Considerations on Polypharmacy and Adverse Drug EventsJonathan H. Watanabe, PharmD, PhD, BCGPAssistant ProfessorDivision of Clinical Pharmacy3rd Annual Clinical Interprofessional Geriatrics SymposiumSunday December 4, 2016

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Consequences of medical care are gaining attention

• The cost of drug-related morbidity and mortality exceeded $177.4 billion in 2000 with $121.5 billion attributed to hospitalizationcosts. 1

• Adverse drug events (ADEs) lead to an estimated 99,628 hospitalizations per year2

• JAMA meta-analysis in 1998 estimated that fatal ADEs may rank between the 4th and 6th leading cause of death in the US3

1. Ersnt FR et al. J Am Pharm Assoc. 2001; 41:192-1992. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency Hospitalizations for Adverse Drug

Events in Older Americans. N Engl J Med 2011;365(21):2002–12.3. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: A

meta- analysis of prospective studies. JAMA 1998;279(15):1200–5.

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….and older adults are at elevated risk of hospitalizations due to ADEs

• While people over 65 represent 14.1% of the US population,10 seniors account for more than 49% of ADE-related hospitalizations1-3

• The risk of ADEs accelerates beyond age 65 years old. Patients 85 and older accounted for more than triple the ADE-related hospitalizations in those 65 to 69 years old4

1. Statistics on Aging [Internet]. Available from: http://www.aoa.acl.gov/Aging_Statistics/index.aspx 2. Kongkaew C, Hann M, Mandal J, et al. Risk factors for hospital admissions associated with adverse drug

events. Pharmacotherapy 2013;33(8):827–37. 3. Budnitz DS, Pollock DA, Weidenbach KN, Mendelsohn AB, Schroeder TJ, Annest JL. NAtional surveillance of

emergency department visits for outpatient adverse drug events. JAMA 2006;296(15):1858–66. 4. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency Hospitalizations for Adverse Drug Events in

Older Americans. N Engl J Med 2011;365(21):2002–12

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Polypharmacy associated with ADEs• After adjusting for age, sex, and initial antihypertensive therapy in a cohort

study of 66,161 older adults, the RR was estimated at 4.3 (95% CI, 3.8–4.8) for the polypharmacy group, when compared with the monotherapy group.1

• Retrospective study of seniors observed that seniors with adverse drug reactions (ADRs) were consuming more medications2

• Polypharmacy also observed to influence medication adherence, but findings have been inconsistent3

1. Sato I et al. Drug Healthc Patient Saf. 2013; 5: 143–150.2. Veehof LJ, et al. Adverse drug reactions and polypharmacy in the elderly in general practice. Eur J Clin

Pharmacol. 1999 Sep;55(7):533-6. 3. Watanabe JH et al. Annals of Pharmacotherapy 2013;47(10) 1253–1259

Mean number of Medications for seniors with an ADR

Mean number of Medications for Seniors without an ADR

14.7 5.5

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What is Polypharmacy?• 1st Bullet 24 Point, Color Text 1 Lighter 25%

• 2nd Level Bullet, 20 point• 3rd Level Bullet, 18 Point, Color Accent 2

• 4th Level Bullet, 14 Point, Color Lighter 25%

Definition SourceConcurrent use of multiple medications Kroenke K. Polypharmacy: causes,

consequences, and cure. Am J Med. 1985;79:149-152.

the use of two or more medications, and it is commonly seen in this patient population

Munger, M.A. Drugs Aging (2010) 27: 871. doi:10.2165/11538650-000000000-00000

Use of four or more medications wikiincrease in the number of medications or the use of more medications than are medically necessary

Maher R et al. Expert Opin Drug Saf. 2014 Jan; 13(1): 10.1517/14740338.2013.827660.

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Polypharmacy more pronounced in seniors• Average number of medications used by older adults ranges from

8 to 13 studies1

• Consistent with UCSD SSPPS medication therapeutic management sessions at assisted living facilities

• 36% of community dwelling seniors in the US used 5 or more medications in a nationally representative survey2

• Analysis of Medicare enrollees discharged to SNFs found an average of 14 medications3

• Average of 5.9 (±2.2) medications that could contribute to geriatric syndromes, with falls having the most associated medications at discharge at 5.5 (±2.2).

