JACC Vol. 3, No.6 1521 June 1984:1521-30 REPORTS ON THERAPY Hemodynamic Effects of Vasodilators and Long-Term Response in Heart Failure JOSEPH A. FRANCIOSA, MD, FACC, W. BRUCE DUNKMAN, MD, FACC,* CHERYL L. LEDDY, MD* Philadelphia, Pennsylvania and Little Rock, Arkansas Hemodynamic responses to vasodilators are commonly ml/min per kg (p < 0.01), and exercise duration also assessed when starting long-term vasodilator treatment increased by 1.8 ± 3.5 minutes (p < 0.01). Changes in in patients with chronic left ventricular failure, although maximal oxygen uptake, however, did not correlate with the relation between short- and long-term responses is short-term changes in pulmonary wedge pressure (cor• not established. Thus, short- and long-term hemody• relation coefficient [r] = - 0.14), cardiac index (r = namic responses to placebo and vasodilators (isosorbide - 0.01) or systemic vascular resistance (r = - 0.20). dinitrate, minoxidil and enalapril or captopril) were Long-term hemodynamic changes also failed to correlate measured and long-term clinical efficacy was assessed with changes in exercise capacity. Baseline hemody• by changes in exercise capacity after 1 to 5 months of namics, cardiac dimensions and left ventricular ejection vasodilator administration (plus digitalis and diuretic fraction before vasodilator administration all failed to agents) in 46 patients with New York Heart Association correlate with baseline exercise capacity or with long• fun~tional class II to IV heart failure caused by cardio• term changes in exercise capacity. myopathy. There were no significant changes in hemo• Thus, hemodynamic measurements at initiation or dynamics or exercise capacity during placebo treatment. during follow-up of vasodilator therapy do not relate to After initial doses and during long-term administration long-term clinical efficacy assessed by exercise capacity of vasodilator drugs, hemodynamics were significantly in patients with chronic left ventricular failure. There• improved. After long-term vasodilator treatment, max• fore, the rationale for making invasive hemodynamic imal oxygen uptake during exercise increased by 2.9 ± measurements before initiating long-term vasodilator 5.7 ml/min per kg from a control value of 14.1 ± 5.6 therapy for heart failure is questioned. The widespread use of vasodilator agents in the management hemodynamic responses to initial doses of vasodilators are of congestive heart failure is based largely on the well doc• related to the long-term efficacy of these agents in patients umented hemodynamic efficacy of these agents (I ,2). Whereas with chronic congestive heart failure. Furthermore, hemo• hemodynamic measurements are of clear value in catego• dynamics and left ventricular function are usually assessed rizing the actions of specific drugs, there is no proof that at rest, but measurements at rest do not correlate with the functional capacity of patients with congestive heart failure (3-5). Whether pre-drug baseline measurements help pre• dict long-term responses to therapy is also unknown. Despite From the Cardiovascular Section, Veterans Administration Medical Center and The Hospital of the University of Pennsylvania, Philadelphia. these considerations, it has been suggested (6,7) that selec• Pennsylvania and the Cardiovascular Division. Veterans Administration tion and dose titration of vasodilators be based on acute Medical Center and University of Arkansas for Medical Sciences, Little hemodynamic responses to these drugs. Such an approach Rock, Arkansas. This study was supported in part by a grant from the Medical Research Service of the Veterans Administration. Washington. usually requires costly hospitalization of patients for the D.C. This paper was presented in part at the annual scientific sessions of performance of invasive hemodynamic studies to initiate the American College of Cardiology. New Orleans. Louisiana. March, long-term vasodilator therapy. The present study was de• 1983. Manuscript received August 29, 1983; revised manuscript received December 13, 1983, accepted December 21, 1983. signed to test the validity of this practice. We measured *Current address: Veterans Administration Medical Center, University hemodynamics before and after initial doses of vasodilator and Woodland Avenues, Philadelphia, Pennsylvania 19104. drugs, and examined the relation between these measure• Address for reprints: Joseph A. Franciosa, MD, Cardiovascular Di• vision, University of Arkansas for Medical Sciences, 4301 West Markham ments and the subsequent long-term effects of vasodilators Street, Mail Slot 532, Little Rock, Arkansas 72205. in patients with chronic left ventricular failure. © 1984 by the American College of Cardiology 0735-1097/84/$3.00 1522 FRANCIOSA ET AL. JACC