. 2018 Aug 1;39(37):3417–3438. doi: 10.1093/eurheartj/ehy407

Table 3.

All-cause mortality in randomized and non-randomized beta-blocker HF studies

First author, country, year of publication (study name)	Study design	Study period	Region	Mean follow-up (months)	Patients (n)	Study (n)	Control (n)	All-cause mortality—unadjusted HR (95% CI)	All-cause mortality—adjusted HR (95% CI)
HFrEF
Randomized controlled trials—beneficial treatment effect
Packer, USA, 2001 (COPERNICUS)¹²⁸	RCT	1997–2000	Multiregional	10	2289	1156	1133	RR: 0.65 (0.52–0.81; P < 0.00013)	—
MERIT-HF Study Group, Sweden, 1999 (MERIT-HF)¹²⁹	RCT	1997–1998	Europe, USA	12	3991	1990	2001	RR: 0.66 (0.53–0.81; P < 0.0001)	—
CIBIS Investigators, UK, 1999 (CIBIS-II)¹³⁰	RCT	—	Europe	16	2647	1327	1320	0.66 (0.54–0.81; P < 0.0001)	—
Packer, USA, 1996 (US Carvedilol HF Study Group)¹³¹	RCT	1993–1995	USA	7	1094	696	398	RR: 0.35 (0.20–0.61; P < 0.001)	—
Randomized controlled trials—neutral treatment effect
van Veldhuisen, Netherlands, 2009 (SENIORS)¹³²	Pre-specified subgroup analysis of RCT (EF <35%) (≥70 years)	2000–2002	Europe	21	1359	678	681	0.84 (0.66–1.08)	—
BEST Investigators, USA, 2001 (BEST)¹³³	RCT	1995–1998	USA, Canada	24	2708	1354	1354	0.90 (0.78–1.02; P > 0.10)	—
ANZ HF Research Collaborative Group, New Zealand, 1997 (ANZ)¹³⁴	RCT (IHD)	—	Australia, New Zealand	19	415	207	208	RR: 0.76 (0.42–1.36; P > 0.1)	—
CIBIS Investigators, France, 1994 (CIBIS-I)¹³⁵	RCT	1989–1992	Europe	23	641	320	321	—	RR: 0.80 (0.56–1.15)
Observational studies—beneficial treatment effect
Cadrin-Tourigny, Canada, 2017 (AF-CHF)⁴⁷	Post hoc analysis of RCT (PSM) (AF)	2001–2005	Multiregional	37^a	655	426	229	—	0.72 (0.55–0.95; P < 0.018)
Bhatia, USA, 2015 (Alabama HF Project)⁴⁸	Retrospective cohort study (PSM) (≥65 years)	1998–2001	USA	48	760	380	380	—	0.81 (0.67–0.98)
Ushigome, Japan, 2015 (2. CHART-2)³⁰	Prospective cohort study	2006–2010	Japan	36	1360	870	490	—	0.59 (0.44–0.81; P < 0.001)
Del Carlo, Brazil, 2014⁴⁹	Retrospective cohort study	1992, 1994, 1996, 1999, 2005–2006	Brazil	12	333	199	134	0.3 (0.2–0.5; P < 0.001)	0.3 (0.2–0.5; P < 0.001)
Liu, China, 2014²⁸	Prospective cohort study	2005–2010	China	52^a	2154	1471	683	—	0.75 (0.57–0.999; P < 0.049)
Lund, Sweden, 2014 (Swedish HF Registry)⁵⁰	Registry (PSM)	2005–2012	Sweden	23^a	6081	4054	2027	—	0.89 (0.82–0.97; P < 0.005)
El-Refai, USA, 2013⁵¹	Retrospective cohort study	2000–2008	USA	25^a	1094	927	167	—	0.26 (0.17–0.40; P < 0.001)
Xu, China, 2013⁵²	Retrospective cohort study	2007–2012	China	31^a	685	555	130	—	0.69 (0.50–0.95; P < 0.021)
Teng, Australia, 2010 (WAHMD)⁴⁶	Retrospective cohort study	1996–2006	Australia	12	225	100	125	—	0.53 (0.32–0.87; P < 0.011)
