This may be the author’s version of a work that was submitted/accepted for publication in the following source: Poudel, Arjun, Yates, Patsy, Rowett, Debra, & Nissen, Lisa (2017) Use of preventive medication in patients with limited life expectancy: a systematic 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 a Creative Commons Licence, you must assume that re-use is limited to personal use and that 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 refer to 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 that this work infringes copyright please provide details by email to [email protected]License: Creative Commons: Attribution-Noncommercial-No Derivative Works 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) can be 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
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c Consult author(s) regarding copyright matters License · The most common preventive class of medication used was the lipid-lowering medications, especially the statins reported
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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/
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 [email protected]
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.
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.
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
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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-
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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
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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.
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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.
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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.
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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.
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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.
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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;
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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
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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
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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
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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
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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