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(Circulation. 1997;96:1165-1172.)
© 1997 American Heart Association, Inc.

Articles

Sustained Hemodynamic Efficacy of Therapy Tailored to Reduce Filling Pressures in Survivors With Advanced Heart Failure

Anthony E. Steimle, MD; Lynne Warner Stevenson, MD; Catherine Chelimsky-Fallick, MD; Gregg C. Fonarow, MD; Michele A. Hamilton, MD; Jaime D. Moriguchi, MD; Alex Kartashov, PhD; ; Jan H. Tillisch, MD

From the Ahmanson-UCLA Cardiomyopathy Center, UCLA School of Medicine, Los Angeles, Calif, and the Cardiovascular Division, Brigham and Women's Hospital, Boston, Mass (L.W.S., A.S.).

Correspondence to Lynne Warner Stevenson, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.

	Abstract

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Background During therapy to relieve congestion in advanced heart failure, cardiac filling pressures can frequently be reduced to near-normal levels with improved cardiac output. It is not known whether the early hemodynamic improvement and drug response can be maintained long term.

Methods and Results After referral for cardiac transplantation with initially severe hemodynamic decompensation, 25 patients survived without transplantation to undergo hemodynamic reassessment after 8±6 months of treatment tailored to early hemodynamic response. Initial changes included net diuresis, increased ACE inhibitor doses, and frequent addition of nitrates. After 8 months of therapy, early reductions were sustained for pulmonary wedge pressure (24±9 to 15±5 mm Hg early; 12±6 mm Hg late) and systemic vascular resistance (1651±369 to 1207±281 dynes·s^-1·cm^-5 early; 1003±193 dynes·s^-1·cm^-5 late). Acute response to doses persisted at reevaluation. Sustained reduction in filling pressures was accompanied by a progressive increase in stroke volume (42±10 to 56±13 mL early; 79±20 mL late), improved functional class, and freedom from resting symptoms. Study design did not control for amiodarone, which was initiated for arrhythmias in 12 patients and associated with greater improvement in cardiac index (1.8 to 3.2 L·min^-1·m^-2 late on amiodarone versus 2.0 to 2.6 L·min^-1·m^-2, P<.05).

Conclusions During chronic therapy tailored to early hemodynamic response in advanced heart failure, acute vasodilator response persists, and near-normal filling pressures can be maintained in patients who survive without transplantation. Stroke volumes at low filling pressures increase further over time. Chronic hemodynamic improvement was accompanied by symptomatic improvement, but the contributions of the monitored hemodynamic approach, increased vasodilator doses, and comprehensive outpatient management have not yet been established.

Key Words: heart failure • cardiomyopathy • diuretics • hemodynamics • vasodilation

	Introduction

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Patients referred for cardiac transplantation with dyspnea at rest or with minimal activity often have severely elevated filling pressures and systemic vascular resistance at rest despite treatment with diuretics, digoxin, and ACE inhibitors before referral. Intensive therapy designed to achieve lower ventricular filling pressures and relieve congestive symptoms has at times been limited by concerns that cardiac output may become further compromised and that the hemodynamic responses seen early during adjustment of medications may not be able to be maintained.^{1 2}

Short-term studies of severe dilated heart failure demonstrated increases in stroke volume when ventricular filling pressures were reduced to near-normal levels, largely because of the concomitant decrease in mitral regurgitation^{3 4 5} as described initially by Guiha et al⁶ during nitroprusside therapy. Although many factors could subsequently lead to actual improvements in myocardial performance because of reduced filling pressures,^{7 8 9 10} the ability to maintain adequate cardiac output with near-normal filling pressures after previous chronic decompensation has not been established. In addition, it has not been determined whether a drug regimen of current vasodilators designed for early response causes the same hemodynamic response after chronic therapy.

It has been demonstrated elsewhere that patients referred with heart failure presumed refractory often improve with therapy that includes higher vasodilator and diuretic doses and frequent contact with a dedicated team, including nurse specialists.^{11 12} The impact of specialized care varies, depending on the referral population, and this study was not designed to predict how often improvement occurs or to identify which elements of coordinated care are most critical to improvement. The hypotheses of this study are that among patients who are identified at the time of discharge after tailored therapy, those who survive without transplantation will demonstrate the chronic maintenance of initial reduction of filling pressures to near-normal levels without compromise of cardiac output and persistence of the hemodynamic response to the regimen designed during hemodynamic monitoring.

