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CADTH_2014_E5_Canadian_Network_for_Advanced_Interdisciplinary_Methods_for_Comparative_Effectiveness_Research_-CANAIM-__M Abrahamowicz_S Bernatsky_L Pilote_A Lev_L Levesque_Y Moride
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CADTH_2014_E5_Canadian_Network_for_Advanced_Interdisciplinary_Methods_for_Comparative_Effectiveness_Research_-CANAIM-__M Abrahamowicz_S Bernatsky_L Pilote_A Lev_L Levesque_Y Moride

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Decision Maker: Research interfacing/DSEN Canadian Experience

Decision Maker: Research interfacing/DSEN Canadian Experience

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  • 1. CANADIAN NETWORK FOR ADVANCED INTERDISCIPLINARY METHODS FOR COMPARATIVE EFFECTIVENESS RESEARCH M. Abrahamowicz (McGill), S Bernatsky, (McGill), L. Pilote (McGIll) A. Levy, (Dalhousie) L. Levesque (Queen’s), Y. Moride (U de M) et al.
  • 2. Research scope  To address drug safety & effectiveness from a ‘prospective cohort’ perspective  Over-arching goal  To enhance the validity and accuracy of research on real- world comparative drug effects  Ultimate aim  To better understand which treatment works best for which patients.
  • 3. Cristiano Moura1, Sasha Bernatsky1, Elham Rahme1, Marie-Eve Beauchamp1, Louis Bessette2, Jonathan Adachi3, Alexandra Papaioannou3, David Goltzman1, Jerilynn Prior4, Nancy Kreiger5, Tanveer Towheed6, William Leslie7, Stephanie Kaiser8, Laura Pickard9, George Ioannidis3, Lisa-Ann Fraser9, Michal Abrahamowicz1 1McGill University, 2Université Laval, 3McMaster University, 4University of British Columbia, 5University of Toronto, 6Queen's University, 7University of Manitoba, 8Dalhousie University, 9Western University
  • 4.  Antidepressants are suspected of increasing risk of fractures, especially selective serotonin & serotonin/ norepinephrine reuptake inhibitors, SSRIs, SNRIs  Objective: To evaluate whether SSRI/SNRI use is associated with fracture risk Introduction Sedation, daytime drowsiness Fracture Increase risk of falls Serotonin and bone physiology Decreased BMD
  • 5.  CaMos: prospective cohort  Nine regional centres across the country  Women and men ≥25 years  Recruitment: July 1995 to Sept. 1997  Follow-up: 10-years  Exposure and outcomes  Drug exposure assessed at 3 time points: year zero (baseline) and then at each 5 year follow-up  Annual questionnaires ascertained if subjects had experienced a fracture in the previous year; reports were confirmed by radiography. Fragility fractures were defined as those due to minimal trauma (eg, fall from standing height). For this study, we examined only participants aged >50 Methods
  • 6.  Other covariates  Demographic and socioeconomic  Age, sex, employment status  Bone mineral density, BMD  Lumbar spine (L1–L4) and total hip  History of falls  Depressive symptoms  Mental component score (MCS) from SF-36  Clinical variables and lifestyle-habits  Smoking, alcohol, physical activity, Charlson Comorbidity Index  Other drug exposures  Anxiolytics, other antidepressants, glucocorticoids, bisphosphonates, calcium and vitamin D supplements Methods
  • 7.  Data analysis  Multivariable Cox proportional hazard regression  Time to first fragility fracture  Failure to respond to the annual questionnaire was considered a loss to follow-up  SSRI/SNRIs and other drugs were modeled as time- dependent variables  Adjusted for previously described demographic and clinical variables Methods
  • 8.  Descriptive characteristics  6,645 participants  192 (2.9%) SSRI/SNRI users at baseline  330 (5.9%) at year 5 and 333 (8.3%) at year 10  955 events  74 in the exposed group and 881 in the non-exposed group Results
  • 9. Results: Table 1 - Baseline selected characteristics - N (%) or mean ± SD Variable SSRI+SNRI nonusers SSRI+SNRI users Sex (Female) 1873 (70.97) 32 (83.3) Age (years ± SD) 65.7 ± 8.9 65.2 ± 8.7 Education level (High school or higher) 3896 (60.4) 125 (65.1) Modified Charlson Index (mean ± SD) 0.37 ± 0.74 0.59 ± 0.93 Bone mineral density (mean ± SD) Total hip Lumbar spine 0.88 ± 0.16 0.95 ± 0.18 0.86 ± 0.14 0.95 ± 0.18 Depressive symptoms (MCS<42) 885 (13.8) 75 (39.7) Falls in previous month 398 (6.2) 31 (16.2) Medication use Other antidepressants Anxiolytics Biphosphonates Corticosteroids (oral+IV) 251 (0.04) 294 (0.05) 112 (0.02) 89 (0.01) 19 (9.9) 28 (14.6) 4 (0.02) 2 (0.01)
