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Author: Sandeep Devabhakthuni, PharmD, BCCP

Beta blockers are a fundamental therapy in chronic heart failure (HF); however, controversy exists in how to manage these medications in a patient with acute decompensated heart failure (ADHF).1,2 Specific recommendations for general management of beta blockers in patients presenting with ADHF have been discussed in a previous blog. There is a subset of patients with ADHF on chronic beta blockade who may require initiation of inotropic therapy during due to low cardiac output, hypotension, or cardiogenic shock.3 Healthcare providers frequently ask about the best approach to manage beta blocker therapy when the decompensated HF patient is initiated on an intravenous inotrope. One common concern is that beta blockers may counteract the effects of inotropic therapy; therefore, beta blockers are often discontinued when an inotrope is initiated.3 However, before automatically holding the beta blocker in this situation, here are three considerations in managing concomitant chronic beta blockade and intravenous inotropic therapy:

1) Abrupt discontinuation of beta blocker therapy may worsen ADHF.
If a patient is beta blocker naïve or has been off therapy for a significant period, initiation in the setting of ADHF should be discouraged. However, in recent years, beta blocker therapy for HF is more widespread, and many patients hospitalized with exacerbations of HF are being admitted while receiving chronic beta blocker treatment.4,5 While it may seem counterintuitive, discontinuations in this setting could lead to rebound sympathetic activity, including tachycardia, increased cardiac oxygen consumption,  vasoconstriction, and increased filling pressures.6 This surge of sympathetic activity in conjunction with initiation of inotrope therapy could potentially increase the risk for arrhythmias. Thus, if the patient is hemodynamically stable, continuation of beta blockade may be beneficial as the reduction in heart rate results in decreased myocardial oxygen demand, increased ventricular diastolic filling, and decreased risk of arrhythmias.

2) Decompensated HF patients may have a blunted response to dobutamine.
Dobutamine acts as an agonist for beta-1, beta-2, and alpha-1 receptors to improve cardiac output with a modest reduction in systemic vascular resistance.7 In HF patients receiving chronic beta blocker therapy, the response to treatment with a beta agonist like dobutamine may be blunted.7 Thus, combination therapy is frequently avoided in practice. However, the hemodynamic effect of dobutamine is actually dependent on the specific type of beta blocker. In combination with carvedilol, a non-selective beta blocker with alpha-1 antagonist activity, a low dose of dobutamine increases cardiac output slightly, whereas a higher dose causes a vasopressor effect with no increase in cardiac output.8 As such, even low doses of carvedilol may decrease the favorable effects of dobutamine.9 In contrast, metoprolol, a beta-1 selective antagonist, does not have a similar effect on dobutamine.7 Interestingly, chronic treatment with metoprolol leads to upregulation of beta-1 receptors, which could potentially enhance the contractile response of dobutamine.7 As such, beta blockade with metoprolol may be continued in patients receiving dobutamine in the absence of hemodynamically instability or signs/symptoms of cardiogenic shock.

3) Continuing beta blocker therapy may be beneficial when used with a phosphodiesterase III inhibitor.
Milrinone increases cyclic adenosine monophosphate through inhibition of phosphodiesterase (PDE) III in the myocardium and vascular smooth muscle, resulting in positive inotropic and vasodilatory activity.7 As the site of action is beyond the beta adrenergic receptor, milrinone can still retain its hemodynamic effect in the setting of beta blockade.7 Additionally, beta blockers may reduce the adverse effects of PDE III inhibitors by mitigating the risk of arrhythmias while positive inotropy may counter negative hemodynamic effects of acute beta blocker therapy.10-12

