Drugs 2011; 71 (5): 515-525

CURRENT OPINION 0012-6667/11/0005-0515/$55.55/0

ª 2011 Adis Data Information BV. All rights reserved.

Use of Inotropic Agents in Patients with

Advanced Heart Failure
Lessons from Recent Trials and Hopes for New Agents
Marco Metra,1 Luca Bettari,1 Valentina Carubelli,1 Silvia Bugatti,1 Alessandra Dei Cas,2
Francesca Del Magro,1 Valentina Lazzarini,1 Carlo Lombardi1 and Livio Dei Cas1
1 Institute of Cardiology, Department of Experimental and Applied Medicine, University of Brescia,
Brescia, Italy
2 Department of Internal Medicine and Biomedical Sciences, University of Parma, Parma, Italy

Abstract Abnormalities of cardiac function, with high intraventricular filling pressure

and low cardiac output, play a central role in patients with heart failure. Agents
with inotropic properties are potentially useful to correct these abnormalities.
However, with the exception of digoxin, no inotropic agent has been associated
with favourable effects on outcomes. This is likely related to the mechanism of
action of current agents, which is based on an increase in intracellular cyclic
adenosine monophosphate and calcium concentrations. Novel agents acting
through different mechanisms, such as sarcoplasmic reticulum calcium uptake,
cardiac myosin and myocardial metabolism, have the potential to improve
myocardial efficiency and lower myocardial oxygen consumption. These
characteristics might allow a haemodynamic improvement in the absence of
untoward effects on the clinical course and prognosis of the patients.

Heart failure (HF) represents a major cause tion.[4,9] The administration of inotropic agents is
of morbidity and mortality. Use of neurohor- potentially the only medical treatment that can
monal antagonists, implantable cardiac defibril- improve their haemodynamic abnormalities and
lators (ICDs), cardiac resynchronization therapy symptoms.[10-13] Accordingly, inotropic therapy
(CRT) and left ventricular (LV) assist devices is a major criterion for the indication of LV assist
has improved patient outcomes.[1-3] However, device implantation and/or urgent transplanta-
many patients still report severe symptoms and tion.[14] Unfortunately, most, if not all, of the
show a high rate of hospitalization.[4] Fluid inotropic agents have been associated with poor
overload and pulmonary congestion with ele- tolerance and untoward effects on outcomes.
vated LV end-diastolic pressure and pulmonary Thus, their administration may allow short-term
wedge pressures are the main causes of patient improvement in haemodynamic parameters and
hospitalization.[5-8] Reduced cardiac output and symptoms with longer-term harm. Newer ino-
peripheral hypoperfusion are also important in tropic agents with a better benefit to risk ratio are
some patients. These patients, whose prevalence needed.
can be estimated at approximately 10% of all In this review we summarize the main char-
patients admitted for acute HF, have low blood acteristics and limitations of current inotropic
pressure (BP), signs of end-organ dysfunction, agents and review novel inotropic agents in var-
and severe LV systolic and diastolic dysfunc- ious stages of development.
516 Metra et al.

1. Current Indications symptoms in end-stage HF.[19] Similarly, the

ACC/AHA guidelines state that long-term use of
Inotropic agents are indicated for the treat- an infusion of a positive inotropic drug may be
ment of patients with peripheral hypoperfusion considered only as palliation for patients with
and fluid overload secondary to cardiac dys- end-stage disease who cannot be stabilized with
function (‘cold and wet patients’).[8-12,14] Hypo- standard medical treatment.[17]
tension is the main sign of hypoperfusion and low
cardiac output.[10,12,15] Other signs of hypoperfu- 2. Use of Inotropes in Clinical Practice
sion include cold, clammy skin, renal impairment,
liver dysfunction and/or impaired mentation. For Data from registries show a wide variation in
inotropic agents to be indicated, patients should the proportion of patients treated with inotropes.
also have dilated, hypokinetic ventricles at echo- This ranges from 7% in the OPTIMIZE-HF (see
cardiography. However, although echocardio- table I for a list of trial acronyms) registry[9] to
graphy is ideal, it may not always be possible, and nearly 25% in the EHFS-II.[20] Notably, the ad-
clinical assessment of signs of hypoperfusion ministration of inotropic agents is often not
may be sufficient when urgent therapy is needed. based on current guidelines.[11,16,18] Although
When indicated, inotropes should be adminis- a low SBP is considered a major indication for
tered as soon as possible and discontinued as soon inotropic agents, among the 48 612 patients en-
as organ perfusion is restored and/or congestion rolled in OPTIMIZE-HF, those treated with
is relieved.[11,16-18] inotropic agents were 6.5%, 4.5% and 3.2%, re-
The European Society of Cardiology guide- spectively, of the patients with an SBP of 120–139,
lines state that inotropic agents are indicated only 140–160 and >161 mmHg.[9] In ADHERE, only
for patients with low systolic BP (SBP) or a low 8% of the patients receiving inotropes had a
measured cardiac index in the presence of signs of SBP <90 mmHg, and the SBP on admission
peripheral hypoperfusion or congestion.[16] These was 121 – 27 mmHg and 124 – 29 mmHg in the
indications are in agreement with the current patients receiving dobutamine and milrinone,
American College of Cardiology/American Heart
Association (ACC/AHA)[17] and Heart Failure Table I. Trial name acronyms
Society of America (HFSA)[18] guidelines. They Acronym Definition
state that inotropes are indicated to improve ADHERE Acute Decompensated Heart Failure National
symptoms and end-organ function in patients with Registry

