Table 2.
All-cause mortality in randomized and non-randomized ACEI/ARB 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 (ACEI) | |||||||||
| Randomized controlled trials—beneficial treatment effect | |||||||||
| SOLVD Investigators, USA, 1991 (SOLVD-Treatment)118 | RCT | 1986–1989 | USA, Canada, Belgium | 41 | 2569 | 1285 | 1284 | RR: 0.84 (0.74–0.95; P < 0.004) | — |
| Jong, Canada, 2003 (X-SOLVD Overall)119 | RCT | 1986–1990 | USA, Canada, Belgium | 134–145a | 6797 | 3396 | 3401 | 0.90 (0.84–0.95; P < 0.0003) | — |
| Jong, Canada, 2003 (X-SOLVD-Prevention)119 | RCT | 1986–1990 | USA, Canada, Belgium | 134a | 4228 | 2111 | 2117 | 0.86 (0.79–0.93; P < 0.001) | — |
| Randomized controlled trials—neutral treatment effect | |||||||||
| SOLVD Investigators, USA, 1992 (SOLVD-Prevention)120 | RCT | 1986–1990 | USA, Canada, Belgium | 37 | 4228 | 2111 | 2117 | RR: 0.92 (0.79–1.08; P < 0.30) | — |
| Jong, Canada, 2003 (X-SOLVD-Treatment)119 | RCT | 1986–1990 | USA, Canada, Belgium | 145a | 2569 | 1285 | 1284 | 0.93 (0.85–1.01; P < 0.01) | — |
| Observational studies—beneficial treatment effect | |||||||||
| Masoudi, USA, 2004 (NHC)26 | Retrospective cohort study (≥65 years) | 1998–1999, 2000–2001 | USA | 12 | 17 456 | 12 069 | 13 600 | RR: 0.78 (0.75–0.81; P < 0.0001) | RR: 0.86 (0.82–0.90) |
| HFrEF (ARB) | |||||||||
| Randomized controlled trials—neutral treatment effect | |||||||||
| Granger, USA, 2003 (CHARM-Alternative)121 | RCT | 1999–2001 | Multiregional | 34a | 2028 | 1013 | 1015 | 0.87 (0.74–1.03; P < 0.11) | 0.83 (0.70–0.99; P < 0.033) |
| HFrEF (ACEI + ARB) | |||||||||
| Observational studies—beneficial treatment effect | |||||||||
| Sanam, USA, 2016 (Alabama HF Project)27 | Retrospective cohort study (PSM) (≥65 years) | 1998–2001 | USA | 12 | 954 | 477 | 477 | — | 0.77 (0.62–0.96; P < 0.020) |
| Liu, China, 201428 | Prospective cohort study | 2005–2010 | China | 52a | 2154 | 1421 | 733 | — | 0.43 (0.33–0.57; P < 0.001) |
| Lund, Sweden, 2012 (Swedish HF Registry)29 | Registry (PSM) | 2000–2011 | Sweden | 12 | 4010 | 2005 | 2005 | — | 0.80 (0.74–0.86; P < 0.001) |
| Masoudi, USA, 2004 (NHC)26 | Retrospective cohort study (≥65 years) | 1998–1999, 2000–2001 | USA | 12 | 17 456 | 13 600 | 3856 | — | RR: 0.83 (0.79–0.88) |
| Observational studies—neutral treatment effect | |||||||||
| Ushigome, Japan, 2015 (1. CHART-1)30 | Prospective cohort study | 2000–2005 | Japan | 36 | 543 | 385 | 158 | — | 0.67 (0.40–1.12; P < 0.128) |
| Ushigome, Japan, 2015 (2. CHART-2)30 | Prospective cohort study | 2006–2010 | Japan | 36 | 1360 | 1061 | 299 | — | 0.83 (0.60–1.15; P < 0.252) |
| HFpEF (ACEI) | |||||||||
| Randomized controlled trials—neutral treatment effect | |||||||||
| Cleland, UK, 2006 (PEP-CHF)122 | RCT (≥70 years) | 2000–2003 | Multiregional | 26 | 850 | 424 | 426 | 1.09 (0.75–1.58; P < 0.665) | — |
| Observational studies—beneficial treatment effect | |||||||||
| Gomez-Soto, Spain, 201031 | Prospective cohort study (propensity score adjusted) | 2001–2005 | Spain | 30a | 1120 | 255 | 865 | RR: 0.34 (0.23–0.46; P < 0.001) | 0.67 (0.52–0.71) |
