- Email: [email protected]
Use of Preventive Medication in Patients With Limited Life Expectancy: A Systematic Review
Accepted Manuscript Use of preventive medication in patients with limited life expectancy: a systematic review 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 in patients 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 to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Review Article
16-00497R1
Use of preventive medication in patients with limited life expectancy: a systematic review
Lisa M Nissen, PhD1
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Arjun Poudel, PhD1, Patsy Yates, PhD2, Debra Rowett, BPharm3,
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1. School of Clinical Sciences, Queensland University of Technology, Brisbane, Australia
2. School of Nursing, Queensland University of Technology, Brisbane, Australia
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3. Repatriation General Hospital, Adelaide, Australia
Corresponding author Arjun Poudel, PhD
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Research Associate, School of Clinical Sciences
Faculty of Health, Queensland University of Technology Q Block (Level 9), Brisbane, QLD 4000
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Ph: +61424356506 Email: [email protected]
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Word count: Text: 2603 Abstract: 242
Number of refs: 41
Tables: 2
Figure: 1
1
ACCEPTED MANUSCRIPT ABSTRACT Context: Optimal prescribing in patients with limited life expectancy remains unclear.
Objectives: This study systematically reviews the published literature regarding the use of
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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
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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.
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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
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medication followed by antiplatelets, ACE inhibitors and ARBs, anti-osteoporosis medications, and calcium channel blockers. Only four studies reported the instances of medication withdrawal.
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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
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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.
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ACCEPTED MANUSCRIPT 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
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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
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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,
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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
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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
1.2 Objectives
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achieved if prescribing is appropriate and regularly evaluated in this population.
To assist prescribing in patients with limited life expectancy, various guidelines and a series
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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
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ACCEPTED MANUSCRIPT 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
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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
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as the elderly patients. Conference abstracts and review articles were also excluded.
2.1.2 Participants
prescribed preventive medications.
2.2 Information Source
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Eligible studies included participants with a limited life expectancy of ≤ 2 years who were
The search was conducted using electronic databases including MEDLINE, EMBASE and
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CINAHL. Articles published in English between January 1995 and December 2015 were retrieved for analysis. The bibliographies of relevant articles were hand searched for
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additional studies.
2.3 Search Strategies
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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
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ACCEPTED MANUSCRIPT 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
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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
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potential for small study effects such as publication bias could be assessed but since metaanalysis was not conducted, this was not possible. Also, limiting search to only English
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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.
3.1 Study Selection
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3 RESULTS
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
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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
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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 5
ACCEPTED MANUSCRIPT 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
3.4 Types of preventive medication
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studies.21-23 The average remaining life expectancy was approximately 11 months.
The most common preventive class of medication used was the lipid-lowering medications, 15-19, 21, 23
commonly used preventive medications were antiplatelet,9,
11-13, 18, 20, 21
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especially the statins reported in the majority of studies.9-12,
Other classes of Angiotensin
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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,
4 DISCUSSION
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19
In this review, we compiled studies that documented the use of preventive medication in
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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
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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 6
ACCEPTED MANUSCRIPT 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 shortterm 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
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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-
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morbid conditions, and addition of medications for symptom control.21
Therefore, the continuing challenge for prescribing physicians and patients is to thoroughly
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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 7
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until benefit can be several years.6,
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,
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benefit.28
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which will have no benefit as the onset of measurable effects, will occur too late to be of any
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), short7
ACCEPTED MANUSCRIPT 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
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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
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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
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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
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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
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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
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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 8
ACCEPTED MANUSCRIPT 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
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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.
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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
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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
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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
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trajectory and possible changes in goals of care should be included.41 There should be a plan
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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. 9
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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
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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
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guideline should provide a framework in which decisions can be made based on good clinical
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practice and best interest of the patient and patient’s families.
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ACCEPTED MANUSCRIPT References
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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;19:13131318. 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;11:685693. 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;284:24762482. 12
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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
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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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ACCEPTED MANUSCRIPT Appendix 1: Example of Medline search strategy (online only)
1. life limiting illness 2. life limiting condition 3. advanced cancer
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4. advanced dementia 5. advanced COPD 6. end stage renal failure 7. advanced heart failure
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8. limited life expectancy 9. diminished life expectancy 10. short life expectancy
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11. end of life 12. terminal 13. palliative 14. Combine 1-13 15. preventive medication
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16. preventive medicine 17. preventive medication use 18. statin 19. bisphosphonate
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20. antiplatelet 21. antihypertensive
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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 Population
Remaining
year,
design/setting
characteristics
life
Sample (n);
expectancy
country
Study outcome
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Study
Examples of
Evidence
preventive
of
medication used
medicati
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Reference,
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Age (years)
on discontinua tion
Retrospective
n = 72, mean
Median
Patients were receiving substantial
Antiplatelets, oral
al., 2014,
study in
age 85.4 years
survival of
number of prophylactic medications,
anticoagulants,
Spain9
geriatric ward
≤6 months
medications to prolong life and other
statins, osteoporosis
inappropriate treatments
medications
Patients were prescribed multiple
Antibiotics, pulmonary agents.
