Inotropic agents and vasodilator strategies for acute myocardial infarction complicated by cardiogenic shock or low cardiac output syndrome
Abstract
Background
The recently published German‐Austrian S3 Guideline for the treatment of infarct related cardiogenic shock (CS) revealed a lack of evidence for all recommended therapeutic measures.
Objectives
To determine the effects in terms of efficacy, efficiency and safety of cardiac care with inotropic agents and vasodilator strategies versus placebo or against each other for haemodynamic stabilisation following surgical treatment, interventional therapy (angioplasty, stent implantation) and conservative treatment (that is no revascularization) on mortality and morbidity in patients with acute myocardial infarction (AMI) complicated by CS or low cardiac output syndrome (LCOS).
Search methods
We searched CENTRAL, MEDLINE (Ovid), EMBASE (Ovid) and ISI Web of Science, registers of ongoing trials and proceedings of conferences in January 2013. Reference lists were scanned and experts in the field were contacted to obtain further information. No language restrictions were applied.
Selection criteria
Randomised controlled trials in patients with AMI complicated by CS or LCOS.
Data collection and analysis
Data collection and analysis were performed according to the published protocol. All trials were analysed individually. Hazard ratios (HRs) and odds ratios with 95% confidence intervals (CI) were extracted but not pooled because of high heterogeneity between the control group interventions.
Main results
Four eligible, very small studies were identified from a total of 4065 references. Three trials with high overall risk of bias compared levosimendan to standard treatment (enoximone or dobutamine) or placebo. Data from a total of 63 participants were included in our comparisons, 31 were treated with levosimendan and 32 served as controls. Levosimendan showed an imprecise survival benefit in comparison with enoximone based on a very small trial with 32 participants (HR 0.33; 95% CI 0.11 to 0.97). Results from the other similarly small trials were too imprecise to provide any meaningful information about the effect of levosimendan in comparison with dobutamine or placebo. Only small differences in haemodynamics, length of hospital stay and the frequency of major adverse cardiac events or adverse events overall were found between study groups.
Only one small randomised controlled trial with three participants was found for vasodilator strategies (nitric oxide gas versus placebo) in AMI complicated by CS or LCOS. This study was too small to draw any conclusions on the effects on our key outcomes.
Authors' conclusions
At present there are no robust and convincing data to support a distinct inotropic or vasodilator drug based therapy as a superior solution to reduce mortality in haemodynamically unstable patients with CS or low cardiac output complicating AMI.
PICOs
Plain language summary
Inotropic and vasodilator strategies in patients with a heart attack (acute myocardial infarction) and cardiogenic shock or low cardiac output
Cardiogenic shock occurring in 5% to 10% of patients with acute myocardial infarction still remains a life‐threatening complication. As regards treatment options with inotropic and vasoactive drugs for infarct related cardiogenic shock, there is only very little evidence generated by randomised controlled trials.
We included four small randomised controlled trials with a total of 66 participants. Mortality rates ranged from 18% to 47% in the four studies. Only one inotropic drug and one vasodilative were studied in four different comparisons with other active drugs or placebo.
Levosimendan showed a trend towards beneficial haemodynamic effects and improved survival rates, but this evidence was based on very limited data which were insufficient to draw robust conclusions. This means that there is no trial evidence for inotropic or vasodilator drugs which shows convincing benefits and confirmed superiority regarding haemodynamic management or survival rates.
Authors' conclusions
Background
Worldwide, cardiovascular disease is one of the leading causes of morbidity, death and loss of disability‐adjusted life years (Gaziano 2010; Lozano 2012; Moran 2008; Murray 1996). In the United States (US), the annual incidence of acute myocardial infarction (AMI) is approximately 920,000 cases. About 150,000 of these cases die, accounting for 5.1% of all male deaths and 2.5% of female deaths. In 2008, the estimated direct and indirect cost of coronary heart disease (International Classification of Diseases (ICD)‐10 codes I20 to I25 (WHO 1993)) in the US was $156.4 billion (AHA 2008). The costs of disease are staggering and mortality rates alone cannot describe the burden of heart disease and stroke. The cost of cardiovascular diseases in the US, including healthcare expenditures and lost productivity from deaths and disability, was estimated to be more than $503 billion in 2010. As the US population ages, the economic impact of cardiovascular diseases on the nation’s healthcare system will become even greater (CDC 2011). According to a recently published policy statement from the American Heart Association (AHA), the authors predicted that costs of medical care for heart disease (in 2008 dollar values) will increase from USD 273 billion to USD 818 billion between 2010 and 2030. Heart disease will also cost the nation billions more in lost productivity, increasing from an estimated USD 172 billion in 2010 to USD 276 billion in 2030. Productivity losses include days missed from home or work tasks because of illness and potential lost earnings due to premature death (Heidenreich 2011).
In the United Kingdom, an estimated 227,000 AMIs occur annually and it has been estimated that approximately one million people over the age of 35 years have had a myocardial infarction (BHF 2007). Data from the INTERHEART study showed that rates of cardiovascular disease have greatly increased in low‐income and middle‐income countries, with about 80% of the global burden of cardiovascular disease occurring in these countries (Yusuf 2004).
AMI is complicated by cardiogenic shock (CS) in approximately 5% to 10% of cases (Goldberg 1999; Hochman 1999). Although primary percutaneous coronary intervention (PCI) was established as a standard therapy for revascularization in patients with AMI complicated by CS, mortality rates still remained high and showed only a slight decrease from 60.3% to 47.9% (Babaev 2005) in this period. Other investigators have found more favourable outcome results, with mortality rates in the range of 34% to 43% (Ohman 2005), which might be due to the design of randomised controlled trials with strictly defined inclusion and exclusion criteria. Thom 2006 assumed a 5% to 8% incidence of CS for all hospitalised patients with AMI and estimated 40,000 to 50,000 cases per year in the US and 60,000 to 70,000 cases in Europe.
The poor outcome associated with medical management of CS has spurred more aggressive interventional approaches, including thrombolysis, intra‐aortic balloon support and early diagnostic angiography with primary PCI (Ohman 2005). Over the last 10 years a steady reduction in mortality has been observed, which is mainly attributed to the increased use of PCI for reperfusion (Aissaoui 2012; Jeger 2008). Therapeutic strategies in patients with CS rely predominantly on acute and effective revascularization of the infarct related artery and dependant myocardium (Hochman 1999; Hochman 2001; Hochman 2006) and subsequent drug treatment strategies with dopamine, dobutamine, norepinephrine or epinephrine to increase perfusion pressure as well as to increase the cardiac output (Dickstein 2008; O'Gara 2013; Steg 2012; Werdan 2012). Over the last five years new therapeutic strategies have been established, such as treatment with phosphodiesterase (PDE) inhibitors or calcium sensitisers (Baumann 1996; Buerke 2008; Buerke 2010; Delle Karth 2003; Dickstein 2008; Hönisch 2010; Klocke 1991; Koyanagi 2000; Link 2002; Mager 1991; Meissner 1996; Morelli 2010; Mukae 1997; Olsen 1988; Omerovic 2010; Orime 1998; Price 2010; Russ 2007; Schmid 1989).
Description of the condition
CS with low cardiac output after AMI is a complex syndrome that involves a cascade of acute left ventricular dysfunction, decreased cardiac output, hypotension and tissue hypoperfusion (Hochman 2007). Subsequently, complicating multi‐organ dysfunction may occur due to ischaemia then reperfusion and the following inflammatory response. Clinically defined, CS presents with hypotension (a systolic blood pressure of less than 90 mm Hg for at least 30 minutes or the need for supportive measures to maintain a systolic blood pressure of 90 mm Hg or more) and end‐organ hypoperfusion (cool extremities, urine output of less than 30 ml per hour, altered mental status, or elevated serum lactate). Haemodynamic criteria that are sometimes used include cardiac index (CI) less than 1.8 l/min/m2, or less than 2.2 l/min/m2 if inotropic drugs are administered, and a pulmonary capillary wedge pressure (PCWP) of at least 15 mm Hg (Forrester 1976a; Forrester 1976b; Hochman 1999). Patients with sustained hypotension, suspected CS, or suspected acute heart failure at the time of AMI are at increased risk of death, approaching 30% to 70% mortality within 30 days (Ohman 2005). Fewer than 50% of patients with CS survive up to one year (Hochman 2007).
