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CLINICAL STUDIES

Low-dose enoximone improves exercise capacity in chronic heart failure^*

^a Heart Failure Treatment Program, University of Colorado Health Sciences Center, Denver, Colorado, USA

Manuscript received September 14, 1999; revised manuscript received February 11, 2000, accepted March 30, 2000.

Reprint requests and correspondence: Brian D. Lowes, Heart Failure Treatment Program, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, B120, Denver, Colorado 80126
Brian.Lowes{at}uchsc.edu

	Abstract

Top Abstract Methods Results Global assessments NYHA class, dyspnea scale... Holter monitoring Adverse events (AEs) Discussion Appendix References

 
OBJECTIVES

This study was designed to evaluate the effects of low-dose enoximone on exercise capacity.

BACKGROUND

At higher doses the phosphodiesterase inhibitor, enoximone, has been shown to increase exercise capacity and decrease symptoms in heart failure patients but also to increase mortality. The effects of lower doses of enoximone on exercise capacity and adverse events have not been evaluated.

METHODS

This is a prospective, double-blind, placebo-controlled, multicenter trial (nine U.S. centers) conducted in 105 patients with New York Heart Association class II to III, ischemic or nonischemic chronic heart failure (CHF). Patients were randomized to placebo or enoximone at 25 or 50 mg orally three times a day. Treadmill maximal exercise testing was done at baseline and after 4, 8 and 12 weeks of treatment, using a modified Naughton protocol. Patients were also evaluated for changes in quality of life and for increased arrhythmias by Holter monitoring.

RESULTS

By the protocol-specified method of statistical analysis (the last observation carried-forward method), enoximone at 50 mg three times a day improved exercise capacity by 117 s at 12 weeks (p = 0.003). Enoximone at 25 mg three times a day also improved exercise capacity at 12 weeks by 115 s (p = 0.013). No increases in ventricular arrhythmias were noted. There were four deaths in the placebo group and 2 and 0 deaths in the enoximone 25 mg three times a day and enoximone 50 mg three times a day groups, respectively. Effects on degree of dyspnea and patient and physician assessments of clinical status favored the enoximone groups.

CONCLUSIONS

Twelve weeks of treatment with low-dose enoximone improves exercise capacity in patients with CHF, without increasing adverse events.

Abbreviations and Acronyms   ACEI = angiotensin-converting enzyme inhibitor   AE = adverse event   ANOVA = analysis of variance   CHF = chronic heart failure   LOCF = last observed carry forward   NYHA = New York Heart Association   PDEI = phosphodiesterase inhibitor   PVC = premature ventricular contraction   VT = ventricular tachycardia

Enoximone is an imidazolone derivative that selectively inhibits sarcoplasmic reticulum-associated type III phosphodiesterase, which is expressed at high levels in human ventricular myocardium and vasculature (4–6). Myocardial and vascular phosphodiesterase inhibition (PDEI) increases cAMP levels, respectively activating protein kinase A and G to produce positive inotropic and vasodilator responses (4–9). Enoximone’s inotropic effects are additive with beta-blockers in vitro and in vivo (4). This additive effect means that enoximone and other PDEIs can partially restore the attenuation in myocardial beta-receptor signal transduction (coupled with chronotropic and inotropic responses) that characterizes the failing human heart (9–11). Another way in which enoximone could improve exercise responses is by preferentially increasing skeletal muscle blood flow (12). In contrast with beta-blockers, enoximone improves myocardial function without an increase in myocardial oxygen demand (13), and long-term administration of enoximone is not accompanied by beta-adrenergic receptor desensitization phenomena (14) or tolerance to effects on exercise capacity (15). Thus, oral enoximone is an agent that can potentially be used to increase exercise capacity and/or quality of life in CHF, as shown in previously reported placebo-controlled trials (16,17).

Unfortunately, enoximone used at the higher doses (4–6 mg/kg/day) that were originally tested in CHF increased mortality (18). However, enoximone at doses of 3.0 mg/kg/day has been used successfully as a bridge to heart transplant without an apparent increase in mortality (16). The purpose of this study was to evaluate the effects of lower doses (1–2 mg/kg/day) of enoximone on exercise capacity and adverse events in a placebo-controlled setting.

	Methods

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Patient selection.   This study was conducted at nine heart failure centers in the U.S. patients with symptomatic, New York Heart Association (NYHA) class II to III heart failure between the ages of 18 and 80 years of age and with left ventricular ejection fractions 45% were enrolled. The study was conducted with the approval of the local ethics committee and with written, informed consent signed by each patient.

Study protocol.   This was a multicenter, placebo-controlled, double-blind trial in patients with CHF. Enoximone at 25 (E25) or 50 mg three times a day (E50) was compared with placebo in 105 patients. The primary end point was maximal exercise duration, with various measures of symptoms as secondary end points, assessed by intention-to-treat. The exercise testing protocol consisted of a multistage modified Naughton (19). At baseline, subjects had to be able to exercise for 3 min and for no more than 16 min. Baseline exercise tests were repeated every 10 to 14 days until they were within 15% of each other, at which point the last two tests were averaged to obtain the Time 0 baseline value. If after three tests the exercise duration was not within 15% of the prior two, the average of the last two tests was used as the Time 0 baseline. Patients underwent follow-up exercise tests at 4, 8 and 12 weeks after randomization.

The primary end point of this study was the effect on maximum exercise capacity as assessed by treadmill exercise time at 12 weeks analyzed by the last observation carry-forward method. Secondary end points included adverse events, quality of life and arrhythmias between the treatment and placebo groups.

Concurrent therapy with digoxin, diuretics and sublingual nitroglycerin was allowed. Patients were excluded if they were receiving vasodilators (nitrates, ACEIs, hydralazine or prazosin) or beta-blockers that could not be safely stopped. Women of childbearing potential and patients with recent (<3 months) myocardial infarction were also excluded from the study. Patients with stenotic valvular disease, restrictive or hypertrophic cardiomyopathy or uncontrolled atrial fibrillation (mean heart rate > 110) were also excluded.

After a baseline medical stabilization period of 10 to 42 days, patients were randomized to placebo or to one of the two doses of enoximone. Clinical response was assessed by patient and physician investigator’s overall evaluations of improvement ("Global Assessment Instrument") compared with baseline, and symptoms were assessed by the investigator’s determination of the NYHA classification as well as by a four-tier (none, mild, moderate, severe) dyspnea scale. In a subset of patients, Holter monitoring was performed at baseline, four weeks and 12 weeks.

Statistical analysis.   Statistical analysis of exercise data (intent-to-treat) was evaluated in two ways. One data set was drawn from all subjects who completed each time point ("time course" analysis). The second used the "last observation carried forward" (LOCF) method by imputing missing values from the last available measurement available after baseline testing. The LOCF was the protocol-specified method of primary end point analysis of the exercise data. The between-group statistical methodology used was repeated measures analysis of variance (ANOVA), with specific comparisons between groups being made by using linear contrasts (20). This method compares each dose with placebo (between-group analysis) and each time point with baseline (between-time analysis). In addition, within-group analyses by repeated-measures ANOVA were done for all groups (time-response analysis) and for all times (dose-response analysis). Finally, repeated measures ANOVA was used to assess dose-time response.

Global assessment data were analyzed by comparing the number of subjects who were rated as improved or worsened to subjects in the other two categories in the enoximone groups versus the placebo group. The Global assessment instrument has five rank ordered categories, which were collapsed into three for purposes of data analysis. Data analysis at 4, 8 and 12 weeks was as described for the time-course method for exercise data. New York Heart Association and dyspnea scale data were analyzed by determining the number of subjects who improved or worsened by 1 class, with the statistical methodology as for the time-course method for exercise tolerance.

Holter monitor data were analyzed by comparing changes from baseline 24-h recordings within and between the three treatment groups using nonparametric methods due to skewed distributions. The three Holter parameters analyzed were average heart rate, premature ventricular contraction (PVCs)/h and ventricular tachycardia (VT) events/h. Adverse event data were compared among the three groups by contingency table analysis using Fisher’s Exact Test.

Hospitalizations were retrospectively tabulated from adverse event data reports and compared among the three treatment groups by contingency table analysis.

	Results

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Baseline demographic data.   Of the 105 patients enrolled, 20, 24 and 25 patients completed the study in the placebo, E25 and E50 groups, respectively. The baseline characteristics of the patients evaluated in this study are presented in Table 1. There were no statistically significant baseline differences among the three groups.

View larger version (17K): [in this window] [in a new window]   Figure 1 Time Course Analysis.

View larger version (17K): [in this window] [in a new window]   Figure 2 Last Observation Carried-Forward Analysis.

In the between-group analysis, the E50 group was significantly increased at four weeks compared with the placebo group, and the E25 and E50 groups were at statistical significance at 12 weeks (respective p values of 0.050 and 0.051). On dose-response analysis, the four-week data were statistically significant (p < 0.05), and the 8- (p = 0.18) and 12-week (p = 0.057) data exhibited trends. Compared with the placebo group, the time-response relationship trended towards significance for both the E25 (p = 0.14) and E50 (p = 0.073) groups. The dose-time response analysis of all doses and time points was nearly significant in favor of increasing response with ascending dose (p = 0.079).

LOCF analysis
The protocol-specified method of analyzing the primary end point was the between group analysis of exercise duration at 12 weeks, using the LOCF technique. These data are presented in Figure 2. The E25 group had a greater increase in exercise duration (p = 0.013 for E25 versus placebo, with respective increases of 115 ± [SEM] 36 s vs. 23 ± 30 s). For the E50 group the increase in exercise duration was by 117 ± 31 s (p = 0.003 vs. placebo). Additionally, the E50 group had a greater (p < 0.05) improvement in exercise duration compared with placebo at four weeks (by 80 s, p = 0.026) and eight weeks (by 74 s, p = 0.009) on between-group analysis. At four and eight weeks the E25 group was not significantly different from placebo.

On the within-group analysis, the placebo group was significantly increased versus baseline at eight weeks (p = 0.045) but was not at four and 12 weeks. The E25 group was significantly (p < 0.05) increased versus baseline at eight and 12 weeks, and the E50 group demonstrated an increase versus baseline at 4, 8 and 12 weeks. For the time-response analysis, the placebo group was not increased (p = 0.23) over the four time points, but the E25 (p = 0.0001) and the E50 (p = 0.0001) groups experienced increases.

On the between-group analysis, the time-response relationship was statistically significant from placebo for both the E25 (p = 0.026) and E50 (p = 0.016) groups. The dose-time response was also statistically significant (p = 0.019).

	Global assessments

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As can be observed in Table 2, at four weeks more subjects in the enoximone-treated groups were self-assessed as having improved (77% in the E25 and 70% in the E50 groups vs. 48% in the placebo group, respective p values of 0.019 and 0.055). At week 12 a similar percentage of enoximone-treated subjects (76%) continued to assess their status as improved versus 60% of the placebo patients, which was not statistically significant. In terms of subjects who considered themselves to have worsened, there were no differences between the enoximone- (10% to 15%) and placebo-treated (8% to 18%) subjects at any time point. There were no statistically significant differences between the placebo and enoximone groups in the Physician’s evaluation by Global Assessment (Table 2).

	NYHA class, dyspnea scale and diuretic use

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	Holter monitoring

Top Abstract Methods Results Global assessments NYHA class, dyspnea scale... Holter monitoring Adverse events (AEs) Discussion Appendix References

 
Holter monitoring data available on a subset of subjects are presented in Table 4. Missing data at baseline or on follow-up plus the relatively high dropout rate led to only 29% of subjects in the placebo group having Holter data available at baseline and at 12 weeks. The active treatment groups had heart rate data available on 42% (E25) and 43% (E50) of subjects at baseline and at the end of the study. For heart rate the only within-group change compared with baseline was a reduction in heart rate in the placebo group at weeks 4 and 12. There were no statistically significant changes in heart rate in either enoximone group, with the E25 group tending to have a decrease and the E50 group being unchanged at 12 weeks. Note that the baseline heart rates tended to be higher in the placebo group than in the enoximone groups (p = 0.15), which contributes to a significant between-group change between the placebo group and both enoximone groups at four weeks and the placebo-E50 group at 12 weeks.

	Adverse events (AEs)

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As shown in Table 5, AEs were reported at a nearly identical rate of 1.71/subject in the placebo group, 1.67/subject in the E25 group and 1.76/subject in the E50 group. Both enoximone-treated groups tended to have fewer numbers of subjects reporting dizziness, vertigo or hypotension as an AE (p = 0.05 for the combined enoximone groups vs. placebo).

	Discussion

Top Abstract Methods Results Global assessments NYHA class, dyspnea scale... Holter monitoring Adverse events (AEs) Discussion Appendix References

 
The results of this trial indicate that enoximone at doses of 25 mg three times a day and 50 mg three times a day increases maximal exercise capacity compared with placebo, as assessed by the protocol-specified method of end point analysis (last observation carried-forward at 12 weeks). The favorable effects of enoximone on maximal exercise capacity appeared to be dose-related, as supported by statistically significant dose and dose-time-response analyses with the carry-forward method data set. The improvement in exercise capacity appeared to be accompanied by symptomatic improvement; both the patients’ and the investigators’ assessments of improvement showed significant effects for enoximone 50 mg three times a day at week 4, plus trends for improvement at other time points and for the 25 mg three times a day dose. Additionally, subjects treated with either 25 or 50 mg three times a day had favorable effects on a dyspnea scale provided that they were only mildly symptomatic at baseline. Enoximone was generally well tolerated, as both enoximone groups tended to have fewer numbers of subjects with severe AEs, discontinuations due to AEs and deaths compared with the placebo group. On limited Holter monitor data, there was no evidence of increased arrhythmia in the enoximone-treated patients. These data indicate that enoximone, given at doses of 25 mg three times a day and 50 mg three times a day, improves exercise capacity without increasing serious AEs in subjects with class II to III CHF treated for a 12-week period.

Comparison with previous studies.   Heart failure remains a syndrome characterized by impaired exercise tolerance due to cardiac contractile and chronotropic dysfunction. Despite exercise tolerance being the cornerstone of heart failure drug development from the mid-1980s to the mid-1990s, relatively few placebo-controlled multicenter clinical trials have demonstrated improved functional capacity in the absence of evidence for increased adverse effects. The Captopril Multicenter Study (22), which was the primary basis for that compound’s approval for a heart failure indication, is the most obvious example of a successful exercise trial with an excellent safety profile. Other examples include trials with lisinopril (23) and quinapril (24). However, many trials did not detect an increase in exercise capacity by an active agent compared with placebo (25–28) or documented both an increase in exercise performance and a trend towards increased AEs (29,30) which were subsequently shown to be significant (31,32).

Despite the discouraging survival results with positive inotropic agents (32–37) intermittent or sustained infusions of outpatient inotropic therapy continues as standard therapy for patients with intractable heart failure (38). This therapy persists because of cost efficacy compared with continuous inpatient therapy because it is successful in palliation of advanced symptoms and also because physicians and patients have accepted the possible trade-off of an increase in mortality for an improvement in quality of life (39,40). Oral enoximone has previously been shown to be efficacious in weaning patients from intravenous inotropic therapy and as a bridge to cardiac transplant (14). In addition, low dose enoximone therapy does not appear to increase mortality in subjects in this study or in other previous trials (14,16,40). These results indicate that low dose oral enoximone therapy could be of benefit in inotrope-dependent patients by allowing them to be weaned off intravenous therapy and improving exercise capacity and quality of life. However, this hypothesis will have to be tested in appropriate placebo-controlled trials conducted in advanced heart failure patients.

Study limitations.   This study is limited by its short duration, relatively small sample size and—because it was conducted in the late 1980s—the lack of background ACEI therapy. Therefore, it is possible that a trial of longer duration or on different background treatment would yield different results. However, in a recent trial of low-dose enoximone used in combination with beta-blockers, most subjects were also treated with ACEIs, and enoximone appeared to be beneficial in the presence of full neurohormonal blockade (40).

Conclusions.   Despite these limitations this trial indicates that, at low doses, enoximone has the potential to improve functional capacity in patients with heart failure, without increasing AEs. Further trials are needed to evaluate the effects of low-dose enoximone on survival and quality of life in the setting of current standard medical therapy, particularly in subjects with more advanced heart failure.

	Appendix

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Enoximone Study Group Members and Institutional Affiliations

Michael Higginbotham, MD Duke University Medical Center Lawrence Petrovich, MD Tulane University Marcus A. DeWood, MD Deaconess Medical Center Mark A. Greenberg, MD Albert Einstein College of Medicine Peter S. Rahko, MD University of Wisconsin Medical School G. William Dec, MD Massachusetts General Thierry H. LeJemtel, MD Albert Einstein College of Medicine

	Acknowledgments

 
The authors wish to thank Laurel Hunter and Frank Stewart for editorial assistance and manuscript preparation.

	Footnotes

 
This Phase II clinical trial was sponsored by Marian-Merrell Dow (MMD), now Hoechst Marian Roussel (HMR). At the time of this trial, Margo Schleman was an employee of MMD. Enoximone has since been licensed by HMR to Myogen, Inc., from whom Robert Roden and Alastair Robertson draw partial salary support. Michael Bristow is an Officer and Director of Myogen, in which he holds equity. Richard Gorczynski is an employee of Myogen.

^* A list of the Enoximone Study Group Members and institutional affiliations is provided in the appendix.

	References

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