How robust are clinical trials in heart failure? Kieran F. Docherty1

European Heart Journal

Volumn 38, Issue 5, 2017, Pages 338-345

  Campbell, Ross T ^b   Jhund, Pardeep S ^b   Petrie, Mark C ^a   McMurray, John J V ^b  

^a GOLDEN JUBILEE NATIONAL HOSPITAL   (United Kingdom)

^b UNIVERSITY OF GLASGOW   (United Kingdom)

Author keywords

Clinical trials; Heart failure

Indexed keywords

ARTICLE; CARDIOVASCULAR MORTALITY; CLINICAL TRIAL (TOPIC); EXPERIMENTAL THERAPY; FOLLOW UP; HEART EJECTION FRACTION; HEART FAILURE; HOSPITALIZATION; HUMAN; PRACTICE GUIDELINE; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); CARDIAC RESYNCHRONIZATION THERAPY; CHRONIC DISEASE; KINESIOTHERAPY; MORTALITY; PROCEDURES; STANDARDS; STATISTICS AND NUMERICAL DATA;

ANGIOTENSIN RECEPTOR ANTAGONIST; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR;

ANGIOTENSIN RECEPTOR ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CARDIAC RESYNCHRONIZATION THERAPY; CHRONIC DISEASE; EXERCISE THERAPY; HEART FAILURE; HOSPITALIZATION; HUMANS; PRACTICE GUIDELINES AS TOPIC; RANDOMIZED CONTROLLED TRIALS AS TOPIC;

EID: 85015634477     PISSN: 0195668X     EISSN: 15229645     Source Type: Journal    
DOI: 10.1093/eurheartj/ehw427     Document Type: Article

References (77)

