One-Year Survival Among Patients With Acute Myocardial Infarction Complicated by Cardiogenic Shock, and its Relation to Early Revascularization
Results From the GUSTO-I Trial
Background—Although 30-day survival is increased in patients with acute myocardial infarction complicated by cardiogenic shock who undergo coronary revascularization, the longer-term outcome in such patients and the duration of benefit from revascularization are unknown.
Methods and Results—We analyzed 30-day survivors of acute myocardial infarction in the Global Utilization of Streptokinase and Tissue-Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial and identified 36 333 who had not had cardiogenic shock (systolic blood pressure <90 mm Hg for ≥1 hour, group 1) and 1321 patients who had shock (group 2). Group 2 patients were older and sicker. At 1 year, 97.4% of group 1 patients were alive versus 88.0% of group 2 (P=0.0001). Among group 2 patients, 578 (44%) had undergone revascularization within 30 days (group 2A) and 728 (56%) had not (group 2B). Revascularization was not required by protocol but was selected by the attending physicians. At 1 year, 91.7% of group 2A patients were alive versus 85.3% of group 2B (P=0.0003). With the use of multivariable logistic regression analysis to adjust for differences in baseline characteristics of shock patients alive at 30 days, revascularization within 30 days was independently associated with reduced 1-year mortality (odds ratio 0.6, [95% confidence interval 0.4, 0.9], P=0.007).
Conclusions—Most patients (88%) with acute myocardial infarction complicated by cardiogenic shock who are alive at 30 days survived at least 1 year. Shock patients who underwent revascularization within 30 days had improved survival at 1 year compared with shock patients who did not receive revascularization, even after adjustment for differences in baseline characteristics between the 2 groups.
Cardiogenic shock is the most common cause of death in patients who are hospitalized with acute myocardial infarction.1 Many retrospective analyses have concluded that survival in patients with cardiogenic shock who undergo coronary angioplasty is higher than in patients who do not undergo angioplasty.2 3 4 5 6 7 Although selection bias could have contributed to this finding, studies that have taken into account the differences in baseline characteristics have revealed that revascularization significantly reduces early mortality in these patients.8 9
The Global Utilization of Streptokinase and Tissue Plasminogen Activator (TPA) for Occluded Coronary Arteries (GUSTO-I) trial was designed to test the hypothesis that the more complete and more rapid achievement of coronary artery patency, if sustained, would reduce mortality in patients with acute myocardial infarction.10 Patients with cardiogenic shock were prospectively identified as a subgroup to be extensively studied, and a specific ancillary data collection form was designed for this purpose. It has already been shown that early survival in GUSTO-I patients with cardiogenic shock was improved by early revascularization even after adjusting for differences in baseline characteristics and when other biases were accounted for.9 However, coronary revascularization is expensive, and there are few data regarding the duration of benefit of revascularization in shock patients. In fact, little is known about the long-term outcome of shock patients who survive the first 30 days.
We therefore performed this study to determine whether the demonstrated short-term benefits of early revascularization persisted throughout the subsequent year and to determine 1-year survival among shock patients alive at 30 days.
The details of the GUSTO-I trial have previously been described in detail.10 Briefly, 41 021 patients with acute myocardial infarction were randomized to 1 of 4 thrombolytic regimens: streptokinase with subcutaneous heparin, streptokinase with intravenous heparin, accelerated TPA with intravenous heparin, or a combination of streptokinase plus TPA with intravenous heparin. Patients eligible for enrollment in the trial had ST-segment elevation of 0.1 mV in 2 or more limb leads or >0.2 mV in 2 or more contiguous precordial leads, the onset of ischemic pain within 6 hours of randomization, and no contraindications to thrombolysis. The primary outcome of the trial was 30-day mortality from any cause.
In the trial, 2972 patients met the criteria for cardiogenic shock used in these analyses. Patients were considered to have cardiogenic shock if they had Killip class IV congestive heart failure at study entry or had Killip class IV heart failure or cardiogenic shock (defined as systolic blood pressure <90 mm Hg for ≥1 hour not responsive to fluid administration or the need for positive inotropic agents to maintain a systolic blood pressure >90 mm Hg) after study enrollment but during the initial hospitalization. Of the 2972 patients with shock, 315 patients had shock on enrollment and 2657 had shock after enrollment in the trial.
We analyzed all patients in GUSTO-I alive at 30 days and divided them into patients in whom shock had not occurred (group 1, n=36 333) and those in whom shock had occurred (group 2, n=1321). Patients with cardiogenic shock were divided into those in whom revascularization (coronary angioplasty or coronary artery bypass surgery) had been performed (group 2A, n=578) and those in whom it had not (group 2B, n=728). Shock patients with missing data regarding their revascularization status (15 of 1321 patients, 1.1%) were excluded from the analyses of the relation between survival and early revascularization.
