Study Oversight

The IABP-SHOCK II trial was a multicenter, open-label, randomized study. The design of the trial has been published previously.11 The trial was designed by the first author and modified by the steering committee (see the Supplementary Appendix, available with the full text of this article at NEJM.org); the trial design was approved by the ethics committee at each participating center. Neither Maquet Cardiopulmonary nor Teleflex Medical, both of which supported the study with unrestricted grants, had any involvement in the study. Data were maintained at the Myocardial Infarction Research Institute in Ludwigshafen, Germany, where all the statistical analyses were performed by independent personnel. The steering committee vouches for the integrity and completeness of the data, and the statistician for the accuracy of data analysis; all the authors vouch for the fidelity of the study to the trial protocol, which is available at NEJM.org.

Patients

Patients were eligible for the trial if they presented with an acute myocardial infarction (with or without ST-segment elevation) complicated by cardiogenic shock and if early revascularization (by means of PCI or CABG) was planned. A patient was considered to be in cardiogenic shock if he or she had a systolic blood pressure of less than 90 mm Hg for more than 30 minutes or needed infusion of catecholamines to maintain a systolic pressure above 90 mm Hg, had clinical signs of pulmonary congestion, and had impaired end-organ perfusion. The diagnosis of impaired end-organ perfusion required at least one of the following: altered mental status; cold, clammy skin and extremities; oliguria with urine output of less than 30 ml per hour; or serum lactate level higher than 2.0 mmol per liter.

Patients were not eligible for the study if they had undergone resuscitation for more than 30 minutes; had no intrinsic heart action; were in a coma with fixed dilatation of pupils that was not induced by drugs; had a mechanical cause of cardiogenic shock (e.g., ventricular septal defect or papillary muscle rupture); had onset of shock more than 12 hours before screening; had a massive pulmonary embolism, severe peripheral arterial disease precluding insertion of an intraaortic balloon pump, or aortic regurgitation greater than grade II in severity (on a scale of I to IV, with higher grades indicating more severe regurgitation); were older than 90 years of age; were in shock as a result of a condition other than acute myocardial infarction; or had a severe concomitant disease associated with a life expectancy of less than 6 months. Patients in cardiogenic shock who were not eligible for randomization were entered into a registry. All patients or their legally authorized representatives provided written informed consent.11

Treatment

Eligible patients were randomly assigned, in a 1:1 ratio, to intraaortic balloon counterpulsation (IABP group) or no intraaortic balloon counterpulsation (control group). Randomization was performed centrally with the use of an Internet-based program, with stratification according to center.

The intraaortic balloon pump was inserted either before the PCI or immediately after the PCI, with the timing of the insertion at the discretion of the investigator. Support was initiated with the use of 1:1 electrocardiographic triggering (i.e., balloon inflation and deflation triggered by the R wave) and was maintained until there was sustained hemodynamic stabilization, which was defined as a systolic blood pressure higher than 90 mm Hg for more than 30 minutes without the need for catecholamines.11 Weaning from the pump was achieved by means of reduction of the trigger ratio.11 Crossover of patients in the control group to intraaortic balloon counterpulsation was allowed only if mechanical complications (ventricular septal defect or papillary muscle rupture) developed after randomization.

All the patients were expected to undergo early revascularization and to receive the best available medical treatment according to guidelines.6-8,12 The mode of revascularization (primary PCI with treatment of the target lesion only, PCI of the target lesion plus additional immediate or staged PCI of nontarget lesions, or CABG) was left to the discretion of the operator. Intensive care treatment was standardized according to the German–Austrian S3 Guideline, which was provided to all study sites.12

End Points

The primary study end point was 30-day all-cause mortality. Secondary end points included serial assessments of serum lactate levels, creatinine clearance (measured with the use of the Cockcroft–Gault formula13), C-reactive protein levels, and severity of disease as assessed with the use of the Simplified Acute Physiology Score (SAPS) II. The SAPS II is calculated from 17 variables; scores range from 0 to 163, with higher scores indicating more severe disease.14 We also assessed process-of-care outcomes including blood pressure and heart rate before and after revascularization, the time to hemodynamic stabilization, the dose and duration of catecholamine therapy, the requirement for renal-replacement therapy, the length of stay in the intensive care unit, the requirement for and length of time on mechanical ventilation, and the requirement for implantation of an active (percutaneous or surgical) left ventricular assist device or for heart transplantation.

Safety end points included severe or life-threatening bleeding and moderate bleeding during the hospital stay, as assessed according to the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) criteria15; peripheral ischemic vascular complications requiring surgical or interventional therapy; sepsis with clinical signs of infection and elevated procalcitonin levels (2 ng per milliliter or higher); and stroke, identified by the presence of new neurologic symptoms in conjunction with signs of ischemia or bleeding on computed tomography.

Statistical Analysis

The study was powered to detect a difference of 12 percentage points in 30-day survival rates, assuming a rate of 56% in the control group. An independent data and safety monitoring board conducted interim analyses after enrollment of 33% and 66% of the patients, using a group sequential design with an O'Brien–Fleming boundary.11 The global type I error level was set at 0.05. The trial could be discontinued if the null hypothesis of equal survival rates was rejected at a significance level of 0.0005 at the first interim analysis or 0.014 at the second interim analysis. The final analysis was undertaken at an alpha level of 0.044. Therefore, 282 patients per group were needed to test the null hypothesis with the desired power. The estimate of the sample size took into consideration a putative center effect, which was assumed to be within a range of ±5% for almost all centers (95%). The intraclass correlation coefficient was then 0.0013, yielding a total of 588 patients to be evaluated. To allow for a 2% dropout rate, we recruited 600 patients.

All the data were analyzed according to the intention-to-treat principle. In addition, a per-protocol analysis of the primary end point, which included data from all patients who had confirmed acute myocardial infarction with the exclusion of those who crossed over, was performed to evaluate the robustness of the data. For the primary end point, the chi-square test was used to compare mortality between the two groups. Cumulative mortality throughout the first 30 days after randomization was characterized with the use of Kaplan–Meier plots, with the log-rank test used for the comparison between the two groups. Secondary end points were assessed with the use of Fisher's exact test or the chi-square test for binary end points and a Mann–Whitney U test for quantitative end points.

Prespecified subgroup analyses were performed in subgroups defined according to sex, age (<50 years, 50 to 75 years, or >75 years), presence or absence of diabetes, presence or absence of arterial hypertension, myocardial infarction with ST-segment elevation versus myocardial infarction without ST-segment elevation, anterior versus nonanterior myocardial infarction, and previous or no previous myocardial infarction. Post hoc subgroup analyses were performed in subgroups defined according to the presence or absence of induced mild hypothermia and systolic blood pressure of less than 80 mm Hg versus 80 or more mm Hg at the time of randomization.