1. Rosenberg W, Donald A. Evidence based medicine: an approach to clinical problem-solving. BMJ 1995;310:1122-1126.
2. Pocock SJ, McMurray JJV, Collier TJ. Making sense of statistics in clinical trial reports: part 1 of a 4-part series on statistics for clinical trials. J Am Coll Cardiol 2015;66:2536-2549.
3. Wasserstein RL, Lazar NA. The ASA's statement on p-values: context, process, and purpose. Am Stat 2016;70:129-133.
4. Thorlund K, Imberger G, Walsh M, Chu R, Gluud C, Wetterslev J, Guyatt G, Devereaux PJ, Thabane L. The number of patients and events required to limit the risk of overestimation of intervention effects in meta-analysis-a simulation study. PLoS One 2011;6:e25491.
5. Akl EA, Briel M, You JJ, Sun X, Johnston BC, Busse JW, Mulla S, Lamontagne F, Bassler D, Vera C, Alshurafa M, Katsios CM, Zhou Q, Cukierman-Yaffe T, Gangji A, Mills EJ, Walter SD, Cook DJ, Schünemann HJ, Altman DG, Guyatt GH. Potential impact on estimated treatment effects of information lost to follow-up in randomised controlled trials (LOST-IT): systematic review. BMJ 2012;344:e2809.
6. Walsh M, Srinathan SK, Mcauley DF, Mrkobrada M, Levine O, Ribic C, Molnar AO, Dattani ND, Burke A, Guyatt G, Thabane L, Walter SD, Pogue J, Devereaux PJ. The statistical significance of randomized controlled trial results is frequently fragile: A case for a Fragility Index. J Clin Epidemiol 2014;67:622-628.
7. McMurray JJV, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber L, Lip GYH, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Rønnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Eur Heart J 2012;33:1787-1847.
8. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJV, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WHW, Tsai EJ, Wilkoff BL. 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. J Am Coll Cardiol 2013;128:e147-e239.
9. National Institute for Health and Clinical Excellence. Chronic Heart Failure: Management of Chronic Heart Failure in Adults in Primary and Secondary Care (NICE Clinical Guideline 108). 2010. https://www.nice.org.uk/guidance/cg108/resources/chronic-heart-failure-in-adults-management-35109335688901 (19 December 2015).
10. Krum H, Jelinek MV, Stewart S, Sindone A, Atherton JJ. 2011 update to National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand Guidelines for the prevention, detection and management of chronic heart failure in Australia, 2006. Med J Aust 2011;194:405-409.
11. Moe GW, Ezekowitz JA, O'Meara E, Lepage S, Howlett JG, Fremes S, Al-Hesayen A, Heckman GA, Abrams H, Ducharme A, Estrella-Holder E, Grzeslo A, Harkness K, Koshman SL, McDonald M, McKelvie R, Rajda M, Rao V, Swiggum E, Virani S, Zieroth S, Arnold JMO, Ashton T, D'Astous M, Chan M, De S, Dorian P, Giannetti N, Haddad H, Isaac DL, Kouz S, Leblanc MH, Liu P, Ross HJ, Sussex B, White M. The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update: anemia, biomarkers, and recent therapeutic trial implications. Can J Cardiol 2015;31:3-16.
12. Feinstein AR. The unit fragility index: an additional appraisal of 'statistical significance' for a contrast of two proportions. J Clin Epidemiol 1990;43:201-209.
13. Walter SD. Statistical significance and fragility criteria for assessing a difference of two proportions. J Clin Epidemiol 1991;44:1373-1378.
14. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-1435.
15. Flather MD, Shibata MC, Coats AJS, Veldhuisen DJ, Van Parkhomenko A, Borbola J, Cohen-Solal A, Dumitrascu D, Ferrari R, Lechat P, Soler-Soler J, Tavazzi L, Spinarova L, Toman J, Böhm M, Anker SD, Thompson SG Poole-Wilson PA. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26:215-225.
16. Abraham WT, Adamson PB, Bourge RC, Aaron MF, Costanzo MR, Stevenson LW, Strickland W, Neelagaru S, Raval N, Krueger S, Weiner S, Shavelle D, Jeffries B, Yadav JS. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: A randomised controlled trial. Lancet 2011;377:658-666.
17. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302.
18. Packer M, Poole-Wilson PA, Armstrong PW, Cleland JGF, Horowitz JD, Massie BM, Ryden L, Thygesen K, Uretsky BF. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999;100:2312-2318.