1. Farrell et al. Can Fam Physician. 2011 Feb; 57(2): 168–1692. Qato DM et al. JAMA Intern Med. 2016 Apr;176(4):473-82. 3. Saraf AA et al. J Hosp Med. 2016 Oct;11(10):694-700. 

So what can we do about reducing polypharmacy?

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Medication therapeutic management (MTM) is now a required component of LTC Pharmacy• As of 2013, as a part of the Affordable Care Act, annual

real-time Comprehensive Medication Reviews (CMRs) must be offered to Medicare Part D beneficiaries that meet certain criteria

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CMR Components: Direct patient interaction and patient activation

• Targeted enrollees are multimorbid patients ( > 2 chronic diseases)

• With Polypharmacy (Plan CANNOT require more than 8 drugs as threshold for targeted enrollment)

• With costs expected to exceed ~$3,000 in annual drug costs

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Apply an intervention framework tied to utilization reduction

Ramalho de Olveir et al. J Manag Care Pharm. 2010;16(3):185-95

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How much time is spent talking to the patient about a newly prescribed medication during the physician office visit?

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MTM improves multiple medication related outcomes

OutcomesImproved medication appropriateness on medication appropriateness index 4.9 units at 12 months (P < 0.01)Improved Odds of adherence 4.6% (95% CI, 3.211 to 5.989)

Lowered mean doses (mean difference, −2.2 doses; 95% CI, −3.738 to −0.662 )Lowered health plan medication costs −$293 (95% CI, −501.5 to −84.5) during 6 months

Lowered hospitalization rates for diabetics (Odds Ratio 0.91 to 0.93)

Lowered hospitalization rate for heart failure patients (Hazard Ratio 0.55; 95% CI, 0.39 to 0.77

Lowered hospitalization costs (mean differences ranged from −$363.45 to −$398.98).

Lowered length of stay by 1.8 days

Viswanathan et al. JAMA Intern Med. 2015;175(1):76-87. doi:10.1001/jamainternmed.2014.5841

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Tools for reducing polypharmacyTool Description

Medication Regimen Complexity Index (MRCI)1 65-item validated assessment that (i) dosage formulations, (ii) dosing frequency, and (iii) additional administration directions.

STOPP Criteria2 Designed to address limitations of Beers Criteria for European clinicians

https://www.farmaka.be/frontend/files/publications/files/liste-start-stopp-version.pdf

http://ageing.oxfordjournals.org/2015 Beers Criteria3 Most recent iteration and expanded version of

Beers Criteria

Potentially Inappropriate Medication List developed by Budnitz et al from CDC4,5

Used nationally representative data to identify drugs most associated with ED visits

Comprehensive Medication Review form

1. Hirsch JD et al. Pharmacotherapy. 2014 Aug;34(8):826-35.2. Ryan C et al. of STOPP and START criteria: interrater reliability among pharmacists. Ann Pharmacother.

2009 Jul;43(7):1239-44.3. Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2015

Nov;63(11):2227-46. 4.Budnitz, Daniel S., et al 365.21 (2011): 2002-2012.5.Budnitz, Daniel S., et al. 147.11 (2007): 755-765.

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Is polypharmacy always bad?

• Still must be judicious

• While polypharmacy is a signal that medication review, reconciliation, and MTM should be performed it is not always an indicator of poor care

• Situations where appropriate care will demand additional medications be used

• Each unit increase in MRCI score was associated with a modest but non-significant increase in probability of survival from readmission or ED visit (HR 0.978; 95% CI 0.955, 1.001) in an observational study of HF patients1

Watanabe JH et al. Ann Pharmacother. 2013 Oct;47(10):1253-9

1. Yam FK et al. Res Social Adm Pharm. 2016 Sep-Oct;12(5):713-21

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Implications for polypharmacy and plan ratings

• Pharmacy Quality Alliance (PQA) perfomance measures are often integrated into CMS Star Ratings

