The Influence of Beta Blocker Therapy on the Hemodynamic Response to Inotrope Infusion in Patients With Acute Decompensated Heart Failure
| Status: | Completed |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 99 |
| Updated: | 11/16/2018 |
| Start Date: | December 2010 |
| End Date: | October 2018 |
Purpose: To compare the hemodynamic effects of dobutamine and milrinone in hospitalized
patients who are receiving Beta Blocker Participants: Patients who are admitted to the
General Cardiology and Heart Failure Services at the University of North Carolina Hospitals
with acute decompensated heart failure, who have maintained steady state concentrations of
beta blocker therapy (carvedilol or metoprolol), and who are deemed by the health care team
to require pulmonary artery catheter placement and inotropic therapy with dobutamine or
milrinone by continuous infusion. Patients that are not currently receiving beta blocker
therapy will be enrolled for comparative purposes; however, any patient not at steady state
(on or off beta blocker therapy) will not be enrolled.
Procedures: After obtaining informed consent, patients will be assigned to the appropriate
sub-study group based on beta blocker use (Study A: patients on stable doses of metoprolol
and Study B: patients on stable doses of carvedilol). All patients should receive dobutamine
followed by milrinone as outlined in the dosing algorithm (see inotrope dosing algorithm
attached, as part of the usual standard of practice). Baseline pulmonary artery catheter
hemodynamic parameters will be collected prior to administration of inotrope trial of
dobutamine followed by milrinone. Hemodynamic parameters will be recorded per the dosing
algorithm following initiation and dose titration. Dose titration will be determined by the
health care team based upon patient response or lack thereof and tolerability. Changes in
hemodynamic parameters in response to dobutamine or milrinone will be compared within study
groups. Additionally, data will continue to be collected on patients receiving not beta
blocker therapy for comparative purpose.
patients who are receiving Beta Blocker Participants: Patients who are admitted to the
General Cardiology and Heart Failure Services at the University of North Carolina Hospitals
with acute decompensated heart failure, who have maintained steady state concentrations of
beta blocker therapy (carvedilol or metoprolol), and who are deemed by the health care team
to require pulmonary artery catheter placement and inotropic therapy with dobutamine or
milrinone by continuous infusion. Patients that are not currently receiving beta blocker
therapy will be enrolled for comparative purposes; however, any patient not at steady state
(on or off beta blocker therapy) will not be enrolled.
Procedures: After obtaining informed consent, patients will be assigned to the appropriate
sub-study group based on beta blocker use (Study A: patients on stable doses of metoprolol
and Study B: patients on stable doses of carvedilol). All patients should receive dobutamine
followed by milrinone as outlined in the dosing algorithm (see inotrope dosing algorithm
attached, as part of the usual standard of practice). Baseline pulmonary artery catheter
hemodynamic parameters will be collected prior to administration of inotrope trial of
dobutamine followed by milrinone. Hemodynamic parameters will be recorded per the dosing
algorithm following initiation and dose titration. Dose titration will be determined by the
health care team based upon patient response or lack thereof and tolerability. Changes in
hemodynamic parameters in response to dobutamine or milrinone will be compared within study
groups. Additionally, data will continue to be collected on patients receiving not beta
blocker therapy for comparative purpose.
Background:
First-line management of chronic heart failure includes beta blockers and angiotensin
converting enzyme (ACE) inhibitors, as these agents have been shown to have significant
benefits on morbidity and mortality in large clinical trials. Therefore, a substantial number
of patients with chronic heart failure are receiving chronic beta blocker therapy, most
commonly metoprolol succinate and carvedilol. However, despite significant advancements in
the treatment of chronic heart failure, the natural history of the disease remains
progressive and many patients develop acute decompensations requiring hospitalization. In the
setting of acute decompensated heart failure, the use of inotropic agents may be required for
hemodynamic support. The two most widely used inotropes are dobutamine and milrinone.
Dobutamine primarily acts as a beta-1 receptor agonist with some effects on beta-2 and
alpha-1 receptors. Milrinone is a phosphodiesterase III inhibitor, thus inhibiting the
breakdown of cyclic adenosine monophosphate. As such, milrinone works at a site that is
distal to beta receptors and may be less influenced by chronic beta blocker therapy. As such,
one may speculate that the presence of a beta blocker would influence the hemodynamic
response to dobutamine, but to a much lesser extent to milrinone, if at all.
Two small studies have assessed the hemodynamic response to dobutamine in the presence and
absence of beta blocker therapy in patients with chronic heart failure. In addition, one of
these studies assessed the response to enoximone, another phosphodiesterase III inhibitor.
Both studies demonstrated that metoprolol did not significantly affect the hemodynamic
response to dobutamine infusion, including its effect on cardiac index, heart rate, stroke
volume, and systemic vascular resistance. Conversely, carvedilol was shown to have
significant inhibitory effects on cardiac index, heart rate, and stroke volume during
dobutamine infusion. In addition, carvedilol appeared to increase mean arterial pressure at
higher doses of dobutamine. In the setting of an enoximone infusion, metoprolol increased the
cardiac index and stroke volume responses, while maintaining other hemodynamic parameters.
