Pharmacologic Therapy for

End-Stage Heart Disease Symposium Pharmacologic Therapy for Patients with Congestive Cardiomyopathy Richard A. Goldstein, M.D., and Desmond D. Levin, M.D. Treatment in congestive heartjailure is directed at improving cardiac output and decreasing preload and afterload without significantly increasing the oxygen requirements of the heart. This paper reviews the current approach to heart failure with inotropic and vasodilator drugs in patients with heartfailure. Texas Heart Instiute Journal 1987; 14:341-345) Key words: Cardiac output; cardiomyopathy, congestive; heart failure, congestive; inotropic agents; vasoconstrictor agents; vasodilator agents UNTIL THE 1970s, THERAPY of congestive heart failure consisted of digitalis for its inotropic effects and diuretics to reduce pulmonary and penpheral edema. In the 1970s, vasodilator drugs were used to treat heart failure by unloading the heart. Initially, this treatment was started very cautiously because of the fear that these drugs might lower arterial pressure by interfering with compensatory changes in vascular resistance that were necessary for maintenance of adequate perfusion. However, subsequent clinical studies have demonstrated that vasodilators improve cardiac performance, relieve pulmonary congestion, and reduce afterload while decreasing myocardial oxygen consumption. Recently there has been controversy on the use of inotropic drugs in the treatment of heart failure. One concern is the question of whether drugs that increase contractility might also accelerate death of the patient by increasing myocardial oxygen demand, and hence the work of the heart. In this article, recent developments in the medical treatment of congestive heart failure will be reviewed. Inotropic Drugs Digitalis Glycosides. Digitalis has been used by physicians for two hundred years, yet there is still concern about whether it has a significant beneficial effect in treating patients with congestive heart failure. A multicenter clinical trial sponsored by the National Institutes of Health is being planned to determine if digitalis significantly improves the functional status of the patient and his longevity. A new concem is the possibility that patients to whom digitalis is given following acute myocardial infarction are actually placed at higher risk of death. 1-3 The inotropic action of digitalis glycosides is due to inhibition of the Na-K ATPase pump. The consequent accumulation of extracellular sodium then stimulates the Na-Ca pump, which increases the availability ofcalcium to the contractile proteins. In clinical use in acute heart failure, From the Division of Cardiology, Departnent of Internal Medicine, School of Medicine, The University of Texas Health Science Center at Ho This paper has been adapted from a talk given at a symposium titled "Diagnosis and Treatment of End-Stage Heart Disease: Heart Transplantation and Assist Devices, 1987;' sponsored by the Texas Heart Institute and held February 5-7, 1987 at the Westin Galleria Hotel, Houston. Address for reprints: Richard A. Goldstein, M.D., Division of Cardiology, School of Medicine, Room 1.246, 6431 Fannin Street, Houston, JX 77030. Pharmacologic Therapy for Congestive Cardiomyopathy 341

digoxin increases cardiac output by 5-15%, without a predictable effect on either systemic vascular resistance or left-ventricular filling pressure.4 The onset of drug action does not occur for as long as two hours after administration, and, once administered, digoxin has a long half-life that precludes titration to achieve a particular clinical effect.5 Most cardiologists would agree that in the acute setting, digoxin's role is to treat supraventricular arrhythmias rather than to augment contractile function. In patients with chronic heart failure, the drug appears to be best suited for those with dilated hearts and an S3 gallop on examination.6-7 The duration of physical activity may not be significantly affected, although the National Institutes of Health SOLVD (Studies of Left Ventricular Dysfunction) trial undoubtedly will address this issue. While discussion of the side effects of digitalis glycosides is beyond the scope of this article, numerous reviews that detail its narrow therapeutic-to-toxic ratio5 are available to the