“Don’t trust what you see. Even sugar looks like salt.”
In cardiology, the balance between addressing root causes and treating symptoms is a patient-by-patient consideration. Symptoms such as exertional chest pain reduce an individual’s quality of life, and the effort given to symptom reduction is highly valuable, especially to the patient experiencing those symptoms. But it is hard to address both root cause and symptoms, as the ISCHEMIA trial made clear: making percutaneous coronary intervention (PCI) decisions (“To stent, or not to stent…”) based on stress testing can effectively address angina, but it does not improve long-term patient outcomes.
Then if we need to refocus toward root causes, could we address potential culprit lesions that have not yet shown any symptoms?
Decades of research have pursued a path that might enable a clinically effective intervention before a patient experiences an adverse outcome. In light of the fact that sudden cardiac death, with no prior symptoms, leads to some 325,000 deaths annually in the US, the effort to intervene before the risk becomes a crisis is well founded.
So what are our options? For years, the idea of “prophylactic PCI” or “plaque sealing” driven by the identification of high-risk plaques has been discussed. And with ever-advancing intravascular imaging, we are seeing anatomical risks that were previously only suspected. We can now identify anatomic plaques that are large, lipid rich, fibrous, or are reducing vessel lumens, all characteristics that may be indicative of a future adverse event. This increased knowledge of anatomic abnormalities could push us toward invasive action. If not, how do we explain foregoing intervention on such an identified risk to the patient? Is it possible that this was easier before we could see these risks?
Thankfully, a thoughtful analysis published in JACC: Cardiovascular Interventions makes it clear that there is already an established “quantitative, straightforward, and reproducible metric of plaque vulnerability and burden”. This metric is the lesion-specific physiologic information derived from fractional flow reserve (FFR), and the authors argue that it must remain the central determinant of a clinical decision to intervene.
If high-risk plaques are present in an FFR-positive vessel, then intervention is clearly appropriate. But if these same plaques are identified in an FFR-negative vessel, this could trigger an “ocular-stenotic” reflex in even the most data-driven interventionalist. Just as long-term data demonstrates the value of intervention in patients with abnormal FFR, it details the very low long-term risk (0.1% - 1.4% annually) of cardiac events in patients with CAD associated with normal FFR values. It is this low long-term risk that becomes the baseline against which the risk / benefit of other treatment options must be considered.
PCI is comparatively predictable and safe but is still associated with a death/myocardial infarction (MI) rate of 2% - 3.5% annually, significantly above the risk rate associated with FFR-negative lesions. Therefore, until we have in hand published prospective randomized trial data showing that PCI in some yet-to-be-determined high risk group of FFR negative lesions provides clinical benefits, PCI in such vessels appears to fall into a category where the treatment risk outweighs the benefit.
Given the low event rate seen in FFR-negative vessels, a randomized trial to assess PCI vs non-PCI of plaques deemed by some measure to be “high risk” in such vessels would require invasive screening of anywhere from 9,000 to 25,000 patients to identify even a few thousand patients suitable for randomization. Were such a trial to be undertaken, it would be well served to identify a population truly at high risk based on demographic and risk factor profiles, and to include consideration of non-PCI treatments, for example randomization to more aggressive medical therapy and lifestyle modification as an additional or alternative “intervention”.
With ever-increasing options available to assess and treat at-risk patients, quantitative analyses remind us that lesion-specific physiology remains our best map for determining the right path for each patient. While invasive and non-invasive anatomic insight can appropriately guide many decisions, in the absence of large prospective RCTs which include an intervention arm, the impracticality of visually discerning salt from sugar means that even the most detailed anatomic assessment ought not guide prophylactic PCI in the presence of a negative FFR.