{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,3,15]],"date-time":"2025-03-15T04:17:41Z","timestamp":1742012261231,"version":"3.38.0"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T00:00:00Z","timestamp":1741910400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T00:00:00Z","timestamp":1741910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Vestre Viken Hospital Trust"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Cardiovasc Disord"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>High-sensitive (hs-) cardiac troponin assays provide prognostic information in atrial fibrillation (AF) patients. Few studies have explored the impact of long-term rate control therapy on levels of troponin in AF patients without coronary heart disease and heart failure. This substudy of the RATe control in Atrial Fibrillation (RATAF) II study aimed to compare the effects of six months\u2019 treatment with diltiazem and metoprolol on hs-troponin I (TnI) levels both at rest and during exercise testing in patients with permanent AF.\n<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>This was a parallel-group, randomized, investigator-blinded clinical trial. The cohort consisted of 93 patients (28 women, mean age 71\u2009\u00b1\u20097 years) with symptomatic, permanent AF with preserved left ventricular systolic function and no coronary heart disease. Participants were randomized in a 1:1 ratio to receive either diltiazem 360 mg (<jats:italic>n<\/jats:italic>\u2009=\u200949) or metoprolol 100 mg (<jats:italic>n<\/jats:italic>\u2009=\u200944) once daily for six months. Blood tests were drawn at rest and during peak exercise testing at baseline, one month and six months\u2019 treatment. This research has been supported by grants from the South-Eastern Norway Regional Health Authority and Vestre Viken Hospital Trust.\n<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Six months\u2019 treatment with diltiazem and metoprolol significantly lowered the heart rate at rest and peak exercise. Both treatment groups exhibited a decrease in hs-TnI levels at rest (diltiazem <jats:italic>p<\/jats:italic>\u2009=\u20090.008, metoprolol <jats:italic>p<\/jats:italic>\u2009=\u20090.03) and peak exercise (diltiazem <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001, metoprolol <jats:italic>p<\/jats:italic>\u2009=\u20090.004) at six months compared to baseline levels, with no significant differences observed between the groups.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>In patients with permanent AF, six months of rate control therapy with diltiazem or metoprolol lowered levels of hs-TnI. Further research is warranted to determine whether this reduction translates into an improved prognosis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Trial registration<\/jats:title>\n            <jats:p>NCT02695992. Registration date: 2015\u201304-28.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12872-025-04574-2","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T10:24:53Z","timestamp":1741947893000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of diltiazem and metoprolol on levels of high-sensitivity troponin I in patients with permanent atrial fibrillation: a randomized trial"],"prefix":"10.1186","volume":"25","author":[{"given":"Katrine","family":"Enge","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara Reinvik","family":"Ulimoen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steve","family":"Enger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophia","family":"Onarheim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mona","family":"Olufsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Are Hugo","family":"Pripp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trude","family":"Steinsvik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Hall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathias","family":"Hetland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arnljot","family":"Tveit","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,3,14]]},"reference":[{"issue":"20","key":"4574_CR1","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.1093\/eurheartj\/eht024","volume":"34","author":"Z Hijazi","year":"2013","unstructured":"Hijazi Z, Oldgren J, Siegbahn A, Granger CB, Wallentin L. Biomarkers in atrial fibrillation: a clinical review. Eur Heart J. 2013;34(20):1475\u201380.","journal-title":"Eur Heart J"},{"issue":"30","key":"4574_CR2","doi-asserted-by":"publisher","first-page":"2428","DOI":"10.1093\/eurheartj\/ehw172","volume":"37","author":"S Blankenberg","year":"2016","unstructured":"Blankenberg S, Salomaa V, Makarova N, Ojeda F, Wild P, Lackner KJ, et al. Troponin I and cardiovascular risk prediction in the general population: the