Abstract
Intra-aortic balloon pump counterpulsation is currently the most used mechanical assistance device for patients with cardiogenic shock due to acute myocardial infarction. However, a recently published meta-analysis and trial failed to confirm previous knowledge. We report the results of four patients with ST elevation myocardial infarction, complicated by cardiogenic shock unsuitable for intra-aortic balloon pump counterpulsation treated with early levosimendan infusion during primary percutaneous coronary intervention.
Keywords
Introduction
The in-hospital mortality for ST elevation myocardial infarction (STEMI) within the past 10 years has remained essentially unchanged, as it is mainly related to the development of cardiogenic shock. Despite the advances in treatment, the incidence of this serious complication has remained relatively constant and the mortality rate, although showing some limited improvement, is still high.
The Euro Heart Survey on percutaneous coronary intervention (PCI) previously reported that, among patients with acute myocardial infarction-related cardiogenic shock, only 25% were treated with an intra-aortic balloon pump (IABP), with a European in-hospital mortality ranging from 56.9% to 36.1% with and without IABP, respectively [Zeymer et al. 2011]. A recently published meta-analysis failed to demonstrate an improved 30-day mortality in STEMI IABP treated patients [Sjauw et al. 2009; Bahekar et al. 2011]. Therefore the use of IABP in cardiogenic shock was downgraded in the last version of European guidelines [Steg et al. 2012] from a class I to a class IIb (level of evidence B) recommendation, as confirmed in the randomized multicentre IABP-SHOCK II trial [Thiele et al. 2013]. Otherwise the 1-year mortality in patients who survived cardiogenic shock is similar to that of post-STEMI patients without shock. Moreover there is a subgroup of patients unsuitable for IABP, especially when a vascular complication has occurred or there is a high comorbidity rate, such as bleeding, thrombo-embolism, limb ischemia and aortic wall damage affecting the clinical conditions at the time of shock. The same patients also could not be treated with ventricular assistance devices because of greater complexity in the positioning and increased incidence of periprocedural complications (bleeding and vascular). In this high-risk subset of patients, the priority is to customize pharmacological treatment strategies specifically ‘tailored’ depending on the modality of presentation of the heart attack.
Indeed, recent improvements in reperfusion therapies have not significantly reduced the mortality of cardiogenic shock. This may be due either to the underutilization of life support devices in the acute phase or to the delay of immediate and long-term myocardial protective therapies. In the context of pharmacological treatment, noradrenaline and dobutamine are currently considered as first choice drugs [Sjauw et al. 2009]. More recently, as shown by numerous reports, levosimendan, a calcium sensitizer with positive inotropic and vasodilating properties, has emerged as an alternative pharmacological treatment to inotropic drugs in patients with cardiogenic shock, with more favourable effects also on left ventricular diastolic function [Thiele et al. 2013; Buerke et al. 2011; Buerkem et al. 2011; Dominguez-Rodriguez et al. 2008]. In particular, compared with conventional therapy, levosimendan increases cardiac index, reduces systemic and pulmonary resistances, ischemia-reperfusion injury, cardiomyocyte apoptosis and myocardial stunning.
Case reports
We have analysed the results of four patients with STEMI complicated by cardiogenic shock at the onset, unsuitable for IABP due to: (1) iatrogenic rupture of the superficial femoral artery secondary to percutaneous femoral recanalization failure submitted to surgical repair; (2) aortic aneurism (65 mm) waiting for surgical repair; (3) recent aortobifemoral bypass (day 3 after vascular surgery); and (4) paraprosthetic leak of previously implanted aortic endoprosthesis.
All patients were subjected to emergent primary PCI. In all cases, a transradial left approach was attempted and successfully performed in consideration of peripheral vascular impairment. All patients were treated with levosimendan: the infusion was started in the catheterization laboratory during the procedure with a bolus loading dose of 12 μg/kg intravenous (i.v.), followed by continuous infusion 0.1 μg/kg/min for 24 h. Inotropic drugs (norepinephrine in three cases, dobutamine in one case) were started on average 40 min before the procedure and the ‘overlap’ duration was on average 106 min. In particular, these drugs were interrupted as follows: after 135 min in case 1; after 120 min in case 2; after 80 min in case 3; and after 90 min in case 4. In all cases, considering the high risk of bleeding, an intraprocedural infusion of bivalirudin was performed (i.e. bolus dose of 0.75 mg/kg immediately followed by continuous infusion of 1.75 mg/kg/h). The antiplatelet pretreatment consisted of aspirin (ASA) 300 mg and clopidogrel 300 mg: only one patient (with haemoglobin levels of 6 g/dl) received clopidogrel 300 mg alone. Clinical, angiographic features and in-hospital and 1-month major adverse cardiac events (i.e. cardiovascular death, myocardial infarction, stroke) were also evaluated.
