This may be the author’s version of a work that was submitted/acceptedfor publication in the following source:

Poudel, Arjun, Yates, Patsy, Rowett, Debra, & Nissen, Lisa(2017)Use of preventive medication in patients with limited life expectancy: asystematic review.Journal of Pain and Symptom Management, 53(6), pp. 1097-1110.

This file was downloaded from: https://eprints.qut.edu.au/103694/

c© Consult author(s) regarding copyright matters

This work is covered by copyright. Unless the document is being made available under aCreative Commons Licence, you must assume that re-use is limited to personal use andthat permission from the copyright owner must be obtained for all other uses. If the docu-ment is available under a Creative Commons License (or other specified license) then referto the Licence for details of permitted re-use. It is a condition of access that users recog-nise and abide by the legal requirements associated with these rights. If you believe thatthis work infringes copyright please provide details by email to qut.copyright@qut.edu.au

License: Creative Commons: Attribution-Noncommercial-No DerivativeWorks 2.5

Notice: Please note that this document may not be the Version of Record(i.e. published version) of the work. Author manuscript versions (as Sub-mitted for peer review or as Accepted for publication after peer review) canbe identified by an absence of publisher branding and/or typeset appear-ance. If there is any doubt, please refer to the published source.

https://doi.org/10.1016/j.jpainsymman.2016.12.350

Accepted Manuscript

Use of preventive medication in patients with limited life expectancy: a systematicreview

Arjun Poudel, PhD, Patsy Yates, PhD, Debra Rowett, BPharm, Lisa M. Nissen, PhD

PII: S0885-3924(17)30049-0

DOI: 10.1016/j.jpainsymman.2016.12.350

Reference: JPS 9373

To appear in: Journal of Pain and Symptom Management

Received Date: 4 August 2016

Revised Date: 5 December 2016

Accepted Date: 29 December 2016

Please cite this article as: Poudel A, Yates P, Rowett D, Nissen LM, Use of preventive medication inpatients with limited life expectancy: a systematic review, Journal of Pain and Symptom Management(2017), doi: 10.1016/j.jpainsymman.2016.12.350.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service toour customers we are providing this early version of the manuscript. The manuscript will undergocopyediting, typesetting, and review of the resulting proof before it is published in its final form. Pleasenote that during the production process errors may be discovered which could affect the content, and alllegal disclaimers that apply to the journal pertain.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

1

Review Article 16-00497R1

Use of preventive medication in patients with limited life expectancy: a systematic

review

Arjun Poudel, PhD1, Patsy Yates, PhD2, Debra Rowett, BPharm3,

Lisa M Nissen, PhD1

1. School of Clinical Sciences, Queensland University of Technology, Brisbane, Australia

2. School of Nursing, Queensland University of Technology, Brisbane, Australia

3. Repatriation General Hospital, Adelaide, Australia

Corresponding author

Arjun Poudel, PhD

Research Associate, School of Clinical Sciences

Faculty of Health, Queensland University of Technology

Q Block (Level 9), Brisbane, QLD 4000

Ph: +61424356506 Email: a3.poudel@qut.edu.au

Word count: Text: 2603 Abstract: 242 Number of refs: 41 Tables: 2 Figure: 1

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

2

ABSTRACT

Context: Optimal prescribing in patients with limited life expectancy remains unclear.

Objectives: This study systematically reviews the published literature regarding the use of

preventive medication in patients with reduced life expectancy.

Methods: A systematic literature search was conducted using three databases (MEDLINE,

EMBASE and CINAHL). Articles published in English from January 1995 to December

2015 were retrieved for analysis to identify peer-reviewed, observational studies assessing

use of preventive medications in patients with limited life expectancy. Inclusion criteria were:

patients with a limited life expectancy (≤ 2 years); prescribed/used preventive medications.

Results: Of the 15 studies meeting our eligibility criteria, 6 were from inpatient hospital

settings, 5 in palliative care, 3 in nursing homes and 1 in community settings. The most

common life limiting illness described in the studies was cancer (n =6), cardiovascular

diseases (n = 4), dementia and cognitive impairment (n =2) and other life limiting illnesses (n

= 3). Lipid-lowering medications, especially the statins were frequently prescribed preventive

medication followed by antiplatelets, ACE inhibitors and ARBs, anti-osteoporosis

medications, and calcium channel blockers. Only four studies reported the instances of

medication withdrawal.