19. Cleland JG, Thygesen K, Uretsky BF, Armstrong P, Horowitz JD, Massie B, Packer M, Poole-Wilson PA, Rydén L. Cardiovascular critical event pathways for the progression of heart failure: A report from the ATLAS study. Eur Heart J 2001;22:1601-1612.
20. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-1675.
21. Food and Drug Association (FDA). DiovanVR (Valsartan) Tablets Cardiovascular and Renal Drugs Advisory Committee Briefing Document. 2001. http://www.fda.gov/ohrms/dockets/ac/01/briefing/3793b1-01-NOVARTIS.pdf (17 December 2015).
22. Granger CB, McMurray JJV, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K. 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;362:772-776.
23. McMurray JJV, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensinconverting-enzyme inhibitors: The CHARM-Added trial. Lancet 2003;362: 767-771.
24. Konstam MA, Neaton JD, Dickstein K, Drexler H, Komajda M, Martinez FA, Riegger GAJ, Curie-Paris PM. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): A randomised, double-blind trial. Lancet 2009;374:1840-1848.
25. Dargie HJ, Lechat P. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial. Lancet 1999;353:9-13.
26. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-2007.
27. Hjalmarson A , Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, Wikstrand J, El Allaf D, Vitovec J, Aldershvile J, Halinen M, Dietz R, Neuhaus KL, Janosi A, Thorgeirsson G, Dunselman PH, Gullestad L, Kuch J, Herlitz J, Rickenbacher P, Ball S, Gottlieb SDP. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: The metoprolol cr/xl randomized intervention trial in congestive heart failure (MERIT-HF). JAMA 2000;283:1295-1302.
28. Packer M, Fowler MB, Roecker EB, Coats AJS, Katus H, A, Krum H, Mohacsi P, Rouleau JL, Tendera M, Staiger C, Holcslaw TL, Amann-Zalan I, DeMets DL. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation 2002;106:2194-2199.
29. Food and Drug Association (FDA). CoregVR (Carvedilol) Cardiovascular and Renal Drugs Advisory Committee. 2001. http://www.accessdata.fda.gov/drugsatfda-docs/nda/2001/20-297S007-Coreg-medr.pdf (19 December 2015).
30. Poole-Wilson PA, Swedberg K, Cleland JGF, Lenarda A, Di Hanrath P, Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Pedersen C, Scherhag A, Skene A. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003;362:7-13.
31. Torp-Pedersen C, Poole-Wilson PA, Swedberg K, Cleland JGF, Lenarda A, Di Hanrath P, Komajda M, Lutiger B, Metra M, Remme WJ, Scherhag A, Skene A. Effects of metoprolol and carvedilol on cause-specific mortality and morbidity in patients with chronic heart failure-COMET. Am Heart J 2005;149:370-376.
32. 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. N Engl J Med 1999;341:709-717.
33. Zannad F, McMurray JJV, Krum H, Veldhuisen DJ, van Swedberg K, Shi H, Vincent J, Pocock SJ Pitt B. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11-21.
34. Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049-2057.
35. Food and Drug Association (FDA). BiDilVR (Isosorbide Dinitrate andHydralazine Hydrochloride) Cardiovascular and Renal Drugs Advisory Committee. 2005. http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4145B2-02-01-NitroMEDBackground.pdf (19 December 2015).
36. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525-533.
37. Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet 2010;376:875-885.
38. McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
39. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl JMed 2005;352:225-237.
40. Packer DL, Prutkin JM, Hellkamp AS, Mitchell LB, Bernstein RC, Wood F, Boehmer JP, Carlson MD, Frantz RP, McNulty SE, Rogers JG, Anderson J, Johnson GW, Walsh MN, Poole JE, Mark DB, Lee KL, Bardy GH. Impact of implantable cardioverter-defibrillator, amiodarone, and placebo on the mode of death in stable patients with heart failure: analysis from the sudden cardiac death in heart failure trial. Circulation 2009;120:2170-2176.
41. Cleland JGF, Daubert J-C, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539-1549.
42. Tang ASL, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, Hohnloser SH, Nichol G, Birnie DH, Sapp JL, Yee R, Healey JS, Rouleau JL. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010;363:2385-2395.
43. Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, Long JW, Ascheim DD, Tierney AR, Levitan RG, Watson JT, Meier P, Ronan NS, Shapiro PA, Lazar RM, Miller LW, Gupta L, Frazier OH, Desvigne-Nickens P, Oz MC, Poirier VL. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 2001;345:1435-1443.
44. Food and Drug Association (FDA). CardioMEMS Heart Failure Monitoring System Summary of Safety and Effectiveness-Advisory Committee Meeting. 2011. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-afda-adcom/documents/document/ucm 281517.pdf (20 December 2015).
45. Hindricks G, Taborsky M, Glikson M, Heinrich U, Schumacher B, Katz A, Brachmann J, Lewalter T, Goette A, Block M, Kautzner J, Sack S, Husser D, Piorkowski C, Søgaard P. Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): A randomised controlled trial. Lancet 2014;384:583-590.
46. O'Connor CM, Whellan DJ, Lee KL, Keteyian SJ, Cooper LS, Ellis SJ, Leifer ES, Kraus WE, Kitzman DW, Blumenthal JA, Rendall DS, Miller NH, Fleg JL, Schulman KA, McKelvie RS, Zannad F, Pina IL. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA 2009;301:1439-1450.
47. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-1552.
48. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, Marco T, De Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140-2150.
49. Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes NAM, Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD, Wilber D, Zareba W. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1329-1338.
50. Slaughter MS, Rogers JG, Milano CA, Russell SD, Conte JV, Feldman D, Sun B, Tatooles AJ, Delgado RM, Long JW, Wozniak TC, Ghumman W, Farrar DJ, Frazier OH. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009;361:2241-2251.
51. Velazquez EJ, Lee KL, Deja MA, Jain A, Sopko G, Marchenko A, Ali IS, Pohost G, Gradinac S, Abraham WT, Yii M, Prabhakaran D, Szwed H, Ferrazzi P, Petrie MC, O'Connor CM, Panchavinnin P, She L, Bonow RO, Rankin GR, Jones RH, Rouleau J-L. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011;364:1607-1616.
52. Packer M, Califf RM, Konstam MA, Krum H, McMurray JJ, Rouleau J-LL, Swedberg K. Comparison of omapatrilat and enalapril in patients with chronic heart failure: The omapatrilat versus enalapril randomized trial of utility in reducing events (OVERTURE). Circulation 2002;106:920-926.
53. Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001;344:1659-1667.
54. Singh SN, Fletcher RD, Fisher SG, Singh BN, Lewis HD, Deedwania PC, Massie BM, Colling C, Lazzeri D. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med 1995;333:77-82.
55. Packer M, O'Connor CM, Ghali JK, Pressler ML, Carson PE, Belkin RN, Miller AB, Neuberg GW, Frid D, Wertheimer JH, Cropp AB, DeMets DL. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. Prospective Randomized Amlodipine Survival Evaluation Study Group. N Engl J Med 1996;335:1107-1114.
56. Torre-Amione G, Anker SD, Bourge RC, Colucci WS, Greenberg BH, Hildebrandt P, Keren A, Motro M, Moyé LA, Otterstad JE, Pratt CM, Ponikowski P, Rouleau JL, Sestier F, Winkelmann BR, Young JB. Results of a non-specific immunomodulation therapy in chronic heart failure (ACCLAIM trial): A placebocontrolled randomised trial. Lancet 2008;371:228-236.
57. Kjekshus J, Apetrei E, Barrios V, Böhm M, Cleland JGF, Cornel JH, Dunselman P, Fonseca C, Goudev A, Grande P, Gullestad L, Hjalmarson A, Hradec J, Janosi A, Kamensky G, Komajda M, Korewicki J, Kuusi T, Mach F, Mareev V, McMurray JJV, Ranjith N, Schaufelberger M, Vanhaecke J, Veldhuisen DJ, van Waagstein F, Wedel H, Wikstrand J. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248-2261.
58. McMurray JJV, Krum H, Abraham WT, Dickstein K, Køber LV, Desai AS, Solomon SD, Greenlaw N, Ali MA, Chiang Y, Shao Q, Tarnesby G, Massie BM. Aliskiren, enalapril, or aliskiren and enalapril in heart failure. N Engl J Med 2016;374:1521-1532.
59. Køber L, Torp-Pedersen C, McMurray JJV, Gøtzsche O, Lévy S, Crijns H, Amlie J, Carlsen J. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008;358:2678-2687.
60. Torp-Pedersen C, Møller M, Bloch-Thomsen PE, Køber L, Sandøe E, Egstrup K, Agner E, Carlsen J, Videbaek J, Marchant B, Camm AJ. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl JMed 1999;341:857-865.