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Blass et al.,
Prospective
12 months
2008, USA17
cohort study in age 81.5 (SD
medications and the total number
nursing home
remained fairly stable as death
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n = 125, mean
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Barcelo et
7.1) years
approached. Even during the final stage
No
No
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of dementia, patients were prescribed
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both palliative and non-palliative pharmacological treatment 4 months
As death approached, there was an
al., 2007,
cohort study in age 71 ± 12
increase in number of high risk
inhibitors, digoxin,
Australia13
specialized
inappropriate medications (from 29% to
amiodarone, aspirin,
palliative care
48%). Symptom-specific medications
iron supplements
services.
were prescribed more in people with
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Prospective
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n = 260, mean
Proton pump
Currow et
Yes
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better performance status
Evans et al.,
Cross-sectional n = 688, mean
2014,
retrospective
age; patients
Netherlands
study in a
with cancer
14
general
71.67, organ
care planning early in the chronic disease
practice
failure 82.23
trajectory
network
and old-
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3 months
The findings suggest the need to integrate palliative care with optimal disease management to initiate advance
NA
No
ACCEPTED MANUSCRIPT
age/dementia
n = 87, median
2011, Brazil
study in
10
6 months
Patients with advanced cancer are
Statins, antidiabetic,
age 61 years
prescribed with many unnecessary
gastric protectors
teaching
(range 27-88
medications. Routine medication
hospital
years)
reconciliation in this patient group is
No
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Cross sectional
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Fede et al.,
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87.70
warranted
et al., 2015,
study in
median age 86
New
residential
years
Zealand18
aged care
12 months
Kutner et al.,
Multicenter,
n = 381, mean
Psychotropics, anti-
No
were significantly more common in those hypertensives, anti-
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facility
Cardiovascular preventative medications
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Cross-sectional n = 6196,
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Heppenstall
12 months
who died within 12 months.
platelet, statins,
Psychotropics were prescribed in 70%
bisphosphonates
patients in high-level care. Potentially inappropriate medications were also commonly used Discontinuing statin in populations with
Statins
Yes
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unblinded
age 74.1 ± 11.6
limited life expectancies is safe and is
clinical trial in
associated with improved quality of life
palliative care
as well as reduced medication costs.
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2015, USA19
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Patient-provider discussions regarding the uncertain benefits with statin use in
Lindsay et
Prospective
al., 2015, Australia11
n = 61, median
Of total medications prescribed, 21.4%
Aspirin/
cohort study in age 66 years
were identified as potentially
anticoagulants,
teaching
inappropriate medications (PIMs). Forty-
dyslipidemia,
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< 6 months
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these populations are needed
three (70 %) patients were taking at least antihypertensive,
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hospital
No
24 months
one PIM
psychotropics, steroids
McLean et
Retrospective
n = 52, median
One week before death, one-third of
al., 2013,
review in
age 74.5 years
patients continued to be prescribed
Ireland 21
palliative care
(range 36-91
aspirin, and over one-quarter a statin
Aspirin, statin
No
ACCEPTED MANUSCRIPT
years) n = 372, mean
Observational
24 months
Quality improvement initiatives aimed at
NA
No
2007, Japan
cohort study in age 81 years
the care of vulnerable older adults can
22
community
be based on quality measures that take
settings
into account life expectancy and patient
Life expectancy should be assessed in
Beta blockers,
No
digoxin, antibiotics
Onder et al.,
Cross sectional
n = 822, mean
2013, Italy 12
study in
age 84.6 (SD
older adults to optimize prescribing and
nursing homes
8.0) years
to simplify drug regimens among those
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6 months
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preferences
SC
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Min et al.,
with limited life expectancy
n = 372,
et al., 2009,
study in
median age 66
Canada 15
teaching
years (range
hospital
22-94 years)
Prospective
n = 203, mean
Russell et al.,
Median
About one fifth of cancer patients at the
Statins, allopurinol,
survival of 2
end of life take futile medications
multivitamins
Polypharmacy was prevalent in this
Statins and other
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Retrospective
Yes
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Riechelmann
months
24 months
No
ACCEPTED MANUSCRIPT
review in
Australia23
palliative care
age 72.9 ± 12.6
population, with an average of more
lipid-lowering
than seven medications per patient
medications
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2014,
service Retrospective
n = 4252,
2014, USA 20
cross-sectional
mean age 77.5
being used to treat chronic conditions
anticholinergics,
study in
(SD 14.3) years
such as metoprolol for hypertension,
antipsychotics
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SC
12 months
