Effects of captopril on survival in patients with heart failure.

Results from a large multicenter study and from the published literature suggest that captopril can improve survival in patients with advanced heart failure. The survival status of 105 patients with moderately severe heart failure who participated in a multicenter, double-blind comparison of captopril and placebo therapy was ascertained on an intention-to-treat basis. During the 90-day double-blind portion of this study, 21 percent (11 of 52 patients) of placebo-assigned patients died compared with four percent (two of 53 patients) of captopril-assigned patients (p less than 0.01). In addition, six previously published studies that provided comparative mortality data were identified. In one of these, the survival rate was reported to be improved in those who received captopril; in the other five studies, no conclusion could be drawn with respect to survival since death was an infrequent event within all treatment groups. Mechanisms by which captopril may improve survival include its favorable effects on hemodynamic parameters, its association with reduced ventricular ectopic activity, and its inhibitory effects on the renin-angiotensin and sympathetic nervous systems.

Long-term oral enoximone therapy in chronic cardiac failure.

Sixty-nine patients with chronic heart failure of moderate to advanced severity were treated with oral enoximone (mean dose 1.8 +/- 0.5 mg/kg every 6 to 8 hours) for an average of 35 weeks (range 1 to 129). Before long-term therapy in 56 patients, oral enoximone was shown to augment cardiac output by more than 30%. In 13 outpatients enoximone was initiated without hemodynamic monitoring. Within 12 weeks of therapy the majority of surviving patients were improved by at least 1 New York Heart Association functional class. In a subset of 30 patients who were able to perform reproducible treadmill exercise before entry, average maximal O2 uptake increased from 14.9 ml/kg/min at baseline to 17.6 ml/kg/min (p less than 0.05) at 2 to 4 weeks and remained increased at 17.4 ml/kg/min (p less than 0.05) at 12 weeks. Adverse gastrointestinal effects occurred in 11 patients and were generally mild. The 12 month survival rate was 44%; etiology of death was cardiogenic shock in 17 patients and 10 patients died suddenly while at home. Thus, improvements in symptoms and maximal VO2 were observed in many patients with moderate to severe heart failure during long-term therapy with enoximone. Controlled trials will be needed to establish the safety and efficacy of this promising new drug.

Newer positive inotropic agents in the treatment of chronic cardiac failure. Current status and future directions.

Heart failure is a serious worldwide health problem of major proportions. For many physicians, digitalis (an inotropic agent of limited proportions) and diuretics have proven the standard of treatment for heart failure. Vasodilators have also gained acceptance in recent years. Nevertheless, many patients remain symptomatic and therefore attention has been given to the development of pharmacological agents with mechanisms of action targeted to cardiac and vascular smooth muscle. The newer generation of inotropic agents have clearly been shown to improve the pumping function of the failing heart in patients who remain symptomatic despite digitalis, diuretics and vasodilators, while myocardial oxygen consumption is not enhanced. Several uncontrolled trials with the phosphodiesterase inhibitors enoximone, milrinone and piroximone have concluded that these agents improve exercise capacity and thereby hold promise to enhance quality of life. Large scale controlled trials currently in progress will determine the ultimate efficacy, as well as safety, of these agents. Results to date with several orally active beta-adrenoceptor agonists suggest that their efficacy may be limited by the induction of ventricular arrhythmias.

Cardiopulmonary exercise testing in clinical practice.

Cardiopulmonary exercise testing refers to the noninvasive measurement of respiratory gas exchange and air flow, together with heart rate, blood pressure, and the electrocardiogram. These data, obtained during an incremental exercise test, can be used to derive the aerobic capacity or VO2max, which is an objective measure of the severity of chronic cardiac and circulatory failure, as well as to predict the maximum cardiac output response to exercise. The additional monitoring of minute ventilation and arterial oxygen saturation can be used to distinguish ventilatory from cardiac or circulatory causes of exertional dyspnea. Finally, this information serves as an objective measure of functional capacity which can be monitored over time to assess the natural history of disease as well as its response to medical therapy.

