Enoximone Therapy Research Articles

Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: the randomized, double-blind, placebo-controlled, parallel group ESSENTIAL trials

AimsUse of inotropic agents in patients with heart failure (HF) has been limited by adverse effects on outcomes. However, administration of positive inotropes at lower doses and concomitant treatment with beta-blockers might increase benefit–risk ratio. We investigated the effects of low doses of the positive inotrope enoximone on symptoms, exercise capacity, and major clinical outcomes in patients with advanced HF who were also treated with beta-blockers and other guideline-recommended background therapy.Methods and resultsThe Studies of Oral Enoximone Therapy in Advanced HF (ESSENTIAL) programme consisted of two identical, randomized, double-blind, placebo-controlled trials that differed only by geographic location (North and South America: ESSENTIAL-I; Europe: ESSENTIAL-II). Patients with New York Heart Association class III–IV HF symptoms, left ventricular ejection fraction ≤30%, and one hospitalization or two ambulatory visits for worsening HF in the previous year were eligible for participation in the trials. The trials had three co-primary endpoints: (i) the composite of time to all-cause mortality or cardiovascular hospitalization, analysed in the two ESSENTIAL trials combined; (ii) the 6 month change from baseline in the 6 min walk test distance (6MWTD); and (iii) the Patient Global Assessment (PGA) at 6 months, both analysed in each trial separately. ESSENTIAL-I and -II randomized 1854 subjects at 211 sites in 16 countries. In the combined trials, all-cause mortality and the composite, first co-primary endpoint did not differ between the two treatment groups [hazard ratio (HR) 0.97; 95% confidence interval (CI) 0.80–1.17; and HR 0.98; 95% CI 0.86–1.12, respectively, for enoximone vs. placebo]. The two other co-primary endpoints were analysed separately in the two ESSENTIAL trials, as prospectively designed in the protocol. The 6MWTD increased with enoximone, compared with placebo, in ESSENTIAL-I (P = 0.025, not reaching, however, the pre-specified criterion for statistical significance of P < 0.020), but not in ESSENTIAL-II. No difference in PGA was observed in either trial.ConclusionAlthough low-dose enoximone appears to be safe in patients with advanced HF, major clinical outcomes are not improved.

Rationale and Design of the Enoximone Clinical Trials Program

Background Chronic heart failure is a disease syndrome characterized in its advanced stages by a poor quality of life, frequent hospitalizations, and a high risk of mortality. In advanced and ultra-advanced chronic heart failure, many treatment options, such as cardiac transplantation and mechanical devices, are severely limited by availability and cost. Short-term Phase II clinical trials suggest that low-dose oral inotropic therapy with enoximone may improve hemodynamics and exercise capacity, without adversely affecting mortality, in selected subjects with advanced chronic heart failure. Based on these data, the ability of enoximone to deliver safe and efficacious palliative treatment of advanced/ultra-advanced chronic heart failure is being evaluated in Phase III clinical trials. Methods and Results The Enoximone Clinical Trials Program is a series of 4 clinical trials designed to evaluate the safety and efficacy of oral enoximone in advanced chronic heart failure. ESSENTIAL I and II (The Studies of Oral Enoximone Therapy in Advanced Heart Failure) will investigate the effects of oral enoximone on all-cause mortality and cardiovascular hospitalization, submaximal exercise capacity, and quality of life in subjects with New York Heart Association Class III/IV chronic heart failure. EMOTE (Oral Enoximone in Intravenous Inotrope-Dependent Subjects) will evaluate the potential of oral enoximone to wean subjects with ultra-advanced chronic heart failure from chronic intravenous inotropic therapy to which they have been shown to be dependent. EMPOWER (Enoximone Plus Extended-Release Metoprolol Succinate in Subjects with Advanced Chronic Heart Failure) will explore the potential of enoximone to increase the tolerability of continuous release metoprolol in subjects shown previously to be hemodynamically intolerant to β-blocker treatment. Conclusion These studies are Phase III, multicenter, randomized, double-blinded, placebo-controlled trials designed to test the general hypothesis that chronic oral administration of low doses of enoximone can produce beneficial effects in subjects with advanced or ultra-advanced chronic heart failure.

