Mohammad Z. Tahir ( Department of Cardiology, Al Hada Military Hospital, P.O. Box 1347 HHRC 698, Taif, Saudi Arabia. )
Annual mortality rate of congestive heart failure due to systolic dysfunction with conventional treatment ranges from 15-50% depending upon functional class. Since the use of vasodilators in the management of heart failure due to systolic dysfunction resulted in symptomatic improvement and increase in exercise tolerance, many vasodilators have been tried. Angiotensin converting enzyme inhibitors have shown promising results in decreasing mortality rate and sudden death. All ACE inhibitors are not showing similar results. This article will discuss the different trials done so far, their outcome and the choice of vasodilator in the management of congestive heart failure. Our basic concept about congestive heart failure has been of heart failure due to myocardial dysfunction with dilated left ventricle and depressed ejection fraction. Recently attention has been focused into the following classification: a) systolic dysfunction with depressed ejection fraction such as due to dilated caraiomyopatfly where treatment is digoxin, diuretics and vasodilators. This is the largest group and has mortality rate ranging from 15-50% per year depending upon functional class; b) 30-40% of cases with heart failure present with diastolic dysfunction with normal ejection fraction such as due to hypertrophic cardiomyopathy, restrictive cardiomyopathy, where caution is advised on the use of diuretics and vasodilators. Role of digoxin is controversial unless coexisting atrial fibrillation exists. Prognosis has not been studied in such groups but they do better than with systolic dysfunction1. In this article, attention is focused on heart failure with systolic dysfunction. In heart failure peripheral vasoconstriction causing increased preload and after-load results in peripheral congestion, progressive deterioration of LV function and premature death. Guiha et al in 1974 showed hemodynamic improvement by using nitroprusside which caused arterial and venous relaxation2. Prazosin, alpha adrenoreceptor antagonist a balanced vasodilator, produced similar hemodynamic effects according to some studies but some studies showed no benefit. It did not improve survival which was thought to be either due to tachyphylaxis or failure of the drug to have favourable effect on the course of heart failure3,4. Hydrallazine an arteriolar vasodilator has not shown any improvement in symptoms or exercise tolerance5. Isosorbide dinitrate predominent venous dilator did show reduction in symptoms and increase in exercise tolerance6. Massie et al in 1977 and Pierpont et al in 1978 showed beneficial results of combined administration of hydrallazine and isosorbide dinitrate7,8. So far attention was paid to see iniprovement in symptoms and exercise tolerance in these studies but effect on mortality by these vasodilators was not discussed. In 1985, Veterans Administration Cooperative Trial (V-HeFT I) was completed by using prazosin - balanced vasodilator, combination of isosorbide dinitrate (ISDN) and hydrallazine as balance vasodilator and placebo to see the effect on mortality. Prazosin did not differ from placebo. Mortality rate decreased by 38% after 1 year in hydrallazine ISDN group as compared to placebo, 25% after 2 years and 23% after 3 years. Jn placebo there was 4 year mortality rate of 54% due to sudden death and progressive deterioration of heart failure (Table I).
Failure of prazosin to show improvement in survival may be due to tachyphylaxis or lack of favourable effect on cause of heart failure9. It was known that ACE inhibitors decrease peripheral resistance by decreasing vasoconstriction caused by angiotensin II whereas other conventional vasodilators stimulate renin angiotensin system. Captopril, a balanced vasodilator showed improvement in symptoms and exercise tolerance10 but effect of ACE inhibitors on mortality was studied in consensus trial in NYFIAFC W failure patients. In this trial enalapril was tried which showed 6 months mortality rate of 29% as compared to 48% in placebo (40% reduction in mortality rate) and after 1 year 47% as compared to 63% in placebo (25% reduction in mortality). No effect on sudden cardiac death was observed11 (Table II).
