Clin Res Cardiol DOI 10.1007/s00392-016-0968-y

CRITICAL PERSPECTIVE

Long-term intravenous inotropes in low-output terminal heart failure? Wolfgang von Scheidt1 • Matthias Pauschinger2 • Georg Ertl3

Received: 14 November 2015 / Accepted: 1 February 2016 Ó Springer-Verlag Berlin Heidelberg 2016

Abstract Intravenous inotropic therapy may be necessary to achieve short-term survival in end-stage heart failure patients with cardiogenic shock or extreme low output and severe organ hypoperfusion. However, mid- or long-term intravenous inotropic therapy is associated with an increased mortality in advanced stage D heart failure patients using b-adrenoceptor agonists (dobutamine) or PDE-3-inhibitors (milrinone). Intermittent levosimendan may evolve as a reasonable therapeutic option. Randomized trials or other meaningful scientific evidence addressing the optimal treatment of exclusively the most threatened subgroup of hospitalized patients with persistent severe organ hypoperfusion are missing, but urgently needed. Despite a lack of other beneficial pharmacological options, the use of long-term intravenous inotropic therapy as a treatment for refractory heart failure or as an obligatory criterion for high urgency (HU) listing of heart transplant candidates with a median waiting time of 66 days in Germany is not based on scientific evidence. In addition, it might create a disincentive to achieve the HU status as well as keeping it, thereby potentially exposing the patient to an unnecessary additional risk. Upcoming new allocation algorithms may possibly help to improve & Wolfgang von Scheidt [email protected] 1

I. Medizinische Klinik, Klinikum Augsburg, Herzzentrum Augsburg-Schwaben, Stenglinstr. 2, 86156 Augsburg, Germany

2

Medizinische Klinik 8, Kardiologie, Paracelsus Medizinische Privatuniversita¨t, Universita¨tsklinikum Nu¨rnberg, Nu¨rnberg, Germany

3

Medizinische Klinik und Poliklinik I, Deutsches Zentrum fu¨r Herzinsuffizienz - Comprehensive Heart Failure Center, Universita¨tsklinikum Wu¨rzburg, Wu¨rzburg, Germany

the inadequate present situation. There is need for both, a better definition and a better treatment of high risk terminal heart failure requiring high urgent transplant listing. Keywords Low-output heart failure
Inotropic therapy
Dobutamine
Milrinone
Levosimendan
High urgency heart transplant listing

Current treatment options and guideline recommendations ACE inhibitors or angiotensin-II-receptor blockers, betablockers and mineralocorticoid receptor antagonists have substantially improved prognosis in chronic heart failure. ICD, CRT and assist devices are additional options for advanced heart failure. Heart transplantation offers an essential treatment option for appropriate candidates with terminal heart failure. The breakthrough in medical treatment came with the concept of heart failure as a systemic disorder with neurohormonal activation, which replaced the concept of inotropic stimulation. In contrast, imminent death from severe low output, multi-organ dysfunction, or cardiogenic shock may require short-term inotropic and/or vasopressor stimulation, which is a IIa or IIb recommendation in guidelines for a situation of ‘‘compromised vital organ perfusion’’ [1, 2]. Unfortunately, what may be helpful and indicated transiently is not necessarily so for a longer period of time. This is reflected by the spectrum of recommendations in the most recent 2013 AHA guidelines [2], see Table 1. Of 15 citations in the AHA Guidelines Heart Failure 2013 dealing with inotropic support eight were published before the year 2000, and seven between 2000 and 2009, none thereafter [2].

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Clin Res Cardiol Table 1 Indications for intravenous inotropic support according to the AHAGuidelines 2013 [2]

Indications for intravenous inotropic support

Class

LOE

Cardiogenic shock pending definite therapy or resolution

I

C

Bridge to transplant or mechanical circulatory support in stage D heart failure refractory to guideline-directed medical therapy

IIa

B

Short-term support for threatened end-organ dysfunction in hospitalized patients with stage D and severe HFrEF

IIb

B

Long-term support with continuous infusion palliative therapy in selected stage D heart failure

IIb

B

Routine intravenous use, either continuous or intermittent, is potentially harmful in stage D heart failure

III

B

Short-term intravenous use in hospitalized patients without evidence of shock or threatened end-organ performance is potentially harmful

