Mechanisms
of Action and Efficacy of Nitrates Heart Failure Jay N. Cohn,
Nitrates exert hemodynamic and possibly nonhemodynamic effects that result in reduced cardiic tilling pressures, iweased cardiac output, reduced pulmonary vascular pressures, and improvement in symptoms and exercise tolerance in patients with heart failure. Combined with hydralasine, chronic oral administratlon of isosorbide dir&ate has been demonstrated to improve survival when added to dioxin and diuretic therapy. A long-term improvement in left ventricular ejection fractlon in these clinical studii has raised the possibillty that the nitrates may be acting at least in part by inhibiting left ventricular remodelin$. The precise role of nitrates and the optimal dosing reghnen in the therapeutii armamentarium for heart failure, particularly in patii aheady treated with a converting enzyme inhlbitor, remains to be established. (Am J Cardiil1992;70:99B-92B)
From the Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota. Address for reprints: Jay N. Cohn, MD, Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Box 488 UMHC, 420 Delaware Street SE, Minneapolis, Minnesota 55455. 888
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
70
in
MD
T
he concept that chronic vasodilator therapy could have a favorable effect on the course of chronic congestive heart failure grew out of the observation that acute administration of a variety of vasodilator drugs results in a striking improvement in the function of the left ventricle. The earliest observations with intravenous infusion of nitroprusside and phentolamine demonstrated a striking reduction in the elevated left ventricular filling pressure and a marked augmentation in cardiac output and stroke volume in patients with severe heart fai1ure.l” These observations stimulated the use of oral vasodilator drugs to accomplish the same goal. Initial studies were conducted with the nitrates, which, when given sublingually, orally, or transdermally, resulted in a reduction in the elevated pulmonary capillary wedge pressure and a modest increase in cardiac output.4-6 Subsequently, it was demonstrated that arterial dilators, such as hydralazine and minoxidil,73s could produce an even greater augmentation of cardiac output and that agents that acted on both the arterial and venous circulation, such as hydralazine plus isosorbide dinitrate,9 prazosin,rO or the converting enzyme inhibitors,11J2 could produce a satisfactory hemodynamic response approaching that observed with sodium nitroprusside. At the time these early hemodynamic studies were being carried out, it was the somewhat naive view of the cardiologic community that heart failure was a hemodynamic disorder that could be reversed by drugs that corrected the hemodynamic disturbance. Consequently, the development of oral regimens for the management of heart failure was based on the simple view that a favorable hemodynamic effect would be translated into longterm clinical benefit. The last 15 years, therefore, have seen the development of a variety of vasodilator drugs designed to influence favorably the hemodynamic abnormality in heart failure with the hope that they would also augment exercise performance and relieve the symptoms of heart failure. A further goal of these trials has been an improvement in survival. SEPTEMBER
24, 1992
The nitrates have not been included in most of the trials carried out in recent years, not because they have been found to be ineffective in the syndrome, but because they are generic drugs without an adequate profit margin. The 2 studies that have utilized the nitrates in long-term trials of efficacy were the first and second VasodilatorHeart Failure Trials (V-HeFT I and V-HeFT II), which utilized hydralazine in combination with isosorbide dinitrate as vasodilator therapy. In other trials, nitrates have often been allowed as cotherapy because of the widespread use of these drugs either because of concomitant myocardial ischemia or because of the perception of the physician that nitrates are effective in the treatment of heart failure. Because of uncertainty about the appropriate dosage form of the nitrates and the frequency of their administration, the protocols for use of these agents have been quite variable. Consequently, the only controlled data available on the use of nitrates alone in the chronic management of heart failure come from early studies carried out in very small patient populations in which digitalis and diuretics served as background therapy and nitrates or placebo were given in the experimental design. The purpose of this contribution is to review the possible mechanisms of action of nitrates in the chronic management of heart failure and to review critically the clinical experience with these drugs in an effort to define a place for nitrates in the therapeutic regimen. MECHANISMS
OF ACTION
Nitrates are vasodilator drugs that exert a prominent effect on venous tone and increase capacitance of the venous system.13 This vascular action causes a pooling of blood and reduces the filling pressure of both the right and left ventricles. The pooling effect is, of course, augmented in the upright position and can result in syncope. The arterial effect of nitrates is considerably less prominent. Although an arteriolar dilating effect may occur in response to high doses administered intravascularly,14 systemic administration of nitrates generally does not result in much reduction of systemic vascular resistance. However, nitroglycerin can be demonstrated to have a relaxing effect on conductance arteries, resulting in an increase in arterial compliance and a reduction in reflected waves reaching the root of the aorta.15 This venous and arterial effect of nitrates suggests that the drugs have a preferential effect on the larger blood vessels and a lesser effect on the microcirculation.