Hernandez, USA, 2009 (OPTIMIZE-HF)⁵³	Registry (≥65 years)	—	USA	12	3001	1800	1201	0.65 (0.57–0.73)	0.77 (0.68–0.87)
Miyagishima, Japan, 2009⁵⁴	Retrospective cohort study	2000–2004	Japan	36	431	297	134	—	0.48 (0.32–0.73)
Fauchier, France, 2009 (41% HFrEF)⁵⁵	Retrospective cohort study (AF)	2000–2004	France	29	1269	449	820	—	RR: 0.60 (0.40–0.89; P < 0.01)
Pascual-Figal, Spain, 2008⁵⁶	Registry (>70 years)	2002–2003	Spain	31^a	272	139	133	0.45 (0.31–0.65; P < 0.001)	0.53 (0.34–0.80; P < 0.003)
Jost, Germany, 2005 (Ludwigshafen HF Registry) (1. ‘Trial patients’)⁵⁷	Registry	1995–2004	Germany	31	278	166	112	—	0.57 (0.38–0.86)
Jost, Germany, 2005 (Ludwigshafen HF Registry) (2. ‘Non-trial patients’)⁵⁷	Registry	1995–2004	Germany	31	397	204	193	—	0.72 (0.53–0.97)
Bobbio, Italy, 2003 (BRING-UP)⁵⁸	Prospective cohort study	1998	Italy	12	2843	1582	1261	RR: 0.46 (0.38–0.57)	0.64 (0.48–0.86)
Observational studies—neutral treatment effect
Ushigome, Japan, 2015 (1. CHART-1)³⁰	Prospective cohort study	2000–2005	Japan	36	543	184	359	—	0.87 (0.50–1.50; P < 0.610)
Huan Loh, UK, 2007⁵⁹	Retrospective cohort study	—	UK	36^a	900	738	162	0.54 (0.40–0.73; P < 0.001)	0.73 (0.53–1.02; P < 0.067)
HFpEF
Randomized controlled trials—neutral treatment effect
Yamamoto, Japan, 2013 (J-DHF)¹³⁶	PROBE	2004–2009	Japan	38	245	120	125	0.99 (0.53–1.86; P < 0.975)	—
van Veldhuisen, Netherlands, 2009 (SENIORS)¹³²	Pre-specified subgroup analysis of RCT (EF >35%) (≥70 years)	2000–2002	Europe	21	752	380	372	0.91 (0.62–1.33; P < 0.718)	—
Observational studies—beneficial treatment effect
Ruiz, Spain, 2016⁶⁰	Prospective cohort study (PSM)	2006–2015	Spain	22^a	1970	985	985	RR: 0.76 (0.70–0.83; P < 0.001)	0.78 (0.71–0.85; P < 0.001)
Lund, Sweden, 2014 (Swedish HF Registry)⁵⁰	Registry (PSM)	2005–2012	Sweden	23^a	8244	5496	2748	—	0.93 (0.86–0.996; P < 0.04)
El-Refai, USA, 2013⁵¹	Retrospective cohort study	2000–2008	USA	25^a	741	570	171	—	0.43 (0.27–0.68; P < 0.001)
Nevzorov, Israel, 2012⁶¹	Retrospective cohort study	2001–2005	Israel	24	345	154	191	—	0.69 (0.47–0.99; P < 0.046)
Gomez-Soto, Spain, 2011⁶²	Prospective cohort study (propensity score adjusted)	2001–2005	Spain	30^a	1085	378	707	RR: 0.37 (0.21–0.50; P < 0.001)	0.72 (0.58–0.84)
Teng, Australia, 2010 (WAHMD)⁴⁶	Retrospective cohort study	1996–2006	Australia	12	284	101	183	—	0.62 (0.39–0.99; P < 0.048)
Fauchier, France, 2009 (35% HFpEF)⁵⁵	Retrospective cohort study (AF)	2000–2004	France	29	1269	449	820	—	RR: 0.45 (0.26–0.80; P < 0.006)
Shah, USA, 2008 (NHC)³²	Retrospective cohort study (≥65 years)	1998–1999, 2000–2001	USA	36	13 533	4562	8971	—	RR: 0.92 (0.87–0.97)
Dobre, Netherlands, 2007⁶³	Prospective cohort study (propensity score adjusted)	2000–2005	Netherlands	25	443	227	216	—	0.57 (0.37–0.88; P < 0.01)