There was no significant difference in the hemodynamic response to enoximone infusion in the
presence of carvedilol.
Why This Study is Needed:
Published studies that assessed the hemodynamic response to inotropes in the presence and
absence of beta blockers included less than 50 patients combined. As such, the replication of
their results is warranted in order to use this data to drive changes in clinical practice.
Additionally, and equally as important, no study has been published, to the best of our
knowledge, which has assessed the hemodynamic response to milrinone in the presence of
metoprolol. . Although enoximone is a phosphodiesterase III inhibitor and is theoretically
similar to milrinone, it is not approved for use in the United States, thus making it
difficult to extrapolate these findings to milrinone. Lastly, the severity of illness in
patients included in current literature does not reflect individuals who will receive the
most benefit from therapy i.e. patients with acute decompensated heart failure.
First-line management of chronic heart failure includes beta blockers and angiotensin
converting enzyme (ACE) inhibitors, as these agents have been shown to have significant
benefits on morbidity and mortality in large clinical trials. Therefore, a substantial number
of patients with chronic heart failure are receiving chronic beta blocker therapy, most
commonly metoprolol succinate and carvedilol. However, despite significant advancements in
the treatment of chronic heart failure, the natural history of the disease remains
progressive and many patients develop acute decompensations requiring hospitalization. In the
setting of acute decompensated heart failure, the use of inotropic agents may be required for
hemodynamic support. The two most widely used inotropes are dobutamine and milrinone.
Dobutamine primarily acts as a beta-1 receptor agonist with some effects on beta-2 and
alpha-1 receptors. Milrinone is a phosphodiesterase III inhibitor, thus inhibiting the
breakdown of cyclic adenosine monophosphate. As such, milrinone works at a site that is
distal to beta receptors and may be less influenced by chronic beta blocker therapy. As such,
one may speculate that the presence of a beta blocker would influence the hemodynamic
response to dobutamine, but to a much lesser extent to milrinone, if at all.
Two small studies have assessed the hemodynamic response to dobutamine in the presence and
absence of beta blocker therapy in patients with chronic heart failure. In addition, one of
these studies assessed the response to enoximone, another phosphodiesterase III inhibitor.
Both studies demonstrated that metoprolol did not significantly affect the hemodynamic
response to dobutamine infusion, including its effect on cardiac index, heart rate, stroke
volume, and systemic vascular resistance. Conversely, carvedilol was shown to have
significant inhibitory effects on cardiac index, heart rate, and stroke volume during
dobutamine infusion. In addition, carvedilol appeared to increase mean arterial pressure at
higher doses of dobutamine. In the setting of an enoximone infusion, metoprolol increased the
cardiac index and stroke volume responses, while maintaining other hemodynamic parameters.
There was no significant difference in the hemodynamic response to enoximone infusion in the
presence of carvedilol.
Why This Study is Needed:
Published studies that assessed the hemodynamic response to inotropes in the presence and
absence of beta blockers included less than 50 patients combined. As such, the replication of
their results is warranted in order to use this data to drive changes in clinical practice.
Additionally, and equally as important, no study has been published, to the best of our
knowledge, which has assessed the hemodynamic response to milrinone in the presence of
metoprolol. . Although enoximone is a phosphodiesterase III inhibitor and is theoretically
similar to milrinone, it is not approved for use in the United States, thus making it
difficult to extrapolate these findings to milrinone. Lastly, the severity of illness in
patients included in current literature does not reflect individuals who will receive the
most benefit from therapy i.e. patients with acute decompensated heart failure.
Inclusion Criteria:
- Patients ≥ 18 years of age and English-speaking who are admitted to the General
Cardiology or Heart Failure Services at the University of North Carolina Hospitals
with acute decompensated heart failure (ADHF).
- Patients deemed by the health care team to require hemodynamic monitoring with a
pulmonary artery catheter and inotropic therapy. Patients receiving at least 3 doses
of continued beta blocker therapy with carvedilol, metoprolol succinate, or metoprolol
tartrate and patients receiving no beta blocker therapy or have missed at least 5
doses of beta-blocker therapy.
Exclusion Criteria:
- Concomitant treatment with other beta blockers, non-selective alpha blockers (e.g.
terazosin, prazosin, doxazosin), non-dihydropyridine calcium antagonists,
antiarrhythmic agents except for chronic stables doses of amiodarone, dofetilide or
mexiletine.
- Use of inotropes or IV vasoactive agents within 7 days or at time of enrollment
Patients with hemodynamically unstable arrhythmias (e.g., Systolic Blood Pressure
(SBP) < 80, Heart Rate (HR) > 110), uncorrected primary valvular disease, or current
mechanical support including left ventricular assist device (LVADs), Impella devices
and balloon pumps
- Patients who have missed more than 1 dose of beta blocker within 72 hours of starting
inotrope
- No subjects will be excluded based upon race, gender or ethnicity.
We found this trial at
1
site
Chapel Hill, North Carolina 27599
Principal Investigator: Jo Ellen Rodgers, PharmD
Phone: 919-962-2249
Click here to add this to my saved trials
