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(Circulation. 1999;100:2067-2073.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Cardiogenic Shock in Patients With Acute Ischemic Syndromes With and Without ST-Segment Elevation

David R. Holmes, Jr, MD; Peter B. Berger, MD; Judith S. Hochman, MD; Christopher B. Granger, MD; Trevor D. Thompson, BS; Robert M. Califf, MD; Alec Vahanian, MD; Eric R. Bates, MD; Eric J. Topol, MD

From the Mayo Clinic and Foundation, Rochester, Minn (D.R.H., P.B.B.); Columbia University/St Luke’s/Roosevelt Hospital, New York, NY (J.S.H.); Duke Clinical Research Institute, Durham, NC (C.B.G., R.M.C.); Emory University, Atlanta, Ga (T.D.T.); Hospital Tenon, Paris, France (A.V.); University of Michigan Medical Center, Ann Arbor (E.R.B.); and Cleveland Clinic Foundation, Cleveland, Ohio (E.J.T.).

Correspondence to David R. Holmes, Jr, MD, Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail dholmes{at}mayo.edu

	Abstract

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Background—Cardiogenic shock is usually considered a sequela of ST-segment elevation myocardial infarction. There are limited prospective data on the incidence and significance of shock in non-ST-segment elevation patients. This study assessed the incidence and outcomes of cardiogenic shock developing after enrollment among patients with and without ST-segment elevation in the Global Use of Strategies To Open Occluded Coronary Arteries (GUSTO)-IIb trial.

Methods and Results—Among 12 084 patients in GUSTO-IIb who did not present with cardiogenic shock, 4092 (34%) had and 7991 (66%) did not have ST-segment elevation on the enrollment ECG. Cardiogenic shock developed in 4.2% of ST-segment elevation patients compared with 2.5% of patients without ST-segment elevation (odds ratio, 0.581; 95% CI, 0.472 to 0.715; P<0.001). Shock developed significantly later among patients without ST-segment elevation. There were significant differences in baseline characteristics between shock patients with and without ST-segment elevation: Patients without ST-segment elevation were older, more frequently had diabetes mellitus and 3-vessel disease, but had less TIMI grade 0 flow at angiography. Regardless of the initial ECG, mortality was high: 63% among patients with ST-segment elevation and 73% in those without ST-segment elevation.

Conclusions—Cardiogenic shock occurs in the setting of acute ischemic syndromes regardless of whether ST-segment elevation is present. The incidence, patient characteristics, timing, clinical course, and angiographic findings differ between the 2 groups. Mortality from cardiogenic shock is similarly high among patients with and without ST-segment elevation.

Key Words: shock • myocardial infarction • mortality • acute coronary syndromes • unstable angina

	Introduction

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Cardiogenic shock accounts for most of the mortality in patients hospitalized with ST-segment elevation myocardial infarction (MI).^{1 2} In the Global Utilization of Streptokinase and TPA for Occluded Arteries (GUSTO)-I trial, which had the largest prospectively defined cardiogenic shock population, shock occurred in 7.2% of patients and accounted for 58% of deaths within 30 days.³ Given the magnitude of this problem, intense efforts have focused on identifying patients at risk⁴ and developing treatment strategies.^{5 6 7 8} Although cardiogenic shock can also occur in patients with acute coronary syndromes without ST-segment elevation, there are limited data about its incidence, timing, and outcome relative to patients with ST-segment elevation. This study assessed cardiogenic shock in patients with and without ST-segment elevation in the GUSTO-IIb study.

	Methods

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The GUSTO-IIb trial randomized patients with acute coronary syndromes to a minimum of 72 hours of therapy with either heparin (5000-U bolus followed by 1000 U/h) or hirudin (0.1-mg/kg bolus followed by 0.1 mg · kg^-1 · h^-1).⁹ Entry criteria included chest pain compatible with myocardial ischemia within 12 hours associated with either transient or persistent ST-segment elevation or ST-segment depression >0.5 mm or persistent T-wave inversion >1 mm. Patients with left bundle-branch block and typical symptoms were also eligible.⁹ Patients were prospectively stratified into groups that had ST-segment elevation (4131 patients) or did not have ST-segment elevation (8011 patients). ST-segment elevation patients who were not eligible for either accelerated tissue plasminogen activator or streptokinase therapy were excluded. Other diagnostic and therapeutic procedures, including angiography and revascularization, were performed at the discretion of the patient’s physician, although these specific procedures were discouraged during study drug infusion unless refractory or recurrent ischemia occurred.

