convertidora por intolerancia o contraindicaciones; b) pacientes con fracción de eyección menor o igual al 40% y tratados con inhibidores de la enzima convertidora; c) pacientes con fracción de eyección mayor del 40% y no tratados con inhibidores de la enzima convertidora. El punto final primario de cada subgrupo es evaluar si el candesartán comparado con placebo reducirá el punto final de mortalidad u hospitalización cardiovascular en pacientes con insuficiencia cardíaca. En el año 2003 los resultados del CHARM nos reponderán si el candesartán es capaz de reducir la morbilidad y mortalidad cardiovascular en (1) pacientes con insuficiencia cardíaca que sean intolerantes a los inhibidores de la enzima convertidora, (2) en aquellos habitualmente tratados con inhibidores de la enzima convertidora y (3) en los pacientes con función sistólica conservada.La determinación acerca de si este modo de inhibición del sistema renina-angiotensina-aldosterona es comparable con, mejor que, peor que, o aditivo a un inhibidor de la enzima convertidora todavía no está resuelta. Si bien hay datos a favor de su seguridad y tolerancia, también se encuentran aquellos que señalan que los beneficios no serían tan significativos como los que surgen de los datos preliminares del Val-HeFT y del RESOLVD, por lo cual, hasta el momento, no hay evidencias concluyentes que sugieran que su uso sea equivalente o superior a los inhibidores de la enzima convertidora. Podríamos concluir que su aplicación clínica queda hoy recomendada para aquellos pacientes con demostrada intolerancia (tos intratable y angioedema) a los inhibidores de la enzima convertidora.ConclusiónLa Insuficiencia Cardíaca es una fascinante área de investigación y un importante problema de la salud pública. Los grandes ensayos clínicos aleatorizados y controlados representan hoy un método válido para determinar las estrategias de tratamiento de utilidad clínica y las que no lo son. Las evidencias surgidas de dichos estudios nos permiten formular normas para el tratamiento médico óptimo; de esta manera, contribuyen a la toma de decisiones terapéuticas durante la práctica diaria y constituyen además una fuente genuina de hipótesis para la investigación clínica. Debemos tener en cuenta que aun estudios algo más pequeños con drogas cuyo mecanismo de acción es conocido, y que se hallen dirigidos a modificar variables fisiopatológicas que han demostrado participar en la progresión de la insuficiencia cardíaca, nos permitirán también modificar el pobre pronóstico que aún hoy esta enfermedad implica. Es importante tener en cuenta que el mundo real de pacientes con insuficiencia cardíaca está conformado también por los pacientes «no seleccionados» en los grandes ensayos clínicos. Por lo tanto, un adecuado análisis de los diferentes subgrupos de pacientes tratados, con una correcta interpretación clínica-fisiopatológica de sus resultados y conclusiones se hace necesario hoy a la luz de la creciente polifarmacia para el tratamiento de la enfermedad.Bibliografía1. Cohn JN, Archibald DG, Ziesche S, et al. «Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration cooperative study (V-HeFT)», N Engl Med 314:1547-52, 1986.2. 