Several commonly used drugs were likely Anxiolytics,
Sera et al.,
palliative care
No
simvastatin for hyperlipidemia, and aspirin for cardioprotection in patients in
2008, USA 16
trial in
cases 72.5 ±
Veterans
9.1, controls
medical center
74.6 ± .9
6 months
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n = 1584, age:
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Silveira et al., Case-control
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the last month of life
Statins are prescribed frequently in the last year of life. Patient’s diagnosis had no effect on prescribing patterns
Statins
Yes
ACCEPTED MANUSCRIPT Table 2: List of medications used Author
Medication used
Symptom control
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Preventive
Antiplatelet
ACE inhibitors or ARBs*
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Calcium channel blockers
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Anticoagulants
Diuretics
Corticosteroids Alpha-blockers
Chlorpropamide
Vitamins
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EP
Barcelo et al
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Beta-blockers
Antidepressants Benzodiazepines Opiates
Iron Statins
Antiosteoporosis drugs Antibiotics Non-opiate analgesics
1
ACCEPTED MANUSCRIPT Gastrointestinal Cardiovascular Dermatologic Blass et al Antidementia drugs Antipsychotics
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Opiate analgesics
SC
Oral hypoglycaemic agents Statins
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Gastrointestinal Diuretics
Inhaled corticosteroids and bronchodilators Nitrates
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Beta-blockers
Currow et al
Antiulcer agents Beta-blockers
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Digoxin
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Iron
Evans et al
Antiplatelet
NA
Statins Gastrointestinal
Fede et al
Oral hypoglycaemic agents Vitamin D with calcium
2
ACCEPTED MANUSCRIPT ACE inhibitors or ARBs Beta-blockers Oral hypoglycaemic agents
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Antipsychotics Analgesics
Alpha-blockers
Diuretics Statins
et al
Antiosteoporosis drugs
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Heppenstall
SC
Antiplatelet
Inhaled corticosteroids and bronchodilators Oral hypoglycaemic agents
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Warfarin
Antiparkinsonian drugs
Kutner et al
Statins
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Antiplatelet
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Anticoagulants Alpha-blockers Statins
Antiosteoporosis drugs Gastrointestinal Oral hypoglycaemic agents Opiate analgesics
3
ACCEPTED MANUSCRIPT Lindsay et al
Non-opioid analgesics Corticosteroids Analgesics
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Laxatives Benzodiazepines Antiemetics
SC
Insulins
Inhaled corticosteroids and bronchodilators
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Antipsychotics Antiplatelet
Beta-blockers
Statins
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Diuretics
McLean et al
ACE inhibitors or ARBs
Calcium channel blockers
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EP
Antiosteoporosis drugs
Min et al
Digoxin
NA
Gastrointestinal Antipsychotics Antidementia drugs Antidepressants Diuretics
4
ACCEPTED MANUSCRIPT Antiplatelet ACE inhibitors or ARBs Onder et al
Beta-blockers
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Calcium channel blockers Statins Digoxin
SC
Antiosteoporosis drugs
Oral hypoglycaemic agents
Vitamins
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Insulin
Corticosteroids
Statins Riechelmann
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Benzodiazepines Analgesics
Statins Opiate analgesics
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Russell et al
EP
et al
Multivitamins
Anxiolytic Non opioid analgesic Anticholinergic Antipsychotic
Antihypertensive Statins
5
ACCEPTED MANUSCRIPT Sera et al
Bronchodilator Acid reducer Antiinfective
Multivitamins Diuretics
SC
Corticosteroids
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Antidepressant
Antiplatelet
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Antiemetics
Thyroid Hormones
Silveira et al
Statins
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EP
TE D
*ACEI = angiotensin converting enzyme inhibitor *ARB = angiotensin receptor blocker
6
AC C
EP
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SC
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ACCEPTED MANUSCRIPT
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 in patients 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 to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Review Article
16-00497R1
Use of preventive medication in patients with limited life expectancy: a systematic review
Lisa M Nissen, PhD1
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Arjun Poudel, PhD1, Patsy Yates, PhD2, Debra Rowett, BPharm3,
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1. School of Clinical Sciences, Queensland University of Technology, Brisbane, Australia
2. School of Nursing, Queensland University of Technology, Brisbane, Australia
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3. Repatriation General Hospital, Adelaide, Australia
Corresponding author Arjun Poudel, PhD
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Research Associate, School of Clinical Sciences
Faculty of Health, Queensland University of Technology Q Block (Level 9), Brisbane, QLD 4000
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Ph: +61424356506 Email: [email protected]
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Word count: Text: 2603 Abstract: 242
Number of refs: 41
Tables: 2
Figure: 1
1
ACCEPTED MANUSCRIPT ABSTRACT Context: Optimal prescribing in patients with limited life expectancy remains unclear.
