Latest British Society of Echocardiography recommendations for left ventricular ejection fraction categorisation: potential implications and relevance to contemporary heart failure management

in Echo Research and Practice
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  • 1 Cardiologist, Liverpool University Hospitals, Liverpool, UK
  • | 2 University of Liverpool, Liverpool, UK
  • | 3 University of Leicester, Leicester, UK
  • | 4 National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Centre, Leicester, UK

Correspondence should be addressed to P Kanagala: pkkanagala@googlemail.com
Open access

Letter to the Editor

We read with interest the recent guideline publication from the British Society of Echocardiography (BSE) relating to normal reference intervals for cardiac dimensions and function for use in echocardiographic practice (1). We commend the authors and the Education Committee for attempting to produce updated guidance taking into account contemporary, prospective data to determine new reference ranges for echocardiographic parameters. However, we suggest the newly proposed categories for left ventricular ejection fraction (LVEF) derangements from the BSE may contribute to diagnostic and therapeutic uncertainty and create new challenges for the management of heart failure (HF) patients in the United Kingdom (UK).

It is well recognised that HF transitions across the spectrum of LVEF and irrespective of LVEF, and that the prognosis for patients with HF is worse than in those without this diagnosis. Moreover, recent evidence points to adverse outcomes even in the setting of ‘supra-normal’ LVEF (2). As addressed in the recent publication (1), the latest BSE guidance for LV function categorisation (‘severely impaired’, LVEF ≤35%; ‘impaired’, LVEF 36–49%; ‘borderline low’, LVEF 50–54%; and ‘normal’, LVEF ≥55%) is clearly out of keeping with current guideline documents from international echocardiographic societies (American Society of Echocardiography (3), European Association of Cardiovascular Imaging (4)) and with those from international cardiology societies in Europe (European Society of Cardiology (ESC) (5)) and North America (American College of Cardiology/American Heart Association (6)). Both the ESC and the AHA define (heart failure with reduced ejection fraction) HFrEF at, or below, 40%. The ESC and AHA HF diagnostic thresholds have been reached not just on the basis of prognosis alone. Both heart failure with mid-range ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) groups are characterised by marked heterogeneity and display differing epidemiological and pathophysiological profiles compared to HfrEF (7, 8, 9, 10). While the BSE document suggests that LVEF displays a continuous relation to prognosis ‘i.e. as the LVEF gets progressively lower, survival is progressively poorer’, LVEF exhibits a U-shaped, rather than a linear, relation to mortality (2). Both HFrEF and those with supra-normal LVEF are associated with the highest degrees of mortality, albeit HFmREF and HFpEF patients have poor prognosis relative to those without HF (11).

Current ESC HF diagnostic thresholds have been conceived on the basis of evidence-based treatment response, with the demonstration in multiple clinical trials of clear benefit from various classes of medication and device therapy for patients with HFrEF (defined as LVEF ≤40%), unlike HFmrEF and HFpEF. While the BSE document cites beneficial impacts upon mortality for angiotensin converting enzyme-inhibitors (ACEi), angiotensin receptor blockers (ARB), betablockers, mineralocorticoid receptor antagonists (MRA), If channel inhibitors, angiotensin receptor neprilysin inhibitors (ARNI) and device therapies for those with ‘severely impaired’ systolic function, that is, LVEF ≤35% (1, 12, 13, 14, 15, 16, 17, 18, 19, 20), some of these same classes of pharmacotherapy also (and importantly) have a well-established and evidence-based extended survival benefit in those HF patients with LVEF <40% (e.g. ACEi (21), ARBs (22), MRAs (23), ARNI (17)). The results of the BLOCK HF trial (mean LVEF 40%) support the use of cardiac resynchronisation therapy in HF patients in whom there is conventional pacing indication and with LVEF up to 50% (24). In addition to the aforementioned medications, newer classes of drugs have also recently shown prognostic benefit in large-scale multi-centre HFrEF trials with inclusion of patients with LVEF up to 40%: sodium-glucose cotransporter 2 inhibitors (dapaglifozin) (25) in the DAPA-HF study (study inclusion LVEF <40%) and soluble guanylate cyclase stimulators (vericiguat) in VICTORIA (26) (93% of patients had LVEF <40%). On this background, the apparent distinction in the BSE document of patients with LVEF ≤35% from those with LVEF 35–40% is not based upon the totality of evidence from randomised, controlled trials and carries the risk of some patients being deemed ineligible for specific interventions for which there is evidence of therapeutic benefit.