	Methods

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Study Population
Patients were eligible for reassessment of hemodynamics on chronic oral vasodilator therapy if the following criteria were met: (1) presentation for consideration of transplantation with New York Heart Association class III or IV symptoms between January 1992 and February 1993; (2) initial cardiac index 2.2 L·min^-1·m^-2; and (3) discharge with plans for subsequent follow-up primarily at UCLA (Los Angeles, Calif). Patients were identified prospectively at the time of initial discharge.

Design of Tailored Therapy
Potential candidates with evidence of hemodynamic decompensation were hospitalized for transplant evaluation, during which time they underwent pulmonary artery catheterization. Previous vasodilators were continued until catheterization. Patients with obvious total body volume overload usually underwent considerable diuresis before catheterization. Patients with a cardiac index 2.2 L·min^-1·m^-2 were treated initially with intravenous nitroprusside and diuretics titrated to approach the hemodynamic goals of pulmonary wedge pressure 15 mm Hg, right atrial pressure 8 mm Hg, and systemic vascular resistance of 1000 to 1200 dynes·s·cm^-5, while systolic blood pressure 80 mm Hg was maintained as previously described.¹ After these goals were reached or 48 hours had elapsed, patients were started on captopril four times daily in combination with isosorbide dinitrate three times daily to maintain optimal hemodynamics while the patients were weaned from nitroprusside. Patients who did not match optimal ventricular filling pressures or systemic vascular resistance on the tolerated regimen of captopril and nitrates were also treated with hydralazine. One patient unable to tolerate ACE inhibitors because of hypotension received hydralazine and isosorbide dinitrate and later tolerated enalapril. Patients received extensive education regarding diet and medications and were taught flexible diuretic regimens with guidelines based on daily home weights for adjustment of their loop diuretic doses and/or addition of intermittent metolazone to remain within 2 lb of discharge weight. All patients were evaluated by Electrophysiology Service personnel, who initiated amiodarone in 12 patients, 8 for ventricular arrhythmias or syncope and 4 for atrial fibrillation. Digoxin therapy was continued unless there were specific contraindications.

Hemodynamic Assessment
Right atrial, pulmonary artery, and pulmonary wedge pressures were measured at end-expiration with a balloon-tipped catheter. Thermodilution cardiac output determinations were performed with iced injectate until three readings agreed within 10%. The baseline values for this study were obtained after repeated readings had stabilized over 3 hours, and the "early response" hemodynamics were those after 24 to 72 hours of therapy with oral vasodilators, shortly before catheter removal.

Within 3 to 9 months after the baseline evaluation, hemodynamics were reassessed when possible. The interval before the second study exceeded 9 months in 6 patients. Patients were instructed to take their last dose of medications the evening before undergoing recatheterization as outpatients. Hemodynamic measurements, made with catheters provided by Argon, at follow-up were obtained "premedication," at least 12 hours after the last medication dose, and "postmedication," 1 hour after supervised administration of all vasodilators. Four patients who forgot to hold their medications on the morning of recatheterization had only postmedication measurements. The protocol was approved by the Human Subjects Protection Committee on October 28, 1991.

Additional Evaluation
Echocardiography could be obtained both at initial baseline in hospital and on the day of reassessment on chronic therapy in 23 of 25 patients. Interpretation was done by readers blind to therapy and included quantification of ejection fraction by Simpson's rule, semiquantitative assessment of mitral and tricuspid regurgitation by color-flow Doppler (0=none, 1=mild, 2=moderate, 3=severe), and left ventricular dimensions by M-mode echocardiography. Peak oxygen consumption during bicycle exercise was measured at baseline and at follow-up when possible (17 patients), but baseline exercise was not performed in in-patients transferred for urgent evaluation. The severity of orthopnea (0 to 4 scale¹³ ) and hepatosplanchnic congestion or edema (also 0 to 4 scale) was graded before initial evaluation and on the day of repeated catheterization. Serum sodium, creatinine, and blood urea nitrogen were measured before and after tailoring of vasodilators and again within 1 week of late reassessment.

Follow-up
Patients were followed at the UCLA Cardiomyopathy Center at 1- to 4-week intervals. Review of medications, flexible diuretic regimen guided by daily weight, low-salt diet, fluid restriction, and a progressive walking program were emphasized at each visit by the physicians and specific dedicated nurses. Patients were contacted by phone within 4 days of discharge or after any medication change was made in the clinic.