New strategies to control the inflammatory response in cardiac surgery

To present and interpret data from recent clinical studies (July 2002-August 2003) of strategies to control the inflammatory response after cardiac surgery. Off-pump coronary artery bypass techniques, which avoid the need for extracorporeal circulation, attenuate the inflammatory response and appear to confer clinical benefit. Concerns regarding the quality of the revascularization after off-pump coronary artery bypass appear to have been allayed. At present, ventricular assist devices do not enhance the efficacy of off-pump coronary artery bypass. In patients undergoing cardiopulmonary bypass, heparin-coated circuits, hypothermic pulmonary perfusion, normoxic reperfusion after aortic unclamping, and modified ultrafiltration hold promise. Strategies to maintain perioperative haemodynamic stability, such as enoximone therapy, may be beneficial, particularly in elderly patients. Aprotinin may have important beneficial anti-inflammatory actions in higher-risk adult and paediatric patients. The therapeutic potential of corticosteroids, particularly when administered in multiple dosages is increasingly clear. Direct anti-mediator therapies that focus upon key effector molecules and pathways of the inflammatory response offer future therapeutic options. The potential for strategies that inhibit the inflammatory response to improve outcome after cardiac surgery is clear. Large-scale multicentre trials investigating the most promising strategies, including off-pump coronary artery bypass, heparin-coated circuits, and perioperative corticosteroid and aprotinin therapy, are urgently needed. These trials need to be restricted to the high-risk patient groups most likely to experience benefit. In the interim, the optimal strategy to minimize the inflammatory response to cardiac surgery will remain elusive.

Long-term outcome of enoximone therapy in patients with refractory heart failure

Few options are available for patients with severe heart failure that is unresponsive to therapy with digoxin, diuretics, and vasodilators. The clinical responses and predictors of survival were studied in 41 consecutive patients with New York Heart Association (NYHA) class IV heart failure during long-term oral enoximone therapy (mean dose 232 ± 15 mg/day). The mean age was 60 ± 1 years, and the initial left ventricular ejection fraction was 0.19 ± 0.01. The cause of heart failure was either coronary artery disease ( n = 23) or dilated cardiomyopathy ( n = 18). Symptomatic improvement occurred in the majority (83%) of patients; 24% improved two or more NYHA classes. Although the 12-month mortality rate for the entire group was high (54 ± 8%), a subgroup of patients with dilated cardiomyopathy achieved a sustained benefit with a decrease in symptoms >1 NYHA class, fewer hospitalizations, and a survival rate at 24 months of 60%. Multivariate analysis identified the cause of heart failure, left ventricular ejection fraction, and clinical improvement within 60 days of enoximone therapy as predictors of a favorable long-term outcome. The presence of coronary artery disease was most predictive of early mortality ( p < 0.0002), with only 5% of patients surviving >18 months compared to 66% of those with dilated cardiomyopathy. Median survival rates were 132 ± 31 and 921 ± 214 days ( p < 0.001) for the coronary artery disease and dilated cardiomyopathy populations, respectively. Oral enoximone can provide symptomatic improvement and a palliative option for the majority of patients with refractory heart failure resulting from cardiomyopathy.

Enoximone therapy as pharmacological bridging to cardiac transplantation.