In recent years it has become apparent that the pharmacologic action of nitrates is quite similar to that of endothelial-derived relaxing factor (EDRF), which is at least in part nitric oxide (N0).16 Indeed, the biosynthetic process leading to vascular action of administered organic nitrates involves the pralduction of N0.i7 There is some evidence that nitroglycerin’s effect might be enhanced in thie absence of functioning endothelium.18 This observation raises the possibility that nitrates might havle an even more prominent vascular action in patients with atherosclerosis, hypertension, and heart failure who appear to exhibit impaired endothelialderived relaxation. Another site of action that might contribute to the favorable effect of nitrates in heart failure is their effect on the coronary circulation. Nitratels appear to exert a prominent relaxing effect on the epicardial coronary arteries19 and also dilate the collateral circulation in subjects whose collateral vessels are functional because of coronary stenosis or occlusionzO The coronary arterial relaxing effect of nitrates can lead to a reduction in the severity of fixed stenoses in the coronary arteries and thus augment perfusion to ischemic myocardium.21 Further, the reduction in left ventricular filling pressure induced by the nitrates would be expected to improve subendocardial perfusion in the setting of coronary disease. 22 Thus, an improvement in myocardial perfusion may contribute to a favorable response to these drugs not only in patients with( coronary disease but in patients with heart failure: and elevated left ventricular filling pressures. The nitrates have also been demonstrated toi alter left ventricular compliance. Thus, the decrease in left ventricular filling pressure in response to these drugs may be only partly related to a reduction in ventricular volume resulting from the venodilator effect of the drugs and may be in part related to an alteration in the pressurevolume relation of the ventricle, allowing filling to occur at a lower filling pressure.23 Whether this action of nitrates relates to a direct effect on the myocardium or is via a change in extrinsic forces influencing left ventricular filling is not entirely clear. Actions of the nitrates on the pulmonary circulation may also play a role in the favorable effect of these drugs in heart failure. An increase in pulmonary vascular resistance is a common finding in patients with heart failure and right ventricular function appears to be an important predictor of exercise intolerance.24 Nitrates exert a relaxing effect on the pulmonary vasculature and have been A SYMPOSIUM:
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89B
utilized with some success in the management of pulmonary hypertension. 25 Since right ventricular function is not routinely evaluated in patients with heart failure, the role of nitrates in augmenting performance of the right ventricle has not been well established. A nonhemodynamic mechanism for nitrate efficacy also must be considered. Nitrates exert their effect through stimulation of cyclic guanosine 3’, 5’-monophosphate (cGMP).~~ Considerable data are accumulating to suggest that cGMP as well as other vasodilator mechanisms may have a direct action in inhibiting vascular smooth muscle growth.27 Recent studies from our laboratory have raised the possibility that nitrates can inhibit left ventricular hypertrophy and remodeling.28 Similar data have been reported in patients following acute myocardial infarction.2g It is uncertain how much of these vascular and myocardial inhibitory effects can be attributed to the hemodynamic response to nitrates and how much may be related directly to hormonal intermediaries. Nonetheless, the longterm efficacy of nitrates in heart failure could well be related to these inhibitory processes. EFFICACY OF NITRATES In the first trial of oral nitrate therapy for the treatment of chronic left ventricular failure, we administered isosorbide dinitrate as chronic oral therapy to a patient who had become dependent in the hospital on a nitroprusside infusion for maintenance of adequate peripheral perfusion.30 The patient maintained stability on oral isosorbide dinitrate and was able to leave the hospital with adequate circulatory function. A subsequent effort to withdraw him single-blind from nitrate therapy led to deterioration of left ventricular function and required reinstitution of the drug. This preliminary single-patient, single-blind, controlled observation led us to design a double-blind trial in patients with heart failure. Administration of isosorbide dinitrate in a dose of 40 mg 4 times daily was effective in improving exercise tolerance and in a borderline’reduction of morbid events in a small group of patients with severe congestive heart failure.3i Leier and colleagues32 carried out a larger study with chronic isosorbide dinitrate therapy and demonstrated a progressive improvement of exercise tolerance in the nitrate-treated group. The magnitude of the favorable effect of nitrates on exercise tolerance in these studies was modest at best and was observed at a time when investigators expected a far more dramatic improvement in response to a hemodynamically effective drug. 906
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Only in subsequent years has it become apparent that the magnitude of the hemodynamic effect of the drug bears little relation to its long-term effects on exercise tolerance. Further, exercise tolerance measured by a progressive test to peak capacity bears little relation to the severity of left ventricular dysfunction or to survival.33 Consequently, peak exercise capacity as the major endpoint for efficacy of a treatment for heart failure may be an inadequate guide. The V-HeFT trials utilized isosorbide dinitrate in combination with hydralazine, because the hemodyn.amic effects of the vasodilator combination were greater than the effects of either drug alone.9 In V-HeFT I, hydralazine and isosorbide dinitrate combination exerted a significant effect on survival compared with placebo or prazosin in patients receiving digoxin and diuretic for mild-to-moderate congestive heart failure.34 Peak oxygen consumption measured by gas exchange during a progressive bicycle ergometer test exhibited a slight improvement in the group randomized to hydralazine and isosorbide dinitrate compared with the group randomized to placebo or prazosin.35 Further, the nitrate-hydralazine combination produced a prominent increase in left ventricular ejection fraction that was not observed in the patients randomized to prazosin or placebo.34 These favorable effects of the vasodilator combination in heart failure led us to recommend that this vasodilator therapy should become part of the standard armamentarium for the treatment of heart failure.36y37 V-HeFT II was planned to compare the hydralazine-nitrate combination with the converting enzyme inhibitor, enalapril, which had been demonstrated in severe heart failure to prolong life.38 In this trial 804 patients treated with digoxin and diuretic were randomized into the 2 treatment arms to compare enalapril in a dose of 10 mg twice daily with hydralazine 75 mg and isosorbide dinitrate 40 mg administered 4 times daily.39 The evening and morning doses were scheduled so that patients had at least an 8-hour drug-free interval during the night. In this study enalapril exerted a significantly more favorable effect on survival than did hydralazine and isosorbide dinitrate, but the vasodilator combination exerted a greater effect on exercise capacity and on left ventricular function.39 These observations further support the concept that not all endpoints for clinical efficacy of drugs in heart failure are in concert. Long-term favorable effects on prognosis may relate to actions independent of the vascular effect of the drugs and may SEPTEMBER
