Table 6.
All-cause mortality in randomized and non-randomized digoxin HF studies
| First author, country, year (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—neutral treatment effect | |||||||||
| Digoxin Investigation Group, USA, 1997 (DIG Main Trial)145 | RCT (SR) | 1991–1993 | USA, Canada | 37 | 6800 | 3397 | 3403 | RR: 0.99 (0.91–1.07; P < 0.80) | — |
| Observational studies—beneficial treatment effect | |||||||||
| Andrey, Spain, 2011 (51% HFrEF)105 | Prospective cohort study (PSM) (SR/AF) | 2001–2008 | Spain | 46a | 2842 | 1421 | 1421 | — | 0.92 (0.89–0.95; P < 0.005) |
| Observational studies—neutral treatment effect | |||||||||
| Ushigome, Japan, 2015 (1. CHART-1)30 | Prospective cohort study (SR/AF) | 2000–2005 | Japan | 36 | 543 | 229 | 314 | — | 0.99 (0.61–1.61; P < 0.978) |
| Ushigome, Japan, 2015 (2. CHART-2)30 | Prospective cohort study (SR/AF) | 2006–2010 | Japan | 36 | 1360 | 586 | 774 | — | 1.10 (0.80–1.51; P < 0.558) |
| Fauchier, France, 2009 (41% HFrEF)55 | Retrospective cohort study (AF) | 2000–2004 | France | 29 | 1269 | 591 | 678 | — | RR: 0.79 (0.54–1.16; P < 0.23) |
| Dhaliwal, USA, 2008106 | Retrospective cohort study (SR/AF) | 2002–2004 | USA | 10a | 347 | 155 | 192 | 1.15 (0.85–1.55; P < 0.371) | 1.11 (0.81–1.53; P < 0.521) |
| Observational studies—harmful treatment effect | |||||||||
| Al-Khateeb, Saudi Arabia, 2017107 | Retrospective cohort study (PSM) (SR/AF) | 2000–2015 | Saudi Arabia | 43a | 1075 | 325 | 750 | 1.81 (1.33–2.45; P < 0.001) | 1.74 (1.20–2.38; P < 0.0001) |
| Freeman, USA, 2013 (KPNC)108 | Retrospective cohort study (SR/AF) | 2006–2008 | USA | 30a | 2891 | 529 | 2362 | — | 1.72 (1.25–2.36) |
| Butler, USA, 2010 (Val-HeFT)109 | Post hoc analysis of RCT (SR/AF) | — | Multiregional | 23 | 5010 | 1636 | 3374 | 1.46 (1.23–1.64; P < 0.001) | 1.28 (1.05–1.57; P < 0.02) |
| Domanski, USA, 2005 (SOLVD) (1. female cohort)110 | Post hoc analysis of RCT (SR/AF) | 1986–1989 | USA, Canada, Belgium | 39 | 988 | 370 | 618 | 1.48 (1.10–2.00; P < 0.01) | 1.36 (1.03–1.80; P < 0.03) |
| Domanski, USA, 2005 (SOLVD) (2. male cohort)110 | Post hoc analysis of RCT (SR/AF) | 1986–1989 | USA, Canada, Belgium | 39 | 5809 | 1874 | 3935 | 1.37 (1.20–1.56; P < 0.0001) | 1.42 (1.26–1.61; P < 0.0001) |
| HFpEF | |||||||||
| Randomized controlled trials—neutral treatment effect | |||||||||
| Ahmed, USA, 2006 (DIG Ancillary Trial)146 | RCT (SR) | 1991–1993 | USA, Canada | 37 | 988 | 492 | 496 | 0.99 (0.76–1.28; P < 0.925) | — |
| Observational studies—beneficial treatment effect | |||||||||
| Andrey, Spain, 2011 (49% HFpEF)105 | Prospective cohort study (PSM) (SR/AF) | 2001–2008 | Spain | 46a | 2842 | 1421 | 1421 | — | 0.86 (0.79–0.92; P < 0.008) |
| Observational studies—neutral treatment effect | |||||||||
| Ushigome, Japan, 2015 (1. CHART-1)30 | Prospective cohort study (SR/AF) | 2000–2005 | Japan | 36 | 463 | 249 | 214 | — | 0.92 (0.55–1.54; P < 0.764) |
| Ushigome, Japan, 2015 (2. CHART-2)30 | Prospective cohort study (SR/AF) | 2006–2010 | Japan | 36 | 2316 | 335 | 1981 | — | 1.07 (0.81–1.41; P < 0.632) |
| Fauchier, France, 2009 (35% HFpEF)55 | Retrospective cohort study (AF) | 2000–2004 | France | 29 | 1269 | 591 | 678 | — | RR: 1.21 (0.77–1.89; P < 0.42) |
| Mixed/unspecified HF phenotype | |||||||||
| Randomized controlled trials—neutral treatment effect | |||||||||
| Rich, USA, 2001 (DIG Overall)147 | RCT (SR) | 1991–1993 | USA, Canada | 37 | 7788 | 3889 | 3899 | RR: 0.99 (0.92–1.07; P < 0.7815) | — |
| Observational studies—beneficial treatment effect | |||||||||
| Ahmed, USA, 2014 (Alabama HF Project) (57% HFrEF, 25% HFpEF, 18% unknown)111 | Retrospective cohort study (PSM) (SR/AF) | 1998–2001 | USA | 12 | 1842 | 921 | 921 | — | 0.83 (0.70–0.98) |