To suggest, as proposed by the latest BSE guidelines, that a LVEF of 36% equates to a comparable degree of systolic derangement as a LVEF of 49% (both classed as ‘impaired’ in the recent BSE guideline document) is striking and is not based upon the totality of evidence from large-scale clinical trials. The BSE guidance potentially encompasses both HFrEF and HFmrEF subsets under the umbrella of the newly proposed ‘impaired’ LVEF range raising the following scenarios: (1) a significant proportion of HFrEF patients are denied evidence-based HF therapies and (2) inappropriate and potentially harmful prescription of therapies in those with HFmrEF, for whom there is no evidence of clinical benefit. Additionally, historical data show that a proportion of HFrEF (nearly one in four) demonstrates improved (or recovered) LV function over time (27). Such patients may have inappropriate cessation of prescribed pharmacotherapies by non-HF specialists with potential deleterious consequences (28). Furthermore, in the setting of an individual patient LVEF improving from 36% to 48 or 49% over time, the suggested BSH guideline that this patient’s status would be unchanged, appears illogical.

While we agree that LVEF calculation should not be used as a standalone metric of LV systolic function, it continues to be an extremely important imaging biomarker which not only provides both diagnostic and prognostic information but forms the basis of pharmacological and device management of patients and of enrolment into the majority of HF clinical trials (historical and current). The dichotomisation of reduced LV systolic function into a ‘severely impaired’ and ‘impaired’ range may further impact upon research settings in HF. In the clinical setting, community HF clinics which are predominantly nurse-led could be overwhelmed, since the majority of these services are commissioned by clinical commissioning groups and acceptance criteria often stipulates a diagnosis of HFrEF. However, as we have noted, the basis for inclusion of patients with LVEF >40% in this category is unclear and specific and evidence-based interventions for such patients are lacking.

We do applaud the BSE for recommending that LVEF should be quoted in all patients with ‘impaired’ LV function. However, in typically elderly HF populations with concomitant co-morbidity, endocardial border definition is sub-optimal in nearly one-third, precluding calculation of LVEF using the biplane Simpson’s method (29), and may add to the uncertainty in the ‘impaired’ LV range. We suggest that patients with LVEF in the range of 36–49% in this situation fail to guide management.

The management of patients with heart failure is largely based upon evidence gained from multiple clinical trials performed across three or more decades; these trials have, for the most part, defined HFrEF in the range of LVEF 35–40%. It is our view that to diverge from this classification is unlikely to address the BSE-stated aim of enabling ‘appropriate interpretation of values into a clinically relevant report’ for HF patients. We do, however, welcome the view advocated by the BSE in their latest guidance and supported by British Society for Heart Failure that all echo reports should ideally provide an actual value for LVEF, thereby enabling individualised treatment plans in HF patients (30).

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this letter.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

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    Harkness A, Ring L, Augustine DX, Oxborough D, Robinson S, Sharma V & Education Committee of the British Society of Echocardiography. Normal reference intervals for cardiac dimensions and function for use in echocardiographic practice: a guideline from the British Society of Echocardiography. Echo Research and Practice 2020 7 G1G18. (https://doi.org/10.1530/ERP-19-0050)

    • Search Google Scholar
    • Export Citation
  • 2

    Wehner GJ, Jing L, Haggerty CM, Suever JD, Leader JB, Hartzel DN, Kirchner HL, Manus JNA, James N, Ayar Z, et al.Routinely reported ejection fraction and mortality in clinical practice: where does the nadir of risk lie? European Heart Journal 2020 41 12491257. (https://doi.org/10.1093/eurheartj/ehz550)