24, 1992
relate to inhibition of vascular or myocardial growth, neuroendocrine effects, or metabolic effects that might result directly from the drugs being administered. Further, results from V-HeFT II raise the possibility that hydralazine and isosorbide dinitrate might effectively be added to a converting enzyme inhibitor in an attempt to further augment exercise performance, left ventricular function, and possibly survival. The role of the isosorbide dinitrate in the vasodilator drug combination cannot be clearly identified from these control trials. It is clear from previous studies that nitrates and hydralazine exert independent hemodynamic effects that are additive when the drugs are given in combination. Whether this additive effect on hemodynamics can be translated into an additive effect on the longterm course of the disease cannot be established. Nonetheless, since the drugs are well tolerated in combination and have been in use for many years for treatment of other cardiovascular disorders, use of the 2 drugs in combination would appear to be more prudent than withholding 1 of them because of the possibility that both are not needed in the vasodilator regimen. HEMODYNAMIC
TOLER&CE
A growing concern with chronic nitrate therapy is the development of hemodynamic tolerance. Continuous intravenous infusion of nitroglycerin and transdermal administration of nitroglycerin result in attenuation of the systemic hemodynamic effects.40,41 This hemodynamic tolerance appears to limit the efficacy of orally and transdermally administered nitrates for angina pectoris. Regimens with long drug-free intervals designed to, prevent tolerance have been advocated.42 In heart failure, however, chronic efficacy of isosorbide dinitrate has been demonstrated with a regimen in which the drug is given 4 times daily, usually with an g-hour interval at night without drug administration. The data would suggest that either the drugfree interval is adequate to prevent hemodynamic tolerance, or that the chronic efficacy of nitrates for heart failure is not dependent on persistence of full hemodynamic response. Another possibility is that drug interactions protect against the hemodynamic tolerance to repeated dosing of nitrates. In recent studies Bauer and Fung43 have demonstrated in a rat model that hydralazine coadministration prevents the development of nitroglycerin tolerance on left ventricular filling pressure. If this observation is pertinent in humans, it could help account for the long-term
efficacy of hydralazine and isosorbide combination in heart failure.34p39 FUTURE DIRECTIONS
dinitrate
FOR RESEARCH
Much remains to be learned about therapeutic responses in patients with heart failure. Some of the issues yet to be resolved include the following: What accounts for the temporal delay between a favorable hemodynamic effect of a drug and the favorable effects on exercise performance? Do the vascular effects of nitrates account for their favorable long-term effects in heart failure? Do nitrates alone improve left ventricular function chronically or is hydralazine necessary for this response? Is tolerance to long-term nitrate administration not a problem in heart failure, although it is in patients with angina? Does hydralazine coadministration with nitrates, protect against nitrate tolerance in patients with heart failure? Will nitrates augment the favorable hemody-, namic or clinical effects of other vasodilators or converting enzyme inhibitors in patients with heart: failure? Are nitrates specifically effective in patients with coronary disease or are they equally effective in patients with nonischemic cardiomyopathy? Does the degree of neurohormonal activation influence the response to nitrate therapy in heart failure? Can administration of nitrates in the early stages of left ventricular dysfunction prevent progression of the left ventricular dysfunction and inhibit the onset of heart failure? Need nitrate effect be maintained throughout the 24 hours or will a favorable effect be achieved with less frequent administration? What is the optimal dose of nitrates to achieve the best long-term response? The likelihood of obtaining answers to these and other unresolved issues is slim, because of the absence of research support for studies using generic forms of organic nitrates. Research with newer proprietary nitrate formulations (with patent protection) might partially correct this deficiency, but whether these newer preparations will exert actions similar to those observed with isosorbide dinitrate is not certain. Nonetheless, based on the data available, it appears that oral administration of isosorbide dinitrate exerts a favorable clinical effect in patients with heart failure and might appropriately be added to the regimen in patients with this disorder. A SYMPOSIUM:
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REFEriENCEs L Fr&ciosa JA, Guiha NH, Limas C-J, Rodriguera E, Cohn JN. Improved left ventricular function during nitroprusside infusion in acute myocardial infarction. Lmcet1972;i:650-654. 2. Majid PA, Sharma B, Taylor SH. Phentolamine for vasodiitor treatment of severe heart failure. Lane&1971;&720. 3. Guiha NH, Cohn JN, Mikulic E, Franc&a JA, Lii Cl. Treatment of refractory heart failure with infusion of nitroprusside. N EngJ .I Med l!X’4;291: 587-592.
4. Franciosa JA, Mikulic E, Cohn JN, Jose E, Fabie k Hemodynamic effects of orally administered isosorbide din&ate in patients with congestive heart failure. Circulation 1974;50:1020-1024. Is. Mikulic E, Franc&a JA, Cohn JN. Comparative hemodynamic effects of ctiewable isxorbide din&rate and nitroglycerin in patients with congestive @art failure. Circulation 1975;52:477-482. 6. Franciosa JA, Blank RC, Cohn JN. Nitrate effects on cardiac &put and left ventricular outtlow resistance in chronic conetive heart failure. Am J Med 1978@20-213. 7. Franc&a JA, Pierpont G, Cohn JN. Hemcdynamic iniprovement after oral hydralazine in left ventricular failure: a comparison with nitroprusside infusion in 16 patients. Ann Intern Med 1977;86:388-393, 8. Franciosa JA, Cohn JN. Effects of minoxidil on hemodynamics in patients with congestive heart failure. &u&ion 1981;63:652657: 9. Pierpont GL, Cohn JN, Franciosa Jk combined oral hyd+zine-nitrate therapy in left ventricular failure. Hemodynamic equivalency to sodium nitiprusside. Chest 1978;73%13. 10. Miier RR, Awan NA, Maxwell KS, Mason DT. Sust&ed reduction of cardiac impedance and preload in congestive heart failure with the antihprtensive vasodilator, prazosin N Erg1 JMed 1977;297:303. 11, Levine TR, Franci~a JA, G&n JN. Acute and long-term response to an oral converting-enzyme inhibitor, captopril, in congestive heart fai&te. C&z&ztion 1980;62:3541.