Effects of acute angiotensin converting enzyme inhibition on renal blood flow in patients with stable congestive heart failure.

Renal blood flow was serially measured as the left renal vein blood flow using the continuous thermodilution technique during acute angiotensin converting enzyme inhibition in 20 patients with stable congestive heart failure. Eleven patients received captopril orally, and the remaining nine patients received enalaprilat intravenously. During the control period, left renal vein blood flow and cardiac output did not correlate closely (r = 0.57). Following administration of captopril or enalaprilat, stroke volume index increased from 20 +/- 7 to 25 +/- 8 ml/M2 (p less than 0.001), while pulmonary capillary wedge pressure decreased from 26 +/- 8 to 19 +/- 8 mm Hg (p less than 0.001). Left renal vein blood flow increased in all patients despite a consistent reduction in systemic arterial pressure. At peak effect, left renal vein blood flow increased from 295 +/- 86 to 443 +/- 122 ml/min (p less than 0.001), while mean systemic arterial pressure fell from 81 +/- 13 to 71 +/- 14 mm Hg (p less than 0.001). Thus, in patients with stable congestive heart failure, acute angiotensin converting enzyme inhibition, although decreasing substantially systemic arterial pressure, consistently enhances renal blood flow.

Failure to augment maximal limb blood flow in response to one-leg versus two-leg exercise in patients with severe heart failure.

Lower limb blood flow, oxygen uptake, and femoral vein O2 content were measured at rest and during maximal bicycle exercise, performed with two legs and one leg, in four normal subjects and in five patients with severe congestive heart failure. While in normal subjects femoral vein blood flow and lower limb vascular conductance were significantly greater during one-leg exercise than during two-leg exercise (6084 +/- 745 vs 5370 +/- 803 ml/min, p less than .05, and 52.3 +/- 8.0 vs 45.1 +/- 8.2 U X 10(3), p less than .05, respectively), in patients with severe congestive heart failure these values were similar during the two forms of exercise (1082 +/- 459 vs 1053 +/- 479 ml/min and 9.6 +/- 3.7 vs 9.4 +/- 3.5 U X 10(3), respectively). In five additional patients, one-leg maximal bicycle exercise was performed before and after administration of phentolamine into the femoral artery of the active leg. Regional alpha-adrenergic blockade with phentolamine did not alter maximal oxygen uptake attained during one-leg bicycle exercise (9.8 +/- 1.5 vs 10.3 +/- 1.9 ml/kg). Lower limb blood flow and femoral vein O2 content attained during maximal one-leg exercise were also similar before and after phentolamine. Thus, in contrast with normal subjects, patients with severe congestive heart failure were unable to further increase limb blood flow during one-leg bicycle exercise. Moreover, local alpha-adrenergic blockade does not augment blood flow to the active limb during maximal one-leg bicycle exercise. This suggests that the ability of the muscular vasculature to vasodilate during exercise is impaired and may be a limiting factor to maximal exercise capacity in such patients.

Effects of new inotropic agents on exercise performance.

Symptoms of dyspnea and fatigue limit effort tolerance in patients with chronic cardiac failure. These symptoms may be consequent to an abnormal cardiocirculatory response to the increased O2 demand that accompanies exercise as manifested by: reduced ability to augment cardiac output in response to increased left ventricular filling pressure, inadequate vasodilatory response in exercising limbs, the onset of lactate production by muscle at relatively low levels of work, and increased work of breathing that accompanies pulmonary venous hypertension and abnormal compliance of the lung secondary to left ventricular dysfunction. The clinical experience with new positive inotropic agents in the long-term treatment of patients with chronic cardiac failure is accumulating rapidly. Attention has focused on the ability of these agents to improve exercise performance, particularly their ability to increase the aerobic capacity. The experience to date suggest that beta-adrenergic receptor agonists offer little advantage in this regard while causing ventricular arrhythmias. On the other hand, the phosphodiesterase inhibitors, MDL 17,043 and MDL 19,205, and the bipyridine derivatives, amrinone and milrinone, may improve exercise performance in many patients and exert a sustained effect during long-term therapy. Placebo-controlled, randomized trials will need to be performed, however, to determine the ultimate efficacy and safety of these agents. The most meaningful results for analysis will be obtained when objective parameters of exercise performance, such as aerobic capacity and anaerobic threshold, are monitored that are free of patient or physician bias.