Observational studies—neutral treatment effect
Ushigome, Japan, 2015 (1. CHART-1)³⁰	Prospective cohort study	2000–2005	Japan	36	463	104	359	—	0.89 (0.45–1.75; P < 0.734)
Ushigome, Japan, 2015 (2. CHART-2)³⁰	Prospective cohort study	2006–2010	Japan	36	2316	1018	1298	—	0.94 (0.73–1.22; P < 0.654)
Patel, USA, 2014 (OPTIMIZE-HF)⁶⁴	Registry (PSM) (≥65 years)	2003–2004	USA	72	2198	1099	1099	—	0.99 (0.90–1.10; P < 0.897)
Hernandez, USA, 2009 (OPTIMIZE-HF)⁵³	Registry (≥65 years)	—	USA	12	4153	1621	2532	0.87 (0.77–0.97)	0.94 (0.84–1.07)
Mixed/unspecified HF phenotype
Randomized controlled trials—neutral effect
Flather, UK, 2005 (SENIORS) (65% HFrEF, 35% HFpEF)¹³⁷	RCT (≥70 years)	2000–2002	Multiregional	21	2128	1067	1061	0.88 (0.71–1.08; P < 0.21)	—
Observational studies—beneficial treatment effect
Katz, Israel, 2016 (HFSIS) (38% HFrEF, 15% HFmrEF, 22% HFpEF, 26% unknown)⁶⁵	Prospective cohort study	2003	Israel	120	2402	1481	921	—	0.83 (0.77–0.89; P < 0.001)
Maison, France, 2013⁶⁶	Registry (propensity score adjusted)	2000	France	96	281	101	180	—	0.54 (0.34–0.84)
Gastelurrutia, Spain, 2012 (75% HFrEF, 25% HFrEF)⁴⁵	Prospective cohort study	2001–2008	Spain	44^a	960	776	184	—	0.51 (0.39–0.66; P < 0.001)
Marijon, France, 2010 (EVADEF)⁶⁷	Prospective cohort study (ICD)	2001–2003	France	22	1030	721	309	0.53 (0.30–0.91; P < 0.02)	0.56 (0.32–0.98; P < 0.04)
Teng, Australia, 2010 (WAHMD) (24% HFrEF, 30% HFpEF, 46% unknown)⁴⁶	Retrospective cohort study	1996–2006	Australia	12	944	318	626	—	0.68 (0.53–0.86; P < 0.002)
Fauchier, France, 2009 (41% HFrEF, 35% HFpEF, 24% unknown)⁵⁵	Retrospective cohort study (AF)	2000–2004	France	29	1269	449	820	0.59 (0.45–0.78; P < 0.0002)	0.60 (0.43–0.84; P < 0.003)
Jordán, Spain, 2009 (BADAPIC) (77% HFrEF, 23% HFpEF)⁶⁸	Registry	2000–2002	Spain	35	3162	2242	920	—	RR: 0.82 (0.47–0.95)
Dobre, Netherlands, 2007 (55% HFrEF, 45% HFpEF)⁶⁹	Prospective cohort study (propensity score adjusted)	2000–2004	Netherlands	22	625	308	317		0.55 (0.39–0.78; P < 0.001)
Keyhan, Canada, 2007 (1. female cohort)⁷⁰	Retrospective cohort study (≥65 years)	1998–2003	Canada	30	14 693	7584	7109	0.67 (0.64–0.70)	0.79 (0.75–0.83)
Keyhan, Canada, 2007 (2. male cohort)⁷⁰	Retrospective cohort study (≥65 years)	1998–2003	Canada	30	13 144	6499	6645	0.64 (0.61–0.67)	0.76 (0.72–0.80)
Chan, USA, 2005 (CHS) (19% HFrEF, 36% HFpEF, 45% unknown)⁷¹	Prospective cohort study (≥65 years)	1989–2000	USA	120	950	157	793	0.74 (0.56–0.98)	0.74 (0.56–0.98)
Tandon, Canada, 2004 (75% HFrEF, 25% HFpEF)⁴¹	Prospective cohort study	1989–2001	Canada	32^a	1041	475	566	—	OR: 0.52 (0.39–0.70)
Maggioni, Italy, 2003 (BRING-UP) (1. no BB vs. continued BB)⁷²	Registry	1998	Italy	12	2226	771	1455	—	0.74 (0.55–0.99; P < 0.045)
