{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T11:43:14Z","timestamp":1769514194226,"version":"3.49.0"},"reference-count":45,"publisher":"BMJ","issue":"6","funder":[{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["PR140170 - GRANT11766881"],"award-info":[{"award-number":["PR140170 - GRANT11766881"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2016,4,22]]},"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>A substantial majority of chronic obstructive pulmonary disease (COPD)-related morbidity, mortality and healthcare costs are due to acute exacerbations, but existing medications have only a modest effect on reducing their frequency, even when used in combination. Observational studies suggest \u03b2-blockers may reduce the risk of COPD exacerbations; thus, we will conduct a randomised, placebo-controlled trial to definitively assess the impact of metoprolol succinate on the rate of COPD exacerbations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analyses<\/jats:title>\n                    <jats:p>\n                      This is a multicentre, placebo-controlled, double-blind, prospective randomised trial that will enrol 1028 patients with at least moderately severe COPD over a 3-year period. Participants with at least moderate COPD will be randomised in a 1:1 fashion to receive metoprolol or placebo; the cohort will be enriched for patients at high risk for exacerbations. Patients will be screened and then randomised over a 2-week period and will then undergo a dose titration period for the following 6\u2005weeks. Thereafter, patients will be followed for 42 additional weeks on their target dose of metoprolol or placebo followed by a 4-week washout period. The primary end point is time to first occurrence of an acute exacerbation during the treatment period. Secondary end points include rates and severity of COPD exacerbations; rate of major cardiovascular events; all-cause mortality; lung function (forced expiratory volume in 1\u2005s (FEV\n                      <jats:sub>1<\/jats:sub>\n                      )); dyspnoea; quality of life; exercise capacity; markers of cardiac stretch (pro-NT brain natriuretic peptide) and systemic inflammation (high-sensitivity C reactive protein and fibrinogen). Analyses will be performed on an intent-to-treat basis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The study protocol has been approved by the Department of Defense Human Protection Research Office and will be approved by the institutional review board of all participating centres. Study findings will be disseminated through presentations at national and international conferences and publications in peer-reviewed journals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>NCT02587351; Pre-results.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2016-012292","type":"journal-article","created":{"date-parts":[[2016,6,7]],"date-time":"2016-06-07T22:55:49Z","timestamp":1465340149000},"page":"e012292","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":28,"title":["\u03b2-Blockers for the prevention of acute exacerbations of chronic obstructive pulmonary disease (\u03b2LOCK COPD): a randomised controlled study protocol"],"prefix":"10.1136","volume":"6","clinical-trial-number":[{"clinical-trial-number":"nct02587351","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02587351","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Surya P","family":"Bhatt","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John E","family":"Connett","sequence":"additional","affiliation":[{"name":"Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen","family":"Voelker","sequence":"additional","affiliation":[{"name":"Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah M","family":"Lindberg","sequence":"additional","affiliation":[{"name":"Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Westfall","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J Michael","family":"Wells","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama, USA"},{"name":"Birmingham Veterans Affairs Hospital, Birmingham, Alabama, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen C","family":"Lazarus","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerard J","family":"Criner","sequence":"additional","affiliation":[{"name":"Department of Thoracic Medicine and Surgery, Temple University Hospital, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark T","family":"Dransfield","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama, USA"},{"name":"Birmingham Veterans Affairs Hospital, Birmingham, Alabama, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2016,6,7]]},"reference":[{"key":"2025121601025272000_6.6.e012292.1","doi-asserted-by":"publisher","DOI":"10.3111\/13696998.2012.713880"},{"key":"2025121601025272000_6.6.e012292.2","doi-asserted-by":"publisher","DOI":"10.1513\/pats.200701-001FM"},{"key":"2025121601025272000_6.6.e012292.3","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7015-7-2"},{"key":"2025121601025272000_6.6.e012292.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2013.05.001"},{"key":"2025121601025272000_6.6.e012292.5","doi-asserted-by":"publisher","DOI":"10.1513\/pats.200404-032MS"},{"key":"2025121601025272000_6.6.e012292.6","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201306-1170OC"},{"key":"2025121601025272000_6.6.e012292.7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199808203390801"},{"key":"2025121601025272000_6.6.e012292.8","doi-asserted-by":"publisher","DOI":"10.1001\/archinternmed.2010.112"},{"key":"2025121601025272000_6.6.e012292.9","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2015-207251"},{"key":"2025121601025272000_6.6.e012292.10","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1R600"},{"key":"2025121601025272000_6.6.e012292.11","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.d2549"},{"key":"2025121601025272000_6.6.e012292.