- Email: [email protected]
Usefulness of Intra-aortic Balloon Pump Counterpulsation
Accepted Manuscript Usefulness of Intra-aortic Balloon Pump Counterpulsation Lokien X. van Nunen, MD, Marko Noc, MD PhD, Navin K. Kapur, MD, Manesh R. Patel, MD, Divaka Perera, MD, Nico H.J. Pijls, MD PhD PII:
S0002-9149(15)02255-9
DOI:
10.1016/j.amjcard.2015.10.063
Reference:
AJC 21531
To appear in:
The American Journal of Cardiology
Received Date: 14 September 2015 Revised Date:
30 October 2015
Accepted Date: 30 October 2015
Please cite this article as: van Nunen LX, Noc M, Kapur NK, Patel MR, Perera D, Pijls NHJ, Usefulness of Intra-aortic Balloon Pump Counterpulsation, The American Journal of Cardiology (2015), doi: 10.1016/ j.amjcard.2015.10.063. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Usefulness of Intra-aortic Balloon Pump Counterpulsation Lokien X. van Nunen MDa, Marko Noc MD PhDb, Navin K. Kapur MDc, Manesh R. Patel MDd, Divaka Perera MDe, Nico H.J. Pijls MD PhDa
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a. Department of Cardiology, Catharina Hospital Eindhoven, Eindhoven, The Netherlands b. Center for Intensive Internal Medicine, University Medical Center, Ljubljana, Slovenia c. The Cardiovascular Center, Tufts Medical Center, Boston, USA
d. Division of Cardiology, Department of Medicine, Duke Clinical Research Institute, Duke
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University Medical Center, Durham, USA
e. Cardiovascular Division, British Heart Foundation Centre of Research Excellence, Kings
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College London, St Thomas’ Hospital, Westminster Bridge Road, London, UK
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Running head: IABP
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Corresponding Author:
Nico H.J. Pijls, Professor of Cardiology Catharina Hospital Eindhoven, Department of Cardiology Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands Email: [email protected] Telephone: +31 40 2397004 Fax: +31 40 2447885
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ACCEPTED MANUSCRIPT Abstract Intra-aortic balloon pump counterpulsation (IABP) is the most widely used mechanical circulatory support device due to its ease of use, low complication rate, and fast manner of insertion. Its benefit is still subject of debate and a considerable gap exists between
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guidelines and clinical practice. Retrospective non-randomized studies and animal experiments show benefits of IABP therapy. However, recent large randomized trials do not show benefit of IABP therapy, which has led to a downgrading in the guidelines. In our view, this dichotomy between trials and practice might be the result of insufficient understanding of
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the prerequisites needed for effective IABP therapy, i.e. exhausted autoregulation, and of not including the right patient population in trials. The population included in recent large
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randomized trials has been heterogenous, also including patients in whom benefit of IABP could not be expected. The clinical condition in which most benefit is expected, i.e. persistent ischemia in acute ST-elevation myocardial infarction, is discussed in this review. In conclusion, this review aims to explain the physiologic principles needed for effective IABP
controversies in this field.
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Keywords
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therapy, to reflect critically on the large randomized trials, and to solve some of the
Intra-aortic balloon pump counterpulsation, coronary autoregulation, high-risk percutaneous
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coronary intervention, acute myocardial infarction, cardiogenic shock
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ACCEPTED MANUSCRIPT Introduction Appropriate use of intra-aortic balloon pump counterpulsation has been subject to heavy debate over the past years.1-4 Use of IABP is generally confined to three groups of patients, i.e. high-risk percutaneous coronary intervention (PCI), acute myocardial infarction, and
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cardiogenic shock. There have been large randomized trials for all three indications, which will be discussed below. However, before analyzing these trials in detail, it is mandatory to better understand the presumed physiologic principles of IABP counterpulsation and the
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prerequisites needed for adequate effect (or absence of effect) of IABP.
Physiologic principles and the role of coronary autoregulation
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The intra-aortic balloon pump (IABP), positioned in the descending thoracic aorta through the femoral artery, inflates and deflates in synchrony with the cardiac cycle. By inflating in the diastolic phase of the cardiac cycle, the diastolic aortic pressure is augmented, resulting in higher coronary perfusion pressure (Figure 1). This could theoretically lead to improved
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coronary blood flow and thereby increase of myocardial oxygen supply.5,6 Early in systole, the balloon rapidly deflates, reducing the afterload of the left ventricle (Figure 1). In turn, this is thought to decrease myocardial workload and oxygen demand.7
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However, the supposed direct mechanical effect of counterpulsation on coronary blood flow can be easily undone by the reactive vasoconstriction of the coronary and myocardial bed,
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known as coronary autoregulation. Under normal physiologic circumstances, sphincters at the entrance of coronary arterioles constrict or dilate in response to coronary perfusion pressure, thereby guaranteeing constant myocardial blood flow over a wide range of aortic pressures (60-140 mmHg).8 Therefore, in physiologic conditions with intact coronary autoregulation, myocardial blood flow is not dependent on perfusion pressure and it is illusionary to expect increased coronary blood flow due to higher perfusion pressure by IABP counterpulsation. Thus, improved coronary blood flow by IABP can only be expected in situations with exhausted autoregulation.
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ACCEPTED MANUSCRIPT Recently, De Silva et al. performed intracoronary flow and pressure measurements during IABP counterpulsation with “switched on” and “switched off” coronary autoregulation using intravenous adenosine infusion for minimizing coronary vascular resistance.9 The authors showed that the effect of IABP on coronary flow is directly dependent on coronary
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autoregulation. With intact autoregulation, balloon pump augmentation did lead to an increase in coronary pressure, but also to a reactive increase in microvascular resistance, and as a result unchanged coronary blood flow. On the other hand, with “switched off”
autoregulation, the balloon pump augmentation led to an increase in distal coronary pressure
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and coronary blood flow, while the microvascular resistance remained unchanged. Also in recent studies performed in the isolated beating pig heart, it was documented that with
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exhausted autoregulation, a linear relationship between diastolic aortic pressure and coronary blood flow is present and that IABP increases coronary blood flow by up to 50% in the presence of pump failure due to ongoing myocardial ischemia.10,11 In short, only when autoregulation is exhausted, coronary blood flow is directly dependent
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on perfusion pressure, and effects of IABP on coronary blood flow can be expected. This is the case in the following clinical situations: 1) in the perfusion territory of a critical, subtotal stenosis; 2) in ischemic myocardium, including “stunning” after myocardial infarction or
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during weaning from extracorporeal circulation; and 3) in patients with low mean aortic pressures outside the autoregulatory range (< 60 mmHg).
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The importance of autoregulation when assessing the effect of IABP was not fully understood nor investigated until recently and is not reflected in the inclusion criteria in the large randomized clinical trials, including acute myocardial infarction and cardiogenic shock.