Maggioni, Italy, 2003 (BRING-UP) (2. no BB vs. initiated BB)⁷²	Registry	1998	Italy	12	2320	865	1455	—	0.60 (0.45–0.80; P < 0.0003)
McCullough, USA, 2003 (REACH)⁷³	Retrospective cohort study	1995–1998	USA	12	1317	647	670	—	OR: 0.75 (0.57–0.98; P < 0.04)
Sin, Canada, 2002 (19% HFrEF, 36% HFpEF, 45% unknown)⁴⁴	Retrospective cohort study (≥65 years) (propensity score adjusted)	1994–1998	Canada	21^a	11 942	1162	10 780	—	0.72 (0.65–0.80)
McAlister, Canada, 1999 (78% HFrEF, 22% HFpEF)⁷⁴	Prospective cohort study	1989–1995	Canada	17	566	147	419	—	OR: 0.5 (P < 0.006–95% CI not reported)
Observational studies—neutral treatment effect
Ushigome, Japan, 2015 (1. CHART-1) (54% HFrEF, 46% HFpEF)³⁰	Prospective cohort study	2000–2005	Japan	36	1006	288	718	—	0.96 (0.63–1.44; P < 0.829)
Ushigome, Japan, 2015 (1. CHART-2) (37% HFrEF, 63% HFpEF)³⁰	Prospective cohort study	2006–2010	Japan	36	3676	1886	1790	—	0.82 (0.68–1.00; P < 0.055)

Median.

—, Not reported; AF, atrial fibrillation cohort; AF-CHF, Atrial Fibrillation and Congestive Heart Failure; ANZ, Australia/New Zealand; BADAPIC, Registry of the Working Group on Heart Failure, Heart Transplantation and Other Therapeutic Alternatives of the Spanish Society of Cardiology; BB, beta-blocker; BEST, Beta-blocker Evaluation in Survival Trial; BRING-UP: Beta-Blockers in Patients With Congestive Heart Failure: Guided Use in Clinical Practice; CHS, Cardiovascular Health Study; CHART, Chronic Heart Failure Analysis and Registry in the Tohoku district; CI, confidence interval; CIBIS, Cardiac Insufficiency Bisoprolol Study; COPERNICUS, Carvedilol Prospective Randomized Cumulative Survival; EF, ejection fraction; EVADEF: Évaluation Médico-Économique du Défibrillateur Automatique Implantable; HF, heart failure; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HFSIS, National Heart Failure Survey in Israel; HR, hazard ratio; ICD, implantable cardioverter defibrillator cohort; IHD, ischaemic heart disease cohort; J-DHF, Japanese Diastolic Heart Failure; MERIT-HF, Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure; NHC, National Heart Care; OPTIMIZE-HF, Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure; OR, odds ratio; PROBE, prospective randomized open blind endpoint study; PSM, propensity score matched study; RCT, randomized controlled trial; REACH, Resource Utilization Among Congestive Heart Failure; RR, risk ratio/relative risk; SENIORS, Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure; ‘Trial patients’, patients meeting the inclusion criteria of the MERIT-HF trial; ‘'Non-trial patients’, patients not meeting the inclusion criteria of the MERIT-HF trial; WAHMD, Western Australia Hospital Morbidity Data.