Amsterdam, the Netherlands - The Invasive vs Conservative Treatment in Unstable Coronary Syndromes (ICTUS) trial, suggesting that a selective invasive strategy may be just as effective as a universal early invasive approach in high-risk ACS patients, has been published in the September 15, 2005 issue of the New England Journal of Medicine [1]. The results were first presented at the European Society of Cardiology (ESC) meeting and reported by heartwire last year.

In the paper, the authors explain that although current guidelines recommend an early invasive strategy for patients with non-ST-elevation ACS and an elevated cardiac-troponin T level, randomized trials have not shown an overall reduction in mortality with such a strategy, and the reduction in MI has varied depending on the definition of MI used. They thus conducted a study to look at this issue further and randomized 1200 patients either to an early invasive strategy or a selectively invasive strategy. All patients received aggressive medical therapy, including aspirin, clopidogrel, enoxaparin for 48 hours, abciximab during PCI, and intensive lipid-lowering therapy.

Results showed that the primary end point, a composite of death, MI, or rehospitalization for anginal symptoms within one year, was similar in the two groups, as were mortality rates. MI was significantly more frequent in the group assigned to early invasive management, but rehospitalization was more frequent in the more conservative group.

In an interview with heartwire, lead investigator Dr Robbert de Winter (Academic Medical Center, Amsterdam, the Netherlands) said that because of these results, he was going to campaign for the guidelines to be changed. "Our results suggest the two strategies are equivalent, and so physicians should have a choice as to which strategy they follow." He suggested that larger hospitals with cath labs may choose the early invasive strategy for all patients, as this would "get them out more quickly," but smaller hospitals without cath labs would probably choose the more conservative approach, which would mean that some patients could remain at that hospital for medical treatment.

However, de Winter emphasized that the conservative strategy in this trial was not really conservative, with 40% of patients in this group still receiving a revascularization during the initial hospital stay and 54% within a year. He explained that patients in the conservative group did receive revascularization if they had refractory ischemia despite medical treatment or if they had evidence of ischemia on exercise test before discharge. "Our results allow physicians some leeway. They can try medical treatment first, and if that is not completely effective then they can send the patient for revascularization."

Noting that the ICTUS results appear to contradict the results of several other trials, the most recent being RITA-3, reported last week at the ESC and showing a mortality benefit after five years with an early invasive strategy, de Winter pointed out some important differences between the two trials that could account for their different outcomes. These included the fact that fewer patients in the RITA-3 conservative arm were revascularized and that medical treatment was better in ICTUS. "We have shown that if the optimal medical treatment is given, it is not always necessary to follow an early invasive strategy," he commented to heartwire.

He added that the ICTUS results clearly show an early hazard (increased MI rates) in the early invasive arm, "which has also been shown in other studies but is downplayed by interventionalists." He pointed out that some previous trials have used different definitions for procedural MIs than for spontaneous MIs but that ICTUS had the same definition for both types of event, which made for a fairer comparison of the two strategies. "In some previous trials, a procedural MI was defined as a CK-MB more than three times the upper limit of normal, whereas a spontaneous MI was defined as just one time the upper limit of normal. In this situation, if there were lots of procedural MIs that did not reach the level to actually be defined as an MI, the deck is stacked against the conservative arm. But we had the same definition for procedural and spontaneous MI, so we would have included in our end point some procedural MIs that would not have been counted in some of the other studies."

The ICTUS investigators also report a new subgroup analysis in the paper that shows that there was no significant difference in the frequency of the primary end point among subgroups defined according to age, sex, the presence or absence of diabetes mellitus, the presence or absence of ST-segment deviation, or the level of cardiac-troponin T. De Winter commented to heartwire: "We could not demonstrate a benefit from an early invasive strategy even in the highest-risk patients. This questions a risk-stratification strategy."

In an editorial accompanying the paper, Dr William Boden (Hartford Hospital, CT) describes the ICTUS results as "provocative. [2]"

On the different definitions of MI used in the different trials, he asks: "Since the guidelines of the ACC-AHA and the ESC define myocardial infarction as any elevation in CK-MB or troponin levels above the upper limit of normal, regardless of whether this occurs in the setting of PCI, is it appropriate simply to dismiss PCI-related elevations in biomarkers as trivial and clinically irrelevant?" He adds, "There is mounting evidence that periprocedural myocardial damage is not benign and may rival spontaneous myocardial infarction prognostically."

Boden also notes the "striking difference" in the timing of the procedure between patients who underwent early PCI (median time 23 hours) and those who underwent delayed PCI (median time, 11.8 days) in ICTUS and the absence of worse clinical outcomes in the latter group. "Although US treatment standards preclude hospitalizing for 11 to 12 days patients with acute coronary syndromes without ST-segment elevation, as was done in the study by de Winter and colleagues, the trial suggests nonetheless that such patients, if aggressively treated pharmacologically and stratified appropriately according to risk, could be treated safely without clinical consequences with the use of a more selective approach to intervention," he writes.

He points out that patients in both groups in ICTUS received "robust" medical therapy, which "could have mitigated risk by leveling the playing field between the two strategies," adding that "the low one-year mortality rate in the entire ICTUS cohort and the unexpectedly low event rate among the patients assigned to a selectively invasive strategy underscore the critical role of adjunctive antiplatelet, antithrombin, and intensive lipid-lowering therapies."

Boden concludes: "The results of the study by de Winter and colleagues may serve as a wake-up call, telling us that a routine early invasive strategy for the treatment of patients with acute coronary syndromes without ST-segment elevation—even those who are positive for biomarkers—may not inherently be superior to a more selective approach." He adds: "The findings may move us closer to a point of clinical equipoise at which physicians feel more confident that an early invasive strategy and a selectively invasive strategy are equivalent and defendable treatment options."