Em pacientes com IC, a ocorrência de bloqueio do ramo esquerdo (BRE) ou de outro distúrbio da condução intraventricular associa-se à piora da função sistólica e da classe funcional, assim como a pior prognóstico125,126. Influência
semelhante foi observada em pacientes com marca-passo, com elevado percentual de estimulação ventricular direita127. Essa
influência negativa na função sistólica é causada pela dissincronia interventricular e intraventricular esquerda derivada da ativação tardia do ventrículo esquerdo, assim como por ativação septal mais precoce em relação à parede lateral do ventrículo esquerdo.
A metanálise (1634 pac), que incluiu o CONTAK-CD128,
InSync ICD129, MIRACLE130 e MUSTIC131, mostrou que a
ressincronização cardíaca associou-se à redução estatisticamente significante da mortalidade relacionada à progressão da IC e das hospitalizações entre 3-6 meses de seguimento.
No estudo CARE-HF132, 813 pacientes CFIII e IV, FE ≤ 35% e
QRS ≥ 120 ms foram randomizados para terapia farmacológica apenas ou terapia farmacológica associada à ressincronização cardíaca. Aqueles com duração de QRS < 150 ms deveriam apresentar evidências ecocardiográficas de dissincronia ventricular. O seguimento médio foi de 29,4 meses. No final do estudo, 202 pacientes (24,8%) haviam morrido. A mortalidade total no grupo ressincronizado foi de 20% versus 30% no grupo controle (p < 0,002). Além disso, o grupo ressincronizado obteve maior aumento na pressão arterial sistólica, maior incremento na FE, maior redução no diâmetro diastólico final de VE, maior redução na área de regurgitação mitral e maior redução nos níveis plasmáticos do peptídeo natriurético cerebral.
O estudo COMPANION133 avaliou o impacto da
ressincronização associada ou não ao desfibrilador automático na mortalidade e risco de hospitalização por qualquer causa (objetivo primário). Houve redução do risco de aproximadamente 20% para os grupos ressincronizador isolado ou associado ao desfibrilador. Em relação à mortalidade por qualquer causa, o grupo com ressincronizador mostrou redução na mortalidade com significância estatística marginal. O grupo com ressincronizador associado ao desfibrilador mostrou 36% de redução no risco de mortalidade (p = 0,004).
A necessidade de implante de marca-passo por bradicardia sintomática é comum em cardiopatas com disfunção ventricular grave. A estimulação biventricular mostrou-se superior à estimulação apenas de VD, produzindo redução do diâmetro diastólico e sistólico final de VE e aumento na FE.
A FA é comum em pacientes com IC avançada e muitos deles são candidatos à ressincronização cardíaca. Alguns estudos134-136 mostraram resultados similares em relação à
melhora sintomática e maior sobrevida nos subgrupos com FA ou ritmo sinusal.
Dois estudos137,138 avaliaram os efeitos da ressincronização
cardíaca em pacientes idosos. Em ambos, os pacientes idosos (≥ 70 ou ≥ 75 anos) apresentaram melhora da CF, da FE e da intensidade do remodelamento reverso, bem como da sobrevida, similar a dos subgrupos com idade inferior. Entretanto, vale a pena assinalar que o número de pacientes com mais de 80 anos foi extremamente limitado: apenas 39 pacientes com mais de 80 anos (15% dos pacientes)138.
Embora os dados disponíveis acerca da aplicabilidade da ressincronização cardíaca em idosos e nos muito idosos não sejam definitivos, eles sugerem que este grupo de
pacientes pode apresentar benefícios semelhantes aos do grupo dos mais jovens.
Indicações para ressincronizador cardíaco138
1. Pacientes com FE ≤ 35%, QRS ≤ 0,12 segundos e ritmo sinusal – O ressincronizador está indicado, associado ou não, para o tratamento da ICC em classe funcional III ou IV ambulatorial, associado à terapia farmacológica ótima (grau
de recomendação I, nível de evidência A).
2. Pacientes com FE ≤ 35%, QRS ≥ 0,12 segundos e ritmo de fibrilação atrial – O ressincronizador está indicado, associado ou não, para o tratamento da ICC em classe funcional III ou IV ambulatorial, associado à terapia farmacológica ótima (grau de
recomendação IIa, nível de evidência C).
3. Pacientes com FE ≤ 35% em classe funcional III ou IV ambulatorial que estão recebendo terapia farmacológica ótima e têm dependência de estimulação ventricular (grau
de recomendação IIa, nível de evidência C).