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 316:1429-35, 1987.3. Cohn JN, Johnson G, Ziesche S, et al. «A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure», N Engl J Med 325:303-10, 1991.4. The SOLVD investigators. «Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure», N Engl J Med 325:293-302,1991.5. The SOLVD investigators. «Effect of enalapril on mortality and the development of heart failure in asyntomatic patients with reduced left ventricular ejection fraction», N Engl J Med 327:685-691, 1992.6. Carson P, Ziesche S, Johnson G, Cohn J, for the Vasodilator-Heart Failure Trial Study Group. «Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials», J Card Fail 5:178-187, 1999.7. Packer M, Poole-Wilson PA, Armstrong PW, Cleland JGF, Horowitz JD, Massie BM, Rydén L, Thygesen K, Uretsky BT, on behalf of the ATLAS Study Group. «Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure», Circulation 100:2312-2318, 1999.8. Nicklas JM, Cohn J, Pitt B. «What does ATLAS really tell us about "high" dose angiotensin-converting enzyme inhibition in heart failure», J Card Fail 6:165-168,2000.9. Jorde UP, Ennezat PV, Lisker J, Suryadevara V, Infeld J, Cukon S, Hammer A, Sonnenblick EH, Le Jemtel TH. «Maximally recommended doses of angiotensin. Converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure», Circulation 101:844-846,2000.10. Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, Jolly MK, on behalf of the PROVED Investigative Group. «Randomized study assesing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial», J Am Coll Cardiol 22:955-962, 1993.11. Packer M, Gheorghiade M, Young JB, et al. «Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors», N Engl J Med 329:1-7, 1993.12. The Digitalis Investigation Group. «The effect of digoxin on mortality and morbidity in patients with heart failure», N Engl J Med 336:525-533, 1997. 13. Cohn JN, Goldstein S, Greenberg BH, Lorell BH, Bourge RC, Jaski BE, Gottlieb SO, McGrew F, MeMets DL, White BG, for the Vesnarinone Trial Investigators. «Dose-dependent mortality increase from vesnarinone in severe heart failure: the Vesnarinone Trial results», N Engl J Med 339:1810-6, 1998.14. Soran O, Young LD, Holubkov R, Loftus S, Bourge R, Carson P, Jaski B, White BG, Feldman AM, for the VEST withdrawal substudy group. J Card Fail 5:195-200, 1999.15. Waagstein F, Hjalmarson A, Varnauskas E, Wallentin I. «Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy», Br Heart J 37:1022-36, 1975.16. Cohn JN, Levine B, Olivari MT, Garberg V, Lura D, Francis G, Simon AB, Rector T. «Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure», N Engl J Med 311:819-23, 1984.17. Geslin P, Le Boull A, Furber A, Dupuis JM, Bouhour JB, Lanfranchi J, Monassier JP, Ferrieres M, Tadei A, Allain P. «Plasma noradrenaline and the prognosis of chronic cardiac failure: a multicenter study», Arch Mal Coeur Vaiss 91:191-199, 1998.18. Swedberg K, Waagstein F, Hjalmarson A, Wallentin I. «Prolongation of survival in congestive cardiomyopathy by beta receptor blockade», Lancet 1:1374-1376, 1979.19. Bristow M. «Pathophysiologic and Pharmacologic Rationales for Clinical Management of Chronic Heart Failure with Beta-Blocking Agents», Am J Cardiol 71:12C-22C, 1993. 20. Waagstein F, Bristow M, Swedberg K, Camerini F, Fowler M, Silver M, Gilbert E, Johnson M, Goss F, Hjalmarson A, for the Metopolol in Dilated Cardiomyopathy Trial Study Group. «Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy», Lancet 342:1441-1446, 1993.21. Colucci WS, Packer M, Bristow MR, et al., for the U.S. Carvedilol Heart Failure Study Group. «Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure», Circulation 94:2800-2806, 1996.22. Packer M, Colucci WS, Sackner BJ, et al. «Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure: the Prospective Randomized Evaluation of Carvedilol in Symptoms and Exercise (PRECISE) trial», Circulation 94:2793-9, 1996.23. Bristow MR, Gilbert EM, Abraham WT, et al. For the MOCHA Investigators. «Carvedilol produces dose-related improvements in left ventricular funcion and survival in subjects with chronic heart failure», Circulation 94:2807-16, 1996.24. Packer Milton, Bristow Michael. For The U.S. Carvedilol Heart Failure Study Group. N Engl J Med 334:1349-1355, 1996.25. Australia-New