Survival of patients with severe congestive heart failure treated with oral milrinone

The safety and efficacy of long-term oral milrinone therapy were evaluated over a 2 1/2 year period in 100 patients who had severe congestive heart failure despite conventional therapy. Long-term oral milrinone therapy (27 +/- 8 mg/day initial dose) was well tolerated; drug-related side effects occurred in only 11% of patients and led to drug withdrawal in only 4% of patients. Of 94 patients evaluated after 1 month of therapy, 51% had improved by at least one New York Heart Association functional class. Despite hemodynamic and clinical improvements, life table analysis showed a 39% mortality rate at 6 months and a 63% mortality rate at 1 year of therapy. Characteristics at study entry that predicted death within 6 months included more advanced functional class, impaired renal function, lower right ventricular ejection fraction, presence of nonsustained ventricular tachycardia on 24 hour ambulatory electrocardiography, more impaired baseline hemodynamic function and absence of clinical improvement after 1 month of milrinone therapy. Multivariate analysis selected lower baseline cardiac index and aortic systolic pressure as the most significant variables in predicting death; patients who died of progressive heart failure had less frequent use of antiarrhythmic drugs and greater increases in furosemide and milrinone doses during long-term follow-up than did those who died suddenly. Thus, although milrinone is well tolerated and produces early symptomatic benefits in approximately half of patients with congestive heart failure refractory to conventional therapy, there is no evidence that it improves the high baseline mortality in this disorder.     

Effect of oral milrinone on end-systolic relations in patients with severe congestive heart failure

The new inotropic agent milrinone has both vasodilator and inotropic cardiovascular effects, but the importance of these effects in patients with severe congestive heart failure (CHF) is controversial. The left ventricular (LV) end-systolic pressure-diameter relation was used to determine the independent inotropic effect of milrinone. Seven patients with New York Heart Association class III CHF were invasively monitored with right-sided heart catheters and radial arterial lines. M-mode echocardiography was used to measure LV dimensions. The effect of a 10-mg oral dose of milrinone on hemodynamic, echocardiographic and end-systolic variables was determined. End-systolic pressure was measured at the dicrotic notch of the arterial pressure tracing and end-systolic LV dimensions at the time of aortic valve closure. Methoxamine (n = 6) or nitroprusside (n = 1) was used to alter afterload so that the end-systolic pressure-diameter relation could be determined. Arterial vasodilation from milrinone was evidenced by a decrease in mean arterial blood pressure (88 +/- 5 to 77 +/- 2 mm Hg, p less than 0.025) and an increase in cardiac index (from 2.7 +/- 0.2 to 3.2 +/- 0.2 liters/min/m2, p less than 0.025), with no change in heart rate (80 +/- 5 beats/min). Milrinone decreased preload as assessed by the pulmonary artery wedge pressure (from 17 +/- 2 to 10 +/- 2 mm Hg, p less than 0.01) and end-diastolic LV diameter (from 7.4 +/- 0.4 to 7.0 +/- 0.4 cm, p less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)     

Immediate effects of milrinone on metabolic and sympathetic responses to exercise in severe congestive heart failure

