European Heart Journal: Acute Cardiovascular Care (2021) 10, 676–686 CLINICAL PRACTICE

doi:10.1093/ehjacc/zuab047

Inotropic therapies in heart failure and

cardiogenic shock: an educational review
Jacqueline T. DesJardin1 and John R. Teerlink1,2*
1
Division of Cardiology, School of Medicine, University of California San Francisco, San Francisco, CA, USA; and 2Section of Cardiology, San Francisco Veterans Affairs Medical
Center, 111C, 4150 Clement Street, San Francisco, CA 94121-1545, USA

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Received 18 May 2021; editorial decision 28 May 2021; online publish-ahead-of-print 5 July 2021

Reduced systolic function is central to the pathophysiology and clinical sequelae of acute decompensated heart failure (ADHF) with
reduced ejection fraction and cardiogenic shock. These clinical entities are the final common pathway for marked deterioration of right or
left ventricular function and can occur in multiple clinical presentations including severe ADHF, myocardial infarction, post-cardiac surgery,
severe pulmonary hypertension, and advanced or end-stage chronic heart failure. Inotropic therapies improve ventricular systolic function
and may be divided into three classes on the basis of their mechanism of action (calcitropes, mitotropes, and myotropes). Most currently
available therapies for cardiogenic shock are calcitropes which can provide critical haemodynamic support, but also may increase myocar-
dial oxygen demand, ischaemia, arrhythmia, and mortality. Emerging therapies to improve cardiac function such as mitotropes (e.g. per-
hexiline, SGLT2i) or myotropes (e.g. omecamtiv mecarbil) may provide useful alternatives in the future.
...................................................................................................................................................................................................

Graphical Abstract

The three main mechanisms for increasing cardiac function are drugs that improved myocardial energetics (mitotropes), augment cardiomyocyte calcium
.. adenosine diphosphate; ATP, adenosine triphosphate; Ca, calcium; cAMP.
fluxes (calcitropes) or directly increase sarcomere function (myotropes). ADP,
cyclic adenosine monophosphate; CoA. coenzyme A; K. potassium; Na. sodium; .. Pi . inorganic phosphate; SERCA. sarcoplasmic/endoplasmic reticulum
calcium ATPase; TCA, tricarboxylic acid cycle. Modified from Psotka, et al.1 .
.

* Corresponding author. Tel: þ1-415-221-4810, x24160, Email: john.teerlink@ucsf.edu

Published by Oxford University Press on behalf of the European Society of Cardiology 2021. This work is written by a US Government employee and is in the public domain in
the US.
Inotropic therapies in HF and cardiogenic shock 677

...........................................................................................................................................................................................
Keywords Cardiogenic shock • Inotrope • Myotrope • Calcitrope • Mitotrope • Heart failure

Learning objectives
• Learn the different mechanisms of action of inotropic therapies.
• Learn the different indications for inotropic therapies.
• Learn the currently available inotropic therapies for the treatment of cardiogenic shock.
• Learn potential future inotropic therapies for cardiogenic shock.