Objectives: This study systematically reviews the published literature regarding the use of
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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
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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.
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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
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medication followed by antiplatelets, ACE inhibitors and ARBs, anti-osteoporosis medications, and calcium channel blockers. Only four studies reported the instances of medication withdrawal.
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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
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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.
2
ACCEPTED MANUSCRIPT 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
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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
SC
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,
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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
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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
1.2 Objectives
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achieved if prescribing is appropriate and regularly evaluated in this population.
To assist prescribing in patients with limited life expectancy, various guidelines and a series
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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
3
ACCEPTED MANUSCRIPT 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
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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
SC
as the elderly patients. Conference abstracts and review articles were also excluded.
2.1.2 Participants
prescribed preventive medications.
2.2 Information Source
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Eligible studies included participants with a limited life expectancy of ≤ 2 years who were
The search was conducted using electronic databases including MEDLINE, EMBASE and
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CINAHL. Articles published in English between January 1995 and December 2015 were retrieved for analysis. The bibliographies of relevant articles were hand searched for
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additional studies.
2.3 Search Strategies
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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
4
ACCEPTED MANUSCRIPT 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
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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
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potential for small study effects such as publication bias could be assessed but since metaanalysis was not conducted, this was not possible. Also, limiting search to only English
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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.
3.1 Study Selection
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3 RESULTS
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
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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
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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 5
ACCEPTED MANUSCRIPT 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
3.4 Types of preventive medication
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studies.21-23 The average remaining life expectancy was approximately 11 months.
The most common preventive class of medication used was the lipid-lowering medications, 15-19, 21, 23
commonly used preventive medications were antiplatelet,9,
11-13, 18, 20, 21
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especially the statins reported in the majority of studies.9-12,
Other classes of Angiotensin
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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,
4 DISCUSSION
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19
In this review, we compiled studies that documented the use of preventive medication in
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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
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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 6
ACCEPTED MANUSCRIPT 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 shortterm 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
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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-
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morbid conditions, and addition of medications for symptom control.21
Therefore, the continuing challenge for prescribing physicians and patients is to thoroughly
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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 7
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until benefit can be several years.6,
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,
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benefit.28
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which will have no benefit as the onset of measurable effects, will occur too late to be of any
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), short7
ACCEPTED MANUSCRIPT 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
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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
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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
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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
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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
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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
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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 8
ACCEPTED MANUSCRIPT 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
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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.
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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
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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
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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
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trajectory and possible changes in goals of care should be included.41 There should be a plan
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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. 9
ACCEPTED MANUSCRIPT
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
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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
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guideline should provide a framework in which decisions can be made based on good clinical
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practice and best interest of the patient and patient’s families.
10
ACCEPTED MANUSCRIPT References
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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;19:13131318. 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;11:685693. 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;284:24762482. 12
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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
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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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ACCEPTED MANUSCRIPT Appendix 1: Example of Medline search strategy (online only)
1. life limiting illness 2. life limiting condition 3. advanced cancer
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4. advanced dementia 5. advanced COPD 6. end stage renal failure 7. advanced heart failure
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8. limited life expectancy 9. diminished life expectancy 10. short life expectancy
M AN U
11. end of life 12. terminal 13. palliative 14. Combine 1-13 15. preventive medication
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16. preventive medicine 17. preventive medication use 18. statin 19. bisphosphonate
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20. antiplatelet 21. antihypertensive
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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 Population
Remaining
year,
design/setting
characteristics
life
Sample (n);
expectancy
country
Study outcome
RI PT
Study
Examples of
Evidence
preventive
of
medication used
medicati
SC
Reference,
M AN U
Age (years)
on discontinua tion
Retrospective
n = 72, mean
Median
Patients were receiving substantial
Antiplatelets, oral
al., 2014,
study in
age 85.4 years
survival of
number of prophylactic medications,
anticoagulants,
Spain9
geriatric ward
≤6 months
medications to prolong life and other
statins, osteoporosis
inappropriate treatments
medications
Patients were prescribed multiple
Antibiotics, pulmonary agents.
