Author + information
- Received June 15, 2009
- Revision received October 7, 2009
- Accepted November 9, 2009
- Published online April 6, 2010.
- Paul Sorajja, MD*,
- Bernard J. Gersh, MB, ChB, DPhil*,
- David A. Cox, MD‡,
- Michael G. McLaughlin, MD†,
- Peter Zimetbaum, MD†,
- Costantino Costantini, MD#,**,
- Thomas Stuckey, MD§,
- James E. Tcheng, MD∥,
- Roxana Mehran, MD#,**,
- Alexandra J. Lansky, MD#,**,
- Cindy L. Grines, MD¶ and
- Gregg W. Stone, MD#,**,* ()
- ↵*Reprint requests and correspondence:
Dr. Gregg W. Stone, The Cardiovascular Research Foundation, 111 East 59th Street, 11th Floor, New York, New York 10022
Objectives The aim of this study was to determine the impact of delay to angioplasty in patients with acute coronary syndromes (ACS).
Background There is a paucity of data on the impact of delays to percutaneous coronary intervention (PCI) in patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS) undergoing an invasive management strategy.
Methods Patients undergoing PCI in the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial were stratified according to timing of PCI after clinical presentation for outcome analysis.
Results Percutaneous coronary intervention was performed in 7,749 patients (median age 63 years; 73% male) with NSTE-ACS at a median of 19.5 h after presentation (<8 h [n = 2,197], 8 to 24 h [n = 2,740], and >24 h [n = 2,812]). Delay to PCI >24 h after clinical presentation was significantly associated with increased 30-day mortality, myocardial infarction (MI), and composite ischemia (death, MI, and unplanned revascularization). By multivariable analysis, delay to PCI of >24 h was a significant independent predictor of 30-day and 1-year mortality. The incremental risk of death attributable to PCI delay >24 h was greatest in those patients presenting with high-risk features.
Conclusions In this large-scale study, delaying revascularization with PCI >24 h in patients with NSTE-ACS was an independent predictor of early and late mortality and adverse ischemic outcomes. These findings suggest that urgent angiography and triage to revascularization should be a priority in NSTE-ACS patients.
There is a general consensus that an early invasive strategy leads to improved clinical outcomes in moderate- and high-risk patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS) (1–5). Randomized clinical trials have demonstrated that the benefits of an early invasive strategy in these patients occur early, persist in long-term follow-up, and are particularly evident in high-risk patients. These observations have led to the adoption of an early invasive strategy in the management of many patients with NSTE-ACS, with angiography typically performed within 48 to 72 h of hospital admission (6,7).
Nonetheless, within the framework of an early invasive strategy, there is a paucity of data on precisely when angiography and revascularization should take place in patients with NSTE-ACS (8–12). Expeditious angiography and revascularization might hasten definitive management, reduce the need for prolonged antithrombotic therapy and its potential associated complications (i.e., bleeding), and lead to shortened hospital stay. One modest-sized randomized trial of immediate versus delayed cardiac catheterization in patients with NSTE-ACS found a significant reduction in death and myocardial infarction (MI) among patients who underwent angiography <6 h after hospital admission versus several days later (13). A second, larger randomized trial found no benefit of early intervention for NSTE-ACS, except in those patients who were at high risk (14). Some studies have reported fewer complications when revascularization with percutaneous coronary intervention (PCI) is performed after several days of medical stabilization (11). Because the implications for patient management and the timing of triage are potentially substantial, further data are needed on the relationship between clinical presentation and time to revascularization in patients with NSTE-ACS.
Accordingly, with data from the large-scale, prospective, controlled ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial, we sought to examine the appropriate timing of revascularization with PCI after clinical presentation in patients with NSTE-ACS.
The details of the ACUITY trial protocol have been previously published (15,16). Briefly, the ACUITY trial was a prospective, open-label, randomized, multicenter trial in which patients with NSTE-ACS undergoing an early invasive management strategy were randomized to receive 1 of 3 antithrombotic regimens: 1) unfractionated or low molecular weight heparin plus a glycoprotein IIb/IIIa inhibitor; 2) bivalirudin plus a glycoprotein IIb/IIIa inhibitor; or 3) bivalirudin alone. Patients were eligible for study participation if they were ≥18 years of age with symptoms of NSTE-ACS within the preceding 24 h and if 1 or more of the following criteria were met: new ST-segment depression or transient elevation of ≥1 mm; elevations in the troponin I, troponin T, or creatine kinase-MB levels; known coronary artery disease; or all 4 other variables for predicting Thrombolysis In Myocardial Infarction (TIMI) risk scores for unstable angina (17). Exclusion criteria were ST-segment elevation MI or cardiogenic shock; bleeding diathesis or major bleeding episode within 2 weeks; thrombocytopenia; a calculated creatinine clearance rate of <30 ml/min; recent administration of abciximab, warfarin, fondaparinux, fibrinolytic agents, bivalirudin, or 2 or more doses of low-molecular-weight heparin; and allergy to any of the study drugs or to iodinated contrast medium that could not be controlled in advance with medication.
