Thiele H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J, et al. Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock. N Engl J Med. 2012 Oct 4;367(14):1287–96.
Introduction
The concept of diastolic augmentation of coronary blood flow in patients with left ventricular failure arose in the 1950s. Animal experimenters attempted wrapping of the hemidiaphragm around the distal thoracic aorta with stimulation in diastole to provide counterpulsation (1). Following laboratory studies, early investigations employed a latex balloon at the tip of a small plastic catheter using carbon dioxide as the driving gas (2). The balloon inflated in diastole to augment coronary blood flow and deflated in systole thereby reducing left ventricular afterload. Early attempts at balloon augmentation were unsuccessful, probably because the relatively high viscosity of carbon dioxide resulted in slow transit through the tubing and delayed balloon filling.
Cardiogenic shock carried a mortality of more than 85% in those days, despite pharmacological support. The administration of vasopressors, including norepinephrine by continuous infusion, seemed to have little effect on mortality. In 1968, Kantrovitz and colleagues described their early experience with the “intra-aortic cardiac assistance” device in patients with cardiogenic shock following acute myocardial infarction (3). Their device consisted of a 60 cm long polytetrafluoroethylene tubing with a 14.8 cm long pumping chamber at the distal end. In contrast to earlier studies, they used helium as the driving gas; its low density enabled rapid transit through the tubing. The device was timed to inflate in diastole and deflate in systole by synchronizing with the ECG or the arterial pressure transducer. After many years of animal experimentation, the device was ready for clinical use.
On the early morning of June 29, 1967, a 45-year-old woman presented with acute myocardial infarction to the Maimonides Medical Center in Brooklyn, New York. She was clearly in distress, cold and blue, and had no palpable pulses. She was treated with digitalis, and infusions of norepinephrine and isoprenaline; however, after nearly 5 hours, she was in unrelenting shock. As her condition appeared hopeless, they commenced balloon pumping as a last resort. Within the first few hours, her blood pressures rose, the central venous pressure dropped, and urine started flowing. By 7 hours of pumping, she had turned the corner – the cyanosis had disappeared, and her extremities felt warm. She was off pharmacological support throughout the duration of pumping and remained stable after the removal of the device. Following this, her hospital stay was relatively uneventful, and she was discharged home. Similar encouraging results were observed in a 58-year-old man with acute myocardial infarction and cardiogenic shock. However, during a brief interruption of pumping to reposition the balloon, he developed refractory ventricular fibrillation that rendered the balloon ineffective (3).
Although initial results were encouraging, long years of disappointment followed; there were few survivors in these early case series. The intra-aortic balloon pump (IABP) seemed to be on the verge of quietly fading away into history. However, considering the apparent hemodynamic effects, sporadic use continued among patients with acute low-output syndromes.
More than five decades have passed since the first report of IABP. The management of acute myocardial infarction has witnessed a sea change in the meantime, with several watershed moments, including early revascularization by percutaneous coronary intervention (PCI), the introduction of novel therapeutic agents, and advancements in intensive care support. However, the mortality from cardiogenic shock continues to be high (4). Although the hunt for the holy grail of mechanical support continues, the IABP continues to remain the most used device in cardiogenic shock following acute myocardial infarction.
Background to the study
The earlier IABP-SHOCK trial had evaluated the efficacy of IABP combined with PCI in reducing the onset of multiorgan dysfunction syndrome in patients with cardiogenic shock following acute myocardial infarction. In a randomized controlled trial (RCT) conducted between 2003–2004, 45 consecutive patients were assigned to standard care combined with IABP or standard care alone. IABP support did not lead to a significant improvement in the multiorgan dysfunction syndrome over 4 days, based on the APACHE II scores. IABP use did not have any significant impact on the cardiac index or activation of systemic inflammation, based on plasma IL-6 levels (5). However, the study was limited by a small sample size and its single-center design. The question of any beneficial effect on mortality also remained unanswered. The recommendation for IABP use by the American and European guidelines were largely based on limited evidence from registry data. IABP use had also remained highly variable, ranging between 25–40% (6). Against this background, the IABP-SHOCK II Trial investigators proposed testing their hypothesis that the additional use of this support modality may reduce mortality among patients with acute myocardial infarction and cardiogenic shock compared with medical therapy alone (7).