low output syndrome, LV systolic dysfunction CUPID Calcium Up-Regulation by Percutaneous

Administration of Gene Therapy In Cardiac Disease
and SBP <90 mmHg despite adequate LV filling
DIG Digitalis Investigation Group
pressure.
EHFS-II European Heart Failure Survey-II
The HFSA guidelines expand the indications
FIRST Flolan International Randomized Survival Trial
for inotropic agents to also include patients with
HORIZON-HF Hemodynamic, echocardiographic, and
evidence of fluid overload and lack of response neurohormonal effects of istaroxime, a novel
to intravenous diuretics and/or with reduced or intravenous inotropic and lusitropic agent: a
worsening renal function. Regarding safety, the randomized controlled trial in patients hospitalized
with heart failure
HFSA guidelines state that the administration of
OPTIME-CHF Outcomes of a Prospective Trial of Intravenous
inotropic agents should be accompanied by con- Milrinone for Exacerbations of Chronic Heart Failure
tinuous monitoring of BP and cardiac rhythm, OPTIMIZE-HF Organized Program to Facilitate Life-Saving
with drug withdrawal or dose reduction to be Treatment in Hospitalized Patients with Heart Failure
considered in patients with symptomatic hypo- REVIVE-II Randomised multicentre evaluation of intravenous
tension or development of tachyarrhythmias.[18] levosimendan efficacy versus placebo in the short
term treatment of decompensated heart failure
Notably, inotropes may also be indicated as a
SURVIVE Survival of patients with acute heart failure in need
bridge to heart transplantation or mechanical
of intravenous inotropic support trial
assist device implantation or as palliation for

ª 2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (5)
Inotropic Drugs in Heart Failure 517

