Time to Coronary Angiography and Outcomes Among Patients With High-Risk Non–ST-Segment–Elevation Acute Coronary Syndromes
Results From the SYNERGY Trial
Background— Optimal timing for an early invasive strategy in patients with non–ST-segment–elevation acute coronary syndrome remains unclear. We evaluated the relationship between time from hospital admission to coronary angiography and outcomes in high-risk patients with non–ST-segment–elevation acute coronary syndrome who underwent angiography within 48 hours of admission.
Methods and Results— Data from 10 027 patients enrolled in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial were analyzed. Patients were grouped by 6-hour intervals of time from hospital admission to coronary angiography. Primary outcomes were 30-day death or myocardial infarction, in-hospital Thrombolysis In Myocardial Infarction (TIMI) and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) major bleeding, and blood transfusion. Adjusted estimates of event rates were obtained by use of a multivariable methodology that included possible confounders through baseline and accounted for propensity of time to angiography. The landmark method was used to calculate odds ratios and 95% confidence intervals of outcomes for each time period adjusted for baseline and postbaseline clinical events. Overall, 9216 patients (92%) underwent angiography, 6352 (63%) within 48 hours. Unadjusted and adjusted rates of death/myocardial infarction increased with increasing time to angiography. The adjusted odds ratio for death/myocardial infarction in patients receiving angiography in <6 hours was 0.56 (95% confidence interval 0.41 to 0.74), whereas after 30 hours, there was no significant benefit compared with further delayed angiography. Major bleeding and transfusion did not vary significantly across time-to-angiography intervals.
Conclusions— A decrease in the time to coronary angiography was associated with fewer ischemic outcomes and no increase in bleeding. Randomized clinical trials are needed to provide definitive evidence on optimal timing of coronary angiography but are difficult to design and conduct. Ongoing trials should instead clarify whether delaying angiography to administer aggressive upstream antithrombotic therapies is effective in the current setting of non–ST-segment–elevation acute coronary syndrome management.
Received January 12, 2007; accepted September 14, 2007.
The use of an early invasive strategy in patients with non–ST-segment–elevation acute coronary syndromes (NSTE ACS) is associated with improved outcomes, especially among higher-risk patients, and persistent benefit at long-term follow-up.1–7 The revised American College of Cardiology/American Heart Association guidelines for NSTE ACS released in 2007 include a Class IA recommendation for an early invasive strategy in patients with high-risk features.8
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Clinical Perspective p 2677
Only limited evidence is available, however, on the most appropriate time to perform coronary angiography in NSTE ACS patients scheduled to receive an early invasive strategy because the relationship between time from hospital admission to coronary angiography and outcomes has never been established. The use of an expedited coronary angiography strategy (ie, angiography during the first hours after admission) can hasten the definitive treatment of patients (including the earlier use of percutaneous coronary intervention [PCI]), may reduce the need for prolonged infusion of antithrombotic therapies (thus potentially reducing the risk of bleeding), and may result in a shortened hospitalization. On the other hand, an expedited coronary angiography strategy may render less effective the use of upstream antithrombotic treatments preceding PCI and may increase the number of “off-hours” procedures.
Using data from the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial,9 we sought to evaluate the relationships between the time interval from hospital admission to coronary angiography and ischemic and hemorrhagic outcomes among high-risk patients with NSTE ACS treated with an early invasive strategy (defined as coronary angiography within 48 hours of hospital presentation).
The rationale, enrollment criteria, design, and end points of SYNERGY have been described previously.9,10 In brief, patients admitted to participating hospitals were eligible if they had ischemic symptoms for ≥10 minutes within 24 hours and the presence of ≥2 of the following high-risk characteristics: age ≥60 years, troponin or creatine kinase-MB elevation above the upper limit of normal, or ST-segment depression or transient ST-segment elevation on ECG. Key exclusion criteria were active bleeding, PCI, or thrombolysis within the 24 hours preceding enrollment and calculated creatinine clearance <30 mL/min.
Eligible patients were randomized to receive either enoxaparin or unfractionated heparin (UFH). All patients were treated with aspirin and/or clopidogrel daily, and the use of glycoprotein (GP) IIb/IIIa inhibitors was encouraged.
