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Timing of Catheterization in NSTE-ACS
Abstract & Commentary
By Michael H. Crawford, MD Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco Dr. Crawford is on the speaker's bureau for Pfizer. This article originally appeared in the February 2008 issue of Clinical Cardiology Alert. It was peer reviewed by Rakesh Mishra, MD, FACC. Dr. Mishra is Assistant Professor of Medicine, Weill Medical College, Cornell University; Assistant Attending Physician, NewYork-Presbyterian Hospital.
Source: Tricoci P, et al. Time to coronary angiography and outcomes among patients with high-risk non-ST-segment-elevation acute coronary syndromes: Results from the SYNERGY trial. Circulation. 2007;116:2669-2677.
An early invasive approach is preferred for higher risk non-ST elevation acute coronary syndromes (NSTE-ACS), but the optimal timing of cardiac catheterization is not clear. Thus, Tricoci and colleagues used data from the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein 11b/111a Inhibitors (SYNERGY) trial to evaluate the relationships between the time from hospital admission to coronary angiography and ischemic and hemorrhagic events in over 6000 patients with NSTE-ACS treated with an invasive strategy within 48 hours of hospital admission.
Patients enrolled in SYNERGY had ischemic symptoms within 24 hours, and two or more of the following high risk features: age > 60; biomarker elevations; ST depression; or transient ST elevation. The patients were randomized to unfractionated heparin or enoxaparin; all received antiplatelet therapy, and use of GP11b/111a agents were encouraged. Patients were grouped into 6-hour intervals from hospital admission to coronary angiography. The primary outcomes were: death or myocardial infarction (MI) in 30 days; major bleeding episodes; and need for blood transfusions. Sophisticated multivariate and landmark methods were employed to adjust for confounders. In general, patients who received an earlier catheterization were younger and had ST changes on the ECG. Adjusted estimates of 30-day death/MI increased as time to angiography increased. The adjusted odds ratio for death/MI in those receiving angiography in < 6 hours was 0.56 (95%; CI 0.41 to 0.74) as compared to .84 at > 30 hours. After 30 hours, the benefit on the primary end point plateaued through 48 hours. Major bleeding and transfusion requirements, not related to coronary bypass surgery, were not associated with time of catheterization. Tricoci et al concluded that shorter times from hospital admission to coronary angiography are associated with few deaths and MIs within 30 days, without any increase in bleeding complications.
Most studies of NSTE-ACS have shown an advantage for an early interventional strategy, with regard to subsequent death and MI, but a few have not. Higher risk patients seem to benefit more from the early invasive strategy, but the definition of early in the reported studies has varied from an average of 22 hours after admission to four days. ISAR-COOL compared a < 6 hour invasive strategy to angiography after 3-5 days of cooling-off on maximal medical therapy. In that study, 30-day death or MI was less in the < 6 hour group, but no one had angiography between 6 hours and 3 days, when most cases are done outside of this trial. This timing issue is potentially important on several levels. If the problem is myocardial ischemia, then the earlier you restore adequate blood flow the better, and an early invasive strategy allows for early revascularization. If the results of a percutaneous coronary intervention (PCI) would be improved by 6 hours of preloading with clopridogrel and GP11b/111a agents, then this should be considered. There is also the issue of off-hours procedures, which cost the health care system more and may be conducted under less than ideal circumstances. Consequently, the results of this analysis of the SYNERGY trial is of interest, even though it is not a randomized trial of angiography delay times.
The results showed the best results were with angiography performed < 6 hours after admission (RR = 0.59). Between 6 and 29 hours, the RRs ranged from 0.67 to 0.76, but at 30-48 hours, they jumped to 0.84 to 0.87. Thus, < 6 hours was best, but if that isn't possible then < 30 hours is acceptable. Since this was not a randomized trial, some limitations need to be considered. Factors associated with being selected for an earlier catheterization included admission to a US hospital, younger age, white, positive biomarkers, and a weekday admission. Interestingly, higher risk patients with diabetes or heart failure received later catheterization on average. This may be due to the belief that it is better to control heart failure and diabetes before undertaking angiography. This may be true in some situations, but in ACS, where myocardial ischemia is the issue, it may not be. Clearly, this is a judgment call. I have seen patients thought to have NSTE-ACS with hypotension who, in the middle of a complicated catheterization, were found to have diabetic ketoacidosis when the admission labs came back. Also, I have seen cases thought to have NSTE-ACS with heart failure taken to the cath lab only to find there were no significant coronary lesions. Thus, sometimes in our haste to meet timing goals associated with ACS and PCI we end up putting some patients in more jeopardy.
Although the weight of evidence now seems to say that earlier is better with regard to cardiac catheterization in high risk NSTE-ACS patients, this should not trump good clinical judgment and an appreciation of the resources available at a given time.
Hopefully, < 6 hour angiography will not become some new quality improvement goal like door-to-balloon time has because these data are observational and not robust. Also, there are several problems with this type of study; adjusting for confounders has its limits. For example, PCI was more often done when the patients were cathed early, and less often when done later. Presumably, this was anatomically driven, which suggests that those with true myocardial ischemia were being selected for early intervention. Of course there may be other explanations such as medical therapy reduces the need for PCI. The end point of death or MI is standard in these types of studies, but MI is problematic since many patients with NSTE-ACS have biomarker positivity and presumably have an MI. When does the initial MI end and a new one begin? Of note, when Tricoci et al eliminated the biomarker positive patients, they got the same results. Also, the selection of 6-hour increments in this study was arbitrary. In addition, the timing started at hospital admission, not onset of symptoms. Perhaps the latter should be taken into account. Unfortunately, a true randomized time trial will probably never be done, so we are stuck with the available data. At this time, it would appear that an earlier intervention is better in high-risk NSTE-ACS patients, but good clinical judgment needs to be exercised to avoid unnecessary increases in risk to the patient.