Early Invasive vs Selectively Invasive Management for Acute Coronary Syndrome
Abstract & Commentary
By Jonathan Abrams, MD Dr. Abrams is Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.
Synopsis: An early invasive strategy did not result in an expected differential in the primary end point.
Source: de Winter RJ, et al. Early Invasive Versus Selectively Invasive Management for Acute Coronary Syndromes. N Engl J Med. 2005;353:1095-1104.
This is yet another study of an invasive vs noninvasive approach to acute coronary syndromes (ACS). The ICTUS trial from the Netherlands examined the long-standing controversy about when (and if) to intervene in ACS with coronary angiography and possible revascularization. The study follows a series of reports over the past several years, including VANQWISH, FRISC II, TACTICS-TIMI 18, TIMI IIIB, and RITA-3. In the new study, 1200 patients were enrolled between 2001 and 2003 at 42 Dutch hospitals and were randomized to early invasive (EIS) or a selectively invasive strategy (SIS). Patients had 3 of the following: ischemic symptoms at rest within 24 hours; elevated troponin and one of a variety of other features, including ST-segment depression, T-wave inversion, CAD, or positive exercise test. All patients received 300 mg of aspirin followed by daily aspirin and enoxaparin. Clopidogrel was given as a 300 mg bolus, followed by 75 mg daily. All interventions during the hospital period were performed with concomitant use of abciximab. Lipid therapy (mostly atorvastatin 80 mg) was recommended. The early invasive group had angiography within 24-48 hours, with revascularization decisions made by the attending physicians. The selectively invasive strategy cohort was treated medically, and underwent angiography, followed by revascularization for refractory angina, hemodynamic instability, or "clinical significant ischemia on the pre-discharge exercise test." Subsequent angiography and revascularization occurred for severe angina symptoms. The primary end point was a composite of death, recurrent MI, or re-hospitalization for angina within one year. Patient characteristics were evenly distributed, including median age of 62, 75% males, prior MI 20-25%, prior revascularization 22%, and major CAD risk factors in 30-40%. Half of all subjects had ST-segment deviation; 14% had diabetes.
Results: Virtually all of the EIS subjects underwent early angiography vs 53% of the SIS group, increasing to 67% in the SIS strategy by one year. Revascularization procedures: 80% in the EIS group and 54% in the SIS group at one year. Medical therapy was comparable in both groups at discharge except for somewhat greater use of clopidogrel in revascularized patients. Statin use was over 90%. The primary end point was 23% in the EIS group and 21% in the SIS (NS); one year mortality was 2.5% in both groups; re-MI was higher in the EIS group (15% vs 10%) but this excess was related mostly to procedures. Rehospitalization occurred less often in the EIS group (7.4% vs 10.9% in SIS patients). Angina free status was comparable in both groups, however, it should be stressed that 54% percent of the selective cohort underwent either PCI or CABG by 12 months, compared to 79% of the early invasive patients. Winter and colleagues conclude, "This study did not show that an early invasive strategy was superior to a selectively invasive strategy in ACS without ST elevation. . . .and elevated troponin."
In their discussion, Winter et al stress that comparisons among the various trials is problematic due to differences in study design and therapeutic approaches. They acknowledge that early revascularization rates were high in the selective group (40%), as well as in the early invasive patients (76%), which were 54% and 79% at one year. The rates in VANQWISH were lower, but slightly higher than in TIMI-3B, and comparable to FRISC II at 6 months when compared to ICTUS. Events rates were slightly lower in TACTICS-TIMI 18. However, all ICTUS patients had an elevated troponin, which was not the case in the other studies except VANQUISH. Winter et al believe that their patients were clearly at high risk, possibly contributing to more frequent revascularization in SIS. They point out that there is an early hazard of MI with intervention, similar to that in FRISC II, and presumably small infarctions related to PCI; this is well known. The clinical significance of these observations remains unclear. However, the SIS cohort had a lower rate of MI than expected. Winter et al attribute this observation, as well as the overall equivalence of long-term results to effective preventive pharmacotherapy, including early clopidogrel use on, intensive LDL cholesterol lowering, and use of abciximab for all interventions. "Advances in background medical therapy in combination with better detection of myocardial infarctions . . . best explain differences between our results and those of previous trials." They conclude that an early invasive strategy did not result in an expected differential in the primary end point.
Commentary
These study results would appear to bring the opposing armies of early intervention vs risk stratification-intervention closer together. Lumping all of the trials together is problematic, given the differences in time periods of the studies, different patient populations, and probably more intense vascular-protective therapy in the ICTUS trial. What is quite clear is that patients with ACS often end up having a revascularization, including greater than half of the SIS patients in ICTUS. The revascularization rates for the other major studies at one year are over 50% for the early group in FRISC II, TIMI-3B, and TACTICS-TIMI 18, and under 50% in RITA 3 (6 months). The revascularization rates in the selective strategy arms of previous studies were 58%, 33%, 37%, 44%, and 28% in time periods ranging between 6 months and 2 years. The ICTUS study enrolled only high risk patients, as troponin positivity was required. Excellent follow-up of the selective group was presumably important, but intensive vasculoprotective therapy was received by all patients. Finally, it must be remembered that considerable data has accumulated over that past several years indicating that individuals who present with ACS, with or without troponin elevation, often had multiple and/or complex plaques, and demonstrate many adverse features, such as increased inflammation, cytokine expression, and enhanced procoagulant activity, all adverse features that occur in an activated coronary tree. The ICTUS trial, as well as an overview of all trials, suggests that risk stratification is appropriate in individuals who cool off quickly. The fact that there are virtually no long-term mortality differences in any of the studies should be reassuring that a thoughtful, selective approach is safe and in no way can be construed as abandonment of these patients. And, of course, most ACS patients eventually do get revascularized.
An early invasive strategy did not result in an expected differential in the primary end point.
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