Bathini, Lavanya

Blake, Peter G.

Chauvin, Kianna

Dixon, Stephanie N.

McArthur, Eric

Muanda, Flory T.

Sontrop, Jessica M.

Weir, Matthew A.

English

Scholarship@Western

Western University Scholarship@Western Paediatrics Publications Paediatrics Department 9-1-2021 Association of Baclofen With Falls and Fractures in Patients With CKD Flory T. Muanda ICES Western Peter G. Blake Division of Nephrology Matthew A. Weir ICES Western Lavanya Bathini ICES Western Kianna Chauvin Division of Nephrology See next page for additional authors Follow this and additional works at: https://ir.lib.uwo.ca/paedpub Citation of this paper: Muanda, Flory T.; Blake, Peter G.; Weir, Matthew A.; Bathini, Lavanya; Chauvin, Kianna; Dixon, Stephanie N.; McArthur, Eric; and Sontrop, Jessica M., "Association of Baclofen With Falls and Fractures in Patients With CKD" (2021). Paediatrics Publications. 1582. https://ir.lib.uwo.ca/paedpub/1582 Authors Flory T. Muanda, Peter G. Blake, Matthew A. Weir, Lavanya Bathini, Kianna Chauvin, Stephanie N. Dixon, Eric McArthur, and Jessica M. Sontrop This letter to the editor is available at Scholarship@Western: https://ir.lib.uwo.ca/paedpub/1582 Publication Information: © 2021 by the National Kidney Founda-tion, Inc. Published online February 10, 2021 with doi 10.1053/j.ajkd.2021.05.006References1. Lebedev L, Sapojnikov M, Wechsler A, et al. Minimal changedisease following the Pfizer-BioNTech COVID-19 vaccine. AmJ Kidney Dis. 2021;78(1):142-145.2. Maas RJ, Gianotten S, van der Meijden WAG. Anadditional case of minimal change disease following the Pfizer-BioNTech COVID-19 Vaccine. Am J Kidney Dis. 2021;78(2):312.3. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy ofthe BNT162b2 mRNA Covid-19 vaccine. N Engl J Med.2020;383(27):2603-2615.4. Sahin U, Muik A, Derhovanessian E, et al. COVID-19 vaccineBNT162b1 elicits human antibody and TH1 T cell responses.Nature. 2020;586(7830):594-599.RESEARCH LETTERAssociation of Baclofen With Falls andFractures in Patients With CKDTo the Editor:Baclofen is a popular muscle relaxant that is eliminatedprimarily unchanged in the urine.1 We recently reported ahigher risk of encephalopathy in a cohort of 15,942 olderadults with chronic kidney disease (CKD) who startedbaclofen at ≥20 versus <20 mg/d; a higher risk was alsoobserved in all baclofen users versus nonusers.2 In anotherstudy of patients receiving dialysis, 1 in 14 were hospi-talized with encephalopathy within 3 days of startingbaclofen.3In the present study, we analyzed the same cohort of15,942 older adults with CKD not receiving dialysis,2 andexamined the 30-day risk of a hospital encounter with afall, a fracture, or hypotension in patients newly prescribedbaclofen at ≥20 versus <20 mg/d. The data source, design,and methods were the same as in our prior report2 and aredescribed in Table S1.Briefly, we analyzed linked administrative health caredata housed at ICES in Ontario, Canada, where all residentsaged ≥65 years have universal prescription drug coverage.The primary cohort included adults aged ≥66 (to ensure atleast 1 year of drug coverage) who had an estimatedglomerular filtration rate (eGFR) < 60 mL/min/1.73 m2and who were newly dispensed oral baclofen from anoutpatient pharmacy between January 1, 2007, and March1, 2018. Patients with evidence of baclofen use in the 180-day period before the prescription start date were excluded(this period was extended to 5 years in a sensitivityanalysis).The primary exposure was baclofen ≥ 20 mg/d (20 mg/d is the median dose reported in cases of bac-lofen toxicity, and the median dose prescribed during thestudy period [Table S2]).2 To reduce the potential forindication bias, the prespecified reference group wasbaclofen < 20 mg/d.In a secondary analysis, study outcomes in each groupof baclofen users (≥20 and <20 mg/d) were comparedseparately to nonusers (ie, patients