Conclusions: Patients continue to receive medications that are not prescribed as symptomatic

treatment despite having a limited life expectancy. Very few rigorous studies have been

conducted on minimising preventive medications in patients with limited life expectancy and

expert opinion varies on medication optimisation at the end of life. A consensus guideline

that addresses this gap is of paramount importance.

Keywords: limited life expectancy, optimal prescribing, preventive medication, symptomatic

treatment

Running title: Preventive medications in patients with LLE

Accepted for publication: December 29, 2016.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

3

1 INTRODUCTION

1.1 Rationale

Getting the most from medicines for both patients and the healthcare providers is becoming

increasingly important as more people are taking more medicines. Recent

technological advancement favoured expansion of treatment options that can sustain life in

conditions where it was almost impossible in previous days.1 Advances in treatment options,

while a societal success, presents many challenges to healthcare systems. One such challenge

relates to medication use in patients with life-limiting illness. Life-limiting illnesses include

amongst other conditions, end stage organ failure, neurodegenerative disease, advanced

cancer and AIDS. Many patients with these conditions have other long term comorbidities

that need active management at the end of life including diabetes mellitus, hypertension,

dementia, arrhythmia, dyslipidemia, atrial fibrillation, osteoporosis and thromboembolic

disease. Both the life-limiting illness and comorbidities change clinically over time2 and

polypharmacy becomes prevalent in late life. This polypharmacy can continue even through

the transition into palliative care, where averages of 5-6 medications are prescribed.3 Those

with limited life expectancy (LLE) are at increased risk of adverse drug events4, have

complex health statuses and distinct health care needs.5 Use of preventive medications in

these vulnerable groups may neither maintain health nor provide overall benefits given the

time until benefit can be several years.6, 7 Benefits from such drug therapies will only be

achieved if prescribing is appropriate and regularly evaluated in this population.

1.2 Objectives

To assist prescribing in patients with limited life expectancy, various guidelines and a series

of frameworks have been developed.2, 5 However, it is unclear to what extent unnecessary

preventive medications are prescribed in these patient groups. Hence, the objective of this

review was to evaluate the use of preventive medications in patients with limited life

expectancy. A secondary goal was to identify and review studies that involved ceasing of

these medications.

2 METHODS

This systematic review is reported according to the Preferred Reporting in Systematic

Reviews and Meta-analyses (PRISMA) guidelines.8

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

4

2.1 Eligibility Criteria

2.1.1 Study Types

Original studies that used preventive medications in patients with limited life expectancy

were included in the review. For the purpose of this study, limited life expectancy is defined

as patients with life expectancy less than 24 months; preventive medication is defined as any

medication that is used to proactively manage a disease or symptom, including antidiabetic,

antiplatelet, antihypertensive and lipid-regulating medication. We excluded studies that did

not assess the remaining life expectancy in populations using the preventive medications such

as the elderly patients. Conference abstracts and review articles were also excluded.

2.1.2 Participants

Eligible studies included participants with a limited life expectancy of ≤ 2 years who were

prescribed preventive medications.

2.2 Information Source

The search was conducted using electronic databases including MEDLINE, EMBASE and

CINAHL. Articles published in English between January 1995 and December 2015 were

retrieved for analysis. The bibliographies of relevant articles were hand searched for

additional studies.

2.3 Search Strategies

Keyword searches and MeSH headings were used that included the following terms: life

limiting illness, cancer, dementia, heart failure, end-stage chronic obstructive pulmonary

disease (COPD), advanced Parkinson’s disease, end of life, preventive medicine, preventive

medication use, life expectancy, limited life expectancy, short life expectancy. The search

strategy was modified, when appropriate, to meet the syntax requirements (see Appendix 1).

2.4 Study Selection

The initial screening of titles and abstracts based on the inclusion criteria was conducted by a

single investigator (AP) and was confirmed by a second reviewer (LN). Full text articles and

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

5

data extraction were reviewed by AP for final inclusion. Reference lists of these articles were

scanned to identify additional relevant articles.

2.5 Data Abstraction and Risk of Bias Assessment

We extracted details of articles included in the review, including the study design, sample

size, participant age (details from table) using a specially designed data extraction form.

Although our initial plan was to conduct and report a meta-analysis, narrative summary of the

results are reported because of the heterogeneity of study methodology and outcomes. We

also planned to evaluate funnel plots analogous to meta-analysis of the outcome so that the

potential for small study effects such as publication bias could be assessed but since meta-

analysis was not conducted, this was not possible. Also, limiting search to only English

language might have led to language bias but because of limited resources for translation

available to pursue all language options we decided to use only English-language

publications.