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..
Reduced myocardial contractility has long been recognized as a cen- .. and cytosolic calcium from both extracellular and sarcoplasmic re-
tral feature of heart failure with reduced ejection fraction (HFrEF), .. ticular sources. Three endogenous (norepinephrine, dopamine, epi-
..
and therefore a potential target for pharmacologic therapies. Ever .. nephrine) and two synthetic (dobutamine, isoproterenol)
since the isolation of epinephrine in 1897 by Dr John Jacob Abel at
.. catecholamines continue to be frequently used in clinical practice. In
..
Johns Hopkins University, inotropic agents have been investigated for .. addition to their b1-receptor-mediated inotropic effects, all three en-
the treatment of heart failure (HF). Inotropic agents have favourable
..
.. dogenous catecholamines bind a-receptors and induce peripheral
short-term haemodynamic effects in acute HF, including increased .. vasoconstriction. Compared to the other agents, norepinephrine has
stroke volume and cardiac output. Many also decrease systemic vas-
..
.. relatively limited b1 affinity and augments mean arterial blood pres-
cular resistance, further improving cardiac performance. For this rea- .. sure primarily via increased systemic vascular resistance. Dopamine
..
son, inotropes can be life-saving when used for acute haemodynamic .. has differential effects on D1 and serotonin receptors depending on
stabilization in cardiogenic shock. However, despite their advanta- .. dosing, although its inotropic b1 receptor effects are most pro-
..
geous acute effects, inotropic therapy has shown disappointing .. nounced at intermediate doses (e.g. 3–5 mg/kg/min). Epinephrine acts
results in the treatment of chronic HF. In the past 30 years, numerous .. predominantly on b-receptors at low doses and has progressively
..
clinical trials on a variety of agents have reported increased risk of .. more a-receptor-mediated vasoconstriction at increasing doses.
mortality and progression of HF among patients treated chronically .. Comparatively, dobutamine is considered an inodilator: although it
..
with inotropes. Most of these failed drugs alter intracellular calcium .. also has a1-receptor effects especially at high doses, at low doses
and, in doing so, increase myocardial oxygen demand and arrhyth- ..
.. these are generally offset by vasodilatory b2 stimulation and there is a
mias. Recently, newer inotropic agents, such as omecamtiv mecarbil, .. net reduction in systemic vascular resistance. Isoproterenol is a non-
have been developed which exert their effect via calcium-independ- ..
.. selective b-agonist that is clinically used for its chronotropic rather
ent pathways, and therefore have the potential to achieve increased .. than inotropic effects.
myocardial contractility with safer risk profile. In this manuscript, we
..
.. A second class of calcitropes, phosphodiesterase-3 inhibitors, act
explore the contemporary evidence-based uses for inotropes in HF: .. downstream in the same pathway, and increases intracellular calcium
including chronic HF, acute decompensated HF (ADHF), and cardio-
..
.. by inhibiting the degradation of cAMP. Because they do not rely on
genic shock, with a particular emphasis on high-quality evidence from .. binding to b1-adrenergic receptors to achieve their inotropic effect,
randomized controlled trials (RCTs).
..
.. phosphodiesterase-3 inhibitors are preferentially used by some
..
Mechanisms of action .. physicians in patients on beta-blockers. Furthermore, their chrono-
.. tropic effects are trivial at low and medium doses, and they cause less
..
When organized by the mechanism of action, there are three broad .. tachyarrhythmias relative to catecholamines. Milrinone is the most
groups into which inotropic agents can be categorized: (i) calcitropes,
.. commonly used phosphodiesterase-3 inhibitor, although enoximone
..
(ii) mitotropes, and (iii) myotropes (Table 1). An extensive review of .. and inamrinone are also available in Europe. Some phosphodiester-
.. ase-3 inhibitors, particularly levosimendan, also exhibit calcium sensi-
the biochemical and mechanistic differences between inotropes is be- ..
yond the scope of this review, but is well-covered by Psotka et al. .. tizing properties. Levosimendan, which is available in some countries
..
2019.1 .. in Europe and elsewhere in the world but remains unapproved in
.. North America, exerts some of inotropic effect via by binding cardiac
..
Calcitropes .. troponin C and increasing the myocyte’s sensitivity to calcium. Both
As their name implies, calcitropes increase contractility by altering .. milrinone and levosimendan are also potent vasodilators and so often
..
intracellular calcium, which is also the mechanism by which they in- .. require concurrent use of vasopressors when used in patients with
duce adverse effects, most notably increased myocardial oxygen de- .. refractory hypotension. Still other calcitropes increase intracellular
..
mand and arrhythmias. Calcitropes may increase intracellular calcium .. calcium by impeding the Naþ/Ca2þ exchanger, either via direct inhib-
via a variety of mechanisms. Catecholamines are the most commonly .. ition (flosequinan) or by interfering with the establishment of the
..
used calcitropes; they bind and directly activate b1-adrenergic recep- .. Naþ gradient upon which this transporter relies (istaroxime,
tors, leading to increased cyclic adenosine monophosphate (cAMP)
.. digoxin).2
Table 1 Inotropic agents: mechanisms, dosing, and selected clinical trials

678
Dosing Selected clinical trials
.................................................................................................................................................................................................................................................................................................
Calcitropes
b1-Receptor agonists Dopamine IV: No bolus. 3–5 mg/kg/min for inotropic effects. ADHF: No difference in urine output or change in cystatin C level com-
Half-life 9 min. Weight-based dosing preferred pared to placebo in patients hospitalized with decompensated HF
(ROSE 2013)
Epinephrine IV: 1 mg bolus during resuscitation; 0.05–0.5 mg/kg/min. Half-life <5 min. Shock: Norepinephrine superior to epinephrine in preventing refrac-
Weight-based dosing preferred tory shock in acute myocardial infarction (OptimaCC 2018)
Norepinephrine IV: No bolus. 0.01–0.20 mg/kg/min. Immediate onset. Half-life 2 min. Shock: Norepinephrine superior to dopamine in preventing death in
Weight-based dosing preferred cardiogenic shock from mixed aetiologies (SOAP II 2012)
Dobutamine IV: No bolus. 1–5 mg/kg/min. Onset 1–10 min. Peak effect 15 min. Half-life ADHF: No difference between dobutamine and levosimendan in mor-
2 min tality at 180 days in patients with EF <_30% hospitalized with ADHF
(SURVIVE 2007)
Isoproterenol IV: 2–10 mg/min. Immediate onset. Half-life 3 min N/a—Trials primarily in other patient populations
Dopexamine IV: 0.5–6 mg/kg/min. Not available in USA N/a—Early phase trials or trials in other patient populations
Xamoterol PO: 200 mg BID. Not clinically available Chronic HF: 254% "mortality after 3 months in chronic NYHA III–IV
and EF <35% (Xamoterol Group 2003)
Ibopamine PO: 100 mg TID. Not clinically available Chronic HF: 26% "mortality after 12 months in NYHA III–IV and EF
<35% HF (PRIME II 1997)
Phosphodiesterase-3 Milrinone IV: Optional bolus (25–75 mg/kg over 10–20 min). 0.375–0.75 mg/kg/min. Chronic HF: 28% "mortality (PO immediate release milrinone) after
inhibitors Onset 10 min. Half-life 2.5 h (prolonged in renal failure). Dose reduced 6 months in NYHA
in renal dysfunction III–IV and EF <_35% HF (PROMISE 1991)
PO: immediate release (10 mg QID) or extended release (14 mg BID) ADHF: No difference in days of hospitalization for CV causes compared
to placebo in patients with EF <40% hospitalized with ADHF
(OPTIME-CHF 2002)
Pimobendana PO: 1.25–2.5 mg BID. Not available in USA or Europe Chronic HF: 6% improvement in exercise duration, but 80% increase in
mortality in EF<_45% (PICO 1996)
Chronic HF: 45% #adverse cardiac event (sudden CV death, HF-related
death, HF hospitalization) after 13 months in NYHA II–III and EF
<_45% (EPOCH 2002)
Enoximone IV: Bolus 0.5–1 mg/kg over 15 min, 5–20 mg/kg/min Chronic HF: No difference in symptom score or exercise duration (PO
PO: 50–150 mg TID enoximone) after 4 months in NYHA II–III and EF <40%
(Enoximone Multicenter Trial 1990)