As many infarct related CS patients have undergone initial resuscitation due to cardiac arrest in the context of the onset of AMI, the corresponding evidence for additional vasoconstrictive drugs like vasopressin as a treatment option in CS may in part be applied to the field of CS patients. Nevertheless, the drug treatment strategies in cardiac resuscitation and CS have to be closely evaluated in a pathophysiological and clinical context (Harrois 2011; Hochman 2003).
Description of the intervention
Medical drug therapy in infarct related CS can be characterised under different aspects:
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inotropic myocardial stimulation (inotropes) (Caimmi 2011; Dominguez‐Rodriguez 2008; Krenn 2011; Levy 2011; Nieminen 2009; Omerovic 2010; Orime 1999; Prielipp 1998; Samimi‐Fard 2008; Zobel 2004);
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left ventricular unloading (vasodilators) (Belskii 1987; Bussmann 1983; den Uil 2009; Follath 2011; Hollenberg 2007; Hollenberg 2009).
Medical drug therapy in infarct related CS is predominantly based on inotropic and vasoactive substances that are administered for haemodynamic stabilisation by increasing cardiac output and perfusion pressures by optimising the systemic vascular resistance (SVR). In the early stages of CS increased SVR, usually due to autoregulatory mechanisms, often requires vasodilatory drugs. The following stages of CS are characterised by an escalating systemic inflammatory response syndrome associated with the vasodilatory properties of liberated proinflammatory interleukins and cytokines so that only vasopressors, often in increasing dosages, can elevate the decreased SVR. Therapeutic approaches of anticoagulation and platelet inhibition may also be applied to modulate the systemic inflammatory response and improve the microcirculatory disturbances.
How the intervention might work
To stabilise patients with CS, drugs for inotropic support, vasopressors and sometimes also vasodilators are commonly used. Drugs like dobutamine, dopexamine, enoximone, milrinone, amrinone, levosimendan and istaroxime are used to increase cardiac contractility and induce additional reduction of SVR for left ventricular unloading (El Mokhtari 2008; How 2010; Leone 2004; Mattera 2008; McGhie 1992; Pietrangelo 2010; Rognoni 2011; Sehgal 2011).
While there is some evidence that inotropes like levosimedan might be cost‐effective in treating elective high risk cardiac surgery patients (Severi 2011), there is no comparable evidence in CS. Since there is limited evidence for drug treatment strategies in CS, the beneficial effects on quality of life or cost‐benefits become much more important (Harjola 2010; HFMA 2010; Komamura 2008; Loisance 1991; Loisance 1993). A follow‐up analysis of the SHOCK trial showed that although one‐year mortality after emergency revascularization remained high (54%), most survivors had good functional status. The level of recovery for CS patients undergoing early revascularization was similar to that of historical controls not in CS and undergoing elective revascularization (Sleeper 2005). The use of classic inotropic agents activating the beta‐receptor cyclic adenosine monophosphate (cAMP) pathway (that is dobutamine or milrinone) should be restricted to 'rescue' therapy in patients with acute heart failure and signs of peripheral hypoperfusion (hypotension, renal dysfunction) refractory to volume replacement, diuretics and vasodilators. This approach is largely supported by observations from clinical trials suggesting that both short‐term treatment of acute heart failure without an essential requirement for inotropic support, as well as long‐term inotropic therapy in patients with severe chronic heart failure, with classical inotropic agents can increase arrhythmias and mortality (Landmesser 2007). Overall, the potential benefits of inotropic support in CS can be assumed to provide an opportunity for improving the haemodynamics by enhanced myocardial performance leading to increased cardiac output. With increased dosages of inotropic support, these potential benefits have to be judged against the background of the increased myocardial oxygen consumption by the ischaemic myocardium that is usually associated with improved myocardial performance. Without myocardial revascularization, infarct related CS inotropic support may show temporary beneficial haemodynamic effects superimposed on the background of expanding myocardial infarction. These disadvantages may be seen as general risks or side effects of undergoing inotropic support. At present there is only poor evidence for reduced risks of increased cellular damage or superiority in myocardial protection of the ischaemic myocardium for one of the investigated inotropic drugs (Landmesser 2007; Mentzer 2011; Triposkiadis 2009; Zheng 2009). Pure vasodilators like nitroglycerin or nitroprusside may only be used in certain subgroups of CS (Menon 2000) under conditions of guided haemodynamic monitoring to improve left ventricular performance by left ventricular unloading via vasodilation (Belskii 1987; den Uil 2009; Hollenberg 2007).
The main strategies in the treatment of CS patients remain re‐establishing adequate macro‐ and microcirculatory conditions, for the stabilisation of the oxygen supply at the cellular level and modulation of the systemic inflammatory response to avoid functional and morphological cellular damage, to prevent multi‐organ dysfunction or failure (de Backer 2010; Hermansen 2011; Shpektor 2010). Once cellular damage has become irreversible every further therapeutic intervention, regardless of whether pharmacological or device related, has no significant impact on short‐ or long‐term mortality.
Why it is important to do this review
While there is a broad body of evidence for the treatment of patients with acute coronary syndromes (ACS) under stable haemodynamic conditions, there is only poor evidence for treatment strategies for ACS patients who become haemodynamically unstable or develop CS. These findings are correlated with limited or controversial treatment recommendations in the case of haemodynamic instability or shock (Buerke 2011).
Jung 2010 highlighted the effects of impaired microcirculation on the prognosis of haemodynamically unstable patients. These data may indicate that the existing evidence regarding haemodynamic stabilisation is limited because previous trials have focused on establishing improved macrocirculation, as reflected by cardiac output and mean arterial pressure (MAP), while the effects on the microcirculation have been disregarded (Ferrari 2011). The microcirculation has been regarded as an explicit therapeutic target in CS patients in recent publications (den Uil 2010; Harrois 2011). Fries 2006 reported dramatically decreased microcirculatory blood flow after administration of epinephrine in their model. These findings may in part explain the conflicting evidence for drug treatment strategies in CS. All modalities of modern treatment need to be evaluated for their effect on the microcirculation in CS. Almost all of the clinical trials in CS have not been powered sufficiently to investigate therapeutic effects on mortality. In addition, macrocirculatory parameters like MAP, cardiac output or cardiac index, PCWP and SVR have been used as surrogate markers. As soon as data become available, this review will also search for reported effects of haemodynamic drug treatment strategies on the microcirculation, as microcirculatory impairment may be the interface between haemodynamics, systemic inflammation and multi‐organ dysfunction (den Uil 2009; Wan 2009).
This review therefore aimed at identifying subgroups such as patients with initial cardiac arrest and successful resuscitation, or patients with early or late onset of therapeutic interventions, to evaluate the prognostic impact of the specific interventions. The clinical relevance of early and late onset of therapeutic interventions was, as far as possible, investigated in detail to determine whether the specific drug regime or the early initiation of therapeutic management is the more important factor in successful patient management.
The German‐Austrian S3 Guideline provides the first dedicated guidance for the treatment of infarct related CS (Werdan 2012). These recommendations reveal the lack of evidence for all recommended therapeutic measures (de Waha 2012). In contrast to the established recommendation of intra‐aortic balloon pump (IABP) support in infarct related CS (level IC), it was recently shown in a large randomised controlled trial that there is no survival benefit for patients treated with IABP (Thiele 2012). Randomised clinical trials are difficult to perform and costly in patients with CS or low cardiac output syndrome. However, as AMIs are frequent and CS is associated with high mortality, any intervention which reduces mortality is likely to have major public health implications and should be thoroughly tested.
Vasopressors are relevant to this review but were excluded as they are the topic of another Cochrane review on vasopressors in hypotensive shock (Havel 2011).
All existing randomised trials of patients with CS have been too small to address mortality, but most of them showed improved haemodynamics in CS patients without effects on other relevant outcomes (Hochman 2007 (TRIUMPH); Thiele 2009; Unverzagt 2011). Such improved haemodynamic status might not be a suitable surrogate marker for survival. Provided that quality of life is not compromised, all‐cause mortality constitutes the ultimate proof of patient benefit.