Zealand Heart Failure Research Collaborative Group. «Effects of Carvedilol, a Vasodilator-ß-Blocker, in Patiens with Congestive Heart Failure Due to Ischemic Heart Disease», Circulation 92:212-218, 1995.26. CIBIS Investigators and Committees. «A randomized trial of beta-blockade in heart failure: the Cardiac Insufficiency Bisoprolol Study (CIBIS)», Circulation 90:1765-1773, 1994.27. CIBIS-II Investigators and Committees. «The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial», Lancet 353:9-13, 1999.28. MERIT-HF Study Group. «Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomised intervention trial in congestive heart failure (MERITH-HF)», Lancet 353:2001-07, 1999.29. The BEST Steering Committee. «Design of the Beta-Blocker Evaluation Survival Trial (BEST)», Am J Cardiol 75:1220-3, 1995.30. Witte K, Thackray S, Banerjee T, Lark AL, Cleland JGF. «Update of ELITE-II, BEST, CHAMP, and IMPRESS clinical trials in heart failure», Eur J Heart Failure 2:107-112, 2000.31. Bristow MR. Mechanistic and clinical rationales for using ß-blockers in heart failure», J Card Fail 6(suppl 1):8-14, 2000. 32. Feldman AM. «From clinical trials to clinical practice: what we know and do not know about ß-blockers and the heart», J Card Fail 6(suppl 1):34-39, 2000.33. Bristow MR. «Adrenergic receptor blockade in chronic heart failure», Circulation 101:558-569, 2000.34. 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», N Engl J Med 341:709-17, 1999.35. Juillerat L, Nussberger J, Menard J, Mooser V, Christen Y, Waeber B, Graf P, Brunner HR. «Determinats of angiotensin II generation during converting enzyme inhibition», Hypertension 16:564-572, 1998. 36. Kawamura M, Imanashi M, Matsushima Y, Ito K, Hiramori K. «Circulating angiotensin II levels under repeated administration of lisinopril in normal subjets», Clin Exp Pharmacol Physiol 19:547-553, 1992.37. Lee AFC, MacFadyen RJ, Struthers AD. «Neurohormonal reactivation inheart failure patients on chronic ACE inhibitor therapy: a longitudinal study», Eur J Heart Failure 1:401-406, 1999.38. Urata H, Healy B, Stewart RW, Bumpus FM, Husain A. «Angiotensin II-forming pathways in normal and failing hearts», Cir Res 60:883-890, 1990.39. Haywood GA, Gullestad L, Katsuya T, Hutchinson HG, Pratt RE, Horiuchi M, Fowler MB. «AT1 and AT2 angiotensin receptor gene expression in human failure», Circulation 95:1201-1206, 1997.40. Wolny A, Clozel JP, Rein J, Mory P, Vogt P, Turino M, Kiowski W, Fischli W. «Functional and biochemical analysis of angiotensin II-forming pathways in the human heart», Cir Res 80(2):219-27, 1997.41. Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ. «Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects», N Engl J of Med 339(18):1285-92, 1998.42. Hamroff G, Katz SD, Mancini D, Blaufarb I, Bijou R, Patel R, Jondeau G, Olivari MT, Thomas S, LeJemtel TH. «Addition of angiotensin II receptor blockade tomaximal angiotensin-converting enzyme inhibition improves exercise capacity in patients with severe congestive heart failure», Circulation 99:990-2, 1999. 43. Pitt B, Segal R, Martinez FA, Meuers G, Cowley AJ, Thomas I, Deadwania PC, Ney DE, Shavely DB, Lang PI, on behalf of ELITE Study Investigators. «Randomized trial of losartan versus captopril in patients over 65 with heart failure», Lancet 349:747-52, 1997.44. Houghton AR, Harrison M, Cowley AJ. «Haemodynamic, neurohumoral and exercise effects of losartan vs. captopril in chronic heart failure: results of an ELITE trial substudy», Eur J Heart Failure 1:385-393, 1999.45. McKelvie RS, Yusuf S, Pericak D, Avezum A, Burns RJ, Probstfield J, Tsuyuki RT, White M, Rouleau J, Latini R, Maggioni A, Young J, Pogue J. «Comparison of candesartan, enalapril, and their combination in congestive