interested reader. Inotropic Catecholamines. Inotropic catecholamines include epinephrine, norepineprine, isoproterenol, dopamine, and dobutamine. All of these agents increase contractility by stimulation of PI receptors in the heart; this stimulation then activates cyclic adenosine monophosphate (cyclic AMP) and facilitates release of calcium from the sarcoplasmic reticulum. Epinephrine and norepinephrine are the paradigms of drugs that have the capability of "whipping a dead heart." Both of these drugs increase myocardial contractility, heart rate, systemic vascular resistance, left-ventricular filling pressure, the frequency of supraventricular and ventricular arrhythmias, and infarct size.89 Similar effects are generally observed with dopamine in doses higher than 6,ug/kg/min. '0 These drugs will increase infarct size in experimental preparations. 11-13 Isoproterenol is the most arrhythmogenic of this group and can compromise arterial pressure because of its potent 12 effects.3 In contrast, low doses of dopamine (2-4,ug/kg/ min) or ofthe synthetic compound dobutamine can incease cardiac output with only a minimal effect on myocardial oxygen demand. 14-15 Dobutamine is the most cardioselective of the inotropic catecholamines. Clinical studies have demonstrated that the drug reduces both preload (left-ventricularfilling pressure) and afterload (systemic vascular resistance) with minimal anrhythmogenicity. The inotropic catecholamines have been used primarily in the setting of acute low cardiac output states. In hypotensive patients who have low systemic vascular resistances, the vasoconstrictive effects of norepinephrine and of high-dose dopamine may be useful adjuncts to therapy. Therapy for this group of patients is often complicated by other serious medical problems, such as sepsis, acute respiratory distress syndromes, and bleeding abnormalities that require monitoring of oxygen delivery and consumption in order to optimize treatment. Patients with acute cardiac failure caused by global or regional contractile abnormalities usually present with increased left ventricular filling pressure and systemic vascular resistance. Dobutamine is very effective in most of these patients. There has been recent interest in the use of intermittent infusions of dobutamine in patients with chronic heart failure;16'17 and this has been accompanied by speculation that the drug might have a conditioning effect directly upon the heart. Another possible explanation for dobutamine's observed benefit to patients in heart failure is that the temporary drug-induced improvement in left ventricular function might result in withdrawal of some of the adverse compensatory mechanisms (e.g., increased alpha adrenergic tone and salt and water retention). This phenomenon would be similar to the reduction in circulating toxins following dialysis that grants a brief respite to the kidney patient. Bipyridines. Amrinone is the first of a new group of inotropic drugs to be approved by the United States Food and Drug Administration. Initial reports about its mechanism of action and its potential side effects have been the subject of considerable debate in the literature. These controversies have stemmed in part from some confusion between results obtained with the intravenous form of the drug and those obtained with the oral form; this last was withdrawn voluntarily by the manufacturer because of frequent side effects (especially gastrointestinal distress and thrombocytopenia). Amrinone (5-amino-3,4'-bipyridine-6(lH)- one) is a bipyridine guanide that inhibits subfraction 3 phosphodiesterase and therefore increases cyclic AMP.23 It also directly increases uptake of extracellular calcium, which is the hallmark of all inotropic drugs. In patients, amrinone's effects on cardiac output, left-ventricular filling pressure, and systemic vascular resistance are similar to those of dobutamine.24 Amrinone has several 342 Pharmacologic Therapy for Congestive Cardiomyopathy Vol. 14, No. 4, December, 1987