Objectives
To determine the effects in terms of efficacy, efficiency and safety of cardiac care with inotropic agents and vasodilator strategies versus placebo or against each other for haemodynamic stabilisation following surgical treatment, interventional therapy (angioplasty, stent implantation) and conservative treatment (that is no revascularization) on mortality and morbidity in patients with AMI complicated by CS or LCOS.
Comparisons concentrated on the following strategies as adjuncts to best supportive cardiac care:
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inotropic agents (phosphodiesterase (PDE) inhibitor, calcium sensitiser) versus placebo or against each other;
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therapies involving vasodilator properties versus placebo or against each other.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) that evaluate efficacy and safety, with or without blinding, with follow up and a report of mortality. One study involving only a subset of relevant participants was included in an individual patient data analysis. Observational trials and cross‐over trials were excluded.
Abstracts or unpublished data were to be included only if sufficient information on study design, characteristics of participants, interventions and outcomes was available, or if the full information and final results were confirmed by contact with the first author.
Types of participants
Patients with CS or LCOS due to AMI following surgical treatment, interventional therapy (angioplasty, stent implantation) and conservative treatment (that is no revascularization) with a follow‐up period that included hospitalisation, 30 days and six months.
Types of interventions
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Experimental intervention: treatments with investigational single drugs or combinations (whatever the dosage or intensity and mode, frequency, timing and duration of delivery) were summarised in one intervention group per substance. Therapeutic regimens were 'investigational' if they had been recently introduced into clinical practice or were compared to accepted therapeutic strategies, no matter whether these drugs had been investigated in regard to therapeutic efficacy or superiority.
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Control intervention: treatments without the specific experimental single drugs or corresponding combinations, or treatment options including other inotropic or vasodilative drugs, placebo or no treatment were summarised in one control group.
Types of outcome measures
Primary outcomes
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All‐cause mortality
Secondary outcomes
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Major adverse cardiac events (MACE), including in‐hospital death, coronary artery bypass graft (CABG) surgery, stroke or transient ischaemic attack, AMI, and repeat PCI at the same site during the index hospital stay (Moscucci 2005)
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Length of hospital stay
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Quality of life
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Haemodynamics (cardiac index (CI), MAP, PCWP)
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Costs
Search methods for identification of studies
Searches were conducted in co‐operation with the Cochrane Heart Group to identify published and unpublished RCTs.
Electronic searches
The search strategy for the review was constructed by using a combination of subject headings and text strings relating to CS, LCOS, drug therapy and comparative therapy trials. No language restrictions were imposed. The search strategies for the different databases are documented in Appendix 1.
We searched CENTRAL (The Cochrane Library 2012, Issue 12 of 12) (searched 10 January 2013), MEDLINE Ovid (1946 to week 1 January 2013), EMBASE Classic and Embase Ovid (1947 to 9 January 2013) and ISI Web of Science (1970 to 9 January 2013).
The Cochrane highly sensitive RCT search filter was applied to MEDLINE and adaptations of it to EMBASE and Web of Science (Lefebvre 2011).
We also searched registers of ongoing and completed trials with the search terms: cardiogenic shock, low cardiac output, inotropes and shock, vasodilators and shock, levosimendan, calcium sensitiser, calcium and shock, dopexamine, nitric oxide inhibition, phosphodiesterase inhibitors, enoximone, milrinone, amrinone, nitroglycerin, nitroprusside, nitric oxide, nitrate and shock. The following registers were searched:
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http://www.controlled‐trials.com/ (21 May 2012; 15 January 2013),
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http://www.centerwatch.com (21 May 2012; 5 February 2013), search by medical condition (myocardial infarction) and therapeutic area (cardiology/ vascular diseases),
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http://www.clinicaltrials.gov/ (23 May 2012; 22 January 2013),
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the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on http://apps.who.int/trialsearch/ (23 May 2012; 22 January 2013), and
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metaRegisters of Controlled Trials (http://www.controlled‐trials.com/mrct/archived) (25 May 2012 and 22 January 2013).
Searching other resources
Handsearching included the annual conference proceedings of the following societies:
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American Heart Association (AHA) (1980 to 2012),
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American College of Cardiology (ACC) (1990 to 2012),
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European Society of Cardiology (ESC) (1990 to 2011),
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European Society of Intensive Care (ESICM) (1997 to 2012), and
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Deutsche Gesellschaft für Kardiologie (DGK) (1995 to 2012).
Members of the Cochrane Heart Group, experts in the field, and manufacturers of the drugs (Carinoharm GmbH Germany, Fresenius Kabi Germany, Orion Corporation Finland, UCB Pharma GmbH Germany) were contacted. In addition, reference lists from eligible trials were scanned and the first authors were contacted to obtain further information on study design and to collect individual patient data.
Data collection and analysis
Selection of studies
Studies identified using the search strategy described above were screened by title, keywords and abstract by two independent authors (SU, KH). The full articles were accessed for further assessment if the information given suggested that the study:
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included patients with myocardial infarction complicated by CS or LCOS;
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compared
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cardiac care with versus without inotropic therapies (PDE inhibitor, calcium sensitiser), or
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cardiac care with versus without therapies having vasodilator properties;
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used designs with randomised allocation of participants; and
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included primary data.
Differences in opinion were settled by consensus with a third review author (LW or RP). After the exclusion of non‐relevant publications and duplicates, the full‐text versions of the remaining papers were assessed against the inclusion and exclusion criteria and data were extracted and entered into standardised data extraction tables. The selection process was recorded in a PRISMA flow chart according to Moher 2009.
Data extraction and management
Two authors independently extracted the details of study population, interventions and outcomes (SU, LW). The data extraction tables included the following items.
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General information: title, authors, source, contact address, country, published or unpublished, language and year of publication, sponsoring of trial.
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Trial characteristics including study design, timing and follow up, and quality assessment as specified above.
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Participants: inclusion and exclusion criteria, definition of indication, sample size, baseline characteristics, similarity of groups at baseline, withdrawals and losses to follow up.
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Interventions: dosage, route and timing of drug therapy and comparison intervention.
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Outcomes: participants per group, mortality at specific time points (in hospital or intensive care unit (ICU), 28 or 30 days, 6 and 12 months), adverse effects (with definitions, methods for monitoring), MACE, haemodynamics (CI, MAP, PCWP), length of hospital and ICU stay, quality of life, costs.
Data extraction was performed independently by two authors. Differences in data extraction were resolved by consensus with a third author (RP), referring back to the original article. As this review was planned as an individual patient data (IPD) meta‐analysis, the first authors of all eligible trials were contacted (SU, RP) and asked to provide IPD and other missing information. IPD provided by the authors were compared with the extracted, published results and checked for consistency.
Assessment of risk of bias in included studies
Two authors (SU, LW) independently assessed the internal validity of eligible studies according to the Cochrane Collaboration risk of bias tool (Higgins 2011). Disagreements were resolved by discussion until consensus was obtained. Risk of bias was described and judged as high, low or unclear in six specific domains:
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random sequence generation;
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allocation concealment;
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double blinding of participants, personnel and outcome assessment;
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incomplete outcome data addressed;
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selective reporting;
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other sources of bias (cross‐over, baseline differences regarding the most important prognostic factors, conduct of the study affected by interim results, deviation from the study protocol, not reflecting clinical practice, inappropriate administration of an intervention, contra‐active or similar pre‐randomisation intervention).
We used the following items to assess the quality of evidence on adverse effects (AEs) (Higgins 2011).
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Are definitions of reported AEs given?
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Were the methods that were used for monitoring AEs reported (e.g. use of prospective or routine monitoring; spontaneous reporting; participant checklist, questionnaire or diary; systematic survey of participants)?
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Were any participants excluded from the AE analysis?
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Does the report provide numerical data by intervention group?
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Which categories of AEs were reported by the investigators?