3 RESULTS

3.1 Study Selection

The initial search found 628 citations (Figure 1). Of these, 576 were excluded after reviewing

the abstracts, as they failed to meet the inclusion criteria and 3 were excluded because of

duplication. After abstract review, full text was sought for 49 articles, from which 42 articles

were excluded that did not meet the following criteria: not an original article (n = 11), life

expectancy not defined (n = 24), life expectancy more than 2 years (n = 7). Finally, 15 studies

met the inclusion criteria including 8 additional studies from manual search in bibliographies.

3.2 Study Characteristics

Table 1 presents a detailed description of the reviewed studies. Studies were conducted in the

in-patient hospital settings (n = 6), palliative care settings (n = 5; inpatient palliative care: 3

and community palliative care: 2), nursing homes or assisted living settings (n = 3) and in

community-dwellers (n = 1). The studies were conducted in the Oceania and Asia (n = 5),

USA (n = 4), Europe (n = 4), Brazil (n = 1), and Canada (n = 1).

3.3 Participants

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

6

A total of 15,527 participants were involved in the selected studies. The mean age of

participants ranged from 71.0 to 87.70 years of age. The life limiting illnesses described in

the studies were cancer (n =6), cardiovascular diseases (n = 4), dementia and cognitive

impairment (n =2) and other life limiting illnesses (n = 3). Life expectancy was reported to be

of 6 months or less were in 8 studies,9-16 12 months in 4 studies17-20 and 24 months in 3

studies.21-23 The average remaining life expectancy was approximately 11 months.

3.4 Types of preventive medication

The most common preventive class of medication used was the lipid-lowering medications,

especially the statins reported in the majority of studies.9-12, 15-19, 21, 23 Other classes of

commonly used preventive medications were antiplatelet,9, 11-13, 18, 20, 21 Angiotensin

Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs),9, 10, 12, 21

anti-osteoporosis medications,11, 12, 18, 21 and calcium channel blockers.9, 12, 21 Table 2 presents

a detailed list of medication used in the selected studies. Prescribed medications were

categorised as preventive or symptomatic, and in some cases crossover

preventive/symptomatic. Only 4 studies reported instances of medication withdrawal.13, 15, 16,

19

4 DISCUSSION

In this review, we compiled studies that documented the use of preventive medication in

patients with limited life expectancy. The findings suggest that patients continue to receive

medications that are not prescribed as symptomatic treatment despite having a limited life

expectancy. Lipid-lowering medications, especially the statins were the most frequently used

preventive medication. This finding was supported by other cohort studies, that found statins

continued till last years of life in patients with life limiting illness.24, 25 Furthermore, the

diagnosis of a recognizable, life limiting illness had no influence on the likelihood of statin

discontinuation prior to death.16

Prescribers often encounter emotionally complex decisions and challenges with regard to

withdrawing, stopping or otherwise limiting treatment that possess the potential to sustain

life, but which imposes burden and has potential to cause adverse outcomes or other serious

impacts.1 This is more complex when palliative treatment can still involve active treatment to

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

7

reduce symptoms and improve quality of life. For example, hypoglycemic agents can be used

as both preventive and symptom control as they are used to remove the symptoms and short-

term risks of high blood glucose, to prevent longer term complications, and also used to

detect and treat any complications early if they do arise. This also gives rise to polypharmacy

which is prevalent in patients nearing the end of life.26 Polypharmacy in patients with limited

life expectancy is associated with increased risk of adverse events that leads to poor quality

of life and reduced survival.12 The cumulative dangers of polypharmacy including the rise in

anticholinergic and serotonergic loads in those nearing death are well reported in literatures.26

In these patients, total medication burden increases due to continuation of medications for co-

morbid conditions, and addition of medications for symptom control.21

Therefore, the continuing challenge for prescribing physicians and patients is to thoroughly

reconsider medications that are really needed (prioritization) and medications that could be

stopped (discontinuation) in a timely manner without further contributing to symptom burden

as a result of discontinuation symptoms.27 These aspects of pharmacotherapy are central;

since the goals of care for patients with reduced life expectancy becomes palliative rather

than curative.5 Preventive medications that are used for long-term prevention and

management of chronic conditions in these populations might be inappropriate given the time

until benefit can be several years.6, 7 A common example in a frail patient with a life

expectancy of few months is the use of statins to lower serum cholesterol levels and hence

improve long term cardiovascular disease risk or antiresorptive therapy for osteoporosis,

which will have no benefit as the onset of measurable effects, will occur too late to be of any

benefit.28

A number of tools or indices have been developed to assist clinicians to aid prescribing

decisions in older people.29-34 Inappropriate prescribing can be detected using criterion-based