Captopril digoxin MRG study showed no difference in survival over 6 months period in the three groups (captopril diuretic group, digoxin diuretic group, diuretic group). Majority of patients were in NYHAFC II. Captopril diuretics group showed increased exercise tolerance, decrease in ventricular arryrthmia but ejection fraction was not affected. Digoxin diuretics group showed increase in ejection fraction and ventricular arrythmia was increased by 4%12. Preffer et al demonstrated attenuation of progressive ventricular enlargement with eaptopril with decrease in left ventricular filling pressure and improvement in exercise tolerance after anterior wall myocardial infarction13. Though this study was done with captopril, it may hold true with any other ACE inhibitor. Giles et al compared captopril with lisinopril and found both to be equal in safety profile. Lisinopril increased ejection fraction, functional capacity and quality of life as compared to captopril14. Packer et al have demonstrated captopril to be less effective in heart failure patient with renal insufficiency as compared to lisinopril15. Cohn et al conducted V-HcFT II comparing enalapril with hydrallazine isosorbide dinitrate (ISDN) and found incidence of sudden death 17% in enalapril group and 46% in hydrallazine ISDN group. Decrease in sudden death was thought to be due to non-vasodilator mechanism (Table III).
Previously conducted consensus trial did not show decrease in sudden death. Mortality rate was lower in enalapril group than hydrallazine ISDN group in 3 years of follow-up but mortality rate after 4 years was similar in both groups which suggested that vasodilators delay death but do not prevent progression of the disease16. Recently published hydrallazine captopril trial in Nfl-IA FC III, IV heart failure patients by Fonarow et al in JACC showed significant decrease in mortality (19%) in captopril group as compared to hydrallazine ISDN group (49%). This reduced mortality in captopril group was due to decrease in sudden death. One year incidence of sudden death in captopril treated group was 5% as compared to 37% in hydrallazine ISDN group (Table IV).
These results are in marked contrast to V-HeFT II where incidence of sudden death was 37% and consensus showed no reduction in sudden death in enalapril group. ACE inhibitors influence sudden death by direct antagonism of neuroendocrine activation, antagonism of angiotensin II mediated progressive ventricular hypertrophy, prevention of aldosterone and diuretic induced hypokakmia, direct decrease of myocardial venous oxygen consumption by cardiac renin angiotensin system and restoration of baroreceptor activity. Significant reduction in incidence of sudden death in captopril seen in this study and not in V-HeFT II or consensus - may be due to prevention of nitrate tolerance by captopril nitrate interaction which is not present with other ACE inhibitors and this nitrate tolerance prevention may add benefit of nitrate to that of ACE inhibitors17. SAVE investigators found improved survival and reduction in morbidity and mortality due to major cardiovascular events from long term administration of captopril as compared to placebo in patients with asymptomatic LV dysfunction after myocardial infarction. No difference in incidence of sudden death was observed between the two groups. Risk reduction was 19 percent from mortality from all causes18. SOLVED investigators found 8% risk reduction in mortality from all causes as compared to placebo. No significant reduction in mortality was found from cardiovascular causes as compared to placebo19. From these trials it has become obvious that combination of hydrallazine ISDN have lower mortality than placebo9. ACE inhibitors have lower mortality than combination of hydrallazine ISDN16. This lower mortality in ACE inhibitors and not with conventional vasodilators, may be due to sympathetic stimulation of nervous system without alteration of angiotensin II mediated progressive ventricular enlargement, central autonomic changes and baroreflex abnormalities17. Among ACE inhibitors lower moitality has been observed in captopril vs placebo group than enalapril vs placebo group showing superiority of captopril over enalapril18,19. Reduction in sudden death was first documented in V-HeFT II in enalapril group - predominantly in NYHA FC I, and II heart failure patients. Present study of Fonarow et al has shown significant reduction in mortality in captopril ISDN group and this reduction in mortality was due to significant decrease in sudden death in NYHA FC III and IV patients. Till more trials are done to compare the mortality rate between other ACE inhibitors in combination with nitrates, it is not unwise to say that captopril is so far the vasodilator of choice. One should look for adverse reactions of hypotension, rising creatinine level, hyperkalemia if patient already on spironolactone. Increased incidence of renal failure has been seen and this may be due to factors which stimulate renin angiotensin system and cause renal function to be dependent upon angiotensin II. These factors are dehydration secondary to diuresis, heart failure by itself, hyponatremia and preexisting renal insufficiency.