Vol. 3, No.6 VASODILATORS IN HEART FAILURE June 1984:1521~30 the carbon dioxide rebreathing method, an indirect Fick Methods procedure previously validated by us in patients with heart Study patients. Studies were performed in 47 men with failure (8,9). congestive heart failure caused by ischemic heart disease or Exercise protocol. Control measurements of pressures, primary myocardial disease. Ischemic heart disease was di• heart rate and cardiac output at rest were obtained at 30 agnosed from a history of documented acute myocardial minute intervals until two successive determinations varied infarction or a demonstration of obstructive coronary artery by less than 10%. On completion of baseline measurements disease by coronary arteriography. Primary myocardial dis• at rest, patients performed upright bicycle exercise to symp• ease was diagnosed when no other cause of heart failure tomatic maximum (dyspnea or fatigue without any other was apparent. Patients with primary pulmonary disease, limiting cause) using a Monark bicycle ergometer. During primary valvular heart disease or acute myocardial infarction exercise, hemodynamic variables were monitored and ex• within the preceding 3 months were excluded. Patients whose pired gas was collected for on-line measurement of oxygen exercise ability was limited by angina pectoris or any cause consumption, carbon dioxide production and ventilatory ex• other than fatigue or dyspnea were also excluded. Patients change ratio using techniques described in a previous study were required to have symptoms of exertional dyspnea or (3,10). Exercise was begun at a work load of 150 kilopond• fatigue attributable to cardiac disease for at least 3 months meters (kpm) and increased by 150 kpm every 4 minutes while being treated with digitalis and diuretic drugs. Ad• until exhaustion. The ventilatory exchange ratio is used to ditional selection criteria required objective evidence of left indicate onset of lactate production and achievement of an• ventricular dysfunction manifested as one of the following: aerobic threshold (II). By these criteria all patients achieved left ventricular internal end-diastolic dimension greater than anaerobic threshold on all exercise tests as indicated by a 2.7 cm/m2 by echocardiography; cardiothoracic ratio greater significant increase in ventilatory exchange ratio. than 50% by chest X-ray film and left ventricular ejection Initiation of vasodilator drug therapy. On completion fraction less than 46% by radionuclide angiography. Patients of all baseline measurements, patients were continued in meeting these initial screening criteria gave written informed the study if pulmonary wedge pressure was greater than 15 consent; the consent form and study protocol were approved mm Hg at rest or greater than 20 mm Hg during exercise, by the local Human Studies Committees. or if cardiac index at rest was not more than 2.5 liters/min 2 Hemodynamic study. Consenting patients were then per m . Patients meeting these criteria were then given their brought to a special procedure room adjacent to the medical first dose of vasodilator drug or placebo being tested. Iso• intensive care unit for baseline hemodynamic and exercise sorbide dinitrate was administered as a 40 mg oral dose to evaluation. Vasodilator therapy was discontinued at least eight patients, minoxidil as a 20 mg oral dose to eight 72 hours before hemodynamic studies. Diuretic drugs were patients, captopril as a 25 mg oral dose to eight patients withheld on the day of study, but maintenance digoxin doses and enalapril, a new angiotensin-converting enzyme inhib• were administered. Right heart catheterization was per• itor (12), was administered as a 5 or 10 mg oral dose to formed using a triple lumen Swan-Ganz thermistor-equipped eight patients. lsosorbide dinitrate and minoxidil were ad• catheter, which was inserted percutaneously by way of an ministered in fixed doses, and hemodynamic measurements antecubital or femoral vein and positioned in the pulmonary at rest were repeated 90 minutes after giving isosorbide artery. Pressures were measured with a Bell and Howell dinitrate and 4 hour after the dose of minoxidil; these are transducer positioned at the mid-chest level with the patient times of approximate peak effect based on our previous supine, and were displayed on a multichannel direct writing experience with these agents (13,14). Captopril and ena• Hewlett-Packard recorder. Right atrial and pulmonary artery lapril doses were titrated over 24 hours until pulmonary phasic, mean and occluded pressures were recorded. Pul• wedge pressure decreased or cardiac index increased by monary wedge pressure was taken as occluded pulmonary 30%, or to a maximal dose of 150 mg of captopril and 20 artery pressure