Keeping pre-transplant patients alive while waiting for a suitable donor is still a major challenge. New pharmacological agents which can provide improved hemodynamics are urgently needed in patients with severe heart failure who are on the waiting list for cardiac transplantation. Intravenous enoximone therapy (an initial 0.5 mg/kg bolus, then 1.25-5.0 mcg/kg/min infusion) was administered to 35 transplant candidates with progressive heart failure despite optimal drug regimen including digoxin, diuretics, and ACE-inhibitors. In 18 out of 35 patients complete hemodynamic, echocardiographic, neurohumoral, and Holter-ECG studies were performed before and 24 hours after intravenous enoximone infusion. Patients were then continued on chronic oral therapy of 100 mg twice a day. Enoximone infusion increased the cardiac index (CI) (1.78 +/- 0.45 l/min/m2 vs 3.04 +/- 0.83 l/min/m2; p < 0.001) and stroke volume index (SVI)(22.33 +/- 9.45 ml/m2 vs 32.28 +/- 7.29 ml/m2; p < 0.05) and decreased wedge pressure (PCP)(24.1 +/- 11.98 mmHg vs 17.78 +/- 8.76 mmHg; p < 0.05) while mean arterial pressure (MAP) was unchanged. Left ventricular ejection time (LVET)(225.1 +/- 26.9 ms vs 242.2 +/- 25.8 ms; p < 0.05) was increased whereas other echocardiographic parameters were unchanged (Left ventricular end-diastolic dimension LVEDD, left ventricular end-systolic dimension LVESD, fractional shortening FS, early diastolic relaxation parameter Te). Plasma neurohumoral parameters did not change (Aldosterone, epinephrine, renin, atrial natriuretic factor) except for a significant drop in norepinephrine (936.7 +/- 443.2 pg/ml vs 522.4 +/- 287.6 pg/ml; p < 0.05). Holter-ECG parameters (ventricular premature beats VPB, couplets, ventricular tachycardia VT) were not influenced by enoximone infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk of enoximone therapy during mechanical bridge to transplantation

Risk of enoximone therapy during mechanical bridge to transplantation

Efficacy of Phosphodiesterase Inhibitor Enoximone in Management of Postcardiotomy Cardiogenic Shock

The efficacy of the phosphodiesterase inhibitor enoximone for reversal of severe postcardiotomy low cardiac output syndrome was investigated in 13 cases of cardiogenic shock refractory to conventional treatment consisting of beta-adrenergic agonists (n = 13) combined with vasodilators (n = 7), and intra-aortic balloon counterpulsation (n = 5). Following a bolus of 1 mg/kg enoximone, cardiac and stroke volume indices increased from 1.56 +/- 0.27 l/min/m2 and 16.3 +/- 3.3 ml/m2, respectively, to 2.72 +/- 0.67 and 27.8 +/- 7.1 (both p < 0.001). Mean arterial pressure fell, from 77 +/- 11 to 68 +/- 9 mmHg (p < 0.05), as did atrial filling pressures (LAP and RAP), LAP from 21.3 +/- 5.5 to 15.9 +/- 2.9 and RAP from 16.6 +/- 2.3 to 13.7 +/- 2.1 mmHg (both p < 0.01). The heart rate rose by only 5%. Enoximone therapy was maintained by a continuous infusion (5-7.5 micrograms/kg/min) for 40.6 +/- 8.6 hours (range 14-92). All hemodynamic parameters remained stable throughout treatment. Six patients died of sepsis and/or multiorgan failure but seven were discharged from hospital. Enoximone thus improved hemodynamic performance significantly in cardiogenic shock after open-heart surgery. It also has proved valuable in cardiac failure when conventional therapy was unsuccessful.

Enoximone in newborns with refractory postoperative low-output states (LOS).

Enoximone was administered to 16 newborns with postoperative, catecholamine-refractory cardiac low-output states in addition to high-dose catecholamine treatment. Haemodynamic changes were assessed at baseline and during treatment. Haemodynamic parameters were improved in 12 newborns ("responders"), 9 of these survived. Three responders died; one from cardiac low-output and 2 from uncorrectable congenital heart disease verified by autopsy. Four newborns did not respond to enoximone therapy ("non-responders") and died. The haemodynamic effects of enoximone were characterized by an increase in cardiac index (+160%, P less than 0.0008), and a fall in right (-26%, P less than 0.0004) and left (-34%, P less than 0.003) atrial pressures. It is concluded that enoximone can be an effective agent in the treatment of cardiac low-output states refractory to high-dose catecholamines in neonates up to 7 months old.

Oral treatment with enoximone in patients referred for cardiac transplantation

A prospective, uncontrolled, open ended study was performed to assess the effect of treatment with oral enoximone therapy in patients with end stage cardiac failure unresponsive to conventional treatment. The primary objective of treatment, hospital discharge, was achieved in 27 of 35 patients studied. Baseline haemodynamics were obtained in 21 patients. The mean cardiac index of patients who improved by one or more grades (New York Heart Association) was 2.1 litres/min while, in those who had less improvement, the mean cardiac index was 1.5 l/min ( P < 0.01). The average duration of treatment was 13 weeks, treatment being discontinued in 25 patients within twelve weeks. The main reasons for discontinuation were side effects ( n = 11), and progressive cardiac failure ( n = 7). The prognosis of patients in whom therapy was discontinued was very poor, only 5 of 28 being discharged from hospital without cardiac transplantation. Sudden death was uncommon ( 1 13 ), and Holter monitoring in 17 showed no aggravation of ventricular arrhythmias. Oral treatment with enoximone is a useful adjunct in the treatment of end stage cardiac failure.

Oral enoximone therapy in chronic heart failure: A placebo-controlled randomized trial

In a parallel study design, 164 patients with New York Heart Association Functional class II or III heart failure were randomized to receive either enoximone given as 50 mg three times a day, or 100 mg three times a day, or a matching placebo. All patients were receiving digitalis and/or diuretics and had left ventricular ejection fractions ≤ 45. Exercise tests were performed after 1, 4, 8, and 12 weeks of treatment. Enoximone produced significantly greater increases in exercise time than placebo treatment at weeks 4 and 8 ( p = 0.012, p = 0.029, respectively) but not after 12 weeks. Left ventricular ejection fraction increased significantly after the first dose of enoximone but not after 12 weeks of long-term therapy. Heart failure symptoms and the physicians' evaluations of cardiac status were significantly improved in both enoximone therapy groups during the first 4 weeks of evaluation when compared with evaluations of cardiac status in the placebo group. Diuretic doses were increased more frequently for patients who were receiving a placebo. Adverse events were reported with similar frequency in the placebo and 50 mg enoximone treatment groups; 100 mg enoximone resulted in a significantly greater incidence of adverse events. Mean heart rate and ventricular ectopic activity were not sgnificantly different among the three treatment limbs. Enoximone appears to improve exercise tolerance, ventricular function, and symptoms of heart failure for 4 to 8 weeks. Heart rate, ventricular ectopic activity, and mortality rate were not increased. Enoximone, in a dosage of 50 mg three times a day was well tolerated and may be a useful short-term therapy for patients with chronic heart failure.

Patient Selection for Mechanical Circulatory Support as a Bridge to Cardiac Transplantation

Between 7/87 and 9/90 thirty-four patients underwent total artificial heart (Berlin Heart) (n = 2) or biventricular assist device (Berlin Heart) (n = 32) implantation as a bridge to cardiac transplantation. The time of mechanical support ranged from 2 to 60 days, for a mean of 19.2 days. Twenty-three patients received heart transplants, with 74% 30-day survival and 52% long-term survival. Implantation of a mechanical support system became indicated in those patients whose hemodynamic and clinical condition deteriorated despite treatment with enoximone in addition to maximal sympathomimetic medication. The strategy to administer enoximone routinely was the result of a prospective study on 24 pretransplant patients in whom enoximone therapy reduced the need for mechanical assistance by 62%. At the time of device implantation shock-related organ impairment such as cerebral, renal, hepatic, and respiratory dysfunction was present in 62% of patients. In addition, 7 patients had pneumonia. During mechanical support complete recovery of end-organ failure and resolution of pneumonia was observed in the majority of patients. The results indicate that end-organ dysfunction per se should not be considered a contraindication to mechanical circulatory support as a bridge to cardiac transplantation. However, further clinical investigations are needed to identify predictive indicators of irreversible organ damage.

Acute pulmonary oedema: preliminary results of a randomized trial of the intravenous phosphodiesterase inhibitor, enoximone, vs conventional therapy

The purpose of this open study was to compare the effects of enoximone and conventional therapy in 44 patients with acute pulmonary oedema. In this preliminary report, 22 patients were randomly assigned to the enoximone group (1 mg/kg bolus, every 8 hours for 48 hours) and 22 patients to conventional therapy (frusemide, nitrates, dopamine-dobutamine). Patients were assessed clinically at 0, 1, 2, 24 and 48 hours by the change in their Killip-Kimball score, dyspnoea, pulmonary rales, blood pressure, diuresis, requirement for additional therapy and/or death. Patient characteristics were similar except for distribution of the sexes. Improvements of each clinical parameter seemed more marked in the enoximone group, except during the first hour (due to the diuretics). The general course of the disease was more favourable in the enoximone group (17 cases vs 11 in the conventional therapy group), in which enoximone used alone was sufficient to normalize the haemodynamic variables. On the other hand, in the conventional therapy group, it was necessary to institute enoximone therapy in 9 cases. With the dosage used, enoximone appeared to be at least as effective as conventional therapy in acute pulmonary oedema. Moreover, no side-effects or tachyphylaxis appeared during the hospital assessment.

General pharmacology of CK‐2130: A new selective positive inotrope

AbstractCK‐2130 is a new imidazolone developed to treat congestive heart failure. We compared CK‐2130 to four inodilators and ouabain in several pharmacologic models. Intravenous (i.v.) administration of CK‐2130 to pentobarbital‐anesthetized dogs (0.03 to 1 mg/kg) relatively selectively increased myocardial dP/dT when compared to the dual positive inotropic and vasodilator activity of milrinone, enoximone, imazodan, and piroximone. Milrinone and piroximone (600 mg/kg, p.o., and 30‐300 mg/kg, i.p.) were central nervous system depressants in mice. CK‐2130 (100 mg/kg, i.v. and 600 mg/kg, i.p. and p.o.) was not depressant. Gastric acid secretion in the guinea pig was not affected by CK‐2130 (1 mg/kg, i.v.) and was inhibited by milrinone (1 mg/kg, i.v.) and enhanced by enoximone (1 mg/kg, i.v.). CK‐2130 and milrinone (0.03‐1 mg/kg, i.v.) did not affect rabbit sciatic nerve‐gastrocnemius muscle function. CK‐2130, piroximone, imazodan, and milrinone (100 μM) did not affect sympathetic neurotransmission, postsynaptic receptors, or guinea‐pig nonvascular smooth muscles but relaxed canine arteries and veins. Ouabain (1‐100 μM) initially facilitated, then inhibited, sympathetic neurotransmission, contracted vascular and non‐vascular smooth muscles, enhanced the vas deferens contraction to norepinephrine, and inhibited uterine contractions to bradykinin (10 μM). CK‐2130, milrinone, piroximone, and imazodan (0.1 to 100 μM) inhibited human platelet aggregation produced by adenosine diphosphate and sodium arachidonate. Thus, CK‐2130, a relatively selective positive inotrope, should be devoid of adverse central nervous system; neural, smooth, and skeletal muscle; and gastrointestinal side effects associated with digitalis and enoximone therapy.

Effects of Intravenous Enoximone following Coronary Artery Bypass Surgery

The effects of intravenous enoximone were investigated in patients with reduced left ventricular ejection fraction following coronary artery bypass graft surgery. Pulmonary capillary wedge pressure was maintained at its original level during therapy. Results showed an improvement in cardiac index of approximately 35% and a reduction of systemic vascular resistance of approximately 30% in 10 out of 16 patients. In an attempt to explain the failure of 6 patients to respond to enoximone therapy, preliminary studies revealed that a repeat dose of enoximone may elicit a response. It is further suggested that postsurgical trauma may change the behaviour of the heart in response to this agent, perhaps due to a reduction in high-energy phosphate levels.

Disparity between improvement in left ventricular function and changes in clinical status and exercise capacity during chronic enoximone therapy

Twenty patients with moderately severe congestive heart failure were randomized to chronic enoximone (n = 10) or placebo (n = 10) therapy in a double-blind manner and serially evaluated over a 16-week-period. The purpose of the study was to determine if the addition of standard doses (1 and 2 mg/kg) of this new phosphodiesterase inhibitor to conventional therapy (digitalis and diuretics) would alter the clinical and laboratory course of this patient population. Except for a transient improvement in the quality of life score, none of the symptomatology indicators were significantly affected by enoximone. Similarly, maximal exercise capacity was not altered. Enoximone did elicit a statistically significant augmentation of echocardiographic, radionuclide angiographic, and systolic time interval parameters of left ventricular function. These enoximone-induced effects were accompained by a significant increase (7% to 11%) in resting heart rate. Enoximone is capable of improving ventricular function when added to digitalis-diuretic therapy in moderately severe congestive heart failure. While individual patients may benefit from enoximone, the ability of standard doses of this agent to improve symptoms and exercise capacity over a 16-week period appears somewhat limited in a moderately severe heart failure population as a whole. Furthermore, a disparity between improvement in ventricular function parameters and changes in clinical status and exercise performance is apparent in this heart failure population.