High-risk percutaneous coronary intervention IABP is often used as circulatory support system to prevent major complications during high-risk PCI.12 Patients with severe left ventricular dysfunction undergoing PCI are at higher risk of morbidity and mortality.13,14 This risk increases when the target lesion is supplying a substantial proportion of the myocardium. By inducing ischemia during PCI, left ventricular
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ACCEPTED MANUSCRIPT function will further deteriorate, and patients are at risk of entering a downwards spiral of myocardial ischemia, hemodynamic compromise, cardiogenic shock, and ultimately death. Especially if a subtotal stenosis is present in a large contralateral coronary artery, secondary ischemia of the contralateral myocardial territory due to compensatory hyperkinesia might
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induce a downwards spiral with deleterious outcome. Until 2010, evidence supporting use of IABP in such patients consisted of several
retrospective observational and small randomized studies.15-18 The Balloon Pump-Assisted Coronary Intervention Study (BCIS-1) randomized 301 patients scheduled to undergo high-
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risk single-vessel or multivessel PCI to either IABP insertion prior to PCI or no planned IABP insertion.19 Based on the predicted and actual event rates, the study was adequately
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powered. Outcome at hospital discharge was similar between the two groups, without significant differences in myocardial infarction, death, cerebrovascular accident or further revascularization. In the control group, 12% of the patients needed rescue IABP insertion due to intraprocedural complications, mainly hypotension. Six-month mortality was 4.6% in
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the IABP group and 7.4% in the control group (P=0.32). Although not statistically significant at first, this relative risk reduction of 38% remained constant over time, resulting in a significant benefit in favour of IABP over long-term follow-up, with a hazard ratio of 0.66 (95%
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CI, 0.44-0.98; P=0.039).20 This consistent relative risk reduction by one third is of huge impact in a patient population in which one out of every three patients died within the long-
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term follow-up period (Figure 2). The constant hazard ratio during follow-up implies that this is attributable to an early treatment effect, i.e. IABP insertion before PCI. There were no other detectable procedural differences between the two groups in terms of number of vessels treated, success rate, and proportion of left main or proximal left anterior descending coronary arteries stented. Explanation of this difference in outcome could be the reduction of ischemia by IABP during high-risk PCI, and the prevention of intraprocedural complications. Effects of IABP on coronary blood flow is not undone by coronary autoregulation in these patients, since autoregulation is completely exhausted in the coronary tree distal to a significant stenosis
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ACCEPTED MANUSCRIPT and in the presence of ischemic myocardium during and shortly after balloon inflation. Even small periprocedural myocardial infarctions, only measured by elevated troponin-levels, have shown to affect outcome in cardiac patients.21 In patients with severe ischemic cardiomyopathy as included in BCIS-1, this effect might be more pronounced, causing this
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significant difference in long-term outcome. It is well conceivable that better protection of the myocardium during the procedure itself will result in a decrease in mortality in the long term, explaining the late results of BCIS-1.
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Acute myocardial infarction
Primary PCI in patients presenting with ST-segment elevation myocardial infarction
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(STEMI) has resulted in an impressive improvement in outcome.22 During the last decade, however, despite optimizing time intervals, outcome has not further improved. This may be ascribed to “reperfusion injury”, “no-reflow”, or “persistent ischemia”, which occurs in up to 30% of the patients and is caused by a variety of factors including micro-embolisation of
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atherothrombotic debris, vasospasm, and external compression of the capillaries due to intramyocardial edema, hemorrhage and other factors, suppressing adequate myocardial perfusion after successful epicardial stenting.23 In such patients, this “ongoing” or “persistent”
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ischemia leads to reduced salvage of myocardium, even if the occluded epicardial coronary artery has been opened successfully by primary PCI.
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Animal experiments have shown that IABP is effective in reducing no-reflow, improves myocardial salvage, and decreases infarct size.24,25 A clinical registry in nearly 1500 consecutive patients showed prophylactic insertion of IABP to be associated with fewer events in all high-risk patients presenting with acute myocardial infarction.26 The Counterpulsation to Reduce Infarct Size Pre-PCI Acute Myocardial Infarction (CRISP AMI) trial sought to determine if routine IABP therapy prior to primary PCI in patients with anterior STEMI without shock reduces infarct size as assessed on cardiac magnetic resonance imaging (CMR), and randomized 337 patients.27 The study was designed and powered to detect a 25% reduction in infarct size in the IABP group. Final infarct size as
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ACCEPTED MANUSCRIPT assessed by CMR after 3-5 days showed no difference and a trend towards larger infarctions in the IABP group (42.1% versus 37.5%, P=0.06). All-cause mortality at 6 months occurred less frequent in the IABP group, although not statistically significant (2% versus 5%, P=0.12). The exploratory composite end point of death, shock, or new or worsening heart failure did
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reach statistical significance in favour of the IABP group (5% versus 12%, P=0.03). So, in CRISP AMI, the primary end point was not achieved and some confusion originated with respect to other end points.
However, 40% of the population in CRISP AMI had summed ST-elevation <6mm,
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representing a cohort of patients with relatively small infarctions with a good prognosis
anyway, whether or not treated with IABP or any other additional therapy.28 It is unlikely that
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in these patients, any of the pre-defined end points like death or congestive heart failure would be reached anyway, irrespective if and how they were treated. This is corroborated by the systolic and diastolic blood pressure and heart rate of the study population, not suggesting a very sick trial population. Inclusion of these patients most likely diluted a
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possible effect of IABP insertion by underpowering the study. A recent substudy of CRISP AMI in patients with large myocardial infarction (summed ST-deviation ≥15mm) and persistent ischemia (ST-resolution after PCI < 50%) showed a significant reduction in
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mortality despite a much smaller patient population (Figure 3).29 Furthermore, in CRISP AMI there was a considerable and asymmetrical cross-over from
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control group to IABP group (8%), due to sustained hypotension or cardiogenic shock, failed PCI, or continued chest pain. The impact of this asymmetrical cross-over will be discussed later in this paper.
Finally, the primary end point was infarct size as assessed at 3-5 days using CMR. Using CMR in a patient population with the highest event rate in the first days, will automatically create bias because patients (mainly without IABP) who died in the first days or were too unstable to undergo CMR, are not included in this analysis of infarct size.
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ACCEPTED MANUSCRIPT More in general, it is questionable if CMR 3-5 days after acute myocardial infarction is a reliable method to predict the ultimate infarct size and ejection fraction. Considerable further recovery is reported by consecutive CMR examinations at later follow-up.30,31 Overall, use of IABP is not indicated routinely in acute myocardial infarction. Especially in
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patients with relatively small infarctions or fast successful reperfusion, reflected by complete ST-resolution, there is no effect to be expected by IABP counterpulsation. However, in
patients with large myocardial infarction complicated by persistent ischemia (ongoing pain or insufficient ST-resolution), a significant decrease of mortality was observed, which fits with
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the pathophysiological considerations mentioned above. This decrease of outcome was observed in a substudy, with all its limitations. Therefore, a prospective randomized
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controlled trial in such patients has been started recently to investigate this standpoint (SEMPER FI study: Survival in patients with Extensive Myocardial infarction complicated by PERsistent ischemia Following IABP insertion; NCT02125526).