Statistical Analysis
Continuous variables are expressed as mean±SD. Hemodynamic data at baseline and at reassessment were compared by ANOVA (PROC GLM, SAS) in three modifications: multivariate ANOVA for analyses of overall treatment effect, repeated-measures one-factor ANOVA for hemodynamic comparison variables over the four time points (baseline, early therapy, late predoses, and late postdose), and repeated-measures two-factor ANOVA to determine the effect of time, therapies, and their interaction. Pairwise comparisons between time points were made with the Tukey method. Although amiodarone therapy was not controlled during the study, subsequent post hoc analysis included amiodarone as a potential factor in hemodynamic change by use of repeated-measures two-factor ANOVA.

	Results

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Of the 48 patients meeting inclusion criteria at the time of initial evaluation, 25 underwent late invasive reassessment of hemodynamics after 8±6 months on tailored vasodilator and diuretic therapy. Of the remaining 23 patients, 4 died and 9 underwent transplantation (5 electively, 4 urgently) before restudy, and 10 were excluded because of refusal (3 patients) or mandatory anticoagulation (7 patients with a history of embolic event). During the study period, no patients admitted for transplant evaluation with heart failure died before discharge. Transplantation was performed in 13 patients before discharge. Regardless of hemodynamic or clinical response in the hospital, all 48 other patients meeting hemodynamic criteria for tailored therapy during this period were followed after discharge, representing 79% of the patients.

The initial clinical characteristics and baseline hemodynamic profiles of the 25 study patients and 23 eligible patients who were excluded, transplanted, or died after discharge before restudy were similar (Table 1). Spontaneous improvement of left ventricular function was unlikely in the 13 patients with ischemic disease, 1 patient with valve disease, or the other 11 patients after 3.5±2.9 years of symptoms. The 8 eligible patients who after discharge were not restudied because of death (4 patients) or deterioration to require emergent transplantation (4 patients) had slightly more severe symptoms and hemodynamic derangement at baseline than the study patients, although these differences did not reach statistical significance in this small subgroup.

View this table: [in this window] [in a new window]   Table 1. Baseline Profiles of 48 Followed Patients

Alterations in Drug Regimens
Before baseline evaluation, most of the 25 study patients were on vasodilators, 80% receiving ACE inhibitors without other vasodilators (Table 2). Only 5 patients were on nitrates. At hospital discharge after tailoring of oral vasodilators and diuretics to approach hemodynamic goals, all 25 patients were receiving vasodilators, and all except 1 received ACE inhibitors, some with hydralazine. Nitrates were prescribed in 96% of patients because of experience with similar patients in the Hydralazine Versus Captopril trial.¹⁴ All patients were discharged on a flexible diuretic regimen. Two patients had taken amiodarone chronically before admission. Amiodarone was added during hospitalization in 12 patients, and it was decided after the conclusion of the study that these patients should be compared with the other patients for hemodynamic change between hospitalization and repeated evaluation.

View this table: [in this window] [in a new window]   Table 2. Drug Regimens Before and After Evaluation

When hemodynamics were reassessed 8±6 months later, the drugs prescribed were nearly identical to those at hospital discharge, except that 1 patient initially intolerant to captopril was discharged on hydralazine and later treated with enalapril, 1 patient stopped hydralazine because of a rash, and 1 patient requested a change from captopril to quinipril. The doses of captopril were reduced slightly to average 240 mg/d but remained much higher than on referral. Three patients had discontinued nitrates because of headaches.

Initial Hemodynamic Responses to Therapy
Tailoring therapy to approach hemodynamic goals included invasive monitoring for 2.6±1.7 days and 5.1±4.6 L diuresis. On oral therapy before hospital discharge, the 25 study patients had significant reductions from baseline in pulmonary wedge pressure, right atrial pressure, and systemic vascular resistance and increases in stroke volume and cardiac index (Table 3).

View this table: [in this window] [in a new window]   Table 3. Early and Late Hemodynamic Responses

Long-term Hemodynamic Effects of Therapy
After 8±6 months, the early reductions from baseline in pulmonary capillary wedge pressure, right atrial pressure, and systemic vascular resistance and the increased stroke volumes were sustained on chronic therapy (Figs 1 and 2). Late improvement beyond that observed at 24 to 72 hours was significant for stroke volume and cardiac index, with further change in pulmonary wedge pressure of borderline significance (P=.09). Heart rate decreased significantly between the time of hospital discharge and later restudy (Table 3), even in the group who did not undergo initiation of amiodarone therapy (see below).