with CKD not takingbaclofen). Nonusers were randomly assigned a simulatedbaclofen start date that followed the same distribution ofstart dates as baclofen users.Inverse probability of treatment weighting on the pro-pensity score was used to balance comparison groups on164 indicators of baseline health, including indications forTable 1. Baseline Characteristics of Older Adults With CKD Newly Prescribed Baclofen in Ontario, Canada (2007-2018)Observed Data (N = 15,942) Weighted Data (N = 19,387)aBaclofen DoseStd DiffbBaclofen DoseStdDiffb≥20 mg/d(n = 9,707)<20 mg/d(n = 6,235)≥20 mg/d(n = 9,707)<20 mg/d(n = 9,680)DemographicsWomen 5,719 (58.9%) 3,980 (63.8%) 10% 5,719 (58.9%) 5,702 (58.9%) 2%Men 3,988 (41.1%) 2,255 (36.2%) 10% 3,988 (41.1%) 3,978 (41.1%) 0%Age, y 76.5 ± 6.9 78.0 ± 7.4 21% 76.5 ± 6.9 76.5 ± 8.8 0%ResidenceUrban 8,870 (91.4%) 5,800 (93.0%) 6% 8,870 (91.4%) 8,845 (91.4%) 0%Rural 837 (8.6%) 435 (7.0%) 6% 837 (8.6%) 835 (8.6%) 0%Long-term care 210 (2.2%) 379 (6.1%) 20% 210 (2.2%) 217 (2.2%) 0%Income quintilec1 (lowest) 2,313 (23.8%) 1,508 (24.2%) 1% 2,313 (23.8%) 2,309 (23.9%) 0%2 2,098 (21.6%) 1,345 (21.6%) 0% 2,098 (21.6%) 2,121 (21.9%) 1%3 (middle) 2,010 (20.7%) 1,280 (20.5%) 0% 2,010 (20.7%) 1,988 (20.5%) 0%4 1,893 (19.5%) 1,145 (18.4%) 3% 1,893 (19.5%) 1,871 (19.3%) 1%5 (highest) 1,393 (14.4%) 957 (15.3%) 3% 1,393 (14.4%) 1,389 (14.4%) 0%(Continued)470 AJKD Vol 78 | Iss 3 | September 2021Correspondencebaclofen use.4-6 Weighting methods are described in notesto Table 1 and in Table S1.4-6 Weighted risk ratios (wRR)were obtained using modified Poisson regression,7 andweighted risk differences (wRD) using a binomialregression model with an identity link function. A pre-specified subgroup analysis by baseline eGFR (in 3 cate-gories) was conducted for the most common outcome(hospitalization with a fall).The primary analysis included 15,942 patients.Weighting resulted in 2 well-balanced groups (Table S3);selected characteristics are shown in Table 1. The majorityof prescribing physicians were primary care physicians(86%); <1% were nephrologists (Table 1). Less than 5% ofpatients received the recommended starting dose of 7.5 or5.5 mg/d (Tables S4 and S5). Starting baclofen at ≥20versus <20 mg/d was associated with a higher risk ofTable 1 (Cont'd). Baseline Characteristics of Older Adults With CKD Newly Prescribed Baclofen in Ontario, Canada (2007-2018)Observed Data (N = 15,942) Weighted Data (N = 19,387)aBaclofen DoseStd DiffbBaclofen DoseStdDiffb≥20 mg/d(n = 9,707)<20 mg/d(n = 6,235)≥20 mg/d(n = 9,707)<20 mg/d(n = 9,680)Kidney functioneGFR, mL/min/1.73 m2d 47.5 ± 10.1 47.3 ± 10.2 2% 47.5 ± 10.1 47.5 ± 12.6 0%eGFR category45-<60 mL/min/1.73 m2 6,404 (66.0%) 4,085 (65.5%) 1% 6,404 (66.0%) 6,388 (66.0%) 0%30-<45 mL/min/1.73 m2 2,616 (26.9%) 1,682 (27.0%) 0% 2,616 (26.9%) 2,580 (26.7%) 0%<30 mL/min/1.73 m2 687 (7.1%) 468 (7.5%) 2% 687 (7.1%) 711 (7.4%) 1%Baclofen prescriberGeneral practitioner 8,433 (86.9%) 5,208 (83.5%) 1% 8,433 (86.9%) 8,399 (86.8%) 0%Other 665 (6.9%) 533 (8.5%) 6% 665 (6.9%) 669 (6.9%) 0%Missing 609 (6.3%) 494 (7.9%) 6% 609 (6.3%) 611 (6.3%) 0%ComorbiditiesfAnemia 2,667 (27.5%) 1,719 (27.6%) 0% 2,667 (27.5%) 2,548 (26.3%) 3%Parkinson disease 197 (2.0%) 174 (2.8%) 5% 197 (2.0%) 198 (2.0%) 0%Prior hypotension 190 (2.0%) 125 (2.0%) 0% 190 (2.0%) 190 (2.0%) 0%Rheumatoid arthritis 636 (6.6%) 415 (6.7%) 0% 636 (6.6%) 640 (6.6%) 0%Syncope 168 (1.7%) 112 (1.8%) 1% 168 (1.7%) 163 (1.7%) 0%Ischemic stroke 191 (2.0%) 171 (2.7%) 5% 191 (2.0%) 195 (2.0%) 0%Encephalopathy 352 (3.6%) 305 (4.9%) 6% 352 (3.6%) 346 (3.6%) 0%Prior falls 371 (3.8%) 295 (4.7%) 4% 371 (3.8%) 366 (3.8%) 0%Prior fractures 627 (6.5%) 458 (7.3%) 3% 627 (6.5%) 627 (6.5%) 0%Hemorrhagic stroke 28 (0.3%) 24 (0.4%) 2% 28 (0.3%) 30 (0.3%) 0%Acute urinary retention 210 (2.2%) 161 (2.6%) 3% 210 (2.2%) 199 (2.1%) 1%Health care visits and