III

B

Class class of recommendation: I is indicated, IIa should be considered, IIb may be considered, III is not recommended, LOE level of evidence: B limited populations evaluated (data from either one single randomized trial or nonrandomized studies), C expert consensus, HFrEF heart failure with reduced ejection fraction

Table 2 Indications for intravenous inotropic support according to the ESC-Guidelines 2012 [1] Indications for intravenous inotropic support

Class

LOE

inotropic support is not recommended unless the patient is hypotensive (systolic blood pressure \85 mmHg), hypoperfused, or shocked because of safety concerns (atrial and ventricular arrhythmias, myocardial ischemia, and death)

III

C

An i.v. infusion of an inotrope (e.g. dobutamine) should be considered in patients with hypotension (systolic blood pressure \85 mmHg) and/or hypoperfusion to increase cardiac output, increase blood pressure, and improve peripheral perfusion

IIa

C

An i.v. infusion of levosimendan (or a phophodiesterase inhibitor) may be considered to reverse the effect of beta-blockade, if beta-blockade is thought to be contributing to hypoperfusion

IIb

C

A vasopressor (e.g. dopamine or norepinephrine) may be considered in patients who have cardiogenic shock, despite treatment with an inotrope, to increase blood pressure and vital organ perfusion

IIb

C

Class class of recommendation: I is indicated, IIa should be considered, IIb may be considered, III is not recommended, LOE level of evidence: C expert consensus

The 2012 ESC Guidelines on the Management of Heart Failure [1] propose the following, see Table 2. All recommendations are given with a level of evidence C, i.e. not supported by conclusive results of randomized trials. The paradox is: inotropes are considered harmful, but, lacking convincing alternatives, classified as necessary for a limited period of time in special situations, such as cardiogenic shock or severe end-organ hypoperfusion. There is no recommendation given in the guidelines or a recent consensus paper concerning the maximum reasonable time period of inotropic support [1–3].

Pathophysiology of inotropic regulation in heart failure In chronic human heart failure several changes in the badrenoceptor (b-AR)/G-proteins/adenylyl cyclase (AC) pathway have been well documented (Fig. 1). This includes desensitization and downregulation of b1adrenoceptors, increased concentrations of the alpha

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Fig. 1 Inotropic regulation of the myocardium via the b1-adrenoceptor/Gs- and Gi-protein/adenylyl cyclase/cAMP pathway in heart failure. The main features are: downregulation of b1-adrenoceptors, increase in Gi-protein alpha subunit concentration leading to reduced adenylyl cyclase activity and subsequent reduced cAMP production. In addition, a reduced neuronal norepinephrine reuptake leads to an increased norepinephrine concentration at the synaptic cleft (not shown). b1 = b1-adrenoceptor, b-, y- and a = subunits of the stimulatory G protein Gs or the inhibitory G protein Gi. M-Ch M-cholinoceptor, A1 adenosine A1 receptor

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subunit of the inhibitory G-protein, and impaired neuronal reuptake of norepinephrine [4–14]. b1-AR downregulation and increase of Gi-protein subunit alpha concentration correlate to the severity of heart failure, being most pronounced in terminal heart failure and catecholamine refractory cardiogenic shock [5, 12]. As a result, the adenylyl cyclase activity and subsequent cAMP production are severely reduced in chronic heart failure leading to a desensitization of the whole pathway. The effect of inotropes acting via this pathway is widely blunted. This includes b1-AR-agonists, such as dobutamine, low-dose dopamine and epinephrine (downregulation of the b1-adrenoceptors, increase of Gi-protein subunit alpha, reduced AC activity), as well as PDE-3inhibitors, such as milrinone (reduced effect of inhibition of phosphodiesterase due to a decreased concentration of the substrate, i.e. cAMP). Of note, chronic exogenous application of cAMP-dependent inotropes, such as b-adrenoceptor agonists or PDE-3-inhibitors severely aggravate the desensitization and uncoupling of the pathway by further downregulation of b1-adrenoceptors and increase of the concentration of the Gi-protein alpha subunit. As a clinical proof of this fundamental principle, tachyphylaxis of dobutamine in clinical practice has first been described by Unverferth et al. in 1980. After a 72 and 96 h infusion of dobutamine the initial and over 2 h stable hemodynamic response (cardiac output) was severely reduced to 66 and 57 %, respectively [15].

