Angiotensin receptor blockers for the treatment of covid-19: pragmatic, adaptive, multicentre, phase 3, randomised controlled trial.

OBJECTIVE: To determine whether disrupting the renin angiotensin system with angiotensin receptor blockers will improve clinical outcomes in people with covid-19. DESIGN: CLARITY was a pragmatic, adaptive, multicentre, phase 3, randomised controlled trial. SETTING: 17 hospital sites in India and Australia. PARTICIPANTS: Participants were at least 18 years old, previously untreated with angiotensin receptor blockers, with a laboratory confirmed diagnosis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection who had been admitted to hospital for management of covid-19. INTERVENTION: Oral angiotensin receptor blockers (telmisartan in India) or placebo (1:1) for 28 days. MAIN OUTCOME MEASURES: The primary endpoint was covid-19 disease severity using a modified World Health Organization Clinical Progression Scale (WHO scale) at day 14. Secondary outcomes were WHO scale scores at day 28, mortality, intensive care unit admission, and respiratory failure. Analyses were evaluated on an ordinal scale in the intention-to-treat population. RESULTS: Between 3 May 2020 and 13 November 2021, 2930 people were screened for eligibility, with 393 randomly assigned to angiotensin receptor blockers (of which 388 (98.7%) to telmisartan 40 mg/day) and 394 to the control group. 787 participants were randomised: 778 (98.9%) from India and nine (1.1%) from Australia. The median WHO scale score at day 14 was 1 (interquartile range 1-1) in 384 participants assigned angiotensin receptor blockers and 1 (1-1) in 382 participants assigned placebo (adjusted odds ratio 1.51 (95% credible interval 1.02 to 2.23), probability of an odds ratio of >1 (Pr(OR>1)=0.98). WHO scale scores at day 28 showed little evidence of difference between groups (1.02 (0.55 to 1.87), Pr(OR>1)=0.53). The trial was stopped when a prespecified futility rule was met. CONCLUSIONS: In patients admitted to hospital for covid-19, mostly with mild disease, not requiring oxygen, no evidence of benefit, based on disease severity score, was found for treatment with angiotensin receptor blockers, using predominantly 40 mg/day of telmisartan. TRIAL REGISTRATION: ClinicalTrials.gov NCT04394117.

Effect of Canagliflozin on Total Hospitalization for Heart Failure Events in Patients with Type 2 Diabetes and Chronic Kidney Disease