A randomized, double-blind, placebo-controlled protocol was used to determine whether milrinone exerts an immediate effect on exercise performance in patients with severe congestive heart failure. In each of 14 patients with New York Heart Association class III or IV congestive heart failure, intravenous milrinone (mean 57 +/- 5 micrograms/kg) and placebo were randomly administered just before maximal progressive upright cycle ergometry. The duration of exercise was significantly longer with milrinone than with placebo treatment (placebo 11.0 +/- 0.6 minutes, milrinone 12.5 +/- 0.9 minutes, p = 0.01). Compared with placebo, milrinone caused a higher peak oxygen uptake (placebo 10.8 +/- 0.6 ml/kg/min, milrinone 12.4 +/- 0.7 ml/kg/min, p = 0.001) and oxygen uptake at the anaerobic threshold (placebo 7.8 +/- 0.4 ml/kg/min, milrinone 9.2 +/- 0.4 ml/kg/min, p = 0.001). At peak exercise intensity, systolic blood pressure (placebo 119 +/- 5 mm Hg, milrinone 131 +/- 5 mm Hg, p = 0.001) and heart rate (placebo 114 +/- 5 beats/min, milrinone 126 +/- 6 beats/min, p = 0.001) were both increased with milrinone. Likewise, at matched submaximal exercise intensities, heart rate (placebo 111 +/- 19 beats/min, milrinone 117 +/- 20 beats/min, p less than 0.05) and systolic blood pressure (placebo 116 +/- 19 mm Hg, milrinone 121 +/- 19 mm Hg, p = 0.04) were higher with milrinone; plasma norepinephrine (placebo 1,692 +/- 208 ng/liter, milrinone 1,320 +/- 216 ng/liter, p = 0.05) and blood lactate concentrations (placebo 2.2 +/- 0.2 mM, milrinone 1.9 +/- 0.2 mM, p less than 0.05) were lower.(ABSTRACT TRUNCATED AT 250 WORDS)     

Muscle water and electrolytes in severe chronic congestive heart failure before and after treatment with enalapril.

To investigate the electrolyte and water content in peripheral skeletal muscle in patients suffering from severe chronic congestive heart failure, New York Heart Association functional class IV, and to study the influence of the angiotensin-converting enzyme inhibitor, enalapril, 22 patients were randomized in a double-blind study to receive either placebo (n = 11) or enalapril (n = 11) in addition to their conventional treatment. The patients included a subgroup in the previously published CONSENSUS study. At the beginning of the study, the content of potassium and magnesium was significantly reduced in muscle as compared with healthy subjects while sodium and water were increased. The muscle content was not predictable from the serum concentrations of the electrolytes. Following study treatment no significant changes occurred, neither within nor between the two subgroups. Thus, patients with severe chronic congestive heart failure, New York Heart Association functional class IV, displayed disturbed electrolyte and water content in muscle, which, in this study, was not corrected by treatment with enalapril.     

Effects of milrinone treatment in cardiomyopathic hamsters (CHF 147) with severe congestive heart failure

The effects of oral milrinone treatment in cardiomyopathic hamsters with severe congestive heart failure (CHF) were evaluated. Strict criteria based on increase in body weight were established to define day no 1 of treatment. Survival rate of non-treated hamsters (group 1) ranged between 9 and 16 d, mean 12.9 (SEM 0.8) d, after entering the study. Hamsters treated with milrinone in drinking water (group 2a: 0.3 mg.ml-1, or group 2b: 0.6 mg.ml-1) survived between 6 and 36 d, mean 15.0(2.1) d, NS, for group 2a, and between 6 and 47 d, mean 19.6(4.0) d, NS, for group 2b. There was a significant difference between the number of hamsters that survived longer than 16 d between untreated hamsters (group 1, n = 0/12) and hamsters treated with milrinone (groups 2a, b, n = 7/24). There was no significant correlation between survival duration and milrinone daily dose nor between survival and milrinone plasma concentration at death. Milrinone treatment also significantly decreased pulmonary congestion as measured by the number of pigment containing macrophages per alveolus. No other pathological findings were modified by milrinone. It was concluded that, in addition to exerting a beneficial effect on pulmonary congestion, milrinone improved survival in some CHF hamsters. However, more studies are needed to evaluate the possibility of an arrythmogenic potential that might explain why some treated hamsters died earlier than non-treated hamsters.     