(explicit) or judgment-based (implicit) tools. Explicit criteria are derived from expert reports

or published reviews while implicit criteria rely on evaluator judgments.35 Some widely used

criteria to aid prescribing decisions in older people are the Beers criteria, the Screening Tool

of Older Persons potentially inappropriate Prescribing (STOPP) criteria and the Medication

Appropriateness Index (MAI). Limitation of these criteria is that they focus entirely on older

populations, who are only a subset of persons at end of life. This is of particular concern for

several reasons. Firstly, all patients with life limiting illness are not always older and

secondly, medications such as non –steroidal anti-inflammatory drugs (NSAIDs), short-

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

8

acting benzodiazepines and antidepressants commonly used in a palliative care setting for

symptomatic treatment associated with life limiting illness are considered inappropriate

according to these criteria. Our study reported statins as most frequently used inappropriate

preventive medication but criteria such as Beers and STOPP do not consider lipid-lowering

medications as inappropriate, as this class of drug are not part of these instruments. These

tools require adaptation so that they can be used in all patients with life limiting illnesses

even if they are not under the care of a specialist palliative care service.

Holmes and colleagues have proposed a prescribing model that is specific to this population5

but the framework is highly conceptual and is difficult to apply within a busy clinical setting.

Given this lack of standardisation, there is a clear need for guidelines and frameworks to

guide prescribing for populations with life-limiting illness. Patients with life-limiting illness

should benefit from an approach that evaluates their function level and considers their

remaining life expectancy with frequent monitoring and review. Unfortunately, the currently

available tools, guidelines and algorithms to optimize appropriate use of medication are

applicable only to robust, healthy older adults aged 65 and older which can’t be generalized

in to frail patients with limited life expectancy.35, 36 Moreover, there is minimal consensus on

how best to assess medication use at the end of life because of varied expert opinions and

limited evidence on the safety and efficacy of medications and limited research on the

patient’s views on their preferences with regards which medicines to stop to achieve their

personalised goals of therapy.37, 38

Deprescribing- a term used to describe the rationalisation of medicines has gained particular

attention in recent years. It is defined as the systematic process of identifying and

discontinuing drugs when existing or potential harms outweigh existing or potential benefits

within the context of an individual patient’s care goals, current level of functioning, life

expectancy, values, and preferences.39 From the studies identified in our review, only four

reported instances of medication withdrawal. Currow et al reported a steady reduction in

number of medication for comorbidities as death approached but there was an increase in the

number of medications with a Beers’ criterion of high risk for inappropriate use in older

people for symptom-specific medications (29% to 48%).13 A randomised controlled trial by

Kutner et al in a population with a median survival of approximately 7 months and primary

diseases evenly divided between cancer and noncancer diagnoses had 189 patients whose

statin therapy was discontinued.19 They found that stopping statin therapy is safe and helps

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

9

improve quality of life. Riechelman et al reported that 78 (20%) patients with advanced

cancer after being assessed by the palliative care team, continued on at least one futile

medication while statins were discontinued in four patients.15 Silveria et al observed no

difference in statin prescribing patterns by presence of recognizable, life limiting condition,

but witnessed some statin discontinuation for all patients over time.16 While the studies

involved in this review report increased medication burden towards the end of life,

generalization is difficult because studies were limited only up to two years of life expectancy

which might be significantly confounded by physicians inability to predict survival.

Extensive deprescribing, however, might not be an intervention that directly improves

outcomes. Considering polypharmacy as always hazardous and a powerful indicator for

medication review need to be reconsidered based on the clinical context of the intended use.40

While all long-term preventive medications should be reviewed to determine which

medicines could be discontinued safely in the time available, new symptom control

medications that reduce the risk of adverse events may be introduced which might increase

the number of medications prescribed (appropriate polypharmacy). Deprescribing should be a

part of the good prescribing continuum, which must take into consideration of how long

treatment is required and when and how it should be discontinued when medicines are started

and throughout continuation of treatment. A discussion about patients’ current status and

likely disease trajectory should be initiated with the patient when medicines are started.

Discussion about how the medication fits into a treatment plan given this anticipated

trajectory and possible changes in goals of care should be included.41 There should be a plan

in place for medications that are no longer part of the overall care plan.

