Author + information
- Published online January 16, 2017.
- aKlinikum Ludwigshafen and Institut für Herzinfarktforschung Ludwigshafen, Ludwigshafen, Germany
- bMedical Clinic II, University Heart Center Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany
- ↵∗Reprint requests and correspondence:
Prof. Dr. Uwe Zeymer, Klinikum Ludwigshafen, Institut für Herzinfarktforschung Ludwigshafen, Bremser Strasse 79, 67063 Ludwigshafen, Germany.
Cardiogenic shock (CS) is the most important cause of death in patients admitted with acute myocardial infarction. The randomized “Impella versus IABP reduces mortality in STEMI patients treated with primary PCI in severe cardiogenic shock” IMPRESS in Severe Shock (SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK) trial set the basis for an early invasive management of these patients (1), with subsequent early revascularization. This strategy has dramatically improved outcome and reduced in-hospital mortality of CS patients from 70% to 80% to 40% to 50% (2).
The pathophysiology of CS is complex and is characterized by a profound depression of myocardial contractility, resulting in a vicious spiral of reduced cardiac output, low blood pressure, further coronary ischemia, and subsequent reduction in contractility and cardiac output. Initial compensation mechanisms by vasoconstriction can be off reverted by systemic inflammation leading to subsequent pathologic vasodilatation, occurring frequently with increasing shock duration.
Standard therapy of CS consists primarily of volume management as well as inotropic agents and vasopressors enhancing cardiac output and the vascular tone. The hemodynamic benefits of inotropes and vasopressors are counterbalanced by adverse effects such as increased myocardial oxygen demand, arrhythmogenicity, and compromise of tissue microcirculation translating into a possible increased mortality risk. Mechanical circulatory support (MCS) is an alternative to increase systemic blood flow avoiding the possible cardiotoxicity and long-term morbidity of inotropes and vasopressors and is often believed to be the only option to achieve hemodynamic stability in CS.
Intra-aortic balloon pumping (IABP) has been the most widely used MCS for nearly 5 decades (3). In the only adequately powered randomized trial of IABP in CS secondary to myocardial infarction—IABP-SHOCK II (Intraaortic Balloon Pump in Cardiogenic Shock II) trial—short- and mid-term follow-up data at 30 days and 1 year showed no survival benefit with IABP support in comparison to control, nor any benefit with respect to secondary outcomes, such as hemodynamic parameters, serum lactate levels, catecholamine doses, or renal function (4,5). Accordingly, the IABP has been downgraded in current American and European guidelines (6–8); in Europe IABP use is even a Class III Level of Evidence: B recommendation.
As a consequence of the IABP-SHOCK II trial and the subsequent downgrading in the guidelines, IABP use declined and other MCS use increased (9). Currently, there is growing interest in MCS. The percutaneous devices consist of an axial pump unloading the left ventricle and providing a cardiac output of 2.5 (Impella 2.5, Abiomed, Danvers, Massachusetts) or 3.7 l/min to 4.0 (Impella CP, Abiomed) l/min (2). Evidence for percutaneous MCS including 1 trial with the use of the Impella 2.5 has been limited to 3 small randomized trials which showed superior hemodynamic support by MCS versus IABP. However, there were significantly more device related complications and mortality remained similar (10).
The newer more powerful platform Impella CP has now been tested in a small randomized trial in 48 patients with ST-segment elevation myocardial infarction with CS and the need for mechanical ventilation (11). Although the investigators must be congratulated for performing such a trial without support from the industry, this trial was based on a power calculation with non-realistic mortality rates; thus, this trial is markedly underpowered. The patients included were not in severe CS and mortality rates at 6-month follow-up very similar to other much larger trials (1,4). It is thus not surprising that there was no difference in the primary endpoint of all-cause mortality after 30 days; however, the lack of benefit in any of the other parameters including serum lactate is a concern with respect to the efficacy of the device. Being largely underpowered, the IMPRESS in Severe Shock trial can only be regarded as a feasibility trial. It may serve as basis for a larger clinical trial, preferably versus optimal medical therapy. However, based on the absolute mortality difference of 4%, such a trial would need approximately 2,500 CS patients to show a real mortality difference with a power of 80%.
With the results of IMPRESS in Severe Shock trial, multiple questions remain and need to be discussed:
1. Is any MCS able to reduce CS mortality? This is surely the major question which cannot be finally answered due to the lack of evidence. However, we strongly believe that MCS is able to reduce mortality at least in selected patient groups.
2. Do we have the appropriate device design and sufficient support? According to the technical features, the Impella CP provides a flow of 3.7 l/min to 4.0 l/min. However, these flow data were acquired during bench testing and little is known on the real flow rates in patients with high afterload. Because one-third of the patients died due to refractory CS while being on support by the Impella CP, this suggests that the actual support was not sufficient. This is also supported by the lack of any effect on the serum lactate level. The optimal support with respect to flow rates and also the optimal device itself has not been determined so far.
3. Do we have appropriate patient selection? Currently, MCS is mainly considered in patients with refractory CS (6,8). Furthermore, appropriate patient selection in clinical practice is often based on subjective criteria. Approximately 50% to 60% of CS patients will survive without any MCS (5). There may also be futile situations for which even the best device available will not be able to change clinical outcome. In the current IMPRESS in SHOCK trial, MCS was used in unselected CS patients secondary to ST-segment elevation myocardial infarction being on mechanical ventilation, and a number of patients may not have been in severe refractory CS. Thus, approximately 50% of the patients did not need an MCS. Furthermore, death occurred in 46% of the patients as a result of severe brain injury. Any MCS may thus be able to stabilize the initial hemodynamic situation but not influence the neurological outcome.
4. Do the complications outweigh the benefit? As outlined above, CS pathophysiology is often influenced by inflammation and multi-organ dysfunction syndrome (MODS). The contact with artificial surfaces from MCS and also hemolysis might further promote the systemic inflammatory response syndrome and is also activating the coagulation cascade with subsequent fibrinolysis, which may progress to disseminated intravascular coagulation leading to severe bleeding complications. In the IMPRESS in Severe Shock trial, bleeding rates were significantly higher in the Impella CP arm (33% vs. 8%) supporting this hypothesis.
5. Is the lack of efficacy of MCS based on inappropriate timing of device insertion during the course of CS and also in relation to primary percutaneous coronary intervention (PCI)? Assuming that MCS devices have a beneficial effect on CS, the optimal timing of device insertion remains elusive. A potential benefit of an early use at onset of CS could be prevention of MODS. However, earlier use might also lead to potentially fatal complications associated with invasive MCS. Timing and appropriate patient selection is also influenced by the balance between efficacy of any device and its device-related complications. Devices with low complication rates may be chosen more liberally in the early stages of CS, whereas more aggressive devices with higher flow rates may be reserved for more severe CS. Timing of device insertion in relation to PCI is considered to be of importance based on animal data suggesting infarct size reduction only if support is initiated before reperfusion. Human data failed to show a benefit with the IABP in large anterior infarctions (12). The numerically lower mortality of 25% versus 53% if the percutaneous MCS was inserted before PCI in IMPRESS is once again only hypothesis generating.
The relation of all these above-mentioned considerations is depicted in Figure 1. The failure of the IABP in the IABP-SHOCK II trial and also the failure of Impella in the feasibility IMPRESS in Severe Shock trial should not be considered as the end of MCS device therapy itself. These trials should be more considered as seminal trials for future research in this field to answer all these open questions.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
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