Pierre-Frédéric Keller and Marco Roffi Division of Cardiology, University Hospital of Geneva, Geneva, Switzerland
Acute coronary syndromes (ACS) are the acute manifestation of atherosclerotic coronary artery disease. Based on different presentations and management, patients are classified into nonST-segment elevation ACS (NSTE-ACS) and ST-segment elevation myocardial infarction (STEMI).
In western countries, NSTE-ACS is more frequent than STEMI.
Even if the short-term prognosis (30 days) for NSTE-ACS is more favorable than for STEMI, the long-term prognosis is similar or even worse.
Early invasive strategy is the management of choice in patients with NSTE-ACS, particularly in high-risk subgroups.
Primary percutaneous coronary intervention (PCI) is the treatment of choice for STEMI. Facilitated PCI is of no additional benefit.
The reduction of door-to-balloon time in primary PCI is critical for improved outcomes in STEMI patients.
If fibrinolytic therapy is administered in STEMI, then patients should be routinely transferred for immediate coronary angiography, and if needed, percutaneous revascularization.
High-risk ACS patients (eg, elderly patients, those in cardiogenic shock) have the greatest benefit from PCI.
Antithrombotic therapy in ACS is getting more and more complex. The wide spectrum of antiplatelet agents and anticoagulants requires a careful weighing of ischemic and bleeding risks in each individual patient.
ST-Segment Elevation Myocardial Infarction
The term acute coronary syndrome (ACS) has emerged as useful tool to describe the clinical correlate of acute myocardial ischemia. ST-segment elevation (STE) ACS includes patients with typical and prolonged chest pain and persistent STE on the ECG. In this setting, patients will almost invariably develop a myocardial infarction (MI), categorized as ST-segment elevation myocardial infarction (STEMI). The term non-ST-segment (NSTE) ACS refers to patients with signs or symptoms suggestive of myocardial ischemia in the absence of significant and persistent STE on ECG. According to whether the patient has at presentation, or will develop in the hours following admission, laboratory evidence of myocardial necrosis or not, the working diagnosis of NSTE-ACS will be further specified as NSTE-MI or unstable angina.
Recently, MI was redefined in a consensus document. The 99th percentile of the upper reference limit (URL) of troponin was designated as the cut-off for the diagnosis. By arbitrary convention, a percutaneous coronary intervention (PCI)-related MI and coronary artery bypass grafting (CABG)related MI were defined by an increase in cardiac enzymes more than three and five times the 99th percentile URL, respectively. The application of this definition will undoubtedly increase the number of events detected in the ACS and the revascularization setting. The impact on public health as well as at the clinical trial level of the new MI definition cannot be fully foreseen.
The extent of cellular compromise in STEMI is proportional to the size of the territory supplied by the affected vessel and to the ischemic length of time. Therefore a quick and sustained restoration of normal blood flow in the infarct-related artery is crucial to salvage myocardium and improve survival.
Primary PCI Versus Thrombolytic Therapy
Primary percutaneous coronary intervention became increasingly popular in the early 1990s. Evidence favoring this strategy in comparison with thrombolytic therapy is substantiated by a meta-analysis of 23 randomized trials demonstrating that PCI more efficaciously reduced mortality, nonfatal reinfarction, and stroke (Fig. 1.1). The advantage of primary PCI over thrombolysis was independent of the type of thrombolytic agent used, and was also present for patients who were transferred from one institution to another for the performance of the procedure. Therefore, primary PCI is now considered the reperfusion therapy of choice by all the guidelines. With respect to bleeding complications, a recent meta-analysis demonstrated that the incidence of major bleeding complications was lower in patients treated with primary PCI than in those undergoing thrombolytic therapy. In particular intracranial hemorrhage, the most feared bleeding complication, was encountered in up to 1% of patients treated with fibrinolytic therapy and in only 0.05% of primary PCI patients. The algorithm for treatment of patients admitted for a STEMI is presented in Fig. 1.2.
Advantages of Primary PCI
More than 90% of patients treated by primary PCI achieve normal flow (thrombosis in myocardial infarction [TIMI] grade flow 3) at the end of the intervention, while only 65% of patients treated by thrombolytic therapy benefit from this degree of reperfusion (Table 1.1). In addition, thrombolyis is characterized by a rapidly decreased efficacy after 2 hours of symptom onset (Fig. 1.3). There is a close relationship between the quality of coronary flow obtained after reperfusion therapy and mortality, and the prognosis of patients in whom flow normalization is not achieved is similar to that of patients with persistent vessel occlusion. The classification of TIMI myocardial blush grade allows an estimate of the tissue-level perfusion (Table 1.1). A critical link between lower TIMI myocardial blush grade, expression of a microcirculatory compromise, and mortality has been demonstrated in patients with normal epicardial flow following reperfusion therapy. The improvement of clinical outcomes with primary PCI versus thrombolysis is also the consequence of a lower rate of reocclusion (0-6%). Accordingly, with thrombolytic therapy, reocclusion may occur in over 10% of cases even among patients presenting within the first 2 hours of symptom onset.