Additive effects of milrinone and dobutamine in severe heart failure]

The hemodynamic effects of dobutamine, milrinone, and a combination of both drugs were compared intra-individually in 14 patients with severe heart failure (NYHA III: n = 9; NYHA IV: n = 5). Dobutamine (maximum dose: 9 micrograms/kg/min) and milrinone (0.5 micrograms/kg/min) each induced a comparable increase in stroke volume index (21 to 29 resp. 21 to 30 ml/m2; mean values; p less than 0.001) and reduction in pulmonary capillary wedge pressure (29 to 22 resp. 28 to 21 mm Hg; p less than 0.001), as well as in systemic (1846 to 1218 resp. 1858 to 1276 dyn s/cm5; p less than 0.001) and pulmonary vascular (301 to 195 resp. 293 to 216 dyn s/cm5; p less than 0.001) resistances. The heart rate rose significantly after dobutamine (92 to 107 min-1; p less than 0.05), but did not change after milrinone (94 to 95 min-1; ns). Neither drug had a significant effect on systemic arterial pressures. The combination of milrinone and dobutamine induced a further significant rise in stroke volume index (37 ml/m2; p less than 0.01) when compared to either drug alone. The combination also caused an additional fall in pulmonary capillary wedge pressure (14 mm Hg; p less than 0.01), as well as in systemic (799 dyn s/cm5; p less than 0.001) and pulmonary (133 dyn s/cm5; p less than 0.001) vascular resistances. When compared to dobutamine alone, the combined therapy did not significantly change the heart rate and systemic arterial pressures. The combined administration of a beta-adrenergic agonist and a phosphodiesterase inhibitor induces beneficial hemodynamic effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electrophysiologic effects of milrinone in patients with congestive heart failure

The electrophysiologic effects of milrinone, a new inotropic agent, have not been characterized in humans. Accordingly, 10 patients with class III or IV congestive heart failure underwent hemodynamic and electrophysiologic testing before and during an infusion of milrinone (0.5 micrograms/kg/min). Cardiac index increased from a mean of 1.65 +/- 0.51 to 2.19 +/- 0.68 liters/min/m2 (p less than 0.03) and pulmonary artery capillary pressure decreased from 30 +/- 9 to 22 +/- 9 mm Hg (p less than 0.01), without a significant change in systemic arterial pressure. Holter monitoring was performed for 48 hours at baseline and during infusion of milrinone. Frequency of ventricular premature complexes and ventricular couplets did not change significantly. Frequency of ventricular tachycardia (VT) increased significantly, although no patients would be classified as having a proarrhythmic effect based on a clinical model. PR, QRS, QTc, heart rate, AH, HV, atrial, atrioventricular and ventricular effective and functional refractory periods were not affected. Milrinone decreased 1:1 atrioventricular maximal conduction from 399 +/- 133 to 374 +/- 111 ms (p less than 0.01); ventriculoatrial conduction was not significantly affected. During programmed right ventricular stimulation, 5 patients had inducible VT at baseline (3 sustained, 2 non-sustained), whereas after drug administration, none had it (p less than 0.05). Thus, intravenous milrinone is an effective inotropic drug that also enhances atrioventricular conduction and may decrease the incidence of inducible VT in patients with congestive heart failure.     

Exercise hemodynamics and myocardial metabolism during long-term beta-adrenergic blockade in severe heart failure.

Hemodynamics and myocardial metabolism at rest and during exercise were investigated in 21 patients with heart failure. The patients were evaluated before and after long-term treatment (14 +/- 7 months) with the beta-adrenergic blocking agent metoprolol. Clinical improvement with increased functional capacity occurred during treatment. Maximal work load increased by 25% (104 to 130 W; p less than 0.001). Hemodynamic data showed an increased cardiac index (3.8 to 4.6 liters/min per m2; p less than 0.02) during exercise. Pulmonary capillary wedge pressure decreased at rest (20 to 13 mm Hg; p less than 0.01) and during exercise (32 to 28 mm Hg; p = NS). Stroke volume index (30 to 39 g.m/m2; p less than 0.006) and stroke work index (28 to 46 g.m/m2; p less than 0.006) increased during exercise and long-term metoprolol treatment. The arterial norepinephrine concentration decreased at rest (3.72 to 2.19 nmol/liter; p less than 0.02) but not during exercise (13.2 to 11.1 nmol/liter; p = NS). The arterial-coronary sinus norepinephrine difference suggested a decrease in myocardial spillover during metoprolol treatment (-0.28 to -0.13 nmol/liter; p = NS at rest and -1.13 to -0.27 nmol/liter; p less than 0.05 during exercise). Coronary sinus blood flow was unchanged during treatment. Four patients produced myocardial lactate before the study, but none produced lactate after beta-blockade (p less than 0.05). There was no obvious improvement in a subgroup of patients with ischemic cardiomyopathy. In summary, there were signs of increased myocardial work load without higher metabolic costs after treatment with metoprolol.     