The effects of two new inotropic agents on microsomal liver function in patients with congestive heart failure.

The aminopyrine breath test (APBT) was used to study patients with chronic congestive heart failure before and after treatment with two chemically similar inotropic agents, amrinone (AR) and milrinone (MR), to determine their effects on hepatic microsomal function. Liver chemistries and cardiac indices were measured and correlated with the 2-hour APBT score in 11 patients with chronic congestive heart failure (5 treated with AR, 6 with MR) and five healthy control subjects. Despite normal or near-normal liver chemistries, patients with chronic congestive heart failure demonstrated overall depressed hepatic microsomal oxidative function. Patients with severe congestive heart failure had a lower mean pretreatment APBT score (AR = 3.05 +/- 1.02, MR = 5.38 +/- 3.09) when compared with healthy controls (10.02 +/- 1.02). However, the APBT score for each individual could not be predicted from the cardiac index. Although the mean cardiac index increased significantly in both the AR and the MR treated patients by 26.14% +/- 15.28 (p less than 0.01) and 40.0% +/- 42.27 (p less than 0.025), respectively, compared with pretreatment values, the mean APBT score fell by 62.02% +/- 22.5 (p less than 0.005) in the former and increased by 38.35% +/- 25.69 (p less than 0.01) in the patients receiving MR. This discordance between the effects of AR and MR suggests possible differences in the effects of the two drugs on hepatic microsomal function.

Comparative systemic and renal effects of dopamine and angiotensin-converting enzyme inhibition with enalaprilat in patients with heart failure.

Renal and systemic hemodynamics were measured during titration of dopamine and serially after intravenous administration of enalaprilat in nine patients with chronic severe congestive heart failure. During titration of dopamine, renal blood flow increased by 99%, from 304 +/- 120 to 604 +/- 234 ml/min (p less than .01) at a dose of dopamine of 2.1 micrograms/kg/min, which produced only a 21% increase in cardiac index, from 1.96 +/- 0.36 to 2.38 +/- 0.35 liters/min/m2 (p less than .05). Cardiac index was increased maximally at a dose of 4.0 micrograms/kg/min dopamine; however, renal blood flow was not further augmented. In contrast, after intravenous administration of enalaprilat, peak improvement of renal blood flow and cardiac index occurred concomitantly. Renal blood flow increased by 35%, from 316 +/- 97 to 427 +/- 107 ml/min (p less than .05), and cardiac index increased by 18%, from 1.99 +/- 0.40 to 2.35 +/- 0.40 liters/min/m2 (p less than .05). At similar increases in cardiac index, dopamine produced a greater increase in renal blood flow than enalaprilat: 604 +/- 234 vs 427 +/- 107 ml/min (p less than .05). Mean systemic arterial pressure, however, was greater with dopamine than with enalaprilat (78.1 +/- 16.7 vs 70.2 +/- 17.2 mm Hg; p less than .05) at peak effect. Thus, although both drugs appear to be potent renal vasodilators in patients with severe congestive heart failure, dopamine may be more effective in augmenting renal blood flow.

Systemic and regional hemodynamic effects of captopril and milrinone administered alone and concomitantly in patients with heart failure.

