Periprocedural MIs Associated With PCI Prognostically Relevant: ESC/EAPCI

Significant elevations in cardiac troponin (cTn) levels after PCI for chronic coronary syndromes are a significant predictor of adverse clinical outcomes, particularly mortality, and should be routinely measured before and after the procedure to diagnosis type 4a myocardial infarction, according to a new consensus statement.

While there are a number of different MI definitions out there to choose from, the European Society of Cardiology (ESC) Working Group on Cellular Biology of the Heart and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) recommend diagnosing type 4a MIs using the Fourth Universal Definition of MI (UDMI).

“There is a lot of debate and controversy about how we best define type 4a MIs, with previous studies like EXCEL and ISCHEMIA using their own definitions,” Heerajnarain Bulluck, MD (Norwich University Hospital, England), lead author of the consensus statement, told TCTMD. “Depending on the definition used, this can change the outcomes of these trials quite significantly. The aim of our group was to come together and to critically appraise the literature—what’s been done in the field with respect to validating the type 4a MI definitions—as well as streamline the definition of major and minor myocardial injury.”

Bulluck said they chose the Fourth UDMI because it has been shown to be prognostically relevant. Earlier this year, Bulluck, along with lead researcher Johanne Silvain, MD (Sorbonné University/Hôpital Pitié-Salpêtrière, Paris, France), published a patient-level meta-analysis of 9,081 patients undergoing elective PCI with normal preprocedure cTn levels. In this cohort, of which 12.7% met the criteria for type 4a infarction according to the Fourth UDMI, these events were associated with a more than threefold increased risk of death at 1 year (OR 3.21; 95% CI 1.42-7.27).

The new ESC/EAPCI consensus statement, published recently in the European Heart Journal, recaps the evidence linking postprocedural injury and infarction to future events. It also provides some recommendations on how to manage these adverse events when they occur.  

With the UDMI, a type 4a MI is defined as an increase in cTn values > 5 times the 99th percentile upper reference limit (URL) within 48 hours of the procedure in addition to at least one of the following clinical features: new ischemic ECG changes; development of new pathological Q waves; imaging evidence of new loss of viable myocardium or new regional wall motion abnormalities; or angiographic findings consistent with a flow-limiting complication.

Other definitions of periprocedural infarction, such as those from Society for Cardiovascular Angiography and Interventions (SCAI) and the Academic Research Consortium (ARC), use much different cTn thresholds, and clinical trialists, such as the EXCEL investigators, have adopted modified versions of existing definitions. In EXCEL, for example, a trial that has come under intense criticism for failing to initially publish the UDMI outcomes, investigators used a modified version of the SCAI definition for assessing periprocedural infarctions in patients undergoing PCI or CABG for left main CAD.

“The SCAI and ARC-2 definitions use much higher cardiac troponin thresholds, but in our [previous] meta-analysis we found that even lower thresholds—up to three times elevation in troponin—were prognostic, but the optimal cutoff was five times the upper reference limit, which supported the Universal Definition,” said Bulluck.  

For the ESC/EAPCI, an increase in cTn > 5 x 99th percentile URL without any evidence of myocardial ischemia on ECG, angiography, or imaging is defined as a major myocardial injury and is also associated with increased mortality. Minor myocardial injury is defined as an increase in cTn > 1 x 99th percentile URL, but these events are not associated with an increased risk of MACE.

UDMI vs ARC-2 vs SCAI

The ESC/EAPCI recommends that baseline cTn levels be measured in all patients with chronic coronary syndrome undergoing PCI, suggesting that the blood sample can be taken in the cardiac cath lab prior to the procedure. Afterwards, cTn values should be routinely measured 3 to 6 hours after PCI to detect the occurrence of myocardial injury. Assessment is mandatory in patients who had periprocedural complications associated with reduced coronary blood flow or ECG changes indicative of ischemia, so that a diagnosis of type 4a MI can be made.