Healthcare professionals, patients and families with life-limiting illness continue to need

practical help in making decisions. Therefore, a consensus guideline is needed that aids

decision making which is in the best interest of the patient and patient’s families and in

accordance with the principles of good clinical practice. The consensus framework should

facilitate the development of a pragmatic and easily applied algorithm for medication review

that offers an evidence-based approach for decisions to withhold, withdraw or limit

preventive medications in patients with life-limiting illness. It should also encourage users to

explore evidence-based non-pharmacological methods of treatment as an option and

encourage understanding of patient needs from a biopsychosocial perspective to enable

improved collaboration.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

10

CONCLUSION

Patients continue to receive medications that are not prescribed as symptomatic treatment

despite having a limited life expectancy. Very few rigorous studies have been conducted on

reducing preventive medications in patients with limited life expectancy and expert opinion

varies on medication optimisation at the end of life.

Therefore, bringing together key stakeholders including medical experts to develop a

consensus guideline for practical use that addresses this gap is of paramount importance. The

guideline should provide a framework in which decisions can be made based on good clinical

practice and best interest of the patient and patient’s families.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

11

References

1. Larcher V, Craig F, Bhogal K, Wilkinson D, Brierley J. Making decisions to limit treatment in life-limiting and life-threatening conditions in children: a framework for practice. Arch Dis Child. 2015;100 Suppl 2:s3-23. 2. Stevenson J, Abernethy AP, Miller C, Currow DC. Managing comorbidities in patients at the end of life. BMJ. 2004;329:909-912. 3. Holmes HM. Rational prescribing for patients with a reduced life expectancy. Clin Pharmacol Ther. 2009;85:103-107. 4. Maddison AR, Fisher J, Johnston G. Preventive medication use among persons with limited life expectancy. Progress in palliative care. 2011;19:15-21. 5. Holmes HM, Hayley DC, Alexander GC, Sachs GA. Reconsidering medication appropriateness for patients late in life. Arch Intern Med. 2006;166:605-609. 6. Lee SJ, Leipzig RM, Walter LC. Incorporating lag time to benefit into prevention decisions for older adults. JAMA. 2013;310:2609-2610. 7. Todd A, Husband A, Andrew I, et al. Inappropriate prescribing of preventative medication in patients with life-limiting illness: a systematic review. BMJ supportive & palliative care. 2016. 8. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA StatementThe PRISMA Statement. Ann Intern Med. 2009;151:264-269. 9. Barcelo M, Torres O, Ruiz D, Casademont J. Appropriateness of medications prescribed to elderly patients with advanced heart failure and limited life expectancy who died during hospitalization. Drugs Aging. 2014;31:541-546. 10. Fede A, Miranda M, Antonangelo D, et al. Use of unnecessary medications by patients with advanced cancer: cross-sectional survey. Support Care Cancer. 2011;19:1313-1318. 11. Lindsay J, Dooley M, Martin J, et al. The development and evaluation of an oncological palliative care deprescribing guideline: the 'OncPal deprescribing guideline'. Support Care Cancer. 2015;23:71-78. 12. Onder G, Liperoti R, Foebel A, et al. Polypharmacy and mortality among nursing home residents with advanced cognitive impairment: results from the SHELTER study. J Am Med Dir Assoc. 2013;14:450.e457-412. 13. Currow DC, Stevenson JP, Abernethy AP, Plummer J, Shelby-James TM. Prescribing in palliative care as death approaches. J Am Geriatr Soc. 2007;55:590-595. 14. Evans N, Pasman HRW, Donker GA, et al. End-of-life care in general practice: A cross-sectional, retrospective survey of ‘cancer’, ‘organ failure’ and ‘old-age/dementia’ patients. Palliat Med. 2014;28:965-975 911p. 15. Riechelmann RP, Krzyzanowska MK, Zimmermann C. Futile medication use in terminally ill cancer patients. Support Care Cancer. 2009;17:745-748. 16. Silveira MJ, Kazanis AS, Shevrin MP. Statins in the last six months of life: a recognizable, life-limiting condition does not decrease their use. J Palliat Med. 2008;11:685-693. 17. Blass DM, Black BS, Phillips H, et al. Medication use in nursing home residents with advanced dementia. Int J Geriatr Psychiatry. 2008;23:490-496. 18. Heppenstall CP, Broad JB, Boyd M, et al. Medication use and potentially inappropriate medications in those with limited prognosis living in residential aged care. Australas J Ageing. 2015.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