potentially beneficial properties, including minimal chronotropic and arrhythmogenic effects, and the ability to reduce myocardial oxygen consumption in patients with ischemic cardiomyopathies; so it may be particularly useful in cases of coronary artery disease.2526 Elevation of liver enzymes has occurred after long-term administration of oral amrinone, but studies indicate this is not a problem in the short term.2' Unlike the oral form, intravenous amrinone appears to be very well tolerated. Reversible thrombocytopenia (platelet count <100,000/mm3) has been reported in approximately 2.4% of patients. If therapy is continued for more than 48 hours, daily platelet counts should be obtained and the dosage of the drug reduced if necessary. Well-designed clinical studies comparing intravenous amrinone to other available therapies should be performed before the drug can be recommended for heart failure in acute infarction. Vasodilator Therapy The normal physiologic role of the baroreceptors is to monitor and regulate the pressure-andvolume status of the circulation. When baroreceptors in the atria, ventricles, carotids, and aorta are stretched, afferent signals are transmitted via the glossopharyngeal and vagus nerves to the central nervous system, which then suppresses the output of vasoconstrictive hormones. In patients with congestive heart failure, however, these normal controls are disrupted, and there is a rise in the levels of renin, angiotensin, aldosterone, norepinephrine, and arginine vasopressin. These agents then increase aortic impedance and salt and water reabsorption. Although peripheral vasoconstriction is partly offset by release of local prostaglandins, a dangerous cycle develops, characterized by low cardiac output and elevated systemic vascular resistance, this last causing further decreases in cardiac output. Vasodilators for the therapy of heart failure can be classified according to their sites of action on the peripheral vascular bed. Drugs with venodilating properties reduce venous return to the heart, lower pulmonary and systemic venous pressures, and decrease intracardiac volume, resulting in relief of congestive symptoms. Vasodilators that cause arteriolar relaxation can improve left ventricular function by reducing the load, which in turn decreases impedance to left ventricular emptying and improves cardiac output. Vasodilators that have been used forheart failure include nitrates, nitroprusside, hydralazine, phentolamine, and the angiotensin-converting enzyme inhibitors captopril and enalapril. These drugs often can be given together, and/or in combination with the inotropic drugs, for synergistic effect. Nitroglycerin and Nitrate. Nitroglycerin and other organic nitrates relax the smooth vascular muscle of the venous capacitance bed and to a lesser extent the smooth muscle of the larger arteries of the systemic resistance bed. Whether administered sublingually, orally, or intravenously, nitrates have a rapid onset of action. Reductions in pulmonary capillary wedge pressure and in right atrial pressure are among the hemodynamic effects of nitrates. In addition, most patients display modest declines in systemic and pulmonary arterial pressure, and in pulmonary vascular resistance.27 Cardiac output after administration of nitrates may vary in accordance with leftventricular filling pressure: Patients with normal or low left-ventricular filling pressure tend to have decreased cardiac output, while patients with elevated left-ventricular filling pressure tend to have inreased cardiac output. Systemic vascular resistance can also vary with left-ventricular filling pressure, but usually does not. In addition, nitrates confer beneficial hemodynamic effects on patients with mitral and aortic insufficiency (since regurgitant volumes decrase when left-ventricular filling pressures derease).28 Sodium Nitroprusside. Sodium nitroprusside is a rapid and potent vasodilator that relaxes both arteriolar and venous smooth muscle. The hemodynamic effects of nitroprusside include a significant reduction of systemic vascular resistance, an increase in cardiac output, and a decrease in systemic and pulmonary venous pressure. Systemic and pulmonary arterial pressures tend to decrease, while heart rate is usually unchanged unless left-ventricular filling pressure is low, in which case reflex tachycardia might occur. 29-30 In addition to these actions of benefit to patients with heart failure, sodium nitroprusside can give relief to patients with acute mitral regurgitation and-in higher doses-to those undergoing hypertensive crises. Hydralazine. Hydralazine is an arterial vasodilator that acts directly to cause smooth-muscle relaxation, primarily of the precapillary resistance vessels.3' It has very litfle effect on the venous Pharmacologic Therapy for Congestive Cardiomyopathy 343