Definitions
Patients with cardiogenic shock were a prospectively identified subgroup who had a systolic blood pressure <90 mm Hg persisting for >1 hour despite a fluid challenge and signs of hypoperfusion or a cardiac index of <2.2 L · min^-1 · m^-2. For this study of patients who developed shock after enrollment, the 58 patients who presented in cardiogenic shock (8% of ST-segment elevation and 1% of non-ST-segment elevation patients) were excluded.

MI was defined as occurring at the time of study enrollment if the creatine kinase myocardial band fraction (CK-MB) was elevated and was 3% of the total CK either at baseline or 8 hours after enrollment. If no symptoms occurred between enrollment and a sample taken at 16 hours but the CK was elevated, this was also considered MI at enrollment. Recurrent infarction was defined as recurrent signs, symptoms, and ECG changes of acute MI accompanied by a rise in CK-MB above normal (if it had fallen to normal after enrollment) or 2-fold above the previous value (if it had not returned to normal).

Data and Statistical Analyses
Baseline characteristics and clinical outcomes of shock patients with and without ST-segment elevation were compared. Continuous variables are presented as medians and 25th and 75th percentiles, and discrete variables are given as frequencies and percentages. Statistical testing was performed with the likelihood-ratio ² test or Fisher’s exact test for categorical variables. The Wilcoxon rank-sum test was used for continuous variable assessment. All reported probability values were 2-tailed, and treatments were compared by use of an intention-to-treat analysis.

Logistic regression models were created to determine the effect of ST-segment elevation versus no ST-segment elevation on 30-day mortality and 30-day death or reinfarction. First, univariable models were developed to determine unadjusted effects. Second, multivariable models were created to determine the effect after adjustment for known baseline predictors of each outcome.

In examinations of the effect of revascularization procedures on 30-day outcomes, it is important to account for the failure of many patients to survive long enough to have a procedure. Crediting the nonintervention group with all these early events would unfairly inflate the beneficial effect of the intervention. To adjust for any bias resulting from including these early events in the nonintervention group, time-dependent Cox models were used to determine the effect of procedures on 30-day outcomes. Procedures included as time-dependent covariates in the modeling were PTCA and CABG. First, a univariable comparison was made to determine the unadjusted effect of each procedure on each of the 30-day outcomes. Second, the interaction between each procedure and ST-segment group was tested to determine whether the effect of the given procedure was similar in both groups. Next, each procedure was tested after adjustment for significant baseline predictors. Finally, each procedure was tested after adjustment for both significant baseline predictors and the other procedure. In this model, patients were treated as having only the first procedure performed. Predictors in each model were tested with the Wald ² test.

	Results

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The trial enrolled 12 142 patients, 69 of whom were eliminated from this analysis: 58 presented in shock and 11 were missing data about in-hospital shock status. Of the remaining 12 073 patients, 4087 (34%) had ST-segment elevation (group 1) and 7986 (66%) did not (group 2). Cardiogenic shock developed in 4.2% of group 1 patients (n=173) compared with 2.5% of group 2 patients (n=200) (OR, 0.581; 95% CI, 0.472 to 0.715; P<0 0.001).

Patients who developed cardiogenic shock had more high-risk characteristics (Table 1), including older age, female sex, and a higher incidence of prior MI, prior congestive heart failure, and diabetes mellitus. They also had a higher frequency of elevated CK or CK-MB on admission.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics

As in the group 1 and 2 patients who did not develop shock, there were significant differences in baseline characteristics between group 1 and 2 patients who developed shock (Table 2). Patients in Group 2 had more adverse baseline characteristics, including significantly older age, and a greater frequency of prior infarction, coronary bypass surgery, and congestive heart failure. MI at the time of study enrollment was significantly more frequent in group 1 patients (91% versus 69%, P<0.001); there was no difference in the rate at which patients with MI at enrollment developed shock (group 1, 4.3%; group 2, 3.9%).