EP
Blass et al.,
Prospective
12 months
2008, USA17
cohort study in age 81.5 (SD
medications and the total number
nursing home
remained fairly stable as death
AC C
n = 125, mean
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Barcelo et
7.1) years
approached. Even during the final stage
No
No
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of dementia, patients were prescribed
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both palliative and non-palliative pharmacological treatment 4 months
As death approached, there was an
al., 2007,
cohort study in age 71 ± 12
increase in number of high risk
inhibitors, digoxin,
Australia13
specialized
inappropriate medications (from 29% to
amiodarone, aspirin,
palliative care
48%). Symptom-specific medications
iron supplements
services.
were prescribed more in people with
SC
Prospective
M AN U
n = 260, mean
Proton pump
Currow et
Yes
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better performance status
Evans et al.,
Cross-sectional n = 688, mean
2014,
retrospective
age; patients
Netherlands
study in a
with cancer
14
general
71.67, organ
care planning early in the chronic disease
practice
failure 82.23
trajectory
network
and old-
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3 months
The findings suggest the need to integrate palliative care with optimal disease management to initiate advance
NA
No
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age/dementia
n = 87, median
2011, Brazil
study in
10
6 months
Patients with advanced cancer are
Statins, antidiabetic,
age 61 years
prescribed with many unnecessary
gastric protectors
teaching
(range 27-88
medications. Routine medication
hospital
years)
reconciliation in this patient group is
No
SC
Cross sectional
M AN U
Fede et al.,
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87.70
warranted
et al., 2015,
study in
median age 86
New
residential
years
Zealand18
aged care
12 months
Kutner et al.,
Multicenter,
n = 381, mean
Psychotropics, anti-
No
were significantly more common in those hypertensives, anti-
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facility
Cardiovascular preventative medications
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Cross-sectional n = 6196,
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Heppenstall
12 months
who died within 12 months.
platelet, statins,
Psychotropics were prescribed in 70%
bisphosphonates
patients in high-level care. Potentially inappropriate medications were also commonly used Discontinuing statin in populations with
Statins
Yes
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unblinded
age 74.1 ± 11.6
limited life expectancies is safe and is
clinical trial in
associated with improved quality of life
palliative care
as well as reduced medication costs.
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2015, USA19
SC
Patient-provider discussions regarding the uncertain benefits with statin use in
Lindsay et
Prospective
al., 2015, Australia11
n = 61, median
Of total medications prescribed, 21.4%
Aspirin/
cohort study in age 66 years
were identified as potentially
anticoagulants,
teaching
inappropriate medications (PIMs). Forty-
dyslipidemia,
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< 6 months
M AN U
these populations are needed
three (70 %) patients were taking at least antihypertensive,
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hospital
No
24 months
one PIM
psychotropics, steroids
McLean et
Retrospective
n = 52, median
One week before death, one-third of
al., 2013,
review in
age 74.5 years
patients continued to be prescribed
Ireland 21
palliative care
(range 36-91
aspirin, and over one-quarter a statin
Aspirin, statin
No
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years) n = 372, mean
Observational
24 months
Quality improvement initiatives aimed at
NA
No
2007, Japan
cohort study in age 81 years
the care of vulnerable older adults can
22
community
be based on quality measures that take
settings
into account life expectancy and patient
Life expectancy should be assessed in
Beta blockers,
No
digoxin, antibiotics
Onder et al.,
Cross sectional
n = 822, mean
2013, Italy 12
study in
age 84.6 (SD
older adults to optimize prescribing and
nursing homes
8.0) years
to simplify drug regimens among those
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6 months
M AN U
preferences
SC
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Min et al.,
with limited life expectancy
n = 372,
et al., 2009,
study in
median age 66
Canada 15
teaching
years (range
hospital
