Geriatrics Literature Update

Geriatrics Literature Update2019-21 Geriatrics Journal Clubs, UCLA

Arun Karlamangla, PhD, MDProfessor of Medicine - Geriatrics

David Geffen School of Medicine at UCLA

Disclosures

No underwriting of fellows’ journal club

No financial conflicts of interest

Methods: Study Selection

• Search of studies rated high by the McMaster’s OnlineRating of Evidence (MORE)– Ratings based on clinical relevance and interest to

practitioners

• Augmented by studies identified by trainees in contextof clinical care of individual patients

• Selection criteria: Potential for impact, trainee’sinterest in topic

Methods: Study Appraisal

• Validity of study findingsDo they establish a cause-effect relationship?

• Effect and Effect SizeIs there an effect? Is the effect size clinically meaningful? Is the effect size known precisely?

• RelevanceWill the results help me in caring for my patients? Will it change my clinical practice?

Topics Covered

• Antibiotics for asymptomatic bacteriuria is inappropriate

• Atypical femur fracture risk on bisphosphonates is low

• Bedtime treatment of blood pressure is superior

• Best interventions for agitation in dementia

• Vitamin D supplementation does not prevent falls

• Donanemab did not improve outcomes in mild AD

Asymptomatic Bacteriuria in Hospitalized

Context: Asymptomatic bacteriuria (ASB) is often treated with antibiotics in hospitalized patients

Clinical Take Home:In hospitalized older adults with asymptomatic bacteriuria, antibiotic treatment prolonged hospital stay but did not reduce 30-day readmission or mortality

Petty, et al., Risk factors and outcomes associated with treatmentof asymptomatic bacteriuria in hospitalized patients. JAMA Intern Med 2019 NovemberAppraised by: Ilana Solomon, MD (Class of 2020)

Risk Factors and Outcomes Associated With Treatment of Asymptomatic Bacteriuria in Hospitalized Patients

Lindsay A. Petty, MD; Valerie M. Vaughn, MD, MSc; Scott A. Flanders, MD; Anurag N. Malani, MD; Anna Conlon, PhD; Keith S. Kaye,MD, MPH; Rama Thyagarajan, MD; Danielle Osterholzer, MD; Daniel Nielsen, MS; Gregory A. Eschenauer, PharmD; Sarah Bloemers, MPH; Elizabeth McLaughlin, BSN, MS; Tejal N. Gandhi, MD

JAMA Internal Medicine | Original Investigation | LESS IS MORE

JAMA Intern Med. 2019; 179(11): 1519-1527.

Research

Asymptomatic Bacteriuria Rx: The Study

Study Design: Retrospective chart review; 46 Michigan hospitals

Participants: All 18+ yo patients hospitalized 2016-18 with ASBNot immunocompromised, no other infection / surgeryN: 2,733 Median age: 77 years (IQR, 66-86 years)

Exposure: At least one dose of antibiotic (other than for C diff)2,259 got antibiotics; median length: 7 days (IQR, 4-9 d)

Outcome: Hospital stay; 30-day C diff / readmission / mortalityAnalysis adjusted for demographics, catheter, lab results

Findings: Rx increased stay by 1.37: 4 vs. 3 days; 95% CI: 1.28 to 1.47 No effect on 30-day C diff / re-admission / mortality

Asymptomatic Bacteriuria Rx: Brief Appraisal

• Validity

Observational study; high risk of confounding

• Effect Size

NNT to increase hospital stay by 1 day = 1

• Relevance21% had dementia; 14% had urinary catheters33% had >=2 SIRS criteria84% had >100,000 CFU15% got re-admitted in 30 days

Topics Covered







Bisphosphonates and Atypical Fractures

Context: Bisphosphonates prevent osteoporotic fractures but increase the risk of atypical femur fracture

Clinical Take Home:In 50+ yo women on bisphosphonates, the risk of atypical femur fracture (AFF) is low (4.5 per 10K person-years), and falls rapidly after discontinuation

Black, et al., Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med 2020 August

Appraised by: Vivek Singh, MD (Class of 2021)