    • Search Google Scholar
    • Export Citation
  • 3

    Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, et al.Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Journal of the American Society of Echocardiography 2015 28 1.e1439.e14. (https://doi.org/10.1016/j.echo.2014.10.003)

    • Search Google Scholar
    • Export Citation
  • 4

    Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, et al.Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. European Heart Journal - Cardiovascular Imaging 2015 16 233270. (https://doi.org/10.1093/ehjci/jev014)

    • Search Google Scholar
    • Export Citation
  • 5

    Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, 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. European Heart Journal 2016 37 21292200. (https://doi.org/10.1093/eurheartj/ehw128)

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  • 6

    Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, et al.2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Journal of the American College of Cardiology 2013 62 e147e239. (https://doi.org/10.1016/j.jacc.2013.05.019)

    • Search Google Scholar
    • Export Citation
  • 7

    Kanagala P, Arnold JR, Singh A, Chan DCS, Cheng ASH, Khan JN, Gulsin GS, Yang J, Zhao L, Gupta P, et al.Characterizing heart failure with preserved and reduced ejection fraction: an imaging and plasma biomarker approach. PLoS ONE 2020 15 e0232280. (https://doi.org/10.1371/journal.pone.0232280)

    • Search Google Scholar
    • Export Citation
  • 8

    Streng KW, Nauta JF, Hillege HL, Anker SD, Cleland JG, Dickstein K, Filippatos G, Lang CC, Metra M, Ng LL, et al.Non-cardiac comorbidities in heart failure with reduced, mid-range and preserved ejection fraction. International Journal of Cardiology 2018 271 132139. (https://doi.org/10.1016/j.ijcard.2018.04.001)

    • Search Google Scholar
    • Export Citation
  • 9

    Tromp J, Khan MA, Klip IT, Meyer S, de Boer RA, Jaarsma T, Hillege H, van Veldhuisen DJ, van der Meer P, Voors AA. Biomarker profiles in heart failure patients with preserved and reduced ejection fraction. Journal of the American Heart Association 2017 6 e003989. (https://doi.org/10.1161/JAHA.116.003989)

    • Search Google Scholar
    • Export Citation
  • 10

    Tromp J, Khan MAF, Mentz RJ, O’Connor CM, Metra M, Dittrich HC, Ponikowski P, Teerlink JR, Cotter G, Davison B, et al.Biomarker profiles of acute heart failure patients with a mid-range ejection fraction. JACC: Heart Failure 2017 5 507517. (https://doi.org/10.1016/j.jchf.2017.04.007)

    • Search Google Scholar
    • Export Citation
  • 11

    Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC). The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis. European Heart Journal 2012 33 17501757. (https://doi.org/10.1093/eurheartj/ehr254)

    • Search Google Scholar
    • Export Citation
  • 12

    CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999 353 913. (https://doi.org/10.1016/S0140-6736(98)11181-9)

    • Search Google Scholar
    • Export Citation
  • 13

    Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, et al.Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. New England Journal of Medicine 2004 350 21402150. (https://doi.org/10.1056/NEJMoa032423)

    • Search Google Scholar
    • Export Citation
  • 14

    Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L & Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. New England Journal of Medicine 2005 352 15391549. (https://doi.org/10.1056/NEJMoa050496)

    • Search Google Scholar
    • Export Citation
  • 15

    Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 1995 273 14501456. (https://doi.org/10.1001/jama.273.18.1450)

    • Search Google Scholar
    • Export Citation
  • 16

    SOLVD Investigators, Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. New England Journal of Medicine 1991 325 293302. (https://doi.org/10.1056/NEJM199108013250501)

    • Search Google Scholar
    • Export Citation
  • 17

    McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, et al.Angiotensin-neprilysin inhibition versus enalapril in heart failure. New England Journal of Medicine 2014 371 9931004. (https://doi.org/10.1056/NEJMoa1409077)

    • Search Google Scholar
    • Export Citation
  • 18

    Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, et al.Effect of carvedilol on survival in severe chronic heart failure. New England Journal of Medicine 2001 344 16511658. (https://doi.org/10.1056/NEJM200105313442201)

    • Search Google Scholar
    • Export Citation
  • 19

    Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. New England Journal of Medicine 1999 341 709717. (https://doi.org/10.1056/NEJM199909023411001)