Intravenous inotropic therapy in refractory stage D heart failure: the sobering evidence Intravenous inotropic agents can be divided in cAMPdependent (b1-adrenoceptor agonists such as dobutamine or phosphodiesterase-3-inhibitors such as milrinone) or cAMP-independent (such as the calcium sensitizer and ATP-sensitive potassium channel activator Table 3 Classes of intropic agents and their mechanisms of action

levosimendan). Vasopressors, such as norepinephrine, act predominantly via stimulation of vascular alpha1adrenoceptors with less affinity to the myocardial b1AR, see Table 3. Increased oxygen demand, myocardial ischemia, arrhythmias, and increased mortality are potential consequences of inotropic stimulation with catecholamines oder PDE-3-inhibitors [1, 2, 4, 16–20]. The calcium sensitizer levosimendan may be an exception because of lack of an increased myocardial oxygen demand. The ADHERE registry showed a propensity score-adjusted increased in-hospital mortality in acute decompensated heart failure patients after short-term treatment with inotropes (dobutamine or milrinone) compared to vasodilators (nitroglycerin or nesiritide) in hemodynamically stable patients without signs of low output failure [21]. In the randomized ESCAPE trial, evaluating hemodynamic monitoring plus clinical assessment vs clinical assessment alone in 425 hospitalized heart failure patients with an EF \ 30 % without cardiogenic shock, in-hospital use of inotropes (dobutamine, dopamine or milrinone) resulted in a higher 6-month MACE rate (death, need for assist device or transplantation) independent of systolic blood pressure on admission (SBP, adjusted hazard ratio HR 2.85 in SBP \ 100 mmHg, p \ 0.001, and HR 1.86 in SBP [ 100 mmHg, p = 0.042) or cardiac index (CI, HR 1.48 in CI \ 1.8 l/min 9 m2, p = 0.39, and HR 4.65 in CI [ 1.8 l/min 9 m2, p \ 0.001) and a significantly shorter survival time. The effect was independent of dilated or ischemic etiology of heart failure [22]. The risk-adjusted hazard ratio for 6-month all cause mortality was 2.14 in inotrope-treated patients, p \ 0.001 [23]. Accordingly, the use of inotropes by the treating physicians is heterogenous. A survey from 209 American hospitals including 126,564 patients revealed that ejection fraction was [35 % in one quarter, and systolic blood pressure [100 mmHg in three quarters of patients [24]. Several reviews and meta-analyses have reported the current data on inotropes in systolic end stage heart failure

Class of inotrope

Drug

Mechanism/receptor

Catecholamines/synthetic sympathicomimetic amines

Dobutamine

b1-AR [ b2-AR  alpha1-AR

Dopamine

D1 (low dose) b1-AR, b2-AR (medium dose) alpha1-AR (high dose)

Epinephrine

b1-AR, b2-AR (low dose) alpha1-AR (high dose)

PDE-3-Inhibitors Calcium sensitizer

Norepinephrine

Alpha1-AR [ b1-AR [ b2-AR

Milrinone Levosimendan

Inhibition of PDE-3 Myofilament Ca?? Sensitizer, ATP-sensitive K? channel activator

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[16–20, 25–27]. Thackray et al. reported in 2002 a metaregression analysis of 21 randomized trials of iv use of cAMP-dependent inotropic agents (dobutamine, high-dose dopamine, dopexamine, amrinone, milrinone, enoximone and toborinone) including 632 patients with severe heart failure [16]. In 16 trials, including 474 patients, invasive hemodynamic studies were performed, in five trials, including 158 patients, intermittent inotropes were administered in an outpatient setting. Eleven studies compared two different inotropes (mainly dobutamine vs a PDE-3 inhibitor), whereas ten studies compared an inotrope vs placebo. The number of patients per trial ranged from 14 to 79, in most trials less than 40 patients were included. Compared to placebo, inotropes tended to increase mortality (HR 1.5, ns). Of note, there is no unanimous definition of the terms advanced or end-stage or terminal heart failure. These terms include, at least as a subpopulation, although not exclusively, advanced, unstable stage D heart failure patients requiring continuous in-hospital management, mostly in a ICU setting. These patients with refractory low output and persistent organ hypoperfusion are not adequately represented or selectively investigated in available trials evaluating inotropic agents, since in most trials the majority of patients would be classified as advanced, but not unstable, stage D heart failure. In addition, if inotropic support is estimated as