Atypical Femur Fracture Risk versus Fragility

Fracture Prevention with Bisphosphonates

Dennis M. Black, Ph.D., Erik J. Geiger, M.D., Richard Eastell, M.D.,Eric Vittinghoff, Ph.D., Bonnie H. Li, M.S., Denison S. Ryan, M.P.H.,

Richard M. Dell, M.D., and Annette L. Adams, Ph.D.N ENGL J MED; 383; 8: 743-53 NEJM.ORG AUGUST 20, 2020

The NEW ENGLAND JOURNAL of MEDICINE

ORIGINAL ARTICLE

Bisphosphonates and Fractures: The Study

Study Design: Retrospective EHR Review, 2007-17 (N=196,129)

Participants: 50+ yo women in Kaiser So Cal on bisphosphonates

Exposure: Duration of use; time since discontinuation

Outcomes: Sub-trochanteric femoral shaft fractures w/o trauma

Findings: AFF Incidence per 10K person-years: 0.1 if <3 months use;0.6 if 3 mo – 3 y; 2.5 if 3-5 y; 6.0 if 5-8 y; 13.1 if 8+ yrs use

Risk falls from 4.5 per 10K p-years for current users to 1.8 per 10K at 3-15 months after discontinuation, to0.6 per 10K at 15 months – 4 years after dc, to0.5 per 10K p-years if 4+ years after discontinuation

Risk 4.8 times higher in Asians than in non-Hispanic Whites

Atypical Femur Fractures: Brief Appraisal

• ValidityObservational study, but largeDose response supports causal inference

• Effect SizeRelative increase in Asians and with duration are largeAbsolute risk small: 1 AFF per 25 hip fractures in cohort

• RelevanceRisk outweighed by benefit: With 3 year use, 1 AFF caused for 75 hip fractures prevented in Whites‘Asians’ too disparate a group to draw inferences

Topics Covered







Bedtime Administration of BP Meds

Context: Disruption of the normal 10-20% night-time dipping of blood pressure is common in hypertension, and is associated with worse cardiovascular outcomes

Clinical Take Home:In hypertension patients, bedtime administration of antihypertensive medications improves cardiovascular outcomes compared to daytime administration

Hermida RC, et al., Bedtime hypertension treatment improves cardio-vascular risk reduction: Hygia Chronotherapy Trial. Eur Heart J 2019

Appraised by: Farah Abdi, MD (Class of 2021)

Bedtime hypertension treatment improvescardiovascular risk reduction: The HygiaChronotherapy TrialRamon C. Hermida, Juan J. Crespo, Manuel Domınguez-Sardina,Alfonso Otero, Ana Moya, Marıa T. Rıos, Elvira Sineiro, Marıa C. Castineira,Pedro A. Callejas, Lorenzo Pousa, Jose´ L. Salgado, Carmen Duran,Juan J. Sanchez1, Jose´ R. Fernandez, Artemio Mojon, and Diana E. Ayala;for the Hygia Project Investigators.

European Heart Journal (October 2019); doi:10.1093/eurheartj/ehz754

CLINICAL RESEARCHHypertension

Bedtime BP Meds: The Study

Study Design: Randomized clinical trial (N=19,084)

Participants: 18+ yo from 40 primary care clinics in Northern Spain On at least 1 medicine to control blood pressureExclusion: Night shift workers

Exposure: All BP meds prescribed for bedtime administrationControl: All BP meds taken on waking up

Outcome: Major CV Event (CVD death, MI, coronary revascularization, heart failure, or stroke); median FU 6.3 years

Findings: CVE rate lower in bedtime arm; HR 0.55 (95% CI: 0.50-0.61)

Each component outcome was lower by 40-56%CVD death HR 0.44 (95% CI: 0.34-0.56)Serum Cr & LDL lower; HDL & eGFR higher in bedtime arm

Bedtime BP Meds: Brief Appraisal

• Validity

RCT. Participants and doctors not blinded, but CV event adjudicators were blinded

• Effect Size

NNT to prevent 1 major CV event in 6 years: 16

• RelevanceAverage age 60y in study; all Caucasians in the studyMed titration based on ambulatory BP, not clinic BP

Topics Covered







Interventions for Agitation in Dementia

Context: Agitation and aggression are common in dementia, and cause caregiver burnout and institutionalization. Open question: Which interventions are most effective?