4. Pacientes com FE ≤ 35% em classe funcional III ou IV ambulatorial que estão recebendo terapia farmacológica ótima e que serão submetidos a implante de marca-passo definitivo ou desfibrilador implantável, cuja dependência de estimulação ventricular é previsível (grau de recomendação
IIb, nível de evidência C).
5. O ressincronizador cardíaco não está indicado em pacientes assintomáticos com redução da fração de ejeção na ausência de outra indicação de estimulação ventricular (grau
de recomendação III, nível de evidência C).
6. O ressincronizador cardíaco não está indicado em pacientes cujo estado funcional e expectativa de vida estão limitados por doença não cardíaca (grau de recomendação
III, nível de evidência C)
.
Referências
1. Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol. 1993; 22: 6A-13A.
2. Haney S, Sur D, Xu Z. Diastolic heart failure: a review and primary care perspective. J Am Board Fam Med. 2005; 18 (3): 189-98.
3. Paulus WJ, Tschöpe C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J. 2007; 28 (20): 2539-50. 4. Gottdiener JS, McClelland RL, Marshall R, Shemanski L, Furberg CD,
Kitzman DW, et al. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function: the Cardiovascular Health Study. Ann Intern Med. 2002; 137: 631-9.
5. Masoudi FA, Havranek EP, Smith G, Fish RH, Steiner JF, Ordin DL, et al. Gender, age, and heart failure with preserved left ventricular systolic function. J Am Col Cardiol. 2003; 41: 217-23.
6. Ministério da Saúde. DATASUS. Morbidade hospitalar do SUS. [Acesso em 2009 fev 20]. Disponível em http://www.datasus.gov.br.
7. Albanesi FFM. O que vem ocorrendo com a insuficiência cardíaca no Brasil. Arq Bras Cardiol. 2005; 85: 155-6.
8. Abraham WT, Fonarow GC, Albert NM, Stough WG, Gheorghiade M,
Greenberg BH, et al. on behalf of the OPTIMIZE-HF investigators and coordinators. Predictors of in-hospital mortality in patients hospitalized for heart failure. J Am Coll Cardiol. 2008; 52 (5): 347-56.
9. Weir RAP, Mcmurray JJV, Taylor J, Brady AJB. Heart failure in older patients. Br J Cardiol. 2006; 13 (4): 257-66.
10. Franklin SS, Gustin W, Wong ND, Larson MG, Weber MA, Kannel WB, et al. Hemodynamic patterns of age-related changes in blood pressure: the Framingham Heart Study. Circulation. 1997; 96: 308-15.
11. Abdelhafz AH. Heart failure in older people: causes, diagnosis and treatment. Age Ageing. 2002; 31: 29-36.
12. Gillespie ND. The diagnosis and management of chronic heart failure in older patient. Br Med Bull. 2006; 75/76: 49-62.
13. Rutten FH, Cramer MM, Grobbee DE, Sachs APE, Kirkels JH, Lammers JJ, et al. Unrecognized heart failure in elderly patients with stable chronic obstructive pulmonary disease. Eur Heart J. 2005; 26: 1887-94. 14. Senni M, Redfield MM. Congestive heart failure in elderly patients. Mayo
Clin Proc. 1997; 72: 453-60.
15. Serro-Azul JB, Savioli Neto F, Wajngarten M. Problemática do manuseio cardiológicodo indivíduo idoso. In: Pereira-Barretto AC, Sousa AGMR. Sociedade de Cardiologia do Estado de Säo Paulo. Cardiologia: atualizaçäo e reciclagem. São Paulo: Atheneu; 1994. p. 783-9.
16. Dayer M, Cowie MR. Heart failure: diagnosis and healthcare burden. Clin Med. 2004; 4: 13-8.
17. Batlouni M, Freitas EV, Savioli Neto F. Insuficiência cardíaca no idoso. In: Freitas EV, Doll J, Gorzoni ML. (eds.). Tratado de geriatria e gerontologia. 2ª ed. Rio de Janeiro: Guanabara Koogan; 2006. p. 480-98.
18. McKee PA, Castelli WP, McNamara P, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med. 1971; 285: 1441-6.
19. Harlan WR, Oberman A, Grimm R, Rosati RA. Chronic congestive heart failure in coronary artery disease: clinical criteria. Ann Intern Med. 1977; 86: 133-8.
20. Marantz PR, Tobin JN, Wassertheil-Smoller S, Steingart RM, Wexler JP, Budner N, et al. The relationship between left ventricular systolic function and congestive heart failure diagnosed by clinical criteria. Circulation. 1988; 77: 607-12.
21. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008; 29: 2388-442.
22. Davie AP, Francis CM, Love MP, Caruana L, Starkey IR, Shaw TRD, et al. Value of the electrocardiogram in identifying heart failure due to left ventri- cular systolic dysfunction. Br Med J. 1996; 312: 222-7.
23. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). Circulation. 2005; 112: 1825-52.
24. Sociedade Brasileira de Cardiologia. II Diretrizes para o diagnóstico e tratamento da insuficiência cardíaca. Arq Bras Cardiol. 2002; 79 (supl. 4): 1-30.
25. McCcullough PA, Nowak RM, McCord J, Hollander JE, Hermann HC,Steg PG, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation. 2002; 106: 416-22.
26. Wright SP, Doughty RN, Pearl A, Gamble GD, Whalley GA, Walsh HJ, et al. Plasma amino-terminal pro-brain natriuretic peptide and accuracy of heart failure diagnosis in primary care: a randomized, controlled trial. J Am CollCardiol. 2003; 42: 1793-800.
27. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005). Eur Heart J. 2005; 26: 1115-40. 28. Working Group on Cardiac Rehabilitation and Exercise Physiology and
Working group on Heart Failure of the European Society of Cardiology. Recommendations for exercise testing in chronic heart failure patients. Eur Heart J. 2001; 22: 37-45.
29. Batlouni M, Savioli Neto F, Magalhães HM. Alterações farmacocinéticas e farmacodinâmicas relacionadas à idade: terapêutica cardiovascular no idoso. In: Batlouni M, Ramires JAF. Farmacologia e terapêutica cardiovascular. São Paulo: Atheneu; 1999. p. 27-46.
30. Rich MW. Heart failure: epidemiology, pathophysiology and management. In: Wenger NK. Cardiovascular disease in the octogenarium and beyond. London: Martin Dunitz; 1999. p. 73-91.
31. Anderson GJ. Clinical clues to digitalis toxicity. Geriatrics. 1980; 35: 57-65. 32. Slatton ML, Irani WN, Hall AS, Marcoux LG, Page RL, Grayburn PA, et al.
Does digoxin provide additional hemodynamic and autonomic benefit at higher doses in patients with mild to moderate heart failure and normal sinus rhytm? J Am Coll Cardiol. 1997; 29: 1206-13.
33. Ewi GA, Kapadia CG, Yao L, Lullin M, Marcus FI. Digoxin metabolism in the elderly. Circulation. 1969; 39: 449-53.
34. Aronson JK. Clinical pharmacokinetics of digoxin. Clin Pharmacokinet. 1980; 5: 137-49.
35. Goldsmith S, Marx S. Update use of digitalis and nitrates in the elderly. Geriatrics. 1988; 43: 71-6.
36. Uretrsky BF, Young JB, Sahidi FE, Yellen LG, Harrison MC, Jolly MK. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. J Am Coll Cardiol. 1993; 22: 955-62.
37. Packer M, Gheorghiade M, Young JB, Constantini PJ, Adams KF, Cody RJ, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors (RADIANCE/ Study). N Engl J Med. 1993; 329: 1-7.
38. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitails Investigation Group. N Engl J Med. 1997; 336: 525-33. 39. The Xamoterol in Severe Heart Failure Study Group. Lancet. 1990; 336:
1-6.
40. Packer M, Carver JR, Rodeheffer RI, Ivanhoe RJ, DiBianco R, Zeldis SM, et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med. 1991; 325: 1468-75.
41. Hampton JR, Valdhuisen DJ, Kleber FX, Cowley AJ, Ardia A, Block P, et al. Randomized study of effects of ibopamine on survival in patients with advanced severe heart failure (PRIME II) investigators. Lancet. 1997; 349: 971-7.
42. Cohn JN, Goldenstein SO, Greenberg BH, Lorell BH, Bourge RC, Jaski BE, et al. A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. For the Vesnarinone Trial Investigators. N Eng J Med. 1998; 339: 1810-6.
43. Yussuf S, Teo K. Inotropic agents increase mortality in congestive heart failure. Circulation. 1990; (Suppl III): 673-6.