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2007.06.003"},{"key":"2025121601025272000_6.6.e012292.13","first-page":"190","article-title":"Effects of muliple doses of metoprolol and propranolol on ventilatory function in patients with chronic obstructive lung disease","volume":"57","author":"Tivenius","year":"1976","journal-title":"Scand J Respir Dis"},{"key":"2025121601025272000_6.6.e012292.14","doi-asserted-by":"publisher","DOI":"10.1007\/BF01856511"},{"key":"2025121601025272000_6.6.e012292.15","doi-asserted-by":"crossref","unstructured":"Salpeter S , Ormiston T , Salpeter E . Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005 (4):CD003566. doi:10.1002\/14651858.CD003566.pub2","DOI":"10.1002\/14651858.CD003566.pub2"},{"key":"2025121601025272000_6.6.e012292.16","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201208-1565OC"},{"key":"2025121601025272000_6.6.e012292.17","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1104623"},{"key":"2025121601025272000_6.6.e012292.18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1403086"},{"key":"2025121601025272000_6.6.e012292.19","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-155-3-201108020-00008"},{"key":"2025121601025272000_6.6.e012292.20","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.c3134"},{"key":"2025121601025272000_6.6.e012292.21","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0b013e31829e8776"},{"key":"2025121601025272000_6.6.e012292.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2012.07.013"},{"key":"2025121601025272000_6.6.e012292.23","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-143-5-200509060-00007"},{"key":"2025121601025272000_6.6.e012292.24","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-106-2-196"},{"key":"2025121601025272000_6.6.e012292.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0954-6111(03)00168-9"},{"key":"2025121601025272000_6.6.e012292.26","doi-asserted-by":"publisher","DOI":"10.1001\/jama.283.10.1295"},{"key":"2025121601025272000_6.6.e012292.27","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2007.082636"},{"key":"2025121601025272000_6.6.e012292.28","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200508-1338PP"},{"key":"2025121601025272000_6.6.e012292.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2006.12.035"},{"key":"2025121601025272000_6.6.e012292.30","first-page":"443","article-title":"Sub-clinical left ventricular diastolic dysfunction in early stage of chronic obstructive pulmonary disease","volume":"25","author":"Malerba","year":"2011","journal-title":"J Biol Regul Homeost Agents"},{"key":"2025121601025272000_6.6.e012292.31","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0808836"},{"key":"2025121601025272000_6.6.e012292.32","first-page":"343","article-title":"COPD9USA June 2015","volume":"2","author":"Yawn","year":"2015","journal-title":"Chron Obstruct Pulmon Dis (Miami, Florida)"},{"key":"2025121601025272000_6.6.e012292.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2012.04.007"},{"key":"2025121601025272000_6.6.e012292.34","doi-asserted-by":"crossref","first-page":"e105152","DOI":"10.1371\/journal.pone.0105152","article-title":"Resting heart rate is a risk factor for mortality in chronic obstructive pulmonary disease, but not for exacerbations or pneumonia","volume":"9","author":"Warnier","year":"2014","journal-title":"PLoS ONE"},{"key":"2025121601025272000_6.6.e012292.35","doi-asserted-by":"crossref","first-page":"552","DOI":"10.3109\/15412555.2014.974743","article-title":"Cardiac sympathetic dominance and systemic inflammation in COPD","volume":"12","author":"Chhabra","year":"2015","journal-title":"Copd"},{"key":"2025121601025272000_6.6.e012292.36","doi-asserted-by":"publisher","DOI":"10.1111\/j.1524-6175.2005.04486.x"},{"key":"2025121601025272000_6.6.e012292.37","doi-asserted-by":"publisher","DOI":"10.1378\/chest.121.3.846"},{"key":"2025121601025272000_6.6.e012292.38","doi-asserted-by":"publisher","DOI":"10.1172\/JCI75157"},{"key":"2025121601025272000_6.6.e012292.39","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2007-0279RC"},{"key":"2025121601025272000_6.6.e012292.40","doi-asserted-by":"publisher","DOI":"10.1177\/1753944709339968"},{"key":"2025121601025272000_6.6.e012292.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejheart.2007.04.006"},{"key":"2025121601025272000_6.6.e012292.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2010.01.024"},{"key":"2025121601025272000_6.6.e012292.43","doi-asserted-by":"publisher","DOI":"10.1007\/s00380-003-0706-z"},{"key":"2025121601025272000_6.6.e012292.44","doi-asserted-by":"crossref","first-page":"205","DOI":"10.4321\/S1886-36552009000400003","article-title":"Beta-blocker therapy in patients with left ventricular systolic dysfunction and chronic obstructive lung disease in an ambulatory care setting","volume":"7","author":"Schimmer","year":"2009","journal-title":"Pharm Pract (Granada)"},{"key":"2025121601025272000_6.6.e012292.45","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1994.tb05705.x"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2016-012292","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T09:03:04Z","timestamp":1765875784000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2016-012292"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6]]},"references-count":45,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2016,6,7]]},"published-print":{"date-parts":[[2016,6]]}},"alternative-id":["10.1136\/bmjopen-2016-012292"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2016-012292","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,6]]}}}