The effects of milrinone and captopril on ventricular performance, renal blood flow, and femoral vein oxygen content were compared in 11 patients with severe chronic heart failure. The increase in stroke volume index was greater with milrinone than with captopril (28 +/- 7 vs 24 +/- 7 ml/m2; p less than .05), while pulmonary capillary wedge pressures fell similarly (19 +/- 10 vs 21 +/- 7 mm Hg). Mean systemic arterial pressure decreased significantly from 84 +/- 10 to 73 +/- 11 mm Hg (p less than .05) with captopril but did not with milrinone. Neither drug changed heart rate significantly. Although milrinone produced a greater improvement in ventricular performance than captopril, renal blood flow increased similarly with both drugs from 289 +/- 78 to 417 +/- 111 ml/min (p less than .05) and from 278 +/- 77 to 441 +/- 115 ml/min (p less than .05), respectively. Femoral vein oxygen content was increased by milrinone from 7.9 +/- 2.6 to 9.8 +/- 3.0 ml/100 ml (p less than .05) and was not changed by captopril. In seven additional patients, intravenous milrinone, administered at the peak effect of captopril, further augmented stroke volume index from 24 +/- 6 to 32 +/- 6 ml/m2 (p less than .05) and tended to reduce pulmonary capillary wedge pressure further from 20 +/- 8 to 18 +/- 9 mm Hg (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of a new cardiotonic agent, MDL-17,043, on myocardial contractility and left ventricular performance in congestive heart failure.

MDL-17,043, a newly synthesized imidazole derivative, has been shown to manifest both inotropic and peripheral vasodilating properties in experimental animals and to be effective when administered orally. Although MDL-17,043 has been demonstrated to inhibit cyclic adenosine monophosphate (AMP) phosphodiesterase activity in vitro, whether its inotropic activity derives from increased myocellular levels of cyclic AMP is not yet known. After intravenous administration of MDL-17,043 to seven patients with severe congestive heart failure (CHF) at the time of cardiac catheterization, the rate of left ventricular (LV) pressure rise increased almost immediately from a control of 878 +/- 161 to a peak of 1010 +/- 217 mm Hg/sec (p less than 0.01), while cardiac index tended to increase but not significantly. Subsequently, as mean aortic pressure decreased from 86.4 +/- 15.9 at control to 75.6 +/- 16.4 mm Hg (p less than 0.01), cardiac index rose from 1.87 +/- 0.35 at control to 2.30 +/- 0.27 L/min/m2 at peak effect (p less than 0.01), while pulmonary capillary wedge pressure fell from 23.7 +/- 5.1 to 13.1 +/- 4.6 mm Hg (p less than 0.01). Concomitantly, the rate of LV pressure rise returned to control value. Thus, intravenous administration of MDL-17,043 improves myocardial contractility and LV performance in patients with severe CHF. This manifest improvement in LV performance most probably results from both the positive inotropic and direct vasodilating effects of MDL-17,043.

Pathophysiology of cardiac failure.

The pathophysiologic cycle of heart failure is initiated by myocardial failure that accompanies a reduction in myocardial contractility secondary to ischemic or myopathic heart disease. Reduction in cardiac output and oxygen delivery to the tissues is followed by vasoconstriction that raises systemic vascular resistance to preserve systemic arterial pressure while maintaining regional O2 availability. As a consequence, however, impedance to left ventricular ejection is increased, creating an additional hemodynamic burden for the failing heart. A vicious cycle ensues. Hemodynamic features of acute cardiac failure include decreases in cardiac output and mixed venous O2 saturation, together with increases in left ventricular filling pressure and systemic resistance. If hypotension is present with failure, there is a markedly decreased cardiac output or an inappropriate increase in systemic resistance. If acidosis is also present with hypotension and failure, cardiac output is severely decreased and lactic acid is increased. A major objective of medical therapy in acute heart failure is to enhance ventricular emptying, thereby increasing cardiac output and O2 delivery while decreasing left ventricular filling pressure, pulmonary venous pressure and vascular resistance. Potent intravenous drugs that have a positive inotropic effect on the myocardium, including amrinone and dobutamine, have been shown to increase ventricular emptying in patients with acute heart failure. Intravenous amrinone improves pump performance without adversely raising myocardial O2 consumption, thereby enhancing myocardial efficiency. These drugs also promote a degree of vasodilation through both direct and secondary effects on the systemic circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

High prevalence of nonsustained ventricular tachycardia in severe congestive heart failure.