Overall, 10 027 patients were enrolled in SYNERGY, 9188 (92%) of whom underwent coronary angiography during the index hospitalization. A total of 6352 patients (63%) received coronary angiography within 48 hours of presentation. Patients included in each of the analyses performed are detailed in Figure 1.
The primary efficacy end point was the combined incidence of all-cause death and nonfatal myocardial infarction (MI) during the 30 days after randomization in the trial. A blinded clinical events committee adjudicated all suspected incidents of MI according to prespecified definitions.10 Safety end points were the in-hospital occurrence of non–CABG-related major bleeding, defined with both the Thrombolysis In Myocardial Infarction (TIMI) scale and the Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries (GUSTO) scale, and non–CABG-related transfusions. Transfusion was defined as any transfusion of packed red blood cells or whole blood.
The overarching hypothesis of the present analysis was that time to coronary angiography was related to variations in the risk of ischemic and bleeding events, and the primary goal of the analysis was to evaluate the patterns of ischemic and bleeding complications by time to angiography among high-risk NSTE ACS patients treated with an early invasive strategy. Time from hospital admission to coronary angiography was divided into 6-hour intervals. Differences between groups in baseline characteristics, in-hospital medications/interventions, and crude event rates were tested with the Pearson χ2 test for categorical variables and the Kruskal-Wallis test for continuous variables. A Cox proportional hazards model was used to evaluate the predictors of time from hospitalization to angiography.
Analysis of the outcomes of patients with varying times from hospitalization to angiography with the use of observational data is complicated by several issues. First, patients were not randomized to have angiography within a particular time from hospitalization, and therefore, differences in outcomes may reflect differences in patient characteristics or practice patterns rather than differences in time to angiography. Second, some patients may have had an outcome before having angiography, which makes it difficult to analyze such patients by standard methods. In an attempt to overcome these issues, 2 different approaches were used: (1) a recently developed methodology that obtains the estimated probability of an adverse event as a function of time to treatment,11 and (2) the landmark method, in which time to treatment is divided into “landmark” time intervals, and odds ratios (ORs) are calculated for each landmark time interval.12
Estimated Rates for 30-Day Death or MI and In-Hospital Major Bleeding
A method developed and validated by Johnson and Tsiatis11 was used to estimate the probability of 30-day death/MI, in-hospital major bleeding, and transfusion rates as a function of the time interval between hospitalization and angiography. For any particular category of time from hospitalization to angiography (here denoted as “x”), the method estimates an event rate (mean response) as a weighted average of outcomes from the patients who either (1) had angiography within the time x from hospital admission or (2) had an event within the time period x or earlier. The methodology provides the proportions of events for different time-to-angiography interval “policies”—that is, the mean response that would be observed if all populations were treated according to this policy. The weights were obtained by fitting the Cox proportional hazards model to time from the hospitalization to angiography, with patients who had an event before angiography considered censored at the time of the event. Outcomes of patients who received angiography within the time period x from hospitalization were weighted by the inverse probability of having angiography within that time period x, and the estimate of the event rate for each time-to-angiography interval was calculated as the weighted average of these outcomes.
This method of estimating mean event rates is valid under the assumption that the model for time from hospitalization to angiography is correct. Although this assumption is difficult to verify, investigators selected all potential known confounders when designing this observational analysis, so that no obvious confounder was excluded.
