ICTUS: No Benefit at 10 Years With Early Invasive Strategy in NSTE ACS Patients

Extended follow-up from the Invasive Versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) trial shows that an early invasive approach was no better than a more selective strategy at reducing the long-term risk of death or spontaneous MI in 1,200 patients with NSTE ACS and elevated cardiac troponin T levels.

Senior investigator Robbert de Winter, MD (Academic Medical Center, Amsterdam, the Netherlands), said the 10-year data weren’t too unexpected, given the lack of benefit at 1 and 5 years, but the analysis was needed to confirm “there were no late surprises.” The group had been motivated after seeing data from other studies that have given mixed signals about the long-term value of an early invasive strategy in patients with NSTE ACS.

For example, in FRISC-II, the significant difference in mortality with an early invasive strategy seen at 2 years disappeared by 5 years, but at 15 years, death or MI appeared to be delayed by 18 months with the invasive versus noninvasive approach. In the RITA-3 study, there was no mortality benefit evident at 2 years, but there was a reduction in mortality at 5 years with the early invasive approach. This survival advantage, however, disappeared by 10 years.

With ICTUS showing no survival advantage at any time point, de Winter said the observed mortality benefits seen at different times in FRISC-II and RITA-3 were likely due to chance.

“Taking these three trials together, I think we can reliably conclude that there is no mortality benefit from these different strategies,” he said.

The 10-year results of ICTUS were published April 10, 2017, in the Journal of the American College of Cardiology.

The ICTUS Trial

First published in 2005, ICTUS randomized NSTE ACS patients to an early invasive treatment strategy consisting of intensive antianginal/antithrombotic medication and coronary angiography within 24 to 72 hours (followed by coronary revascularization or continued pharmacotherapy depending on the angiographic results). In the selective invasive treatment arm, patients were treated with pharmacotherapy but referred for coronary angiography only in cases of refractory angina or inducible ischemia with noninvasive stress testing.

At 1 year there was no statistically significant difference in the risk of all-cause mortality, nonfatal MI, or rehospitalization for anginal symptoms, the study’s primary endpoint—setting ICTUS apart from the positive studies in this space (RITA-3, FRISC-II, and TACTICS-TIMI 18).

Speaking to the apparent disparity, de Winter pointed out that more than half of the patients in the “conservative” arm of ICTUS underwent catheterization during the initial hospitalization and 40% underwent coronary revascularization. In fact, “the more conservative arm in ICTUS had the same rate of angiography as the invasive arm in RITA-3,” he said. As a result, the high rates of angiography and revascularization in the “control” arm made it difficult to see a difference between the early and selectively invasive approaches.

To TCTMD, de Winter said they currently follow the European Society of Cardiology recommendations for treating NSTE ACS patients. When the clinical diagnosis of NSTE ACS is established, patients are stratified by risk—designated as high, intermediate, and low risk—and treated accordingly. High-risk patients with NSTE ACS, with risk based on dynamic ECG changes, troponin elevations, or GRACE score, are admitted to the coronary care unit and undergo coronary angiography within 24 hours.

For the intermediate-risk patient, a delayed strategy is recommended, with the patient undergoing invasive angiography between 24 and 72 hours. With low-risk NSTE ACS patients, a delayed invasive or an ischemia-driven strategy is an option for physicians.

At their center, if a patient presents with NSTE ACS, de Winter said they are stabilized with medical therapy and then sent to coronary angiography within 24 to 72 hours. If they fail to stabilize with medical therapy, the patient is sent for coronary angiography sooner.

The American College of Cardiology/American Heart Association (ACC/AHA) guidelines also recommend NSTE ACS patients undergo invasive therapy, with patients undergoing diagnostic angiography urgently (< 2 hours), early (< 24 hours), or delayed (25 to 72 hours), depending on clinical characteristics. An ischemia-driven approach can be considered for low-risk patients, according to the ACC/AHA recommendations.

Not All NSTE ACS Patients Created Equally

Chandan Devireddy, MD (Emory University School of Medicine, Atlanta, GA), who was not involved in the study, said that while physicians do try to get NSTE ACS patients into the cath lab quickly, the clinical trials testing the early versus delayed approach have included heterogeneous patient populations. He noted that high-sensitivity troponin assays also have the ability to detect small changes, changes that might not have been detected in the past.  

“You have a patient that comes in [who is] technically troponin positive, but doesn’t have a very high GRACE score,” Devireddy told TCTMD. “Is that somebody we need to rush through the system and get [to the cath lab] the same day or within 24 hours? Or do you have time to think about it, think about the patient overall, and start them on guideline-supported therapy, and then see which way to go? I think you can go different ways with the patients we’re seeing now.”

To TCTMD, Sunil Rao, MD (Duke Clinical Research Institute, Durham, NC), echoed those thoughts.

“Most patients with NSTE ACS get early invasive risk stratification, but there are times when a selective strategy may be preferred,” he said. “The guidelines also endorse this approach in patients where the risk of early invasive outweighs the benefit, [such as] very frail patients, patients with dynamic renal function, patients with type 2 MIs where the overall risk for adverse outcomes is low or when the MI is due to some underlying condition like sepsis.”

Both Devireddy and Rao also highlighted the high rate of catheterization and coronary revascularization during the initial hospitalization period in ICTUS as potential reasons for the lack of benefit observed with the early invasive approach, compared with other trials. Devireddy also noted that patient risk level likely varied in the different studies, too, making comparisons between trials difficult. “Even in the meta-analyses, there are some groups of trials supporting early invasive, but there’s always one or two trials that have varied outcomes despite trying to answer the same question,” he said.

While the controversy may continue to simmer with the publication of the long-term ICTUS data, the question really comes down to just how quickly physicians need to take a NSTE ACS patient to the cath lab, said Devireddy.  

He noted that speed to the lab varies in different centers, with not all hospitals running the cath lab on Saturday and Sunday. If a patient presents on a Friday, some might keep the cath lab open late and do the angiogram that night while others will stabilize the patient with medication, making an assessment on the need for coronary angiography based on their clinical judgement or an exercise test over the weekend.

To TCTMD, de Winter noted that invasive coronary revascularization has altered since the ICTUS trial was conducted, with patients receiving better drug-eluting stents to reduce the risk of repeat revascularization (the majority of patients in ICTUS received bare-metal stents). Medical therapy has also changed significantly, with greater emphasis paid to secondary prevention, including the use of high-intensity statin therapy and the introduction of newer, more potent P2Y12 inhibitor treatment.

Anthony Bavry, MD (University of Florida, Gainesville), echoed many of these same points in an editorial accompanying the study, acknowledging the challenges of interpreting older studies that do not represent current medical practice.