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Cardiogenic shock
Treatment of cardiogenic shock complicating acute myocardial infarction remains a challenge with persisting high mortality rates.32,33 Pharmacological therapy often fails to
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stabilize the patient in cardiogenic shock, and carries the additional risk of increasing myocardial ischemia due to increased myocardial oxygen demand. This is the reason why
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physicians attempted to improve treatment of these patients by the use of mechanical circulatory support devices, one of them being the intra-aortic balloon pump. Most trials with favourable results regarding IABP use in acute myocardial infarction complicated by cardiogenic shock were performed in the thrombolytic era.34,35 Registries and retrospective studies in the era of primary PCI showed no difference in outcome by the use of IABP.36,37 The IABP-SHOCK II trial prospectively randomized 600 patients with acute myocardial infarction (with or without ST-segment elevation) complicated by cardiogenic shock to primary PCI with adjunctive IABP support or PCI alone.33 This landmark study
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ACCEPTED MANUSCRIPT showed no reduction in short-term and long-term mortality (30-day mortality 39.7% versus 41.3%; 1-year mortality 52% versus 51%, respectively) (Figure 4).38 Strengths and limitations of this landmark trial have been discussed extensively. It is the largest randomized trial performed in patients with cardiogenic shock, including 600 patients
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in 32 months, and with a very high percentage of follow-up (1-year follow-up completed in 99.2%). Apart from the fact that the study was underpowered due to a lower event rate in the control group than anticipated, several other important limitations were present in this study, questioning its conclusions.
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First, there was a large asymmetrical crossover from control group to the IABP group and an increase in the use of left ventricular assist devices in the control group of together 17.4%
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of the patients not randomized to IABP. The impact of this high and asymmetrical cross-over on statistical analysis and conclusions of the study will be discussed further on. Second, almost half of the patients randomized were resuscitated before PCI and almost 40% received induced hypothermia after PCI. Outcome in these patients is poor irrespective
salvage by IABP.
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of the use of IABP and primarily dependent on neurologic recovery rather than myocardial
Finally, the time-windows in these patients were very wide; patients could be included up
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to 12 hours after onset of cardiogenic shock. If a patient with acute myocardial infarction complicated by cardiogenic shock presents too late (i.e. there is no persisting ischemia,
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neither viable myocardium in the infarcted area anymore), no salvage of myocardium leading to a better prognosis can be expected anyway. In such patients, in the best case, IABP therapy will lead to temporary relieve and stabilization of hemodynamics. Volume pumps are more effective to increase output in such patients, but these effects are temporary as well and will disappear as soon as the device is removed. Although IABP-SHOCK II definitely questions the routine use of IABP in patients presenting with acute myocardial infarction complicated by cardiogenic shock, these limitations exemplify the difficulties in interpreting randomized open trials involving very sick patients. The question is if outcome would be different by including a more specific group of
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ACCEPTED MANUSCRIPT STEMI patients, rather than a heterogenous group of patients with respect to presence of persistent ischemia, time-intervals, concomitant neurologic deficits, and the use of or crossover to additional mechanical support strategies. Cardiogenic shock should not be seen as a yes-or-no phenomenon like cardiac arrest, but
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rather as a very heterogenous condition which requires a tailored treatment. By solely including the patients presenting with STEMI complicated by cardiogenic shock with still viable myocardium and persistent ischemia as reflected by ongoing chest pain and persisting ST-deviation, and by excluding resuscitated patients, IABP therapy could be expected to be
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more effective based on pathophysiological grounds, as discussed here above.
A recent study in the isolated beating pig heart simulated large myocardial infarction
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whether or not complicated by cardiogenic shock, and tested the effects of IABP counterpulsation in healthy state, pre-shock state, and shock state, with and without superimposed myocardial ischemia.11 These experiments showed a strong increase by IABP of coronary flow (up to 50%), cardiac output (up to 20%) and myocardial oxygen utilisation
& 6).
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(up to 25%) in large myocardial infarction, cardiogenic shock and ongoing ischemia (Figure 5
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Statistical Limitations of prospective randomized IABP trials In both the CRISP AMI and IABP-SHOCK II trials, there was a large percentage of cross-
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over from control group to IABP group. One can wonder why the treating physician in such open trials decides for cross-over from the control group to the IABP group, and in which patients this happens. It is likely that the patients in whom cross-over occurred, were those in the worst condition, i.e. at highest risk for events. This cross-over also occurs in other large randomized open studies in critically ill patients in Intensive Care Units (like the use of steroids in septic shock), and is almost inevitable in patients randomized to the control group (“back-against-the-wall”-situations), but it hampers correct interpretation of data. It is impossible to fully comprehend the effect of such a high asymmetrical cross-over on trial results, but it should be clearly recognized that this high asymmetrical cross-over in an
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ACCEPTED MANUSCRIPT open trial is prohibitive for an intention-to-treat analysis. Any possible positive effect of a study drug or device will automatically be masked when the worst patients in the control group are subject to cross-over and receive the device, in this case IABP. In an attempt to avoid such bias, the authors of the IABP-SHOCK II trial also perfomed a
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per-protocol analysis and as-treated analysis. However, in a per-protocol analysis, the crossover patients (i.e. those at highest risk) are excluded for analysis and the control group is most likely in more healthy baseline condition in comparison with the IABP group. In addition, when using an as-treated analysis, all cross-over patients are included in the IABP group,
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thereby creating a less healthy IABP group at baseline. Absence of a difference in such
analyses, in 2 groups with different characteristics, cannot exclude effectiveness of the study
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device.
Thus, conclusions from such open randomized trials in critically ill patients with a high and asymmetrical cross-over rate remain controversial.
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Recent Guidelines, Recommendations & Conclusions
The intra-aortic balloon pump is a therapeutic device advocated to be used in critically ill patients with cardiogenic shock or myocardial infarction. After 40 years, despite clear
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improvement in individual patients, there are still extensive discussions about its potential benefits. Most likely, it is too good to simply abandon, but not good enough to recommend
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without restrictions in patients with cardiogenic shock or myocardial infarction in general. A key issue in this respect is the better understanding of the underlying physiological principles, and more specifically the role of coronary autoregulation, which was insufficiently recognized and investigated until recently. Recent guidelines by the European Society of Cardiology (ESC) downgraded routine use of IABP in patients with cardiogenic shock (Class of Recommendation III, Level of Evidence A).39 Undoubtedly, routine use of IABP in cardiogenic shock without ischemia is not indicated. In such patients, hemodynamic support using flow-driven support devices like Impella or
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ACCEPTED MANUSCRIPT LVAD is more effective.40 Similarly, IABP is not indicated as a routine device in STEMI, as learned from the CRISP AMI trial. However, in subgroup analysis of this trial based upon recent pathophysiologic insights from experimental and human studies, a decrease of mortality by IABP and improved outcome was observed. Especially in case of patients with
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persistent ischemia and large myocardial infarction (whether or not complicated by cardiogenic shock), there are arguments for the effectiveness of IABP to reduce ischemia, leading to salvage of myocardium, decreased mortality and improved long-term outcome. The key message of this discussion is that in selecting patients who might benefit from
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IABP therapy, a more tailored and patient-specific approach is paramount. Presence of
ischemia, whether in high-risk PCI, acute myocardial infarction, or cardiogenic shock, seems
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to be the key factor in selecting patients who might benefit from IABP therapy. The rationale for effective IABP therapy is the trinity of exhausted autoregulation, persistent ischemia, and still viable myocardium. We should be careful not to throw out the baby with the bathwater.