The Landmark Method
The landmark method was used to evaluate the effect of coronary angiography as a time-dependent variable on a “delayed” outcome (30-day death/MI and in-hospital major bleeding).12 The time to angiography was broken into the same 6-hour periods (landmark times). The null hypothesis underlying the landmark analysis was that the risk of ischemic and bleeding events from the landmark does not depend on time of angiography. For each of the 6-hour periods, the analysis compared patients who had angiography within this period with those who had angiography any time later during the index hospitalization or who never had angiography, within the subset of patients who had not yet had an outcome before the end of this 6-hour period. Thus, the end of each subsequent 6-hour period was treated as a new “baseline.” The comparison was made by fitting a logistic regression model for 30-day death/MI with angiography within the 6-hour period in the model and adjusting for baseline variables (age, Killip class 3 or 4, US patient, white race, sex, heart rate, diabetes mellitus, ST elevation, positive biomarker, creatinine clearance, hemoglobin, hematocrit, randomized treatment [UFH or enoxaparin], time of hospital admission [morning, afternoon, evening, or night], hospital admission on a Friday, and hospital admission on a Saturday), and events (shock, investigator-diagnosed recurrent ischemia, or GUSTO bleeding) that occurred before the end of the 6-hour period. The model incorporated correlation between patients within hospitals and was fitted with generalized estimating equation methodology. ORs for 30-day death/MI and 95% confidence intervals were calculated. Because the interest of the analysis was in the overall pattern of results according to landmark times (rather than single landmarks), no correction for multiple comparisons was done. The same methodology was adopted for the analysis of major bleeding and transfusion. The advantage of this approach is that it minimizes survivor bias by only comparing patients who were free of events at the end of each 6-hour time period during which a patient could have had angiography and also that it incorporates time-dependent clinical events that may have been associated with both timing of angiography and outcome. A more extensive statistical methods section is provided as an online-only Data Supplement.
The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
Baseline Characteristics and Predictors of Timing of Cardiac Catheterization
Baseline characteristics of patients grouped by time-to-angiography intervals are shown in Table 1 and Data Supplement Table I. Overall, patients who received an earlier angiography tended to be slightly younger, less frequently had a history of MI and PCI, and less frequently presented with positive cardiac markers but had a higher prevalence of ST-segment changes.
The multivariable Cox model showed that admission to a US hospital was the variable most strongly associated with shorter time to cardiac catheterization (Table 2). Admission on Friday and Saturday was associated with longer time to angiography. Increasing age, elevated cardiac markers at presentation, and signs of heart failure (increased heart rate and Killip class ≥2) were also associated with longer time to angiography.
In-Hospital Treatment and Procedures
Table 3 and Data Supplement Table II display in-hospital treatments and procedures by time-to-angiography intervals. Patients who received coronary angiography earlier more often received a periprocedural GP IIb/IIIa inhibitor but less often received treatment with upstream GP IIb/IIIa inhibitors. Patients with shorter time to angiography also more frequently received PCI.
Thirty-Day Death or MI
Unadjusted rates of 30-day ischemic events are reported in Table 4 and Data Supplement Table III. For descriptive purposes, unadjusted 6-month event rates are also shown in Data Supplement Table IV. Adjusted estimates of 30-day death/MI rates increased as time-to-angiography intervals became longer (Figure 2). Similar results were found in the landmark analysis, in which patients who received earlier coronary angiography in each time interval up to 30 hours had a significant reduction in the risk of 30-day death/MI compared with patients who received angiography at any later time or who never received angiography (Figure 3).
This observational analysis from a large, randomized, multicenter clinical trial examining patients with high-risk NSTE ACS who were treated with an early invasive strategy shows that shorter time to coronary angiography was associated with decreased risk of 30-day death/MI, whereas bleeding did not appear to be associated with time to angiography. The analysis also shows that the strongest predictors of time to coronary angiography were characteristics unrelated to patients’ clinical status, such as admission to US hospitals, which highlights regional differences in strategies for treating patients with NSTE ACS, and day of admission. On the other hand, patients with higher-risk features tended to receive later angiography.
Previous Data on Timing of Coronary Angiography in NSTE ACS
The results of trials comparing an early invasive versus a conservative approach in patients with NSTE ACS and the subsequent guidelines recommendation based on them support the use of an early invasive strategy.1–3,8 However, there are still several unanswered questions about the optimization of an early invasive strategy, including the choice of concomitant antithrombotic and antiplatelet strategies and the optimal timing of coronary angiography. In this context, the benefit of an early invasive strategy over a conservative approach has recently been questioned.13
The median time to coronary angiography adopted in the 3 major randomized clinical trials showing the superiority of an early invasive strategy ranged from 22 hours to 4 days.1–3 Because the FRagmin and fast revascularization during InStability in Coronary artery disease (FRISC) II trial,1 which had the longest time to angiography, was the only study that demonstrated a reduction in mortality, it has been hypothesized that delaying coronary angiography may reduce potential complications of coronary interventions by allowing a more sustained administration of antithrombotic therapies.