J.T. DesJardin and J.R. Teerlink

Vesnarinone PO: 30–60 mg daily Chronic HF: 21% "mortality (60 mg qD) after 10 months in NYHA III–
IV and EF <_30% HF (VEST 1998)
Inamrinone (aka amirinone) PO: 120–200 mg TID Chronic HF: No difference in symptoms, NYHA class, or EF in NYHA
III–IV HF between inamrinone and placebo, more adverse events
with inamrinone (Massie et al. 1985).
Levosimendana IV: Optional bolus (12 mg/kg over 10 min). 0.05–0.2 mg/kg/min. Not available ADHF: Improved short-term symptoms over 5 days after 24-h infusion
in USA. Half-life 80 h, peak 30 min in patients hospitalized with ADHF, although more hypotension,
Continued

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 Inotropic therapies in HF and cardiogenic shock
Table 1 Continued

Dosing Selected clinical trials

.................................................................................................................................................................................................................................................................................................
arrhythmias, and possibly mortality with levosimendan (REVIVE
2013)
Cilostazol PO: 100 mg BID N/a—Cilostazol is approved for claudication, but contraindicated in
HF due to evidence for harm from other phosphodiesterase-3
inhibitors
Naþ/Ca2þ inhibition Digoxin PO: 0.125–0.25 mg daily or every other day. Dose reduced in renal dys- Chronic HF: 6% #hospitalization but no difference in mortality after
function. Maintain digoxin level <_0.9 ng/mL 37 months in EF <_45% (DIG trial 1997)
Flosequinan PO: 75–100 mg daily Chronic HF: 39% "mortality after 10 months in NYHA III–IV and EF
<_35% (PROFILE 1997)
Istaroxime IV: 0.5–1.5 mg/kg/min ADHF: Decreased pulmonary capillary wedge pressure and increased
systolic blood pressure with 6-h infusion of istaroxime compared to
placebo in patients with EF <_35% hospitalized with ADHF
(HORIZON-HF 2009)
Mitotropes
# Fatty acid use SGLT2Is PO: 10 mg daily (dapagliflozin or empagliflozin) Chronic HF: In NYHA II–IV and EF <_40%, treatment with dapagliflozin
resulted in 17% #mortality after 18 months (DAPA-HF 2019) and
treatment with empagliflozin resulted in 25% #adverse CV events
(CV death or HF hospitalization) after 16 months (EMPEROR-
REDUCED 2020)
Perhexiline PO: 100 mg BID N/a—Early phase trials only (Lee et al. 2005)
Trimetazidine PO: 20 mg TID N/a—Early phase trials only (Fragasso et al. 2006)
Electron Transport Chain Coenzyme Q PO: 100 mg TID Chronic HF: 50% #adverse CV events at 24 months in NYHA III–IV HF
(Q-SYMBIO 2014), results not confirmed in subsequent trials
Elamipretide IV: 0.005–0.25 mg/kg/h. Not approved for clinical use N/a—Early phase trials only (Daubert et al. 2017)
Myotropes
Cardiac Myosin Activator Omecamtiv mecarbil IV: 20 mg/h for loading dose; 4 mg/h for maintenance dose ADHF: Greater dyspnoea relief compared to placebo with 48-h infusion
PO: 25–50 mg BID of high-dose IV omecamtiv mecarbil through 5 days in patients with
EF <_40% hospitalized with ADHF (ATOMIC-AHF 2016)
Chronic HF: 8% #adverse HF event (HF hospitalization, HF urgent care
visit, or CV death) after 22 months in inpatients or outpatients with
NYHA II–IV and EF <_35% treated with PO omecamtiv mecarbil
(GALACTIC-HF 2021)

a
May also have myotropic effect.
ADHF, acute decompensated heart failure; CV, Cardiovascular; EF, ejection fraction; HF, heart failure; IV, Intravenous; N/a, Not available/ applicable; NYHA, New York Heart Association; PO, per os (oral); SGLT2Is, sodium–glucose co-
transporter 2 inhibitors.

