2. Objectives a) Determine the proportion of drug therapy RCTs that include patients 80 years.

Transcription

1 Research Protocol Study Title: Respect your elders: How often are the very elderly represented in drug therapy trials? Principal Investigator: Timothy Lim, BSc (Pharm) Co- Investigators: Greg Egan, BSc (Pharm), ACPR, PharmD Aaron Tejani, BSc (Pharm), PharmD Hans Haag, BSc Protocol Outline 1. Background The elderly population is among the fastest growing age group in Canada. In 2016, 16.6 % of Canadians were seniors (1). By 2036, it is projected that seniors will account for 25% of the Canadian population (2). More specifically, the very elderly (80 years or older) demographic has increased 10.8% from 2012 to 2016 (1). It has been reported that elderly individuals consume a large portion of health care services secondary to greater comorbidities and use of institutions with 45% of provincial and territorial governments public sector health care expenditure is spent on seniors in Canada (3). Older adults often have multiple chronic medical comorbidities, cognitive and functional impairment which consequently requires more medical therapies and/or prescription medications (4,5). Despite this, several studies have discussed the underrepresentation of elders in RCTs, where such under- representation can be associated to specified age restrictions, comorbidities, co- medication, or other patient- specific factors that disproportionately exclude elders (6,7,8,9). In addition, a systematic review that quantified the proportion of RCT s specifically designed for older adults yielded a mere 7% (6). Finally, Van Spall et al., found that in RCTs in MEDLINE database between 1994 and 2006, 38.5% of older adults (age ³ 65 years old) were excluded due to age (10). While selection criteria of RCTs are important for internal validity, such exclusions can minimize the generalizability of results found in RCTs to the treatment of older adults (10). Additionally, in a study by Cox et al. which looked to see if 2272 studies used as evidence for recommendations of 14 clinical practice guidelines in Canada included individuals 80 years of age or older, only 31 studies (1.4%) had a mean age of 80 years or older (11). As a result, clinicians more often than not extrapolate results from RCTs or clinical practice guidelines that have included younger, more robust individuals with fewer confounding variables to the treatment of their elderly patients. This practice may not be the most appropriate due to the heterogeneous age related changes that affect both pharmacokinetics and pharmacodynamics response to drugs, ultimately altering its efficacy and safety in the elderly or very elderly (12). The purpose of this study is to determine the proportion of representation of very elderly persons within RCTs of three common chronic conditions (DM, HTN, HF) seen in this age group. These medical conditions were selected based on data regarding the prevalence of chronic conditions in older adults posted by the Canadian Institute of Health Information, and the suggestion from previous studies that there is a lack of representation of elders for these conditions stated in previous RCTs (i13,14,15). 2. Objectives a) Determine the proportion of drug therapy RCTs that include patients 80 years.

2 b) Determine the following characteristics: i. Describe the medications/medical conditions studied that include this population versus those that do not ii. iii. Size of studies, location of publication, date of publication and funding source Why elderly patients were not included (i.e. specifically age or age related exclusion criteria such as comorbidities, co- medications, etc.) 3. Abbreviations RCT s: randomized controlled trials DM: diabetes mellitus HTN: hypertension HF: heart failure 4. Methods a) Design i. Descriptive analysis ii. Database: PubMed b) Inclusion Criteria i. All phase III and IV full text RCTs with drug therapy interventions assessing clinical outcomes in adults for DM, HF, and HTN a. Date of publication: most recent 10 years ii. 500 participants iii. English language iv. Drug therapy primary intervention c) Exclusion Criteria i. Sub- study publications from a larger RCT ii. Extension trials from an original RCT d) Search Terms The following filters were applied to all searches: i. Article Types: clinical trial; clinical trial, phase III; clinical trial, phase Iv; randomized controlled trial ii. Text Availability: full text iii. Publication dates: 10 years iv. Species: human v. Languages: English Additionally, the following search terms will be used for each medical condition being studied: vi. Heart Failure: (((((randomized controlled trial[pt]) OR (controlled clinical trial[pt]) OR (randomized[tiab]) OR (placebo[tiab]) OR (clinical trials as topic[mesh:noexp]) OR (randomly[tiab])))) AND congestive heart failure) AND drug therapy[mesh Subheading] vii. Diabetes Mellitus: (((((randomized controlled trial[pt]) OR (controlled clinical trial[pt]) OR (randomized[tiab]) OR (placebo[tiab]) OR (clinical trials as topic[mesh:noexp]) OR (randomly[tiab])))) AND ((type 2 diabetes mellitus) OR diabetic ketoacidosis)) AND drug therapy[mesh Subheading] viii. Hypertension: (((((randomized controlled trial[pt]) OR (controlled clinical trial[pt]) OR (randomized[tiab]) OR (placebo[tiab]) OR (clinical trials as topic[mesh:noexp]) OR (randomly[tiab])))) AND ((hypertension) NOT hypertension, pregnancy induced)) AND drug therapy[mesh Subheading]

