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Three Part Question

In [adults suffering from a STEMI complicated by cardiogenic shock] does [treatment with levosimendan] [improve outcome]?

Clinical Scenario

A 56 year old is brought to the ED suffering from a STEMI. He is hypotensive and suffering from cardiogenic shock. He has been started on dobutamine but he has failed to respond to this initial treatment. The Cardiologist asks if the ED has levosimendan as he would like this started on the patient since there is already another patient in the Cath lab. You wonder whether there is any evidence for this treatment.

Search Strategy

Search Strategy Medline (1950 – August week 1 2013) was searched via an Ovid interface: [Levosimendan] and [cardiogenic shock OR hypotension] and [myocardial infarction OR heart attack OR STEMI]. Embase (1980 – August 2013) was searched via an Ovid interface: [Levosimendan] and [exp cardiogenic shock] and [exp heart infarction]. Search was limited to English language and Humans

Search Outcome

Medline: 64 references were found, of which 5 were felt to be relevant to the question. Embase: 66 references were found, with four of the above relevant references duplicated. No relevant Cochrane reviews were identified.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Fuhrmann et al. 2008 Germany	32 patients presenting with AMI with persisting CS despite revascularisation, IABP and optimal medical management including ionotropes. Randomized to receive either levosimendan or enoximone	RCT	30 day mortality. Haemodynamic parameters	30-day survival greater in the levosimendan group 68.7% vs. 37.5% (p=0.023) Trend towards improved parameters of cardiac work e.g. cardiac index.	Unblinded. Excluded those not requiring an IABP. Single centre. Small numbers. ? how often enoximone used in UK
Samimi-Fard et al. 2008 Spain	22 patients with CS within 24 hours following PCI for acute MI. Randomized to receive either levosimendan or dobutamine as inotropic agent	RCT	Cardiac death at one year follow-up	No difference in mortality. Levosimendan 27% vs. dobutamine 9% (p=0.24)	Unblinded. Unclear randomization process. Excluded patients with right ventricle infarct. Single centre. Small numbers.
Christoph et al. 2008 Germany	22 patients presenting with AMI with persisting CS despite revascularisation and inotropic and/or vasopressor support. Patients either had IABP placed or started on levosimendan infusion	Prospective, observational	Mortality at day 3 and haemodynamic parameters	No difference in mortality. Levosimendan 30% vs IABP 25% (p=0.79) Trend to early improvement in CI with levosimendan (p=0.76) but no real difference at 48 hours	Non-randomized. Observational. Single centre. Small numbers.
Omerovic et al, 2010 Sweden	94 patients with CS secondary to AMI. All patients revascularised +/- IABP. Patients presenting pre-December 2005 all patients received levosimendan as first-line inotrope. Post-December 2005 levosimendan no longer used.	Prospective, observational	30-day and 1-year mortality	No difference in mortality between groups at either time point. 30-day: Levosimendan 32.6% vs. 35.4% (p=0.93) and then 43.5% vs. 34.4% at one-year (p=0.87)	Non-randomised. Control group may have benefitted from other advances in critical care. Single centre.
Landoni et al. 2012 Italy	5,480 patients in 45 randomised trials of levosimendan in any clinical setting	Systematic review and meta-analysis	Overall mortality	507/2915 (17.4%) vs 598/2565 (23.3%) (risk ratio 0.80 [95% CI 0.72-0.89] p<0.01)	The meta-analysis did not specifically address patients with AMI or with cardiogenic shock. In fact cardiogenic shock was an exclusion criteria in some of the studies, which may explain the low mortality rate.
			Cardiology studies	441/2207 (20.0%) vs 484/1893 (25.6%) (RR 0.67 [0.51-0.86] p=0.002
Husebye et al. 2013, Norway	9 patients with CS secondary to acute STEMI. Sub-group of 61 patients presenting with heart failure. All patients underwent PCI. Randomized to receive either levosimendan or placebo.	Placebo-controlled, double-blind, RCT	WMSI and NT-proBNP at day 5 and 42 and 6 month mortality	Significant improvement in whole group’s WMSI at day 5 but not at day 42 No change in mortality in CS group	Small numbers of patient with cardiogenic shock. Not powered adequately for mortality. Single centre.