Measures of treatment effect
No meta‐analysis was conducted due to heterogeneity between the studies. Effect measures for the primary endpoint (all‐cause mortality) of the RCTs were presented as hazard ratios (HRs) (Cox 1972) with their 95% confidence intervals (CI). Kaplan‐Meier curves and mortality rates were generated (KH) from the IPD (Husebye 2013) or reported data and curves (Fuhrmann 2008; Garcίa‐González 2006).
Odds ratios (ORs) and 95% CIs were used to compare frequencies of AEs and MACE events. Weighted mean differences and 95% CIs were calculated as effect measures for haemodynamic measures. The data on haemodynamics (CI, MAP, PCWP), length of hospital and ICU stay were reported differently for the included studies and are summarised in an additional table. No information on quality of life or costs was available from the eligible trials.
Unit of analysis issues
Participants were individually randomised into treatment groups. The effect of the intervention was measured and analysed on the basis of single measurements for each outcome for each participant.
Dealing with missing data
If data were not available in the trial report or data collection, the investigators were contacted to provide missing data.
Assessment of heterogeneity
This systematic review brings together diverse material, with studies differing in the participants, interventions and exposure times. Therefore we did not expect a single study effect and planned to apply a random‐effects model. To quantify the extent of variability among the studies we planned to estimate the Q‐test for heterogeneity in order to quantify heterogeneity as a proportion of variability with Thompson’s I2 statistic and to calculate the between‐study variance τ2 (Higgins 2002; Rücker 2008).
The following factors are possible sources of clinically relevant heterogeneity and were summarised in the table Characteristics of included studies.
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Different variations of standard therapies (other vasoactive drugs, revascularization, intra‐aortic balloon pump (IABP), mechanical ventilation, renal replacement therapy).
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Different variations of the experimental intervention (doses and scheduling).
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Different variations of control groups (treatment without investigated single drugs or combinations, treatment with placebo, or no treatment).
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Differences in outcome relevant prognostic factors (age, gender, comorbidities, CI, ejection fraction, time from symptom onset to intervention).
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Different definition of the indication (CS versus LCOS).
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Quality of studies.
Assessment of reporting biases
The use of funnel plots for the graphical detection of publication bias was not possible due to the small number of eligible trials.
Data synthesis
The analysis was based on the intention‐to‐treat (ITT) principle. Kaplan‐Meier curves were generated with SAS software. All trials were analysed individually. A meta‐analysis was not possible due to heterogeneity between the eligible trials with different treatments in the control groups. We extracted data from published survival curves and calculated the HRs and survival rates. Forest plots were used to visualise the findings from the included studies.
Subgroup analysis and investigation of heterogeneity
Possible sources of heterogeneity are defined above. Subgroup analyses were not possible due to the small number of participants in the trial with available IPD (Husebye 2013) and missing subgroup analyses in the other trials.
Sensitivity analysis
Sensitvity analyses were not performed.
Results
Description of studies
Results of the search
Having used the above search strategy to identify potentially relevant references, a total of 4065 references were identified (CENTRAL 475, MEDLINE 2300, EMBASE 775, Web of Science 489, and other 26). In total, 105 full‐text papers were thought to be of relevance and the papers were assessed against the inclusion and exclusion criteria. Of these only four studies (reported in six full‐text papers) met our predefined inclusion criteria (see Characteristics of included studies). The remaining studies are listed in Characteristics of excluded studies. This process was recorded in a PRISMA flow chart (Figure 1).
Study flow diagram.
Included studies
Published clinical trials on inotropic strategies for patients with AMI and CS or LCOS were limited to levosimendan (Fuhrmann 2008; Garcίa‐González 2006; Husebye 2013). Only one trial on vasodilators was found for the investigated indication (Baldassarre 2008). Three studies compared levosimendan to different substances and one study compared nitric oxide to placebo. Control group participants were treated with dobutamine (Garcίa‐González 2006), enoximone (Fuhrmann 2008) or placebo (Baldassarre 2008; Husebye 2013).
Three studies were conducted as single‐centre trials in Europe: in Spain (Garcίa‐González 2006), Germany (Fuhrmann 2008), and Norway (Husebye 2013). One trial (Baldassarre 2008) was planned as a multi‐centre trial in the US and Europe. This trial was stopped early due to low enrolment rates.
Each study characteristic is presented briefly in the table Characteristics of included studies. Information from two secondary publications of one included trial (Garcίa‐González 2006) was included. A more comprehensive assessment of the included studies is given below.
Participants
Altogether, 66 participants with AMI and CS were enrolled in the trials on levosimendan; 31 were treated with levosimendan, and 32 served as controls and were treated with dobutamine (11 participants in Garcίa‐González 2006), enoximone (16 participants in Fuhrmann 2008) or placebo (5 participants in Husebye 2013). Husebye 2013 included 61 participants with AMI complicated by acute heart failure. The authors provided additional information and IPD on all participants with CS (n = 9).
The trial on vasodilators (Baldassarre 2008) included only three participants at two centres in the US. These were two men and one woman, with a mean age of 69 years. Two of them received nitric oxide and one placebo. No further information on the participants was provided for this trial.
Baseline information in Fuhrmann 2008 and Garcίa‐González 2006 described participants with AMI and CS. In Husebye 2013 the baseline information was not restricted to participants with AMI and CS. The mean or median age varied between 64 and 68 years. Husebye 2013 excluded participants under 20 years of age, no age restriction was described in Fuhrmann 2008 and Garcίa‐González 2006. Between 62% (Fuhrmann 2008) and 81% (Garcίa‐González 2006) of participants in the included trials were male. All trials included only participants with an open infarct‐related artery. Patency was generally achieved by PCI. Time of randomisation varied between trials. Participants in Fuhrmann 2008 had to be included within two hours following PCI and 24 hours of CS, and participants in Husebye 2013 needed a median time of three hours from start of symptoms to PCI. In Garcίa‐González 2006 this information was unavailable.
Baseline MAP varied between median values of 72 (interquartile range (IQR) 63 to 80) mm Hg and 67 (60 to 77) mm Hg in the two treatment groups of Fuhrmann 2008, mean 76 ± 9 mm Hg in Garcίa‐González 2006; the CI between 1.8 ± 0.4 l/min*m2 (Garcίa‐González 2006), 2.3 (IQR 2.1 to 2.5) l/min*m2 and 2.2 (IQR 1.7 to 2.4) l/min*m2 in Fuhrmann 2008; and PCWP between 22 (IQR 18 to 24) mm Hg and 20 (IQR 17 to 31) mm Hg (Fuhrmann 2008) and 27 ± 5 mm Hg in Garcίa‐González 2006.
Participants in all trials were treated at the time of randomisation with different inotropic or vasoactive drugs. Dobutamine and norepinephrine were used in Fuhrmann 2008; sodium nitroprusside, nitroglycerin and digitalis in Garcίa‐González 2006; and unspecified inotropic support by catecholamine infusion was possible in Husebye 2013.
Interventions
Three included trials investigated the efficacy and safety of the calcium sensitiser levosimendan in combination with established therapeutic regimens. The comparisons were the following.
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In Garcίa‐González 2006, levosimendan 24 μg/kg over 10 min, followed by a constant rate of 0.1 μg/kg/min, was compared with 5 μg/kg/min dobutamine. If an adequate haemodynamic response was not achieved after two hours, the infusion rate of dobutamine was doubled until the desired haemodynamic response was achieved. Infusions were maintained at a constant rate for 24 hours, unless otherwise required by the condition of the participant.
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In Fuhrmann 2008, levosimendan 12 μg/kg over 10 min, followed by 0.1 μg/kg/min for 50 min and 0.2 μg/kg/min infused over the next 23 hours, and compared with 0.5 μg/kg over 30 min of the PDE inhibitor enoximone followed by 2 to 10 μg/kg/min continuously titrated to the best haemodynamic response.
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In Husebye 2013, levosimendan 0.2 μg/kg/min over 1 hr levosimendan, followed by 0.1 μg/kg/min was infused over the next 24 hours and compared with placebo.
One included trial (Baldassarre 2008) planned to investigate the efficacy and safety of inhaled nitric oxide and compared:
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nitric oxide, 80 ppm or 40 ppm over 8 hr, followed by a constant rate of 40 ppm, given via facemask or via mechanical ventilation and compared to placebo (40 ppm nitrogen gas) over 8 hr.