22-94 years)
Prospective
n = 203, mean
Russell et al.,
Median
About one fifth of cancer patients at the
Statins, allopurinol,
survival of 2
end of life take futile medications
multivitamins
Polypharmacy was prevalent in this
Statins and other
EP
Retrospective
Yes
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Riechelmann
months
24 months
No
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review in
Australia23
palliative care
age 72.9 ± 12.6
population, with an average of more
lipid-lowering
than seven medications per patient
medications
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2014,
service Retrospective
n = 4252,
2014, USA 20
cross-sectional
mean age 77.5
being used to treat chronic conditions
anticholinergics,
study in
(SD 14.3) years
such as metoprolol for hypertension,
antipsychotics
M AN U
SC
12 months
Several commonly used drugs were likely Anxiolytics,
Sera et al.,
palliative care
No
simvastatin for hyperlipidemia, and aspirin for cardioprotection in patients in
2008, USA 16
trial in
cases 72.5 ±
Veterans
9.1, controls
medical center
74.6 ± .9
6 months
EP
n = 1584, age:
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Silveira et al., Case-control
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the last month of life
Statins are prescribed frequently in the last year of life. Patient’s diagnosis had no effect on prescribing patterns
Statins
Yes
ACCEPTED MANUSCRIPT Table 2: List of medications used Author
Medication used
Symptom control
RI PT
Preventive
Antiplatelet
ACE inhibitors or ARBs*
M AN U
Calcium channel blockers
SC
Anticoagulants
Diuretics
Corticosteroids Alpha-blockers
Chlorpropamide
Vitamins
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EP
Barcelo et al
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Beta-blockers
Antidepressants Benzodiazepines Opiates
Iron Statins
Antiosteoporosis drugs Antibiotics Non-opiate analgesics
1
ACCEPTED MANUSCRIPT Gastrointestinal Cardiovascular Dermatologic Blass et al Antidementia drugs Antipsychotics
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Opiate analgesics
SC
Oral hypoglycaemic agents Statins
M AN U
Gastrointestinal Diuretics
Inhaled corticosteroids and bronchodilators Nitrates
TE D
Beta-blockers
Currow et al
Antiulcer agents Beta-blockers
EP
Digoxin
AC C
Iron
Evans et al
Antiplatelet
NA
Statins Gastrointestinal
Fede et al
Oral hypoglycaemic agents Vitamin D with calcium
2
ACCEPTED MANUSCRIPT ACE inhibitors or ARBs Beta-blockers Oral hypoglycaemic agents
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Antipsychotics Analgesics
Alpha-blockers
Diuretics Statins
et al
Antiosteoporosis drugs
M AN U
Heppenstall
SC
Antiplatelet
Inhaled corticosteroids and bronchodilators Oral hypoglycaemic agents
TE D
Warfarin
Antiparkinsonian drugs
Kutner et al
Statins
EP
Antiplatelet
AC C
Anticoagulants Alpha-blockers Statins
Antiosteoporosis drugs Gastrointestinal Oral hypoglycaemic agents Opiate analgesics
3
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Non-opioid analgesics Corticosteroids Analgesics
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Laxatives Benzodiazepines Antiemetics
SC
Insulins
Inhaled corticosteroids and bronchodilators
M AN U
Antipsychotics Antiplatelet
Beta-blockers
Statins
TE D
Diuretics
McLean et al
ACE inhibitors or ARBs
Calcium channel blockers
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EP
Antiosteoporosis drugs
Min et al
Digoxin
NA
Gastrointestinal Antipsychotics Antidementia drugs Antidepressants Diuretics
4
ACCEPTED MANUSCRIPT Antiplatelet ACE inhibitors or ARBs Onder et al
Beta-blockers
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Calcium channel blockers Statins Digoxin
SC
Antiosteoporosis drugs
Oral hypoglycaemic agents
Vitamins
M AN U
Insulin
Corticosteroids
Statins Riechelmann
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Benzodiazepines Analgesics
Statins Opiate analgesics
AC C
Russell et al
EP
et al
Multivitamins
Anxiolytic Non opioid analgesic Anticholinergic Antipsychotic
Antihypertensive Statins
5
ACCEPTED MANUSCRIPT Sera et al
Bronchodilator Acid reducer Antiinfective
Multivitamins Diuretics
SC
Corticosteroids
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Antidepressant
Antiplatelet
M AN U
Antiemetics
Thyroid Hormones
Silveira et al
Statins
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EP
TE D
*ACEI = angiotensin converting enzyme inhibitor *ARB = angiotensin receptor blocker
6
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M AN U
SC
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