British journal of clinical pharmacology最新文献

{"title":"Exposure-response relationships of mirvetuximab soravtansine in patients with folate receptor-α-positive ovarian cancer: Justification of therapeutic dose regimen.","authors":"Ya-Ping Tu, H Maxime Lagraauw, Michael Method, Yuemei Wang, Eva Hanze, Lingling Li, Timothy Parrott, Callum M Sloss, Eric H Westin","doi":"10.1111/bcp.16250","DOIUrl":"https://doi.org/10.1111/bcp.16250","url":null,"abstract":"<p><strong>Aims: </strong>This study aimed to investigate exposure-response (ER) relationships in efficacy and safety for mirvetuximab soravtansine (MIRV) which is a first-in-class antibody-drug conjugate approved for the treatment of folate receptor-α-positive platinum-resistant ovarian cancer.</p><p><strong>Methods: </strong>MIRV was characterized in 4 clinical studies. Exposure metrics for MIRV, its payload and a metabolite were derived from a population pharmacokinetic model. Efficacy was analysed in MIRV-treated patients (n = 215) in a recent confirmatory, randomized, chemotherapy-controlled MIRASOL trial and safety was evaluated in patients pooled across all 4 clinical studies (n = 757).</p><p><strong>Results: </strong>In the MIRASOL trial (NCT04209855), MIRV demonstrated significant benefit over chemotherapy in progression-free survival (PFS), objective response rate (ORR) and overall survival (OS). The most common adverse events (AEs) included ocular disorders, peripheral neuropathy and pneumonitis. For PFS, ORR and OS, the trough concentration of MIRV was the predictor consistently found in ER models for efficacy. In contrast, for ocular AEs (as well as the time to onset of ocular AEs) and peripheral neuropathy, the area under the concentration-time curve (AUC) of MIRV was identified as the exposure metric in ER models for safety. No exposure parameters were found to correlate with pneumonitis. Covariates in all models did not show clinically meaningful impact on efficacy or safety. Logistic regression models for ORR and ocular AEs based on AUC of MIRV were used to justify the clinical dose regimen approved for MIRV.</p><p><strong>Conclusion: </strong>The trough concentration of MIRV correlated with efficacy whereas the AUC of MIRV was associated with major AEs. The ER relationships supported the selected therapeutic dose regimen.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcium channel blocker overdose: Not all the same toxicity.","authors":"Geoffrey K Isbister, Shane Jenkins, Keith Harris, Michael A Downes, Katherine Z Isoardi","doi":"10.1111/bcp.16258","DOIUrl":"https://doi.org/10.1111/bcp.16258","url":null,"abstract":"<p><strong>Aims: </strong>Calcium channel blocker (CCB) overdose remains an important poisoning, with increasing availability of dihydropyridines. We aimed to compare the severity and treatment of CCB overdoses.</p><p><strong>Methods: </strong>We reviewed CCB overdoses presenting to two toxicology services from 2014 to 2023. We extracted prospectively collected data from a clinical database, including demographics, dose, co-ingestants, complications, treatments and outcomes, to compare different CCBs.