respectively.[21] Data from EHFS-II indicate that pump, hence increasing intracellular calcium. Its
more than 4% of patients with hypertensive HF beneficial effects on LV function, symptoms and
(with high BP defined as >180/100 mmHg) re- exercise tolerance were first shown by prospective
ceived dobutamine or dopamine.[20] Thus, in- controlled trials[26] as well as studies based on
travenous inotropic agents are still administered digoxin withdrawal.[27]
to a significant proportion of patients admitted The effects of digoxin on outcomes were as-
for acute HF, despite some patients likely not sessed in the DIG trial.[28] In this study, 6800
needing them. patients in sinus rhythm and with an LV ejection
fraction (LVEF) £45% were randomized to pla-
3. Adverse Effects cebo or digoxin (mean dose 0.25 mg/day) and
followed for an average of 37 months. Most
A thorough description of the general mech- patients were on ACE inhibitors and diuretics.
anisms of action of inotropic agents goes beyond The primary endpoint, all-cause mortality, was
the aims of this review and has been discussed in unaffected. However, there was a trend to a lower
detail in many previous reviews.[10-12,15,22] Their mortality rate for worsening HF (risk ratio [RR]
untoward effects are, however, important to 0.88; 95% CI 0.77, 1.01; p = 0.06), and a reduction
point out as they still represent the main limita- in HF hospitalizations (RR 0.72; 95% CI 0.66,
tion to this otherwise probably beneficial class of 0.79; p < 0.001) and cardiovascular hospitaliza-
agents. tions (RR 0.87; 95% CI 0.81, 0.93; p < 0.001), as
The main adverse effects of inotropic agents well as in the combined endpoints of all-cause
are tachyarrhythmias, myocardial ischaemia and death and HF hospitalizations and of HF deaths
myocardial damage. These last two effects are or hospitalizations, in the digoxin versus the
favoured by the concomitant vasodilatory action placebo group.[28] Further analyses from the DIG
of most of the traditional inotropic agents that trial showed the importance of serum digoxin
may cause hypotension, coronary hypoperfusion, levels with respect to the effects of digoxin on
myocardial ischaemia and necrosis.[12,23] Further outcomes. Compared with placebo, digoxin ad-
mechanisms are the increase in myocardial oxy- ministration to patients with serum digoxin con-
gen consumption caused by tachycardia and centrations of 0.5–0.9 ng/mL was associated with
enhanced myocardial contractility.[24] These ne- lower mortality (29% vs 33% on placebo; ad-
gative attributes may have differential effects justed RR 0.77; 95% CI 0.67, 0.89), all-cause
depending on the underlying cardiac substrate. hospitalizations (64% vs 67% placebo; adjusted
Thus, a retrospective analysis of the OPTIME- RR 0.85; 95% CI 0.78, 0.92) and HF hospitali-
CHF trial has shown an increased mortality with zations (23% vs 33% placebo; adjusted RR 0.62;
milrinone administration in patients with ischae- 95% CI 0.54, 0.72). Patients with serum digoxin
mic heart disease, but not in those with non- concentrations ‡1.0 ng/mL had lower HF hospi-
ischaemic cardiomyopathy.[25] talizations (29% vs 33% placebo; adjusted RR
The adverse effects on outcomes of inotropic 0.68; 95% CI 0.59, 0.79), without any difference
agents are related to their mechanisms of action, in mortality, than patients on placebo.[29]
based on an increase in cyclic adenosine mono- The prespecified long duration of follow-up in
phosphate (cAMP) and intracellular calcium. the DIG trial might have had an influence on the
Thus, inotropic agents with different mechanisms results. In a retrospective study, data were anal-
of action may be better tolerated. ysed after only 1 year of follow-up: digoxin had
favourable effects on all the major endpoints with
4. Digoxin, the First and Only Oral a reduction in 1-year all-cause mortality (hazard
Inotropic Agent Currently Available ratio [HR] 0.87; 95% CI 0.76, 0.995; p = 0.043),
cardiovascular mortality (HR 0.87; 95% CI 0.75,
Digoxin is a cardiac glycoside acting through 1.01; p = 0.072), HF mortality (HR 0.66; 95% CI
inhibition of the sarcolemmal Na+/K+ ATPase 0.52, 0.85; p = 0.001) and all-cause hospitalization

ª 2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (5)
518 Metra et al.