1. Kessler, K.M. Heart failure with normal systolic function. Arch. Intern. Med., 1988;148:2109-11.
2. Guiha, N.H., Coh, J.N., Mikulic, E., Franciosa. 3.A. and Limas, C.J. Treatment of refractory heart failure with infusion of nitroprusside. N.Engl.J.Med., 1974;291:587-92.
3, Miller, R.P., Awan, N.A., Maxwell, K.S., and Mason, D.T. Sustained reduction ofcardiac impedance and preload in congestive heartfailure with theantihypertenaivevasodilator pracosin. N.Engl.J.Med., 1977;297:303-7.
4, Packer, M., Meller, 3., Gorlin, P.. and Herman, MV. Flemodynamic and clinical tachyphylaxis to prazosin-mediated aftcrload reduction in severe chronic congestive heart failure, circulation, 1979;59:531-9.
5. Franciosa, J.A., Weber, K.T., Levine, T.B. et al. Hydrsllazine in the long-term treatment of chronic heart failure: lack of difference from placebo. Am.Heart.J., 1982;104:587-94.
6. Franciosa, J.A., Nordstrom, LA. and cohn. iN. Nitrate therapy for congestive heart failure. JAMA., 1971;240:443-6.
7. Massie, B., Chattcrjcc, K., Werner, 3., Greenberg. B., Hart, P.. and Parmeley, W.W. Ilemodynamic advantage of combined administration of hydrallazine orally and nitrates non- parenterally in the vasodilator therapy of chronic heart failure. Am.J.Cardiol., 1977;40:794-601.
8. Pierpont, G.L., Cohn, iN. and Franciosa, 3k combined oral hydrallazine nitrate therapy in left ventricular failure; hemodynamic equivalency to sodium nitroprusside. Chest, 1978;73:8-13.
9. Cob, J.N., Archibald, D.G., Ziesche, S., etal. Effects ofvasodilator therapy on mortality in chronic congestive heart failure: results of Veterans Administration cooperative Study. N. Engl.J. Med., 1966;314:1547-52.
10. Captoprit Multicenter Research Group. A placebo-controlled trial of captopril in refractory chronic congestive heart failure. J.Am.Coll.Cardiol., 1983;2:755-63.
11. The consensus Trial Study Group. Effect of enalapril on mortality in aevere congestive heart failure: results of the Coperative North Scandinavian Enalapril aurvival study (Consensus). N.Engl.J.Med., 1987;316:1429-35.
12. The Captopril-Digoxin Multicenter Research Group. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. 3AMA., 1988;259:539-44.
13. I’fcffer, MA., Gervasio, LA., Doughlas, yE., Parisi, A.F. and Brannwald, E. Effects of captopril on progressive ventricular dilatation after anterior myocardial infarction. N.Engl.J.Med., 1986;319:80-6.
14. Gilea, T.D., Katz, P.., Sullivan, 3M., Wolfson, P., Haughland, M. et at Short and long acting angiotenain converting enzyme inhibitor: a randomized trial of lisinopril versus captopril in the treatmentofcongcstive heartfailure. 3. Am. CoIl. Cardiol., 1989;13:1240
15. Packer, M., Lee, W.H., Medina, N., Yushalt, Metal. Influenceofrenalfunctiononthe hemodynamic and clinical responses to long term captopril therapy in severe chronic heart failure. Ann. Intern. Med., 1986;104:147-54.
16. Coh, N.J., Johnson, G., Zieche, S., Cobb, F., Francis, G. et al. A comparison of enalapril with hydrallazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N.Engl.J.Med., 1991;325:303-10.
17. Fonarow, G.C., Follick, C.C., Stevenson, LW., Luu, M., Hamilton, MA. etal. Effects of directvasodilatation with hydrallazineversus angiotension convertingenzyme inhibition with csptopril on mortality in advanced heart failure: the Hy-c trial. J.Am.Coll.Cardiol., 1992; 19:842-50.
18. Preffer, M.A., Braunwald, E., Moye, L.A., Basta, L., Brown, E.J. et al Effectofcaptopril on mortality and morbidity in patients with leftventricular dysfunction after myocardial infarction, N.EnglJ.Med., 1992;327:669-77.
19. The SOLVED lnvcatigatora. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced leftventricular ejection fractions. N.Engl.J.Med., 1992;327:685-91.