Patients who were randomized to a glycoprotein IIb/IIIa receptor inhibitor were randomized further to receive the drug immediately after randomization (i.e., upstream) or only at the time of PCI. Angiography was performed within 72 h in all patients. Of the 13,819 patients enrolled in the ACUITY trial, 7,789 patients (56%) underwent PCI at the discretion of the local physician after diagnostic angiography. The timing of angiography was known in 7,749 of these patients who comprise the study cohort examined in the present investigation.
Definitions and end points
Clinical follow-up was performed at 1 month and 12 months. As previously described, 3 primary end points at 30 days were prespecified: composite ischemia (death from any cause, MI, or unplanned revascularization for ischemia), major bleeding (not related to coronary artery bypass grafting [CABG]), and net adverse clinical events (composite ischemia or major bleeding) (15,16). Major bleeding was defined as intracranial or intraocular bleeding, hemorrhage at the access site requiring intervention, hematoma with a diameter of >5 cm, a reduction in hemoglobin levels of ≥4 g/dl without an overt bleeding source or ≥3 g with such a source, reoperation for bleeding, or transfusion of a blood product (15,16). A clinical events committee that was blinded to treatment assignment adjudicated all study end points (15,16).
Patients were stratified by time from hospital presentation to revascularization with PCI into 3 approximately equal-size groups: <8 h, 8 to 24 h, and ≥24 h. To analyze the acute risk of the patient as a potential confounder, the TIMI risk score for NSTE-ACS was calculated for each patient (0 to 2 = low-risk; 3 to 4 = intermediate-risk; 5 to 7 = high-risk) (17). Cox proportional hazards models were constructed to determine the independent correlates of adverse event outcomes with the following nominal candidate variables: age ≥75 years, male sex, diabetes mellitus, current smoker, hypertension, abnormal cardiac biomarkers, ST-segment deviation ≥1 mm, prior transient ischemic attack or stroke, anemia (baseline hemoglobin <12 g/dl or hematocrit <36% for women and hemoglobin <13 g/dl or hematocrit <39% for men), creatinine clearance <60 ml/min, multivessel coronary disease, recent medication use before admission (aspirin, beta-blockers, statins, prior antithrombin use, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, thienopyridines), and time duration ≥24 h from hospital admission to PCI. Event rates were determined and displayed with the Kaplan-Meier method with comparisons performed with the log-rank test. Categorical variables were compared with the Fisher exact test for pairwise comparisons and the chi-square test for trend for multiple comparisons. Continuous variables are expressed as medians with interquartile ranges in parentheses and were compared with the nonparametric Kruskal-Wallis test.
Tables 1 and 2⇓⇓ list the baseline, clinical, and angiographic characteristics of the overall study cohort, stratified according to time from hospital presentation to revascularization with PCI. Median time to PCI was 19.5 h in all patients and 3.5 h, 18.1 h, and 39.2 h in those undergoing PCI in <8 h, 8 to 24 h, and >24 h, respectively, after hospital presentation. Patients who underwent PCI >24 h after hospital presentation more frequently had elevation of cardiac troponins, high TIMI risk score (5 to 7), left main culprit lesion, baseline TIMI flow grade 3, prior history of diabetes mellitus, MI, left main disease, CABG, and prior use of antithrombins and thienopyridines. Patients with delay to PCI also had a lower incidence of home aspirin and beta-blocker use compared with patients who underwent earlier PCI. There was no difference in procedural success and final TIMI flow after PCI for the 3 patient groups.
30-day and 1-year clinical outcomes
Clinical follow-up was available in 7,627 patients (98%) at 30 days. There were no significant differences in the 30-day or 1-year rates of death or the combined end point of death or MI in patients who underwent PCI <8 h versus those who had PCI >8 to 24 h after clinical presentation. In contrast, patients who underwent PCI >24 h after clinical presentation had higher rates of death, MI, composite ischemia, and net adverse clinical events at 30 days in comparison with those who underwent earlier PCI (Fig. 1,Table 3). The increase in mortality and combined death or MI among patients who underwent PCI >24 h after clinical presentation persisted at 1-year follow-up (Fig. 2).
