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

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

…..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): 1452-1456

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

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

‘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):795-801 8

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

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

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

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 12

DEFINITION Edwards & Aronson. Lancet. 2000;356: 1255-59 13

Why are the elderly at risk of ADRs?

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

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

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

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) 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.

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

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

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 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)

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 25

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

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

ADR by Location (Wiffen et al 2002)

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

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

16.6% 4.1% 4.9%

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

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. 33

“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) Antibiotics Hypoglycemic agents Psychotropic agents Anticoagulants Others 28 15 12 8 6 4 10 34 18 7 5 37

Lecturer Level of performance Audience Time

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

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

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

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