BiomarCaRE consortium. Eur Heart J. 2016;37(30):2428\u201337.","journal-title":"Eur Heart J"},{"issue":"22","key":"4574_CR3","doi-asserted-by":"publisher","first-page":"2503","DOI":"10.1001\/jama.2010.1768","volume":"304","author":"JA de Lemos","year":"2010","unstructured":"de Lemos JA, Drazner MH, Omland T, Ayers CR, Khera A, Rohatgi A, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA. 2010;304(22):2503\u201312.","journal-title":"JAMA"},{"issue":"18","key":"4574_CR4","doi-asserted-by":"publisher","first-page":"2252","DOI":"10.1093\/eurheartj\/ehn327","volume":"29","author":"KM Eggers","year":"2008","unstructured":"Eggers KM, Lind L, Ahlstr\u00f6m H, Bjerner T, Ebeling Barbier C, Larsson A, et al. Prevalence and pathophysiological mechanisms of elevated cardiac troponin I levels in a population-based sample of elderly subjects. Eur Heart J. 2008;29(18):2252\u20138.","journal-title":"Eur Heart J"},{"issue":"16","key":"4574_CR5","doi-asserted-by":"publisher","first-page":"1958","DOI":"10.1161\/CIRCULATIONAHA.105.609974","volume":"113","author":"TW Wallace","year":"2006","unstructured":"Wallace TW, Abdullah SM, Drazner MH, Das SR, Khera A, McGuire DK, et al. Prevalence and determinants of troponin T elevation in the general population. Circulation. 2006;113(16):1958\u201365.","journal-title":"Circulation"},{"issue":"1","key":"4574_CR6","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.ahj.2013.10.003","volume":"167","author":"M Rienstra","year":"2014","unstructured":"Rienstra M, Yin X, Larson MG, Fontes JD, Magnani JW, McManus DD, et al. Relation between soluble ST2, growth differentiation factor-15, and high-sensitivity troponin I and incident atrial fibrillation. Am Heart J. 2014;167(1):109-15.e2.","journal-title":"Am Heart J"},{"issue":"6","key":"4574_CR7","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1161\/CIRCULATIONAHA.113.006286","volume":"129","author":"Z Hijazi","year":"2014","unstructured":"Hijazi Z, Siegbahn A, Andersson U, Granger CB, Alexander JH, Atar D, et al. High-sensitivity troponin I for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation. 2014;129(6):625\u201334.","journal-title":"Circulation"},{"issue":"6","key":"4574_CR8","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1002\/clc.22251","volume":"37","author":"K Gupta","year":"2014","unstructured":"Gupta K, Pillarisetti J, Biria M, Pescetto M, Abu-Salah TM, Annapureddy C, et al. Clinical utility and prognostic significance of measuring troponin I levels in patients presenting to the emergency room with atrial fibrillation. Clin Cardiol. 2014;37(6):343\u20139.","journal-title":"Clin Cardiol"},{"issue":"5","key":"4574_CR9","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1093\/eurheartj\/ehaa612","volume":"42","author":"G Hindricks","year":"2021","unstructured":"Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomstr\u00f6m-Lundqvist C, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2021;42(5):373\u2013498.","journal-title":"Eur Heart J."},{"issue":"1","key":"4574_CR10","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.jacc.2013.07.093","volume":"63","author":"Z Hijazi","year":"2014","unstructured":"Hijazi Z, Wallentin L, Siegbahn A, Andersson U, Alexander JH, Atar D, et al. High-sensitivity troponin T and risk stratification in patients with atrial fibrillation during treatment with apixaban or warfarin. J Am Coll Cardiol. 2014;63(1):52\u201361.","journal-title":"J Am Coll Cardiol"},{"issue":"20","key":"4574_CR11","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1093\/eurheartj\/ehw054","volume":"37","author":"Z Hijazi","year":"2016","unstructured":"Hijazi Z, Lindb\u00e4ck J, Alexander JH, Hanna M, Held C, Hylek EM, et al. The ABC (age, biomarkers, clinical history) stroke risk score: a biomarker-based risk score for predicting stroke in atrial fibrillation. Eur Heart J. 2016;37(20):1582\u201390.","journal-title":"Eur Heart J"},{"issue":"10035","key":"4574_CR12","doi-asserted-by":"publisher","first-page":"2302","DOI":"10.1016\/S0140-6736(16)00741-8","volume":"387","author":"Z Hijazi","year":"2016","unstructured":"Hijazi Z, Oldgren J, Lindb\u00e4ck J, Alexander JH, Connolly SJ, Eikelboom JW, et al. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet (London, England). 2016;387(10035):2302\u201311.","journal-title":"Lancet (London, England)"},{"issue":"6","key":"4574_CR13","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1093\/eurheartj\/ehx584","volume":"39","author":"Z Hijazi","year":"2018","unstructured":"Hijazi Z, Oldgren J, Lindb\u00e4ck J, Alexander JH, Connolly SJ, Eikelboom JW, et al. A biomarker-based risk score to predict death in patients with atrial fibrillation: the ABC (age, biomarkers, clinical history) death risk score. Eur Heart J. 2018;39(6):477\u201385.","journal-title":"Eur Heart J"},{"issue":"36","key":"4574_CR14","doi-asserted-by":"publisher","first-page":"3314","DOI":"10.1093\/eurheartj\/ehae176","volume":"45","author":"IC Van Gelder","year":"2024","unstructured":"Van Gelder IC, Rienstra M, Bunting KV, Casado-Arroyo R, Caso V, Crijns H, et al. 2024 ESC guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2024;45(36):3314\u2013414.","journal-title":"Eur Heart J."