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Funding Sources
This work was supported by the Dutch Technology Foundation STW (Stichting voor de
Disclosures
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Technische Wetenschappen) under project number 11052.
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Lokien X. van Nunen received reimbursement for travel expenses and speaker fees from Maquet. Marko Noc received speaker fees from Maquet, Astra Zeneca, Ely Lilly and Krka, and is on the advisory board for Zoll. Navin Kapur received institutional research funding from Abiomed, Cardiac Assist, and Maquet, and received speaker fees from Abiomed, Cardiac Assist, Maquet, Thoratec, and Heartware. Manesh R. Patel received institutional research funding and reimbursement for travel expenses from Maquet. Divaka Perera received institutional research funding from Maquet. Nico H.J. Pijls received institutional research funding, reimbursements for travel expenses and speaker fees from Maquet.
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randomized trial. JAMA 2011;306:1329-1337. 28. Schröder K, Wegscheider K, Zeymer U, Tebbe U, Schröder R. Extent of ST-segment
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deviation in a single electrocardiogram lead 90 min after thrombolysis as a predictor of medium-term mortality in acute myocardial infarction. Lancet 2001;358:1479-1486. 29. van Nunen LX, van 't Veer M, Schampaert S, Rutten MC, van de Vosse FN, Patel MR, Pijls NH. Intra-aortic balloon counterpulsation reduces mortality in large anterior myocardial infarction complicated by persistent ischaemia: a CRISP-AMI substudy. EuroIntervention 2015;11:286-292. 30. Engblom H, Hedström E, Heiberg E, Wagner GS, Pahlm O, Arheden H. Rapid initial reduction of hyperenhanced myocardium after reperfused first myocardial infarction
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ACCEPTED MANUSCRIPT suggests recovery of the peri-infarction zone: one-year follow-up by MRI. Circ Cardiovasc Imaging 2009;2:47-55. 31. Limalanathan S, Eritsland J, Andersen GØ, Kløw NE, Abdelnoor M, Hoffmann P. Myocardial salvage is reduced in primary PCI-treated STEMI patients with
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microvascular obstruction, demonstrated by early and late CMR. PLoS One 2013;8:e71780.
32. Hochman JS, Sleeper LA, Webb JG, Dzavik V, Buller CE, Aylward P, Col J, White HD.
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myocardial infarction. JAMA 2006;295:2511-2515.
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Early revascularization and long-term survival in cardiogenic shock complicating acute
33. Thiele H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J, Richardt G, Hennersdorf M, Empen K, Fuernau G, Desch S, Eitel I, Hambrecht R, Fuhrmann J, Bohm M, Ebelt H, Schneider S, Schuler G, Werdan K. Intraaortic balloon support for
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myocardial infarction with cardiogenic shock. N Engl J Med 2012;367:1287-1296. 34. Sanborn TA, Sleeper LA, Bates ER, Jacobs AK, Boland J, French JK, Dens J, Dzavik V, Palmeri ST, Webb JG, Goldberger M, Hochman JS. Impact of thrombolysis, intra-
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aortic balloon pump counterpulsation, and their combination in cardiogenic shock complicating acute myocardial infarction: a report from the SHOCK Trial Registry.
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SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK? J Am Coll Cardiol 2000;36:1123-1129. 35. Ohman EM, Nanas J, Stomel RJ, Leesar MA, Nielsen DW, O'Dea D, Rogers FJ, Harber D, Hudson MP, Fraulo E, Shaw LK, Lee KL. Thrombolysis and counterpulsation to improve survival in myocardial infarction complicated by hypotension and suspected cardiogenic shock or heart failure: results of the TACTICS Trial. J Thromb Thrombolysis 2005;19:33-39.
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ACCEPTED MANUSCRIPT 36. Vis MM, Sjauw KD, van der Schaaf RJ, Baan J Jr, Koch KT, DeVries JH, Tijssen JG, de Winter RJ, Piek JJ, Henriques JP. In patients with ST-segment elevation myocardial infarction with cardiogenic shock treated with percutaneous coronary intervention, admission glucose level is a strong independent predictor for 1-year mortality in
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patients without a prior diagnosis of diabetes. Am Heart J 2007;154:1184-1190. 37. Zeymer U, Bauer T, Hamm C, Zahn R, Weidinger F, Seabra-Gomes R, Hochadel M, Marco J, Gitt A. Use and impact of intra-aortic balloon pump on mortality in patients
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with acute myocardial infarction complicated by cardiogenic shock: results of the Euro Heart Survey on PCI. EuroIntervention 2011;7:437-441.
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38. Thiele H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J, de Waha A, Richardt G, Hennersdorf M, Empen K, Fuernau G, Desch S, Eitel I, Hambrecht R, Lauer B, Böhm M, Ebelt H, Schneider S, Werdan K, Schuler G. Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock
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(IABP-SHOCK II): final 12 month results of a randomised, open-label trial. Lancet 2013;382:1638-1645.
39. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C,
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Head SJ, Jüni P, Kappetein AP, Kastrati A, Knuuti J, Landmesser U, Laufer G, Neumann FJ, Richter DJ, Schauerte P, Sousa Uva M, Stefanini GG, Taggart DP,
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Torracca L, Valgimigli M, Wijns W, Witkowski A. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for CardioThoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541-2619. 40. Cheng JM, den Uil CA, Hoeks SE, van der Ent M, Jewbali LS, van Domburg RT, Serruys PW. Percutaneous left ventricular assist devices vs. intra-aortic balloon pump
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ACCEPTED MANUSCRIPT counterpulsation for treatment of cardiogenic shock: a meta-analysis of controlled trials. Eur Heart J 2009;30:2102-2108. 41. Myat A, McConkey H, Chick L, Baker J, Redwood S. The intra-aortic balloon pump in high-risk percutaneous coronary intervention: is counterpulsation counterproductive?
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ACCEPTED MANUSCRIPT Figures Figure 1. Hemodynamic effects of intra-aortic balloon pump counterpulsation Waveform of an unassisted and assisted heartbeat. After the aortic valve closes, the IABP inflates, increasing the diastolic pressure. Before systole, the balloon deflates, resulting in
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lower end diastolic pressure, reflecting afterload for the left ventricle. Reprinted from Myat et al with permission.41
Figure 2. Long-term outcome of BCIS-1
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Panel A shows the Kaplan Meier curves of patients treated with and without elective IABP support in the BCIS-1 trial, with 42 deaths in the elective IABP group versus 58 deaths in the
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control group (hazard ratio 0.66; 95% CI, 0.44-0.98; P=0.039). Panel B shows the hazard ratios at different lengths of follow-up, showing a consistent hazard ratio over time. CI indicates confidence interval; HR, hazard ratio; IABP, intra-aortic balloon pump.