l2. Levine TB, Olivari MT, Garberg v, Sharkey SW, C&n JN. Hemodynamic and clinical response to enalapril, a long-acting converting-enzyme inhIbitor, in patients with congestive heart failure. Cti&tion 1984;69:5&-553. is. Honig CR’ Tenney SM, Gabel PV. Th$ mechanism of cardiovascular action of nitroglycerin.Am JMed 1960,29:910-923. ” 14. Opie LH. Nitrates. Lmcet198O;i:7%-753. l5.Yaginuma T, Avolio A, G’Rourke M, Nichols W, Morgan JJ, Roy P, Baron D, Branson J, Feneley M. Effect of glyceryl trinitrate on peripheral arteries alters left ventricular hydraulic load in man. Caniiovnc Res 1986;20:153160. l& Ignarro LJ. Biological actions and properties of endoth+imnderived nitric oxide‘ formed and released from artery and vein. Circ Res 1989;65:1-21. 17. Ignarro LJ, Lippton H, Edwards JC, saricos WH, Hyman AL, Kadowitz PJ, Gruetter CA, Mechanism of vascular smooth muscle relaxation by orgqic nitrates, nitrite, nitro@usside and nitric oxide: evid&% for the involvement of S-nitrosothiols as active intermediates. J phmmacol Eq i’her 1981;218:739-749. 18. Bassenge E, Heusch G. Endothelial and neutihumoral control of c&onary blood flow in health and disease. Rev PhysiolBio&m PhnrmacoZ1990;116: 77-165. 19. Feldman RC, Pepine c> Conti R. Magnitude of dilatation of large and small coronary arteries by nitroglycerbi. Cinxiuh’on 1981;64:32&332. 20. Brown BG, Bolson E, Peterson RB, Pierce CD, Dodge HT. The mtihanism of nitroglycerin action: stenosis vasodiiation as a major coinponent of the drug response. Circulation 1981;64:1@89. 21 Capurro NL, Kent KM, Epstein SE. Comparison of nitroglycerin-, nitroprusside-, and phentolamineinduced changes in coronary collateral functicin in dogs. J Clin Invest1977$Oz295-301. 22. SaIisbmy PF, Cross CE$ Rieban PA. Acute ischemia of inner layers of ventricular wall. Am Heart J 1963;66:650.
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23. Ludbrook PA, Byrne JD, Kurnik PB, M&night RC. Mluence of reduction of preload and afterload by nitroglycerin on left ventricular diastolic pressure-volume relations and relaxation in man. Ctiulatin 1977,56:937-943. 2A Baker BJ, WiIen MM, Boyd LM, Dink H, Franciosa JA. Relation of right ventricular ejection fraction to exercise capacity in chronic left ventricular faiIme.Ain J Cam%1 19&1,54:590-599. 2S.Pearl RG, Rosenthal MH, Schroeder JS, Ashton JPA. Acute hemodynamic effects of nitroglycerin in pulmonary hypertension. Ann In&m ied 1983;99%13. 26. Ahlner J, Axelsson Ki,. Nitrates: mode of action at a cellular level. Dmgx 1987;33(suppl4):32-38. 27. G‘arg VC, Hassid A. Nitric oxide-generating vasodiIators and &bromocy‘clic guanosine monophosphate inhibit nitrogen&s and proliferation of cultured rat v&scuIar smooth muscle cells. J CZin Invest 198%83:1774-1777. 28. McDonald KM, Francis GS, Matthews J, Hunter DW, Cohn JN. Oral nitrate therapy prevents early left ventricular mass increase following left ventricular daniage. (Abstr) Clin Rev 1991;393346A. 29. Jugdutt BI, Wamica JW. Intravenous nitroglycerin therapy to limit myccardial infarct size, expansion, and complications-effect of timing, dosage and infarct location. Circulanb 1988,78:906-919. 30. Cohn JN, Mathew KJ, Franciosa JA, Snow JA. Chronic vasodiiator therapy in the managemerit of cardiogenic shock and intractable left ventricular failure. Am Intern Med 1974;81:777-780. 3L Franciosa JA, Nordstroni LG Cohn JN. Nitrate therapy for congestive heart failure. JAMA 1978;240:443-4%. 32. Leier CV, Huss P, Magorien RD, Unverfertb DV. Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide din&ate therapy for congestive heart failme. Circulatio 1983,67:817-&Q. 33. Cohn JN, Rector TS. Prognosis of congestive heart failure and predictors of qortality. Am J Can&l 1988,62:25A-30A. 34. Cohn JN, Archibald DG, Ziesche S, Ftanciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Francis GS, FIohr KH, doldman S, Cobb FR, Shah PM, Saundixs R, Fletcher RD, Loeb HS., H&es VC, Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study (V-Hem. N EngZ JMed 1986,314: 1547-1552. 3S. Cohn JN, Archibald D, Johnson G, and VA Cooperative Study Group. Effects of vasodilator therapy on peak exercise oxygen consmnption in heart failure: V-Hem. &x&ion 1987;76(suppl IV):IV-443. 36. Cohn JN. Im&ations from the Veterans Administration Cooperative Study on vasodilator therapy of heart failure. Heari Fqilure 1986;2:151-15.5. 37. Cohn JN. C&r&t therapy of the fail@g heart. @c&don 1988;78:109!% 1107. 38. The CONSEtiSUS Trial Study Group. Effects of enalaprii on mortality in severe &gestive heart failure. N Engf J Med 1987;316:1~2%1435. 39. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkn&m WB, Lomb H, Wong M, Bhat G, Goldman S, Fletcher RD, Doherty J, Hughes CV, Carson P, Cintron G, Shabetai R, Haakenson C. A comparison of enalapril with hydralazine-isosorbide dmitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-310. 40. Abrams J. Tolerance to organic nitrates. Circularion 1986;74:1181-1185. 4L Elkayam V, Kulick D, McIntosh M, Roth A, Hsueh W, Rahimtoola SH. Incidence of early tdlerance to hemodynamic effects of continuous infusion of nitroglycerin in patients with coronaq artery disease and heart failure. C&&ztion 19873:577-584. 42. Rudolph W, Blasini R, Kraus F. Clinical efficacy of nitrates in the treatment of exertional angina pectoris. Hen 1982;7:286. 43. Bauer JA, Fung H-L. Concurrent hydralazine adminiitration prevents nitm glycerin-induced hemodynamic tolerance in eqerimental heart failure. Circu[at+m 1991;84:35-39.