testsePrimary care visits 11.2 ± 9.6 11.8 ± 10.2 6% 11.2 ± 9.6 11.2 ± 11.4 0%Emergency department visits 0.7 ± 1.4 0.7 ± 1.4 4% 0.7 ± 1.4 0.7 ± 1.9 1%Serum creatinine tests 2.6 ± 2.2) 2.7 ± 2.3 0% 2.6 ± 2.2 2.6 ± 2.9 0%Medication usefSelective serotonin reuptake inhibitors 991 (10.2%) 750 (12.0%) 6% 991 (10.2%) 994 (10.3%) 0%Benzodiazepines 1,897 (19.5%) 1,152 (18.5%) 3% 1,897 (19.5%) 1,885 (19.5%) 0%Antipsychotics 376 (3.9%) 284 (4.6%) 3% 376 (3.9%) 378 (3.9%) 0%Opioids 2,749 (28.3%) 1,594 (25.6%) 6% 2,749 (28.3%) 2,734 (28.2%) 0%Anticonvulsants 435 (4.5%) 261 (4.2%) 1% 435 (4.5%) 451 (4.7%) 1%Unless otherwise specified, baseline characteristics were assessed on the date the patient filled the baclofen prescription. Values given as count (percentage) ormean ± SD.aWeighted using inverse probability of exposure weighting based on propensity scores. The propensity score was estimated using multivariable logistic regression with164 covariates chosen a priori.2 Probabilities of treatment were determined separately for the primary and secondary analyses. Patients in the reference groups received aweight of [propensity score / (1 – propensity score)] and those in the exposed groups a weight of 1 (Table S1).4-6 This method produces a weighted pseudosample ofpatients in the reference group with the same distribution of measured covariates as the exposure group.4,5bStandardized difference: difference between the groups divided by the pooled SD; a value greater than 10% is interpreted as a meaningful difference.cBased on average neighborhood income on the index date. Missing data on income quintile (0.3%) were recorded as the middle quintile.dThe most recent eGFR in the 7-365 days before the index date; eGFR calculated by CKD-EPI equation (Table S1); information on race was not available and all patientswere assumed not to be of African-Canadian race (African-Canadians represented <5% of Ontario population in 2006).eBaseline comorbidities were assessed in the 5-year (comorbidities) or 1-year (total visits or tests) period before the prescription start date.fMedication use examined in the 120-day period before the prescription start date (the Ontario Drug Benefit program dispenses a maximum 100-day supply).AJKD Vol 78 | Iss 3 | September 2021 471Correspondencehospitalization with a fall (wRR, 1.38 [95% CI, 1.01-1.90]; wRD, 0.36% [95% CI, 0.03%-0.70%]) and hypo-tension (wRR, 3.06 [95% CI, 1.26-7.47]; wRD, 0.22%[95% CI, 0.08%-0.37%]), but not fracture (wRR, 1.23[95% CI, 0.70-2.19]; wRD, 0.07% [95% CI, –0.12% to0.26%]) (Table 2). Results were consistent in 2 sensitivityanalyses (Tables S6 and S7). The association with falls wasnot significantly modified by baseline eGFR (Fig S1),acknowledging there was limited statistical power to detectit if it exists.The secondary analysis included 15,942 baclofenusers and 284,263 nonusers; characteristics of high-dosebaclofen users versus nonusers and low-dose usersversus nonusers are in Tables S8 and S9, respectively.Compared with nonusers, high-dose users had a higherrisk of hospitalization with a fall, fracture, and hypo-tension; low-dose users had a higher risk of hospitali-zation with a fall, but not fracture or hypotension(Table S10).In summary, older adults with CKD starting baclofenat ≥20 versus <20 mg/d were at higher risk for hospi-talization with a fall and hypotension; for every 278patients prescribed baclofen at ≥20 versus <20 mg/d, 1was hospitalized with a fall. Although comparisongroups were well balanced, residual confounding is stillpossible, and we did not account for dose changes inother medications such as opioids or benzodiazepines,which could influence study outcomes. Nonetheless,taken together the results of this study and otherssuggest that baclofen should be used with caution inolder adults with CKD, and only at low doses.2,3 Tobetter protect patients with CKD, the