(HR 0.89; 95% CI 0.83, 0.96; p = 0.002).[30] This with epoprostenol. An analysis of the patients
13% reduction in 1-year mortality matched the included in this trial showed that those on dobu-
statistical significance requirements prespecified tamine infusion (mean dose 9 mg/kg/min, range
for the DIG trial, designed to enrol at least 7000 5–12 mg/kg/min, median duration 14 days) had a
patients with an LVEF <0.45, to have 90% power higher rate of adverse events (worsening HF,
to detect a 12% reduction in mortality by treat- need for vasoactive medications, resuscitated
ment. However, DIG was designed to assess cardiac arrest, myocardial infarction), higher total
events at 3 years.[31] mortality (85.3% vs 64.5%; p = 0.0006) and higher
The data from the DIG trial cannot be con- mortality (70.5% vs 37.1%; p = 0.0001) than the
sidered as conclusive. High doses of digoxin were others.[34] Subsequent analyses showed trends
used in this trial, with 70% of the patients on di- towards increased mortality in the patients on
goxin 0.25 mg/day, whereas retrospective ana- dobutamine versus the control groups and a meta-
lyses have indicated the beneficial effects of lower analysis confirmed the increased risk of death
doses of digoxin targeted to serum digoxin con- with dobutamine administration.[35]
centrations of 0.5–0.9 ng/mL.[29] In addition, Dopamine acts on dopaminergic, b- and a-
patients with a recent hospitalization were not adrenergic receptors. It is used to improve diur-
included in the DIG trial and this study was esis and renal blood flow in patients with acute
performed before the introduction of b-adrener- HF or those at risk of acute renal failure. How-
gic receptor antagonists (b-blockers), ICDs and ever, only data collected in small study groups,
CRT in the treatment of HF. It is likely, but not and generally not from controlled studies, sup-
proven, that these additional treatments may in- port these indications.[11] A recent meta-analysis
crease the beneficial effects of digoxin, i.e. b- of 61 trials, including 3359 patients at risk of
blockers and devices should decrease the role of acute renal failure, has shown a 24% increase in
arrhythmias and sudden cardiac death, which diuresis during the first 24 hours of dopamine
were the main causes for concern for digoxin, administration in the absence of any effect on
versus placebo, in the DIG trial. Therefore, a new serum creatinine levels, acute renal failure devel-
randomized controlled trial studying the effects opment and death.[36]
of digoxin on outcomes is needed.[32] Type 3 phospodiesterase inhibitors (milrinone,
enoximone) inhibit cAMP hydrolysis and in-
5. Drugs Acting via an Increase in Cyclic crease its concentrations in the cardiomyocytes
Adenosine Monophosphate and smooth muscle vascular cells, with an im-
provement in myocardial contractility, diastolic
Dobutamine is an agonist of b1-adrenergic function and peripheral vasodilation.[37] Phos-
receptors, which mediate the increase in myo- phodiesterase inhibitors have similar effects and
cardial contractility and heart rate, and, to a les- limitations to sympathomimetic amines (namely,
ser extent, of b2- and a1-adrenergic receptors.[33] dobutamine) with, as the main difference, a
It has beneficial short-term effects on haemo- greater peripheral and pulmonary vasodilating
dynamic variables, namely cardiac output and activity. In contrast to sympathomimetic amines,
pulmonary wedge pressure, but it has generally because their site of action is downstream from
been associated with poorer outcomes. One of the the b-adrenergic receptor, they also maintain
first studies was an analysis of 471 patients en- their effects when the patient is on b-blockers.[38]
rolled in FIRST, a randomized controlled trial of As in the case of dobutamine, the use of
continuous intravenous epoprostenol plus con- phosphodiesterase inhibitors has also been lim-
ventional therapy of ACE inhibitors, diuretics ited by the increased mortality associated with
and digoxin, versus conventional therapy alone, their administration. This is mainly based on
in patients with advanced HF. This study was retrospective analyses of trials and registries
prematurely terminated because of a strong trend consistently showing an increase in mortality in
towards decreased survival in the patients treated the patients receiving intravenous phosphodies-

ª 2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (5)
Inotropic Drugs in Heart Failure 519