The question of optimal timing of an early invasive strategy in NSTE ACS has been investigated directly in only 1 small randomized clinical trial, the Intracoronary Stenting with Antithrombotic Regimen COOLing-off (ISAR-COOL) study, which randomized patients to receive either 3 to 5 days (median time 86 hours) of prolonged antithrombotic therapy followed by coronary angiography (“cooling off” strategy) or an expedited coronary angiography strategy (within 6 hours, median time 2.4 hours).14 The trial showed that a significant benefit in rates of 30-day death/MI was derived from the use of an expedited angiography strategy (11.6% versus 5.9%). However, the study had a modest sample size and did not include patients who received angiography between 6 and 48 hours, when most coronary angiographies are performed in current practice.15 Results from observational analyses, which generally use categorization of times to coronary angiography into large groups, have shown contradictory results.15–18 Furthermore, such studies adopted standard statistical methodologies that were not tailored for this particular type of analysis.
Despite the lack of definitive data, the time to coronary angiography has decreased progressively in the United States over the past decade, perhaps indicating increased acceptance of the expedited coronary angiography strategy by clinicians and hospitals.9,15,19,20 Clarification of whether time to angiography has any impact on outcomes in high-risk NSTE ACS patients, therefore, is important for balancing optimal patient care with resource use and availability, especially as the latter pertain to access to rapid coronary angiography and duration of hospital stay.
Implications of Different Time-to-Angiography Strategies
The results of the present analysis indicate a trend of increased risk of 30-day death/MI associated with delayed coronary angiography, which was observed up to 30 hours. Even if the present analysis was not intended to provide pairwise comparisons among time-to-angiography subgroups, patients who received coronary angiography in the first 6 hours appeared to have the greatest risk reduction. The analysis did not suggest that delaying coronary angiography provides any benefit. Major bleeding and transfusion did not appear to be affected by the time to coronary angiography.
A statistical methodology designed to account for issues related to this particular type of analysis, including lack of randomization, time sensitivity, survivor bias, and postbaseline nature of the variable, was adopted,11,12 yet the role of unmeasured confounders or other potential methodological limitations cannot be excluded. Nonetheless, the results of the present study are consistent with the data from the ISAR-COOL study.14
In addition to the findings of the ISAR-COOL trial, the present analysis provides information on the association between time to coronary angiography and outcomes in the entire 48-hour time window during which most coronary angiographies are performed in current practice of care.15 The benefits of earlier angiography and interventions are indeed clinically plausible. First, a faster characterization of the coronary anatomy with the possible identification of a culprit lesion allows a rapid adoption of the definitive treatment (ie, PCI, CABG, or medical management). Interestingly, we observed that the frequency of PCI as definitive treatment decreased as the time to coronary angiography increased, a finding similar to that of the ISAR-COOL trial.14 Whether this finding reflects a higher likelihood of identifying a culprit lesion suitable for PCI during the first hours or is due to other factors, including the play of chance or increasing comorbidity, requires further evaluation. Second, for those patients undergoing PCI, a delayed intervention may be associated with an older and more organized intracoronary thrombus and may result in a higher incidence of distal microembolization, which leads to an increased risk of periprocedural myocardial necrosis.21,22
Although a large randomized clinical trial would be required to identify definitively the optimal time for coronary angiography in NSTE ACS, such a trial would be challenging for practical, financial, and methodological reasons. Participating sites may be unwilling or unable to change their policies and practices on timing of coronary angiography. Moreover, such a study would be difficult to fund because it would not involve a marketable product. Methodological challenges include the natural lag from hospitalization to randomization, the large sample size required, and the adjudication of postprocedural MIs in patients receiving expedited interventions. In spite of these considerations, we believe that a well-designed observational analysis may provide useful information on optimal timing of coronary angiography in the management of NSTE ACS. Other relevant questions related to the timing of coronary angiography need to be answered, in particular whether there is any advantage in delaying coronary angiography to administer upstream treatments with aggressive antithrombotic agents, such as GP IIb/IIIa inhibitors, before PCI23 or whether hastening coronary angiography may reduce the need for complex antithrombotic regimens in favor of more moderate antithrombotic strategies.24
