Polypharmacy and Adverse Drug Reactions (ADR) in the Elderly

1. Polypharmacy and Adverse Drug Reactions (ADR) in theElderly 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. Lecturer Level of performance Audience Time Lloyd (1968)

4. “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

5. 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. 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

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

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

11. 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 Classification

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: 1255-59

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

14. Why are the elderly at risk of ADRs?

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

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

18. 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 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)

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

20. 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

21. Table: The Prescribing Cascade (Source: Adapted from Rochon and Gurwitz, 1997)

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

23. 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

24. 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)

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

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

28. 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)

29. 16.6% 4.9% 4.1%

30. 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)

31. 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 ADR causing hospital admission 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.

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

34. 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

35. Drugs Causing ADR

36. Lecturer Level of performance Audience Time

37. 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)

38. Review Preventability • 2 panels (Doctors & Pharmacists) • 16 preventable cases reviewed

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

40. Drug’s Commonly Implicated

41. 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?

42. 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)

43. 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

44. 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.

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