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Reprinted from Perera et al. with permission.20
Figure 3. All-cause mortality at six months in different (sub)-populations of the CRISP AMI trial
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All-cause mortality rates at 6 months in all patients receiving IABP as adjunct to PCI (blue line) or PCI alone (red line) in the CRISP AMI population (3 deaths versus 9 deaths; log-rank
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P=0.12; panel A); in patients with large myocardial infarction (1 deaths versus 6 deaths; logrank P=0.10; panel B); in patients with large myocardial infarction complicated by persistent ischemia (0 deaths versus 5 deaths; log-rank P=0.046; Panel C). IABP indicates intra-aortic balloon pump; PCI, percutaneous coronary intervention; ST-D, ST-deviation; ST-R, STresolution. Reprinted from EuroIntervention 2015, van Nunen LX et al, Intra-aortic balloon counterpulsation reduces mortality in large anterior myocardial infarction complicated by persistent ischaemia: a CRISP-AMI substudy, 2015;11:286-292, with permission from Europa Digital & Publishing.29
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Figure 4. One-year all-cause mortality of the IABP-SHOCK II Trial One-year follow-up of the IABP-SHOCK II Trial. IABP indicates intra-aortic balloon pump.
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Reprinted from Thiele et al. with permission.38
Figure 5. Effect of IABP on hemodynamic parameters in the isolated beating pig heart
Effect of IABP on hemodynamic parameters in a beating pig heart in pre-shock. Without ischemia (left part of the figure), cardiac output equals 4.6 L min-1 (red dot), blood pressure
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equals 76 mmHg (black dot), left atrial pressure equals 16 mmHg (blue dot), and coronary blood flow equals 1.2 L min-1 (green dot). Hereafter, additional global ischemia is slowly
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created by decreasing arterial oxygen saturation in the extracorporeal circulation. This is accompanied by a slow decrease of cardiac output, coronary blood flow, and blood pressure and an increase in left atrial pressure. At a particular point in time (called t = 0 min), the downward spiral is accelerated and progressive deterioration occurs. Next, without any
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change in external oxygen supply or any of the other controllable parameters, the IABP is switched on (t ≈ 5 min) and within two minutes, a significant improvement of cardiac output, coronary blood flow and blood pressure occurs, while left atrial pressure decreases
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dramatically. All parameters stabilize within a few minutes. At t ≈ 10 min, the IABP is switched off again without any change in any of the controllable parameters, whereafter the
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heart rapidly deteriorates and enters the negative vicious circle again. By switching on the IABP (t ≈ 15 min), significant improvement and stabilization occurs again. Reprinted from Schampaert et al. with permission.11
Figure 6. Effect of IABP on coronary blood flow, cardiac output and myocardial oxygen consumption in 12 beating pig hearts Mean change (± standard error) by IABP support compared to the status without IABP of coronary blood flow (panel A), cardiac output (panel B), and myocardial oxygen consumption
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S0002-9149(15)02255-9
DOI:
10.1016/j.amjcard.2015.10.063
Reference:
AJC 21531
To appear in:
The American Journal of Cardiology
Received Date: 14 September 2015 Revised Date:
30 October 2015
Accepted Date: 30 October 2015
Please cite this article as: van Nunen LX, Noc M, Kapur NK, Patel MR, Perera D, Pijls NHJ, Usefulness of Intra-aortic Balloon Pump Counterpulsation, The American Journal of Cardiology (2015), doi: 10.1016/ j.amjcard.2015.10.063. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Usefulness of Intra-aortic Balloon Pump Counterpulsation Lokien X. van Nunen MDa, Marko Noc MD PhDb, Navin K. Kapur MDc, Manesh R. Patel MDd, Divaka Perera MDe, Nico H.J. Pijls MD PhDa
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a. Department of Cardiology, Catharina Hospital Eindhoven, Eindhoven, The Netherlands b. Center for Intensive Internal Medicine, University Medical Center, Ljubljana, Slovenia c. The Cardiovascular Center, Tufts Medical Center, Boston, USA
d. Division of Cardiology, Department of Medicine, Duke Clinical Research Institute, Duke
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University Medical Center, Durham, USA
e. Cardiovascular Division, British Heart Foundation Centre of Research Excellence, Kings
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College London, St Thomas’ Hospital, Westminster Bridge Road, London, UK
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Running head: IABP
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Corresponding Author:
Nico H.J. Pijls, Professor of Cardiology Catharina Hospital Eindhoven, Department of Cardiology Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands Email: [email protected] Telephone: +31 40 2397004 Fax: +31 40 2447885
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ACCEPTED MANUSCRIPT Abstract Intra-aortic balloon pump counterpulsation (IABP) is the most widely used mechanical circulatory support device due to its ease of use, low complication rate, and fast manner of insertion. Its benefit is still subject of debate and a considerable gap exists between
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guidelines and clinical practice. Retrospective non-randomized studies and animal experiments show benefits of IABP therapy. However, recent large randomized trials do not show benefit of IABP therapy, which has led to a downgrading in the guidelines. In our view, this dichotomy between trials and practice might be the result of insufficient understanding of
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the prerequisites needed for effective IABP therapy, i.e. exhausted autoregulation, and of not including the right patient population in trials. The population included in recent large
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randomized trials has been heterogenous, also including patients in whom benefit of IABP could not be expected. The clinical condition in which most benefit is expected, i.e. persistent ischemia in acute ST-elevation myocardial infarction, is discussed in this review. In conclusion, this review aims to explain the physiologic principles needed for effective IABP
controversies in this field.
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Keywords
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therapy, to reflect critically on the large randomized trials, and to solve some of the
Intra-aortic balloon pump counterpulsation, coronary autoregulation, high-risk percutaneous
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coronary intervention, acute myocardial infarction, cardiogenic shock
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ACCEPTED MANUSCRIPT Introduction Appropriate use of intra-aortic balloon pump counterpulsation has been subject to heavy debate over the past years.1-4 Use of IABP is generally confined to three groups of patients, i.e. high-risk percutaneous coronary intervention (PCI), acute myocardial infarction, and
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cardiogenic shock. There have been large randomized trials for all three indications, which will be discussed below. However, before analyzing these trials in detail, it is mandatory to better understand the presumed physiologic principles of IABP counterpulsation and the
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prerequisites needed for adequate effect (or absence of effect) of IABP.
Physiologic principles and the role of coronary autoregulation
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The intra-aortic balloon pump (IABP), positioned in the descending thoracic aorta through the femoral artery, inflates and deflates in synchrony with the cardiac cycle. By inflating in the diastolic phase of the cardiac cycle, the diastolic aortic pressure is augmented, resulting in higher coronary perfusion pressure (Figure 1). This could theoretically lead to improved
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coronary blood flow and thereby increase of myocardial oxygen supply.5,6 Early in systole, the balloon rapidly deflates, reducing the afterload of the left ventricle (Figure 1). In turn, this is thought to decrease myocardial workload and oxygen demand.7
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However, the supposed direct mechanical effect of counterpulsation on coronary blood flow can be easily undone by the reactive vasoconstriction of the coronary and myocardial bed,
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known as coronary autoregulation. Under normal physiologic circumstances, sphincters at the entrance of coronary arterioles constrict or dilate in response to coronary perfusion pressure, thereby guaranteeing constant myocardial blood flow over a wide range of aortic pressures (60-140 mmHg).8 Therefore, in physiologic conditions with intact coronary autoregulation, myocardial blood flow is not dependent on perfusion pressure and it is illusionary to expect increased coronary blood flow due to higher perfusion pressure by IABP counterpulsation. Thus, improved coronary blood flow by IABP can only be expected in situations with exhausted autoregulation.