Discussion
The study population was relatively elderly (mean age 72.2 years) with a high rate of comorbidities and bleeding risk score (Table 1). As a consequence of vascular bleeding, one patient received blood transfusion due to the low levels of haemoglobin (6 g/dl) before the procedure (PCI). All patients were suffering from chronic renal failure with a mean creatinine level of 1.72 mg/dl and a mean estimated glomerular filtration rate of 42 ml/min, consistent with a stage 3B (moderately reduced) renal impairment (Patient 1: creatinine level of 1.4 mg/dl, glomerular filtration rate of 43 ml/min; Patient 2: creatinine level of 1.5 mg/dl, glomerular filtration rate of 47 ml/min; Patient 3: creatinine level of 1.9 mg/dl, glomerular filtration rate of 41 ml/min; Patient 4: creatinine level of 2.1 mg/dl, glomerular filtration rate of 37 ml/min). Although the use of levosimendan is contraindicated in the case of severe renal impairment (creatinine clearance <30 ml/min), our report confirms that this drug, in patients with mild to moderate renal impairment, can be safely and effectively used without requiring dose adjustments.
Clinical risk assessment and follow-up features.
ASA, aspirin; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; GRACE, Global Registry of Acute Coronary Events; MACE, major adverse cardiac event; MI, myocardial infarction.
A mean value of systolic arterial pressure of 83.25 mmHg was found at the beginning of the procedures, before levosimendan infusion (Patient 1, 78 mmHg; Patient 2, 88 mmHg; Patient 3, 85 mmHg; Patient 4, 82 mmHg). After the full bolus dose (12 μg/kg i.v.), as expected and previously reported, a negligible mean pressure drop of ~8 mmHg (nearly 10%) versus baseline values was documented followed by a slight increase and a plateau phase until 36 hours after the start of the infusion. All the patients received levosimendan infusion on top of ongoing inotropic drugs with an ‘overlap’ duration on average of 106 min from the beginning of the infusion, clarifying the haemodynamic data observed. Given the reduction in mortality and length of stay in hospital [Landoni et al. 2012], due to its cardioprotective inodilator effect, the advantages of using levosimendan are:
early improvement of haemodynamic performance
negligible increase in oxygen consumption versus other inotropes
improvement of acute heart failure related symptoms preventing them worsening
improvement of neurohormonal, i.e. brain natriuretic peptide, interleukin-6 (IL-6) to interleukin-10 (IL10) imbalance
a positive synergistic effect on mortality with beta-blocker therapy.
These benefits are principally mediated through a triple mechanism of action involving an increased cardiac contractility by calcium sensitization of troponin C and vasodilation through the opening of potassium channels in both vascular smooth muscle and cardiomyocyte mitochondria with final anti-apoptopic and antiremodeling effects.
Despite these beneficial effects, the use of levosimendan presents some limitations:
the need to customize the treatment according to a case-by-case clinical setting and dose response
no unequivocal data about the loading dose
particular caution in patients with severe hypotension, which represent the majority of patients with cardiogenic shock
relative contraindication in the case of hypovolemia and hypokalemia (both avoided before and during the treatment).
The average length of hospital stay was 11.25 days, consistent with a large published meta-analysis showing a cost-effective impact due to shorter hospitalization [Landoni et al. 2012]. The procedural success was 100% (Table 2). All patients were discharged alive and no major cardiovascular events at 1 month were recorded (Table 1).
Angiographic and procedural features.
TIMI, thrombolysis in myocardial infarction.
Conclusion
Despite the small number of patients, this study shows that, in high risk STEMI complicated by cardiogenic shock submitted to primary PCI, early ‘in-lab’ use of levosimendan seems to be effective and a possible alternative when mechanical haemodynamic support is not suitable. Additional prospective studies, adequately powered for clinical endpoints with direct comparison of different pharmacological treatment, are needed to better evaluate the efficacy of prompt intraprocedural use of levosimendan in cardiogenic shock complicating acute myocardial infarction when a mechanical support is unsuitable.
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors declare on conflicts of interest in preparing this article.