capacitance bed. Characteristic hemodynamic effects of hydralazine are an increase in cardiac output and a fall in systemic vascular resistance. Arterial pressure either remains unchanged or drops slightly.32 Reflex tachycardia occurs frequently in patients with normal cardiac dimensions, but only rarely in the presence of heart failure. Pulmonary vascular resistance decreases in most patients, although the magnitude of decrease is much smaller than with agents that predominantly affect venous capacitance. Hydralazine, in combination with nitrates, has been found useful for the long-term management of patients with chronic heart failure. It also produces substantial hemodynamic and clinical benefits in patients with chronic mitral and aortic insufficiency, conferring marked increases in forward stroke volume and in cardiac output, and a concomitant decrease in regurgitant volume.33 Phentolamine. Phentolamine is an alpha adrenergic blocking agent with a prominent directrelaxing effect on vascular smooth muscle. The drug has mild intrinsic beta adrenergic stimulating properties. The hemodynamic effects are similarto those of sodium nitroprusside. Arterial pressure, systemic vascular resistance, pulmonary capillary wedge pressure, right atrial pressure, and pulmonary arterial pressure are generally decreased, while cardiac output is increased. In contrast to sodium nitroprusside, phentolamine tends to increase the heart rate. The effects of phentolamine on left ventricular function are influenced by the initial level of left-ventricular filling pressure. In patients with high filling pressures, cardiac output increases and left-ventricular filling pressure decreases, whereas in the presence of normal-baseline left-ventricular filling pressures, cardiac output usually is unchanged or slightly increased, even though left-ventricular filling pressure decreases. Angiotensin-Converting Enzyme Inhibitors. Captopril and enalapril are vasodilators that work by blocking the conversion of angiotensin I to angiotensin II, thereby decreasing the levels of both angiotensin II and aldosterone, and reducing vasoconstriction and fluid retention. In patients with heart failure, cardiac output increases and is accompanied by a decrease in right atrial and pulmonary capillary wedge pressures. Mean arterial pressure, systemic vascular resistance, and pulmonary artery pressures usually decline, while heart rate and pulmonary vascular resistance do not change. Recent studies suggest that these drugs improve prognosis in patients with chronic heart failure. CONCLUSION The last ten years have seen a promising increase in the number of pharmacologic agents available for the tatment of congestive heart failure. One hopes that the decade yet to come will produce drugs capable of improving both the length and quality of life for patients suffering fiom this condition, a condition that at present may be described as "end stage," short of cardiac transplantation. REFERENCES 1. Chatterjee K, Parmley WW. The role of vasodilator therapy in heart failure. Prog Cardiovasc Dis 1977; 19:301-325. 2. Maroko PR, Kjekshus JK, Sobel BE, Watanabe T, Covell JW, Ross J, Jr., Braunwald E. Factors influencing infarct size following experimental coronary artery occlusion. Circulation 1971; 3:67-82. 3. Shell WE, Sobel BE. Deleterious effects of increased heart rate on infarct size in the conscious dog. Am J Cardiol 1973; 31:474-479. 4. Shell WE, Sobel BE. Protection of jeopardized ischemic myocardium by reduction of ventricular afterload. N Engl J Med 1974; 291:481-486. 5. Packer M, Medina N, Yushak M. Hemodynamic and clinical limitations of long-term inotropic therapy with amrinone in patients with severe chronic heart failure. Circulation 1984; 70:1038-1047. 6. Bigger JT, Weld FM, Rotinitzky LM, Ferrick KJ. Is digitalis treatment harmful in the year after acute myocardial infarction? Circulation 1981; 64(Suppl IV):83. 7. Moss AJ, Davis HT, Conrad DL, DeCamilla SJ, Odoroff CL. Digitalis-associated cardiac mortality after myocardial infarction? Circulation 1981; 64:1150-1156. 