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of Action and Efficacy of Nitrates Heart Failure Jay N. Cohn,
Nitrates exert hemodynamic and possibly nonhemodynamic effects that result in reduced cardiic tilling pressures, iweased cardiac output, reduced pulmonary vascular pressures, and improvement in symptoms and exercise tolerance in patients with heart failure. Combined with hydralasine, chronic oral administratlon of isosorbide dir&ate has been demonstrated to improve survival when added to dioxin and diuretic therapy. A long-term improvement in left ventricular ejection fractlon in these clinical studii has raised the possibillty that the nitrates may be acting at least in part by inhibiting left ventricular remodelin$. The precise role of nitrates and the optimal dosing reghnen in the therapeutii armamentarium for heart failure, particularly in patii aheady treated with a converting enzyme inhlbitor, remains to be established. (Am J Cardiil1992;70:99B-92B)
From the Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota. Address for reprints: Jay N. Cohn, MD, Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Box 488 UMHC, 420 Delaware Street SE, Minneapolis, Minnesota 55455. 888
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
70
in
MD
T
he concept that chronic vasodilator therapy could have a favorable effect on the course of chronic congestive heart failure grew out of the observation that acute administration of a variety of vasodilator drugs results in a striking improvement in the function of the left ventricle. The earliest observations with intravenous infusion of nitroprusside and phentolamine demonstrated a striking reduction in the elevated left ventricular filling pressure and a marked augmentation in cardiac output and stroke volume in patients with severe heart fai1ure.l” These observations stimulated the use of oral vasodilator drugs to accomplish the same goal. Initial studies were conducted with the nitrates, which, when given sublingually, orally, or transdermally, resulted in a reduction in the elevated pulmonary capillary wedge pressure and a modest increase in cardiac output.4-6 Subsequently, it was demonstrated that arterial dilators, such as hydralazine and minoxidil,73s could produce an even greater augmentation of cardiac output and that agents that acted on both the arterial and venous circulation, such as hydralazine plus isosorbide dinitrate,9 prazosin,rO or the converting enzyme inhibitors,11J2 could produce a satisfactory hemodynamic response approaching that observed with sodium nitroprusside. At the time these early hemodynamic studies were being carried out, it was the somewhat naive view of the cardiologic community that heart failure was a hemodynamic disorder that could be reversed by drugs that corrected the hemodynamic disturbance. Consequently, the development of oral regimens for the management of heart failure was based on the simple view that a favorable hemodynamic effect would be translated into longterm clinical benefit. The last 15 years, therefore, have seen the development of a variety of vasodilator drugs designed to influence favorably the hemodynamic abnormality in heart failure with the hope that they would also augment exercise performance and relieve the symptoms of heart failure. A further goal of these trials has been an improvement in survival. SEPTEMBER
24, 1992
The nitrates have not been included in most of the trials carried out in recent years, not because they have been found to be ineffective in the syndrome, but because they are generic drugs without an adequate profit margin. The 2 studies that have utilized the nitrates in long-term trials of efficacy were the first and second VasodilatorHeart Failure Trials (V-HeFT I and V-HeFT II), which utilized hydralazine in combination with isosorbide dinitrate as vasodilator therapy. In other trials, nitrates have often been allowed as cotherapy because of the widespread use of these drugs either because of concomitant myocardial ischemia or because of the perception of the physician that nitrates are effective in the treatment of heart failure. Because of uncertainty about the appropriate dosage form of the nitrates and the frequency of their administration, the protocols for use of these agents have been quite variable. Consequently, the only controlled data available on the use of nitrates alone in the chronic management of heart failure come from early studies carried out in very small patient populations in which digitalis and diuretics served as background therapy and nitrates or placebo were given in the experimental design. The purpose of this contribution is to review the possible mechanisms of action of nitrates in the chronic management of heart failure and to review critically the clinical experience with these drugs in an effort to define a place for nitrates in the therapeutic regimen. MECHANISMS
OF ACTION
Nitrates are vasodilator drugs that exert a prominent effect on venous tone and increase capacitance of the venous system.13 This vascular action causes a pooling of blood and reduces the filling pressure of both the right and left ventricles. The pooling effect is, of course, augmented in the upright position and can result in syncope. The arterial effect of nitrates is considerably less prominent. Although an arteriolar dilating effect may occur in response to high doses administered intravascularly,14 systemic administration of nitrates generally does not result in much reduction of systemic vascular resistance. However, nitroglycerin can be demonstrated to have a relaxing effect on conductance arteries, resulting in an increase in arterial compliance and a reduction in reflected waves reaching the root of the aorta.15 This venous and arterial effect of nitrates suggests that the drugs have a preferential effect on the larger blood vessels and a lesser effect on the microcirculation.