679
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680
Mitotropes
Conversely, mitotropes improve the efficiency of mitochondrial en-
ergy production. Some mitotropes shift metabolism away from fatty
acids and towards a more efficient energy sources, others supple-
ment components of the electron transport chain or stabilize the
inner mitochondrial membrane. Perhexiline and trimetazidine are
mitotropes that improve mitochondrial bioenergetics by encouraging
glucose-based metabolism, both have been studied in early small clin-
ical trials for the treatment of HFrEF.3,4 Similarly, sodium–glucose co-
transporter 2 inhibitors (SGLT2Is) shift oxidative metabolism away
from fatty acids in favour of ketones, although the mechanisms by
which they exert beneficial cardiorenal effects are debated and likely
multifactorial.5 Elamipretide concentrates in the inner mitochondrial
membrane and binds and stabilizes cardiolipin in order to augment
adenosine triphosphate (ATP) production.6 Coenzyme Q10, which
continues to be frequently used as a supplement, is an obligate cofac-
tor in the electron transport chain and has been shown in a single
small trial to improve cardiovascular outcomes, although these
results have not been replicated or confirmed.7 As a class, mitotropes
are emerging potential therapies for the treatment of HFrEF, al-
though most (with the exception of SGLT2Is) require larger clinical
trials to establish their safety and efficacy.
Myotropes
The third and final class of inotropes, myotropes, directly increase
the function of the sarcomere via calcium-independent mechanisms.
Omecamtiv mecarbil is the first exclusively myotropic agent, although
levosimendan demonstrates some myotropic effect. Omecamtiv
mecarbil binds to cardiac myosin and promotes increased interaction
between myosin and actin in order to increase myocardial force pro-
duction. Myotropes do not affect cytosolic calcium, with no effect on
arrhythmias or ischemia. Furthermore, they improve the efficiency
and duration of contraction without increased ATP or oxygen
utilization.
Inotropes in contemporary
clinical practice
HF is the clinical syndrome that occurs when the heart is unable to
deliver an adequate flow of blood to the tissues to meet their meta-
bolic needs at normal filling pressures. The symptoms and signs of HF
are manifestations of congestion and decreased organ perfusion.
There are multiple aetiologies of HFrEF which can progress to neces-
sitate hospitalization and some of these patients with ADHF may re-
quire inotropic therapy. Cardiogenic shock represents an extreme
manifestation of HFrEF where the poor cardiac output results in evi-
dence of tissue hypoperfusion in the absence of hypovolemia. There
are multiple aetiologies for cardiogenic shock, including mixed aetiol-
ogies, acute myocardial infarction, post-cardiac surgery, and right
ventricular (RV) failure, all of which could potentially benefit from
inotropic therapy. In addition, many patients with advanced chronic
HF may benefit from inotropic therapy either as a primary therapy or
as a bridge to more advanced therapies. Inotropes also have the po-
tential to improve or palliate symptoms in patients with pre-terminal
HF.
J.T. DesJardin and J.R. Teerlink
.. Inotropes in acute decompensated heart
..
.. failure without cardiogenic shock
..
.. Once a cornerstone of medical therapy for ADHF, calcitropes have
.. now fallen out of favour for the management of ADHF without car-
..
.. diogenic shock due to evidence suggesting no benefit and the poten-
.. tial for harm. The ‘Outcomes of a Prospective Trial of Intravenous
..
.. Milrinone for Exacerbation of Chronic Heart Failure’ (OPTIME-
..
.. CHF), published in 2002, was double-blinded, placebo-controlled
.. study of 951 patients with ADHF (ejection fraction, EF < 40%)
..
.. randomized to placebo or a 48-h infusion of milrinone at 0.5 mg/kg.8
.. The population studied was not in cardiogenic shock, as the exclusion
..
.. criteria included need for inotropes for shock, acidosis, or hypoten-
.. sion. There was no difference in the primary outcome of length of
..
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.. hospitalization for cardiovascular causes in the 2 months after ran-
.. domization. Milrinone infusion was associated with more episodes of
..
.. sustained hypotension (3.2% vs. 10.7%, P < 0.001) and a higher inci-
... dence of new atrial arrhythmias (1.5% vs. 4.6%, P = 0.004) during the
.. index hospitalization.8 Furthermore, there was a non-significant trend
..
.. towards higher in-hospital mortality in the milrinone arm (3.8% v
..
.. 2.3%, P = 0.19), and subsequent analyses suggested that patients with
.. ischaemic aetiologies had particularly poor outcomes when treated
..
.. with milrinone.9 Non-catecholamine calcitropes similarly have poor
.. evidence for use in this setting. As noted above, levosimendan has
..
.. multiple mechanisms of action, including potent vasodilating effects.
.. In the 600 patients admitted for ADHF in the REVIVE trial, levosimen-
..
.. dan improved a clinical composite of clinical status through 5 days
.. compared to placebo, but was also associated with hypotension and
..
.. arrhythmias during the infusion and an early increase in mortality that
.. persisted through 90 days.10 Similarly, the ‘Survival of Patients with
..
.. Acute Heart Failure in Need of Intravenous Inotropic Support’
.. (SURVIVE) trial found no mortality difference between infusions of
..
.. dobutamine and levosimendan for the treatment of ADHF, although
..
.. levosimendan was associated with a lower blood pressure during in-
.. fusion and higher rates of atrial fibrillation, hypokalaemia, and
..
.. headache.11
.. Omecamtiv mecarbil is a myotrope and cardiac myosin activator
..
.. with no effects on calcium transients or vasodilating effects, and thus
.. avoids the adverse effects associated with calcitropes. In the ‘Acute
..
.. Treatment with Omecamtiv Mecarbil to Increase Contractility in
.. Acute Heart Failure’ (ATOMIC-AHF) trial, 606 patients with EF
..
.. <_40% admitted for ADHF were randomized to a 48-h infusion of
.. omecamtiv mecarbil or placebo in sequential ascending dose cohorts.
..
.. Patients treated with the highest dose of omecamtiv mecarbil had
.. greater dyspnoea relief compared to placebo with no difference in
..
.. hypotension, ischaemic events, or ventricular or atrial arrhythmias.12
..
.. Studies designed to examine renal outcomes in ADHF have been
.. disappointing. The 2013 ‘Renal Optimization Strategies Evaluation’
..
.. (ROSE) trial was a multicentre, double-blinded, placebo-controlled
.. clinical trial designed to test the hypothesis inotropes may be helpful
..
.. for renal optimization in ADHF.13 Investigators randomized 360
.. patients hospitalized with ADHF and renal impairment to 72 h infu-
..
.. sions of dopamine, placebo, or the recombinant B-type natriuretic
.. peptide nesiritide. Patients were excluded if they had hypotension
..
.. (systolic blood pressure (SBP) < 90 mmHg), required renal replace-
.. ment therapy, or needed vasoactive or mechanical support. There
..
. was no beneficial effect of low-dose (2 mg/kg/min) dopamine nor
Inotropic therapies in HF and cardiogenic shock
..
nesiritide on either of the co-primary end points of 72 h urine output ..
and change in cystatin C. Furthermore, dopamine was associated ..
