Design and rationale of the Danish trial of beta-blocker treatment after myocardial infarction without reduced ejection fraction: study protocol for a randomized controlled trial

Anna Meta Dyrvig Kristensen, Ann Bovin, Ann Dorthe Zwisler, Charlotte Cerquira, Christian Torp-Pedersen, Hans Erik Bøtker, Ida Gustafsson, Karsten Tange Veien, Kristian Korsgaard Thomsen, Michael Hecht Olsen, Mogens Lytken Larsen, Olav Wendelboe Nielsen, Per Hildebrandt, Sussie Foghmar, Svend Eggert Jensen, Theis Lange, Thomas Sehested, Tomas Jernberg, Dan Atar, Borja Ibanez, Eva Prescott, Anna Meta Dyrvig Kristensen, Ann Bovin, Ann Dorthe Zwisler, Charlotte Cerquira, Christian Torp-Pedersen, Hans Erik Bøtker, Ida Gustafsson, Karsten Tange Veien, Kristian Korsgaard Thomsen, Michael Hecht Olsen, Mogens Lytken Larsen, Olav Wendelboe Nielsen, Per Hildebrandt, Sussie Foghmar, Svend Eggert Jensen, Theis Lange, Thomas Sehested, Tomas Jernberg, Dan Atar, Borja Ibanez, Eva Prescott

Abstract

Background: Treatment with beta-blockers is currently recommended after myocardial infarction (MI). The evidence relies on trials conducted decades ago before implementation of revascularization and contemporary medical therapy or in trials enrolling patients with heart failure or reduced left ventricular ejection fraction (LVEF ≤ 40%). Accordingly, the impact of beta-blockers on mortality and morbidity following acute MI in patients without reduced LVEF or heart failure is unclear.

Methods/design: The Danish trial of beta-blocker treatment after myocardial infarction without reduced ejection fraction (DANBLOCK) is a prospective, randomized, controlled, open-label, non-blinded endpoint clinical trial designed to evaluate the efficacy of beta-blocker treatment in post-MI patients in the absence of reduced LVEF or heart failure. We will randomize 3570 patients will be randomized within 14 days of index MI to beta-blocker or control for a minimum of 2 years. The primary endpoint is a composite of all-cause mortality, recurrent MI, acute decompensated heart failure, unstable angina pectoris, or stroke. The primary composite endpoint will be assessed through locally reported and adjudicated endpoints supplemented by linkage to the Danish national registers. A number of secondary endpoints will be investigated including patient reported outcomes and cardiovascular mortality. Data from similar ongoing trials in Norway and Sweden will be pooled to perform an individual patient data meta-analysis.

Discussion: DANBLOCK is a randomized clinical trial investigating the effect of long-term beta-blocker therapy after myocardial infarction in patients without heart failure and reduced LVEF. Results from the trial will add important scientific evidence to inform future clinical guidelines.

Trial registration: Clinicaltrials.gov, NCT03778554. Registered on 19 December 2018. European Clinical Trials Database, 2018-002699-42, registered on 28 September 2018.

Keywords: Beta-blocker treatment; Long-term prognosis; Myocardial infarction; Randomized controlled trial.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Study overview
Fig. 2
Fig. 2
Minimal detectable difference between groups (HR) and statistical power in the planned meta-analyses of the three Scandinavian trials. For comparison the greater statistical power in a single multicenter trial with the same number of events is also depicted. The solid line indicates analysis based on data from a single multicenter trial; the dashed line indicates meta-analysis performed with a random-effects model

