News Release 

Canakinumab shows promise for treatment of large joint osteoarthritis

Embargoed news from Annals of Internal Medicine

American College of Physicians

Below please find summaries of new articles that will be published in the next issue of Annals of Internal Medicine. The summaries are not intended to substitute for the full articles as a source of information. This information is under strict embargo and by taking it into possession, media representatives are committing to the terms of the embargo not only on their own behalf, but also on behalf of the organization they represent.

1. Canakinumab shows promise for treatment of large joint osteoarthritis

Abstract: https://www.acpjournals.org/doi/10.7326/M20-0527

Editorial: https://www.acpjournals.org/doi/10.7326/M20-4938

URL goes live when the embargo lifts

An exploratory analysis of data from the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) randomized double-blind, placebo-controlled trial found that patients receiving interleukin-1β (IL-1β) inhibitors had significantly lower rates of total hip or total knee replacements over an average follow up of 3.7 years. These findings are important, as no treatments currently exist that can either prevent or slow progression of osteoarthritis. The study is published in Annals of Internal Medicine.

In the CANTOS trial, more than 10,000 patients with elevated high-sensitivity C-reactive protein (hs-CRP) levels and a history of myocardial infarction were randomly assigned canakinumab or placebo injections every 3 months for up to 5 years to determine the cardiovascular effects. Cardiovascular event rates fell among participants receiving a higher dose range of canakinumab, with the greatest magnitude of effect accruing among those with the most robust reductions in hs-CRP and IL-6. CANTOS, therefore, provided the researchers with a unique opportunity to explore the effects of IL-1β -targeted therapy versus placebo on incidence rates of total hip or total knee replacement surgeries.

In their analysis, researchers from the Novartis Institutes for BioMedical Research (NIBR), University of Leeds and Brigham and Women's Hospital, Harvard Medical School found that the combined incidence rates for total hip or total knew replacements were 40 to 47 percent lower with canakinumab treatment, with all canakinumab doses reducing the number of joint replacements similarly. The reduction in joint replacements among patients who received canakinumab versus the placebo group became apparent after only one year of treatment and remained statistically significant when CANTOS participants with a history of crystalline or inflammatory arthritis were excluded. However, the authors provide a cautionary note that the number of women in the trial was relatively low, while knee osteoarthritis is a disease that predominates in older women.

According to the authors of an accompanying editorial from the UC Davis Health, the results of this analysis are both unexpected and exciting. The investigators used elevated hs-CRP level as an entry criterion, and may have identified a subgroup of persons with osteoarthritis in whom inflammatory cytokines activate pathways that accelerate joint degeneration. The authors also note that joint replacement is a robust endpoint and one that might be adapted by the U.S. Food and Drug Administration for evaluating disease-modifying osteoarthritis drugs.

Media contacts: For an embargoed PDF please contact Lauren Evans at laevans@acponline.org. The lead author, Paul M Ridker, MD, can be reached at pridker@bwh.harvard.edu. The lead author of the editorial, Nancy Lane, MD, can be reached through Charles Casey at cecasey@UCDAVIS.EDU.

2. Statin toxicity could occur when rosuvastatin and canagliflozin are prescribed together

Abstract: https://www.acpjournals.org/doi/10.7326/L20-0549

URL goes live when the embargo lifts

Physicians should be aware that canagliflozin could cause rosuvastatin toxicity when the two drugs are prescribed together. This is an important finding because these drugs are taken by millions of patients worldwide and are increasingly prescribed together. The first report of an interaction between these two drugs is published in Annals of Internal Medicine.

Rosuvastatin is a commonly prescribed statin and canagliflozin is one of a newer class of diabetes drugs, the sodium-glucose cotransporter-2 (SGLT2) inhibitors. It is common for patients with diabetes to also take a statin. In fact, the American College of Cardiology currently recommends adding an SGLT2 inhibitor, such as canagliflozin, to the regimens of patients with diabetes and cardiovascular disease.

Researchers from the University of Toronto describe the case of a patient who was hospitalized with severe rosuvastatin toxicity (manifesting as muscle damage and inability to walk) 2 weeks after starting canagliflozin. Although she had taken rosuvastatin uneventfully for more than 5 years, her blood rosuvastatin concentration when she arrived at the hospital was 15 times higher than expected for her dose. The authors speculate that canagliflozin caused rosuvastatin toxicity by increasing rosuvastatin absorption, and by reducing its elimination by the liver and kidney. The authors encourage clinicians to remain vigilant for features of myotoxicity when canagliflozin and rosuvastatin are co-prescribed.

Media contacts: For an embargoed PDF please contact Lauren Evans at laevans@acponline.org. To speak with the lead author, David Juurlink, MD, PhD, please contact Monica Matys at Monica.Matys@sunnybrook.ca.

3. Clinicians go 'Beyond the Guidelines' to debate management of advanced kidney disease in a patient with dementia Annals Beyond the Guidelines discussions are based on real Beth Israel Deaconess Medical Center Grand Rounds

Abstract: https://www.acpjournals.org/doi/10.7326/M20-2640

URL goes live when the embargo lifts

In a new Annals 'Beyond the Guideline's feature, clinicians discuss appropriate care for an 85-year-old with advanced kidney disease and dementia. This is an important discussion, as chronic kidney disease (CKD) is more common in persons older than 65 years, which is also an age when coexisting conditions are likely to be present. The grand rounds presentation and accompanying videos are published in Annals of Internal Medicine.

Sushrut S. Waikar, MD, MPH, is Chief of the Section of Nephrology as well as the Norman G. Levinsky Professor of Medicine at Boston University. Dr. Waikar suggests that in-patient hemodialysis may be the best option for this patient, as it might improve symptoms of uremia, and may be more compatible with the patient's living situation than in-home dialysis. Dr. Waikar recognizes that dialysis may not provide a survival benefit to the patient. For the same reason, Dr. Waikar does not recommend kidney transplantation.

Melissa W. Wachterman, MD, MPH, MSc, holds joint appointments in General Medicine at VA Boston Healthcare System and Brigham and Women's Hospital and in the Department of Psychosocial Oncology and Palliative Care at Dana-Farber Cancer Institute. She is an Assistant Professor of Medicine at Harvard Medical School. Dr. Wachterman believes that the care of patients with advanced kidney disease should be tailored to the individual patient based on their values, preferences, and goals rather than conceptualized as a dichotomous choice between conventional "one size fits all" dialysis and conservative management in which symptom management is limited to non-dialytic interventions. Based on the conversation with the patient's family about what matters most to the patient, Dr. Wachterman recommends a conservative management approach, while also noting that if the patient develops bothersome symptoms that do not respond to conservative interventions, they can discuss a trial of dialysis would potentially improve his quality of life.

All 'Beyond the Guidelines' papers are based on the Department of Medicine Grand Rounds at BIDMC in Boston and include print, video, and educational components. A list of topics is available at http://www.annals.org/grandrounds.

Media contacts: For an embargoed PDF please contact Lauren Evans at laevans@acponline.org. To speak with author, Melissa W. Wachterman, MD, MPH, MSc, please contact Kendra McKinnon at kmckinn1@bidmc.harvard.edu.

Also in this issue:

Health Professionals, Violence, and Social Change

Garen Wintemute, MD, MPH

Ideas & Opinions

Abstract: https://www.acpjournals.org/doi/10.7326/M20-4411

In The Clinic: COPD Update

Wassim W. Labaki, MD, MS; Sharon R. Rosenberg, MD, MS

In The Clinic

Abstract: https://www.acpjournals.org/doi/10.7326/AITC202008040

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