    • Search Google Scholar
    • Export Citation
  • 20

    Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L & SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010 376 875885. (https://doi.org/10.1016/S0140-6736(10)61198-1)

    • Search Google Scholar
    • Export Citation
  • 21

    Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. New England Journal of Medicine 1992 327 669677. (https://doi.org/10.1056/NEJM199209033271001)

    • Search Google Scholar
    • Export Citation
  • 22

    Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K & CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003 362 772776. (https://doi.org/10.1016/S0140-6736(03)14284-5)

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    Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M, et al.Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. New England Journal of Medicine 2003 348 13091321. (https://doi.org/10.1056/NEJMoa030207)

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    Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, Hernandez AF, Butler J, Lam CSP, Ponikowski P, Voors AA, Jia G, et al.Vericiguat in patients with heart failure and reduced ejection fraction. New England Journal of Medicine 2020 382 18831893. (https://doi.org/10.1056/NEJMoa1915928)

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  • 27

    Lupon J, Diez-Lopez C, de Antonio M, Domingo M, Zamora E, Moliner P, Gonzalez B, Santesmases J, Troya MI, Bayes-Genis A. Recovered heart failure with reduced ejection fraction and outcomes: a prospective study. European Journal of Heart Failure 2017 19 16151623. (https://doi.org/10.1002/ejhf.824)

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  • 28

    Halliday BP, Wassall R, Lota AS, Khalique Z, Gregson J, Newsome S, Jackson R, Rahneva T, Wage R, Smith G, et al.Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet 2019 393 6173. (https://doi.org/10.1016/S0140-6736(18)32484-X)

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  • 29

    Bellenger NG, Burgess MI, Ray SG, Lahiri A, Coats AJ, Cleland JG, Pennell DJ. Comparison of left ventricular ejection fraction and volumes in heart failure by echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance; are they interchangeable? European Heart Journal 2000 21 13871396. (https://doi.org/10.1053/euhj.2000.2011)

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  • 30

    British Society for Heart Failure. British Society of Echocardiography Guideline: Normal reference intervals for cardiac dimensions and function for use in echocardiographic practice. Practical recommendations from the British Society for Heart Failure. London, UK: British Society for Heart Failure, 2020. (available at: https://www.bsh.org.uk/wp-content/uploads/2020/05/Practical-recommendations-from-the-BSH-on-the-BSE-Guideline-V1-PDF.pdf)

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    • Export Citation

 

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  • 1

    Harkness A, Ring L, Augustine DX, Oxborough D, Robinson S, Sharma V & Education Committee of the British Society of Echocardiography. Normal reference intervals for cardiac dimensions and function for use in echocardiographic practice: a guideline from the British Society of Echocardiography. Echo Research and Practice 2020 7 G1G18. (https://doi.org/10.1530/ERP-19-0050)

    • Search Google Scholar
    • Export Citation
  • 2

    Wehner GJ, Jing L, Haggerty CM, Suever JD, Leader JB, Hartzel DN, Kirchner HL, Manus JNA, James N, Ayar Z, et al.Routinely reported ejection fraction and mortality in clinical practice: where does the nadir of risk lie? European Heart Journal 2020 41 12491257. (https://doi.org/10.1093/eurheartj/ehz550)

    • Search Google Scholar
    • Export Citation
  • 3

    Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, et al.Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Journal of the American Society of Echocardiography 2015 28 1.e1439.e14. (https://doi.org/10.1016/j.echo.2014.10.003)

    • Search Google Scholar
    • Export Citation
  • 4

    Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, et al.Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. European Heart Journal - Cardiovascular Imaging 2015 16 233270. (https://doi.org/10.1093/ehjci/jev014)

    • Search Google Scholar
    • Export Citation
  • 5

    Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, 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. European Heart Journal 2016 37 21292200. (https://doi.org/10.1093/eurheartj/ehw128)

    • Search Google Scholar
    • Export Citation
  • 6

    Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, et al.2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Journal of the American College of Cardiology 2013 62 e147e239. (https://doi.org/10.1016/j.jacc.2013.05.019)