Background: The sodium glucose co-transporter 2 inhibitor canagliflozin reduced the risk of first hospitalization for heart failure (HHF) in the CREDENCE trial. The prevention of recurrent events is important to patients, clinicians and payers. In this post-hoc analysis, we evaluated the effect of canagliflozin on total HHF events. Methods: The CREDENCE trial compared canagliflozin or matching placebo and followed patients for a median of 2.6 years. The study included 4401 participants with type 2 diabetes, substantial albuminuria and estimated glomerular filtration rate (eGFR) 30 to <90 ml/min/1.73 m2 receiving renin-angiotensin system blockade. Negative binomial regression models were performed to assess the effect of canagliflozin on the total number of HHF events. Results: The mean age of participants was 63 years, with a mean eGFR of 56.3 ml/min/1.73 m2, while 50% had a history of previous cardiovascular disease and 15% had a history of heart failure. During the trial, 230 people experienced 326 total HHF events, with 166 having 1 event, 43 having 2 events, 15 having 3 events, and 6 having ≥4 events;thus, 42% of those experiencing at least 1 event went on to suffer a recurrent event during the follow up. Canagliflozin reduced first HHF events by 39% (hazard ratio [HR], 0.61;95% confidence interval [CI] 0.47-0.80;P <0.001;number needed to treat [NNT], 46;95% CI 29-124) and total HHF events by 36% (event rates of 22.0 and 34.8 participants with an event/1000 patient-years with canagliflozin and placebo, respectively;incidence rate ratio [RR], 0.64;95% CI 0.56-0.73;P <0.001). Conclusions: Canagliflozin significantly reduced first and recurrent HHF events. These findings provide further support for the benefit of continuing canagliflozin therapy after an index heart failure presentation to prevent recurrent HHF events. Disclosure: J. Li: Employee;Self;George Institute. M.J. Jardine: Other Relationship;Self;See Other Relationship field. B. Neal: Research Support;Self;Janssen Research & Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship;Self;Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. H.L. Heerspink: Consultant;Self;AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. C. Cannon: None. R. Agarwal: Other Relationship;Self;AbbVie Inc., Akebia Therapeutics, Amgen, AstraZeneca, Bayer Inc., Bird Rock Bio, Boehringer Ingelheim Pharmaceuticals, Inc., Celgene, Daiichi Sankyo, Eli Lilly and Company, GlaxoSmithKline plc., Ironwood Pharmaceuticals, Johnson & Johnson, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, OPKO Health, Inc., Reata, Relypsa, Inc., Sandoz, Sanofi, Takeda Pharmaceutical Company Limited, ZS Pharma. G. Bakris: Consultant;Self;Alnylam, Merck & Co., Inc., Relypsa, Inc., Teijin Pharma Limited. Other Relationship;Self;Bayer AG, Novo Nordisk Inc., Vascular Dynamics. D.M. Charytan: Advisory Panel;Self;Allena Pharmaceuticals, AstraZeneca, Merck & Co., Inc., PLC Medical. Employee;Self;BAIM Institute. Research Support;Self;Janssen Pharmaceuticals, Inc. Other Relationship;Self;Baim, Amgen, Medtronic/Covidien, Zoll, Fresenius, Daiichi Sankyo, Douglas and London, Eli Lilly, Merck, Gilead, and Novo Nordisk. D. de Zeeuw: Advisory Panel;Self;AbbVie Inc., Bayer AG, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Janssen Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. R. Edwards: Employee;Self;Janssen. T. Greene: Other Relationship;Self;Janssen, Durect, and Pfizer. A. Levin: Consultant;Self;Janssen Pharmaceuticals, Inc. Research Support;Self;AstraZeneca K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Gilead Sciences, Inc. C.A. Pollock: Advisory Panel;Self;AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Otsuka Pharmaceutical Co., Ltd., Vifor Pharma Group. Research Support;Self;Diabetes Australia. Speaker's Bureau;Self;AstraZeneca, Cipla Inc., MedErgy, Medscape, Mitsubishi Tanabe Pharma Corporation, Novartis AG, Otsuka Pharmaceutical Co., Ltd., Vifor Pharma Group. Other Relationship;Self;Amgen, George Institute for Global Health, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc. N. Rosenthal: None. D.C. Wheeler: Advisory Panel;Self;Boehringer Ingelheim Pharmaceuticals, Inc., Reata. Consultant;Self;AstraZeneca, Bayer AG, GlaxoSmithKline, Janssen Pharmaceuticals, Inc. Speaker's Bureau;Self;Amgen, Astellas Pharma Inc., Mundipharma International, Napp Pharmaceuticals. H. Zhang: Employee;Self;Renal Division of Peking University First Hospital. B. Zinman: Advisory Panel;Self;Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. V. Perkovic: Other Relationship;Self;See Other Relationship field. K.W. Mahaffey: Consultant;Self;Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support;Self;Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. C. Arnott: Employee;Self;George Institute for Global Health. Funding: Janssen Research & Development, LLC [ABSTRACT FROM AUTHOR] Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Acute Declines in EGFR during Treatment with Canagliflozin and Its Implications for Clinical Practice: Insights from CREDENCE