necessary, randomized, placebo-controlled trials are difficult to perform and not available yet. Dobutamine In a systematic review and meta-analysis Tacon et al. report on the effect of dobutamine compared to placebo or standard care on mortality and secondary outcomes in severe heart failure. Fourteen prospective randomized clinical trials, published between 1982 and 2010, were identified including all together 673 patients [17]. NYHA class was III or IV in all patients, and mean EF between 20 and 26 %. Duration of dobutamine treatment (24 h to 7 days, mostly less than 72 h), single or repetitive (3 weeks to 6 months) administration, and duration of follow-up (3 days to 32 months) differed considerably. The dosages of dobutamine ranged between 1–7.5 and 15–35 lg/ kg 9 min. The odds ratio for mortality was 1.47 for dobutamine compared to placebo (ten studies) or standard care (four studies), p = 0.06, see Fig. 2. Only three of 14 studies described an adequate method of allocation concealment, and two studies only met all four prespecified validity criteria of the meta-analysis (use of a randomization method maintaining allocation concealment, use of blinding for outcome assessment, presentation of an intention-to-treat analysis, presentation of predefined

Fig. 2 Forrest plot showing the pooled estimate of the odds ratio for mortality for dobutamine compared with placebo or standard care in patients with severe heart failure. With permission of Tacon et al. [17]

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outcomes). There were no hints for symptomatic improvement in dobutamine treated patients. The increased mortality with dobutamine was independent from a hospitalized (five studies) or outpatient status (nine studies) of the patients [28–41]. The majority of the studies had a poor methodological quality. Three studies, including more than 50 % of all patients in the meta-analysis, were published as abstracts only. In a subanalysis of the FIRST trial, evaluating iv epoprostenol vs placebo in advanced heart failure, including 471 patients, dobutamine infusion performed in 80 patients (mean dosage 9 lg/kg 9 min) over a median duration of 14 days was associated with a higher MACE-rate (worsening heart failure, need for vasopressors, resuscitated cardiac arrest, myocardial infarction, death) of 85 vs 65 % and a higher mortality of 71 vs 37 % at 6 months compared to 391 non-dobutamine-treated patients. Intravenous continuous dobutamine was an independent risk factor for death after adjusting for baseline differences [42]. Given the available data concerning duration and dosage, it has been concluded that prolonged administration and higher doses of dobutamine ([5 lg/kg 9 min) are associated with a poorer outcome [19]. It is puzzling that catecholamines seem to increase mortality while they rapidly lose their inotropic effect. These negative side effects, e.g. ventricular arrhythmias, may be mediated by b2-adrenoceptors, which are not downregulated in heart failure and not only coupled to Gs-proteins, but also to Giproteins exhibiting potential negative inotropic and noninotropic effects [9–11, 43]. In addition, the catecholamineinduced inotropic desensitization itself may aggravate the prognosis. Milrinone More than 20 years ago a first meta-analysis was published reporting the effect of oral PDE-3-inhibitors on mortality in chronic heart failure [25]. 13 randomized, placebo-controlled trials including 2808 patients were evaluated. A significantly increased mortality was observed (OR 1.41, p \ 0.001). The OPTIME-CHF trial is the only randomized, controlled, prospective trial evaluating iv milrinone vs placebo in 949 patients with acute decompensation of chronic severe systolic heart failure. Patients received a 48–72 h infusion of milrinone or placebo. Milrinone therapy was associated with significant more episodes of hypotension and arrhythmias. The in-hospital mortality was not significantly higher (3.8 vs 2.3 %), as well as the 2-months mortality (10.3 vs 8.9 %). The composite endpoint death or readmission did not differ [44]. A later subanalysis of the OPTIME-CHF trial reported a higher mortality of milrinone in ischemic cardiomyopathy [45]. A limitation of the

