How Early Should We Intervene in Non-ST Elevation ACS?
Abstract & Commentary
By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco Dr. Boyle reports no financial relationships relevant to this field of study.
Source: Mehta SR, Granger CB, Boden WE et al. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med. 2009;360:2165-2175
Numerous studies have demonstrated the benefit of an early invasive strategy in patients presenting with non-ST elevation acute coronary syndromes (ACS). In the case of ST elevation myocardial infarction (STEMI), the optimal timing of percutaneous coronary intervention (PCI) is clear - the earlier the better - because the infarct-related artery is often occluded and there is ongoing transmural myocardial ischemia. However, in non-ST elevation ACS, the timing is less clear and observational clinical trial results are conflicting. While there may be benefit in earlier revascularization if there is ongoing ischemia, alternatively, there also may be benefit to a period of intensive medical therapy with anticoagulants and anti-thrombotic agents prior to invasive management. To determine the optimal timing of early invasive therapy, Mehta et al performed a randomized, multi-center study, the Timing of Intervention in Acute Coronary Syndromes (TIMACS) study.
The study began as a randomized substudy of the OASIS-5 trial (comparing fondaparinux to enoxaparin in ACS) and recruited the first 1,633 patients this way, then continued after the conclusion of OASIS-5 to recruit another 1,398 patients. Patients presenting with ACS, either unstable angina or non-ST elevation myocardial infarction (MI), within 24 hours of symptom onset, were recruited if they had two of the following three high-risk features: age > 60 years, elevated cardiac biomarkers, or electrocardiogram (ECG) changes consistent with myocardial ischemia. All were planned for an early invasive strategy during the index hospitalization. Patients were randomized to undergo early coronary angiography (within 24 hours of randomization) or delayed coronary angiography (later than 36 hours after randomization). Suggested medical therapy prior to coronary angiography included aspirin, clopidogrel, and an anti-thrombin. Patients enrolled during OASIS-5 received wither fondaparinux or enoxaparin; the later patients could also receive unfractionated heparin or bivalirudin at the clinicians' discretion. The use of glycoprotein IIb/IIIa inhibitors was also at the treating physicians' discretion. Crossover from delayed to early intervention was permitted for refractory angina with ECG changes, new ST elevation or T-wave inversion > 3mm, development of refractory heart failure, or hemodynamic instability. The primary outcome was the first occurrence of the composite of death, new myocardial infarction, or stroke at six months. The two secondary outcomes were the first occurrence of the composite of death, myocardial infarction, or refractory ischemia and the composite of death, myocardial infarction, stroke, refractory ischemia, or repeat intervention at six months. Other outcomes included each of the individual components analyzed separately.
The baseline characteristics of the 3,031 patients randomized to early intervention (n = 1,593) or delayed intervention (n = 1,438) were well matched. Medical therapies were similar in the two groups, with the exception of the loading dose of clopidogrel. Patients in the early intervention group were more likely to receive a 600 mg loading dose (9.8% vs. 6.9%; p = 0.009), while those in the delayed intervention group were more likely to receive a 300 mg loading dose (85.7% vs. 81.0%; p < 0.001). Time from randomization to coronary angiography was 14 hours in the early intervention group and 50 hours in the delayed intervention group (p < 0.001). Patients in the early intervention group were more likely to undergo PCI (59.6% vs. 55.1%; p = 0.01).
At six months, the primary outcome (death, new MI, or stroke) occurred in 9.6% of patients in the early intervention group, compared with 11.3% in the delayed intervention group (p = 0.15). There was no significant difference between the early intervention group and the delayed intervention group in the individual components of the composite primary endpoint: rate of death (4.8% vs. 5.9%), new MI (4.8% vs. 5.7%), and stroke (1.3% vs. 1.4%). Early intervention resulted in a significant reduction in the secondary composite endpoint of death, MI, or refractory ischemia, compared to delayed intervention (9.5% vs. 12.9%; p = 0.003). This is largely related to a reduction in refractory ischemia in the early intervention group (1.0% vs. 3.3%; p < 0.001). Among those patients who did develop refractory ischemia, the rate of MI was increased four-fold (20.6% vs. 4.8%; p < 0.001). No significant difference in bleeding was noted between the two treatment strategies. Pre-specified subgroup analysis showed no difference in the primary outcome based on age above or below 65 years, gender, presence of ischemic ECG changes, or elevated cardiac biomarkers. However, patients presenting with elevated clinical risk, defined as a GRACE risk score of over 140, had a 35% reduction in the primary endpoint with early intervention compared to delayed intervention (13.9% vs. 21.0%; p = 0.006). Mehta et al conclude that early intervention did not differ greatly from delayed intervention in preventing the primary outcome, but it did reduce the rate of the composite secondary outcome of death, myocardial infarction, or refractory ischemia and was superior to delayed intervention in high-risk patients.
Commentary
Patients presenting with ACS are a heterogeneous group and, thus, it is difficult to recommend a single treatment strategy for all ACS patients. Recent guidelines have focused on risk assessment as an integral aid in decision making about which patients derive most benefit from invasive treatment compared to conservative treatment. This study adds valuable information to inform us about the optimal timing of intervention in those patients undergoing an early invasive approach. There was no difference in the primary endpoint when patients are taken to the cardiac catheterization laboratory with 24 hours of presentation or when this is delayed to ≥ 36 hours. Importantly, this study enrolled patients with some high-risk features, so the results may not apply to lower-risk ACS patients. Furthermore, within the study population, the highest-risk patients seemed to benefit from earlier intervention. This is consistent with current guidelines that the higher the clinical risk profile, the more benefit derived from invasive therapy. Perhaps earlier is also better in higher-risk patients; however, caution should be exercised when examining subgroups like this, and no firm recommendations can be made based on this subgroup analysis. The impact of these different treatment strategies on length of stay and cost per patient is not presented in this paper.
Numerous studies have demonstrated the benefit of an early invasive strategy in patients presenting with non-ST elevation acute coronary syndromes (ACS).You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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