For patients with a type 4a MI diagnosis, postprocedure echocardiography or other cardiac imaging is recommended to detect new loss of viable myocardium or new wall motion abnormalities and to assess ejection fraction. In such patients, guideline-directed pharmacotherapy should be optimized to reduce the risk of MACE. However, it’s not known if patients with type 4a MI not currently on ACE inhibitors or beta-blockers would benefit from the addition of these therapies. That needs to be studied in future trials, according to the ESC/EAPCI consensus group.

Chronic coronary syndrome patients diagnosed with type 4a MI should also be tracked for long-term follow-up, said Bulluck.    

“Because the previous work has shown that procedural myocardial injury and infarction is prognostic, we think it’s important in clinical practice to track that data and to have an idea of the true incidence of events,” he said. “Possibly, it’ll be important to then include these patients in a registry, which would be the easiest way to get a large number of patients and to then follow them up for clinical outcomes. . . . The data will provide further insights into whether what we’re seeing is accurate now or if we need to further streamline the [MI] definition.”    

Bulluck is optimistic physicians and researchers will come to agree on a single type 4a MI definition, particularly as hospitals move towards standardized collection and high-sensitivity (hs) assays to measure cTn. “It could be used as a surrogate marker in clinical trials, but to also measure patients at risk who might benefit from other therapies,” he said.

Hector Garcia-Garcia, MD, PhD (MedStar Washington Hospital Center, DC), who led the writing committee that drafted the ARC-2 criteria, said their definitions were intended standardize clinical endpoints in intervention trials and to capture clinical events that affect future outcomes, such as mortality. While the new ESC/EAPCI consensus statement shows that interventional cardiologists and clinicians believe elevations in cardiac biomarkers after PCI to be a truly important issue, he questioned adopting the UDMI for type 4a infarction, stating that it is not prognostically relevant.

“We’re just accumulating more and more evidence that the threshold isn’t five times the upper limit of troponin,” he told TCTMD.

For the ARC-2 group, a post-PCI increase of cTn > 35 times ULN is considered most appropriate for detecting a large, prognostically relevant MI for both PCI (and CABG surgery). In a 2019 meta-analysis of stable patients, Garcia-Garcia even found that CK-MB was a better predictor of mortality at 1 year than elevations in cTn. However, he noted that other studies, including a recent analysis from EXCEL, have shown different results. The prognostic relevance of the various cutoffs and different biomarkers may vary between patient populations, he suggested. 

Given the uncertainty around the optimal cutoff, as well as the best biomarker to use, Garcia-Garcia said there is little consensus in this area despite the publication of a consensus statement. He suspects clinical trialists will continue to include multiple definitions for MI in future studies. “I’m sure the community will continue to be divided over the significance of biomarker elevation post-PCI,” he said. “What’s important is that we’re consistent in reporting, at least in terms of providing the information for the [UDMI, ARC-2, and SCAI] definitions.”

Gaps in Knowledge

To TCTMD, Bulluck said the ESC/EAPCI consensus statement highlights a number of gaps in knowledge about periprocedural myocardial injury and type 4a MI. Studies will be needed to assess the prognostic significance of changes in hs-cTn in patients undergoing PCI, because most studies used conventional cTn. The optimal time points for measuring post-PCI cTn are not yet known. Future studies looking at different treatments to potentially reduce the risk of periprocedural injury and MI are also needed.

Finally, the ESC/EAPCI writing group states that better research is needed to define periprocedural MI when used as part of a primary endpoint in clinical trials, although they would recommend measuring type 4a events captured with the UDMI.    

The US Food and Drug Administration does not preference one MI definition over another, and there has been some debate about whether periprocedural MI should even be included as part of the primary composite endpoint. Garcia-Garcia said that trialists will have to make that decision “based on the study question in terms of what you’re trying to compare.” As long as trialists are consistent and adhere to reporting the required data, the different definitions can each provide valuable information, he said.