The rate of non-CABG–related major bleeding was lowest among patients who underwent PCI between 8 and 24 h after clinical presentation, with no significant difference present between patients who underwent PCI <8 h and those who underwent PCI >24 h after hospital admission. There also was no relation between PCI timing and final TIMI flow grade achieved with PCI. However, patients who underwent PCI >24 h after clinical presentation had the lowest incidence of early and late unplanned revascularization (Table 3). This lower incidence was present even though both the prevalence of multivessel disease and number of vessels treated with PCI were similar across the 3 PCI timing groups.
Impact of randomization
Within each of the 3 PCI timing groups, there were no significant differences in 30-day mortality, MI, unplanned revascularization, or composite ischemia among the 3 randomized antithrombotic regimens (p > 0.05 for all comparisons). The rate of non-CABG major bleeding, however, was lower among patients assigned to bivalirudin alone compared with a glycoprotein IIb/IIIa inhibitor-based regimen, regardless of the time delay to PCI (Fig. 3).
TIMI risk score, PCI timing, and outcome
Delay to PCI >24 h after clinical presentation was associated with significant increases in the rates of 30-day death and death or MI among both intermediate and high-risk patients (Fig. 4). In comparison with patients who had earlier PCI, high-risk patients (TIMI score = 5 to 7) who had PCI delay >24 h also demonstrated an approximately 2-fold increase in 30-day mortality. The relation between PCI delay >24 h and risk of death at 1-year follow-up persisted irrespective of the baseline TIMI risk score, although the greatest difference in death was evident in the higher-risk patients (Fig. 5).
After multivariable adjustment for differences in baseline characteristics, a delay to PCI >24 h after clinical presentation was a strong independent predictor of both death and the combined end point of death or MI at 30 days and 1 year (Tables 4 and 5).⇓
The principal findings of this investigation are: 1) delay to PCI >24 h after clinical presentation in patients with NSTE-ACS is a strong, independent predictor of increased 30-day and 1-year mortality and combined death or MI; 2) the hazard of PCI delay is greatest in the highest-risk patients and is independent of antithrombin randomization; and 3) the benefits of bivalirudin monotherapy in reducing hemorrhagic complications while affording similar suppression of ischemic complications compared with a glycoprotein IIb/IIIa inhibitor based-regimen is independent of time from presentation to PCI.
Although clinical trials have established the benefits of an early invasive strategy for the majority of patients presenting with NSTE-ACS, the appropriate timing of angiography and revascularization has not been resolved. In prior ACS studies, the timing of angiography among patients managed with an invasive strategy has varied considerably, ranging from 1 to 4 days after clinical presentation (1–5). One small randomized study has been published in which the optimal timing of PCI in patients with NSTE-ACS has been examined, the ISAR-COOL (Intracoronary Stenting With Antithrombotic Regimen Cooling-Off) trial. In this study there was a significantly lower risk of death or MI in patients with NSTE-ACS who underwent angiography <6 h after clinical presentation (median time, 2.4 h) in comparison with those randomized to angiography after 3 to 5 days of antithrombotic therapy (5.9% vs. 11.6%, p = 0.04) (13). In a second, larger randomized trial of 3,031 patients with NSTE-ACS, the TIMACS (Timing of Intervention in Acute Coronary Syndromes) trial, early angiography (median time, 14 h) did not lead to better outcomes except in patients who were at high risk (14). Other observational studies describing the impact of the timing of angiography and revascularization on the outcomes of patients with ACS have been inconsistent, with clinical benefit from expeditious angiography being evident in some but not all studies (8–12).
In the present large-scale, multicenter, randomized trial, there was a strong, independent association of PCI delay >24 h after clinical presentation with NSTE-ACS and subsequent mortality and adverse clinical outcomes. An increase in mortality was observed early with PCI delay and persisted throughout the 1-year follow-up period and was particularly evident among high-risk patients. There also was an increased risk of MI and composite ischemia among patients with PCI delay >24 h. Of note, the 30-day rate of death or MI for patients undergoing PCI <8 h after hospital admission in the present investigation (5.6%) was similar to that observed among patients who underwent early angiography in the ISAR-COOL trial (5.9%) (13). The present findings also are consistent with those recently reported in a post hoc analysis from the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa inhibitors) trial, which reported less death and MI for patients undergoing angiography within 6 h after clinical presentation (12).
In the ACUITY trial, timing of angiography and PCI was left to the discretion of the local investigator. Prior studies have identified clinical variables predictive of angiographic delay in NSTE-ACS patients (12). To help address potential selection bias, we examined the hazard of PCI delay according to patient risk at presentation (i.e., TIMI score) and also after multivariable adjustment for differences in baseline characteristics. In these analyses, there was an association between increased patient risk and the hazard of PCI delay. These findings are consistent with those of the TIMACS trial, which demonstrated less death, MI, and stroke for high-risk patients with NSTE-ACS who were randomized to earlier angiography (14). Nonetheless, even among the low-risk patients (TIMI score = 0 to 2), there was a significantly higher 1-year mortality rate in our study among those who had PCI >24 h after clinical presentation than among patients who had earlier PCI. Furthermore, multivariable analyses confirmed the independent impact of PCI delay >24 h in the overall study population for both early and late adverse events.