• Polypharmacy/Inappropriate/Unnecessary Therapy: Inappropriate combination therapies that are potential safety concerns is now being considered as a measure by PQA

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Acknowledgements

Dr. Diane Chau

Sammi Tam, PharmD candidate

Dr. Paula Park

Kamal Kejriwal M.D., CMD, AGSF, FAAFP

Program DirectorGeriatric Medicine Fellowship

SCPMGFontana

Polypharmacy and DE prescribing

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Disclosure

No relevant financial relationships with commercial interests

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Topics Covered

• Challenges of geriatric pharmacology

Updated Beers Criteria

• Tools for De Prescribing

• Psychotropic use in Nursing Facilities

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The central question in all of modern

American medicine…

Well, what pills should I give her for

that?

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“It’s just because I’m OLD”

FALSEYou must understand the underlying

pathophysiology of diseases, normal pharmacodynamics and pharmacokinetic changes with aging, and drug-drug and drug-disease interactions!!

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Why Geriatric Pharmacotherapy is Important

Persons aged 65 and older are prescribed thehighest proportion of medications in relation to theirpercentage of the U.S. population

• Now, 13% of total population buy 33% of all prescription drugs.

• In Elderly populations there are more deaths due to ADE than MVA, Breast cancer or AIDS.

• By 2040, 25% of total population will buy 50% of all prescription drugs.

23WHY GERIATRIC PHARMACOTHERAPY IS IMPORTANT

Present 20400

102030405060708090

100

People 65+ 65+ share of prescriptionsPeople <65 <65 share of presciptions

Now, people age 65+ are 13% of US population, buy 33% of prescription drugsBy 2040, will be 25% of population, will buy 50% of prescription drugs

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Why Geriatric Pharmacotherapy is Challenging?

• FDA- approved and off-label indications expansion

• Managed-care formularies change frequently• Knowledge of drug-drug interactions

advances• Drugs change from prescription to OTC• “Nutriceuticals” (herbal preparations,

nutritional supplements) are booming

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• Older adults rank concerns about medication sides effects as highest on their health priorities.

• 89% with chronic conditions willing to attempt cessation if deemed necessary by their providers.

• Despite the Beers criteria, inappropriate prescriptions persists in 25% of the community non hospitalized elderly.

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• Interventions aimed at physicians and pharmacist such as medication reviews and best practice alerts.

• Per EMPOWER study patients states in 33% of the cases physicians were reluctant to change the medications.

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• Benzodiazepines one of the most prevalent inappropriate medications consumed: 19%

• Per Beers criteria Benzos should be avoided in older adults due to an excessive risk of delirium, falls, fractures and motor vehicle accidents.

• Shown to increase the risk of amnestic and non amnestic cognitive impairment and may lead to incident dementia.

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Benzodiazepines

• The Number Needed to Harm is very low compared to Number Needed To Treat

• NNT >> NNH

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• Chronic benzo users develop psychological dependence to it.

• Makes it difficult for physicians and consumers in implementing the tapering protocols.

• Pt deny or minimize side effects.• Fear of upsetting Doctor – Patient

relationship.

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What are Patients Thinking

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Empower s tudyWhat pat ients Th ink

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Patient Perspectives

• Valium is a mild tranquilizer and safe when taken for long periods of time.

• Dose I am taking is causing no side effects• Without Valium I would be unable to sleep

or will experience unwanted anxiety.• Valium is best available option to treat my

symptoms.

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Effects of Aging on Volume of Distribution (Vd)

• body water lower VD for hydrophilic drugs

• lean body mass lower VD for drugs that bind to muscle

• fat stores higher VD for lipophilic drugs

• plasma protein (albumin) higher percentage of drug that is unbound (active)

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Changes in Distribution: Protein Binding

• Reduced protein binding with age• Reduced protein concentrations with

disease• Affects serum levels of drugs that bind to

proteins• Examples: fentanyl, theophylline,

sulfonylureas, warfarin and digoxin

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ADEs Prescribing Cascade

Source Note: Rochon PA, Gurwitz JH. Optimising drug treatment for elderly people: the prescribing cascade. BMJ. 1997;315(7115):1097. Reprinted with permission.