For continuous variables, medians are presented with the 25th and 75th percentiles given in parentheses. Discrete variables are expressed as frequencies with percentages given in parentheses. Differences in continuous variables between groups were tested using a Wilcoxon rank-sum test. Differences in discrete variables were examined with the use of the χ2 test. Results of both tests were interpreted as statistically significant when P<0.05.
To determine whether revascularization within the first 30 days after an acute myocardial infarction was an independent predictor of 1-year survival after adjusting for other important predictors, a multivariable logistic regression model was generated. Candidate variables were considered on the basis of univariable association, significance in a prior 30-day mortality model,11 and clinical relevance. In addition to those variables presented in a previous report on the GUSTO-I study developing a 30-day mortality model,11 other candidate predictors examined were diastolic blood pressure, time to randomization, and race. All continuous variables were examined to ensure that the assumption of a linear relation between the independent variables and the outcome was upheld. Forward stepwise selection was used to determine those variables that were statistically significant contributors to the model at α=0.05. Because there was some censoring (<4%) of values less than 1 year (365 days), survival analysis using Cox proportional hazards modeling confirmed the validity of the logistic regression results. In addition, Kaplan-Meier curves, stratified on revascularization, were generated to show the unadjusted 1-year survival rates of the 30-day survivors who had shock. The log-rank test was used to assess whether the differences between the survival curves were statistically significant at P<0.05.
There were important differences in the clinical characteristics of patients who survived 30 days without having shock and those who had shock (Table 1⇓). Patients who had shock were older, had a higher percentage of female subjects, and were more likely to have had an anterior infarction and have a history of hypertension, prior myocardial infarction, cerebrovascular disease, and coronary artery bypass surgery. Shock patients had a longer duration of symptoms before enrollment, were treated more rapidly after enrollment, and were less likely to have been treated with TPA.
Angiographic data are available from 20 799 (57%) patients without shock and 915 (69%) patients with shock (Table 2⇓). These data indicate that shock patients more frequently had occlusion of the infarct artery despite lytic therapy (TIMI 0 or 1 flow 42.9% vs 27.7%, P<0.001) and a significantly lower ejection fraction (44.1% vs 52.4%, P<0.001) than patients without shock, respectively. The persistent occlusion and lower ejection fraction undoubtedly contributed to the development of shock in these patients.
Revascularization in Shock Patients
Cardiogenic shock patients alive at 30 days were separated into those who underwent revascularization within the first 30 days (n=578, 44%; group 2A) and those who did not (n=728, 56%; group 2B); the baseline characteristics of these 2 groups are presented in Table 3⇓. Among shock patients who underwent revascularization, coronary angioplasty alone was performed in 334 (58%) patients, and bypass surgery alone was performed in 193 (34%) patients; 47 (8%) patients underwent both coronary angioplasty and bypass surgery. Shock patients who underwent revascularization were younger, less likely to be female, and more likely to have a history of hypercholesterolemia and a history of angina than shock patients who had not undergone revascularization within 30 days.
Angiographic data from shock patients who did (n=575, 99.5%) and did not (n=333, 45.7%) undergo revascularization are presented in Table 4⇓. Shock patients who underwent revascularization had more frequent occlusion of the infarct artery (50.7% vs 29.9%, P=0.001) and a more severe stenosis of the infarct artery than shock patients who did not undergo revascularization. A patent infarct artery and less severe stenosis of the infarct artery undoubtedly contributed to the decision not to perform revascularization in many shock patients.
Of the 578 patients who underwent revascularization within 30 days, the exact time of the procedure was available in 489 (85%) patients. The median time of the revascularization procedure (coronary angioplasty or bypass surgery) was 62 hours after the onset of symptoms of myocardial infarction, with 25th and 75th percentiles of 8 and 164 hours.
Clinical Outcome at 1 Year
One-year survival among patients alive at 30 days is seen in Figure 1⇓. One-year survival was significantly greater in patients who had not had early shock than in those who had (97.4% vs 88.0%, respectively, P=0.0001). As displayed by the survival curves in Figure 2⇓, survival among shock patients alive at 30 days who had undergone revascularization was 91.7% vs 85.3% in those who had not (P=0.0003).
The aggregate mortality from study entry to 1 year was 36.9% in patients who underwent early revascularization within 30 days and 70.3% in patients who did not (Figure 3⇓).
To determine whether the improved 1-year survival in shock patients who had undergone revascularization within 30 days was due to differences in baseline clinical and demographic characteristics, multivariable logistic regression analysis was performed (Table 5⇓). This modeling revealed that revascularization within 30 days of infarction was independently associated with a reduction in 1 year mortality, with an odds ratio of 0.6 (95% confidence interval 0.4, 0.9,P=0.007) after controlling for older age, higher pulse rate, longer time to randomization in minutes, a history of prior myocardial infarction, the presence of diabetes mellitus, and increased diastolic blood pressure. The thrombolytic regimen received, while not associated with 1-year mortality in this model, was included in the model because of its clinical relevance in the trial.