The prevalence of ventricular arrhythmias was evaluated in 35 patients with severe congestive heart failure (CHF) in New York Heart Association functional class III to IV. The etiology of CHF was equally distributed between ischemic and nonischemic cardiomyopathy. The severity of cardiac dysfunction was evidenced by left ventricular ejection fraction of less than 20%, mean cardiac index of 1.75 +/- 0.40 L/min/m2, pulmonary capillary wedge pressure of 28.1 +/- 7.1 mm Hg, and mean exercise capacity of 6.0 +/- 3.6 minutes. During 24-hour ambulatory Holter monitoring, 71% of these patients demonstrated repetitive episodes of ventricular tachycardia (VT), 92% had multifocal ventricular ectopic beats, and 88% had greater than or equal to 10 ventricular ectopy/1000 normal heart beats. Within 1 to 72 weeks of the Holter monitoring 25 patients died. Death could be attributed to VT in only one patient. In all the others, death was secondary to worsening CHF. Thus, although asymptomatic malignant ventricular arrhythmia occurred frequently in our patients, sudden death was rarely observed.

Acute inotropic stimulation with dopamine in severe congestive heart failure: beneficial hemodynamic effect at rest but not during maximal exercise.

Hemodynamic and metabolic effects of dopamine were studied at rest and during maximal exercise in 13 patients with severe chronic congestive heart failure (CHF). During exercise before the administration of dopamine, the stroke volume index increased from 17.1 +/- 5.2 ml/m2 at rest to 28.1 +/- 10.9 ml/m2 (p less than 0.001) at exhaustion, while pulmonary capillary wedge (PCW) pressure increased from 22.7 +/- 12.7 to 43.9 +/- 11.9 mm Hg (p less than 0.001). The arteriovenous oxygen difference increased from 8.9 +/- 2.3 ml/100 ml to 12.4 +/- 2.0 ml/100 ml (p less than 0.001) and oxygen uptake increased from 3.5 +/- 0.6 0.6 to 11.9 +/- 2.5 ml/kg/min (p less than 0.001). At rest, dopamine increased the stroke volume index to 23.3 +/- 8.1 ml/m2 (p less than 0.001) and reduced the PCW pressure to 20.5 +/- 1.1 mm Hg (p less than 0.05). However, during maximal exercise, the stroke volume index and PCW pressure were not changed by dopamine: 28.1 +/- 10.9 versus 28.6 +/- 10.2 ml/m2 (difference not significant [NS]) and 43.9 +/- 11.9 versus 42.5 +/- 11.2 mm Hg (NS), respectively. In contrast, the maximal heart rate achieved during exercise was significantly higher with dopamine, 140.3 +/- 29.3 versus 136.0 +/- 29.7 beats/min (p less than 0.05), which contributed to a slight augmentation in the maximal cardiac index, 3.82 +/- 1.13 versus 3.64 +/- 1.17 liters/min/m2 (p less than 0.05). Nonetheless, neither peak arteriovenous oxygen difference nor maximal oxygen uptake were significantly changed by dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term therapy with a new cardiotonic agent, WIN 47203: drug-dependent improvement in cardiac performance and progression of the underlying disease.