Population and design
The IABP-SHOCK II trial was conducted between June 2009 to March 2012 across 37 centers in Germany. Patients who presented with acute myocardial infarction and cardiogenic shock and planned for early revascularization were eligible. Cardiogenic shock was defined as a systolic BP of <90 mm Hg for >30 minutes, or the requirement for catecholamines, with pulmonary congestion and impaired organ perfusion. The diagnosis of organ perfusion was based on one of the following features: altered sensorium, cold and clammy extremities, urine output of <30 ml/hour, or serum lactate levels >2 mmol/l. Patients were randomly assigned to receive IABP or standard care alone (control group).
Excluded
They study excluded patients older than 90 years, those who had undergone resuscitation for >30 min, had fixed dilated pupils, or developed a mechanical complication leading to shock, including ventricular septal defect or ruptured papillary muscle. Patients who were in shock for >12 hours, had severe peripheral vascular disease that prevented device insertion, severe aortic regurgitation, or were not expected to survive for >6 months were also excluded.
IABP group
Device insertion was carried out before or immediately after PCI based on clinician judgment. Support was commenced with 1:1 triggering and weaned down once the systolic BP remained >90 mm Hg for 30 minutes without catecholamine support.
Common management
Early revascularization was planned along with the most optimal medical management based on guidelines. The mode of revascularization – target lesion alone, or correction of other lesions, either at the same time or at a later stage, was at clinician discretion. The option for coronary artery bypass grafting was also left to clinician judgment.
Sample size
The study was powered to detect a difference of 12 percentage points in the 30-day survival, the primary endpoint, assuming 56% mortality in the control group. The type I error level was set at 0.05. The authors calculated a sample size of 282 patients in each group with two planned interim analysis after enrollment of 33% and 66% of the original sample size.
Results
Seven-hundred and ninety patients were screened over a 3-year period; 600 were included – 301 in the IABP group and 299 in the control group. Patients were well-matched at baseline. Similar number of patients in both groups underwent resuscitation and fibrinolysis before randomization. The baseline systolic BP and lactate levels were also similar. ST-elevation myocardial infarction occurred in 66.7% of patients in the IABP group compared with 71.1% in the control group. IABP was inserted in 30 patients who were randomized to the control group; 26 of these crossovers were protocol violations. Thirteen patients randomized to undergo IABP did not receive the intervention; most had died before the procedure could be carried out. Revascularization was by PCI in most patients (95.8%), while 3.5% underwent emergency coronary artery bypass surgery. In the final analysis, there were 300 patients in the IABP group and 298 in the control group.
The primary outcome: 30-day mortality
There was no significant difference in the primary outcome, the 30-day mortality, between the IABP and control groups. In the IABP group, 39.7% of patients died, compared with 41.3% in the control group (relative risk: 0.96; 95% CI, 0.79 to 1.17; P = 0.69). On per protocol analysis, the relative risk of mortality was similar.
The relative risk of mortality remained similar after multivariate modelling adjusting for variables including non-ST-elevation myocardial infarction, anterior wall myocardial infarction, resuscitation before randomization, and the study site. On subgroup analysis, there was no difference in the 30-day survival based on age, gender, history of hypertension, type of myocardial infarction, previous infarction, the presence of hypothermia, or systolic BP <80 mm Hg.
Secondary outcomes
Among the secondary outcomes, no significant difference was noted in the time to hemodynamic stabilization, ICU length of stay, the serum lactate levels, dose and duration of treatment with catecholamine infusions, and renal function between the two groups. The timing of IABP insertion – whether before or after revascularization did not affect outcomes. The incidence of reinfarction in hospital and stent thrombosis were also similar in both groups.
Overall, 33 patients (5.5%) received a ventricular assist device. More patients in the control group underwent insertion of a ventricular assist device. Mortality was higher among patients who received a ventricular assist device compared to those who did not.
Safety outcomes
Safety outcomes, including major bleeding, limb ischemia requiring intervention, stroke (ischemic or hemorrhagic), and sepsis were similar in both groups.
Strengths
The IABP shock trial, in a large RCT, questioned the perceived benefits of IABP in cardiogenic shock following acute myocardial infarction.
The authors carried out an RCT employing a device that was widely considered to be beneficial and recommended by guidelines, over a 3-year period across 37 centers in Germany. This represents a commendable achievement and posed several questions regarding the appropriateness of IABP use in patients with cardiogenic shock. All except two patients were included in the primary outcome analysis with minimal loss to follow-up. This landmark study was a logical culmination of several previous studies, including the IABP-SHOCK trial, that had raised questions regarding the perceived usefulness of IABP. After the publication of this trial, IABP use has been downgraded in guidelines (8) with a decline in clinical use (9). The use of IABP before coronary revascularization had been proposed as a measure to improve left ventricular unloading, thereby improving outcomes (10). However, the IABP-SHOCK II trial did not corroborate these findings – the mortality was similar among patients who underwent balloon counterpulsation before and after revascularization.