44. Wenger NK, Gregoratos G, Kitzman DW, Scheidt S, Weber MA, Alpert JS, Editorial Board Members of The American Journal of Geriatric Cardiology. Guidelines of the Cardiogeriatrics Department of the Brazilian Cardiology Society: commentary by Editorial Board Members of The American Journal of Geriatric Cardiology. Am J Geriatr Cardiol. 2004; 13 (4): 209-16. 45. Juurlink D, Mamdani M, Kopp A, Laupacis A, Redelmeier DA. Drug-drug
interactions among elderly patients hospitalized for drug toxicity. JAMA. 2003; 289: 1652.
46. Pitt B, Zannad F, Remme W, Cody R, Castaigne A, Perez A, et al. for the Randomized Aldactone Evaluation Study (RALES) investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999; 341: 709-17.
47. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker,in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309-21. 48. Schwartz S, Zipes DP. Doença cardiovascular em populações especiais.
In: Zipes DP, Libby P, Bonow R, Braunwand E. Tratado de doenças cardiovasculares. New York: Saunders; 2006. p. 1925-49.
49. Savioli Neto F, Borges JL, Araújo NNF. Insuficiência cardíaca no idoso: qual a diferença? In: Serrano Junior CV, Timerman A, Stefanini E. Tratado de cardiologia Socesp. Barueri: Manole; 2008. p. 2308-18.
50. Cody RJ. Characteristics of the elderly patient with congestive heart failure. Am J Geriatric Card. 1992; 68: 30-41.
51. Baruch L, Glazer RD , Aknay ET, Vanhaecke J, Heywood JT, Anand I, et al. Morbidity, mortality, physiological and functional parameters in elderly and non-elderly in Valsartan-Heft Trial. Am Heart J. 2004; 148: 951-7. 52. Shlipak M: Pharmacotherapy for heart failure in patients with renal
insufficiency. Ann Intern Med. 2003; 139: 917-24.
53. Wang T, Levy D, Benjamin E, Vasan R. The epidemiology of “ asymptomatic” left ventricular systolic dysfunction: implications for screening. Ann Intern Med. 2003; 138: 907.
54. Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, et al. Comparative effects of low and high doses of the angiotensin- converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation. 1999; 100 (23): 2312-8.
55. ACC/AHA Chronic Heart Failure Evaluation and Management guidelines: relevance to the geriatric practice. J Am Geriatr Soc. 2003; 51: 123-6. 56. Nohria A, Lewis E, Stevenson LW. Medical management of advanced heart
failure. JAMA. 2002; 287 (5): 628-40.
57. Opie LH, Poole-Wilson PA, Pfeffer MA. Angiotensin-converting enzyme inhibitors, angiotensin-II receptors blockers and aldosterone antagonists. In: Opie L. Drugs for the heart. 6th ed. New York: Saunders; 2006. p. 104-48. 58. Pfisterer M, Buser P, Rickli H, Gutmann M, Eme P, Rickenbacher P, et al. BNP-
guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME-CHF) randomized trial. JAMA. 2009; 301: 383-92.
59. Gandhi TK, Weingart SN, Borus J, Seger AC, Peterson J, Burdick E, et al. Adverse drug events in ambulatory care. N Engl J Med. 2003; 348:1556. 60. López-Sendón J, Sweldberg K, McMurray J, Tamargo J, Maggioni AP, Dargie
H, et al. Expert consensus document on angiotensin converting enzyme in cardiovascular disease. The task force on ACE-inhibitors of the European Society of Cardiology. Eur Heart J. 2004; 25: 1454-70.
61. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Køber L, Maggioni AP, et al. Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003; 349: 1893-906. 62. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, et al.
CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM- Alternative trial. Lancet. 2003; 362: 772-6.
63. Flather M, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G, et al. for the ACE-inhibitor Myocardial Infarction Collaborative Group. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. Lancet. 2000; 355: 1575.
64. Hall S, Cigarroa CG, Marxoux L, Risser RC, Grayburn PA, Eichhorn EJ. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with b-adrenergic blockade. J Am Coll Cardiol. 1995; 25: 1154-61.
65. Sabbah HN, Shimoyama H, Kono T, Gupta RC, Sharov VG, Scicli G, et al. Effects of long-term monotherapy with enalapril, metoprolol and digoxin on the progression of left ventricular dysfunction and dilation in dogs with reduced ejection fraction. Circulation. 1994; 89: 2852-9.
66. McDonald KM, Rector R, Carlyle PF, Francis GS, Cohn JN. Angiotensin- converting enzyme inhibition and beta-adrenoceptor blockade regress established ventricular remodeling in a canine model of discrete myocardial damage. J Am Coll Cardiol. 1994; 24: 1762-8.
