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Prospective Evaluation of Early Abciximab and Primary Percutaneous Intervention for Patients with ST Elevation Myocardial Infarc
July 2003
Cardiogenic shock occurs in about 10% of hospitalized patients with acute myocardial infarction (AMI).1 Despite the use of early reperfusion therapies with thrombolysis or percutaneous coronary intervention (PCI), the mortality in these patients remains extraordinarily high.2 In GUSTO III, the mortality of patients treated with alteplase or reteplase and cardiogenic shock was about 60%, which is somewhat lower than the 70–80% mortality rate reported in historical control groups without thrombolysis.3 However, in GISSI I, there was no benefit of thrombolysis in patients with cardiogenic shock.4 In small, retrospective, non-randomized observational studies, a low mortality rate of about 40% in patients with cardiogenic shock treated with primary percutaneous intervention was reported.5,6 In a large German percutaneous transluminal coronary angioplasty registry, in-hospital mortality was about 46% and TIMI 3 patency after PCI was the most powerful predictor of survival.7 The randomized SHOCK trial showed a benefit in patients with early invasive therapy, especially at long-term follow-up.8,9 Thus, historical comparisons among different studies have influenced therapeutic strategies and primary PCI is the recommended treatment strategy in patients presenting with cardiogenic shock. Platelet glycoprotein IIb/IIIa receptor inhibitors have been shown to improve periprocedural and intermediate events after PCI in patients with AMI.10–13 Therefore, we sought to prospectively evaluate a routine strategy of PCI and abciximab as standard reperfusion therapy for patients with cardiogenic shock in the REO-SHOCK trial.
Methods
The REO-SHOCK trial was an open, prospective, non-randomized study performed in 12 community hospitals of the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte (ALKK) in Germany (Appendix 1). It was approved by the ethics committee of the University of Göttingen. Patients. Eligible patients for inclusion were those presenting with acute ST elevation myocardial infarction (STEMI) complicated by cardiogenic shock within 24 hours from the onset of symptoms, in whom PCI was planned. STEMI was defined as prolonged (>= 30 minutes) symptoms of myocardial infarction (chest pain or equivalent symptoms) and the following electrographic criteria: >= 2 leads with ST elevation (>= 2 mm precordial leads, >= 1 mm limb leads) or >= 1 mm precordial ST depression known to reflect posterior STEMI or presumably new left bundle branch block or new pathologic Q-waves in >= 2 related leads. Cardiogenic shock was defined as resting systolic blood pressure of 60 beats per minute. Written or witnessed informed consent from the patient or relatives was obtained before the patient was included. Important exclusion criteria included the use of thrombolytic therapy within the past 24 hours, therapeutic anticoagulation with an international normalized ratio > 1.5, platelet count Treatment protocol. Abciximab was initiated immediately after the decision to intervene and consisted of an initial bolus of 0.25 mg/kg followed by an infusion of 0.125 mg/kg/minute over 12 hours. All patients received an initial intravenous or oral hospital dose of aspirin (250–500 mg) followed by 100 mg/day aspirin orally. Patients also received 70 U/kg intravenous heparin followed by a heparin infusion of 7 U/kg/hour. Additional heparin was given, as needed, to achieve an activated clotting time of > 200 seconds during PCI and to maintain an activated partial thromboplastin time of 40–50 seconds after the intervention. Patients were followed prospectively for 30 days after the acute event. Endpoints. The primary endpoint was the all-cause 30-day mortality rate. Secondary endpoints included patency (TIMI classification) of the infarct-related artery before and after intervention; in-hospital and 30-day course rates of reinfarction; need for (re-)intervention; cardiovascular death and/or stroke (ischemic or hemorrhagic). Safety endpoints included major and minor bleeding complications according to the TIMI classification. Statistical analysis. Continuous variables were expressed as mean values ± standard deviation. Comparisons were made with Fisher`s exact test. Multivariate correlates for the prediction of 30-day mortality were analyzed with a logistic regression model.Results
Between May 2000 and May 2001, a total of 42 patients with cardiogenic shock were enrolled. Two patients were excluded from further analysis: one had normal coronary arteries and shock was caused by dilated cardiomyopathy and the other had a dissection of the ascending aorta. All other patients were treated with PCI and adjunctive therapy with abciximab. The baseline demographics of these 40 patients are shown in Table 1. The mean time interval between symptom onset and admission was 3.6 hours. Almost half (n = 19) of the patients had to be resuscitated before admission and 26 (65%) required endotracheal intubation and mechanical ventilation. A temporary pacemaker for complete atrioventricular block had to be inserted in 2 patients (5%). Table 2 provides the TIMI patency data before and after PCI. The intervention was successful (defined as achieving TIMI 2/3 patency with a residual stenosis of Mortality. The total mortality after 30 days was 42.5% (17/40). Most of these patients (10/17) died within 48 hours after admission because of refractory cardiogenic shock. A highly significant difference in mortality was seen between the 11 patients > 75 years old and the 29 patients Multivariate analysis. A multivariate analysis including age, cardiopulmonary resuscitation before admission, female gender and TIMI flow grade Discussion The REO-SHOCK trial is the first study to prospectively evaluate a strategy of early abciximab and PCI in patients with STEMI complicated by cardiogenic shock. In contrast to most