terase inhibitors.[20,21,25,35,39] In the only pro- duration of hospital stay. No difference in 90-day
spective randomized trial comparing intravenous mortality was found (35 deaths on placebo [12%]
milrinone with placebo, which included 951 vs 45 deaths [15%] with levosimendan; p = 0.210).
patients with acutely decompensated HF, milri- Moreover, treatment with levosimendan was
none administration did not improve any of associated with a higher rate of adverse effects
the prespecified outcomes and was associated than placebo: hypotension (50% vs 36%), ven-
with a higher rate of sustained hypotension re- tricular tachycardia (24% vs 17%) and atrial fi-
quiring intervention (10.7% vs 3.2%; p < 0.001) brillation (8% vs 2%).[46]
and new atrial arrhythmias (4.6% vs 1.5%; In the SURVIVE trial, 1327 patients with
p = 0.004).[40] acute HF needing inotropic support were ran-
An increase in mortality in the patients re- domized to levosimendan or dobutamine.[47]
ceiving phosphodiesterase inhibitors has been Mortality at 180 days (primary endpoint) was
consistently shown in long-term studies with the similar between the two study groups (26% with
oral agents.[41-43] However, these data were col- levosimendan vs 28% with dobutamine; p = 0.40).
lected before the introduction of b-blockers in The BNP decrease was larger in the patients
HF treatment and there were data suggesting that assigned to levosimendan and the rate of wor-
lower doses of these agents might have had a sening HF was greater in the dobutamine group,
better benefit to risk ratio. More recently, the whereas the rate of new-onset atrial fibrillation
effects on outcomes of low doses of oral en- was greater in the levosimendan group.[47]
oximone has been assessed in 1854 patients with Peripheral vasodilation and hypotension are
advanced HF on current medical treatment with the most likely causes of the lack of beneficial
b-blockers and ACE inhibitors.[44] Enoximone effects on survival of levosimendan compared
did not affect mortality, hospitalizations, symp- with dobutamine.[12,23] The likelihood of hypo-
toms or exercise capacity, assessed by the 6-minute tensive episodes was likely favoured by the study
walk test, compared with placebo.[44] protocol as an insufficient response to diuretics
and/or vasodilators was an inclusion criterion so
6. Other Mechanisms: The Case of that patients were already on maximal doses of
Levosimendan these agents at the time of entry into the trial.
In addition, a relatively high-dose 12 mg/kg in-
Levosimendan acts through sensitizing con- travenous bolus had to be administered before
tractile proteins to calcium and opening ATP- continuous infusion at 0.1 mg/kg/min. SURVIVE
dependent potassium channels;[45] the opening of also suggested a greater efficacy of levosimendan
potassium channels causes peripheral vasodila- compared with dobutamine in the patients
tion. Levosimendan also has some degree of type on concomitant b-blocker therapy.[48] In these
3 phosphodiesterase inhibitor activity, which can patients, mortality at day 5 was lower in the
cause an increase in intracellular cAMP and cal- group treated with levosimendan than in those on
cium concentrations. dobutamine (1.5% vs 5.1%; RR 0.29; 95% CI
The two larger randomized controlled trials 0.11, 0.78; p = 0.01). However, no difference was
with levosimendan were the REVIVE-II trial and found at 14 and 31 days.[48]
the SURVIVE trial, which compared levosi- Few data are available about oral levosi-
mendan with placebo and dobutamine, respect- mendan. In a recent randomized, double-blind,
ively.[46] The primary endpoint of REVIVE-II multicentre trial, 307 HF patients (New York
was an improvement in the signs and symptoms Heart Association [NYHA] class IIIB–IV, LVEF
of HF at 24 hours, 48 hours and 5 days. Levosi- £30%) on ACE inhibitors and b-blockers were
mendan treatment was associated with a favour- randomized to placebo or oral levosimendan
able effect on the primary endpoint (p = 0.015), (1 mg once or twice daily for at least 180 days).
with a larger decline in plasma B natriuretic There were no differences between levosimendan
peptide (BNP) levels and a shorter (2 days) and placebo in symptoms and episodes of worsening

ª 2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (5)
520 Metra et al.

HF (p = 0.567), but there was an improvement in output. However, in contrast to the other in-
the Minnesota Living with Heart Failure quality- otropic agents, istaroxime decreases heart rate
of-life score (p < 0.001) and a decrease in N-terminal and increases SBP. These effects are potentially
proBNP (NT-proBNP, -30–40%; p < 0.001) in the useful in patients with low cardiac output and
levosimendan group.[49] hypotension as the increase in BP might increase
coronary and end-organ perfusion pressure,
whereas the decrease in heart rate may allow a
7. Novel Agents with Inotropic Effects
longer diastolic filling time, better coronary per-
7.1 Istaroxime fusion and decreased myocardial oxygen con-
sumption.[23] In addition, this agent has a direct
Istaroxime is a new agent with inotropic and effect on LV diastolic function. However, further
lusitropic effects. It acts through the stimu- studies are needed.[53]
lation of the sarcoplasmic reticulum (SR) calcium
ATPase isoform-2 (SERCA2), which enhances 7.2 Cardiac Myosin Activators
calcium reuptake by the SR during diastole with
the subsequent release of a greater amount during Cardiac myosin activators are new agents that
systole and an improvement in LV diastolic and accelerate the transition of the actin-myosin
systolic function. Istaroxime also inhibits the complex from a weakly bound to a strongly
sarcolemmal Na+/K+ ATPase with an increase in bound configuration, thus increasing the number
intracellular calcium.[50] of myosin heads interacting with the actin fila-
The HORIZON-HF study assessed the haemo- ment while at the same time reducing the rate of
dynamic effects of istaroxime in 120 patients nonproductive ATP hydrolysis. They increase the
admitted for acute HF with an LVEF £35% duration of systole and, hence, stroke volume in
(mean 27% – 7%) and a SBP between 90 and the absence of any change in intracellular calcium
150 mmHg (mean 116 – 3 mmHg). Patients were concentrations and in the rate of contraction so
randomized 3 : 1 to a 6-hour continuous infusion that the improvement in myocardial systolic func-
of three different doses of istaroxime (0.5, 1.0 or tion may occur in the absence of arrhythmogenesis
1.5 mg/kg/min) or placebo. Compared with pla- and increased oxygen consumption.[13,54]
cebo, istaroxime was associated with a reduction The administration of omecamtiv mecarbil
in the pulmonary capillary wedge pressure (pri- (formerly called CK-1827452) in two different
mary endpoint; p < 0.05 for all three doses), and experimental models of HF with LV systolic
with a decreased heart rate and increased SBP. dysfunction was associated with a sustained in-
The cardiac index increased and LV end-diastolic crease, without desensitization, in LV wall thick-
volume decreased significantly with istaroxime ening, stroke volume (by 44 – 6.5%) and cardiac
1.5 mg/kg/min.[51] With respect to changes in LV output (22 – 2.8%), with a decrease in LV end-
diastolic function, istaroxime was associated with diastolic pressure and in heart rate (-15 – 3.0%)
a dose-dependent increase in E0 velocity, E-wave and no effect on BP. In contrast to catechola-
deceleration time and a decreased E/E0 ratio. LV mines, omecamtiv mecarbil did not increase the
pressure-volume analysis showed a decrease in rate of rise of LV pressure (dP/dt) but increased
LV end-diastolic elastance after istaroxime ad- LV systolic ejection time (+26 – 2.9%) and did not
ministration.[52] There were no changes in neuro- change myocardial oxygen consumption.[55]
hormones, renal function or troponin I. These results in animal models have been
These studies have shown a unique profile of confirmed by preliminary findings in patients
haemodynamic effects for istaroxime compared with chronic HF and low LVEF, with a con-
with the other previously mentioned inotropic centration-dependent increase in LV systolic
agents. Similar to the other inotropic agents, is- ejection time, stroke volume and cardiac output,
taroxime is associated with a decrease in LV fill- and a reduction in heart rate after omecamtiv
ing pressure and a tendency to greater cardiac mecarbil administration.[54] These agents may