| Andrey, Spain, 2011 (51% HFrEF, 49% HFpEF)105 | Prospective cohort study (PSM) (SR/AF) | 2001–2008 | Spain | 46a | 2842 | 1421 | 1421 | — | 0.90 (0.84–0.97) |
| Observational studies—neutral treatment effect | |||||||||
| Ushigome, Japan, 2015 (1. CHART-1) (54% HFrEF, 46% HFpEF)30 | Prospective cohort study (SR/AF) | 2000–2005 | Japan | 36 | 1006 | 478 | 528 | — | 0.97 (0.69–1.38; P < 0.875) |
| Ushigome, Japan, 2015 (2. CHART-2) (37% HFrEF, 63% HFpEF)30 | Prospective cohort study (SR/AF) | 2006–2010 | Japan | 36 | 3676 | 921 | 2755 | — | 1.06 (0.87–1.31; P < 0.555) |
| Flory, USA, 2012 (THIN) (1. female cohort)112 | Retrospective cohort study (SR/AF) | 1986–2008 | UK | — | 30 035 | 10 808 | 19 227 | — | 1.00 (0.96–1.06) |
| Flory, USA, 2012 (THIN) (2. male cohort)112 | Retrospective cohort study (SR/AF) | 1986–2008 | UK | — | 27 194 | 9487 | 17 707 | — | 1.00 (0.95–1.06) |
| Fauchier, France, 2009 (41% HFrEF, 35% HFpEF, 24% unknown)55 | Retrospective cohort study (AF) | 2000–2004 | France | 29 | 1269 | 591 | 678 | — | 0.90 (0.66–1.24; P < 0.53) |
| Hallberg, Sweden, 2007 (RIKS-HIA) (58% HFrEF, 42% HFpEF) (1. AF cohort)113 | Registry (propensity score adjusted) | 1995–2003 | Sweden | 12 | 16 960 | 7758 | 9202 | RR: 1.07 (1.01–1.14) | RR: 1.00 (0.94–1.06) |
| Pedone, Italy, 2004 (GIFA)42 | Prospective cohort study (SR/AF) | 1998 | Italy | 10 | 818 | 539 | 279 | — | 0.75 (0.51–1.10) |
| Observational studies—harmful treatment effect | |||||||||
| Eisen, USA, 2017 (ENGAGE AF-TIMI 48) (41% HFrEF, 34% HFpEF, 24% unknown)114 | Post hoc analysis of RCT (IPTW) (AF) | 2008–2010 | Multiregional | 34a | 8102 | 4051 | 4051 | — | 1.29 (1.15–1.44) |
| Katz, Israel, 2016 (HFSIS) (38% HFrEF, 15% HFmrEF, 22% HFpEF, 26% unknown)65 | Prospective cohort study (SR/AF) | 2003 | Israel | 120 | 2402 | 380 | 2022 | — | 1.27 (1.16–1.42; P < 0.001) |
| Madelaire, Denmark, 2016115 | Retrospective cohort study (PSM) (SR) | 1996–2012 | Denmark | 32a | 15 981 | 5327 | 10 654 | — | 1.19 (1.15–1.24; P < 0.001) |
| Shah, Canada, 2014116 | Retrospective cohort study (PSM) (≥65 years) (AF) | 1998–2012 | Canada | 37 | 27 972 | 13 986 | 13 986 | 1.14 (1.11–1.17) | 1.14 (1.10–1.17) |
| Whitbeck, USA, 2013 (AFFIRM)117 | Post hoc analysis of RCT (AF) | — | Multiregional | 42 | 1076 | — | — | — | 1.41 (1.09–1.84; P < 0.01) |
| Hallberg, Sweden, 2007 (RIKS-HIA) (58% HFrEF, 42% HFpEF) (2. SR cohort)113 | Registry (propensity score adjusted) | 1995–2003 | Sweden | 12 | 22 345 | 3796 | 18 549 | RR: 1.35 (1.26–1.44) | RR: 1.11 (1.04–1.19) |
| Tandon, Canada, 2004 (75% HFrEF, 25% HFpEF)41 | Prospective cohort study (SR/AF) | 1989–2001 | Canada | 32a | 1041 | 671 | 370 | — | OR: 1.51 (1.10–2.07) |
a
Median.
—, Not reported; AF, atrial fibrillation cohort; AFFIRM, Atrial Fibrillation Follow-up Investigation of Rhythm Management; CHART, Chronic Heart Failure Analysis and Registry in the Tohoku district; CI, confidence interval; DIG, Digitalis Investigation Group; ENGAGE AF-TIMI 48, Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation - Thrombolysis in Myocardial Infarction 48; GIFA, Gruppo Italiano di Farmacovigilanza nell'Anziano; 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; KPNC, Kaiser Permanente Northern California; IPTW, inverse-probability-of-treatment weighted study; OR, odds ratio; PSM, propensity score matched study; RCT, randomized controlled trial; RIKS-HIA, Registry of Information and Knowledge about Swedish Heart Intensive Care Admissions; RR, risk ratio/relative risk; SOLVD, Studies of Left Ventricular Dysfunction; SR, sinus rhythm cohort; SR/AF, sinus rhythm and atrial fibrillation cohort; THIN, The Health Improvement Network; Val-HeFT, Valsartan Heart Failure Trial.