trial is the exclusion of unstable patients requiring definite inotropic support at time of randomization. A recent publication reported continuous inotropic therapy (85 % milrinone, 15 % dobutamine) in 197 patients in an ambulatory setting suffering from refractory heart failure [46]. 50 % of patients received inotropes as palliative therapy, and 41 % as candidates for either HTX or assist device implantation. The 1-year mortality was 52 %. No control group is presented, thus preventing a conclusion whether this ambulatory feasible therapy was beneficial or detrimental. Randomized, controlled trials evaluating long-term continuous or repetitive iv administration of a PDE-3-inhibitor are not published. Levosimendan Levosimendan provides a rapid inotropic and vasodilating (both systemic and pulmonary circulation) effect. The half life of levosimendan is 1.3 h, while the concentration of the equally active metabolite OR-1896 peaks at 2–3 days. This results in long-lasting hemodynamic effects on cardiac output, PCW-pressure and vascular resistance for at least 1 week [26]. An initial bolus application used in early studies has been largely abandoned, and a continuous application of 0.1–0.2 lg/kg 9 min for 24 h without initial bolus is the present standard. Some investigators have used a shorter duration of 6 h only [26]. In the LIDO trial, 203 patients with low-output heart failure were treated with levosimendan (bolus plus 24 h infusion) or dobutamine for 24 h in a randomized, controlled, double-blind trial with a hemodynamic primary endpoint (increase of CO [30 % and decrease of PCWP [25 %). The hemodynamic endpoint was reached in 28 % in the levosimendan vs 15 % in the dobutamine group (HR 1.9, p = 0.02). Mortality at 6 months was 26 vs 38 % in the two groups (HR 0.57, p = 0.03). The study was not powered, however, for mortality endpoints [47]. The Revive II trial compared levosimendan (bolus plus 24 h infusion) with placebo in acute decompensated heart failure. Levosimendan was superior to placebo with regard to the primary endpoint (improvement of symptoms and signs of heart failure at day 1, 2 and 5, p = 0.015), and a greater decrease in BNP levels was observed. Adverse effects were more frequently observed in the levosimendan group: hypotension 50 vs 36 %, ventricular tachycardia 24 vs 17 %, and atrial fibrillation 8 vs 2 %. Mortality at 3 months was not different (15 vs 12 %, p = 0.21). However, the study was not powered for a mortality endpoint [48]. In the SURVIVE trial, 1327 patients with acute decompensated chronic systolic heart failure requiring inotropic treatment were randomized to levosimendan (bolus plus a mean dosage of 0.2 lg/kg 9 min for 24 h) or

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Fig. 3 Effect of a single dose of levosimendan (24 h) vs short-term dobutamine (39 h) on all-cause mortality at 180 days in acute decompensated chronic heart failure patients. Data from the SURVIVE-Trial. With permission of Mebazaa [49]

dobutamine (mean dosage 5.9 lg/kg 9 min for a mean duration of 39 h). The primary endpoint all-cause mortality at 180 days was not different between the two groups: 26 vs 28 %, p = 0.40, see Fig. 3 [49]. Levosimendan was associated with a significantly greater decrease of BNP at day 1 and day 5, whereas other secondary endpoints did not differ (dyspnea and global assessment at 24 h, mortality at day 31, number of days alive and out of hospital at day 180, cardiovascular mortality at day 180). Cardiac failure occurred more often in the dobutamine group during follow up (17 vs 12.3 %, p = 0.02). A non-significant trend to a lower mortality at 5 days (HR 0.72) was found in a post hoc analysis. The authors conclude that a single short-term application of two different inotropes most probably is insufficient to influence long-term mortality [49]. Trials reporting long-term intermittent levosimendan application are available [26, 50–58]. The prospective, randomized, double-blind, placebo-controlled LevoRep trial investigated levosimendan (0.2 lg/kg 9 min for 6 h) vs placebo (6 h) at 2-week intervals over 6 weeks (i.e. 4 infusions) in 120 outpatients with end-stage chronic heart failure (EF \ 35 %, NYHA class III or IV). The combined primary endpoint improvement of 6-min walk test [20 % and improvement of questionnaire-assessed QOL [ 15 % was not significantly different (19 vs 15.8 %, OR 1.25, p = 0.81). Levosimendan was superior regarding the secondary endpoint event-free survival at 6 months (freedom from death, HTX or acute heart failure): 82.6 vs 64.9 %, OR 0.39, p = 0.037, see Fig. 4. A more than 30 % drop in NT-proBNP levels at 8 weeks occurred in 32 % of patients in the levosimendan group compared to 14 % in the placebo group (p = 0.03), but no difference was found at 6 months. Side effects were not different in both groups [50].