Pharmacological bridge to cardiac transplantation

From September 1985 to August 1988, 32 patients were referred from various intensive care units throughout Paris for urgent cardiac transplantation or for a mechanical bridge to transplantation. At time of admission, under maximal sympathomimetic therapy, the cardiac index (CI) was 1.81 +/- 0.26 l/min per m2, the pulmonary capillary wedge pressure (PCWP 31 +/- 7 mmHg), systemic vascular resistances (SVR) 2053 +/- 469 dynes s cm-5. In 25, diuresis was less than 25 ml/h. Five were anuric. Prior to any final decision, a new inotropic agent, enoximone, was infused in addition to previous treatment as a 10 min bolus iv 1.5-2 mg/kg every 8 h. In 3, the situation further deteriorated, leading to a Jarvik 7-70 implantation within 12 h. In 29 however, within 3 h, the Cl increased to 2.69 +/- 0.56 as SVR dropped to 1410 +/- 453 and PCWP to 18 +/- 7. Diuresis increased to more than 100 ml/h in all. This permitted an indepth evaluation of the transplant candidates leading to contraindications to transplantation in 16. Nine patients could be weaned off iv enoximone. Four of these are still living (NYHA class III) with a follow up of 6-17 months. In 11, transplantation was performed within 2 days. Four died within a month, 2 with multiple organ failure. One patient died after 5 months. Six are back to normal life, NYHA class I (follow up 10 months-2.5 years). This protocol suggests that in patients with extreme heart failure, immediate survival may be increased by iv enoximone therapy, permitting a better selection of the recipients, more efficient pre-transplantation intensive care and consequently a decrease in the indications for a temporary mechanical bridge to a staged transplantation.

Long-Term Enoximone Therapy in Unstable Chronic Heart Failure

Long-term safety and efficacy of oral enoximone were evaluated in 32 patients with unstable chronic heart failure despite digitalis, diuretics, and vasodilator therapy. Oral enoximone, 75-150 mg t.i.d. was given for an average of 32 weeks. At baseline, 21 patients were in NYHA functional class IV, 10 patients in class III, and 1 patient in class II. Within 12 weeks, 14 of 20 patients surviving for more than 26 weeks had improved by at least one functional class. Hemodynamic data showed an 18% increase of cardiac index and a 34% decrease of diastolic pulmonary artery pressure. Echocardiographic recordings revealed an increase of fractional shortening from 13.9 +/- 7 to 15.6 +/- 5% after 12 weeks and 20.3 +/- 5% after 26 weeks. The 1-year survival rate was 40%. Sudden death occurred in three patients and pump failure in 11 patients. No serious side effects were reported. Holter monitoring did not show a significant proarrhythmic drug effect. Thus, long-term enoximone therapy is safe and produces sustained clinical and functional improvement in unstable chronic heart failure. However, overall survival appears not to be influenced in this patient group.

The electrophysiologic effects of enoximone in patients with preexisting ventricular tachyarrhythmias