Mechanical complications of STEMI, such as acute mitral regurgitation and ventricular septal defect, were reduced by 86% by primary PCI compared with thrombolytic therapy in a meta-analysis of the GUSTO-1 and PAMI trials. Free wall rupture was also significantly reduced by primary PCI. Finally, primary PCI may allow earlier discharge (2-3 days following PCI versus 7 days following fibrinolytic therapy for uncomplicated courses).
Decreasing the Time to Reperfusion in Primary PCI
The survival benefit of reperfusion associated with thrombolytic therapy shrinks with increasing delay in the administration of the agent. For stable patients undergoing primary PCI, no association between symptom-onset-to-balloon time and mortality was observed in the U.S. NRMI registry. In contrast, a significant increase in mortality was detected for patients with a door-to-balloon-time greater than 2 hours. Therefore, the findings of primary PCI trials may be only applicable to hospitals with established primary PCI programs, experienced teams of operators, and a sufficient volume of interventions. Indeed, an analysis of the NRMI-2 registry demonstrated that hospitals with less than 12 primary PCIs per year have a higher rate of mortality than those with more than 33 primary PCIs per year. Useful tools to decrease the door-to-balloon time are described in Table 1.2.
Challenging Groups of Patients
Concomitant High-Grade Non-Culprit Lesions
The timing of revascularization of severe nonculprit lesion treatment in patients with multivessel disease undergoing primary PCI has long been debated. Multivessel PCI in stable STEMI patients was found to be an independent predictor of major adverse cardiac events (MACE) at 1 year. However, a recent study suggested that systematic revascularization of multivessel disease at the time of primary PCI in contrast to ischemiadriven revascularization may be of advantage because incomplete revascularization was found to be a strong and independent risk predictor for death and MACE. Another study supported the notion that complete revascularization improved clinical outcomes in STEMI patients with multivessel disease. Accordingly, the study showed a significant lower rate of recurrent ischemic events and acute heart failure during the indexed hospitalization. Nevertheless, current American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend that PCI of the non-infarct artery should be avoided in the acute setting in patients without hemodynamic instability.
The incidence of cardiogenic shock in acute MI patients is in decline, accounting for approximately 6% of all cases. As the result of the increasing use of primary PCI, the shock-related mortality has decreased. Accordingly, a U.S. analysis showed mortality rates in shock of 60% in 1995 and 48% in 2004, while the corresponding primary PCI rates were 27% to 54%. In the SHOCK trial, early revascularization was associated with a significant survival advantage. In the study, approximately two-thirds of patients in the invasive arm were revascularized by PCI and one-third by CABG surgery. Thrombolysis was administered in 63% of patients allocated to the medical stabilization arm. Early revascularization is strongly recommended for shock patients younger than 75 years. In older patients, revascularization may be considered in selected patients.
In the last two decades, hemodynamic support devices have been developed to limit endorgan failure in the setting of cardiogenic shock. The intraaortic balloon pump (IABP) is the most commonly used mechanical support device. Percutaneous left atrial-to-femoral arterial bypass assistance, and more recently the Impella Recover microaxial left ventricular and/or right ventricular assist device, have been developed to increase cardiac output. However, no randomized clinical data exist to support the benefit of this device. Percutaneous cardiopulmonary bypass support using extracorporeal membrane oxygenation (ECMO) can be used in cardiogenic shock for a longer period of time than the other devices just described. However, while ECMO has excellent oxygenation properties, it provides only limited cardiac output support.
Elderly patients present more frequently with nonST-segment elevation myocardial infarction (NSTEMI) than with STEMI. As many as 80% of all deaths related to MI occur in persons older than 75 years of age. With respect to STEMI, up to two-thirds may occur in patients older than 65 years of age. Although, fibrinolytic therapy has been shown to be as effective in the elderly as in younger patients for achieving TIMI-3 flow, the percentage of patients eligible for this therapy decreases with advancing age due to comorbid conditions. The Senior PAMI trial randomized 483 patients [greater than or equal to] 70 years old who were eligible for thrombolysis to primary PCI versus thrombolytic therapy. A substantial benefit of PCI was seen in patients aged 70 to 80 with a 37% reduction in death, and a 55% reduction in the composite end point of death, MI, or stroke. Among patients older than 80 years of age, the prognosis was poor in both the PCI and thrombolytic arms. Based on these findings and on the increased delay of reperfusion observed in this population, primary PCI is the preferred revascularization approach.