The efficacy of milrinone versus dobutamine was compared in twenty ADHF patients on chronic carvedilol therapy.13 In this study, milrinone increased cardiac index (2 to 2.6 L/min/m2, p=0.0001) and decreased mean pulmonary artery pressure (36 to 29 mm Hg, p=0.00021), pulmonary capillary wedge pressure (24 to 18 mm Hg, p=0.0001) and mean arterial pressure (78 to 75 mm Hg, p=0.0002) without significantly altering heart rate (70-75 bpm, p=0.19). On the other hand, dobutamine produced an increase in cardiac index (2.4 to 3.3 L/min/m2, p=0.0001) only at doses higher than those commonly used for heart failure (15-20 mcg/kg/min). Dobutamine also increased both heart rate (68-82 bpm, p=0.008) and mean systemic pressure (90 to 117 mm Hg, p=0.0001). The hemodynamic effects of dobutamine and enoximone (PDE III inhibitor) were also compared before and after long-term beta blocker therapy with metoprolol or carvedilol in patients with chronic HF.14 Both beta blockers significantly inhibited the favorable hemodynamic response to dobutamine while the hemodynamic response to enoximone was either maintained or enhanced in the presence of carvedilol or metoprolol. Overall, these data support the use of PDE III inhibitors preferentially over dobutamine when an inotropic agent is needed in a patient with ADHF on chronic carvedilol therapy.15 Combination therapy with beta blocker and PDE III inhibitor in patients with advanced HF is generally well tolerated and may even confer long-term benefits such as improvement in left ventricular ejection fraction and functional class as well as a decrease in hospitalizaions.11

Bottom Line
Beta blockers are standard of care in the management of chronic HF. However, patients on chronic beta blocker therapy may require inotropic agents in the setting of acute decompensation. Unless in the presence of hemodynamic instability or cardiogenic shock, beta blocker continuation is preferred and may even prevent further clinical deterioration. If concomitant therapy is planned, either a beta agonist or PDE III inhibitor may be safely initiated depending on the clinical scenario. If a beta agonist is selected, the contractile response may be preserved with concomitant metoprolol but would be blunted with carvedilol.7 As such, PDE III inhibitors are preferred in patients on carvedilol.15 If a PDE III inhibitor is selected, continuing chronic beta blockade is safe regardless of individual agent.15 For those patients planned for long-term inotropic therapy post discharge, the combination of PDE III inhibitor and beta blocker therapy may provide additional clinical benefit.11

Sandeep Devabhakthuni, PharmD, BCCP

Sandeep Devabhakthuni is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in advanced heart failure at the University of Maryland Medical Center in Baltimore, MD. Follow him on Twitter @deepdev511

References:

  1. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardilogy/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136:e137-e161.
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  5. Adams KF, Fonarow GC, Emerman CL, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2005;149:209-16.
  6. Hjemdahl P, Olsson G. Rebound phenomena following withdrawal of long-term beta-adrenoreceptor blockade. Acta Med Scand Suppl. 1982;665:43-7.
  7. Lowes BD, Simon MA, Tsvetkova TO, Bristow MR. Inotropes in the beta-blocker era. Clin Cardiol. 2000;23(3 Suppl):11-6.
  8. Bollano E, Scharin TM, Hjalmarson A, et al. Different responses to dobutamine in the presence of carvedilol or metoprolol in patients with chronic heart failure. Heart. 2003;89:621-4.
  9. Triposkiadis F, Dalampiras P, Kelepeshis G, et al. Hemodynamic effects of dobutamine in patients with exacerbation of chronic systolic heart failure treated with low doses of carvedilol. Int J Clin Pharmacol Ther. 2008;46:136-9.
  10. Kobayashi S, Susa T, Tanaka T, et al. Low dose beta-blocker in combination with milrinone safely improves cardiac function and eliminates pulsus alternans in patients with acute decompensated heart failure. Circ J. 2012;76:1646-53.
  11. Shakar SF, Abraham WT, Gilbert EM, et al. Combined oral positive inotropic and beta-blocker therapy for treatment of refractory class IV heart failure. J Am Coll Cardiol. 1998;31:1336-40.
  12. Jaiswal A, Nguyen VQ, Carry B, Jemtel THL. Combination therapy with beta blocker and inotrope in decompensated heart failure: a clinical observation. Heart Res Open J. 2017;4:18-22.
  13. Lowes BD, Tsvetkova T, Eihhorn EJ, et al. Milrinone vs. dobutamine in heart failure subjects treated chronically with carvedilol. Int J Cardiol. 2001;81:141-9.
  14. Metra M, Nodari S, D’Aloia S, et al. Beta blocker therapy influences the hemodynamic response to inotropic agents in patients with heart failure: a randomized comparison of dobutamine and enoximone before and after chronic treatment with metoprolol or carvedilol. J Am Coll Cardiol. 2002;40:1248-8.
  15. Jennings DL, Thompson ML. Use of combination therapy with a beta blocker and milrinone in patients with advanced heart failure. Ann Pharmacother. 2009;43:1872-6.

 

 

Can beta-blockers be continued in patients requiring inotropic therapy?

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