View this table: [in this window] [in a new window]   Table 2. Baseline Characteristics of Patients Developing Cardiogenic Shock in GUSTO-IIb

Medication use at any time during hospitalization and resource consumption differed between the 2 groups (Table 3). Oral ß-blockers and calcium channel antagonists were used more frequently in group 2. There was no difference in ACE inhibitors, which were used in less than one half of all patients. Clinically indicated revascularization patterns differed significantly between the 2 groups of patients: Patients with ST-segment elevation underwent PTCA more frequently but CABG less frequently.

View this table: [in this window] [in a new window]   Table 3. Medication1 and Resource Use

In-hospital events preceding or occurring in conjunction with shock differed in the groups (Table 4). Shock occurred considerably later in group 2 (median, 76.2 hours after study entry versus 9.6 hours in group 1; Table 2). Recurrent ischemia occurred almost twice as frequently, and recurrent infarction was 3 times as common in group 2. A mechanical cause of shock, such as ventricular septal defect or mitral regurgitation, was uncommon. The median maximum CK elevation was significantly higher in group 1 (2133 versus 883).

View this table: [in this window] [in a new window]   Table 4. In-Hospital Events Preceding Shock

Angiography was performed in 181 patients, 90 in group 1 (52%) and 91 in group 2 (46%) (Table 5). There were significant differences in TIMI flow in the culprit vessel at the time of angiography (P=0.014). More patients in group 1 had TIMI grade 0 flow, whereas more patients in group 2 had TIMI grade 3 flow. Three-vessel disease was more common in group 2 patients. There were also differences in infarct-related artery location. In 24% of group 2 patients, the infarct-related artery could not be identified.

View this table: [in this window] [in a new window]   Table 5. Angiographic Factors

Thirty-day mortality was high in patients with shock regardless of the initial ECG. Mortality was 63.0% among shock patients with ST-segment elevation compared with 3.0% in patients without shock (Table 6). Similarly, in the non-ST-segment elevation group, 30-day mortality was 72.5% in patients with shock versus 2.0% in patients without shock. Mortality among the 2 groups of shock patients did not differ significantly. There was also no difference in outcome between shock patients with and without ST-segment elevation for the combined end point of death, MI, or recurrent MI. Recurrent infarction was higher in group 2 patients (37.5% versus 25.4%).

View this table: [in this window] [in a new window]   Table 6. Thirty-Day Outcomes

Thirty-Day Mortality Modeling Results
In the univariable model, there was a borderline effect for increased 30-day mortality in the group without ST-segment elevation (OR, 1.55; 95% CI, 1.00 to 2.40; P=0.050). In the multivariable model, no ST-segment elevation was a significant predictor of 30-day mortality (Wald ²=6.06, P=0.048), as was male sex (P=0.022).

In the unadjusted time-dependent models, PTCA was associated with reduced 30-day mortality (hazard ratio [HR], 0.64; 95% CI, 0.44 to 0.92; P=0.017), and CABG was associated with increased 30-day mortality (HR, 1.50; 95% CI, 1.08 to 2.09; P=0.017). After adjustment for baseline differences, the effect of CABG on mortality was even more significant (HR, 2.03; 95% CI, 1.42 to 2.92; P<0.001), and there remained a strong trend toward reduced mortality with PTCA (HR, 68; 95% CI, 0.45 to 1.00; P=0.052). A time-dependent model including the baseline characteristics and both procedures was then run in which patients receiving both CABG and PTCA were counted as receiving only the first procedure performed. After adjustment for baseline differences and the other procedure, CABG remained associated with increased 30-day mortality (HR, 2.17; 95% CI, 1.48 to 3.19; P<0.001), whereas there was no longer a PTCA effect (HR, 0.79; 95% CI, 0.53 to 1.18; P=0.241).

Thirty-Day Death or Reinfarction Modeling Results
In the univariable model, ST-segment elevation did not have a significant effect on the composite end point (OR, 1.41; 95% CI, 0.86 to 2.30; P=0.170). There was no significant interaction with sex (P=0.768).