</p><p><strong>Results: </strong>There were 236 overdoses; median age 55 years (interquartile range [IQR]: 41-65 years); 130 (55%) were females. Dihydropyridine overdoses increased significantly: median of nine cases annually (IQR: 8.8-12.3) during the study compared to a median of three cases annually (IQR: 1-4.3; P < 0.001) in the 10 years prior. The commonest agent was amlodipine (147), then lercanidipine (28), diltiazem (27), verapamil (23) and felodipine (11). Median defined daily dose ingested was higher for dihydropyridines, and cardiac co-ingestants were common except verapamil. Median length of stay was 21 h (IQR: 13-43 h), which was similar except longer for diltiazem (median, 39 h). Fifty-six patients (24%) were admitted to intensive care, more often for diltiazem (14; 52%) and verapamil (7; 30%). Dysrhythmias occurred in 19 patients (diltiazem [9], verapamil [8], amlodipine [2]), and included 13 junctional dysrhythmias. Hypotension occurred in 91 patients (39%), 62 (26%) received inotropes/vasopressors (adrenaline 32 [52%], noradrenaline 48 [77%]), 21 (9%) high-dose insulin and 44 (19%) calcium. Adrenaline and high-dose insulin were more commonly given in diltiazem and verapamil overdoses, compared to vasopressors in dihydropyridine overdoses. Acute kidney injury occurred in 39 patients. Seven (3%) patients died.</p><p><strong>Conclusions: </strong>Dihydropyridines were the commonest CCB overdoses, with amlodipine making up half. More severe toxicity occurred with diltiazem and verapamil.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The association between use of proton pump inhibitors and frailty index among middle-aged and older adults.","authors":"Rui Wu, Guojun Hong, Xiankun Cheng, Yue Zhu","doi":"10.1111/bcp.16260","DOIUrl":"https://doi.org/10.1111/bcp.16260","url":null,"abstract":"<p><strong>Aims: </strong>This study aimed to investigate the association between use of proton pump inhibitors (PPI) and frailty index (FI), and to assess the causality relationship using Mendelian randomization (MR).</p><p><strong>Methods: </strong>A total of 9756 middle-aged and older adults from the National Health and Nutrition Examination Survey were included. The FI was evaluated using a previously validated 49-item deficit model to assess frailty status, which is one of the common approaches to measure overall health burden. We performed weighted multivariable-adjusted linear regression to assess the association between PPI use and FI, and conducted a two-sample MR to evaluate causality, employing various sensitivity analyses for robustness. The inverse variance weighted (IVW) method was used as the primary analysis.</p><p><strong>Results: </strong>Multiple linear regression analysis revealed a positive association between PPI use and FI (β = 0.048, 95% confidence interval [CI]: 0.042-0.054, P < .001). This association was observed in both short-term (≤ 1 year) and long-term (> 1 year) PPI users (P for trend < 0.001). The MR study also revealed a positive association between PPI use and FI based on the IVW method (β = 1.183, 95% CI: 0.474-1.892, P = .001).</p><p><strong>Conclusions: </strong>While our findings suggest a potential link between PPI use and FI, they should be interpreted with caution due to the study's limitations. Although the MR analysis suggests a causal relationship, further research, particularly longitudinal studies, is needed to confirm these findings and better establish temporality.