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ACCEPTED MANUSCRIPT Recently, De Silva et al. performed intracoronary flow and pressure measurements during IABP counterpulsation with “switched on” and “switched off” coronary autoregulation using intravenous adenosine infusion for minimizing coronary vascular resistance.9 The authors showed that the effect of IABP on coronary flow is directly dependent on coronary
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autoregulation. With intact autoregulation, balloon pump augmentation did lead to an increase in coronary pressure, but also to a reactive increase in microvascular resistance, and as a result unchanged coronary blood flow. On the other hand, with “switched off”
autoregulation, the balloon pump augmentation led to an increase in distal coronary pressure
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and coronary blood flow, while the microvascular resistance remained unchanged. Also in recent studies performed in the isolated beating pig heart, it was documented that with
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exhausted autoregulation, a linear relationship between diastolic aortic pressure and coronary blood flow is present and that IABP increases coronary blood flow by up to 50% in the presence of pump failure due to ongoing myocardial ischemia.10,11 In short, only when autoregulation is exhausted, coronary blood flow is directly dependent
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on perfusion pressure, and effects of IABP on coronary blood flow can be expected. This is the case in the following clinical situations: 1) in the perfusion territory of a critical, subtotal stenosis; 2) in ischemic myocardium, including “stunning” after myocardial infarction or
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during weaning from extracorporeal circulation; and 3) in patients with low mean aortic pressures outside the autoregulatory range (< 60 mmHg).
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The importance of autoregulation when assessing the effect of IABP was not fully understood nor investigated until recently and is not reflected in the inclusion criteria in the large randomized clinical trials, including acute myocardial infarction and cardiogenic shock.
High-risk percutaneous coronary intervention IABP is often used as circulatory support system to prevent major complications during high-risk PCI.12 Patients with severe left ventricular dysfunction undergoing PCI are at higher risk of morbidity and mortality.13,14 This risk increases when the target lesion is supplying a substantial proportion of the myocardium. By inducing ischemia during PCI, left ventricular
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ACCEPTED MANUSCRIPT function will further deteriorate, and patients are at risk of entering a downwards spiral of myocardial ischemia, hemodynamic compromise, cardiogenic shock, and ultimately death. Especially if a subtotal stenosis is present in a large contralateral coronary artery, secondary ischemia of the contralateral myocardial territory due to compensatory hyperkinesia might
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induce a downwards spiral with deleterious outcome. Until 2010, evidence supporting use of IABP in such patients consisted of several
retrospective observational and small randomized studies.15-18 The Balloon Pump-Assisted Coronary Intervention Study (BCIS-1) randomized 301 patients scheduled to undergo high-
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risk single-vessel or multivessel PCI to either IABP insertion prior to PCI or no planned IABP insertion.19 Based on the predicted and actual event rates, the study was adequately
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powered. Outcome at hospital discharge was similar between the two groups, without significant differences in myocardial infarction, death, cerebrovascular accident or further revascularization. In the control group, 12% of the patients needed rescue IABP insertion due to intraprocedural complications, mainly hypotension. Six-month mortality was 4.6% in
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the IABP group and 7.4% in the control group (P=0.32). Although not statistically significant at first, this relative risk reduction of 38% remained constant over time, resulting in a significant benefit in favour of IABP over long-term follow-up, with a hazard ratio of 0.66 (95%
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CI, 0.44-0.98; P=0.039).20 This consistent relative risk reduction by one third is of huge impact in a patient population in which one out of every three patients died within the long-
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term follow-up period (Figure 2). The constant hazard ratio during follow-up implies that this is attributable to an early treatment effect, i.e. IABP insertion before PCI. There were no other detectable procedural differences between the two groups in terms of number of vessels treated, success rate, and proportion of left main or proximal left anterior descending coronary arteries stented. Explanation of this difference in outcome could be the reduction of ischemia by IABP during high-risk PCI, and the prevention of intraprocedural complications. Effects of IABP on coronary blood flow is not undone by coronary autoregulation in these patients, since autoregulation is completely exhausted in the coronary tree distal to a significant stenosis
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ACCEPTED MANUSCRIPT and in the presence of ischemic myocardium during and shortly after balloon inflation. Even small periprocedural myocardial infarctions, only measured by elevated troponin-levels, have shown to affect outcome in cardiac patients.21 In patients with severe ischemic cardiomyopathy as included in BCIS-1, this effect might be more pronounced, causing this
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significant difference in long-term outcome. It is well conceivable that better protection of the myocardium during the procedure itself will result in a decrease in mortality in the long term, explaining the late results of BCIS-1.
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Acute myocardial infarction
Primary PCI in patients presenting with ST-segment elevation myocardial infarction
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(STEMI) has resulted in an impressive improvement in outcome.22 During the last decade, however, despite optimizing time intervals, outcome has not further improved. This may be ascribed to “reperfusion injury”, “no-reflow”, or “persistent ischemia”, which occurs in up to 30% of the patients and is caused by a variety of factors including micro-embolisation of
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atherothrombotic debris, vasospasm, and external compression of the capillaries due to intramyocardial edema, hemorrhage and other factors, suppressing adequate myocardial perfusion after successful epicardial stenting.23 In such patients, this “ongoing” or “persistent”
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ischemia leads to reduced salvage of myocardium, even if the occluded epicardial coronary artery has been opened successfully by primary PCI.
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Animal experiments have shown that IABP is effective in reducing no-reflow, improves myocardial salvage, and decreases infarct size.24,25 A clinical registry in nearly 1500 consecutive patients showed prophylactic insertion of IABP to be associated with fewer events in all high-risk patients presenting with acute myocardial infarction.26 The Counterpulsation to Reduce Infarct Size Pre-PCI Acute Myocardial Infarction (CRISP AMI) trial sought to determine if routine IABP therapy prior to primary PCI in patients with anterior STEMI without shock reduces infarct size as assessed on cardiac magnetic resonance imaging (CMR), and randomized 337 patients.27 The study was designed and powered to detect a 25% reduction in infarct size in the IABP group. Final infarct size as
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ACCEPTED MANUSCRIPT assessed by CMR after 3-5 days showed no difference and a trend towards larger infarctions in the IABP group (42.1% versus 37.5%, P=0.06). All-cause mortality at 6 months occurred less frequent in the IABP group, although not statistically significant (2% versus 5%, P=0.12). The exploratory composite end point of death, shock, or new or worsening heart failure did
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reach statistical significance in favour of the IABP group (5% versus 12%, P=0.03). So, in CRISP AMI, the primary end point was not achieved and some confusion originated with respect to other end points.