References

    1. Group NMS Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med. 1981;304:801–807.
    1. The National Heart L, and Blood Institute, Bethesda, MD A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. JAMA. 1982;247:1707–1714.
    1. Hjalmarson A, Herlitz J, Holmberg S, Ryden L, Swedberg K, Vedin A, et al. The Goteborg metoprolol trial. Effects on mortality and morbidity in acute myocardial infarction. Circulation. 1983;67:I26–I32.
    1. McCance AJ, Thompson PA, Forfar JC. Increased cardiac sympathetic nervous activity in patients with unstable coronary heart disease. Eur Heart J. 1993;14:751–757.
    1. Paladino L, Sinert R, Brandler E. A review and meta-analysis of studies on the effect and timing of beta-blocker administration in patients with ST-segment elevation myocardial infarction. Hosp Pract (1995) 2010;38:63–68.
    1. Rogers WJ, Frederick PD, Stoehr E, Canto JG, Ornato JP, Gibson CM, et al. Trends in presenting characteristics and hospital mortality among patients with ST elevation and non-ST elevation myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006. Am Heart J. 2008;156:1026–1034.
    1. Ibanez B, Heusch G, Ovize M, Van de Werf F. Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol. 2015;65:1454–1471.
    1. O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Jr, Chung MK, de Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61:e78–e140.
    1. Mickley H, Eiskjaer H, Botker HE. Is an additional post-myocardial infarction beta-blocker trial required in the era of early revascularization? Eur Heart J. 2004;25:96–97.
    1. Freemantle N, Cleland J, Young P, Mason J, Harrison J. beta Blockade after myocardial infarction: systematic review and meta regression analysis. BMJ. 1999;318:1730–1737.
    1. Bangalore S, Makani H, Radford M, Thakur K, Toklu B, Katz SD, et al. Clinical outcomes with beta-blockers for myocardial infarction: a meta-analysis of randomized trials. Am J Med. 2014;127:939–953.
    1. Watanabe H, Ozasa N, Morimoto T, Shiomi H, Bingyuan B, Suwa S, et al. Long-term use of carvedilol in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. PLoS One. 2018;13:e0199347.
    1. Dahl Aarvik M, Sandven I, Dondo TB, Gale CP, Ruddox V, Munkhaugen J, et al. Effect of oral beta-blocker treatment on mortality in contemporary post-myocardial infarction patients: a systematic review and meta-analysis. Eur Heart J Cardiovasc Pharmacother. 2019;5:12–20.
    1. Li J, Chen Z, Gao X, Zhang H, Xiong W, Ju J, et al. Meta-analysis comparing metoprolol and carvedilol on mortality benefits in patients with acute myocardial infarction. Am J Cardiol. 2017;120:1479–1486.
    1. Misumida N, Harjai K, Kernis S, Kanei Y. Does oral beta-blocker therapy improve long-term survival in ST-segment elevation myocardial infarction with preserved systolic function? A meta-analysis. J Cardiovasc Pharmacol Ther. 2016;21:280–285.
    1. Huang BT, Huang FY, Zuo ZL, Liao YB, Heng Y, Wang PJ, et al. Meta-analysis of relation between oral beta-blocker therapy and outcomes in patients with acute myocardial infarction who underwent percutaneous coronary intervention. Am J Cardiol. 2015;115:1529–1538.
    1. Dondo TB, Hall M, West RM, Jernberg T, Lindahl B, Bueno H, et al. beta-Blockers and mortality after acute myocardial infarction in patients without heart failure or ventricular dysfunction. J Am Coll Cardiol. 2017;69:2710–2720.
    1. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC) Eur Heart J. 2018;39:119–177.
    1. Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Jr, Ganiats TG, Holmes DR, Jr, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:2354–2394.
    1. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC) Eur Heart J. 2016;37:267–315.
    1. The National Institute for Health and Care Excellence. Myocardial infarction: cardiac rehabilitation and prevention of further cardiovascular disease. Available from: . Accessed 10 May 2019.
    1. Gislason GH, Rasmussen JN, Abildstrom SZ, Gadsboll N, Buch P, Friberg J, et al. Long-term compliance with beta-blockers, angiotensin-converting enzyme inhibitors, and statins after acute myocardial infarction. Eur Heart J. 2006;27:1153–1158.
    1. Korhonen MJ, Robinson JG, Annis IE, Hickson RP, Bell JS, Hartikainen J, et al. Adherence tradeoff to multiple preventive therapies and all-cause mortality after acute myocardial infarction. J Am Coll Cardiol. 2017;70:1543–1554.
    1. Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA. 2002;288:351–357.
    1. The National Institute for Health and Care Excellence. Surveillance report 2017 – Myocardial infarction: cardiac rehabilitation and prevention of further cardiovascular disease (2013) NICE guideline CG172. Available from: . Accessed 10 May 2019.
    1. Ibanez B, Raposeiras-Roubin S, Garcia-Ruiz JM. The Swing of beta-Blockers: time for a system reboot. J Am Coll Cardiol. 2017;69:2721–2724.
    1. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol. 2012;60:1581–1598.