The most important findings of this study are that most patients with cardiogenic shock who survive 30 days remain alive at 1 year and that the mortality reduction associated with early revascularization in GUSTO-I remains apparent at 1 year. This benefit was independent of differences in baseline clinical characteristics between shock patients who did and did not undergo revascularization within 30 days.
Many studies have suggested that angioplasty reduces the mortality of patients with acute myocardial infarction complicated by cardiogenic shock.2 3 4 5 6 7 Most of these studies have been unable to avoid 3 important sources of bias.8 9 One is the significant bias that exists in the referral of less ill shock patients for coronary angioplasty and bypass surgery. A second source of bias is the exclusion of patients in a “conservative strategy without revascularization” group who die so shortly after the development of shock that revascularization could not have been performed. The third bias is the inclusion of patients in the revascularization group who underwent revascularization late in their hospital course after their shock had resolved. Revascularization cannot be concluded to have helped such patients survive the cardiogenic shock. When these biases were taken into account and adjusted for or eliminated, an aggressive strategy of early angiography and revascularization was still associated with a lower 30-day mortality, with an odds ratio of 0.43 and confidence interval of 0.34-0.54 (P=0.0001).9
However, an aggressive revascularization strategy in shock patients is expensive, and little is known about longer-term survival among shock patients and the duration of benefit of early revascularization. For these reasons, among others, there is significant variation throughout the world in the frequency with which coronary revascularization and other expensive resources such as respiratory support with mechanical ventilators, intravenous inotropes, and pulmonary artery catheterization are administered to treat cardiogenic shock patients in whom the early mortality is so high.12 In the present study, we sought to determine whether the survival benefit from early revascularization persists beyond the first 30 days after infarction. It is clear from these results that most patients (88%) with cardiogenic shock who survived the first 30 days are alive at 1 year, and that 1-year survival is greater among patients who underwent early revascularization than in those who did not (91.7% vs 85.3%, P=0.0003). Revascularization remained a statistically significant predictor of survival (P=0.007) after adjusting for differences in baseline characteristics between the groups. These data are consistent with earlier, smaller studies suggesting benefit from revascularization and that most patients who survive the acute phase of shock are alive 1 year later.13 14
Intra-aortic balloon counterpulsation was used more frequently in shock patients alive at 30 days who had undergone revascularization than in those who had not undergone revascularization (54.2% vs 11.9%, P=0.0001). However, it is unlikely that this contributed to the difference in survival between the 2 groups. Data from GUSTO-1 suggest that although intra-aortic balloon counterpulsation was associated with improved outcome in shock patients, intra-aortic balloon counterpulsation was not independently associated with improved outcome when early revascularization was included in a multivariable analysis.9 Intra-aortic balloon counterpulsation was not associated with improved outcome in shock patients managed medically.9
To validate these results, a randomized trial is underway to confirm whether early revascularization improves survival among patients with cardiogenic shock as suggested by these retrospective analyses. In this study, the “Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock” (SHOCK) trial, patients are randomized to immediate revascularization (with coronary angioplasty or bypass surgery) versus late revascularization, deferred for at least 54 hours. Both arms receive maximal medical therapy, which can include thrombolytic therapy and intra-aortic balloon counterpulsation, if appropriate. The planned enrollment is 328 patients, which is sufficient to detect a 20% reduction in all-cause mortality at 30 days. The “Swiss Multicenter Evaluation of Early Angioplasty for Shock following Myocardial Infarction” (SMASH) trial, another randomized trial of early angioplasty versus medical therapy in shock patients at 9 European centers, was recently terminated after only 57 patients had been enrolled in 4 years.15 Mortality rates were similar among the 32 patients assigned to revascularization versus the 22 patients assigned to the medical therapy (69% vs 78%, respectively, RR=0.88, 95% confidence interval 0.6 to 1.2).
In conclusion, it has now been demonstrated that in GUSTO-I, which has the largest cohort of prospectively identified cardiogenic shock patients in a randomized clinical trial, an aggressive invasive strategy (within 24 hours of shock onset) increased survival at 30 days (from 38% in patients treated conservatively to 62% in patients treated with an aggressive invasive strategy, P=0.0001);9 that among 30-day survivors, having undergone revascularization increases the likelihood of survival to 1 year; and that most shock patients who survive 30 days remained alive at 1 year (88%). These data support an early aggressive revascularization strategy in shock patients, pending the results of the SHOCK trial.
Although differences in the analyzed baseline clinical characteristics could not explain the improved survival among patients with cardiogenic shock who underwent revascularization, characteristics that were not analyzed may have contributed to the improved survival at 1 year associated with early revascularization. Randomized clinical trials do not have this limitation; a randomized clinical trial of early revascularization in shock patients is underway. It is likely that some patients underwent revascularization between 30 days and 1 year, but only survival data were collected on GUSTO-I patients after 30 days. Data were not collected about the frequency in which patients crossed over into the revascularization group after the 30-day window or the outcome of such patients, nor was information available describing adverse events other than death, such as subsequent nonfatal myocardial infarction.
Among GUSTO-I patients with acute myocardial infarction and cardiogenic shock treated with thrombolytic therapy who survived 30 days, most (88%) survived at least 1 year. Early revascularization (within 30 days of myocardial infarction) was associated with a marked reduction in 1-year mortality independent of differences in baseline clinical characteristics between patients who did and did not undergo early revascularization.
This study was funded by grants from Bayer (New York, NY), CIBA-Corning (Medfield, Mass), Genentech (South San Francisco, Calif), ICI Pharmaceuticals (Wilmington, Del), and Sanofi Pharmaceuticals (Paris, France). The authors gratefully acknowledge Penny Hodgson and Linda Shaw for their invaluable editorial contributions.
- Received August 6, 1998.
- Revision received October 28, 1998.
- Accepted November 6, 1998.
- Copyright © 1999 by American Heart Association
Lee L, Bates ER, Pitt B, Walton JA, Laufer N, O’Neill WW. Percutaneous transluminal coronary angioplasty improves survival in acute myocardial infarction complicated by cardiogenic shock. Circulation. 1988;78:1345–1351.
Verna E, Repetto S, Boscarini M, Ghezzi I, Binaghi G. Emergency coronary angioplasty in patients with severe left ventricular dysfunction or cardiogenic shock after acute myocardial infarction. Eur Heart J. 1989;10:58–66.
Meyer P, Blanc P, Baudouy M, Morand P. Treatment de choc cardiogenique primaire par angioplastie transluminale coronarienne a la phase aigue de l’infarctus. Arch Mal Coeur. 1990;83:329–334.
Hochman JS, Boland J, Sleeper JA, Porway M, Brinker J, Col J, Jacobs A, Slater J, Miller D, Wasserman H, Menegus MA, Talley JD, McKinlay S, Sanborn T, LeJemtel T, and the SHOCK Registry Investigators. Current spectrum of cardiogenic shock and effect of early revascularization of mortality. Circulation. 1995;91:873–881.
Berger PB, Holmes DR Jr, Stebbins AL, Bates ER, Califf RM, Topol EJ for the GUSTO-I Investigators. Impact of an aggressive invasive catheterization and revascularization strategy on mortality in patients with cardiogenic shock: results from the GUSTO-I trial. Circulation. 1997;96:122–127.
Lee KL, Woodlief LH, Topol EJ, Weaver WD, Betriu A, Col J, Simoons M, Aylward P, Van de Werf F, Califf RM, for the GUSTO-I Investigators. Predictors of 30-day mortality in the era of reperfusion: results from an international trial of 41,021 patients. Circulation. 1995;91:1659–1668.
Holmes DR Jr, Califf RM, Van de Werf F, Berger PB, Bates ER, Simoons ML, White HD, Thompson, TD, Topol EJ for the GUSTO-I Investigators. Difference in countries’ use of resources and clinical outcome for patients with cardiogenic shock after myocardial infarction: results from the GUSTO trial. Lancet. 1997;349:75–78.
Eltchaninoff H, Simpfendorfer C, Franco I, Raymond RE, Casale PN, Whitlow PL. Early and 1-year survival rates in acute myocardial infarction complicated by cardiogenic shock: a retrospective study comparing coronary angioplasty with medical treatment. Am Heart J. 1995;130:130:459–464.
Stauffer J-C, Urban P, Bleed D, Pfisterer ME, Bertel O, Amann FW, Meier B, Machecourt JM, van den Brand M JBM, Danchin N. Results of the “Swiss” Multicenter evaluation of early angioplasty for shock following myocardial infarction. Circulation. 1997;96(suppl I)-I-206. Abstract.We analyzed 30-day survivors of acute myocardial infarction in the Global Utilization of Streptokinase and Tissue-Plasminogen Activator for Occluded Coronary Arteries-I trial and identified 1321 who had had cardiogenic shock (systolic blood pressure <90 mm Hg for ≥1 hour). Among these patients, 578 (44%) had undergone revascularization within 30 days and 728 (56%) had not. At 1 year, 91.7% patients who had undergone revascularization were alive versus 85.3% of those who had not (P=0.0003). Revascularization within 30 days was independently associated with reduced 1-year mortality (odds ratio 0.6, [95% confidence interval 0.4, 0.9], P=0.007).