12

19. Kutner JS, Blatchford PJ, Taylor DH, Jr., et al. Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial. JAMA internal medicine. 2015;175:691-700. 20. Sera L, McPherson ML, Holmes HM. Commonly prescribed medications in a population of hospice patients. Am J Hosp Palliat Care. 2014;31:126-131. 21. McLean S, Sheehy-Skeffington B, O'Leary N, O'Gorman A. Pharmacological management of co-morbid conditions at the end of life: is less more? Ir J Med Sci. 2013;182:107-112. 22. Min LC, Wenger NS, Fung C, et al. Multimorbidity is associated with better quality of care among vulnerable elders. Med Care. 2007;45:480-488. 23. Russell BJ, Rowett D, Abernethy AP, Currow DC. Prescribing for comorbid disease in a palliative population: focus on the use of lipid-lowering medications. Intern Med J. 2014;44:177-184. 24. Stavrou EP, Buckley N, Olivier J, Pearson S-A. Discontinuation of statin therapy in older people: does a cancer diagnosis make a difference? An observational cohort study using data linkage. BMJ open. 2012;2:e000880. 25. Tjia J, Cutrona SL, Peterson D, et al. Statin discontinuation in nursing home residents with advanced dementia. J Am Geriatr Soc. 2014;62:2095-2101. 26. LeBlanc TW, McNeil MJ, Kamal AH, Currow DC, Abernethy AP. Polypharmacy in patients with advanced cancer and the role of medication discontinuation. Lancet Oncol. 2015;16:e333-341. 27. Alexander GC, Sayla MA, Holmes HM, Sachs GA. Prioritizing and stopping prescription medicines. CMAJ. 2006;174:1083-1084. 28. Sergi G, De Rui M, Sarti S, Manzato E. Polypharmacy in the elderly: can comprehensive geriatric assessment reduce inappropriate medication use? Drugs Aging. 2011;28:509-518. 29. Campanelli CM. American Geriatrics Society updated beers criteria for potentially inappropriate medication use in older adults: the American Geriatrics Society 2012 Beers Criteria Update Expert Panel. J Am Geriatr Soc. 2012;60:616. 30. O'Mahony D, O'Sullivan D, Byrne S, et al. STOPP/START criteria for potentially inappropriate prescribing in older people: version 2. Age Ageing. 2014:afu145. 31. Knight EL, Avorn J. Quality indicators for appropriate medication use in vulnerable elders. Ann Intern Med. 2001;135:703-710. 32. McLeod PJ, Huang AR, Tamblyn RM, Gayton DC. Defining inappropriate practices in prescribing for elderly people: a national consensus panel. Can Med Assoc J. 1997;156:385-391. 33. Basger BJ, Chen TF, Moles RJ. Inappropriate medication use and prescribing indicators in elderly Australians. Drugs Aging. 2008;25:777-793. 34. Hanlon JT, Schmader KE, Samsa GP, et al. A method for assessing drug therapy appropriateness. J Clin Epidemiol. 1992;45:1045-1051. 35. Poudel A, Hubbard RE, Nissen L, Mitchell C. Frailty: a key indicator to minimize inappropriate medication in older people. QJM. 2013:hct146. 36. Poudel A, Peel NM, Nissen L, et al. A systematic review of prescribing criteria to evaluate appropriateness of medications in frail older people. Rev Clin Gerontol. 2014;24:304-318. 37. Greene B. Transformative advance care planning: the Honoring Choices Minnesota experience. Creat Nurs. 2013;19:200-204. 38. Steinhauser KE, Christakis NA, Clipp EC, et al. Factors considered important at the end of life by patients, family, physicians, and other care providers. JAMA. 2000;284:2476-2482.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

13

39. Scott IA, Hilmer SN, Reeve E, et al. Reducing inappropriate polypharmacy: the process of deprescribing. JAMA internal medicine. 2015;175:827-834. 40. Payne RA, Abel GA, Avery AJ, Mercer SW, Roland MO. Is polypharmacy always hazardous? A retrospective cohort analysis using linked electronic health records from primary and secondary care. Br J Clin Pharmacol. 2014;77:1073-1082. 41. Todd A, Holmes HM. Recommendations to support deprescribing medications late in life. Int J Clin Pharm. 2015;37:678-681.