Clinical Take Home:Non-pharmacologic interventions (outdoor activities, massage and touch therapy, exercise, ADL modification) more effective than drugs

Watt JA, et al., Comparative efficacy of interventions for aggressive and agitated behaviors in dementia. Annals Intern Med 2019 November

Appraised by: Vivek Singh, MD (Class of 2021)

Ann Intern Med. 2019; 171: 633-642

Annals of Internal Medicine

Comparative Efficacy of Interventions for Aggressive and AgitatedBehaviors in DementiaA Systematic Review and Network Meta-analysisJennifer A. Watt, MD, PhD; Zahra Goodarzi, MD, MSc; Areti Angeliki Veroniki, PhD; Vera Nincic, PhD; Paul A. Khan, PhD;Marco Ghassemi, MSc; Yuan Thompson, PhD; Andrea C. Tricco, PhD; and Sharon E. Straus, MD, MSc

REVIEW

Agitation in Dementia: The Study

Study Design: Network meta-analysis of 163 RCTs

Participants: Dementia patients (23,143) with aggression (verbal or physical) and/or agitation (physical or verbal)

Interventions: Non-pharmacologic or medications or usual care

Outcomes: Aggression (verbal, physical, combined), agitation (physical, verbal), combined agitation and aggression

Findings: Outdoor activities most effective for both kinds of aggression and combined aggression and agitationMassage and touch therapy as effective for verbal aggression Exercise and ADL modification most effective for physical agitationAnticonvulsants most effective for verbal agitation

Agitation in Dementia: Brief Appraisal

• Validity ThreatsHeterogeneity in study populations and interventionsHigh rates of missing data in individual studies

• Effect SizeComparisons against usual care exceeded MCID

• Relevance63% of studies had mean age >= 80 years65% of studies were in LTC/ALFsMajority of studies were <3 months long

Topics Covered







Vitamin D Supplements to Reduce Fall Risk

Context: High doses of Vit D supplementation may increase fallsThere could be a (low) dose that reduces fall risk

Clinical Take Home:In 70+ yo adults with low 25-(OH)D levels, Vitamin D supplementation does not lower fall risk

Appel LJ, et al., The effects of four doses of vitamin D supplements on falls in older adults. A response-adaptive, randomized clinical trial. Annals Intern Med 2021 February

Appraised by: David Biobaku, MD (Class of 2021)

The Effects of Four Doses of Vitamin D Supplements on Falls inOlder AdultsA Response-Adaptive, Randomized Clinical Trial

Lawrence J. Appel, MD, MPH; Erin D. Michos, MD, MHS; Christine M. Mitchell, ScM; Amanda L. Blackford, ScM;Alice L. Sternberg, ScM; Edgar R. Miller III, MD, PhD; Stephen P. Juraschek, MD, PhD; Jennifer A. Schrack, PhD, MS;Sarah L. Szanton, PhD, ANP; Jeanne Charleston, BSN, RN; Melissa Minotti, MPH; Sheriza N. Baksh, PhD, MPH;Robert H. Christenson, PhD; Josef Coresh, MD, PhD; Lea T. Drye, PhD; Jack M. Guralnik, MD, PhD; Rita R. Kalyani, MD, MHS;Timothy B. Plante, MD, MHS; David M. Shade, JD; David L. Roth, PhD; and James Tonascia, PhD, for the STURDY Collaborative Research Group.

