Very EARLY Invasive Angiography in NSTE ACS Patients Reduces Risk of Recurrent Ischemia

One expert, however, questions the findings, noting the study is open-label and the soft recurrent ischemia endpoint is open to potential bias.

Very EARLY Invasive Angiography in NSTE ACS Patients Reduces Risk of Recurrent Ischemia

CHICAGO, IL (UPDATED)—Sending patients with NSTE ACS not pretreated with a P2Y12 adenosine diphosphate (ADP)-receptor antagonist to the catheterization laboratory for invasive angiography within 2 hours of presentation reduced the risk of cardiovascular death or recurrent ischemia at 30 days when compared with a delayed strategy, a new study suggests.

The benefit of very early invasive angiography, however, was overwhelmingly driven by a reduction in recurrent ischemic events that occurred among patients in the delayed treatment arm (4.1% vs 20.7%; P <0.001).

“There was a fivefold lower rate of MACE in the very-early group compared with the [delayed] group,” said lead investigator Laurent Bonello, MD, PhD (Centre Hospitalier Universitaire de Marseille, France). “This highly significant difference is mainly obtained in the waiting time for coronary angiography. At 30 days, for the components of the composite primary endpoint, there was no difference in cardiovascular death, but there was a very significant difference in recurrent ischemic events which led to urgent revascularization."

For those randomized to the early invasive approach, 4.4% of patients experienced a major adverse cardiovascular event at 30 days compared with 21.3% in the delayed group (P < 0.001).

Bonello, who presented the results of the EARLY trial at the American Heart Association 2018 Scientific Sessions, said the question of early versus delayed angiography in NSTE ACS patients remains an unsettled issue. “In fact, there is no conclusive evidence in the literature,” he said.

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 NSTE ACS management make similar recommendations.

C. Michael Valentine, MD (Stroobants Cardiovascular Center/Centra Health, Lynchburg, VA), who was not involved in the trial, said the “real mystery” of the study stems from the lack of P2Y12 inhibition on hospital admission, the standard practice for the medical management in patients with NSTE ACS. Had physicians pretreated patients with one of the P2Y12 inhibitors, the number of recurrent ischemic events in the delayed angiography arm might have been lowered and reduced the difference between the two strategies.

“Obviously, for the group that went within 2 hours, it doesn’t really matter,” said Valentine. “The question was in delaying [P2Y12 inhibition], to some people, meant that you were obviously going to have a higher rate of urgent revascularization and trouble afterwards. If some were delayed for up to 72 hours, you’ve kind of missed your window to help.” In the setting of NSTE ACS, where there is a milieu of thrombus formation and platelet activation, treatment with a P2Y12 inhibitor, such as clopidogrel, on admission would be beneficial, said Valentine.

Taking a glass half-full view of the data, Valentine said these new data clearly show patients managed with a very early invasive angiography did very well. “That’s encouraging for centers who are taking patients to the lab quickly,” he said. “There seemed to be no problems with ‘too quick.’ The overall trends to be aggressive with non-STEMI patients were encouraging.”

Testing Early vs Delayed Angiography Without P2Y12 Inhibition    

Speaking during the late-breaking clinical trial session, Bonello highlighted a 2016 meta-analysis of seven randomized trials comparing early versus delayed coronary angiography in patients with NSTE ACS. Overall, there was no difference in the risk of death or MI between the two strategies, although the early treatment approach was associated with a reduction in recurrent ischemia or refractory angina. “However, in all these randomized clinical trials, patients were pretreated with a P2Y12 ADP-receptor antagonist,” said Bonello.

Explaining the rationale for EARLY, Bonello said the ACCOAST study questioned the benefit of pretreatment with prasugrel (Effient; Eli Lilly/Daiichi Sankyo), noting the pretreatment strategy didn’t reduce the risk of recurrent ischemic events but did increase the risk of major bleeding. “We believe there was a gap in the evidence,” said Bonello. “A significant proportion of non-ST-elevation acute coronary syndrome patients are not pretreated anymore when scheduled for an invasive strategy.”

To TCTMD, Mamas Mamas, BMBCh (Keele University, Stoke-on-Trent, England), said that when the NSTE ACS patient presents at the hospital, typical treatment had been aspirin and clopidogrel, although many would have opted for a stronger antiplatelet agent, such as prasugrel or ticagrelor (Brilinta; AstraZeneca). The ACCOAST study, in fact, did suggest that pretreatment with prasugrel increased the risk of bleeding which led to a shift in care.