Seven patients with severe chronic congestive heart failure were treated with a new cardiotonic agent, WIN 47203 (an analog of amrinone), for an average of 7.4 weeks (range 2 to 15). At the initiation of therapy, hemodynamic improvement occurred in all patients as the cardiac index increased from 1.79 +/- 0.39 to 2.30 +/- 0.44 liters/min per m2 (probability [p] less than 0.05) and pulmonary capillary wedge pressure decreased from 24.1 +/- 6.7 to 16.1 +/- 7.8 mm Hg (p less than 0.05). Long-term therapy produced a substantial symptomatic improvement in five of the seven patients. This improvement was fully sustained in two patients and the remaining three experienced a partial return of their symptoms even though the initial hemodynamic improvements at rest remained evident in all seven patients. Withdrawal of WIN 47203 precipitated hemodynamic deterioration in all patients. The cardiac index decreased from 2.25 +/- 0.40 to 1.64 +/- 0.46 liters/min per m2 (p less than 0.05) while the pulmonary capillary wedge pressure increased from 17.1 +/- 7.8 to 23.2 +/- 12.0 mm Hg (p less than 0.05). Stroke volume index after withdrawal was lower than the control level before therapy (17.0 +/- 6.6 versus 20.3 +/- 4.7 ml/m2; p less than 0.05) and pulmonary capillary wedge pressure was similar. During long-term therapy, no undesirable side effects or hematologic changes were observed. Thus, drug-dependent hemodynamic benefits and apparent progression of the underlying cardiac disease were demonstrated during long-term therapy with WIN 47203.

Sustained hemodynamic and clinical effects of a new cardiotonic agent, WIN 47203, in patients with severe congestive heart failure.

The hemodynamic and clinical effects of WIN 47203, a newly synthesized noncatecholamine, nonglycosidic inotropic agent, were studied in 11 patients with severe chronic congestive heart failure. Intravenous WIN 47203 increased cardiac index from 1.93 +/- 0.36 to 2.87 +/- 0.45 l/min/m2 (p less than 0.001) and reduced pulmonary capillary wedge pressure from 27.0 +/- 8.4 to 16.3 +/- 6.1 mm Hg (p less than 0.001). Mean systemic arterial pressure decreased from 75.2 +/- 6.7 to 72.4 +/- 6.3 mm Hg (p less than 0.01) and systemic vascular resistance from 1591 +/- 397 to 1071 +/- 293 dyn-sec-cm5 (p less than 0.001); heart rate was unchanged. Oral WIN 47203 produced similar hemodynamic improvement. Hemodynamic monitoring of six consecutive doses did not demonstrate evidence for attenuation of effectiveness. Chronic therapy with WIN 47203 produced substantial symptomatic improvement and increased maximal oxygen uptake at 1 week. Patients were further improved after 4 weeks of WIN 47203, and maximal oxygen uptake increased from 9.0 +/- 1.9 to 11.6 +/- 2.5 ml/kg/min (p less than 0.01 vs control). No overt clinical or laboratory manifestations of toxicity were observed. Withdrawal of WIN 47203 in two patients in whom clinical benefit was not sustained resulted in clinical and hemodynamic deterioration, which was reversed by reinstitution of the drug. Therefore, this study demonstrates the acute and sustained cardiotonic efficacy of WIN 47203 in man. If long-term administration remains well tolerated and without side effects, this drug appears to be very promising for treatment of chronic severe congestive heart failure.

Failure of dobutamine to increase exercise capacity despite hemodynamic improvement in severe chronic heart failure.