View larger version (18K): [in this window] [in a new window]   Figure 1. Relationship between pulmonary capillary wedge pressure and stroke volume in 25 patients at baseline evaluation, on initial therapy 24 to 72 hours later, and after 8 months of therapy. Despite progressively lower left ventricular filling pressure, stroke volume continued to increase.

View larger version (20K): [in this window] [in a new window]   Figure 2. Response to medications during early dosing and again after 8 months on tailored therapy. There is no apparent tolerance to the net hemodynamic effects of the medical regimens on loading conditions. Maintenance of a low pulmonary capillary wedge pressure (PCW) required continued drug effect, as evidenced by the increase seen when medications (Rx) were held 12 hours. Improvement in stroke volume (SV) and systemic vascular resistance (SVR) persisted beyond the dosing interval and may represent an improvement in overall circulatory compensation. Note that the 4 patients who did not hold their drug doses before study are not represented in this figure (*P<.05). CI indicates cardiac index.

Comparison of premedication to postmedication measurements at late follow-up revealed that pulmonary wedge pressure at 12 hours without vasodilators was markedly elevated but decreased into the normal range by 1 hour after vasodilator administration (Fig 2). In contrast, improved systemic vascular resistance, cardiac index, and stroke volume were evident compared with previous hospital baseline, even after medications had been held for 12 hours (Fig 2). Using the two-factor analysis allowed comparison of early versus late and predrug versus postdrug. This analysis showed that both time and medication affected filling pressures, cardiac index, stroke volume, and systemic vascular resistance. More importantly, there was no significant interaction between time and drug response, indicating that the initial observed hemodynamic benefit of treatment was neither blunted nor enhanced by the time of late reassessment.

Other Assessment on Chronic Therapy
Between baseline and late follow-up with echocardiography, left ventricular ejection fraction increased, and mitral regurgitation decreased, with a trend for less tricuspid regurgitation (Table 4). Peak oxygen consumption increased from 12±3 to 14±6 mL·kg^-1·min ^-1 (P=.16) in the 17 patients who had undergone baseline evaluation, but the most compromised patients had not undergone initial testing. New York Heart Association functional class improved by more than one class from 3.5±0.4 to 2.2±0.5. Orthopnea decreased markedly and was present in only 4 of 25 patients at 8 months compared with 18 patients at baseline (P<.05, Table 4). On chronic therapy, serum sodium remained unchanged, whereas both creatinine and blood urea nitrogen increased slightly.

View this table: [in this window] [in a new window]   Table 4. Changes in Profile of Heart Failure

Post Hoc Analysis After Initiation of Amiodarone
The study design did not take into account the potential confounding contribution of amiodarone initiated for arrhythmias. The subsequent data suggesting an effect on heart failure end points, however, mandated retrospective analysis for potential contribution to the results of this study.^{15 16} Analysis of the 12 patients in whom amiodarone was initiated revealed no significant baseline differences from the other 13 patients but a trend for all baseline parameters to be slightly worse (Table 3). Between early and late study, the improvements in heart rate, stroke volume, and cardiac index were more marked on amiodarone (Fig 3), although the heart rate and stroke volume improvements between early and late study were also significant for the group who did not begin amiodarone after baseline. Amiodarone was initiated for atrial fibrillation in 4 patients, all of whom were in sinus rhythm at late reassessment with hemodynamic changes that were not different from the 8 patients in whom amiodarone was initiated for ventricular arrhythmias. Amiodarone did not appear to influence the changes in filling pressures.

View larger version (24K): [in this window] [in a new window]   Figure 3. Progressive changes in heart rate, stroke volume, and cardiac index after adjustment of vasodilator and diuretic therapy for the 25 patients divided into 2 groups: 12 patients who underwent initiation of amiodarone therapy for arrhythmias after the baseline hemodynamic measurements vs the 13 patients who did not. Changes are expressed in relation to initial baseline hemodynamics.

	Discussion

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Most patients with heart failure demonstrate only mild to moderate symptoms on ACE inhibitors, digoxin, and diuretics and would not be expected to derive major benefit from either cardiac transplantation or invasive hemodynamic assessment. The potential option of transplantation has focused increasing attention on patients with severe symptoms of hemodynamic decompensation despite previous adjustment of these medications. In this study, chronic therapy tailored initially to hemodynamic goals was accompanied by sustained vasodilator response and hemodynamic improvement in those patients who survived without transplantation. These patients also demonstrated marked improvement in the symptoms of congestion, but this study was not designed to attribute this clinical improvement to any specific aspect of therapy.