of the studies in patients with cardiogenic shock, the patient population enrolled in this study represents a definitely high-risk group as demonstrated by the high number of patients requiring resuscitation and intubation. No age limit was given for inclusion and more than one-quarter of the patients were > 75 years old. Almost three-quarters of patients had 3-vessel coronary disease. The rate of patients resulted within our study was even higher compared to the rate in the SHOCK study, which is the largest prospective randomized trial in patients with STEMI complicated by cardiogenic shock.8 In contrast to recent retrospective studies, patients who died during the procedure and patients with unsuccessful PCI were not excluded. Inclusion in the study was done before angiography and patients with difficult anatomy for PCI were not excluded. Thus, there was certainly no selection bias that might confound the results of the study. Our strategy resulted in a high procedural success rate of 92.5% (less than 50% post-PCI stenosis with TIMI 2 or 3 flow), with TIMI 3 flow achieved in 80% of the patients. These rates are higher compared to the results in the SHOCK trial, where glycoprotein IIb/IIIa receptor blockers were given in 42% of patients and the procedural success rate was 77%.8 Our results are comparable to recent reports about retrospective studies, in which abciximab use was related to increased procedural success rates.14–16 These data suggest that standard adjunctive abciximab in AMI patients with cardiogenic shock is associated with higher procedural success rates. In the light of the results of the ADMIRAL study, where the largest benefit was observed in STEMI patients when abciximab was given as early as possible before PCI,11 our results reinforce this strategy in patients with cardiogenic shock. The overall 30-day mortality in REO-SHOCK patients was 42.5%. This compares favorably with the 30-day mortality rate of 46.7% in the invasive group in the SHOCK trial.11 In recent observational studies, the mortality in patients with cardiogenic shock who were treated with PCI and abciximab was 20–30%.13–15 However, all these studies were retrospective and excluded some patients. In a recent retrospective comparative study, abciximab was associated with a significantly lower mortality rate compared to stent implantation alone in PCI for cardiogenic shock.15 In this study, the advantage of abciximab was not dependent on the patency rate of the infarct-related artery. One possible explanation is the improvement of microvascular flow by abciximab,10 which might be of importance in these high-risk patients in whom even small improvements in perfusion status might have an impact on hemodynamics and outcome. Platelets have been shown to have an important role in reperfusion in AMI patients and are therefore an important target in improving reperfusion therapy17 by reducing microvascular sludging promoted by larger vessel embolism and local platelet aggregation. Therefore, our data and the previous experience suggest that standard adjunctive abciximab in AMI patients with cardiogenic shock is associated with decreased 30-day mortality rates by improving both procedural success and microvascular flow. Contrary to what might have been expected, a major finding of our study is that abciximab given in this high-risk group of STEMI patients is safe and was not associated with a high rate of major bleeding complications. Only 2 patients (5%) experienced major bleeding, which is in the range of bleeding complications reported from other trials where cardiopulmonary resuscitation was an exclusion criterion.12 Based on this observation, we suggest that there should be no exclusion criteria for abciximab use in AMI patients with cardiogenic shock other than intracranial hemorrhage or ongoing bleeding. Furthermore, patients who have been resuscitated should not be denied abciximab, as has previously been common practice. In REO-SHOCK, patients 75 years old (24% versus 91%, respectively). In the SHOCK trial, 30-day mortality rates in the invasive group were 41.4% in patients 75 years. A multivariate analysis of the REO-SHOCK results confirmed age as the largest independent predictor of death at 30 days. This is supported by an analysis in the SHOCK study; of 10 prespecified subgroup analyses, only age ( 75 years) interacted significantly with treatment at 30 days and 6 months (p = 0.01 and p = 0.03, respectively), in that treatment benefit was only apparent in those patients 75 years old presenting with cardiogenic shock. Study limitations. There was no control group in REO-SHOCK because randomized studies are difficult to perform in such high-risk patients.18 Due to the proven efficacy of abciximab in high-risk patients, the investigators considered that withholding the drug in a control group would be unethical and might make the study impossible due to the unwillingness of investigators to randomize patients in the placebo group. The sample size in this study was small (n = 40), which may have affected the results of the multivariate analysis. An intraaortic balloon pump was used only in a minority of the patients. This is due to the fact that an intraaortic balloon pump is used only rarely in German hospitals, even in patients with cardiogenic shock. Since most cardiac events occur during the first weeks after STEMI, we have limited our observation period to 30 days. However, a longer follow-up would be desirable to evaluate the impact of this strategy on long-term outcome. Conclusion. Adjunctive therapy with abciximab is safe in high-risk patients with AMI and cardiogenic shock treated with primary PCI and is associated with a high procedural success rate and seems to improve outcome in patients1. Goldberg RJ, Gore JM, Alpert JS, et al. Cardiogenic shock after acute myocardial infarction. Incidence and mortality from a community-wide perspective. N Engl J Med 1991;325:1117‚Äì1122.
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