| Shah, USA, 2008 (NHC)32 | Retrospective cohort study (≥65 years) | 1998–1999, 2000–2001 | USA | 36 | 13 533 | 6413 | 7120 | — | RR: 0.93 (0.89–0.98) |
| Tribouilloy, France, 200833 | Prospective cohort study (PSM) | 2000 | France | 60 | 240 | 120 | 120 | 0.61 (0.43–0.87; P < 0.006) | 0.58 (0.40–0.82; P < 0.002) |
| Grigorian Shamagian, Spain, 200634 | Prospective cohort study | 1991–2002 | Spain | 31 | 416 | 210 | 206 | 0.56 (0.40–0.79; P < 0.001) | 0.63 (0.44–0.90; P < 0.012) |
| Observational studies—neutral treatment effect | |||||||||
| Mujib, USA, 2013 (OPTIMIZE-HF)35 | Registry (PSM) (≥65 years) | 2003–2004 | USA | 29a | 2674 | 1337 | 1337 | — | 0.96 (0.88–1.05; P < 0.373) |
| Dauterman, USA, 2001 (Medicare)36 | Retrospective cohort study (≥65 years) | 1993–1994, 1996 | USA | 12 | 430 | 206 | 224 | — | 1.15 (0.79–1.67; P < 0.46) |
| Philbin, USA, 2000 (MISCHF)37 | Registry | 1995, 1996–1997 | USA | 6 | 302 | 137 | 165 | OR: 0.72 (0.38–1.39) | OR: 0.61 (0.30–1.25) |
| Philbin, USA, 1997 (MISCHF)38 | Registry | 1995 | USA | 6 | 350 | 190 | 160 | — | OR: 0.63 (P < 0.15–95% CI not reported) |
| HFpEF (ARB) | |||||||||
| Randomized controlled trials—neutral treatment effect | |||||||||
| Massie, USA, 2008 (I-PRESERVE)123 | RCT | 2002–2005 | Multiregional | 50 | 4128 | 2067 | 2061 | 1.00 (0.88–1.14; P < 0.98) | — |
| Yusuf, Canada, 2003 (CHARM-Preserved)124 | RCT | 1999–2000 | Multiregional | 37a | 3023 | 1514 | 1509 | 1.02 (0.85–1.22; P < 0.836) | — |
| Observational studies—neutral treatment effect | |||||||||
| Patel, USA, 2012 (OPTIMIZE-HF)39 | Registry (PSM) (≥65 years) | 2003–2004 | USA | 72 | 592 | 296 | 296 | 0.93 (0.76–1.14; P < 0.509) | — |
| HFpEF (ACEI + ARB) | |||||||||
| Observational studies—beneficial treatment effect | |||||||||
| Lund, Sweden, 2012 (Swedish HF Registry)29 | Registry (PSM) | 2000–2011 | Sweden | 12 | 6658 | 3329 | 3329 | — | 0.91 (0.85–0.98; P < 0.008) |
| Observational studies—neutral treatment effect | |||||||||
| Ushigome, Japan, 2015 (1. CHART-1)30 | Prospective cohort study | 2000–2005 | Japan | 36 | 463 | 304 | 159 | — | 0.86 (0.51–1.47; P < 0.592) |
| Ushigome, Japan, 2015 (2. CHART-2)30 | Prospective cohort study | 2006–2010 | Japan | 36 | 2316 | 1619 | 697 | — | 1.01 (0.77–1.32; P < 0.924) |
| Mixed/unspecified HF phenotype (ACEI) | |||||||||
| Randomized controlled trials—beneficial treatment effect | |||||||||
| Cohn, USA, 1991 (V-HeFT-II)125 | RCT | 1986–1990 | USA | 24 | 804 | 403 | 401 (H-ISDN) | RR: 0.72 (P < 0.016–95% CI not reported) | — |
| CONSENSUS Trial Study Group, Sweden, 1987 (CONSENSUS)126 | RCT | 1985–1986 | Sweden, Norway, Finland | 12 | 245 | 127 | 126 | RR: 0.69 (P < 0.001–95% CI not reported) | — |
| Observational studies—beneficial treatment effect | |||||||||
| Keyhan, Canada, 2007 (1. female cohort)40 | Retrospective cohort study (≥65 years) | 1998–2003 | Canada | 12 | 14 693 | 9801 | 4892 | 0.75 (0.71–0.78) | 0.80 (0.76–0.85) |