Excluded studies
Many trials on inotropic agents or vasodilator strategies investigated patients with pre‐ or post‐operative low cardiac output following elective CABG or mitral valve surgery but without AMI (Al‐Shawaf 2006; Alvarez 2005; Alvarez 2006; Atallah 1990; Barisin 2004; De Hert 2007; Dupuis 1992; Feneck 2001; Gunnicker 1995; Kikura 1997; Kikura 2002; Lancon 1990; Levin 2008; Lilleberg 1998; Nijhawan 1999; Patel 1993; Rosseel 1997; Tarr 1993; Tritapepe 2009; Tzimas 2009; Zerkowski 1992; Zwölfer 1995). Moreover, 21 trials investigated inotropic and vasodilator drugs in patients with severe heart failure without AMI (Adamopoulos 2006; Avgeropoulou 2005; Berger 2007; Carmona 2010; Duygu 2008; Flevari 2006; Follath(LIDO) 2002; Galinier 1990; Kivikko 2003; Mebazaa (SURVIVE) 2007; Moertl 2005; Nieminem 2000; Packer (REVIVE‐1) 2003; Packer(REVIVE‐2) 2005; Parissis 2004; Parissis 2005; Seino 1996; Slawsky 2000; Tsiakas 2005; Wimmer 1999; Zairis(CASINO) 2004), six trials excluded patients with CS or low cardiac output (Flather 1994; Jugdutt 1988; Levy 2011; Moiseyev(RUSSLAN) 2002; Rentrop 1989; Zeymer 2001), five trials investigated vasopressor strategies (Cotter 2003; De Backer 2010; Džavik 2007 (SHOCK‐2); Hochman 2007 (TRIUMPH); Myburgh 2008) and one trial described an animal experiment (Misra 1973). In addition, 25 trials were not RCTs (Cattaneo 2009; Chatterjee 1979; Cohn 1974; Coma Canella 1981; Delle Karth 2003; De Luca 2008; De Monte 1986; Döring 1969; Döring 1971; El Mokhtari 2008; Forrester 1975; Gratsianskii 1970; Guglina 1997; Holzer 1973; Inzoli 1973; Lazarev 1995; Lehmann 2004; Mueller 1972; Orellano 1991; Sabin 1976; Schuren 1970; Takkunen 1972; Talley 1969; Vander Ark 1970; Wilcken 1970) and four trials used a cross‐over design (Ferrario 1994; Francis 1982; Loeb 1971; Richard 1983). Furthermore, we screened seven systematic reviews (Delaney 2010; De Luca 2006; Elahi 2011; Landoni 2010; Landoni 2012; Maharaj 2011; O'Connor 2009) and six older style reviews (De Backer 2011; Eichna 1967; Goldberg 1977; Goldberg 1978; Gunnar 1972; Mueller 1985) for eligible trials. Finally, two trials were registered but not published and information on mortality was missing (Grant 2008; van Straaten 2007).
Reasons for exclusion are presented briefly in tabulated form (see Characteristics of excluded studies).
Risk of bias in included studies
All trials on levosimendan were published in peer‐reviewed journals. No trial acknowledged funding by the pharmaceutical industry. No clinical report or final publication was published on the trial on nitric oxide but the results were confirmed by contact with the responsible investigator.
All included trials were very small and the number of included participants with AMI and CS ranged from 3 to 32. In all trials the analysis was done by ITT. Figure 2 and Figure 3 present a summary of all investigated sources of bias in the four eligible studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Sequence generation
The method of sequence generation was reported in two trials (Fuhrmann 2008; Husebye 2013). The trials used blocked random tables and Husebye 2013 used an extra stratum for participants with CS.
Allocation
The method of allocation concealment was described in Husebye 2013, where allocation was performed by a blinded investigator according to a pre‐determined list. No information was available from the two other trials.
Blinding
The trials by Husebye 2013 and Baldassarre 2008 were placebo controlled. In Fuhrmann 2008 blinding was not possible because of the different timing of administration of the study drug. In Garcίa‐González 2006 haemodynamic measurements were performed by research team members blinded to treatment allocation. Risk of bias due to different behaviour or co‐interventions, or risk of detection bias due to outcome assessment of the more subjective outcomes (haemodynamics, AEs) cannot be ruled out in the two non‐placebo controlled trials.
Incomplete outcome data
All‐cause mortality, haemodynamics, MACE and AEs were investigated. Complete 30‐day follow‐up data were available in three studies (Fuhrmann 2008; Garcίa‐González 2006; Husebye 2013). Six‐month follow‐up data on the all‐cause mortality distribution were available in only two trials (Garcίa‐González 2006; Husebye 2013).
Haemodynamic post‐interventional data were reported in full in two trials with follow‐up times ranging from 30 to 48 hours. Fuhrmann 2008 reported the haemodynamic changes in 36 participants but randomised only 32 participants. MACE events were reported during the study drug infusion, time in hospital or over 30 days.
Selective reporting
All pre‐specified primary outcomes were reported in Fuhrmann 2008, Garcίa‐González 2006 and Husebye 2013. Pre‐specified secondary endpoints were missing in Garcίa‐González 2006. Baldassarre 2008 had restricted reporting on mortality and adverse events.
Other potential sources of bias
No cross‐over was reported in the included trials. Some potentially important baseline differences in prognostic factors such as the timetable, haemodynamics or comorbidities were observed in all trials. No information on baseline differences was available for the trial with a subgroup of participants with CS (Husebye 2013).
The conduct of one trial (Fuhrmann 2008) was affected by interim results. It was stopped after recruitment of 36% of the pre‐planned sample size as a result of a planned interim analysis, due to a trend toward reduced mortality for levosimendan.
Inappropriate delivery, with interruptions of study drug administration, was reported in one trial (Husebye 2013). Discontinuation was necessary in one participant from the levosimendan group because of atrial fibrillation and one participant from the placebo group because of hypotension, although these participants were in CS.
No participants discontinued treatment in Fuhrmann 2008 and Garcίa‐González 2006.
All clinical trials evaluating shock participants addressed the problem of pre‐randomisation drug treatment strategies. Most of the included trial participants were not randomised to the study drug at the index event (onset of CS) and they were therefore pretreated with different inotropic and vasoactive drugs, which could have influenced the microcirculation and thereby affected the prognosis.
To the best of our knowledge no trial used a complex standardised study protocol for vasopressor down‐titration for the assessment of the lowest necessary vasopressor dosage in each individual participant. In all other trial designs vasopressor management was at the investigator's discretion without haemodynamic target corridors for MAP and SVR.
Although the title and inclusion criteria of the study conducted by Garcίa‐González 2006 implied that the enrolled participants suffered from CS complicating AMI, there remained major concerns regarding the eligibility of the included participants. This was because none of them developed multi‐organ failure and the mortality rates appeared very low in comparison to commonly reported data.
Bias affecting the quality of evidence on adverse events
Definitions of the reported AEs were given in Husebye 2013. Husebye 2013 categorised AEs; Fuhrmann 2008 described the AEs in the text; Baldassarre 2008 described all reported AEs; and Garcίa‐González 2006 reported no AEs at all. In Husebye 2013, AEs were monitored by study personnel blinded to treatment allocation throughout the study period of five days and at the six‐week follow‐up. AEs in Fuhrmann 2008 and Garcίa‐González 2006 trials were monitored without blinding. Information on length of follow‐up was not available for these trials. No trial excluded participants from the AEs analysis.
Although we were aware of the methodological problems and restrictions, especially in regard to the definition of CS in the study of Garcίa‐González 2006, we nevertheless decided to include all studies that randomised participants with AMI complicated by CS or LCOS, mainly because of the limited number of trials that were available. The risk of bias tables of the individual trials are given in Characteristics of included studies.