However, 40% of the population in CRISP AMI had summed ST-elevation <6mm,
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representing a cohort of patients with relatively small infarctions with a good prognosis
anyway, whether or not treated with IABP or any other additional therapy.28 It is unlikely that
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in these patients, any of the pre-defined end points like death or congestive heart failure would be reached anyway, irrespective if and how they were treated. This is corroborated by the systolic and diastolic blood pressure and heart rate of the study population, not suggesting a very sick trial population. Inclusion of these patients most likely diluted a
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possible effect of IABP insertion by underpowering the study. A recent substudy of CRISP AMI in patients with large myocardial infarction (summed ST-deviation ≥15mm) and persistent ischemia (ST-resolution after PCI < 50%) showed a significant reduction in
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mortality despite a much smaller patient population (Figure 3).29 Furthermore, in CRISP AMI there was a considerable and asymmetrical cross-over from
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control group to IABP group (8%), due to sustained hypotension or cardiogenic shock, failed PCI, or continued chest pain. The impact of this asymmetrical cross-over will be discussed later in this paper.
Finally, the primary end point was infarct size as assessed at 3-5 days using CMR. Using CMR in a patient population with the highest event rate in the first days, will automatically create bias because patients (mainly without IABP) who died in the first days or were too unstable to undergo CMR, are not included in this analysis of infarct size.
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ACCEPTED MANUSCRIPT More in general, it is questionable if CMR 3-5 days after acute myocardial infarction is a reliable method to predict the ultimate infarct size and ejection fraction. Considerable further recovery is reported by consecutive CMR examinations at later follow-up.30,31 Overall, use of IABP is not indicated routinely in acute myocardial infarction. Especially in
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patients with relatively small infarctions or fast successful reperfusion, reflected by complete ST-resolution, there is no effect to be expected by IABP counterpulsation. However, in
patients with large myocardial infarction complicated by persistent ischemia (ongoing pain or insufficient ST-resolution), a significant decrease of mortality was observed, which fits with
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the pathophysiological considerations mentioned above. This decrease of outcome was observed in a substudy, with all its limitations. Therefore, a prospective randomized
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controlled trial in such patients has been started recently to investigate this standpoint (SEMPER FI study: Survival in patients with Extensive Myocardial infarction complicated by PERsistent ischemia Following IABP insertion; NCT02125526).
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Cardiogenic shock
Treatment of cardiogenic shock complicating acute myocardial infarction remains a challenge with persisting high mortality rates.32,33 Pharmacological therapy often fails to
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stabilize the patient in cardiogenic shock, and carries the additional risk of increasing myocardial ischemia due to increased myocardial oxygen demand. This is the reason why
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physicians attempted to improve treatment of these patients by the use of mechanical circulatory support devices, one of them being the intra-aortic balloon pump. Most trials with favourable results regarding IABP use in acute myocardial infarction complicated by cardiogenic shock were performed in the thrombolytic era.34,35 Registries and retrospective studies in the era of primary PCI showed no difference in outcome by the use of IABP.36,37 The IABP-SHOCK II trial prospectively randomized 600 patients with acute myocardial infarction (with or without ST-segment elevation) complicated by cardiogenic shock to primary PCI with adjunctive IABP support or PCI alone.33 This landmark study
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ACCEPTED MANUSCRIPT showed no reduction in short-term and long-term mortality (30-day mortality 39.7% versus 41.3%; 1-year mortality 52% versus 51%, respectively) (Figure 4).38 Strengths and limitations of this landmark trial have been discussed extensively. It is the largest randomized trial performed in patients with cardiogenic shock, including 600 patients
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in 32 months, and with a very high percentage of follow-up (1-year follow-up completed in 99.2%). Apart from the fact that the study was underpowered due to a lower event rate in the control group than anticipated, several other important limitations were present in this study, questioning its conclusions.
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First, there was a large asymmetrical crossover from control group to the IABP group and an increase in the use of left ventricular assist devices in the control group of together 17.4%
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of the patients not randomized to IABP. The impact of this high and asymmetrical cross-over on statistical analysis and conclusions of the study will be discussed further on. Second, almost half of the patients randomized were resuscitated before PCI and almost 40% received induced hypothermia after PCI. Outcome in these patients is poor irrespective
salvage by IABP.
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of the use of IABP and primarily dependent on neurologic recovery rather than myocardial
Finally, the time-windows in these patients were very wide; patients could be included up
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to 12 hours after onset of cardiogenic shock. If a patient with acute myocardial infarction complicated by cardiogenic shock presents too late (i.e. there is no persisting ischemia,
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neither viable myocardium in the infarcted area anymore), no salvage of myocardium leading to a better prognosis can be expected anyway. In such patients, in the best case, IABP therapy will lead to temporary relieve and stabilization of hemodynamics. Volume pumps are more effective to increase output in such patients, but these effects are temporary as well and will disappear as soon as the device is removed. Although IABP-SHOCK II definitely questions the routine use of IABP in patients presenting with acute myocardial infarction complicated by cardiogenic shock, these limitations exemplify the difficulties in interpreting randomized open trials involving very sick patients. The question is if outcome would be different by including a more specific group of
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ACCEPTED MANUSCRIPT STEMI patients, rather than a heterogenous group of patients with respect to presence of persistent ischemia, time-intervals, concomitant neurologic deficits, and the use of or crossover to additional mechanical support strategies. Cardiogenic shock should not be seen as a yes-or-no phenomenon like cardiac arrest, but
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rather as a very heterogenous condition which requires a tailored treatment. By solely including the patients presenting with STEMI complicated by cardiogenic shock with still viable myocardium and persistent ischemia as reflected by ongoing chest pain and persisting ST-deviation, and by excluding resuscitated patients, IABP therapy could be expected to be
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more effective based on pathophysiological grounds, as discussed here above.
A recent study in the isolated beating pig heart simulated large myocardial infarction
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whether or not complicated by cardiogenic shock, and tested the effects of IABP counterpulsation in healthy state, pre-shock state, and shock state, with and without superimposed myocardial ischemia.11 These experiments showed a strong increase by IABP of coronary flow (up to 50%), cardiac output (up to 20%) and myocardial oxygen utilisation
& 6).
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(up to 25%) in large myocardial infarction, cardiogenic shock and ongoing ischemia (Figure 5
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Statistical Limitations of prospective randomized IABP trials In both the CRISP AMI and IABP-SHOCK II trials, there was a large percentage of cross-
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over from control group to IABP group. One can wonder why the treating physician in such open trials decides for cross-over from the control group to the IABP group, and in which patients this happens. It is likely that the patients in whom cross-over occurred, were those in the worst condition, i.e. at highest risk for events. This cross-over also occurs in other large randomized open studies in critically ill patients in Intensive Care Units (like the use of steroids in septic shock), and is almost inevitable in patients randomized to the control group (“back-against-the-wall”-situations), but it hampers correct interpretation of data. It is impossible to fully comprehend the effect of such a high asymmetrical cross-over on trial results, but it should be clearly recognized that this high asymmetrical cross-over in an
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ACCEPTED MANUSCRIPT open trial is prohibitive for an intention-to-treat analysis. Any possible positive effect of a study drug or device will automatically be masked when the worst patients in the control group are subject to cross-over and receive the device, in this case IABP. In an attempt to avoid such bias, the authors of the IABP-SHOCK II trial also perfomed a
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per-protocol analysis and as-treated analysis. However, in a per-protocol analysis, the crossover patients (i.e. those at highest risk) are excluded for analysis and the control group is most likely in more healthy baseline condition in comparison with the IABP group. In addition, when using an as-treated analysis, all cross-over patients are included in the IABP group,
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thereby creating a less healthy IABP group at baseline. Absence of a difference in such
analyses, in 2 groups with different characteristics, cannot exclude effectiveness of the study
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device.
Thus, conclusions from such open randomized trials in critically ill patients with a high and asymmetrical cross-over rate remain controversial.
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Recent Guidelines, Recommendations & Conclusions
The intra-aortic balloon pump is a therapeutic device advocated to be used in critically ill patients with cardiogenic shock or myocardial infarction. After 40 years, despite clear
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improvement in individual patients, there are still extensive discussions about its potential benefits. Most likely, it is too good to simply abandon, but not good enough to recommend
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without restrictions in patients with cardiogenic shock or myocardial infarction in general. A key issue in this respect is the better understanding of the underlying physiological principles, and more specifically the role of coronary autoregulation, which was insufficiently recognized and investigated until recently. Recent guidelines by the European Society of Cardiology (ESC) downgraded routine use of IABP in patients with cardiogenic shock (Class of Recommendation III, Level of Evidence A).39 Undoubtedly, routine use of IABP in cardiogenic shock without ischemia is not indicated. In such patients, hemodynamic support using flow-driven support devices like Impella or
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ACCEPTED MANUSCRIPT LVAD is more effective.40 Similarly, IABP is not indicated as a routine device in STEMI, as learned from the CRISP AMI trial. However, in subgroup analysis of this trial based upon recent pathophysiologic insights from experimental and human studies, a decrease of mortality by IABP and improved outcome was observed. Especially in case of patients with
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persistent ischemia and large myocardial infarction (whether or not complicated by cardiogenic shock), there are arguments for the effectiveness of IABP to reduce ischemia, leading to salvage of myocardium, decreased mortality and improved long-term outcome. The key message of this discussion is that in selecting patients who might benefit from
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IABP therapy, a more tailored and patient-specific approach is paramount. Presence of
ischemia, whether in high-risk PCI, acute myocardial infarction, or cardiogenic shock, seems
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to be the key factor in selecting patients who might benefit from IABP therapy. The rationale for effective IABP therapy is the trinity of exhausted autoregulation, persistent ischemia, and still viable myocardium. We should be careful not to throw out the baby with the bathwater.
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Funding Sources
This work was supported by the Dutch Technology Foundation STW (Stichting voor de
Disclosures
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Technische Wetenschappen) under project number 11052.
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Lokien X. van Nunen received reimbursement for travel expenses and speaker fees from Maquet. Marko Noc received speaker fees from Maquet, Astra Zeneca, Ely Lilly and Krka, and is on the advisory board for Zoll. Navin Kapur received institutional research funding from Abiomed, Cardiac Assist, and Maquet, and received speaker fees from Abiomed, Cardiac Assist, Maquet, Thoratec, and Heartware. Manesh R. Patel received institutional research funding and reimbursement for travel expenses from Maquet. Divaka Perera received institutional research funding from Maquet. Nico H.J. Pijls received institutional research funding, reimbursements for travel expenses and speaker fees from Maquet.
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ACCEPTED MANUSCRIPT Figures Figure 1. Hemodynamic effects of intra-aortic balloon pump counterpulsation Waveform of an unassisted and assisted heartbeat. After the aortic valve closes, the IABP inflates, increasing the diastolic pressure. Before systole, the balloon deflates, resulting in
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lower end diastolic pressure, reflecting afterload for the left ventricle. Reprinted from Myat et al with permission.41
Figure 2. Long-term outcome of BCIS-1
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Panel A shows the Kaplan Meier curves of patients treated with and without elective IABP support in the BCIS-1 trial, with 42 deaths in the elective IABP group versus 58 deaths in the
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control group (hazard ratio 0.66; 95% CI, 0.44-0.98; P=0.039). Panel B shows the hazard ratios at different lengths of follow-up, showing a consistent hazard ratio over time. CI indicates confidence interval; HR, hazard ratio; IABP, intra-aortic balloon pump.
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Reprinted from Perera et al. with permission.20
Figure 3. All-cause mortality at six months in different (sub)-populations of the CRISP AMI trial
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All-cause mortality rates at 6 months in all patients receiving IABP as adjunct to PCI (blue line) or PCI alone (red line) in the CRISP AMI population (3 deaths versus 9 deaths; log-rank
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P=0.12; panel A); in patients with large myocardial infarction (1 deaths versus 6 deaths; logrank P=0.10; panel B); in patients with large myocardial infarction complicated by persistent ischemia (0 deaths versus 5 deaths; log-rank P=0.046; Panel C). IABP indicates intra-aortic balloon pump; PCI, percutaneous coronary intervention; ST-D, ST-deviation; ST-R, STresolution. Reprinted from EuroIntervention 2015, van Nunen LX et al, Intra-aortic balloon counterpulsation reduces mortality in large anterior myocardial infarction complicated by persistent ischaemia: a CRISP-AMI substudy, 2015;11:286-292, with permission from Europa Digital & Publishing.29
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Figure 4. One-year all-cause mortality of the IABP-SHOCK II Trial One-year follow-up of the IABP-SHOCK II Trial. IABP indicates intra-aortic balloon pump.
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Reprinted from Thiele et al. with permission.38
Figure 5. Effect of IABP on hemodynamic parameters in the isolated beating pig heart
Effect of IABP on hemodynamic parameters in a beating pig heart in pre-shock. Without ischemia (left part of the figure), cardiac output equals 4.6 L min-1 (red dot), blood pressure
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equals 76 mmHg (black dot), left atrial pressure equals 16 mmHg (blue dot), and coronary blood flow equals 1.2 L min-1 (green dot). Hereafter, additional global ischemia is slowly
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created by decreasing arterial oxygen saturation in the extracorporeal circulation. This is accompanied by a slow decrease of cardiac output, coronary blood flow, and blood pressure and an increase in left atrial pressure. At a particular point in time (called t = 0 min), the downward spiral is accelerated and progressive deterioration occurs. Next, without any
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change in external oxygen supply or any of the other controllable parameters, the IABP is switched on (t ≈ 5 min) and within two minutes, a significant improvement of cardiac output, coronary blood flow and blood pressure occurs, while left atrial pressure decreases
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dramatically. All parameters stabilize within a few minutes. At t ≈ 10 min, the IABP is switched off again without any change in any of the controllable parameters, whereafter the
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heart rapidly deteriorates and enters the negative vicious circle again. By switching on the IABP (t ≈ 15 min), significant improvement and stabilization occurs again. Reprinted from Schampaert et al. with permission.11
Figure 6. Effect of IABP on coronary blood flow, cardiac output and myocardial oxygen consumption in 12 beating pig hearts Mean change (± standard error) by IABP support compared to the status without IABP of coronary blood flow (panel A), cardiac output (panel B), and myocardial oxygen consumption
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