The acute hemodynamic and metabolic effects of dobutamine administered during exercise were studied in 8 patients with severe chronic heart failure. Exercise was performed on an upright bicycle ergometer using a graded protocol. During exercise performed without administration of dobutamine, exhaustion occurred after 4.5 +/- 1.2 minutes of exercise. The cardiac index increased from 1.61 +/- 0.25 to 2.67 +/- 0.59 liters/min/m2 (p less than 0.001), the arteriovenous oxygen difference from 7.8 +/- 1.7 to 12.5 +/- 2.4 ml/100 ml (p less than 0.001), and oxygen uptake from 7.9 +/- 3.0 to 41.2 +/- 15.7 mg/100 ml (p less than 0.001). During exercise performed with the administration of dobutamine, the cardiac index was significantly greater than during the control state, 3.23 +/- 0.78 versus 2.67 +/- 0.59 liters/min/m2 (p less than 0.001), while the arteriovenous oxygen difference was significantly lower, 11.2 +/- 2.1 vs 12.5 +/- 2.4 ml/100 ml (p less than 0.01). The arterial lactate level was not significantly changed, 45.3 +/- 17.6 versus 41.2 +/- 15.7 mg/100 ml. Although the dobutamine level tended to increase maximal oxygen uptake compared with the control period of exercise, 9.1 +/- 1.2 versus 8.5 +/- 1.4 ml/kg/min (p less than 0.05), it did not significantly increase exercise capacity, 4.8 +/- 1.5 versus 4.5 +/- 1.2 min. Thus administration of dobutamine in patients with severe chronic heart failure increased the cardiac index during maximal exercise but failed to increase exercise capacity. Since arteriovenous oxygen difference is reduced, dobutamine probably increases blood flow to the nonexercising tissues and not to the actively metabolizing muscles.

Variable clinical response to long-term angiotensin inhibition in severe heart failure: demonstration of additive benefits of alpha-receptor blockade.

The effects of long-term therapy with captopril (CPT) were studied in 11 patients with severe chronic congestive heart failure (CHF). At initiation of therapy, cardiac index increased from 1.88 +/- 0.56 to 2.12 +/- L/min/m2 (p less than 0.05), while pulmonary capillary wedge pressure decreased from 27.9 +/- 7.2 to 17.8 +/- 7.6 mm Hg (p less than 0.01). This improvement in resting cardiac performance was maintained during maximal exercise; however, maximal oxygen uptake was not acutely increased by CPT. During chronic therapy, 6 of 11 patients showed symptomatic improvements; however, only three of these six patients demonstrated an increase in maximal oxygen uptake, which was measured at an average of 13.2 weeks following initiation of therapy. Five patients did not improve clinically during chronic therapy. In these patients, hemodynamic measurements that had improved initially after CPT returned to baseline values during chronic therapy. The addition of prazosin to chronic CPT therapy elicited a beneficial hemodynamic response in all five patients. Thus, the results of long-term therapy with CPT are variable in patients with severe CHF, and symptomatic improvement does not always correlate with objective measurement of exercise capacity. Combined alpha-adrenergic blockade and angiotensin-converting enzyme inhibition appears safe in patients who failed to exhibit a sustained improvement on CPT alone.

Long-term amrinone therapy in patients with severe heart failure: drug-dependent hemodynamic benefits despite progression of disease.

Six patients with severe congestive heart failure refractory to conventional therapy, including vasodilators, were treated with oral amrinone for a mean duration of 41 weeks (range 20 to 72 weeks). At initiation of therapy, the cardiac index increased from 1.74 +/- 0.31 to 2.62 +/- 0.52 (mean +/- SD) liters/min/m2 (p less than 0.01) and pulmonary capillary wedge pressure decreased from 26.5 +/- 3.5 to 19.5 +/- 5.4 mm Hg (p less than 0.05). Symptoms were alleviated and exercise capacity increased from 5.9 +/- 2.9 to 11.5 +/- 4.5 minutes (p less than 0.05). During long-term therapy, exercise capacity remained constants in three patients whereas it decreased in three others. All patients demonstrated an increase in heart size. Withdrawal of amrinone therapy precipitated severe symptoms at rest and hemodynamic deterioration in all patients. The cardiac index decreased from 1.87 +/- 0.49 to 1.32 +/- 0.30 liter/min/m2 (p less than 0.05) and pulmonary capillary wedge pressure rose from 20.6 +/- 2.9 to 28.8 +/- 5.6 mm Hg (p less than 0.05). These changes were reversed by reinstitution of therapy. Thus, amrinone-dependent hemodynamic benefits were demonstrated during long-term therapy without tachyphylaxis. In addition, progression of the underlying cardiac disease was observed in every patient.