  • 10. Results Incidence & unadjusted/adjusted* hazard ratios (HR) with confidence intervals (CI): SSRI/SNRIs & fragility fractures User Non-User Events 74 881 - Person-years 2257 50216 - Incidence/100 person-years 3.3 1.7 - HR (unadjusted) and 95% CI - - 1.87 (1.48-2.39) HR (adjusted) and 95% CI - - 1.68 (1.32-2.14) *adjusted for age, sex, Charlson, depressive symptoms, falls at baseline, BMD  Time-to-event analysis: SSRI/SNRI use was associated with fragility fracture
  • 11. Sensitivity analyses  Using separate time-dependent indicators of recent and former use, the adjusted HR for recent use was 1.62 (95%CI: 1.20-2.19), and for former use HR: 1.42; 95%CI: 0.88- 2.31)  Dose effect analysis: using reference categories based on ‘defined daily dose*’, the effect of these drugs in the highest dose group was greater (2.02; 95% CI=1.24- 3.17) than the reference group *average maintenance dose per day
  • 12.  Our results regarding antidepressants use & fracture risk are consistent with previous investigations  Case-control study in Denmark (Vestergaard et al. 2013)  Meta-analysis including 34 studies (Rabenda et al. 2013)  CaMos report of 5 years follow-up (Richards et al. 2007)  Confounding by indication  Depression itself has been associated with fracture risk  We attempted to control for depressive symptoms Discussion
  • 13.  Strengths  Large longitudinal cohort, 10-year period  Fractures were confirmed by radiology  Limitations  Impossible to know if individuals started or stopped these therapies between assessment points  Sensitivity analysis showed consistent results under differents assumptions for exposure  SNRI and fracture risk  Limited number of participants under this drugs Discussion
  • 14. Conclusions  SSRI/SNRI use was associated with an important increased risk of fragility fractures, after controlling for important confounders and/or effect modifiers.  Risks and benefits should be carefully considered when these drugs are prescribed for older people.  Risk stratification: History of falls, concurrent use of anxiolytics  Consider monitoring/prophylaxis
  • 15. • Moura C, Bernatsky S, Rahme E, Beauchamp M-E, Bessette L, Adachi J, Papaioannou A, Goltzman D, Prior J, Kreiger N, Towheed T, Leslie W, Kaiser, Pickard L, Ioannidis, Fraser L-A, Abrahamowicz M. Psychotropic medication use and 10-year incident fracture risk in men and women ages 50 and older in the population-based Canadian Multicentre Osteoporosis Study Canadian Association for Population Therapeutics Conference Toronto, November 17-19, 2013. • Moura C, Bernatsky S, Rahme E, et al. SSRIs and fracture risk in a population based population: Preliminary Results CaMOS Investigators meeting, Montreal, April 2013 • Upcoming teleconference (April 10th) with stakeholders • Webinar later this year (CANRAD network)
  • 16. • CAN-AIM team • CIHR-DSEN • CaMos
  • 17. Baseline Year 5 Year 10 SSRI/SNRI non-users SSRI/SNRI users SSRI/SNRI non-users SSRI/SNRI users SSRI/SNRI non-users SSRI/SNRI users N 6453 192 5226 330 3678 333 Female (%) 4580 (71) 160 (83.3) 3752 (71.8) 290 (87.9) 2677 (72.8) 285 (85.6) Age (years±SD) 65.71 (8.9) 65.25 (8.7) 64.96 (8.5) 65 (8.2) 63.43 (7.9) 63.65 (8.0) High school +(%) 3896 (60.4) 125 (65.1) 3238 (62) 201 (60.9) 2408 (65.5) 198 (59.5) Employed (%) 1082 (16.8) 24 (12.5) 943 (18) 44 (13.3) 782 (21.3) 53 (15.9) Regular activity 3699 (57.3) 106 (55.2) 3082 (59) 184 (55.8) 2225 (60.5) 182 (54.7) Smoker (%) 930 (14.4) 39 (20.3) 711 (13.6) 48 (14.5) 458 (12.5) 53 (15.9) Alcohol mean±SD) 0.462 (3) 0.231 (2) 0.462 (4) 0.231 (2) 0.692 (4) 0.231 (2) Comorbidities 1583 (24.5) 70 (36.5) 1170 (22.4) 74 (22.4) 730 (19.8) 74 (22.2) Depressive (%) 885 (13.8) 75 (39.7) 649 (12.5) 121 (36.9) 426 (11.7) 101 (30.3) Falls 398 (6.2) 31 (16.1) 313 (6) 30 (9.1) 220 (6) 24 (7.2) Other antidepressants Anxiolytics Antihypertensives Antipsychotics Biphosphonates Corticosteroids 251 (3.9) 294 (4.6) 1276 (19.8) 28 (0.4) 112 (1.7) 89 (1.4) 19 (9.9) 28 (14.6) 34 (17.7) 0 (0) 4 (2.1) 2 (1) 183 (3.5) 198 (3.8) 955 (18.3) 21 (0.4) 86 (1.6) 69 (1.3) 47 (14.2) 49 (14.8) 66 (20) 2 (0.6) 9 (2.7) 6 (1.8) 111 (3) 113 (3.1) 586 (15.9) 13 (0.4) 50 (1.4) 36 (1) 44 (13.2) 39 (11.7) 66 (19.8) 2 (0.6) 11 (3.3) 3 (0.9) Calcium Vitamin D 902.9 (754.0) 3.214 (8.9) 969.4 (810.9) 4.7 (9.4) 907.9 (751.9) 3.393 (8.9) 1028 (867.0) 3.75 (9.7) 914.4 (743.1) 3.393 (8.9) 974.9 (925.5) 3.661 (9.5) *19% loss to follow up by year 5, 40% by year 10