..
with greater risk of tachycardia. Interesting, in a post hoc analysis of ..
the ROSE trial, EF (EF <_ 40% vs. EF > 40%) significantly modified the ..
..
treatment effect of dopamine compared to placebo. In patients with ..
EF >40%, dopamine treatment decreased urine output, tempered
..
..
weight reduction, and increased the incidence of worsening HF as ..
..
well as demonstrated a nominal increase in mortality at 60 and 180 ..
days. Intriguingly, dopamine-treated patients with EF <_40% had ..
..
increased urine output, greater weight reduction, and nominally ..
reduced death at 60 and 180 days.14 The smaller single-blind ..
..
‘Dopamine in Acute Decompensated Heart Failure II’ (DAD-HF II) ..
trial found that addition of low-dose dopamine infusion to furosem- ..
..
ide did not decrease mortality or hospitalizations, nor did dopamine ..
improve renal function or symptoms.15 A small clinical trial which
..
..
enrolled 32 patients found greater increases in glomerular filtration ..
rate with levosimendan compared to dobutamine among patients
..
..
with EF <40% who are hospitalized with ADHF and renal ..
..
impairment.16 ..
At this time inotrope infusions with currently available agents in ..
..
ADHF without cardiogenic shock should be avoided due to limited ..
evidence of benefit and the potential for harm. However, omecamtiv ..
..
mecarbil and other future drugs merit further investigation in ADHF. ..
The 2013 American College of Cardiology and American Heart ..
..
Association (ACC/AHA) guidelines recommended against short-
term inotrope infusions in hospitalized patients without cardiogenic
shock, although continued to recommend low-dose dopamine infu-
sions for renal optimization.17 In light of the ROSE trial, the recom-
mendation for dopamine should likely be revised. The most recent
European Society of Cardiology (ESC) guidelines appropriately re-
flect that there is no current evidence-based role for inotropes in
ADHF without cardiogenic shock.18
Inotropes in cardiogenic shock
Data from RCTs demonstrating the benefit of inotropes in cardio-
genic shock are lacking due to the inability to ethically perform trials
with inactive treatment arms. Despite a lack of RCTs supporting their
use, inotropes demonstrate beneficial short-term haemodynamic
effects in patients with end-organ hypoperfusion and hypotension
from cardiogenic shock, and consensus agreement dictates their use
for acute haemodynamic stabilization. The ESC, ACC/AHA, and the
Heart Failure Society of America (HFSA) all recommend the use of
inotropic agents in cardiogenic shock.17–19 While not the focus of
this review, mechanical support options should also be actively con-
sidered for patients in cardiogenic shock. Clinical trials on inotropes
in shock have largely focused on comparing various agents rather
than comparing to placebo. Review of the literature on the use of
inotropes in cardiogenic shock is further complicated by heterogen-
eity. Cardiogenic shock is not a single entity but rather the end result
of multiple aetiologies, each of which may require a slightly different
approach.
Cardiogenic shock from undifferentiated or mixed
aetiologies
The ‘Comparison of Dopamine and Norepinephrine in the
Treatment of Shock’ (SOAP II) trial randomized 1679 patients in
681
shock from multiple aetiologies to dopamine or norepinephrine. In
the full analysis, there was no difference between agents on the pri-
mary outcome of death at 28 days; however, dopamine was associ-
ated with more arrhythmic episodes (24% vs. 12%, P < 0.001). Pre-
specified subgroup analysis on 280 patients with cardiogenic shock
found that the rate of death was significantly higher with dopamine
compare to norepinephrine (P = 0.03).20 Importantly, the patients
with cardiogenic shock included in the SOAP II trial had mixed aetiol-
ogies, including myocardial infarction, dilated cardiomyopathy, tam-
ponade, pulmonary embolism, and cardiopulmonary bypass. In large
part due to the SOAP II trial, dopamine has fallen out of favour as a
first line agent in cardiogenic shock. Similarly, epinephrine has some
evidence suggesting harm. In a small randomized trial of 30 patients
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with HFrEF (EF < 30%) and cardiogenic shock, treatment with epi-
nephrine was associated with more lactic acidosis and arrhythmias
compared to a regimen of norepinephrine and dobutamine.21
Observation data have also suggested that epinephrine is associated
with worse outcomes compared to other inotropic options (e.g.
combination norepinephrine and dobutamine) in patients with car-
diogenic shock from mixed aetiologies.22,23 For this reason, major
guidelines recommend norepinephrine over dopamine or epineph-
rine in cardiogenic shock.18,24–26
There is less clarity regarding whether clinically significant differen-
ces exist between dobutamine and levosimendan in the treatment of
.. cardiogenic shock. A Cochrane Systematic review of six studies
.. comparing levosimendan and dobutamine in cardiogenic shock found
..
.. that levosimendan may reduce short-term mortality [Relative risk
.. (RR) 0.60; 95% confidence interval (CI) 0.37–0.95] based on low-
..
.. quality data, although there was no difference on long-term follow
..
.. up.27 There is also some signal for harm with levosimendan in the
.. treatment of other types of shock. In a major clinical trial comparing
..
.. levosimendan to placebo in 516 patients with septic shock, levosi-
.. mendan did not decrease 28-day mortality but was associated with
..
.. more tachyarrhythmias and inability to wean from mechanical ventila-
.. tion.28 Furthermore, levosimendan was not beneficial in pre-specified
..
.. subgroup analysis of the tercile of patients with low baseline cardiac
.. indices (<_2.44 L/min/m2).28 Dobutamine and levosimendan are both
..
.. discussed as options in the ESC guidelines, although dobutamine
..
.. remains the most commonly used inotropic agent for cardiogenic
.. shock in clinical practice.17,26,29
..
.. In conclusion, in undifferentiated or mixed cardiogenic shock
.. norepinephrine should be used as a first line agent for blood pressure
..
.. support, with additional inotropic agents (preferably dobutamine or
.. levosimendan) as adjunctive therapy for patients with ongoing end-
..
.. organ hypoperfusion in continued low cardiac output states.
..
..
.. Cardiogenic shock from acute myocardial infarction
.. Patients suffering acute myocardial infarctions often have shock and
..
.. haemodynamic profiles (e.g. low cardiac output, high systemic
..
.. vascular resistance) which might benefit from use of inotropic agents.
.. However, these patients are also primed to experience the
..
.. deleterious effects of inotropes, including ventricular arrhythmias and
.. worsening ischaemia from increased myocardial oxygen demand.
..
.. The SOAP II trial, discussed above, may provide some support for
.. the use of norepinephrine over dopamine in this setting given the
..
. majority (60%) of enrolled cardiogenic shock patients had acute
682
..
myocardial infarction.20 Major guidelines recommend against use of
dopamine in acute myocardial infarction.24,25 Further evidence for
the use of norepinephrine comes from the OptimaCC trial, which
was a dedicated clinical trial on cardiogenic shock from acute myo-