},{"issue":"7","key":"4574_CR15","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1002\/clc.22281","volume":"37","author":"SR Ulimoen","year":"2014","unstructured":"Ulimoen SR, Enger S, Norseth J, Pripp AH, Abdelnoor M, Arnesen H, et al. Improved rate control reduces cardiac troponin T levels in permanent atrial fibrillation. Clin Cardiol. 2014;37(7):422\u20137.","journal-title":"Clin Cardiol"},{"key":"4574_CR16","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1186\/s12872-016-0255-x","volume":"16","author":"AW Horjen","year":"2016","unstructured":"Horjen AW, Ulimoen SR, Enger S, Norseth J, Seljeflot I, Arnesen H, et al. Troponin I levels in permanent atrial fibrillation-impact of rate control and exercise testing. BMC Cardiovasc Disord. 2016;16:79.","journal-title":"BMC Cardiovasc Disord"},{"issue":"6","key":"4574_CR17","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1093\/ehjcvp\/pvae032","volume":"10","author":"K Enge","year":"2024","unstructured":"Enge K, Tveit A, Enger S, Onarheim S, Pripp AH, R\u00f8nningen PS, et al. Diltiazem reduces levels of NT-proBNP and improves symptoms compared with metoprolol in patients with permanent atrial fibrillation. Eur Heart J Cardiovasc Pharmacother. 2024;10(6):515\u201325.","journal-title":"Eur Heart J Cardiovasc Pharmacother."},{"key":"4574_CR18","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.c332","volume":"340","author":"KF Schulz","year":"2010","unstructured":"Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340: c332.","journal-title":"BMJ"},{"issue":"8","key":"4574_CR19","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1093\/eurheartj\/eht429","volume":"35","author":"SR Ulimoen","year":"2014","unstructured":"Ulimoen SR, Enger S, Pripp AH, Abdelnoor M, Arnesen H, Gjesdal K, et al. Calcium channel blockers improve exercise capacity and reduce N-terminal pro-B-type natriuretic peptide levels compared with beta-blockers in patients with permanent atrial fibrillation. Eur Heart J. 2014;35(8):517\u201324.","journal-title":"Eur Heart J"},{"issue":"15","key":"4574_CR20","first-page":"1193","volume":"100","author":"Z Hijazi","year":"2014","unstructured":"Hijazi Z, Oldgren J, Andersson U, Connolly SJ, Ezekowitz MD, Hohnloser SH, et al. Importance of persistent elevation of cardiac biomarkers in atrial fibrillation: a RE-LY substudy. Heart (British Cardiac Society). 2014;100(15):1193\u2013200.","journal-title":"Heart (British Cardiac Society)"},{"issue":"17","key":"4574_CR21","doi-asserted-by":"publisher","first-page":"1698","DOI":"10.1093\/eurheartj\/ehab141","volume":"42","author":"K Oyama","year":"2021","unstructured":"Oyama K, Giugliano RP, Berg DD, Ruff CT, Jarolim P, Tang M, et al. Serial assessment of biomarkers and the risk of stroke or systemic embolism and bleeding in patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial. Eur Heart J. 2021;42(17):1698\u2013706.","journal-title":"Eur Heart J."},{"issue":"6","key":"4574_CR22","doi-asserted-by":"publisher","first-page":"e004851","DOI":"10.1161\/JAHA.116.004851","volume":"6","author":"Z Hijazi","year":"2017","unstructured":"Hijazi Z, Lindahl B, Oldgren J, Andersson U, Lindback J, Granger CB, et al. Repeated measurements of cardiac biomarkers in atrial fibrillation and validation of the ABC stroke score over time. Journal of the American Heart Association. 2017;6(6):e004851.","journal-title":"Journal of the American Heart Association"},{"issue":"13","key":"4574_CR23","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1161\/CIRCULATIONAHA.111.038729","volume":"125","author":"Z Hijazi","year":"2012","unstructured":"Hijazi Z, Oldgren J, Andersson U, Connolly SJ, Ezekowitz MD, Hohnloser SH, et al. Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a randomized evaluation of long-term anticoagulation therapy (RE-LY) substudy. Circulation. 2012;125(13):1605\u201316.","journal-title":"Circulation"},{"issue":"5","key":"4574_CR24","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1016\/S0735-1097(99)00382-4","volume":"34","author":"C Aim\u00e9-Semp\u00e9","year":"1999","unstructured":"Aim\u00e9-Semp\u00e9 C, Folliguet T, R\u00fccker-Martin C, Krajewska M, Krajewska S, Heimburger M, et al. Myocardial cell death in fibrillating and dilated human right atria. J Am Coll Cardiol. 