Relationship Between Pulmonary Wedge Pressure and Cardiac Index
It has at times in the past been assumed that filling pressures close to those causing congestive symptoms were necessary to maintain perfusion in patients with heart failure and chronically dilated ventricles. This assumption was based in part on observations of patients with acute myocardial infarction.¹⁷ In the dilated ventricles of chronic heart failure, cardiac output can initially be maintained when ventricular filling pressures are reduced acutely to near-normal levels,¹ but the present study demonstrates that cardiac output can also be maintained chronically with these low filling pressures on vasodilators and diuretics.

Progressive Improvement in Stroke Volume
Multiple factors may contribute to maintenance and later improvement in stroke volume. Vasodilator therapy increases the fraction of ventricular stroke volume which is ejected forward^{3 4 5 6 18} ; valvular regurgitation on echocardiography was also reduced chronically in this study, as has been shown for other patients.¹⁹ Maintenance of smaller regurgitant volumes with lower filling pressures should decrease chronic wall stress and myocardial oxygen requirements.^{7 8 9} Reduction of right atrial pressure may improve fiber shortening by reducing coronary venous pressure and myocardial turgor.¹⁰

More intensive ACE inhibition may contribute to the progressive improvement seen.^{20 21 22 23 24} Combination with nitrates may contribute to chronic improvement.²⁵ The chronic decrease in heart rate may contribute to improvement, as has been suggested for amiodarone.^{26 27} At 8 months, left ventricular ejection fraction increased by 24%, similar to changes observed during vasodilator therapy of milder heart failure.^{28 29} The progressive increase in stroke volume did not reflect increased vasodilator drug response but may be due in part to lower premedication systemic vascular resistance (Fig 2).

Sustained Hemodynamic Efficacy
Late tolerance or decreased sensitivity to vasodilators has been suggested as a limitation of benefit from hemodynamically guided titration of vasodilator therapy in advanced heart failure.² However, the hemodynamic response to vasodilator doses seen after 8 months demonstrated sustained hemodynamic efficacy in the patients restudied. Moreover, pulmonary wedge pressure after medications were interrupted for 12 hours was still elevated, even though volume status, as gauged by weight and clinical examination, was held nearly constant after the initial average 5 L diuresis. Maintenance of near-normal filling pressures thus did not result solely from maintenance of initial fluid reduction but required continued pharmacological vasodilation.

Role of Amiodarone in Hemodynamic Improvement
The potential for amiodarone to cause clinical improvement in heart failure was not widely appreciated when this trial was initiated. Although not part of the study design, it would be misleading to omit post hoc analysis of this potential confounding factor. The hemodynamic improvement in patients after initiation of amiodarone for arrhythmias exceeded that observed on the tailored vasodilator/diuretic regimens alone. The benefit of amiodarone to improve left ventricular ejection fraction and decrease hospitalizations has recently been established^{15 16} and may be most pronounced in patients with elevated baseline heart rates.^{26 27}

Clinical Improvement
Patients surviving without transplantation demonstrated symptomatic and hemodynamic improvement. Orthopnea and peripheral edema were nearly eliminated without clinically significant deterioration in renal function, although the older population with heart failure may tolerate aggressive therapy less well.³⁰ In contrast to symptoms, the smaller improvement in peak oxygen consumption is consistent with past experience with tailored therapy in which about half of the ambulatory transplant candidates improve their peak oxygen consumption and few have deteriorated.¹² Similar small net increases in peak VO₂ have been seen in large trials in milder heart failure.^{31 32 33 34} The disparity between hemodynamic improvement and exercise tolerance reflects the influence of multiple factors other than resting central hemodynamics on exercise capacity in heart failure.^{35 36 37} In addition, the patients with most severe decompensation did not undergo baseline exercise.