cardial infarction.30 The OptimaCC trial randomized patients with
cardiogenic shock after acute myocardial infarction to epinephrine or
norepinephrine and looked at a primary efficacy outcome of change
in cardiac index and a primary safety outcome of refractory cardio-
genic shock. The trial was discontinued early due to harm in the epi-
nephrine group. The investigators detected higher rates of refractory
shock with epinephrine (37% vs. 7%, P = 0.008) after enrolling just 57
patients. Epinephrine was associated with higher rates of lactic acid-
osis and there was a trend towards increased short-term mortality,
which was not statistically significant likely due to early termination.
Furthermore, there was no difference in cardiac index between the
two groups, despite epinephrine causing more tachycardia and an
increased double product. Given the signal for harm with epinephrine
and dopamine, the 2019 ESC updated guidelines recommend nor-
epinephrine as the first line agent for cardiogenic shock from acute
myocardial infarction (Class IIB, level of evidence B).26 Adjunctive
inotropic medications can be considered in patients who require add-
itional support. Data from very small clinical trial trials have suggested
that levosimendan may be beneficial in this setting, although larger-
scale trials are needed to confirm safety and efficacy.31,32 The 2017
ESC Guidelines specify that either dobutamine or levosimendan may
be considered, although the 2019 update indicates a preference to-
wards dobutamine, acknowledging that there is limited evidence for
other inodilators in this setting.26,33 A recent meta-analysis of 19
RCTs, including OptimaCC, found that there was insufficient evi-
dence to support the use of any particular inotropic agent over an-
other in the setting of shock from acute myocardial infarction.34 As
with undifferentiated and mixed cardiogenic shock, the data currently
support the use of norepinephrine as first line for cardiogenic shock
from acute myocardial infarction. Again, dobutamine or levosimen-
dan can be used as adjunctive agents.
Cardiogenic shock during and after cardiac surgery
Inotropes are frequently, and often prophylactically, used in patients
undergoing cardiac surgery. Data from the Society of Thoracic
Surgeons’ National Database found that 90% of patients undergoing
cardiac surgery are administered vasoactive medications, including
vasopressors, inotropes, vasodilators, or combination therapy.35
Data supporting the prophylactic use of inotropes during cardiac sur-
gery are scarce.36 A recent clinical trial of patients without HF found
no difference in clinical outcomes between a dobutamine-to-all vs. a
dobutamine-sparing strategy.37 Similarly, prophylactic levosimendan
showed no benefit over placebo in two major clinical trials of patients
with HFrEF undergoing cardiac surgery.38,39 In patients with ‘low car-
diac output syndrome’, as shock is referred to in the cardiac surgery
literature, there is more consensus regarding the need for inotropic
agents. Dobutamine and milrinone have shown similar haemodynam-
ic effects among patients with low cardiac output coming off cardio-
pulmonary bypass.40 Dobutamine tends to be more commonly used
due to concerns for vasodilation and systemic hypotension with milri-
none which often necessitates vasopressors. When milrinone is used,
either norepinephrine or vasopressin are effective in counteracting
J.T. DesJardin and J.R. Teerlink
.. milrinone-induced decreased systemic vascular resistance during cor-
.. onary artery bypass surgery.41 Historically, levosimendan has been
..
.. frequently used in patients receiving cardiac surgery based on meta-
.. analyses suggesting cardioprotective effects over other calcitropes.42
..
.. However, clinical trial data supporting this approach are lacking. In an
.. RCT of 506 patients requiring inotropes or mechanical support for
..
.. weaning from cardiopulmonary bypass, levosimendan was no better
.. 43
.. than placebo in decreasing 30-day mortality. Whether or not levo-
.. simendan benefits patients being weaned from extracorporeal mem-
..
.. brane oxygenation is a topic of ongoing clinical investigation.44 Most
.. societies do not comment on the preferred inotropic agent in the
..
.. setting of cardiogenic shock associated with cardiac surgery. The
.. Scandinavian Society of Anesthesiology and Intensive Care Medicine
..
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.. recommends dobutamine based on very low quality of evidence.36
..
..
.. Cardiogenic shock from right ventricular failure due to
..
.. decompensated pulmonary arterial hypertension
.. Limited data and no clinical trials exist to guide inotropic manage-
..
.. ment in cardiogenic shock from RV failure due to decompensated
.. pulmonary arterial hypertension (PAH). Management decisions are
..
.. therefore being made by extrapolating from preclinical or small de-
.. scriptive studies on the short-term haemodynamic effects of inotrop-
..
.. ic agents. b1-Adrenergic agents are typically used to support RV
.. output in settings of RV failure. In an animal model of acute RV failure
..
.. from pulmonary artery (PA) constriction, dobutamine was superior
.. to norepinephrine in restoring RV–PA coupling and cardiac output.45
..
.. Phosphodiesterase inhibitors are also considered because up-regula-
..
.. tion of cAMP causes vasodilation in both the systemic and pulmonary
.. vasculature. Small studies of patients undergoing cardiac transplant
..
.. or coronary artery bypass surgery have shown that milrinone
.. decreases pulmonary vascular resistance (PVR).41,46 Nonetheless use
..
.. of phosphodiesterase-3 inhibitors in PAH is still often limited by
.. hypotension given proportional decline in systemic and PVRs.
..
.. Levosimendan has preclinical data suggesting an advantage over
.. dobutamine in terms of RV–PA coupling.47 Digoxin is sometimes
..
.. used chronically in patients with PAH and RV dysfunction as it has
..
.. been shown to increased cardiac output in idiopathic PAH, although
.. its utility in cardiogenic shock is unclear.48 Oral omecamtive mecarbil
..
.. was shown to increase RV function in patients with EF <_40%, suggest-
.. ing it may have a role in patients with RV failure.49 In conclusion, there
..
.. is a lack of high-quality data to guide inotropic management in cardio-
.. genic shock from decompensated PAH, although current guidelines
..
.. provide recommendation for dobutamine as the preferred agent.50
..
..
.. Inotropes in severe chronic heart failure
.. Inotropes for treatment of chronic heart failure
..
.. The long-term use of oral calcitropic agents in the treatment of
.. chronic HF has consistently been found to decrease survival. In 1990,
..
.. Xamoterol, a b1-selective partial agonist, was found to increase mor-
..
.. tality compared to placebo within 100 days of randomization in
.. patients with chronic HFrEF.51 Subsequent trials on various calci-
..
.. tropes have now accumulated, many demonstrating increased mor-
.. tality in chronic HF. The PROMISE,52 PROFILE,53 PRIME II,54 and
..
.. VEST55 HF trials all found higher rates of death with milrinone, flose-
.. quinan, ibopamine, and vesnarinone, respectively. These trials all
..
. examined oral inotropic formulations; however, continuous
Inotropic therapies in HF and cardiogenic shock 683

