Clinically Important Benefits and Harms of Monoclonal Antibodies Targeting Amyloid for the Treatment of Alzheimer Disease: A Systematic Review and Meta-Analysis

An evidence-based review of monoclonal antibody treatment of patients with Alzheimer's Disease. Very little benefit and significant risk. James W. Mold, MD, MPH

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Purpose: We conducted a meta-analysis to evaluate clinically meaningful benefits and harms of monoclonal antibodies targeting amyloid in patients with Alzheimer dementia.

Methods: We searched PubMed, Cochrane CENTRAL, and 5 trial registries, as well as the reference lists of identified studies. We included randomized controlled trials comparing a monoclonal antibody with placebo at a dose consistent with that used in phase 3 trials or for Food and Drug Administration approval. Studies had to report at least 1 clinically relevant benefit or harm. Data were extracted independently by at least 2 researchers for random effects meta-analysis. Changes in cognitive and functional scales were compared between groups, and each difference was assessed to determine if it met the minimal clinically important difference (MCID).

Results: We identified 19 publications with 23,202 total participants that evaluated 8 anti-amyloid antibodies. There were small improvements over placebo in the Alzheimer's Disease Assessment Scale (ADAS)-Cog-11 to -14 score (standardized mean difference = -0.07; 95% CI, -0.10 to -0.04), Mini Mental State Examination score (0.32 points; 95% CI, 0.13 to 0.50), and Clinical Dementia Rating-Sum of Boxes scale score (mean difference =-0.18 points; 95% CI, -0.34 to -0.03), and the combined functional scores (standardized mean difference = 0.09; 95% CI, 0.05 to 0.13). None of the changes, including those for lecanemab, aducanumab, and donanemab, exceeded the MCID. Harms included significantly increased risks of amyloid-related imaging abnormalities (ARIA)-edema (relative risk [RR] = 10.29; number needed to harm [NNH] = 9), ARIA-hemorrhage (RR = 1.74; NNH = 13), and symptomatic ARIA-edema (RR = 24.3; NNH = 86).

Conclusions: Although monoclonal antibodies targeting amyloid provide small benefits on cognitive and functional scales in patients with Alzheimer dementia, these improvements are far below the MCID for each outcome and are accompanied by clinically meaningful harms.

Keywords: ARIA; Alzheimer dementia; Alzheimer disease; aducanumab; aged; amyloid; antibodies, monoclonal; biological therapy; cerebral edema; cerebral hemorrhage; chronic disease; dementia; donanemab; drug approval; lecanemab; meta-analysis; risks and benefits; systematic review.

Author/s:

Mark H Ebell, Henry C Barry, Kanishka Baduni, Gabrielle Grasso

Bisphosphonates for Postmenopausal Osteoporosis

John Bayhi — Sat, 19 Oct 2019 14:38:56 +0000

Date Added:

October 19, 2019

Journal/Publication:

JAMA

Publisher:

American Medical Association

Publication Date:

October 17, 2019

URL:

Bisphosphonates for Postmenopausal Osteoporosis

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1001/jama.2019.15781

Keywords

post-menopausal osteoporosis

bisphosphonates

antiresorptive agents

PMID (1):

31621799

MeSH

Bone Density Conservation Agents

Raloxifene Hydrochloride

Risedronate Sodium

Alendronate

Osteoporosis, Postmenopausal

Selective Estrogen Receptor Modulators

Gatroesophageal Reflux

Estrogens

vitamin D deficiency

Peptic Ulcer

risk reduction behavior

A short, sweet review of how, when, and for how long to treat postmenopausal osteoporosis. James W. Mold, MD, MPH

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Bisphosphonates are the first-line pharmacologic treatment for postmenopausal osteoporosis and the most commonly prescribed medication for this condition.1 Bisphosphonates, classified as antiresorptive agents, have a very high affinity for bone mineral and bind to hydroxyapatite crystals on bony surfaces, where they inhibit osteoclast-mediated bone resorption.

Author/s:

Ensrud, KE, Crandall, CJ