Background: Canagliflozin (CANA) slows progression of chronic kidney disease (CKD) in people with type 2 diabetes. CANA also induces a reversible acute decline in estimated glomerular filtration rate (eGFR), which is believed to be a hemodynamic effect. Predictors of the initial decline and its association with long-term eGFR trajectories and safety outcomes are unknown. Methods: This post-hoc study of the CREDENCE trial included 4289 patients with type 2 diabetes and CKD who had eGFR measured at both baseline and week 3. Participants were categorized by percentage decline in eGFR at week 3: >10%, ≤10% to >0%, and ≤0%. Baseline characteristics associated with acute eGFR declines >10% were evaluated using logistic regression. Long-term eGFR decline and safety outcomes were estimated in each eGFR decline category by linear mixed effects models and Cox regression after adjustment for laboratory measures and medication use. Results: More participants in the CANA (956 [45%]) versus placebo (PBO) group (450 [21%]) had an acute eGFR decline >10% (p<0.001). A >30% decline occurred infrequently (89 [4%] with CANA and 39 [2%] with PBO;p<0.001). In the CANA but not in the PBO group, older age (OR CANA 1.17, 95% CI 1.05-1.31;per 10 years) and history of heart failure (OR CANA 0.77, 0.59-0.99) were associated with a higher and lower likelihood of an acute eGFR decline >10%, respectively (both p for interaction <0.05). Following the initial eGFR change, long-term eGFR trajectories as well as overall safety profiles were similar across eGFR decline categories (all p values >0.05). Results were consistent when other decline thresholds (>20%) were used and in subgroup analysis by baseline eGFR (30-<45, 45-<60, and 60-<90 ml/min/1.73 m2). Conclusions: Although acute eGFR declines >10% occurred in nearly half of all patients following initiation of CANA, the benefit of CANA compared with placebo was observed regardless of the acute eGFR decline and safety profiles were similar. Disclosure: M. Oshima: Research Support;Self;Japan Society for the Promotion of Science Program for Fostering Globally Talented Researchers. M.J. Jardine: Other Relationship;Self;See Other Relationship field. R. Agarwal: Other Relationship;Self;AbbVie Inc., Akebia Therapeutics, Amgen, AstraZeneca, Bayer Inc., Bird Rock Bio, Boehringer Ingelheim Pharmaceuticals, Inc., Celgene, Daiichi Sankyo, Eli Lilly and Company, GlaxoSmithKline plc., Ironwood Pharmaceuticals, Johnson & Johnson, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, OPKO Health, Inc., Reata, Relypsa, Inc., Sandoz, Sanofi, Takeda Pharmaceutical Company Limited, ZS Pharma. G. Bakris: Consultant;Self;Alnylam, Merck & Co., Inc., Relypsa, Inc., Teijin Pharma Limited. Other Relationship;Self;Bayer AG, Novo Nordisk Inc., Vascular Dynamics. C. Cannon: None. D.M. Charytan: Advisory Panel;Self;Allena Pharmaceuticals, AstraZeneca, Merck & Co., Inc., PLC Medical. Employee;Self;BAIM Institute. Research Support;Self;Janssen Pharmaceuticals, Inc. Other Relationship;Self;Baim, Amgen, Medtronic/Covidien, Zoll, Fresenius, Daiichi Sankyo, Douglas and London, Eli Lilly, Merck, Gilead, and Novo Nordisk. D. de Zeeuw: Advisory Panel;Self;AbbVie Inc., Bayer AG, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Janssen Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. R. Edwards: Employee;Self;Janssen. T. Greene: Other Relationship;Self;Janssen, Durect, and Pfizer. A. Levin: Consultant;Self;Janssen Pharmaceuticals, Inc. Research Support;Self;AstraZeneca K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Gilead Sciences, Inc. K.W. Mahaffey: Consultant;Self;Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support;Self;Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. B. Neal: Research Support;Self;Janssen Research & Development LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship;Self;Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. C.A. Pollock: Advisory Panel;Self;AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Otsuka Pharmaceutical Co., Ltd., Vifor Pharma Group. Research Support;Self;Diabetes Australia. Speaker's Bureau;Self;AstraZeneca, Cipla Inc., MedErgy, Medscape, Mitsubishi Tanabe Pharma Corporation, Novartis AG, Otsuka Pharmaceutical Co., Ltd., Vifor Pharma Group. Other Relationship;Self;Amgen, George Institute for Global Health, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc. N. Rosenthal: None. D.C. Wheeler: Advisory Panel;Self;Boehringer Ingelheim Pharmaceuticals, Inc., Reata. Consultant;Self;AstraZeneca, Bayer AG, GlaxoSmithKline, Janssen Pharmaceuticals, Inc. Speaker's Bureau;Self;Amgen, Astellas Pharma Inc., Mundipharma International, Napp Pharmaceuticals. H. Zhang: Employee;Self;Renal Division of Peking University First Hospital. B. Zinman: Advisory Panel;Self;Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. V. Perkovic: Other Relationship;Self;See Other Relationship field. H.L. Heerspink: Consultant;Self;AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. Funding: Janssen Research & Development, LLC [ABSTRACT FROM AUTHOR] Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Forgotten Technology in the COVID-19 Pandemic: Filtration Properties of Cloth and Cloth Masks-A Narrative Review.

Management of the global crisis of the coronavirus disease 2019 pandemic requires detailed appraisal of evidence to support clear, actionable, and consistent public health messaging. The use of cloth masks for general public use is being debated, and is in flux. We searched the MEDLINE and EMBASE databases and Google for articles reporting the filtration properties of flat cloth or cloth masks. We reviewed the reference lists of relevant articles to identify further articles and identified articles through social and conventional news media. We found 25 articles. Study of protection for the wearer used healthy volunteers, or used a manikin wearing a mask, with airflow to simulate different breathing rates. Studies of protection of the environment, also known as source control, used convenience samples of healthy volunteers. The design and execution of the studies was generally rigorously described. Many descriptions of cloth lacked the detail required for reproducibility; no study provided all the expected details of material, thread count, weave, and weight. Some of the homemade mask designs were reproducible. Successful masks were made of muslin at 100 threads per inch (TPI) in 3 to 4 layers (4-layer muslin or a muslin-flannel-muslin sandwich), tea towels (also known as dish towels), made using 1 layer (2 layers would be expected to be better), and good-quality cotton T-shirts in 2 layers (with a stitched edge to prevent stretching). In flat-cloth experiments, linen tea towels, 600-TPI cotton in 2 layers, and 600-TPI cotton with 90-TPI flannel performed well but 80-TPI cotton in 2 layers did not. We therefore recommend cotton or flannel at least 100 TPI, at least 2 layers. More layers, 3 or 4, will provide increased filtration but there is a trade-off in that more layers increases the resistance to breathing. Although this is not a systematic review, we included all the articles that we identified in an unbiased way. We did not include gray literature or preprints. A plain language summary of these data and recommendations, as well as information on making, wearing and cleaning cloth masks is available at www.clothmasks.ca.