GIP and insulin responses to oral glucose in coeliac patients before and after treatment

The responses of plasma gastric inhibitory polypeptide (GIP) and insulin to oral glucose were studied in five patients with untreated coeliac disease. These patients were restudied after one year on a gluten-free diet. In the untreated patients, the blood glucose, serum insulin, and GIP levels were significantly lower than in the controls. After gluten withdrawal there was an improvement towards normality in the responses of blood glucose, serum insulin, and GIP. The results show that untreated coeliac disease is associated with abnormalities of intestinal and pancreatic hormone secretion and that these abnormalities are improved by gluten withdrawal.     

Xamoterol in severe congestive heart failure: long-term oral treatment, a double-blind randomised study.

Twelve patients in severe congestive heart failure were given placebo, 100 mg xamoterol (Corwin) twice daily and 200 mg xamoterol twice daily, respectively, in 3 two-week periods in a double-blind randomised study. At the end of each treatment period the patients were evaluated. No differences were found between placebo and xamoterol in the following parameters: New York Heart Association function group index, heart volume, body weight, exercise duration on bicycle and treadmill, heart rate and systolic and diastolic blood pressure at rest. However, during exercise we found significantly lower heart rate and rate-pressure product during xamoterol treatment. This reduction is probably indicating occupation of beta-adrenoreceptors with concomitant reduced oxygen consumption during exercise.     

Intravenous milrinone in treatment of advanced congestive heart failure

Phosphodiesterase inhibitors such as milrinone can relieve symptoms and improve hemodynamics in patients with advanced congestive heart failure. We retrospectively evaluated the hemodynamic and clinical outcomes of long-term combination therapy with intravenous milrinone and oral beta-blockers in 65 patients with severe congestive heart failure (New York Heart Association class IV function and ejection fraction <25%) refractory to oral medical therapy. Fifty-one patients successfully began beta-blocker therapy while on intravenous milrinone. Oral medical therapy was maximized when possible. The mean duration of milrinone treatment in this combination-treatment group was 269 days (range, 14-1,026 days). Functional class improved from IV to II-III with milrinone therapy. Twenty-four such patients tolerated beta-blocker up-titration and were successfully weaned from milrinone. Sixteen patients (31%) died while receiving combination therapy; one died of sudden cardiac death (on treatment day 116); the other 15 died of progressive heart failure or other complications. Hospital admissions during the previous 6 months and admissions within 6 months after milrinone initiation stayed the same. Meanwhile, the total number of hospital days decreased from 450 to 380 (a 15.6% reduction), and the mean length of stay decreased by 1.4 days (a 14.7% reduction). We conclude that 1) milrinone plus beta-blocker combination therapy is an effective treatment for heart failure even with beta-blocker up-titration, 2) weaning from milrinone may be possible once medications are maximized, 3) patients' functional status improves on the combination regimen, and 4) treatment-related sudden death is relatively infrequent during the combination regimen.     