67. Waagstein F, Bristow MR, Swedberg, Camerini F, Fowler MB, Silver MA, et al. for the Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet. 1993; 342: 1141-6.
68. Doughty RN, Mac-Mahon S, Sharpe N. Beta-blockers in heart failure: promising or proved? J Am Coll Cardiol. 1994; 23: 814-21.
69. Krum H, Sackner-Bernstein JD, Goldsmith RL, Kukin ML, Shwartz B, Penn J, et al. Double-blind, placebo controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation. 1995; 92: 1499-506.
70. Packer M, Collucci WS, Sackner-Bernstein JD, Liang CS, Goldscher DA, Freeman I, et al. for the PRECISE Study Group. Double-blind, placebo- controlled study of the effects of carvedilol in patients with moderate to severe heart failure: The PRECISE trial. Circulation. 1996; 94: 2793-9. 71. Colucci WS, Packer M, Bristow MR, Gilbert EM, Cohn JN, Fowler MB, et al.
for the US Carvedilol Study Group. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation. 1996; 94: 2800-6. 72. Lowes BD, Gill EA, Abraham WT, Larrain JR, Robertson AD, Bristow MR, et al.
Effects of carvedilol on left ventricular mass, chamber geometria, and mitral regurgitation in chronic heart failure. Am J Cardiol. 1999; 83: 1201-5. 73. Hjalmarson A, Kneider M, Waagstein E. The role of b-blockers in left
ventricular dysfunction and heart failure. Drugs. 1997; 54: 501-10. 74. Eichorn EJ, Bristow MR. Medical therapy can improve the biological
properties of chronically failure heart: a new era in the treatment of heart failure. Circulation. 1996; 94: 2285-96.
75. Bristow MR. Pathophysiologic and pharmacologic rationales for clinical management of chronic heart failure with beta-blocking agents. Am J Cardiol. 1993; 71: 12C-22C.
76. Bristow MR, Roden R, Lowes BD, Gilbert EM, Eichorn EJ. The role of third- generation beta-blocking agents in chronic heart failure. Clin Cardiol. 1988; 21(Suppl I): I3-I13.
77. Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Herswberger RE, et al. for the MOCHA Investigators. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation. 1996; 94: 2807-16.
78. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999; 353: 2001-7.
79. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study (CIBIS II): a randomized trial. Lancet. 1999; 353: 9-13.
80. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al. for the US Carvedilol Heart Failure Study Group. The effects of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996; 334; 1349-55.
81. Packer M, Coats AJS, FowlerMB, Katus HA, Krum H, Mohacsi P, et al. for the Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of Carvedilol in several chronic heart failure. N Engl J Med. 2001; 344: 1651-8. 82. Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko A, Borbola J, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005; 26: 215-25.
83. Packer M, Cohn JN, on behalf of the streering Committee and Membership of the Advisory Council to Improve Outcomes Natiowide in Heart Failure. Consensus Recommendations for the Mangement of Chronic Heart Failure. Am J Cardiol. 1999; 83: 1A-38A.
84. Eichorn EJ, Bristow MR. Practical guidelines for initiation of ß-adrenergic blockade in patients with cronic heart failure. Am J Cardiol. 1997; 79: 794-8.
85. Massie B, Chatterjee K, Werner J, Greenberg B, Hart R, Parmley WW. Haemodynamic advantage of combined administration of hydralazine orally and nitrates nonparenterally in the vasodilator therapy of chronic heart failure. Am J Cardiol. 1977; 40: 794-801.
86. Pierpont GL, Cohn JN, Franciosa JA. Combined oral hydralazine-nitrate therapy in left ventricular failure. Hemodynamic equivalent to sodium nitroprusside. Chest. 1978; 73: 8-13.
87. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromocyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989; 83: 1774-7. 88. Gogia H, Mehra A, Parikh S, Raman M, Ajit-Uppal J, Johnson JV, et
al. Prevention of tolerance to hemodynamic effects of nitrates with concomitant use of hydralazine in patients with chronic heart failure. J Am Coll Cardiol. 1995; 26: 1575-80.
89. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study – V-HeFT I Study. N Engl J Med. 1986; 314: 1547-52.
90. Cohn JN, Johnson G, Ziesche S, Cobbs F, Francis G, Tristani F, et al. A comparison of enalapril with hydralazine-isossorbide dinitrate in the treatment of chronic congestive heart failure – V-HeFT II Study. N Engl J Med. 1991; 325: 303-10.
91. Taylor AL, Ziesche S, Yancy C, Carson P, D’Agostino R Jr, Ferdinand K, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart