Beta-blocker medications have been shown to improve heart function and prolong the lives of
patients with chronic heart failure (CHF). Some people with advanced CHF have difficulty
taking beta-blocker medications due to troublesome side effects, such as low blood pressure
and/or low heart rate, severe tiredness, dizziness, or shortness of breath. In other words,
they have difficulty tolerating beta-blocker medications. The purpose of this study is to
determine if enoximone can improve a patient's ability to tolerate a beta-blocker
Minimum age: 18 Years.
Maximum age: N/A.
In order to be considered an eligible subject, all of the following entry criteria must be
- Subjects must be competent to provide informed written consent. Subjects must sign an
IRB/IEC approved informed consent form prior to the initiation of any study
- Subjects must be 18 years of age or older.
- Subjects must have ischemic or nonischemic cardiomyopathy with symptoms of NYHA Class
III or IV chronic heart failure.
- Subjects must have a LVEF of less than or equal to 35%, measured within 60 days of the
Screening Visit. LVEF must be assessed by radionuclide ventriculography (MUGA). If
the subject has experienced any cardiovascular events, has undergone any
interventions, or received any changes in treatment that may have affected LV function
since the most recent EF measurement, an LVEF measurement must be completed prior to
the subject being randomized.
- Subjects must have a left ventricular end diastolic dimension (LVEDD) of >2. 7 cm/m2 as
measured by 2-D ECHO within 12 months of the Screening Visit.
- Subjects must be on optimal conventional heart failure therapy (with the exception of
a beta-blocker), including an ACEI for at least 30 days prior to the Screening Visit,
or the subject must have had a trial of an ACEI and proven to be intolerant, or the
subject must be taking an ARB for at least 30 days prior to the Screening Visit or
proved to be intolerant. Optimal conventional therapy may also include
spironolactone, digitalis glycosides, diuretics, or other vasodilators.
- Subjects must have failed the initiation, or the up-titration, of a beta-blocker drug
due to hemodynamic intolerance within 12 months prior to the Screening Visit. Failure
to tolerate beta-blockade for hemodynamic reasons is defined as worsening signs and
symptoms of chronic heart failure, hypotension accompanied with symptoms, or evidence
of organ hypoperfusion, which in the judgment of the treating physician precluded
further treatment with the beta-blocker. This beta-blocker intolerance must have been
documented prior to Screening, and a narrative description of the intolerance must be
approved by Myogen prior to Randomization.
Subjects who meet any one of the following criteria will be deemed ineligible for
participation in the study:
- Subjects with CHF due to or associated with uncorrected primary valvular disease,
uncorrected thyroid disease, obstructive/hypertrophic cardiomyopathy, pericardial
disease, amyloidosis, active myocarditis, malfunctioning artificial heart valve,
uncorrected congenital heart disease, isolated right-sided heart failure, or primary
- Subjects who have undergone a cardiac revascularization, valvular surgery, or
bi-ventricular resynchronization procedure within 60 days prior to the Screening
- Subjects listed for heart transplantation who are expected to be transplanted within 6
months of randomization.
- Subjects who have had a myocardial infarction within 90 days prior to the Screening
- Subjects with an ECG recorded at the Screening Visit showing any of the following: 1)
evidence of transmural ischemia (dynamic ST elevation or ST elevation associated with
ischemic symptoms), or 2) ventricular tachycardia (VT) or premature ventricular
complexes (PVCs) associated with symptoms, or 3) VT of greater than or equal to 6
- Subjects with sustained (>15 seconds) VT, unless precipitated by an event such as an
acute myocardial infarction, induction by catheter placement, or by an
electrophysiology procedure, or addressed by AICD placement.
- Subjects with an AICD that has fired for any ventricular arrhythmia within 90 days of
the Randomization Visit.
- Subjects with a documented diagnosis of angina that meets either of the following
criteria: 1) angina diagnosed as unstable at any time within the 60 days prior to the
Screening Visit or 2) angina is the primary symptom that limits daily physical
- Subjects who have had ventricular reduction surgery or cardiac myoplasty.
- Subjects on a mechanical assist device.
- Subjects with evidence of a concomitant disease that may interfere with the natural
course of the subject’s underlying heart failure for the duration of the trial.
- Subjects having a concomitant life-threatening disease for which their life expectancy
is estimated to be less than one year.
- Subjects with uncontrolled insulin-dependent diabetes mellitus with a history of
frequent hypoglycemic episodes or frequent hospitalizations for hyperglycemia.
- Subjects on the following concomitant medications at the time of Screening are
excluded from participating in the study: 1) Calcium antagonists other than amlodipine
or felodipine; 2) Flecainide, encainide, propafenone, sotalol, dofetalide or
disopyramide; 3) Subjects receiving i. v. positive inotropic agents within seven days
of the Screening Visit or Randomization Visit; 4) Subjects receiving a human BNP,
including nesiritide, within seven days of the Screening Visit or Randomization Visit;
5) Subjects receiving oral or i. v. type-III PDE inhibitors within seven days of the
Screening Visit or Randomization Visit.
- Subjects with a contraindication to treatment with a positive inotropic agent (defined
as a serious adverse event attributed to previous treatment with a positive
- Subjects with a known contraindication to beta-blocker therapy. This may include
beta-agonist-dependent chronic obstructive pulmonary disease or asthma, a heart rate
<55 BPM, the presence of second- or third-degree heart block without an implanted
pacemaker, and first-degree heart block with a PR interval >220 milliseconds.
- Subjects with active hepatic (screening serum total bilirubin greater than or equal to
3. 0 mg/dL), renal (screening serum creatinine greater than or equal to 2. 0 mg/dL),
hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous
system disease, which in the opinion of the Investigator, may adversely affect the
safety and efficacy of the study drug or the life span of the subject.
- Subjects known to abuse or actively abusing alcohol or illicit drugs. Abuse of
alcohol is defined as the usual daily intake of more than 100 grams of ethanol per
day, or more than approximately 6 twelve-ounce bottles of beer, one 750 mL bottle of
wine or 250 mL of 80 proof spirits.
- Subjects with a serum potassium <4. 0 mEq/L or >5. 5 mEq/L at Screening.
- Subjects with a serum digoxin of >1. 2 ng/mL at Screening are excluded.
- Pregnant women and women at risk of becoming pregnant (i. e., not using effective
methods of birth control).
- Subjects who have participated in a clinical trial involving another investigational
drug or device within 30 days of the Screening Visit or at any time during the study.
- Subjects who have demonstrated noncompliance with previous medical regimens.
- Subjects who are hospitalized at the time of the Randomization Visit and are not
hemodynamically stable, or for whom there is an acute cardiac or non-cardiac illness
that requires further hospitalization.