Nebulized Inhaled Milrinone in a Hospitalized Advanced Heart Failure Population

Approximately 5.7 million Americans have heart failure, a leading cause of both morbidity and
mortality in the United States. Heart failure was listed as a contributing cause in more than
280,000 deaths in 2008 in the U.S. (1 in 9) and about half of patients diagnosed with heart
failure die within 5 years. Patients with end stage heart failure have significant symptoms
(including fatigue and dyspnea) which prevent them from being able to perform most activities
of daily living. These patients often require repeated or prolonged hospitalizations for
disease management which contributes significantly to the cost of heart failure for the
United States (34.4 billion each year).

Milrinone, a phosphodiesterase III inhibitor, is one of the inotropic medications that has
been studied and used in the treatment of acutely decompensated heart failure. Several
studies have evaluated chronic intravenous (IV) inotrope use in end stage heart failure for
palliation of symptoms as well as evaluated effect on cost through decreased hospital
readmissions. Hauptman et al and Harjai et al demonstrated significant decreases in hospital
costs due to reductions in days hospitalized and readmissions after initiation of inotropes
including milrinone. However, the concern with IV milrinone use is the possibility of
increased mortality associated with therapy despite improved hemodynamics (increased cardiac
output, decreased filling pressures) and symptoms as was observed with chronic use of oral
inotropes. The OPTIME-CHF study confirmed this concern regarding the use of IV milrinone by
reporting increased mortality in patients with New York Heart Association (NYHA) class III-IV
ischemic heart failure without hemodynamic compromise as well as statistically significant
increases in atrial and ventricular arrhythmias when using intravenous milrinone. For this
reason, the American Heart Association/American College of Cardiology practice guidelines,
recommend use of IV milrinone only for patients presenting with clinical evidence of
hypotension associated with hypo-perfusion and elevated cardiac filling pressures in order to
maintain systemic perfusion and preserve end-organ performance. Administration of chronic IV
inotropes in heart failure patients with refractory symptoms is categorized as a class IIb
indication ("usefulness/efficacy is less well established by expert opinion").

This is a prospective, dual center, drug-interventional, non-blinded, open-label, randomized
controlled clinical trial. Anticipated number of patients enrolled in this study is n = 20
(10 patients randomized to nebulized inhaled milrinone and intravenous milrinone groups).
Patients with end stage HF, at the discretion of their treating cardiologist who ordered the
initial right heart catheterization (RHC) for evaluation of HF therapy, are sent for right
heart catheterization (RHC) to determine if inotropic therapy would be beneficial. If the
treating cardiologist decides to initiate inotropic therapy based on current
guideline-recommended therapies after RHC is performed, the patient will undergo
randomization to either the intervention arm (inhaled milrinone) or the control arm
(intravenous milrinone) prior to RHC. Randomization will be performed by randomized block
design using a randomization tool embedded within a REDCAP secure database with 2 blocks.
Because of the significant accumulation of milrinone in renal dysfunction, patients with a
creatinine clearance less than or equal to 40ml/min, as calculated by the Cockcroft-Gault
equation using the serum creatinine prior to randomization, will be placed into a separate
block from those with a creatinine clearance greater than 40ml/min.

The investigators goal is to show that inhaled milrinone is equivalent to "standard of care"
IV milrinone in improving hemodynamics in end stage heart failure patients (who respond to
milrinone therapy) in a prospective, randomized, controlled clinical trial. Change in patient
hemodynamic measurements before and during treatment will be assessed by right heart
catheterization hemodynamic variables (including right ventricle (RV) stroke work index,
Cardiac output (CO), mixed venous oxygen saturation, pulmonary venous resistence (PVR), and
systemic vascular resistence (SVR). Recognizing invasive hemodynamic studies are at the
discretion of the treating physicians decision and may also be challenging to complete or
deemed unnecessary in some patients, the primary endpoint will include 1) invasive
hemodynamic criteria consisting of PA catheter measurement of > 20% decrease in PCWP or > 20%
increase in Thermodilution or Fick Cardiac Index (CI) at time of second RHC compared to
baseline measurements or; 2) centrally (ie: PICC access) measured SVO2 which will be used to
determine Fick calculation of CI (a >20% increase in CI will be required to meet primary end
point compared to Fick CI from baseline) without need for PA catheter placement or; 3) in the
absence of PA catheter placement and central access for SVO2 determination, a > 30% decline
in laboratory based BNP measurements compared to baseline BNP and an improvement of 15
percentage points from baseline in the dyspnea visual analog scale (range 0-100) will also be
considered to meet primary endpoint.

Inclusion Criteria:

1. Patients age > 18 years old

2. Symptomatic Stage D heart failure requiring initiation of inotropic medication at the
discretion of their cardiologist

3. Signed informed consent

Exclusion Criteria:

1. Patients incapable of signing informed consent for any reason

2. Patients who are pregnant or breastfeeding

3. Systolic blood pressure less than 85 mmHg prior to randomization

4. Documented allergy or adverse reaction to milrinone