ª 2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (5)
Inotropic Drugs in Heart Failure 521

potentially lower the threshold of myocardial FFAs are the preferred metabolic substrate used
ischaemia in patients with coronary artery dis- by the heart to produce energy. This is primarily
ease as they increase systolic time at the expense due to the fact that FFA oxidation generates a
of diastole with potential limitations to coronary greater amount of ATP than the glycolytic path-
perfusion and filling. However, no untoward ef- way, although a greater amount of oxygen is re-
fects on exercise tolerance have been shown after quired and, hence, myocardial efficiency, i.e. the
omecamtiv mecarbil administration to patients ATP production to oxygen consumption ratio, is
with ischaemic cardiomyopathy.[56] Therefore, lower.[62,63] Moreover, high levels of FFA deri-
omecamtiv mecarbil could be a promising agent vatives may inhibit pyruvate dehydrogenase and
for the treatment of HF patients. A programme glucose oxidation, resulting in increased conver-
of clinical studies is ongoing.[55] sion of pyruvate to lactate, tissue acidosis and im-
paired myocyte contractility. Metabolic modulators
7.3 Urocortin were initially developed for patients with recurrent
angina pectoris and/or with diabetes mellitus but
The urocortin peptides Ucn1, Ucn2 and Ucn3
their mechanisms of action also make them po-
are recently isolated members of the cortico-
tentially useful for the treatment of HF.[64,65]
tropin-releasing factor (CRF) family. These
Perhexiline is an inhibitor of carnitine palmi-
peptides act through the two G protein-coupled
toyl transferase-1, an enzyme critical to mitochon-
CRF receptors CRF1 (localized almost exclusively
drial FFA uptake. Its inhibition causes the shift of
in the central nervous system) and CRF2 (present
myocardial substrate from FFAs to carbohy-
in both brain and peripheral tissues, including the
drates. Early trials demonstrated that perhexiline
myocardium and blood vessels, where it is strongly
used at doses of 100 to 200 mg twice daily effec-
expressed). In contrast to Ucn1, which binds sim-
tively relieves anginal symptoms and improves
ilarly to both receptor subtypes, Ucn2 and
exercise tolerance, but later studies demonstrated
Ucn3 are selective for the CRF2 receptors.[57,58]
that perhexiline has a narrow therapeutic index
The administration of urocortins, namely Ucn2
with an increased risk of hepatotoxicity and per-
or Ucn3, in experimental models of HF has been
ipheral neuropathy. Toxicity is a result of phos-
associated with an increase in cardiac output and
pholipid accumulation mediated by carnitine
a fall in peripheral resistance, left atrial pressure
palmitoyl transferase inhibition, which mainly oc-
and mean arterial pressure. It has induced a per-
curs in patients with slowed hepatic metabolism
sistent, dose-dependent decrease in plasma vaso-
(cytochrome P450 [CYP]2D6) of perhexiline. Fur-
pressin, renin activity, aldosterone, natriuretic
ther studies demonstrated that cautious dose titra-
peptides and endothelin-1 plasma levels, with an
tion to maintain plasma concentrations within a
acute rise in adrenocorticotrophic hormone (cor-
relatively narrow range may avoid serious adverse
ticotrophin) and cortisol levels. Lastly, a dose-
effects.[66] However, further studies are needed,
dependent, sustained increase in diuresis, natriuresis
especially given the safety concerns of this agent.
and creatinine clearance was found.[58-60] A fa-
One small, short-term trial has suggested a
vourable interaction with diuretic treatment that
significant benefit of perhexiline in patients with
leads to increased diuretic responsiveness and
chronic HF.[67] Fifty-six patients with HF (LVEF
blunting of furosemide-induced renin increase
£40%, NYHA class II/III) were randomized to
has also been described.[61] Ucn3 (stresscopin) is
perhexiline or placebo with serial measurements
now undergoing further assessment in larger
of blood perhexiline levels to prevent toxicity. Eight
clinical trials in patients with HF.
weeks of perhexiline administration was associated
.
7.4 Metabolic Modulators with improvements in peak oxygen uptake (VO2)
[from 16.1 – 0.6 to 18.8 – 1.1 mL/kg/min; p < 0.001],
The mechanism of action of metabolic mod- the Minnesota Living with Heart Failure quality-
ulators is mainly based on a shift in energy utili- of-life score and LVEF (24 – 1% to 34 – 2%;
zation from free fatty acids (FFAs) to glucose. p < 0.001), with no significant adverse effects.

