‘Hot’ Plaques on PET Scans Prognostic After MI: PRE-18FFIR

Intravascular ultrasound and other invasive coronary imaging techniques eventually were able to shine some light on which plaques seem vulnerable to rupture and therefore at risk for triggering ischemic events. But for an existing imaging technology to accomplish that noninvasively, perhaps it’s the plaque that needs to shine a light.

A scoring system that reflects the total coronary burden of high-risk, potentially vulnerable plaques, which appear as bright spots on PET scans, suggests that it could predict risk for death and cardiac events in secondary analysis of a prospective study of patients with recent acute myocardial infarction (MI). The scoring system just missed being predictive in the study’s primary analysis based on a more expansive endpoint.

The radiotracer picked up on the PET scans, ¹⁸F-sodium fluoride (18F-NaF), concentrates in plaques with ongoing microcalcification activity, part of an inflammatory process associated with potentially unstable lesions that tend to be lipid-rich with necrotic cores.

A coronary microcalcification activity (CMA) score above 0 in the study, compared to 0, corresponded to an 82% increased risk for cardiac death or nonfatal MI over about 4 years, and a more than 2-fold jump in risk of death from any cause (hazard ratio, 2.43), all secondary endpoints.

However, no significant effect was seen in the analysis for the primary endpoint, a composite of cardiac death, nonfatal MI, or unscheduled revascularization.

The study, called PRE-¹⁸FFIR, suggests that residual plaque CMA after MI is a determinant of long-term outcomes and could potentially be used for risk stratification, said the study’s chief investigator David E. Newby, PhD, MD, University of Edinburgh, United Kingdom.

“I think this is the first description of a noninvasive test that identifies the potential to identify the future risk of spontaneous coronary atherothrombotic events,” Newby said when presenting the PRE-¹⁸FFIR results August 28 at the European Society of Cardiology (ESC) Congress 2022, held in Barcelona, Spain.

Some intravascular imaging techniques can reveal plaque features that predict risk for future cardiac events, he observed, but the approach “requires cardiac catheterization, instrumentation of all three coronary arteries, and doesn’t lend itself to being very practical in application to broad populations of patients.”

But PET imaging, Newby said, “is arguably one of the only techniques that will give us the sensitivity and the specificity to really identify plaque biology externally in a noninvasive manner.” In a previously published study, he noted, increased 18F-NaF uptake at PET imaging predicted ischemic events in a mixed group of patients with established coronary artery disease (CAD).

The CMA score may invite comparison with angiographic coronary artery calcium (CAC) scores, which also noninvasively stratify cardiovascular risk. But CAC scores reflect burden of a more advanced form of calcification associated with plaque stability.

In contrast, the CMA score reflects burden of potentially unstable, angiographically invisible plaques elsewhere in the coronary tree, Newby said. So, it isn’t simply “a posh calcium score.”

Redundant or Added Value?

PET imaging capability at major centers “is more common than it used to be,” largely because of its expanding role in oncology, observed Jagat Narula, MD, PhD, Icahn School of Medicine at Mount Sinai, New York City. So, the PRE-¹⁸FFIR imaging technique, if validated in appropriate trials, could probably be easily adopted into mainstream cardiology practice, he told theheart.org | Medscape Cardiology.

But the PRE-¹⁸FFIR study has a few limitations and begs some questions about the technique’s potential, said Narula, who wasn’t part of this study group. For example, the trial called for patients to undergo both PET imaging and, for anatomic reference, coronary computed tomographic angiography (CTA).

A comparison of coronary CTA and 18F-NaF PET for their proficiency in predicting CV risk would have been welcome, he said. That might have helped clarify whether the PET technique is redundant or has added value. “If CT angiography is giving me the same amount of information, then why should I do a PET on top of that?”

Also, if 18F-NaF PET turns out to be additive compared with current risk assessments, Narula said, “which patients should receive the additional scan? Because it’s not going to be cost effective, nor is it going to be practical, for every patient having a heart attack to get a PET scan.”

Potentially, he proposed, the proportion of such patients who get PET scans could be brought down to a more practical 1% or less with guidance from other risk stratifiers, perhaps a clinical algorithm like the GRACE score or even an inflammatory biomarker.

Expression of CMA scores on a continuous scale that shows gradations of CV risk might also help in this regard, proposed Narula, and would be better than a binary scoring system of zero or not zero, “which does not make sense to me.” Such a scale that discriminates risk levels could potentially help identify which “hot” plaques are “imminently likely to rupture and result in an event.”

Speculating, Narula said such plaques at near-term risk for rupture might potentially be targeted for intervention, possibly with stents, should such a strategy be appropriately validated.

The CMA score was adapted to a binary outcome for the PRE-¹⁸FFIR study, “but it is a continuous variable,” Newby told theheart.org | Medscape Cardiology. He and his colleagues, he said, are exploring whether CMA as a continuous variable might be useful combined with other prognosticators, such as the GRACE score.

In the current analysis, Newby observed, CMA was predictive independently of GRACE score and CAD severity, and so presumably would be additive in predicting risk.

Primary and Secondary Outcomes

PRE-¹⁸FFIR prospectively followed 704 predominantly male patients with acute MI within the past 3 weeks, two thirds of whom had ST-segment elevation MI and 89% had multivessel disease, for a median of 4 years. They underwent 18F-NaF PET imaging and CTA of the coronary tree, with CMA scores determined at a blinded core laboratory.

Of the overall cohort, 283 had CMA scores of 0 and 421 patients had scores greater than 0; the two groups were similar with respect to GRACE scores, CAD severity, and CV medications, Newby reported.

The primary endpoint hazard ratio (HR) for CMA greater than 0 vs 0 was nonsignificant at 1.25 (95% CI, 0.89 – 1.76, P = .20). Newby proposed that the lack of significance owed mainly to one of the events making up the composite endpoint. The component endpoints, he said, showed “a doubling to tripling of event rates in terms of having a high plaque activity, with the exception of unscheduled coronary revascularization, which was completely neutral.”

• 3.51 (95% CI, 0.77 – 16.04, P = .10) for cardiac death

• 1.61 (95% CI, 0.91 – 2.86), P = .10) for nonfatal MI

• 0.98 (95% CI, 0.64 – 1.49, P = .91) for unscheduled revascularization

• 1.82 (95% CI, 1.07 – 3.10, P = .03) for cardiac death or nonfatal MI

• 2.43 (95% CI, 1.15 – 5.12, P = .02) for all-cause mortality

The HR for cardiac death or nonfatal MI was similar, and similarly significant, after adjustment for GRACE score and, separately, for obstructive CAD severity. The HR for all-cause mortality and its significance was comparable adjusting for obstructive CAD severity, but lost significance on adjustment for GRACE score.

Newby speculated on potential applications for the CMA scores in practice, especially if they could identify patients at especially high risk. For example, he told theheart.org | Medscape Cardiology, the scores might guide the selective use of pricier agents such as the PCSK9 inhibitors or anti-inflammatory antibodies or flag a patient’s need for intensified therapy.

Or, he further proposed, pharmaceutical companies might potentially test drugs in development for coronary disease for their effects on CMA score as a surrogate for treatment effect. In that way, “you might be able to more rapidly assess the treatment, rather do a massive, large trial over 5 or 6 years.”

Newby discloses receiving grant support from Siemens Healthineers. Narula has reported no relevant financial relationships.

European Society of Cardiology Congress 2022. Hot Line Session 7: Presented August 28, 2022.

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