In recent years it has become apparent that the pharmacologic action of nitrates is quite similar to that of endothelial-derived relaxing factor (EDRF), which is at least in part nitric oxide (N0).16 Indeed, the biosynthetic process leading to vascular action of administered organic nitrates involves the pralduction of N0.i7 There is some evidence that nitroglycerin’s effect might be enhanced in thie absence of functioning endothelium.18 This observation raises the possibility that nitrates might havle an even more prominent vascular action in patients with atherosclerosis, hypertension, and heart failure who appear to exhibit impaired endothelialderived relaxation. Another site of action that might contribute to the favorable effect of nitrates in heart failure is their effect on the coronary circulation. Nitratels appear to exert a prominent relaxing effect on the epicardial coronary arteries19 and also dilate the collateral circulation in subjects whose collateral vessels are functional because of coronary stenosis or occlusionzO The coronary arterial relaxing effect of nitrates can lead to a reduction in the severity of fixed stenoses in the coronary arteries and thus augment perfusion to ischemic myocardium.21 Further, the reduction in left ventricular filling pressure induced by the nitrates would be expected to improve subendocardial perfusion in the setting of coronary disease. 22 Thus, an improvement in myocardial perfusion may contribute to a favorable response to these drugs not only in patients with( coronary disease but in patients with heart failure: and elevated left ventricular filling pressures. The nitrates have also been demonstrated toi alter left ventricular compliance. Thus, the decrease in left ventricular filling pressure in response to these drugs may be only partly related to a reduction in ventricular volume resulting from the venodilator effect of the drugs and may be in part related to an alteration in the pressurevolume relation of the ventricle, allowing filling to occur at a lower filling pressure.23 Whether this action of nitrates relates to a direct effect on the myocardium or is via a change in extrinsic forces influencing left ventricular filling is not entirely clear. Actions of the nitrates on the pulmonary circulation may also play a role in the favorable effect of these drugs in heart failure. An increase in pulmonary vascular resistance is a common finding in patients with heart failure and right ventricular function appears to be an important predictor of exercise intolerance.24 Nitrates exert a relaxing effect on the pulmonary vasculature and have been A SYMPOSIUM:
NITROGLYCERIN
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utilized with some success in the management of pulmonary hypertension. 25 Since right ventricular function is not routinely evaluated in patients with heart failure, the role of nitrates in augmenting performance of the right ventricle has not been well established. A nonhemodynamic mechanism for nitrate efficacy also must be considered. Nitrates exert their effect through stimulation of cyclic guanosine 3’, 5’-monophosphate (cGMP).~~ Considerable data are accumulating to suggest that cGMP as well as other vasodilator mechanisms may have a direct action in inhibiting vascular smooth muscle growth.27 Recent studies from our laboratory have raised the possibility that nitrates can inhibit left ventricular hypertrophy and remodeling.28 Similar data have been reported in patients following acute myocardial infarction.2g It is uncertain how much of these vascular and myocardial inhibitory effects can be attributed to the hemodynamic response to nitrates and how much may be related directly to hormonal intermediaries. Nonetheless, the longterm efficacy of nitrates in heart failure could well be related to these inhibitory processes. EFFICACY OF NITRATES In the first trial of oral nitrate therapy for the treatment of chronic left ventricular failure, we administered isosorbide dinitrate as chronic oral therapy to a patient who had become dependent in the hospital on a nitroprusside infusion for maintenance of adequate peripheral perfusion.30 The patient maintained stability on oral isosorbide dinitrate and was able to leave the hospital with adequate circulatory function. A subsequent effort to withdraw him single-blind from nitrate therapy led to deterioration of left ventricular function and required reinstitution of the drug. This preliminary single-patient, single-blind, controlled observation led us to design a double-blind trial in patients with heart failure. Administration of isosorbide dinitrate in a dose of 40 mg 4 times daily was effective in improving exercise tolerance and in a borderline’reduction of morbid events in a small group of patients with severe congestive heart failure.3i Leier and colleagues32 carried out a larger study with chronic isosorbide dinitrate therapy and demonstrated a progressive improvement of exercise tolerance in the nitrate-treated group. The magnitude of the favorable effect of nitrates on exercise tolerance in these studies was modest at best and was observed at a time when investigators expected a far more dramatic improvement in response to a hemodynamically effective drug. 906
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Only in subsequent years has it become apparent that the magnitude of the hemodynamic effect of the drug bears little relation to its long-term effects on exercise tolerance. Further, exercise tolerance measured by a progressive test to peak capacity bears little relation to the severity of left ventricular dysfunction or to survival.33 Consequently, peak exercise capacity as the major endpoint for efficacy of a treatment for heart failure may be an inadequate guide. The V-HeFT trials utilized isosorbide dinitrate in combination with hydralazine, because the hemodyn.amic effects of the vasodilator combination were greater than the effects of either drug alone.9 In V-HeFT I, hydralazine and isosorbide dinitrate combination exerted a significant effect on survival compared with placebo or prazosin in patients receiving digoxin and diuretic for mild-to-moderate congestive heart failure.34 Peak oxygen consumption measured by gas exchange during a progressive bicycle ergometer test exhibited a slight improvement in the group randomized to hydralazine and isosorbide dinitrate compared with the group randomized to placebo or prazosin.35 Further, the nitrate-hydralazine combination produced a prominent increase in left ventricular ejection fraction that was not observed in the patients randomized to prazosin or placebo.34 These favorable effects of the vasodilator combination in heart failure led us to recommend that this vasodilator therapy should become part of the standard armamentarium for the treatment of heart failure.36y37 V-HeFT II was planned to compare the hydralazine-nitrate combination with the converting enzyme inhibitor, enalapril, which had been demonstrated in severe heart failure to prolong life.38 In this trial 804 patients treated with digoxin and diuretic were randomized into the 2 treatment arms to compare enalapril in a dose of 10 mg twice daily with hydralazine 75 mg and isosorbide dinitrate 40 mg administered 4 times daily.39 The evening and morning doses were scheduled so that patients had at least an 8-hour drug-free interval during the night. In this study enalapril exerted a significantly more favorable effect on survival than did hydralazine and isosorbide dinitrate, but the vasodilator combination exerted a greater effect on exercise capacity and on left ventricular function.39 These observations further support the concept that not all endpoints for clinical efficacy of drugs in heart failure are in concert. Long-term favorable effects on prognosis may relate to actions independent of the vascular effect of the drugs and may SEPTEMBER