The present investigation, the largest to date examining the impact of treatment-related delays on patient outcomes, in which antithrombotic therapy was systematically administered to all patients before an early invasive management strategy, reconciles and extends the conflicting findings from previous reports examining the implications of treatment delays in ACS patients. In the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) trial, the lowest rates of death and MI occurred among those treated with eptifibatide and PCI within 24 h of clinical presentation (18). In this study, however, no difference in death or MI according to timing of PCI was noted for patients treated without a glycoprotein IIb/IIIa receptor inhibitor (18). Benefits of expeditious angiography for patients with NSTE-ACS have been observed in other studies in which antithrombotic and antiplatelet therapy was administered early as per current guideline recommendations (6,8,12) but not in others in which these therapies were used less frequently (10,11). Intense antiplatelet and antithrombotic therapy might be specifically beneficial in patients with NSTE-ACS undergoing very early PCI, in whom platelet activation is heightened, facilitating the safe performance of early PCI (19).
Prolonged medical therapy might theoretically be beneficial in decreasing the angiographic thrombus burden in patients with NSTE-ACS (20,21). In a pooled analysis of angiographic trials, the presence of thrombus was associated with a higher rate of abrupt closure, MI, and in-hospital repeat revascularization (22). Nevertheless, in the present study, rates of death and MI were lowest among patients who had early PCI, without increased bleeding, although the rates of unplanned revascularization were higher in this group. The explanation underlying the increased incidence of both early and late unplanned repeat revascularization among the early PCI group, also noted from the PURSUIT trial (8), is not known but might be due to more extensive and/or severe vascular disease in patients requiring earlier intervention or greater systemic inflammation in patients with NSTE-ACS requiring early PCI (8,23,24). Nonetheless, these data in aggregate support expeditious angiography and revascularization when appropriate in moderate- and high-risk patients with NSTE-ACS after initial treatment with antiplatelet and antithrombotic therapy.
Several inherent limitations of the present analysis should be acknowledged, including selection and survivor biases. Precise reasons for PCI delay were not prospectively collected, and there were significant baseline differences between groups. Although multivariable adjustment was used to correct for measured differences between the groups, we cannot exclude the presence of unmeasured confounders. For example, it cannot be known with certainty whether patients who underwent late PCI did so because they were too ill for earlier angiography or were more stable, thus not requiring very early angiography. It is important to note that this study is a post hoc analysis, and our findings should therefore be interpreted as hypothesis-generating. Of note, in analyses that examined outcome according weekend or weekday presentation, there were no differences in mortality, ischemic events, or bleeding. Bleeding rates were lower in the bivalirudin monotherapy arms for each of the PCI timing groups. Mortality did not differ according to the randomized antithrombotic regimen within each PCI timing group, but the 30-day death rates were low (≤1%).
Despite these caveats, the present findings—taken in concert with those from earlier observational studies, the randomized ISAR-COOL trial, and the randomized TIMACS trial—suggest that patients with moderate- and high-risk NSTE-ACS in whom an early invasive strategy is planned benefit from urgent triage (within 8 h) to angiography and revascularization when appropriate, particularly for those patients in whom high-risk features are present. Adopting a policy of expedited angiography for all patients with NSTE-ACS would require additional hospital staffing and potentially greater resource use and costs due to the large number of NSTE-ACS patients admitted to hospitals each year (>1.5 million in the U.S.) (25). However, this economic burden might be counterbalanced by significant reductions in mortality, ischemic outcomes, and shorter hospital stays. The present study thus warrants further large-scale, randomized investigations of expedited versus delayed angiography in patients with NSTE-ACS in whom an invasive management strategy is planned, with co-primary end points of clinical efficacy and cost-effectiveness.
Dr. Gersh is a member of the Data Safety Monitoring Board for Boston Scientific, Abbott Laboratories, Bristol-Myers Squibb, and AstraZeneca, and is a stock shareholder for CV Therapeutics. Dr. Tcheng is on the Scientific Board for Schering-Plough, and on the Speakers' Bureau for Schering-Plough and Eli Lilly. Dr. Stone is on the advisory board for Abbott Vascular and Boston Scientific.
- Abbreviations and Acronyms
- coronary artery bypass grafting
- myocardial infarction
- non–ST-segment elevation acute coronary syndrome
- percutaneous coronary intervention
- Thrombolysis In Myocardial Infarction
- Received June 15, 2009.
- Revision received October 7, 2009.
- Accepted November 9, 2009.
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