DRUG 1

DRUG 2

Adverse drug effect- misinterpreted as a new medical condition-

Adverse drug effect- misinterpreted as a new medical condition

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How to Avoid Getting Into Trouble with Drugs in the Elderly

• Use proper prescribing etiquette• Watch for drug-drug, drug-disease, and

drug-food interactions• Don’t prescribe bad medications

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Appropriate Drug Prescribing (proper etiquette)

• Review current prescription and non-prescription medications, medical history, labs

• Ask about drug allergies, adverse reactions, use of alcohol

• Start low and go slow but treat adequately• Maximize dose before switching to another

drug• Avoid starting two drugs at the same time

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Watch for Drug-Drug, Drug-Disease, and Drug-Food Interactions

Beers list of PIMS2015 Update

Guideline for nitrofurantoin is relaxed for Creatinine Cl from 60 to 30

Opioids been added to list of CNS drugs to avoid in pt with h/o falls and fractures.

Anticoagulants dose should be adjusted based on Cr Cl.

Avoid PPI for greater than 8 weeksNasal Saline to use as alternative to

antihistamines41

CHOOSING

WISELY

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Don’t prescribe a medication without conducting a drug regimen review.

#1 Older patients disproportionately use more prescription and non-prescription drugs than other populations, increasing the risk for side effects and inappropriate prescribing.

#2Polypharmacy may lead to diminished adherence, adverse drug reactions and increased risk of cognitive impairment, falls and functional decline

#3 Annual review of medications is an indicator for quality prescribing in vulnerable elderly.

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Don’t use benzodiazepines or other sedative-hypnotics in older adults as first choice for

insomnia, agitation or delirium. #1Large scale studies consistently show that the risk of motor

vehicle accidents, falls and hip fractures leading to hospitalization and death can more than double in older adults taking benzodiazepines and other sedative-hypnotics.

#2 Older patients, their caregivers and their providers should recognize these potential harms when considering treatment strategies for insomnia, agitation or delirium.

#3 Use of benzodiazepines should be reserved for alcohol withdrawal symptoms/delirium tremens or severe generalized anxiety disorder unresponsive to other therapies

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c 2007 ASCP 45

F329 - Unnecessary Meds Regulations

• Antipsychotics - Based on a comprehensive assessment of a resident, the facility must ensure that:– Residents who have not used antipsychotic drugs are

not given these drugs unless antipsychotic drug therapy is necessary to treat a specific condition as diagnosed and documented in the clinical record; and

– Residents who use antipsychotic drugs receive gradual dose reductions, and behavioral interventions, unless clinically contraindicated, in an effort to discontinue these drugs

Psychotropic Use in Long Term Care Facilities

Please do not use the above medications as your First Line

Non Pharmacological Approaches first

Title 22 requires the consent to be taken by the provider prior to administration of these meds.

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Targeted Medication Classes

Anticholinergic(Antihistamines )

LA sulfonylureas

NSAIDS

Confusion, dry mouth, constipation and functional decline

11% ED visits.52% greater risk of at least

one hypogly. Episode

Increase risk of GI bleeding /PUD

Use of misoprostol reduces but does not eliminate.

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Does this sound Familiar?

Decreased use of Inappropriate meds in Elderly ( 65 yrs. and older) improves hospital safety, reduces length of stay and rate of readmissions.

Examples of potentially inappropriate meds to avoid in Elderly:

-Diphenhyramine, Promethazine, Hydroxyzine, amitriptyline, imipramine, methocarbamol, trimethobenzamide, meperidine and diazepam.

Innovative pill box reminders

Medminder® : $40-65 per month. Looks like traditional pill boxes, 7 day (qid) boxes that lock. Flashing light/audible/text message/phone calls for reminders. Also, caregivers can get reports via text/emails/internet

Locked medication systems (eg e-pill): $200-500. Dispensers that lock/alarm, like a small omnicell/pyxis machine.

iPhone apps: Free-$3.99. Virtual pillbox. Can set medications, dosages and times a dose is needed. Alarms, reminders, etc.

https://www.youtube.com/watch?v=PXoLsW0w1FE

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Thank you!