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relate to inhibition of vascular or myocardial growth, neuroendocrine effects, or metabolic effects that might result directly from the drugs being administered. Further, results from V-HeFT II raise the possibility that hydralazine and isosorbide dinitrate might effectively be added to a converting enzyme inhibitor in an attempt to further augment exercise performance, left ventricular function, and possibly survival. The role of the isosorbide dinitrate in the vasodilator drug combination cannot be clearly identified from these control trials. It is clear from previous studies that nitrates and hydralazine exert independent hemodynamic effects that are additive when the drugs are given in combination. Whether this additive effect on hemodynamics can be translated into an additive effect on the longterm course of the disease cannot be established. Nonetheless, since the drugs are well tolerated in combination and have been in use for many years for treatment of other cardiovascular disorders, use of the 2 drugs in combination would appear to be more prudent than withholding 1 of them because of the possibility that both are not needed in the vasodilator regimen. HEMODYNAMIC
TOLER&CE
A growing concern with chronic nitrate therapy is the development of hemodynamic tolerance. Continuous intravenous infusion of nitroglycerin and transdermal administration of nitroglycerin result in attenuation of the systemic hemodynamic effects.40,41 This hemodynamic tolerance appears to limit the efficacy of orally and transdermally administered nitrates for angina pectoris. Regimens with long drug-free intervals designed to, prevent tolerance have been advocated.42 In heart failure, however, chronic efficacy of isosorbide dinitrate has been demonstrated with a regimen in which the drug is given 4 times daily, usually with an g-hour interval at night without drug administration. The data would suggest that either the drugfree interval is adequate to prevent hemodynamic tolerance, or that the chronic efficacy of nitrates for heart failure is not dependent on persistence of full hemodynamic response. Another possibility is that drug interactions protect against the hemodynamic tolerance to repeated dosing of nitrates. In recent studies Bauer and Fung43 have demonstrated in a rat model that hydralazine coadministration prevents the development of nitroglycerin tolerance on left ventricular filling pressure. If this observation is pertinent in humans, it could help account for the long-term
efficacy of hydralazine and isosorbide combination in heart failure.34p39 FUTURE DIRECTIONS
dinitrate
FOR RESEARCH
Much remains to be learned about therapeutic responses in patients with heart failure. Some of the issues yet to be resolved include the following: What accounts for the temporal delay between a favorable hemodynamic effect of a drug and the favorable effects on exercise performance? Do the vascular effects of nitrates account for their favorable long-term effects in heart failure? Do nitrates alone improve left ventricular function chronically or is hydralazine necessary for this response? Is tolerance to long-term nitrate administration not a problem in heart failure, although it is in patients with angina? Does hydralazine coadministration with nitrates, protect against nitrate tolerance in patients with heart failure? Will nitrates augment the favorable hemody-, namic or clinical effects of other vasodilators or converting enzyme inhibitors in patients with heart: failure? Are nitrates specifically effective in patients with coronary disease or are they equally effective in patients with nonischemic cardiomyopathy? Does the degree of neurohormonal activation influence the response to nitrate therapy in heart failure? Can administration of nitrates in the early stages of left ventricular dysfunction prevent progression of the left ventricular dysfunction and inhibit the onset of heart failure? Need nitrate effect be maintained throughout the 24 hours or will a favorable effect be achieved with less frequent administration? What is the optimal dose of nitrates to achieve the best long-term response? The likelihood of obtaining answers to these and other unresolved issues is slim, because of the absence of research support for studies using generic forms of organic nitrates. Research with newer proprietary nitrate formulations (with patent protection) might partially correct this deficiency, but whether these newer preparations will exert actions similar to those observed with isosorbide dinitrate is not certain. Nonetheless, based on the data available, it appears that oral administration of isosorbide dinitrate exerts a favorable clinical effect in patients with heart failure and might appropriately be added to the regimen in patients with this disorder. A SYMPOSIUM:
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REFEriENCEs L Fr&ciosa JA, Guiha NH, Limas C-J, Rodriguera E, Cohn JN. Improved left ventricular function during nitroprusside infusion in acute myocardial infarction. Lmcet1972;i:650-654. 2. Majid PA, Sharma B, Taylor SH. Phentolamine for vasodiitor treatment of severe heart failure. Lane&1971;&720. 3. Guiha NH, Cohn JN, Mikulic E, Franc&a JA, Lii Cl. Treatment of refractory heart failure with infusion of nitroprusside. N EngJ .I Med l!X’4;291: 587-592.
4. Franciosa JA, Mikulic E, Cohn JN, Jose E, Fabie k Hemodynamic effects of orally administered isosorbide din&ate in patients with congestive heart failure. Circulation 1974;50:1020-1024. Is. Mikulic E, Franc&a JA, Cohn JN. Comparative hemodynamic effects of ctiewable isxorbide din&rate and nitroglycerin in patients with congestive @art failure. Circulation 1975;52:477-482. 6. Franciosa JA, Blank RC, Cohn JN. Nitrate effects on cardiac &put and left ventricular outtlow resistance in chronic conetive heart failure. Am J Med 1978@20-213. 7. Franc&a JA, Pierpont G, Cohn JN. Hemcdynamic iniprovement after oral hydralazine in left ventricular failure: a comparison with nitroprusside infusion in 16 patients. Ann Intern Med 1977;86:388-393, 8. Franciosa JA, Cohn JN. Effects of minoxidil on hemodynamics in patients with congestive heart failure. &u&ion 1981;63:652657: 9. Pierpont GL, Cohn JN, Franciosa Jk combined oral hyd+zine-nitrate therapy in left ventricular failure. Hemodynamic equivalency to sodium nitiprusside. Chest 1978;73%13. 10. Miier RR, Awan NA, Maxwell KS, Mason DT. Sust&ed reduction of cardiac impedance and preload in congestive heart failure with the antihprtensive vasodilator, prazosin N Erg1 JMed 1977;297:303. 11, Levine TR, Franci~a JA, G&n JN. Acute and long-term response to an oral converting-enzyme inhibitor, captopril, in congestive heart fai&te. C&z&ztion 1980;62:3541.