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Fig. 4 Event-free survival at 6 months in the LevoRep trial. Kaplan– Meier curves for the secondary endpoint comprising freedom from death, heart transplantation, or acute heart failure. Censored for patients withdrawn prematurely. Intention-to-treat analysis. With permission of Altenberger [50]

Probably, the cumulative dose per short 6 h infusion of levosimendan was too low and/or the repetition interval of 2 weeks too long to achieve a more convincing benefit from repetitive levosimendan in the LevoRep trial. There are eight additional small trials (five randomized, three non-randomized, including 25–75 patients per study) evaluating repetitive application of levosimendan in advanced heart failure [51–58]. The comparator is placebo in three studies, dobutamine in two, prostaglandin E1 in one, furosemide in one, and no comparator in one study. The number of cycles varies from 4 to 24, the duration of infusion from 6 to 24 h, the repetition interval from weekly to monthly, and the length of treatment from 6 weeks to 6 months [26]. The endpoints are symptomatic or hemodynamic in most trials. An international expert consensus group published a meta-analysis of these eight studies and the LevoRep study [26]. A significant benefit of levosimendan on mortality is suggested, see Fig. 5. A comparable conclusion was drawn in another meta-analysis on intermittent levosimendan use [59]. The expert panel concluded that the available data on repetitive use of levosimendan are encouraging for selected patients to maintain clinical stability [26]. An accompanying editorial states that after removal of an open label, non randomized and another yet unpublished study from the two meta-analyses mentioned, the effect of levosimendan on mortality is not statistically significant (RR 0.56, p = 0.11). It supports, however, the suggestion that ‘‘repetita iuvant’’ and recommends further evaluation and

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Fig. 5 Meta-analysis of mortality in trials using repetitive levosimendan therapy. With permission of Nieminen et al. [26]

points to upcoming three trials [27]. In a recent metaanalysis exclusion of these two studies and inclusion of initial results of the LION Heart trial resulted in a significantly lower long-term mortality (mean follow up 8 months) in levosimendan treated patients compared to placebo [60]. Three large trials with levosimendan are under way: LION Heart (levosimendan vs placebo 6 h every 2 weeks for 3 months, endpoints: change in NT-proBNP), LAICA (24 h-levosimendan vs placebo in outpatients every 30 days for 1 year, combined endpoint: overall mortality and hospital admission for heart failure decompensation or worsening, several secondary endpoints) and ELEVATE (levosimendan vs diuretics in patients with early signs of decompensation, endpoint: hospitalization-free survival) [26, 61, 62]. The results of the LION Heart trial were reported at the ESC Heart Failure Congress 2015 in Sevilla. Levosimendan vs placebo resulted in a significantly greater change in NT-proBNP, significantly fewer heart failure rehospitalizations and all-cause mortality/HF-rehospitalizations [62].

Single, intermittent/repetitive or continuous application Single short-term (mostly less than 72 h) or intermittent longer-term application of inotropes has been reported, see above. There is not a single study published performing a continuous intravenous inotropic therapy with either a sympathicomimetic amine (either b-adrenoceptor stimulating such as dobutamine, or alpha-adrenoceptor and badrenoceptor stimulating such as norepinephrine) or a PDE-3 inhibitor (e.g. milrinone) over weeks or even months compared to placebo or another therapeutic measure. Due to its specific pharmacokinetics levosimendan is only suited for intermittent therapy.

Clinical scenarios for long-term inotropic support The ESC guidelines on heart failure do not comment on the problem of long-term inotropic support [1]. The AHA guidelines state that long-term use of either continuous or intermittent, intravenous positive inotropic agents, in the absence of specific indications or for reasons other than palliative care is potentially harmful and therefore not indicated [2]. Besides the palliative, ambulatory application of iv inotropes which is uncommon in Germany, long-term inotropic support is considered only for patients with severe low output heart failure awaiting heart transplantation. The INTERMACS classification is often used for categorizing patients with advanced heart failure: 1 = critical cardiogenic shock, 2 = progressive decline despite inotropic therapy, 3 = stable, but inotrope-dependent or treated (in hospital or at home), 4 = resting symptoms, frequent re-admissions, 5 = exertion intolerant, 6 = exertion limited, 7 = advanced NYHA class III [63, 64]. INTERMACS class 1 and 2 patients need an immediate or very urgent definite solution (e.g. assist device), whereas class 3 patients may be stabilized over a longer period until a donor heart is available. At present, there is no scientific evidence-based concept how to pharmacologically treat chronic severe low output heart failure patients with persisting organ hypoperfusion over weeks or even months (INTERMACS class 3 patients). The definition ‘‘inotropedependency’’ is misleading for this population, since it is at least in part due to tachyphylaxis of cAMP-dependent inotropes, as explained above. Alternatives to inotropes include mechanical support, which may be a reasonable option, but has inherent risks. Intravenous vasodilators (nitroglycerine, sodium-nitroprusside, nesiritide) are suited for short-term use and in normotensive or mildly hypotensive patients only. Whether upcoming inotropic agents, such as the selective cardiac