productmonograph should contain clear dose recommendationsbased on kidney function,1 and computerizedmedication-order entry warnings with dosing promptsare also recommended.8,9Flory T. Muanda, MD, PhD, Peter G. Blake, MB, FRCPC,Matthew A. Weir, MD, MSc, Lavanya Bathini, MD, KiannaChauvin, BSc, Stephanie N. Dixon, PhD, EricMcArthur, MSc, Jessica M. Sontrop, PhD, Louise Moist, MD,MSc, Richard B. Kim, MD, FRCPC, Amit X. Garg, MD, PhDSupplementary MaterialSupplementary File (PDF)Figure S1; Tables S1-S10.Article InformationAuthors’ Affiliations: ICES Western (FTM, MAW, LB, SND, EM,AXG), and the Department of Epidemiology & Biostatistics (FTM,MAW, SND, JMS, LM, AXG), Division of Nephrology, Departmentof Medicine (PGB, MAW, LB, KC, JMS, LM, AXG), and Division ofClinical Pharmacology, Department of Medicine (RBK), WesternUniversity, London ON, Canada.Address for Correspondence: Flory T. Muanda, MD, PhD, ICESWestern, Victoria Hospital, 800 Commissioners Rd, Room ELL-215,London, ON, Canada N6A 5W9. Email: Flory.Muanda-Tsobo@lhsc.on.caAuthors’ Contributions: Developed the initial concept and plan:FTM, PGB, AXG; performed initial literature review: FTM; providedinput and approved the study and analysis plan: FTM, SND, EM,AXG; completed all statistical analyses: FTM; interpreted theresults: all authors. Each author contributed important intellectualcontent during manuscript drafting or revision and agrees to bepersonally accountable for the individual’s own contributions andto ensure that questions pertaining to the accuracy or integrity ofTable 2. Risk of a Fall, Fracture, and Hypotension in Older Adults With CKD Newly Prescribed Baclofen at ≥20 Versus <20 mg/dOutcome:HospitalEncounterWithObserved No. of Patients,by Baclofen DoseWeighteda No. ofPatients, by BaclofenDoseRisk Difference(95% CI)NumberNeededto Harm(95% CI)Risk Ratio(95% CI)≥20 mg/d(n = 9,707)<20 mg/d(n = 6,235)≥20 mg/d(n = 9,707)<20 mg/d(n = 9,680)Fallb 127 (1.31%) 65 (1.04%) 127 (1.31%) 92 (0.94%) 0.36%(0.03% to 0.70%)278 (143-3333)c 1.38 (1.01-1.90)Fractured 36 (0.37%) 20 (0.32%) 36 (0.37%) 29 (0.30%) 0.07%(–0.12% to 0.26%)Notavailable1.23 (0.70-2.19)Hypotensione 32 (0.33%) 6 (0.10%) 32 (0.33%) 10 (0.11%) 0.22%(0.08% to 0.37%)456 (270-1250)f 3.06 (1.26-7.47)Reference group: Baclofen dose < 20 mg/d.aInverse probability of treatment weighting on the propensity score was used to balance comparison groups on indicators of baseline health4-6; further details in Table 1and Table S1. Weighted risk ratios were obtained using modified Poisson regression7; weighted risk differences, by using a binomial regression model with an identity linkfunction.bPatient seen in the emergency department or admitted to the hospital with a fall diagnosis (ICD-10 code W00-W19).cFor every 278 patients prescribed baclofen at ≥20 vs <20 mg/d in the outpatient setting, 1 patient was hospitalized or visited an emergency department with a fall within30 days of starting baclofen.dIncludes major fractures of hip (ICD-10 code S720, S721; S722. Canadian Classification of Health Interventions [CCI] code 1VA73, 1VC73, 1VA74, 1VA53, 1VC74,1VA80), pelvis (ICD-10 code S321, S322, S324, S323, S325, S327, S328), humerus (ICD-10 code S422), and radius (ICD-10 code S52; CCI code 1TV73, 1TV74,1TV03; Ontario Health Insurance Program [OHIP] code F014, F022, F023, F025, F026, F028, F030, F032, F033, F046, F024, F027, F031, Z203).ePatient seen in the emergency department or admitted to the hospital with a hypotension diagnosis (ICD-10 code I95).fFor every 456 patients prescribed baclofen at ≥20 vs <20 mg/d in the outpatient setting, 1 patient was hospitalized or visited an emergency department with hypotensionwithin 30 days of starting baclofen.472 AJKD Vol 78 | Iss 3 | September 2021Correspondenceany portion of the work, even one in which the author was notdirectly involved, are appropriately investigated and