l2. Levine TB, Olivari MT, Garberg v, Sharkey SW, C&n JN. Hemodynamic and clinical response to enalapril, a long-acting converting-enzyme inhIbitor, in patients with congestive heart failure. Cti&tion 1984;69:5&-553. is. Honig CR’ Tenney SM, Gabel PV. Th$ mechanism of cardiovascular action of nitroglycerin.Am JMed 1960,29:910-923. ” 14. Opie LH. Nitrates. Lmcet198O;i:7%-753. l5.Yaginuma T, Avolio A, G’Rourke M, Nichols W, Morgan JJ, Roy P, Baron D, Branson J, Feneley M. Effect of glyceryl trinitrate on peripheral arteries alters left ventricular hydraulic load in man. Caniiovnc Res 1986;20:153160. l& Ignarro LJ. Biological actions and properties of endoth+imnderived nitric oxide‘ formed and released from artery and vein. Circ Res 1989;65:1-21. 17. Ignarro LJ, Lippton H, Edwards JC, saricos WH, Hyman AL, Kadowitz PJ, Gruetter CA, Mechanism of vascular smooth muscle relaxation by orgqic nitrates, nitrite, nitro@usside and nitric oxide: evid&% for the involvement of S-nitrosothiols as active intermediates. J phmmacol Eq i’her 1981;218:739-749. 18. Bassenge E, Heusch G. Endothelial and neutihumoral control of c&onary blood flow in health and disease. Rev PhysiolBio&m PhnrmacoZ1990;116: 77-165. 19. Feldman RC, Pepine c> Conti R. Magnitude of dilatation of large and small coronary arteries by nitroglycerbi. Cinxiuh’on 1981;64:32&332. 20. Brown BG, Bolson E, Peterson RB, Pierce CD, Dodge HT. The mtihanism of nitroglycerin action: stenosis vasodiiation as a major coinponent of the drug response. Circulation 1981;64:1@89. 21 Capurro NL, Kent KM, Epstein SE. Comparison of nitroglycerin-, nitroprusside-, and phentolamineinduced changes in coronary collateral functicin in dogs. J Clin Invest1977$Oz295-301. 22. SaIisbmy PF, Cross CE$ Rieban PA. Acute ischemia of inner layers of ventricular wall. Am Heart J 1963;66:650.
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23. Ludbrook PA, Byrne JD, Kurnik PB, M&night RC. Mluence of reduction of preload and afterload by nitroglycerin on left ventricular diastolic pressure-volume relations and relaxation in man. Ctiulatin 1977,56:937-943. 2A Baker BJ, WiIen MM, Boyd LM, Dink H, Franciosa JA. Relation of right ventricular ejection fraction to exercise capacity in chronic left ventricular faiIme.Ain J Cam%1 19&1,54:590-599. 2S.Pearl RG, Rosenthal MH, Schroeder JS, Ashton JPA. Acute hemodynamic effects of nitroglycerin in pulmonary hypertension. Ann In&m ied 1983;99%13. 26. Ahlner J, Axelsson Ki,. Nitrates: mode of action at a cellular level. Dmgx 1987;33(suppl4):32-38. 27. G‘arg VC, Hassid A. Nitric oxide-generating vasodiIators and &bromocy‘clic guanosine monophosphate inhibit nitrogen&s and proliferation of cultured rat v&scuIar smooth muscle cells. J CZin Invest 198%83:1774-1777. 28. McDonald KM, Francis GS, Matthews J, Hunter DW, Cohn JN. Oral nitrate therapy prevents early left ventricular mass increase following left ventricular daniage. (Abstr) Clin Rev 1991;393346A. 29. Jugdutt BI, Wamica JW. Intravenous nitroglycerin therapy to limit myccardial infarct size, expansion, and complications-effect of timing, dosage and infarct location. Circulanb 1988,78:906-919. 30. Cohn JN, Mathew KJ, Franciosa JA, Snow JA. Chronic vasodiiator therapy in the managemerit of cardiogenic shock and intractable left ventricular failure. Am Intern Med 1974;81:777-780. 3L Franciosa JA, Nordstroni LG Cohn JN. Nitrate therapy for congestive heart failure. JAMA 1978;240:443-4%. 32. Leier CV, Huss P, Magorien RD, Unverfertb DV. Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide din&ate therapy for congestive heart failme. Circulatio 1983,67:817-&Q. 33. Cohn JN, Rector TS. Prognosis of congestive heart failure and predictors of qortality. Am J Can&l 1988,62:25A-30A. 34. Cohn JN, Archibald DG, Ziesche S, Ftanciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Francis GS, FIohr KH, doldman S, Cobb FR, Shah PM, Saundixs R, Fletcher RD, Loeb HS., H&es VC, Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study (V-Hem. N EngZ JMed 1986,314: 1547-1552. 3S. Cohn JN, Archibald D, Johnson G, and VA Cooperative Study Group. Effects of vasodilator therapy on peak exercise oxygen consmnption in heart failure: V-Hem. &x&ion 1987;76(suppl IV):IV-443. 36. Cohn JN. Im&ations from the Veterans Administration Cooperative Study on vasodilator therapy of heart failure. Heari Fqilure 1986;2:151-15.5. 37. Cohn JN. C&r&t therapy of the fail@g heart. @c&don 1988;78:109!% 1107. 38. The CONSEtiSUS Trial Study Group. Effects of enalaprii on mortality in severe &gestive heart failure. N Engf J Med 1987;316:1~2%1435. 39. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkn&m WB, Lomb H, Wong M, Bhat G, Goldman S, Fletcher RD, Doherty J, Hughes CV, Carson P, Cintron G, Shabetai R, Haakenson C. A comparison of enalapril with hydralazine-isosorbide dmitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-310. 40. Abrams J. Tolerance to organic nitrates. Circularion 1986;74:1181-1185. 4L Elkayam V, Kulick D, McIntosh M, Roth A, Hsueh W, Rahimtoola SH. Incidence of early tdlerance to hemodynamic effects of continuous infusion of nitroglycerin in patients with coronaq artery disease and heart failure. C&&ztion 19873:577-584. 42. Rudolph W, Blasini R, Kraus F. Clinical efficacy of nitrates in the treatment of exertional angina pectoris. Hen 1982;7:286. 43. Bauer JA, Fung H-L. Concurrent hydralazine adminiitration prevents nitm glycerin-induced hemodynamic tolerance in eqerimental heart failure. Circu[at+m 1991;84:35-39.
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