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A randomized phase I study of the safety and pharmacokinetics of BI 1291583 in healthy Japanese male subjects","authors":"Yusuke Tadayasu, Donald Sarubbi, Takumi Furuichi, Anastasia Eleftheraki, Shuhei Nakamura, Wiebke Sauter, Ryuzo Hanada","doi":"10.1111/bcp.16249","DOIUrl":"https://doi.org/10.1111/bcp.16249","url":null,"abstract":"Bronchiectasis patients face an unmet need for treatment options that reduce inflammation. Cathepsin C inhibition is expected to achieve this by reducing the activation of neutrophil-derived serine proteases. Here, we present safety and pharmacokinetic (PK) data from a Phase I trial evaluating the novel cathepsin C inhibitor BI 1291583 in healthy Japanese male subjects.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparing regulatory guidance on risk minimization/mitigation and the Reporting recommendation Intended for pharmaceutical Risk Minimization Evaluation Studies checklist","authors":"Sonia Guleria, Emily Brouwer, David A. Brown, Katja M. Hakkarainen","doi":"10.1111/bcp.16259","DOIUrl":"https://doi.org/10.1111/bcp.16259","url":null,"abstract":"The latest country-specific regulatory guidance for assessing effectiveness of risk minimization measures (RMM) strategies was identified across five continents—Africa (Egypt, South Africa), Asia (Australia, China, Japan, South Korea, Singapore), Europe (EU-27, United Kingdom), North America (Unites States, Canada) and South America (Brazil)—and compared to the Reporting recommendation Intended for pharmaceutical Risk Minimization Evaluation Studies (RIMES) checklist, developed to assess the quality of effectiveness evaluations and endorsed by the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). RIMES checklist items address study hypothesis, participants, measures, statistical analysis and results. European Medical Agency (EMA) and Food and Drug Administration (FDA) guidance only partially aligned with RIMES, primarily for measures and results. In the absence of country-specific guidance, most countries recommended following EMA or FDA guidelines; Japan and South Africa mentioned the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH E2E) guideline; Brazil and China had no guidance/recommendations. Worldwide, there was a lack of RMM-specific guidance and, when guidance existed, they were not harmonized, and alignment with the RIMES checklist was limited.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of codeine rescheduling on prescribing of codeine and other opioids: Interrupted time series analyses using Australian general practice data","authors":"Helena Cangadis-Douglass, Ting Xia, J. Simon Bell, Suzanne Nielsen","doi":"10.1111/bcp.16246","DOIUrl":"https://doi.org/10.1111/bcp.16246","url":null,"abstract":"We aimed to determine the impact of codeine rescheduling on prescribing of codeine and other opioids, with a focus on demographic and diagnoses associated with codeine prescribing before and after rescheduling of codeine to prescription-only in February 2018.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Incorporating the One Health philosophy into pharmacovigilanc: Pharmacovigilance","authors":"Montserrat García, Jerin Jose Cherian, Unax Lertxundi","doi":"10.1111/bcp.16254","DOIUrl":"https://doi.org/10.1111/bcp.16254","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing β‐lactam‐containing antibiotic combination therapy for the treatment of Buruli ulcer","authors":"Salvatore D'Agate, Peter Velickovic, Noelia García‐Barrios, Santiago Ramón‐García, Oscar Della Pasqua","doi":"10.1111/bcp.16209","DOIUrl":"https://doi.org/10.1111/bcp.16209","url":null,"abstract":"AimsThe current treatment for Buruli ulcer is based on empirical evidence of efficacy. However, there is an opportunity for shortening its duration and improving response rates. Evolving understanding of the pharmacokinetic–pharmacodynamic relationships provides the basis for a stronger dose rationale for antibiotics. In conjunction with modelling and simulation, it is possible to identify dosing regimens with the highest probability of target attainment (PTA). This investigation aims to: (i) assess the dose rationale for a new combination therapy including amoxicillin/clavulanic acid (AMX/CLV) currently in clinical trials; and (ii) compare its performance with alternative dosing regimens including rifampicin, clarithromycin and AMX/CLV.MethodsIn vitro estimates of the minimum inhibitory (MIC) concentration were selected as a measure of the antibacterial activity of different drug combinations. Clinical trial simulations were used to characterize the concentration <jats:italic>vs</jats:italic>. time profiles of rifampicin, clarithromycin and amoxicillin in a virtual cohort of adult and paediatric patients, considering the effect of baseline covariates on disposition parameters and interindividual variability in exposure. The PTA of each regimen was then assessed using different thresholds of the time above MIC.ResultsA weight‐banded dosing regimen including 150–600 mg rifampicin once daily, 250–1000 mg clarithromycin and AMX/CLV 22.5 mg/kg /1000 mg twice daily ensures higher PTA than the standard of care with AMX/CLV 45 mg/kg/2000 mg once daily.ConclusionThe higher PTA values support the proposed 4‐drug combination (rifampicin, clarithromycin, AMX/CLV) currently under clinical investigation. Our findings also suggest that higher rifampicin doses might contribute to enhanced treatment efficacy.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstracts of the International Workshop on Clinical Pharmacology of HIV, Hepatitis, and other Antiviral Drugs","authors":"","doi":"10.1111/bcp.16208","DOIUrl":"https://doi.org/10.1111/bcp.16208","url":null,"abstract":"&lt;p&gt;Acosta, Edward, 22&lt;/p&gt;&lt;p&gt;Aladwani, Mary, 18&lt;/p&gt;&lt;p&gt;Ali, Ahlam, 22&lt;/p&gt;&lt;p&gt;Alpert, Pamela, 10&lt;/p&gt;&lt;p&gt;Anaam, Emad, 14&lt;/p&gt;&lt;p&gt;Anderson, Peter, 7, 10, 15, 23&lt;/p&gt;&lt;p&gt;Antinori, Spinello, 19&lt;/p&gt;&lt;p&gt;Antonucci, Miriam, 11&lt;/p&gt;&lt;p&gt;Arora, Priyanka, 19&lt;/p&gt;&lt;p&gt;Arraki Zava, Selim, 10&lt;/p&gt;&lt;p&gt;Arshad, Usman, 3, 18&lt;/p&gt;&lt;p&gt;Atoyebi, Shakir, 5&lt;/p&gt;&lt;p&gt;Avedissian, Sean, 20&lt;/p&gt;&lt;p&gt;Bamford, Alasdair, 