Disclosures and Acknowledgments

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

14

Appendix 1: Example of Medline search strategy (online only)

1. life limiting illness

2. life limiting condition

3. advanced cancer

4. advanced dementia

5. advanced COPD

6. end stage renal failure

7. advanced heart failure

8. limited life expectancy

9. diminished life expectancy

10. short life expectancy

11. end of life

12. terminal

13. palliative

14. Combine 1-13

15. preventive medication

16. preventive medicine

17. preventive medication use

18. statin

19. bisphosphonate

20. antiplatelet

21. antihypertensive

22. vitamins

23. minerals

24. Combine 15-23

25. Combine 14 and 24

Filters: Publication date from 1995/01/01 to 2015/12/31;

Humans;

English;

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

Table 1: An overview of included studies

Reference,

year,

country

Study

design/setting

Population

characteristics

Sample (n);

Age (years)

Remaining

life

expectancy

Study outcome Examples of

preventive

medication used

Evidence

of

medicati

on dis-

continua

tion

Barcelo et

al., 2014,

Spain9

Retrospective

study in

geriatric ward

n = 72, mean

age 85.4 years

Median

survival of

≤6 months

Patients were receiving substantial

number of prophylactic medications,

medications to prolong life and other

inappropriate treatments

Antiplatelets, oral

anticoagulants,

statins, osteoporosis

medications

No

Blass et al.,

2008, USA17

Prospective

cohort study in

nursing home

n = 125, mean

age 81.5 (SD

7.1) years

12 months Patients were prescribed multiple

medications and the total number

remained fairly stable as death

approached. Even during the final stage

Antibiotics,

pulmonary agents.

No

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

of dementia, patients were prescribed

both palliative and non-palliative

pharmacological treatment

Currow et

al., 2007,

Australia13

Prospective

cohort study in

specialized

palliative care

services.

n = 260, mean

age 71 ± 12

4 months As death approached, there was an

increase in number of high risk

inappropriate medications (from 29% to

48%). Symptom-specific medications

were prescribed more in people with

better performance status

Proton pump

inhibitors, digoxin,

amiodarone, aspirin,

iron supplements

Yes

Evans et al.,

2014,

Netherlands

14

Cross-sectional

retrospective

study in a

general

practice

network

n = 688, mean

age; patients

with cancer

71.67, organ

failure 82.23

and old-

3 months The findings suggest the need to

integrate palliative care with optimal

disease management to initiate advance

care planning early in the chronic disease

trajectory

NA No

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

age/dementia

87.70

Fede et al.,

2011, Brazil

10

Cross sectional

study in

teaching

hospital

n = 87, median

age 61 years

(range 27-88

years)

6 months Patients with advanced cancer are

prescribed with many unnecessary

medications. Routine medication

reconciliation in this patient group is

warranted

Statins, antidiabetic,

gastric protectors

No

Heppenstall

et al., 2015,

New

Zealand18

Cross-sectional

study in

residential

aged care

facility

n = 6196,

median age 86

years

12 months Cardiovascular preventative medications

were significantly more common in those

who died within 12 months.

Psychotropics were prescribed in 70%

patients in high-level care. Potentially

inappropriate medications were also

commonly used

Psychotropics, anti-

hypertensives, anti-

platelet, statins,

bisphosphonates

No

Kutner et al., Multicenter, n = 381, mean 12 months Discontinuing statin in populations with Statins Yes

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

2015, USA19

unblinded

clinical trial in

palliative care

age 74.1 ± 11.6

limited life expectancies is safe and is

associated with improved quality of life

as well as reduced medication costs.

Patient-provider discussions regarding

the uncertain benefits with statin use in

these populations are needed

Lindsay et

al., 2015,

Australia11

Prospective

cohort study in

teaching

hospital

n = 61, median

age 66 years

< 6 months Of total medications prescribed, 21.4%

were identified as potentially

inappropriate medications (PIMs). Forty-

three (70 %) patients were taking at least

one PIM

Aspirin/

anticoagulants,

dyslipidemia,

antihypertensive,

psychotropics,

steroids

No

McLean et

al., 2013,

Ireland 21

Retrospective

review in

palliative care

n = 52, median

age 74.5 years

(range 36-91

24 months One week before death, one-third of

patients continued to be prescribed

aspirin, and over one-quarter a statin

Aspirin, statin No

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

years)

Min et al.,

2007, Japan

22

Observational

cohort study in

community

settings

n = 372, mean

age 81 years

24 months Quality improvement initiatives aimed at

the care of vulnerable older adults can

be based on quality measures that take

into account life expectancy and patient

preferences

NA No

Onder et al.,

2013, Italy 12

Cross sectional

study in

nursing homes

n = 822, mean

age 84.6 (SD

8.0) years

6 months Life expectancy should be assessed in

older adults to optimize prescribing and

to simplify drug regimens among those

with limited life expectancy

Beta blockers,

digoxin, antibiotics

No

Riechelmann

et al., 2009,

Canada 15

Retrospective

study in

teaching

hospital

n = 372,

median age 66

years (range

22-94 years)