heart failure: Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) Pilot Study», Circulation 100:1056-1064, 1999.46. Greenberg BH. «Role of angiotensin receptor blockers in heart failure. Not yet RESOLVD», Circulation 100:1032-1034, 1999.47. Pitt B, Poole-Wilson PA, Segal R y col. «Effects of losartan versus captoptil on mortality in patients with symptomatic heart failure: rationale, design and baseline characteristics of patients in the Losartan Heart Failure Survival Study - ELITE II», J Card Fail 5:146-154, 1999.48. Cohn JN, Tognoni G, Glazer RD, Spormann D, Hester A. «Rationale and design of the valsartan heart failure trial: a large multinational trial to acces the effects of valsartan, and angiotensin-receptor blocker, on morbidity and mortality in chronic heart failure», J Card Fail 5:155-160, 1999.49. «Valsartan in Heart Failure (Val-HeFT)», 73rd Scientific Sessions of American Heart Association, New Orleans, EE.UU., Nov 15 de 2000.50. Swedberg K, Pfeffer M,Granger Ch, Held P, McMurray J, Ohlin G, Olafsson B, Östergren J, Yusuf S, for the CHARM-Programme Investigators. «Candesartan in heart failure-assessment of reduction in mortality and morbidity (CHARM): rationale and design», J Card Fail 5:276-282, 1999.
inhibidores de la enzima convertidora; c) pacientes con fracción de eyección mayor del 40% y no tratados con inhibidores de la enzima convertidora. El punto final primario de cada subgrupo es evaluar si el candesartán comparado con placebo reducirá el punto final de mortalidad u hospitalización cardiovascular en pacientes con insuficiencia cardíaca. En el año 2003 los resultados del CHARM nos reponderán si el candesartán es capaz de reducir la morbilidad y mortalidad cardiovascular en (1) pacientes con insuficiencia cardíaca que sean intolerantes a los inhibidores de la enzima convertidora, (2) en aquellos habitualmente tratados con inhibidores de la enzima convertidora y (3) en los pacientes con función sistólica conservada.La determinación acerca de si este modo de inhibición del sistema renina-angiotensina-aldosterona es comparable con, mejor que, peor que, o aditivo a un inhibidor de la enzima convertidora todavía no está resuelta. Si bien hay datos a favor de su seguridad y tolerancia, también se encuentran aquellos que señalan que los beneficios no serían tan significativos como los que surgen de los datos preliminares del Val-HeFT y del RESOLVD, por lo cual, hasta el momento, no hay evidencias concluyentes que sugieran que su uso sea equivalente o superior a los inhibidores de la enzima convertidora. Podríamos concluir que su aplicación clínica queda hoy recomendada para aquellos pacientes con demostrada intolerancia (tos intratable y angioedema) a los inhibidores de la enzima convertidora.ConclusiónLa Insuficiencia Cardíaca es una fascinante área de investigación y un importante problema de la salud pública. Los grandes ensayos clínicos aleatorizados y controlados representan hoy un método válido para determinar las estrategias de tratamiento de utilidad clínica y las que no lo son. Las evidencias surgidas de dichos estudios nos permiten formular normas para el tratamiento médico óptimo; de esta manera, contribuyen a la toma de decisiones terapéuticas durante la práctica diaria y constituyen además una fuente genuina de hipótesis para la investigación clínica. Debemos tener en cuenta que aun estudios algo más pequeños con drogas cuyo mecanismo de acción es conocido, y que se hallen dirigidos a modificar variables fisiopatológicas que han demostrado participar en la progresión de la insuficiencia cardíaca, nos permitirán también modificar el pobre pronóstico que aún hoy esta enfermedad implica. Es importante tener en cuenta que el mundo real de pacientes con