3 e) Sample Size: i. Systematic Random Sampling a. The total sample size will be 100 articles which is a sample size of convenience b. For each medical condition a proportion of RCTs will be included for review based on the total number of RCTs with that medical condition relative to the total number for all medical conditions f) Data Collection A standardized form will be used to extract the following listed items from the sample of RCTs. Consensus in data collection was practiced to resolve discrepancies in data collection. Items related to the trial: i. Medical condition being studied ii. PMID, first author, year of publication, journal of publication, sample size, geographic region, number of centers involved (single, multicentre, none declared), duration of study, and funding (industry, non- industry, both, none declared) iii. Type of control intervention (=placebo, active treatment, usual care, others) iv. Age of study sample a. Average age b. Age range c. Any patients aged >80 years d. Any patients aged years v. Exclusion criteria that may disproportionately affect elders a. Subgroup b. Age limit c. Multiple comorbidities d. Life expectancy e. Cognitive disabilities f. Physical disabilities g. Polypharmacy h. Other vi. Authors conclusion on generalizability to elders a. Proportion of AE by age b. No comment on elders vii. Bias a. Risk of bias will be assessed using Cochrane Risk of Bias assessment tool g) Outcomes i. Primary Outcome: proportion of RCTs that include patients 80 years. ii. Secondary Outcome: a. Proportion of RCTs that include patients years old b. Medications/medical conditions studied that include this population versus those that do not c. Size of studies, location of publication and funding source d. Why elderly patients were not included e. Logistic regression for factors that are associated with inclusion of the very elderly patients 5. Definitions Very Elderly: persons 80 years old Elder/Elderly: person years old Seniors: person 65

4 Drug: as defined by the Food and Drug Act of Canada (16) i. Does not include natural health products as defined by the Natural Health Products Regulations of Canada (17) Clinical outcomes: morbidity and mortality 6. Statistics Descriptive Analysis of the included RCTs will be summarized and presented. Multivariate logistic regression analysis for characteristics associated with inclusion of the very elderly 7. Ethical Considerations None to declare as this project does not involve any patient information. All researchers are familiar with best practices regarding handling of data. 8. Foreseen Risks There are no foreseen risks 9. Potential Benefits The results of this study can help guide clinical practice in geriatric patients and provide insight on the external validity of RCTs in the advance age population group. 10. Timeline a) Protocol Finalized: July 2016 b) Data collection commencement: August 2016 c) Data collection completion: January 2017 d) Data analysis complete: April 2017 e) Poster/slides complete: May 2017 f) Manuscript complete: June Funding None 12. Conflicts of Interest None References 1. Statistics Canada, Population by sex and age groups (table ). From: CANSIM (Ottawa, Ont.: Statistics Canada, 2016). 2. Statistics Canada, Population Projections for Canada, Provinces and Territories: 2009 to 2036 (Ottawa, Ont.: Statistics Canada, 2010). 3. Canadian Institute for Health Information, National Health Expenditure Trends, 1975 to 2015 (Ottawa, Ont.: CIHI, 2015). 4. Ramage- Morin P. Medication use among senior Canadians. Statistics Canada Health. Reports. March 2009; Vol. 20, no. 1. Accessed on March 10, 2014, from < x/ /article/ eng.pdf>. Catalogue no XPE. 5. Kwan D, Farrell B. Polypharmacy optimizing medication use in elderly patients. Pharmacy Practice (2012): 29(2) pp Broekhuizen K, Pothof A, de Craen AJM, Mooijaart SP. Characteristics of randomized controlled trials designed for elderly: a systematic review. PLoS One. 2015;10:e Konrat C, Boutron I, Trinquart L, Auleley GR, Ricordeau P, Ravaud P. Underrepresentation of elderly people in randomised controlled trials. The example of trials of 4 widely prescribed drugs. PLoS One. 2012;7:e33559.

5 8. Zulman DM, Sussman JB, Chen X, Cigolle CT, Blaum CS, Hayward RA. Examining the evidence: a systematic review of the inclusion and analysis of older adults in randomized controlled trials. J Gen Intern Med. 2011;26(7): doi: /s x. 9. Dodd KS, Saczynski JS, Zhao Y, Goldberg RJ, Gurwitz JH. (2011) Exclusion of older adults and women from recent trials of acute coronary syndromes. J Am Geriatr Soc. 59(3): doi: / j x 10. Van Spall HG, Toren A, Kiss A, Fowler RA (2007) Eligibility criteria of randomized controlled trials published in high- impact general medical journals: a systematic sampling review. JAMA 297: Cox L, Kloseck M, Crilly R, McWilliam C, Diachun L. Underrepresentation of individuals 80 years of age and older in chronic disease clinical practice guidelines. Canadian family physician 57:e263- e Hämmerlein A, Derendorf H, Lowenthal DT. Pharmacokinetic and pharmacodynamic changes in the elderly. Clinical implications.clin Pharmacokinet. 1998;35: Cherubini A, Oristrell J, Pla X, Ruggiero C, Ferretti R, Diestre G, et al. (2011) The persistent exclusion of older patients from ongoing clinical trials regarding heart failure. Arch Intern Med. 171: doi: /archinternmed Arnberg FK, Alaie I, Parling T, Jonsson U (2013) Recent randomized controlled trials of psychological interventions in healthcare: a review of their quantity, scope, and characteristics. J Psychosom Res 75: doi: /j.jpsychores Canadian Institute for Health Information, Seniors and health care system: what is the impact of multiple chronic condition? (Ottawa, Ont.: CIHI, 2011) 16. Food and Drugs Act, CA [statute on the internet]. c1985. [cited 2016 Oct 4]. Available from: lois.justice.gc.ca/eng/acts/f- 27/ 17. Natural Health Products Regulations, CA. [statute on the internet]. c2003. [cited 2016 Oct 4]. Available from: lois.justice.gc.ca/eng/regulations/sor /