8. Mueller H, Ayres SM, Gregory JJ, et al. Hemodynamics, coronary blood flow and myocardial metabolism in coronary shock response to L-norepinephrine and isoproterenol. J Clin Invest 1970; 49:1885-1900. 9. Goldstein RA, Passamani ER, Roberts R. A comparison of digoxin and dobutamine in patients with acute infarction and cardiac failure. N Engl J Med 1980; 303:846-850. 10. Smith TW, Haber E. Digitalis. N Engl J Med 1973; 289:1010. 11. Dodek A, Kassebaum DG, Bristow JD. Pulmonary edema in coronary artery disease without cardiomegaly: Paradox of the stiff heart. N Engl J Med 1972; 286:1347-1350. 344 Pharmacologic Therapy for Congestive Cardiomyopathy Vol. 14, No. 4, December, 1987

12. Dougherty AH, Naccarelli GV, Gray EL, Hicks CH, Goldstein RA. Congestive heart failure with normal systolic function. Am J Cardiol 1984; 54:778-782. 13. Allwood MJ, Cobbold AF, Gingburg J. Peripheral vascular effects of noradrenaline, isopropyl noradrenaline and dopamine. Br Med Bull 1963; 19:132. 14. Gilman AC, Goodman LS, Gilman A (eds). The phamracological basis of therapeutics. New York, Macmillan, 1980; p.153. 15. Leier CV, Heban PT, Huss P. Comparative systemic and regional hemodynamic effects of dopamine and dobutamine in patients with cardiomyopathic heart failure. Circulation 1978; 58:466-475. 16. Goldberg LI. Dopamine: Clinical uses of an endogenous catecholamine. N Engl J Med 1974; 707-710. 17. Goldberg LI, Hsuh Y, Resenekov L. Newer catecholamines for treatment of heart failure and shock: An update on dopamine and a first look at dobutamine. Prog Cardiovasc Dis 1977; 19:327-340. 18. Leier CV, Huss P, Lewis RP, et al. Drug-induced conditioning in congestive heart failure. Circulation 1982; 65:1382-1387. 19. Applefeld MM, Newman KA, Grove WR, Sutton FJ, Roffman DS, Reed WP, Linberg SE. Intermittent, continuous outpatient dobutamine infusion in the management of congestive heart failure. Am J Cardiol 1983; 51:455458. 20. Goldstein RA. When to use amrinone for the failing heart. Cardio 1986; 3:55. 21. Goldstein RA. Clinical effects of intravenous amrinone in patients with congestive heart failure. Circulation; (Suppl III): 191-194. 22. Franciosa JA. Effectiveness of long-term vasodilator administration in the treatment of chronic left ventricular failure. Prog Cardiovasc Dis 1982; 14:319-330. 23. Alousi AA, Farah AE, Lesher GY, Opalka CJ. Cardiotonic activity of amrinone. Circ Res 1979; 45:666-667. 24. Klein NA, Siskind SJ, Frishman WH. Hemodynamic comparison of intravenous amrinone and dobutamine in patients with congestive heart failure. Am J Cardiol 1981; 48:170-175. 25. Benotti JR, Grossman W, Braunwald E. Carabello BA. Effects of amrinone on myocardial energy metabolism and hemodynamics in patients with severe congestive heart failure due to coronary artery disease. Circulation 1980; 62:28-34. 26. Naccarelli GV, Gray EL, Dougherty AH, Hanna JE, Goldstein RA. Amrinone: Acute electrophysiologic and hemodynamic effects in patients with congestive heart failure. Am J Cardiol 1984; 54:600. 27. Chatterjee K, et al. Long-term outpatient vasodilator therapy of chronic congestive heart failure. Am J Med 1978; 65:134-144. 28. Sniderman, et al. Response of the LV to nitroglycerin in patients with and without mitral regurgitation. Br Heart J 1978; 36:357-359. 29. Chatterjee K, Ports TA, Parmley WW. Nitroprusside: Its clinical pharmacology and application in acute heart failure, in Gould and Reddy (eds) Vasodilator Therapy for Cardiac Disorders. New York, Future Publishing 1979. 30. FranciosaJA, Guiha NH, Limas CJ, etal. Improved left ventricular function during nitroprusside infusion in acute myocardial infarction. Lancet 1972; 1:640-647. 31. Fries ED, Rose JC, Higgins TF, et al. The hemodynamic effects of hypotensive drugs in man: (Part IV) I -hydrazinopthalazine. Circulation 1953; 8:199-204. 32. Chatterjee K, Ports T, Brundage B, et al. Oral hydralazine in chronic heart failure: Sustained beneficial hemodynamic effects. Ann Intern Med 1980; 92:600-604. 33. Greenberg BH, Massie BM. Beneficial effects of afterload reduction therapy in patients with congestive heart failure and moderate aortic stenosis. Circulation 1981; 62:1212-1216. Pharmacologic Therapy for Congestive Cardiomyopathy 345