Early Invasive Strategy Benefits Select High-Risk NSTE ACS Patients, Meta-analysis Suggests

Early invasive coronary angiography is not associated with a reduction in mortality when compared with a delayed invasive strategy in patients with NSTE ACS, but there appears to be a benefit in certain high-risk patients, according to a new meta-analysis.

In NSTE ACS patients with elevated cardiac biomarkers, an elevated GRACE risk score, diabetes, or older age, early invasive angiography reduced the risk of mortality when compared with patients who were treated with a delayed strategy.

Senior author Holger Thiele, MD (University of Leipzig, Germany), told TCTMD there is an ongoing debate about the optimal timing of coronary angiography for patients with NSTE ACS but that these results support the current US and European clinical guidelines recommending invasive angiography within 24 hours for patients with elevated troponin and/or a GRACE risk score greater than 140.

“For the first time, we could also show that this approach of early invasive angiography reduces mortality in those high-risk subgroups,” he said. “Furthermore, patients with diabetes and those 75 years and older seem to have a mortality benefit. This is currently not covered in the guidelines and may need confirmation in separate randomized trials.”

In an editorial, Peter Damman and Robbert de Winter, MD (Academic Medical Center-University of Amsterdam, the Netherlands), state that since the overall results were neutral, the mortality benefit in the subgroups can only be considered hypothesis-generating at this point. The results suggests no evidence of harm resulting from the early invasive approach, and given the overall neutral findings, most patients with NSTE ACS can be treated safely with either an early or delayed intervention.

Mortality Benefit Seen in Subgroups, Not Overall

The meta-analysis, published online August 1, 2017, ahead of print in the Lancet, included eight trials with 5,324 patients. The timing of the early invasive strategy varied in the studies, with the ABOARD trial investigators taking patients immediately to the cath lab and the TIMACS group defining early angiography as patients treated within 24 hours. Similarly, the timing in the delayed-intervention group ranged as well, with patients treated the next working day in ABOARD and two trials treating patients within 72 hours of symptom onset. The median follow-up was 180 days. 

Overall, there was no significant reduction in the risk of death among patients randomized to the early invasive strategy and those treated with the delayed approach (HR 0.81; 95% CI 0.64-1.03). In the prespecified analysis of high-risk patients, there was a significant reduction in mortality among patients with elevated cardiac biomarkers at baseline (HR 0.76; 95% CI 0.58-1.00), diabetes (HR 0.67; 95% CI 0.45-0.99), a GRACE risk score > 140 (HR 0.70, 0.52-0.95), and age 75 years or older (HR 0.65; 95% CI 0.46-0.93).

The European Society of Cardiology clinical guidelines recommend that high-risk NSTE ACS patients undergo invasive angiography within 24 hours and intermediate-risk patients within 72 hours. An immediate invasive strategy is recommended for very high-risk patients, such as those with refractory angina or hemodynamic instability, for example. The American College of Cardiology/American Heart Association clinical guidelines for the management of NSTE ACS are similar.

“All guideline recommendations currently rely on a subgroup analysis from TIMACS showing that for high-risk patients with a GRACE score greater than 140, the combined endpoint of death, myocardial infarction, or stroke can be reduced by angiography within 24 hours,” said Thiele. He added that the major benefit of the early invasive strategy is the reduction in refractory ischemia and no study has shown that angiography within 24 hours reduces mortality.

Evidence Base Largely Comprised of TIMACS Subanalysis

To TCTMD, de Winter said the strategy of taking high-risk patients to angiography within 24 hours of presentation is controversial particularly since not all hospitals have catheterization labs available.

“It puts pressure on the system,” said de Winter. “If you’re admitted to a non-PCI center, basically, it means that you should transfer that patient within 24 hours if the troponin is positive. That’s a lot of patient transfers and ambulance capacity that’s needed to get those patients back and forth. And if you look at the evidence that the recommendation is based on, one of the major components of the evidence [base] is the subanalysis of the TIMACS study.”

In TIMACS, which was published in 2009, NSTE ACS patients were randomized to invasive angiography within 24 hours after symptom onset while those assigned to delayed intervention underwent coronary angiography after a minimum delay of 36 hours. As Thiele pointed out, there was no difference in the primary composite endpoint between the early- and delayed-intervention arms, but investigators did observe a significant benefit when patients were stratified by baseline GRACE risk score (those with a score greater than 140 benefited from early angiography).

de Winter said he doesn’t feel the evidence base is strong enough to support the current ESC recommendation that all high-risk NSTE ACS patients undergo angiography within 24 hours. Under the care of an experienced cardiologist, a stable patient, even one with elevated troponin levels assessed by a high-sensitivity assay, is safe beyond the 24-hour window. If the clinical situation changes, then the patient can be transferred.

“What’s happening is that with high-sensitivity troponin tests, you have a lot of patients that have slight troponin elevations,” said de Winter. “These patients don’t have to be high-risk patients. They stabilize and they don’t need to undergo angiography within 24 hours if they are stable. But if you follow the guidelines to the letter, you need to transfer all these patients.”   

At his center, de Winter said most NSTE ACS patients are treated within 24 hours, but it’s more for logistical reasons. If a stable NSTE ACS patient is admitted to the coronary care unit on Friday afternoon, they will wait until Monday to do the angiogram. “However, what often happens is that the program is already overloaded for Monday,” he said. “If I’m on call on the weekend and do a STEMI patient, and the other non-STEMI patient is waiting, I might as well do that patient as well. But it’s a logistical issue. It’s not done on the ground that there is a mortality benefit to be expected from the angiogram.”

In their editorial, Damman and de Winter point out that the studies included in the meta-analysis enrolled patients between 2000 and 2016. Drug-eluting stents, troponin assays, and pharmacotherapy, including the use of more potent antiplatelet agents, have changed substantially. Given this, as well as the limitations with the available evidence, an adequately powered randomized trial comparing the early versus delayed invasive strategy is still needed in NSTE ACS, they write.