Effects of interventions
All‐cause mortality
Three trials with 63 participants on levosimendan (Fuhrmann 2008; Garcίa‐González 2006; Husebye 2013) reported 5/31 (16.1%) deaths in the intervention arm compared with 11/32 (34.4%) deaths in the control groups treated with dobutamine, enoximone or placebo over a 30‐day follow‐up period (Figure 4). A benefit in overall survival was shown in the comparison of levosimendan with enoximone. Fuhrmann 2008 reported 5/16 (31.2%) deaths in the levosimendan group compared to 10/16 (62.5%) in the enoximone group. The HR indicated a survival benefit for participants treated with levosimendan (HR 0.33; 95% CI 0.11 to 0.97). Garcίa‐González 2006 reported no deaths in either group over a six‐month follow‐up period. However, four participants died during the 12‐month follow‐up: 3/11 (27.2%) participants in the levosimendan group compared to 1/11 (9.1%) participants in the dobutamine group. The HR of 3.43 (95% CI 0.36 to 33.14) indicated a high level of uncertainty in the mortality distribution between the groups. Husebye 2013 reported, over a six‐month follow‐up period, 1/4 (25%) deaths in the levosimendan group on day 41 compared to 2/5 (40%) with placebo on days 3 and 58 (HR 0.59; 95% CI 0.05 to 6.55).
Survival curves of included trials on levosimendan.
One trial on inhaled nitric oxide with three participants (Baldassarre 2008) reported one death (1/1) in the placebo group and no deaths (0/2) in the group with nitric oxide.
Major adverse cardiovascular events (MACE)
Data were available from two trials with 31 participants (Garcίa‐González 2006; Husebye 2013). In one study, no reinfarction or cerebrovascular accident was documented in either group during hospitalisation (Garcίa‐González 2006). On the other hand, 4/9 (44%) participants with CS suffered from MACE in Husebye 2013 (Table 1).
| Comparison | study | MACE | Intervention | Control | OR; 95%CI | ||
| Events | Total | Events | Total | ||||
| Levosimendan versus enoximone | Fuhrmann 2008 | death (within 30 days) | 5 (31%) | 16 | 10 (52%) | 16 | 0.27; 0.06‐1.18 |
| death (within 30 days) caused by refractory heart failure | 5 (31%) | 16 | 4 (25%) | 16 | 1.36; 0.29‐6.42 | ||
| death (within 30 days) caused by multiple organ failure | 0 (0%) | 16 | 4 (25%) | 16 | 0.08; 0.00‐1.71 | ||
| death (within 30 days) caused by rhythm disorder | 0 (0%) | 16 | 1 (6%) | 16 | 0.01; 0.01‐8.28 | ||
| death (within 30 days) caused by stroke | 0 (0%) | 16 | 1 (6%) | 16 | 0.01; 0.01‐8.28 | ||
| Levosimendan versus dobutamine | García‐González 2006 | death (within 30 days) | 0 (0%) | 11 | 0 (0%) | 11 | Not estimable |
| reinfarction (in‐hospital) | 0 (0%) | 11 | 0 (0%) | 11 | Not estimable | ||
| cerebrovascular accidents (in‐hospital) | 0 (0%) | 11 | 0 (0%) | 11 | Not estimable | ||
| Levosimendan versus placebo | Husebye 2013 | death during 6‐month follow‐up | 1 (25%) | 4 | 2 | 5 | 0.5; 0.03‐151.5 |
| MACE (death, non‐fatal myocardial infarction, revascularization of the infarct‐related artery) | 2 (50%) | 4 | 2 (40%) | 5 | 1.5; 0.11‐21.31 | ||
| repeat PCI | 1 (25%) | 4 | 0 | 5 | 4.71; 0.15‐151.5 | ||
| Nitric oxide versus placebo | Baldassarre 2008 | death | 0 (0%) | 2 | 1 (100%) | 1 | |
| myocardial infarction | 1 (50%) | 2 | 1 (100%) | 1 | |||
Length of hospital stay
Information on length of hospital stay was restricted to Fuhrmann 2008. He reported a shorter median intensive care unit (ICU) time in the levosimendan group compared to the enoximone group, with high imprecision (10 (IQR 5 to 23) days compared to 13 (IQR 7 to 19) days) (Table 2).
| Comparison | Primary studies | Reported information | Intervention | Control | ||
| Events/time | Total | Events/time | Total | |||
| Levosimendan versus enoximone | Fuhrmann 2008 | stay in ICU in days, median (IQR) | 10 (5‐23) | 16 | 13 (7‐19) | 16 |
Haemodynamics
Cardiac index (CI) after treatment over 24 hours with and without levosimendan was available for 55 participants from two of the eligible trials (Fuhrmann 2008; Garcίa‐González 2006). In Fuhrmann 2008, no differences were found between participants randomised to levosimendan (n = 16) or to enoximone (n = 17) (median CI 3.2 l/min/m2 in both groups; IQR 2.7 to 3.2 on levosimendan versus 2.8 to 3.5 on enoximone). After 24 hours of treatment, participants randomised to levosimendan (n = 11) had a clinically relevant improved mean CI compared to participants in the dobutamine group (n = 11) (MD 0.50 l/min/m2; 95% CI 0.16 to 0.84) (Garcίa‐González 2006).
Mean arterial pressure (MAP) after treatment over 24 hours with and without levosimendan was available for 33 participants from one eligible study (Fuhrmann 2008). Only small differences were found between participants randomised to levosimendan (n = 16) and enoximone (median MAP 73 mm Hg (IQR 67 to 77) on levosimendan versus 68 mm Hg (IQR 63 to 71) on enoximone).
Pulmonary capillary wedge pressure (PCWP) after treatment over 24 hours with and without levosimendan was available for 33 participants from one eligible study (Fuhrmann 2008). The reported PCWP showed no differences between participants randomised to levosimendan (n = 16) and enoximone (n = 17) (median PCWP 19 mm Hg (IQR 18 to 21) on levosimendan versus 18 mm Hg (IQR 15 to 24) on enoximone).
Quality of life and costs
No results were available from the included studies.
Adverse events (AEs)
Data were available from three trials on levosimendan, with 63 participants, but the results were too imprecise to provide any meaningful information about the effect of levosimendan (Table 3). Levosimendan showed a slightly better safety profile compared to enoximone (Fuhrmann 2008). No AEs were reported in either intervention group in Garcίa‐González 2006. Restricting the results from Husebye 2013 to nine participants with CS, 2/4 (50%) participants with levosimendan compared to 1/5 (20%) participants with placebo suffered from hypotension during drug infusion, with a decrease in MAP of > 10 mm Hg. Furthermore, for all randomised participants (with AMI and acute heart failure), 20/30 (67%) participants with levosimendan compared to 11/31 (36%) participants with placebo suffered from worsening hypotension during infusion.
| Comparison | study | MACE | Intervention | Control | OR; 95%CI | ||
| Events | Total | Events | Total | ||||
| Levosimendan versus enoximone | Fuhrmann 2008 (development of organ failure) | need of mechanical ventilation | 13 (81%) | 16 | 15 (94%) | 16 | 0.29; 0.03‐3.13 |
| acute renal failure | 5 (31%) | 16 | 8 (50%) | 16 | 0.45; 0.11‐1.92 | ||
| need of continuous renal replacement therapy | 5 (31%) | 16 | 8 (50%) | 16 | 0.45; 0.11‐1.92 | ||
| new onset atrial fibrillation | 7 (44%) | 16 | 9 (56%) | 16 | 0.60; 0.15‐2.45 | ||
| ventricular tachycardia or fibrillation | 8 (50%) | 16 | 11 (69%) | 16 | 0.45; 0.11‐1.92 | ||
| development of systemic inflammatory response | 8 (50%) | 16 | 13 (81%) | 16 | 0.23; 0.05‐1.13 | ||
| pneumonia | 7 (44%) | 16 | 7 (44%) | 16 | 1.00; 0.25‐4.04 | ||
| urinary infections | 0 (0%) | 16 | 2 (12%) | 16 | 0.18; 0.01‐3.97 | ||
| sepsis | 3 (19%) | 16 | 2 (12%) | 16 | 1.62; 0.23‐11.26 | ||
| Levosimendan versus dobutamine | García‐González 2006 | multiple organ failure | 0 (0%) | 11 | 0 (0%) | 11 | Not estimable |
| reinfarction | 0 (0%) | 11 | 0 (0%) | 11 | Not estimable | ||
| cerebrovascular accidents | 0 (0%) | 11 | 0 (0%) | 11 | Not estimable | ||
| Levosimendan versus placebo | Husebye 2013 | non‐sustained ventricular tachycardia | 1 (25%) | 4 | 3 (60%) | 5 | 0.22; 0.01‐3.98 |
| atrial fibrillation | 1 (25%) | 4 | 0 (0%) | 5 | 4.71; 0.15‐151.5 | ||
| Episodes of hypotension during drug infusion (MAP fall > 10 mmHg) | 2 (50%) | 4 | 1(20%) | 5 | 4.0; 0.21‐75.7 | ||
Baldassarre 2008 reported seven serious AEs in three participants. Two participants recovered from gastrointestinal or chest pain, bleeding, sinus bradycardia or myocardial infarction and one participant died after right ventricular failure. No AE was considered drug‐related.