A Canadian multicentre study of a 48 h infusion of milrinone in patients with severe heart failure

Milrinone is a nonglycoside, nonsympathomimetic bipyridine with positive inotropic and systemic vasodilator properties. In order to evaluate the efficacy and safety of a short term infusion of milrinone, 105 patients with stable New York Heart Association (NYHA) class III or IV heart failure received a loading dose (50 micrograms/kg) and a 48 h continuous infusion (0.5 micrograms/kg/min). Administration of the loading dose resulted in a 28% decrease in pulmonary capillary wedge pressure (PCWP) (P less than 0.001), a 38% increase in cardiac index (P less than 0.001), and a 34% increase in stroke volume index (P less than 0.001) within 15 mins. Milrinone infusion maintained an average 27% and 24% reduction in PCWP during the first and second days, respectively (P less than 0.001). Cardiac index was 32% and 34% above baseline during the same intervals (P less than 0.001). There were no clinically significant changes in heart rate or mean arterial blood pressure during the study period. In a subset of 47 patients who underwent Holter monitoring before and during infusion, a significant increase in ventricular arrhythmias (premature ventricular complexes per hour, ventricular couplets per hour and ventricular runs greater than or equal to three) was demonstrated (P less than 0.0001). In general, milrinone was well tolerated. Of the 105 patients entered, one died of an acute myocardial infarction after premature termination of the infusion, and the infusion rate was decreased in two others because of supraventricular arrhythmias. In patients with severe heart failure, intravenous milrinone has significant beneficial hemodynamic effects. ECG monitoring for arrhythmias is recommended during milrinone infusion.     

Repetitive milrinone therapy in ambulatory advanced heart failure patients

BackgroundAdvanced heart failure (HF) patients usually poorly tolerate guideline‐directed HF medical therapy (GDMT) and suffer high rates of morbidity and mortality. The use of continuous inotropes in the outpatient settings is hampered by previous data showing excess morbidity. We aimed to assess the safety and efficacy of repetitive, intermittent, short‐term intravenous milrinone therapy in advanced HF patients with an intention to introduce and up‐titrate GDMT and improve functional class.HypothesisRepetitive, intermittent milrinone therapy may assist with the stabilization of advanced HF patients.MethodsAdvanced HF patients treated with beta‐blockers and implanted with defibrillators were initiated with repetitive, intermittent short‐term intravenous milrinone therapy at our HF outpatient unit. Patients were prospectively followed with defibrillator interrogation, functional class assessment, B‐natriuretic peptide (BNP) levels, and echocardiography parameters.ResultsThe cohort included 24 patients with a mean 330 ± 240 days of milrinone therapy exposure. Mean age was 73 ± 6 years with male predominance (96%). Following milrinone therapy, median BNP levels decreased significantly (882 [286−3768] to 631 [278−1378] pg/ml, p = .017) with a significant reduction in the number of patients with New York Heart Association (NYHA) Class III and IV (p = .012, 0.013) and an increase in number of patients on GDMT. Importantly, the number of total sustained ventricular tachycardia events and HF hospitalizations did not change.ConclusionsIn this small cohort of advanced HF, repetitive, intermittent, short‐term milrinone therapy was found to be safe and potentially efficacious.     

Acute and long-term hemodynamic effects of oral pirbuterol in patients with chronic severe congestive heart failure: randomized double-blind trial