Limitations
The study had a few limitations. Blinding was not feasible and could have led to bias. The 40% mortality was slightly lower than expected, which may suggest a less severely ill patient population at baseline. Hence, the question arises whether IABP would be beneficial in patients who are more severely ill. The lack of benefit in the subgroup of patients with a systolic BP of <80 mm Hg makes this conclusion less likely. There were many crossovers from the control to the IABP arm which could have impacted the results of the study; however, this appears unlikely as borne out by multivariate and per protocol analysis. A type II error from a small sample size also appeared improbable, considering the minimal difference in mortality and no signal of difference in secondary outcomes. The study evaluated outcomes at 30 days; the question remained whether there may be a difference in longer-term outcomes.
Summary
Over half a century, the IABP evolved as the cornerstone of care in patients with cardiogenic shock following acute myocardial infarction. Conventional wisdom suggested efficacy based on its salutary effects on improved coronary circulation and reduced left ventricular afterload. Limited evidence of efficacy from observational studies also led to guidelines recommending its use. The earlier IABP-SHOCK trial, although of small sample size, had raised questions regarding impact on clinical outcomes, with no evidence to support improved organ function by balloon counterpulsation. The IABP-SHOCK II trial remains the largest RCT that evaluated the efficacy of balloon counterpulsation in patients with acute myocardial infarction and cardiogenic shock. This well-conducted RCT clearly showed that balloon counterpulsation does not improve survival in this patient population. Besides, it failed to reveal a significant impact on hemodynamic stabilization, catecholamine use, or renal function. Predictably, this landmark trial led to a drastic reduction in the clinical use of what was once considered to be a life-saving mechanical device.
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References
1. Kantrowitz A, McKINNON WM. The experimental use of the diaphragm as an auxiliary myocardium. Surg Forum. 1958;9:266–8.
2. Moulopoulos SD, Topaz S, Kolff WJ. Diastolic balloon pumping (with carbon dioxide) in the aorta–a mechanical assistance to the failing circulation. Am Heart J. 1962 May;63:669–75.
3. Kantrowitz A, Tjonneland S, Freed PS, Phillips SJ, Butner AN, Sherman JL. Initial clinical experience with intraaortic balloon pumping in cardiogenic shock. JAMA. 1968 Jan 8;203(2):113–8.
4. Thiele H, Zeymer U, Thelemann N, Neumann FJ, Hausleiter J, Abdel-Wahab M, et al. Intraaortic Balloon Pump in Cardiogenic Shock Complicating Acute Myocardial Infarction. Circulation. 2019 Jan 15;139(3):395–403.
5. Prondzinsky R, Lemm H, Swyter M, Wegener N, Unverzagt S, Carter JM, et al. Intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock: The prospective, randomized IABP SHOCK Trial for attenuation of multiorgan dysfunction syndrome*: Crit Care Med. 2010 Jan;38(1):152–60.
6. Thiele H, Allam B, Chatellier G, Schuler G, Lafont A. Shock in acute myocardial infarction: the Cape Horn for trials? Eur Heart J. 2010 Aug;31(15):1828–35.
7. Thiele H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J, et al. Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock. N Engl J Med. 2012 Oct 4;367(14):1287–96.
8. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018 Jan 7;39(2):119–77.
9. Shah M, Patnaik S, Patel B, Ram P, Garg L, Agarwal M, et al. Trends in mechanical circulatory support use and hospital mortality among patients with acute myocardial infarction and non-infarction related cardiogenic shock in the United States. Clin Res Cardiol Off J Ger Card Soc. 2018 Apr;107(4):287–303.
10. Abdel-Wahab M, Saad M, Kynast J, Geist V, Sherif MA, Richardt G, et al. Comparison of hospital mortality with intra-aortic balloon counterpulsation insertion before versus after primary percutaneous coronary intervention for cardiogenic shock complicating acute myocardial infarction. Am J Cardiol. 2010 Apr 1;105(7):967–71.
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Though the history was quite dramatic evidence could’nt support. Quite a good assist device otherwise.