In general, the relationship of hemodynamic improvement to clinical outcome may be strongest in patients with the most evidence of hemodynamic compromise. Even in this study in which decompensation was a criterion for inclusion, it is not possible to compare hemodynamic with clinical improvement because late hemodynamic status is not known for patients who died or underwent early transplantation. One of the strongest predictors for mortality remains New York Heart Association class IV status, usually characterized by congestive symptoms during rest or minimal exertion, the symptoms most responsive to reduction of filling pressures. Although the magnitude of acute hemodynamic improvement has not predicted the magnitude of clinical improvement, those patients with high filling pressures during vasodilator therapy have been less likely to survive in several experiences.^{38 39 40} The pulmonary wedge and right atrial pressures maintained chronically in this study were lower than have been reported for patients with comparably severe heart failure treated empirically without central hemodynamic guidance.^{39 41 42} In the absence of a randomized trial, however, it is unclear whether measurement of hemodynamics helps to achieve near-normal filling pressures and whether such achievement actually creates survivors or instead identifies those patients who are most likely to survive regardless of the design of therapy.

The revised medical regimens included larger doses of ACE inhibitors than at referral and standard addition of isosorbide dinitrate, which may have multiple benefits.^{25 43 44} Flexible diuretic regimens limited large fluctuations in volume status. Finally, all patients received focused attention from a team of nurses and physicians dedicated to the ongoing care of heart failure patients, which has also been found to improve outcomes for elderly patients with heart failure.⁴⁵ These benefits do not necessarily require invasive hemodynamic monitoring, although it may aid identification of optimal drug doses, "dry" weight, and blood pressure for subsequent outpatient therapy. Hemodynamic monitoring also facilitates simultaneous rather than stepwise correction of elevated volume status and elevated vascular resistance by use of intravenous nitroprusside and diuretics, as described by Pierpont and Francis⁴⁶ >10 years ago for potential transplant candidates. With increasing sophistication of echocardiographic techniques, it is likely that other methods besides invasive monitoring may be used in future to achieve and monitor similar early hemodynamic benefits that can be maintained.

Study Limitations
Because 13 patients underwent transplantation before discharge and another 13 died or underwent transplantation after discharge before recatheterization, the late hemodynamic responses reported here apply only to patients discharged to remain alive at home without transplantation. For those lost to death or urgent transplantation, hemodynamic status might be expected to be worse. It should be emphasized that the patient population referred for transplantation is younger than the overall population with heart failure. Older patients might do less well with this therapy, particularly in terms of renal function.³⁰ In the absence of placebo administration, some of the changes after dosing may have represented spontaneous variation. The magnitude of hemodynamic improvement and the accompanying late clinical improvement, however, make it unlikely that this accounts for all the changes seen. Although all consecutive patients were included, there were no patients with a poor initial response to therapy who could be followed to determine whether any late hemodynamic improvement was achieved. This study does not determine the specific role of invasive hemodynamic monitoring in comprehensive care for advanced heart failure.

Implications
The implications of this study are limited to those patients who are referred for consideration for transplantation with New York Heart Association class III or IV symptoms of heart failure despite previous therapy, including, in most cases, ACE inhibitors, diuretics, and digoxin. Hemodynamic monitoring is generally not indicated for initiation of these agents, which are usually effective in relieving symptoms to a level at which serious consideration of transplantation would not be indicated. Even in advanced decompensation, this study does not isolate the specific contribution of hemodynamic monitoring to the clinical improvement observed, which would be better addressed by a randomized trial comparing invasive to clinical assessment during redesign of therapy.

In the specific population studied, the serial hemodynamic measurements demonstrate the potential for those patients surviving without transplantation to achieve near-normal filling pressures chronically with continued maintenance of and increase in stroke volume. Furthermore, when combined with a flexible diuretic regimen, there was continued acute response to the oral regimens of ACE inhibitors, nitrates, and hydralazine designed initially to meet hemodynamic goals.

	Acknowledgments

 
Drs Steimle and Fonarow were supported by the NIH Training Grant No. 1T32-HL-07412-10. Dr Stevenson was a Clinician-Scientist of the American Heart Association, Greater Los Angeles (Calif) Affiliate, and was supported by the Eastern Star Foundation and the Helen Wolfe Estate in memory of Peter D. Wolfe (Los Angeles, Calif). This work was also supported in part by the Fannie Rippel Foundation Grant for Novel Therapies in Heart Failure. We gratefully acknowledge the secretarial support and editorial assistance of Joan Rothenberg and Michelle Moravec and the unfailing dedication of the ACE unit nurses.

	Footnotes

 
Alex Kartashov is currently at the Beth Israel Hospital, Boston, Mass.

Received October 31, 1996; revision received March 17, 1997; accepted March 18, 1997.

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