4&lt;/p&gt;&lt;p&gt;Baril, Jean-Guy, 9&lt;/p&gt;&lt;p&gt;Barker, Nicholas, 7, 10&lt;/p&gt;&lt;p&gt;Barlow, Eleanor, 3&lt;/p&gt;&lt;p&gt;Bekker, Adrie, 21&lt;/p&gt;&lt;p&gt;Best, Brookie, 25&lt;/p&gt;&lt;p&gt;Bevers, Lisanne, 4&lt;/p&gt;&lt;p&gt;Bin, Jiang, 24&lt;/p&gt;&lt;p&gt;Bin, Su, 17–18, 20–21&lt;/p&gt;&lt;p&gt;Boglione-Kerrien, Christelle, 6&lt;/p&gt;&lt;p&gt;Bolton, Carolyn, 25&lt;/p&gt;&lt;p&gt;Bonora, Stefano, 11&lt;/p&gt;&lt;p&gt;Boucoiran, Isabelle, 9&lt;/p&gt;&lt;p&gt;Branchford, Brian, 7&lt;/p&gt;&lt;p&gt;Bérard, Anne-Marie, 9&lt;/p&gt;&lt;p&gt;Brooks, Kristina, 7, 10, 21–23&lt;/p&gt;&lt;p&gt;Brown, Ashley, 20&lt;/p&gt;&lt;p&gt;Brummel, Sean, 21&lt;/p&gt;&lt;p&gt;Buchanan, Ann, 21&lt;/p&gt;&lt;p&gt;Burger, David, 4, 12&lt;/p&gt;&lt;p&gt;Bush, Mark, 22, 25&lt;/p&gt;&lt;p&gt;Bushman, Lane, 7, 10, 23&lt;/p&gt;&lt;p&gt;Bwakura-Dangarembizi, Mutsa, 12&lt;/p&gt;&lt;p&gt;Calcagno, Andrea, 11&lt;/p&gt;&lt;p&gt;Capparelli, Edmund, 25&lt;/p&gt;&lt;p&gt;Carnes, Tony, 10&lt;/p&gt;&lt;p&gt;Carroll, Miles, 22&lt;/p&gt;&lt;p&gt;Castagna, Antonella, 19&lt;/p&gt;&lt;p&gt;Castillo-Mancilla, Jose, 10&lt;/p&gt;&lt;p&gt;Cattaneo, Dario, 19&lt;/p&gt;&lt;p&gt;Chabala, Chishala, 4, 12&lt;/p&gt;&lt;p&gt;Challenger, Elizabeth, 8, 13&lt;/p&gt;&lt;p&gt;Chandasana, Hardik, 21–22&lt;/p&gt;&lt;p&gt;Chen, Buyun, 15&lt;/p&gt;&lt;p&gt;Cheung, Amy, 25&lt;/p&gt;&lt;p&gt;Chiong, Justin, 8&lt;/p&gt;&lt;p&gt;Ciuffa, Marika, 21&lt;/p&gt;&lt;p&gt;Colbers, Angela, 4, 12, 21&lt;/p&gt;&lt;p&gt;Collins, Jon, 25&lt;/p&gt;&lt;p&gt;Coppinger, Corwin, 10, 23&lt;/p&gt;&lt;p&gt;Cottrell, Mackenzie, 16&lt;/p&gt;&lt;p&gt;Cox, Helen, 3, 18&lt;/p&gt;&lt;p&gt;Coyle, Ryan, 7, 10&lt;/p&gt;&lt;p&gt;Cressey, Tim, 21–22&lt;/p&gt;&lt;p&gt;Cruz, Kimberly, 15&lt;/p&gt;&lt;p&gt;Curley, Paul, 3, 14, 18&lt;/p&gt;&lt;p&gt;Cusato, Jessica, 11&lt;/p&gt;&lt;p&gt;D'Amico, Ronald, 14&lt;/p&gt;&lt;p&gt;Davis, Casey, 19&lt;/p&gt;&lt;p&gt;D'avolio, Antonio, 11&lt;/p&gt;&lt;p&gt;de Vries, Christiaan, 15&lt;/p&gt;&lt;p&gt;Denti, Paolo, 5–6&lt;/p&gt;&lt;p&gt;Deprez, Isabelle, 25&lt;/p&gt;&lt;p&gt;Dhamani, Karim, 8&lt;/p&gt;&lt;p&gt;Di Perri, Giovanni, 11&lt;/p&gt;&lt;p&gt;Dickinson, Laura, 8, 13&lt;/p&gt;&lt;p&gt;Dooley, Kelly, 6&lt;/p&gt;&lt;p&gt;Dorse, Gillian, 6&lt;/p&gt;&lt;p&gt;Dumas, Marie-Eve, 9&lt;/p&gt;&lt;p&gt;Dumond, Julie, 16&lt;/p&gt;&lt;p&gt;Dwyer, Andrew, 3&lt;/p&gt;&lt;p&gt;Ellis, Samuel, 10&lt;/p&gt;&lt;p&gt;Ellison, Lucas, 7, 10&lt;/p&gt;&lt;p&gt;Else, Laura, 8, 13&lt;/p&gt;&lt;p&gt;Enever, Yvanne, 8&lt;/p&gt;&lt;p&gt;Ferrara, Micol, 11&lt;/p&gt;&lt;p&gt;FitzGerald, Richard, 8, 13&lt;/p&gt;&lt;p&gt;Fletcher, Tom, 8, 13&lt;/p&gt;&lt;p&gt;Flynn, Patricia, 22&lt;/p&gt;&lt;p&gt;Ford, Susan, 14, 25&lt;/p&gt;&lt;p&gt;Fortin, Claude, 9&lt;/p&gt;&lt;p&gt;Franck, Bénédicte, 6&lt;/p&gt;&lt;p&gt;Franco, Evelyn, 20&lt;/p&gt;&lt;p&gt;Fréchette-Le Bel, Myriam, 9&lt;/p&gt;&lt;p&gt;Fromage, Yeleen, 10&lt;/p&gt;&lt;p&gt;Gallardo Toledo, Eduardo, 14&lt;/p&gt;&lt;p&gt;Gallardo-Toledo, Eduardo, 3&lt;/p&gt;&lt;p&gt;Gandhi, Monica, 15&lt;/p&gt;&lt;p&gt;Garst, Erin, 7&lt;/p&gt;&lt;p&gt;Gaur, Aditya, 25&lt;/p&gt;&lt;p&gt;Gervasoni, Cristina, 19&lt;/p&gt;&lt;p&gt;Ghosn, Jade, 12&lt;/p&gt;&lt;p&gt;Giacomelli, Andrea, 19&lt;/p&gt;&lt;p&gt;Gibb, Diana, 