“So, more conventionally these days, we only treat the patient with the second antiplatelet agent once they’ve had the diagnostic cath and the decision has been made for PCI,” said Mamas. “In doing these cases, some of the patients you’ll manage medically, so giving them a more potent antiplatelet agent without doing the PCI has less benefit compared with those who undergo PCI.” The NSTE ACS patient might still receive clopidogrel in addition to aspirin when they present and will then be switched to ticagrelor before the PCI, but “en masse” pretreatment with potent dual antiplatelet agents would increase the bleeding risk in medically managed patients, said Mamas.  

GRACE Score Suggests Not Very High Risk

Based on that background, the researchers sought to compare two strategies—very early invasive angiography (< 2 hours) versus a delayed approach (12-72 hours)—in 709 intermediate- and high-risk NSTE ACS patients not pretreated with a P2Y12 ADP-receptor antagonist at 13 French hospitals.

More than 92% of patients in both arms were high-risk NSTE ACS patients, with 70% being troponin-positive on admission. The average GRACE score was 123.4 in the delayed-treatment group and 121.2 in the very-early-treatment arm. In total, 78% of patients in the delayed arm underwent PCI, 3.0% underwent CABG surgery, and 19.0% were treated with medical therapy. Conversely, 71.7% of those in the very-early invasive strategy underwent PCI, 2.8% were treated surgically, and 25.5% received medical therapy.

The benefit of the very-early invasive strategy was consistent across all subgroups, according to Bonello, including those with lower GRACE risk scores (109 to 140). There was a significant interaction by sex—men had a larger reduction in the primary endpoint compared with women when undergoing angiography within 2 hours of presentation—and by therapeutic strategy (only those treated with PCI had a reduction in events with the very early invasive strategy).

To TCTMD, Mamas said an early strategy is typically defined as invasive angiography within 12-24 hours, whereas in the EARLY trial such an approach would be considered delayed. Mamas noted that the benefit of an early invasive approach has been shown to be beneficial in very-high-risk patients, such as those with a GRACE score > 140, but the EARLY data challenge those findings given that the benefit was also observed in those with lower scores.

Despite the positive findings, Mamas questioned whether the patients were managed optimally with medical therapy. In the delayed group, just 44.3% of patients were taking aspirin at the time of study inclusion and it’s not clear what medical therapy they received while waiting for the invasive angiography. “It seems that less than half received aspirin which would go against all guidelines,” said Mamas. “Perhaps the very high rate of ischemic events was not related to the strategy but more related to the fact that they weren’t managed optimally for their acute coronary syndrome.”   

Gilles Montalescot, MD, PhD (Centre Hospitalier Universitaire Pitié–Salpêtrière, Paris, France), the scheduled discussant during the session, didn’t appear particularly impressed with the findings. For one, he pointed out that the time to coronary angiography in EARLY—both with the very early and delayed approaches—are some of the quickest when compared with timing in other clinical trials. In addition, the average GRACE score is lower than in other trials, suggesting these patients weren’t very high risk, but rather intermediate to high risk.

Montalescot said there is a “disconnect” between the rate of recurrent ischemia in EARLY based on the risk levels and waiting time for coronary angiography. For example, 72 patients had recurrent ischemia while waiting for angiography in the delayed group even though the waiting time was just 12 to 72 hours (average 18 hours).

Montalescot also homed in on the clinical endpoints, highlighting the lack of difference between the early and delayed invasive strategies on mortality, MI, urgent revascularization, or bleeding. For the reduction in recurrent ischemia with very early invasive angiography, Montalescot urged caution, noting it is a soft endpoint at risk of bias in an open-label trial.

To TCTMD, Mamas noted that recurrent ischemic events were driven by “symptoms of ischemia” but what this entails is uncertain. “Were these ischemic symptoms defined as the patient developing chest pain? By dynamic ECG changes? Those are very different,” said Mamas. “The symptoms don’t seem to have a prognostic impact. All-cause mortality was similar and risk of MI, which is the main thing if you’re having ischemic events, is incredibly low in both study arms.” 

If a conservative treatment strategy is chosen, or if the waiting period for coronary angiography is 48 hours or longer, a P2Y12 receptor antagonist should be considered, according to Montalescot. Valentine told TCTMD that if patients don’t go for angiography early, pretreatment with a P2Y12 inhibitors creates a safety margin. “This way you’re not taking patients in the middle of the night who are pain free and stable,” said Valentine.

  • Lemesle G, Laine M, Pankert M, et al. Optimal timing of intervention in non-ST-segment elevation coronary syndromes without pretreatment with P2Y12-ADP receptor antagonists: the EARLY randomized trial. Presented at: AHA 2018. November 11, 2018. Chicago, IL.

  • The EARLY study was funded by the French Ministry of Health

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