Older drugs continue to be the most commonly
implicated in causing admissions.”
Low dose aspirin 18% cases

36. 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

37. 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 7 5 37

38. Lecturer
Level of performance
Audience
Time

39. 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)

40. Review Preventability
Decision
Doctors
P’cists
Remove label 5 2
Change decision 11 7
Closer monitoring 16
2 panels (Doctors & Pharmacists)
16 preventable cases reviewed

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

42. Drug’s Commonly Implicated
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

43. 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?

44. 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)

45. 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

46. 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.

47. Poly-pharmacy and Adverse Drug Reactions in the Elderly
Graham Davies,
Professor of Clinical Pharmacy & Therapeutics,
King’s College, London