insuficiencia cardíaca está conformado también por los pacientes «no seleccionados» en los grandes ensayos clínicos. Por lo tanto, un adecuado análisis de los diferentes subgrupos de pacientes tratados, con una correcta interpretación clínica-fisiopatológica de sus resultados y conclusiones se hace necesario hoy a la luz de la creciente polifarmacia para el tratamiento de la enfermedad.Bibliografía1. Cohn JN, Archibald DG, Ziesche S, et al. «Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration cooperative study (V-HeFT)», N Engl Med 314:1547-52, 1986.2. 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 316:1429-35, 1987.3. Cohn JN, Johnson G, Ziesche S, et al. «A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure», N Engl J Med 325:303-10, 1991.4. The SOLVD investigators. «Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure», N Engl J Med 325:293-302,1991.5. The SOLVD investigators. «Effect of enalapril on mortality and the development of heart failure in asyntomatic patients with reduced left ventricular ejection fraction», N Engl J Med 327:685-691, 1992.6. Carson P, Ziesche S, Johnson G, Cohn J, for the Vasodilator-Heart Failure Trial Study Group. «Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials», J Card Fail 5:178-187, 1999.7. Packer M, Poole-Wilson PA, Armstrong PW, Cleland JGF, Horowitz JD, Massie BM, Rydén L, Thygesen K, Uretsky BT, on behalf of the ATLAS Study Group. «Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure», Circulation 100:2312-2318, 1999.8. Nicklas JM, Cohn J, Pitt B. «What does ATLAS really tell us about "high" dose angiotensin-converting enzyme inhibition in heart failure», J Card Fail 6:165-168,2000.9. Jorde UP, Ennezat PV, Lisker J, Suryadevara V, Infeld J, Cukon S, Hammer A, Sonnenblick EH, Le Jemtel TH. «Maximally recommended doses of angiotensin. Converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure», Circulation 101:844-846,2000.10. Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, Jolly MK, on behalf of the PROVED Investigative Group. «Randomized study assesing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial», J Am Coll Cardiol 22:955-962, 1993.11. Packer M, Gheorghiade M, Young JB, et al. «Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors», N Engl J Med 329:1-7, 1993.12. The Digitalis Investigation Group. «The effect of digoxin on mortality and morbidity in patients with heart failure», N Engl J Med 336:525-533, 1997. 13. Cohn JN, Goldstein S, Greenberg BH, Lorell BH, Bourge RC, Jaski BE, Gottlieb SO, McGrew F, MeMets DL, White BG, for the Vesnarinone Trial Investigators. «Dose-dependent mortality increase from vesnarinone in severe heart failure: the Vesnarinone Trial results», N Engl J Med 339:1810-6, 1998.14. Soran O, Young LD, Holubkov R, Loftus S, Bourge R, Carson P, Jaski B, White BG, Feldman AM, for the VEST withdrawal substudy group. J Card Fail 5:195-200, 1999.15. Waagstein F, Hjalmarson A, Varnauskas E, Wallentin I. «Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy», Br Heart J 37:1022-36, 1975.16. Cohn JN, Levine B, Olivari MT, Garberg V, Lura D, Francis G, Simon AB, Rector T. «Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure», N Engl J Med 311:819-23, 1984.17. Geslin P, Le Boull A, Furber A, Dupuis JM, Bouhour JB, Lanfranchi J, Monassier JP, Ferrieres M, Tadei A, Allain P. «Plasma noradrenaline and the prognosis of chronic cardiac failure: a multicenter study», Arch Mal Coeur Vaiss 91:191-199, 1998.18. Swedberg K, Waagstein F, Hjalmarson A, Wallentin I. «Prolongation of survival in congestive cardiomyopathy by beta receptor blockade», Lancet 1:1374-1376, 1979.19. Bristow M. «Pathophysiologic and Pharmacologic Rationales for Clinical Management of Chronic Heart Failure with Beta-Blocking Agents», Am J Cardiol 71:12C-22C, 1993. 