ª 2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (5)
522 Metra et al.

Other available carnitine palmitoyl transfer- CA2a has many consequences: (i) reduced and
ase-1 inhibitors include trimetazidine, ranolazine slower calcium reuptake during cell relaxation
and etomoxir. Etomoxir is no longer studied be- causing impaired LV diastolic function; (ii) in-
cause of its adverse effects. In contrast, preliminary creased free intracytoplasmatic calcium in the
data from small studies have shown encouraging cardiomyocytes, a mechanism that favours car-
results with trimetazidine and ranolazine. diac dysfunction and tachyarrhythmias; and
Trimetazidine has been associated with an im- (iii) reduced calcium accumulation within the SR,
provement in NYHA functional class, a reduc- with a reduction in the amount of calcium re-
tion in LV end-systolic volume and an increase in leased by the SR during systole and, hence, re-
LVEF, compared with conventional therapy, in duced myocardial contractility.[79]
patients with HF caused by LV systolic dysfunc- SERCA2a is a major target for treatment of
tion.[68-70] An improvement in exercise tolerance HF. In addition to istaroxime, another agent
and outcomes has also been shown in a small, under development is an adenovirus-associated
retrospective study.[71] Changes in LV function vector (AAV) carrying the gene for SERCA2a
after trimetazidine are associated with an increase (AAV1/SERCA2). In the CUPID trial,[80] AAV1/
in the phosphocreatine to adenosine triphosphate SERCA2 was administered as a single intra-
(PCr/ATP) ratio, assessed by 31P-magnetic re- coronary infusion to nine patients with end-stage
.
sonance spectroscopy,[72] and by reduced FFA HF (NYHA class III/IV, LVEF £30%, peak VO2
oxidation and unchanged myocardial oxidative <16 mL/kg/min). Several of these patients showed
rate, implying increased glucose oxidation.[70] an improvement from baseline in parameters
These data suggest that a drug-induced change in related to HF severity (NYHA class, Minnesota
myocardial metabolism, with an increase in glu- Living with Heart .Failure Questionnaire, 6-minute
cose compared with FFA oxidation, may have walk test, peak VO2, NT-proBNP, LVEF and
beneficial effects on myocardial function. end-systolic volume). Two patients who failed to
Ranolazine is a new drug that acts through the improve had pre-existing anti-AAV1-neutralizing
inhibition of the late sodium channel current, antibodies. No serious adverse events occurred.
hence preventing intracellular calcium overload These data supported the initiation of a larger
during myocardial ischaemia, and through the phase II trial.[80]
inhibition of FFA oxidation. It is now indicated In addition to gene therapy, a class of novel
for the treatment of angina. However, beneficial small molecules, acting as allosteric compounds,
effects on LV diastolic function, likely mediated is under development and has been found to
by the prevention of intracellular calcium over- modulate SERCA2a activity and increase myo-
load, [73,74] and on LV remodelling and myocardial cardial contractility without increasing energy
fibrosis have also been shown in experimental utilization in preclinical models.[13] Other studies
models.[75] of gene therapy of HF are based on the inhibition
Glucagon-like peptide (GLP)-1 and its analo- of G protein-coupled receptor kinase 2 (GRK2),
gues are new antidiabetic agents. Beneficial ef- an enzyme that is upregulated in HF causing b-
fects of GLP-1 on LVEF and exercise tolerance adrenergic pathway dysfunction.[81] These agents
have been shown in patients with HF in some,[76,77] would be expected, however, to cause increased
but not all,[78] of the studies. As with the previous cardiac sympathetic drive, with the potential ad-
compounds, a larger, controlled trial with clinical verse effects of sympathetic stimulation.
endpoints is needed.
8. Conclusions
7.5 Agents Acting on SERCA2a
A fraction of patients with acutely decom-
Calcium reuptake into the SR occurs by a pensated HF and signs of peripheral hypoperfu-
calcium-dependent ATPase (SERCA2a), which sion and fluid overload may need treatment with
is downregulated in HF. This deficiency in SER- agents with inotropic properties. Current inotropic