..
intravenous therapies have also shown disappointing results. .. (INTERMACS) profiles have been created to stratify patients with
Continuous intravenous dobutamine infusion has been associated .. advanced HF, with Profile 1 being critical cardiogenic shock. The
..
with increased 6-month mortality.56 Given the current overwhelming .. need for inotropic support defines INTERMACS 3 or lower, and 80%
evidence for harm with the use of calcitropes in chronic HF, all major .. of mechanical support devices are implanted in patients in
..
guidelines recommend against their use in the treatment of chronic .. INTERMACS Profiles 1 and 2.64 Inotropic dependence is also used in
HF, except in cases of palliation.17,18 The only potential exception
.. heart transplant allocation, with requirement for high-dose inpatient
..
among calcitropes is digoxin, which has been shown to reduce hospi- .. inotropes conferring Status 3 listing and need for ambulatory ino-
talizations but not mortality among patients with HFrEF
.. tropes conferring Status 4.65
..
(EF <_ 45%).57 The benefit of digoxin is closely tied to dosing, with .. Recent LVAD trials have compared newer LVADs such as the
..
serum drug concentrations of 0.5–0.9 ng/mL being associated with .. HeartMate3 against active mechanical support treatment arms rather
reduced hospitalizations, while higher drug concentrations may in- .. than medical therapy.66 Earlier trials, such as the Randomized
..
crease mortality.58 .. Evaluation of Mechanical Assistance in Treatment of Congestive
Cardiac mitotropes and myotropes, unlike calcitropes, are associ- .. Heart Failure (REMATCH) trial, suggested that even the first-gener-
..