12&lt;/p&gt;&lt;p&gt;Girish, Sandhya, 19&lt;/p&gt;&lt;p&gt;Goldan, Razvan, 11&lt;/p&gt;&lt;p&gt;Griffiths, Gareth, 8&lt;/p&gt;&lt;p&gt;Hale, Colin, 8, 13&lt;/p&gt;&lt;p&gt;Hamani, Naima, 12&lt;/p&gt;&lt;p&gt;Han, Kelong, 14, 25&lt;/p&gt;&lt;p&gt;Hanrahan, Kaley, 20&lt;/p&gt;&lt;p&gt;Hao, Jia, 15&lt;/p&gt;&lt;p&gt;Hao, Wu, 17–18, 20–21&lt;/p&gt;&lt;p&gt;Harrington, Conn, 25&lt;/p&gt;&lt;p&gt;Hassman, Howard, 15&lt;/p&gt;&lt;p&gt;Hawkes, Jennifer, 23&lt;/p&gt;&lt;p&gt;Herriott, Joanne, 3&lt;/p&gt;&lt;p&gt;Hindman, Jason, 19&lt;/p&gt;&lt;p&gt;Hobson, James, 3&lt;/p&gt;&lt;p&gt;Ho","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16208","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142244538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of down‐titration and discontinuation of heart failure pharmacotherapy in older people: A systematic review and meta‐analysis","authors":"Mai H. Duong, Danijela Gnjidic, Andrew J. McLachlan, Mitchell R. Redston, Parag Goyal, Stephanie Mathieson, Sarah N. Hilmer","doi":"10.1111/bcp.16223","DOIUrl":"https://doi.org/10.1111/bcp.16223","url":null,"abstract":"The aim of this study was to investigate whether interventions to discontinue or down‐titrate heart failure (HF) pharmacotherapy are feasible and associated with risks in older people. A systematic review and meta‐analysis were conducted according to PRISMA 2020 guidelines. Electronic databases were searched from inception to 8 March 2023. Randomized controlled trials (RCTs) and observational studies included people with HF, aged ≥50 years and who discontinued or down‐titrated HF pharmacotherapy. Outcomes were feasibility (whether discontinuation or down‐titration of HF pharmacotherapy was sustained at follow‐up) and associated risks (mortality, hospitalization, adverse drug withdrawal effects [ADWE]). Random‐effects meta‐analysis was performed when heterogeneity was not substantial (Higgins <jats:italic>I</jats:italic><jats:sup>2</jats:sup> &lt; 70%). Sub‐analysis by frailty status was conducted. Six RCTs (536 participants) and 27 observational studies (810 499 participants) across six therapeutic classes were included, for 3–260 weeks follow‐up. RCTs were conducted in patients presenting with stable chronic HF. Down‐titrating a renin‐angiotensin system inhibitor (RASI) in patients with chronic kidney disease was 76% more likely than continuation (risk ratio [RR] 1.76, 95% confidence interval [CI] 1.14–2.73), with no difference in mortality (RR 0.64, 95% CI 0.30–1.64). Discontinuation of beta‐blockers were feasible compared to continuation in preserved ejection fraction (RR 1.00, 95% CI 0.68–1.47). Participants were 25% more likely to re‐initiate discontinued diuretics (RR 0.75, 95% CI 0.66–0.86). Digoxin discontinuation was associated with 5.5‐fold risk of hospitalization compared to continuation. Worsening HF was the most common ADWE. One observational study measured frailty but did not report outcomes by frailty status. The appropriateness and associated risks of down‐titrating or discontinuing HF pharmacotherapy in people aged ≥75 years is uncertain. Evaluation of outcomes by frailty status necessitates investigation.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}