Patients were not randomized to a particular time to angiography, and therefore, those with different times to angiography may not be directly comparable. Despite the use of a propensity-based methodology, we cannot rule out that unmeasured confounders may have affected our results. Second, time to coronary angiography is a postbaseline, time-dependent variable that may be influenced by several factors. Furthermore, patients may have had an MI or died before having angiography, and patients who had angiography later had to be event-free long enough to have undergone angiography. We have attempted to address these issues by using statistical methodologies previously developed and validated to deal with analyses of time-dependent and postbaseline variables. Third, the 6-hour definition of time-to-angiography intervals was arbitrary but was decided during the design of the present analysis. Fourth, the analysis focused on actual time to angiography (from hospital admission) instead of time from randomization to angiography, which would have led to spurious time-to-angiography data. Therefore, we could not include potential events that occurred from hospital presentation to randomization in the analysis. However, given the short time from hospitalization to randomization (median time 10 hours) and the exclusion criteria of the trial, it is unlikely that such a significant number of events occurred before randomization as to flaw the present results. Finally, the definition of recurrent MI in patients with ACS is complex. Most patients enrolled in the SYNERGY trial had positive markers at baseline, and, in the first hours after an acute event, postprocedural release of cardiac markers is more difficult to distinguish from raised levels due to the baseline MI. We performed a sensitivity analysis among patients with negative cardiac markers, and the results were consistent with the overall analysis. However, the complexity in the definition of recurrent MI in this particular setting should be taken into account when the present results are interpreted.
The data from this observational analysis from the SYNERGY trial suggest that high-risk patients with NSTE ACS who received earlier coronary angiography had a decreased risk of death/MI through 30 days, whereas timing of angiography did not appear to be related to bleeding. Although randomized clinical trials that would provide definitive evidence on optimal timing of coronary angiography in NSTE ACS may prove challenging, ongoing trials will clarify whether delaying coronary angiography for the administration of aggressive upstream antiplatelet treatments is an effective strategy. Meanwhile, the results of the present analysis support the use of a rapid invasive coronary angiography strategy as a viable management strategy.
The authors thank Amanda McMillan for her expert editorial assistance in preparing the manuscript.
Source of Funding
The SYNERGY trial was funded by sanofi-aventis.
Drs White, Kleiman, Aylward, Langer, Califf, Ferguson, Antman, Harrington, Goodman, and Mahaffey have received research grants from sanofi-aventis. Drs Gulba, White, Aylward, Ferguson, and Newby have served on the speakers’ bureau for sanofi-aventis. The following authors have received honoraria or consulting fees from sanofi-aventis: Drs Steinhubl, White, Aylward, Langer, Califf, Ferguson, Antman, Harrington, Goodman, and Mahaffey. The remaining authors report no conflicts.
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The use of an early invasive strategy in patients with non–ST-segment–elevation acute coronary syndromes (NSTE ACS) is associated with improved outcomes, especially among higher-risk patients, and persistent benefit at long-term follow-up. Because of this association, the revised American College of Cardiology/American Heart Association guidelines for NSTE ACS released in 2007 include a Class IA recommendation for an early invasive strategy in patients with high-risk features. However, optimal timing for early invasive strategy in patients with NSTE ACS remains unclear. In this study, we evaluated the relationship between time from hospital admission to coronary angiography and outcomes in high-risk patients with NSTE ACS who underwent angiography within 48 hours. The results of our analyses showed that a shorter time to coronary angiography was associated with decreased risk of 30-day death/myocardial infarction, whereas bleeding did not appear to be associated with time to angiography. The analyses also showed that 2 variables, admission to US hospitals and day of admission, both of which are unrelated to patient clinical status, were the most powerful predictors of time to angiography, which underscores regional differences in the treatment of patients with NSTE ACS. Although randomized clinical trials could be expected to provide convincing evidence on the optimal timing of coronary angiography in NSTE ACS, they will prove challenging to complete. Current ongoing trials will at least clarify whether delaying coronary angiography for the administration of aggressive upstream antiplatelet treatments is an effective strategy. Meanwhile, the results of these analyses support the use of a rapid invasive coronary angiography strategy as a viable management strategy.
Guest Editor for this article was Thomas Ryan, MD.
The online-only Data Supplement, consisting of tables and an expanded Methods section, is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.690081/DC1.
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00043784.