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myosin activator omecamtiv mecarbil [65], the sodium– potassium ATPase inhibitor and sarcoplasmatic reticulum calcium ATPase 2a (SERCA-2a) stimulator istaroxime [66], or SERCA-2a gene therapy may play a role in the setting of refractory low output, is unknown. Recently, SERCA-2a gene therapy yielded neutral results in the CUPID-2 trial [67]. The sparse registry or observational data dealing with high-urgency listed heart transplant candidates document the hemodynamic low output profile and a serious prognosis, but cannot adequately answer the question of an optimal therapeutic strategy [68, 69].

Criteria for high urgency (HU) listing According to Eurotransplant (ET) regulations (as of October 1st, 2013), the listing in the international HU status of a patient without being on an assist device requires the following: inotropic therapy: Swan Ganz catheter showing a CI \ 2.2 l/min 9 m2 and SVO2 \ 55 % and PC [ 9 mmHg, while on inotropic therapy for at least 48 h with dobutamine[7.5 lg/kg/min or equivalent inotropes, or milrinone[0.5 lg/kg/min or equivalent PDE inhibitor, and signs of beginning secondary organ failure: sodium \136 mmol/l or increase of creatinine during clinical course in spite of treatment or increase of transaminases or symptomatic of cerebral perfusion deficit (neurological report). The HU status requires that the patient is hospitalized in the transplant center or in a hospital cooperating with the transplant center and using the same medical therapy guidelines as the transplant center. This hospital is to be situated at such a distance that a transplant center physician is able to visit the patient at least once a week. The visit is to be documented. The international HU status is valid for a period of 8 weeks [70]. The national regulations of the German Federal Chamber of Physicians (Instructions for Organ Transplantation, as of Dec 9th, 2013) require the following for HU status: the patient is in an acute lifethreatening cardiac condition, treatment according to intensive care medicine conditions, lack of recompensation in spite of high dose catecholamine therapy and/or phosphodiesterase therapy, signs of Table 4 Numbers for 2014 of all HTX (from HU and elective status) and from HU-status only in ET countries, Germany (D) and ET countries without Germany. Median waiting times from listing to HTX for HUand elective HTX

beginning organ failure. The HU status requires that the patient is hospitalized in the transplant center or in a hospital cooperating with the transplant center and using the same medical therapy guidelines as the transplant center. This hospital is to be situated at such a distance that a transplant center physician is able to visit the patient at least once a week. The visit is to be documented. The HU status is valid for a period of 8 weeks [71].

HTX waiting list and waiting times in Eurotransplant 617 isolated heart transplantations (HTX) were performed in 2014 in ET countries (Austria, Belgium, Croatia, Germany, Hungary, Luxembourg, the Netherlands, Slovenia), 292 of these (47 %) in Germany. 365 of 617 HTX (59 %) were performed in HU listed recipients. Of 292 HTX in Germany in 2014, 245 candidates were listed as HU (84 %). In all other ET countries without Germany, 120 of 325 HTX pts (37 %) were listed as HU, see Table 4. 245 of 365 HU transplants (67 %) and 47 of 252 elective transplants (19 %) were performed in Germany [72]. Is unstable, terminal heart failure requiring HU-listing more frequent in Germany than in other ET countries? In 2014, the median waiting time of heart-only listed candidates for ET was 50 days in HU status (41 days in 2009) and 219 days in non-HU status (149 days in 2009). In Germany, the median waiting time of a HU listed candidate in 2014 was 66 days (47 days in 2009), and 235 days for a non-HU listed candidate (209 days in 2009). For ET without Germany the median waiting time in 2014 was 13.5 days in HU status (7 days in 2009) and 209 days in non-HU status (140 days in 2009), see Table 4 [73].