Electrophysiologic and hemodynamic effects of intravenous enoximone were studied in 15 male patients, mean age 62.2 years, with New York Heart Association classes II to IV congestive heart fallure (coronary artery disease in 10 and idlopathic dllated cardiomyopathy in five patients; mean ejection fraction, 0.19). All patients had spontaneous ventricular tachyarrhythmias: eight had sustained ventricular tachycardia (VT), one had ventricular fibrillation, and six had nonsustained VT. Hemodynamic and electrophysiologic parameters including VT induction were determined before and during an intravenous infusion of enoximone. The cardiac index increased (2.49 ± 0.89 to 2.96 ± 0.78), and the pulmonary capillary wedge pressure decreased (22.4 ± 13.2 to 10.0 ± 9.0) after enoximone per predefined protocol endpoints. There was a significant decrease in spontaneous sinus cycle length, corrected sinus nodal recovery time, AH interval during atrial pacing, shortest cycle length at which 1:1 atrioventricular nodal conduction occurred, and refractory periods of the atrium, ventricle, and atrioventricular node. Enoximone did not alter the cycle length of induced VT, and there was no consistent change in the number of extrastimuli required for VT induction. A baseline 24-hour ECG recording was obtained on 14 patients (while recelving a long-term antiarrhythmic drug regimen, if needed) and repeated after 1 week and 1 month of oral enoximone therapy. There was no significant increase in the number of premature ventricular complexes per hour or VT episodes per 24 hours after 1 week or 1 month of therapy with enoximone. However, if four patients who received amiodarone and may not yet have reached steady state were excluded from analysis, there was a significant increase in the frequency of premature ventricular complexes per hour 1 month after initiation of enoximone. We conclude that intravenous enoximone reduces pulmonary capillary wedge pressure and increases cardiac output in most patients. Intravenous enoximone in doses sufficlent to have hemodynamic effects shortens atrial, ventricular, and atrioventricular nodal refractoriness and decreases AV nodal conduction time but has no consistent effect on VT induction or VT cycle length. The frequency of spontaneous ventricular ectopy may increase in some patients after oral enoximone, but its clinical significance is undefined. Enoximone may be administered cautiously to patients with congestive heart fallure and preexisting ventricular tachyarrhythmias.

Controlled and uncontrolled studies of phosphodiesterase III inhibitors in contemporary cardiovascular medicine

The phosphodiesterase inhibitors are new inotrope vasodilators that have beneficial hemodynamic effects in patients with congestive heart failure (CHF). The most extensively studied agents are milrinone and enoximone. Both drugs have clearly been shown in numerous studies to improve hemodynamics in patients with CHF when given acutely by either the intravenous or oral route. In long-term studies, milrinone has been shown to have sustained beneficial hemodynamic effects during active treatment. Effects on exercise tolerance have been less clear-cut in several uncontrolled trials, but a recent large-scale randomized trial does show sustained improvement in exercise performance. When milrinone is withdrawn after long-term therapy, some studies show worsened cardiac performance; the exact cause remains ill-defined, but could be due to deterioration of baseline ventricular function or to “rebound.” Both uncontrolled studies and a large recently reported randomized trial show that the hemodynamic response to readministration of milrinone after withdrawal is well-preserved, i.e., no tolerance is observed. Studies of enoximone show that its acute hemodynamic effects are similar to those of milrinone, but its long-term efficacy, using both hemodynamic and exercise end points, is less clear-cut, and no large-scale randomized trials of enoximone therapy have yet been reported. The studies of both these agents performed thus far indicate that the phosphodiesterase inhibitors have considerable promise for both acute and long-term treatment of patients with CHF.

Intravenous use of enoximone

To assess the efficacy and safety of acute therapy with intravenous enoximone in patients with severe congestive heart failure, 118 patients from 5 centers were treated with incremental doses following 2 schedules: to a maximum cumulative dose of 3.0 mg/kg (44 patients) and to a maximum cumulative dose of 10.5 mg/kg (74 patients). Both schedules produced significant increases in cardiac index (55% and 68%, p < 0.01 for both) and decreases in pulmonary capillary wedge pressure (−29% and −42%, p < 0.01 for both). Similar beneficial effects were observed in systemic vascular resistance (−33% and −44%) and right atrial pressure (−30% and −46%), which also were statistically significant (p < 0.01). Heart rate increased modestly (6% and 13%) and mean systemic arterial pressure decreased (−5% and −14%). Some adverse effect occurred in 20% of the patients. Cardiovascular (10%) and central nervous system (6.7%) were the most frequent side effects. However, a direct relation to enoximone therapy could not be established in this uncontrolled open-label study of acutely ill patients. It is concluded that intravenous enoximone produces beneficial hemodynamic effects in patients with severe congestive heart failure with minimal changes in heart rate and blood pressure at cumulative doses < 3 mg/kg.