    1. Chen ZM, Pan HC, Chen YP, Peto R, Collins R, Jiang LX, et al. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:1622–1632.
    1. Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, Dunn B, et al. 2017 Cardiovascular and stroke endpoint definitions for clinical trials. J Am Coll Cardiol. 2018;71:1021–1034.
    1. Ko DT, Hebert PR, Krumholz HM. Review: Beta-blockers increase fatigue and sexual dysfunction but not depression after myocardial infarction. ACP J Club. 2003;138:30.
    1. Huffman JC, Celano CM, Beach SR, Motiwala SR, Januzzi JL. Depression and cardiac disease: epidemiology, mechanisms, and diagnosis. Cardiovasc Psychiatry Neurol. 2013;2013:695925.
    1. Hayek SS, Ko YA, Awad M, Del Mar Soto A, Ahmed H, Patel K, et al. Depression and chest pain in patients with coronary artery disease. Int J Cardiol. 2017;230:420–426.
    1. Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34:2949–3003.
    1. EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy. 1990;16:199–208.
    1. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67:361–370.
    1. Rosen RC, Cappelleri JC, Gendrano N., 3rd The International Index of Erectile Function (IIEF): a state-of-the-science review. Int J Impot Res. 2002;14:226–244.
    1. Isidori AM, Pozza C, Esposito K, Giugliano D, Morano S, Vignozzi L, et al. Development and validation of a 6-item version of the female sexual function index (FSFI) as a diagnostic tool for female sexual dysfunction. J Sex Med. 2010;7:1139–1146.
    1. Pallesen S, Bjorvatn B, Nordhus IH, Sivertsen B, Hjornevik M, Morin CM. A new scale for measuring insomnia: the Bergen Insomnia Scale. Percept Mot Skills. 2008;107:691–706.
    1. Spertus JA, Winder JA, Dewhurst TA, Deyo RA, Prodzinski J, McDonell M, et al. Development and evaluation of the Seattle Angina Questionnaire: a new functional status measure for coronary artery disease. J Am Coll Cardiol. 1995;25:333–341.
    1. Lithell HO. Insulin resistance and diabetes in the context of treatment of hypertension. Blood Press Suppl. 1998;3:28–31.
    1. Vardeny O, Uno H, Braunwald E, Rouleau JL, Gersh B, Maggioni AP, et al. Opposing effects of beta blockers and angiotensin-converting enzyme inhibitors on development of new-onset diabetes mellitus in patients with stable coronary artery disease. Am J Cardiol. 2011;107:1705–1709.
    1. Lindholm LH, Ibsen H, Borch-Johnsen K, Olsen MH, Wachtell K, Dahlof B, et al. Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study. J Hypertens. 2002;20:1879–1886.
    1. Gupta AK, Dahlof B, Dobson J, Sever PS, Wedel H, Poulter NR. Determinants of new-onset diabetes among 19,257 hypertensive patients randomized in the Anglo-Scandinavian Cardiac Outcomes Trial--Blood Pressure Lowering Arm and the relative influence of antihypertensive medication. Diabetes Care. 2008;31:982–988.
    1. Munkhaugen J, Ruddox V, Halvorsen S, Dammen T, Fagerland MW, Hernaes KH, et al. BEtablocker Treatment After acute Myocardial Infarction in revascularized patients without reduced left ventricular ejection fraction (BETAMI): Rationale and design of a prospective, randomized, open, blinded end point study. Am Heart J. 2019;208:37–46.
    1. Hansson L, Hedner T, Dahlof B. Prospective randomized open blinded end-point (PROBE) study. A novel design for intervention trials. Prospective randomized open blinded end-point. Blood Press. 1992;1:113–119.
    1. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet. 2001;357:1385–1390.
    1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–2200.
    1. Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, et al. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J. 2018;39:26–35.
    1. Hong J, Barry AR. Long-term beta-blocker therapy after myocardial infarction in the reperfusion era: a systematic review. Pharmacotherapy. 2018;38:546–554.
    1. Goldberger JJ, Bonow RO, Cuffe M, Dyer A, Rosenberg Y, O'Rourke R, et al. beta-Blocker use following myocardial infarction: low prevalence of evidence-based dosing. Am Heart J. 2010;160:435–42.e1.
    1. Goldberger JJ, Bonow RO, Cuffe M, Liu L, Rosenberg Y, Shah PK, et al. Effect of beta-blocker dose on survival after acute myocardial infarction. J Am Coll Cardiol. 2015;66:1431–1441.
    1. Allen JE, Knight S, McCubrey RO, Bair T, Muhlestein JB, Goldberger JJ, et al. beta-blocker dosage and outcomes after acute coronary syndrome. Am Heart J. 2017;184:26–36.
    1. Charlesworth CJ, Smit E, Lee DS, Alramadhan F, Odden MC. Polypharmacy among adults aged 65 years and older in the United States: 1988-2010. J Gerontol A Biol Sci Med Sci. 2015;70:989–995.
    1. Nieuwlaat R, Wilczynski N, Navarro T, Hobson N, Jeffery R, Keepanasseril A, et al. Interventions for enhancing medication adherence. Cochrane Database Syst Rev. 2014:CD000011. 10.1002/14651858.CD000011.pub4.
    1. Bueno H, Armstrong PW, Buxton MJ, Danchin N, Lubsen J, Roland E, et al. The future of clinical trials in secondary prevention after acute coronary syndromes. Eur Heart J. 2011;32:1583–1589.

Source: PubMed

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