Median

survival of 2

months

About one fifth of cancer patients at the

end of life take futile medications

Statins, allopurinol,

multivitamins

Yes

Russell et al., Prospective n = 203, mean 24 months Polypharmacy was prevalent in this Statins and other No

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

2014,

Australia23

review in

palliative care

service

age 72.9 ± 12.6

population, with an average of more

than seven medications per patient

lipid-lowering

medications

Sera et al.,

2014, USA 20

Retrospective

cross-sectional

study in

palliative care

n = 4252,

mean age 77.5

(SD 14.3) years

12 months Several commonly used drugs were likely

being used to treat chronic conditions

such as metoprolol for hypertension,

simvastatin for hyperlipidemia, and

aspirin for cardioprotection in patients in

the last month of life

Anxiolytics,

anticholinergics,

antipsychotics

No

Silveira et al.,

2008, USA 16

Case-control

trial in

Veterans

medical center

n = 1584, age:

cases 72.5 ±

9.1, controls

74.6 ± .9

6 months Statins are prescribed frequently in the

last year of life. Patient’s diagnosis had

no effect on prescribing patterns

Statins Yes

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

1

Table 2: List of medications used

Author Medication used

Preventive Symptom control

Barcelo et al

Antiplatelet

Anticoagulants

ACE inhibitors or ARBs*

Calcium channel blockers

Diuretics

Corticosteroids

Alpha-blockers

Beta-blockers

Chlorpropamide

Vitamins

Antidepressants

Benzodiazepines

Opiates

Iron

Statins

Antiosteoporosis drugs

Antibiotics

Non-opiate analgesics

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

2

Blass et al

Gastrointestinal

Cardiovascular

Dermatologic

Opiate analgesics

Antidementia drugs

Antipsychotics

Oral hypoglycaemic agents

Statins

Currow et al

Gastrointestinal

Diuretics

Inhaled corticosteroids and bronchodilators

Nitrates

Beta-blockers

Antiulcer agents

Beta-blockers

Digoxin

Iron

Antiplatelet

Evans et al NA

Fede et al

Statins

Gastrointestinal

Oral hypoglycaemic agents

Vitamin D with calcium

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

3

ACE inhibitors or ARBs

Beta-blockers

Oral hypoglycaemic agents

Heppenstall

et al

Antipsychotics

Analgesics

Alpha-blockers

Antiplatelet

Diuretics

Statins

Antiosteoporosis drugs

Inhaled corticosteroids and bronchodilators

Oral hypoglycaemic agents

Warfarin

Antiparkinsonian drugs

Kutner et al Statins

Antiplatelet

Anticoagulants

Alpha-blockers

Statins

Antiosteoporosis drugs

Gastrointestinal

Oral hypoglycaemic agents

Opiate analgesics

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

4

Lindsay et al

Non-opioid analgesics

Corticosteroids

Analgesics

Laxatives

Benzodiazepines

Antiemetics

Insulins

Inhaled corticosteroids and bronchodilators

Antipsychotics

McLean et al

Antiplatelet

Beta-blockers

Statins

Diuretics

ACE inhibitors or ARBs

Calcium channel blockers

Antiosteoporosis drugs

Digoxin

Min et al NA

Gastrointestinal

Antipsychotics

Antidementia drugs

Antidepressants

Diuretics

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

5

Onder et al

Antiplatelet

ACE inhibitors or ARBs

Beta-blockers

Calcium channel blockers

Statins

Digoxin

Antiosteoporosis drugs

Oral hypoglycaemic agents

Insulin

Vitamins

Corticosteroids

Riechelmann

et al

Statins

Multivitamins

Benzodiazepines

Analgesics

Russell et al Statins

Opiate analgesics

Anxiolytic

Non opioid analgesic

Anticholinergic

Antipsychotic

Antihypertensive

Statins

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

6

Sera et al

Bronchodilator

Acid reducer

Antiinfective

Antidepressant

Multivitamins

Diuretics

Corticosteroids

Antiplatelet

Antiemetics

Thyroid Hormones

Silveira et al Statins

*ACEI = angiotensin converting enzyme inhibitor *ARB = angiotensin receptor blocker

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT