The effect of digoxin on mortality and morbidity in patients with heart failure
Perry, G; Brown, E; Thornton, R; Shiva, T; Hubbard, J; Reddy, KR; Doherty, JE; Cardello, FP; Fast, A; Radford, MJ; Folger, JS; Bhaskar, G; Zoble, RG; Sridharan, V; Sridharan, MR; Loungani, RR; Gheorghiade, M; Hsieh, A; Tommaso, C; Mansuri, M; Guess, MA; Akhtar, S; Wagner, S; Hagan, K; McIntyre, KM; Ruble, P; Moten, M; Riley, A; Pierpont, G; Anand, I; Patel, G; Puram, BS; Eladasari, BR; Karnegis, J; Gillie, E; Crawford, MH; Graettinger, WF; Shah, A; Sacco, J; Chaudhry, MA; Dolen, D; ElSherif, N; BekheitSaad, S; Campos, EE; Greene, JG; Khanijo, V; Kumar, U; Mallis, GI; Mookherjee, S; DibnerDunlap, M; Gupta, SC; Danisa, K; Thadani, U; Tan, A; Rajachar, M; Amidi, M; OReilly, MV; Hassapoyannes, CA; Davies, ML; Kumar, VA; Okerson, D; Ramanathan, KB; Putatunda, B; Gollapudi, A; Montero, A; Mohanty, PK; Lui, C; Thagirisa, S; Lee, RW; Glatter, TR; Bodine, K; Roberts, D; Bertoglio, M; Dennish, GW; Sarma, RJ; Gregoratos, G; Rausch, DC; Pitt, WA; Kennelly, BM; Fahrenholtz, D; Gordon, R; Horwitz, L; Rothbart, R; Nutting, P; Lutz, L; Copen, DL; Rashkow, A; Babb, J; VanVoorhees, L; Silverman, A; Stillabower, ME; Miller, AB; NguyenPho, HT; Safford, RE; Fishman, S; Neiman, JC; Stein, M; Dominguez, JC; Abernathy, GT; Nair, PH; Goodman, LS; Cook, TH; Wickemeyer, WJ; Berkson, DM; Mathew, J; Richman, HG; Lubell, DL; Lang, R; Zajac, EJ; Rosenstein, R; Silver, MA; Shanes, JG; Kelly, KJ; Pequignot, MH; Campbell, R; Kirlin, PC; Ziperman, DB; Denny, DM; Gamble, L; Weiss, M; Kaimal, PK; Dhurandhar, RW; Ventura, H; Godley, ML; Pu, C; Schick, EC; Barbour, DJ; Salmon, D; Goldstein, M; Effron, MB; Fleg, JL; Baughman, KL; Weiss, R; Ericson, K; Sturrock, WA; Heinsimer, J; Timmis, GC; Smith, S; Shrestha, DD; Duvernoy, WFC; Hickner, J; Lewis, BK; OBrien, TK; Yarows, SA; Willens, HJ; Mast, DJ; Johnson, TH; Rodeheffer, RJ; Siefert, M; Swenson, L; Denes, P; Gudapati, R; Charles, FR; Rich, MW; Beckham, V; Hamilton, WP; Abele, PB; Harper, DM; OKelly, RL; Forker, AD; Kahl, FR; Garrou, BW; Klang, TE; Popio, K; Mohiuddin, S; Pollak, EM; Chiaramida, A; Gregory, JJ; Papa, LA; Abrams, J; Ung, S; Jutila, CK; Croke, RP; Chiaramida, S; Lucariello, R; Rim, DA; Goldberger, MH; Kohn, RM; Graham, S; Philbin, EF; Sheesley, K; Nafziger, A; Macina, G; Hsueh, JT; Zoneraich, S; Binder, A; Weinstein, C; Morrison, J; Cameron, A; Vanderbush, E; Brown, J; Pande, PN; Lader, E; Kay, R; Bloomfield, D; Costantino, T; Heiselman, DE; Radwany, S; Smith, MR; Hobbs, RE; Fraker, TD; Frerking, TR; DeLeon, AC; Christie, LG; Toren, M; Grover, J; McBarron, FD; Harris, DE; McLean, RW; Morris, L; Zatuchni, J; Boehmer, JP; Clemson, BS; Lipshutz, H; Small, RS; Ufret, R; LugoRodriquez, JE; Khan, AH; Yousefian, M; Friesinger, GC; Ely, D; Farmer, JA; Young, JB; Payne, RM; Fowles, RE; Lee, AB; Shalev, Y; AlBitar, I; Schroeder, GS; Radant, L; Hankey, TL; Rezkalla, S; Groden, DL; Teo, KK; Humen, DP; Wong, D; Greenwood, PV; Talibi, T; Hui, W; Klinke, WP; Senaratne, MPJ; Goeres, M; Hughes, DF; Sayeed, MAR; Roth, DL; Belenkie, I; Manyari, DE; Borgersen, K; Read, L; Kinloch, D; Reid, R; Barber, NC; Horner, BA; Kenefick, G; Kuritzky, RA; Imrie, JR; Wagner, KR; Rabkin, SW; Mizgala, HF; Tarry, L; Dodek, A; Kornder, JM; Ashton, T; Barr, D; Dufton, J; Sweeny, R; Morris, A; Bessoudo, R; Marr, D; Milton, JR; Thompson, B; Robinson, V; Sussex, BA; Tobin, M; McMahon, DP; Folkins, D; Crowell, R; Lalonde, LD; Koilpillai, C; Hatheway, RJ; OReilly, MG; Machel, T; Hack, I; Stewart, JW; Tanser, PH; Sullivan, B; Hagar, S; Quinn, B; Davies, RA; Baird, MG; Williams, WL; LeMay, M; Higginson, L; Turek, M; Sochowski, RA; Weeks, A; Jacobs, MH; Baigrie, R; DeVilla, MA; Vertes, G; Bozek, B; Goode, JE; Ricci, AJ; Swan, J; Fell, DA; LevinoffRoth, SN; Arnold, JMO; Patrick, L; Southern, RF; Rinne, C; Brisbin, D; DeYoung, JP; Baitz, T; Vizel, S; Minkowitz, J; Letarte, P; Chan, YK; Kwok, KK; Nawaz, S; Ganjavi, F; Yao, L; Misterski, J; Raco, DL; Hess, AR; Kuruvilla, G; Silverberg, L; Borts, D; Fulop, JC; Weingert, ME; Carter, RP; Sahay, BM; Hickey, JE; Lalonde, G; Gosselin, G; Bourassa, MG; Goulet, C; Joyal, M; Methe, M; Honos, G; Fitchett, D; Serpa, A; Sestier, F; Roberge, G; Latour, Y; Rondeau, C; Gossard, D; Lenis, JHF; Brossoit, R; Simard, L; Delage, F; Auger, P; Saulnier, D; Talbot, P; Beaudoin, J; Campeau, J; Pruneau, G; Tamilia, M; Boutros, G; Comeau, B; Starra, R; StHilaire, R; Veilleux, J; Mercier, M; Poulin, JF; Maclellan, K; Lepage, S; Rouleau, JL; Bruinsma, N; Levesque, C; DeLarochelliere, R; LeBlanc, M; Kouz, S; Kiwan, GS; Laforest, M; Brooks, J; Bouchard, G; Gervais, PB; Brophy, J; Gagnon, J; Habib, N; Basu, AK; Lutterodt, AT; Khouri, M; Gorlin, R; Egan, D; Garg, R; Yusuf, S; Montague, T; Smith, TW; Cohn, JN; Dagenais, GR; Davies, R; Johnstone, DE; Fye, C; Sather, MR; Deykin, D; Francis, G; Collins, JF; Williford, WO; Singh, BN
Background The role of cardiac glycosides in treating patients with chronic heart failure and normal sinus rhythm remains controversial. We studied the effect of digoxin on mortality and hospitalization in a randomized, double-blind clinical trial. Methods In the main trial, patients with left ventricular ejection fractions of 0.45 or less were randomly assigned to digoxin (3397 patients) or placebo (3403 patients) in addition to diuretics and angiotensin-converting-enzyme inhibitors (median dose of digoxin, 0.25 mg per day; average follow-up, 37 months). In an ancillary trial of patients with ejection fractions greater than 0.45, 492 patients were randomly assigned to digoxin and 496 to placebo. Results In the main trial, mortality was unaffected. There were 1181 deaths (34.8 percent) with digoxin and 1194 deaths (35.1 percent) with placebo (risk ratio when digoxin was compared with placebo, 0.99; 95 percent confidence interval, 0.91 to 1.07; P = 0.80). In the digoxin group, there was a trend toward a decrease in the risk of death attributed to worsening heart failure (risk ratio, 0.88; 95 percent confidence interval, 0.77 to 1.01; P = 0.06). There were 6 percent fewer hospitalizations overall in that group than in the placebo group, and fewer patients were hospitalized for worsening heart failure (26.8 percent vs. 34.7 percent; risk ratio, 0.72; 95 percent confidence interval, 0.66 to 0.79; P < 0.001). In the ancillary trial, the findings regarding the primary combined outcome of death or hospitalization due to worsening heart failure were consistent with the results of the main trial. Conclusions Digoxin did not reduce overall mortality, but it reduced the rate of hospitalization both overall and for worsening heart failure. These findings define more precisely the role of digoxin in the management of chronic heart failure. (C) 1997, Massachusetts Medical Society. $$:
ISI:A1997WJ24000001
ISSN: 0028-4793
CID: 108143
Rationale, design, implementation, and baseline characteristics of patients in the DIG trial: A large, simple, long-term trial to evaluate the effect of digitalis on mortality in heart failure
Abernathy, GT; Abrams, J; Akhtar, S; Albitar, I; Amidi, M; Anand, IS; Arnold, JMO; Ashton, T; Aubrey, B; Auger, P; Babb, J; Baigrie, R; Baird, MG; Baitz, T; Barber, NC; Barbour, DJ; Barr, DM; Basu, AK; Baughman, KL; Beckham, V; BekheitSaad, S; Berkson, DM; Bertoglio, M; Bessoudo, R; Beaudoin, J; Bhaskar, G; Binder, A; Bloomfield, D; Bodine, K; Boehmer, JP; Borgersen, K; Borts, D; Bouchard, G; Bourassa, MG; Boutros, G; Bozek, B; Brisbin, D; Brophy, J; Brossoit, R; Brown, E; Brown, J; Bruinsma, N; Burton, G; Cameron, A; Campbell, R; Campeau, J; Campos, EE; Cardello, FP; Carter, RP; Chan, YK; Charles, FR; Chaudhry, MA; Chiaramida, A; Chiaramida, S; Chohan, A; Christie, LG; Clemson, BS; Collin, R; Cook, TH; Copen, DL; Cossett, J; Costantino, T; Crawford, MH; Croke, RP; Crowell, R; DAmours, G; Dagenais, GR; Danisa, K; Davidson, S; Davies, ML; Davies, R; Davies, RA; DeLarochelliere, R; DeLeon, AC; Delage, F; Denes, P; Dennish, GW; Denny, DM; DeVilla, MA; DeYoung, JP; Dhurandhar, RW; DibnerDunlap, M; Dodek, A; Doherty, JE; Dominguez, J; Dubbin, J; Dufton, J; Effron, MB; ElSherif, N; Eladasari, B; Fly, D; Ericson, K; Fahrenholtz, D; Fast, A; Fell, DA; Fishman, S; Fitchett, D; Fleg, JL; Flint, E; Folger, JS; Folkins, D; Forker, AD; Fowles, RE; Fraker, TD; Francis, G; Frerking, TR; Friesinger, GC; Fulop, JC; Gagnon, J; Gamble, L; Ganjavi, F; Garrou, BW; Gervais, PB; Gheorghiade, M; Gilbert, L; Gillie, E; Glatter, TR; Godley, ML; Goeres, M; Goldberger, MH; Gollapudi, A; Goode, JE; Goodman, LS; Gordon, R; Gossard, D; Gosselin, G; Goulet, C; Grant, C; Graettinger, WF; Greene, JG; Greenwood, PV; Gregoratos, G; Gregory, JJ; Groden, DL; Grover, J; Gudapati, R; Guess, MA; Gupta, SC; Habib, N; Hack, I; Hamilton, WP; Hankey, TL; Hanna, M; Harper, D; Harris, DE; Hassapoyannes, CA; Hatheway, RJ; Heinsimer, J; Pequignot, MH; Heiselman, DE; Hess, AR; Hickner, J; Hickey, JE; Higgins, T; Higginson, L; Hill, L; Hobbs, RE; Honos, G; Horner, BA; Horwitz, L; Hsieh, A; Hsueh, JT; Hubbard, J; Hughes, DF; Hui, W; Imrie, JR; Jacobs, MH; Jarmukli, N; Johnson, TH; Johnstone, D; Jutila, CK; Kadri, N; Kahl, FR; Kaimal, PK; Karnegis, J; Kay, R; Kelly, KJ; Kenefick, G; Kennelly, BM; Kent, E; Khan, AH; Khanijo, V; Khouri, M; Kinloch, D; Kirlin, PC; Kiwan, GS; Kline, MD; Kohn, RM; Koilpillai, C; Kornder, JM; Kouz, S; Kumar, VA; Kumar, U; Kuntz, A; Kuritzky, RA; Kuruvilla, G; Kwok, KK; Lader, E; Laforest, M; LaForge, D; Lalonde, G; Lalonde, L; Lang, RM; Latour, Y; Lawal, O; LeBlanc, MH; Lee, AB; Lee, RW; Legault, C; Lemay, M; Lenis, JHF; Lepage, S; Letarte, P; Levesque, C; LevinoffRoth, SN; Lewis, BK; Lipshutz, H; Loungani, RR; Lowery, ML; Lubell, DL; Lucariello, R; LugoRodriguez, JE; Lui, C; Lutterodt, AT; Lutz, L; Machel, T; Macina, G; MacLellan, K; Magnan, O; Mansuri, M; Manyari, DE; Mallis, GI; Marr, D; Mast, DJ; Mathew, J; McBarron, FD; McIntyre, KM; McLean, RW; McMahon, DP; Mercier, M; Methe, M; Miller, AB; Minkowitz, J; Milton, JR; Mizgala, HF; Mohanty, PK; Mohiuddin, S; Montero, A; Mookherjee, S; Morris, A; Morris, L; Morrison, J; Moten, M; Nafziger, A; Nair, PH; Nawaz, S; Neiman, JC; Nutting, P; NguyenPho, HT; OBrien, TK; OKelly, RL; OReilly, MV; Okerson, D; Patel, G; Pande, PN; Papa, LA; Patrick, L; Payne, RM; Perry, G; Philbin, EF; Pierpont, G; Pitt, WA; Poirier, C; Pollak, EM; Popio, K; Poulin, JF; Probst, PA; Pruneau, G; Pu, C; Puram, BS; Putatunda, B; Quinn, B; Rabkin, SW; Racine, N; Raco, DL; Radant, L; Radford, MJ; Radwany, S; Rajachar, M; Ramanathan, KB; Rashkow, A; Rausch, DC; Read, L; Reddy, KR; Reid, R; Rich, MW; Ricci, AJ; Richman, HG; Riley, A; Rim, DA; Rinne, C; Roberge, G; Roberts, DK; Robinson, V; Rodeheffer, RT; Rosenstein, R; Roth, DL; Rothbart, R; Rouleau, JL; Ruble, P; Sacco, J; Safford, RE; Salmon, D; Sahay, BM; Sarma, RJ; Sayeed, MAR; Schick, EC; Schroeder, GS; Seifert, M; Senaratne, MPJ; Sestier, F; Shah, A; Shanes, JG; Sheesley, K; Silverman, A; Shiva, T; Shrestha, DD; Silver, MA; Silverberg, L; Simard, L; Singh, BN; Small, RS; Smith, MR; Smith, S; Sochowski, RA; Southern, RF; Sridharan, MR; StHilaire, R; Stein, M; Stewart, JW; Stillabower, ME; Sullivan, BHM; Sturrock, WA; Sussex, BA; Swan, J; Swenson, L; Talbot, P; Talibi, T; Tamilia, M; Tan, A; Tanser, PH; Tarry, L; Teo, KK; Thadani, U; Thagirisa, S; Thompson, B; Thornton, R; Timmis, GC; Tobin, M; Tommaso, C; Toren, M; Tsuyuki, R; Turek, M; Utley, K; Vanderbush, EJ; VanVoorhees, L; Ventura, H; Vertes, G; Vizel, S; Wagner, KR; Wagner, S; Weeks, A; Weingert, ME; Weinstein, C; Weiss, MM; Weiss, R; Wickemeyer, W; Wielgoz, A; Willens, HJ; Williams, WL; Wong, D; Yarows, SA; Yao, L; Shalev, Y; Young, JB; Yousefian, M; Zajac, EJ; Zatuchni, J; Ziperman, DB; Zoble, RG; Zoneraich, S; Gorlin, R; Sleight, P; Cohn, JN; Collins, R; Deykin, D; Hennekens, C; Kjekshus, J; Smith, TW; Tognoni, G; Collins, JF; Williford, WO; Fye, C; Sather, R; Jolly, MK; Held, CP; Verter, J; Yusuf, S; Egan, D; Garg, R; Johnstone, DE; Montague, T; Bristow, D; Engelhardt, HT; Gent, M; Hood, WB; Jones, S; Meier, P; Pitt, B; Waters, D; Arnold, JMO; Baker, A; Barnhill, S; Carew, B; Hagar, S; Liuni, C; Martin, S; Miles, R; Arthur, MM; Feldbush, MW; Highfield, DA; Hobbins, TE; Kurz, R; Leviton, SP; Libonati, JP; Moore, M; Perez, E; Mills, P; Geller, N; Hunsberger, S; Gold, J; Huang, PC; Burns, A; Caleb, H; Cline, DR; Harris, S; Hockenbrock, R; Horney, RA; Jadwin, LM; King, J; Sexton, P; Spence, ME; Chacon, F; Gagne, W; Maple, S; Martinez, G
This article provides a detailed overview of the rationale for key aspects of the protocol of the Digitalis Investigation Group (DIG) trial. It also highlights unusual aspects of the study implementation and the baseline characteristics. The DIG trial is a large, simple, international placebo-controlled trial whose primary objective is to determine the effect of digoxin on all cause mortality in patients with clinical heart failure who are in sinus rhythm and whose ejection fraction is less than or equal to 0.45. An ancillary study examines the effect in those with an ejection fraction > 0.45. Key aspects of the trial include the simplicity of the design, broad eligibility criteria, essential data collection, and inclusion of various types of centers. A total of 302 centers in the United States and Canada enrolled 7788 patients between February 1991 and September 1993. Follow-up continued until December 1995 with the results available in Spring 1996. $$:
ISI:A1996UA39800009
ISSN: 0197-2456
CID: 108145