In 20 patients with severe congestive heart failure (CHF), we studied the effects of the beta-adrenergic agonist pirbuterol compared to placebo in both an acute double-blind randomized trial and after long-term treatment. Acutely, pirbuterol patients (n = 10) demonstrated a significant rise in cardiac index (2.2 +/- 0.14 to 3.2 +/- 0.32 L/min/m2), stroke index (26 +/- 2.6 to 35 +/- 2.9 ml/beat/m2), stroke work index (22 +/- 2.4 to 30 +/- 2.7 gm X m/m2), and ejection fraction (22 +/- 4 to 30 +/- 5%). These hemodynamic variables did not significantly change in placebo patients (n = 10). After 3 weeks of pirbuterol therapy, 14 patients (70%) were symptomatically improved and were continued on the drug for another 3 weeks; 13 of 14 patients who were symptomatically improved underwent restudy. Compared to pretreatment baseline, there was continued improvement in cardiac index (2.5 +/- 0.16 to 3.2 +/- 0.24 L/min/m2), stroke index (30 +/- 2.5 to 38 +/- 2.9 ml/beat/m2), stroke work index (26 +/- 2.3 to 35 +/- 3.1 gm X m/m2), and ejection fraction (24 +/- 1 to 28 +/- 4%). Patients more frequently improved were those with nonischemic cardiomyopathy and those with higher initial ejection fractions. These results demonstrate the acute beneficial effects of oral pirbuterol versus placebo in a double-blind randomized trial. Improvement was maintained during long-term therapy in the majority of CHF patients.     

Exercise endpoints in patients with chronic heart failure

BACKGROUND: Peak oxygen consumption (V(O(2))) is a powerful predictor of outcome in patients with chronic heart failure. This is not a test that is readily clinically available. We therefore sought to establish a method of assessing peak V(O(2)) from non-invasively acquired data. METHODS: We analysed the results from incremental treadmill exercise tests in 60 patients [aged 59.0 (S.D. 12.4) years] with chronic heart failure or left ventricular dysfunction [left ventricular ejection fraction (29.6 (15.2)%)] and 52 control subjects [aged 36.7 (12.3)]. Metabolic gas exchange during exercise was measured with a respiratory mass spectrometer. Heart rate and blood pressure were measured. RESULTS: Peak V(O(2)) was lower in patients than controls [19.9 (7.7) ml/kg/min vs. 38.3 (9.0), P<0. 001]. Exercise time (r=0.84, P<0.001), heart rate at peak exercise (r=0.63, P<0.0001), change in heart rate (r=0.72, P<0.0001), rate pressure product at peak exercise (r=0.64, P<0.0001) and change in systolic blood pressure (r=0.31, P=0.002) all correlated with peak V(O(2)). In a stepwise regression model, exercise time was the most powerful predictor of peak V(O(2)) (r(2)=0.79). The only additional independent variable was change in heart rate from rest to peak exercise, which increased r(2) to 0.80. In a survival analysis, measured peak V(O(2)) and the peak V(O(2)) estimated from exercise time and change in heart rate had similar predictive power. CONCLUSIONS: In this preliminary study, peak V(O(2)) can be estimated from non-invasively acquired parameters. Estimated peak V(O(2)) and measured peak V(O(2)) have similar predictive power for outcome. Further work is necessary to see if estimated peak V(O(2)) is widely applicable in a clinical setting.     

Baroreflex sensitivity might predict responders to milrinone in patients with heart failure

The phosphodiesterase III inhibitor milrinone (MIL) is considered to be effective for "wet and cold" heart failure. In some cases, however, the inotropic effects of milrinone are insufficient. A previous study suggested that baroreflex sensitivity (BRS) predicts the cases in which MIL increases left ventricular dp/dt. The aim of this study was to determine whether BRS measured using the spontaneous sequence method predicts the MIL responders. Twenty-four patients with "wet and cold" heart failure whose systolic blood pressure > 100 mmHg were enrolled. At 2 hours MIL improved dys-pnea, general fatigue, urine volume, and tricuspid regurgitant pressure gradient in 13 patients (responders; R group), whereas it failed to improve in 11 patients (nonresponders; NR group). BRS in the R group was significantly higher than that in the NR group prior to the MIL infusion. At 2 hours after the MIL infusion, BRS was further increased in the R group, but did not increase in the NR group. The sensitivity and specificity of BRS at a cut-off level of 5 ms/mmHg for the prediction of R group were 0.94 and 0.93, respectively. BRS might be useful for identifying potential responders to milrinone in patients with blood pressure-preserved "wet and cold" heart failure.