The dilemma: how to treat low output terminal heart failure patients while waiting for HTX? The available scientific knowledge may be summarized as follows. To limit the harm and to preserve a potential benefit, an individual approach for every patient is mandatory. This includes interindividual differences and

2014

ET

D

HTX (HU ? elective), n

617

292

325

HTX (HU), n (%)

365 (59 %)

245 (84 %)

120 (37 %)

Median waiting time HU-HTX (days)

50

66

13.5

Median waiting time elective HTX (days)

219

235

209

From Eurotransplant Annual Report [72] and Samuel, ET, personal communication [73]

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time-dependent intraindividual differences in the dosage and duration of an inotropic support. Careful attention should be given to an adequate volume status with a PCWpressure of 14–18 mmHg. At least cAMP-dependent inotropic agents should be used for the shortest time and in the lowest dosage necessary to achieve an adequate organ perfusion, i.e. a borderline recompensation [19]. A highly individualized regimen with increasing and decreasing dosages according to the circulatory response, if possible or necessary, should be preferred over a fixed-dose regimen. Based on the pathophysiological considerations, a repetitive, intermittent administration seems to be preferable over a continuous administration, but evidence supporting this concept is missing. Intermittent application of b1adrenoceptor agonists would allow for at least a partial resensitization of the b-adrenergic-receptor/Gs-protein/ adenylyl cyclase pathway in order to induce an intermittent partial inotropic response. In contrast, continuous application leads to loss of an inotropic answer due to persisting desensitization of the receptor–effector pathway, a situation known as catecholamine refractoriness. The PDE-3 inhibitor milrinone is independent of the b-adrenoceptor, but acts via inhibition of breakdown of cAMP. Due to an increase in Gi-proteins and subsequent reduced activity of the adenylyl cyclase less cAMP is produced minimizing the effect of milrinone. Repetitive levosimendan, eventually in combination with short-term vasopressor therapy (low dose norepinephrine) in case of hypotension, may have the best benefit/risk ratio. The time intervals may range from once a week to once every 4 weeks. A routine use of continuous or intermittent infusions of high dose dobutamine or milrinone over weeks to months in HU-listed HTX-candidates is not supported by any scientific evidence. Due to the unavailability of ad hoc definite solutions (i.e. transplantation), a short-term bridge (iv inotropes, helpful and acceptable for days) is switched into a long-term bridge (weeks to months), and a short-term benefit into a long-term harm. The point in time, when benefit turns into harm most probably is reached in days, not weeks. Since a high dose iv administration of dobutamine or milrinone is an obligatory requirement for preserving the HU-status of a HTX-candidate, there is no incentive for individual adaptation of therapy. The treatment of these patients should become a key task for upcoming heart failure units in tertiary care and university hospitals, which are predestinated for an optimal management of these most critical and challenging heart failure patients. Experienced heart failure specialists from cardiology and cardiac surgery have to join and to care for these patients on a highly individual basis with the highest available expertise.

Admittedly, the present therapeutic choices for true low output patients with persisting organ hypoperfusion are very limited. However, a multicenter trial (or at least consented treatment protocols) evaluating several strategies, e.g. repetitive levosimendan vs intermittent cAMP-dependent inotropes (in lowest dosages and longest possible intervals providing borderline recompensation) vs Assist Device, would rapidly yield important scientific answers.

Conclusion There is no scientific evidence of any benefit of long-term iv inotropic therapy in end-stage heart failure with low output and organ hypoperfusion. Mortality most probably is increased with b-adrenoceptor agonists (dobutamine) or PDE-3-inhibitors (milrinone). Intermittent levosimendan may evolve as a reasonable therapeutic option. Randomized trials addressing exclusively this specific patient population are missing, but urgently needed. The definition of HU status by therapy, i.e. the dependence on inotropes, is highly questionable. Low output terminal heart failure must be defined by other measures than a potentially harmful therapy. A median waiting time of 66 days in HU status eliminates a meaningful definition of HU classification, i.e. rapid access for those facing imminent death. There is need for a better definition of HU. A change of the allocation is under way. A new cardiac allocation score CAS, a modified Seattle Heart Failure Model score, most probably will be used. Whether this new algorithm is not only appropriate to discriminate the comparative risks of severe heart failure versus HTX to provide a correct listing decision, but also appropriate to identify the most threatened of the listed candidates to select the correct high urgent patients, is unknown. All those who care for waiting list patients are encouraged to solve or at least improve this burning problem: accurate definition and adequate treatment of severe, low output terminal heart failure patients requiring high urgent HTX. Compliance with ethical standards Conflict of interest

All authors do not have a conflict of interest.

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