Discussion
Summary of main results
This systematic review includes four RCTs. Overall, 66 participants in trials with greatly differing mortality rates of between 18% and 47% were analysed.
Drugs examined
Three studies investigated levosimendan and compared its efficacy and safety with standard treatment (dobutamine or enoximone) or placebo. One small RCT on vasodilator strategies compared the effects of nitric oxide, a gas for inhalation, with placebo.
Endpoints
All studies reported mortality outcomes, while length of hospital and ICU stay were reported in one trial only (Fuhrmann 2008). Haemodynamic parameters (as a surrogate marker for morbidity) were available in two trials (Fuhrmann 2008; Garcίa‐González 2006). No data were available for quality of life and costs in any of the trials.
As regards the development of multi‐organ failure, it became obvious that the participants included in one of the trials (Garcίa‐González 2006) must have been less severely compromised compared to the participants in the other eligible trials because none of these participants developed multi‐organ failure. Organ failure determines the clinical course and outcome of CS patients much more than haemodynamics alone (Prondzinsky 2010).
Mortality
There was weak evidence from single small trials that participants on levosimendan had lower mortality rates compared to those on enoximone (Fuhrmann 2008), while the estimated effect from another trial was compatible with both benefit and harm (Garcίa‐González 2006). Husebye 2013 reported a trend for reduced mortality rates on levosimendan compared to placebo. These data are to be interpreted very carefully bearing in mind that all three RCTs with levosimendan included a very small number of participants and correlated events. Summarising all mortality data there is no convincing evidence showing superiority of any one of these investigated inotropic drugs in terms of survival. Vasodilator substances were investigated in one trial (Baldassarre 2008) which enrolled only three participants, and one participant on placebo died.
Haemodynamics
All three drugs, levosimendan as well as enoximone and dobutamine, were able to increase CI. Whereas Fuhrmann 2008 could not show any significant differences in CI in comparison to enoximone, Garcίa‐González 2006 reported a significantly higher CI in participants receiving levosimendan for 24 hours in comparison to dobutamine. Levosimendan showed no clinically relevant differences in MAP and PCWP in comparison to enoximone.
Length of hospital and ICU stay
Only one (Fuhrmann 2008) of the three trials with levosimendan reported length of stay and showed a shorter time in ICU on levosimendan compared to enoximone, but the results in both groups showed a high level of uncertainty.
Quality of life and costs
No data were available to address quality of life and costs in any of these trials.
Overall completeness and applicability of evidence
Data are too limited to justify clinical strategies on the basis of the derived evidence on the efficacy and safety of levosimendan or nitric oxide. This statement is strictly related to the limited evidence from RCTs. It is not a judgement concerning the potential benefits of the investigated drugs and does not rule out the possibility that larger RCTs might in future verify the expected beneficial effects.
Quality of the evidence
It is to be emphasized that the results of this review are limited by several issues including the very small number of trials and events, the overall very small number of participants, the heterogeneity of enrolled participants at baseline and the fact that different substances were analysed in the control groups.
It should also be mentioned that there was a high overall risk of bias and therefore the data have to be interpreted very carefully considering that the four RCTs included only 66 eligible participants in total so that possible implications are limited. With no mortality in either of the groups over a six‐month follow‐up period, the mortality rates reported by Garcίa‐González 2006 were surprisingly low and in marked contrast to the expected mortality rates of between 40% and 80%.
As stated above, the limited data available for haemodynamic parameters showed clinically relevant differences in CI at baseline in the different studies. The heterogeneity in the baseline haemodynamic characteristics introduces relevant concerns regarding the definitions of CS used in these trials. This could also be an explanation for the surprising differences in mortality rates.
Considering that the trial by Fuhrmann 2008 did not show clinically relevant improvements in haemodynamic parameters with levosimendan compared to enoximone, it remains unclear why this lack of haemodynamic improvement could be associated with beneficial survival rates.
While patients with acute non‐ST elevation myocardial infarction (NSTEMI) or ST‐elevation myocardial infarction (STEMI) can be described very well in terms of their baseline conditions, haemodynamically unstable CS patients show a greater variation at baseline. It has recently been published that multi‐organ failure and systemic inflammation have the greatest impact on prognosis in infarct‐related CS (Prondzinsky 2010). Nevertheless, most baseline data available provide only limited information for the quantifiable estimation of multi‐organ failure and inflammation at baseline; they generally use socio‐demographic and haemodynamic data to assess baseline comparability and therefore full comparability of all included participants cannot be assured under these conditions, not least due to the limited size of the studies.
Because of the heterogenous mortality rates in the analysed trials, additional limitations can arise from the groups of participants included in the trials, in particular if zero per cent mortality rates have been reported at 30 days and six months (Garcίa‐González 2006). This may possibly indicate a relevant selection bias that influences the outcome data.
Potential biases in the review process
All authors of eligible trials have been contacted with a request for IPD. Considering that the total number of eligible studies and included participants was relatively small, bias could have been introduced by the mere fact that IPD were not provided, especially in trials reporting favourable effects for the study drug.
As CS is a haemodynamically defined diagnostic term, it is of concern that haemodynamic parameters were not available for all participants. The result was that inclusion criteria and CS definitions relied on the diagnostic definitions being established and reported in the included studies. For this reason it cannot be assured that all reported data refer to CS patients as commonly defined in the SHOCK trial. The clinical criteria were hypotension (a systolic blood pressure of less than 90 mm Hg for at least 30 minutes or the need for supportive measures to maintain a systolic blood pressure of greater than 90 mm Hg) and end‐organ hypoperfusion (cool extremities or a urine output of less than 30 ml per hour) and a heart rate of greater than 60 beats per minute. The haemodynamic criteria were a CI of no more than 2.2 l/m2/min of body surface area and a PCWP of at least 15 mm Hg (Hochman 1999).
Agreements and disagreements with other studies or reviews
During the last decades several RCTs, cohort studies and systematic reviews have investigated levosimendan and included participants with AMI complicated by CS or LCOS. These trials have recently been investigated and analysed in five systematic reviews (Delaney 2010; De Luca 2006; Landoni 2010; Landoni 2012; Maharaj 2011).
Delaney 2010 describes the efficacy and safety of levosimendan for the treatment of acute severe heart failure. This meta‐analysis included 19 randomised trials with 3650 participants with acute severe heart failure. Six studies including 1578 participants compared levisomendan with placebo and reported a non‐significant reduction in mortality for levosimendan (OR 0.83; 95% CI 0.62 to 1.10) with low level heterogeneity between the results of the individual trials (I2 = 25.7%). The systematic search was finalised in June 2007. Eight studies with a total of 1979 participants compared levosimendan to dobutamine and reported a significant reduction in mortality on levosimendan (OR 0.75; 95% CI 0.61 to 0.92) with moderate heterogeneity (I2 = 44.6%). In the current meta‐analysis on CS, no trial that was included in the previous meta‐analysis was eligible due to the lack of CS patients at inclusion.
Landoni 2010 investigated the impact of levosimendan on mortality in any setting dealing with critically ill patients. The systematic search was finalised in November 2008 and identified 27 RCTs that compared levosimendan versus control, with a total of 3350 participants, including one trial included in this review (Garcίa‐González 2006). Levosimendan was associated with a significant reduction in mortality (OR 0.74; 95% CI 0.62 to 0.89) with low heterogeneity between the results of individual studies (I2 = 11.3%) and an increase in the number of hypotensive patients (OR 1.38; 95% CI 1.06 to 1.80) with moderate heterogeneity (I2 = 37.7%).