In the unadjusted time-dependent models, there was not a significant PTCA effect (HR, 0.95; 95% CI, 0.69 to 1.31; P=0.767), whereas CABG was associated with increased events (HR, 1.56; 95% CI, 1.13 to 2.15; P=0.006). After adjustment for baseline differences, there remained no PTCA effect (HR, 1.01; 95% CI, 0.71 to 1.43; P=0.951); CABG was still associated with a harmful effect (HR, 1.80; 95% CI, 1.29 to 2.53; P=0.001). The CABG effect remained after adjustment for baseline differences and the other procedure (HR, 2.10; 95% CI, 1.46 to 3.02; P<0.001). PTCA was still not predictive of the 30-day composite end point (HR, 1.18; 95% CI, 0.82 to 1.68; P=0.371).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
GUSTO-IIb⁹ was designed to include a broad range of acute coronary syndrome patients, such as those with ST-segment elevation, ST-segment depression, and T-wave inversion. The present study documents significant differences in the clinical and angiographic characteristics and outcome of patients with and without ST elevation and, in particular, those who developed cardiogenic shock. It also points out differences in the timing of shock that could affect the clinical management of such patients.

Patients who developed shock had more adverse baseline characteristics regardless of whether they presented with ST-segment elevation. However, among patients who developed shock, those who presented without ST-segment elevation had more adverse risk factors than those who presented with ST-segment elevation. In each group, the development of shock was associated with a marked increase in mortality.

Classically, cardiogenic shock has been considered a sequela of ST-segment elevation MI, most commonly caused by left ventricular dysfunction resulting from continued ischemia and cell death.¹⁰ In ST-segment elevation patients, the incidence of shock in published series has varied from 6% to 20%.^{1 10 11 12} In GUSTO-I, with the largest prospectively defined population of shock patients, the incidence was 7.2%.³ The incidence of shock may be higher in unselected populations because patients presenting with cardiogenic shock have often been excluded from randomized trials.¹³

There are very limited prospective data regarding the development of shock in patients without ST-segment elevation. This is a very diverse group of patients with variable prognoses.^{14 15 16 17 18 19 20 21} In the prospective Should We Revascularize Occluded Coronaries for Cardiogenic Shock? (SHOCK) registry, 214 patients were found to have left ventricular failure causing shock; of these, only 14% did not have ST-segment elevation.²² This GUSTO-IIb study also documents a significant difference in the incidence of cardiogenic shock, which was seen in 4.2% of patients with ST-segment elevation but only 2.5% of those without ST-segment elevation.

Patients who developed shock were at higher risk initially and were characterized by older age, female sex, and a higher incidence of prior MI, prior congestive heart failure, and diabetes mellitus. There were likewise differences in baseline characteristics among shock patients with and without ST-segment elevation. Patients without ST-segment elevation in whom shock developed were at higher risk than patients with ST elevation, as evidenced by their older age and increased frequency of prior MI, CABG, and congestive heart failure, all of which were associated with increased mortality in the GUSTO-I trial.²³ Age was one of the most important factors associated with poor outcome in GUSTO-I.^{24 25}

There were other very important differences between the patient groups. Shock patients without ST-segment elevation who underwent coronary angiography had significantly more extensive disease: 65% had 3-vessel disease compared with 30% in the group with ST-segment elevation. Patients without ST-segment elevation had less TIMI grade 0 flow, consistent with the theory that ST-segment elevation usually results from acute coronary occlusion, whereas more preserved antegrade flow causes ischemia, ST-segment depression, or T-wave inversion, often without infarction.

There were also significant differences in in-hospital events preceding or occurring coincidentally with the diagnosis of shock. The time to development of shock was longer in patients without ST-segment elevation, and shock was more often associated with recurrent ischemia or reinfarction in this group. The origin of the shock accordingly may differ between the 2 groups; in patients with ST-segment elevation, acute occlusion may occur with massive necrosis and irreversible loss of a large amount of myocardium, whereas in patients without ST-segment elevation, it may be a result of recurrent ischemia or reinfarction. Both of these findings afford a potential to intervene before shock onset in patients with highest risk if means can be found to identify them.