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ated with improved cardiovascular outcomes. SGLT2Is have mito- .. ation pulsatile flow LVAD models were superior to medical therapy,
tropic effects and are considered standard of care in the treatment of .. such as with ambulatory infusions of inotropes. In the REMATCH
..
HFrEF. In the landmark DAPA-HF trial, dapagliflozin decreased ad- .. trial, half of the patients enrolled were inotropic-dependent at the
verse cardiovascular events (worsening HF or CV death) by 30% and
.. time of randomization; these patients experienced an almost 80% 1-
..
all-cause mortality by 17% among 4744 patients with New York .. year mortality with medical therapy.67,68 The HeartMate XVE LVAD
..
Heart Association (NYHA) II–IV and EF <_40%.59 Similarly, empagli- .. treatment arm had a 48% decreased risk of death compared to med-
flozin decreased the composite outcome of HF hospitalizations and .. ical therapy.68 LVADs, either as destination or as a bridge to trans-
..
CV death in a similar population of patients with HFrEF.60 .. plant, are preferred to ambulatory inotropic infusion in patients with
Pimobendan, which acts as a phosphodiesterase-3 inhibitor but also .. advanced HF. When mechanical support options are not immediately
..
has some calcium sensitizing effects, was found to increase mortality .. available or are contraindicated (e.g. due to RV dysfunction, patient
by 80% in an early 317 patient trial,61 but decreased adverse cardiac .. preference), ambulatory inotropic infusions can be continued to
..
events in a clinical trial in 306 patients with HF and NYHA II–III and .. maintain clinical stability. In these settings, there is not high-quality
EF <_45%.62 Larger clinical trials are required to confirm its safety and
.. data from clinical trials to guide a preference for any one inotropic
..
efficacy, and pimobendan remains unapproved in the USA and .. agent over another. Observational data suggest a potential benefit of
Europe. The recent GALACTIC-HF trial randomized 8256 inpatient
.. milrinone over dobutamine, and the long-acting pharmacokinetic
..
or outpatients with HFrEF (EF <_ 35%) and NYHA II–IV symptoms to .. profile of intravenous milrinone may make it the preferred agent in
..
either omecamtiv mecarbil or placebo.63 There was an 8% reduction .. this setting.69
(hazard ratio 0.92; 95% CI 0.86–0.99) in the composite primary out- ..
..
come of first HF event or cardiovascular death. HF events included .. Inotropes for symptom management and palliation
emergency department visits, urgent care visits, or HF hospitaliza- .. Advanced HF is associated with high symptom burden, poor quality
..
tions. Omecamtiv mecarbil had neutral effects on blood pressure, .. of life, frequent hospitalizations, and limited life expectancy.70
serum potassium, and serum creatinine levels, and was not associated .. Despite their associated increased mortality, use of chronic calci-
..
with increased risk of myocardial ischaemia or ventricular arrhyth- .. tropic agents is sometimes considered in patients with end-stage HF
mias. On subgroup analyses, patients with more advanced HF (as
.. who have opted to focus on quality of life and palliation over longev-
..
measured by either LVEF or NYHA class) may have benefitted the .. ity. American guidelines acknowledge a role for inotropic therapy in
..
most. Therefore, although calcitropes have no role in the treatment .. palliation and end-of-life care in advanced HF.17,19 However, there
of chronic HF, omecamtiv mecarbil may have a role in the future .. have been few RCTs focusing on quality of life or symptom manage-
..
treatment of patients who continue to have NYHA II–IV symptoms .. ment in advanced HF. Most of the major trials of clinically available
despite maximally tolerated guideline-directed medical therapy. .. calcitropes were not designed to examine outcomes relating to
..
.. symptom burden or quality of life. Among those trials which have
Inotropes for bridge to advanced therapies .. evaluated symptom burden or functional capacity, calitropes have
..
In some patients with advanced HF, inpatient initiation of continuous .. shown mixed results. Although a small trial of 29 patients reported
inotropic therapy is required for acute stabilization, and subsequent
.. marked improvement in 6-min walk test with inotropes (milrinone
..
attempts at weaning result in recurrent hypotension and/or end- .. or dobutamine) compared to placebo, larger trials have been less
organ hypoperfusion. Given the mortality associated with long-term
.. encouraging.71 The LevoRep trial randomized 120 outpatients with
..
inotropic therapy, several attempts to wean should be attempted be- .. advanced HF (EF <_ 35%; NYHA III–IV) to intermittent levosimendan
..
fore declaring a patient to be ‘inotropic-dependent’. In such patients, .. (0.2 mg/kg/min for 6 h every 2 weeks for 6 months) or placebo and
continuous ambulatory low-dose intravenous inotropic therapy is .. investigated primary outcomes relating to quality of life.
..
considered as a bridge to more definitive therapies, namely a left ven- .. Levosimendan failed to demonstrate a beneficial effect on the com-
tricular assist device (LVAD) or cardiac transplantation.17 .. posite primary outcome of improvement in 6-min walking test and
..
Dependence on inotropes provides important prognostic informa- .. Kansas City Cardiomyopathy Questionnaire.72 In the small DICE trial,
tion in advanced HF and is used to grade HF severity. Seven
.. intermittent low-dose dobutamine (2.5 mg/kg/min 48 h/week for
..
‘Interagency Registry for Mechanically Assisted Circulatory Support’ . 6 months) neither improved NYHA functional class nor 6-min
684 J.T. DesJardin and J.R. Teerlink

..
walking test.73 A recent meta-analysis including 13 RCTs and 53 ob- .. shock, although further investigation may discover a role for mito-
servational studies found that ambulatory inotropic infusions were .. tropic and myotropic agents in renal optimization or symptom man-
..
associated with a marginal improvement in NYHA functional class .. agement in ADHF.
(mean difference 0.6 NYHA classes; 95% CI 0.2–1.0, P = 0.001), but ..
.. Conflict of interest: JTD reports no conflicts of interest. JRT
also came with significant risks such as central line complications.74 ..
Ambulatory intravenous inotropes can be trialled for select patients
.. reports Research Grants and/ or Consulting fees from Abbott,
.. Amgen, Astra Zeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers
with end-stage HF and high symptom burden. However, limited high- ..
quality data exists to support the use of intravenous inotropes in this
.. Squibb, Cytokinetics, EBR Sytems, LivaNova, Medtronic, Merck,
.. Novartis, Servier, Windtree Therapeutics.
setting, and so providers should consider logistical barriers and fre- ..
quently re-assess if treatment goals are being met. Home intravenous
..
..
inotrope therapy is not feasible for all patients, and requires extensive ..
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