1999;34(5):1577\u201386.","journal-title":"J Am Coll Cardiol"},{"issue":"5923","key":"4574_CR25","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1126\/science.1164680","volume":"324","author":"O Bergmann","year":"2009","unstructured":"Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnab\u00e9-Heider F, Walsh S, et al. Evidence for cardiomyocyte renewal in humans. Science. 2009;324(5923):98\u2013102.","journal-title":"Science"},{"issue":"9","key":"4574_CR26","doi-asserted-by":"publisher","first-page":"786","DOI":"10.7326\/0003-4819-142-9-200505030-00015","volume":"142","author":"A Jeremias","year":"2005","unstructured":"Jeremias A, Gibson CM. Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded. Ann Intern Med. 2005;142(9):786\u201391.","journal-title":"Ann Intern Med"},{"issue":"24","key":"4574_CR27","doi-asserted-by":"publisher","first-page":"2406","DOI":"10.1016\/j.jacc.2011.01.029","volume":"57","author":"HD White","year":"2011","unstructured":"White HD. Pathobiology of troponin elevations: do elevations occur with myocardial ischemia as well as necrosis? J Am Coll Cardiol. 2011;57(24):2406\u20138.","journal-title":"J Am Coll Cardiol"},{"issue":"11","key":"4574_CR28","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1038\/nrcardio.2013.129","volume":"10","author":"E Giannitsis","year":"2013","unstructured":"Giannitsis E, Katus HA. Cardiac troponin level elevations not related to acute coronary syndromes. Nat Rev Cardiol. 2013;10(11):623\u201334.","journal-title":"Nat Rev Cardiol"},{"issue":"3","key":"4574_CR29","doi-asserted-by":"publisher","first-page":"2734","DOI":"10.1016\/j.ijcard.2013.03.087","volume":"168","author":"AS Parwani","year":"2013","unstructured":"Parwani AS, Boldt LH, Huemer M, Wutzler A, Blaschke D, Rolf S, et al. Atrial fibrillation-induced cardiac troponin I release. Int J Cardiol. 2013;168(3):2734\u20137.","journal-title":"Int J Cardiol"},{"issue":"15","key":"4574_CR30","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1056\/NEJMoa1001337","volume":"362","author":"IC Van Gelder","year":"2010","unstructured":"Van Gelder IC, Groenveld HF, Crijns HJ, Tuininga YS, Tijssen JG, Alings AM, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010;362(15):1363\u201373.","journal-title":"N Engl J Med"},{"issue":"1","key":"4574_CR31","doi-asserted-by":"publisher","first-page":"40","DOI":"10.3109\/10641963.2012.689044","volume":"35","author":"S Hoshide","year":"2013","unstructured":"Hoshide S, Fukutomi M, Eguchi K, Watanabe T, Kabutoya T, Kario K. Change in high-sensitive cardiac troponin T on hypertensive treatment. Clin Exp Hypertens. 2013;35(1):40\u20134.","journal-title":"Clin Exp Hypertens"},{"issue":"12","key":"4574_CR32","doi-asserted-by":"publisher","first-page":"1877","DOI":"10.1373\/clinchem.2017.275289","volume":"63","author":"A Jagodzinski","year":"2017","unstructured":"Jagodzinski A, Neumann JT, Ojeda F, S\u00f6rensen NA, Wild P, M\u00fcnzel T, et al. Cardiovascular biomarkers in hypertensive patients with medical treatment-results from the randomized TEAMSTA protect I trial. Clin Chem. 2017;63(12):1877\u201385.","journal-title":"Clin Chem"},{"issue":"6","key":"4574_CR33","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1002\/ejhf.2844","volume":"25","author":"K Oyama","year":"2023","unstructured":"Oyama K, Giugliano RP, Ruff CT, Berg DD, Jarolim P, Tang M, et al. Serial assessment of biomarkers and heart failure outcomes in patients with atrial fibrillation. Eur J Heart Fail. 2023;25(6):832\u201341.","journal-title":"Eur J Heart Fail"}],"container-title":["BMC Cardiovascular Disorders"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12872-025-04574-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12872-025-04574-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12872-025-04574-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T10:24:58Z","timestamp":1741947898000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmccardiovascdisord.biomedcentral.com\/articles\/10.1186\/s12872-025-04574-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,14]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["4574"],"URL":"https:\/\/doi.org\/10.1186\/s12872-025-04574-2","relation":{},"ISSN":["1471-2261"],"issn-type":[{"value":"1471-2261","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,14]]},"assertion":[{"value":"25 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 February 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 March 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The RATAF II trial was approved by the Norwegian Medicines Agency and the Regional Ethics Committee (2015\/1302). The trial was registered at  (NCT02695992). Each patient gave informed consent in agreement with the Helsinki Declaration before participating in any study-related activity.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"181"}}