| Keyhan, Canada, 2007 (2. male cohort)40 | Retrospective cohort study (≥65 years) | 1998–2003 | Canada | 12 | 13 144 | 9419 | 3725 | 0.62 (0.59–0.65) | 0.71 (0.67–0.75) |
| Tandon, Canada, 2004 (75% HFrEF, 25% HFpEF)41 | Prospective cohort study | 1989–2001 | Canada | 32a | 1041 | 878 | 163 | — | OR: 0.60 (0.39–0.91) |
| Pedone, Italy, 2004 (GIFA)42 | Prospective cohort study (≥65 years) | 1998 | Italy | 10 | 818 | 550 | 268 | 0.56 (0.41–0.78) | 0.60 (0.42–0.88) |
| Ahmed, USA, 2003 (Medicare)43 | Retrospective cohort study (PSM) | 1994 | USA | 36 | 1090 | 528 | 562 | 0.77 (0.66–0.91) | 0.81 (0.69–0.97) |
| Sin, Canada, 2002 (19% HFrEF, 36% HFpEF, 45% unknown)44 | Retrospective cohort study (≥65 years) (propensity score adjusted) | 1994–1998 | Canada | 21a | 11 942 | 4908 | 7034 | — | 0.59 (0.55–0.62) |
| Mixed/unspecified HF phenotype (ARB) | |||||||||
| Randomized controlled trials—neutral treatment effect | |||||||||
| Pfeffer, USA, 2003 (CHARM Overall Programme) (60% HFrEF, 40% HFpEF)127 | RCT | 1999–2001 | Multiregional | 40a | 7599 | 3803 | 3796 | 0.91 (0.83–1.00; P < 0.055) | 0.90 (0.82–0.99; P < 0.032) |
| Mixed/unspecified HF phenotype (ACEI + ARB) | |||||||||
| Observational studies—beneficial treatment effect | |||||||||
| Gastelurrutia, Spain, 2012 (75% HFrEF, 25% HFrEF)45 | Prospective cohort study | 2001–2008 | Spain | 44a | 960 | 846 | 114 | — | 0.52 (0.39–0.69; P < 0.001) |
| Teng, Australia, 2010 (WAHMD) (24% HFrEF, 30% HFpEF, 46% unknown)46 | Retrospective cohort study | 1996–2006 | Australia | 12 | 944 | 701 | 243 | — | 0.71 (0.57–0.89; P < 0.003) |
| Observational studies—neutral treatment effect | |||||||||
| Ushigome, Japan, 2015 (1. CHART-1) (54% HFrEF, 46% HFpEF)30 | Prospective cohort study | 2000–2005 | Japan | 36 | 1006 | 689 | 317 | — | 0.79 (0.55–1.14; P < 0.208) |
| Ushigome, Japan, 2015 (2. CHART-2) (37% HFrEF, 63% HFpEF)30 | Prospective cohort study | 2006–2010 | Japan | 36 | 3676 | 2677 | 999 | — | 0.94 (0.76–1.15; P < 0.534) |
a
Median.
—, Not reported; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CHARM, Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity; CHART, Chronic Heart Failure Analysis and Registry in the Tohoku district; CI, confidence interval; CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study; GIFA, Gruppo Italiano di Farmacovigilanza nell'Anziano; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; H-ISDN, hydralazine-isosorbide dinitrate; HR, hazard ratio; I-PRESERVE, Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction; MISCHF, Management to Improve Survival 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; PEP-CHF, Perindopril in Elderly People with Chronic Heart Failure; PSM, propensity score matched study; RCT, randomized controlled trial; RR, risk ratio/relative risk; SOLVD, Studies of Left Ventricular Dysfunction; V-HeFT-II, Vasodilator Heart Failure Trial II; WAHMD, Western Australia Hospital Morbidity Data; X-SOLVD, Extended follow-up of the SOLVD trials.