Few studies have evaluated whether mechanical reperfusion is beneficial in patients presenting >12 hours from symptom onset. The OAT trial demonstrated in patients randomized to conservative medical therapy or late PCI that stable patients do not clinically benefit from late invasive strategy after MI. This was confirmed with the DECOPI trial. However, in the latter trial at 6 months, left ventricular ejection fraction was 5% higher in the invasive compared with the medical group (p = 0.013), suggesting that mechanical revascularization may improve ventricular remodeling and function. The BRAVE-2 investigators randomized 365 patients with STEMI (between 12 and 48 hours from symptom onset) to PCI with abciximab versus conservative care. Infarct size measured by sestamibi was smaller in the invasive group, with a favorable trend with respect to composite clinical end points. These data suggest that the benefit of primary PCI may extend beyond the traditional 12-hour window.
Rescue and Urgent PCI Following Thrombolytic Therapy
Because of the high rate of primary failure of fibrinolysis, in the absence of reperfusion rescue PCI must be considered 60 to 90 minutes after thrombolytic therapy. Suggestive of primary failure are persistent, severe, or worsening chest pain, dyspnea, diaphoresis, persistent or worsening ST segment elevation, and hemodynamic or rhythmic instability. According to the ACC/AHA guidelines, reduction of > 50% of the initial ST segment elevation on ECG at 60 to 90 minutes after thrombolytic therapy is suggestive of reperfusion, and > 70% reduction is considered as complete resolution. Among 1398 STEMI patients presenting within 6 hours of symptom onset, the 35-day mortality rate for complete, partial (30-70%), or no resolution of ST segment elevation at 3 hours was 2.5%, 4.3%, and 17.5%, respectively (p < 0.0001). This relationship was observed in both anterior and inferior wall infarction. In the study, the degree of ST segment resolution was the most powerful clinical predictor of 35-day mortality. In the InTIME-II trial, the prognostic impact of ST segment resolution at 60 versus 90 minutes was compared among 1797 patients. Patients with ST segment resolution at 60 minutes had a lower mortality rate at 30 days and 1 year compared to those with resolution at 90 minutes. These findings suggest that ST segment should be routinely reassessed at 60 minutes and, in the absence of reperfusion, patients should undergo rescue PCI.
Facilitated PCI refers to the administration of an urgent pharmacologic therapy (ie, thrombolysis, GP IIb/IIIa inhibitor, or a combination) followed by systematic early PCI. Although the international European Society of Cardiology (ESC) and ACC/AHA guidelines recommended a door-to-balloon time for primary PCI of less than 90 minutes, a survey of 4278 patients transferred for primary PCI from the U.S. NRMI registry found that only 4% and 15% of them were treated within 90 and 120 minutes, respectively. In the CAPITAL AMI trial, 170 high-risk STEMI patients were randomized to full-dose tenecteplase or full-dose tenecteplase followed by immediate transfer for PCI. The composite primary end point of death, recurrent MI, recurrent unstable ischemia, or stroke at 6 months was significantly decreased by facilitated PCI (11.6% vs. 24.4 %, p = 0.04). The reduction was driven by a decrease in recurrent ischemia.
The ASSENT-4 trial randomized 4000 patients with STEMI of less than 6 hours from symptom onset to full dose tenecteplase or placebo prior to primary PCI. The composite primary end point was death, heart failure, or shock within 90 days. The study was stopped prematurely because of a significant increase in mortality in the tenecteplase group (6% vs. 3%, p = 0.0105) (Fig. 1.4). A meta-analysis of facilitated PCI trials showed that GP IIb/IIIa inhibitor-facilitated PCI had no advantages in term of post-procedure TIMI 3 grade flow and clinical end points. Similarly, no benefit in terms of ischemic event reduction but a greater bleeding risk was observed in facilitated PCI with abciximab and half-dose reteplase compared with primary PCI. Therefore, facilitated PCI should be avoided.
Adjunctive PCI After Successful Thrombolysis
In the CARESS-in-AMI trial, among 600 high-risk STEMI patients treated with reteplase, randomization to immediate transfer for urgent PCI was associated with a significant decrease in the composite end point of death, reinfarction, or refractory ischemia at 30 days compared to a conservative approach. In the TRANSFER-AMI trial, high-risk STEMI patients were randomized to tenecteplase or tenecteplase and transfer for PCI within 6 hours of fibrinolysis. The 30-day composite primary end point of death, recurrent MI, congestive heart failure, severe recurrent ischemia, or shock occurred in 16.6% of patients in the control group and in 10.6% of patients in the invasive group (p = 0.0013). No difference was noted in bleeding complications. The optimal timing of routine angiography and possible PCI after fibrinolytic therapy for STEMI has not been determined. Evidence from the GRACIA-2 trial suggests that PCI within 3 to 12 hours after fibrinolysis is both safe and effective. Therefore following fibrinolytic therapy, patients should be routinely transferred for immediate coronary angiography.
Excerpted from Current Best Practice in Interventional Cardiology Copyright © 2010 by Blackwell Publishing. Excerpted by permission.
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