61. Homma S, Thompson JLP, Pullicino PM, Levin B, Freudenberger RS, Teerlink JR, Ammon SE, Graham S, Sacco RL, Mann DL, Mohr JP, Massie BM, Labovitz AJ, Anker SD, Lok DJ, Ponikowski P, Estol CJ, Lip GYH, Tullio MR, Di Sanford AR, Mejia V, Gabriel AP, Valle ML, del Buchsbaum R. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med 2012;366:1859-1869.
62. Metra M, Eichhorn E, Abraham WT, Linseman J, Böhm M, Corbalan R, DeMets D, Marco T, De Elkayam U, Gerber M, Komajda M, Liu P, Mareev V, Perrone SV, Poole-Wilson P, Roecker E, Stewart J, Swedberg K, Tendera M, Wiens B, Bristow MR. Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: The randomized, double-blind, placebo-controlled, parallel group ESSENTIAL trials. Eur Heart J 2009;30:3015-3026.
63. Ruschitzka F, Abraham WT, Singh JP, Bax JJ, Borer JS, Brugada J, Dickstein K, Ford I, Gorcsan J, Gras D, Krum H, Sogaard P, Holzmeister J. Cardiac-resynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med 2013;369:1395-1405.
64. Roy D, Talajic M, Nattel S, Wyse DG, Dorian P, Lee KL, Bourassa MG, Arnold JMO, Buxton AE, Camm AJ, Connolly SJ, Dubuc M, Ducharme A, Guerra PG, Hohnloser SH, Lambert J, Heuzey J-Y, Le O'Hara G, Pedersen OD, Rouleau J-L, Singh BN, Stevenson LW, Stevenson WG, Thibault B, Waldo AL. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667-2677.
65. Califf RM, Adams KF, McKenna WJ, Gheorghiade M, Uretsky BF, McNulty SE, Darius H, Schulman K, Zannad F, Handberg-Thurmond E, Harrell FEJ, Wheeler W, Soler-Soler J, Swedberg K. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST). Am Heart J 1997;134:44-54.
66. Packer M, Carson P, Elkayam U, Konstam MA, Moe G, O'Connor C, Rouleau J-L, Schocken D, Anderson SA, DeMets DL. Effect of amlodipine on the survival of patients with severe chronic heart failure due to a nonischemic cardiomyopathy: results of the PRAISE-2 study (prospective randomized amlodipine survival evaluation 2). JACC Heart Fail 2013;1:308-314.
67. Torp-Pedersen C, Køber L, Carlsen JE, Akkan D, Bruun NE, Dacoronias D, Dickstein K, Haghfelt T, Ohlin H, McMurray JJV. A randomised trial of a pre-synaptic stimulator of DA2-dopaminergic and alpha2-adrenergic receptors on morbidity and mortality in patients with heart failure. Eur J Heart Fail 2008;10:89-95.
68. Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, Maggioni AP, McMurray JJV, O'Connor C, Pfeffer MA, Solomon SD, Sun Y, Tendera M, van Veldhuisen DJ. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med 2013;368:1210-1219.
69. Levine TB, Bernink PJ, Caspi A, Elkayam U, Geltman EM, Greenberg B, McKenna WJ, Ghali JK, Giles TD, Marmor A, Reisin LH, Ammon S, Lindberg E. Effect of mibefradil, a T-type calcium channel blocker, on morbidity and mortality in moderate to severe congestive heart failure: The MACH-1 study. Mortality Assessment in Congestive Heart Failure Trial. Circulation 2000;101:758-764.
70. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, Lucci D, Nicolosi GL, Porcu M, Tognoni G. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): A randomised, double-blind, placebo-controlled trial. Lancet 2008;372:1231-1239.
71. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-1321.
72. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685-691.
73. Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown EJ, 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. N Engl J Med 1992;327:669-677.
74. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821-828.
75. Køber L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, Videbaek J, Cole DS, Auclert L, Pauly NC. A clinical trial of the angiotensinconverting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995;333:1670-1676.
76. Wikstrand J, Wedel H, Castagno D, McMurray JJV. The large-scale placebo-controlled beta-blocker studies in systolic heart failure revisited: results from CIBISII, COPERNICUS and SENIORS-SHF compared with stratified subsets from MERIT-HF. J Intern Med 2014;275:134-143.
77. Velazquez EJ, Lee KL, Jones RH, Al-Khalidi HR, Hill JA, Panza JA, Michler RE, Bonow RO, Doenst T, Petrie MC, Oh JK, She L, Moore VL, Desvigne-Nickens P, Sopko G, Rouleau JL. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N Engl J Med 2016;374:1511-1520.