The Effect of Routine, Early Invasive Management on Outcome for Elderly Patients with NonST-Segment Elevation Acute Coronary Syndromes

Context Older patients with coronary disease are often managed conservatively. Contribution This multicenter trial involved 2220 patients with unstable angina and nonST-segment elevation myocardial infarction (MI). Subgroup analyses by age showed the following absolute reductions in 6-month death and MI for patients randomly assigned to early invasive therapy involving angiography versus medical therapy: 0.4 percentage point in patients younger than age 65 years, 4.8 percentage points in patients age 65 years or older, and 10.8 percentage points in patients older than age 75 years. Patients older than age 75 years had an absolute increase of 10.1 percentage points in major bleeding with early invasive therapy. Implications Older patients with unstable angina and nonST-segment elevation MI have fewer ischemic but more bleeding events with early invasive therapy than do younger patients. The Editors Unstable angina and nonST-segment elevation myocardial infarction (MI) result in more than 1.4 million hospital admissions in the United States each year (1). Most of these admissions involve patients older than 65 years of age, and increased age has been identified as an important risk factor for death or recurrent MI. Physicians caring for these patients are faced with immediate decisions about substantially different management strategies that may significantly affect short- and long-term outcome. The early invasive strategy entails routine cardiac catheterization and revascularization when deemed appropriate. The conservative strategy calls for in-hospital observation and predischarge stress testing; cardiac catheterization is reserved for spontaneous or inducible high-risk ischemia. Results of the recent Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative StrategyThrombolysis in Myocardial Infarction (TACTICSTIMI) 18 trial (2), the Fast Revascularisation during InStability in Coronary artery disease (FRISC) II trial (3, 4), the Randomized Intervention Trial of unstable Angina 3 (RITA 3) (5), and other studies (6, 7) suggest that routine early invasive management yields superior outcomes in a broad population of patients with unstable angina and nonST-segment elevation MI. However, because elderly persons are at greater risk for complications with catheterization and revascularization procedures, the benefit of such a strategy in this subgroup remains uncertain. Elderly persons have traditionally been underrepresented in clinical trials of acute coronary syndromes (8). Previous studies examining outcomes in elderly patients with nonST-segment elevation acute coronary syndromes who were randomly assigned to an invasive or conservative strategy have shown conflicting results. Among patients 65 years of age and older, the TIMI IIIB trial (9) demonstrated reduced occurrence of death or nonfatal MI at 1 year in those randomly assigned to a routine invasive strategy. However, for patients 60 years of age and older who had nonQ-wave MI, early invasive management in the Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) trial (10) resulted in increased rates of death and MI at 6 months. In current clinical practice, older patients with acute coronary syndromes are less likely to undergo invasive procedures than are younger patients (11-15). In addition, the cost-effectiveness of an invasive management strategy in elderly persons has not been well defined. Therefore, to help resolve current uncertainties regarding appropriate management of elderly patients with nonST-segment elevation acute coronary syndromes, we analyzed clinical outcome by age in patients who were randomly assigned to an early invasive or conservative management strategy in the TACTICSTIMI 18 trial. Methods Study Sample The study group included the 2220 patients participating in the TACTICSTIMI 18 trial. The design and methods (16, 17) and primary results (2) have been reported elsewhere. In brief, eligible patients were older than 18 years of age, presented to 169 participating hospitals in 9 countries between 18 December 1997 and 22 December 1999, and had had an episode of angina in the preceding 24 hours. The episode of angina had to be characterized by an accelerating pattern and prolonged (>20 minutes) or recurrent episodes at rest or with minimal effort. In addition, patients had to be candidates for coronary revascularization and had to have at least 1 of the following: ST-segment depression of 0.05 mV or greater, transient (<20 minutes) ST-segment elevation ( 0.1 mV), or T-wave ( 0.3 mV) inversion in 2 or more leads not known to be old; elevated levels of cardiac markers; or documented history of coronary disease. Patients were excluded if they had persistent ST-segment elevation; secondary angina; percutaneous coronary revascularization or coronary bypass surgery within the previous 6 months; a history of gastrointestinal bleeding, platelet disorder, or thrombocytopenia; any history of hemorrhagic cerebrovascular disease or a history of nonhemorrhagic cerebrovascular disease or transient ischemic attack within 1 year; left bundle-branch block or paced rhythm; severe congestive heart failure or cardiogenic shock; clinically important systemic disease; serum creatinine concentration greater than 220 mol/L (>2.5 mg/dL); treatment with a glycoprotein IIb/IIIa antagonist within the past 96 hours; or ongoing long-term treatment with ticlopidine, clopidogrel, or warfarin. The institutional review board at each center approved the study protocol. Written informed consent was required from all patients before participation. Interventions The protocol directed that participants receive aspirin, 325 mg/d (unless contraindicated); intravenous unfractionated heparin at an initial bolus of 5000 U, followed by an infusion at a rate of 1000 U/h for 48 hours titrated to an activated partial thromboplastin time of approximately 60 to 85 seconds; and tirofiban (Aggrastat, formerly owned by Merck & Co., West Point, Pennsylvania; currently owned by Guilford Pharmaceuticals Inc., Baltimore, Maryland), administered intravenously in a loading dose of 0.4 g/kg of body weight per minute for 30 minutes and followed by a maintenance infusion of 0.1 g/kg per minute for 48 hours or until revascularization (and for 12 hours after percutaneous coronary revascularization procedures). The treating physician decided whether to use other medications, such as -blockers or angiotensin-converting enzyme inhibitors. Through a centralized system, patients were randomly assigned, stratified by center, to the early invasive or conservative treatment strategy (Figure 1). Patients assigned to the early invasive treatment strategy were to undergo coronary angiography 4 to 48 hours after randomization and have revascularization when appropriate. Patients assigned to the early conservative strategy were treated medically and, if stable, underwent an exercise tolerance test before discharge. Coronary angiography was reserved for patients who had certain high-risk characteristics consistent with failure of medical therapy or stress-induced ischemia (16). Creatine kinase and the MB isoform of creatine kinase were measured on site every 8 hours for 24 hours after randomization, as well as for episodes of recurrent angina suggestive of MI and after all revascularization procedures. The TIMI risk score for patients with unstable angina and MI without ST-segment elevation was determined at baseline; this is a simple prognostication scheme providing a numerical score by summing 7 variables (age 65 years, 3 risk factors for coronary artery disease, previous coronary stenosis of 50%, ST-segment deviation on electrocardiogram at presentation, 2 anginal events in the previous 24 hours, use of aspirin in the previous 7 days, and elevated serum levels of cardiac markers) that predict death and ischemic events (18). The TIMI risk score groupings of 0 to 2, 3 to 4, and 5 to 7 have been previously shown to predict low, intermediate, and high risk for death and ischemic events (16). Figure 1. Flow diagram of the study. Outcomes and Follow-up Each patient was monitored for clinical end points before hospital discharge and had a follow-up telephone interview at day 30 and at 6 months. The last follow-up was completed in June 2000. Medical records were examined to verify all end points. Twenty-seven patients (1.2%) were lost to follow-up at 6 months and were censored at time of last documented contact. End points were defined by using standard TIMI definitions (19). The primary end point of the overall TACTICSTIMI 18 trial was the combined incidence of death, nonfatal MI, and rehospitalization for an acute coronary syndrome at 6 months. We chose the composite of death and nonfatal MI as the primary outcome measure to provide an objectively determined and widely used end point for similar outcome trials of acute coronary syndromes. Patients were monitored on site for complications of management, and bleeding was monitored for at least 24 hours after the study medication was withdrawn. Major bleeding was defined as a decrease in blood hemoglobin level of at least 50 g/L ( 5 g/dL), bleeding requiring transfusion of 2 or more units of blood, bleeding requiring corrective surgery, intracranial or retroperitoneal hemorrhage or cardiac tamponade, or any combination of these events. An independent committee whose members were unaware of patients' treatment assignments adjudicated all primary end points. Statistical Analysis The comparison of end points in patients stratified by age (<65 years vs. 65 years) was a prespecified analysis of the protocol. An additional post hoc analysis stratified patients into 4 age groups: 55 years of age or younger, older than 55 to 65 years of age, older than 65 to 75 years of age, and older than 75 years of age. Pearson chi-square analysis was used to compare categorical end points. Logistic regression analysis was used to ev