20. Waagstein F, Bristow M, Swedberg K, Camerini F, Fowler M, Silver M, Gilbert E, Johnson M, Goss F, Hjalmarson A, for the Metopolol in Dilated Cardiomyopathy Trial Study Group. «Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy», Lancet 342:1441-1446, 1993.21. Colucci WS, Packer M, Bristow MR, et al., for the U.S. Carvedilol Heart Failure Study Group. «Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure», Circulation 94:2800-2806, 1996.22. Packer M, Colucci WS, Sackner BJ, et al. «Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure: the Prospective Randomized Evaluation of Carvedilol in Symptoms and Exercise (PRECISE) trial», Circulation 94:2793-9, 1996.23. Bristow MR, Gilbert EM, Abraham WT, et al. For the MOCHA Investigators. «Carvedilol produces dose-related improvements in left ventricular funcion and survival in subjects with chronic heart failure», Circulation 94:2807-16, 1996.24. Packer Milton, Bristow Michael. For The U.S. Carvedilol Heart Failure Study Group. N Engl J Med 334:1349-1355, 1996.25. Australia-New Zealand Heart Failure Research Collaborative Group. «Effects of Carvedilol, a Vasodilator-ß-Blocker, in Patiens with Congestive Heart Failure Due to Ischemic Heart Disease», Circulation 92:212-218, 1995.26. CIBIS Investigators and Committees. «A randomized trial of beta-blockade in heart failure: the Cardiac Insufficiency Bisoprolol Study (CIBIS)», Circulation 90:1765-1773, 1994.27. CIBIS-II Investigators and Committees. «The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial», Lancet 353:9-13, 1999.28. MERIT-HF Study Group. «Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomised intervention trial in congestive heart failure (MERITH-HF)», Lancet 353:2001-07, 1999.29. The BEST Steering Committee. «Design of the Beta-Blocker Evaluation Survival Trial (BEST)», Am J Cardiol 75:1220-3, 1995.30. Witte K, Thackray S, Banerjee T, Lark AL, Cleland JGF. «Update of ELITE-II, BEST, CHAMP, and IMPRESS clinical trials in heart failure», Eur J Heart Failure 2:107-112, 2000.31. Bristow MR. Mechanistic and clinical rationales for using ß-blockers in heart failure», J Card Fail 6(suppl 1):8-14, 2000. 32. Feldman AM. «From clinical trials to clinical practice: what we know and do not know about ß-blockers and the heart», J Card Fail 6(suppl 1):34-39, 2000.33. Bristow MR. «Adrenergic receptor blockade in chronic heart failure», Circulation 101:558-569, 2000.34. 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», N Engl J Med 341:709-17, 1999.35. Juillerat L, Nussberger J, Menard J, Mooser V, Christen Y, Waeber B, Graf P, Brunner HR. «Determinats of angiotensin II generation during converting enzyme inhibition», Hypertension 16:564-572, 1998. 36. Kawamura M, Imanashi M, Matsushima Y, Ito K, Hiramori K. «Circulating angiotensin II levels under repeated administration of lisinopril in normal subjets», Clin Exp Pharmacol Physiol 19:547-553, 1992.37. Lee AFC, MacFadyen RJ, Struthers AD. «Neurohormonal reactivation inheart failure patients on chronic ACE inhibitor therapy: a longitudinal study», Eur J Heart Failure 1:401-406, 1999.38. Urata H, Healy B, Stewart RW, Bumpus FM, Husain A. «Angiotensin II-forming pathways in normal and failing hearts», Cir Res 60:883-890, 1990.39. Haywood GA, Gullestad L, Katsuya T, Hutchinson HG, Pratt RE, Horiuchi M, Fowler MB. «AT1 and AT2 angiotensin receptor gene expression in human failure», Circulation 95:1201-1206, 1997.40. Wolny A, Clozel JP, Rein J, Mory P, Vogt P, Turino M, Kiowski W, Fischli W. «Functional and biochemical analysis of angiotensin II-forming pathways in the human heart», Cir Res 80(2):219-27, 1997.41. Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ. «Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects», N Engl J of Med 339(18):1285-92, 1998.42. Hamroff G, Katz SD, Mancini D, Blaufarb I, Bijou R, Patel R, Jondeau G, Olivari MT, Thomas S, LeJemtel TH. «Addition of angiotensin II receptor blockade tomaximal angiotensin-converting enzyme inhibition improves exercise capacity in patients with severe congestive heart failure», Circulation 99:990-2, 1999. 43. Pitt B, Segal R, Martinez FA, Meuers G, Cowley AJ, Thomas I, Deadwania PC, Ney DE, Shavely DB, Lang PI, on behalf of ELITE Study Investigators. «Randomized trial of losartan versus captopril in patients over 65 with heart failure», Lancet 349:747-52, 1997.44. Houghton AR, Harrison M, Cowley AJ. «Haemodynamic, neurohumoral and exercise effects of losartan vs. captopril in chronic heart failure: results of an ELITE trial substudy», Eur J Heart Failure 1:385-393, 1999.45. McKelvie RS, Yusuf S, Pericak D, Avezum A, Burns RJ, Probstfield J, Tsuyuki RT, White M, Rouleau J, Latini R, Maggioni A, Young J, Pogue J. «Comparison of candesartan, enalapril, and their combination in congestive heart failure: Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) Pilot Study», Circulation 100:1056-1064, 1999.46. Greenberg BH. «Role of angiotensin receptor blockers in heart failure. Not yet RESOLVD», Circulation 100:1032-1034, 1999.47. Pitt B, Poole-Wilson PA, Segal R y col. «Effects of losartan versus captoptil on mortality in patients with symptomatic heart failure: rationale, design and baseline characteristics of patients in the Losartan Heart Failure Survival Study - ELITE II», J Card Fail 5:146-154, 1999.48. Cohn JN, Tognoni G, Glazer RD, Spormann D, Hester A. «Rationale and design of the valsartan heart failure trial: a large multinational trial to acces the effects of valsartan, and angiotensin-receptor blocker, on morbidity and mortality in chronic heart failure», J Card Fail 5:155-160, 1999.49. «Valsartan in Heart Failure (Val-HeFT)», 73rd Scientific Sessions of American Heart Association, New Orleans, EE.UU., Nov 15 de 2000.50. Swedberg K, Pfeffer M,Granger Ch, Held P, McMurray J, Ohlin G, Olafsson B, Östergren J, Yusuf S, for the CHARM-Programme Investigators. «Candesartan in heart failure-assessment of reduction in mortality and morbidity (CHARM): rationale and design», J Card Fail 5:276-282, 1999.
(RESOLV Pilot Study», Circulation 100:1056-1064, 1999.46. Greenberg BH. «Role of angiotensin receptor blockers in heart failure. Not yet RESOLVD», Circulation 100:1032-1034, 1999.47. Pitt B, Poole-Wilson PA, Segal R y col. «Effects of losartan versus captoptil on mortality in patients with symptomatic heart failure: rationale, design and baseline characteristics of patients in the Losartan Heart Failure Survival Study - ELITE II», J Card Fail 5:146-154, 1999.48. Cohn JN, Tognoni G, Glazer RD, Spormann D, Hester A. «Rationale and design of the valsartan heart failure trial: a large multinational trial to acces the effects of valsartan, and angiotensin-receptor blocker, on morbidity and mortality in chronic heart failure», J Card Fail 5:155-160, 1999.49. «Valsartan in Heart Failure (Val-HeFT)», 73rd Scientific Sessions of American Heart Association, New Orleans, EE.UU., Nov 15 de 2000.50. Swedberg K, Pfeffer M,Granger Ch, Held P, McMurray J, Ohlin G, Olafsson B, Östergren J, Yusuf S, for the CHARM-Programme Investigators. «Candesartan in heart failure-assessment of reduction in mortality and morbidity (CHARM): rationale and design», J Card Fail 5:276-282, 1999.

La respuesta correcta se infiere al leer atentamente el trabajo:

EL CONCEPTO CARDIO-NEURO-ENDOCRINO, PRINCIPIO DE GRANDES Y NUEVOS ENSAYOS EN INSUFICIENCIA CARDIACA

Programa SIIC  de Eduación Médica Contínua (PEMC-SIIC)