Comment(s)

Levosimendan has several favourable properties that could potentially confer some advantage over traditional inotropic agents in the treatment of cardiogenic shock following acute myocardial infarction (AMI). Its primary mode of action is sensitising the myocytes to calcium, thereby increasing the force of contraction and improving cardiac output. This is in contrast to the traditional β-receptor agonists, which may increase the myocardial oxygen demand, favour the development of cardiac arrhythmias and compromise coronary perfusion pressures. The calcium-dependent binding of levosimendan means that during diastole it has minimal effects and therefore does not impair relaxation of the ventricle. In addition, it decreases cardiac work by opening ATP-dependent potassium channels in vascular smooth muscles, resulting in systemic vasodilation and cardiac afterload reduction. Importantly, augmentation of cardiac performance with levosimendan is achieved without increasing myocardial oxygen demand unlike the other pharmacological treatment options. The meta-analysis by Landoni et al (2008) suggests an improvement in mortality with levosimendan when all clinical uses are considered. However, this meta-analysis did not address cardiogenic shock as such. The properties of levosimendan may explain its haemodynamic benefit in cardiogenic shock following AMI (eg, in Fuhrmann et al, 2008 and Christoph et al, 2008). However, this improvement in cardiac performance has not been shown to result in more favourable outcomes. In four out of the five studies (table 1), levosimendan failed to improve outcome both in the short and long term. The small numbers of patients recruited hamper all these papers. The largest number of patients was recruited by Omerovic et al (2010), a study not included in Landoni et al (2008), and this reinforces the suggestion that levosimendan produces no improvement in outcome. The lack of improvement in outcome in this patient group is also apparent when different comparators are used; for example, dobutamine, intra-aortic balloon pump and placebo. While levosimendan does have some potentially attractive benefits in enhancing cardiac performance, it is costly, does not have a product licence in the UK, and has not been shown consistently to improve outcome in patients with AMI requiring percutaneous coronary intervention (PCI). There are no studies showing any benefit of its use as a bridging therapy before PCI or guidance on what loading dose you would consider in this circumstance.

Editor Comment

AMI, acute myocaridal infarction; CS, cardiogenic shock; IABP, intra-aortic balloon pump; NT-proBNP, N-terminal prohormone of brain natriuretic hormone; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; RR, risk ratio; STEMI, ST-elevation myocardial infarction; WMSI, wall motion score index.

Clinical Bottom Line

In patients attending the ED with AMI complicated by cardiogenic shock there is currently no evidence to support the use of levosimendan in improving their outcome before or after re-vascularisation.

References

1. Fuhrmann JT, Schmeisser A, Schulze MR et al. Levosimendan is superior to enoximone in refractory cardiogenic shock complicating acute myocardial infarction. Crit Care Med 2008; 36: 2257-2266.
2. Samimi-Fard S, Garcia-Gonzalez MJ, Dominguez-Rodriguez A et al. Effects of levosimendan versus dobutamine on longterm survival of patients with cardiogenic shock after primary coronary angioplasty. Int J Cardiol 2008; 127: 284-287.
3. Christoph, A, R. Prondzinsky, Russ M, et al. Early and sustained haemodynamic improvement with levosimendan compared to intraaortic balloon counterpulsation (IABP) in cardiogenic shock complicating acute myocardial infarction. Acute Cardiac Care 2008; 10: 49-57.
4. Omerovic E, Ramunddal T, Albertsson P et al. Levosimendan neither improves nor worsens mortality in patients with cardiogenic shock due to ST-elevation myocardial infarction. Vascular Health & Risk Management. 2010; 6: 657-663.
5. Landoni G, Biondi-Zoccai G, Greco M et al. Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies. Critical Care Medicine 2012; 40(2): 634-646.
6. Husebye T, Eritsland J, Muller C, et al. Levosimendan in acute heart failure following primary percutaneous coronary intervention-treated acute ST-elevation myocardial infarction. Results from the LEAF trial: a randomized, placebo-controlled European Journal of Heart Failure 2013; 15 :565-572.