ª 2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (5)
Inotropic Drugs in Heart Failure 523

agents have been associated with poorer out- 9. Gheorghiade M, Abraham WT, Albert NM, et al. Systolic
comes, but no alternative medical treatments are blood pressure at admission, clinical characteristics, and
outcomes in patients hospitalized with acute heart failure.
available to improve the abnormal haemody- JAMA 2006; 296: 2217-26
namics and end-organ perfusion of patients with 10. Stevenson LW. Clinical use of inotropic therapy for heart
low cardiac output. New agents with different failure: looking backward or forward? Part I: inotropic
infusions during hospitalization. Circulation 2003; 108:
mechanisms of action, including sarcolemma and 367-72
SR ion currents, LV systole duration and myo- 11. Nieminen MS, Böhm M, Cowie MR, et al. Executive sum-
cardial metabolism, seem promising and are mary of the guidelines on the diagnosis and treatment of
associated with a lower likelihood of untoward acute heart failure: the Task Force on Acute Heart Failure
of the European Society of Cardiology. Eur Heart J 2005;
effects. However, larger studies are needed to 26: 384-416
prove this hypothesis. 12. Gheorghiade M, Pang PS. Acute heart failure syndromes.
J Am Coll Cardiol 2009; 53: 557-73
13. Teerlink JR, Metra M, Zacà V, et al. Agents with inotropic
Acknowledgements properties for the management of acute heart failure syn-
dromes: traditional agents and beyond. Heart Fail Rev
2009; 14: 243-53
No funding was provided for the preparation of this paper.
Marco Metra has received honoraria for speeches and parti- 14. Stevenson LW, Pagani FD, Young JB, et al. INTERMACS
profiles of advanced heart failure: the current picture.
cipation to advisory boards from Cardiokine, Corthera,
J Heart Lung Transplant 2009; 28: 535-41
Merck, Novartis and Servier. No potential conflicts of interest
are reported by the other authors. 15. Nohria A, Lewis E, Stevenson LW. Medical management of
advanced heart failure. JAMA 2002; 287: 628-40
16. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC
guidelines for the diagnosis and treatment of acute and
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Correspondence: Professor Marco Metra, Institute of Cardi-
diabetes and ischemic cardiomyopathy. Am Heart J 2003; ology, Department of Experimental and Applied Medicine,
146: E18 University of Brescia, c/o Spedali Civili, Piazzale Spedali
69. Fragasso G, Palloshi A, Puccetti P, et al. A randomized Civili, 1 – 25123 Brescia, Italy.
clinical trial of trimetazidine, a partial free fatty acid oxi- E-mail: [email protected]

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