    • Search Google Scholar
    • Export Citation
  • 7

    Kanagala P, Arnold JR, Singh A, Chan DCS, Cheng ASH, Khan JN, Gulsin GS, Yang J, Zhao L, Gupta P, et al.Characterizing heart failure with preserved and reduced ejection fraction: an imaging and plasma biomarker approach. PLoS ONE 2020 15 e0232280. (https://doi.org/10.1371/journal.pone.0232280)

    • Search Google Scholar
    • Export Citation
  • 8

    Streng KW, Nauta JF, Hillege HL, Anker SD, Cleland JG, Dickstein K, Filippatos G, Lang CC, Metra M, Ng LL, et al.Non-cardiac comorbidities in heart failure with reduced, mid-range and preserved ejection fraction. International Journal of Cardiology 2018 271 132139. (https://doi.org/10.1016/j.ijcard.2018.04.001)

    • Search Google Scholar
    • Export Citation
  • 9

    Tromp J, Khan MA, Klip IT, Meyer S, de Boer RA, Jaarsma T, Hillege H, van Veldhuisen DJ, van der Meer P, Voors AA. Biomarker profiles in heart failure patients with preserved and reduced ejection fraction. Journal of the American Heart Association 2017 6 e003989. (https://doi.org/10.1161/JAHA.116.003989)

    • Search Google Scholar
    • Export Citation
  • 10

    Tromp J, Khan MAF, Mentz RJ, O’Connor CM, Metra M, Dittrich HC, Ponikowski P, Teerlink JR, Cotter G, Davison B, et al.Biomarker profiles of acute heart failure patients with a mid-range ejection fraction. JACC: Heart Failure 2017 5 507517. (https://doi.org/10.1016/j.jchf.2017.04.007)

    • Search Google Scholar
    • Export Citation
  • 11

    Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC). The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis. European Heart Journal 2012 33 17501757. (https://doi.org/10.1093/eurheartj/ehr254)

    • Search Google Scholar
    • Export Citation
  • 12

    CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999 353 913. (https://doi.org/10.1016/S0140-6736(98)11181-9)

    • Search Google Scholar
    • Export Citation
  • 13

    Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, et al.Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. New England Journal of Medicine 2004 350 21402150. (https://doi.org/10.1056/NEJMoa032423)

    • Search Google Scholar
    • Export Citation
  • 14

    Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L & Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. New England Journal of Medicine 2005 352 15391549. (https://doi.org/10.1056/NEJMoa050496)

    • Search Google Scholar
    • Export Citation
  • 15

    Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 1995 273 14501456. (https://doi.org/10.1001/jama.273.18.1450)

    • Search Google Scholar
    • Export Citation
  • 16

    SOLVD Investigators, Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. New England Journal of Medicine 1991 325 293302. (https://doi.org/10.1056/NEJM199108013250501)

    • Search Google Scholar
    • Export Citation
  • 17

    McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, et al.Angiotensin-neprilysin inhibition versus enalapril in heart failure. New England Journal of Medicine 2014 371 9931004. (https://doi.org/10.1056/NEJMoa1409077)

    • Search Google Scholar
    • Export Citation
  • 18

    Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, et al.Effect of carvedilol on survival in severe chronic heart failure. New England Journal of Medicine 2001 344 16511658. (https://doi.org/10.1056/NEJM200105313442201)

    • Search Google Scholar
    • Export Citation
  • 19

    Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. New England Journal of Medicine 1999 341 709717. (https://doi.org/10.1056/NEJM199909023411001)

    • Search Google Scholar
    • Export Citation
  • 20

    Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L & SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010 376 875885. (https://doi.org/10.1016/S0140-6736(10)61198-1)

    • Search Google Scholar
    • Export Citation
  • 21

    Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. New England Journal of Medicine 1992 327 669677. (https://doi.org/10.1056/NEJM199209033271001)

    • Search Google Scholar
    • Export Citation
  • 22

    Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K & CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003 362 772776. (https://doi.org/10.1016/S0140-6736(03)14284-5)

    • Search Google Scholar
    • Export Citation
  • 23

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