Maharaj 2011 evaluated the effect of levosimendan versus control on mortality after coronary revascularization. This systematic review was based on a search period until August 2010 and included 17 RCTs involving 729 participants. Levosimendan was associated with a mortality reduction after general coronary revascularization (OR 0.40; 95%CI 0.21 to 0.76) with small heterogeneity of study results (I2=12%). Elective revascularization showed a significant benefit (OR 0.36; 95%CI 0.18 to 0.72) compared with emergency revascularization (OR 0.61; 95%CI 0.19 to 1.89). The emergency revascularization group included two of our included studies in patients with CS (Fuhrmann 2008; Garcίa‐González 2006).
Landoni 2012 devised an updated meta‐analysis of all RCTs of levosimendan to reach a definite conclusion for this substance in the management of patients requiring inotropic drugs. The search was updated in November 2010 and identified 45 RCTs with 5480 participants. Levosimendan was associated with a significant reduction in mortality (risk ratio (RR) 0.80; 95% CI 0.72 to 0.89) and low heterogeneity between study results. This result was confirmed in studies with different control groups and in different settings. Two of our included studies (Fuhrmann 2008; Garcίa‐González 2006) were in the subgroup of trials performed in cardiology where a similar reduction of mortality was confirmed (RR 0.75; 95% CI 0.63 to 0.91) with low heterogeneity (I2 = 25.5%).
In conclusion, while some of our included studies were used in recently published reviews, our systematic review differs from previously published reviews for several major reasons.
(a) This review is restricted to patients with AMI complicated by CS.
(b) None of the other meta‐analyses were based on a previously published protocol, as recommended in Shea 2009.
(c) Our literature search was updated in January 2013 and is more up‐to‐date. We have included data from a recently published RCT comparing levosimendan and placebo (Husebye 2013), which has not been included in previous publications.
(d) Finally, no systematic review investigated vasodilator drugs on patients with AMI and CS or LCOS.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Survival curves of included trials on levosimendan.
Comparison 1 Levosimendan versus control, Outcome 1 All cause mortality distribution.
Comparison 1 Levosimendan versus control, Outcome 2 All‐cause 30‐day mortality rates.
Comparison 1 Levosimendan versus control, Outcome 3 All‐cause 6‐month mortality rates.
Comparison 1 Levosimendan versus control, Outcome 4 All‐cause 12‐months mortality rates.
| Comparison | study | MACE | Intervention | Control | OR; 95%CI | ||
| Events | Total | Events | Total | ||||
| Levosimendan versus enoximone | Fuhrmann 2008 | death (within 30 days) | 5 (31%) | 16 | 10 (52%) | 16 | 0.27; 0.06‐1.18 |
| death (within 30 days) caused by refractory heart failure | 5 (31%) | 16 | 4 (25%) | 16 | 1.36; 0.29‐6.42 | ||
| death (within 30 days) caused by multiple organ failure | 0 (0%) | 16 | 4 (25%) | 16 | 0.08; 0.00‐1.71 | ||
| death (within 30 days) caused by rhythm disorder | 0 (0%) | 16 | 1 (6%) | 16 | 0.01; 0.01‐8.28 | ||
| death (within 30 days) caused by stroke | 0 (0%) | 16 | 1 (6%) | 16 | 0.01; 0.01‐8.28 | ||
| Levosimendan versus dobutamine | García‐González 2006 | death (within 30 days) | 0 (0%) | 11 | 0 (0%) | 11 | Not estimable |
| reinfarction (in‐hospital) | 0 (0%) | 11 | 0 (0%) | 11 | Not estimable | ||
| cerebrovascular accidents (in‐hospital) | 0 (0%) | 11 | 0 (0%) | 11 | Not estimable | ||
| Levosimendan versus placebo | Husebye 2013 | death during 6‐month follow‐up | 1 (25%) | 4 | 2 | 5 | 0.5; 0.03‐151.5 |
| MACE (death, non‐fatal myocardial infarction, revascularization of the infarct‐related artery) | 2 (50%) | 4 | 2 (40%) | 5 | 1.5; 0.11‐21.31 | ||
| repeat PCI | 1 (25%) | 4 | 0 | 5 | 4.71; 0.15‐151.5 | ||
| Nitric oxide versus placebo | Baldassarre 2008 | death | 0 (0%) | 2 | 1 (100%) | 1 | |
| myocardial infarction | 1 (50%) | 2 | 1 (100%) | 1 | |||
| Comparison | Primary studies | Reported information | Intervention | Control | ||
| Events/time | Total | Events/time | Total | |||
| Levosimendan versus enoximone | Fuhrmann 2008 | stay in ICU in days, median (IQR) | 10 (5‐23) | 16 | 13 (7‐19) | 16 |
| Comparison | study | MACE | Intervention | Control | OR; 95%CI | ||
| Events | Total | Events | Total | ||||
| Levosimendan versus enoximone | Fuhrmann 2008 (development of organ failure) | need of mechanical ventilation | 13 (81%) | 16 | 15 (94%) | 16 | 0.29; 0.03‐3.13 |
| acute renal failure | 5 (31%) | 16 | 8 (50%) | 16 | 0.45; 0.11‐1.92 | ||
| need of continuous renal replacement therapy | 5 (31%) | 16 | 8 (50%) | 16 | 0.45; 0.11‐1.92 | ||
| new onset atrial fibrillation | 7 (44%) | 16 | 9 (56%) | 16 | 0.60; 0.15‐2.45 | ||
| ventricular tachycardia or fibrillation | 8 (50%) | 16 | 11 (69%) | 16 | 0.45; 0.11‐1.92 | ||
| development of systemic inflammatory response | 8 (50%) | 16 | 13 (81%) | 16 | 0.23; 0.05‐1.13 | ||
| pneumonia | 7 (44%) | 16 | 7 (44%) | 16 | 1.00; 0.25‐4.04 | ||
| urinary infections | 0 (0%) | 16 | 2 (12%) | 16 | 0.18; 0.01‐3.97 | ||
| sepsis | 3 (19%) | 16 | 2 (12%) | 16 | 1.62; 0.23‐11.26 | ||
| Levosimendan versus dobutamine | García‐González 2006 | multiple organ failure | 0 (0%) | 11 | 0 (0%) | 11 | Not estimable |
| reinfarction | 0 (0%) | 11 | 0 (0%) | 11 | Not estimable | ||
| cerebrovascular accidents | 0 (0%) | 11 | 0 (0%) | 11 | Not estimable | ||
| Levosimendan versus placebo | Husebye 2013 | non‐sustained ventricular tachycardia | 1 (25%) | 4 | 3 (60%) | 5 | 0.22; 0.01‐3.98 |
| atrial fibrillation | 1 (25%) | 4 | 0 (0%) | 5 | 4.71; 0.15‐151.5 | ||
| Episodes of hypotension during drug infusion (MAP fall > 10 mmHg) | 2 (50%) | 4 | 1(20%) | 5 | 4.0; 0.21‐75.7 | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All cause mortality distribution Show forest plot | 3 | Hazard Ratio (Random, 95% CI) | Totals not selected | |
| 1.1 Levosimendan versus dobutamine | 1 | Hazard Ratio (Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Levosimendan versus enoximone | 1 | Hazard Ratio (Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.3 Levosimendan versus placebo | 1 | Hazard Ratio (Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 All‐cause 30‐day mortality rates Show forest plot | 3 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.1 Levosimendan versus dobutamine | 1 | Odds Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 Levosimendan versus enoximone | 1 | Odds Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 Levosimendan versus placebo | 1 | Odds Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 All‐cause 6‐month mortality rates Show forest plot | 2 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.1 Levosimendan versus dobutamine | 1 | Odds Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.2 Levosimendan versus placebo | 1 | Odds Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 All‐cause 12‐months mortality rates Show forest plot | 1 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4.1 Levosimendan versus dobutamine | 1 | Odds Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