Patients with non-ST-segment elevation acute ischemic syndromes are a very heterogeneous group.^{14 15 16 17 18 19 20 21} Many studies have documented a more favorable initial hospital outcome in these patients, which has been felt to be related to early spontaneous infarct-related artery patency and a resultant limitation in infarct size. However, Gruppo Italiano per lo Studio della Streptochinasi Nell’infarto Miocardico (GISSI)-I²⁶ and International Study of Infarct Survival (ISIS)-2²⁷ reported a mortality rate of 20% among patients with non-ST-segment elevation infarction, which was similar to the prognosis of patients with placebo-treated anterior infarctions.

Perhaps the most striking finding in this GUSTO-IIb study was that although cardiogenic shock was less likely to develop in patients without ST-segment elevation, it was associated with an even higher mortality than shock patients with ST-segment elevation (72.5% versus 63.0%, P=0.05). Regardless of the initial ECG findings, cardiogenic shock remains highly lethal.

The role of aggressive treatment in patients with shock remains promising but controversial. In the SHOCK registry, Hochman et al²² found that selection for angiography identified a group of patients with improved outcome regardless of subsequent treatment. The randomized SHOCK trial assessed a strategy of early emergency revascularization compared with initial medical stabilization followed by delayed revascularization if clinically indicated. There was a small but statistically insignificant improvement in outcome in the former group.²⁸ In contrast to the SHOCK registry, there are increasing data on the promising role of revascularization in very-high-risk patients. In the larger GUSTO-I trial,^{3 29} an aggressive treatment approach with angiography and PTCA was associated with improved survival at 30 days, which persisted for 1 year. These data suggest that these high-risk patients appear to have the most to gain from invasive therapeutic approaches. The number of patients with shock in the GUSTO-IIb study who underwent revascularization was small. Although PTCA was associated with improved mortality at 30 days, there was no significant difference in survival after adjustment for differences in baseline characteristics, whereas shock patients who underwent CABG had worse outcomes.

Study Limitations
Although GUSTO-IIb encompassed a larger group of patients with acute coronary syndromes than other thrombolytic trials of acute MI, it did not include all patients with these syndromes; eg, patients with ST-segment elevation were excluded if they were not candidates for thrombolytic therapy. No screening log was kept of all patients with infarction who may have been candidates for reperfusion therapy. Concern has been raised that the incidence of shock is higher in unselected patients because patients may have been excluded by physician or patient bias.¹³ Such bias would likely affect the outcome similarly for patients both with and without ST-segment elevation.

Conclusions
This study documents cardiogenic shock occurring in the setting of acute ischemic syndromes regardless of whether ST-segment elevation is present. Shock occurred in this large trial in only 2.5% of patients without compared with 4.2% of patients with ST-segment elevation. Shock patients without ST-segment elevation had more high-risk clinical characteristics, more extensive coronary artery disease, and more frequent recurrent ischemia and infarction before the development of shock. Patients without ST-segment elevation developed shock much later than those with ST-segment elevation, suggesting a window of opportunity to prevent shock. Regardless of the initial ECG findings of patients who developed shock, it was associated with a marked increase in mortality.

	Acknowledgments

 
This study was supported by Boehringer-Mannheim (Mannheim, Germany), Ciba-Geigy Corporation (Summit, NJ), and Advanced Cardiovascular Systems (Mountain View, Calif).

Received May 25, 1999; revision received July 16, 1999; accepted July 20, 1999.

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				M. Singh, J. White, D. Hasdai, P. K. Hodgson, P. B. Berger, E. J. Topol, R. M. Califf, and D. R. Holmes Jr Long-Term Outcome and its Predictors Among Patients With ST-Segment Elevation Myocardial Infarction Complicated by Shock: Insights From the GUSTO-I Trial J. Am. Coll. Cardiol., October 30, 2007; 50(18): 1752 - 1758. [Abstract] [Full Text] [PDF]

				J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine J. Am. Coll. Cardiol., August 14, 2007; 50(7): e1 - e157. [Full Text] [PDF]

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