Ann Intern Med. 2021;174:145–156

ORIGINAL RESEARCHAnnals of Internal Medicine

Vitamin D and Falls: The Study

Study Design: Response-adaptive RCT; N=688

Participants: 70+ yo adults at high fall riskSerum 25-(OH)D level 10-30 ng/mLExclusions: Hypercalcemia, taking > 1000 IU of Vit D3 /day

Intervention: Vitamin D3 (best of 1000, 2000, 4000 IU /day)Control: 200 IU of Vitamin D3

Outcome: Time to first fall or death; Median FU 22 months

Findings: More falls in 2000 IU dose; HR 2.69 (95% CI: 1.50 to 4.82)DSMB stopped higher doses; ppts switched to 1000 IU/dayTrail terminated for futility; HR 0.94 (95% CI: 0.76 to 1.15)More falls-related hospitalization; HR 2.48 (95% CI: 1.13 to 5.56)

Vitamin D and Falls: Brief Appraisal

• ValidityRandomized trial4 in 10 ppts were taking additional Vit D (median 700 IU)40% of active arm took high dose for 15 of 22 months

• Effect sizeIncrease in fall hospitalization: 3.4 per 100 person-yearsNNH = 29

• RelevanceMean age 77.2 years; mean (25-OH)D 23 ng/mL

Topics Covered







Donanemab for Early Alzheimer’s

Context: Amyloid-β accumulates in brain in Alzheimer’s diseaseAducanumab, a directed antibody Rx, reduces Amyloid-β

Clinical Take Home:In early symptomatic AD, donanemab Rx slowed worsening of cognitive and functional impairment by a clinically non-significant amount at 76 weeks.

Mintun AM, et al., Donanemab in early Alzheimer’s disease. N Engl J Med 2021 March

Appraised by: David Lee, MD (Class of 2021)

Donanemab in Early Alzheimer’s Disease

Mark A. Mintun, M.D., Albert C. Lo, M.D., Ph.D., Cynthia Duggan Evans, Ph.D.,

Alette M. Wessels, Ph.D., Paul A. Ardayfio, Ph.D., Scott W. Andersen, M.S.,Sergey Shcherbinin, Ph.D., JonDavid Sparks, Ph.D., John R. Sims, M.D.,

Miroslaw Brys, M.D., Ph.D., Liana G. Apostolova, M.D.,Stephen P. Salloway, M.D., and Daniel M. Skovronsky, M.D., Ph.D.

This article was published on March 13, 2021, at NEJM.orgDOI: 10.1056/NEJMoa2100708

The New England Journal of Medicine

ORIGINAL ARTICLE

Donanemab and AD: The Study

Study Design: Phase 2, placebo-controlled RCT; 56 centers

Participants: 60-85 yo with MCI or dementia, MMSE 20-28; N = 257PET-confirmed amyloid-β and tau deposits in brain

Intervention: Donanemab 1400 mg IV every 4 weeks for 72 weeksDose reduced if Aβ burden on PET reduced at 24 or 52 wk

Outcomes: Change in iADRS (range, 0-144) at 76 weeksMRI-based detection of amyloid-related edema & hemorrhage

Findings: Smaller decline in iADRS : -6.9 vs. -10.1Effect size: 3.2; 95% CI 0.1 to 6.3

ARIA-Edema: 27% vs. 1%ARIA-Hemorrhage: 30% vs. 7%

Donanemab and AD: Brief Appraisal

• ValidityPhase 2 RCT in early AD - MCI or mild dementia

• Effect SizeEffect on 144 point iADRS: 3.2; 95% CI 0.1 to 6.3Expected effect size (for which study was powered) 6.8

• RelevanceNo current Rx meaningfully slows cognitive decline 30% discontinuation due to adverse effects

Take Home Messages







Acknowledgements

UCLA and Greater Los Angeles VA Faculty in Geriatrics

Faculty mentored fellows and assisted in appraising research studies

UCLA Multi-campus Fellowship in Geriatrics

Fellowship trainees evaluated the quality of these research studies in bi-monthly journal clubs

Acknowledgements

Faculty who mentored fellows for journal club

• Dave Reuben (Geriatrics)• David Ganz (Geriatrics)• Erin Cook (Geriatrics)• Peifeng (Perry) Hu (Geriatrics & Palliative Care)• Deena Goldwater (Geriatrics & Cardiology)• Gail Greendale (Geriatrics & Women’s Health)• Melissa Cohen (Geriatrics & Oncology)• Maryum Merchant (Pulmonary)• Tara Vijayan (Infectious Diseases)• Nancy Weintraub (Geriatrics)

Documents

Geriatrics Literature Update