resolved,including with documentation in the literature if appropriate.Support: This study was supported by the ICESWestern Site. ICESis funded by an annual grant from the Ontario Ministry of Health andLong-Term Care (MOHLTC). Core funding for ICES Western isprovided by the Academic Medical Organization of SouthwesternOntario (AMOSO), the Schulich School of Medicine and Dentistry(SSMD), Western University, and the Lawson Health ResearchInstitute (LHRI). The research was conducted by members of theICES Kidney, Dialysis and Transplantation team, at the ICESWestern facility, who are supported by a grant from the CanadianInstitutes of Health Research (CIHR). Dr Muanda was supportedby a CIHR and Mitacs postdoctoral award. Dr Garg wassupported by the Dr Adam Linton Chair in Kidney Health Analyticsand a CIHR Clinician Investigator Award. The study sponsors hadno role in the design and conduct of the study; collection,management, analysis, and interpretation of the data; preparation,review, or approval of the manuscript; and decision to submit themanuscript for publication.Financial Disclosure: Dr Moist reports receipt of personal fees(honoraria) from Otsuka and Janssen outside the submitted work.The other authors declare that they have no relevant financialinterests.Acknowledgements: We thank Dr Shayan Kassirian for hiscontribution to the literature review.Disclaimer: Parts of this material are based on data and informationcompiled and provided by the Canadian Institutes of HealthInformation (CIHI). However, the analyses, conclusions, opinions,and statements expressed herein are those of the author, are notnecessarily those of CIHI, and are independent from the fundingsources. No endorsement by ICES, AMOSO, SSMD, LHRI,CIHR, or the MOHLTC is intended or should be inferred.Peer Review: Received September 30, 2020. Evaluated by 2external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief.Accepted in revised form December 31, 2020.Publication Information: © 2021 by the National Kidney Founda-tion, Inc. Published online February 10, 2021 with doi 10.1053/j.ajkd.2020.12.017References1. Vlavonou R, Perreault MM, Barriere O, et al. Pharmacokineticcharacterization of baclofen in patients with chronic kidneydisease: dose adjustment recommendations. J Clin Pharmacol.2014;54(5):584-592.2. Muanda FT, Weir MA, Bathini L, et al. Association of baclofenwith encephalopathy in patients with chronic kidney disease.JAMA. 2019;9(2754806):17725.3. Chauvin KJ, Blake PG, Garg AX, et al. Baclofen has a risk ofencephalopathy in older adults receiving dialysis. Kidney Int.2020;98(4):979-988.4. Sato T, Matsuyama Y. Marginal structural models as a tool forstandardization. Epidemiology. 2003;14(6):680-686.5. Brookhart MA,Wyss R, Layton JB, Sturmer T. Propensity scoremethods for confounding control in nonexperimental research.Circ Cardiovasc Qual Outcomes. 2013;6(5):604-611.6. Austin PC. An introduction to propensity score methods forreducing the effects of confounding in observational studies.Multivariate Behav Res. 2011;46(3):399-424.7. Zou G. A modified poisson regression approach to prospectivestudies with binary data. Am J Epidemiol. 2004;159(7):702-706.8. Erler A, Beyer M, Petersen JJ, et al. How to improve drugdosing for patients with renal impairment in primary care - acluster-randomized controlled trial. BMC Fam Pract.2012;13(91):1471-2296.9. Tawadrous D, Shariff SZ, Haynes RB, Iansavichus AV, Jain AK,Garg AX. Use of clinical decision support systems for kidney-related drug prescribing: a systematic review. Am J KidneyDis. 2011;58(6):903-914.AJKD Vol 78 | Iss 3 | September 2021 473Correspondence

Association of Baclofen With Falls and Fractures in Patients With CKD

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Association of Baclofen With Falls and Fractures in Patients With CKD

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